HK40015008A

HK40015008A - Substituted n-arylethyl-2-aminoquinoline-4-carboxamides and use thereof

Info

Publication number: HK40015008A
Application number: HK62020004353.2A
Authority: HK
Inventors: Hartmut Beck; Raimund Kast; Mark Meininghaus; Chantal FÜRSTNER; Timo Stellfeld; Clemens-Jeremias VON BÜHLER; Lisa Dietz; Michaela Bairlein; Johanna Anlahr; Hannah JÖRIßEN; Peter Hauff; Jörg Müller; Karoline DRÖBNER; Jens Nagel
Original assignee: Bayer Aktiengesellschaft; Bayer Pharma Aktiengesellschaft
Priority date: 2017-04-10
Filing date: 2018-04-04
Publication date: 2020-08-28

Description

Substituted N-arylethyl-2-aminoquinoline-4-carboxamides and their use

The present application relates to novel substituted N-arylethyl-2-aminoquinoline-4-carboxamide derivatives, to a process for their preparation, to their use alone or in combination for the treatment and/or prophylaxis of diseases and to their use for the preparation of medicaments for the treatment and/or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of fibrotic and inflammatory diseases.

Prostaglandin F2 α (PGF2 α) belongs to the family of bioactive prostaglandins that are derivatives of arachidonic acid. Upon release from membrane phospholipids by a2 phospholipase, arachidonic acid is oxidized by cyclooxygenase to prostaglandin H2(PGH2), which is then further converted by PGF synthase to PGF2 α. PGF2a can also be enzymatically formed in much smaller proportions from other prostaglandins such as PGE2 or PGD2 [ Watanabe et al,J. Biol. Chem.1985,260,7035-7041]. PGF2 α is not stored but is released immediately after synthesis, as a result of which its effect is shown locally. PGF2 alpha is an unstable molecule (t)_1/2<1 minute) that rearranges rapidly in the lung, liver and kidney by enzymatic means to produce the inactive metabolite 15-keto dihydro-PGF 2 alpha [ Basu et al,Acta Chem. Scand. 1992,46, 108-110]. Under both physiological and pathophysiological conditions, larger amounts of 15-ketodihydro-PGF 2 α were detectable in both plasma and subsequently in urine.

The biological effects of PGF2 α are produced by the binding and activation of membrane-borne receptors, PGF2 α receptors or the so-called FP receptors. The FP receptor belongs to a G protein-coupled receptor and is characterized by seven transmembrane domains. In addition to the human FP receptor, mouse and rat FP receptors can be cloned [ Abramovitz et al,J. Biol. Chem.1994,2692632-2636, Sugimoto et al,J. Biol. Chem.1994,2691356-,Prostaglandins1994,48, 31-41]. In humans, the FP receptor exists in two isoforms, FPA and FPB. The FP receptor is the least selective of the prostanoid receptors, since not only PGF2a but also PGD2 and PGE2 bind to it with nanomolar affinity [ Woodward et al,Pharmacol. Rev.2011,63, 471-538]. Stimulation of the FP receptor results primarily in Gq-dependent activation of phospholipase C, which leads to calcium release and activation of diacylglycerol-dependent protein kinase C (pkc). Elevated intracellular calcium levels lead to calmodulin-mediated myosinLight Chain Kinase (MLCK) stimulation. In addition to coupling to the G protein Gq, FP receptors also activate the Rho/Rho kinase signal transduction cascade via G12/G13 and may instead stimulate the Raf/MEK/MAP signaling pathway via Gi coupling [ Woodward et al, Pharmacol. Rev.2011,63,471-538]。

PGF2 α is involved in the regulation of many physiological functions, such as ovarian function, embryonic development, endometrial changes, uterine contractions, luteolysis, and induction of uterine contraction and labor. PGF2 alpha is also synthesized in the endometrium in epithelial cells where it stimulates cell proliferation [ Woodward et al, Pharmacol. Rev. 2011, 63: 471-538-]. In addition, PGF2 α is a potent stimulator of smooth muscle contraction, vasoconstriction and bronchoconstriction and is involved in acute and chronic inflammatory processes [ Basu, mol. Cells 2010, 30:383-]. It can thus be shown that 15-ketodihydro-PGF 2 α, a stable PGF2 α metabolite, can be detected systemically in patients with rheumatoid arthritis, psoriatic arthritis and osteoarthritis. In the kidney, PGF2 α is involved in water absorption, natriuresis and diuresis. In the eye, PGF2a modulates intraocular pressure. PGF2 α also plays an important role in bone metabolism: prostaglandins stimulate sodium-dependent transport of inorganic phosphate into osteoblasts and promote the release of interleukin-6 and Vascular Endothelial Growth Factor (VEGF) in osteoblasts; in addition, PGF2 α is a strong mitogen and survival factor for osteoblasts [ Agas et al,J. Cell Physiol.2013,228, 25-29]。

increased PGF2 α/FP receptor activity also leads to the development of tumorigenic and angiogenic genes such as COX-2 [ Sales et al, 2007,Endocrinology148:3635–44]FGF-2 and VEGF [ Sales et al, 2010)Am J Pathol176:431]Up-regulation of the FP receptor, which suggests that the FP receptor stimulates the growth of endometrial tumors by modulating vascular function. In addition, FP receptors are involved in the regulation of endometrial epithelial cell proliferation and may influence their adhesion and motility to the extracellular matrix. These findings suggest that the PGF2 α/FP receptor plays a multifactorial role in endometrial adenocarcinoma [ Yang et al, 2013J Recept Signal Transduct,33(1): 14–27]。

Oligodendrocyte (OPC) precursor fineIncreased expression of FP receptors in cells may be a marker of oligodendrocyte and active myelin damage [ Soldan et al,Neurology2015, 84]. FP receptor expression on OPCs near the MS plaque edges can be observed in tissues of Multiple Sclerosis (MS) patients after necropsy. No FP receptor expression was found in the white brain matter control samples. This suggests that the FP receptor plays a role in the pathogenesis of multiple sclerosis [ Carlson et al, 2015,Mult. Sclerosis.23 (11) 467-468]。

brain injury leads to upregulation of prostaglandins, particularly the pro-inflammatory PGF2 α, and to over-activation of FP receptors. For example, for FP receptor deficient mice, treatment with the FP antagonist AL-8810 may show significant neuroprotective effects after cerebral artery occlusion [ Kim et AL, 2012,Neurobiol Disease48, 58-65]。

in addition, PGF2 α -FP receptor activation has been shown to be involved in a variety of cardiovascular dysfunctions, such as myocardial fibrosis, myocardial infarction and hypertension [ Zhang et al,Frontiers in Pharmacol.2010,11-7; the result of the Ding et al,Int. J. Biochem. Cell. Biol.,2012,441031-; the result of the Ding et al,J. Mol. Med.,2014,6, 629-640]。

thus, the major metabolite 15-keto-dihydro-PGF 2 α of PGF2 α is elevated in people with high cardiovascular risk in living conditions [ Helmersson-Karlquist et al, Eur Heart J2015, 36, 238-]E.g. in smokers [ Sinaiko et al, 2005Circulation111, 1985–1991]Obesity [ Sinaiko et al, 2005)Circulation111, 1985–1991]Type I diabetes [ Basu et al, 2005, 28, 1371-]And type II diabetes [ Helmersson et al, 2004,Circulation109, 1729–1734]the same is true in the case of (2). [ Zhang et al in a human being,Frontiers in Pharmacol2010, 1:1-7]. It can also be shown that genetic polymorphisms in the chinese subgroup lead to increased transcription and increased vasoconstriction of the FP gene [ Xiao et al, 2015,Arterioscler Thromb Vasc Biol. 35:1687-1695]。

in addition, the PGF2 α receptor (FP) is involved in the regulation of joint inflammation and Bone Morphogenetic Protein (BMP) signaling cascades, and promotes the differentiation of chondrocytes [ Kim et al,Biochim. Biophys. Acta,2015,1853,500-512]. More stable analogs of PGF2 alpha have been developed for estrus synchronization and affecting human reproductive function, as well as lowering intraocular pressure to treat glaucoma [ Basu,Mol. Cells2010,30, 383-391]. In the latter application, the side effect observed is the stimulation of the growth of hair, such as eyelashes, by a chemically more stable PGF2 α analogue, such as latanoprost. [ Johnston et al,Am J Ophthalmol1997, 124-544-547]. The FP receptor gene is also expressed in human hair follicles on the scalp [ khidkir et al,J Invest Dermatol,2009, Abstr 607]. For example, these findings suggest that FP receptors are involved in the regulation of hair growth and may also be involved in diseases such as hirsutism.

The role of the FP receptor in the signaling cascade in the pathogenesis of visceral pain (dysmenorrhea) is also well described. Dysmenorrhea pain is therefore most correlated with the rate of PGF release during menstruation (see Powell et al,Prostaglandins1985,29273- > 290; dawood and Khan-Dawood,Am. J. Obstet. Gynecol.2007,19635.e1-35.e 5; hsia et al, to a human,Endocrinology2011,152, 2090-2099). To date, there has been no description of the association of FP receptor signaling pathways in peripherally mediated inflammatory pain. The data submitted herewith shows this surprising connection for the first time.

In patients with Idiopathic Pulmonary Fibrosis (IPF), it has been demonstrated that the stable PGF2 α metabolite 15-ketodihydro-PGF 2 α is significantly elevated in plasma and that the levels of 15-ketodihydro-PGF 2 α are correlated with functional parameters such as Forced Vital Capacity (FVC), diffusion distance of carbon monoxide in the lung (DLCO) and 6-minute walk tests. In addition, a relationship between elevated plasma-15-keto dihydro-PGF 2 alpha and patient mortality has been established [ Aihara et al,PLoS One2013,8, 1-6]. In line with this, it has also been demonstrated that stimulation of human lung fibroblasts with naturally occurring silica dust, which in humans under chronic inhalation can lead to silicosis and thus to pulmonary fibrosis, leads to a strong upregulation of PGF2 α -synthesis [ O' Reilly et al,Am. J. Physiol. Lung Cell. Mol. Physiol.2005,288,L1010–L1016]. In bleomycin inductionIn mice with pulmonary fibrosis, elimination of the FP receptor by knock-down (FP-/-) results in significantly reduced pulmonary fibrosis compared to wild-type mice [ Oga et al,Nat. Med.2009,15, 1426-1430]. In FP-/-mice, a significant decrease in hydroxyproline content and a decrease in the induction of the profibrotic (profibrotic) gene in lung tissue was observed after bleomycin administration. Furthermore, lung function was significantly improved in FP-/-mice compared to wild type mice. In human lung fibroblasts, PGF2a stimulates proliferation and collagen production through the FP receptor. Since this is done independently of the pro-fibrotic mediator TGF β, the PGF2/FP receptor signaling cascade is an independent pathway in the context of the pathogenesis of pulmonary fibrosis [ Oga et al,Nat. Med.2009,15, 1426-1430]. These findings indicate that the FP receptor is a therapeutic target protein for the treatment of IPF [ Olman,Nat. Med.2009,15, 1360-1361]. The involvement of PGF2 α in the induction of fibrotic lesions has also been shown in mouse cardiac fibroblasts (kardianalen Maus-fibroblastin) [ Ding et al,Int. J. Biochem. & Cell Biol.2012, 44, 1031-1039]in an animal model of scleroderma [ Kanno et al,Arthritis Rheum.2013,65, 492-502]and in synovial cells of patients with knee arthropathy [ Bastiaansen et alArthritis Rheum.2013,65, 2070-2080]It was confirmed.

It is therefore hypothesized that the FP receptor plays an important role in many diseases, injuries and pathological changes whose pathogenesis and/or progression is associated with inflammatory events and/or hyperplastic and fibroproliferative tissue-and vascular remodeling. These may be, in particular, diseases and/or damage of the lungs, cardiovascular system or kidneys, or here blood diseases, tumor diseases or other inflammatory diseases.

Inflammatory and fibrotic diseases and lesions of the lung which may be mentioned herein are in particular idiopathic pulmonary fibrosis, rheumatoid arthritis-associated interstitial lung diseases, pulmonary hypertension, Bronchiolitis Obliterans Syndrome (BOS), Chronic Obstructive Pulmonary Disease (COPD), asthma and cystic fibrosis. Diseases and damage of the cardiovascular system involving the FP receptor are e.g. tissue pathologies after myocardial infarction and associated with cardiac insufficiency. Renal diseases are, for example, renal insufficiency and renal failure. The blood disorder is, for example, sickle cell anemia. Examples of tissue degradation and reconstruction during the course of a tumor are the invasion of healthy tissue by cancer cells (metastasis formation) and the newly formation of blood-supply vessels (neovascularization). Other inflammatory diseases in which the FP receptor plays a role are, for example, arthrosis and multiple sclerosis.

Idiopathic pulmonary fibrosis or Idiopathic Pulmonary Fibrosis (IPF) is a progressive lung disease that, untreated, results in death within an average of 2.5 to 3.5 years after diagnosis. At the time of diagnosis, patients are mostly over 60 years old, and men are more frequently ill than women. The onset of IPF is unconsciously worsening and is characterized by progressive dyspnea and irritating dry cough. IPF belongs to the group of Idiopathic Interstitial Pneumonia (IIP), a heterogeneous class of lung diseases characterized by fibrosis and varying degrees of inflammation and distinguished by clinical, imaging and fine-tissue criteria. Within this category, idiopathic pulmonary fibrosis is of particular interest due to its common and aggressive course [ Ley et al, Am. J. Respir. Crit. Care Med.2011,183, 431-440]. IPF can be sporadic or genetic. The reason is not clear so far. However, in recent years, many indications have been found that chronic damage to the alveolar epithelium results in the release of profibrotic cytokines/mediators with subsequent increased fibroblast proliferation and increased collagen fibril formation, thereby leading to plaque fibrosis and the typical cellular structure of the lung [ striester et al, Chest2009,136, 1364-1370]. The clinical consequences of fibrosis are decreased elasticity of lung tissue, decreased dispersion and the development of severe hypoxia. In terms of lung function, exacerbations of Forced Vital Capacity (FVC) and dispersion capacity (DLCO) can be found accordingly. The major and prognostic major complication of IPF is acute exacerbation and pulmonary hypertension [ von der Beck et al, Der Pneumologe2013,10(2), 105-111]. The incidence of pulmonary hypertension in interstitial lung disease is 10-40% [ Lettieri et al, Chest2006,129746 Across 752; Behr et al, Eur. Respir. J.2008,31,1357-1367]. Currently, there is no effective treatment for IPF other than lung transplantation.

Rheumatoid Arthritis (RA) is a progressive, systemic autoimmune diseaseIt is characterized by chronic erosive synovitis. Interstitial Lung Disease (ILD) is one of the most common extra-articular manifestations of RA [ Wells et alNat Rev Rheumatol2014, 10, 728–739]. About 10% of RA patients have clinically proven interstitial lung disease (RA-ILD); another third showed subclinical ILD in the chest CT scan. RA-ILD patients have three times the mortality rate of RA patients without ILD, and the average life expectancy after diagnosis of ILD is only 2.6 years [ Olson et alAm J Respir Crit Care Med2011183, 372, 378; doyle et alChest 2014, 145(3), 454-463]。

Inflammatory and autoimmune diseases of the lung, as well as various environmental triggers (e.g., smoke, fine dust, chemical irritants) and genetic predisposition play an important role in the development and progression of RA-ILD [ Catrina et alNat Rev Rheumatol2014, 10(11), 645-653]。

Pulmonary Hypertension (PH) is a progressive lung disease that, untreated, results in death within an average of 2.8 years after diagnosis. By definition, in the case of chronic pulmonary hypertension, the pulmonary arterial mean pressure (mPAP) is at rest>25 mmHg or under load>30 mmHg (normal value)<20 mmHg). The pathophysiology of pulmonary hypertension is characterized by vasoconstriction and remodeling of pulmonary blood vessels. In chronic PH, new myogenesis of the primary non-myogenic pulmonary vessels occurs and the circumference of the vascular muscle of the myogenic vessels increases. The progressive loading of the right heart due to the progressive occlusion of the pulmonary circulation, which results in a reduction in the output of the right heart, and eventually culminates in right heart failure [ m. Humbert et al,J. Am. Coll. Cardiol.2004,43,13S-24S]. Idiopathic (or primary) pulmonary hypertension (IPAH) is a very rare disease, while secondary pulmonary hypertension (non-PAH PH, NPAHPH) is very common, and it is now believed that PH is the third most common cardiovascular disease category after coronary heart disease and systemic hypertension [ naiije, a.j. peach et al (editors),Pulmonary Circulation. Diseases and their treatment3 rd edition, Hodder Arnold pub.2011, 3]. Since 2008, pulmonary hypertension has been classified into different categories according to the Dana Point classification based on the respective etiology [ d. Montana and g.simoneau, a.j. Peacock et al (editors),Pulmonary Circulation. Diseases and their treatment3 rd edition, Hodder Arnold Publ, 2011, 197-]。

Despite all these advances in the treatment of PH, there is no prospect to date for a cure for this serious disease. Therapies (e.g., prostacyclin analogues, endothelin receptor antagonists, phosphodiesterase inhibitors) exist on the market that improve the quality of life, exercise tolerance and prognosis of patients. These are therapeutic principles administered systemically, primarily hemodynamic in effect, which affect vascular tone. The applicability of these drugs is limited by sometimes severe side effects and/or complex administration forms. The time during which a patient's clinical condition can be stabilized or improved by specific monotherapy is limited (e.g., due to the development of tolerance). Finally, treatment escalates and, therefore, combination therapies are performed in which multiple drugs must be administered simultaneously. Currently, these standard therapies are only allowed for the treatment of Pulmonary Arterial Hypertension (PAH). In the case of secondary forms of PH, such as PH-COPD, these therapeutic principles (e.g. sildenafil, bosentan) have failed in clinical studies because they lead to a reduction in arterial oxygen content (desaturation) of patients due to non-selective vasodilation. The reason for this may be due to systemic administration of non-selective vasodilators, adverse effects of intrapulmonary ventilation perfusion adaptation in the case of heterogeneous lung diseases i. Blanco et al,Am. J. Respir. Crit. Care Med.2010,181270-,Eur. Respir. J.2008,32, 619-628]。

new combination therapies are the most promising future treatment options for the treatment of pulmonary hypertension. In this regard, the discovery of new pharmacological mechanisms for the treatment of PH is of particular interest [ Ghofrani et al,Herz2005,30,296-302; E. B. Rosenzweig,Expert Opin. Emerging Drugs2006,11609-,Curr. Med. Chem.2007,14, 719-733]. In particular those novel treatments which can be combined with the therapeutic concepts already existing on the market can be the basis of more effective treatments, thus bringing great advantages to the patient.

In the context of the present inventionPulmonary hypertension includes primary and secondary (NPAHPH) subforms as defined by their respective etiologies according to the Dana Point classification [ d. Montana and g. simoneau, a. j. peach et al (ed.),Pulmonary Circulation. Diseases and their treatment3 rd edition, Hodder Arnold publication, 2011, 197-,J. Am. Coll. Cardiol.,2009,54 (1)s, supply, page 85 to page 96]. Specifically included in category 1 are Pulmonary Arterial Hypertension (PAH), including inter alia idiopathic and inherited forms (IPAH and FPAH). In addition, PAH also includes persistent pulmonary hypertension in newborns and Associated Pulmonary Arterial Hypertension (APAH) associated with the following diseases: collagen diseases, congenital-pulmonary shunt lesions (shuntvitiens), portal hypertension, HIV infection, the ingestion of certain drugs and agents (e.g., appetite suppressants), diseases with significant venous/capillary involvement, such as pulmonary vein occlusive disease and pulmonary capillary angiomatosis, or other diseases such as thyroid disease, glycogen storage disease, gaucher's disease, hereditary telangiectasia, hemoglobinopathy, myeloproliferative diseases, and splenectomy. Included in category 2 of the Dana Point classification are PH patients with pathogenic left heart disease, such as ventricular, atrial or valvular disease. Category 3 includes forms of pulmonary hypertension associated with pulmonary diseases such as Chronic Obstructive Pulmonary Disease (COPD), Interstitial Lung Disease (ILD), pulmonary fibrosis (IPF), and/or hypoxemia (e.g., sleep apnea syndrome, alveolar hypoventilation, chronic altitude disease, hereditary malformations). Category 4 includes PH patients with chronic thrombotic and/or embolic disease, for example in the case of thromboembolic obstruction (CTEPH) of the proximal and distal pulmonary arteries or in the case of non-thromboembolism (e.g. due to tumor disease, parasites, foreign bodies). The rare forms of pulmonary hypertension, for example for patients with sarcoidosis, histiocytosis X or lymphangiomatosis, are summarized in category 5.

Bronchiolitis Obliterans Syndrome (BOS) is a chronic rejection reaction after successful lung transplantation. In the first five years after lung transplantation, about 50-60% of all patients were affected, while over 90% in the first 9 years were affected [ Estene et al, Am. J. Respir. Crit. Care Med. 2003, 166, 440-. The cause of the disease is unknown. Despite advances in the treatment of transplant patients, the number of cases of BOS has changed little in recent years. BOS is the most important long-term complication in lung transplantation and is considered to be the main reason why survival rates remain significantly lower than in other organ transplants. BOS is an inflammatory event that occurs with changes in lung tissue that primarily affect the small respiratory tract. Damage and inflammatory changes to epithelial cells and subepithelial structures of the small respiratory tract cause excessive fibroplasia due to inefficient regeneration of epithelial cells and abnormal tissue repair. Scarring and eventual destruction of the bronchioles and blockage of granulation tissue occurs in the small airways and alveoli, occasionally with vascular intervention. The diagnosis is based on lung function. In BOS, a deterioration of FEV1 occurs compared to the average of the two optimal values measured after surgery. Currently, there is no effective therapy for treating BOS. Some patients are improved under the condition of strengthening immunosuppression; patients who do not respond to this experience a sustained deterioration, thus indicating the need for a re-transplant (re-transplant).

Chronic Obstructive Pulmonary Disease (COPD) is a chronic progressive lung disease characterized by obstruction of the airways due to emphysema and/or chronic bronchitis. The first symptoms of the disease usually manifest from the age of forty to fifty years. In the following years of life, breathlessness often worsens and manifests itself as coughing, with large and sometimes purulent sputum and narrowing of breath until dyspnea (dyspnea). COPD is mainly a disease of smokers: smoking is responsible for 90% of all COPD cases and 80-90% of all COPD deaths. COPD is a great medical problem and the sixth leading cause of death worldwide. About 4-6% of people over 45 years of age are involved. Although airway obstruction may be only partial and temporary, COPD is not curable. Thus, the therapeutic goals are to improve quality of life, alleviate symptoms, prevent acute exacerbations, and slow the progressive impairment of lung function. An existing drug therapy that has changed little over the last two to thirty years has been the use of bronchodilators to open up obstructed airways, and in some cases corticosteroids to prevent lung inflammation p.j. Barnes,N. Engl. J. Med.2000,343, 269-280]. Chronic inflammation of the lungs caused by cigarette smoke or other irritants is the driving force for disease development. The basic mechanisms include immune cells, which release proteases and various cytokines that cause emphysema and bronchial remodeling during the inflammatory response of the lung.

It is an object of the present invention to identify and provide novel substances which are potent, chemically and metabolically stable, non-prostanoid antagonists of the FP receptor and which are suitable as such for the treatment and/or prophylaxis, in particular of fibrotic and inflammatory diseases.

WO 95/32948-A1, WO 96/02509-A1, WO 97/19926-A1 and WO 2000/031038-A1 disclose inter alia as NK₃Or dual NK₂/NK₃An antagonist of 2-arylquinoline-4-carboxamide useful in the treatment of disorders of the lung and central nervous system. WO 2016/004035 discloses 2-arylquinoline-4-carboxamides as TSH receptor agonists which are useful for the treatment of disorders and malignant thyroid pathologies. WO 2000/064877 claims to be useful as NK₃Quinoline-4-carboxamide derivatives of antagonists useful in the treatment of various diseases, especially diseases of the lung and central nervous system. WO 2004/045614-a1 describes specific quinoline carboxamides as glucokinase ligands for the treatment of diabetes. WO 2006/094237-a2 discloses quinoline derivatives as Sirtuin modulators, which may be used for the treatment of various diseases. WO 2011/153553-a2 claims various bicyclic heteroaryl compounds as kinase inhibitors, which are particularly useful for the treatment of neoplastic diseases. EP 2415755-A1 describes, inter alia, quinoline derivatives which are suitable for the treatment of diseases which are associated with the activity of plasminogen activator-inhibitor 1 (PAI-1). WO 2013/074059-A2 details various quinoline-4-carboxamide derivatives which can be used as inhibitors of cytosine deaminase to facilitate DNA transfection of cells. WO 2013/164326-A1 discloses compounds as agonists of EP2 prostaglandin receptorN3-diphenylnaphthalene-1-carboxamides for use in the treatment of respiratory diseases. WO 2014/117090-A1 describes various 2-arylquinoline derivatives as metalloenzyme inhibitors. WO 2012/122370-a2 discloses quinoline-4-carboxamide derivatives useful in the treatment of autoimmune and neoplastic diseases. WO 2015/094912-A1 is particularly disclosedIs open to substitutionN2-diphenylquinoline-4-carboxamide derivatives which are suitable as antagonists of the prostaglandin EP4 receptor for the treatment of arthritis and pain states associated therewith. WO 2016/061280 discloses protein-tyrosine-phosphatase modulators with a 4-amino-2-arylquinoline infrastructure, which are particularly useful for the treatment of disorders of fat metabolism, diabetes and cardiovascular diseases.

The invention relates to compounds of general formula (I) and to the use thereofN-oxides, salts, solvates,NSalts of oxides andNsolvates of oxides and salts

Wherein

Ar is a phenyl group or a pyridyl group,

where phenyl can be up to tetrasubstituted and pyridyl can be up to disubstituted, which phenyl or pyridyl can in each case be fluorine, chlorine, up to trisubstituted by fluorine (C)₁-C₄) Alkyl, up to tetra-substituted by fluorine (C)₃-C₄) Cycloalkyl, (C) trisubstituted by fluorine up to₁-C₂) Alkoxy or (C) trisubstituted by fluorine at most₁-C₂) -alkylsulfanyl is substituted identically or differently, or wherein two substituents of the phenyl or pyridyl group, if bonded to adjacent ring atoms, are optionally bonded to each other to form together methylenedioxy or ethylenedioxy,

or

Wherein the phenyl group may be up to penta-substituted with fluorine,

y is a bond or a group of the formula

#¹−X−(CR^10AR^10B)_k−#²

Wherein

#¹Is a site of attachment to a carbon atom,

#²is the site of attachment to the carboxyl group,

x is a bond, -CH₂−、−O−、−S(=O)_m-or-N (R)¹¹) -, wherein

m is 0, 1 or 2, and

R¹¹is hydrogen or a methyl group, or a mixture thereof,

R^10Aand R^10BIndependently of one another, hydrogen, fluorine or methyl,

or

R^10AAnd R^10BTogether with the carbon atoms to which they are bonded form a cyclopropyl group,

k is 1,2,3 or 4,

R¹is halogen, up to penta-substituted by fluorine (C)₁-C₄) -alkyl, methoxy which is at most trisubstituted by fluorine, (trifluoromethyl) sulfanyl, pentafluorosulfanyl, trimethylsilyl, ethynyl, cyclopropyl or cyclobutyl,

wherein cyclopropyl and cyclobutyl may be up to tetrasubstituted by fluorine,

R²、R³and R⁴Independently of one another, hydrogen, halogen or methyl which is trisubstituted by fluorine up to three,

R⁵is halogen, up to penta-substituted by fluorine (C)₁-C₄) Alkyl, methoxy, hydroxy, methylsulfanyl, (trifluoromethyl) sulfanyl, cyano, vinyl, cyclopropyl or cyclobutyl which are trisubstituted by fluorine,

wherein cyclopropyl and cyclobutyl may be up to tetrasubstituted by fluorine,

R⁶is-NR¹²R¹³

Wherein

R¹²Is hydrogen or (C)₁-C₃) -alkyl, and

R¹³is (C)₁-C₄) -alkyl or (C)₃-C₇) -a cycloalkyl group,

wherein (C)₃-C₇) Cycloalkyl can be up to tetrasubstituted by fluorine and (C)₁-C₄) Alkyl may be up to penta-substituted by fluorine or may be (C)₃-C₆) -cycloalkyl, methoxy, trifluoromethoxy or phenyl monosubstitution,

wherein the phenyl group may be up to trisubstituted by fluorine,

or

Is a saturated or partially unsaturated 4-to 8-membered monocyclic or 6-to 10-membered bicyclic heterocyclic ring which is linked via a nitrogen atom and which may contain a further ring member selected from N, O, S, SO and SO₂As ring members, identical or different heteroatoms of,

wherein the 4-to 8-membered monocyclic and 6-to 10-membered bicyclic heterocycles may each be selected from (C) independently of one another by 1 to 3₁-C₄) -alkyl, hydroxy, oxo, (C)₁-C₃) -alkoxy, difluoromethoxy, trifluoromethoxy, cyano, amino, monomethylamino, dimethylamino, aminocarbonyl, monomethylaminocarbonyl, dimethylaminocarbonyl and additionally up to tetrasubstituted by fluorine,

wherein (C)₁-C₄) Alkyl may be up to penta-substituted by fluorine or may be mono-substituted by hydroxy or methoxy,

R^7Aand R^7BIndependently of one another, is hydrogen or methyl,

or

R^7AAnd R^7BTogether with the carbon atoms to which they are bonded form a cyclopropyl group,

R⁸is hydrogen, fluorine, methyl, trifluoromethyl, ethyl or hydroxy,

R⁹is hydrogen or methyl.

The compounds of the present invention are compounds of formula (I) and salts, solvates and solvates of salts, compounds of the following formulae encompassed by formula (I) and salts, solvates and solvates of salts thereof, and compounds of the following formulae mentioned below as examples encompassed by formula (I) and salts, solvates and solvates of salts thereof, provided that the compounds mentioned below encompassed by formula (I) are not already salts, solvates and solvates of salts.

The compounds of the invention are likewise of the formula (I)NOxides and salts, solvates and solvates of salts thereof.

In the context of the present invention, preferred salts are physiologically acceptable salts of the compounds of the invention. Also included are salts which are not suitable per se for pharmaceutical use, but which may be used, for example, for isolating, purifying or storing the compounds of the invention.

Physiologically acceptable salts of the compounds of the invention include in particular those derived from customary bases, such as, for example and with preference, alkali metal salts (e.g.sodium and potassium salts), alkaline earth metal salts (e.g.calcium and magnesium salts), zinc salts and ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms, such as, for example and with preference, ethylamine, diethylamine, triethylamine, DIPEA, monoethanolamine, diethanolamine, triethanolamine, dimethylaminoethanol, diethylaminoethanol, tris (hydroxymethyl) aminomethane, choline (2-hydroxy-N,N,N-trimethylethylammonium), procaine, dicyclohexylamine, dibenzylamine, N-methylmorpholine, N-methylpiperidine, arginine, lysine and 1, 2-ethylenediamine.

In addition, physiologically acceptable salts of the compounds of the invention also include acid addition salts of inorganic acids, carboxylic acids and sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenedisulfonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, succinic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, benzoic acid and pamoic acid.

Solvates in the context of the present invention refer to those forms of the compounds of the invention which form complexes in the solid or liquid state by coordination with solvent molecules. Hydrates are a particular form of solvates in which coordination is made with water. As solvate, hydrates are preferred in the context of the present invention.

Depending on their structure, the compounds of the invention may exist in different stereoisomeric forms, i.e. in the form of configurational isomers, or optionally also as conformational isomers (enantiomers and/or diastereomers, including those in atropisomers). Thus, the present invention includes enantiomers and diastereomers and mixtures of each thereof. The stereoisomerically identical components can be separated from such mixtures of enantiomers and/or diastereomers in a known manner. Preference is given to using chromatographic methods for this purpose, in particular HPLC chromatography on achiral or chiral separation phases. In the case of carboxylic acids as intermediates or end products, separation via diastereomeric salts can alternatively be carried out with the aid of chiral amine bases.

In the context of the present invention, the term "enantiomerically pure" is understood to mean that the compound concerned is present in an enantiomeric excess of greater than 95%, preferably greater than 98%, relative to the absolute configuration of the chiral center. Enantiomeric excess (English: enantiomeric excess ee value) is calculated here by evaluating HPLC analysis chromatograms on chiral phases using the following formula:

the present invention includes all tautomeric forms as long as the compounds of the present invention can exist in tautomeric forms.

The present invention also includes all suitable isotopic variations of the compounds of the present invention. Isotopic variations of the compounds of the present invention are understood herein to mean compounds which: wherein at least one atom has been replaced within a compound of the invention with another atom of the same atomic number, but having an atomic mass different from the atomic mass usually or predominantly found in nature. Examples of isotopes that can be incorporated into the compounds of the invention are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as²H (deuterium),³H (tritium),¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、³²P、³³P、³³S、³⁴S、³⁵S、³⁶S、¹⁸F、³⁶Cl、⁸²Br、¹²³I、¹²⁴I、¹²⁹I and¹³¹I. certain isotopic variations of the compounds of the present invention (such as, inter alia, those into which one or more radioactive isotopes have been incorporated) can be useful, for example, for examining the mechanism of action or the distribution of the active ingredient in the body; due to the relative ease of preparation and inspectionMeasuring properties, especially by³H-or¹⁴C-isotopically labelled compounds are suitable for this purpose. In addition, due to the greater metabolic stability of the compound, the incorporation of isotopes such as deuterium can produce certain therapeutic benefits, such as increased in vivo half-life or reduction in the requisite active dose; thus, such modifications of the compounds of the invention may also optionally constitute preferred embodiments of the invention. Isotopic variations of the compounds of the present invention can be prepared by conventionally employed methods known to those skilled in the art, for example, by following the procedures described further below and in the examples, and by using the respective reagents and/or the corresponding isotopic variations of the starting compounds herein.

In addition, the present invention also includes prodrugs of the compounds of the present invention. The term "prodrug" refers herein to a compound that: which may be biologically active or inactive per se, but which is converted to the compounds of the invention during in vivo residence, for example, by metabolic or hydrolytic pathways.

The invention comprises in particular as prodrugs hydrolysable ester derivatives of carboxylic acids of formula (I) according to the invention. These are understood to mean esters which can be hydrolyzed enzymatically or chemically into the free carboxylic acids as the main biologically active compounds in physiological media, under the conditions of the biological tests described below and in particular in vivo. Preferred esters of this type are (C) of the formula (IV)₁-C₄) Alkyl esters, wherein the alkyl group may be linear or branched. Methyl, ethyl or tert-butyl esters are particularly preferred.

In the context of the present invention, unless otherwise indicated, the substituents have the following meanings:

the term "halogen" or "halogen atom" denotes a fluorine, chlorine, bromine or iodine atom.

The term "C₁-C₄Alkyl "denotes a straight-chain or branched, saturated, monovalent hydrocarbon radical having 1,2,3 or 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl or tert-butyl or isomers thereof.

The term "C₃-C₇-cycloalkyl "Involving a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3,4, 5, 6 or 7 carbon atoms ("C)₃-C₇-cycloalkyl "). E.g. C₃-C₇Cycloalkyl is a monocyclic hydrocarbon ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

The term "C₁-C₃-alkoxy "represents formula (C)₁-C₃A linear or branched saturated monovalent radical of-alkyl) -O-, wherein the term "C" is₁-C₃Alkyl "is as defined above, for example methoxy, ethoxy, n-propoxy or isopropoxy or isomers thereof.

In the context of the present invention, the term "4-to 8-membered monocyclic heterocycle" denotes monocyclic saturated or partially unsaturated heterocycles which have a total of 4 to 8 ring atoms and may contain further substituents selected from N, O, S, SO and SO₂And is bonded through a ring nitrogen atom. Preference is given to 5-to 7-membered heterocycloalkyl having one ring nitrogen atom and optionally a further ring heteroatom selected from N, O and S. Particular preference is given to 5-, 6-or 7-membered heterocycloalkyl having one ring nitrogen atom. For example, the following may be mentioned: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, thietanyl, 1-thiacyclopentane-yl, 1, 2-oxazolidinyl, 1, 3-thiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1, 3-dioxanyl, 1, 4-dioxanyl, 1, 2-oxazinyl, morpholinyl, thiomorpholinyl, 1-thiomorpholinyl, azepanyl, 1, 4-diazepanyl, 1, 4-oxazepanyl, 2, 5-dihydro-1H-pyrrol-1-yl, 3, 6-dihydropyridin-1 (2H) -yl and 3, 6-dihydro-2H-1, 2-oxazin-2-yl. Preference is given to azetidinyl, pyrrolidinyl, imidazolidinyl, 1, 2-oxazolidinyl, piperidinyl, piperazinyl, 1, 2-oxazinylalkyl, morpholinyl, thiomorpholinyl, 2, 5-dihydro-1H-pyrrol-1-yl, 3, 6-dihydropyridin-1 (2H) -yl and 3, 6-dihydro-2H-1, 2-oxazin-2-yl. Pyrrolidinyl, piperidinyl and azepanyl groups are particularly preferred.

In the context of the present invention, the term "6-to 10-membered bicyclic heterocycle"denotes a bicyclic saturated or partially unsaturated heterocycle having a total of 6 to 10 ring atoms and which may contain a further ring member selected from N, O, S, SO and SO₂And is bonded through a ring nitrogen atom. Preference is given to 7-to 10-membered heterocycloalkyl having one ring nitrogen atom and optionally a further ring heteroatom selected from N, O and S. In the context of the present invention, bicyclic spiroheterocyclic groups shall be included by the definition of "bicyclic heterocycle". Preferred examples may include the following: azabicyclo [3.1.1]Hept-3-yl, 3-azabicyclo [3.2.1]Oct-3-yl, 3, 4-dihydroisoquinolin-2 (1H) -yl, octahydro-2H-isoindol-2-yl, and 5-azaspiro [2.5 ]]Oct-5-yl.

The term "C₁-C₂-alkylsulfanyl "represents formula (C)₁-C₂-alkyl) -S-, linear or branched saturated monovalent radical, wherein the term "C₁-C₂Alkyl "is as defined above, for example methylsulfanyl or ethylsulfanyl.

In the context of the present invention, an oxo substituent is an oxygen atom bonded to a carbon atom via a double bond.

In the context of the present invention, all multiply occurring radicals are defined independently of one another. When a group in a compound of the present invention is substituted, the group may be mono-or polysubstituted unless otherwise specified. Preferably by one substituent or by two identical or different substituents. Particularly preferably by one substituent.

In the context of the present invention, preference is given to compounds of the formula (I) and salts, solvates and solvates of the salts, where

Ar is a phenyl group, and Ar is a phenyl group,

wherein phenyl can be up to tetrasubstituted by fluorine or up to trisubstituted, identically or differently, by fluorine, chlorine, methyl, trifluoromethyl, difluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy,

y is a bond or a group of the formula

#¹−(CH₂)_n−#²

Wherein

#¹Is a site of attachment to a carbon atom,

#²is the site of attachment to the carboxyl group,

n is 1,2 or 3,

R¹is a bromine or acetylene group, and the compound is,

R²、R³and R⁴Each of which is a hydrogen atom,

R⁵is a chlorine or a methyl group, and the compound is,

and

R⁶is-NR¹²R¹³

Wherein

R¹²Is hydrogen or methyl, and

R¹³is (C)₁-C₄) -an alkyl group,

wherein (C)₁-C₄) Alkyl may be up to trisubstituted by fluorine or may be monosubstituted by phenyl,

or

Is a saturated or partially unsaturated 5-to 7-membered monocyclic or 7-to 10-membered bicyclic heterocyclic ring which is linked via a nitrogen atom and which may contain as ring members a further identical or different heteroatom selected from N, O and S,

wherein the 5-to 7-membered monocyclic and 7-to 10-membered bicyclic heterocycles may each be substituted by 1 or 2 substituents which are selected independently of one another from methyl, difluoromethyl, trifluoromethyl, ethyl, 2,2, 2-trifluoroethyl, 2, 2-difluoroethyl, isopropyl and may in addition be up to tetrasubstituted by fluorine,

R^7A、R^7B、R⁸and R⁹Each is hydrogen.

Ar is a phenyl group, and Ar is a phenyl group,

wherein the phenyl radical may be trisubstituted identically or differently by fluorine, chlorine, methyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy,

y is a radical of the formula

#¹−CH₂CH₂−#²

Wherein

#¹Is a site of attachment to a carbon atom,

#²is the site of attachment to the carboxyl group,

R¹is a bromine compound, and is,

R²、R³、R⁴each of which is a hydrogen atom,

R⁵is a methyl group, and the compound is,

R⁶is a radical of the formula

Wherein

#³Is the site of attachment to the rest of the molecule,

R¹⁴is a fluorine or a methyl group, and the compound is,

R¹⁵is a fluorine, a methyl or an ethyl radical,

R^7A、R^7B、R⁸and R⁹Each is hydrogen.

A particular embodiment of the invention comprises compounds of formula (I) and their useN-oxides, salts, solvates,NSalts of oxides andNsolvates of oxides and salts, wherein

R¹Is bromine, and

R²、R³and R⁴Each is hydrogen.

Another particular embodiment of the invention comprises compounds of formula (I) and their useN-oxides, salts, solvates,NSalts of oxides andNsolvates of oxides and salts, wherein

R⁵Is methyl.

R⁶Is a radical of the formula

Wherein

#³Is the site of attachment to the rest of the molecule,

R¹⁴is a fluorine or a methyl group, and the compound is,

R¹⁵is fluorine, methyl or ethyl.

R⁶Is pyrrolidine.

Y is a radical of the formula

#¹−CH₂−#²

Wherein

#¹Is a site of attachment to a carbon atom,

#²is the site of attachment to the carboxyl group.

Y is a radical of the formula

#¹−CH₂CH₂−#²

Wherein

#¹Is a site of attachment to a carbon atom,

#²is the site of attachment to the carboxyl group.

Ar is a phenyl group, and Ar is a phenyl group,

wherein the phenyl radical may be trisubstituted identically or differently by fluorine, chlorine, methyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy.

R¹Is a bromine compound, and is,

R²、R³、R⁴each of which is a hydrogen atom,

R⁵is methyl.

R^7A、R^7B、R⁸And R⁹Each is hydrogen.

The radical definitions specified in each combination or preferred combination of radicals are independent of the radical definitions specified in each case and are optionally also replaced by radical definitions of other combinations.

Very particular preference is given to combinations of two or more of the abovementioned preferred ranges.

The radical definitions mentioned as preferred, particularly preferred and very particularly preferred apply both to the compounds of the formula (I) and correspondingly to all intermediates.

Another subject of the invention is a process for preparing the compounds of the formula (I) according to the invention, characterized in that a compound of the formula (II)

Wherein R is¹、R²、R³、R⁴、R⁵、R^7A、R^7B、R⁸、R⁹And Ar has the definitions given above,

and

t is an ester protecting group, especially (C)₁-C₄) -an alkyl group,

in the first step of the process, the first step,

[A] with amine compounds of the formula (III)

Wherein R is⁶With the definitions given above, it is possible to use,

and in a subsequent step(s),

[B] removing the ester group T of the compound of formula (IV) obtained after the reaction with the amine compound (III) from step [ A ]

Wherein R is¹、R²、R³、R⁴、R⁵、R⁶、R^7A、R^7B、R⁸、R⁹And Ar has the definitions given above,

and

t is an ester protecting group, especially (C)₁-C₄) -an alkyl group,

and the compounds of the formula (I) thus obtained

optionally separated into their enantiomers and/or diastereomers and/or converted into solvates, salts and/or solvates of the salts thereof with the appropriate (i) solvent and/or (ii) base or acid.

The reaction in step [ a ]: (II) + (III) → (IV) can proceed via a nucleophilic substitution reaction.

Nucleophilic substitution reactionPreferably with an excess of amine compound and optionally in the presence of a base. Suitable bases are the customary inorganic or organic bases. These preferably include alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali metal or alkaline earth metal carbonates, such as lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate, alkali metal alkoxides, such as lithium tert-butoxide, sodium tert-butoxide or potassium tert-butoxide, alkali metal hydrides, such as sodium hydride or potassium hydride, or organic amines, such asN,N-Diisopropylethylamine (DIPEA), 1, 5-diazabicyclo [ 4.3.0%]Non-5-ene (DBN) and 1, 8-diazabicyclo [5.4.0]Undec-7-ene (DBU). Is preferably usedN,NDiisopropylethylamine (DIPEA). The reaction is generally carried out at a temperature in the range of from 30 ℃ to + 130 ℃, preferably from + 90 ℃ to + 110 ℃.

For method step [ A]The inert solvent of (A) is, for example, an ether such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether, an alcohol such as methanol, ethanol, propanol, butanol, isopropanol and tert-butanol, a hydrocarbon such as benzene, toluene, xylene, hexane, cyclohexane or a mineral oil fraction, a halogenated hydrocarbon such as dichloromethane, trichloromethane, tetrachloromethane, 1, 2-dichloroethane, trichloroethylene or chlorobenzene, or another solvent such as acetone, ethyl acetate, acetonitrile, pyridine, dimethyl sulfoxide, dimethyl ether,N,N-Dimethylformamide (DMF),N,N'-Dimethylpropyleneurea (DMPU) or N-methylpyrrolidone (NMP). Mixtures of the solvents mentioned can likewise be used. Butanol or N-methylpyrrolidone (NMP) is preferably used.

The removal of the ester protecting group T in process step [ B ] (IV) → (I) is carried out by customary methods by treating the ester with an acid or a base in an inert solvent, wherein in the latter variant the first formed carboxylic acid salt is converted into the free carboxylic acid after subsequent treatment with an acid. In the case of tert-butyl esters, the ester cleavage is preferably carried out with an acid. The methyl and ethyl esters are preferably cleaved using a base. Alternatively, the benzyl ester can also be cleaved by hydrogenation (hydrogenolysis) in the presence of a suitable catalyst such as palladium on charcoal. Silyl esters can be cleaved by treatment with an acid or a fluoride, such as tetrabutylammonium fluoride.

Suitable for these reactionsInert solvents are water and common organic solvents for ester cleavage. These include in particular alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers, such as diethyl ether, tetrahydrofuran, 1, 4-dioxane or 1, 2-dimethoxyethane or other solvents, such as dichloromethane, acetonitrile, methanol, ethanol,N,N-dimethylformamide or dimethylsulfoxide. Mixtures of these solvents may also be used. In the case of basic ester hydrolysis, preference is given to using mixtures of water with tetrahydrofuran, 1, 4-dioxane, methanol and/or ethanol. In the case of reaction with trifluoroacetic acid, preference is given to using dichloromethane, and in the case of reaction with hydrogen chloride, preference is given to using 1, 4-dioxane, in each case under anhydrous conditions.

Suitable bases for the hydrolysis reaction are the customary inorganic bases. These include, in particular, alkali metal or alkaline earth metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal or alkaline earth metal carbonates, such as sodium carbonate, potassium carbonate or calcium carbonate. Preferably, an aqueous lithium hydroxide solution or a sodium hydroxide solution (sodium hydroxide solution) is used.

Suitable acids for the cleavage of the esters are usually sulfuric acid, hydrogen chloride/hydrochloric acid, hydrogen bromide/hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid or mixtures thereof, optionally with addition of water. Preference is given to using hydrogen chloride or trifluoroacetic acid.

The ester cleavage is generally carried out at a temperature in the range from-20 ℃ to + 100 ℃, preferably in the range from 0 ℃ to + 80 ℃.

The compounds of formula (I) may be converted into their corresponding salts derived from bases or acids by conventional methods. Acid salts (acid addition salts) may be converted to the corresponding acid addition salts, for example by adding a strong acid such as the mineral acid hydrochloric acid or sulfuric acid to the compound of formula (I). The preferred acid salt is a salt of hydrochloric acid. Preference is given to using a dioxane solution of hydrochloric acid. The acidic salt concerned can also be prepared by adding a strong acid, such as the mineral acid hydrochloric acid or sulfuric acid, to the ester compound of formula (IV) (this forms the salt concerned by first removing the ester group T and directly in situ (i.e. without isolating the free carboxylic acid)). The preferred ester group T is tert-butyl for removal by acid.

Salts of compounds of formula (I) derived from conventional bases may be prepared, for example, by adding a base such as an alkali metal and alkaline earth metal hydroxide solution to a compound of formula (I). Preferably, an aqueous hydroxide solution (e.g., sodium hydroxide solution) is used. Aqueous hydroxide solutions (e.g., potassium hydroxide solutions) can also be generated in situ by mixing an organometallic compound (e.g., potassium tert-butoxide in THF) dissolved in an organic solvent with water or an aqueous solution. The salts derived from bases referred to can also be prepared by adding bases such as alkali metal and alkaline earth metal hydroxide solutions to the ester compounds of formula (IV) (this is by first removing the ester group T and forming the salts referred to in situ (i.e. without isolating the free carboxylic acid)). Preferred ester groups T are methyl and ethyl groups in respect of removal by bases.

The compounds of formula (II) may be prepared by: reacting a carbonyl chloride of formula (V)

Wherein R is¹、R²、R³、R⁴And R⁵Having the definitions given above

With amine compounds of the formula (VI)

Wherein R is^7A、R^7B、R⁸、R⁹And Ar has the definitions given above

And

t is an ester protecting group, especially (C)₁-C₄) -an alkyl group,

and optionally using an auxiliary base to obtain the compounds of formula (II) of the invention

and

t is an ester protecting group, especially (C)₁-C₄) -an alkyl group.

The reaction (V) + (VI) → (II) is preferably carried out in the presence of customary auxiliary bases, such as sodium or potassium carbonate, sodium or potassium hydrogencarbonate, triethylamine, DIPEA,N-methylmorpholine (NMM),NMethylpiperidine (NMP), pyridine, 2, 6-lutidine, 4-N,N-Dimethylaminopyridine (DMAP), 1, 8-diazabicyclo [5.4.0]Undec-7-ene (DBU), 1, 5-diazabicyclo [4.3.0]Non-5-ene (DBN), sodium or potassium methoxide, sodium or potassium ethoxide, sodium or potassium tert-butoxide, sodium or potassium hydride or sodium or potassium bicarbonate. Preferably DIPEA is used as base.

Inert solvents for the coupling reactions mentioned are, depending on the process used, for example ethers, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane or bis (2-methoxyethyl) ether, hydrocarbons, such as benzene, toluene, xylene, pentane, hexane or cyclohexane, halogenated hydrocarbons, such as dichloromethane, trichloromethane, carbon tetrachloride, 1, 2-dichloroethane, trichloroethylene or chlorobenzene, polar aprotic solvents, such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, butyronitrile, pyridine, dimethyl sulfoxide (DMSO),N,N-Dimethylformamide (DMF),N,N'-Dimethylpropyleneurea (DMPU) orN-methylpyrrolidone (NMP), or alcohols, such as methanol, ethanol and isopropanol. Mixtures of such solvents may also be used. Preferably, dichloromethane is used. The coupling is generally carried out at a temperature in the range from 0 ℃ to + 130 ℃, preferably from + 20 ℃ to + 80 ℃.

Suitable ester protecting groups T are in general all protecting groups known to the person skilled in the art, for example suitably substituted methyl groups such as methylthiomethyl (MTM), Tetrahydropyranyl (THP), 2- (trimethylsilyl) ethoxymethyl (SEM), Benzyloxymethyl (BOM), benzoylmethyl andNphthalimidomethyl, suitably 2-substitutedSubstituted ethyl groups such as 4-methylphenylsulfonylethyl (TSE), 2,2, 2-trichloroethyl, 2- (trimethylsilyl) ethyl and 2- (2' -Pyridyl) Ethyl (PET), allyl, benzyl, suitably substituted benzyl groups such as Diphenylmethyl (DPM), bis (o-nitrophenyl) methyl, 9-anthrylmethyl, 2,4, 6-trimethylbenzyl, 4-bromobenzyl, 4-methoxybenzyl (PMB), piperonyl and suitably substituted silyl groups such as Triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS) and di-tert-butylmethylsilyl (DTBMS); the ester protecting group T used in the process of the invention is especially and preferably (C)₁-C₄) -an alkyl group.

Depending on the respective substitution pattern, the compounds of the formula (V) can be prepared as follows: the isatin derivative of the formula (VII) is reacted with an acid anhydride (VIII) in an acylation reaction by a method similar to that known from the literature (J. Med. chem. 2005, 48 (10), 3564-3575) to give a compound of the formula (IX), which is then reacted with a sodium hydroxide solution in a rearrangement reaction to give a carboxylic acid of the formula (X). Alternatively, it is also possible to convert the isatin derivative of formula (VII) directly into the carboxylic acid of formula (X) by reaction with the anhydride (VIII) without isolation of Intermediate (IX). The acid chloride of formula (XI) can then be obtained from the carboxylic acid of formula (X) by methods known to those skilled in the art, for example by reaction with phosphorus oxychloride or thionyl chloride (scheme 1).

Scheme 1:

[R¹、R²、R³、R⁴and R⁵As given above; a) Δ T, e.g., overnight; b) Δ T, for example 1-3 h; c) NaOH, Δ T; d) POCl₃Or SOCl₂, ΔT]。

Depending on the respective substitution pattern, the compounds of the formula (VI) can be prepared, for example, by the synthetic routes described in the following schemes 2 to 8 and in the experimental part of the respective examples and synthetic methods known analogously to the literature:

scheme 2(when Y = #)¹−(CH₂)_n−#²And n = 0, 1,2,3 (VI-1)

Ar = substituted phenyl, substituted pyridyl; t = ester protecting groups such as methyl, ethyl, tert-butyl; n = 0, 1,2, 3; a) when n = 0, di-tert-butyl dicarbonate, LDA, -78 ℃; when n = 1, tert-butyl bromoacetate, LDA or LiHMDS-78 ℃; when n = 2, 3-bromopropionic acid tert-butyl ester, LDA or LiHMDS-78 ℃; or tert-butyl acrylate, potassium carbonate or sodium hydride; when n = 3, 4-bromobutyric acid tert-butyl ester, LDA, b) at-78 ℃₂Raney nickel or PtO₂. LDA = lithium diisopropylamide, LiHMDS = lithium bis (trimethylsilyl) amide]。

Scheme 3(when R is⁸(= fluorine (VI-2), hydroxy group (VI-3))

[ Ar = substituted phenyl, substituted pyridyl; t = ester protecting groups such as methyl, ethyl, tert-butyl; n = 0, 1,2, 3; a) e.g., KCN or TMSCN; b) DAST; c) h₂Catalysts, e.g. Raney nickel or PtO₂. DAST = diethylaminosulfur trifluoride]。

Scheme 4(when R is^7A/R^7B= H, Me (VI-4)

[ Ar = substituted phenyl, substituted pyridyl; t = ester protecting groups such as methyl, ethyl, tert-butyl; a) nitroethane, bases such as 2-tert-butyl-1, 1,3, 3-tetramethylguanidine; b) zinc powder, hydrochloric acid ].

^10A ^10BScheme 5 (when R/R = Me, Me (VI-5) or F, F (VI-6))

[ Ar = substituted phenyl, substituted pyridyl; t = ester protecting groups such as methyl, ethyl, tert-butyl; a) LDA, -78 ℃; b) zinc; c) h₂Raney nickel; d) h₂, PtO₂LDA = lithium diisopropylamide]。

Scheme 6(when X = NH (VI-7) or NMe (VI-8)).

[ Ar = substituted phenyl, substituted pyridyl; t = ester protecting groups such as methyl, ethyl, tert-butyl; a) TMS-CN, b) H₂Raney nickel]。

Scheme 7(when X = S (VI-9) or SO₂(VI-10) hour)

[ Ar = substituted phenyl, substituted pyridyl; t = ester protecting groups such as methyl, ethyl, tert-butyl; a) for example in DCM; b) SnCl₂C) protection of the amino function, for example in the form of NH-Boc di-tert-butyl dicarbonate, triethylamine; d) mCPBA, e) deprotection of amino functionality, e.g., HCl/dioxane Boc = tert-butoxycarbonyl; DCM = dichloromethane]。

Scheme 8(when X = O (VI-11))

[ Ar = substituted phenyl, substituted pyridyl; t = ester protecting groups such as methyl, ethyl, tert-butyl; PG = protecting group, e.g. Boc, a) Rh₂(OAc)₄B) deprotection of amino functions, e.g. HCl/dioxane Boc = tert-butoxycarbonyl]。

If appropriate, the compounds according to the invention can also optionally already be separated off in the stage of intermediates (II), (IV) or (VIII) into the corresponding enantiomers and/or diastereomers, and then be reacted further in isolated form according to the abovementioned reaction sequence. It may be appropriate to provide the amine functions of intermediates (III-A) and (III-B) with protecting groups such as Boc prior to such isolation and then deprotect them again after isolation. For this separation of the stereoisomers of the intermediates, preference is likewise given to using chromatographic methods on achiral or chiral separation phases.

The compounds of the formulae (VII), (VIII), (XII), (XIV), (XVI), (XVIII), (XIX), (XXI), (XXIII), (XXIV), (XXVI), (XVII) and (XXVIII) are likewise commercially available or are described in the literature themselves, or they can be prepared in a simple manner analogously to methods known from the literature starting from other commercially available compounds.

Detailed protocols and other literature specifications can also be found in the experimental section in the section on the preparation of the starting compounds and intermediates.

If appropriate, further compounds of the formula (I) according to the invention can also be substituted by individual radicals or substituents, in particular R¹And R⁵The functional groups of those listed below, starting from other compounds of formula (I) or precursors thereof obtained by the above-mentioned process. These transformations are carried out by conventional methods familiar to those skilled in the art and include, for example, reactions such as nucleophilic or electrophilic substitution reactions, transition metal-mediated coupling reactions, preparation and addition reactions of metallo-organics (e.g., grignard compounds or lithium organics), oxidation and reduction reactions, hydrogenation, halogenation (e.g., fluorination, bromination), dehalogenation, amination, alkylation and acylation, carboxylate formation, carboxamide and sulfonamide formation, ester cleavage and hydrolysis, and the introduction and removal of temporary protecting groups.

The compounds of the invention have valuable pharmacological properties and are useful for the treatment and/or prevention of diseases in humans and animals.

The compounds of the present invention are potent, chemically and metabolically stable antagonists of the FP receptor ("FP antagonists") and are therefore suitable for use in the treatment and/or prevention of diseases and pathological processes, in particular those in which the FP receptor is involved in inflammatory events and/or in the process of tissue or vascular remodeling.

Within the scope of the present invention, these include in particular diseases of the kind such as interstitial idiopathic pneumonia, including Idiopathic Pulmonary Fibrosis (IPF), acute interstitial pneumonia, non-specific interstitial pneumonia, lymphatic interstitial pneumonia, bronchiolitis respiratory with interstitial lung diseases, cryptogenic organisational pneumonia, desquamating interstitial pneumonia and non-classifiable idiopathic interstitial pneumonia, as well as granulomatous interstitial lung diseases, rheumatoid arthritis with interstitial lung diseases, interstitial lung diseases of known etiology and interstitial lung diseases of other unknown etiology, pulmonary hypertension (PAH) and other forms of Pulmonary Hypertension (PH), Bronchiolitis Obliterans Syndrome (BOS), Chronic Obstructive Pulmonary Disease (COPD), pulmonary sarcoidosis, Acute Respiratory Distress Syndrome (ARDS), Acute Lung Injury (ALI), alpha-1-antitrypsin deficiency (AATD), Emphysema (e.g. emphysema caused by cigarette smoke), Cystic Fibrosis (CF), inflammatory and fibrotic diseases of the kidney, chronic inflammatory bowel disease (IBD, crohn's disease, ulcerative colitis), peritonitis, peritoneal fibrosis, rheumatoid disease, multiple sclerosis, inflammatory and fibrotic skin diseases, sickle cell anemia and inflammatory and fibrotic eye diseases.

The compounds of the invention are also useful in the treatment and/or prevention of asthma of varying severity with intermittent or sustained progression (refractory asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, drug or dust induced asthma), various forms of bronchitis (chronic bronchitis, infectious bronchitis, eosinophilic bronchitis), bronchiectasis, pneumonia, farmer's lung and related diseases, cough and cold (chronic inflammatory cough, iatrogenic cough), mucositis (including rhinitis medicamentosa, vasomotor rhinitis and seasonal-dependent allergic rhinitis, e.g. pollen allergy) and polyps.

Furthermore, the compounds of the invention are useful for the treatment and/or prophylaxis of cardiovascular diseases, such as hypertension (hypertension), cardiac insufficiency, coronary heart disease, stable and unstable angina, renal hypertension, peripheral and cardiovascular diseases, arrhythmias, atrial and ventricular arrhythmias, and also conduction disorders, such as atrioventricular block I-III, supraventricular tachyarrhythmias, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia, torsades de pointes, atrial and ventricular extrasystoles, AV junctional extrasystoles, sick sinus syndrome, syncope, AV node reentrant tachycardia, Wolff-Parkinson-Wharton syndrome, Acute Coronary Syndrome (ACS), autoimmune heart disease (pericarditis, endocarditis, valvulitis (Vallvolitis), aortic inflammation, myocardial inflammation, peripheral and ventricular disorders, Cardiomyopathy), boxer cardiomyopathy, aneurysms, shock, such as cardiogenic shock, septic shock and anaphylactic shock, and furthermore for the treatment and/or prophylaxis of thromboembolic diseases and ischaemia, such as myocardial ischaemia, myocardial infarction, stroke, cardiac hypertrophy, transient and ischaemic attacks, preeclampsia, inflammatory cardiovascular diseases, spasms of the coronary and peripheral arteries, oedema formation, for example pulmonary oedema, cerebral oedema, renal oedema or oedema caused by cardiac insufficiency, peripheral circulatory disorders, reperfusion injury, arterial and venous thrombosis, microalbuminuria, cardiac insufficiency, endothelial dysfunction, damage to the micro-and large vessels (vasculitis)), and for the prevention of restenosis, such as following thrombolytic therapy, Percutaneous Transluminal Angioplasty (PTA), Percutaneous Transluminal Coronary Angioplasty (PTCA), heart transplantation, and bypass surgery.

Within the scope of the present invention, the term cardiac insufficiency includes acute and chronic manifestations of cardiac insufficiency, as well as specific or related disease types such as acute decompensated cardiac insufficiency, right heart insufficiency, left heart insufficiency, systemic insufficiency, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, diabetic cardiomyopathy, congenital heart defects, heart valve defects, cardiac insufficiency associated with heart valve defects, mitral stenosis, mitral insufficiency, aortic stenosis, aortic insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary stenosis, pulmonary valve insufficiency, combined heart valve defects, myocardial inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic cardiac insufficiency, acute myocarditis, chronic myocarditis, cardiac insufficiency, alcoholic cardiomyopathy, cardiac storage disorders, and diastolic and systolic cardiac insufficiency.

The compounds according to the invention are furthermore suitable for the treatment and/or prophylaxis of kidney diseases, in particular renal insufficiency and renal failure. Within the scope of the present invention, the terms renal insufficiency and renal failure include acute and chronic manifestations thereof, but also underlying or associated kidney diseases, such as hypoperfusion of the kidney, dialysis-related hypotension, obstructive urinary tract disease, glomerulopathy, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases, nephropathy, such as primary and congenital nephropathy, nephritis, immunological nephropathy, such as renal transplant rejection and immune complex-induced nephropathy, nephropathy induced by toxic substances, nephropathy induced by contrast agents, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndrome, which may be caused, for example, by abnormally reduced creatinine and/or water excretion, abnormally increased blood concentrations of urea, nitrogen, potassium and/or creatinine, abnormal elevated blood levels of blood, kidney deficiency, and/or other kidney diseases, which may be caused, for example, by abnormally reduced creatinine and/or water excretion, urea, nitrogen, potassium and, Altered activity of a renalase such as glutamyl synthase, altered urinary osmolality or urine volume, elevated microalbuminuria, macroalbuminuria, glomerular and arteriolar injury, tubular dilatation, hyperphosphatemia, and/or the need for dialysis for diagnostic characterization. The invention also encompasses the use of the compounds according to the invention for the treatment and/or prevention of the sequelae of renal insufficiency, such as hypertension, pulmonary edema, cardiac insufficiency, uremia, anemia, electrolyte disorders (e.g. hyperkalemia, hyponatremia) and disorders in the bone and carbohydrate metabolism.

Furthermore, the compounds of the invention are suitable for the treatment and/or prophylaxis of diseases of the urogenital system, such as Benign Prostatic Syndrome (BPS), Benign Prostatic Hyperplasia (BPH), Benign Prostatic Enlargement (BPE), Bladder Outlet Obstruction (BOO), Lower Urinary Tract Syndrome (LUTS), neurogenic overactive bladder (OAB), urinary incontinence, such as mixed, urge, stress or overflow urinary incontinence (MUI, UUI, SUI, OUI), pelvic pain, as well as erectile and female sexual dysfunction.

The compounds of the invention are also useful in the treatment of diseases of the female reproductive system such as uterine fibroids, endometriosis, dysmenorrhea and extra-systolic, as well as peripherally mediated inflammatory pain (e.g. in the case of symptomatic endometriosis). Furthermore, they are suitable for the prophylaxis or treatment of hirsutism (Hirsutismus) and hypertrichosis (Hypertrichose).

Furthermore, the compounds of the present invention have anti-inflammatory effects and thus can be used as anti-inflammatory agents for the treatment and/or prevention of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory diseases of the kidney, chronic enteritis (IBD, crohn's disease, ulcerative colitis), pancreatitis, peritonitis, cystitis, urethritis, prostatitis, epididymitis, oophoritis, salpingitis, vulvovaginitis, rheumatoid diseases, arthritis, inflammatory diseases of the central nervous system, multiple sclerosis, inflammatory skin diseases and inflammatory eye diseases.

The compounds according to the invention are also suitable for the treatment and/or prophylaxis of fibrotic diseases of internal organs, such as the lung, the heart, the kidney, the bone marrow and in particular the liver, and also of skin fibrosis and of the eye. Within the scope of the present invention, the term fibrotic diseases especially includes diseases such as liver fibrosis, liver cirrhosis, lung fibrosis, endomyocardial fibrosis, kidney disease, glomerulonephritis, interstitial kidney fibrosis, fibrotic damage caused by diabetes, myelofibrosis, peritoneal fibrosis and similar fibrotic diseases, scleroderma, maculopathy, keloids, hypertrophic scar formation, nevi, diabetic retinopathy, proliferative vitreoretinopathy and diseases of the connective tissue (e.g. sarcoidosis). The compounds of the invention are likewise useful for promoting wound healing, for preventing post-operative scarring, for example after glaucoma surgery, and for cosmetic purposes on aged or keratinized skin.

The compounds of the invention are also useful for the treatment and/or prophylaxis of anemias, such as hemolytic anemias, in particular haemoglobinopathies, such as sickle cell anemia and thalassemia, megaloblastic anemia, iron deficiency anemia, anemia arising from acute blood loss, bone marrow invasive anemia (Verdrängungsanämien) and aplastic anemia.

Furthermore, the compounds of the invention are suitable for the treatment of cancers, such as skin cancer, brain tumors, breast cancer, myeloma, leukemia, liposarcoma, cancers of the gastrointestinal tract, liver, pancreas, lung, kidney, ureter, prostate and reproductive tract, and malignancies of the lymphoproliferative system, such as hodgkin's lymphoma and non-hodgkin's lymphoma.

Furthermore, the compounds of the invention can be used for the treatment and/or prevention of arteriosclerosis, lipid metabolism disorders and dyslipidemia (hypolipoproteinemia, hypertriglyceridemia, hyperlipidemia, combined hyperlipidemia, hypercholesterolemia, betalipoproteinemia, sitosterolemia), xanthomatosis, red-rooted morbid disease, obesity (obesity), hyperlipidemia (adiposis), metabolic diseases (metabolic syndrome, hyperglycemia, insulin-dependent diabetes mellitus, non-insulin-dependent diabetes mellitus, gestational diabetes, hyperinsulinemia, insulin resistance, glucose intolerance and diabetic sequelae such as retinopathy, nephropathy and neuropathy), gastrointestinal and abdominal diseases (glossitis, gingivitis, periodontitis, esophagitis, cytogastroenteritis, mastocytosis, colitis, proctitis, anal pruritus, diarrhea, celiac sprue, hepatitis, liver cirrhosis, pancreatitis and cholecystitis), central nervous system diseases and neurodegenerative disorders (stroke, alzheimer's disease, dementia, psoriasis, scleroderma, mucositis disease, mucositis, scleroderma, mucositis, scleroderma, mucositis, scleroderma, mucositis, scleroderma, mucositis, scleroderma, mucositis, scleroderma, mucositis, scleroderma, mucositis, scleroderma, mucositis, scleroderma, mucositis, scleroderma, mucositis, scleroderma, mucositis, scleroderma, mucositis, scleroderma, mucositis, scleroderma, mucositis, scleroderma, mucositis, scleroderma, mucositis, muco.

Due to their biochemical and pharmacological profile, the compounds of the invention are particularly suitable for the treatment and/or prevention of interstitial lung diseases, in particular Idiopathic Pulmonary Fibrosis (IPF) and Pulmonary Hypertension (PH), Bronchiolitis Obliterans Syndrome (BOS), inflammatory and fibrotic skin diseases and ocular diseases and fibrotic diseases of internal organs.

The well-characterized human diseases described above can also occur with comparable etiology in other mammals, and can likewise be treated there with the compounds of the invention.

Within the scope of the present invention, the terms "treat" or "treatment" include inhibiting, delaying, arresting, alleviating, attenuating, limiting, reducing, suppressing, reversing or curing a disease, illness, condition, injury or health disorder, the development, progression or progression of such a condition and/or symptoms of such a condition. Herein, the term "therapy" is understood to be synonymous with the term "treatment".

Within the scope of the present invention, the terms "prevent", "preventing" or "prevention" are used synonymously and mean avoiding or reducing the risk of developing or progressing from, being infected with, suffering from or having a disease, illness, condition, injury or health disorder, such a condition and/or symptoms of such a condition.

Treatment or prevention of a disease, ailment, condition, injury or health disorder may be partially or fully effected.

Therefore, a further subject of the present invention is the use of the compounds according to the invention for the treatment and/or prophylaxis of diseases, in particular of the abovementioned diseases.

Another subject of the invention is the use of the compounds according to the invention for the preparation of medicaments for the treatment and/or prophylaxis of diseases, in particular of the abovementioned diseases.

A further subject of the invention is a medicament comprising at least one compound according to the invention for the treatment and/or prophylaxis of diseases, in particular of the abovementioned diseases.

Another subject of the invention is the use of the compounds according to the invention in a method for the treatment and/or prophylaxis of diseases, in particular of the abovementioned diseases.

A further subject of the present invention is a method for the treatment and/or prophylaxis of diseases, in particular of the abovementioned diseases, using an effective amount of at least one compound according to the invention.

The compounds of the present invention may be used alone or in combination with one or more other pharmacologically effective agents as desired, provided that such combination does not cause undesirable and unacceptable side effects. A further subject of the present invention is therefore, inter alia, a medicament for the treatment and/or prophylaxis of the abovementioned diseases, which comprises at least one compound according to the invention and one or more further active ingredients. As combined active ingredients suitable for this, mention may be made, by way of example and preferably, of:

organic nitrates and NO-donors, such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO;

a compound that inhibits degradation of cyclic guanosine monophosphate (cGMP) and/or cyclic adenosine monophosphate (cAMP), for example an inhibitor of Phosphodiesterase (PDE) 1,2,3, 4 and/or 5, in particular a PDE5 inhibitor, such as sildenafil, vardenafil, tadalafil, udenafil, dartazinafil, avanafil, milonafil or Lodenafil;

NO and heme independent activators of soluble guanylate cyclase (sGC), such as the compounds described in particular in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO 02/070510;

NO-independent, but heme-dependent soluble guanylate cyclase (sGC) stimulators such as in particular Riociguat (Riociguat) and the compounds described in WO 00/06568, WO 00/06569, WO 02/42301, WO 03/095451, WO2011/147809, WO 2012/004258, WO 2012/028647 and WO 2012/059549;

prostacyclin analogues and IP receptor agonists, such as and preferably iloprost, beraprost, treprostinil, epoprostenol or Selexipag;

an endothelin receptor antagonist such as, and preferably, bosentan, darussan, ambrisentan or Sitaxsentan (Sitaxsentan);

a compound that inhibits Human Neutrophil Elastase (HNE), for example and preferably cevelstat or DX-890 (relatran);

a compound inhibiting the signal transduction cascade, for example and preferably selected from kinase inhibitors, in particular from tyrosine kinase inhibitors and/or serine/threonine kinase inhibitors, for example and preferably of nintedanib, dasatinib, nilotinib, bosutinib, regorafenib, sorafenib, sunitinib, cediranib, axitinib, tiratinib, imatinib, brimonib, pazopanib, vatalanib, gefitinib, erlotinib, lapatinib, canertinib, pelitinib, Semaxanib or tandatinib;

compounds which inhibit degradation and remodeling of the extracellular matrix, for example and preferably are inhibitors of Matrix Metalloproteinases (MMP), in particular stromelysin, collagenase, gelatinase and aggrecanase (herein especially MMP-1, MMP-3, MMP-8, MMP-9, MMP-10, MMP-11 and MMP-13) and metalloelastase (MMP-12);

compounds which block the binding of serotonin to its receptor, for example and preferably 5-HT_2BAntagonists of the receptor, such as PRX-08066;

antagonists of growth factors, cytokines and chemokines, such as, and preferably, antagonists of TGF-beta, CTGF, IL-1, IL-4, IL-5, IL-6, IL-8, IL-13 and integrins;

a compound that inhibits Rho kinase, such as, and preferably fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049;

a compound that inhibits soluble epoxide hydrolase (sEH), such as N, N' -dicyclohexylurea, 12- (3-adamantan-1-ylureido) dodecanoic acid, or 1-adamantan-1-yl-3- {5- [2- (2-ethoxyethoxy) ethoxy ] pentyl } urea;

a compound that affects cardiac energy metabolism, such as and preferably, etolimus, dichloroacetate, ranolazine, or trimetazidine;

an anti-obstructive agent as e.g. for use in the treatment of Chronic Obstructive Pulmonary Disease (COPD) or bronchial asthma, for example and preferably selected from inhaled or systemically administered beta-adrenergic receptor agonists (beta-mimetics) and inhaled administered antimuscarinic (anti-muscarinergen) substances;

an anti-inflammatory, immunomodulatory, immunosuppressive and/or cytotoxic agent, for example and preferably selected from the group consisting of corticosteroids and acetylcysteine, montelukast, azathioprine, cyclophosphamide, hydroxyurea, azithromycin, pirfenidone or etanercept administered systemically or by inhalation;

anti-fibrotic agents, such as and preferably the multi-kinase inhibitor nintedanib, adenosine A2b receptor antagonists, sphingosine-1-phosphate receptor 3(S1P3) antagonists, autotoxin inhibitors, lysophosphatidic acid receptor 1(LPA-1) antagonists and lysophosphatidic acid receptor 2(LPA-2) antagonists, Lysyl Oxidase (LOX) inhibitors, lysyl oxidase-like 2 inhibitors, CTGF inhibitors, IL-4 antagonists, IL-13 antagonists, alpha-agonists_vβ₆-an integrin antagonist, a TGF- β antagonist, a Wnt signaling pathway inhibitor or a CCR2 antagonist;

an antithrombotic agent, for example and preferably selected from platelet aggregation inhibitors, anticoagulants and fibrinolytic substances;

a blood pressure lowering active ingredient, such as, and preferably, selected from calcium antagonists, angiotensin AII antagonists, ACE inhibitors, vasopeptidase inhibitors, endothelin antagonists, renin inhibitors, alpha receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists and diuretics;

an active ingredient which alters lipid metabolism, for example and preferably selected from thyroid receptor agonists, cholesterol synthesis inhibitors, for example and preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR- α, PPAR- γ and/or PPAR- δ agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors and lipoprotein (a) antagonists; and/or

Chemotherapeutic agents, as they are e.g. used for the treatment of new formations (tumors) in the lung or other organs.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a beta-adrenergic receptor agonist such as, and preferably, albuterol, isoproterenol, metaproterenol, terbutaline, fenoterol, formoterol, reproterol, terbutaline or salmeterol.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an antimuscarinic substance, such as, and preferably, ipratropium bromide, tiotropium bromide or oxitropium bromide.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a corticosteroid, such as, and preferably, prednisone, prednisolone, methylprednisolone, triamcinolone acetonide, dexamethasone, beclomethasone, betamethasone, flunisolide, budesonide or fluticasone.

An antithrombotic agent is preferably understood to mean a compound selected from the group consisting of platelet aggregation inhibitors, anticoagulants and fibrinolytic substances.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a platelet aggregation inhibitor, such as, and preferably, aspirin, clopidogrel, ticlopidine or dipyridamole.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a thrombin inhibitor, such as, and preferably, cimagliflozin, melagatran, dabigatran, bivalirudin or cricetrin.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a GPIIb/IIIa antagonist, such as and preferably tirofiban or abciximab.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a factor Xa inhibitor, such as, and preferably, rivaroxaban, apixaban, fidaxaban (Fidexaban), rizoxaban, fondaparinux, idaparinux (Idraparinux), DU-176b, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a heparin small molecular weight (LMW) heparin derivative.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a vitamin K antagonist, such as, and preferably, coumarin.

By a hypotensive agent is preferably understood a compound selected from the group consisting of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists and diuretics.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a calcium antagonist such as, and preferably, nifedipine, amlodipine, verapamil or diltiazem.

In a preferred embodiment of the invention, the compounds of the invention are reacted with alpha₁-receptor blocker combined administration, said alpha₁Receptor blockers such as and preferably being prazosin.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a beta-receptor blocker, such as, and preferably, propranolol, atenolol, timolol, pindolol, Alprenolol (Alprenolol), oxprenolol, penbutolol, bucindolol, metiprolol, nadolol, mepindolol, caraanolol (Carazalol), sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, atenolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, eparnolol or bucindolol.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an angiotensin AII-antagonist, such as and preferably losartan, candesartan, valsartan, telmisartan or embsartan.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an ACE-inhibitor, such as, and preferably, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinapril (Quinopril), perindopril or Trandopril (Trandopril).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an endothelin-antagonist such as, and preferably, bosentan, darussan, ambrisentan or Sitaxsentan (Sitaxsentan).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a renin-inhibitor, such as, and preferably, aliskiren, SPP-600 or SPP-800.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a mineralocorticoid-receptor-antagonist, such as and preferably spironolactone, eplerenone or Finerenon.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a diuretic, such as, and preferably, furosemide, bumetanide, torasemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methylchlorothiazide, polythiazide, trichlorthiazide, chlorthalidone, indapamide, metolazone, quinethazone (quinethazone), acetazolamide, diclofenamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene.

An agent that alters fat metabolism is preferably understood to mean a compound selected from the group consisting of: CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors, such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR-alpha-, PPAR-gamma-and/or PPAR-delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors, lipase inhibitors and lipoprotein (a) -antagonists.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a CETP-inhibitor, such as, and preferably, Tochester (CP-529414), JJT-705, or CETP-vaccine (Avant).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a thyroid receptor-agonist such as, and preferably, D-thyroxine, 3,5,3' -triiodothyronine (T3), CGS23425 or acitirome (CGS 26214).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an HMG-CoA-reductase-inhibitor selected from the group of statins, such as and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a squalene synthesis-inhibitor, such as, and preferably, BMS-188494 or TAK-475.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACAT-inhibitor, such as, and preferably, avasimibe, melinamide, petibobu, Eflucmitibe or SMP-797.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an MTP-inhibitor, such as, and preferably, Implitapide (Impliptaside), BMS-201038, R-103757 or JTT-130.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a PPAR-gamma-agonist, such as and preferably pioglitazone or rosiglitazone.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a PPAR-delta agonist, such as, and preferably, GW-501516 or BAY 68-5042.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a cholesterol-absorption inhibitor, such as, and preferably, ezetimibe, tiquinan or pamoside.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a lipase-inhibitor, such as, and preferably, orlistat.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a polymeric bile acid adsorbent, such as and preferably colestyramine, colestipol, Colesolvam, Colestimide or Colestimide.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a bile acid-reabsorption inhibitor, such as, and preferably, an ASBT (= IBAT) -inhibitor, such as AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a lipoprotein (a) -antagonist, such as, and preferably, Gemcabene (Gemcabene) calcium (CI-1027) or niacin.

Particularly preferred are combinations of the compounds of the present invention with one or more other active ingredients selected from the group consisting of: PDE5 inhibitors, sGC activators, sGC stimulators, prostacyclin analogs, IP receptor agonists, endothelin antagonists, compounds that inhibit the transduction cascade of signals, and pirfenidone.

Another subject of the invention is a medicament comprising at least one compound according to the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and its use for the purposes described above.

The compounds of the invention may act systemically and/or locally. For this purpose, they can be administered in a suitable manner, for example orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, vaginally, dermally, transdermally, conjunctivally, otically or as an implant or stent.

For these routes of administration, the compounds of the present invention may be administered in a suitable manner of administration.

Suitable for oral administration are administration forms which act according to the prior art and deliver the compounds of the invention rapidly and/or in a modified manner, containing the compounds of the invention in crystalline and/or amorphous and/or dissolved form, for example tablets (uncoated or coated tablets, for example with enteric coatings or coatings with delayed or insoluble dissolution, which control the release of the compounds of the invention), tablets or films/wafers which disintegrate rapidly in the oral cavity, films/lyophilisates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pills, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be accomplished by avoiding a resorption step (e.g., by intravenous, intraarterial, intracardiac, intraspinal or intralumbar routes) or by including resorption (e.g., by intramuscular, subcutaneous, intradermal, transdermal, intravitreal or intraperitoneal routes). Administration forms suitable for parenteral administration include, in particular, injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

Suitable for other routes of administration are, for example, pharmaceutical forms for inhalation (including powder inhalants, nebulizers), nasal drops, nasal solutions or sprays; tablets, films/sheets or capsules for lingual, sublingual or buccal administration, suppositories, eye drops, ophthalmic ointments, eye washes, ophthalmic inserts, ear drops, otic sprays, powders, lotions or tampons, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, emulsions, microemulsions, ointments, creams, transdermal therapeutic systems (e.g. patches), milks, pastes, foams, dusting powders, implants or stents.

Oral and parenteral administration are preferred, especially oral, intravenous and intrapulmonary (inhalation) administration.

The compounds of the invention can be converted into the administration forms mentioned. This can be achieved in a manner known per se by mixing with pharmaceutically suitable excipients. These excipients include, inter alia

Fillers and carrier materials (e.g., cellulose, microcrystalline cellulose such as Avi-cel @, lactose, mannitol, starch, calcium phosphate such as Di-Cafos),

ointment bases (e.g., petrolatum, paraffin, triglycerides, waxes, wool wax, lanolin alcohols, lanolin, hydrophilic ointments, polyethylene glycols),

suppository bases (e.g., polyethylene glycol, cocoa butter, stearin),

solvents (e.g. water, ethanol, isopropanol, glycerol, propylene glycol, medium chain triglyceride fatty oils, liquid polyethylene glycols, paraffin wax),

surfactants, emulsifiers, dispersants or wetting agents (e.g., sodium dodecyl sulfate, lecithin, phospholipids, fatty alcohols such as Lanete, sorbitan fatty acid esters such as Span, polyoxyethylene sorbitan fatty acid esters such as Tween, polyoxyethylene glycerol fatty acid esters such as Cremophor, polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamer such as Pluronic),

buffer substances, and acids and bases (e.g. phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide, ammonium carbonate, tromethamine, triethanolamine),

isotonic agents (e.g. glucose, sodium chloride),

an adsorbent (e.g. finely divided silica),

viscosity increasing agents, gel forming agents, thickening agents or binders (e.g., polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, starch, carbomer, polyacrylic acid such as Carbopol @, alginate, gelatin),

disintegrating agent (e.g. modified starch, sodium carboxymethylcellulose, sodium starch glycolate such as Explotab, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose such as AcDiSol @),

flow regulators, lubricants, glidants and mold release agents (e.g. magnesium stearate, stearic acid, talc, finely divided silicon dioxide such as Aerosil),

coating agents (e.g., sugar, shellac) and film forming agents for rapidly or improving the dissolution of the film or diffusion film (e.g., polyvinylpyrrolidone such as Kollidon, polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, polyacrylate, polymethacrylate such as Eudragit @),

capsule materials (e.g. gelatin, hydroxypropylmethylcellulose),

synthetic polymers (e.g., polylactide, polyglycolide, polyacrylate, polymethacrylate such as Eudragit @, polyvinylpyrrolidone such as Kollidon @, polyvinyl alcohol, polyvinyl acetate, polyethylene oxide, polyethylene glycol and copolymers and block copolymers thereof),

plasticizers (e.g., polyethylene glycol, propylene glycol, glycerin, triacetin, triacetyl citrate, dibutyl phthalate),

a penetration enhancer,

stabilizers (e.g. antioxidants such as ascorbic acid, ascorbyl palmitate, sodium ascorbate, butyl hydroxyanisole, butyl hydroxytoluene, propyl gallate),

preservatives (e.g., parabens, sorbic acid, thimerosal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate),

dyes (e.g., inorganic pigments such as iron oxide, titanium dioxide),

aroma, sweetener, flavor and/or odor remediation agent.

In general, it has been found that in the case of parenteral administration, an amount of about 0.001 to 1 mg/kg body weight, preferably about 0.01 to 0.5 mg/kg body weight, is useful to achieve effective results. In the case of oral administration, the dose is about 0.01 to 100 mg/kg body weight, preferably about 0.01 to 20 mg/kg body weight, and most preferably 0.1 to 10 mg/kg body weight. In the case of intrapulmonary administration, the amount per inhalation is usually about 0.1 to 50 mg.

However, in some cases it may be necessary to deviate from the stated amounts and depend on the body weight, the route of administration, the individual response to the active ingredient, the nature of the formulation and the time or interval over which the administration takes place. Thus, in some cases it may be sufficient to go below the minimum amount mentioned above, while in other cases the upper limit must be exceeded. In the case of larger amounts, it is advisable to divide them into several individual doses per day.

Another subject of the invention is a pharmaceutical composition comprising at least one compound according to the invention, usually together with one or more pharmaceutically suitable excipients, and its use according to the invention.

The following examples illustrate the invention. The invention is not limited to this embodiment.

A. Examples of the embodiments

Abbreviations and acronyms:

[α]_D ²⁰specific Angle of rotation (in polarimetry)

atm atmospheric pressure; pressure unit

br. Wide (in NMR)

c concentration

ca. about

d doublet (in NMR)

DAD diode array Detector (in HPLC)

DBU 1, 8-diazabicyclo [5.4.0] undec-7-ene

dd doublet (in NMR)

DIPEAN,N-diisopropylethylamine

DMFN,N-dimethylformamide

DMSO dimethyl sulfoxide

Δ T heating, temperature increase (in reaction scheme)

d. Th. theoretical (in chemical yield)

ee enantiomeric excess

EI Electron bombardment ionization (in MS)

eq. equivalent

ESI electrospray ionization (in MS)

Et Ethyl group

Gew.% in weight

h hours

HPLC high pressure high performance liquid chromatography

IPr isopropyl group

LC liquid chromatography

LC-MS liquid chromatography-mass spectrometry combination

LDA lithium diisopropylamide

m multiplet (in NMR)

M mol

Me methyl group

min for

MS Mass Spectrometry

MWD Multi-wavelength Detector (in HPLC, UV detector)

NMPN-methyl-2-pyrrolidone

NMR nuclear magnetic resonance spectrum

MTB Ether tert-butyl methyl Ether

MTP Multi-well Titer plate

q quartet (in NMR)

qd quadruple doublet (in NMR)

RP reverse phase (reverse phase, in HPLC)

RT Room temperature

R_tRetention time (in HPLC, LC/MS)

s singlet (in NMR)

SFC supercritical fluid chromatography

t triplet (in NMR)

td triple doublet (in NMR)

TFA trifluoroacetic acid

tertTertiary amine

THF tetrahydrofuran

ULC ultra liquid chromatography

UPLC ultra-high performance liquid chromatography

UV ultraviolet spectrum

Vol.% volume percent

Other abbreviations have the meaning familiar to those skilled in the art.

HPLC and LC/MS methods:

method 1 (LC-MS):

MS instrument type is Thermo Scientific FT-MS, UHPLC + instrument type is Thermo Scientific ultimate 3000, column is Waters, HSST3, 2.1 x 75 mm, C181.8 mu m, eluent A is 1 l of water +0.01% formic acid, eluent B is 1 l of acetonitrile +0.01% formic acid, gradient is 0.0min 10% B → 2.5 min95% B → 3.5 min95% B, oven is 50 ℃, flow rate is 0.90 ml/min, UV detection is 210 nm/optimal integration path 210nm and 300 nm.

Method 2 (LC-MS):

the instrument comprises the following steps: waters ACQUITY SQD UPLC System, column Waters Acquisity UPLC HSS T31.8 μm50 x 1 mm, eluent A1 l water +0.25 ml 99% formic acid, eluent B1 l acetonitrile +0.25 ml 99% formic acid, gradient 0.0min 90% A → 1.2 min 5% A → 2.0 min 5% A, oven: 50 ℃ and flow rate: 0.40ml/min, UV detection: 208-400 nm.

Method 3 (LC-MS):

instrument: Waters Single Quad MS System; instrument: Waters UPLC Acquity; column: Waters BEH C181.7 μm50 x 2.1 mm; eluent A: 1 l water + 1.0 ml (25% ammonia)/l; eluent B: 1 l acetonitrile; gradient: 0.0min 92% A → 0.1 min 92% A → 1.8 min 5% A → 3.5 min 5% A; oven: 50 ℃ and flow rate: 0.45 ml/min, UV detection: 210nm (208-400 nm).

Method 4 (LC-MS):

the instrument comprises the following steps: agilent MS Quad 6150, HPLC: Agilent 1290, column: waters Acquity UPLC HSST 31.8 μm50 x 2.1 mm, eluent A1 l water +0.25 ml 99% formic acid, eluent B1 l acetonitrile +0.25 ml 99% formic acid, gradient: 0.0min 90% A → 0.3 min 90% A → 1.7 min 5% A → 3.0min 5% A, oven: 50 ℃ and flow rate: 1.20 ml/min, UV detection: 205-305 nm.

Method 5 (GC-MS):

the instrument comprises the following steps: thermo Scientific DSQII, Thermo Scientific Trace GC Ultra, column: RestekRTX-35MS, 15m x 200, 200 mu m x 0.33, 0.33 mu m, constant flow rate of helium: 1.20 ml/min, oven: 60 ℃, inlet: 220 ℃ and gradient: 60 ℃, 30 ℃/min → 300 ℃ (hold for 3.33 min).

Method 6 (preparative HPLC):

column: chromatorex C18, 10 μm, 250 x 40 mm, eluent A: water, eluent B: acetonitrile, injection at 3min, gradient: 0.0min 30% B → 6.0 min30% B → 27min 95% B → 38min 95% B → 39min 30% B → 40.2 min30% B, flow rate: 50 ml/min, UV detection: 210 nm.

Method 7 (preparative HPLC):

column: chromatorex C18, 10 μm, 125 x 30mm, eluent A: water, eluent B: acetonitrile, injection at 3min, gradient: 0.0min 30% B → 5.5min 30% B → 17.65 min95% B → 19.48 min95% B → 19.66 min30% B → 20.51 min30% B, flow rate: 75 ml/min, UV detection: 210 nm.

Method 8 (preparative HPLC):

column: chromatorex C18, 10 μm, 250 x 40 mm, eluent A: water, eluent B: acetonitrile, injection at 3min, gradient: 0.0min 10% B → 6.0 min10% B → 27min 95% B → 38min 95% B → 39min 10% B → 40.2 min10% B, flow rate: 50 ml/min, UV detection: 210 nm.

Method 9 (preparative HPLC):

column: chromatorex C18, 10 μm, 250 x 40 mm, eluent A water + 0.1% TFA, eluent B acetonitrile, injection at 3min, gradient: 0.0min 10% B → 6.0 min10% B → 27min 95% B → 38min 95% B → 39min 10% B → 40.2 min10% B, flow rate: 50 ml/min, UV detection: 210 nm.

Method 10 (preparative HPLC):

column: chromatorex C18, 10 μm, 125 x 30mm, eluent A water + 0.1% TFA, eluent B acetonitrile, injection at 3min, gradient: 0.0min 10% B → 5.5min 10% B → 17.65 min95% B → 19.48 min95% B → 19.66 min10% B → 20.51 min10% B, flow rate: 75 ml/min, UV detection: 210 nm.

Method 11 (preparative HPLC):

column: chromatorex C18, 10 μm, 125 x 30mm, eluent A: water, eluent B: acetonitrile, injection at 3min, gradient: 0.0min 10% B → 5.5min 10% B → 17.65 min95% B → 19.48 min95% B → 19.66 min10% B → 20.51 min10% B, flow rate: 75 ml/min, UV detection: 210 nm.

Method 12 (preparative HPLC):

column: chromatorex C18, 10 μm, 250 x 40 mm, eluent A water + 0.1% TFA, eluent B acetonitrile, injection at 3min, gradient: 0.0min 30% B → 6.0 min30% B → 27min 95% B → 38min 95% B → 39min 30% B → 40.2 min30% B, flow rate: 50 ml/min, UV detection: 210 nm.

Method 13 (preparative HPLC):

column: chromatorex C18, 10 μm, 125 mm x 30mm, eluent A water + 0.1% formic acid, eluent B acetonitrile + 0.1% formic acid, injection at 3min, gradient: 0.0min 10% B → 6.0 min10% B → 27min 95% B → 38min 95% B → 39min 10% B → 40 min10% B, flow rate: 75 ml/min, UV detection: 210 nm.

Method 14 (preparative HPLC):

column: chromatorex C18, 10 μm, 250 mm x 40 mm, eluent A of water + 0.1% formic acid, eluent B of acetonitrile + 0.1% formic acid, gradient: 0.0min 10% B → 6.0 min10% B → 27min 95% B → 38min 95% B → 39min 10% B → 40 min10% B, flow rate: 75 ml/min, UV detection: 210 nm.

Method 15 (preparative HPLC):

column: chromatorex C18, 10 μm, 250 mm x 40 mm, eluent A of water + 0.1% formic acid, eluent B of methanol + formic acid, gradient: 0.0min 20% B → 6.2 min20% B → 6.5 min 40% B → 15.5min 60% B → 16 min100% B → 23 min100% B → 23.6 min20% B → 25.8 min20% B, flow rate: 75 ml/min, UV detection: 210 nm.

Method 16 (preparative HPLC-MS):

MS instrument: waters SQD, HPLC Instrument: waters UPLC: zorbax SB-Aq (Agilent), 50 mmx 2.1 mm, 1.8 μm, eluent A water + 0.025% formic acid, eluent B acetonitrile (ULC) + 0.025% formic acid, gradient: 0.0min 98% A → 0.9 min 25% A → 1.0 min 5% A → 1.4 min 5% A → 1.41min 98% A → 1.5 min 98% A, oven: 40 ℃, flow rate: 0.600 ml/min, UV detection: DAD, 210 nm.

Method 17 (preparative HPLC-MS):

MS instrument: Waters, HPLC instrument: Waters (column: Phenomenex, Luna, 5 μm, C18(2) 100 Å AXIA Tech, 50x 21.2 mm), eluent A: water +0.0375% formic acid, eluent B: acetonitrile (ULC) +0.0375% formic acid, gradient, flow rate: 40ml/min, UV detection: DAD, 210-400 nm.

Method 18 (preparative HPLC):

the instrument comprises the following steps: waters Prep LC/MS System, column: phenomenex Kinetex, C18, 5 μm, 100 x 30mm, column injection (full injection), eluent A: water, eluent B: acetonitrile, eluent C: 2% formic acid/water, flow rate of eluent (A + B) 65 ml/min, flow rate of eluent C: constant 5 ml/min, gradient (A/B) 0.0min 20% B → 2 min20% B → 7min 92% B → 9min 92% B → 20% B → 7min, UV detection: 210 nm.

Method 19 (preparative HPLC):

the instrument comprises the following steps: waters Prep LC/MS System, column: phenomenex Kinetex, C18, 5 μm, 100 x 30mm, column injection (full injection), eluent A: water, eluent B: acetonitrile, eluent C: 2% formic acid/water, flow rate of eluent (A + B) 65 ml/min, flow rate of eluent C5 ml/min constant, gradient (A/B) 0.0min 30% B → 2 min30% B → 2.2 min50% B → 7min 90% B → 7.5 min 92% B → 9min 92% B → 30% B → 7, UV detection: 200-400 nm.

Method 20 (preparative HPLC):

the instrument comprises the following steps: waters Prep LC/MS System, column: phenomenex Kinetex, C18, 5 μm, 100 x 30mm, column injection (full injection), eluent A: water, eluent B: acetonitrile, eluent C: 2% formic acid/water, flow rate of eluent (A + B) 65 ml/min, flow rate of eluent C5 ml/min constant, gradient (A/B) 0.0min 10% B → 2 min10% B → 2.2 min30% B → 7min 70% B → 7.5 min 92% B → 9min 92% B → 10% B → 7, UV detection: 200-400 nm.

Method 21 (preparative HPLC):

the instrument comprises the following steps: waters Prep LC/MS System, column: phenomenex Kinetex, C18, 5 μm, 100 x 30mm, column injection (full injection), eluent A: water, eluent B: acetonitrile, eluent C: 2% formic acid/water, flow rate of eluent (A + B) 65 ml/min, flow rate of eluent C5 ml/min constant, gradient (A/B) 0.0min 10% B → 2 min10% B → 2.2 min20% B → 7min 60% B → 7.5 min 92% B → 9min 92% B → 10% B → 7.5 min, UV detection: 200-400 nm.

Method 22 (preparative HPLC):

the instrument comprises the following steps: waters Prep LC/MS System, column: phenomenex Kinetex, C18, 5 μm, 100 x 30mm, column injection (full injection), eluent A: water, eluent B: acetonitrile, eluent C: 2% formic acid/water, flow rate of eluent (A + B) 65 ml/min, flow rate of eluent C5 ml/min constant, gradient (A/B) 0.0min 7.5% B → 2 min7.5% B → 7min 35% B → 7.5 min 92% B → 9min 92% B → 10% B, UV detection: 200-400 nm.

Method 23 (preparative HPLC):

the instrument comprises the following steps: waters Prep LC/MS System, column: phenomenex Kinetex, C18, 5 μm, 100 x 30mm, column injection (full injection), eluent A: water, eluent B: acetonitrile, eluent C: 2% formic acid/water, flow rate of eluent (A + B) 65 ml/min, flow rate of eluent C5 ml/min constant, gradient (A/B) 0.0min 50% B → 2 min50% B → 2.2 min 70% B → 7min 92% B → 9min 92% B → 10% B, UV detection: 200-400 nm.

Method 24 (preparative HPLC):

column: chromatorex C18, 10 μm, 125 mm x 30mm, eluent A water, eluent B acetonitrile, injection at 3min, gradient: 0.0min 10% B → 6 min10% B → 27min 95% B → 38min 95% B → 39min 10% B → 40 min10% B, flow rate: 75 ml/min, UV detection: 210 nm.

Method 25 (LC-MS):

the instrument comprises the following steps: waters Acquity UPLCMS singleQuad column: acquisty UPLC BEH C181.7 μm50 x 2.1 mm, eluent A water + 0.1 vol% formic acid (99%), eluent B acetonitrile, gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B, flow rate: 0.8 ml/min, temperature: 60 ℃, DAD scanning: 210-400 nm.

Method 26 (LC-MS):

the instrument comprises the following steps: waters Acquity UPLCMS singleQuad column: acquisty UPLC BEH C181.7 μm50 x 2.1 mm, eluent A water +0.2 vol% ammonia (32%), eluent B acetonitrile, gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B, flow rate: 0.8 ml/min, temperature: 60 ℃, DAD scanning: 210-400 nm.

Method 27 (preparative HPLC):

the instrument comprises the following steps: waters Autopurion MS singleQuad column: waters XBrigde C185 μm100 x 30mm, eluent A water +0.2 vol% ammonia (32%), eluent B acetonitrile, gradient: 0-5.5 min5-100% B, flow rate 70 ml/min, temperature: 25 ℃ DAD scanning: 210-400 nm.

Method 28 (preparative HPLC):

waters Xbridge C185 μm100 x 30mm, eluent A water + 0.1% formic acid, eluent B acetonitrile, gradient: 0min 5% B → 5.5min 100% B, flow rate 70 ml/min, DAD assay: 210-400 nm.

Method 29 (preparative HPLC):

column: reprosil C1810 mu m, 250 mm x 40 mm, flow rate: 75 ml/min, detected at 210nm, eluent A water, eluent B acetonitrile, 0-6 min10% B, 6-27 min gradient to 95% B, 27-38 min95% B, 38-39min gradient to 10% B, 39-40 min10% B.

Method 30 (preparative HPLC):

column: reprosil C1810 [ mu ] m, 250 mm x 40 mm, eluent A, water and 0.1% formic acid, eluent B, acetonitrile and 0.1% formic acid, 0-6 min10% B, 6-27 min gradient to 95% B, 27-38 min95% B, 38-39min gradient to 10% B, 39-40 min10% B, flow rate: 75 ml/min, UV detection: 210 nm.

Method 31 (preparative HPLC):

column: chromatorex C1810 [ mu ] m, 125 mm x 30mm, flow rate: 75 ml/min, detected at 210nm, eluent A water + 0.1% formic acid, eluent B methanol + formic acid, 0-7.2 min 5% B, 7.2-7.45 min gradient to 20% B, 7.45-14.5 min gradient to 40% B, 14.5-15 min gradient to 100% B, 15-24.3 min100% B, 24.2-24.5 min gradient to 5% B, 24.5-27.3 min 5% B.

Method 32 (preparative HPLC):

reprosil C18, 10 μm, 205 x 50 mm, eluent A: water, eluent B: acetonitrile, injection at 3min, gradient: 0.0min 30% B → 5.5min 30% B → 17.65 min95% B → 20.79 min95% B → 20.97min 30% B → 22.65 min30% B, flow rate: 150 ml/min, UV detection: 210 nm.

Method 33 (preparative HPLC):

reprosil C18, 10 μm, 205 x 50 mm, eluent A: water, eluent B: acetonitrile, injection at 3min, gradient: 0.0min 10% B → 5.5min 10% B → 17.65 min95% B → 20.79 min95% B → 20.97min 10% B → 22.65 min10% B, flow rate: 150 ml/min, UV detection: 210 nm.

Method 34 (quantitative ion chromatography):

measuring ions by using an external standard; the instrument comprises the following steps: thermo Scientific ICS 5000+; capillary IC column: IonPac AS11-HC and IonPac CS16, eluent: eluent gradient [ H]⁺[OH]^-The detector comprises: conductivity detection

Other details:

percentages in the following examples and test descriptions are percentages by weight, unless otherwise indicated; parts are parts by weight. The solvent ratio, dilution ratio and concentration data for the liquid/liquid solutions are in each case based on volume.

In the case of purification of the compounds of the invention by preparative HPLC by the described methods, wherein the eluent contains an additive, such as trifluoroacetic acid, formic acid or aqueous ammonia, the compounds of the invention can be obtained in the form of a salt, for example as the trifluoroacetate, formate or ammonium salt, if they contain a sufficient basic or acidic functionality. Such salts can be converted to the corresponding free base or acid by various methods known to those skilled in the art.

The purity data are usually based on the integration of the corresponding peaks in the LC/MS chromatogram, but can also be additionally aided¹H NMR spectrum was measured. The compound may still contain solvent residues which are generally not considered in specifying purity. If purity is not specified, it is indicated as 100% (based on the integration of the automatic peaks in the LC/MS chromatogram), or purity has not been clearly determined.

If purity is stated to be less than 100%, the yield stated as a theoretical% is usually corrected for yield. In solvent-containing or contaminated batches, yields may formally be "> 100%"; in these cases, the yield was not corrected for solvent or purity.

In some cases, the following¹The following description of the coupling mode of the H NMR signals is taken directly from the recommendations of ACD SpecManager (ACD/Labs release 12.00, product version 12.5) or ACD/Spectrus Processor 2014 (File version S20S41, build 72444, 2014 8/21) or ACD/Spektrus Processor 2015 Pack2 (File version S40S41, build 79720, 2015 7/30), and does not have to be strictly reviewed. In some cases, the SpecManager's recommendation was manually adjusted. The manual adjustment or assignment of the specification is usually based on the optical appearance of the signal concerned, and does not necessarily correspond to a strict, physically correct interpretation. Typically, the specification of a chemical shift refers to the center of the signal involved. If the peak is a broad multiple peak, a section is indicated. Signals that are covered or partially covered by solvent or water are presumably assigned values or not listed. Significantly broad signals (e.g., caused by rapid rotation of molecular moieties or due to proton exchange) are also putatively assigned (often referred to as broad multiplets or broad singlet) or not listed.

In some cases, it is selectedExamples of the invention¹H NMR data of¹Tabulated form of H NMR peaks. For each signal peak, the δ values in ppm are listed first, followed by the signal intensities in parentheses. The delta value/signal intensity digital pairs of different signal peaks are listed, separated from each other by commas. Thus, an exemplary peak list takes the form: delta₁(strength)₁),δ₂(strength)₂), ... ,δ_i(strength)_i), ... ,δ_n(strength)_n)。

The intensity of the sharp signal correlates with the signal height (in cm) in the example of a printout of the NMR spectrum and shows the true proportion of the signal intensity compared to the other signals. In the case of a broad signal, multiple peaks or centers of the signal and the relative intensity of the signal may be displayed compared to the strongest signal in the spectrum.¹List and convention of H NMR peaks¹HNMR printouts are similar and therefore typically contain all the peaks listed in conventional NMR interpretation. In addition, compared with the conventional¹As well as H NMR printouts, they may show peaks for solvent signals, stereoisomers of the target compound that are also the subject of the invention, and/or impurities. The peaks of the stereoisomers of the target compounds and/or the peaks of the impurities typically have, on average, a lower intensity (e.g., purity) than the peaks of the target compounds>90%). Such stereoisomers and/or impurities may be typical for the respective preparation process. Their peaks can therefore help identify the reproducibility of our preparation method with reference to the "by-product fingerprint". If desired, an expert calculating the target compound peak by known methods (MestreC, ACD simulation or using empirically estimated expectations) can isolate the target compound peak, optionally using other intensity filters. This separation will be similar to conventional¹Peak picking involved in H NMR interpretation.

A detailed description of the presentation of NMR Data in the form of a list of peaks can be found in the publication "circulation of NMR PeakList Data with PatentPastations" (see Research Disclosure Database Number 605005, 2014, 8.1.2014 or http:// www.researchdisclosure.com/searching-disorders). In the peak sorting routine described in the Research Disclosure Database Number 605005, the parameter "minimum height" may be set to 1% to 4%. Depending on the type of chemical structure and/or depending on the concentration of the compound to be analyzed, it may be meaningful to set the parameter "minimum height" to a value of < 1%.

If stated, the melting points and melting point ranges are uncorrected.

All reactants or reagents for which the preparation is not explicitly described below are suitable for use as they are commercially available from commonly available sources. For all other reactants or reagents whose preparation is likewise not described below and which are not commercially available or are obtained from sources which are not generally available, reference is made to the publications describing their preparation.

Starting compounds and intermediates

Example 1A

5-bromo-1-propionyl-1H-indole-2, 3-diones

Reacting 5-bromo-1HA mixture of indole-2, 3-dione (35.0 g, 155 mmol) and propionic anhydride (150 ml, 1.2 mol) was heated to reflux while stirring for 3 h. After cooling to room temperature, the solid present is filtered off, washed with tert-butyl methyl ether and dried in vacuo. 16.20 g (60% purity, H NMR, 22% of theory) of the title compound are obtained as a product mixture. Some of the title compound had rearranged according to the H NMR of the product mixture to give the reaction product 6-bromo-2-hydroxy-3-methylquinoline-4-carboxylic acid.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.23 (d, 1H), 8.03-7.86 (m, 2H),3.01 (q, 2H), 1.14 (t, 3H)。

Example 2A

6-bromo-2-hydroxy-3-methylquinoline-4-carboxylic acid

The method A comprises the following steps:

to 5-bromo-1-propionyl-1 at room temperatureHTo a mixture of indole-2, 3-dione (16.2 g, 57.4 mmol, not corrected for purity, example 1A) in water (100ml) was added sodium hydroxide (13.8 g, 345 mmol) and the mixture was stirred at reflux for 2 h. After cooling to room temperature, the mixture was acidified with 3M hydrochloric acid and the solid formed was filtered off. The solid was dissolved in 1M sodium hydroxide solution (400 ml) and the solution was washed five times with ethyl acetate (200 ml each). The aqueous solution is then acidified with concentrated hydrochloric acid and the solid formed is filtered off, washed with water and dried in vacuo. 8.30 g (95% purity, 49% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 0.65 min; MS (ESIpos): m/z = 282/284 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 14.28 (br. s, 1H), 12.13 (br. s, 1H),7.85-7.07 (m, 3H), 2.09 (br. s, 3H)。

Purification by preparative HPLC:

batches purified by preparative HPLC from similarly performed preliminary experiments were obtained as follows: the crude product (4.4 g, 9% purity, LC-S) was dissolved under heating in a 50ml mixture of methanol, DMSO and THF and purified by preparative HPLC [ column: chromatorex Spring column, C18, 10 μm, 290 mm x 100 mm, flow rate: 250 ml/min, detection: 210nm, temperature: 22 ℃ and injection: 30 ml, acetonitrile/water gradient 0:100 → 9:1, run time 41 min. 248mg (100% purity) of the title compound are obtained.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 14.26 (br. s, 1H), 12.13 (s, 1H),7.67 (dd, 1H), 7.50 (d, 1H), 7.30 (d, 1H), 2.09 (s, 3H)。

The method B comprises the following steps:

reacting 5-bromo-1-propionyl-1HA mixture of indole-2, 3-dione (99.3 g, 352 mmol, example 1A), water (615 ml) and sodium hydroxide (84.5 g, 2.11 mol) was stirred at 100 ℃ for 2 h. After cooling to room temperature, the mixture was mixed with water (1400 ml) and washed with ethyl acetate (1400 ml). The aqueous phase is acidified with concentrated hydrochloric acid, and the solid formed is filtered off with suction and dried in vacuo. 74.4 g (100% purity, 75% of theory according to LC-MS) of the title compound are obtained.

LC-MS (method 1) R_t= 0.65 min; MS (ESIpos): m/z = 282/284 [M+H]⁺。

The method C comprises the following steps:

reacting 5-bromo-1HA mixture of indole-2, 3-dione (58.8 g, 260.2 mmol) and propionic anhydride (250 ml, 1.95 mol) was heated to reflux under argon (internal temperature: 160 ℃ C.) while stirring overnight. The mixture was then cooled to 0 ℃, MTB ether (500 ml) was added and the mixture was dried at 0 ℃ for 1 h. The solid present is filtered off, washed again with MTB ether and dried under air. 43.0 g (100% purity, 59% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 0.69 min; MS (ESIpos): m/z = 282/284 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 14.26 (br. s, 1H), 12.13 (s, 1H), 7.67(dd, 1H), 7.50 (d, 1H), 7.30 (d, 1H), 2.09 (s, 3H)。

Example 3A

6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride

The method A comprises the following steps:

a mixture of 6-bromo-2-hydroxy-3-methylquinoline-4-carboxylic acid (8.30 g, 29.4 mmol, example 2A) and phosphorus oxychloride (60 ml, 641 mmol) was stirred under argon at reflux for 3 h. After cooling to room temperature, the mixture was slowly poured into ice water (600 ml). The resulting solution was extracted three times with dichloromethane (300 ml each). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was purified by flash column chromatography (320 g of silica gel, first cyclohexane, then cyclohexane/ethyl acetate 98:2, then cyclohexane/ethyl acetate 96:4, Isolera). The combined target fractions were concentrated and the residue was dried in vacuo. 3.74 g (83% purity, 33% of theory) of the first title compound and 1.90 g (88% purity, 18% of theory, cf. analysis) of the second title compound are obtained.

LC-MS (method 2) R_t= 1.35 min; MS (ESIpos): m/z = 320 [M+H]⁺

The method B comprises the following steps:

to a mixture of 6-bromo-2-hydroxy-3-methylquinoline-4-carboxylic acid (20.0 g, 70.9 mmol) in acetonitrile (400 ml) under argon was added thionyl chloride (52 ml, 710 mmol) and DMF (11ml, 140 mmol) at room temperature. The mixture was slowly heated to reflux with stirring, during which time gas evolution was observed. After stirring at reflux for about 1 hour, the mixture was allowed to cool to room temperature and the volatile components were removed on a rotary evaporator. The resulting residue was purified by flash column chromatography (200 g silica gel, dichloromethane). The combined target fractions were concentrated and the residue was dried in vacuo. 16.4g (97% purity, 70% of theory) of the title compound are obtained.

LC-MS (method 4) R_t= 1.66 min; MS (ESIpos): m/z = 320 [M+H]⁺

Example 4A

(6-chloro-2, 3-difluorophenyl) methanol

To a solution of 6-chloro-2, 3-difluorobenzaldehyde (5.00 g, 28.3 mmol) in THF (20ml) was added sodium borohydride (1.39 g, 36.8 mmol) (evolved gas) in portions at room temperature. Then, another 20ml of THF was added, and the mixture was stirred at room temperature for 45 min. Thereafter, methylene chloride (100ml), water (100ml) and a saturated aqueous ammonium chloride solution (50ml) were added to the mixture, which was shaken. During which the aqueous phase is acidified with concentrated acetic acid. After phase separation, the organic phase is washed once with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated, and the residue is dried briefly in vacuo. 5.35 g (100% purity, "> 106% of theory", not completely dried) of the title compound are obtained.

GC-MS (method 5) R_t= 3.23 min, MS (EIpos): m/z = 178 [M]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.45 (dd, 1H), 7.36 (ddd, 1H), 5.36(t, 1H), 4.59 (dd, 3H)。

Example 5A

2- (bromomethyl) -1-chloro-3, 4-difluorobenzene

To a solution of (6-chloro-2, 3-difluorophenyl) methanol (5.34 g, 29.9 mmol, example 4A) in dichloromethane (30 ml) was added dropwise phosphorus tribromide (1.6 ml,16 mmol) with stirring at-15 ℃. Then, the cooling bath was removed and the mixture was stirred at room temperature for an additional 2 h. After this time, saturated aqueous sodium bicarbonate solution, water and dichloromethane (50ml each) were slowly added to the mixture, which was shaken. After phase separation, the organic phase was washed with saturated aqueous sodium chloride solution (100ml), dried over sodium sulfate, filtered and concentrated, and the residue was dried briefly in vacuo. 3.88 g (94% purity, GC-MS, 51% of theory) of the title compound are obtained.

GC-MS (method 5) R_t= 3.57 min, MS (EIpos): m/z = 240 [M]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.55 (dd, 1H), 7.45 (ddd, 1H), 4.71(d, 3H)。

Example 6A

2- (bromomethyl) -1- (difluoromethoxy) -3-fluorobenzene

To a solution of [2- (difluoromethoxy) -6-fluorophenyl ] methanol (9.90 g, 51.5 mmol, prepared according to WO 2016/168633A 1, page 71) in dichloromethane (60 ml) at-15 ℃ a solution of phosphorus tribromide (1.6 ml,16 mmol) in dichloromethane (20ml) was added dropwise with stirring. Then, the cooling bath was removed and the mixture was stirred at room temperature for an additional 2 h. After this time, saturated aqueous sodium bicarbonate solution, water and dichloromethane (100ml each) were slowly added to the mixture, which was shaken. After phase separation, the organic phase was washed with saturated aqueous sodium chloride solution (200 ml), dried over sodium sulfate, filtered and concentrated, and the residue was dried briefly in vacuo. 9.60 g (95% purity, 69% of theory) of the title compound are obtained.

GC-MS (method 5) R_t= 3.38 min, MS (EIpos): m/z = 254/256 [M]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.238 (0.57), 1.255 (1.12), 1.273(0.58), 4.610 (15.58), 4.614 (16.00), 7.105 (3.32), 7.126 (3.80), 7.161(2.02), 7.184 (8.39), 7.205 (2.57), 7.366 (8.46), 7.470 (2.03), 7.487 (2.27),7.491 (3.74), 7.508 (3.68), 7.512 (2.00), 7.529 (1.66), 7.549 (4.14).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.60-7.03 (m, 4H), 4.61 (d, 2H)。

Example 7A

(2-chloro-3-fluorophenyl) acetonitrile

To a solution of 1- (bromomethyl) -2-chloro-3-fluorobenzene (6.96 g, 31.1 mmol) in dichloromethane (60 ml) was added water (60 ml) and tetrabutylammonium bromide (1.00 g, 3.11 mmol) with stirring. Then, a solution of potassium cyanide (6.08 g,93.4 mmol) in water (60 ml) was added and the mixture was stirred at room temperature for 2.5 h. The phases were then separated and the organic phase was washed three times with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated, and the residue was dried briefly in vacuo. 4.98 g (100% purity, 94% of theory) of the title compound are obtained.

GC-MS (method 5) R_t= 4.03 min, MS (EIpos): m/z = 169[M]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 4.175 (16.00), 7.400 (0.90), 7.408(1.10), 7.414 (1.15), 7.417 (1.13), 7.424 (2.60), 7.440 (2.84), 7.443 (2.99),7.459 (5.37), 7.468 (1.52), 7.474 (1.39).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.50-7.37 (m, 3H), 4.18 (s, 2H)。

Example 8A

(6-chloro-2, 3-difluorophenyl) acetonitrile

To a solution of 2- (bromomethyl) -1-chloro-3, 4-difluorobenzene (3.87 g, 16.0 mmol, example 5A) in acetonitrile (48 ml) was added trimethylsilylcyanide (2.5 ml, 18 mmol) and 1M tetrabutylammonium fluoride in THF (19 ml, 19 mmol) with stirring, and the mixture was stirred at 80 ℃ for 30 min. After cooling to room temperature, the solvent was removed on a rotary evaporator. The residue was dissolved in ethyl acetate (80 ml), and the solution was washed with water and saturated aqueous sodium chloride solution (80 ml each), dried over sodium sulfate, filtered and concentrated. The residue was dissolved in dichloromethane and purified by flash chromatography (100 g silica gel Biotage Snap cartridge KP-Sil, cyclohexane/ethyl acetate gradient 93:7 → 7:3, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 2.24 g (71% purity, GC-MS, 96% of theory) of the title compound are obtained.

GC-MS (method 5) R_t= 3.92 min, MS (EIpos): m/z = 187 [M]⁺

LC-MS (method 1) R_t= 1.57 min; MS (ESIneg): m/z = 186 [M-H]^-

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.58 (dd, 1H), 7.49 (ddd, 1H), 4.16(d, 2H)。

Example 9A

(2-chloro-3, 6-difluorophenyl) acetonitrile

To a solution of 2- (bromomethyl) -3-chloro-1, 4-difluorobenzene (4.80 g, 19.9 mmol, CAS number 90292-67-4, commercially available) in dichloromethane (40 ml) was added water (40 ml) and tetrabutylammonium bromide (641 mg, 1.99mmol) with stirring. Then, a solution of potassium cyanide (3.88 g, 59.6 mmol) in water (40 ml) was added and the mixture was stirred at room temperature for 2.5 h. 3.80 g (94% purity, 96% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 1.59 min; MS (ESIneg): m/z = 186 [M-H]^-

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.57 (td, 1H), 7.44 (td, 1H), 4.15 (d,2H)。

Example 10A

[2- (difluoromethoxy) -6-fluorophenyl ] acetonitrile

To a solution of 2- (bromomethyl) -1- (difluoromethoxy) -3-fluorobenzene (9.60 g, 37.6 mmol, example 6A) in dichloromethane (60 ml) was added water (60 ml) and tetrabutylammonium bromide (1.21 g, 3.76 mmol) with stirring. Then, a solution of potassium cyanide (7.35 g, 113 mmol) in water (120 ml) was added and the mixture was stirred at room temperature for 2.5 h. The phases were then separated and the organic phase was washed twice with saturated aqueous sodium bicarbonate solution (100ml each), dried over sodium sulfate, filtered and concentrated, and the residue was dried briefly in vacuo. 7.26g (98% purity, 94% of theory) of the title compound are obtained.

GC-MS (method 5) R_t= 3.70 min, MS (EIpos): m/z = 201 [M]⁺

LC-MS (method 1) R_t= 1.56 min

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.937 (0.68), 3.164 (0.78), 3.177(0.77), 3.952 (16.00), 7.152 (3.20), 7.171 (6.16), 7.215 (2.00), 7.237(3.89), 7.259 (2.35), 7.353 (6.55), 7.489 (1.60), 7.509 (2.98), 7.526 (3.04),7.531 (1.93), 7.535 (3.48), 7.547 (1.32).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.58-7.43 (m, 1H), 7.39-7.05 (m, 3H),3.95 (s, 2H)。

Example 11A

(+/-) -3- (2-chloro-6-fluorophenyl) -3-cyanopropanoic acid tert-butyl ester(raceme)

To a solution of (2-chloro-5-fluorophenyl) acetonitrile (25.0 g, 147 mmol) under argon in THF (200 ml) was slowly added 2M LDA in THF (110 ml, 220 mmol) with stirring at-78 ℃. The mixture was brought to 0 ℃ and after 15min, cooled again back to-78 ℃. Tert-butyl bromoacetate (33 ml, 220 mmol) was then slowly added dropwise thereto at-78 ℃ with stirring. The mixture was allowed to reach RT over 3h, then water (100ml) was added and the mixture was stirred at room temperature for 10 min. Water (200 ml) was added again, followed by ethyl acetate (200 ml), and the phases were separated. The aqueous phase was extracted with ethyl acetate (200 ml). The combined organic phases were washed once with saturated aqueous sodium chloride solution (300 ml), dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (1 kg silica gel, cyclohexane/ethyl acetate 9: 1). The combined target fractions were concentrated and the residue was dried in vacuo. 15.2 g (64% purity, 23% of theory) of the first title compound and 28.6 g (87% purity, 59% of theory, see analysis) of the second title compound are obtained.

LC-MS (method 2) R_t= 1.09 min; MS (ESIpos): m/z = 284 [M+H]⁺

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 0.934 (1.18), 0.947 (1.27), 1.343(16.00), 1.392 (1.87), 1.401 (1.18), 2.976 (0.49), 2.991 (0.48), 3.081(0.60), 3.316 (0.94), 4.854 (0.42), 7.452 (0.69), 7.500 (0.48), 7.512 (0.47).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.55-7.47 (m, 1H), 7.47-7.42 (m, 1H),7.40-7.33 (m, 1H), 4.85 (td, 1H), 3.10 (dd, 1H), 2.97 (dd, 1H), 1.34 (s, 9H)。

Example 12A

(+/-) -4- (2-chloro-5-fluorophenyl) -4-cyanobutyric acid tert-butyl ester(raceme)

To a solution of (2-chloro-5-fluorophenyl) acetonitrile (10.0 g, 59.0 mmol) under argon in THF (75 ml) was slowly added 2M LDA in THF (44 ml, 88 mmol) with stirring at-78 ℃. The mixture was brought to 0 ℃ and cooled again to-78 ℃ after 15 min. Then, tert-butyl 3-bromopropionate (11ml, 71 mmol) was slowly added dropwise thereto at-78 ℃ under stirring. The mixture was stirred further overnight, during which time the cooling bath (dry ice/acetone) was slowly brought to room temperature. Then, water was slowly added to the mixture, which was extracted twice with ethyl acetate. The combined organic phases were washed once with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated, and the residue was purified by flash column chromatography (340 g silica gel Biotage Snap cartridge KP-Sil, cyclohexane/ethyl acetate gradient 93:7 → 3:7, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 14.8 g (93% purity, 78% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.22 min; MS (ESIpos): m/z = 298 [M+H]⁺

Example 13A

(+/-) -4- (2-chlorophenyl) -4-cyanobutyric acid tert-butyl ester(raceme)

To a solution of (2-chlorophenyl) acetonitrile (5.00 g, 33.0 mmol) under argon in THF (46ml) was slowly added a solution of 2M LDA in THF (25 ml, 49 mmol) with stirring at-78 ℃. The mixture was brought to 0 ℃ and cooled again to-78 ℃ after 15 min. Then, tert-butyl 3-bromopropionate (8.28 g,39.6 mmol) was slowly added dropwise thereto under stirring at-78 ℃. The mixture was stirred further overnight, during which time the cooling bath (dry ice/acetone) was slowly brought to room temperature. Then, water was slowly added to the mixture, which was extracted twice with ethyl acetate. The combined organic phases were washed once with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated, and the residue was purified by preparative HPLC (method 8). The combined target fractions were concentrated and the residue was dried in vacuo. 5.20 g (75% purity, 42% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.22 min; MS (ESIpos): m/z = 280 [M+H]⁺

Example 14A

(+/-) -4-cyano-4- [2- (trifluoromethyl) phenyl]Tert-butyl butyrate(raceme)

To a solution of [2- (trifluoromethyl) phenyl ] acetonitrile (14.8 g, 79.8 mmol, CAS No. 3038-47-9, commercially available) in THF (100ml) under argon was slowly added a solution of 2M LDA in THF (48 ml, 96 mmol) with stirring, during which the internal temperature was kept at-70 ℃ to-60 ℃. The mixture was brought to 0 ℃ and cooled again to-70 ℃ after 15 min. Then, a solution of tert-butyl 3-bromopropionate (15 ml, 96 mmol) in THF (70 ml) was slowly added dropwise thereto under stirring at 70 ℃. The mixture was stirred further overnight, during which time the cooling bath (dry ice/acetone) was slowly brought to room temperature. Then, water (200 ml) and ethyl acetate (250 ml) were slowly added to the mixture at about 0 ℃ and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (150 ml). The combined organic phases were washed once with saturated aqueous sodium chloride solution (250 ml), dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (400g silica gel, cyclohexane/ethyl acetate 9: 1). The combined target fractions were concentrated and the residue was dried in vacuo. 18.7g (100% purity, 75% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.26 min; MS (ESIpos): m/z = 314 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.91-7.75 (m, 3H), 7.62 (t, 1H), 4.35(dd, 1H), 2.44-2.33 (m, 2H), 2.31-2.19 (m, 1H), 2.18-2.06 (m, 1H), 1.39 (s,9H)。

Example 15A

(+/-) -4-cyano-4- [2- (trifluoromethoxy) phenyl]Tert-butyl butyrate(raceme)

To a solution of [2- (trifluoromethoxy) phenyl ] acetonitrile (5.00 g, 24.9 mmol) in THF (65 ml) under argon was slowly added a solution of 2M LDA in THF (15 ml, 30 mmol) with stirring at-78 ℃. The mixture was brought to 0 ℃ and cooled again to-78 ℃ after 15 min. Then, a solution of tert-butyl 3-bromopropionate (4.7 ml, 30 mmol) in THF (45 ml) was slowly added dropwise thereto under stirring at-78 ℃. The mixture was stirred further overnight, during which time the cooling bath (dry ice/acetone) was slowly brought to room temperature. Then, water and ethyl acetate (100ml each) were slowly added to the mixture at about 0 ℃ and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (100 ml). The combined organic phases were washed once with saturated aqueous sodium chloride solution (150 ml), dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (100 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 93:7 → 7:3, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 3.13 g (80% purity, 31% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.27 min; MS (ESIpos): m/z = 330 [M+H]⁺。

Example 16A

(+/-) -4- (2-chloro-3-fluorophenyl) -4-cyanobutyric acid tert-butyl ester(raceme)

To a solution of (2-chloro-3-fluorophenyl) acetonitrile (4.00 g, 23.6 mmol, example 7A) under argon in THF (30 ml) was slowly added 2M LDA in THF (14 ml, 28 mmol) with stirring at-78 ℃. The mixture was brought to 0 ℃ and cooled again to-78 ℃ after 15 min. Then, a solution of tert-butyl 3-bromopropionate (4.5 ml, 28 mmol) in THF (20ml) was slowly added dropwise thereto under stirring at-78 ℃. The mixture was stirred further overnight, during which time the cooling bath (dry ice/acetone) was slowly brought to room temperature. Then, water and ethyl acetate (100ml each) were slowly added to the mixture at about 0 ℃ and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (100 ml). The combined organic phases were washed once with saturated aqueous sodium chloride solution (150 ml), dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (100 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 93:7 → 7:3, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 4.36 g (95% purity, 59% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.24 min; MS (ESIpos): m/z = 298 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.007 (0.14), 1.174 (0.02), 1.222(0.06), 1.342 (0.84), 1.346 (0.35), 1.382 (16.00), 1.429 (0.05), 1.539(0.06), 1.987 (0.03), 2.071 (0.04), 2.090 (0.09), 2.106 (0.20), 2.125 (0.45),2.142 (0.53), 2.162 (0.44), 2.182 (0.23), 2.196 (0.08), 2.217 (0.06), 2.252(0.02), 2.302 (0.07), 2.317 (0.08), 2.343 (0.38), 2.358 (0.60), 2.362 (0.45),2.376 (0.75), 2.395 (0.29), 2.417 (0.12), 2.436 (0.04), 2.669 (0.03), 2.709(0.02), 3.730 (0.02), 4.174 (0.10), 4.566 (0.34), 4.586 (0.43), 4.603 (0.33),7.426 (0.24), 7.431 (0.29), 7.444 (0.48), 7.449 (0.60), 7.460 (0.54), 7.466(0.30), 7.476 (0.47), 7.482 (0.52), 7.491 (0.55), 7.508 (0.28), 7.529 (0.09).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.55-7.40 (m, 3H), 4.59 (dd, 1H),2.45-2.29 (m, 2H), 2.23-2.06 (m, 2H), 1.38 (s, 9H)。

Example 17A

(+/-) -4- (6-chloro-2, 3-difluorophenyl) -4-cyanobutyric acid tert-butyl ester(raceme)

To a solution of (6-chloro-2, 3-difluorophenyl) acetonitrile (2.23 g, 11.9 mmol, not corrected for purity, example 8A) in THF (15 ml) under argon was slowly added a solution of 2M LDA in THF (7.1 ml,14 mmol) with stirring at-78 ℃. The mixture was brought to 0 ℃ and cooled again to-78 ℃ after 15 min. Then, a solution of tert-butyl 3-bromopropionate (4.5 ml, 28 mmol) in THF (10 ml) was slowly added dropwise thereto under stirring at-78 ℃. The mixture was stirred further overnight, during which time the cooling bath (dry ice/acetone) was slowly brought to room temperature. Then, water (50ml) and ethyl acetate (100ml) were slowly added to the mixture at about 0 ℃ and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (50 ml). The combined organic phases were washed once with saturated aqueous sodium chloride solution (80 ml), dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (50 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 93:7 → 7:3, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 2.29 g (83% purity, 51% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.17 min; MS (ESIpos): m/z = 316 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.73-7.53 (m, 1H), 7.52-7.41 (m, 1H),4.68 (t, 1H), 2.43-2.32 (m, 2H), 2.32-2.18 (m, 1H), 2.18-2.04 (m, 1H), 1.37(s, 9H)。

Example 18A

(+/-) -4-cyano-4- (5-fluoro-2-methylphenyl) butanoic acid tert-butyl ester(raceme)

To a solution of (5-fluoro-2-methylphenyl) acetonitrile (4.00 g, 26.8 mmol) under argon in THF (30 ml) was slowly added 2M LDA in THF (16 ml, 32 mmol) with stirring at-78 ℃. The mixture was brought to 0 ℃ and cooled again to-78 ℃ after 15 min. Then, a solution of tert-butyl 3-bromopropionate (5.1 ml, 32 mmol) in THF (20ml) was slowly added dropwise thereto under stirring at-78 ℃. The mixture was stirred further overnight, during which time the cooling bath (dry ice/acetone) was slowly brought to room temperature. Then, water and ethyl acetate (100ml each) were slowly added to the mixture at about 0 ℃ and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (100 ml). The combined organic phases were washed once with saturated aqueous sodium chloride solution (150 ml), dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (100 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 93:7 → 7:3, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 4.94 g (100% purity, 66% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.18 min; MS (ESIpos): m/z = 278 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.29 (dd, 1H), 7.23 (dd, 1H), 7.11(td, 1H), 4.34 (dd, 1H), 2.42-2.34 (m, 2H), 2.30 (s, 3H), 2.17-1.96 (m, 2H),1.40 (s, 9H)。

Example 19A

(+/-) -4- (2-chloro-3, 6-difluorophenyl) -4-cyanobutyric acid tert-butyl ester(raceme)

To a solution of (2-chloro-3, 6-difluorophenyl) acetonitrile (3.84 g, 20.5 mmol, example 9A) in THF (15 ml) under argon was slowly added a 2M solution of LDA in THF (12 ml, 25 mmol) with stirring at-78 ℃. The mixture was brought to 0 ℃ and cooled again to-78 ℃ after 15 min. Then, a solution of tert-butyl 3-bromopropionate (2.6 ml,16 mmol) in THF (10 ml) was slowly added dropwise thereto under stirring at-78 ℃. The mixture was stirred further overnight, during which time the cooling bath (dry ice/acetone) was slowly brought to room temperature. Then, water and ethyl acetate (100ml each) were slowly added to the mixture at about 0 ℃ and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (100 ml). The combined organic phases were washed once with saturated aqueous sodium chloride solution (150 ml), dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (100 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 93:7 → 7:3, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 4.14 g (95% purity, 61% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.17 min; MS (ESIpos): m/z = 338 [M+Na]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.58 (td, 1H), 7.45 (td, 1H), 4.68 (t,1H), 2.39-2.32 (m, 2H), 2.29-2.17 (m, 1H), 2.17-2.05 (m, 1H), 1.37 (s, 9H)。

Example 20A

(+/-) -4-cyano-4- [ 2-fluoro-6- (trifluoromethyl) phenyl]Tert-butyl butyrate(raceme)

The reaction was carried out under argon. To prepare the LDA solution, butyllithium (1.6M in hexane, 27 ml,43 mmol) was added slowly to a solution of diisopropylamine (6.2 ml, 44 mmol) in THF (27 ml) at-15 deg.C and the mixture was stirred at 0 deg.C for a further 10 min. This solution was slowly added dropwise to a solution of [ 2-fluoro-6- (trifluoromethyl) phenyl ] acetonitrile (8.01 g, 98% purity, 38.7 mmol, CAS number 179946-34-0, commercially available) in 74 ml THF cooled to-78 ℃. After the addition was complete, the cooling bath was removed, the mixture was brought to 0 ℃ and cooled again to-78 ℃ after 15 min. Then, a solution of tert-butyl 3-bromopropionate (8.0 ml, 97% purity, 46 mmol) in 27 ml of THF is slowly added dropwise and the mixture is stirred at-78 ℃ for a further 1 h. The cooling bath was removed and the reaction mixture was stirred at room temperature overnight. For work-up, an ammonium chloride solution (10% in water, 300 ml) was added and the mixture was stirred vigorously for 5min and then extracted twice with ethyl acetate. The combined organic phases were washed successively with 1M hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, twice each solution, then dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in a mixture of cyclohexane, a little ethyl acetate and dichloromethane and purified by flash chromatography on silica gel (cyclohexane/ethyl acetate gradient 100:0-70: 30). The combined target fractions were concentrated and the residue was dried in vacuo and then further purified by preparative HPLC (method 24). The product containing fractions were concentrated and the residue was dried in vacuo. 4.52 g (100% purity, 35% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.23 min; MS (ESIpos): m/z = 332 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.219 (0.06), 1.379 (16.00), 1.536(0.07), 2.073 (0.16), 2.091 (0.22), 2.107 (0.28), 2.125 (0.26), 2.144 (0.10),2.213 (0.07), 2.231 (0.19), 2.250 (0.22), 2.267 (0.18), 2.285 (0.13), 2.302(0.08), 2.327 (0.07), 2.365 (0.07), 2.384 (0.36), 2.393 (0.38), 2.402 (0.59),2.410 (0.56), 2.420 (0.29), 2.428 (0.27), 2.452 (0.06), 2.669 (0.06), 4.373(0.20), 4.390 (0.39), 4.407 (0.19), 7.698 (0.31), 7.711 (1.11), 7.722 (0.54),7.748 (0.35), 7.766 (0.11)。

Example 21A

(+/-) -4-cyano-4- (2,3, 6-trichlorophenyl) butanoic acid tert-butyl ester(raceme)

The reaction was carried out under argon. To prepare the LDA solution, butyllithium (1.6M in hexane, 30 ml,48 mmol) was added slowly to a solution of diisopropylamine (7.1 ml, 51 mmol) in THF (30 ml) at-15 deg.C and the mixture was stirred at 0 deg.C for a further 10 min. This solution was slowly added dropwise to a solution of (2,3, 6-trichlorophenyl) acetonitrile (10.0 g,97% pure, 44.0 mmol, CAS number 3215-65-4, commercially available) in THF (84 ml) cooled to-78 ℃. After the addition was complete, the cooling bath was removed, the mixture was brought to 0 ℃ and cooled again to-78 ℃ after 15 min. Then, a solution of tert-butyl 3-bromopropionate (9.1 ml, 97% purity, 53 mmol) in THF (30 ml) was slowly added dropwise and the mixture was stirred at-78 ℃ for a further 1 h. The cooling bath was removed and the reaction mixture was stirred at room temperature overnight. For work-up, an ammonium chloride solution (10% in 300 ml of water) was added and the mixture was stirred vigorously for 5min and then extracted twice with ethyl acetate. The combined organic phases were washed successively with 1M hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, twice each solution, then dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC (method 24). The combined target fractions were concentrated and the residue was dried in vacuo. 10.2 g (95% purity, 63% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.41 min; MS (ESIpos): m/z = 348 [M+H]⁺

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.382 (16.00), 1.997 (0.45), 2.316(0.42), 2.367 (0.45), 2.381 (0.71), 2.403 (0.63), 3.322 (0.80), 5.002 (0.48),7.620 (0.69), 7.637 (0.90), 7.746 (0.92), 7.763 (0.70)。

Example 22A

(+/-) -4-cyano-4- [2- (difluoromethoxy) -6-fluorophenyl]Tert-butyl butyrate(raceme)

To a solution of [2- (difluoromethoxy) -6-fluorophenyl ] acetonitrile (7.24g, 36.0 mmol, example 10A) in THF (30 ml) under argon was slowly added a 2M solution of LDA in THF (22 ml,43 mmol) with stirring at about-70 to-60 ℃. The mixture was brought to 0 ℃ and cooled again to-70 ℃ after 15 min. Then, a solution of tert-butyl 3-bromopropionate (6.8 ml,43 mmol) in THF (15 ml) was slowly added dropwise thereto under stirring at about-70 to-60 ℃. The mixture was stirred further overnight, during which time the cooling bath (dry ice/isopropanol) slowly reached room temperature. Then, water and ethyl acetate (100ml each) were slowly added to the mixture at about 0 ℃ and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (100 ml). The combined organic phases were washed once with saturated aqueous sodium chloride solution (150 ml), dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (400g silica gel, cyclohexane/ethyl acetate gradient 10: 1). The combined target fractions were concentrated and the residue was dried in vacuo. 7.11 g (74% purity, 45% of theory) of the title compound are obtained.

LC-MS (method 2) R_t= 1.10 min; MS (ESIpos): m/z = 330 [M+H]⁺

Example 23A

(+/-) -4-amino-3- (2-chloro-6-fluorophenyl) butanoic acid tert-butyl ester(raceme)

To a solution of tert-butyl (+/-) -3- (2-chloro-6-fluorophenyl) -3-cyanopropionate (43.9 g, 79% purity, 122 mmol, example 11A) in tert-butanol (500 ml) was added Raney nickel (7.15 g, 122 mmol) and hydrogenation was carried out under standard pressure (1atm) for four days. Then, Raney nickel (7.15 g, 122 mmol) was added again to the mixture and hydrogenation was carried out under standard pressure (1atm) for a further 24 h. After this time, the catalyst was filtered off over celite and washed twice more with tert-butanol (15 ml each). The filtrate was concentrated and the residue was dissolved in ethyl acetate (300 ml) and extracted twice with 1M hydrochloric acid (250 ml each). The aqueous phase is then adjusted to pH 8-9 with saturated aqueous sodium bicarbonate solution and extracted twice with ethyl acetate (200 ml each). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was dried in vacuo. 20.11 g (99% purity, 57% of theory) of the title compound are obtained.

LC-MS (method 2) R_t= 0.55 min; MS (ESIpos): m/z = 288 [M+H]⁺

Example 24A

(+/-) -5-amino-4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester(raceme)

To a solution of tert-butyl (+/-) -4- (2-chloro-5-fluorophenyl) -4-cyanobutyrate (14.0 g, 93% pure, 43.7 mmol, example 12A) in tert-butanol (260 ml) was added Raney nickel (2.57 g, 43.7 mmol) and hydrogenated under standard pressure (1atm) overnight. Then, Raney nickel (2.57 g, 43.7 mmol) was added again to the mixture and hydrogenated under standard pressure (1atm) for another 24 h. Then, Raney nickel (2.57 g, 43.7 mmol) was added to the mixture again and hydrogenation was carried out under standard pressure (1atm) for a further 24 h. After this time, the catalyst was filtered off through celite and the mother liquor was concentrated. 14.4 g (60% purity, 65% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 1.14 min; MS (ESIpos): m/z = 302 [M+H]⁺

Example 25A

(+/-) -5-amino-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(raceme)

To a solution of (+/-) -tert-butyl 4- (2-chlorophenyl) -4-cyanobutyrate (4.50 g, 16.1 mmol, example 13A) in tert-butanol (90 ml) was added Raney nickel (944 mg, 16.1 mmol) and hydrogenated under standard pressure (1atm) overnight. Then, Raney nickel (944 mg, 16.1 mmol) was added again to the mixture and hydrogenation was carried out under standard pressure (1atm) for a further 24 h. After this time, the catalyst was filtered off through celite and the mother liquor was concentrated. The residue was dissolved in dichloromethane and purified by flash chromatography (100 g silica gel Biotage Snap cartridge KP-Sil, cyclohexane/ethyl acetate gradient 93:7 → 7:3, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 1.62 g (91% purity, 32% of theory) of the title compound are obtained.

LC-MS (method 3) R_t= 1.70 min; MS (ESIpos): m/z = 284 [M+H]⁺

Example 26A

(+/-) -5-amino-4- [2- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(raceme)

To a solution of tert-butyl (+/-) -4-cyano-4- [2- (trifluoromethyl) phenyl ] butanoate (18.6 g, 59.5 mmol, example 14A) in tert-butanol (200 ml) was added Raney nickel (3.49 g, 59.5 mmol) and hydrogenated at standard pressure (1atm) for 24 h. After this time, the catalyst was filtered off over celite and washed twice more with tert-butanol (50ml each). The filtrate was concentrated and the residue was dried in vacuo. 17.8 g (82% purity, 77% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 1.23 min; MS (ESIpos): m/z = 318 [M+H]⁺

Example 27A

(+/-) -5-amino-4- [2- (trifluoromethoxy) phenyl]Glutaric acid tert-butyl ester(raceme)

To a solution of tert-butyl (+/-) -4-cyano-4- [2- (trifluoromethoxy) phenyl ] butyrate (3.13 g, 80% purity, 7.59mmol, example 15A) in tert-butanol (45 ml) was added Raney nickel (446 mg, 7.59 mmol) and hydrogenated under standard pressure (1atm) overnight. Then, Raney nickel (446 mg, 7.59 mmol) was added again and the mixture was hydrogenated under standard pressure (1atm) for a further 24 h. After this time, the catalyst was filtered off through celite, the filtrate was concentrated and dried in vacuo. 3.00 g (83% purity, 98% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 1.29 min; MS (ESIpos): m/z = 334 [M+H]⁺

Example 28A

(+/-) -5-amino-4- (2-chloro-3-fluorophenyl) pentanoic acid tert-butyl ester(raceme)

To a solution of tert-butyl (+/-) -4- (2-chloro-3-fluorophenyl) -4-cyanobutyrate (4.32 g, 14.5 mmol, example 16A) in tert-butanol (85 ml) was added Raney nickel (852 mg, 14.5 mmol) and hydrogenated under standard pressure (1atm) overnight. The catalyst was then filtered off through celite, washed twice more with tert-butanol (15 ml) and the mother liquor concentrated. The residue was dissolved in ethyl acetate (80 ml) and extracted successively with 1M hydrochloric acid and water (80 ml each). The combined aqueous phases were adjusted to pH 8-9 with saturated aqueous sodium bicarbonate and extracted twice with ethyl acetate (80 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was dried in vacuo. 2.43 g (85% purity, 47% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 1.28 min; MS (ESIpos): m/z = 302 [M+H]⁺

Example 29A

(+/-) -5-amino-4- (6-chloro-2, 3-difluorophenyl) pentanoic acid tert-butyl ester(raceme)

To a solution of tert-butyl (+/-) -4- (6-chloro-2, 3-difluorophenyl) -4-cyanobutyrate (2.26 g, 83% purity, 5.95mmol, example 17A) in tert-butanol (35ml) was added Raney nickel (349 mg, 5.95 mmol) and hydrogenated at standard pressure (1atm) overnight. The catalyst was then filtered off through celite, washed twice more with tert-butanol (10 ml) and the filtrate was concentrated. The residue was dissolved in ethyl acetate (50ml) and extracted successively with 1M hydrochloric acid and water (50ml each). The combined aqueous phases were adjusted to pH 8-9 with saturated aqueous sodium bicarbonate and extracted twice with ethyl acetate (50 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was dried in vacuo. 1.05 g (97% purity, 53% of theory) of the title compound are obtained.

LC-MS (method 4) R_t= 1.82 min; MS (ESIpos): m/z = 320 [M+H]⁺

Example 30A

(+/-) -5-amino-4- (5-fluoro-2-methylphenyl) pentanoic acid tert-butyl ester(raceme)

To a solution of tert-butyl (+/-) -4-cyano-4- (5-fluoro-2-methylphenyl) butyrate (4.92 g, 17.7 mmol, example 18A) in tert-butanol (100ml) was added Raney nickel (1.04 g, 17.7 mmol) and hydrogenated at standard pressure (1atm) for 24 h. The catalyst was then filtered off through celite, washed twice more with tert-butanol (15 ml) and the filtrate was concentrated. The residue was dissolved in ethyl acetate (80 ml) and extracted successively with 1M hydrochloric acid and water (80 ml each). The combined aqueous phases were adjusted to pH 8-9 with saturated aqueous sodium bicarbonate and extracted twice with ethyl acetate (80 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was dried in vacuo. 2.04 g (92% purity, 38% of theory) of the title compound are obtained.

LC-MS (method 4) R_t= 1.94 min; MS (ESIpos): m/z = 282 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.109 (0.34), 1.197 (0.07), 1.293(0.03), 1.357 (16.00), 1.394 (0.15), 1.513 (0.24), 1.609 (0.11), 1.621(0.11), 1.638 (0.25), 1.648 (0.17), 1.663 (0.22), 1.681 (0.14), 1.709 (0.06),1.927 (0.05), 1.943 (0.10), 1.950 (0.13), 1.964 (0.28), 1.986 (1.50), 1.995(1.06), 2.011 (0.26), 2.018 (0.20), 2.072 (0.03), 2.232 (3.57), 2.303 (0.20),2.366 (0.03), 2.641 (0.07), 2.659 (0.11), 2.672 (0.57), 2.681 (0.59), 2.690(0.75), 2.696 (0.71), 2.711 (0.09), 2.728 (0.08), 2.851 (0.21), 2.863 (0.20),3.172 (0.05), 3.312 (0.65), 6.866 (0.17), 6.873 (0.21), 6.887 (0.37), 6.894(0.43), 6.909 (0.20), 6.916 (0.23), 6.968 (0.43), 6.974 (0.37), 6.994 (0.42),7.001 (0.36), 7.105 (0.03), 7.150 (0.35), 7.166 (0.40), 7.187 (0.30).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.17 (dd, 1H), 6.99 (dd, 1H), 6.89(td, 1H), 2.93-2.80 (m, 1H), 2.74-2.62 (m, 2H), 2.23 (s, 3H), 2.06-1.87 (m,3H), 1.74-1.60 (m, 1H), 1.50 (br. s, 2H), 1.36 (s, 9H)。

Example 31A

(+/-) -5-amino-4- (2-chloro-3, 6-difluorophenyl) pentanoic acid tert-butyl ester(raceme)

To a solution of tert-butyl (+/-) -4- (2-chloro-3, 6-difluorophenyl) -4-cyanobutyrate (4.10 g, 13.0 mmol, example 19A) in tert-butanol (75 ml) was added Raney nickel (762 mg, 13.0 mmol) and hydrogenated at standard pressure (1atm) for 24 h. The catalyst was then filtered off through celite, washed twice more with tert-butanol (15 ml) and the mother liquor concentrated. The residue was dissolved in ethyl acetate (80 ml) and the solution was extracted successively with 1M hydrochloric acid and water (80 ml each). The combined aqueous phases were adjusted to pH 8-9 with saturated aqueous sodium bicarbonate and extracted twice with ethyl acetate (100ml each). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was dried in vacuo. 1.76 g (100% purity, 42% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 1.21 min; MS (ESIpos): m/z = 320 [M+H]⁺

Example 32A

(+/-) -5-amino-4- [ 2-fluoro-6- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(raceme)

To a solution of (+/-) -4-cyano-4- [ 2-fluoro-6- (trifluoromethyl) phenyl ] butanoic acid tert-butyl ester (4.52 g, 13.6mmol, example 20A) in tert-butanol (100ml) and methanol (15 ml) was added Raney nickel (801 mg, 13.6mmol) and the mixture was hydrogenated at standard pressure (1atm) overnight. Raney nickel (2 g,34.0 mmol) was added again to the reaction mixture and stirred vigorously with hydrogen for 40 h at standard pressure (1 atm). The catalyst was then filtered off through celite, washed three more times with methanol (30 ml each) and the filtrate concentrated in vacuo. The residue is dissolved in 200ml of ethyl acetate. The organic phase is extracted twice with 200ml of 1M hydrochloric acid. The combined aqueous phases were brought to pH 8-9 by slow addition of sodium bicarbonate and then extracted twice with 200ml of each of ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. The residue was dried in vacuo. 3.32 g (92% purity, 67% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 1.21 min; MS (ESIpos): m/z = 336 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.109 (0.25), 1.156 (0.06), 1.167(0.07), 1.174 (0.12), 1.191 (0.06), 1.327 (16.00), 1.390 (0.40), 1.484(0.07), 1.882 (0.09), 1.905 (0.14), 1.930 (0.25), 1.946 (0.23), 1.965 (0.29),1.979 (0.15), 1.987 (0.45), 2.006 (0.19), 2.034 (0.10), 2.055 (0.30), 2.074(0.35), 2.093 (0.31), 2.118 (0.16), 2.129 (0.11), 2.150 (0.04), 2.310 (0.07),2.365 (0.02), 2.669 (0.02), 2.782 (0.10), 2.799 (0.17), 2.812 (0.24), 2.828(0.25), 2.872 (0.18), 2.876 (0.18), 2.890 (0.29), 2.895 (0.30), 2.920 (0.37),3.494 (0.02), 3.522 (0.03), 4.019 (0.05), 4.037 (0.05), 7.476 (0.66), 7.485(0.49), 7.489 (0.49), 7.501 (0.31), 7.509 (0.87), 7.521 (0.09), 7.550 (0.51),7.557 (0.32), 7.564 (0.37), 7.573 (0.26), 7.614 (0.04), 7.637 (0.04)。

Example 33A

(+/-) -5-amino-4- (2,3, 6-trichlorophenyl) pentanoic acid tert-butyl ester(raceme)

To a solution of tert-butyl (+/-) -4-cyano-4- (2,3, 6-trichlorophenyl) butyrate (10.2 g, 95% purity, 27.9mmol, example 21A) in tert-butanol (210 ml) and methanol (9.1 ml) was added Raney nickel (1.64 g, 27.9mmol) and the mixture was hydrogenated under standard pressure (1atm) overnight with stirring. An additional amount of raney nickel (2.0g, 34.0 mmol) was added and the mixture was hydrogenated under standard pressure (1atm) for a further three days with stirring. The catalyst was then filtered off through celite, washed three more times with methanol (30 ml each) and the filtrate was concentrated. The residue was dissolved in ethyl acetate (400 ml). The organic phase was extracted twice with 1M hydrochloric acid (300 ml). The combined aqueous phases were brought to pH 8-9 by slow addition of sodium bicarbonate and then extracted twice with ethyl acetate (300 ml each). The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. After drying in vacuo, 2.54 g (89% purity, 23% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 1.30 min; MS (ESIpos): m/z = 352 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.336 (16.00), 1.352 (1.85), 1.492(0.42), 2.013 (0.65), 2.022 (0.61), 2.030 (0.63), 2.042 (0.89), 2.055 (0.81),2.070 (0.42), 2.082 (0.42), 2.097 (0.43), 3.049 (0.54), 3.069 (0.57), 7.426(0.52), 7.506 (0.64), 7.532 (0.56), 7.544 (0.61), 7.553 (0.41)。

Example 34A

(+/-) -5-amino-4- [2- (difluoromethoxy) -6-fluorophenyl]Glutaric acid tert-butyl ester(raceme)

To a solution of tert-butyl (+/-) -4-cyano-4- [2- (difluoromethoxy) -6-fluorophenyl ] butyrate (7.07 g, 74% purity, 16.0 mmol, example 22A) in tert-butanol (97 ml) was added Raney nickel (937 mg, 16.0 mmol) and hydrogenation was carried out at standard pressure (1atm) for three days. The catalyst was then filtered off over celite and washed twice more with tert-butanol (30 ml each). The filtrate was concentrated and the residue was dried in vacuo. 6.21 g (65% purity, 76% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 1.16 min; MS (ESIpos): m/z = 334 [M+H]⁺

Example 35A

(+/-) -4- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -3- (2-chloro-6-fluorophenyl) butanoic acid tert-butyl ester(raceme)

DIPEA (820. mu.l, 4.7 mmol) was added to a suspension of tert-butyl (+/-) -4-amino-3- (2-chloro-6-fluorophenyl) butyrate (541 mg, 1.88 mmol, example 23A) in dichloromethane (10 ml) at room temperature. Then, a suspension of 6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (500 mg, 1.57 mmol, example 3A) in dichloromethane (5 ml) was added and the mixture was stirred at room temperature for 16 h. Then, methylene chloride and water (30 ml each) were added to the mixture, which was shaken. After phase separation, the aqueous phase was extracted once with dichloromethane (30 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (50 g silica gel Biotage Snap cartridge KP-Sil, cyclohexane/ethyl acetate gradient 93:7 → 7:3, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 804 mg (96% purity, 86% of theory) of the title compound are obtained.

LC-MS (method 2) R_t= 1.30 min; MS (ESIpos): m/z = 569/571 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.241 (16.00), 1.397 (0.24), 2.250(0.33), 2.755 (0.40), 2.770 (0.37), 3.730 (0.13), 4.051 (0.16), 7.206 (0.19),7.219 (0.23), 7.246 (0.21), 7.340 (0.65), 7.882 (0.19), 7.905 (1.60), 7.934(0.13), 8.968 (0.22), 8.983 (0.44), 8.998 (0.22).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.98 (t, 1H), 7.97-7.86 (m, 2H), 7.86-7.43 (br., 1H), 7.38-7.31 (m, 2H), 7.26-7.17 (m, 1H), 4.16-3.92 (m, 1H),3.91-3.55 (m, 2H), 2.85-2.62 (m, 2H), 2.25 (br. s, 3H), 1.24 (s, 9H)。

Example 36A

(+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester(raceme)

To a suspension of tert-butyl (+/-) -5-amino-4- (2-chloro-5-fluorophenyl) pentanoate (2.73 g, 9.03 mmol, example 24A) in dichloromethane (50ml) was added DIPEA (3.9 ml, 23 mmol) at room temperature. Then, a suspension of 6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (2.45 g, 98% purity, 7.53 mmol, example 3A) in dichloromethane (35ml) was added and the mixture was stirred at room temperature overnight. The mixture was then stirred at 50 ℃ for a further 20 h. After cooling to room temperature, methylene chloride and water (50ml each) were added to the mixture, which was shaken. After phase separation, the aqueous phase was extracted once with dichloromethane (50 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (100 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 93:7 → 6:4, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 1.49 g (98% purity, 33% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.58 min; MS (ESIpos): m/z = 583/585 [M+H]⁺

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 8.87 (t,1H), 7.93-7.86 (m, 2H), 7.65(br. m,1H, partial coverage), 7.51 (dd, 1H), 7.43 (dd, 1H), 7.19-7.11 (m,1H), 3.73(br. s,2H), 3.58 (br. s, 1H), 2.23 (br. s, 3H), 2.14-2.07 (m, 2H), 2.06-1.96(m, 1H), 1.88-1.73 (m,1H), 1.37 (s, 9H).

Example 37A

(+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2-chlorophenyl) pentanoic acid tert-butyl ester(raceme)

To a suspension of tert-butyl (+/-) -5-amino-4- (2-chlorophenyl) pentanoate (800 g, 80% purity, 22.6 mmol, example 25A) in dichloromethane (200 ml) was added DIPEA (9.8 ml, 56 mmol) at room temperature. Then, a suspension of 6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (5.99 g, 18.8 mmol, example 3A) in dichloromethane (30 ml) was added and the mixture was stirred at room temperature overnight. Then, methylene chloride and water (50ml each) were added to the mixture, which was shaken. After phase separation, the aqueous phase was extracted once with dichloromethane (50 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (340 g silica gel Biotage Snap cartridge, cyclohexane/ethyl acetate gradient 97:3 → 7:3, Isolera One). The combined target fractions were concentrated to obtain two product fractions, and the residue was dried in vacuo. 2.52 g (92% purity, 22% of theory, see analysis) of the first crop of the title compound are obtained. The second product fraction from chromatography was redissolved in dichloromethane and repurified by flash chromatography (100 g silica gel Biotage Snap cartridge KP-Sil, cyclohexane/ethyl acetate gradient 97:3 → 7:3, Isolera One). 1.35 g (88% purity, 11% of theory) of the second crop of the title compound are obtained.

LC-MS (method 1) R_t= 2.54 min; MS (ESIpos): m/z = 565/567 [M+H]⁺

Example 38A

(+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- [2- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(raceme)

To a suspension of tert-butyl (+/-) -5-amino-4- [2- (trifluoromethyl) phenyl ] pentanoate (12.0 g, 82% purity, 30.9 mmol, example 26A) in dichloromethane (250 ml) was added DIPEA (13 ml, 77 mmol) at room temperature. Then, a suspension of 6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (8.22 g, 25.8 mmol, example 3A) in dichloromethane (50ml) was added and the mixture was stirred at room temperature for 18 h. Then, water (400 ml) was added to the mixture, which was shaken. After phase separation, the aqueous phase was extracted once with dichloromethane (200 ml). The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated, and the residue was purified by flash column chromatography (100 g silica gel biotagenap cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3 → 75:25, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 11.7 g (100% purity, 76% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.60 min; MS (ESIpos): m/z = 599/601 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.188 (0.07), 1.318 (0.14), 1.349(16.00), 1.398 (0.94), 1.505 (0.07), 1.871 (0.13), 1.894 (0.17), 1.909(0.20), 2.004 (0.25), 2.024 (0.50), 2.039 (0.49), 2.058 (0.33), 2.087 (0.27),2.240 (0.18), 2.366 (0.11), 2.670 (0.06), 3.670 (0.14), 3.752 (0.17), 5.754(0.11), 7.487 (0.36), 7.505 (0.24), 7.692 (0.19), 7.712 (0.44), 7.728 (0.81),7.747 (0.98), 7.765 (0.28), 7.904 (2.33), 7.930 (0.08), 8.907 (0.34)。

Separation of enantiomers:

the title compound (7.0 g) was dissolved in isopropanol (140 ml) and separated into enantiomers on the chiral phase by preparative SFC (see examples 39A and 40A) [ column: daicel Chiralcel OD-H, 5 μm, 250 mm x 50 mm, flow rate: 175 ml/min, injection: 1.2 ml, eluent 17% isopropanol/83% carbon dioxide, running time 15min, isocratic, UV detection 210nm, temperature 38 ℃. The combined target fractions were each concentrated and the respective residue was lyophilized.

Example 39A

(-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- [2- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(enantiomer 1)

In the enantiomeric separation described in example 38A, 3.37 g (100% purity, ee >99%) of the title compound were obtained as the earlier eluting enantiomer.

[α]_D ²⁰= 19.3 °, 589 nm, c = 0.38 g/100 ml, methanol

LC-MS (method 1) R_t= 2.60 min; MS (ESIpos): m/z = 599/601 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.009 (0.17), 0.007 (0.15), 1.029(2.07), 1.044 (2.09), 1.187 (0.07), 1.310 (0.10), 1.317 (0.13), 1.348(16.00), 1.503 (0.06), 1.871 (0.11), 1.894 (0.15), 1.908 (0.18), 1.918(0.15), 1.941 (0.10), 1.963 (0.05), 1.984 (0.07), 2.003 (0.23), 2.023 (0.46),2.038 (0.45), 2.057 (0.31), 2.080 (0.22), 2.087 (0.25), 2.100 (0.18), 2.117(0.18), 2.130 (0.14), 2.151 (0.11), 2.239 (0.15), 2.365 (0.07), 2.669 (0.04),3.669 (0.12), 3.751 (0.22), 3.762 (0.20), 3.766 (0.22), 3.777 (0.19), 3.782(0.16), 3.792 (0.14), 4.323 (0.26), 4.334 (0.26), 7.467 (0.17), 7.485 (0.32),7.503 (0.21), 7.691 (0.18), 7.710 (0.40), 7.727 (0.74), 7.745 (0.90), 7.764(0.24), 7.881 (0.08), 7.902 (2.20), 7.929 (0.06), 8.907 (0.31)。

Example 40A

(+) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- [2- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(enantiomer 2)

In the enantiomeric separation described in example 38A, 3.32 g (100% purity, ee value 99%) of the title compound were obtained as the later eluting enantiomer.

[α]_D ²⁰= 18.0 °, 589 nm, c = 0.33 g/100 ml, methanol

LC-MS (method 1) R_t= 2.60 min; MS (ESIpos): m/z = 599/601 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.029 (2.26), 1.044 (2.27), 1.187(0.07), 1.317 (0.13), 1.347 (16.00), 1.503 (0.06), 1.870 (0.12), 1.894(0.16), 1.908 (0.19), 1.941 (0.10), 2.003 (0.24), 2.023 (0.48), 2.038 (0.47),2.057 (0.32), 2.086 (0.26), 2.117 (0.18), 2.222 (0.16), 2.365 (0.08), 2.669(0.05), 3.669 (0.13), 3.751 (0.24), 3.762 (0.22), 3.766 (0.24), 3.777 (0.21),3.792 (0.15), 4.323 (0.32), 4.333 (0.31), 7.466 (0.17), 7.484 (0.34), 7.503(0.23), 7.691 (0.18), 7.710 (0.42), 7.727 (0.77), 7.745 (0.94), 7.764 (0.25),7.881 (0.08), 7.902 (2.28), 7.929 (0.07), 8.906 (0.32)。

Example 41A

(+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- [2- (trifluoromethoxy) phenyl group]Glutaric acid tert-butyl ester(raceme)

To a suspension of (+/-) -5-amino-4- [2- (trifluoromethoxy) phenyl ] pentanoic acid tert-butyl ester (10.0 g, 78% purity, 23.4 mmol, example 27A) in dichloromethane (250 ml) was added DIPEA (10 ml, 58 mmol) at room temperature. Then, a suspension of 6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (6.21 g, 19.5 mmol, example 3A) in dichloromethane (50ml) was added and the mixture was stirred at room temperature for 18 h. Then, water (400 ml) was added to the mixture, which was shaken. After phase separation, the aqueous phase was extracted once with dichloromethane (200 ml). The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated, and the residue was purified by flash column chromatography (100 g silica gel biotagenap cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3 → 75:25, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 9.91 g (92% purity, 76% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.63 min; MS (ESIpos): m/z = 615/617 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.202 (0.07), 1.300 (0.34), 1.361(16.00), 1.787 (0.09), 1.807 (0.20), 1.830 (0.19), 2.038 (0.28), 2.062(0.92), 2.069 (1.14), 2.096 (0.23), 2.219 (0.18), 2.308 (0.23), 2.365 (0.08),3.385 (0.19), 3.632 (0.13), 3.650 (0.24), 3.665 (0.31), 3.683 (0.28), 3.702(0.29), 3.720 (0.24), 7.370 (0.40), 7.405 (0.64), 7.428 (0.48), 7.554 (0.40),7.567 (0.37), 7.578 (0.29), 7.879 (0.11), 7.901 (1.98), 8.882 (0.34)。

Separation of enantiomers:

the title compound (5.26 g) was dissolved in isopropanol (120 ml). Then filtered, the filter residue is washed again with 12 ml isopropanol and the solution is separated into enantiomers on the chiral phase by preparative SFC (see examples 42A and 43A) [ column: daicel Chiralcel OD-H, 5 μm, 250 mm x 50 mm, flow rate: 175 ml/min, injection: 0.8ml, eluent 15% isopropyl alcohol/85% carbon dioxide, running time 14.5 min, isocratic, UV detection 210nm, temperature 40 deg.C ]. The combined target fractions were concentrated and the respective residue was lyophilized.

Example 42A

(+) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- [2- (trifluoromethoxy) phenyl group]Glutaric acid tert-butyl ester(enantiomer 1)

In the enantiomeric separation described in example 41A, 2.37 g (100% purity, ee value 100%) of the title compound were obtained as the earlier eluting enantiomer.

[α]_D ²⁰= 16.3 °, 589 nm, c = 0.45 g/100 ml, methanol

LC-MS (method 1) R_t= 2.64 min; MS (ESIpos): m/z = 615/617 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.029 (0.18), 1.044 (0.18), 1.201(0.07), 1.300 (0.06), 1.317 (0.07), 1.325 (0.09), 1.361 (16.00), 1.517(0.07), 1.788 (0.10), 1.807 (0.21), 1.830 (0.21), 1.877 (0.06), 2.038 (0.31),2.063 (1.04), 2.069 (1.28), 2.096 (0.25), 2.223 (0.20), 2.365 (0.06), 2.669(0.05), 3.384 (0.22), 3.617 (0.08), 3.632 (0.14), 3.650 (0.27), 3.665 (0.35),3.683 (0.32), 3.702 (0.31), 3.720 (0.26), 3.735 (0.13), 3.754 (0.08), 7.370(0.43), 7.405 (0.68), 7.422 (0.54), 7.428 (0.52), 7.554 (0.44), 7.567 (0.41),7.577 (0.32), 7.879 (0.11), 7.901 (2.03), 7.928 (0.08), 8.882 (0.39)。

Example 43A

(-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- [2- (trifluoromethoxy) phenyl group]Glutaric acid tert-butyl ester(enantiomer 2)

In the enantiomeric separation described in example 41A, 2.40 g (100% purity, ee value 99%) of the title compound were obtained as the later eluting enantiomer.

[α]_D ²⁰= 15.9 °, 589 nm, c = 0.44 g/100 ml, methanol

LC-MS (method 1) R_t= 2.63 min; MS (ESIpos): m/z = 615/617 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.029 (0.50), 1.044 (0.50), 1.201(0.07), 1.316 (0.07), 1.325 (0.09), 1.361 (16.00), 1.517 (0.06), 1.788(0.09), 1.807 (0.20), 1.830 (0.20), 2.038 (0.28), 2.063 (0.96), 2.069 (1.20),2.096 (0.22), 2.222 (0.17), 2.308 (0.19), 2.365 (0.06), 2.669 (0.05), 3.384(0.20), 3.617 (0.08), 3.632 (0.13), 3.650 (0.25), 3.666 (0.32), 3.683 (0.29),3.702 (0.29), 3.720 (0.24), 3.736 (0.12), 3.754 (0.08), 4.323 (0.07), 4.333(0.07), 7.369 (0.40), 7.405 (0.64), 7.421 (0.50), 7.428 (0.50), 7.554 (0.40),7.567 (0.37), 7.577 (0.31), 7.879 (0.11), 7.901 (1.97), 8.882 (0.36)。

Example 44A

(+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2-chloro-3-fluorophenyl) pentanoic acid tert-butyl ester(raceme)

To a solution of tert-butyl (+/-) -5-amino-4- (2-chloro-3-fluorophenyl) pentanoate (1.40 g, 85% purity, 3.94mmol, example 28A) in dichloromethane (45 ml) was added DIPEA (1.7 ml, 9.9 mmol) at room temperature. Then 6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (1.07 g, 98% purity, 3.29 mmol, example 3A) was added and the mixture was stirred at room temperature for 20 h. Then, water and methylene chloride (150 ml each) were added to the mixture, which was shaken. After phase separation, the aqueous phase was extracted once with dichloromethane (150 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (100 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3 → 7:3, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 206 mg (100% purity, 11% of theory) of the title compound are obtained.

LC-MS (method 2) R_t= 1.32 min; MS (ESIpos): m/z = 583/585 [M-H]^-

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.210 (0.08), 1.370 (16.00), 1.397(2.57), 1.828 (0.24), 2.035 (0.25), 2.052 (0.26), 2.071 (0.32), 2.090 (1.00),2.106 (1.01), 2.126 (0.40), 2.218 (0.37), 3.603 (0.25), 3.733 (0.32), 7.313(0.33), 7.335 (0.25), 7.355 (0.33), 7.374 (0.52), 7.419 (0.29), 7.896 (2.22),7.923 (0.14), 8.855 (0.29), 8.870 (0.52)。

Example 45A

(+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (6-chloro-2, 3-difluorophenyl) pentanoic acid tert-butyl ester(raceme)

To a solution of tert-butyl (+/-) -5-amino-4- (6-chloro-2, 3-difluorophenyl) pentanoate (400 mg, 96% purity, 1.20 mmol, example 29A) in dichloromethane (12 ml) was added DIPEA (520. mu.l, 3.0 mmol) at room temperature. Then 6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (326 mg, 98% purity, 1.00 mmol, example 3A) was added and the mixture was stirred at room temperature for 20 h. Then, water and methylene chloride (10 ml each) were added to the mixture, which was shaken. After phase separation, the aqueous phase was extracted once with dichloromethane (100 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (25 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3 → 7:3, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 156 mg (87% purity, 23% of theory) of the title compound are obtained.

LC-MS (method 2) R_t= 1.34 min; MS (ESIpos): m/z = 601/603 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.007 (0.31), 1.203 (0.08), 1.260(0.09), 1.309 (0.11), 1.363 (16.00), 1.397 (2.44), 1.970 (0.12), 2.056(0.23), 2.075 (0.22), 2.159 (0.48), 2.176 (0.70), 2.242 (1.02), 2.351 (0.88),2.365 (0.11), 2.669 (0.08), 2.709 (0.08), 3.097 (0.10), 3.702 (0.26), 3.804(0.30), 7.402 (0.45), 7.737 (0.19), 7.878 (0.19), 7.901 (1.91), 7.908 (1.10),7.929 (0.48), 8.965 (0.37)。

Example 46A

(+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (5-fluoro-2-methylphenyl) pentanoic acid tert-butyl ester(raceme)

To a solution of tert-butyl (+/-) -5-amino-4- (5-fluoro-2-methylphenyl) pentanoate (1.40 g, 92% purity, 4.58 mmol, example 30A) in dichloromethane (45 ml) was added DIPEA (2.0 ml, 11 mmol) at room temperature. Then 6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (1.25 g,97% pure, 3.81 mmol, example 3A) was added and the mixture was stirred at room temperature for 20 h. Then, water and methylene chloride (150 ml each) were added to the mixture, which was shaken. After phase separation, the aqueous phase was extracted once with dichloromethane (100 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (100 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3 → 7:3, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 538 mg (100% purity, 25% of theory) of the title compound are obtained.

LC-MS (method 2) R_t= 1.34 min; MS (ESIpos): m/z = 563/565 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.007 (0.21), 1.211 (0.07), 1.300(0.11), 1.332 (0.11), 1.372 (16.00), 1.397 (2.79), 1.755 (0.12), 1.789(0.19), 1.812 (0.17), 1.969 (0.16), 1.982 (0.20), 1.999 (0.20), 2.019 (0.15),2.032 (0.13), 2.067 (0.69), 2.084 (0.98), 2.103 (0.46), 2.283 (1.44), 3.504(0.12), 3.517 (0.18), 3.537 (0.20), 3.551 (0.24), 3.565 (0.15), 3.706 (0.13),3.724 (0.19), 3.744 (0.16), 3.758 (0.14), 6.957 (0.24), 7.156 (0.31), 7.162(0.31), 7.183 (0.32), 7.206 (0.36), 7.221 (0.40), 7.242 (0.31), 7.876 (0.11),7.898 (2.22), 7.925 (0.09), 8.851 (0.31)。

Example 47A

(+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid tert-butyl ester(raceme)

To a solution of tert-butyl (+/-) -5-amino-4- (2-chloro-3, 6-difluorophenyl) pentanoate (9.53 g, 81% purity, 24.0 mmol, example 31A) in dichloromethane (200 ml) was added DIPEA (10 ml, 60 mmol) at room temperature. Then 6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (6.38 g, 20.0 mmol, example 3A) was added and the mixture was stirred at room temperature for 20 h. Then, water and methylene chloride (150 ml each) were added to the mixture, which was shaken. After phase separation, the aqueous phase was extracted once with dichloromethane (150 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (100 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3 → 7:3, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 8.40 g (90% purity, 63% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.54 min; MS (ESIpos): m/z = 601/603 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.157 (0.23), 1.175 (0.45), 1.193(0.24), 1.202 (0.08), 1.268 (0.07), 1.311 (0.35), 1.321 (0.40), 1.363(16.00), 1.380 (0.76), 1.407 (0.25), 1.519 (0.07), 1.989 (0.95), 2.046(0.21), 2.060 (0.26), 2.077 (0.24), 2.097 (0.18), 2.143 (0.58), 2.161 (0.76),2.237 (0.60), 2.351 (0.07), 2.366 (0.05), 2.670 (0.04), 2.711 (0.03), 3.697(0.24), 3.800 (0.28), 4.003 (0.08), 4.021 (0.21), 4.039 (0.21), 4.057 (0.08),7.312 (0.25), 7.327 (0.19), 7.417 (0.21), 7.750 (0.05), 7.882 (0.18), 7.905(2.10), 7.934 (0.14), 8.950 (0.24), 8.964 (0.43)。

Separation of enantiomers:

the title compound (4.8 g) was dissolved in acetonitrile and separated by preparative HPLC on chiral phase into enantiomers (see example 48A and 49A) [ column: daicel Chiralcel OX-H, 5 μm, 250 mm x20 mm, flow rate: 20ml/min, detection: 220nm, temperature: 30 ℃ and injection: 30 ml, eluent 20% isopropanol/80% heptane, run time 18 min, isocratic ]. The combined target fractions were each concentrated and the residue was dried in vacuo.

Example 48A

(+) -4- { [ (6-bromo-2-chloro-3-methylquinolin-5-yl) carbonyl]Amino } -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid tert-butyl ester(enantiomer 1)

In the enantiomeric separation described in example 47A, 1.52 g (81% purity, ee value 100%) of the title compound was obtained as the earlier eluting enantiomer.

[α]_D ²⁰= 31.9 °, 589 nm, c = 0.31 g/100 ml, methanol

LC-MS (method 1) R_t= 2.56 min; MS (ESIpos): m/z = 601/603 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.151 (0.03), 1.009 (0.23), 1.029(3.00), 1.044 (3.00), 1.105 (0.49), 1.108 (0.83), 1.120 (0.35), 1.139 (0.06),1.201 (0.08), 1.267 (0.07), 1.309 (0.32), 1.362 (16.00), 1.406 (0.23), 1.518(0.07), 1.595 (0.04), 1.681 (0.12), 1.979 (0.14), 2.045 (0.23), 2.059 (0.28),2.075 (0.27), 2.096 (0.21), 2.142 (0.65), 2.160 (0.82), 2.236 (0.67), 2.350(0.12), 2.417 (0.04), 2.669 (0.04), 3.533 (0.53), 3.696 (0.29), 3.741 (0.21),3.756 (0.35), 3.772 (0.47), 3.787 (0.49), 3.802 (0.40), 7.311 (0.29), 7.326(0.21), 7.417 (0.25), 7.748 (0.07), 7.881 (0.20), 7.904 (2.30), 7.928 (0.16),8.963 (0.48)。

Example 49A

(-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid tert-butyl ester(enantiomer 2)

In the enantiomeric separation described in example 47A, 1.46 g (82% purity, ee value 97%) of the title compound were obtained as the later eluting enantiomer.

[α]_D ²⁰= 32.3 °, 589 nm, c = 0.36 g/100 ml, methanol

LC-MS (method 1) R_t= 2.56 min; MS (ESIpos): m/z = 601/603 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.850 (0.05), 1.009 (0.34), 1.029(2.07), 1.044 (2.03), 1.104 (0.77), 1.108 (1.13), 1.120 (0.64), 1.139 (0.11),1.155 (0.06), 1.201 (0.08), 1.267 (0.10), 1.309 (0.37), 1.320 (0.47), 1.362(16.00), 1.378 (0.57), 1.406 (0.24), 1.518 (0.07), 1.681 (0.09), 1.974(0.16), 2.044 (0.25), 2.061 (0.32), 2.075 (0.30), 2.095 (0.24), 2.142 (0.72),2.159 (0.86), 2.236 (0.75), 2.669 (0.05), 3.533 (0.56), 3.567 (0.54), 3.697(0.34), 3.756 (0.32), 3.771 (0.43), 3.787 (0.47), 3.802 (0.41), 4.270 (0.05),7.311 (0.32), 7.326 (0.22), 7.417 (0.28), 7.763 (0.07), 7.881 (0.28), 7.904(2.52), 7.932 (0.15), 8.963 (0.51)。

Example 50A

(+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- [ 2-fluoro-6- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(raceme)

To a solution of (+/-) -5-amino-4- [ 2-fluoro-6- (trifluoromethyl) phenyl ] pentanoic acid tert-butyl ester (2.15 g, 92% purity, 5.91 mmol, example 32A) and DIPEA (2.6 ml, 15 mmol) in dichloromethane (57 ml) was added a solution of 6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (1.57 g, 4.92 mmol, example 3A) in a small amount of dichloromethane at room temperature. The mixture was stirred at room temperature overnight. For working up, water and dichloromethane (200 ml each) were added. The phases were separated. The aqueous phase was extracted once with dichloromethane (200 ml). The combined organic phases were washed with saturated aqueous sodium chloride (200 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in a small amount of cyclohexane and ethyl acetate and purified by column chromatography (Biotage, 100 g silica gel, Snap cartridge Ultra, eluent: cyclohexane/ethyl acetate 8: 2). The product fractions obtained were concentrated in vacuo and the residue was dried in vacuo. 2.20 g (97% purity, 70% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.57 min; MS (ESIpos): m/z = 617 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.96 (t, 1H), 7.94-7.86 (m, 2H) 7.87-7.25 (m, 4H), 3.93 (br. s, 1H), 3.73 (br. s, 1H), 3.34-3.24 (1H, concealed),2.45-1.99 (m, 7H), 1.34 (s, 9H)。

Example 51A

(+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2,3, 6-trisChlorophenyl) pentanoic acid tert-butyl ester(raceme)

To a solution of tert-butyl (+/-) -5-amino-4- (2,3, 6-trichlorophenyl) pentanoate (1.84 g, 89% purity, 4.64mmol, example 33A) and DIPEA (2.0 ml, 12 mmol) in dichloromethane (45 ml) was added a solution of 6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (1.23 g, 3.87 mmol, example 3A) in a small amount of dichloromethane at room temperature. The mixture was stirred at room temperature for 2 h. For working up, water and dichloromethane (200 ml each) were added. The phases were separated. The aqueous phase was extracted once with dichloromethane (200 ml). The combined organic phases were washed with saturated aqueous sodium chloride (200 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in a small amount of DMSO and purified by preparative HPLC (method 13). The product fractions obtained were concentrated in vacuo and the residue was dried in vacuo. 2.03 g (93% purity, 77% of theory) of the title compound are obtained.

LC-MS (method 4) R_tIonization without detecting target mass

¹H-NMR (500 MHz, DMSO-d ₆): δ [ppm]= 8.98-8.88 (m, 1H), 7.97-7.34 (m,5H), 4.22-3.95 (m, 2H), 3.95-3.79 (m, 1H), 2.35-1.99 (m, 7H), 1.37-1.34 (m,9H)。

Example 52A

(+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- [2- (difluoromethoxy) -6-fluorophenyl]Glutaric acid tert-butyl ester(raceme)

To a solution of tert-butyl (+/-) -5-amino-4- [2- (difluoromethoxy) -6-fluorophenyl ] pentanoate (5.51 g, 65% purity, 10.7 mmol, example 34A) in dichloromethane (100ml) at room temperature was added DIPEA (4.7 ml, 27 mmol). Then 6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (2.85 g, 8.94 mmol, example 3A) was added and the mixture was stirred at room temperature for 20 h. Then, water and methylene chloride (150 ml each) were added to the mixture, which was shaken. After phase separation, the aqueous phase was extracted once with dichloromethane (150 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (100 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3 → 7:3, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 4.78 g (91% purity, 79% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.49 min; MS (ESIpos): m/z = 615/617 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.158 (0.05), 1.175 (0.11), 1.199(0.07), 1.292 (0.08), 1.308 (0.28), 1.320 (0.37), 1.337 (1.76), 1.360(16.00), 1.372 (0.72), 1.394 (0.28), 1.516 (0.07), 1.957 (0.22), 1.989(0.32), 1.998 (0.30), 2.011 (0.25), 2.031 (0.28), 2.047 (0.23), 2.067 (0.18),2.086 (0.80), 2.103 (0.80), 2.120 (0.32), 2.224 (0.28), 2.343 (0.12), 2.635(0.07), 2.672 (0.09), 2.848 (0.04), 3.522 (0.22), 3.741 (0.20), 3.797 (0.16),4.021 (0.05), 4.039 (0.05), 6.965 (0.07), 6.985 (0.12), 7.028 (0.46), 7.048(0.53), 7.069 (0.41), 7.097 (0.32), 7.120 (0.46), 7.144 (0.34), 7.161 (0.08),7.179 (0.10), 7.253 (0.70), 7.288 (0.09), 7.305 (0.11), 7.323 (0.07), 7.364(0.17), 7.385 (0.25), 7.402 (0.24), 7.436 (0.37), 7.751 (0.07), 7.878 (0.17),7.901 (1.98), 7.930 (0.15), 8.918 (0.25), 8.933 (0.50), 8.948 (0.26)。

Example 53A

(+/-) -4- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -3- (2-chloro-6-fluorophenyl) butanoic acid tert-butyl ester(raceme)

To a suspension of (+/-) -4- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -3- (2-chloro-6-fluorophenyl) butanoic acid tert-butyl ester (300 mg, 526 μmol, example 35A) in 1-butanol (3.8 ml) was added piperidine (160 μ l,1.6 mmol) and the mixture was stirred at 100 ℃ for 16 h. After cooling to room temperature, water and ethyl acetate (50ml each) were added to the mixture, which was shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (50 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and pre-purified by flash column chromatography (25 g silica gel Biotage Snap cartridge KP-Sil, cyclohexane/ethyl acetate gradient 93:7 → 6:4, Isolera One). Followed by repurification by preparative HPLC (method 9). The combined target fractions were concentrated and the residue was dried in vacuo. 184 mg (98% purity, 55% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.74 min; MS (ESIpos): m/z = 618/620 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.236 (16.00), 1.613 (0.55), 1.678(1.07), 2.169 (1.96), 2.758 (0.44), 2.772 (0.40), 3.161 (1.37), 3.704 (0.19),4.052 (0.23), 7.213 (0.31), 7.239 (0.27), 7.326 (1.03), 7.333 (0.91), 7.354(0.27), 7.647 (0.36), 7.669 (1.51), 7.678 (0.99), 7.683 (0.88), 7.705 (0.21),8.825 (0.26), 8.840 (0.53), 8.855 (0.26).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.84 (t, 1H), 7.72-7.63 (m, 2H), 7.50(br. s, 1H), 7.39-7.30 (m, 2H), 7.25-7.17 (m, 1H), 4.13-3.96 (m, 1H), 3.87-3.57 (m, 2H), 3.16 (br. s, 4H), 2.86-2.60 (m, 2H), 2.17 (s, 3H), 1.79-1.55(m, 6H), 1.24 (s, 9H)。

Example 54A

(+/-) -4- [ ({ 6-bromo-3-methyl-2- [ (2-phenylethyl) amino group]Quinolin-4-yl } carbonyl) amino]-3- (2-chloro-6-fluorophenyl) butanoic acid tert-butyl ester(raceme)

To a suspension of (+/-) -4- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -3- (2-chloro-6-fluorophenyl) butanoic acid tert-butyl ester (300 mg, 526 μmol, example 35A) in 1-butanol (3.8 ml) was added 2-phenylethylamine (200 μ l,1.6 mmol) and the mixture was stirred at 100 ℃ overnight. The mixture was then stirred at 130 ℃ for a further 24 h. After cooling to room temperature, water and ethyl acetate (50ml each) were added to the mixture, which was shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (50 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and pre-purified by flash column chromatography (25 g silica gel Biotage Snap cartridge KP-Sil, cyclohexane/ethyl acetate gradient 93:7 → 6:4, Isolera One). Followed by repurification by preparative HPLC (method 9). The combined target fractions were concentrated and the residue was dried in vacuo. 162 mg (98% purity, 46% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.41 min; MS (ESIpos): m/z = 654/656 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.88 (br. s, 1H), 7.68 (br. s, 1H),7.41-7.15 (m, 11H), 4.04 (br. s, 1H), 3.90-3.62 (m, 4H), 2.97 (br. t, 2H),2.82-2.66 (m, 2H), 2.10-1.88 (m, 3H), 1.24 (s, 9H)。

Example 55A

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester(raceme)

To a suspension of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester (1.10 g, 1.88 mmol, example 36A) in 1-butanol (14 ml) was added piperidine (560 μ l,5.6 mmol) and the mixture was stirred at 100 ℃ for three days. After cooling to room temperature, water and ethyl acetate (50ml each) were added to the mixture, which was shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (50 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (100 g silica gel Biotage Snap cartridge KP-Sil, cyclohexane/ethyl acetate gradient 93:7 → 6:4, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 676 mg (98% pure, 56% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.83 min; MS (ESIpos): m/z = 632/634 [M+H]⁺

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 8.72 (t,1H), 7.69-7.61 (m, 2H), 7.50(dd, 1H), 7.47 (br. s, 1H, partial coverage), 7.41 (dd, 1H), 7.14 (td, 1H), 3.74-3.64(m, 2H), 3.63-3.53 (m,1H), 3.17-3.10 (m, 4H), 2.17-1.94 (m,6H), 1.86-1.74(m, 1H), 1.72-1.55 (m,6H), 1.37 (s, 9H).

Separation of enantiomers:

the title compound (675 mg) was dissolved in ethanol (7 ml) and separated by preparative HPLC on the chiral phase into enantiomers (see example 56A and 57A) [ column: daicel Chiralcel OX-H, 5 μm, 250 mm x20 mm, flow rate: 40ml/min, injection: 0.1 ml, eluent 20% ethanol/80% heptane, run time 10 min, isocratic. The combined target fractions were concentrated and the residue was lyophilized.

Example 56A

(-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester(enantiomer 1)

In the enantiomeric separation described in example 55A, 237 mg (98% purity, ee value 99%) of the title compound are obtained as the earlier eluting enantiomer.

[α]_D ²⁰= 12.8 °, 589 nm, c = 0.34 g/100 ml, methanol

LC-MS (method 1) R_t= 2.83 min; MS (ESIpos): m/z = 632/634 [M+H]⁺

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 8.72 (t,1H), 7.69-7.61 (m, 2H), 7.50(dd, 1H), 7.47 (br. s, 1H, partial coverage), 7.41 (dd, 1H), 7.14 (td, 1H), 3.74-3.64(m, 2H), 3.63-3.53 (m,1H), 3.17-3.09 (m, 4H), 2.16-1.97 (m,6H), 1.87-1.74(m, 1H), 1.72-1.55 (m,6H), 1.37 (s, 9H).

Example 57A

(+) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl)Quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester(enantiomer 2)

In the enantiomeric separation described in example 55A, 207 mg (98% purity, ee value 99%) of the title compound were obtained as the later eluting enantiomer.

[α]_D ²⁰= 13.1 °, 589 nm, c = 0.38 g/100 ml, methanol

LC-MS (method 1) R_t= 2.83 min; MS (ESIpos): m/z = 632/634 [M+H]⁺

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 8.72 (t,1H), 7.70-7.60 (m, 2H), 7.50(dd, 1H), 7.47 (br. s, 1H, partial coverage), 7.41 (dd, 1H), 7.14 (td, 1H), 3.74-3.64(m, 2H), 3.63-3.53 (m,1H), 3.17-3.10 (m, 4H), 2.16-1.96 (m,6H), 1.87-1.74(m, 1H), 1.73-1.54 (m,6H), 1.37 (s, 9H).

Example 58A

(+/-) -5- ({ [ 6-bromo-2- (4, 4-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester(raceme)

To a suspension of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester (135 mg, 231. mu. mol, example 36A) in 1-butanol (1.7 ml) was added 4, 4-difluoropiperidine (84 mg, 693. mu. mol), and the mixture was stirred at 100 ℃ for four days. After cooling to room temperature, water and ethyl acetate (20ml each) were added to the mixture, which was shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (20 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and pre-purified by flash column chromatography (25 g silica gel Biotage Snap cartridge KP-Sil, cyclohexane/ethyl acetate gradient 93:7 → 5:5, IsoleraOne). Followed by repurification by preparative HPLC (method 9). The combined target fractions were concentrated and the residue was dried in vacuo. 19 mg (72% purity, 9% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.72 min; MS (ESIpos): m/z = 668/670 [M+H]⁺

Example 59A

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (morpholin-4-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester(raceme)

To a suspension of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester (135 mg, 231. mu. mol, example 36A) in 1-butanol (1.7 ml) was added morpholine (60. mu.l, 690. mu. mol) and the mixture was stirred at 100 ℃ for four days. After cooling to room temperature, water and ethyl acetate (20ml each) were added to the mixture, which was shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (20 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and pre-purified by flash column chromatography (25 g silica gel Biotage Snap cartridge KP-Sil, cyclohexane/ethyl acetate gradient 93:7 → 6:4, Isolera One). Followed by repurification by preparative HPLC (method 9). The combined target fractions were concentrated and the residue was dried in vacuo. 61 mg (98% purity, 41% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.55 min; MS (ESIpos): m/z = 634/636 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.009 (0.21), 0.007 (0.19), 1.211(0.06), 1.296 (0.07), 1.328 (0.09), 1.371 (16.00), 1.527 (0.06), 1.773(0.12), 1.790 (0.14), 1.808 (0.16), 1.829 (0.13), 1.999 (0.14), 2.011 (0.18),2.029 (0.18), 2.050 (0.15), 2.063 (0.12), 2.085 (0.65), 2.102 (0.88), 2.122(0.35), 2.147 (1.79), 2.327 (0.04), 2.365 (0.04), 2.669 (0.04), 2.709 (0.04),3.172 (1.20), 3.177 (1.21), 3.185 (0.93), 3.587 (0.21), 3.692 (0.46), 3.753(1.33), 3.764 (1.83), 3.775 (1.35), 3.838 (0.55), 7.115 (0.13), 7.123 (0.15),7.137 (0.24), 7.143 (0.26), 7.157 (0.15), 7.165 (0.15), 7.395 (0.34), 7.402(0.35), 7.420 (0.36), 7.428 (0.34), 7.483 (0.48), 7.496 (0.50), 7.505 (0.47),7.518 (0.43), 7.661 (0.18), 7.683 (1.46), 7.691 (0.90), 7.708 (0.11), 7.713(0.13), 8.731 (0.20), 8.746 (0.40), 8.760 (0.19).

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 8.75 (t,1H), 7.73-7.65 (m, 2H), 7.50(dd, 1H), 7.46 (br. s, 1H, masked), 7.41 (dd, 1H), 7.14 (td, 1H), 3.80-3.65 (m,6H, partially masked), 3.59 (br. s, 1H), 3.25-3.12 (m, 4H), 2.20-1.95 (m,6H), 1.87-1.73 (m,1H), 1.37 (s, 9H).

Example 60A

(+/-) -5- ({ [ 6-bromo-2- (3, 6-dihydropyridin-1 (2H) -yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester(raceme)

To a suspension of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester (100 mg, 171. mu. mol, example 36A) in 1-butanol (1.2 ml) was added 1,2,3, 6-tetrahydropyridine (43 mg, 513. mu. mol), and the mixture was stirred at 100 ℃ for three days. After cooling to room temperature, the mixture was directly purified by preparative HPLC (method 18) (without further work-up). The combined target fractions were concentrated and the residue was lyophilized. 50 mg (98% purity, 45% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.73 min; MS (ESIpos): m/z = 630/632 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (0.07), -0.009 (0.56), 0.007(0.62), 0.146 (0.07), 1.213 (0.06), 1.297 (0.06), 1.331 (0.09), 1.373(16.00), 1.529 (0.07), 1.780 (0.12), 1.814 (0.18), 1.836 (0.14), 2.007(0.15), 2.019 (0.18), 2.037 (0.18), 2.057 (0.17), 2.070 (0.16), 2.086 (0.71),2.103 (0.93), 2.124 (0.46), 2.140 (2.18), 2.302 (0.44), 2.365 (0.07), 2.669(0.07), 2.709 (0.06), 3.274 (0.31), 3.587 (0.19), 3.689 (0.35), 3.795 (0.79),5.817 (0.15), 5.843 (0.49), 5.863 (0.45), 5.888 (0.14), 7.123 (0.16), 7.144(0.28), 7.158 (0.16), 7.165 (0.16), 7.397 (0.35), 7.404 (0.37), 7.422 (0.38),7.429 (0.37), 7.482 (0.48), 7.496 (0.48), 7.504 (0.45), 7.517 (0.41), 7.619(0.38), 7.641 (1.32), 7.654 (0.81), 7.659 (0.75), 7.677 (0.22), 7.682 (0.24),8.720 (0.21), 8.734 (0.41), 8.748 (0.20).

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 8.73 (t,1H), 7.69-7.61 (m, 2H), 7.50(dd, 1H), 7.47 (br. s, 1H), 7.41 (dd, 1H), 7.14 (td, 1H), 5.91-5.79 (m, 2H),3.80 (br. s,2H), 3.69 (br. s,2H), 3.59 (br. s, 1H), 3.27 (br. s,2H, partial coverage), 2.30 (br. s,2H), 2.18-1.97 (m,6H), 1.88-1.74 (m,1H), 1.37 (s, 9H).

Example 61A

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (thiomorpholin-4-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester(raceme)

To a suspension of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester (100 mg, 171. mu. mol, example 36A) in 1-butanol (1.2 ml) was added thiomorpholine (53mg, 513. mu. mol), and the mixture was stirred at 100 ℃ for 18 h. Then, thiomorpholine (53mg, 513 μmol) was added again, and the mixture was stirred at 100 ℃ for another four days. After cooling to room temperature, the mixture was directly purified by preparative HPLC (method 18) (without further work-up). The combined target fractions were concentrated and the residue was lyophilized. 55 mg (98% purity, 48% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.69 min; MS (ESIpos): m/z = 650/652 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (0.07), -0.009 (0.65), 0.007(0.57), 0.145 (0.08), 1.212 (0.06), 1.298 (0.07), 1.329 (0.09), 1.372(16.00), 1.528 (0.07), 1.775 (0.12), 1.809 (0.18), 1.830 (0.15), 2.000(0.15), 2.013 (0.19), 2.030 (0.19), 2.051 (0.16), 2.064 (0.14), 2.084 (0.71),2.101 (0.99), 2.128 (2.24), 2.327 (0.06), 2.365 (0.05), 2.669 (0.07), 2.709(0.06), 2.785 (1.20), 2.797 (1.13), 3.424 (1.18), 3.583 (0.20), 3.687 (0.35),7.124 (0.16), 7.144 (0.28), 7.165 (0.17), 7.395 (0.35), 7.402 (0.36), 7.420(0.37), 7.427 (0.36), 7.482 (0.49), 7.495 (0.51), 7.504 (0.48), 7.517 (0.44),7.656 (0.22), 7.678 (1.47), 7.683 (1.07), 7.688 (0.88), 7.706 (0.15), 7.710(0.17), 8.714 (0.22), 8.728 (0.43), 8.742 (0.21).

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 8.73 (t,1H), 7.72-7.65 (m, 2H), 7.50(dd, 1H), 7.46 (br. s, 1H, partial coverage), 7.41 (dd, 1H), 7.14 (td, 1H), 3.69 (br.s, 2H), 3.58 (br. s, 1H), 3.46-3.39 (m, 4H), 2.82-2.75 (m, 4H), 2.17-1.97 (m,6H), 1.88-1.74 (m,1H), 1.37 (s, 9H).

Example 62A

(+/-) -5- [ ({ 6-bromo-2- ], a salt thereof, and a salt thereofCis-alpha-carboxylic acid derivatives2, 6-dimethylmorpholin-4-yl]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester(raceme)

To (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]To a suspension of amino } -4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester (100 mg, 171 μmol, example 36A) in 1-butanol (1.2 ml) was addedCis-alpha-carboxylic acid derivatives2, 6-dimethylmorpholine (59 mg, 513 μmol) and the mixture was stirred at 100 ℃ for three days. After cooling to room temperature, the mixture was directly purified by preparative HPLC (method 18) (without further work-up). The combined target fractions were concentrated and the residue was lyophilized. 70 mg (98% purity, 60% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.71 min; MS (ESIpos): m/z = 662/664 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.06), 0.007 (0.42), 0.146(0.06), 1.133 (3.52), 1.148 (3.54), 1.212 (0.07), 1.299 (0.08), 1.330 (0.09),1.372 (16.00), 1.528 (0.07), 1.813 (0.18), 2.017 (0.18), 2.035 (0.17), 2.055(0.15), 2.067 (0.15), 2.085 (0.69), 2.101 (0.90), 2.121 (0.34), 2.156 (2.32),2.327 (0.08), 2.366 (0.07), 2.669 (0.09), 2.709 (0.08), 3.431 (0.58), 3.461(0.54), 3.581 (0.19), 3.685 (0.31), 3.777 (0.41), 7.124 (0.16), 7.145 (0.28),7.159 (0.16), 7.393 (0.35), 7.400 (0.35), 7.418 (0.36), 7.425 (0.35), 7.483(0.49), 7.496 (0.50), 7.505 (0.46), 7.518 (0.42), 7.655 (0.08), 7.676 (2.30),8.707 (0.22), 8.721 (0.42).

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 8.72 (t,1H), 7.71-7.64 (m, 2H), 7.50(dd, 1H), 7.46 (br. s, 1H, partial coverage), 7.41 (dd, 1H), 7.14 (td, 1H), 3.84-3.73(m, 2H), 3.69 (br. s,2H), 3.58 (br. s, 1H), 3.45 (br. d, 2H), 2.54-2.48 (coverage, 2H), 2.16 (s, 3H), 2.13-1.96 (m,3H), 1.87-1.75 (m,1H), 1.37 (s,9H), 1.15 (s, 3H), 1.13 (s, 3H).

Example 63A

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester(raceme)

To a suspension of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester (100 mg, 171. mu. mol, example 36A) in 1-butanol (1.2 ml) was added pyrrolidine (43. mu.l, 510. mu. mol) and the mixture was stirred at 100 ℃ for three days. After cooling to room temperature, the mixture was directly purified by preparative HPLC (method 20) (without further work-up). The combined target fractions were concentrated and the residue was lyophilized. 63mg (98% purity, 58% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.28 min; MS (ESIpos): m/z = 618/620 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (0.06), -0.008 (0.54), 0.007(0.50), 0.146 (0.06), 1.211 (0.06), 1.299 (0.08), 1.332 (0.11), 1.343 (0.12),1.371 (16.00), 1.527 (0.07), 1.775 (0.13), 1.791 (0.16), 1.809 (0.20), 1.831(0.21), 1.870 (1.32), 1.999 (0.16), 2.012 (0.20), 2.030 (0.20), 2.050 (0.18),2.083 (0.71), 2.100 (0.91), 2.120 (0.36), 2.155 (1.44), 2.327 (0.05), 2.366(0.05), 2.669 (0.06), 2.709 (0.06), 3.567 (1.08), 3.670 (0.36), 7.118 (0.15),7.138 (0.27), 7.152 (0.16), 7.385 (0.41), 7.392 (0.43), 7.410 (0.41), 7.418(0.40), 7.466 (0.74), 7.474 (0.45), 7.488 (1.61), 7.496 (0.45), 7.510 (0.39),7.544 (0.66), 7.549 (0.62), 7.566 (0.39), 7.572 (0.38), 8.674 (0.39).

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 8.67 (t,1H), 7.56 (dd, 1H),7.52-7.46 (m, 2H), 7.40 (dd, 1H), 7.37 (br. s, 1H, masked), 7.14 (td, 1H), 3.67 (br. s,2H), 3.57 (br. s, 5H), 2.20-1.96 (m,6H), 1.91-1.74 (m, 5H).

Example 64A

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (1, 2-oxazolidin-2-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester(raceme)

To a suspension of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester (100 mg, 171 μmol, example 36A) in 1-butanol (1.2 ml) was added 1, 2-oxazolidine (37.5 mg, 513 μmol) and the mixture was stirred at 100 ℃ for three days. After cooling to room temperature, the mixture was directly purified by preparative HPLC (method 23) (without further work-up). The combined target fractions were concentrated and the residue was lyophilized. 35 mg (98% purity, 32% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.57 min; MS (ESIpos): m/z = 620/622 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (0.04), -0.009 (0.31), 0.145(0.04), 1.212 (0.06), 1.288 (0.06), 1.324 (0.09), 1.373 (16.00), 1.529(0.07), 1.757 (0.05), 1.775 (0.13), 1.792 (0.16), 1.810 (0.19), 1.831 (0.15),2.000 (0.16), 2.013 (0.20), 2.031 (0.20), 2.051 (0.18), 2.062 (0.13), 2.087(0.71), 2.104 (0.92), 2.122 (0.32), 2.210 (1.47), 2.239 (0.64), 2.257 (0.85),2.275 (0.62), 2.293 (0.19), 2.331 (0.05), 2.365 (0.04), 2.669 (0.04), 2.709(0.04), 3.590 (0.20), 3.686 (0.39), 3.700 (0.53), 3.773 (0.37), 3.819(0.64),3.837 (1.08), 3.856 (0.58), 7.124 (0.15), 7.145 (0.27), 7.159 (0.16), 7.394(0.36), 7.401 (0.36), 7.419 (0.36), 7.426 (0.35), 7.486 (0.43), 7.499 (0.46),7.508 (0.45), 7.521 (0.43), 7.709 (0.11), 7.731 (2.33), 7.757 (0.09), 8.772(0.22), 8.787 (0.42), 8.800 (0.21).

1H-NMR (400 MHz, DMSO-d6) = 8.79 (t,1H), 7.77-7.69 (m, 2H),7.53 (br. s, 1H, masked), 7.50(dd, 1H), 7.41 (dd, 1H), 7.14 (td, 1H), 3.84 (t,2H), 3.77 (br. s,2H), 3.74-3.65 (m, 2H), 3.65-3.54 (m,1H), 2.31-2.17 (m,5H), 2.15-2.07 (m, 2H), 2.07-1.97 (m,1H), 1.88-1.73 (m,1H), 1.37 (s, 9H).

Example 65A

(+/-) -5- ({ [ 6-bromo-2- (2, 5-dihydro-1)H-pyrrol-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester(raceme)

To (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]To a suspension of amino } -4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester (100 mg, 171 μmol, example 36A) in 1-butanol (1.2 ml) was added 2, 5-dihydro-1H-pyrrole (36 mg, 513 μmol) and the mixture was stirred at 100 ℃ for three days. After cooling to room temperature, the mixture was directly purified by preparative HPLC (method 23) (without further work-up). The combined target fractions were concentrated and the residue was lyophilized. 32 mg (81% purity, 25% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.55 min; MS (ESIpos): m/z = 616/618 [M+H]⁺

1H-NMR (400 MHz, DMSO-d6) = 8.69 (t,1H), 7.57 (dd, 1H),7.52-7.46 (m, 2H), 7.40 (dd, 1H), 7.36 (wide, shaded, 1H), 7.17-7.10 (m,1H), 5.96 (s,2H), 4.53 (br. s, 4H), 3.77-3.52 (m,3H), 2.25 (br. s, 3H), 2.14-1.95 (m,3H), 1.87-1.74(m, 1H), 1.37 (s, 9H).

Example 66A

5- [ ({ 6-bromo-2- [ 3-hydroxypyrrolidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester(mixture of diastereomers)

To a suspension of tert-butyl (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chloro-5-fluorophenyl) valerate (100 mg, 171. mu. mol, example 36A) in 1-butanol (1.2 ml) was added (+/-) -pyrrolidin-3-ol (45 mg, 513. mu. mol), and the mixture was stirred at 100 ℃ for three days. After cooling to room temperature, the mixture was directly purified by preparative HPLC (method 20) (without further work-up). The combined target fractions were concentrated and the residue was lyophilized. 60 mg (98% purity, 54% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.02 min; MS (ESIpos): m/z = 634/636 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.82), 0.008 (0.78), 1.371(16.00), 1.832 (0.42), 2.084 (0.90), 2.101 (1.17), 2.122 (0.54), 2.146(1.73), 3.669 (0.41), 4.331 (0.42), 4.897 (0.43), 4.905 (0.74), 4.912 (0.46),7.390 (0.51), 7.416 (0.50), 7.466 (0.85), 7.478 (0.44), 7.488 (1.75), 7.497(0.43), 7.500 (0.41), 7.545 (0.70), 7.548 (0.65), 7.567 (0.41), 8.696 (0.44).

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 8.70 (br. t,1H), 7.59-7.53 (m,1H), 7.52-7.46(m, 2H), 7.43-7.38 (m,1H), 7.36 (br. s, partial coverage, 1H), 7.18-7.09(m, 1H), 4.90 (t,1H), 4.33 (br. s, 1H), 3.90-3.46 (m, 7H), 2.19-1.72 (m,9H), 1.37 (s, 9H).

Example 67A

5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester(mixture of diastereomers)

To a suspension of tert-butyl (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chloro-5-fluorophenyl) valerate (100 mg, 171. mu. mol, example 36A) in 1-butanol (1.2 ml) was added (+/-) -3-methylpiperidine (51mg, 513. mu. mol), and the mixture was stirred at 100 ℃ for two days. After cooling to room temperature, the mixture was directly purified by preparative HPLC (method 18) (without further work-up). The combined target fractions were concentrated and the residue was lyophilized. 78 mg (98% purity, 69% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.89 min; MS (ESIpos): m/z = 646/648 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (0.63), 0.919 (1.45), 0.936(1.34), 1.373 (16.00), 1.794 (0.50), 2.084 (0.80), 2.101 (1.03), 2.132(2.37), 3.459 (0.49), 3.678 (0.42), 7.483 (0.57), 7.496 (0.55), 7.505 (0.51),7.518 (0.42), 7.648 (1.52), 7.656 (0.95), 8.717 (0.41).

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 8.72 (t,1H), 7.68-7.62 (m, 2H), 7.50(dd, 1H), 7.46 (br. s, partial coverage, 1H), 7.41 (dd, 1H), 7.19-7.10 (m,1H), 3.78-3.39 (m,5H), 2.69 (br. d, 1H), 2.45-2.41 (coverage, 1H), 2.18-1.94 (m,6H), 1.86-1.58 (m,5H), 1.37 (s,9H), 1.17-1.01 (m,1H), 0.93 (d, 3H).

Example 68A

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (4-methylpiperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester(raceme)

To a suspension of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester (100 mg, 171. mu. mol, example 36A) in 1-butanol (1.2 ml) was added 4-methylpiperidine (51mg, 513. mu. mol), and the mixture was stirred at 100 ℃ for two days. After cooling to room temperature, the mixture was directly purified by preparative HPLC (method 18) (without further work-up). The combined target fractions were concentrated and the residue was lyophilized. 72 mg (98% purity, 64% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.88 min; MS (ESIpos): m/z = 646/648 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.009 (0.32), 0.007 (0.30), 0.865(0.06), 0.964 (1.71), 0.980 (1.80), 1.212 (0.06), 1.285 (0.31), 1.314 (0.35),1.372 (16.00), 1.562 (0.16), 1.717 (0.43), 1.747 (0.39), 1.774 (0.14), 1.809(0.17), 1.829 (0.14), 2.001 (0.14), 2.014 (0.18), 2.031 (0.18), 2.051 (0.17),2.065 (0.15), 2.084 (0.69), 2.100 (0.98), 2.119 (2.48), 2.327 (0.06), 2.365(0.07), 2.669 (0.07), 2.709 (0.10), 2.756 (0.29), 2.777 (0.32), 2.805 (0.16),3.508 (0.47), 3.540 (0.46), 3.580 (0.20), 3.683 (0.41), 7.123 (0.16), 7.144(0.28), 7.157 (0.17), 7.165 (0.17), 7.391 (0.36), 7.398 (0.37), 7.416 (0.38),7.424 (0.36), 7.481 (0.49), 7.495 (0.48), 7.503 (0.44), 7.517 (0.40), 7.618(0.33), 7.640 (1.38), 7.650 (0.88), 7.655 (0.78), 7.673 (0.19), 7.678 (0.21),8.704 (0.21), 8.719 (0.42), 8.733 (0.21).

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 8.72 (t,1H), 7.69-7.61 (m, 2H), 7.50(dd, 1H), 7.47 (br. s, partial coverage, 1H), 7.41 (dd, 1H), 7.14 (td, 1H), 3.74-3.64(m, 2H), 3.63-3.56 (m,1H), 3.52 (br. d, 2H), 2.83-2.70 (m, 2H), 2.15-1.97(m, 6H), 1.86-1.76 (m,1H), 1.73 (br. d, 2H), 1.62-1.50 (m,1H), 1.37 (s,9H), 1.36-1.22 (m, 2H), 0.97 (d, 3H).

Example 69A

5- [ ({ 6-bromo-2- [ 3-methoxypiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester(mixture of diastereomers)

To a suspension of tert-butyl (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chloro-5-fluorophenyl) valerate (100 mg, 171. mu. mol, example 36A) in 1-butanol (1.2 ml) was added (+/-) -3-methoxypiperidine (59.1 mg, 513. mu. mol), and the mixture was stirred at 100 ℃ for two days. After cooling to room temperature, the mixture was directly purified by preparative HPLC (method 18) (without further work-up). The combined target fractions were concentrated and the residue was lyophilized. 68 mg (98% purity, 58% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.66 min; MS (ESIpos): m/z = 662/664 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.007 (0.53), 1.233 (0.14), 1.373(16.00), 1.573 (0.15), 1.794 (0.35), 2.035 (0.36), 2.085 (0.75), 2.102(0.96), 2.133 (2.46), 2.731 (0.18), 2.840 (0.18), 3.301 (6.14), 3.425 (0.25),3.585 (0.45), 3.614 (0.33), 3.687 (0.47), 7.122 (0.18), 7.143 (0.30), 7.156(0.18), 7.395 (0.37), 7.402 (0.37), 7.420 (0.38), 7.428 (0.36), 7.479 (0.54),7.493 (0.55), 7.502 (0.49), 7.515 (0.43), 7.635 (0.30), 7.657 (1.46), 7.664(1.01), 7.669 (0.84), 7.691 (0.18), 8.721 (0.43).

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 8.72 (t,1H), 7.70-7.62 (m, 2H), 7.50(dd, 1H), 7.46 (br. s, partial coverage, 1H), 7.41 (dd, 1H), 7.14 (td, 1H), 3.76-3.64(m, 2H), 3.64-3.54 (m, 2H), 3.47-3.38 (m,1H), 3.30 (s, partial coverage, 3H), 2.92-2.79 (m,1H), 2.78-2.67 (m,1H), 2.18-1.95 (m, 7H), 1.87-1.74(m, 2H), 1.65-1.52 (m,1H), 1.46-1.32 (m, partial coverage, 1H), 1.37 (s, 9H).

Example 70A

5- [ ({ 6-bromo-2- [2- (hydroxymethyl) morpholin-4-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester(mixture of diastereomers)

To a suspension of tert-butyl (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chloro-5-fluorophenyl) valerate (100 mg, 171. mu. mol, example 36A) in 1-butanol (1.2 ml) was added (+/-) -morpholin-2-ylmethanol (60 mg, 513. mu. mol), and the mixture was stirred at 100 ℃ for two days. After cooling to room temperature, the mixture was directly purified by preparative HPLC (method 23) (without further work-up). The combined target fractions were concentrated and the residue was lyophilized. 35 mg (98% purity, 30% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.28 min; MS (ESIpos): m/z = 664/666 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.009 (0.40), 0.007 (0.40), 1.213(0.06), 1.329 (0.08), 1.372 (16.00), 1.529 (0.06), 1.776 (0.12), 1.810(0.17), 1.832 (0.14), 2.000 (0.14), 2.013 (0.18), 2.031 (0.17), 2.051 (0.15),2.086 (0.66), 2.103 (0.89), 2.123 (0.35), 2.153 (1.90), 2.327 (0.08), 2.366(0.07), 2.669 (0.23), 2.692 (0.17), 2.710 (0.12), 2.898 (0.16), 3.380 (0.32),3.417 (0.42), 3.481 (0.21), 3.494 (0.42), 3.508 (0.51), 3.522 (0.45), 3.535(0.25), 3.549 (0.29), 3.618 (0.29), 3.680 (0.41), 3.708 (0.52), 3.737 (0.22),3.908 (0.32), 3.935 (0.26), 4.748 (0.34), 4.762 (0.68), 4.776 (0.32), 7.123(0.15), 7.144 (0.27), 7.158 (0.15), 7.396 (0.30), 7.403 (0.31), 7.421 (0.32),7.428 (0.30), 7.482 (0.48), 7.496 (0.50), 7.504 (0.47), 7.517 (0.43), 7.661(0.14), 7.683 (1.97), 7.689 (0.99), 7.711 (0.12), 8.749 (0.37).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.75 (t, 1H), 7.72-7.65 (m, 2H), 7.50(dd, 1H), 7.47 (br s, 1H), 7.41 (dd, 1H), 7.14 (td, 1H), 4.76 (t, 1H), 3.92(br d, 1H), 3.77-3.47 (m, 7H), 3.46-3.35 (m, 2H), 2.96-2.82 (m, 1H), 2.74-2.60 (m, 1H), 2.15 (s, 3H), 2.13-2.07 (m, 2H), 2.07-1.96 (m, 1H), 1.88-1.73(m, 1H), 1.37 (s, 9H)。

Example 71A

5- [ ({ 6-bromo-2- [3- (hydroxymethyl) piperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester(mixture of diastereomers)

To a suspension of tert-butyl (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chloro-5-fluorophenyl) valerate (100 mg, 171. mu. mol, example 36A) in 1-butanol (1.2 ml) was added (+/-) -piperidin-3-ylmethanol (59 mg, 513. mu. mol), and the mixture was stirred at 100 ℃ for three days. After cooling to room temperature, the mixture was directly purified by preparative HPLC (method 23) (without further work-up). The combined target fractions were concentrated and the residue was lyophilized. 63mg (98% purity, 54% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.43 min; MS (ESIpos): m/z = 662/664 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.154 (0.04), 0.142 (0.04), 1.118(0.19), 1.141 (0.21), 1.209 (0.07), 1.295 (0.07), 1.326 (0.10), 1.369(16.00), 1.525 (0.07), 1.640 (0.17), 1.747 (0.56), 1.773 (0.71), 1.807(0.34), 1.999 (0.16), 2.011 (0.20), 2.029 (0.20), 2.049 (0.18), 2.062 (0.16),2.081 (0.76), 2.098 (1.02), 2.128 (2.35), 2.323 (0.05), 2.362 (0.04), 2.665(0.06), 2.721 (0.17), 2.741 (0.19), 3.356 (0.20), 3.368 (0.37), 3.381 (0.33),3.394 (0.23), 3.407 (0.13), 3.438 (0.24), 3.468 (0.21), 3.585 (0.48), 3.613(0.36), 3.680 (0.34), 4.505 (0.34), 4.517 (0.69), 4.530 (0.33), 7.118 (0.17),7.139 (0.31), 7.153 (0.18), 7.160 (0.18), 7.388 (0.36), 7.395 (0.37), 7.413(0.38), 7.421 (0.37), 7.477 (0.50), 7.490 (0.50), 7.499 (0.45), 7.513 (0.41),7.623 (0.21), 7.645 (1.52), 7.654 (0.92), 7.676 (0.15), 8.728 (0.41).

Preparation of H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 8.73 (t,1H), 7.69-7.62 (m, 2H), 7.50(dd, 1H), 7.47 (br. s, partial hiding, 1H), 7.41 (dd, 1H), 7.14 (td, 1H), 4.52 (t,1H), 3.75-3.53 (m, 4H), 3.46 (br. d, 1H), 3.42-3.35 (m,1H), 3.33-3.26 (m, hiding, 2H), 2.81-2.64 (m,1H), 2.18-1.96 (m,6H), 1.87-1.71 (m, 4H), 1.69-1.57(m, 1H), 1.37 (s,9H), 1.21-1.05 (m, 1H).

Example 72A

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester(raceme)

To a suspension of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chlorophenyl) pentanoic acid tert-butyl ester (1.10 g, 1.94 mmol, example 37A) in 1-butanol (14 ml) was added piperidine (580. mu.l, 5.8mmol) and the mixture was stirred at 100 ℃ for three days. After cooling to room temperature, water and ethyl acetate (50ml each) were added to the mixture, which was shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (50 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (100 g silica gel BiotageSnap cartridge KP-Sil, cyclohexane/ethyl acetate gradient 93:7 → 6:4, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 557 mg (84% purity, 39% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.82 min; MS (ESIpos): m/z = 614/616 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.72 (t, 1H), 7.69-7.61 (m, 2H), 7.51-7.43 (m, 2H), 7.49 (br., 1H), 7.40-7.34 (m, 1H), 7.30-7.24 (m, 1H), 3.73-3.53(m, 3H), 3.13 (br s, 4H), 2.17-2.00 (m, 6H), 1.87-1.75 (m, 1H), 1.71-1.55 (m,6H), 1.37 (s, 9H)。

Separation of enantiomers:

the title compound (550 mg) was dissolved in methanol (20ml) and separated into enantiomers on the chiral phase by preparative SFC (see example 73A and 74A) [ column: daicel Chiralpak OX-H, 5 μm, 250 mm x20 mm, flow rate: 80 ml/min, detection: 210nm, temperature: injection at 40 ℃: 0.3 ml, eluent 15% isopropanol/85% heptane, run time 16 min, isocratic ]. The combined target fractions were concentrated and the residue was dried in vacuo.

Example 73A

(-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester(enantiomer 1)

In the enantiomeric separation described in example 72A, the title compound was obtained as a previously purified enantiomer eluting earlier (ee value 99%). Followed by repurification by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was dried in vacuo. 150 mg (95% purity) of the repurified title compound are obtained.

[α]_D ²⁰= 8.4 °, 589 nm, c = 0.31 g/100 ml, methanol

LC-MS (method 2) R_t= 1.51 min; MS (ESIpos): m/z = 614/616 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.208 (0.07), 1.312 (0.09), 1.333(0.12), 1.368 (16.00), 1.525 (0.08), 1.604 (0.60), 1.668 (1.18), 1.814(0.26), 2.045 (0.27), 2.074 (1.54), 2.085 (0.84), 2.108 (0.38), 2.131 (1.97),3.132 (1.52), 3.584 (0.27), 3.671 (0.49), 7.251 (0.23), 7.270 (0.53), 7.289(0.37), 7.351 (0.32), 7.370 (0.57), 7.388 (0.30), 7.438 (0.79), 7.458 (0.67),7.479 (0.73), 7.497 (0.64), 7.623 (0.30), 7.645 (1.58), 7.652 (1.07), 7.675(0.20), 8.705 (0.28), 8.720 (0.54), 8.733 (0.26).

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 8.72 (t,1H), 7.69-7.61 (m, 2H), 7.47(dd, 2H), 7.49 (br., mask, 1H), 7.37 (t,1H), 7.27 (t,1H), 3.74-3.50 (m,3H), 3.13 (br. s, 4H), 2.17-1.98 (m,6H), 1.89-1.74 (m,1H), 1.72-1.55 (m,6H), 1.37 (s, 9H).

Example 74A

(+) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester(enantiomer 2)

In the enantiomeric separation described in example 72A, the title compound was obtained as a previously purified enantiomer eluting later (ee value 98%). And then purified again by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was dried in vacuo. 141 mg (98% purity) of the repurified title compound are obtained.

[α]_D ²⁰= 8.0 °, 589 nm, c = 0.26 g/100 ml, methanol

LC-MS (method 2) R_t= 1.51 min; MS (ESIpos): m/z = 614/616 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.368 (16.00), 1.604 (0.61), 1.669(1.21), 1.814 (0.27), 2.073 (1.61), 2.085 (0.85), 2.107 (0.39), 2.131 (2.06),3.132 (1.57), 3.584 (0.28), 3.672 (0.51), 7.251 (0.24), 7.270 (0.55), 7.289(0.39), 7.351 (0.33), 7.370 (0.60), 7.388 (0.31), 7.438 (0.83), 7.458 (0.71),7.479 (0.78), 7.498 (0.66), 7.622 (0.31), 7.645 (1.57), 7.653 (1.05), 7.675(0.20), 8.720 (0.56).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.72 (t, 1H), 7.70-7.61 (m, 2H), 7.47(dd, 2H), 7.49 (br., 1H), 7.37 (t, 1H), 7.27 (t, 1H), 3.74-3.52 (m, 3H), 3.13(br. s, 4H), 2.18-1.99 (m, 6H), 1.88-1.74 (m, 1H), 1.72-1.54 (m, 6H), 1.37(s, 9H)。

Example 75A

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (thiomorpholin-4-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester(raceme)

To a suspension of tert-butyl (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chlorophenyl) pentanoate (250 mg, 91% purity, 402 μmol, example 37A) in 1-butanol (2.9 ml) was added thiomorpholine (124 mg, 1.21 mmol) and the mixture was stirred at 100 ℃ for two days. After cooling to room temperature, the mixture was directly purified by preparative HPLC (method 6) (without further work-up). The combined target fractions were concentrated and the residue was dried in vacuo. 77mg (98% purity, 30% of theory) of the title compound are obtained.

LC-MS (method 2) R_t= 1.42 min; MS (ESIpos): m/z = 632/634 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.51), 0.008 (0.46), 1.369(16.00), 2.073 (1.08), 2.086 (0.66), 2.132 (1.34), 2.774 (0.88), 2.786(1.01), 2.798 (0.95), 3.413 (0.94), 3.419 (0.94), 3.426 (0.99), 3.437 (0.86),7.372 (0.41), 7.438 (0.61), 7.441 (0.57), 7.458 (0.51), 7.461 (0.48), 7.479(0.49), 7.482 (0.49), 7.499 (0.41), 7.678 (1.34), 7.684 (0.99), 7.688 (0.81).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.72 (t, 1H), 7.74-7.62 (m, 2H), 7.60-7.42 (m, 3H), 7.37 (t, 1H), 7.31-7.23 (m, 1H), 3.67 (br. s, 2H), 3.62-3.53(m, 1H), 3.46-3.38 (m, 4H), 2.83-2.74 (m, 4H), 2.19-1.97 (m, 6H), 1.88-1.73(m, 1H), 1.37 (s, 9H)。

Example 76A

(+/-) -5- ({ [ 6-bromo-2- (4, 4-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester(raceme)

To a suspension of tert-butyl (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chlorophenyl) pentanoate (100 mg, 88% purity, 155. mu. mol, example 37A) in 1-butanol (1.1 ml) was added 4, 4-difluoropiperidine (94 mg, 777. mu. mol), and the mixture was stirred at 100 ℃ for two days. After cooling to room temperature, the mixture was purified by preparative HPLC (method 18). The combined target fractions were concentrated and the residue was dried in vacuo. 28 mg (98% purity, 27% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.71 min; MS (ESIpos): m/z = 650/652 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.67), 1.369 (16.00), 2.075(1.36), 2.088 (0.85), 2.111 (0.57), 2.167 (1.98), 2.523 (0.67), 7.272 (0.44),7.373 (0.48), 7.439 (0.66), 7.459 (0.57), 7.486 (0.59), 7.503 (0.48), 7.682(1.32), 7.691 (0.87), 7.695 (0.76), 8.738 (0.45).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.74 (t, 1H), 7.74-7.64 (m, 2H), 7.59-7.42 (m, 3H), 7.37 (t, 1H), 7.30-7.23 (m, 1H), 3.68 (br. s, 2H), 3.62-3.53(m, 1H), 2.23-1.94 (m, 11H), 1.89-1.70 (m, 1H), 1.37 (s, 9H)。

Example 77A

(+/-) -5- ({ [ 6-bromo-2- (3, 6-dihydropyridin-1 (2H) -yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester(raceme)

To a suspension of (+/-) -tert-butyl 5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chlorophenyl) pentanoate (250 mg, 91% purity, 402 μmol, example 37A) in 1-butanol (2.9 ml) was added 1,2,3, 6-tetrahydropyridine (100 mg, 1.21 mmol) and the mixture was stirred at 100 ℃ for two days. After cooling to room temperature, the mixture was directly purified by preparative HPLC (method 6) (without further work-up). The combined target fractions were concentrated and the residue was dried in vacuo. 158 mg (98% purity, 63% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.75 min; MS (ESIpos): m/z = 612/614 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.370 (16.00), 2.077(1.26), 2.089(0.70), 2.144 (1.50), 2.303 (0.46), 3.797 (0.80), 5.844 (0.51), 5.864 (0.46),7.273 (0.41), 7.374 (0.45), 7.439 (0.61), 7.441 (0.64), 7.458 (0.53), 7.461(0.54), 7.485 (0.60), 7.502 (0.47), 7.642 (1.32), 7.655 (0.81), 7.660 (0.74),8.732 (0.44).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.73 (t, 1H), 7.70-7.60 (m, 2H), 7.58-7.41 (m, 3H), 7.37 (t, 1H), 7.31-7.23 (m, 1H), 5.95-5.77 (m, 2H), 3.80 (br.s, 2H), 3.68 (br. s, 2H), 3.63-3.53 (m, 1H), 3.28 (br. s, 2H), 2.30 (br. s,2H), 2.18-1.98 (m, 6H), 1.87-1.74 (m, 1H), 1.37 (s, 9H)。

Example 78A

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (1, 2-oxaazacyclohex-2-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester(raceme)

To a suspension of tert-butyl (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chlorophenyl) pentanoate (100 mg, 88% purity, 155. mu. mol, example 37A) in 1-butanol (1.1 ml) was added 1, 2-oxaazacyclohexane (67.7 mg, 777. mu. mol) and DIPEA (140. mu.l, 780. mu. mol), and the mixture was stirred at 100 ℃ for two days. After cooling to room temperature, the mixture was purified by preparative HPLC (method 18). The combined target fractions were concentrated and the residue was dried in vacuo. 24 mg (98% purity, 25% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.75 min; MS (ESIpos): m/z = 616/618 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.369 (16.00), 1.697 (0.63), 1.870(0.56), 1.884 (0.67), 1.898 (0.45), 2.075 (1.56), 2.086 (0.82), 2.145 (1.44),3.573 (0.69), 3.680 (0.54), 4.041 (0.59), 4.053 (0.94), 4.065 (0.59), 7.274(0.52), 7.371 (0.56), 7.444 (0.75), 7.464 (0.65), 7.479 (0.65), 7.498 (0.50),7.731 (2.67), 8.805 (0.54).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.81 (t, 1H), 7.73 (s, 2H), 7.55 (br.s, 1H), 7.47 (dd, 2H), 7.37 (t, 1H), 7.31-7.24 (m, 1H), 4.05 (t, 2H), 3.77-3.48 (m, 5H), 2.20-1.98 (m, 6H), 1.93-1.75 (m, 3H), 1.74-1.64 (m, 2H), 1.37(s, 9H)。

Example 79A

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester(raceme)

To a suspension of tert-butyl (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chlorophenyl) pentanoate (500 mg, 91% purity, 803 μmol, example 37A) in 1-butanol (5.8 ml) was added pyrrolidine (200 μ l, 2.4 mmol) and the mixture was stirred at 100 ℃ for two days. After cooling to room temperature, the mixture was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was dried in vacuo. 450 mg (96% purity, 89% of theory) of the title compound are obtained.

LC-MS (method 2) R_t= 1.08 min; MS (ESIpos): m/z = 600/602 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.67 (t, 1H), 7.56 (dd, 1H), 7.52-7.40(m, 4H), 7.37 (t, 1H), 7.30-7.23 (m, 1H), 3.76-3.47 (m, 7H), 2.23-1.98 (m,6H), 1.92-1.73 (m, 5H), 1.37 (s, 9H)。

Example 80A

5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpyrrolidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(mixture of diastereomers)

To a suspension of tert-butyl (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chlorophenyl) pentanoate (100 mg, 88% purity, 155. mu. mol, example 37A) in 1-butanol (1.1 ml) was added (+/-) -3-methylpyrrolidine hydrochloride (95 mg, 777. mu. mol) and DIPEA (140. mu.l, 780. mu. mol), and the mixture was stirred at 100 ℃ for two days. After cooling to room temperature, the mixture was purified by preparative HPLC (method 19). The combined target fractions were concentrated and the residue was dried in vacuo. 27 mg (98% purity, 28% of theory according to LC-MS) of the title compound in mixture with the corresponding n-butyl ester are obtained.

LC-MS (method 1) R_t= 2.41 min; MS (ESIpos): m/z = 614/616 [M+H]⁺

Example 81A

(+/-) -5- ({ [ 6-bromo-2- (3, 3-difluoropyrrolidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester(raceme)

To a suspension of tert-butyl (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chlorophenyl) pentanoate (100 mg, 88% purity, 155. mu. mol, example 37A) in 1-butanol (1.1 ml) was added difluoropyrrolidine hydrochloride (112 mg, 777. mu. mol) and DIPEA (140. mu.l, 780. mu. mol), and the mixture was stirred at 100 ℃ for two days. After cooling to room temperature, the mixture was purified by preparative HPLC (method 18). The combined target fractions were concentrated and the residue was dried in vacuo. 32 mg (98% purity, 32% of theory according to LC-MS) of the title compound in mixture with the corresponding n-butyl ester are obtained.

LC-MS (method 1) R_t= 2.66 min; MS (ESIpos): m/z = 636/638 [M+H]⁺

Example 82A

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (1, 2-oxazolidin-2-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester(raceme)

To a suspension of tert-butyl (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chlorophenyl) pentanoate (250 mg, 91% purity, 402 μmol, example 37A) in 1-butanol (2.9 ml) was added 1, 2-oxazolidine (88 mg, 1.21 mmol) and the mixture was stirred at 100 ℃ for two days. After cooling to room temperature, the mixture was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was dried in vacuo. 137 mg (98% purity, 55% of theory) of the title compound are obtained.

LC-MS (method 2) R_t= 1.31 min; MS (ESIpos): m/z = 602/604 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.326 (0.11), 1.345 (0.22), 1.368(16.00), 1.812 (0.20), 2.051 (0.20), 2.073 (1.19), 2.085 (0.63), 2.102(0.25), 2.212 (0.90), 2.239 (0.67), 2.257 (0.83), 2.275 (0.61), 2.293 (0.19),3.594 (0.21), 3.681 (0.40), 3.773 (0.40), 3.819 (0.60), 3.838 (1.03), 3.856(0.56), 7.253 (0.18), 7.272 (0.41), 7.291 (0.29), 7.352 (0.24), 7.371 (0.44),7.390 (0.23), 7.443 (0.65), 7.461 (0.53), 7.483 (0.54), 7.501 (0.42), 7.708(0.11), 7.730 (2.34), 8.783 (0.42), 8.797 (0.22).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.78 (t, 1H), 7.79-7.69 (m, 2H), 7.55(br. s, 1H), 7.51-7.43 (m, 2H), 7.37 (t, 1H), 7.31-7.23 (m, 1H), 3.84 (t,2H), 3.80-3.52 (m, 5H), 2.31-2.15 (m, 5H), 2.12-1.98 (m, 3H), 1.89-1.74 (m,1H), 1.37 (s, 9H)。

Example 83A

5- ({ [ 6-bromo-2- (3-methoxypyrrolidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid butyl ester(mixture of diastereomers)

To a suspension of tert-butyl (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chlorophenyl) pentanoate (100 mg, 88% purity, 155. mu. mol, example 37A) in 1-butanol (1.1 ml) was added (+/-) -3-methoxypyrrolidine hydrochloride (107 mg, 777. mu. mol) and DIPEA (140. mu.l, 780. mu. mol), and the mixture was stirred at 100 ℃ for two days. After cooling to room temperature, the mixture was purified by preparative HPLC (method 19). The combined target fractions were concentrated and the residue was dried in vacuo. 36 mg (98% purity, 36% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.38 min; MS (ESIpos): m/z = 630/632 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.841 (6.92), 0.859 (16.00), 0.878(8.20), 1.242 (0.62), 1.260 (2.27), 1.279 (3.99), 1.297 (4.01), 1.316 (2.45),1.335 (0.68), 1.472 (1.34), 1.488 (3.43), 1.508 (4.15), 1.525 (3.19), 1.542(0.92), 1.836 (0.66), 1.849 (0.86), 1.870 (1.04), 1.884 (0.78), 1.904 (0.42),2.050 (0.40), 2.070 (1.08), 2.082 (1.26), 2.101 (1.32), 2.123 (1.34), 2.132(1.26), 2.170 (7.46), 2.190 (4.09), 2.209 (1.68), 2.229 (0.50), 2.327 (0.46),2.422 (0.74), 2.440 (1.52), 2.458 (2.17), 2.476 (3.21), 2.669 (0.40), 3.585(1.18), 3.675 (1.62), 3.783 (2.51), 3.910 (0.72), 3.926 (1.48), 3.937 (3.09),3.944 (3.49), 3.953 (5.65), 3.961 (5.89), 3.970 (3.85), 3.978 (3.23), 3.988(1.62), 4.004 (1.04), 7.252 (0.96), 7.271 (2.27), 7.289 (1.70), 7.351 (1.40),7.369 (2.51), 7.388 (1.38), 7.436 (4.09), 7.455 (3.47), 7.480 (3.31), 7.500(2.49), 7.570 (3.37), 7.592 (6.68), 7.630 (3.79), 7.636 (3.45), 7.653 (1.86),7.658 (1.76), 8.693 (1.22), 8.706 (2.39), 8.720 (1.20)。

Example 84A

(+/-) -5- ({ [ 6-bromo-2- (3, 3-dimethylpiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester(raceme)

To a suspension of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chlorophenyl) pentanoic acid tert-butyl ester (500 mg, 883 μmol, example 37A) in 1-butanol (6.4 ml) was added 3, 3-dimethylpiperidine (370 μ l,2.6 mmol) and the mixture was stirred at 100 ℃ for two days. Then, 3-dimethylpiperidine (370 μ l,2.6 mmol) was added again, and the mixture was stirred at 100 ℃ for another three days. After cooling to room temperature, the mixture was concentrated and the residue was dissolved in dichloromethane and purified by flash column chromatography (50 g silica gel, Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 93:7 → 7:3, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 420mg (94% purity, 69% of theory) of the title compound are obtained.

LC-MS (method 2) R_t= 1.58 min; MS (ESIpos): m/z = 642/644 [M+H]⁺

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 8.72 (t,1H), 7.70-7.61 (m, 2H), 7.59-7.42 (m,3H), 7.37 (t,1H), 7.30-7.24 (m,1H), 3.75-3.62 (m, 2H), 3.62-3.53(m, 1H), 3.05 (br. s,2H), 2.86 (s,2H), 2.17 (s, 3H), 2.13-1.99 (m,3H), 1.92-1.75 (m,1H), 1.75-1.65 (m, 2H), 1.44-1.35 (m, 2H, partial coverage), 1,37 (s,9H), 1.00 (s, 6H).

Example 85A

5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(mixture of diastereomers)

To a suspension of tert-butyl (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chlorophenyl) pentanoate (1.10 g, 1.94 mmol, example 37A) in 1-butanol (14 ml) was added (+/-) -3-methylpiperidine (680 μ l, 5.8mmol) and the mixture was stirred at 100 ℃ for two days. After cooling to room temperature, the mixture was concentrated, the residue was dissolved in dichloromethane and purified by flash column chromatography (50 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 93:7 → 7:3, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 982 mg (96% purity, 77% of theory) of the title compound are obtained.

LC-MS (method 2) R_t= 1.54 min; MS (ESIpos): m/z = 628/630 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.72 (t, 1H), 7.71-7.60 (m, 2H), 7.59-7.41 (m, 3H), 7.37 (t, 1H), 7.31-7.23 (m, 1H), 3.67 (br. s, 2H), 3.62-3.54(m, 1H), 3.46 (br. t, 2H), 2.78-2.64 (m, 1H), 2.48-2.39 (m, 1H), 2.19-2.00(m, 6H), 1.89-1.57 (m, 5H), 1.37 (s, 9H), 1.15-1.02 (m, 1H), 0.93 (d, 3H)。

Separation of diastereoisomers/enantiomers:

the title compound (850 mg) was dissolved in a mixture of isopropanol (5 ml) and heptane (6 ml) and initially subjected to preliminary separation by preparative HPLC on the chiral phase [ column: daicel Chiralcel OX-H, 5 μm, 250 mm x20 mm, flow rate: 15 ml/min, injection: 0.13 ml, eluent 20% isopropanol/80% heptane, run time 16 min, isocratic ]. One sufficiently pure fraction (peak 1, see example 86A) and two mixed fractions were obtained. The first mixed fraction (peak 2 and peak 3) was separated by preparative HPLC on the chiral phase [ column: daicel Chiralcel OZ-H, 5 μm, 250 mm x20 mm, flow rate: 15 ml/min, eluent 15% isopropanol/85% heptane (see examples 87A and 88A). The second mixed fraction (mainly peak 4) was also separated by preparative HPLC on the chiral phase [ column: daicel Chiralcel OZ-H, 5 μm, 250 mm x20 mm, flow rate: 15 ml/min, eluent 10% isopropanol/90% heptane (see example 89A). The combined target fractions were each concentrated and the respective residue was lyophilized.

Example 86A

(-) -5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(diastereomer 1)

In the diastereoisomeric separation described in example 85A, 194 mg (96% purity, ee value 99%) of the title compound are obtained as the first eluting diastereoisomer (peak 1).

[α]_D ²⁰= 16.2 °, 589 nm, c = 0.38 g/100 ml, methanol

LC-MS (method 1) R_t= 2.90 min; MS (ESIpos): m/z = 628/630 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.945 (1.66), 0.961 (1.68), 1.103(0.18), 1.131 (0.20), 1.159 (0.16), 1.177 (0.21), 1.195 (0.10), 1.235 (0.07),1.340 (0.34), 1.359 (0.12), 1.395 (16.00), 1.420 (0.31), 1.551 (0.07), 1.645(0.16), 1.676 (0.19), 1.755 (0.33), 1.790 (0.37), 1.817 (0.52), 1.846 (0.44),2.056 (0.20), 2.073 (0.25), 2.082 (0.22), 2.100 (1.31), 2.111 (0.75), 2.127(0.30), 2.134 (0.28), 2.162 (1.64), 2.353 (0.03), 2.392 (0.03), 2.443 (0.15),2.472 (0.24), 2.711 (0.14), 2.737 (0.26), 2.768 (0.14), 2.928 (0.08), 2.947(0.08), 3.463 (0.27), 3.486 (0.45), 3.514 (0.24), 3.610 (0.23), 3.698 (0.40),7.280 (0.20), 7.296 (0.45), 7.314 (0.35), 7.351 (0.07), 7.379 (0.28), 7.397(0.47), 7.415 (0.24), 7.464 (0.64), 7.466 (0.61), 7.483 (0.54), 7.507 (0.60),7.523 (0.51), 7.652 (0.18), 7.674 (1.58), 7.682 (0.94), 7.699 (0.12), 7.704(0.14), 8.727 (0.22), 8.741 (0.43), 8.755 (0.20)。

Example 87A

(+) -5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(diastereomer 2)

In the diastereoisomeric separation described in example 85A, 157 mg (100% purity, ee value 99%) of the title compound are obtained as the second eluting diastereomer (peak 2).

[α]_D ²⁰= 15.5 °, 589 nm, c = 0.37 g/100 ml, methanol

LC-MS (method 1) R_t= 2.90 min; MS (ESIpos): m/z = 628/630 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.919 (1.60), 0.935 (1.63), 1.077(0.18), 1.101 (0.19), 1.139 (0.11), 1.157 (0.10), 1.176 (0.05), 1.208 (0.07),1.311 (0.08), 1.333 (0.11), 1.368 (16.00), 1.525 (0.07), 1.619 (0.15), 1.649(0.18), 1.729 (0.31), 1.764 (0.36), 1.791 (0.51), 1.820 (0.43), 2.046 (0.24),2.056 (0.21), 2.074 (1.34), 2.085 (0.75), 2.101 (0.29), 2.107 (0.27), 2.136(1.68), 2.327 (0.04), 2.365 (0.04), 2.417 (0.15), 2.446 (0.24), 2.475 (0.18),2.685 (0.14), 2.710 (0.26), 2.741 (0.13), 3.437 (0.27), 3.461 (0.45), 3.488(0.24), 3.584 (0.23), 3.672 (0.40),7.253 (0.19), 7.271 (0.44), 7.288 (0.31),7.353 (0.27), 7.371 (0.48), 7.389 (0.25), 7.440 (0.63), 7.457 (0.54), 7.480(0.62), 7.497 (0.52), 7.625 (0.20), 7.648 (1.58), 7.655 (0.94), 7.673 (0.12),7.678 (0.14), 8.701 (0.23), 8.715 (0.44), 8.729 (0.21)。

Example 88A

(+) -5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(diastereomer 3)

In the diastereoisomeric separation described in example 85A, 169 mg (100% purity, ee value 99%) of the title compound are obtained as the third eluting diastereomer (peak 3).

[α]_D ²⁰= 9.6 °, 436 nm, c = 0.42 g/100 ml, methanol

LC-MS (method 1) R_t= 2.91 min; MS (ESIpos): m/z = 628/630 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.920 (1.65), 0.936 (1.68), 1.078(0.18), 1.101 (0.19), 1.139 (0.15), 1.157 (0.18), 1.176 (0.09), 1.208 (0.07),1.314 (0.08), 1.331 (0.10), 1.369 (16.00), 1.525 (0.07), 1.626 (0.16), 1.656(0.19), 1.728 (0.33), 1.760 (0.36), 1.794 (0.49), 1.820 (0.43), 2.047 (0.23),2.056 (0.21), 2.074 (1.37), 2.085 (0.79), 2.102 (0.29), 2.137 (1.81), 2.327(0.04), 2.365 (0.04), 2.431 (0.17), 2.459 (0.27), 2.669 (0.16), 2.699 (0.24),2.728 (0.13), 2.923 (0.03), 3.434 (0.28), 3.462 (0.49), 3.492 (0.23), 3.583(0.23), 3.668 (0.37), 7.253 (0.19), 7.272 (0.44), 7.292 (0.31), 7.353 (0.27),7.372 (0.49), 7.390 (0.26), 7.440 (0.66), 7.460 (0.56), 7.481 (0.65), 7.498(0.52), 7.626 (0.18), 7.649 (1.66), 7.655 (0.96), 7.677 (0.14), 8.702 (0.25),8.716 (0.49), 8.730 (0.24)。

Example 89A

(-) -5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(enantiomer 4)

In the diastereoisomeric separation described in example 85A, 158 mg (96% purity, ee value 99%) of the title compound are obtained as the last eluting diastereoisomer (peak 4).

[α]_D ²⁰= 10.4 °, 436 nm, c = 0.44 g/100 ml, methanol

LC-MS (method 1) R_t= 2.90 min; MS (ESIpos): m/z = 628/630 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.920 (1.61), 0.936 (1.63), 1.077(0.17), 1.100 (0.18), 1.139 (0.09), 1.157 (0.06), 1.208 (0.06), 1.314 (0.10),1.331 (0.09), 1.369 (16.00), 1.525 (0.06), 1.626 (0.15), 1.657 (0.18), 1.728(0.32), 1.761 (0.34), 1.794 (0.46), 1.820 (0.40), 2.047 (0.22), 2.056 (0.20),2.074 (1.27), 2.086 (0.74), 2.102 (0.28), 2.137 (1.67), 2.327 (0.04), 2.365(0.04), 2.431 (0.16), 2.460 (0.25), 2.669 (0.16), 2.699 (0.22), 2.728 (0.12),3.433 (0.26), 3.462 (0.46), 3.493 (0.21), 3.583 (0.21), 3.667 (0.34), 7.254(0.18), 7.272 (0.43), 7.288 (0.33), 7.325 (0.05), 7.353 (0.26), 7.372 (0.46),7.390 (0.24), 7.437 (0.63), 7.440 (0.64), 7.457 (0.54), 7.460 (0.54), 7.481(0.60), 7.498 (0.48), 7.626 (0.18), 7.649 (1.60), 7.655 (0.94), 7.678 (0.14),8.702 (0.23), 8.716 (0.45), 8.730 (0.22)。

Example 90A

(+/-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester(raceme)

To a suspension of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chlorophenyl) pentanoic acid tert-butyl ester (1.50 g, 98% purity, 2.60 mmol, example 37A) in NMP (24 ml) was added 3, 3-difluoropiperidine hydrochloride (3.27 g, 20.8 mmol) and DIPEA (5.42 ml, 31.15 mmol) and the mixture was stirred at 120 ℃ for 18 h. After cooling to room temperature, water (200 ml) and ethyl acetate (100ml) were added to the mixture, which was shaken. After phase separation, the aqueous phase was extracted repeatedly with ethyl acetate (100ml each). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was purified by flash column chromatography (100 g silica gel, Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3 → 9:1, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 933mg (96% purity, 53% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.70 min; MS (ESIpos): m/z = 650/652 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.04), 0.146 (0.04), 1.210(0.08), 1.234 (0.04), 1.311 (0.07), 1.333 (0.09), 1.370 (16.00), 1.398(3.71), 1.526 (0.08), 1.764 (0.07), 1.797 (0.17), 1.817 (0.23), 1.880 (0.52),2.046 (0.34), 2.056 (0.38), 2.076 (1.68), 2.088 (1.06), 2.110 (0.55), 2.152(1.68), 2.327 (0.05), 2.366 (0.05), 2.670 (0.04), 2.710 (0.04), 3.167 (0.60),3.447 (0.40), 3.476 (0.76), 3.505 (0.38), 3.587 (0.24), 3.683 (0.40), 7.254(0.20), 7.273 (0.48), 7.291 (0.35), 7.355 (0.28), 7.374 (0.51), 7.392 (0.26),7.441 (0.69), 7.461 (0.57), 7.485 (0.60), 7.504 (0.47), 7.674 (0.26), 7.696(1.50), 7.703 (0.97), 7.707 (0.83), 7.729 (0.17), 8.718 (0.24), 8.732 (0.49),8.746 (0.24)。

Separation of enantiomers:

the title compound (1.51 g) was dissolved in methanol (40 ml) and separated by preparative SFC on the chiral phase into enantiomers (see examples 91A and 92A) [ column: daicel Chiralcel OZ-H, 5 μm, 250 mm x 30mm, flow rate: 114 ml/min, injection: 0.40ml, eluent 22% methanol/78% carbon dioxide, run time 9min, isocratic. The combined target fractions were concentrated and the respective residue was dried in vacuo.

Example 91A

5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester(enantiomer 1)

In the enantiomeric separation described in example 90A, 672 mg (97% purity, ee value 98%) of the title compound were obtained as the earlier eluting enantiomer.

R_t= 2.35 min (chiral analytical SFC; Agilent phenyl cellulose-2 column, 3 μm, 50 mm x4.6 mm, eluent: carbon dioxide/methanol 95:5 → 4:6; flow rate 3 ml/min; temperature 40 ℃; detection 220nm)

LC-MS (method 1) R_t= 2.70 min; MS (ESIpos): m/z = 650/652 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.009 (0.28), 0.007 (0.29), 1.038(0.05), 1.055 (0.10), 1.073 (0.05), 1.209 (0.06), 1.310 (0.07), 1.332 (0.10),1.369 (16.00), 1.525 (0.06), 1.795 (0.14), 1.816 (0.18), 1.879 (0.44), 2.045(0.28), 2.075 (1.41), 2.087 (0.90), 2.109 (0.46), 2.151 (1.41), 2.327 (0.05),2.669 (0.06), 2.709 (0.04), 3.162 (0.52), 3.446 (0.34), 3.475 (0.65), 3.504(0.32), 3.586 (0.20), 3.681 (0.34), 7.255 (0.17), 7.273 (0.40), 7.290 (0.30),7.355 (0.24), 7.373 (0.43), 7.391 (0.22), 7.439 (0.60), 7.442 (0.58), 7.459(0.50), 7.462 (0.48), 7.486 (0.50), 7.502 (0.40), 7.674 (0.24), 7.696 (1.37),7.702 (0.97), 7.707 (0.83), 7.724 (0.15), 7.729 (0.17), 8.716 (0.21), 8.731(0.43), 8.745 (0.21)。

Example 92A

5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester(enantiomer 2)

In the enantiomeric separation described in example 90A, 634 mg (98% purity, ee value 98%) of the title compound are obtained as the later eluting enantiomer.

R_t= 2.67 min (chiral analytical SFC; Agilent phenyl cellulose-2 column, 3 μm, 50 mm x4.6 mm, eluent: carbon dioxide/methanol 95:5 → 4:6; flow rate 3 ml/min; temperature 40 ℃; detection 220nm)

LC-MS (method 1) R_t= 2.70 min; MS (ESIpos): m/z = 650/652 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.038 (0.09), 1.055 (0.18), 1.073(0.09), 1.208 (0.06), 1.310 (0.06), 1.332 (0.09), 1.369 (16.00), 1.525(0.07), 1.796 (0.15), 1.816 (0.20), 1.878 (0.45), 2.045 (0.28), 2.075 (1.47),2.087 (0.94), 2.110 (0.47), 2.151 (1.50), 2.327 (0.05), 2.669 (0.06), 3.162(0.54), 3.446 (0.36), 3.475 (0.67), 3.504 (0.33), 3.587 (0.21), 3.681 (0.36),4.335 (0.06), 7.254 (0.17), 7.273 (0.41), 7.290 (0.29), 7.355 (0.24), 7.373(0.45), 7.391 (0.23), 7.439 (0.64), 7.459 (0.53), 7.483 (0.52), 7.502 (0.42),7.674 (0.24), 7.696 (1.40), 7.702 (0.97), 7.707 (0.82), 7.724 (0.15), 7.729(0.17), 8.717 (0.22), 8.731 (0.45), 8.745 (0.22)。

Example 93A

5- [ ({ 6-bromo-3-methyl-2- [3- (trifluoromethyl) piperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(mixture of diastereomers)

To a suspension of tert-butyl (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chlorophenyl) pentanoate (250 mg, 98% purity, 433 μmol, example 37A) in NMP (4 ml) was added (+/-) -3- (trifluoromethyl) piperidine (530 mg, 3.46 mmol) and DIPEA (602 μ l, 3.46 mmol). And the mixture was stirred at 120 ℃ for two days. After cooling to room temperature, the mixture was concentrated and the residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was dried in vacuo. 156 mg (98% purity, 52% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.85 min; MS (ESIpos): m/z = 682/684 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.153 (3.05), 1.181 (2.46), 1.268(0.43), 1.284 (0.44), 1.308 (0.41), 1.370 (16.00), 1.504 (0.40), 1.521(0.50), 2.076 (1.13), 2.089 (0.66), 2.144 (1.11), 7.271 (0.44), 7.373 (0.43),7.436 (0.60), 7.456 (0.49), 7.484 (0.58), 7.488 (0.55), 7.503 (0.47), 7.689(2.18)。

Example 94A

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (4-methylpiperazin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester(raceme)

To a suspension of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chlorophenyl) pentanoic acid tert-butyl ester (200 mg, 98% purity, 346 μmol, example 37A) in NMP (4 ml) was added 1-methylpiperazine (277mg, 2.77 mmol) and DIPEA (482 μ l, 2.77 mmol), and the mixture was stirred at 120 ℃ for two days. After cooling to room temperature, the mixture was concentrated and the residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was dried in vacuo. 135 mg (98% purity, 61% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 1.72 min; MS (ESIpos): m/z = 629/631 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.023 (0.08), -0.008 (0.22), 0.008(0.24), 1.027 (0.04), 1.208 (0.06), 1.234 (0.21), 1.312 (0.07), 1.333 (0.09),1.368 (16.00), 1.525 (0.06), 1.793 (0.13), 1.813 (0.17), 2.052 (0.17), 2.073(1.11), 2.085 (0.60), 2.102 (0.29), 2.108 (0.28), 2.132 (1.31), 2.242 (3.22),2.327 (0.06), 2.366 (0.06), 2.670 (0.06), 2.710 (0.06), 3.178 (1.02), 3.584(0.19), 3.672 (0.32), 7.253 (0.17), 7.272 (0.37), 7.289 (0.27), 7.353 (0.23),7.371 (0.42), 7.388 (0.21), 7.438 (0.59), 7.441 (0.57), 7.458 (0.50), 7.461(0.48), 7.481 (0.52), 7.497 (0.44), 7.640 (0.20), 7.662 (1.35), 7.666 (1.05),7.671 (0.81), 7.688 (0.12), 7.693 (0.14), 8.712 (0.20), 8.727 (0.40), 8.741(0.19)。

Example 95A

5- [ ({ 6-bromo-2- [ 3-hydroxypiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(mixture of diastereomers)

To a suspension of tert-butyl (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chlorophenyl) pentanoate (200 mg, 98% purity, 346 μmol, example 37A) in NMP (3 ml) was added (+/-) -piperidin-3-ol (280 mg, 2.77 mmol) and DIPEA (482 μ l, 2.77 mmol), and the mixture was stirred at 120 ℃ for two days. After cooling to room temperature, the mixture was concentrated and the residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was dried in vacuo. 154 mg (98% purity, 69% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.39 min; MS (ESIpos): m/z = 630/632 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.24), 0.008 (0.23), 1.209(0.06), 1.313 (0.17), 1.369 (16.00), 1.526 (0.07), 1.603 (0.13), 1.783(0.25), 1.813 (0.28), 1.922 (0.18), 1.943 (0.17), 2.052 (0.18), 2.074 (1.10),2.087 (0.64), 2.110 (0.30), 2.132 (1.38), 2.327 (0.05), 2.366 (0.06), 2.635(0.16), 2.665 (0.13), 2.710 (0.07), 2.778 (0.17), 3.356 (0.21), 3.387 (0.19),3.512 (0.22), 3.543 (0.22), 3.589 (0.19), 3.677 (0.47), 4.852 (0.66), 4.864(0.65), 7.254 (0.16), 7.272 (0.37), 7.291 (0.27), 7.353 (0.22), 7.372 (0.41),7.391 (0.21), 7.439 (0.62), 7.442 (0.63), 7.458 (0.53), 7.462 (0.52), 7.482(0.55), 7.501 (0.44), 7.621 (0.36), 7.643 (1.27), 7.656 (0.83), 7.661 (0.76),7.678 (0.23), 7.684 (0.24), 8.713 (0.19), 8.727 (0.39), 8.741 (0.19)。

Example 96A

5- { [ (6-bromo-2- {3- [ (tert-butoxycarbonyl) amino)]Piperidin-1-yl } -3-methylquinolin-4-yl) carbonyl]Amino } -4- (2-chlorophenyl) pentanoic acid tert-butyl ester(mixture of diastereomers)

To a suspension of tert-butyl (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chlorophenyl) pentanoate (200 mg, 98% purity, 346 μmol, example 37A) in NMP (3 ml) was added tert-butyl (+/-) -piperidin-3-ylcarbamate (555 mg, 2.77 mmol) and DIPEA (482 μ l, 2.77 mmol), and the mixture was stirred at 120 ℃ for two days. After cooling to room temperature, the mixture was concentrated and the residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was dried in vacuo. 162 mg (98% purity, 63% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.78 min; MS (ESIpos): m/z = 729/731 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.209 (0.07), 1.235 (0.09), 1.369(16.00), 1.395 (10.53), 1.525 (0.08), 1.551 (0.07), 1.643 (0.13), 1.797(0.32), 1.831 (0.36), 2.073 (1.14), 2.086 (0.69), 2.103 (0.26), 2.155 (0.93),2.328 (0.06), 2.615 (0.10), 2.670 (0.10), 2.752 (0.19), 3.369 (0.20), 3.401(0.18), 3.473 (0.18), 3.501 (0.18), 3.581 (0.33), 3.679 (0.35), 6.961 (0.19),7.251 (0.16), 7.269 (0.39), 7.289 (0.27), 7.352 (0.22), 7.371 (0.41), 7.389(0.22), 7.436 (0.57), 7.455 (0.49), 7.482 (0.55), 7.499 (0.46), 7.631 (0.31),7.653 (1.19), 7.665 (0.76), 7.670 (0.69), 7.687 (0.20), 7.692 (0.21), 8.730(0.34)。

Example 97A

5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(mixture of diastereomers)

To a suspension of tert-butyl (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chlorophenyl) pentanoate (2.50 g, 98% purity, 4.33 mmol, example 37A) in NMP (37 ml) was added (+/-) -3-ethylpiperidine (3.92 g, 34.6 mmol) and DIPEA (6.0 ml, 34.6 mmol) and the mixture was stirred at 120 ℃ for 4 h. After cooling to room temperature, the mixture was concentrated, the residue was dissolved in dichloromethane and washed with water and saturated aqueous sodium chloride solution. The combined aqueous phases were then extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was dried in vacuo. 2.40 g (98% purity, 85% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 3.04 min; MS (ESIpos): m/z = 642/644 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.078 (0.08), 0.218 (0.08), 0.962(0.85), 0.980 (2.01), 0.999 (1.05), 1.135 (0.19), 1.158 (0.20), 1.187 (0.09),1.228 (0.15), 1.246 (0.30), 1.264 (0.15), 1.281 (0.08), 1.329 (0.39), 1.347(0.51), 1.364 (0.36), 1.403 (0.11), 1.440 (16.00), 1.636 (0.22), 1.817(0.28), 1.849 (0.27), 1.889 (0.24), 1.917 (0.27), 1.948 (0.22), 2.059 (0.56),2.118 (0.24), 2.146 (1.40), 2.157 (0.81), 2.201 (1.34), 2.816 (0.18), 3.566(0.40), 3.591 (0.36), 3.658 (0.24), 3.744 (0.46), 4.092 (0.14), 4.110 (0.13),5.825 (0.10), 7.322 (0.20), 7.341 (0.49), 7.359 (0.36), 7.423 (0.27), 7.442(0.51), 7.460 (0.26), 7.506 (0.65), 7.526 (0.55), 7.554 (0.67), 7.571 (0.54),7.697 (0.19), 7.720 (1.78), 7.749 (0.15), 8.772 (0.24), 8.787 (0.50), 8.801(0.24)。

Separation of diastereoisomers/enantiomers:

the title compound (2.4 g) was dissolved in methanol (60 ml) and separated by preparative SFC on the chiral phase into the diastereomers [ column: daicel Chiralcel OX-H, 5 μm,250 mm x 30mm, flow rate: 80 ml/min, detection: 210 nm, temperature: at 40 ℃, injection: 0.40 ml, eluent 22% methanol/78% carbon dioxide, isocratic ]. One mixed fraction (peak 1 and peak 2) and two fractions each well purified (peak 3, see example 100A, and peak 4, see example 101A) were obtained. The mixed fractions were again separated by preparative SFC on the chiral phase into diastereomers [ column: DaicelChiralcel OX-H, 5 μm,250 mm x20 mm, flow rate: 80 ml/min, detection: 210 nm, temperature: at 40 ℃, injection: 2.20 ml, eluent 15% isopropanol/85% carbon dioxide, isocratic ]. Two fractions each well purified were obtained (peak 1, see example 98A, and peak 2, see example 99A). The combined target fractions were each concentrated and the respective residue was lyophilized.

Example 98A

(+) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(diastereomer 1)

In the diastereoisomeric separation described in example 97A, 200 mg (100% purity, ee >99%) of the title compound are obtained as the first eluting diastereoisomer (peak 1).

[α]_D ²⁰= 7.7 °, 589 nm, c = 0.39 g/100 ml, methanol

LC-MS (Method 1) R_t= 3.03 min; MS (ESIpos): m/z = 642/644 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.976 (0.88), 0.995 (2.21), 1.014(1.10), 1.121 (0.06), 1.149 (0.17), 1.179 (0.17), 1.200 (0.08), 1.294 (0.07),1.325 (0.13), 1.342 (0.35), 1.360 (0.47), 1.377 (0.32), 1.397 (0.17), 1.415(0.11), 1.454 (16.00), 1.611 (0.12), 1.649 (0.22), 1.682 (0.20), 1.713(0.17), 1.831 (0.24), 1.872 (0.23), 1.902 (0.21), 1.930 (0.23), 1.961 (0.19),2.131 (0.24), 2.140 (0.20), 2.158 (1.28), 2.169 (0.75), 2.203 (1.17), 2.413(0.04), 2.755 (0.04), 2.804 (0.13), 2.832 (0.23), 2.861 (0.13), 3.584 (0.38),3.607 (0.28), 3.671 (0.21), 3.757 (0.39), 7.336 (0.18), 7.354 (0.42), 7.371(0.30), 7.436 (0.25), 7.455 (0.46), 7.473 (0.23), 7.519 (0.57), 7.537 (0.47),7.568 (0.57), 7.584 (0.48), 7.711 (0.19), 7.733 (1.47), 7.741 (0.89), 7.759(0.12), 7.764 (0.14), 8.786 (0.21), 8.801 (0.43), 8.815 (0.21)。

Example 99A

(-) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(diastereomer 2)

In the diastereoisomeric separation described in example 97A, 219 mg (100% purity, ee value 95%) of the title compound are obtained as the second eluting diastereomer (peak 2).

[α]_D ²⁰= 23.1 °, 589 nm, c = 0.42 g/100 ml, methanol

LC-MS (method 1) R_t= 3.02 min; MS (ESIpos): m/z = 642/644 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.961 (0.87), 0.979 (2.07), 0.998(1.02), 1.107 (0.07), 1.135 (0.17), 1.157 (0.17), 1.187 (0.08), 1.280 (0.08),1.311 (0.15), 1.329 (0.34), 1.346 (0.45), 1.364 (0.31), 1.385 (0.18), 1.440(16.00), 1.597 (0.15), 1.629 (0.19), 1.675 (0.18), 1.706 (0.16), 1.816(0.25), 1.849 (0.24), 1.888 (0.21), 1.917 (0.23), 1.948 (0.19), 2.118 (0.22),2.128 (0.23), 2.147 (1.23), 2.158 (0.74), 2.180 (0.37), 2.201 (1.75), 2.239(0.09), 2.399 (0.04), 2.473 (0.12), 2.776 (0.11), 2.803 (0.20), 2.831 (0.11),3.559 (0.38), 3.588 (0.35), 3.658 (0.21), 3.744 (0.41), 3.791 (0.10), 3.896(0.07), 4.109 (0.04), 7.324 (0.19), 7.342 (0.41), 7.362 (0.30), 7.425 (0.25),7.443 (0.44), 7.461 (0.23), 7.507 (0.62), 7.509 (0.57), 7.526 (0.53), 7.529(0.49), 7.554 (0.60), 7.570 (0.47), 7.697 (0.19), 7.720 (1.51), 7.727 (0.87),7.744 (0.12), 7.749 (0.14), 7.960 (0.11), 8.773 (0.23), 8.787 (0.45), 8.801(0.21)。

Example 100A

(-) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(diastereomer 3)

In the diastereoisomeric separation described in example 97A, 462 mg (100% purity, ee >99%) of the title compound are obtained as the third eluting diastereomer (peak 3).

[α]_D ²⁰= 6.9 °, 589 nm, c = 0.36 g/100 ml, methanol

LC-MS (method 1) R_t= 3.03 min; MS (ESIpos): m/z = 642/644 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.077 (0.11), 0.093 (0.12), 0.976(0.84), 0.995 (2.12), 1.014 (1.04), 1.121 (0.06), 1.150 (0.16), 1.179 (0.16),1.201 (0.08), 1.294 (0.07), 1.325 (0.13), 1.342 (0.33), 1.359 (0.45), 1.377(0.31), 1.397 (0.16), 1.416 (0.11), 1.454 (16.00), 1.611 (0.12), 1.649(0.20), 1.682 (0.19), 1.713 (0.15), 1.831 (0.23), 1.863 (0.22), 1.901 (0.20),1.930 (0.22), 1.961 (0.18), 2.131 (0.22), 2.140 (0.19), 2.158 (1.19), 2.169(0.70), 2.203 (1.05), 2.413 (0.04), 2.755 (0.04), 2.805 (0.12), 2.832 (0.21),2.861 (0.11), 3.584 (0.35), 3.605 (0.26), 3.671 (0.19), 3.757 (0.36), 7.336(0.17), 7.354 (0.39), 7.371 (0.29), 7.437 (0.24), 7.455 (0.43), 7.474 (0.22),7.517 (0.53), 7.520 (0.55), 7.537 (0.44), 7.539 (0.45), 7.565 (0.52), 7.568(0.53), 7.584 (0.45), 7.711 (0.18), 7.734 (1.41), 7.736 (1.18), 7.741 (0.85),7.759 (0.12), 7.764 (0.14), 8.786 (0.20), 8.801 (0.40), 8.815 (0.20)。

Example 101A

(+) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(diastereomer 4)

In the diastereoisomeric separation described in example 97A, 483 mg (100% purity, ee value 93%) of the title compound is obtained as the last eluted diastereoisomer (peak 4).

[α]_D ²⁰= 23.3 °, 589 nm, c = 0.39 g/100 ml, methanol

LC-MS (method 1) R_t= 3.02 min; MS (ESIpos): m/z = 642/644 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.931 (0.89), 0.950 (2.16), 0.968(1.10), 1.077 (0.07), 1.106 (0.18), 1.136 (0.19), 1.156 (0.08), 1.251 (0.08),1.282 (0.15), 1.299 (0.35), 1.317 (0.48), 1.334 (0.34), 1.356 (0.18), 1.374(0.13), 1.411 (16.00), 1.599 (0.20), 1.646 (0.19), 1.677 (0.19), 1.787(0.27), 1.819 (0.26), 1.858 (0.23), 1.886 (0.26), 1.919 (0.21), 2.089 (0.21),2.099 (0.21), 2.117 (1.38), 2.129 (0.83), 2.151 (0.35), 2.172 (2.06), 2.370(0.04), 2.445 (0.13), 2.472 (0.21), 2.746 (0.12), 2.775 (0.23), 2.804 (0.13),3.530 (0.42), 3.559 (0.40), 3.628 (0.24), 3.715 (0.46), 7.294 (0.20), 7.312(0.47), 7.330 (0.33), 7.395 (0.28), 7.414 (0.51), 7.432 (0.27), 7.478 (0.68),7.498 (0.58), 7.524 (0.68), 7.541 (0.54), 7.668 (0.17), 7.691 (1.78), 7.697(0.99), 7.719 (0.14), 8.743 (0.25), 8.758 (0.50), 8.772 (0.24)。

Example 102A

5- [ ({ 6-bromo-2- [ 3-hydroxy-3-methylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(mixture of diastereomers)

To a suspension of tert-butyl (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chlorophenyl) pentanoate (200 mg, 98% purity, 346 μmol, example 37A) in NMP (3.0 ml) was added (+/-) -3-methylpiperidine-3-ol hydrochloride (420 mg, 2.77 mmol) and DIPEA (482 μ l, 2.77 mmol), and the mixture was stirred at 120 ℃ for two days. After cooling to room temperature, the mixture was concentrated and the residue was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was dried in vacuo. 148 mg (98% purity, 65% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.52 min; MS (ESIpos): m/z = 644/646 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.024 (0.28), 1.190 (2.69), 1.333(0.13), 1.356 (0.61), 1.370 (16.00), 1.558 (0.67), 1.571 (0.73), 1.612(0.18), 1.819 (0.32), 2.047 (0.21), 2.075 (1.34), 2.087 (0.74), 2.103 (0.26),2.167 (1.65), 2.327 (0.05), 2.393 (0.05), 2.411 (0.05), 3.022 (1.29), 3.076(0.57), 3.587 (0.22), 3.672 (0.40), 4.100 (0.08), 4.603 (0.40), 4.617 (0.43),7.254 (0.20), 7.273 (0.46), 7.290 (0.32), 7.354 (0.28), 7.372 (0.50), 7.391(0.26), 7.439 (0.70), 7.459 (0.60), 7.483 (0.66), 7.500 (0.53), 7.616 (0.38),7.638 (1.32), 7.651 (0.85), 7.656 (0.75), 7.674 (0.23), 7.678 (0.23), 8.709(0.24), 8.723 (0.48), 8.737 (0.23)。

Example 103A

5- [ ({ 6-bromo-2- [3, 5-dimethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(mixture of diastereomers)

To (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]To a mixture of tert-butyl amino } -4- (2-chlorophenyl) valerate (200 mg, 353. mu. mol, example 37A) in NMP (2.5 ml) was added (+/-) -propionic acid(cis-form-trans form)-3, 5-dimethylpiperidine (80 mg, 706 μmol,mixtures of diastereomersCAS number 35794-11-7) and DIPEA (140 μ l, 780 μmol), and mixing the mixturesStirring was carried out at 100 ℃ for 18 h. Then, (+/-) -once again was added(cis-form-trans form)-3, 5-dimethylpiperidine (40 mg, 353 μmol,mixtures of diastereomersCAS number 35794-11-7) and DIPEA (76 μ l, 425 μmol), and the mixture was continued to be stirred at 100 ℃. After a total of 42 h, the mixture was cooled to room temperature and filtered. The filtrate was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was dried in vacuo. 91 mg (100% purity, 40% of theory) of the title compound are obtained.

LC-MS (method 2) R_t= 1.59 min; MS (ESIpos): m/z = 642/644 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (0.63), 0.719 (0.19), 0.749(0.22), 0.897 (2.28), 0.913 (2.32), 1.007 (0.49), 1.020 (0.49), 1.234 (0.32),1.369 (16.00), 1.438 (0.18), 1.807 (0.53), 1.988 (0.18), 2.074 (1.32), 2.085(0.78), 2.137 (1.33), 2.170 (0.39), 2.327 (0.25), 3.490 (0.35), 3.518 (0.33),3.583 (0.21), 3.669 (0.33), 5.754 (1.78), 7.255 (0.17), 7.272 (0.41), 7.290(0.29), 7.354 (0.24), 7.373 (0.45), 7.391 (0.25), 7.440 (0.61), 7.458 (0.53),7.481 (0.59), 7.498 (0.47), 7.649 (2.04), 8.708 (0.37)。

Example 104A

5- [ ({ 6-bromo-2- [3- (difluoromethyl) piperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(mixture of diastereomers)

To a mixture of tert-butyl (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chlorophenyl) pentanoate (200 mg, 353 μmol, example 37A) in NMP (2.5 ml) was added (+/-) -3- (difluoromethyl) piperidine hydrochloride (121 mg, 706 μmol) and DIPEA (140 μ l, 780 μmol), and the mixture was stirred at 100 ℃ for 18 h. Then (+/-) -3- (difluoromethyl) piperidine hydrochloride (60 mg, 353 μmol) and DIPEA (70 μ l, 390 μmol) were added again and the mixture was stirred at 100 ℃ for an additional 24 h. Thereafter, the mixture was stirred in a closed glass vessel in a microwave apparatus (Biotage) for 15min at 100 ℃. After cooling to room temperature, the mixture was mixed with saturated aqueous sodium bicarbonate and extracted repeatedly with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (100 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 95:5 → 20:80, Isolera One). The two combined target fractions were concentrated and the respective residue was dried in vacuo. 98 mg (41% purity, 17% of theory) of the first title compound and 18 g (54% purity, 4% of theory, see analysis) of the second title compound are obtained and subsequently combined.

LC-MS (method 1) R_t= 2.75 min; MS (ESIpos): m/z = 664/666 [M+H]⁺

Example 105A

5- [ ({ 6-bromo-2- [ ((6-bromo-2-) ]3S) -3-fluoropyrrolidin-1-yl]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(Epimer mixture)

To (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Tert-butyl amino } -4- (2-chlorophenyl) valerate (200 mg, 353 μmol, example 37A) was added to a mixture of NMP (2.5 ml) ((R))3S) -3-fluoropyrrolidine hydrochloride (89 mg, 706 μmol) and DIPEA (140 μ l, 780 μmol), and the mixture was stirred at 100 ℃ for 18 h. Then, adding (A) again3S) -3-fluoropyrrolidine hydrochloride (45 mg, 353 μmol) and DIPEA (76 μ l, 425 μmol), and the mixture was stirred at 100 ℃ for another 24 h. After cooling to room temperature, the mixture was filtered. The filtrate was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was dried in vacuo. 141 mg (89% purity, 57% of theory) of the title compound are obtained.

LC-MS (method 2) R_t= 1.26 min; MS (ESIpos): m/z = 618/620 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (0.32), -0.008 (3.09), 0.007(3.00), 0.146 (0.31), 1.156 (0.38), 1.175 (0.78), 1.192 (0.41), 1.366(15.46), 1.370 (16.00), 1.818 (0.30), 1.988 (1.44), 2.074 (1.85), 2.175(1.40), 2.327 (0.23), 2.366 (0.27), 2.523 (0.66), 2.669 (0.21), 2.709 (0.24),3.598 (0.58), 3.867 (0.24), 4.020 (0.45), 4.038 (0.40), 5.330 (0.35), 5.464(0.34), 7.260 (0.44), 7.277 (0.49), 7.362 (0.56), 7.380 (0.52), 7.435 (0.94),7.454 (0.79), 7.476 (0.57), 7.504 (0.83), 7.526 (1.00), 7.531 (1.04), 7.575(0.54), 7.581 (0.97), 7.587 (0.53), 7.603 (0.55), 7.895 (0.27), 8.688 (0.52)。

Example 106A

5- [ ({ 6-bromo-2- ](3R)-3-fluoropyrrolidin-1-yl]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(Epimer mixture)

To (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Tert-butyl amino } -4- (2-chlorophenyl) valerate (200 mg, 353 μmol, example 37A) was added to a mixture in NMP (2.6 ml) ((R))3R) -3-fluoropyrrolidine hydrochloride (89 mg, 706 μmol) and DIPEA (140 μ l, 780 μmol), and the mixture was stirred at 100 ℃ for 18 h. Then, adding (A) again3R) -3-fluoropyrrolidine hydrochloride (45 mg, 353 μmol) and DIPEA (76 μ l, 425 μmol), and the mixture was stirred at 100 ℃ for another 24 h. After cooling to room temperature, the mixture was mixed with saturated aqueous sodium bicarbonate and extracted repeatedly with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (100 g silica gel, Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3 → 4:6, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 98 mg (41% purity, 17% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.50 min; MS (ESIpos): m/z = 618/620 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.50), 0.008 (0.91), 1.157(0.46), 1.175 (0.91), 1.192 (0.46), 1.366 (16.00), 1.370 (14.31), 1.817(0.28), 1.988 (1.65), 2.074 (1.82), 2.085 (1.02), 2.174 (1.43), 2.327 (0.20),2.366 (0.24), 2.669 (0.21), 2.709 (0.24), 3.595 (0.63), 3.867 (0.27), 4.020(0.51), 4.038 (0.47), 5.330 (0.36), 5.465 (0.36), 7.261 (0.44), 7.278 (0.48),7.344 (0.31), 7.363 (0.56), 7.379 (0.49), 7.435 (0.95), 7.455 (0.80), 7.476(0.59), 7.504 (0.86), 7.508 (0.77), 7.526 (1.06), 7.530 (1.06), 7.575 (0.58),7.581 (1.00), 7.587 (0.55), 7.598 (0.33), 7.603 (0.57), 7.609 (0.32), 8.689(0.55)。

Example 107A

5- [ ({ 6-bromo-2- [ trans-3, 4-difluoropyrrolidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(mixture of diastereomers)

To (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Tert-butyl amino } -4- (2-chlorophenyl) valerate (200 mg, 353 μmol, example 37A) was added to a mixture of (+/-) -trans-3, 4-difluoropyrrolidine hydrochloride (101 mg, 706 μmol) and DIPEA (140 μ l, 780 μmol) in NMP (2.5 ml) and the mixture was stirred at 100 ℃ for 18 h. Then, the (+/-) -trans-alpha-ion was added again3,4-Difluoropyrrolidine hydrochloride (50 mg, 353 μmol) and DIPEA (70 μ l, 390 μmol), and the mixture was stirred at 100 ℃ for an additional 24 h. Thereafter, the mixture was stirred in a closed glass vessel in a microwave apparatus (Biotage) for 15min at 100 ℃. After cooling to room temperature, the mixture was filtered and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was dried in vacuo. 169 mg (77% purity, 58% of theory) of the title compound are obtained.

LC-MS (method 2) R_t= 1.33 min; MS (ESIpos): m/z = 636/638 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (0.49), 1.157 (2.03), 1.175(4.09), 1.193 (2.07), 1.333 (0.19), 1.367 (13.18), 1.371 (16.00), 1.820(0.30), 1.988 (7.63), 2.076 (1.81), 2.089 (1.06), 2.106 (0.39), 2.192 (1.13),2.327 (0.11), 2.366 (0.09), 3.596 (0.32), 3.714 (0.37), 4.003 (0.63), 4.021(1.85), 4.039 (1.84), 4.056 (0.69), 4.185 (0.19), 5.360 (0.41), 5.494 (0.41),7.261 (0.39), 7.280 (0.47), 7.345 (0.22), 7.364 (0.49), 7.382 (0.47), 7.437(0.79), 7.457 (0.66), 7.480 (0.48), 7.490 (0.55), 7.508 (0.39), 7.549 (0.48),7.568 (0.84), 7.571 (0.84), 7.617 (0.73), 7.639 (0.40), 7.895 (0.86), 8.696(0.43), 8.859 (0.16)。

Example 108A

(+/-) -5- [ ({ 6-bromo-2- ], a salt thereof, and a salt thereofCis-alpha-carboxylic acid derivatives3, 4-difluoropyrrolidin-1-yl]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(raceme)

To (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Tert-butyl amino } -4- (2-chlorophenyl) valerate (200 mg, 353. mu. mol, example 37A) in a mixture of NMP (2.5 ml) was added cis-3, 4-difluoropyrrolidine hydrochloride (101 mg, 706 μmol) and DIPEA (140 μ l, 780 μmol), and the mixture was stirred at 100 ℃ for 18 h. Then, cis-form is added again-3,4-Difluoropyrrolidine hydrochloride (50 mg, 353 μmol) and DIPEA (70 μ l, 390 μmol), and the mixture was stirred at 100 ℃ for an additional 24 h. After cooling to room temperature, the mixture was filtered and purified by preparative HPLC (method 6). The combined target fractions were each concentrated and the residue was dried in vacuo. 60 mg (97% pure, 26% of theory) of the first title compound and 100 mg (88% pure, 39% of theory) of the second title compound are obtained and combined for subsequent reactions.

The first batch was analyzed:

LC-MS (method 2) R_t= 1.31 min; MS (ESIpos): m/z = 636/638 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.157 (1.14), 1.175 (2.31), 1.192(1.17), 1.308 (0.09), 1.335 (0.15), 1.368 (16.00), 1.818 (0.20), 1.988(4.34), 2.074 (1.23), 2.086 (0.67), 2.103 (0.28), 2.159 (0.85), 3.581 (0.22),3.670 (0.24), 3.782 (0.23), 4.002 (0.52), 4.020 (1.17), 4.038 (1.12), 4.056(0.38), 5.298 (0.23), 5.426 (0.20), 5.435 (0.20), 5.461 (0.22), 7.251 (0.17),7.269 (0.39), 7.289 (0.28), 7.353 (0.25), 7.371 (0.44), 7.389 (0.25), 7.435(0.70), 7.455 (0.58), 7.481 (0.56), 7.498 (0.41), 7.542 (0.67), 7.564 (1.21),7.610 (0.68), 7.616 (0.62), 7.633 (0.36), 7.638 (0.35), 8.690 (0.40)。

The second batch was analyzed:

LC-MS (method 2) R_t= 1.31 min; MS (ESIpos): m/z = 636/638 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.009 (0.47), 0.007 (0.35), 1.156(1.58), 1.174 (3.21), 1.192 (1.61), 1.208 (0.07), 1.308 (0.10), 1.335 (0.15),1.368 (16.00), 1.524 (0.06), 1.817 (0.19), 1.988 (5.93), 2.046 (0.19), 2.074(1.20), 2.086 (0.64), 2.103 (0.26), 2.158 (0.75), 2.327 (0.06), 2.365 (0.06),3.582 (0.21), 3.670 (0.22), 3.779 (0.20), 4.002 (0.61), 4.020 (1.51), 4.038(1.48), 4.056 (0.49), 5.298 (0.20), 5.324 (0.16), 5.426 (0.17), 5.435 (0.18),5.460 (0.20), 7.251 (0.15), 7.269 (0.34), 7.288 (0.25), 7.353 (0.22), 7.371(0.40), 7.390 (0.23), 7.434 (0.64), 7.437 (0.62), 7.454 (0.55), 7.481 (0.51),7.497 (0.39), 7.542 (0.63), 7.564 (1.13), 7.610 (0.63), 7.616 (0.57), 7.632(0.34), 7.638 (0.33), 7.894 (0.26), 8.690 (0.36)。

Example 109A

5- [ ({ 6-bromo-2- [ 3-fluoro-3-methylpyrrolidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(mixture of diastereomers)

To a mixture of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chlorophenyl) pentanoic acid tert-butyl ester (200 mg, 353 μmol, example 37A) in NMP (2.5 ml) was added (+/-) -3-fluoro-3-methylpyrrolidine hydrochloride (99 mg, 706 μmol) and DIPEA (140 μ l, 780 μmol) and the mixture was stirred at 100 ℃ for 18 h. Then (+/-) -3-fluoro-3-methylpyrrolidine hydrochloride (50 mg, 353 μmol) and DIPEA (76 μ l, 425 μmol) were added again and the mixture was stirred at 100 ℃ for a further 24 h. After cooling to room temperature, the mixture was mixed with saturated aqueous sodium bicarbonate and extracted repeatedly with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (100 g silica gel, Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3 → 4:6, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 98 mg (41% purity, 17% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.58 min; MS (ESIpos): m/z = 632/634 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.009 (0.89), 0.007 (0.80), 1.366(11.66), 1.370 (10.65), 1.398 (16.00), 1.539 (2.15), 1.591 (2.13), 1.815(0.21), 2.073 (1.38), 2.084 (0.84), 2.100 (0.38), 2.169 (1.12), 2.327 (0.17),2.365 (0.21), 2.669 (0.18), 2.709 (0.21), 3.608 (0.44), 3.798 (0.16), 3.920(0.28), 7.259 (0.33), 7.278 (0.37), 7.343 (0.23), 7.362 (0.42), 7.378 (0.36),7.434 (0.71), 7.454 (0.59), 7.473 (0.40), 7.494 (0.66), 7.499 (0.63), 7.517(0.80), 7.521 (0.79), 7.567 (0.41), 7.573 (0.72), 7.579 (0.39), 7.595 (0.43),8.688 (0.37)。

Example 110A

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (3,3,4, 4-tetrafluoropyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester(raceme)

To a mixture of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chlorophenyl) pentanoic acid tert-butyl ester (200 mg, 353. mu. mol, example 37A) in NMP (2.5 ml) was added (+/-) -3,3,4, 4-tetrafluoropyrrolidine hydrochloride (127 mg, 706. mu. mol) and DIPEA (140. mu.l, 780. mu. mol), and the mixture was stirred at 100 ℃ for 18 h. Then (+/-) -3,3,4, 4-tetrafluoropyrrolidine hydrochloride (64 mg, 353 μmol) and DIPEA (76 μ l, 425 μmol) were added again and the mixture was stirred at 100 ℃ for an additional 24 h. Thereafter, the mixture was stirred in a closed glass vessel in a microwave apparatus (Biotage) for 15min at 100 ℃. The mixture was then stirred in a closed glass vessel in a microwave apparatus (Biotage) at 120 ℃ for 1 h. After cooling to room temperature, the mixture was mixed with saturated aqueous sodium bicarbonate and extracted repeatedly with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (100 g silica gel, Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3 → 7:3, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 71 mg (9% purity, 3% of theory) of the title compound are obtained.

LC-MS (method 2) R_t= 1.43 min; MS (ESIpos): m/z = 672/674 [M+H]⁺

Example 111A

(+/-) -5- [ ({2- [ 3-azabicyclo [3.1.1] 1)]Hept-3-yl]-6-bromo-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(raceme)

To a mixture of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chlorophenyl) pentanoic acid tert-butyl ester (200 mg, 353 μmol, example 37A) in NMP (1.9 ml) was added 3-azabicyclo [3.1.1] heptane hydrochloride (92 mg, 689 μmol) and DIPEA (150 μ l, 860 μmol), and the mixture was stirred at 100 ℃ for four days. After cooling to room temperature, the mixture was filtered and purified by preparative HPLC (method 8). The combined target fractions were concentrated and the residue was dried in vacuo. 66 mg (100% purity, 31% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.81 min; MS (ESIpos): m/z = 626/628 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.234 (0.16), 1.330 (0.12), 1.367(16.00), 1.438 (0.73), 1.444 (0.67), 1.454 (0.69), 1.460 (0.77), 1.816(0.21), 2.045 (0.25), 2.074 (1.55), 2.086 (1.09), 2.102 (0.76), 2.192 (1.21),3.584 (0.24), 3.663 (0.33), 3.868 (0.34), 7.249 (0.19), 7.269 (0.44), 7.287(0.32), 7.351 (0.28), 7.370 (0.51), 7.388 (0.29), 7.436 (0.77), 7.456 (0.61),7.480 (0.59), 7.497 (0.43), 7.524 (0.63), 7.546 (1.26), 7.583 (0.68), 7.588(0.63), 7.605 (0.33), 7.610 (0.32), 8.713 (0.45)。

Example 112A

(+/-) -5- [ ({2- [ 3-azabicyclo [3.2.1] C]Oct-3-yl]-6-bromo-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(raceme)

To a mixture of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chlorophenyl) pentanoic acid tert-butyl ester (108 mg, 98% purity, 185 μmol, example 37A) in NMP (1.0ml) was added 3-azabicyclo [3.2.1] octane hydrochloride (219 mg, 1.48 mmol) and DIPEA (390 μ l, 2.2 mmol) and the mixture was stirred at 100 ℃ for 48 h. After cooling to room temperature, water and ethyl acetate (50 ml each) were added to the mixture, which was shaken. After phase separation, the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was purified by preparative HPLC (method 8). The combined target fractions were concentrated and the residue was lyophilized. 80 mg (100% purity, 67% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 3.01 min; MS (ESIpos): m/z = 640/642 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.028 (0.90), -0.013 (0.70), 0.848(0.17), 1.229 (2.08), 1.254 (0.24), 1.364 (16.00), 1.547 (0.92), 1.659(0.41), 1.742 (0.48), 1.761 (0.50), 1.810 (0.21), 2.040 (0.21), 2.068 (1.18),2.079 (0.59), 2.095 (0.22), 2.178 (1.29), 2.292 (0.63), 2.361 (0.15), 2.664(0.12), 2.705 (0.16), 2.906 (0.35), 2.932 (0.29), 3.577 (0.20), 3.662 (0.35),7.251 (0.17), 7.270 (0.38), 7.286 (0.28), 7.349 (0.24), 7.368 (0.43), 7.386(0.22), 7.440 (0.60), 7.460 (0.54), 7.475 (0.59), 7.491 (0.44), 7.602 (0.41),7.624 (1.25), 7.642 (0.77), 7.647 (0.69), 7.664 (0.25), 7.669 (0.25), 8.728(0.42)。

Example 113A

(+/-) -5- ({ [ 6-bromo-2- (3, 3-difluoroazetidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester(raceme)

To a mixture of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chlorophenyl) pentanoic acid tert-butyl ester (200 mg, 353 μmol, example 37A) in NMP (2.5 ml) was added 3, 3-difluoroazetidine hydrochloride (92 mg, 706 μmol) and DIPEA (140 μ l, 780 μmol), and the mixture was stirred at 100 ℃ for 18 h. Then, 3-difluoroazetidine hydrochloride (46 mg, 353 μmol) and DIPEA (76 μ l, 425 μmol) were added again and the mixture was stirred at 100 ℃ for an additional 24 h. Thereafter, the mixture was stirred in a closed glass vessel in a microwave apparatus (Biotage) for 15min at 100 ℃. After cooling to room temperature, the mixture was mixed with saturated aqueous sodium bicarbonate and extracted repeatedly with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (100 g silica gel, Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 95:5 → 5:5, Isolera One). The combined target fractions were concentrated and the residue was lyophilized. 32 mg (96% purity, 14% of theory) of the title compound are obtained.

LC-MS (method 2) R_t= 1.35 min; MS (ESIpos): m/z = 622/624 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.48), -0.008 (4.16), 0.008(4.20), 0.146 (0.48), 1.367 (16.00), 1.398 (1.97), 2.070 (1.48), 2.084(0.81), 2.327 (0.52), 2.366 (0.69), 2.523 (1.89), 2.670 (0.58), 2.710 (0.67),4.581 (0.48), 4.613 (0.89), 4.645 (0.44), 7.435 (0.60), 7.455 (0.50), 7.475(0.50), 7.492 (0.40), 7.589 (0.60), 7.611 (1.20), 7.648 (0.64), 7.654 (0.60)。

Example 114A

5- [ ({ 6-bromo-2- [ 3-cyanopiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(mixture of diastereomers)

To a mixture of tert-butyl (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chlorophenyl) pentanoate (250 mg, 441 μmol, example 37A) in NMP (2.0 ml) was added (+/-) -piperidine-3-carbonitrile (389 mg, 3.53 mmol) and DIPEA (620 μ l, 3.5mmol), and the mixture was stirred at 110 ℃ for 42 h. After cooling to room temperature, the mixture was filtered and purified by preparative HPLC (method 8). The combined target fractions were concentrated and the residue was lyophilized. 197 mg (91% purity, 63% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.58 min; MS (ESIpos): m/z = 639/641 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.209 (0.07),1.309 (0.05), 1.333(0.10), 1.369 (16.00), 1.526 (0.08), 1.714 (0.17), 1.819 (0.35), 1.876(0.37), 1.889 (0.55), 1.902 (0.46), 2.046 (0.19), 2.075 (1.26), 2.088 (0.72),2.104 (0.25), 2.183 (1.43), 2.327 (0.05), 2.365 (0.05), 2.669 (0.05), 2.709(0.05), 3.020 (0.16), 3.268 (0.30), 3.293 (0.34), 3.444 (0.22), 3.458 (0.22),3.475 (0.18), 3.490 (0.14), 3.588 (0.21), 3.683 (0.36), 7.254 (0.18), 7.272(0.41), 7.292 (0.29), 7.354 (0.25), 7.373 (0.45), 7.391 (0.23), 7.441 (0.59),7.461 (0.49), 7.486 (0.54), 7.505 (0.42), 7.671 (0.21), 7.693 (1.42), 7.697(1.08), 7.702 (0.83), 7.724 (0.14), 7.894 (0.21), 8.723 (0.21), 8.737 (0.42),8.751 (0.20)。

Example 115A

(+/-) -5- ({ [ 6-bromo-2- (3, 6-dihydro-2H-1, 2-oxazin-2-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester(raceme)

To (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]To a mixture of tert-butyl amino } -4- (2-chlorophenyl) valerate (300 mg, 530 μmol, example 37A) in NMP (3.0 ml) was added 3, 6-dihydro-2H-1, 2-oxazine hydrochloride (515 mg, 4.24 mmol) and DIPEA (920 μ l, 5.3 mmol) and the mixture was stirred at 120 ℃ for 44 h. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated. The residue was dissolved in DMSO and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was dried in vacuo. 70 mg (100% purity, 21% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.70 min; MS (ESIpos): m/z = 614/616 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (0.08), -0.023 (0.15), 0.007(0.69), 0.146 (0.08), 1.233 (0.28), 1.312 (0.08), 1.330 (0.11), 1.370(16.00), 1.826 (0.20), 2.051 (0.24), 2.079 (1.25), 2.090 (0.67), 2.106(0.25), 2.188 (0.96), 2.327 (0.08), 2.669 (0.08), 3.596 (0.21), 3.691 (0.36),4.069 (0.88), 4.503 (0.49), 5.991 (0.19), 6.017 (0.46), 6.050 (0.40), 6.075(0.17), 7.259 (0.21), 7.275 (0.39), 7.294 (0.27), 7.356 (0.23), 7.375 (0.42),7.393 (0.22), 7.445 (0.61), 7.465 (0.51), 7.486 (0.48), 7.502 (0.37), 7.749(2.16), 7.752 (2.17), 8.830 (0.21), 8.844 (0.42)。

Example 116A

5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(mixture of diastereomers)

To a mixture of tert-butyl (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chlorophenyl) pentanoate (3.00 g, 98% purity, 5.19 mmol, example 37A) in NMP (48 ml) were added (+/-) -3-fluoropiperidine hydrochloride (3.99 g, 28.6 mmol) and DIPEA (5.0 ml, 29 mmol) and the mixture was stirred at 120 ℃ for two days. After cooling to room temperature, water (200ml) and ethyl acetate (100 ml) were added to the mixture, which was shaken. After phase separation, the aqueous phase was extracted repeatedly with ethyl acetate (100 ml each). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was purified by flash column chromatography (100 g silica gel, Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 95:5 → 7:3, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 2.61 g (98% purity, 78% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.69 min; MS (ESIpos): m/z = 632/634 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.209 (0.07), 1.333 (0.09), 1.369(16.00), 1.398 (5.31), 1.526 (0.07), 1.644 (0.17), 1.813 (0.31), 1.898(0.28), 2.054 (0.19), 2.074 (1.20), 2.087 (0.67), 2.103 (0.27), 2.144 (1.42),2.327 (0.06), 2.670 (0.06), 3.093 (0.19), 3.160 (0.20), 3.376 (0.18), 3.406(0.10), 3.433 (0.17), 3.466 (0.11), 3.586 (0.20), 3.677 (0.36), 4.815 (0.13),4.938 (0.13), 7.254 (0.17), 7.272 (0.41), 7.290 (0.30), 7.354 (0.24), 7.373(0.45), 7.391 (0.23), 7.439 (0.61), 7.458 (0.52), 7.484 (0.54), 7.500 (0.45),7.647 (0.26), 7.669 (1.41), 7.676 (0.96), 7.681 (0.83), 7.699 (0.17), 7.704(0.18), 8.712 (0.21), 8.726 (0.43), 8.740 (0.20)。

Example 117A

5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]2S) -2-methylpyrrolidin-1-yl]Quinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(Epimer mixture)

To (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Tert-butyl amino } -4- (2-chlorophenyl) valerate (450 mg, 795. mu. mol, example 37A) was added to a mixture in NMP (4.0 ml) (2S) -2-methylpyrrolidine (650 μ l, 6.4 mmol) and DIPEA (1.4 ml, 7.9 mmol) and the mixture was stirred at 100 ℃ for 3 h. After cooling to room temperature, the mixture was filtered and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was dried in vacuo. 391 mg (100% purity, 80% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.70 min; MS (ESIpos): m/z = 614/616 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.42), 0.008 (0.37), 1.142(2.75), 1.157 (2.75), 1.208 (0.09), 1.234 (0.15), 1.301 (0.11), 1.330 (0.16),1.366 (16.00), 1.369 (14.87), 1.541 (0.23), 1.557 (0.27), 1.579 (0.27), 1.607(0.18), 1.687 (0.22), 1.812 (0.28), 1.897 (0.31), 2.045 (0.38), 2.072 (1.98),2.084 (1.41), 2.103 (1.71), 2.327 (0.10), 2.366 (0.10), 2.669 (0.09), 2.710(0.09), 3.610 (0.34), 3.694 (0.29), 3.716 (0.45), 3.736 (0.45), 4.361 (0.23),4.376 (0.38), 4.398 (0.35), 4.414 (0.21), 7.241 (0.17), 7.259 (0.47), 7.278(0.52), 7.296 (0.22), 7.341 (0.28), 7.360 (0.62), 7.379 (0.55), 7.398 (0.22),7.434 (0.98), 7.454 (0.83), 7.474 (0.62), 7.499 (0.87), 7.503 (0.82), 7.521(1.03), 7.526 (1.04), 7.569 (0.53), 7.575 (0.94), 7.580 (0.52), 7.591 (0.30),7.597 (0.51), 7.603 (0.30), 8.698 (0.57)。

Separation of the epimer mixture:

the title compound (376 mg) was dissolved in methanol (30 ml) and separated by preparative SFC on the chiral phase into enantiomers/epimers (see examples 118A and 119A) [ column: daicel Chiralcel OX-H, 5 μm,250 mm x20 mm, flow rate: 80 ml/min, injection: 1.0ml, eluent 17% ethanol/83% carbon dioxide, running time 11 min, isocratic, UV detection 210 nm, temperature 40 deg.C ]. The combined target fractions were concentrated and the respective residue was lyophilized.

Example 118A

5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]2S) -2-methylpyrrolidin-1-yl]Quinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(Epimers1)

In the epimer separation described in example 117A, 150 mg (100% purity, ee >99%) of the title compound were obtained as the epimer/enantiomer eluting earlier.

[α]_D ²⁰= 29.3 °, 589 nm, c = 0.37 g/100 ml, methanol

LC-MS (method 1) R_t= 2.67 min; MS (ESIpos): m/z = 614/616 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.140 (1.67), 1.155 (1.68), 1.205(0.07), 1.300 (0.10), 1.333 (0.09), 1.365 (16.00), 1.540 (0.14), 1.556(0.16), 1.562 (0.16), 1.578 (0.16), 1.606 (0.10), 1.662 (0.14), 1.688 (0.14),1.708 (0.09), 1.794 (0.13), 1.812 (0.18), 1.895 (0.18), 2.050 (0.22), 2.072(1.24), 2.085 (1.14), 2.124 (0.28), 2.327 (0.03), 2.669 (0.03), 3.285 (0.15),3.580 (0.24), 3.625 (0.16), 3.691 (0.14), 3.715 (0.33), 3.732 (0.36), 3.755(0.21), 4.360 (0.14), 4.375 (0.23), 4.390 (0.19), 4.397 (0.22), 4.413 (0.14),7.259 (0.15), 7.277 (0.35), 7.295 (0.25), 7.360 (0.26), 7.379 (0.43), 7.397(0.25), 7.434 (0.62), 7.436 (0.60), 7.454 (0.50), 7.456 (0.48), 7.481 (0.42),7.499 (0.90), 7.521 (1.12), 7.568 (0.59), 7.573 (0.55), 7.590 (0.32), 7.596(0.32), 8.683 (0.19), 8.697 (0.32)。

Example 119A

5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]2S) -2-methylpyrrolidin-1-yl]Quinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(Epimers2)

In the epimer separation described in example 117A 147 mg (100% purity, ee value 97%) of the title compound were obtained as epimer/enantiomer which eluted later.

[α]_D ²⁰= -10.3 °, 589 nm, c = 0.46 g/100 ml, methanol

LC-MS (method 1) R_t= 2.64 min; MS (ESIpos): m/z = 614/616 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.142 (2.01), 1.157 (2.03), 1.209(0.07), 1.318 (0.08), 1.329 (0.15), 1.369 (16.00), 1.512 (0.06), 1.527(0.12), 1.540 (0.15), 1.556 (0.18), 1.563 (0.17), 1.579 (0.17), 1.591 (0.13),1.607 (0.12), 1.659 (0.14), 1.684 (0.14), 1.793 (0.15), 1.813 (0.19), 1.896(0.20), 1.910 (0.19), 2.045 (0.28), 2.073 (1.27), 2.105 (1.49), 2.156 (0.20),2.202 (0.04), 2.327 (0.03), 2.669 (0.03), 3.605 (0.29), 3.695 (0.27), 3.712(0.27), 3.720 (0.35), 3.736 (0.31), 3.744 (0.19), 3.760 (0.13), 4.362 (0.15),4.377 (0.24), 4.392 (0.20), 4.399 (0.23), 4.414 (0.14), 7.240 (0.20), 7.259(0.44), 7.275 (0.32), 7.278 (0.32), 7.340 (0.29), 7.359 (0.53), 7.376 (0.28),7.432 (0.65), 7.435 (0.65), 7.452 (0.59), 7.470 (0.64), 7.474 (0.65), 7.490(0.49), 7.504 (0.76), 7.526 (1.26), 7.575 (0.72), 7.580 (0.63), 7.597 (0.39),7.602 (0.36), 8.685 (0.22), 8.699 (0.41)。

Example 120A

5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]2R) -2-methylpyrrolidin-1-yl]Quinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(Epimer mixture)

To (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Tert-butyl amino } -4- (2-chlorophenyl) valerate (450 mg, 795. mu. mol, example 37A) was added to a mixture in NMP (4.0 ml) (2R) -2-methylpyrrolidine (650 μ l, 6.4 mmol) and DIPEA (1.4 ml, 7.9 mmol) and the mixture was stirred at 100 ℃ for 3 h. After cooling to room temperature, the mixture was filtered and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was dried in vacuo. 391 mg (100% purity, 80% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.69 min; MS (ESIpos): m/z = 614/616 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.141 (2.84), 1.156 (2.86), 1.207(0.09), 1.234 (0.15), 1.300 (0.09), 1.329 (0.14), 1.365 (16.00), 1.369(15.64), 1.540 (0.25), 1.557 (0.29), 1.579 (0.29), 1.607 (0.20), 1.662(0.25), 1.812 (0.31), 1.896 (0.33), 2.044 (0.39), 2.072 (2.12), 2.084 (1.52),2.103 (1.85), 2.327 (0.07), 2.365 (0.06), 2.669 (0.08), 2.709 (0.06), 3.610(0.37), 3.694 (0.31), 3.718 (0.49), 3.735 (0.50), 4.361 (0.23), 4.376 (0.39),4.398 (0.37), 4.413 (0.23), 7.240 (0.18), 7.259 (0.50), 7.278 (0.56), 7.295(0.24), 7.340 (0.30), 7.359 (0.66), 7.378 (0.59), 7.397 (0.23), 7.434 (1.03),7.454 (0.88), 7.474 (0.66), 7.499 (0.93), 7.503 (0.87), 7.521 (1.07), 7.525(1.10), 7.568 (0.54), 7.574 (0.96), 7.580 (0.54), 7.591 (0.31), 7.596 (0.54),7.602 (0.31), 8.698 (0.61)。

Separation of the epimer mixture:

the title compound (376 mg) was dissolved in a mixture of methanol and acetonitrile (5 ml) and separated by preparative SFC on the chiral phase into enantiomers/epimers (see examples 121A and 122A) [ column: daicel Chiralcel OX-H, 5 μm,250 mm x20 mm, flow rate: 80 ml/min, injection: 0.3 ml, eluent 17% isopropyl alcohol/83% carbon dioxide, running time 15min, isocratic, UV detection 210 nm, temperature 40 deg.C ]. The combined target fractions were concentrated and the respective residue was lyophilized.

Example 121A

(+) -5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]2R) -2-methylpyrrolidin-1-yl]Quinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(Epimers1)

In the epimer separation described in example 120A, 144 mg (95% purity, ee >99%) of the title compound were obtained as the epimer/enantiomer eluting earlier.

[α]_D ²⁰= 7.9 °, 589 nm, c = 0.49 g/100 ml, methanol

LC-MS (method 2): R_t= 1.37 min; MS (ESIpos): m/z = 614/616 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.142 (2.00), 1.157 (2.00), 1.209(0.08), 1.231 (0.05), 1.317 (0.09), 1.329 (0.16), 1.369 (16.00), 1.511(0.06), 1.526 (0.13), 1.540 (0.16), 1.556 (0.19), 1.562 (0.19), 1.578 (0.18),1.606 (0.12), 1.658 (0.15), 1.684 (0.16), 1.702 (0.10), 1.794 (0.17), 1.812(0.21), 1.895 (0.22), 1.909 (0.21), 2.033 (0.19), 2.045 (0.32), 2.073 (1.39),2.105 (1.59), 2.156 (0.22), 2.202 (0.04), 2.327 (0.03), 2.365 (0.03), 2.669(0.02), 2.709 (0.02), 3.605 (0.32), 3.694 (0.29), 3.711 (0.29), 3.719 (0.36),3.735 (0.32), 3.760 (0.13), 4.361 (0.15), 4.377 (0.25), 4.392 (0.21), 4.399(0.24), 4.414 (0.14), 7.240 (0.21), 7.258 (0.47), 7.275 (0.35), 7.340 (0.31),7.357 (0.55), 7.376 (0.30), 7.432 (0.68), 7.452 (0.62), 7.470 (0.69), 7.490(0.53), 7.504 (0.73), 7.526 (1.19), 7.575 (0.69), 7.580 (0.61), 7.597 (0.38),7.602 (0.35), 7.845 (0.02), 8.685 (0.23), 8.699 (0.42)。

example 122A

(+) -5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]2R) -2-methylpyrrolidin-1-yl]Quinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(Epimers2)

In the epimer separation described in example 120A, 142 mg (100% purity, ee value 96%) of the title compound were obtained as epimer/enantiomer which eluted later.

[α]_D ²⁰= 25.9 °, 589 nm, c = 0.36 g/100 ml, methanol

LC-MS (method 2) R_t= 1.36 min; MS (ESIpos): m/z = 614/616 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.141 (1.99), 1.155 (1.99), 1.205(0.10), 1.232 (0.06), 1.301 (0.11), 1.334 (0.13), 1.365 (16.00), 1.540(0.17), 1.556 (0.22), 1.579 (0.21), 1.606 (0.13), 1.663 (0.20), 1.687 (0.20),1.794 (0.20), 1.812 (0.27), 1.896 (0.26), 2.072 (1.75), 2.085 (1.56), 2.327(0.04), 3.285 (0.22), 3.581 (0.34), 3.625 (0.25), 3.690 (0.20), 3.715 (0.43),3.732 (0.47), 3.755 (0.28), 4.360 (0.18), 4.376 (0.31), 4.397 (0.29), 4.413(0.17), 7.258 (0.24), 7.277 (0.49), 7.295 (0.35), 7.360 (0.39), 7.378 (0.60),7.397 (0.35), 7.435 (0.82), 7.454 (0.66), 7.481 (0.59), 7.499 (1.04), 7.521(1.19), 7.569 (0.66), 7.591 (0.36), 8.697 (0.45)。

Example 123A

(+/-) -5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester(raceme)

To a mixture of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chlorophenyl) pentanoic acid tert-butyl ester (1.50 g, 2.65 mmol, example 37A) in NMP (15 ml) were added azepane (2.4ml, 21 mmol) and DIPEA (4.6 ml, 26mmol) and the mixture was stirred at 100 ℃ for 3 h. After cooling to room temperature, the mixture was concentrated, the residue was dissolved in DMSO and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was dried in vacuo. 1.40 g (97% purity, 84% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.89 min; MS (ESIpos): m/z = 628/630 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.234 (0.16), 1.368 (16.00), 1.602(1.61), 1.779 (1.14), 2.046 (0.30), 2.073 (1.46), 2.085 (0.83), 2.126 (1.55),2.731 (2.95), 2.890 (3.44), 3.489 (1.34), 3.503 (1.82), 3.518 (1.20), 3.582(0.26), 3.662 (0.35), 7.251 (0.21), 7.270 (0.46), 7.289 (0.33), 7.352 (0.30),7.371 (0.51), 7.389 (0.29), 7.436 (0.80), 7.456 (0.65), 7.479 (0.61), 7.498(0.44), 7.526 (0.69), 7.548 (1.23), 7.593 (0.70), 7.598 (0.62), 7.615 (0.37),7.621 (0.34), 7.952 (0.45), 8.696 (0.47)。

Separation of enantiomers:

the title compound (1.4 g) was dissolved in a methanol/acetonitrile mixture (70 ml) and separated into enantiomers by preparative SFC on the chiral phase (see examples 124A and 125A) [ column: daicel Chiralcel OX-H, 5 μm,250 mm x20 mm, flow rate: 80 ml/min, injection: 1.50 ml, UV detection: 210 nm, temperature: 40 deg.C, eluent 17% ethanol/83% carbon dioxide, running time 14 min, isocratic. The combined target fractions were concentrated and the residue was lyophilized.

Example 124A

(-) -5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester(enantiomer 1)

In the enantiomeric separation described in example 123A, 496 mg (100% purity, ee >99%) of the title compound were obtained as the earlier eluting enantiomer.

[α]_D ²⁰= 7.2 °, 589 nm, c = 0.36 g/100 ml, methanol

LC-MS (method 1) R_t= 2.90 min; MS (ESIpos): m/z = 628/630 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.208 (0.07), 1.309 (0.09), 1.330(0.12), 1.368 (16.00), 1.524 (0.07), 1.602(1.44), 1.779 (0.99), 1.838(0.14), 2.046 (0.23), 2.055 (0.20), 2.074 (1.33), 2.085 (0.74), 2.107 (0.35),2.127 (1.42), 3.489 (1.18), 3.503 (1.67), 3.517 (1.15), 3.583 (0.22), 3.661(0.30), 7.252 (0.18), 7.270 (0.42), 7.288 (0.31), 7.352 (0.26), 7.371 (0.47),7.389 (0.26), 7.437 (0.73), 7.455 (0.58), 7.480 (0.56), 7.497 (0.40), 7.526(0.66), 7.548 (1.22), 7.592 (0.66), 7.598 (0.62), 7.615 (0.35), 7.620 (0.34),8.682 (0.22), 8.696 (0.43), 8.710 (0.21)。

Example 125A

(+) -5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester(enantiomer 2)

In the enantiomeric separation described in example 123A, 490 mg (100% purity, ee value 97%) of the title compound were obtained as the later eluting enantiomer.

[α]_D ²⁰= 8.6 °, 589 nm, c = 0.35 g/100 ml, methanol

LC-MS (method 1) R_t= 2.90 min; MS (ESIpos): m/z = 628/630 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.208 (0.07), 1.309 (0.09), 1.331(0.14), 1.368 (16.00), 1.524 (0.08), 1.601 (1.71), 1.779 (1.22), 1.838(0.16), 2.046 (0.29), 2.074 (1.56), 2.085 (0.86), 2.108 (0.48), 2.127 (1.68),2.327 (0.03), 2.669 (0.03), 3.488 (1.38), 3.503 (1.93), 3.517 (1.26), 3.584(0.28), 3.661 (0.37), 7.251 (0.22), 7.270 (0.48), 7.288 (0.33), 7.351 (0.31),7.370 (0.54), 7.388 (0.30), 7.436 (0.82), 7.456 (0.67), 7.479 (0.65), 7.498(0.47), 7.526 (0.69), 7.548 (1.24), 7.593 (0.69), 7.597 (0.62), 7.615 (0.36),7.620 (0.34), 8.682 (0.28), 8.696 (0.50), 8.710 (0.25)。

Example 126A

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(raceme)

To a mixture of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- [2- (trifluoromethyl) phenyl ] pentanoic acid tert-butyl ester (1.00 g, 1.67 mmol, example 38A) in NMP (6 ml) was added piperidine (1.3ml, 13 mmol) and DIPEA (2.3 ml, 13 mmol), and the mixture was stirred at 110 ℃ for two days. After cooling to room temperature, the mixture was purified by flash column chromatography (100 g silica gel, Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3 → 8:2, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 648mg (100% purity, 60% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.84 min; MS (ESIpos): m/z = 648/650 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.31), 0.008 (0.32), 0.924(0.26), 0.939 (1.95), 0.955 (1.87), 1.186 (0.07), 1.346 (16.00), 1.398(0.63), 1.503 (0.09), 1.613 (0.43), 1.679 (0.81), 1.919 (0.14), 1.949 (0.10),1.971 (0.09), 1.989 (0.24), 2.012 (0.34), 2.024 (0.27), 2.033 (0.32), 2.054(0.25), 2.074 (0.09), 2.094 (0.21), 2.166 (1.19), 2.328 (0.07), 2.366 (0.07),2.417 (0.11), 2.435 (0.11), 2.670 (0.07), 2.968 (0.10), 3.151 (1.04), 3.225(0.08), 3.680 (0.18), 7.462 (0.25), 7.481 (0.41), 7.500 (0.24), 7.636 (0.22),7.658 (1.37), 7.663 (1.06), 7.668 (0.86), 7.685 (0.27), 7.706 (0.42), 7.722(0.85), 7.733 (0.64), 8.761 (0.20), 8.776 (0.41), 8.791 (0.19)。

Separation of enantiomers:

the title compound (560 mg) was dissolved in a mixture of isopropanol and heptane (4 ml each) and separated by preparative HPLC on the chiral phase into the enantiomers (see examples 127A and 128A) [ column: daicel Chiralpak IA, 5 μm,250 mm x20 mm, flow rate: 15 ml/min, injection: 0.14 ml, UV detection: 220 nm, temperature: at 40 deg.C, eluent 15% isopropanol/85% heptane, running time 11 min, isocratic. The combined target fractions were each concentrated and the respective residue was lyophilized from acetonitrile/water.

Example 127A

(-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(enantiomer 1)

In the enantiomeric separation described in example 126A, 241 mg (100% purity, ee value 99%) of the title compound were obtained as the earlier eluting enantiomer.

[α]_D ²⁰= 14.5 °, 589 nm, c = 0.38 g/100 ml, methanol

LC-MS (method 2) R_t= 1.50 min; MS (ESIpos): m/z = 648/650 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.187 (0.07), 1.243 (0.06), 1.258(0.07), 1.273 (0.05), 1.312 (0.11), 1.324 (0.17), 1.347 (16.00), 1.503(0.08), 1.613 (0.49), 1.679 (0.96), 1.888 (0.16), 1.897 (0.16), 1.909 (0.16),1.920 (0.16), 1.949 (0.12), 1.972 (0.10), 1.990 (0.27), 2.003 (0.20), 2.013(0.39), 2.025 (0.32), 2.034 (0.36), 2.056 (0.28), 2.075 (0.11), 2.096 (0.24),2.110 (0.18), 2.128 (0.24), 2.167 (1.40), 2.328 (0.03), 2.671 (0.02), 3.151(1.24), 3.640 (0.20), 3.662 (0.18), 3.680 (0.22), 3.696 (0.17), 7.462 (0.30),7.481 (0.47), 7.499 (0.29), 7.636 (0.21), 7.658 (1.49), 7.663 (1.15), 7.668(0.90), 7.686 (0.29), 7.706 (0.48), 7.721 (0.97), 7.734 (0.78), 7.751 (0.24),8.763 (0.23),8.778 (0.46), 8.792 (0.22)。

Example 128A

(+) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(enantiomer 2)

In the enantiomeric separation described in example 126A, 249 mg (100% purity, ee value 99%) of the title compound are obtained as the enantiomer which elutes later.

[α]_D ²⁰= 14.3 °, 589 nm, c = 0.38 g/100 ml, methanol

LC-MS (method 2) R_t= 1.50 min; MS (ESIpos): m/z = 648/650 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.187 (0.07), 1.243 (0.08), 1.258(0.09), 1.273 (0.06), 1.312 (0.09), 1.324 (0.16), 1.347 (16.00), 1.503(0.08), 1.612 (0.48), 1.679 (0.94), 1.897 (0.15), 1.908 (0.16), 1.920 (0.16),1.949 (0.12), 1.971 (0.09), 1.990 (0.26), 2.012 (0.38), 2.025 (0.31), 2.034(0.36), 2.055 (0.28), 2.074 (0.10), 2.095 (0.24), 2.109 (0.17), 2.128 (0.23),2.167 (1.39), 2.328 (0.04), 2.670 (0.03), 3.151 (1.22), 3.639 (0.20), 3.662(0.18), 3.680 (0.21), 3.696 (0.17), 7.462 (0.30), 7.481 (0.47), 7.499 (0.29),7.636 (0.21), 7.658 (1.47), 7.663 (1.14), 7.667 (0.91), 7.685 (0.29), 7.706(0.48), 7.721 (0.97), 7.734 (0.76), 7.750 (0.24), 8.762 (0.23), 8.777 (0.46),8.792 (0.22)。

Example 129A

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethyl) phenyl]Glutaric acid tert-butylEsters(raceme)

To a mixture of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- [2- (trifluoromethyl) phenyl ] pentanoic acid tert-butyl ester (600 mg, 1.00 mmol, example 38A) in NMP (4 ml) was added pyrrolidine (670. mu.l, 8.0 mmol) and DIPEA (1.4 ml, 8.0 mmol) and the mixture was stirred at 110 ℃ for two days. After cooling to room temperature, the mixture was purified by flash column chromatography (100 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3 → 8:2, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 551 mg (100% purity, 87% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.27 min; MS (ESIpos): m/z = 634/636 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.58), 0.008 (0.56), 0.923(0.30), 0.938 (2.40), 0.955 (2.28), 1.344 (16.00), 1.398 (1.68), 1.879(1.44), 1.942 (0.15), 1.965 (0.11), 1.983 (0.24), 2.006 (0.30), 2.018 (0.37),2.034 (0.32), 2.056 (0.27), 2.074 (0.12), 2.093 (0.27), 2.182 (0.53), 2.327(0.08), 2.416 (0.14), 2.434 (0.14), 2.967 (0.12), 3.584 (1.09), 3.689 (0.17),7.457 (0.19), 7.478 (0.97), 7.501 (1.24), 7.553 (0.65), 7.558 (0.60), 7.575(0.36), 7.580 (0.35), 7.684 (0.16), 7.703 (0.47), 7.713 (0.66), 7.731 (1.08),7.747 (0.20), 8.719 (0.37)。

Separation of enantiomers:

the title compound (463 mg) was dissolved in methanol (30 ml) and separated into enantiomers on the chiral phase by preparative SFC (see examples 130A and 131A) [ column: daicel Chiralcel OD-H, 5 μm,250 mm x20 mm, flow rate: 80 ml/min, injection: 1.0ml, UV detection: 210 nm, temperature: at 40 deg.C, eluent 15% ethanol/85% carbon dioxide, and running time 10 min. The combined target fractions were each concentrated and the respective residue was lyophilized from acetonitrile/water.

Example 130A

(+) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(enantiomer 1)

In the enantiomeric separation described in example 129A, 177 mg (100% purity, ee >99%) of the title compound were obtained as the earlier eluting enantiomer.

[α]_D ²⁰= 13.9 °, 589 nm, c = 0.43 g/100 ml, methanol

LC-MS (method 1) R_t= 2.26 min; MS (ESIpos): m/z = 634/636 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.184 (0.07), 1.312 (0.12), 1.323(0.19), 1.344 (16.00), 1.501 (0.07), 1.880 (1.62), 1.944 (0.17), 1.967(0.12), 1.985 (0.28), 1.998 (0.19), 2.007 (0.35), 2.019 (0.42), 2.035 (0.37),2.057 (0.31), 2.076 (0.14), 2.094 (0.31), 2.122 (0.25), 2.138 (0.26), 2.183(0.61), 2.281 (0.04), 2.327 (0.04), 2.670 (0.03), 3.585 (1.24), 3.689 (0.20),7.344 (0.07), 7.457 (0.21), 7.480 (0.76), 7.503 (0.95), 7.554 (0.56), 7.559(0.55), 7.577 (0.32), 7.582 (0.32), 7.684 (0.18), 7.704 (0.52), 7.714 (0.75),7.731 (1.21), 7.748 (0.24), 8.707 (0.21), 8.721 (0.41), 8.736 (0.21)。

Example 131A

(-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(enantiomer 2)

In the enantiomeric separation described in example 129A, 183 mg (100% purity, ee value 96%) of the title compound were obtained as the enantiomer which eluted later.

[α]_D ²⁰= 11.9 °, 589 nm, c = 0.41 g/100 ml, methanol

LC-MS (method 1) R_t= 2.27 min; MS (ESIpos): m/z = 634/636 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.183 (0.07), 1.311 (0.28), 1.343(16.00), 1.499 (0.07), 1.878 (1.68), 1.942 (0.18), 1.966 (0.13), 1.984(0.29), 2.006 (0.37), 2.018 (0.44), 2.034 (0.38), 2.056 (0.32), 2.075 (0.15),2.093 (0.32), 2.121 (0.27), 2.137 (0.30), 2.180 (0.64), 2.279 (0.05), 2.327(0.04), 2.669 (0.03), 3.583 (1.31), 3.688 (0.21), 7.347 (0.07), 7.456 (0.24),7.479 (0.86), 7.502 (1.07), 7.553 (0.64), 7.558 (0.57), 7.575 (0.36), 7.580(0.33), 7.683 (0.21), 7.703 (0.58), 7.712 (0.81), 7.730 (1.20), 7.746 (0.24),8.705 (0.24), 8.720 (0.43), 8.734 (0.21)。

Example 132A

(+/-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(raceme)

To a mixture of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- [2- (trifluoromethyl) phenyl ] pentanoic acid tert-butyl ester (600 mg, 1.00 mmol, example 38A) in NMP (4 ml) was added 3, 3-difluoropiperidine hydrochloride (1.26 g, 8.00 mmol) and DIPEA (1.7 ml, 10 mmol) and the mixture was stirred at 110 deg.C for two days. After cooling to room temperature, the mixture was purified by flash column chromatography (100 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3 → 8:2, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 415 mg (98% purity, 59% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.72 min; MS(ESIpos): m/z = 684/686 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.009 (0.79), 0.919 (0.53), 0.934(4.45), 0.950 (4.42), 1.345 (16.00), 1.397 (0.88), 1.889 (0.53), 1.992(0.25), 2.014 (0.44), 2.033 (0.37), 2.054 (0.35), 2.093 (0.42), 2.187 (1.12),2.327 (0.16), 2.391 (0.18), 2.408 (0.52), 2.426 (0.52), 2.444 (0.19), 2.944(0.28), 2.960 (0.37), 2.976 (0.28), 3.183 (0.51), 3.462 (0.31), 3.491 (0.60),3.519 (0.29), 3.689 (0.17), 5.753 (1.38), 7.483 (0.46), 7.502 (0.29), 7.686(0.32), 7.708 (1.77), 7.716 (1.09), 7.738 (1.04), 8.785 (0.41)。

Separation of enantiomers:

the title compound (327 mg) was dissolved in methanol (30 ml) and separated into enantiomers on the chiral phase by preparative SFC (see examples 133A and 134A) [ column: daicel Chiralcel OX-H, 5 μm,250 mm x 30mm, flow rate: 100 ml/min, injection: 3.0 ml, UV detection: 210 nm, temperature: at 40 deg.C, eluent 15% methanol/85% carbon dioxide, running time 15min, isocratic. The combined target fractions were each concentrated and the respective residue was lyophilized.

Example 133A

(-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(enantiomer 1)

In the enantiomeric separation described in example 132A, 104 mg (100% purity, ee >99%) of the title compound were obtained as the earlier eluting enantiomer.

[α]_D ²⁰= 12.1 °, 589 nm, c = 0.39 g/100 ml, methanol

LC-MS (method 1) R_t= 2.71 min; MS (ESIpos): m/z = 684/686 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.185 (0.06), 1.305 (0.17), 1.311(0.11), 1.322 (0.16), 1.345 (16.00), 1.502 (0.06), 1.889 (0.64), 1.946(0.12), 1.974 (0.09), 1.993 (0.27), 2.016 (0.49), 2.034 (0.42), 2.055 (0.40),2.095 (0.51), 2.119 (0.41), 2.141 (0.36), 2.188 (1.32), 2.327 (0.03), 2.669(0.03), 3.183 (0.62), 3.463 (0.37), 3.492 (0.71), 3.520 (0.36), 3.648 (0.19),3.689 (0.20), 7.463 (0.27), 7.482 (0.52), 7.500 (0.33), 7.686 (0.34), 7.708(2.09), 7.715 (1.26), 7.721 (0.97), 7.738 (1.17), 7.755 (0.24), 8.772 (0.24),8.787 (0.48), 8.801 (0.23)。

Example 134A

(+) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethyl) phenyl]Glutaric acid tert-butylEsters(enantiomer 2)

In the enantiomeric separation described in example 132A, 75 mg (100% purity, ee value 97%) of the title compound were obtained as the later eluting enantiomer.

[α]_D ²⁰= 13.5 °, 589 nm, c = 0.45 g/100 ml, methanol

LC-MS (method 1) R_t= 2.70 min; MS (ESIpos): m/z = 684/686 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.009 (0.18), 1.185 (0.06), 1.311(0.08), 1.322 (0.14), 1.345 (16.00), 1.502 (0.06), 1.889 (0.54), 1.945(0.10), 1.974 (0.08), 1.993 (0.24), 2.016 (0.43), 2.034 (0.37), 2.055 (0.35),2.095 (0.44), 2.119 (0.35), 2.188 (1.15), 2.327 (0.04), 3.184 (0.52), 3.463(0.33), 3.492 (0.63), 3.520 (0.31), 3.648 (0.16), 3.689 (0.17), 7.463 (0.24),7.482 (0.47), 7.501 (0.30), 7.686 (0.32), 7.708 (1.90), 7.715 (1.12), 7.721(0.84), 7.738 (1.08), 7.755 (0.22), 8.772 (0.21), 8.787 (0.43), 8.802 (0.20)。

Example 135A

(+/-) -5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(raceme)

To a mixture of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- [2- (trifluoromethyl) phenyl ] pentanoic acid tert-butyl ester (600 mg, 1.00 mmol, example 38A) in NMP (4 ml) was added azepane (900. mu.l, 8.0 mmol) and DIPEA (1.4 ml, 8.0 mmol) and the mixture was stirred at 110 ℃ for two days. After cooling to room temperature, the mixture was purified by flash column chromatography (100 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3 → 8:2, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 303 mg (100% purity, 46% of theory) of the title compound are obtained.

LC-MS(method 1) R_t= 2.91 min; MS (ESIpos): m/z = 662/664 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (0.09), -0.009 (0.77), 0.007(0.77), 0.146 (0.09), 0.926 (0.28), 0.941 (2.02), 0.957 (1.89), 1.184 (0.07),1.345 (16.00), 1.501 (0.07), 1.609 (1.32), 1.789 (0.86), 1.905 (0.16), 1.946(0.13), 1.987 (0.25), 2.009 (0.38), 2.029 (0.34), 2.051 (0.26), 2.070 (0.10),2.092 (0.19), 2.153 (0.93), 2.327 (0.10), 2.366 (0.11), 2.440 (0.12), 2.669(0.08), 2.709 (0.10), 2.973 (0.08), 3.505 (1.11), 3.519 (1.48), 3.534 (1.07),3.623 (0.14), 3.680 (0.16), 7.389 (0.08), 7.461 (0.19), 7.479 (0.39), 7.498(0.24), 7.538 (0.60), 7.560 (1.16), 7.601 (0.65), 7.607 (0.60), 7.624 (0.33),7.629 (0.33), 7.686 (0.16), 7.705 (0.45), 7.717 (0.69), 7.735 (1.02), 7.751(0.20), 8.734 (0.20), 8.749 (0.41), 8.764 (0.19)。

Separation of enantiomers:

the title compound (215 mg) was dissolved in methanol (30 ml) and separated by preparative SFC on chiral phase into enantiomers (see example 136A and 137A) [ column: daicel Chiralcel OX-H, 5 μm,250 mm x20 mm, flow rate: 80 ml/min, injection: 1.0ml, UV detection: 210 nm, temperature: 40 deg.C, eluent 17% methanol/83% carbon dioxide, running time 9 min, isocratic. The combined target fractions were each concentrated and the respective residue was lyophilized.

Example 136A

(-) -5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(enantiomer 1)

In the enantiomeric separation described in example 135A, 86 mg (99% purity, ee >99%) of the title compound were obtained as the earlier eluting enantiomer.

[α]_D ²⁰= 12.1 °, 589 nm, c = 0.36 g/100 ml, methanol

LC-MS (method 2) R_t= 1.53 min; MS (ESIpos): m/z = 662/664 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.185 (0.07), 1.311 (0.12), 1.346(16.00), 1.502 (0.08), 1.610 (1.59), 1.790 (1.05), 1.908 (0.19), 1.947(0.16), 1.970 (0.11), 1.988 (0.30), 2.011 (0.46), 2.023 (0.36), 2.031 (0.42),2.052 (0.32), 2.072 (0.13), 2.094 (0.24), 2.109 (0.24), 2.154 (1.14), 2.327(0.05), 2.670 (0.05), 3.505 (1.26), 3.520 (1.78), 3.534 (1.23), 3.625 (0.18),3.682 (0.20), 7.393 (0.10), 7.461 (0.23), 7.480 (0.47), 7.498 (0.30), 7.539(0.64), 7.561 (1.22), 7.602 (0.67), 7.607 (0.62), 7.625 (0.34), 7.630 (0.33),7.686 (0.19), 7.706 (0.54), 7.718 (0.85), 7.736 (1.20), 7.751 (0.26), 8.735(0.24), 8.751 (0.48), 8.765 (0.24)。

Example 137A

(+) -5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(enantiomer 2)

In the enantiomeric separation described in example 135A, 83 mg (100% purity, ee value 97%) of the title compound were obtained as the enantiomer which eluted later.

[α]_D ²⁰= 12.6 °, 589 nm, c = 0.37 g/100 ml, methanol

LC-MS (method 2) R_t= 1.53 min; MS (ESIpos): m/z = 662/664 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.185 (0.06), 1.310 (0.09), 1.322(0.15), 1.344 (16.00), 1.501 (0.07), 1.609 (1.35), 1.789 (0.88), 1.907(0.16), 1.946 (0.14), 1.969 (0.09), 1.987 (0.26), 2.010 (0.38), 2.023 (0.30),2.030 (0.36), 2.052 (0.28), 2.071 (0.11), 2.094 (0.20), 2.154 (0.96), 3.504(1.11), 3.519 (1.52), 3.533 (1.10), 3.623 (0.15), 3.681 (0.17), 7.390 (0.09),7.460 (0.20), 7.479 (0.41), 7.497 (0.26), 7.538 (0.62), 7.560 (1.18), 7.601(0.65), 7.606 (0.63), 7.623 (0.33), 7.629 (0.33), 7.686 (0.17), 7.705 (0.47),7.717 (0.73), 7.734 (1.07), 7.751 (0.22), 8.735 (0.20), 8.750 (0.41), 8.765(0.20)。

Example 138A

5- [ ({ 6-bromo-2- [ 3)-fluoropiperidin-1-yl]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(mixture of diastereomers)

To a mixture of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- [2- (trifluoromethyl) phenyl ] pentanoic acid tert-butyl ester (600 mg, 1.00 mmol, example 38A) in NMP (4.0 ml) were added (+/-) -3-fluoropiperidine hydrochloride (1.12 g, 8.00 mmol) and DIPEA (1.7 ml, 10 mmol), and the mixture was stirred at 110 ℃ for two days. After cooling to room temperature, the mixture was filtered and purified by flash column chromatography (100 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3 → 8:2, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 452 mg (100% purity, 68% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.69 min; MS (ESIpos): m/z = 666/668 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.007 (0.52), 0.923 (0.29), 0.939(2.28), 0.955 (2.16), 1.345 (16.00), 1.397 (1.13), 1.652 (0.17), 1.906(0.40), 1.990 (0.32), 2.013 (0.41), 2.033 (0.34), 2.054 (0.26), 2.093 (0.24),2.178 (1.15), 2.435 (0.12), 2.669 (0.12), 3.115 (0.19), 3.173 (0.19), 3.393(0.19), 3.451 (0.17), 3.684 (0.18), 4.823 (0.14), 4.942 (0.14), 7.463 (0.27),7.482 (0.45), 7.500 (0.27), 7.659 (0.19), 7.681 (1.39), 7.685 (1.19), 7.690(0.93), 7.707 (0.53), 7.721 (0.80), 7.738 (0.86), 8.780 (0.39)。

Example 139A

(+/-) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(mixture of diastereomers)

To a mixture of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- [2- (trifluoromethyl) phenyl ] pentanoic acid tert-butyl ester (600 mg, 1.00 mmol, example 38A) in NMP (4.0 ml) were added (+/-) -3-ethylpiperidine (906 mg, 8.00 mmol) and DIPEA (1.4 ml, 8.0 mmol) and the mixture was stirred at 110 ℃ for two days. After cooling to room temperature, the mixture was filtered and purified by flash column chromatography (100 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3 → 8:2, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 546 mg (100% purity, 81% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 3.04 min; MS (ESIpos): m/z = 676/678 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.895 (0.88), 0.913 (2.18), 0.934(3.62), 0.950 (2.84), 1.072 (0.17), 1.102 (0.18), 1.185 (0.09), 1.263 (0.33),1.281 (0.44), 1.346 (16.00), 1.397 (2.53), 1.569 (0.21), 1.641 (0.17), 1.753(0.24), 1.884 (0.32), 1.990 (0.26), 2.012 (0.49), 2.027 (0.45), 2.051 (0.24),2.140 (0.56), 2.166 (0.81), 2.327 (0.08), 2.390 (0.14), 2.408 (0.42), 2.426(0.43), 2.443 (0.27), 2.669 (0.08), 2.727 (0.13), 2.755 (0.23), 2.784 (0.13),2.927 (0.08), 2.943 (0.19), 2.960 (0.24), 2.976 (0.18), 2.993 (0.07), 3.514(0.34), 3.536 (0.31), 3.635 (0.20), 3.696 (0.21), 5.753 (0.93), 7.461 (0.28),7.479 (0.46), 7.497 (0.27), 7.637 (0.13), 7.659 (1.99), 7.686 (0.26), 7.706(0.49), 7.720 (0.60), 7.735 (1.01), 7.753 (0.22), 8.753 (0.22), 8.768 (0.44),8.782 (0.21)。

Example 140A

5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(mixture of diastereomers)

To a mixture of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- [2- (trifluoromethyl) phenyl ] pentanoic acid tert-butyl ester (600 mg, 1.00 mmol, example 38A) in NMP (4.0 ml) was added (+/-) -3-methylpiperidine (940. mu.l, 8.0 mmol) and DIPEA (1.4 ml, 8.0 mmol) and the mixture was stirred at 110 ℃ for two days. After cooling to room temperature, the mixture was purified by flash column chromatography (100 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3 → 8:2, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 543 mg (100% purity, 82% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.93 min; MS (ESIpos): m/z = 662/664 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.007 (0.26), 0.927 (1.58), 0.936(2.24), 0.942 (1.80), 0.953 (1.81), 1.086 (0.16), 1.109 (0.17), 1.186 (0.07),1.305 (0.09), 1.322 (0.14), 1.346 (16.00), 1.397 (0.61), 1.502 (0.07), 1.633(0.14), 1.662 (0.17), 1.737 (0.28), 1.797 (0.34), 1.828 (0.22), 1.908 (0.15),1.948 (0.11), 1.970 (0.08), 1.989 (0.25), 2.011 (0.46), 2.029 (0.38), 2.051(0.26), 2.070 (0.09), 2.096 (0.14), 2.110 (0.17), 2.169 (1.03), 2.327 (0.06),2.365 (0.05), 2.413 (0.12), 2.431 (0.18), 2.466 (0.24), 2.694 (0.12), 2.722(0.23), 2.750 (0.12), 2.948 (0.07), 2.964 (0.08), 2.980 (0.06), 3.453 (0.24),3.480 (0.44), 3.510 (0.21), 3.679 (0.18), 7.461 (0.26), 7.481 (0.42), 7.500(0.25), 7.638 (0.13), 7.660 (2.06), 7.665 (1.00), 7.687 (0.26), 7.706 (0.45),7.721 (0.82), 7.737 (0.80), 7.751 (0.21), 8.757 (0.21), 8.771 (0.42), 8.786(0.20)。

Example 141A

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethoxy) phenyl]Glutaric acid tert-butyl ester(raceme)

To a mixture of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- [2- (trifluoromethoxy) phenyl ] pentanoic acid tert-butyl ester (1.00 g, 1.62 mmol, example 41A) in NMP (6 ml) was added piperidine (1.3ml, 13 mmol) and DIPEA (2.3 ml, 13 mmol), and the mixture was stirred at 110 ℃ for two days. After cooling to room temperature, the mixture was purified by flash column chromatography (100 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3 → 8:2, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 351mg (92% purity, 30% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.86 min; MS (ESIpos): m/z = 664/666 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.009 (0.40), 0.007 (0.37), 0.922(0.14), 0.937 (1.10), 0.953 (1.05), 1.200 (0.07), 1.301 (0.27), 1.325 (0.11),1.360 (16.00), 1.373 (0.47), 1.381 (0.28), 1.397 (0.20), 1.516 (0.08), 1.610(0.44), 1.674 (0.84), 1.805 (0.19), 1.829 (0.19), 1.855 (0.11), 2.033 (0.24),2.066 (1.13), 2.088 (0.27), 2.142 (0.91), 2.208 (0.15), 2.327 (0.08), 2.366(0.07), 2.430 (0.08), 2.669 (0.08), 2.709 (0.07), 2.965 (0.07), 3.143 (1.07),3.386 (0.18), 3.612 (0.21), 3.628 (0.40), 3.643 (0.37), 3.661 (0.20), 7.362(0.35), 7.386 (0.19), 7.398 (0.69), 7.403 (0.52), 7.410 (0.51), 7.416 (0.48),7.422 (0.61), 7.472 (0.12), 7.544 (0.44), 7.557 (0.35), 7.568 (0.30), 7.631(0.24), 7.653 (1.28), 7.661 (0.88), 7.665 (0.76), 7.683 (0.18), 7.688 (0.17),8.729 (0.19), 8.744 (0.39), 8.758 (0.19)。

Separation of enantiomers:

the title compound (262 mg) was dissolved in a mixture of ethanol (3 ml) and acetonitrile (2 ml) and separated by preparative HPLC on the chiral phase into enantiomers (see examples 142A and 143A) [ column: daicel Chiralcel OZ-H,5 μm,250 mm x20 mm, flow rate: 20 ml/min, injection: 0.04 ml, UV detection: 220 nm, temperature: 40 deg.C, eluent 20% ethanol/80% heptane, running time 7 min, isocratic. The combined target fractions were each concentrated and the respective residue was lyophilized.

Example 142A

(-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethoxy) phenyl group]Glutaric acid tert-butyl ester(enantiomer 1)

In the enantiomeric separation described in example 141A, 104 mg (89% purity, ee value 100%) of the title compound were obtained as the earlier eluting enantiomer.

[α]_D ²⁰= 11.9 °, 589 nm, c = 0.36 g/100 ml, methanol

LC-MS (method 1) R_t= 2.86 min; MS (ESIpos): m/z = 664/666 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (0.03), 0.857 (0.03), 1.038(0.14), 1.055 (0.28), 1.073 (0.15), 1.199 (0.09), 1.210 (0.06), 1.242 (0.24),1.257 (0.25), 1.272 (0.18), 1.301 (0.54), 1.316 (0.11), 1.325 (0.13), 1.360(16.00), 1.381 (0.51), 1.516 (0.09), 1.609 (0.55), 1.673 (1.07), 1.787(0.10), 1.805 (0.23), 1.830 (0.22), 1.855 (0.13), 2.015 (0.07), 2.034 (0.27),2.045 (0.33), 2.066 (1.36), 2.089 (0.32), 2.142 (1.11), 2.208 (0.29), 2.327(0.04), 2.669 (0.04), 2.974 (0.07), 3.143 (1.36), 3.369 (0.25), 3.386 (0.24),3.431 (0.10), 3.449 (0.09), 3.466 (0.04), 3.612 (0.26), 3.628 (0.49), 3.644(0.46), 3.661 (0.25), 7.362 (0.41), 7.378 (0.22), 7.385 (0.25), 7.398 (0.84),7.410 (0.60), 7.416 (0.56), 7.421 (0.67),7.434 (0.15), 7.474 (0.15), 7.544(0.52), 7.557 (0.40), 7.568 (0.33), 7.631 (0.26), 7.653 (1.42), 7.661 (0.97),7.665 (0.83), 7.683 (0.20), 7.687 (0.17), 8.730 (0.23), 8.744 (0.46), 8.758(0.23)。

Example 143A

(+) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethoxy) phenyl]Glutaric acid tert-butyl ester(enantiomer 2)

In the enantiomeric separation described in example 141A, 95 mg (97% purity, ee value 97%) of the title compound were obtained as the enantiomer which eluted later.

[α]_D ²⁰= 13.8 °, 589 nm, c = 0.37 g/100 ml, methanol

LC-MS (method 1) R_t= 2.86 min; MS (ESIpos): m/z = 664/666 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.857 (0.06), 1.101 (0.05), 1.119(0.05), 1.199 (0.08), 1.242 (0.43), 1.257 (0.43), 1.272 (0.28), 1.325 (0.11),1.359 (16.00), 1.373 (0.55), 1.516 (0.08), 1.609 (0.49), 1.673 (0.95), 1.805(0.22), 1.830 (0.22), 1.856 (0.12), 2.034 (0.28), 2.066 (1.32), 2.089 (0.30),2.143 (1.07), 3.144 (1.24), 3.369 (0.27), 3.613 (0.26), 3.628 (0.48), 3.644(0.43), 3.662 (0.21), 7.362 (0.40), 7.385 (0.18), 7.398 (0.76), 7.410 (0.57),7.416 (0.55), 7.421 (0.67), 7.474 (0.16), 7.544 (0.45), 7.557 (0.38), 7.568(0.32), 7.631 (0.26), 7.653 (1.39), 7.660 (0.96), 7.665 (0.82), 7.683 (0.16),7.687 (0.17), 8.730 (0.22), 8.744 (0.44), 8.759 (0.21)。

Example 144A

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethoxy) phenyl]Glutaric acid tert-butyl ester(raceme)

To a mixture of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- [2- (trifluoromethoxy) phenyl ] pentanoic acid tert-butyl ester (600 mg, 974 μmol, example 41A) in NMP (4 ml) was added pyrrolidine (650 μ l, 7.8 mmol) and DIPEA (1.4 ml, 7.8 mmol) and the mixture was stirred at 110 ℃ for two days. After cooling to room temperature, the mixture was purified by flash column chromatography (100 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3 → 8:2, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 564 mg (95% purity, 85% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.41 min; MS (ESIpos): m/z = 650/652 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.920 (0.21), 0.935 (1.75), 0.951(1.69), 1.198 (0.08), 1.301 (0.37), 1.314 (0.09), 1.326 (0.12), 1.358(16.00), 1.380 (0.40), 1.397 (0.73), 1.514 (0.07), 1.805 (0.23), 1.827(0.26), 1.875 (1.57), 2.033 (0.27), 2.043 (0.32), 2.064 (1.48), 2.085 (0.30),2.160 (0.54), 2.239 (0.17), 2.327 (0.06), 2.365 (0.05), 2.391 (0.06), 2.409(0.17), 2.427 (0.17), 2.444 (0.07), 2.669 (0.05), 2.944 (0.10), 2.961 (0.13),2.977 (0.10), 3.367 (0.22), 3.384 (0.23), 3.575 (1.25), 3.627 (0.32), 3.645(0.31), 3.663 (0.24), 7.355 (0.49), 7.379 (0.30), 7.394 (0.81), 7.405 (0.62),7.417 (0.64), 7.475 (0.67), 7.497 (1.15), 7.541 (0.49), 7.552 (0.93), 7.557(0.88), 7.564 (0.41), 7.574 (0.40), 7.579 (0.37), 8.679 (0.21), 8.693 (0.40),8.707 (0.21)。

Separation of enantiomers:

the title compound (475 mg) was dissolved in methanol (30 ml) and separated by preparative SFC on the chiral phase into enantiomers (see example 145A and 146A) [ column: daicel Chiralcel OH-X, 5 μm,250 mm X30 mm, flow rate: 100 ml/min, injection: 1.00 ml, UV detection: 210 nm, temperature: 40 deg.C, eluent 20% methanol/80% carbon dioxide, running time 9 min, isocratic. The combined target fractions were each concentrated and the respective residue was lyophilized.

Example 145A

(-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethoxy) phenyl]Glutaric acid tert-butyl ester(enantiomer 1)

In the enantiomeric separation described in example 144A, 159 mg (100% purity, ee >99%) of the title compound were obtained as the earlier eluting enantiomer.

[α]_D ²⁰= 13.2 °, 589 nm, c = 0.33 g/100 ml, methanol

LC-MS (method 1) R_t= 2.34 min; MS (ESIpos): m/z = 650/652 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.145 (0.03), 1.198 (0.07), 1.301(0.28), 1.314 (0.08), 1.327 (0.12), 1.358 (16.00), 1.380 (0.29), 1.514(0.07), 1.786 (0.10), 1.805 (0.22), 1.828 (0.25), 1.875 (1.49), 2.034 (0.25),2.043 (0.31), 2.065 (1.44), 2.085 (0.29), 2.161 (0.52), 2.240 (0.07), 2.327(0.04), 2.669 (0.03), 3.311 (6.84), 3.367 (0.22), 3.384 (0.23), 3.627 (0.31),3.646 (0.28), 3.663 (0.22), 7.355 (0.47), 7.379 (0.27), 7.394 (0.78), 7.405(0.61), 7.417 (0.63), 7.429 (0.15), 7.475 (0.66), 7.497 (1.12), 7.541 (0.48),7.552 (0.91), 7.557 (0.87), 7.564 (0.39), 7.574 (0.38), 7.579 (0.36), 8.680(0.20), 8.694 (0.39), 8.708 (0.20)。

Example 146A

(+) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethoxy) phenyl]Glutaric acid tert-butyl ester(enantiomer 2)

In the enantiomeric separation described in example 144A, 146 mg (100% purity, ee value 98%) of the title compound were obtained as the enantiomer which eluted later.

[α]_D ²⁰= 14.4 °, 589 nm, c = 0.35 g/100 ml, methanol

LC-MS (method 1) R_t= 2.33 min; MS (ESIpos): m/z = 650/652 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.198 (0.07), 1.315 (0.08), 1.327(0.12), 1.358 (16.00), 1.515 (0.07), 1.806 (0.24), 1.828 (0.28), 1.876(1.60), 2.034 (0.28), 2.044 (0.34), 2.065 (1.61), 2.086 (0.32), 2.161 (0.57),2.327 (0.04), 3.311 (7.94), 3.367 (0.24), 3.385 (0.25), 3.628 (0.33), 3.646(0.31), 3.663 (0.23), 7.356 (0.52), 7.380 (0.27), 7.394 (0.84), 7.405 (0.66),7.417 (0.71), 7.430 (0.17), 7.475 (0.70), 7.498 (1.19), 7.541 (0.51), 7.553(1.00), 7.557 (0.92), 7.564 (0.44), 7.574 (0.41), 7.579 (0.38), 8.680 (0.23),8.694 (0.43), 8.708 (0.23)。

Example 147A

(+/-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethoxy) phenyl]Glutaric acid tert-butyl ester(raceme)

To a mixture of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- [2- (trifluoromethoxy) phenyl ] pentanoic acid tert-butyl ester (600 mg, 974 μmol, example 41A) in NMP (4 ml) was added 3, 3-difluoropiperidine hydrochloride (1.23 g, 7.79 mmol) and DIPEA (1.4 ml, 7.8 mmol) and the mixture was stirred at 110 ℃ for two days. After cooling to room temperature, the mixture was purified by flash column chromatography (100 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3 → 8:2, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 493 mg (92% purity, 66% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.73 min; MS (ESIpos): m/z = 700/702 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.937 (0.80), 0.953 (0.74), 1.301(0.37), 1.360 (16.00), 1.398 (0.44), 1.808 (0.24), 1.831 (0.25), 1.884(0.57), 2.067 (1.68), 2.098 (0.61), 2.161 (1.10), 2.227 (0.16), 2.327 (0.12),2.366 (0.11), 3.176 (0.67), 3.370 (0.24), 3.455 (0.39), 3.484 (0.73), 3.512(0.38), 3.638 (0.46), 3.654 (0.43), 7.363 (0.43), 7.401 (0.82), 7.413 (0.62),7.424 (0.67), 7.549 (0.49), 7.561 (0.43), 7.572 (0.35), 7.683 (0.24), 7.704(1.40), 7.710 (1.04), 7.732 (0.18), 8.755 (0.46)。

Separation of enantiomers:

the title compound (405 mg) was dissolved in methanol (30 ml) and separated into enantiomers on the chiral phase by preparative SFC (see example 148A and 149A) [ column: daicel Chiralcel OX-H, 5 μm,250 mm x 30mm, flow rate: 100 ml/min, injection: 0.7 ml, UV detection: 210 nm, temperature: 40 deg.C, eluent of 12% methanol/88% carbon dioxide, running time 11 min, isocratic. The combined target fractions were each concentrated and the respective residue was lyophilized.

Example 148A

(-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethoxy) phenyl]Glutaric acid tert-butyl ester(enantiomer 1)

In the enantiomeric separation described in example 147A, 134 mg (98% purity, ee >99%) of the title compound were obtained as the earlier eluting enantiomer.

[α]_D ²⁰= 12.4 °, 589 nm, c = 0.41 g/100 ml, methanol

LC-MS (method 1) R_t= 2.73 min; MS (ESIpos): m/z = 700/702 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.199 (0.07), 1.269 (0.03), 1.301(0.37), 1.314 (0.07), 1.325 (0.09), 1.360 (16.00), 1.380 (0.42), 1.516(0.07), 1.789 (0.09), 1.808 (0.23), 1.832 (0.24), 1.885 (0.53), 2.017 (0.08),2.036 (0.30), 2.067 (1.63), 2.098 (0.58), 2.162 (1.09), 2.327 (0.04), 2.669(0.03), 3.177 (0.64), 3.371 (0.23), 3.388 (0.23), 3.455 (0.39), 3.484 (0.74),3.513 (0.37), 3.623 (0.25), 3.639 (0.46), 3.654 (0.42), 3.673 (0.21), 7.363(0.41), 7.387 (0.19), 7.400 (0.78), 7.412 (0.60), 7.418 (0.56), 7.424 (0.67),7.436 (0.13), 7.511 (0.14), 7.549 (0.50), 7.561 (0.43), 7.572 (0.36), 7.682(0.23), 7.704 (1.46), 7.709 (1.06), 7.714 (0.88), 7.732 (0.14), 7.736 (0.16),8.740 (0.24), 8.755 (0.48), 8.769 (0.24)。

Example 149A

(+) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethoxy) phenyl]Glutaric acid tert-butyl ester(enantiomer 2)

In the enantiomeric separation described in example 147A, 122 mg (100% purity, ee value 98%) of the title compound were obtained as the enantiomer which eluted later.

[α]_D ²⁰= 13.3 °, 589 nm, c = 0.36 g/100 ml, methanol

LC-MS (method 1) R_t= 2.73 min; MS (ESIpos): m/z = 700/702 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.200(0.07), 1.315 (0.08), 1.325(0.11), 1.360 (16.00), 1.516 (0.07), 1.790 (0.09), 1.809 (0.23), 1.833(0.24), 1.885 (0.51), 2.018 (0.08), 2.037 (0.30), 2.068 (1.61), 2.099 (0.56),2.162 (1.07), 2.326 (0.04), 3.177 (0.62), 3.371 (0.22), 3.388 (0.22), 3.456(0.38), 3.485 (0.72), 3.513 (0.36), 3.624 (0.24), 3.639 (0.45), 3.655 (0.41),3.673 (0.20), 7.363 (0.42), 7.387 (0.18), 7.400 (0.78), 7.412 (0.59), 7.418(0.56), 7.424 (0.67), 7.436 (0.13), 7.509 (0.14), 7.549 (0.49), 7.561 (0.42),7.572 (0.35), 7.682 (0.24), 7.704 (1.48), 7.709 (1.07), 7.714 (0.88), 7.736(0.16), 8.741 (0.24), 8.755 (0.48), 8.770 (0.24)。

Example 150A

(+/-) -5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethoxy) phenyl]Glutaric acid tert-butyl ester(raceme)

To a mixture of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- [2- (trifluoromethoxy) phenyl ] pentanoic acid tert-butyl ester (600 mg, 974 μmol, example 41A) in NMP (4 ml) was added azepane (880 μ l, 7.8 mmol) and DIPEA (1.4 ml, 7.8 mmol) and the mixture was stirred at 110 ℃ for 30 h. After cooling to room temperature, dichloromethane (150 ml) was added to the mixture and it was washed once with water (120 ml) and once with a mixture of 1M hydrochloric acid (20 ml) in water (100 ml). The organic phase was dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (50 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3 → 7:3, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 557 mg (100% purity, 84% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.94 min; MS (ESIpos): m/z = 678/680 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.009 (0.15), 0.007 (0.15), 1.199(0.06), 1.234 (0.05), 1.301 (0.35), 1.313 (0.08), 1.324 (0.10), 1.359(16.00), 1.373 (0.45), 1.382 (0.35), 1.397 (1.92), 1.515 (0.07), 1.606(1.33), 1.786 (0.91), 1.829 (0.22), 1.856 (0.12), 2.014 (0.06), 2.033 (0.25),2.044 (0.27), 2.065 (1.16), 2.089 (0.32), 2.097 (0.28), 2.128 (0.68), 2.201(0.10), 2.327 (0.04), 2.669 (0.03), 3.369 (0.18), 3.387 (0.19), 3.496 (1.06),3.511 (1.44), 3.525 (1.04), 3.602 (0.18), 3.618 (0.24), 3.631 (0.24), 3.646(0.24), 3.663 (0.18), 7.358 (0.37), 7.362 (0.34), 7.384 (0.23), 7.397 (0.75),7.401 (0.60), 7.408 (0.60), 7.414 (0.57), 7.420 (0.68), 7.432 (0.18), 7.534(0.65), 7.545 (0.46), 7.557 (1.42), 7.569 (0.32), 7.600 (0.64), 7.606 (0.60),7.623 (0.34), 7.628 (0.33), 8.704 (0.19), 8.718 (0.37), 8.733 (0.19)。

Separation of enantiomers:

the title compound (450 mg) was dissolved in methanol (30 ml) and separated into enantiomers on the chiral phase by preparative SFC (see examples 151A and 152A) [ column: daicel Chiralcel OH-X, 5 μm,250 mm X20 mm, flow rate: 80 ml/min, injection: 0.40 ml, UV detection: 210 nm, temperature: 40 deg.C, eluent 20% methanol/80% carbon dioxide, running time 5min, isocratic. The combined target fractions were each concentrated and the respective residue was lyophilized.

Example 151A

(-) -5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethoxy) phenyl]Glutaric acid tert-butyl ester(enantiomer 1)

In the enantiomeric separation described in example 150A, 154 mg (100% purity, ee >99%) of the title compound was obtained as the earlier eluting enantiomer.

[α]_D ²⁰= 12.0 °, 589 nm, c = 0.47 g/100 ml, methanol

LC-MS (method 1) R_t= 2.95 min; MS (ESIpos): m/z = 678/680 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.200 (0.08), 1.301 (0.35), 1.313(0.09), 1.324 (0.11), 1.359 (16.00), 1.381 (0.38), 1.515 (0.08), 1.606(1.70), 1.786 (1.21), 1.856 (0.15), 2.033 (0.31), 2.066 (1.56), 2.089 (0.40),2.129 (0.92), 2.201 (0.09), 3.369 (0.24), 3.387 (0.25), 3.496 (1.27), 3.511(1.87), 3.525 (1.28), 3.602 (0.24), 3.618 (0.33), 3.631 (0.32), 3.646 (0.31),3.663 (0.23), 7.358 (0.47), 7.397 (0.94), 7.408 (0.75), 7.420 (0.83), 7.534(0.71), 7.546 (0.53), 7.557 (1.60), 7.569 (0.39), 7.601 (0.64), 7.605 (0.67),7.623 (0.35), 7.627 (0.36), 8.704 (0.25), 8.718 (0.49), 8.733 (0.25)。

Example 152A

(+) -5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethoxy) phenyl]Glutaric acid tert-butyl ester(enantiomer 2)

In the enantiomeric separation described in example 150A, 149 mg (100% purity, ee value 97%) of the title compound were obtained as the later eluting enantiomer.

[α]_D ²⁰= 13.3 °, 589 nm, c = 0.40 g/100 ml, methanol

LC-MS (method 1) R_t= 2.95 min; MS (ESIpos): m/z = 678/680 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (0.03), 0.145 (0.03), 1.199(0.06), 1.313 (0.08), 1.324 (0.10), 1.359 (16.00), 1.515 (0.07), 1.606(1.36), 1.786 (0.95), 1.829 (0.23), 1.856 (0.12), 2.014 (0.07), 2.033 (0.27),2.044 (0.29), 2.065 (1.27), 2.089 (0.32), 2.096 (0.28), 2.128 (0.72), 2.327(0.04), 2.669 (0.04), 3.369 (0.20), 3.386 (0.20), 3.496 (1.10), 3.511 (1.53),3.525 (1.08), 3.602 (0.20), 3.618 (0.27), 3.630 (0.26), 3.645 (0.24), 3.663(0.18), 7.358 (0.39), 7.384 (0.20), 7.397 (0.78), 7.408 (0.64), 7.414 (0.61),7.420 (0.72), 7.432 (0.19), 7.534 (0.65), 7.546 (0.46), 7.556 (1.45), 7.569(0.34), 7.600 (0.62), 7.606 (0.59), 7.623 (0.33), 7.628 (0.32), 8.703 (0.21),8.718 (0.40), 8.732 (0.20)。

Example 153A

5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Glutaric acid tert-butyl ester(mixture of diastereomers)

To a mixture of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- [2- (trifluoromethoxy) phenyl ] pentanoic acid tert-butyl ester (600 mg, 974 μmol, example 41A) in NMP (3.9 ml) was added (+/-) -3-fluoropiperidine hydrochloride (1.09 g, 7.79 mmol) and DIPEA (1.7 ml, 9.7 mmol) and the mixture was stirred at 110 ℃ for 30 h. After cooling to room temperature, dichloromethane (150 ml) was added to the mixture and it was washed once with water (120 ml) and once with a mixture of 1M hydrochloric acid (25 ml) in water (100 ml). The organic phase was dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (50 g silica gel BiotageSnap cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3 → 7:3, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 463 mg (92% purity, 64% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.74 min; MS (ESIpos): m/z = 682/684 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.199 (0.07), 1.233 (0.05), 1.301(0.32), 1.314 (0.07), 1.325 (0.09), 1.360 (16.00), 1.381 (0.37), 1.397(3.74), 1.516 (0.07), 1.646 (0.18), 1.807 (0.33), 1.831 (0.31), 1.855 (0.18),1.902 (0.27), 1.952 (0.17), 2.036 (0.24), 2.067 (1.20), 2.089 (0.27), 2.156(0.93), 2.222 (0.14), 2.327 (0.04), 3.104 (0.18), 3.181 (0.18), 3.333 (0.26),3.353 (0.21), 3.387 (0.36), 3.412 (0.15), 3.444 (0.16), 3.472 (0.10), 3.618(0.21), 3.634 (0.38), 3.650 (0.35), 4.818 (0.14), 4.938 (0.14), 7.362 (0.37),7.386 (0.19), 7.399 (0.69), 7.410 (0.52), 7.417 (0.49), 7.422 (0.59), 7.434(0.12), 7.491 (0.13), 7.546 (0.43), 7.559 (0.38), 7.570 (0.30), 7.656 (0.23),7.677 (1.30), 7.683 (0.96), 7.688 (0.80), 7.706 (0.17), 7.711 (0.16), 7.901(0.04), 8.735 (0.20), 8.750 (0.39), 8.765 (0.19)。

Example 154A

5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (tris)Fluoromethoxy) phenyl]Glutaric acid tert-butyl ester(mixture of diastereomers)

To a mixture of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- [2- (trifluoromethoxy) phenyl ] pentanoic acid tert-butyl ester (600 mg, 974. mu. mol, example 41A) in NMP (4.0 ml) was added (+/-) -3-ethylpiperidine (882 mg, 7.79 mmol) and DIPEA (1.4 ml, 7.8 mmol) and the mixture was stirred at 110 ℃ for two days. After cooling to room temperature, the mixture was purified by flash column chromatography (100 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3 → 8:2, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 501 mg (98% purity, 73% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 3.07 min; MS (ESIpos): m/z = 692/694 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.964 (0.91), 0.983 (2.24), 1.002(1.37), 1.023 (0.48), 1.141 (0.18), 1.170 (0.19), 1.271 (0.09), 1.333 (0.37),1.350 (0.49), 1.372 (0.61), 1.432 (16.00), 1.452 (0.35), 1.469 (0.15), 1.636(0.22), 1.822 (0.26), 1.855 (0.25), 1.873 (0.25), 1.898 (0.22), 1.924 (0.31),1.952 (0.22), 2.103 (0.27), 2.137 (1.26), 2.188 (0.46), 2.215 (0.65), 2.272(0.11), 2.398 (0.08), 2.437 (0.09), 2.741 (0.08), 2.823 (0.23), 2.852 (0.13),3.458 (0.21), 3.569 (0.37), 3.598 (0.35), 3.701 (0.31), 3.716 (0.34), 3.733(0.27), 3.750 (0.17), 7.430 (0.34), 7.468 (0.71), 7.480 (0.54), 7.492 (0.61),7.549 (0.12), 7.620 (0.40), 7.632 (0.34), 7.643 (0.28), 7.705 (0.17), 7.727(1.51), 7.757 (0.11), 8.795 (0.22), 8.810 (0.42), 8.825 (0.21)。

Example 155A

5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Glutaric acid tert-butyl ester(mixture of diastereomers)

To a mixture of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- [2- (trifluoromethoxy) phenyl ] pentanoic acid tert-butyl ester (600 mg, 974 μmol, example 41A) in NMP (3.9 ml) was added (+/-) -3-methylpiperidine (910 μ l, 7.8 mmol) and DIPEA (1.4 ml, 7.8 mmol) and the mixture was stirred at 110 ℃ for 30 h. After cooling to room temperature, dichloromethane (150 ml) was added to the mixture and it was washed once with water (120 ml) and once with a mixture of 1M hydrochloric acid (25 ml) in water (100 ml). The organic phase was dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (50 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3 → 7:3, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 646 mg (100% purity, 98% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.97 min; MS (ESIpos): m/z = 678/680 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.833 (0.04), 0.849 (0.05), 0.922(1.43), 0.938 (1.46), 1.082 (0.16), 1.111 (0.18), 1.200 (0.08), 1.233 (0.08),1.301 (0.35), 1.324 (0.10), 1.360 (16.00), 1.381 (0.36), 1.397 (3.29), 1.516(0.07), 1.628 (0.15), 1.657 (0.17), 1.733 (0.30), 1.765 (0.31), 1.804 (0.43),1.830 (0.37), 2.014 (0.07), 2.033 (0.25), 2.066 (1.17), 2.092 (0.29), 2.146(0.69), 2.210 (0.14), 2.327 (0.03), 2.435 (0.12), 2.461 (0.19), 2.687 (0.12),2.717 (0.21), 2.747 (0.12), 3.369 (0.19), 3.386 (0.20), 3.442 (0.24), 3.471(0.44), 3.502 (0.21), 3.611 (0.21), 3.629 (0.35), 3.647 (0.31), 3.666 (0.20),7.361 (0.38), 7.378 (0.15), 7.385 (0.20), 7.398 (0.74), 7.403 (0.56), 7.410(0.55), 7.416 (0.51), 7.421 (0.63), 7.434 (0.15), 7.472 (0.14), 7.546 (0.43),7.558 (0.35), 7.570 (0.29), 7.634 (0.17), 7.657 (1.59), 7.663 (0.95), 7.681(0.13), 7.685 (0.12), 8.725 (0.20), 8.739 (0.40), 8.754 (0.20)。

Example 156A

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-3-fluorophenyl) pentanoic acid tert-butyl ester(raceme)

To a mixture of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chloro-3-fluorophenyl) pentanoic acid tert-butyl ester (204 mg, 349 μmol, example 44A) in NMP (3.4 ml) was added piperidine (280 μ l,2.8 mmol) and DIPEA (490 μ l,2.8 mmol) and the mixture was stirred at 100 ℃ overnight. After cooling to room temperature, the mixture was filtered and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was dried in vacuo. 175 mg (100% purity, 79% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.81 min; MS (ESIpos): m/z = 632/634 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (0.06), -0.023 (0.27), 0.007(0.41), 0.145 (0.05), 1.208 (0.07), 1.233 (0.57), 1.303 (0.08), 1.327 (0.10),1.368 (16.00), 1.525 (0.07), 1.606 (0.45), 1.670 (0.88), 1.808 (0.14), 1.826(0.19), 2.048 (0.17), 2.061 (0.18), 2.086 (1.12), 2.100 (0.81), 2.130 (1.45),2.327 (0.06), 2.365 (0.06), 2.669 (0.06), 2.709 (0.06), 3.134 (1.16), 3.604(0.21), 3.692 (0.32), 7.286 (0.18), 7.306 (0.40), 7.329 (0.27), 7.345 (0.30),7.363 (0.54), 7.394 (0.26), 7.413 (0.35), 7.427 (0.36), 7.447 (0.19), 7.624(0.26), 7.646 (1.35), 7.653 (0.89), 7.658 (0.80), 7.675 (0.17), 7.680 (0.19),8.716 (0.21), 8.730 (0.45), 8.744 (0.22)。

Example 157A

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (6-chloro-2, 3-difluorophenyl) pentanoic acid tert-butyl ester(raceme)

To a mixture of tert-butyl (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (6-chloro-2, 3-difluorophenyl) pentanoate (154 mg, 87% purity, 222 μmol, example 45A) in NMP (2 ml) was added piperidine (180 μ l, 1.8 mmol) and DIPEA (310 μ l, 1.8 mmol), and the mixture was stirred at 100 ℃ overnight. After cooling to room temperature, the mixture was filtered and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was dried in vacuo. 126 mg (100% purity, 87% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.82 min; MS (ESIpos): m/z = 650/652 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (0.07), -0.023 (0.47), 1.202(0.10), 1.233 (0.72), 1.362 (16.00), 1.518 (0.09), 1.606 (0.59), 1.670(1.09), 1.981 (0.14), 2.064 (0.26), 2.143 (3.28), 2.169 (0.73), 2.327 (0.09),2.365 (0.09), 2.670 (0.08), 2.709 (0.07), 3.134 (1.42), 3.689 (0.24), 3.766(0.34), 7.377 (0.42), 7.389 (0.49), 7.412 (0.33), 7.433 (0.29), 7.627 (0.40),7.649 (1.50), 7.659 (0.92), 7.664 (0.81), 7.681 (0.21), 7.686 (0.21), 8.811(0.45)。

Example 158A

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (5-fluoro-2-methylphenyl) pentanoic acid tert-butyl ester(raceme)

To a mixture of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (5-fluoro-2-methylphenyl) pentanoic acid tert-butyl ester (200 mg, 355 μmol, example 46A) in NMP (2 ml) was added piperidine (280 μ l,2.8 mmol) and DIPEA (620 μ l, 3.5mmol) and the mixture was stirred at 100 ℃ overnight. After cooling to room temperature, the mixture was filtered and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was dried in vacuo. 190 mg (100% purity, 87% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.83 min; MS (ESIpos): m/z = 612/614 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.023 (0.35), 0.852 (0.06), 1.211(0.08), 1.233 (0.83), 1.317 (0.07), 1.337 (0.10), 1.371 (16.00), 1.528(0.08), 1.606 (0.47), 1.669 (0.92), 1.754 (0.13), 1.787 (0.20), 1.811 (0.16),2.000 (0.19), 2.016 (0.18), 2.036 (0.20), 2.061 (0.78), 2.077 (0.97), 2.099(1.51), 2.291 (2.74), 2.365 (0.06), 2.669 (0.07), 2.709 (0.06), 3.135 (1.22),3.478 (0.17), 3.497 (0.20), 3.512 (0.23), 3.635 (0.15), 3.653 (0.23), 3.671(0.21), 3.686 (0.17), 3.706 (0.10), 6.928 (0.17), 6.943 (0.33), 6.949 (0.37),6.971 (0.20), 7.136 (0.36), 7.142 (0.37), 7.163 (0.37), 7.169 (0.36), 7.198(0.35), 7.213 (0.40), 7.234 (0.31), 7.455 (0.20), 7.628 (0.26), 7.650 (1.44),7.657 (0.95), 7.662 (0.83), 7.679 (0.16), 7.684 (0.18), 8.702 (0.23), 8.717(0.39), 8.730 (0.23)。

Example 159A

(+/-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (5-fluoro-2-methylphenyl) pentanoic acid tert-butyl ester(raceme)

To a mixture of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (5-fluoro-2-methylphenyl) pentanoic acid tert-butyl ester (336 mg, 596 μmol, example 46A) in NMP (4.0 ml) was added 3, 3-difluoropiperidine hydrochloride (751 mg, 4.77 mmol) and DIPEA (1.0ml, 6.0 mmol) and the mixture was stirred at 100 ℃ for 44 h. Then, the temperature was increased to 120 ℃ and the mixture was stirred for another 24 h. After cooling to room temperature, the mixture was filtered and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was dried in vacuo. 265 mg (100% purity, 69% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.70 min; MS (ESIpos): m/z = 648/650 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.212 (0.07), 1.316 (0.06), 1.337(0.10), 1.372 (16.00), 1.528 (0.07), 1.757 (0.13), 1.790 (0.21), 1.814(0.18), 1.829 (0.12), 1.878 (0.50), 1.988 (0.16), 2.002 (0.21), 2.018 (0.21),2.064 (0.98), 2.080 (1.25), 2.099 (0.84), 2.119 (1.49), 2.291 (2.79), 3.166(0.61), 3.449 (0.39), 3.478 (0.84), 3.507 (0.56), 3.523 (0.27), 3.646 (0.16),3.664 (0.25), 3.681 (0.22), 3.698 (0.18), 3.717 (0.10), 6.930 (0.19), 6.945(0.35), 6.951 (0.38), 6.972 (0.20), 7.142 (0.38), 7.148 (0.38), 7.169 (0.39),7.175 (0.37), 7.199 (0.37), 7.215 (0.43), 7.236 (0.33), 7.492 (0.19), 7.679(0.24), 7.701 (1.55), 7.706 (1.07), 7.711 (0.88), 7.734 (0.16), 8.716 (0.25),8.730 (0.42), 8.744 (0.25)。

Example 160A

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid tert-butyl ester(raceme)

To a mixture of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid tert-butyl ester (314 mg, 521 μmol, example 47A) in NMP (3.1 ml) was added piperidine (410 μ l, 4.2 mmol) and DIPEA (730 μ l, 4.2 mmol), and the mixture was stirred at 100 ℃ overnight. After cooling to room temperature, the mixture was filtered and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was dried in vacuo. 272 mg (100% purity, 80% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.80 min; MS (ESIpos): m/z = 650/652 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.022 (0.18), -0.008 (0.77), 0.008(0.66), 1.234 (0.33), 1.361 (16.00), 1.608 (0.43), 1.673 (0.83), 2.142(2.24), 2.366 (0.22), 2.710 (0.22), 3.138 (1.09), 3.759 (0.22), 7.303 (0.24),7.317 (0.19), 7.421 (0.24), 7.630 (0.32), 7.652 (1.33), 7.662 (0.94), 7.667(0.81), 7.684 (0.21), 7.690 (0.22), 8.814 (0.34)。

Example 161A

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid tert-butyl ester(raceme)

To a mixture of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid tert-butyl ester (600 mg, 996 μmol, example 47A) in NMP (4.0 ml) was added pyrrolidine (670 μ l, 8.0 mmol) and DIPEA (1.4 ml, 8.0 mmol) and the mixture was stirred at 110 ℃ for 5 h. After cooling to room temperature, methylene chloride (150 ml) was added to the mixture, which was successively washed with water and 1M hydrochloric acid (100 ml each). The organic phase was dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (50 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3 → 7:3, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 90 mg (100% purity, 14% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.25 min; MS (ESIpos): m/z = 636/638 [M+H]⁺

Example 162A

(+/-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid tert-butyl ester(raceme)

To a mixture of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid tert-butyl ester (536 mg, 890 μmol, example 47A) in NMP (3.6 ml) was added 3, 3-difluoropiperidine hydrochloride (1.12 g, 7.12 mmol) and DIPEA (1.6 ml, 8.9 mmol) and the mixture was stirred at 110 ℃ for three days. After cooling to room temperature, dichloromethane (150 ml) was added to the mixture and it was washed once with water (120 ml) and once with a mixture of 1M hydrochloric acid (25 ml) in water (100 ml). The organic phase was dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (50 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3 → 7:3, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 204 mg (100% purity, 33% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.67 min; MS (ESIpos): m/z = 686/688 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.156 (0.07), 1.174 (0.12), 1.200(0.08), 1.233 (0.12), 1.269 (0.09), 1.315 (0.44), 1.360 (16.00), 1.377(0.68), 1.406 (0.22), 1.517 (0.07), 1.883 (0.55), 1.987 (0.32), 2.082 (0.53),2.097 (0.54), 2.136 (0.81), 2.163 (2.62), 2.327 (0.07), 2.669 (0.05), 3.171(0.66), 3.450 (0.40), 3.479 (0.77), 3.508 (0.39), 3.696 (0.24), 3.771 (0.26),4.020 (0.06), 4.038 (0.05), 7.270 (0.14), 7.281 (0.16), 7.294 (0.28), 7.305(0.29), 7.319 (0.22), 7.330 (0.20), 7.410 (0.28), 7.421 (0.27), 7.681 (0.32),7.703 (1.51), 7.711 (1.02), 7.716 (0.87), 7.734 (0.20), 7.738 (0.21), 8.828(0.41)。

Example 163A

5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chloro-3, 6-difluorophenyl) pentanoic acid tert-butyl ester(mixture of diastereomers)

To a mixture of tert-butyl (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chloro-3, 6-difluorophenyl) pentanoate (600 mg, 996 μmol, example 47A) in NMP (4.0 ml) was added (+/-) -3-fluoropiperidine hydrochloride (1.11 g, 7.97 mmol) and DIPEA (1.7 ml, 10 mmol) and the mixture was stirred at 110 ℃ for 30 h. After cooling to room temperature, dichloromethane (150 ml) was added to the mixture and it was washed once with water (120 ml) and once with a mixture of 1M hydrochloric acid (25 ml) in water (100 ml). The organic phase was dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (50 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3 → 7:3, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 463 mg (100% purity, 69% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.68 min; MS (ESIpos): m/z = 668/670 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.17), 1.157 (0.10), 1.175(0.20), 1.193 (0.11), 1.201 (0.08), 1.235 (0.07), 1.268 (0.07), 1.316 (0.43),1.361 (16.00), 1.378 (0.68), 1.398 (2.22), 1.518 (0.07), 1.646 (0.20), 1.808(0.18), 1.901 (0.32), 1.920 (0.30), 1.952 (0.27), 1.989 (0.53), 2.067 (0.21),2.084 (0.21), 2.103 (0.18), 2.137 (0.65), 2.157 (2.66), 2.260 (0.06), 2.670(0.04), 3.099 (0.21), 3.168 (0.22), 3.349 (0.16), 3.380 (0.21), 3.410 (0.11),3.437 (0.19), 3.468 (0.12), 3.698 (0.22), 3.767 (0.25), 4.003 (0.04), 4.021(0.09), 4.039 (0.09), 4.057 (0.04), 4.820 (0.15), 4.940 (0.15), 7.269 (0.13),7.280 (0.15), 7.293 (0.26), 7.304 (0.28), 7.318 (0.21), 7.329 (0.19), 7.410(0.26), 7.421 (0.26), 7.499 (0.08), 7.655 (0.32), 7.677 (1.46), 7.686 (0.97),7.691 (0.89), 7.709 (0.21), 7.713 (0.23), 7.906 (0.04), 8.823 (0.37)。

Example 164A

5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- (2-chloro-3, 6-difluorophenyl) pentanoic acid tert-butyl ester(mixture of diastereomers)

To a mixture of tert-butyl (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chloro-3, 6-difluorophenyl) pentanoate (600 mg, 996 μmol, example 47A) in NMP (4.0 ml) was added (+/-) -3-methylpiperidine (940 μ l, 8.0 mmol) and DIPEA (1.4 ml, 8.0 mmol), and the mixture was stirred at 110 ℃ for 30 h. After cooling to room temperature, dichloromethane (150 ml) was added to the mixture and it was washed once with water (120 ml) and once with a mixture of 1M hydrochloric acid (25 ml) in water (100 ml). The organic phase was dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (50 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3 → 7:3, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 550 mg (100% purity, 83% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.90 min; MS (ESIpos): m/z = 664/666 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.867 (0.06), 0.884 (0.06), 0.954(1.62), 0.970 (1.65), 1.114 (0.19), 1.142 (0.20), 1.165 (0.08), 1.235 (0.08),1.267 (0.11), 1.303 (0.07), 1.348 (0.51), 1.395 (16.00), 1.411 (0.72), 1.431(5.54), 1.551 (0.07), 1.663 (0.17), 1.686 (0.19), 1.765 (0.35), 1.796 (0.33),1.826 (0.41), 1.857 (0.26), 2.017 (0.12), 2.102 (0.22), 2.118 (0.22), 2.138(0.22), 2.181 (2.31), 2.280 (0.06), 2.361 (0.04), 2.478 (0.17), 2.752 (0.17),3.470 (0.28), 3.498 (0.51), 3.528 (0.24), 3.730 (0.23), 3.795 (0.26), 7.301(0.14), 7.312 (0.16), 7.325 (0.27), 7.336 (0.28), 7.351 (0.22), 7.362 (0.20),7.421 (0.18), 7.432 (0.21), 7.443 (0.28), 7.454 (0.28), 7.465 (0.18), 7.476(0.15), 7.667 (0.24), 7.689 (1.52), 7.694 (1.18), 7.698 (0.95), 7.716 (0.16),7.721 (0.18), 8.828 (0.22), 8.842 (0.38), 11.235 (0.02)。

Example 165A

5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chloro-3, 6-difluorophenyl) pentanoic acid tert-butyl ester(mixture of diastereomers)

To a mixture of tert-butyl (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chloro-3, 6-difluorophenyl) pentanoate (600 mg, 996 μmol, example 47A) in NMP (4.0 ml) was added (+/-) -3-ethylpiperidine (1.1 ml, 8.0 mmol) and DIPEA (1.4 ml, 8.0 mmol), and the mixture was stirred at 110 ℃ for 30 h. After cooling to room temperature, dichloromethane (150 ml) was added to the mixture and it was washed once with water (150 ml) and once with a mixture of 1M hydrochloric acid (20 ml) in water (100 ml). The organic phase was dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (50 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3 → 7:3, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 558 mg (100% purity, 83% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 3.00 min; MS (ESIpos): m/z = 678/680 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.890 (0.96), 0.909 (2.20), 0.927(1.16), 1.065 (0.24), 1.095 (0.25), 1.200 (0.09), 1.259 (0.54), 1.276 (0.70),1.294 (0.48), 1.313 (0.75), 1.360 (16.00), 1.377 (0.79), 1.396 (1.93), 1.566(0.29), 1.747 (0.34), 1.779 (0.23), 1.847 (0.29), 1.877 (0.29), 1.973 (0.15),2.066 (0.28), 2.082 (0.29), 2.139 (2.33), 2.241 (0.08), 2.424 (0.20), 2.695(0.12), 2.752 (0.22), 3.490(0.54), 3.519 (0.51), 3.694 (0.28), 3.763 (0.32),7.276 (0.19), 7.290 (0.33), 7.300 (0.34), 7.314 (0.25), 7.325 (0.22), 7.404(0.35), 7.415 (0.35), 7.632 (0.27), 7.654 (1.72), 7.686 (0.19), 8.809 (0.48)。

Example 166A

(+/-) -5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid tert-butyl ester(raceme)

To a mixture of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid tert-butyl ester (600 mg, 996 μmol, example 47A) in NMP (4.0 ml) was added azepane (900 μ l, 8.0 mmol) and DIPEA (1.4 ml, 8.0 mmol) and the mixture was stirred at 110 ℃ for 5 h. After cooling to room temperature, dichloromethane (150 ml) was added to the mixture and it was washed once with a mixture of 1M hydrochloric acid (20 ml) in water (100 ml) and once with water (150 ml). The organic phase was dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (50 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3 → 7:3, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 599 mg (100% purity, 90% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.85 min; MS (ESIpos): m/z = 664/666 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.851 (0.05), 1.200 (0.08), 1.234(0.20), 1.267 (0.10), 1.312 (0.62), 1.360 (16.00), 1.377 (0.75), 1.397(4.30), 1.517 (0.09), 1.602 (1.91), 1.780 (1.21), 1.882 (0.08), 1.901 (0.11),1.920 (0.13), 1.972 (0.15), 2.065 (0.25), 2.082 (0.27), 2.133 (2.63), 2.150(1.06), 2.195 (0.12), 2.236 (0.07), 2.328 (0.05), 2.670 (0.04), 2.695 (0.40),3.285 (0.13), 3.492 (1.43), 3.506 (2.16), 3.520 (1.38), 3.708 (0.30), 7.266(0.15), 7.277 (0.18), 7.290 (0.31), 7.301 (0.33), 7.315 (0.24), 7.326 (0.22),7.407 (0.35), 7.418 (0.34), 7.532 (0.71), 7.554 (1.27), 7.602 (0.76), 7.607(0.67), 7.624 (0.42), 7.629 (0.39), 8.789 (0.43)。

Example 167A

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [ 2-fluoro-6- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(raceme)

To a mixture of tert-butyl (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- [ 2-fluoro-6- (trifluoromethyl) phenyl ] pentanoate (300 mg, 97% purity, 471 μmol, example 50A) in NMP (4.0 ml) in a thick-walled glass vessel (microwave vessel) was added piperidine (230 μ l, 2.4mmol) and DIPEA (410 μ l, 2.4 mmol). The vessel was purged with argon, sealed and shaken overnight at 100 ℃ by a heated shaker. Then shaken for a further 24h at 130 ℃. After cooling to room temperature, the mixture was directly purified by preparative HPLC (method 14) (without further work-up). The combined target fractions were concentrated, the residue dissolved in dichloromethane, concentrated again and dried in vacuo. 258 mg (100% purity, 82% of theory) of the title compound are obtained.

LC-MS (method 4) R_t= 1.80 min, ionization without detection of target mass

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.10), -0.008 (0.85), 0.008(0.95), 0.146 (0.10), 1.307 (0.15), 1.340 (16.00), 1.613 (0.43), 1.678(0.85), 2.042 (0.25), 2.073 (0.48), 2.093 (0.35), 2.114 (0.48), 2.141 (0.39),2.168 (1.23), 2.328 (0.11), 2.670 (0.11), 3.151 (1.11), 3.700 (0.12), 3.849(0.11), 5.754 (0.33), 7.561 (0.48), 7.571 (0.44), 7.594 (0.69), 7.622 (0.44),7.634 (0.51), 7.656 (1.32), 7.661 (0.97), 7.666 (0.84), 7.688 (0.17), 8.803(0.21), 8.818 (0.42), 8.833 (0.21)。

Separation of enantiomers:

the title compound (188 mg) was separated by preparative SFC on a chiral column into enantiomers (see examples 168A and 169A) [ column: daicel Chiralcel OX-H, 5 μm,250 mm x20 mm, flow rate: 60 ml/min, UV detection: 260 nm, temperature: 25 ℃, eluent 10% methanol/90% carbon dioxide, outlet pressure 150 bar, isocratic. The combined target fractions were each concentrated and the residue was dried in vacuo.

Example 168A

5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [ 2-fluoro-6- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(enantiomer 1)

In the enantiomeric separation described in example 167A, 85 mg (100% purity, ee value 99%) of the title compound were obtained as the earlier eluting enantiomer.

R_t= 11.5 min (chiral analytical HPLC; column: Chiralpak IE, 5 μm,250 mm x 4.6mm, eluent: heptane/isopropanol/diethylamine 80:20:0.1; flow rate 1 ml/min; temperature 25 ℃; detection 225 nm)

LC-MS (method 2) R_t= 1.48 min; MS (ESIpos): m/z = 666/668 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.348 (16.00), 1.621 (0.41), 1.687(0.81), 2.080 (0.44), 2.122 (0.46), 2.177 (1.18), 3.158 (1.06), 7.569 (0.47),7.579 (0.44), 7.603 (0.69), 7.631 (0.44), 7.642 (0.51), 7.664 (1.33), 7.669(1.00), 7.674 (0.86), 8.826 (0.40)。

Example 169A

5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [ 2-fluoro-6- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(enantiomer 2)

In the enantiomeric separation described in example 167A, 93 mg (100% purity, ee value 97%) of the title compound were obtained as the enantiomer which eluted later.

R_t= 10.3 min (chiral analytical HPLC; column: Chiralpak IE, 5 μm,250 mm x 4.6mm, eluent: heptane/isopropanol/diethylamine 80:20:0.1; flow rate 1 ml/min; temperature 25 ℃; detection 225nm)

LC-MS (method 2) R_t= 1.48 min; MS (ESIpos): m/z = 666/668 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.009 (0.46), 0.007 (0.43), 1.029(0.54), 1.044 (0.55), 1.235 (0.26), 1.307 (0.15), 1.340 (16.00), 1.613(0.42), 1.678 (0.83), 2.041 (0.24), 2.072 (0.47), 2.092 (0.34), 2.114 (0.47),2.140 (0.39), 2.167 (1.21), 2.327 (0.11), 2.669 (0.11), 3.154 (1.12), 3.714(0.12), 3.847 (0.11), 7.561 (0.47), 7.570 (0.43), 7.594 (0.69), 7.622 (0.44),7.633 (0.49), 7.655 (1.31), 7.661 (0.93), 7.666 (0.80), 7.688 (0.16), 8.802(0.20), 8.817 (0.41), 8.832 (0.20)。

Example 170A

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [ 2-fluoro-6- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(raceme)

To a mixture of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- [ 2-fluoro-6- (trifluoromethyl) phenyl ] pentanoic acid tert-butyl ester (300 mg, 97% purity, 471 μmol, example 50A) in NMP (4.0 ml) in a thick-walled glass vessel (microwave vessel) was added pyrrolidine (200 μ l, 2.4mmol) and DIPEA (410 μ l, 2.4 mmol). The vessel was purged with argon, sealed and shaken overnight at 100 ℃ by a heated shaker. After cooling to room temperature, the mixture was directly purified by preparative HPLC (method 14) (without further work-up). The combined target fractions were concentrated, the residue dissolved in dichloromethane, concentrated again and dried in vacuo. 239 mg (100% purity, 78% of theory) of the title compound are obtained.

LC-MS (method 4) R_t= 1.46 min; MS (ESIpos): m/z = 652/654 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.10), -0.008 (0.85), 0.008(0.95), 0.146 (0.10), 1.290 (0.07), 1.308 (0.14), 1.337 (16.00), 1.879(1.23), 2.038 (0.27), 2.067 (0.53), 2.093 (0.41), 2.115 (0.61), 2.144 (0.39),2.178 (0.48), 2.328 (0.11), 2.669 (0.10), 3.581 (0.86), 3.867 (0.11), 5.754(0.65), 7.476 (0.63), 7.499 (1.10), 7.552 (0.74), 7.557 (0.95), 7.574 (0.65),7.580 (0.59), 7.590 (0.62), 7.613 (0.41), 8.745 (0.19), 8.760 (0.38), 8.775(0.20)。

Separation of enantiomers:

the title compound (163 mg) was separated by preparative SFC on a chiral column into enantiomers (see examples 171A and 172A) [ column: daicel Chiralpak IG, 5 μm,250 mm x20 mm, flow rate: 60 ml/min, UV detection: 230 nm, temperature: 25 deg.C, eluent 20% (methanol + 1% diethylamine)/80% carbon dioxide, outlet pressure 150 bar, isocratic. The combined target fractions were each concentrated and the residue was dried in vacuo.

Example 171A

5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [ 2-fluoro-6- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(enantiomer 1)

In the enantiomeric separation described in example 170A, 75 mg (98% purity, ee value 98%) of the title compound were obtained as the earlier eluting enantiomer.

R_t= 10.8 min (chiral analytical HPLC; column: Chiralpak IC, 5 μm,250 mm x 4.6mm, eluent: heptane/isopropanol/diethylamine 70:30:0.1; flow rate 1 ml/min; temperature 25 ℃; detection 260 nm)

LC-MS (method 2) R_t= 1.11 min; MS (ESIpos): m/z = 652/654 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.029 (0.47), 1.045 (0.47), 1.337(16.00), 1.879 (1.24), 2.038 (0.29), 2.067 (0.55), 2.092 (0.43), 2.115(0.62), 2.144 (0.40), 2.179 (0.49), 2.327 (0.16), 2.669 (0.15), 3.581 (0.87),7.476 (0.64), 7.498 (1.12), 7.552 (0.76), 7.557 (0.98), 7.574 (0.67), 7.580(0.60), 7.590 (0.64), 7.613 (0.42), 8.760 (0.38)。

Example 172A

5- ({ [ 6-bromo-3-methyl-2- (pyrrolidine)-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [ 2-fluoro-6- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(enantiomer 2)

In the enantiomeric separation described in example 170A, 79 mg (97% purity, ee value 98%) of the title compound were obtained as the enantiomer which eluted later.

R_t= 13.4 min (chiral analytical HPLC; column: Chiralpak IC, 5 μm,250 mm x 4.6mm, eluent: heptane/isopropanol/diethylamine 70:30:0.1; flow rate 1 ml/min; temperature 25 ℃; detection 260 nm)

LC-MS (method 2) R_t= 1.11 min; MS (ESIpos): m/z = 652/654 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.030 (1.27), 1.045 (1.26), 1.235(0.11), 1.308 (0.16), 1.337 (16.00), 1.879 (1.30), 1.960 (0.11), 2.037(0.29), 2.067 (0.56), 2.093 (0.44), 2.115 (0.64), 2.144 (0.41), 2.178 (0.52),2.327 (0.12), 3.580 (0.92), 3.864 (0.12), 7.476 (0.67), 7.498 (1.16), 7.552(0.83), 7.557 (1.01), 7.574 (0.69), 7.580 (0.63), 7.589 (0.66), 7.613 (0.43),8.760 (0.40)。

Example 173A

(+/-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- [ 2-fluoro-6- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(raceme)

To a mixture of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- [ 2-fluoro-6- (trifluoromethyl) phenyl ] pentanoic acid tert-butyl ester (300 mg, 98% purity, 476 μmol, example 50A) in NMP (4.0 ml) in a thick-walled glass vessel (microwave vessel) was added 3, 3-difluoropiperidine hydrochloride (387 mg, 97% purity, 2.38 mmol) and DIPEA (410 μ l, 2.4 mmol). The vessel was purged with argon, sealed and shaken overnight at 100 ℃ by a heated shaker. Then shaken for a further 24h at 130 ℃. After cooling to room temperature, the mixture was directly purified by preparative HPLC (method 14) (without further work-up). The combined target fractions were concentrated, the residue dissolved in dichloromethane, concentrated again and dried in vacuo. 248 mg (100% purity, 74% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.72 min; MS (ESIpos): m/z = 702/704 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.05), -0.008 (0.42), 0.008(0.38), 0.146 (0.05), 1.180 (0.06), 1.290 (0.07), 1.307 (0.14), 1.340(16.00), 1.497 (0.06), 1.889 (0.41), 2.049 (0.30), 2.078 (0.59), 2.100(0.65), 2.117 (0.70), 2.141 (0.44), 2.189 (1.10), 2.328 (0.07), 2.670 (0.07),3.181 (0.46), 3.462 (0.32), 3.491 (0.63), 3.520 (0.31), 3.717 (0.11), 3.864(0.10), 5.754 (0.18), 7.565 (0.44), 7.574 (0.43), 7.598 (0.65), 7.625 (0.43),7.634 (0.28), 7.648 (0.20), 7.684 (0.20), 7.706 (1.32), 7.710 (1.02), 7.715(0.83), 7.733 (0.12), 7.737 (0.15), 8.815 (0.20), 8.831 (0.42), 8.846 (0.20)。

Separation of enantiomers:

the title compound (179 mg) was separated by preparative SFC on a chiral column into enantiomers (see examples 174A and 175A) [ column: daicel Chiralpak AD-H, 5 μm,250 mm x 30mm, flow rate: 120 ml/min, UV detection: 260 nm, temperature: 25 ℃, eluent 10 percent of isopropanol/90 percent of carbon dioxide, outlet pressure 150 bar, isocratic degree. The combined target fractions were each concentrated and the residue was dried in vacuo.

Example 174A

5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- [ 2-fluoro-6- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(enantiomer 1)

In the enantiomeric separation described in example 173A, 91 mg (100% purity, ee >99%) of the title compound were obtained as the earlier eluting enantiomer.

R_t= 18.1 min (chiral analytical HPLC; column: Chiralpak IC, 5 μm,250 mm x 4.6mm, eluent: heptane/isopropanol/diethylamine 90:10:0.1; flow rate 1 ml/min; temperature 25 ℃; detection 225 nm)

LC-MS (method 2) R_t= 1.43 min; MS (ESIpos): m/z = 702/704 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.91), 0.008 (0.87), 1.030(1.67), 1.045 (1.69), 1.237 (0.39), 1.340 (16.00), 1.888 (0.40), 2.100(0.64), 2.117 (0.68), 2.141 (0.43), 2.189 (1.08), 2.328 (0.16), 2.670 (0.17),3.187 (0.45), 3.462 (0.32), 3.491 (0.62), 3.520 (0.31), 4.323 (0.21), 4.334(0.21), 7.565 (0.44), 7.575 (0.42), 7.598 (0.64), 7.625 (0.42), 7.684 (0.20),7.706 (1.29), 7.710 (1.00), 7.715 (0.82), 7.737 (0.15), 8.830 (0.40)。

Example 175A

5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- [ 2-fluoro-6- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(enantiomer 2)

In the enantiomeric separation described in example 173A, 93 mg (100% purity, ee >99%) of the title compound were obtained as the later eluting enantiomer.

R_t= 21.4 min (chiral analytical HPLC; column: Chiralpak IC, 5 μm,250 mm x 4.6mm, eluent: heptane/isopropanol/diethylamine 90:10:0.1; flow rate 1 ml/min; temperature 25 ℃; detection 225 nm)

LC-MS (method 2) R_t= 1.43 min; MS (ESIpos): m/z = 702/704 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.007 (0.93), 1.029 (1.51), 1.044(1.53), 1.236 (0.47), 1.340 (16.00), 1.889 (0.45), 2.100 (0.71), 2.115(0.76), 2.140 (0.47), 2.188 (1.18), 2.327 (0.16), 2.669 (0.17), 3.183 (0.50),3.462 (0.34), 3.490 (0.67), 3.519 (0.33), 4.322 (0.21), 4.333 (0.20), 7.564(0.46), 7.574 (0.46), 7.597 (0.67), 7.624 (0.45), 7.683 (0.20), 7.705 (1.37),7.709 (1.07), 7.714 (0.86), 7.737 (0.15), 8.830 (0.43)。

Example 176A

5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [ 2-fluoro-6- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(diastereoisomers)Mixture)

To a mixture of tert-butyl (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- [ 2-fluoro-6- (trifluoromethyl) phenyl ] pentanoate (400 mg, 98% purity 634. mu.mol, example 50A) in NMP (4.0 ml) in a thick-walled glass vessel (microwave vessel) was added (+/-) -3-fluoropiperidine hydrochloride (457 mg, 97% purity, 3.17mmol) and DIPEA (550. mu.l, 3.2 mmol). The vessel was purged with argon, sealed and shaken overnight at 130 ℃ by a heated shaker. After cooling to room temperature, the mixture was directly purified by preparative HPLC (method 14) (without further work-up). The combined target fractions were concentrated, the residue dissolved in dichloromethane, concentrated again and dried in vacuo. 351mg (100% purity, 81% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.71 min; MS (ESIpos): m/z = 684/686 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.42), 0.008 (0.45), 1.307(0.13), 1.340 (16.00), 1.654 (0.14), 1.813 (0.14), 1.906 (0.24), 2.075(0.45), 2.097 (0.36), 2.116 (0.48), 2.142 (0.31), 2.181 (1.06), 2.328 (0.11),2.670 (0.12), 3.113 (0.17), 3.179 (0.17), 3.391 (0.18), 3.449 (0.16), 3.482(0.10), 3.705 (0.11), 3.861 (0.11), 4.825 (0.12), 4.945 (0.12), 5.754 (0.82),7.562 (0.45), 7.573 (0.42), 7.595 (0.65), 7.623 (0.43), 7.636 (0.28), 7.657(0.21), 7.679 (1.15), 7.712 (0.12), 8.824 (0.35)。

Example 177A

5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [ 2-fluoro-6- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(mixture of diastereomers)

To a mixture of tert-butyl (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- [ 2-fluoro-6- (trifluoromethyl) phenyl ] pentanoate (400 mg, 98% purity 634. mu.mol, example 50A) in NMP (4.0 ml) in a thick-walled glass vessel (microwave vessel) was added (+/-) -3-ethylpiperidine (378 mg, 95% purity, 3.17mmol) and DIPEA (550. mu.l, 3.2 mmol). The vessel was purged with argon, sealed and shaken overnight at 130 ℃ by a heated shaker. After cooling to room temperature, the mixture was directly purified by preparative HPLC (method 14) (without further work-up). The combined target fractions were concentrated, the residue dissolved in dichloromethane, concentrated again and dried in vacuo. 383 mg (100% purity, 87% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 3.01 min; MS (ESIpos): m/z = 684/686 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.009 (0.42), 0.007 (0.45), 1.306(0.13), 1.339 (16.00), 1.653 (0.14), 1.812 (0.14), 1.905 (0.24), 2.075(0.45), 2.096 (0.36), 2.116 (0.48), 2.141 (0.31), 2.180 (1.06), 2.327 (0.11),2.669 (0.12), 3.112 (0.17), 3.178 (0.17), 3.390 (0.18), 3.448 (0.16), 3.482(0.10), 3.704 (0.11), 3.860 (0.11), 4.825 (0.12), 4.944 (0.12), 5.753 (0.82),7.562 (0.45), 7.572 (0.42), 7.595 (0.65), 7.622 (0.43), 7.635 (0.28), 7.656(0.21), 7.679 (1.15), 7.711 (0.12), 8.823 (0.35)。

Example 178A

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2,3, 6-trichlorophenyl) pentanoic acid tert-butyl ester(raceme)

To a mixture of tert-butyl (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2,3, 6-trichlorophenyl) pentanoate (300 mg, 472 μmol, example 51A) in NMP (4.0 ml) in a thick-walled glass vessel (microwave vessel) was added piperidine (230 μ l, 2.4mmol) and DIPEA (410 μ l, 2.4 mmol). The vessel was purged with argon, sealed and shaken overnight at 130 ℃ by a heated shaker. After cooling to room temperature, the mixture was directly purified by preparative HPLC (method 14) (without further work-up). The combined target fractions were concentrated, the residue dissolved in dichloromethane, concentrated again and dried in vacuo. 242 mg (100% purity, 75% of theory) of the title compound are obtained.

LC-MS (method 4) R_t= 1.87 min, ionizing without detecting target mass

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.20), 0.008 (1.31), 1.351(14.79), 1.355 (16.00), 1.610 (0.78), 1.674 (1.51), 2.073 (3.11), 2.138(2.16), 2.156 (0.92), 2.169 (3.50), 2.327 (0.31), 2.670 (0.18), 3.141 (1.94),3.819 (0.29), 4.033 (0.51), 7.473 (0.58), 7.495 (0.81), 7.532 (0.71), 7.554(1.23), 7.593 (0.84), 7.614 (0.57), 7.631 (0.37), 7.637 (0.35), 7.653 (1.38),7.659 (1.35), 7.669 (1.22), 7.674 (0.69), 7.691 (0.30), 8.806 (0.51)。

Separation of enantiomers:

the title compound (194 mg) was separated by preparative SFC on a chiral column into enantiomers (see examples 179A and 180A) [ column: daicel Chiralpak IG, 5 μm,250 mm x20 mm, flow rate: 60 ml/min, UV detection: 260 nm, temperature: 25 ℃, eluent 35% (isopropanol + 1% diethylamine)/65% carbon dioxide, outlet pressure 150 bar, isocratic ]. The combined target fractions were each concentrated and the residue was dried in vacuo. Peak 2 was re-separated by chiral HPLC [ column: daicel Chiralpak IG, 5 μm,250 mm x20 mm, flow rate: 20 ml/min, UV detection: 260 nm, temperature: 25 deg.C, eluent 20% ethyl acetate/80% heptane, isocratic ]

Example 179A

5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2,3, 6-trichlorophenyl) pentanoic acid tert-butyl ester(enantiomer 1)

In the enantiomeric separation described in example 178A, 92 mg (100% purity, ee value 98%) of the title compound were obtained as the earlier eluting enantiomer.

R_t= 8.3 min (chiral analytical HPLC; column: Chiralpak IG, 5 μm)250mm x 4.6mm, eluent heptane/isopropanol/diethylamine 70:30:0.1, flow rate 1 ml/min, temperature 25 deg.C, detection 225 nm)

LC-MS (method 2) R_t= 1.58 min; MS (ESIpos): m/z = 682/684/686 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.84), 0.008 (0.66), 1.029(4.38), 1.045 (4.40), 1.236 (0.62), 1.351 (15.34), 1.355 (16.00), 1.609(0.80), 1.673 (1.53), 2.083 (0.46), 2.098 (0.48), 2.112 (0.60), 2.137 (2.18),2.156 (0.97), 2.169 (3.55), 2.523 (0.44), 3.141 (1.98), 4.032 (0.52), 4.323(0.54), 4.334 (0.53), 7.473 (0.56), 7.495 (0.78), 7.532 (0.67), 7.554 (1.18),7.593 (0.80), 7.599 (0.70), 7.615 (0.56), 7.653 (1.35), 7.659 (1.31), 7.662(1.07), 7.669 (1.19), 7.674 (0.67), 8.792 (0.44), 8.806 (0.51)。

Example 180A

5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2,3, 6-trichlorophenyl) pentanoic acid tert-butyl ester(enantiomer 2)

In the enantiomeric separation described in example 178A, 96 mg (100% purity, ee >99%) of the title compound are obtained as the enantiomer which elutes later.

R_t= 11.0 min (chiral analytical HPLC; column: Chiralpak IG, 5 μm,250 mm x 4.6mm, eluent: heptane/isopropanol/diethylamine 70:30:0.1; flow rate 1 ml/min; temperature 25 ℃; detection 225 nm)

LC-MS (method 2) R_t= 1.58 min; MS (ESIpos): m/z = 682/684/686 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.62), 0.008 (0.63), 0.854(0.49), 0.858 (0.46), 1.237 (2.83), 1.249 (1.11), 1.258 (0.60), 1.336 (0.75),1.351 (15.06), 1.355 (16.00), 1.610 (0.78), 1.673 (1.51), 2.083 (0.45), 2.098(0.47), 2.111 (0.58), 2.137 (2.17), 2.156 (0.95), 2.169 (3.50), 3.141 (1.96),4.032 (0.52), 7.473 (0.54), 7.495 (0.77), 7.532 (0.67), 7.554 (1.15), 7.593(0.79), 7.599 (0.69), 7.615 (0.55), 7.653 (1.32), 7.658 (1.27), 7.662 (1.06),7.668 (1.15), 7.674 (0.65), 8.791 (0.43), 8.806 (0.50)。

Example 181A

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2,3, 6-trichlorophenyl) pentanoic acid tert-butyl ester(raceme)

To a mixture of tert-butyl (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2,3, 6-trichlorophenyl) pentanoate (300 mg, 472 μmol, example 51A) in NMP (4.0 ml) in a thick-walled glass vessel (microwave vessel) was added pyrrolidine (200 μ l, 2.4mmol) and DIPEA (410 μ l, 2.4 mmol). The vessel was purged with argon, sealed and shaken overnight at 130 ℃ by a heated shaker. After cooling to room temperature, the mixture was directly purified by preparative HPLC (method 14) (without further work-up). The combined target fractions were concentrated, the residue dissolved in dichloromethane, concentrated again and dried in vacuo. 261 mg (100% purity, 82% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.45 min; MS (ESIpos): m/z = 668/670/672 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.69), -0.008 (5.80), 0.008(5.56), 0.146 (0.67), 1.349 (16.00), 1.353 (15.98), 1.875 (2.13), 2.073(0.92), 2.095 (0.52), 2.121 (0.82), 2.134 (1.09), 2.158 (1.22), 2.174 (0.95),2.193 (2.16), 2.327 (0.75), 2.669 (0.62), 3.575 (1.49), 4.035 (0.47), 7.473(1.07), 7.480 (0.77), 7.495 (1.59), 7.502 (1.19), 7.522 (0.70), 7.544 (1.21),7.553 (0.77), 7.560 (0.99), 7.566 (0.60), 7.576 (0.52), 7.587 (0.94), 7.608(0.50), 8.754 (0.54)。

Separation of enantiomers:

the title compound (199 mg) was separated into enantiomers by preparative SFC on chiral column (see examples 182A and 183A) [ column: daicel Chiralpak IG, 5 μm,250 mm x20 mm, flow rate: 60 ml/min, UV detection: 230 nm, temperature: 25 ℃, eluent 40 percent (isopropanol and 1 percent diethylamine)/60 percent carbon dioxide, and outlet pressure of 150 bar, isocratic degrees. The combined target fractions were each concentrated and the residue was dried in vacuo.

Example 182A

5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2,3, 6-trichlorophenyl) pentanoic acid tert-butyl ester(enantiomer 1)

In the enantiomeric separation described in example 181A, 92 mg (100% purity, ee >99%) of the title compound were obtained as the earlier eluting enantiomer.

R_t= 12.0 min (chiral analytical HPLC; column: Chiralpak IG, 5 μm,250 mm x 4.6mm, eluent: heptane/isopropanol/diethylamine 70:30:0.1; flow rate 1 ml/min; temperature 25 ℃; detection 225 nm)

LC-MS (method 2) R_t= 1.21 min; MS (ESIpos): m/z = 668/670/672 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.88), 0.008 (0.72), 1.030(1.55), 1.045 (1.56), 1.236 (1.18), 1.349 (15.95), 1.353 (16.00), 1.875(2.18), 2.080 (0.50), 2.095 (0.55), 2.108 (0.59), 2.121 (0.86), 2.135 (1.11),2.158 (1.23), 2.174 (0.99), 2.193 (2.17), 2.327 (0.41), 3.574 (1.54), 4.037(0.49), 7.473 (1.01), 7.480 (0.76), 7.495 (1.53), 7.502 (1.18), 7.522 (0.66),7.544 (1.14), 7.554 (0.74), 7.560 (0.96), 7.566 (0.59), 7.576 (0.51), 7.588(0.95), 7.609 (0.51), 8.755 (0.50)。

Example 183A

5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2,3, 6-trichlorophenyl) pentanoic acid tert-butyl ester(enantiomer 2)

In the enantiomeric separation described in example 181A, 98 mg (100% purity, ee value 99%) of the title compound were obtained as the enantiomer which eluted later.

R_t= 16.7 min (chiral analytical HPLC; column: Chiralpak IG, 5 μm,250 mm x 4.6mm, eluent: heptane/isopropanol/diethylamine 70:30:0.1; flow rate 1 ml/min; temperature 25 ℃; detection 225 nm)

LC-MS (method 2) R_t= 1.21 min; MS (ESIpos): m/z = 668/670/672 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.95), 0.008 (0.59), 0.854(0.51), 1.030 (1.60), 1.045 (1.59), 1.092 (0.52), 1.236 (2.83), 1.259 (0.57),1.331 (0.85), 1.349 (16.00), 1.353 (15.73), 1.875 (2.07), 1.961 (0.65), 2.081(0.48), 2.095 (0.54), 2.108 (0.58), 2.120 (0.84), 2.134 (1.06), 2.158 (1.19),2.174 (0.97), 2.193 (2.12), 2.327(0.40), 3.574 (1.44), 4.037 (0.47), 7.473(1.00), 7.480 (0.76), 7.495 (1.52), 7.502 (1.18), 7.522 (0.67), 7.544 (1.15),7.554 (0.74), 7.560 (0.97), 7.567 (0.59), 7.576 (0.49), 7.588 (0.93), 7.609(0.51), 8.756 (0.50)。

Example 184A

(+/-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2,3, 6-trichlorophenyl) pentanoic acid tert-butyl ester(raceme)

To a mixture of tert-butyl (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2,3, 6-trichlorophenyl) pentanoate (300 mg, 472 μmol, example 51A) in NMP (4.0 ml) in a thick-walled glass vessel (microwave vessel) was added 3, 3-difluoropiperidine hydrochloride (372 mg, 2.36 mmol) and DIPEA (410 μ l, 2.4 mmol). The vessel was purged with argon, sealed and shaken overnight at 130 ℃ by a heated shaker. Then stirred at 140 ℃ for 24 h. After cooling to room temperature, the mixture was directly purified by preparative HPLC (method 14) (without further work-up). The combined target fractions were concentrated, the residue dissolved in dichloromethane, concentrated again and dried in vacuo. 241 mg (100% purity, 71% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.83 min; MS (ESIpos): m/z = 718/720/722 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.55), 0.008 (2.50), 1.331(0.53), 1.351 (14.99), 1.355 (16.00), 1.883 (0.79), 2.100 (0.98), 2.115(0.97), 2.128 (1.23), 2.159 (1.91), 2.189 (3.51), 2.328 (0.53), 3.177 (0.91),3.453 (0.61), 3.483 (1.16), 3.511 (0.61), 4.035 (0.51), 7.476 (0.52), 7.498(0.75), 7.534 (0.65), 7.556 (1.20), 7.595 (0.89), 7.617 (0.61), 7.704 (1.44),7.711 (1.65), 7.718 (1.30), 7.724 (0.76), 8.819 (0.53)。

Separation of enantiomers:

the title compound (172 mg) was separated by preparative SFC on a chiral column into enantiomers (see examples 185A and 186A) [ column: daicel Chiralpak IG, 5 μm,250 mm x20 mm, flow rate: 60 ml/min, UV detection: 260 nm, temperature: 25 ℃, eluent of 25 percent isopropanol/75 percent carbon dioxide, outlet pressure of 150 bar, isocratic degree. The combined target fractions were each concentrated and the residue was dried in vacuo. Peak 2 was re-isolated by chiral HPLC. [ column: daicel Chiralpak IG, 5 μm,250 mm x20 mm, flow rate: 20 ml/min, UV detection: 260 nm, temperature: 25 deg.C, eluent 20% ethyl acetate/80% heptane, isocratic ]

Example 185A

5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2,3, 6-trichlorophenyl) pentanoic acid tert-butyl ester(enantiomer 1)

In the enantiomeric separation described in example 184A, 79 mg (100% purity, ee value 97%) of the title compound were obtained as the earlier eluting enantiomer.

R_t= 7.9 min (chiral analytical HPLC; column: Chiralpak IG, 5 μm,250 mm x 4.6mm, eluent: heptane/isopropanol/diethylamine 70:30:0.1; flow rate 1 ml/min; temperature 25 ℃; detection 225 nm)

LC-MS (method 2) R_t= 1.49 min; MS (ESIpos): m/z = 718/720/722 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.18), 0.008 (1.05), 1.029(2.87), 1.045 (2.90), 1.236 (1.65), 1.330 (0.53), 1.351 (15.41), 1.355(16.00), 1.884 (0.77), 2.085 (0.83), 2.100 (0.95), 2.115 (0.96), 2.128(1.21), 2.159 (1.89), 2.173 (0.76), 2.189 (3.45), 3.176 (0.89), 3.453 (0.59),3.482 (1.14), 3.511 (0.60), 4.036 (0.49), 7.476 (0.50), 7.498 (0.72), 7.534(0.62), 7.556 (1.17), 7.595 (0.80), 7.617 (0.56), 7.704 (1.34), 7.711 (1.51),7.718 (1.22), 7.724 (0.71), 8.805 (0.43), 8.819 (0.52)。

Example 186A

5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2,3, 6-trichlorophenyl) pentanoic acid tert-butyl ester(enantiomer 2)

In the enantiomeric separation described in example 184A, 100 mg (100% purity, ee >99%) of the title compound are obtained as the enantiomer which elutes later.

R_t= 10.1 min (chiral analytical HPLC; column: Chiralpak IG, 5 μm,250 mm x 4.6mm, eluent: heptane/isopropanol/diethylamine 70:30:0.1; flow rate 1 ml/min; temperature 25 ℃; detection 225 nm)

LC-MS (method 2) R_t= 1.49 min; MS (ESIpos): m/z = 718/720/722 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.56), 0.008 (1.36), 0.836(0.55), 0.854 (1.20), 0.858 (0.83), 0.870 (0.53), 1.237 (6.54), 1.249 (2.69),1.259 (1.82), 1.298 (1.07), 1.335 (1.81), 1.351 (15.42), 1.355 (16.00), 1.883(0.75), 2.085 (0.81), 2.100 (0.95), 2.115 (0.92), 2.128 (1.16), 2.159 (1.85),2.189 (3.47), 2.322 (0.42), 2.327 (0.45), 3.176 (0.87), 3.453 (0.60), 3.482(1.12), 3.511 (0.57), 4.036 (0.49), 7.476 (0.51), 7.498 (0.72), 7.534 (0.62),7.556 (1.16), 7.595 (0.80), 7.617 (0.57), 7.704 (1.36), 7.711 (1.52), 7.718(1.22), 7.724 (0.72), 8.806 (0.41), 8.819 (0.51)。

Example 187A

5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2,3, 6-trichlorophenyl) pentanoic acid tert-butyl ester(mixture of diastereomers)

To a mixture of tert-butyl (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2,3, 6-trichlorophenyl) pentanoate (400 mg, 630. mu. mol, example 51A) in NMP (4.0 ml) in a thick-walled glass vessel (microwave vessel) was added (+/-) -3-fluoropiperidine hydrochloride (440 mg, 3.15 mmol) and DIPEA (550. mu.l, 3.1 mmol). The vessel was purged with argon, sealed and shaken overnight at 130 ℃ by a heated shaker. After cooling to room temperature, the mixture was directly purified by preparative HPLC (method 14) (without further work-up). The combined target fractions were concentrated, the residue dissolved in dichloromethane, concentrated again and dried in vacuo. 355 mg (100% purity, 80% of theory) of the title compound are obtained.

LC-MS (method 4) R_t= 1.80 min, ionization without detection of target mass

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.330 (0.83), 1.351 (14.93), 1.354(16.00), 1.899 (0.53), 2.085 (0.47), 2.099 (0.52), 2.126 (0.99), 2.139(1.04), 2.155 (2.15), 2.182 (3.06), 2.327 (0.43), 4.036 (0.55), 5.754 (0.98),7.475 (0.50), 7.496 (0.70), 7.533 (0.63), 7.554 (1.12), 7.593 (0.76), 7.615(0.53), 7.677 (1.36), 7.683 (1.42), 7.692 (1.25), 8.800 (0.49), 8.814 (0.55)。

Example 188A

5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2,3, 6-trichlorophenyl) pentanoic acid tert-butyl ester(mixture of diastereomers)

To a mixture of tert-butyl (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2,3, 6-trichlorophenyl) pentanoate (400 mg, 630. mu. mol, example 51A) in NMP (4.0 ml) in a thick-walled glass vessel (microwave vessel) was added (+/-) -3-ethylpiperidine (356 mg, 3.15 mmol) and DIPEA (550. mu.l, 3.1 mmol). The vessel was purged with argon, sealed and shaken overnight at 130 ℃ by a heated shaker. After cooling to room temperature, the mixture was directly purified by preparative HPLC (method 14) (without further work-up). The combined target fractions were concentrated, the residue dissolved in dichloromethane, concentrated again and dried in vacuo. 383 mg (100% purity, 85% of theory) of the title compound are obtained.

LC-MS (method 4) R_t= 1.80 min, ionization without detection of target mass

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.66), 0.008 (1.50), 0.893(1.23), 0.912 (2.91), 0.930 (1.51), 1.263 (0.60), 1.281 (0.76), 1.303 (0.62),1.352 (15.56), 1.356 (16.00), 2.086 (0.46), 2.099 (0.52), 2.133 (1.62), 2.158(2.77), 2.163 (1.99), 3.494 (0.64), 3.525 (0.59), 4.025 (0.41), 4.037 (0.41),5.754 (1.33), 7.473 (0.59), 7.495 (0.85), 7.527 (0.71), 7.549 (1.21), 7.588(0.74), 7.596 (0.78), 7.610 (0.51), 7.617 (0.44), 7.656 (1.49), 7.660 (2.02),7.665 (1.35), 8.790 (0.44)。

Example 189A

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (difluoromethoxy) -6-fluorophenyl]Glutaric acid tert-butyl ester(raceme)

To a mixture of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- [2- (difluoromethoxy) -6-fluorophenyl ] pentanoic acid tert-butyl ester (1.00 g, 1.62 mmol, example 52A) in NMP (5.8ml) was added piperidine (1.3ml, 13 mmol) and DIPEA (2.3 ml, 13 mmol) and the mixture was stirred at 110 deg.C for 5 h. After cooling to room temperature, dichloromethane (150 ml) was added to the mixture and it was washed once with water (150 ml) and once with a mixture of 1M hydrochloric acid (40 ml) in water (100 ml). The organic phase was dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (50 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3 → 7:3, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 933 mg (96% purity, 83% of theory) of the title compound are obtained.

LC-MS (Square-tube Mass Spectrometry)Method 1) R_t= 2.73 min; MS (ESIpos): m/z = 664/666 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.833 (0.05), 0.850 (0.06), 1.196(0.08), 1.234 (0.17), 1.289 (0.08), 1.307 (0.33), 1.311 (0.43), 1.356(16.00), 1.369 (0.64), 1.397 (5.74), 1.512 (0.08), 1.607 (0.50), 1.672(0.95), 1.881 (0.06), 1.901 (0.09), 1.920 (0.12), 1.937 (0.14), 1.954 (0.18),2.027 (0.16), 2.042 (0.21), 2.056 (0.20), 2.079 (1.01), 2.093 (0.71), 2.114(0.39), 2.133 (1.36), 2.175 (0.13), 2.195 (0.07), 2.240 (0.10), 2.294 (0.03),2.327 (0.03), 2.669 (0.03), 2.694 (0.32), 3.137 (1.23), 3.284 (0.10), 3.516(0.18), 3.661 (0.08), 3.676 (0.13), 3.693 (0.24), 3.709 (0.30), 3.727 (0.24),3.746 (0.21), 3.765 (0.17), 3.799 (0.06), 7.019 (0.42), 7.039 (0.45), 7.060(0.33), 7.089 (0.29), 7.111 (0.42), 7.135 (0.31), 7.244 (0.63), 7.357 (0.17),7.378 (0.33), 7.395 (0.31), 7.415 (0.15), 7.428 (0.34), 7.485 (0.11), 7.627(0.32), 7.650 (1.43), 7.659 (0.90), 7.664 (0.80), 7.682 (0.20), 7.686 (0.21),8.772 (0.23), 8.787 (0.45), 8.801 (0.22)。

Separation of enantiomers:

the title compound (810 mg) was dissolved in methanol (30 ml) and separated by preparative SFC on the chiral phase into enantiomers (see examples 190A and 191A) [ column: daicel Chiralcel OX-H, 5 μm,250 mm x 30mm, flow rate: 90 ml/min, injection: 0.3 ml, UV detection: 210 nm, temperature: 40 deg.C, eluent 15% methanol/85% carbon dioxide, running time 6 min, isocratic. The combined target fractions were each concentrated and the respective residue was lyophilized.

Example 190A

(-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (difluoromethoxy) -6-fluorophenyl]Glutaric acid tert-butyl ester(enantiomer 1)

In the enantiomeric separation described in example 189A, 810 mg (96% purity, ee >99%) of the title compound were obtained as the earlier eluting enantiomer.

[α]_D ²⁰= -23.0 °, 589 nm, c = 0.36 g/100 ml, methanol

LC-MS (method 2) R_t= 1.47 min; MS (ESIpos): m/z = 664/666 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.889 (5.96), 0.908 (13.53), 0.926(6.80), 1.034 (0.52), 1.062 (1.29), 1.085 (1.31), 1.114 (0.57), 1.240 (1.11),1.256 (2.40), 1.274 (3.14), 1.283 (2.64), 1.291 (2.25), 1.301 (1.76), 1.558(1.43), 1.604 (1.33), 1.635 (1.24), 1.665 (0.54), 1.745 (1.84), 1.779 (1.51),1.813 (1.49), 1.835 (2.39), 1.854 (2.18), 1.877 (1.62), 2.033 (1.16), 2.048(3.43), 2.077 (3.31), 2.085 (3.74), 2.093 (4.43), 2.124 (16.00), 2.138(2.92), 2.162 (0.92), 2.402 (0.93), 2.429 (1.47), 2.701 (0.89), 2.730 (1.56),2.757 (0.85), 3.484 (2.87), 3.515 (2.61), 3.596 (1.53), 3.661 (1.81), 3.675(2.56), 7.254 (1.40), 7.271 (3.10), 7.289 (2.16), 7.355 (1.92), 7.374 (3.34),7.392 (1.74), 7.438 (4.62), 7.458 (4.18), 7.481 (4.49), 7.500 (3.11), 7.624(1.31), 7.647 (11.41), 7.671 (0.73), 7.675 (0.82), 8.697 (1.73), 8.712(3.17), 8.726 (1.55), 12.043 (3.31)。

Example 191A

(+) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (difluoromethoxy) -6-fluorophenyl]Glutaric acid tert-butyl ester(enantiomer 2)

In the enantiomeric separation described in example 189A, 159 mg (100% purity, ee value 94%) of the title compound were obtained as the enantiomer which eluted later.

[α]_D ²⁰= 24.9 °, 589 nm, c = 0.38 g/100 ml, methanol

LC-MS (method 2) R_t= 1.47 min; MS (ESIneg): m/z = 664/666 [M+H]^-

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.197 (0.07), 1.290 (0.06), 1.311(0.12), 1.356 (16.00), 1.513 (0.08), 1.608 (0.51), 1.672 (0.99), 1.955(0.20), 2.043 (0.23), 2.056 (0.21), 2.079 (1.09), 2.093 (0.76), 2.134 (1.45),3.138 (1.29), 3.518 (0.20), 3.676 (0.14), 3.694 (0.25), 3.709 (0.31), 3.727(0.26), 3.747 (0.24), 3.765 (0.19), 7.019 (0.44), 7.040 (0.49), 7.061 (0.33),7.089 (0.29), 7.112 (0.45), 7.136 (0.33), 7.245 (0.65), 7.358 (0.17), 7.378(0.34), 7.395 (0.32), 7.416 (0.16), 7.429 (0.36), 7.489 (0.12), 7.628 (0.33),7.650 (1.42), 7.659 (0.88), 7.664 (0.86), 7.682 (0.19), 7.686 (0.22), 8.772(0.24), 8.787 (0.47), 8.802 (0.24)。

Example 192A

(-) -5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(diastereomer 1)

[ see example 116A for structural formula: (Mixtures of diastereomers)]

Separation of diastereoisomers/enantiomers from example 116A:

5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester (C:)Mixtures of diastereomers2.53 g, example 116A) were dissolved in ethanol (60 ml), filtered and initially subjected to preliminary separation on the chiral phase by preparative SFC [ column: daicel Chiralpak OX-H, 5 μm,250 mm x 30mm, flow rate: 125 ml/min, injection: 0.6 ml, 38 deg.C, UV detection 210 nm, eluent 80% carbon dioxide/20% ethanol, running time 19 min, isocratic]. One mixed fraction (peak 1) and two sufficiently pure fractions (peak 2 and peak 3, see examples 194A and 195A) were obtained. The mixed fraction (peak 1) was purified by preparative SFC [ column: DaicelChiralpak IC, 5 μm,250 mm x20 mm, flow rate: 80 ml/min, injection: 0.35 ml, 40 deg.C, UV detection 210 nm, eluent of 76% carbon dioxide/24% ethanol, running time 10.5 min, isocratic](see examples 192A and 193A). The combined target fractions were each concentrated and the respective residue was lyophilized.

In the diastereoisomeric separation of the mixed fraction (peak 1, see above), 485 mg (100% purity, ee >99%) of the title compound were obtained as the first eluting diastereomer (peak 1-1).

[α]_D ²⁰= 6.3 °, 589 nm, c = 0.40 g/100 ml, methanol

LC-MS (method 1) R_t= 2.66 min; MS (ESIpos): m/z = 632/634 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.370 (16.00), 1.639 (0.22), 1.795(0.34), 1.815 (0.41), 1.837 (0.27), 1.898 (0.35), 1.917 (0.31), 1.948 (0.22),2.027 (0.17), 2.047 (0.24), 2.055 (0.24), 2.075 (1.54), 2.087(0.82), 2.104(0.33), 2.110 (0.30), 2.145 (1.93), 3.092 (0.24), 3.160 (0.26), 3.177 (0.25),3.292 (0.20), 3.341 (0.17), 3.380 (0.23), 3.437 (0.22), 3.589 (0.26), 3.678(0.51), 4.817 (0.18), 4.937 (0.18), 7.252 (0.21), 7.271 (0.50), 7.289 (0.36),7.352 (0.30), 7.371 (0.55), 7.389 (0.29), 7.439 (0.71), 7.459 (0.59), 7.482(0.67), 7.501 (0.56), 7.648 (0.27), 7.670 (1.50), 7.677 (1.05), 7.681 (0.86),7.699 (0.17), 7.704 (0.18), 8.712 (0.27), 8.727 (0.54), 8.741 (0.26)。

Example 193A

(-) -5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(diastereomer 2)

In the diastereoisomeric separation of the mixed fractions (peak 1, see above) described in example 192A, 437 mg (100% purity, ee >99%) of the title compound were obtained as the second eluting diastereomer (peaks 1-2).

[α]_D ²⁰= 11.5 °, 589 nm, c = 0.44 g/100 ml, methanol

LC-MS (method 1) R_t= 2.66 min; MS (ESIpos): m/z = 632/634 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.369 (16.00), 1.644 (0.19), 1.802(0.30), 1.814 (0.35), 1.837 (0.23), 1.900 (0.32), 1.921 (0.26), 1.947 (0.16),2.046 (0.20), 2.055 (0.21), 2.075 (1.37), 2.087 (0.76), 2.104 (0.30), 2.110(0.28), 2.144 (1.53), 3.102 (0.22), 3.148 (0.23), 3.164 (0.22), 3.295 (0.18),3.324 (0.30), 3.377 (0.21), 3.434 (0.19), 3.586 (0.23), 3.676 (0.39), 7.254(0.19), 7.273 (0.44), 7.292 (0.31), 7.354 (0.27), 7.373 (0.49), 7.391 (0.25),7.439 (0.64), 7.441 (0.64), 7.459 (0.54), 7.484 (0.60), 7.503 (0.51), 7.648(0.25), 7.670 (1.41), 7.676 (0.97), 7.681 (0.83), 7.703 (0.17), 8.712 (0.24),8.726 (0.46), 8.740 (0.23)。

Example 194A

(+) -5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(diastereomer 3)

In the diastereoisomeric separation described in example 192A, 593 mg (100% purity) of the title compound was obtained as the third eluting diastereomer (peak 3).

[α]_D ²⁰= 7.2 °, 436 nm, c = 0.36 g/100 ml, methanol

LC-MS (method 1) R_t= 2.69 min; MS (ESIpos): m/z = 632/634 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.40), 0.008 (0.38), 1.369(16.00), 1.640 (0.16), 1.795 (0.24), 1.813 (0.29), 1.836 (0.19), 1.897(0.25), 1.918 (0.22), 2.047 (0.17), 2.053 (0.17), 2.074 (1.13), 2.086 (0.61),2.103 (0.24), 2.109 (0.23), 2.144 (1.45), 2.523 (0.16), 3.092 (0.17), 3.161(0.19), 3.178 (0.18), 3.380 (0.18), 3.438 (0.16), 3.589 (0.19), 3.677 (0.36),7.254 (0.17), 7.272 (0.38), 7.289 (0.27), 7.292 (0.27), 7.354 (0.24), 7.372(0.43), 7.391 (0.22), 7.439 (0.59), 7.441 (0.58), 7.458 (0.50), 7.462 (0.48),7.480 (0.51), 7.484 (0.52), 7.500 (0.43), 7.503 (0.42), 7.648 (0.26), 7.670(1.32), 7.677 (0.92), 7.682 (0.81), 7.704 (0.18), 8.712 (0.21), 8.726 (0.42),8.741 (0.20)。

Example 195A

(+) -5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(diastereomer 4)

In the diastereoisomeric separation described in example 192A, 621 mg (100% purity) of the title compound was obtained as the diastereomer (peak 4) eluting at the fourth position.

[α]_D ²⁰= +20.8°, 589 nm, c = 0.49 g/100 ml, DMSO

LC-MS (method 1) R_t= 2.69 min; MS (ESIpos): m/z = 632/634 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.038 (0.20), 1.056 (0.41), 1.073(0.21), 1.369 (16.00), 1.644 (0.19), 1.795 (0.28), 1.814 (0.34), 1.837(0.22), 1.900 (0.32), 1.921 (0.26), 1.948 (0.16), 2.045 (0.19), 2.054 (0.21),2.075 (1.31), 2.087 (0.75), 2.103 (0.29), 2.109 (0.28), 2.143 (1.52), 3.101(0.22), 3.147 (0.23), 3.162 (0.33), 3.175 (0.25), 3.376 (0.21), 3.426 (0.26),3.438 (0.22), 3.456 (0.17), 3.585 (0.22), 3.675 (0.39), 7.255 (0.19), 7.273(0.43), 7.291 (0.30), 7.354 (0.26), 7.373 (0.48), 7.392 (0.25), 7.441 (0.63),7.459 (0.52), 7.484 (0.59), 7.501 (0.50), 7.648 (0.26), 7.670 (1.41), 7.676(0.95), 7.681 (0.82), 7.699 (0.16), 7.703 (0.17), 8.711 (0.24), 8.726 (0.47),8.740 (0.23)。

Example 196A

(+) -5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(diastereomer 1)

[ see example 138A for Structure ]Mixtures of diastereomers)]

Separation of diastereomer/enantiomer from example 138A:

5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Tert-butyl valerate (Mixtures of diastereomers364 mg, example 138A) were dissolved in a mixture of methanol and acetonitrile (5 ml) and purified by preparative SFC on chiral phase [ column: daicel Chiralpak OX-H, 5 μm,250 mm x20 mm, flow rate: 80 ml/min, injection: 0.35 ml, 40 deg.C, UV detecting at 210 nm, eluting with 86% carbon dioxide/14% ethanol, running time 15min, isocratic]. One mixed fraction (peak 1) and two sufficiently pure fractions (peak 2 and peak 3, see examples 196A and 197A) were obtained. Will mergeThe target fractions of (4) are each concentrated and the respective residue is lyophilized. The mixed fraction (peak 1) was used directly in the reaction described in example 191.

In the described separation of the diastereomers, 72 mg (100% purity, ee >99%) of the title compound are obtained as peak 2.

[α]_D ²⁰= 10.9 °, 589 nm, c = 0.34 g/100 ml, methanol

LC-MS (method 2) R_t= 1.45 min; MS (ESIpos): m/z = 666/668 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.323 (0.17), 1.347 (16.00), 1.650(0.21), 1.813 (0.20), 1.875 (0.22), 1.907 (0.50), 1.921 (0.44), 1.953 (0.29),1.973 (0.18), 1.992 (0.39), 2.005 (0.26), 2.015 (0.49), 2.027 (0.37), 2.035(0.42), 2.057 (0.32), 2.095 (0.29), 2.108 (0.18), 2.126 (0.24), 2.143 (0.25),2.180 (1.55), 3.114 (0.24), 3.174 (0.25), 3.190 (0.24), 3.340 (0.48), 3.359(0.23), 3.395 (0.23), 3.452 (0.21), 3.631 (0.18), 3.646 (0.22), 3.667 (0.23),3.684 (0.25), 3.700 (0.19), 4.824 (0.17), 4.943 (0.17), 7.462 (0.34), 7.481(0.58), 7.500 (0.35), 7.661 (0.24), 7.683 (1.73), 7.707 (0.62), 7.722 (1.07),7.738 (0.99), 7.753 (0.27), 8.768 (0.26), 8.783 (0.53), 8.797 (0.25)。

Example 197A

(+) -5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(diastereomer 2)

In the diastereoisomeric separation described in example 196A, 72 mg (100% purity, ee >99%) of the title compound are obtained as peak 3.

[α]_D ²⁰= 16.2 °, 589 nm, c = 0.37 g/100 ml, methanol

LC-MS (method 2) R_t= 1.45 min; MS (ESIpos): m/z = 666/668 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.324 (0.18), 1.347 (16.00), 1.652(0.22), 1.812 (0.20), 1.830 (0.18), 1.907 (0.53), 1.920 (0.46), 1.944 (0.28),1.953 (0.30), 1.974 (0.19), 1.992 (0.41), 2.016 (0.56), 2.027 (0.39), 2.034(0.45), 2.056 (0.33), 2.095 (0.29), 2.108 (0.20), 2.126 (0.25), 2.143 (0.27),2.179 (1.49), 3.117 (0.25), 3.172 (0.25), 3.187 (0.24), 3.341 (0.50), 3.359(0.23), 3.394 (0.24), 3.452 (0.22), 3.628 (0.19), 3.644 (0.23), 3.671 (0.18),3.688 (0.24), 3.704 (0.20), 4.823 (0.18), 4.942 (0.18), 7.463 (0.34), 7.482(0.56), 7.500 (0.35), 7.660 (0.21), 7.682 (1.69), 7.708 (0.67), 7.722 (0.98),7.738 (1.19), 7.754 (0.28), 8.766 (0.26), 8.780 (0.52), 8.795 (0.26)。

Example 198A

(+) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(diastereomer 1)

[ structural formula see example 139A: (Mixtures of diastereomers)]

Separation of diastereoisomers/enantiomers from example 139A:

5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Tert-butyl valerate (Mixtures of diastereomers548 mg, 677 μmol, example 139A) were dissolved in a mixture of methanol (20 ml) and acetonitrile (20 ml) and separated into diastereomers on the chiral phase by preparative SFC [ column: daicel Chiralcel OZ-H,5 μm,250 mm x 30mm, flow rate: 100 ml/min, injection: 0.3 ml, 40 deg.C, UV detection 210 nm, eluent 80% carbon dioxide/20% methanol, running time 9.8 min, isocratic]. Four fractions were obtained (peak 1 to peak 4, see examples 198A and 201A). The combined target fractions were each concentrated and the respective residue was lyophilized.

In the described separation of the diastereomers, 63 mg (100% purity) of the title compound was obtained as the first eluting diastereomer (peak 1).

[α]_D ²⁰= 19.1 °, 436 nm, c = 0.32 g/100 ml, methanol

LC-MS (method 1) R_t= 3.02 min; MS (ESIpos): m/z = 676/678 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.895 (0.93), 0.914 (2.23), 0.932(1.13), 1.070 (0.18), 1.101 (0.20), 1.264 (0.37), 1.281 (0.50), 1.299 (0.36),1.321 (0.27), 1.347 (16.00), 1.570 (0.23), 1.608 (0.22), 1.639 (0.18), 1.754(0.27), 1.786 (0.18), 1.884 (0.36), 1.991 (0.29), 2.014 (0.51), 2.031 (0.44),2.053 (0.32), 2.094 (0.28), 2.140 (1.02), 2.431 (0.21), 2.758 (0.27), 3.514(0.39), 3.536 (0.35), 3.619 (0.19), 3.637 (0.21), 3.680 (0.17), 3.697 (0.29),3.713 (0.24), 7.461 (0.35), 7.480 (0.56), 7.498 (0.33), 7.661 (2.27), 7.687(0.30), 7.706 (0.58), 7.714 (0.73), 7.724 (0.54), 7.735 (1.21), 7.755 (0.27),8.755 (0.24), 8.770 (0.47), 8.785 (0.24)。

Example 199A

(-) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(diastereomer 2)

In the diastereoisomeric separation described in example 198A, 57 mg (100% purity) of the title compound were obtained as the second eluting diastereomer (peak 2).

[α]_D ²⁰= 25.0 °, 589 nm, c = 0.34 g/100 ml, methanol

LC-MS (method 1) R_t= 3.03 min; MS (ESIpos): m/z = 676/678 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.895 (0.88), 0.914 (2.18), 0.932(1.09), 1.073 (0.17), 1.102 (0.18), 1.263 (0.32), 1.281 (0.45), 1.293 (0.39),1.310 (0.31), 1.346 (16.00), 1.570 (0.20), 1.612 (0.19), 1.643 (0.17), 1.753(0.24), 1.786 (0.16), 1.853 (0.24), 1.886 (0.33), 1.917 (0.16), 1.993 (0.27),2.014 (0.51), 2.029 (0.56), 2.050 (0.27), 2.113 (0.18), 2.133 (0.26), 2.168(1.42), 2.444 (0.23), 2.473 (0.16), 2.753 (0.22), 3.508 (0.36), 3.540 (0.33),3.621 (0.18), 3.637 (0.21), 3.684 (0.21), 3.699 (0.18), 7.461 (0.27), 7.480(0.46), 7.499 (0.28), 7.660 (2.23), 7.687 (0.27), 7.707 (0.49), 7.720 (0.80),7.737 (1.06), 7.754 (0.23), 8.754 (0.23), 8.769 (0.47), 8.784 (0.22)。

Example 200A

5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(diastereomer 3)

In the diastereoisomeric separation described in example 198A, 72 mg (100% purity) of the title compound was obtained as the diastereomer (peak 3) eluting in the third position.

LC-MS (method 1) R_t= 3.02 min; MS (ESIpos): m/z = 676/678 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6)δ [ppm]: 0.895 (0.90), 0.913 (2.13), 0.932(1.03), 1.071 (0.16), 1.093 (0.17), 1.246 (0.17), 1.263 (0.36), 1.281 (0.46),1.287 (0.39), 1.298 (0.36), 1.306 (0.38), 1.312 (0.35), 1.322 (0.43), 1.347(16.00), 1.570 (0.21), 1.596 (0.19), 1.606 (0.19), 1.753 (0.23), 1.850(0.24), 1.884 (0.32), 1.991 (0.27), 2.014 (0.46), 2.032 (0.37), 2.053 (0.27),2.094 (0.27), 2.139 (0.86), 2.432 (0.18), 2.755 (0.23), 3.505 (0.34), 3.515(0.35), 3.535 (0.30), 3.619 (0.18), 3.636 (0.19), 3.697 (0.25), 3.713 (0.21),7.461 (0.32), 7.479 (0.48), 7.497 (0.28), 7.639 (0.19), 7.661 (2.09), 7.666(1.01), 7.688 (0.28), 7.706 (0.54), 7.714 (0.66), 7.724 (0.49), 7.735 (1.00),7.755 (0.22), 8.755 (0.22), 8.770 (0.40), 8.785 (0.19)。

Example 201A

(+) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(diastereomer 4)

In the diastereoisomeric separation described in example 198A, 62 mg (100% purity) of the title compound was obtained as the diastereomer (peak 4) eluting at the fourth position.

[α]_D ²⁰= 27.0 °, 589 nm, c = 0.33 g/100 ml, methanol

LC-MS (method 2) R_t= 1.63 min; MS (ESIpos): m/z = 676/678 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.895 (0.96), 0.914 (2.24), 0.932(1.16), 1.072 (0.21), 1.101 (0.22), 1.246 (0.17), 1.263 (0.37), 1.280 (0.53),1.292 (0.48), 1.310 (0.38), 1.346 (16.00), 1.569 (0.24), 1.612 (0.23), 1.643(0.21), 1.753 (0.29), 1.784 (0.20), 1.862 (0.29), 1.884 (0.41), 1.992 (0.32),2.013 (0.61), 2.028 (0.66), 2.049 (0.32), 2.098 (0.17), 2.112 (0.22), 2.132(0.29), 2.167 (1.77), 2.415 (0.18), 2.443 (0.29), 2.501 (6.18), 2.754 (0.27),3.508 (0.44), 3.538 (0.40), 3.619 (0.22), 3.637 (0.25), 3.652 (0.17), 3.666(0.18), 3.682 (0.27), 3.699 (0.21), 7.461 (0.32), 7.480 (0.54), 7.499 (0.33),7.659 (2.38), 7.686 (0.30), 7.706 (0.57), 7.720 (0.97), 7.736 (1.22), 7.753(0.27), 8.754 (0.27), 8.768 (0.55), 8.783 (0.27)。

Example 202A

(+) -5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(diastereomer 1)

[ structural formula see example 140A: (Mixtures of diastereomers)]

Separation of diastereoisomers/enantiomers from example 140A:

5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Tert-butyl valerate (Mixtures of diastereomers455 mg, example 140A) were dissolved in a mixture of methanol and acetonitrile (6 ml) and purified by preparative SFC on chiral phase [ column: daicel Chiralpak OX-H, 5 μm,250 mm x20 mm, flow rate: 80 ml/min, injection: 0.25 ml, 40 deg.C, UV detecting at 210 nm, eluting with 89% carbon dioxide/11% ethanol, running time 19 min, isocratic]. One mixed fraction (peak 1) and two sufficiently pure fractions were obtained(Peak 2 and Peak 3, see examples 202A and 203A). The combined target fractions were each concentrated and the respective residue was lyophilized. The mixed fraction (peak 1) was used directly in the reaction described in example 199.

In the described separation of the diastereomers, 80 mg (100% purity) of the title compound is obtained as peak 2.

[α]_D ²⁰= 17.0 °, 589 nm, c = 0.35 g/100 ml, methanol

LC-MS (method 2) R_t= 1.59 min; MS (ESIpos): m/z = 662/664 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.927 (1.56), 0.943 (1.58), 1.085(0.17), 1.116 (0.17), 1.324 (0.18), 1.347 (16.00), 1.662 (0.17), 1.737(0.30), 1.772 (0.30), 1.798 (0.37), 1.828 (0.23), 1.908 (0.16), 1.990 (0.27),2.013 (0.47), 2.031 (0.39), 2.052 (0.28), 2.097 (0.16), 2.111 (0.18), 2.130(0.24), 2.166 (1.28), 2.465 (0.25), 2.723 (0.25), 3.454 (0.25), 3.480 (0.47),3.510 (0.23), 3.640 (0.19), 3.659 (0.21), 3.677 (0.22), 3.694 (0.17), 7.462(0.29), 7.481 (0.47), 7.500 (0.29), 7.661 (2.16), 7.688 (0.27), 7.707 (0.48),7.721 (0.89), 7.737 (0.91), 7.752 (0.24), 8.757 (0.21), 8.772 (0.44), 8.787(0.21)。

Example 203A

(+) -5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(diastereomer 2)

In the diastereoisomeric separation described in example 202A, 82 mg (100% purity) of the title compound are obtained as peak 3.

[α]_D ²⁰= 7.3 °, 589 nm, c = 0.36 g/100 ml, methanol

LC-MS (method 2) R_t= 1.59 min; MS (ESIpos): m/z = 662/664 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.928 (1.80), 0.944 (1.86), 1.087(0.22), 1.115 (0.23), 1.324 (0.21), 1.347 (16.00), 1.635 (0.20), 1.665(0.23), 1.738 (0.39), 1.771 (0.38), 1.798 (0.48), 1.829 (0.30), 1.889 (0.20),1.898 (0.20), 1.909 (0.22), 1.920 (0.21), 1.990 (0.33), 2.013 (0.63), 2.030(0.55), 2.052 (0.35), 2.099 (0.18), 2.114 (0.23), 2.133 (0.28), 2.174 (1.76),2.440 (0.22), 2.469 (0.35), 2.694 (0.17), 2.722 (0.30), 2.751 (0.16), 3.455(0.35), 3.482 (0.62), 3.513 (0.29), 3.619 (0.21), 3.634 (0.24), 3.683 (0.26),3.698 (0.21), 7.463 (0.34), 7.482 (0.56), 7.501 (0.34), 7.661 (2.34), 7.688(0.31), 7.707 (0.59), 7.722 (1.10), 7.737 (1.07), 7.752 (0.29), 8.759 (0.29),8.774 (0.57), 8.788 (0.28)。

Example 204A

(-) -5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Glutaric acid tert-butyl ester(diastereomer 1)

[ structural formula see example 153A: (Mixtures of diastereomers)]

Separation of diastereoisomers/enantiomers from example 153A:

5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Tert-butyl valerate (Mixtures of diastereomers359 mg, 486 μmol, example 153A) were separated into diastereomers by preparative HPLC [ method 1: column: daicel Chiralcel OZ-H,5 μm,250 mm x20 mm, flow rate: 20 ml/min, 25 ℃, eluent 90% heptane/10% ethanol, 255 nm UV detection, isocratic, method 2: daicel Chiralcel OZ-H,5 μm,250 mm x20 mm, flow rate: 20 ml/min, 25 deg.C, 90% heptane/10% isopropanol as eluent, 255 nm UV detection, isocratic]. Four fractions were obtained (peak 1 to peak 4, see examples 204A and 207A). The combined target fractions were in each case concentrated (conditions: 25 ℃ C., 40 mbar).

In the described diastereoisomeric separation, 85 mg (90% purity, ee >98%) of the title compound are obtained as the first eluting diastereomer (peak 1).

[α]_D ²⁰= 9.4 °, 436 nm, c = 0.38 g/100 ml, methanol

LC-MS (method 2) R_t= 1.43 min; MS (ESIpos): m/z = 682/684 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.234 (0.80), 1.258 (0.70), 1.301(0.94), 1.336 (0.21), 1.360 (16.00), 1.381 (0.64), 1.646 (0.25), 1.808(0.42), 1.831 (0.39), 1.855 (0.23), 1.903 (0.37), 1.922 (0.32), 1.954 (0.23),2.036 (0.29), 2.068 (1.52), 2.089 (0.32), 2.156 (1.22), 2.222 (0.27), 3.106(0.24), 3.168 (0.25), 3.186 (0.25), 3.333 (0.33), 3.352 (0.27), 3.388 (0.45),3.413 (0.20), 3.445 (0.21), 3.619 (0.28), 3.634 (0.50), 3.650 (0.49), 3.666(0.27), 4.820 (0.18), 4.940 (0.19), 7.363 (0.48), 7.379 (0.23), 7.386 (0.26),7.399 (0.90), 7.411 (0.64), 7.417 (0.60), 7.422 (0.70), 7.495 (0.17), 7.547(0.52), 7.559 (0.48), 7.570 (0.36), 7.656 (0.27), 7.678 (1.54), 7.685 (1.05),7.689 (0.93), 7.707 (0.21), 8.736 (0.25), 8.751 (0.50), 8.765 (0.25)。

Example 205A

(-) -5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Glutaric acid tert-butyl ester(diastereomer 2)

In the diastereoisomeric separation described in example 204A, 85 mg (100% purity, ee value 97%) of the title compound are obtained as the second eluting diastereomer (peak 2).

[α]_D ²⁰= 14.3 °, 589 nm, c = 0.39 g/100 ml, methanol

LC-MS (method 2) R_t= 1.42 min; MS (ESIpos): m/z = 682/684 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.853 (0.18), 1.234 (1.31), 1.249(0.44), 1.259 (1.44), 1.299 (1.16), 1.326 (0.17), 1.336 (0.40), 1.360(16.00), 1.381 (0.22), 1.646 (0.21), 1.808 (0.39), 1.831 (0.36), 1.856(0.20), 1.903 (0.32), 1.924 (0.27), 1.951 (0.18), 2.036 (0.27), 2.067 (1.41),2.090 (0.29), 2.156 (1.05), 3.109 (0.21), 3.164 (0.22), 3.179 (0.21), 3.337(0.29), 3.356 (0.26), 3.387 (0.42), 3.412 (0.16), 3.444 (0.19), 3.618 (0.24),3.635 (0.44), 3.651 (0.38), 3.671 (0.21), 4.938 (0.16), 7.363 (0.45), 7.388(0.19), 7.400 (0.79), 7.412 (0.61), 7.418 (0.58), 7.424 (0.68), 7.548 (0.45),7.560 (0.40), 7.571 (0.33), 7.656 (0.24), 7.678 (1.42), 7.684 (1.00), 7.689(0.87), 7.707 (0.18), 7.711 (0.19), 8.736 (0.22), 8.751 (0.44), 8.765 (0.23)。

Example 206A

(+) -5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Glutaric acid tert-butyl ester(diastereomer 3)

In the diastereoisomeric separation described in example 204A, 79 mg (98% purity, ee >98%) of the diastereomer (peak 3) eluting as the third position were obtained.

[α]_D ²⁰= 14.1 °, 589 nm, c = 0.37 g/100 ml, methanol

LC-MS (method 2) R_t= 1.43 min; MS (ESIpos): m/z = 682/684 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.360 (16.00), 1.644 (0.23), 1.808(0.45), 1.830 (0.42), 1.854 (0.24), 1.901 (0.38), 1.922 (0.32), 1.953 (0.23),2.036 (0.38), 2.067 (1.64), 2.089 (0.34), 2.156 (1.32), 3.100 (0.25), 3.168(0.28), 3.185 (0.26), 3.332 (0.40), 3.353 (0.30), 3.388 (0.49), 3.413 (0.21),3.445 (0.23), 3.620 (0.33), 3.634 (0.56), 3.649 (0.52), 3.666 (0.26),4.820(0.18), 4.939 (0.19), 7.363 (0.47), 7.386 (0.25), 7.399 (0.89), 7.410 (0.66),7.417 (0.62), 7.422 (0.72), 7.495 (0.17), 7.547 (0.53), 7.559 (0.45), 7.570(0.37), 7.656 (0.31), 7.678 (1.54), 7.684 (0.98), 7.688 (0.86), 7.711 (0.16),8.737 (0.29), 8.751 (0.53), 8.765 (0.25)。

Example 207A

(+) -5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Glutaric acid tert-butyl ester(diastereomer 4)

In the diastereoisomeric separation described in example 204A, 79 mg (100% purity, ee >99%) of the diastereomer (peak 4) are obtained as the fourth eluting diastereomer.

[α]_D ²⁰= 55.1 °, 436 nm, c = 0,081 g/100 ml, methanol

LC-MS (method 2) R_t= 1.42 min; MS (ESIpos): m/z = 682/684 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.234 (0.20), 1.258 (0.18), 1.360(16.00), 1.646 (0.22), 1.789 (0.23), 1.808 (0.43), 1.831 (0.41), 1.855(0.23), 1.903 (0.36), 1.923 (0.30), 1.953 (0.20), 2.036 (0.30), 2.068 (1.63),2.090 (0.33), 2.156 (1.21), 3.110 (0.24), 3.169 (0.27), 3.335 (0.42), 3.356(0.32), 3.387 (0.49), 3.412 (0.20), 3.443 (0.22), 3.618 (0.28), 3.635 (0.50),3.652 (0.43), 3.670 (0.24), 4.819 (0.17), 4.938 (0.17), 7.363 (0.46), 7.388(0.20), 7.400 (0.86), 7.412 (0.65), 7.418 (0.63), 7.423 (0.73), 7.435 (0.16),7.486 (0.17), 7.548 (0.49), 7.560 (0.44), 7.571 (0.36), 7.656 (0.26), 7.678(1.51), 7.684 (1.05), 7.688 (0.92), 7.711 (0.17), 8.737 (0.26), 8.752 (0.50),8.766 (0.25)。

Example 208A

(+) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Glutaric acid tert-butyl ester(diastereomer 1)

[ structural formula see example 154A: (Mixtures of diastereomers)]

Separation of diastereoisomers/enantiomers from example 154A:

5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Tert-butyl valerate (Mixtures of diastereomers458 mg, 648 μmol, example 154A) in a mixture of methanol (12 ml) and acetonitrile (5 ml) and filteredOver-prepared SFC separates on chiral phase into diastereomers [ column: daicel Chiralcel OZ-H,5 μm,250 mm x20 mm, flow rate: 80 ml/min, injection: 0.3 ml, 40 deg.C, UV detection 210 nm, eluent 88% carbon dioxide/12% methanol, running time 9.5 min, isocratic]. Four fractions were obtained (peak 1 to peak 4, see examples 208A and 211A). The combined target fractions were each concentrated and the respective residue was lyophilized.

In the described diastereoisomeric separation 64 mg (99% purity, ee >95%) of the title compound are obtained as the first eluting diastereomer (peak 1).

[α]_D ²⁰= 17.0 °, 436 nm, c = 0.35 g/100 ml, methanol

LC-MS (method 1) R_t= 3.05 min; MS (ESIpos): m/z = 692/694 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.893 (0.87), 0.912 (2.16), 0.930(1.06), 1.069 (0.16), 1.098 (0.17), 1.260 (0.35), 1.278 (0.46), 1.301 (0.60),1.315 (0.18), 1.360 (16.00), 1.382 (0.29), 1.565 (0.20), 1.600 (0.18), 1.751(0.23), 1.784 (0.23), 1.802 (0.23), 1.827 (0.20), 1.854 (0.28), 1.881 (0.19),2.033 (0.24), 2.065 (1.20), 2.089 (0.38), 2.118 (0.69), 2.422 (0.17), 2.755(0.23), 3.370 (0.19), 3.388 (0.19), 3.497 (0.33), 3.525 (0.32), 3.609 (0.23),3.625 (0.27), 3.644 (0.26), 3.661 (0.28), 3.679 (0.23), 7.356 (0.37), 7.383(0.18), 7.396 (0.70), 7.408 (0.57), 7.414 (0.51), 7.420 (0.62), 7.549 (0.44),7.555 (0.28), 7.562 (0.37), 7.573 (0.32), 7.635 (0.19), 7.657 (1.45), 7.664(0.92), 8.725 (0.20), 8.740 (0.38), 8.754 (0.20)。

Example 209A

(-) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Glutaric acid tert-butyl ester(diastereomer 2)

In the diastereoisomeric separation described in example 208A, 48mg (100% purity, ee >95%) of the title compound are obtained as the second eluting diastereomer (peak 2).

[α]_D ²⁰= 25.7 °, 589 nm, c = 0.34 g/100 ml, methanol

LC-MS (method 1) R_t= 3.05 min; MS (ESIpos): m/z = 692/694 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.893 (0.84), 0.912 (2.08), 0.930(1.04), 1.070 (0.16), 1.101 (0.17), 1.261 (0.31), 1.270 (0.28), 1.279 (0.42),1.287 (0.37), 1.297 (0.32), 1.325 (0.18), 1.361 (16.00), 1.564 (0.19), 1.607(0.18), 1.640 (0.17), 1.749 (0.23), 1.784 (0.22), 1.803 (0.23), 1.828 (0.21),1.854 (0.28), 1.883 (0.20), 2.033 (0.26), 2.047 (0.31), 2.067 (1.23), 2.092(0.29), 2.144 (1.08), 2.437 (0.20), 2.749 (0.20), 3.370 (0.20), 3.388 (0.20),3.499 (0.35), 3.530 (0.33), 3.617 (0.27), 3.632 (0.46), 3.647 (0.43), 3.663(0.22), 7.359 (0.37), 7.385 (0.17), 7.398 (0.72), 7.410 (0.57), 7.416 (0.53),7.421 (0.65), 7.547 (0.42), 7.560 (0.36), 7.571 (0.30), 7.634 (0.16), 7.657(1.61), 7.663 (0.91), 8.725 (0.22), 8.739 (0.44), 8.754 (0.22)。

Example 210A

(-) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Glutaric acid tert-butyl ester(diastereomer 3)

In the diastereoisomeric separation described in example 208A, 59 mg (98% purity, ee >93%) of the title compound are obtained as the third eluting diastereomer (peak 3).

[α]_D ²⁰= 17.5 °, 436 nm, c = 0.32 g/100 ml, methanol

LC-MS (method 1) R_t= 3.05 min; MS (ESIpos): m/z = 692/694 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.893 (0.89), 0.912 (2.18), 0.930(1.08), 1.069 (0.17), 1.091 (0.17), 1.261 (0.36), 1.278 (0.48), 1.296 (0.34),1.315 (0.18), 1.361 (16.00), 1.565 (0.21), 1.601 (0.20), 1.633 (0.16), 1.750(0.23), 1.784 (0.23), 1.802 (0.24), 1.828 (0.22), 1.853 (0.30), 1.880 (0.20),2.033 (0.26), 2.065 (1.28), 2.090 (0.38), 2.119 (0.72), 2.422 (0.18), 2.754(0.24), 3.371 (0.20), 3.388 (0.20), 3.495 (0.35), 3.526 (0.33), 3.610 (0.24),3.625 (0.29), 3.643 (0.28), 3.662 (0.28), 3.679 (0.24), 7.356 (0.38), 7.396(0.72), 7.408 (0.57), 7.414 (0.52), 7.420 (0.65), 7.550 (0.45), 7.555 (0.29),7.562 (0.38), 7.573 (0.33), 7.635 (0.19), 7.657 (1.52), 7.665 (0.91), 8.726(0.20), 8.740 (0.41), 8.754 (0.20)。

Example 211A

(+) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Glutaric acid tert-butyl ester(diastereomer 4)

In the diastereoisomeric separation described in example 208A, 65 mg (100% purity, ee >95%) of the title compound are obtained as the fourth eluting diastereomer (peak 4).

[α]_D ²⁰= 26.9 °, 589 nm, c = 0.34 g/100 ml, methanol

LC-MS (method 1) R_t= 3.05 min; MS (ESIpos): m/z = 692/694 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.893 (0.99), 0.912 (2.18), 0.930(1.09), 1.071 (0.20), 1.092 (0.21), 1.261 (0.41), 1.269 (0.39), 1.279 (0.52),1.287 (0.46), 1.297 (0.39), 1.305 (0.36), 1.325 (0.40), 1.361 (16.00), 1.565(0.24), 1.607 (0.22), 1.639 (0.20), 1.749 (0.29), 1.784 (0.27), 1.803 (0.29),1.828 (0.28), 1.854 (0.36), 1.884 (0.23), 2.033 (0.35), 2.048 (0.45), 2.066(1.46), 2.092 (0.36), 2.144 (1.32), 2.408 (0.17), 2.436 (0.27), 2.747 (0.25),3.369 (0.25), 3.387 (0.25), 3.498 (0.46), 3.529 (0.40), 3.618 (0.36), 3.632(0.57), 3.648 (0.52), 3.663 (0.26), 7.359 (0.46), 7.385 (0.25), 7.398 (0.86),7.410 (0.67), 7.416 (0.62), 7.421 (0.72), 7.434 (0.20), 7.466 (0.19), 7.547(0.50), 7.560 (0.42), 7.571 (0.34), 7.633 (0.22), 7.656 (1.87), 8.725 (0.29),8.740 (0.51), 8.754 (0.24)。

Example 212A

5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Glutaric acid tert-butyl ester(diastereomer 1)

[ structural formula see example 155A: (Mixtures of diastereomers)]

Separation of diastereoisomers/enantiomers from example 155A:

5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Tert-butyl valerate (Mixtures of diastereomers539 mg, 781 μmol, example 155A) were separated into diastereomers on the chiral phase by preparative HPLC [ column: daicel Chiralcel AD-H, 5 μm,250 mm x20 mm, flow rate: 7 ml/min, 25 deg.C, UV detection 240 nm, eluent 95% heptane/5% isopropanol, isocratic]. Four fractions (peak 1 to peak 4, see examples 212A and 215A) were obtained. The combined target fractions were each concentrated, each repurified by the same method one to three times, then concentrated again (rotary evaporator at 40 ℃) and dried in vacuo.

In the described separation of the diastereomers, 55 mg (100% purity) of the title compound was obtained as the first eluting diastereomer (peak 1).

LC-MS (method 1) R_t= 2.99 min; MS (ESIpos): m/z = 678/680 [M+H]⁺

Example 213A

5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Glutaric acid tert-butyl ester(diastereomer 2)

In the diastereoisomeric separation described in example 212A, 54 mg (100% purity) of the title compound were obtained as the second eluting diastereomer (peak 2).

LC-MS (method 1)): R_t= 2.99 min; MS (ESIpos): m/z = 678/680 [M+H]⁺

Example 214A

5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Glutaric acid tert-butyl ester(diastereomer 3)

In the diastereoisomeric separation described in example 212A, 43 mg (100% purity) of the title compound was obtained as the diastereomer (peak 3) eluting in the third position.

LC-MS (method 1) R_t= 2.99 min; MS (ESIpos): m/z = 678/680 [M+H]⁺

Example 215A

5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Glutaric acid tert-butyl ester(diastereomer 4)

In the diastereoisomeric separation described in example 212A, 53 mg (100% purity) of the title compound were obtained as the diastereomer (peak 4) eluting at the fourth position.

LC-MS (method 1) R_t= 2.99 min; MS (ESIpos): m/z = 678/680 [M+H]⁺

Example 216A

(+) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid tert-butyl ester(enantiomer 1)

[ structural formula see example 162A: (Racemic modification)]

The enantiomer from example 162A was isolated:

(+/-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid tert-butyl esterRacemic modification185 mg, 269 μmol, example 162A) was separated into enantiomers on a chiral column by preparative SFC [ column: daicel Chiralpak AD-H, 5 μm,250 mm x 30mm, flow rate: 120 ml/min, 25 deg.C, UV detection 230 nm, eluent 85% heptane/15% isopropanol, isocratic]. The combined target fractions were each concentrated at 30 ℃/30 mbarAnd (4) shrinking.

In the described enantiomeric separation, 85 mg (98% purity, ee >99%) of the title compound are obtained as the earlier eluting enantiomer.

[α]_D ²⁰= 32.2 °, 589 nm, c = 0.32 g/100 ml, methanol

LC-MS (method 2) R_t= 1.40 min; MS (ESIpos): m/z = 686/688 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.235 (0.22), 1.311 (0.16), 1.362(16.00), 1.884 (0.53), 2.066 (0.38), 2.083 (0.51), 2.099 (0.52), 2.115(0.43), 2.137 (0.79), 2.165 (2.62), 3.172 (0.64), 3.451 (0.40), 3.480 (0.76),3.509 (0.38), 3.699 (0.23), 3.774 (0.26), 7.295 (0.27), 7.306 (0.28), 7.321(0.21), 7.332 (0.19), 7.390 (0.16), 7.402 (0.20), 7.412 (0.27), 7.423 (0.26),7.682 (0.31), 7.704 (1.50), 7.712 (0.98), 7.717 (0.88), 7.735 (0.19), 7.739(0.20), 8.815 (0.22), 8.830 (0.41), 8.844 (0.21)。

Example 217A

(-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid tert-butyl ester(enantiomer 2)

In the enantiomeric separation described in example 216A, 85 mg (100% purity, ee >98%) of the title compound were obtained as the enantiomer which eluted later.

[α]_D ²⁰= 28.0 °, 589 nm, c = 0.38 g/100 ml, methanol

LC-MS (method 2) R_t= 1.40 min; MS (ESIpos): m/z = 686/688 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.235 (0.31), 1.361 (16.00), 1.884(0.70), 1.975 (0.18), 2.082 (0.68), 2.098 (0.69), 2.115 (0.58), 2.137 (1.03),2.164 (3.20), 3.172 (0.85), 3.451 (0.49), 3.480 (0.92), 3.508 (0.47), 3.699(0.31), 3.773 (0.36), 7.271 (0.16), 7.282 (0.19), 7.295 (0.34), 7.305 (0.35),7.320 (0.26), 7.331 (0.23), 7.391 (0.21), 7.412 (0.34), 7.422 (0.33), 7.444(0.17), 7.681 (0.34), 7.704 (1.55), 7.712 (1.11), 7.716 (0.97), 7.735 (0.21),7.739 (0.22), 8.829 (0.52)。

Example 218A

5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid tert-butyl ester(enantiomer 1)

[ structural formula see example 166A: (Racemic modification)]

The enantiomer from example 166A was isolated:

(+/-) -5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid tert-butyl esterRacemic modification489 mg, 735 μmol, example 166A) was separated into enantiomers on a chiral column by preparative SFC [ column: daicel Chiralpak AD-H, 5 μm,250 mm x20 mm, flow rate: 80 ml/min, injection: 0.3 ml, 40 deg.C, UV detection 210 nm, eluent 85% heptane/15% isopropanol, running time 13 min, isocratic]. The combined target fractions were each concentrated and the respective residue was lyophilized from acetonitrile/water.

In the described enantiomeric separation, 39 mg (93% purity, ee >99%) of the title compound were obtained as the earlier eluting enantiomer.

LC-MS (method 2) R_t= 1.50 min; MS (ESIpos): m/z = 664/666 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.360 (16.00), 1.371 (1.06), 1.603(1.40), 1.780 (0.84), 2.080 (0.23), 2.133 (1.95), 2.150 (0.79), 3.492 (1.08),3.506 (1.58), 3.521 (1.04), 3.706 (0.25), 7.278 (0.16), 7.290 (0.27), 7.302(0.27), 7.316 (0.21), 7.327 (0.19), 7.408 (0.31), 7.420 (0.29), 7.532 (0.64),7.554 (1.12), 7.602 (0.66), 7.607 (0.60), 7.624 (0.35), 7.629 (0.34), 8.788(0.31)。

Example 219A

5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid tert-butyl ester(enantiomer 2)

In the enantiomeric separation described in example 218A, 32 mg (93% purity, ee value 89%) of the title compound were obtained as the later eluting enantiomer.

LC-MS (method 2) R_t= 1.50 min; MS (ESIpos): m/z = 664/666 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.309 (0.17), 1.361 (16.00), 1.603(1.35), 1.780 (0.81), 2.066 (0.24), 2.082 (0.22), 2.103 (0.22), 2.134 (1.94),2.151 (0.80), 3.492 (1.06), 3.507 (1.53), 3.521 (1.01), 3.711 (0.25), 7.278(0.16), 7.290 (0.27), 7.301 (0.27), 7.316 (0.22), 7.327 (0.19), 7.386 (0.20),7.398 (0.24), 7.408 (0.31), 7.419 (0.29), 7.532 (0.60), 7.555 (1.06), 7.602(0.61), 7.607 (0.55), 7.624 (0.34), 7.630 (0.32), 8.775 (0.18), 8.789 (0.32)。

Example 220A

5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2,3, 6-trichlorophenyl) pentanoic acid tert-butyl ester(diastereomer 1)

[ structural formula see example 187A: (Mixtures of diastereomers)]

Separation of diastereoisomers/enantiomers from example 187A:

5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-tert-butyl 4- (2,3, 6-trichlorophenyl) pentanoate (C:)Mixtures of diastereomers294 mg, 419 μmol, example 187A) were separated by preparative HPLC on chiral phase into diastereomers using three different separation methods [ method 1: column: DaicelChiralpak AD-H, 5 μm,250 mm x20 mm, flow rate: 14 ml/min, temperature 25 ℃, UV detection 240 nm, eluent 90% heptane/10% isopropanol, isocratic, method 2: daicel Chiralpak AD-H, 5 μm,250 mm x20mm, flow rate: 9 ml/min, temperature 25 ℃, UV detection 240 nm, eluent 100% ethanol, method 3: daicel Chiralcel OD-H, 5 μm,250 mm x20 mm, flow rate: 9 ml/min, 25 deg.C, UV detection 240 nm, eluent 90% heptane/10% isopropanol, isocratic]. Four fractions were obtained (see examples 219A and 222A), with the order of the peaks in some cases depending on the preparative separation method used. The sequence of examples 219A-222A followed the elution sequence of peaks 1-4 in the following analytical HPLC procedure: column: daicel ChiralpakOD-H, 5 μm,250 mm x 4.6mm, flow rate: 0.3 ml/min, 25 deg.C, UV detection 240 nm, eluent 90% heptane/10% isopropanol, isocratic. The combined target fractions were each concentrated (rotary evaporator at 40 ℃) and then dried in vacuo.

In the described separation of the diastereomers, 14 mg (100% purity) of the title compound (peak 1 in analytical HPLC, see above) are obtained.

LC-MS (method 1) R_t= 2.83 min; MS (ESIpos): m/z = 700/702/704 [M+H]⁺

Example 221A

5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2,3, 6-trichlorophenyl) pentanoic acid tert-butyl ester(diastereomer 2)

In the diastereoisomeric separation described in example 220A, 17 mg (100% purity) of the title compound are obtained (peak 2 in analytical HPLC, see example 220A).

LC-MS (method 1) R_t= 2.84 min; MS (ESIpos): m/z = 700/702/704 [M+H]⁺

Example 222A

5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2,3, 6-trichlorophenyl) pentanoic acid tert-butyl ester(diastereomer 3)

In the diastereoisomeric separation described in example 220A, 32 mg (100% purity) of the title compound are obtained (peak 3 in analytical HPLC, see example 220A).

LC-MS (method 1) R_t= 2.83 min; MS (ESIpos): m/z = 700/702/704 [M+H]⁺

Example 223A

5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2,3, 6-trichlorophenyl) pentanoic acid tert-butyl ester(diastereomer 4)

In the diastereoisomeric separation described in example 220A, 27 mg (94% purity) of the title compound are obtained (peak 4 in analytical HPLC, see example 220A).

LC-MS (method 1) R_t= 2.83 min; MS (ESIpos): m/z = 700/702/704 [M+H]⁺

Example 224A

(+/-) -4-cyano-4- (2, 5-difluorophenyl) butanoic acid tert-butyl ester(raceme)

Diisopropylamine (10 ml, 74 mmol) was initially charged in THF (44 ml) under argon at-78 deg.C and an n-butyllithium solution (1.6M in hexane, 44 ml, 70mmol) was slowly added to prepare a LDA solution. After the addition was complete, the solution was stirred at 0 ℃ for a further 10 min. The LDA solution was slowly added dropwise to a solution of (2, 5-difluorophenyl) acetonitrile (8.1 ml, 98% purity, 64 mmol) in THF (120 ml) cooled to-78 deg.C. After the addition was complete, the cooling bath was removed, the reaction mixture was brought to 0 ℃ and cooled again to-78 ℃ after 15 min. A solution of tert-butyl 3-bromopropionate (13 ml,97% purity, 77 mmol) in 44 ml of THF is then slowly added dropwise and the mixture is stirred at-78 ℃ for a further 1h, then warmed to room temperature and stirred at room temperature overnight. For work-up, ammonium chloride solution (300 ml, 10% in water) was added. The mixture was stirred vigorously for 5 minutes, and then extracted twice with ethyl acetate. The combined organic phases were washed successively with 1M hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution, twice each. The organic phase is then dried over sodium sulfate and concentrated on a rotary evaporator. The residue was dissolved in a small amount of DMSO and purified by preparative HPLC (method 29) in 4 parts. The product containing fractions were combined and concentrated on a rotary evaporator. 8.05g (100% purity, 45% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.11 min; MS (ESIpos): m/z = 282 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.381 (16.00), 2.313 (0.86), 2.332(1.28), 2.350 (0.44), 4.414 (0.63), 7.353 (0.40), 7.366 (0.62), 7.374 (0.51),7.377 (0.49)。

Example 225A

(+/-) -5-amino-4- (2, 5-difluorophenyl) pentanoic acid tert-butyl ester(raceme)

Tert-butyl (+/-) -4-cyano-4- (2, 5-difluorophenyl) butyrate obtained in example 224A (b)Racemic modification8.05g, 100% pure, 28.6 mmol) was initially charged in t-butanol (210 ml, 2.2 mol) and methanol (9.3 ml) and raney nickel (1.68 g, 28.6 mmol) was added. The reaction mixture was stirred under standard hydrogen pressure for 9 days. The reaction was stopped despite incomplete conversion. The catalyst was filtered off through celite and washed three times with methanol (30 ml each). The filtrate was concentrated by rotary evaporation and the residue was dissolved in ethyl acetate (200 ml). The organic phase was extracted twice with 1M hydrochloric acid (200ml each). The combined aqueous phases were brought to pH 8 by slow addition of sodium bicarbonate and extracted twice with dichloromethane (200ml each). The combined organic phases were dried over sodium sulfate, filtered and concentrated. 3.84 g (100% purity, 47% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 1.12 min; MS (ESIpos): m/z = 286 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d ₆): δ [ppm]= 7.29-7.04 (m, 3H), 2.92-2.84 (m,1H), 2.79-2.67 (m, 2H), 2.05-1.91 (m, 3H), 1.74-1.61 (m, 1H), 1.35 (s, 9H).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.111 (0.42), 1.354 (16.00), 2.012(1.26), 2.025 (0.85), 2.728 (0.47), 2.736 (0.51), 2.747 (0.69), 2.751 (0.69)。

Example 226A

(+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2, 5-difluorophenyl) pentanoic acid tert-butyl ester(raceme)

Tert-butyl (+/-) -5-amino-4- (2, 5-difluorophenyl) pentanoate obtained in example 225A (b)Racemic modification3.00 g, 10.5 mmol) in dichloromethane (80 ml) and at room temperature DIPEA (4.6 ml, 26mmol) was added followed by 6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (2.79 g, 8.76 mmol, example 3A) in dichloromethane (20 ml). The reaction mixture was stirred for 2 hours, then diluted with dichloromethane (100 ml) and washed twice with 1M hydrochloric acid and then twice with saturated sodium bicarbonate solution. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was dried in vacuo. 4.92 g (99% purity, 98% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.48 min; MS (ESIneg): m/z = 565/567 [M-H]^-

¹H-NMR (400 MHz, DMSO-d ₆): δ [ppm]= 8.89 (t, 1H), 7.94-7.86 (m, 2H),7.82-7.40 (br. m, 1H), 7.34-7.29 (m, 1H), 7.24 (td, 1H), 7.19-7.07 (m, 1H),3.81-3.62 (m, 2H), 3.41-3.34 (m, 1H), 2.30-2.15 (m, 3H), 2.14-2.06 (m, 2H),2.05-1.98 (m, 1H), 1.88-1.73 (m, 1H), 1.37 (s, 9H)。

Example 227A

5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2, 5-difluorophenyl) pentanoic acid tert-butyl ester(mixture of diastereomers)

Tert-butyl 5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2, 5-difluorophenyl) pentanoate (400 mg, 704 μmol, example 226A) was initially charged in NMP (4.5 ml) in a thick-walled microwave vessel, with 3-ethylpiperidine (399 mg, 3.52 mmol) and DIPEA (610 μ l, 3.5mmol) added successively. The vessel was closed and shaken overnight at 130 ℃. The reaction solution was cooled to room temperature and purified directly (without further work-up) by preparative HPLC (method 14). The product containing fractions were concentrated and dried in vacuo. The residue obtained is dissolved in a small amount of dichloromethane and foamed under vacuum. 375 mg (100% purity, 83% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.90 min; MS (ESIpos): m/z = 644/646 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d ₆): δ [ppm]= 8.73 (br t, 1H), 7.70-7.60 (m, 2H),7.44 (br s, 1H), 7.33-7.27 (m, 1H), 7.26-7.19 (m, 1H), 7.16-7.09 (m, 1H),3.74-3.59 (m, 2H), 3.55-3.42 (m, 2H), 3.40-3.34 (m, 1H), 2.80-2.69 (m, 1H),2.48-2.37 (m, 1H), 2.16-1.98 (m, 6H), 1.91-1.72 (m, 3H), 1.68-1.51 (m, 2H),1.37 (s, 9H), 1.34-1.21 (m, 2H), 1.13-1.02 (m, 1H), 0.91 (t, 3H)。

Separation of diastereoisomers/enantiomers:

the title compound (316 mg, 490 μmol) was dissolved in methanol (12 ml) and attempted to be separated into diastereomers on the chiral phase by preparative SFC [ column: daicel Chiralcel OX-H, 5 μm,250 mm x20 mm, injection: 0.30 ml, eluent 82% carbon dioxide/18% methanol, flow rate: 80 ml/min, 40 ℃, 210 nm UV detection, 6.1 min running time, isocratic ]. Three fractions (peaks 1-3) were obtained, where peak 1 was obtained as a mixture of two diastereomers/enantiomers (see example 228A) and peak 2 and peak 3 were obtained each as an individual diastereomer (see examples 229A and 230A). The combined target fractions were each concentrated and the respective residue was lyophilized.

Example 228A

5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2, 5-difluorophenyl) pentaneTert-butyl ester(mixture of two diastereomers)

In the diastereoisomeric separation described in example 227A, 125 mg (100% purity) of the title compound (mixture of two diastereomers) are obtained as fraction 1.

LC-MS (method 1) R_t= 2.92 min; MS (ESIpos): m/z = 644/646 [M+H]⁺

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 0.893 (0.86), 0.908 (1.93), 0.923(0.96), 1.084 (0.16), 1.090 (0.16), 1.244 (0.19), 1.258 (0.30), 1.272 (0.40),1.281 (0.30), 1.286 (0.31), 1.294 (0.24), 1.372 (16.00), 1.560 (0.17), 1.748(0.23), 1.754 (0.20), 1.774 (0.26), 1.799 (0.17), 1.848 (0.19), 1.873 (0.18),2.010 (0.19), 2.025 (0.20), 2.085 (0.63), 2.099 (1.07), 2.104 (0.83), 2.113(1.02), 2.741 (0.18), 3.340 (1.17), 3.358 (0.24), 3.360 (0.22), 3.494 (0.35),3.512 (0.29), 3.642 (0.21), 3.651 (0.22), 7.122 (0.24), 7.203 (0.20), 7.212(0.21), 7.222 (0.33), 7.231 (0.32), 7.240 (0.17), 7.289 (0.20), 7.296 (0.27),7.304 (0.20), 7.632 (0.23), 7.649 (1.27), 7.655 (0.79), 7.658 (0.68), 8.725(0.21), 8.736 (0.36), 8.747 (0.20)。

Example 229A

5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2, 5-difluorophenyl) pentanoic acid tert-butyl ester(diastereomer 1)

In the diastereoisomeric separation described in example 227A, 43 mg (100% purity) of the title compound was obtained as peak 2.

LC-MS (method 1) R_t= 2.92 min; MS (ESIpos): m/z = 644/646 [M+H]⁺

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 0.894 (0.95), 0.909 (2.24), 0.924(1.09), 1.084 (0.16), 1.090 (0.16), 1.244 (0.20), 1.258 (0.30), 1.272 (0.42),1.286 (0.35), 1.294 (0.23), 1.372 (16.00), 1.560 (0.18), 1.567 (0.16), 1.748(0.23), 1.754 (0.20), 1.773 (0.27), 1.786 (0.20), 1.792 (0.16), 1.800 (0.18),1.806 (0.16), 1.849 (0.19), 1.873 (0.18), 2.010 (0.20), 2.024 (0.21), 2.051(0.17), 2.085 (0.68), 2.098 (1.17), 2.111 (0.81), 2.743 (0.21), 3.494 (0.35),3.511 (0.26), 3.631 (0.20), 3.642 (0.27), 3.689 (0.16), 7.122 (0.23), 7.203(0.19), 7.212 (0.21), 7.221 (0.32), 7.231 (0.31), 7.240 (0.16), 7.277 (0.17),7.283 (0.21), 7.288 (0.21), 7.295 (0.29), 7.302 (0.21), 7.306 (0.20), 7.313(0.16), 7.632 (0.26), 7.650 (1.35), 7.655 (0.95), 7.659 (0.81), 7.673 (0.16),7.677 (0.17), 8.723 (0.23), 8.734 (0.39), 8.746 (0.22)。

Example 230A

5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2, 5-difluorophenyl) pentanoic acid tert-butyl ester(diastereomer 2)

In the diastereoisomeric separation described in example 227A, 48mg (100% purity) of the title compound was obtained as peak 3.

LC-MS (method 1) R_t= 2.92 min; MS (ESIpos): m/z = 644/646 [M+H]⁺

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 0.892 (1.06), 0.907 (2.36), 0.922(1.19), 1.066 (0.21), 1.084 (0.22), 1.245 (0.24), 1.260 (0.41), 1.274 (0.54),1.287 (0.40), 1.372 (16.00), 1.558 (0.23), 1.580 (0.20), 1.606 (0.21), 1.631(0.22), 1.748 (0.31), 1.773 (0.34), 1.783 (0.30), 1.797 (0.25), 1.804 (0.22),1.817 (0.20), 1.848 (0.26), 1.872 (0.25), 1.999 (0.20), 2.010 (0.25), 2.024(0.25), 2.041 (0.18), 2.050 (0.19), 2.085 (0.75), 2.099 (1.24), 2.114 (1.70),2.421 (0.19), 2.737 (0.25), 3.490 (0.48), 3.512 (0.43), 3.624 (0.19), 3.639(0.29), 3.651 (0.40), 3.662 (0.30), 3.682 (0.23), 7.105 (0.16), 7.122 (0.32),7.138 (0.21), 7.203 (0.24), 7.213 (0.27), 7.222 (0.40), 7.231 (0.39), 7.241(0.20), 7.250 (0.18), 7.279 (0.22), 7.285 (0.27), 7.290 (0.28), 7.297 (0.37),7.304 (0.28), 7.315 (0.20), 7.631 (0.27), 7.649 (1.49), 7.653 (1.13), 7.657(0.93), 7.671 (0.18), 7.675 (0.18), 8.725 (0.30), 8.737 (0.53), 8.748 (0.28)。

Example 231A

(+/-) -4-cyano-4- (2-methylphenyl) butanoic acid tert-butyl ester(raceme)

(2-methylphenyl) acetonitrile (7.08 g, 54.0 mmol) was dissolved in DMF, sodium hydride was slowly added, and the mixture was stirred at room temperature for a further 10 min. Tert-butyl 3-bromopropionate (9.0 ml, 54 mmol) was then slowly added dropwise, during which mild foaming occurred and about 35 ℃ was reached. The reaction vessel was cooled in a water bath during further addition. The water bath was then removed and stirring continued at room temperature for 2.5 h. The reaction mixture was added to water, extracted with dichloromethane, dried (sodium sulfate) and concentrated on a rotary evaporator. The crude product was purified by flash column chromatography (Isolera, KP-Sil, eluent: hexane/ethyl acetate, gradient: 1-30% ethyl acetate). 8.32 g (74% purity, 44% of theory) of the title compound are obtained.

LC-MS (method 25) R_t= 1.39 min; MS (ESIpos): m/z = 260 [M+H]⁺

H-NMR (400 MHz, chloroform-d) delta [ ppm ]: 1.494 (16.00), 2.146 (0.44), 2.148(0.40), 2.382 (0.77), 2.411 (3.67), 2.491 (0.43), 2.522 (0.58), 3.702 (0.51),7.241 (0.45), 7.279 (0.68), 7.288 (0.62).

Example 232A

(+/-) -5-amino-4- (2-methylphenyl) pentanoic acid tert-butyl ester(raceme)

Reacting (+/-) -4-cyano-4- (2-methylphenyl) butyric acid tert-butyl ester (b: [ (+/-) -4-cyano-4- (2-Racemic modification8.32 g, 74% pure, 23.8mmol, example 231A) initial charge in tert-butanol (200ml) and addition of Raney nickel (1.88 g, 32.1 mmol). Hydrogenation was carried out with hydrogen at standard pressure for 6 h. Then, Raney nickel (1.88 g, 32.1 mmol) was added again and hydrogenation was carried out for 8 h. Thereafter, the same amount of catalyst was added again and hydrogenation was carried out for 5 h. The reaction mixture was filtered through celite, the filtrate was concentrated on a rotary evaporator and the residue was purified by column chromatography (Isolera,RP18 eluent water + 0.1% by volume formic acid/acetonitrile, gradient 5-95% acetonitrile). 5.74 g (98% purity, 90% of theory) of the title compound are obtained.

LC-MS (method 25) R_t= 0.71 min; MS (ESIpos): m/z = 264 [M+H]⁺

H-NMR (400 MHz, chloroform-d) delta [ ppm ]: 1.517 (16.00), 2.171 (1.18), 2.178(0.59), 2.432 (3.54), 3.574 (2.02), 7.250 (0.67), 7.254 (0.75), 7.256 (0.51),7.400 (1.05), 8.286 (0.70).

Example 233A

(+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2-methylphenyl) pentanoic acid tert-butyl ester(raceme)

Tert-butyl (+/-) -5-amino-4- (2-methylphenyl) pentanoate (5.74 g, 98% purity, 21.4 mmol, example 232A) and 6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (6.32 g, 19.8 mmol, example 3A) were dissolved in dichloromethane, aqueous sodium bicarbonate (240 ml, 1.0M, 240 mmol) was added and the reaction mixture was stirred vigorously at room temperature for 1.5 h. The reaction mixture was added to water and extracted with dichloromethane, and the organic phase was washed with 1M hydrochloric acid and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The crude product was purified by column chromatography (Isolera, KP-Sil, eluent: hexane/ethyl acetate, gradient: 0-100% ethyl acetate). 7.72 g (84% purity, 61% of theory) of the title compound are obtained.

LC-MS (method 26) R_t= 1.59 min; MS (ESIpos): m/z = 545/547 [M+H]⁺

Example 234A

(+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2-methylphenyl) pentanoic acid(Xiaoxiao externally) Rotary body)

(+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2-methylphenyl) pentanoic acid tert-butyl ester (Racemic modification7.72 g, 84% pure, 11.9 mmol, example 233A) are dissolved in dichloromethane (25 ml). Then, TFA (22 ml, 280 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified by column chromatography (Isolera, LiChroprep RP-18 (40-63 μm), eluent: water +0.1 vol% ammonia/acetonitrile, gradient: 10-90% acetonitrile). 6.71 g (86% purity, 99% of theory) of the title compound are obtained.

LC-MS (method 26) R_t= 0.76 min; MS (ESIneg): m/z = 487/489 [M-H]^-

Example 235A

(+/-) -4-cyano-4- (2-methoxyphenyl) butanoic acid tert-butyl ester(raceme)

The method A comprises the following steps:

to a solution of (2-methoxyphenyl) acetonitrile (2.00 g, 13.6 mmol) under argon in THF (17 ml) was slowly added a solution of 2M LDA in THF (10 ml, 20 mmol) with stirring at-78 ℃. The mixture was brought to 0 ℃ and cooled again to-78 ℃ after 15 min. Then, tert-butyl 3-bromopropionate (2.6ml, 16 mmol) was slowly added dropwise thereto at-78 ℃ under stirring. The mixture was stirred further overnight, during which time the cooling bath (dry ice/acetone) was slowly brought to room temperature. Then, water was slowly added to the mixture, which was extracted twice with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated, and the residue was previously purified by flash column chromatography (100 g silica gel Biotage Snap cartridge KP-Sil, cyclohexane/ethyl acetate gradient 93:7 → 6:4, Isolera One). And then purified again by preparative HPLC (method 12). The combined target fractions were concentrated and the residue was dried in vacuo. 495 mg (98% purity, 13% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.13 min; MS (ESIpos): m/z = 276 [M+H]⁺

The method B comprises the following steps:

(2-methoxyphenyl) acetonitrile (7.98 g, 54.2 mmol) was dissolved in DMF (200ml), sodium hydride was added slowly, and the mixture was stirred at room temperature for 10 min. Then, while cooling (water bath), tert-butyl 3-bromopropionate (11.3 g, 54.2 mmol) was slowly added dropwise, during which time the reaction solution was heated up to about 35 ℃. After stirring at room temperature for 3h, the reaction mixture was added to water and extracted with dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated, and the residue was purified by flash column chromatography (silica gel, gradient: 1-30% ethyl acetate/hexane). 9.79 g (62% purity, 40% of theory) of the title compound are obtained.

LC-MS (method 25) R_t= 1.32-1.35 min; MS (ESIpos): m/z = 276 [M+H]⁺

Example 236A

(+/-) -5-amino-4- (2-methoxyphenyl) pentanoic acid tert-butyl ester(raceme)

The method A comprises the following steps:

to a solution of tert-butyl (+/-) -4-cyano-4- (2-methoxyphenyl) butyrate (495 mg, 1.80 mmol, example 235A, method A) in tert-butanol (11 ml) was added Raney nickel (106 mg, 1.80 mmol) and hydrogenation was carried out overnight at standard pressure. The catalyst was then filtered off through celite and the mother liquor was concentrated. 269 mg (85% purity, 46% of theory) of the title compound are obtained.

LC-MS (method 2) R_t= 0.68 min; MS (ESIpos): m/z = 280 [M+H]⁺

The method B comprises the following steps:

to a solution of tert-butyl (+/-) -4-cyano-4- (2-methoxyphenyl) butyrate (9.79 g, 62% purity, 22.4 mmol, example 235A, method B) in tert-butanol (350 ml) was added Raney nickel (2.09 g, 35.6 mmol) and hydrogenated at standard pressure for 6 h. Then, Raney nickel (2.09 g, 35.6 mmol) was added again to the mixture, and hydrogenation was carried out for 8 h. Raney nickel (2.09 g, 35.6 mmol) was added again and hydrogenated for a further 5 h. The solid was filtered off through celite and washed with ethyl acetate and the filtrate was concentrated. The crude product was purified by flash chromatography (LiChroprep RP-1840-63 μm; gradient: 5-95% acetonitrile/0.1% aqueous formic acid). 2.69 g (99% purity, 42% of theory) of the title compound are obtained.

LC-MS (method 25) R_t= 0.74 min; MS (ESIpos): m/z = 280 [M+H]⁺

Separation of enantiomers:

the title compound (2.69 g, 99% purity from method B) was separated by preparative HPLC on chiral phase into enantiomers [ column: cellulose SC 10 mu m 250 x 50mm, flow rate: 120 ml/min, eluent 20% isopropanol/(80% hexane + 0.1% diethylamine), isocratic ]. The combined target fractions were each concentrated and the residue was dried in vacuo.

Example 237A

5-amino-4- (2-methoxyphenyl) pentanoic acid tert-butyl ester(enantiomer 1)

In the enantiomeric separation described in example 236A, 1.16 g (45% purity, ee value 99%) of the title compound (impurity obtained in the separation) was obtained as the earlier eluting enantiomer.

LC-MS (method 25) R_t= 0.74 min; MS (ESIpos): m/z = 280 [M+H]⁺

Example 238A

5-amino-4- (2-methoxyphenyl) pentanoic acid tert-butyl ester(enantiomer 2)

In the enantiomeric separation described in example 236A, 1.19 g (33% purity, ee value 99%) of the title compound (impurity obtained in the separation) were obtained as the enantiomer eluting later.

LC-MS (method 25) R_t= 0.75 min; MS (ESIpos): m/z = 280 [M+H]⁺

Example 239A

5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2-methoxyphenyl) pentanoic acid tert-butyl ester(pair) Enantiomer 1)

To 6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (1.21 g, 3.78 mmol, example 3A) and tert-butyl 5-amino-4- (2-methoxyphenyl) pentanoate (1.16 g, 45% purity, 1.87 mmol,enantiomer 1Example 237A) to a mixture in dichloromethane (25 ml) was added 1M aqueous sodium bicarbonate solution (25 ml) and the reaction mixture was shaken vigorously at room temperature for 2 h. The organic phase was separated, dried over sodium sulfate, filtered and concentrated and the residue was purified by flash column chromatography (LiChroprep RP-1840-63 μm; gradient: 50-100% acetonitrile/water). 1.27 g (73% purity, 88% of theory) of the title compound are obtained.

LC-MS (method 25) R_t= 1.54 min; MS (ESIpos): m/z = 561/563 [M+H]⁺

Example 240A

5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2-methoxyphenyl) pentanoic acid tert-butyl ester(pair) Enantiomer 2)

To 6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (1.24 g, 3.90 mmol, example 3A) and tert-butyl 5-amino-4- (2-methoxyphenyl) pentanoate (1.19 g, 33% purity, 1.41 mmol,enantiomer 2Example 238A) to a mixture in dichloromethane (25 ml) was added 1M aqueous sodium bicarbonate solution (25 ml) and the reaction mixture was shaken vigorously at room temperature for 2 h. The organic phase was separated, dried over sodium sulfate, filtered and concentrated, and the residue was purified by flash column chromatography (LiChroprep RP-1840-63 μm; gradient: 50-100% acetonitrile/water). 693 mg (97% pure, 85% of theory) of the title compound are obtained.

LC-MS (method 25) R_t= 1.54 min; MS (ESIpos): m/z = 561/563 [M+H]⁺

H-NMR (400 MHz, chloroform-d) delta [ ppm ]: 1.390 (0.43), 1.428 (16.00), 2.160(0.41), 2.190 (0.50), 2.280 (1.48), 3.751 (5.16), 6.858 (0.50), 6.878 (0.54),6.994 (0.51), 7.218 (0.55), 7.237 (0.47), 7.243 (0.46), 7.720 (0.49), 7.725(0.70), 7.761 (1.42), 7.783 (0.51).

Example 241A

5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2-methoxyphenyl) pentanoic acid(enantiomer isomerization) Body 1)

To the 5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl group]Tert-butyl amino } -4- (2-methoxyphenyl) pentanoate (1.27 g, 73% purity, 1.65 mmol,enantiomer 1Example 239A) in dichloromethane (15 ml) was added TFA (3.5 ml) and the mixture was stirred at room temperature overnight. Then, the reaction mixture was concentrated, and the residue was purified by flash column chromatography (LiChroprep RP-1840-63 μm; gradient: 20-90% acetonitrile/water). 800 mg (85% purity, 81% of theory) of the title compound are obtained.

LC-MS (method 25) R_t= 1.19 min; MS (ESIpos): m/z = 505/507 [M+H]⁺

Example 242A

5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2-methoxyphenyl) pentanoic acid(enantiomer isomerization) Body 2)

To the 5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl group]Tert-butyl amino } -4- (2-methoxyphenyl) pentanoate (690 mg, 97% purity, 1.19 mmol,enantiomer 2Example 240A) in dichloromethane (7 ml) TFA (1.9 ml) was added and the mixture was stirred at room temperature overnight. Then, the reaction mixture was concentrated, and the residue was purified by flash column chromatography (LiChroprep RP-1840-63 μm; gradient: 20-80% acetonitrile/water). 482 mg (87% purity, 70% of theory) of the title compound are obtained.

LC-MS (method 25) R_t= 1.19 min; MS (ESIpos): m/z = 505/507 [M+H]⁺

H-NMR (400 MHz, chloroform-d) delta [ ppm ]: 1.262 (0.78), 2.044 (0.43), 2.049(0.43), 2.132 (0.59), 2.144 (0.71), 2.152 (0.41), 2.165 (0.59), 2.279 (4.28),2.291 (1.50), 2.301 (1.46), 2.306 (1.22), 2.311 (1.15), 2.320 (1.60), 2.340(0.70), 2.472 (0.42), 3.480 (0.50), 3.492 (0.62), 3.504 (0.52), 3.713 (0.42),3.760 (16.00), 84 (0.44), 3.40), 3.943 (0.42), 3.957 (0.72), 3.972(0.45), 3.991 (0.41), 0.48 (24.48), 5848 (0.48), 3756 (24.599), 581.47 (0.599), 375.70 (0.70), 2.9), 2.26 (0.42), 3.480 (0.50), 3.492 (0.62), 3.504), 6.998 (1.55), 7.015(0.94), 7.017 (0.87), 7.218 (1.09), 7.221 (1.57), 7.233 (1.33), 7.237 (1.62),7.240 (1.40), 7.254 (1.31), 7.693 (0.80), 7.698 (0.88), 7.715 (1.75), 7.720(2.24), 7.750 (3.37), 7.761 (1.28), 7.772 (1.63).

Example 243A

(+/-) -4-cyano-4- (2, 6-dichlorophenyl) butanoic acid tert-butyl ester(raceme)

(2, 6-dichlorophenyl) acetonitrile (10.0 g, 54.0 mmol) was dissolved in DMF (200ml, 2.6 mol), NaH (2.59 g, 60% purity, 64.8 mmol) was added slowly and the mixture was stirred at room temperature for a further 10 min. Tert-butyl 3-bromopropionate (9.0 ml, 54 mmol) was then slowly added dropwise during which time mild foaming occurred and heating to about 35 ℃. During further addition, the reaction vessel was cooled in a water bath, then the water bath was removed and the mixture was stirred at room temperature for 2.5 h. The reaction mixture was added to water and extracted with dichloromethane. The organic phase was dried and concentrated on a rotary evaporator. The crude product was purified by column chromatography (Isolera, KP-Sil, eluent: hexane/ethyl acetate, gradient: 1-30% ethyl acetate). 13.2 g (75% purity, 59% of theory) of the title compound are obtained.

LC-MS (method 25) R_t= 1.43 min; MS (ESIpos): m/z = 314 [M+H]⁺

H-NMR (400 MHz, chloroform-d) delta [ ppm ]: 1.170 (0.43), 1.369 (16.00), 1.957(0.77), 2.323 (0.44), 2.343 (0.91), 2.354 (0.40), 4.770 (0.57), 7.128 (0.41),7.147 (0.55), 7.150 (0.58), 7.169 (0.69).

Example 244A

(+/-) -5-amino-4- (2, 6-dichlorophenyl) pentanoic acid tert-butyl ester(raceme)

Tert-butyl (+/-) -4-cyano-4- (2, 6-dichlorophenyl) butyrate (tert-butyl ester: (n-butyl)) (Racemic modification2.00 g, 75% pure, 4.78mmol, example 243A) initial charge in tert-butanol (3.9 ml, 67 mmol) and addition of Raney nickel. The reaction mixture was hydrogenated with hydrogen at standard pressure for 6 h. Then, the catalyst was added again and hydrogenation was carried out for 8 hours. The catalyst was filtered through celite and the filtrate was concentrated on a rotary evaporator. The residue was purified by column chromatography (Isolera, LiChroprepRP-18, eluent: water +0.1 vol% formic acid/acetonitrile, gradient: 5-95% acetonitrile). 660 mg (99% purity, 44% of theory) of the title compound are obtained.

LC-MS (method 25) R_t= 0.76 min; MS (ESIpos): m/z = 318 [M+H]⁺

H-NMR (400 MHz, chloroform-d) delta [ ppm ]: 1.403 (16.00), 7.115 (0.42), 7.135(1.08), 7.155 (0.65), 7.287 (0.47), 7.290 (0.46), 7.321 (0.70), 7.324 (0.62),7.341 (0.67), 7.344 (0.61).

Example 245A

(+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2, 6-dichlorophenyl) pentanoic acid tert-butyl ester(raceme)

6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (4.31 g, 13.5 mmol, example 3A) and (+/-) -5-amino-4- (2, 6-dichlorophenyl) pentanoic acid tert-butyl ester (c) (m)Racemic modification4.74 g, 14.9 mmol, example 244A) were dissolved in dichloromethane (25 ml, 390 mmol) and aqueous sodium bicarbonate (25 ml, 1.0M, 25mmol) was added to the solution. The reaction mixture was shaken vigorously at room temperature for 1.5 h. The reaction mixture is then added to water and extracted with dichloromethane, and the organic phase is washed with 1M hydrochloric acid and saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. The crude product was purified by column chromatography (Isolera, LiCH)roprep RP-18, eluent water/acetonitrile, gradient 40-100% acetonitrile). 2.33 g of the title compound (contaminated) were obtained and used in the subsequent stages without further purification.

LC-MS (method 25) R_t= 1.60 min; MS (ESIneg): m/z = 597/599 [M-H]^-

Example 246A

(+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2, 6-dichlorophenyl) pentanoic acid(outer) Racemate)

(+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2, 6-dichlorophenyl) pentanoic acid tert-butyl ester (C:)Racemic modification2.33 g, example 245A) were dissolved in dichloromethane (29 ml, 460 mmol). At room temperature, TFA (6.0 ml, 77 mmol) was added and the mixture was stirred at room temperature for 16 h. The reaction mixture was then concentrated on a rotary evaporator, repeatedly dissolved again in dichloromethane and concentrated again. The crude product was purified by column chromatography (Isolera, LiChroprep RP-18, eluent: water +0.1 vol% ammonia/acetonitrile, gradient: 5-40% acetonitrile, then re-washed with methanol to completely wash the product to the bottom). The combined target fractions were concentrated and the residue was dried in vacuo. 950 mg (72% purity, 26% of theory, over two steps) of the title compound are obtained.

LC-MS (method 26) R_t= 0.74 min; MS (ESIpos): m/z = 543/545 [M+H]⁺

Example 247A

(+/-) -4-cyano-4- (2, 6-difluorophenyl) butanoic acid tert-butyl ester(raceme)

The method A comprises the following steps:

to a solution of (2, 6-difluorophenyl) acetonitrile (5.00 g, 32.7 mmol) in THF (30 ml) under argon was slowly added a 2M solution of LDA in THF (20 ml, 39 mmol) with stirring at-78 ℃. The mixture was brought to 0 ℃ and cooled again to-78 ℃ after 15 min. Then, a solution of tert-butyl 3-bromopropionate (6.2ml, 39 mmol) in THF (10 ml) was slowly added dropwise thereto under stirring at-78 ℃. The mixture was stirred further overnight, during which time the cooling bath (dry ice/acetone) was slowly brought to room temperature. Then, water and ethyl acetate (100 ml each) were slowly added to the mixture at about 0 ℃ and shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (100 ml). The combined organic phases were washed once with saturated sodium chloride solution (150 ml), dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (100 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 93:7 → 7:3, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 4.87 g (76% purity, 40% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.06 min; MS (ESIpos): m/z = 282 [M+H]⁺

The method B comprises the following steps:

diisopropylamine (10 ml, 71 mmol) was initially charged in THF (43 ml) under argon at-15 deg.C and an n-butyllithium solution (1.6M in hexane, 43 ml, 68 mmol) was slowly added to prepare a LDA solution. After the addition was complete, the solution was stirred at 0 ℃ for a further 10 min. The LDA solution was slowly added dropwise to a solution of (2, 6-difluorophenyl) acetonitrile (9.90 g, 96% purity, 62.1 mmol) in THF (119 ml) cooled to-78 deg.C. After the addition was complete, the reaction mixture was brought to 0 ℃ and cooled again to-78 ℃ after 15 min. A solution of tert-butyl 3-bromopropionate (13 ml,97% purity, 74 mmol) in 45 ml of THF is then slowly added dropwise. The mixture was stirred at-78 ℃ for 1h and then at room temperature overnight. For work-up, an ammonium chloride solution (400 ml, 10% in water) was added. The mixture was stirred vigorously for 5 minutes, and then extracted twice with ethyl acetate. The combined organic phases were washed successively with 1M hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution, twice each. The organic phase is then dried over sodium sulfate and concentrated on a rotary evaporator. The oily residue was dissolved in dichloromethane, celite was added, and the mixture was concentrated on a rotary evaporator. The collected residue was purified by multiple passes through flash column chromatography (silica gel, Isolera, 100 g Ultra Snap cartridge; gradient: cyclohexane/ethyl acetate 100:0 to 70: 30). The product containing fractions were concentrated together. 12.9 g (100% purity, 74% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.08 min; MS (ESIpos): m/z = 282 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.374 (16.00), 2.313 (0.89), 2.331(1.31), 2.349 (0.45), 4.499 (0.52), 7.197 (0.60), 7.219 (1.24), 7.240 (0.68),7.519 (0.45)。

Example 248A

(+/-) -5-amino-4- (2, 6-difluorophenyl) pentanoic acid tert-butyl ester(raceme)

The method A comprises the following steps:

to a solution of tert-butyl (+/-) -4-cyano-4- (2, 6-difluorophenyl) butyrate (4.80 g, 17.1 mmol, example 247A, method A) in tert-butanol (100 ml) was added Raney nickel (1.00 g, 17.1 mmol) and hydrogenated at standard pressure overnight. The catalyst was then filtered off through celite and the mother liquor was concentrated. 4.06 g (81% purity, 67% of theory) of the title compound are obtained.

LC-MS (method 2) R_t= 0.64 min; MS (ESIpos): m/z = 286 [M+H]⁺

The method B comprises the following steps:

tert-butyl (+/-) -4-cyano-4- (2, 6-difluorophenyl) butyrate (12.9 g, 100% purity, 46.0 mmol, example 247A, method B) was initially charged in a mixture of tert-butanol (340 ml) and methanol (15 ml) and Raney nickel (2.00 g, 34.1 mmol) was added. The reaction mixture was stirred under standard hydrogen pressure overnight. Thereafter, 2 g of raney nickel was added to the reaction mixture and the reaction was stirred under standard hydrogen pressure for two more nights. The catalyst was filtered off through celite and washed three times with methanol (50 ml each). The filtrate was concentrated and the residue was dissolved in 400 ml of ethyl acetate. The solution was extracted twice with 1M hydrochloric acid (400 ml each). The combined aqueous phases were partitioned in three erlenmeyer flasks. One of the three portions was brought to pH 8-9 with sodium bicarbonate (powder) and extracted twice with 200ml of ethyl acetate. Due to the large amount of sodium bicarbonate required, the lower two aqueous fractions were brought to a pH of 8-10 with lithium hydroxide and extracted twice with 200ml each of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was treated with ethyl acetate and water. After phase separation, the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were concentrated and the residue was dried in vacuo. 7.76 g (76% purity, 45% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 1.05 min; MS (ESIpos): m/z = 286 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d ₆): δ [ppm]= 7.35-7.24 (m, 1H), 7.08-6.98 (m,2H), 3.10-2.95 (m, 1H), 2.91-2.73 (m, 2H), 2.09-1.99 (m, 3H), 1.85-1.70 (m,1H), 1.60-1.40 (m, 2H), 1.34 (s, 9H)。

Example 249A

(+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2, 6-difluorophenyl) pentanoic acid tert-butyl ester(raceme)

(+/-) -5-amino-4- (2, 6-difluorophenyl) pentanoic acid tert-butyl ester (b)Racemic modification3.12 g, 76% purity, 8.31 mmol, example 248A, method B) initial charge in dichloromethane (65 ml). DIPEA (3.6ml, 21 mmol) was added followed by a solution of 6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (2.21 g, 6.93 mmol, example 3A) in dichloromethane (15 ml). The reaction mixture was stirred overnight, then water and dichloromethane (200ml each) were added. The phases were separated and the aqueous phase was extracted with dichloromethane (200 ml). The combined organic phases were washed with saturated sodium chloride solution (200ml), dried over sodium sulfate, filtered and concentrated. The residue was dissolved in a small amount of DMSO and purified by preparative HPLC (method 30) in two portions. To be combinedThe standard fraction was concentrated and the residue was dried in vacuo. 3.77 g (98% purity, 94% of theory) of the title compound are obtained.

LC-MS (method 2) R_t= 1.30 min; MS (ESIneg): m/z = 565/567 [M-H]^-

¹H-NMR (400 MHz, DMSO-d ₆): δ [ppm]= 8.97 (t, 1H), 7.94-7.86 (m, 2H),7.84-7.46 (extremely wide m,1H), 7.43-7.29 (m,1H), 7.09 (t, 2H), 3.83-3.68 (m, 2H),3.57-3.41 (m,1H), 2.35-1.99 (m,6H), 1.96-1.83 (m,1H), 1.37 (s, 9H).

Example 250A

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid tert-butyl ester(raceme)

Tert-butyl (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2, 6-difluorophenyl) pentanoate (300 mg, 98% purity, 518 μmol, example 249A) was initially charged in NMP (4.4ml) and piperidine (260 μ l,2.6 mmol) and DIPEA (450 μ l,2.6 mmol) were added sequentially in a thick-walled microwave vessel. The vessel was closed and filled with argon through a cannula. The reaction solution was stirred at 100 ℃ overnight and then at 130 ℃ for a further 20 h. After cooling to room temperature, the reaction solution was purified by preparative HPLC (method 14). The product containing fractions were concentrated and dried in vacuo. The residue was dissolved in dichloromethane and foamed under vacuum. 252 mg (100% purity, 79% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.76 min; MS (ESIpos): m/z = 616/618 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d ₆): δ [ppm]= 8.81 (t, 1H), 7.71-7.61 (m, 2H),7.57-7.42 (m, 1H), 7.42-7.30 (m, 1H), 7.08 (t, 2H), 3.83-3.63 (m, 2H), 3.56-3.42 (m, 1H), 3.13 (br. d, 4H), 2.22-2.00 (m, 6H), 1.97-1.84 (m, 1H), 1.73-1.54 (m, 6H), 1.36 (s, 9H)

Separation of enantiomers:

the title compound (169 mg) was separated by preparative HPLC on chiral phase into enantiomers (see examples 251A and 252A) [ column: daicel Chiralpak IG, 5 μm,250 mm. times.20 mm, eluent n-heptane/isopropanol 90:10, flow rate: 25 ml/min, UV detection: 225 nm, temperature: 25 ℃ C. The combined target fractions were concentrated in each case (22 ℃ C., 40 mbar).

Example 251A

5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid tert-butyl ester(enantiomer 1))

In the enantiomeric separation described in example 250A, 88 mg (99% purity, ee >95%) of the title compound were obtained as the earlier eluting enantiomer.

Chiral analytical HPLC [ column: daicel Chiralpak IG, 5 μm,250 mm. times.4.6 mm, eluent n-heptane/isopropanol 90:10, flow rate: 1 ml/min, UV detection: 225 nm, temperature: 25 deg.C]: R_t= 28.9min.

LC-MS (method 1) R_t= 2.73 min; MS (ESIpos): m/z = 616/618 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.236 (0.76), 1.259 (0.48), 1.364(16.00), 1.607 (0.49), 1.671 (0.94), 2.096 (0.45), 2.113 (0.86), 2.135(1.82), 3.134 (1.22), 3.707 (0.42), 7.057 (0.50), 7.079 (0.89), 7.102 (0.58),7.647 (1.36), 7.658 (0.88), 7.663 (0.81), 8.811 (0.46)。

Example 252A

5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid tert-butyl ester(enantiomer 2))

In the enantiomeric separation described in example 250A, 66 mg (95% purity, ee value 98%) of the title compound were obtained as the enantiomer which eluted later.

Chiral analytical HPLC [ column: daicel Chiralpak IG, 5 μm,250 mm. times.4.6 mm, eluent n-heptane/isopropanol 90:10, flow rate: 1 ml/min, UV detection: 225 nm, temperature: 25 deg.C]: R_t= 34.9min.

LC-MS (method 1) R_t= 2.73 min; MS (ESIpos): m/z = 616/618 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.236 (0.63), 1.259 (0.47), 1.364(16.00), 1.606 (0.44), 1.670 (0.85), 2.095 (0.41), 2.112 (0.81), 2.135(1.69), 3.133 (1.12), 7.057 (0.47), 7.079 (0.84), 7.101 (0.55), 7.647 (1.32),7.658 (0.86), 7.663 (0.75), 8.811 (0.44)。

Example 253A

(+/-) - (5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid tert-butyl ester(raceme)

Tert-butyl (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2, 6-difluorophenyl) pentanoate (300 mg, 98% purity, 518 μmol, example 249A) was initially charged in NMP (4.4ml) and pyrrolidine (220 μ l,2.6 mmol) and DIPEA (450 μ l,2.6 mmol) were added sequentially in a microwave vessel. The vessel was closed and filled with argon through a cannula. The reaction solution was stirred at 100 ℃ overnight. After cooling to room temperature, the reaction solution was purified by preparative HPLC (method 14). The product containing fractions were concentrated and dried in vacuo. The residue was dissolved in a small amount of dichloromethane and foamed under vacuum. 193 mg (100% purity, 62% of theory) of the title compound are obtained.

LC-MS (method 4) R_t= 1.37 min; MS (ESIpos): m/z = 602/604 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d ₆): δ [ppm]= 8.76 (t, 1H), 7.56 (dd, 1H), 7.48(d, 1H), 7.42-7.27 (m, 2H), 7.07 (t, 2H), 3.73 – 3.66 (m, 2H), 3.57 (br s,4H), 3.52-3.40 (m, 1H), 2.22-2.01 (m, 6H), 1.95-1.82 (m, 5H), 1.36 (s, 9H)。

Separation of enantiomers:

119 mg of the title compound are separated by preparative HPLC on the chiral phase into the enantiomers (see examples 254A and 255A) [ column: daicel Chiralpak IC, 5 μm,250 mm. times.30 mm, eluent n-heptane/isopropanol 80:20, flow rate: 42.5 ml/min, UV detection: 225 nm, temperature: 25 ℃ C. The combined target fractions were concentrated in each case (22 ℃ C., 40 mbar).

Example 254A

(5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl)]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid tert-butyl ester(enantiomer 1)

In the enantiomeric separation described in example 253A, 57 mg (95% purity, ee value 96%) of the title compound were obtained as the earlier eluting enantiomer.

Chiral analytical HPLC [ column: daicel Chiralpak IC, 5 μm,250 mm. times.4.6 mm, eluent n-heptane/isopropanol 80:20, flow rate: 1 ml/min, UV detection: 260 nm, temperature: 25 deg.C]: R_t= 23.1min.

LC-MS (method 1) R_t= 2.14 min; MS (ESIpos): m/z = 602/604 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.235 (0.87), 1.258 (0.56), 1.298(0.40), 1.362 (16.00), 1.871 (1.37), 2.095 (0.48), 2.111 (0.81), 2.129(0.63), 2.160 (0.80), 3.566 (0.86), 7.050 (0.50), 7.072 (0.90), 7.094 (0.57),7.467 (0.69), 7.489 (1.13), 7.549 (0.60), 7.554 (0.55), 8.763 (0.47)。

Example 255A

(5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl)]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid tert-butyl ester(enantiomer 2)

In the enantiomeric separation described in example 253A, 50 mg (95% purity, ee value 99%) of the title compound were obtained as the enantiomer which eluted later.

Chiral analytical HPLC [ column: daicel Chiralpak IC, 5 μm,250 mm. times.4.6 mm, eluent n-heptane/isopropanol 80:20, flow rate: 1 ml/min, UV detection: 260 nm, temperature: 25 deg.C]: R_t= 28.2min.

LC-MS (method 1) R_t= 2.14 min; MS (ESIpos): m/z = 602/604[M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.15), 0.008 (0.74), 0.859(0.62), 1.245 (0.48), 1.362 (16.00), 1.872 (1.21), 2.096 (0.42), 2.111(0.72), 2.129 (0.57), 2.160 (0.70), 2.523 (0.69), 3.566 (0.77), 7.050 (0.45),7.072 (0.79), 7.095 (0.51), 7.468 (0.69), 7.490 (1.11), 7.549 (0.62), 7.555(0.57), 8.763 (0.41)。

Example 256A

(+/-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid tert-butyl ester(raceme)

(+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2, 6-difluorophenyl) pentanoic acid tert-butyl ester (b-butyl ester)Racemic modification300 mg, 98% purity, 518 μmol, example 249A) was initially charged in NMP (4.4ml) and 3, 3-difluoropiperidine hydrochloride (421 mg, 97% purity, 2.59 mmol) and DIPEA (450 μ l,2.6 mmol) were added sequentially. The vessel was closed and filled with argon through a cannula. The reaction solution was stirred at 100 ℃ overnight and then shaken at 130 ℃ for another 20 h. After cooling to room temperature, the reaction solution was purified by preparative HPLC (method 14). The product containing fractions were concentrated and dried in vacuo. The residue was dissolved in dichloromethane and foamed under vacuum. 234 mg (100% purity, 69% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.64 min; MS (ESIpos): m/z = 652/654 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d ₆): δ [ppm]= 8.83 (t, 1H), 7.76-7.65 (m, 2H),7.61-7.43 (m, 1H), 7.42-7.30 (m, 1H), 7.08 (t, 2H), 3.83-3.64 (m, 2H), 3.53 -3.42 (m, 3H), 3.22-3.11 (m, 2H), 2.22-1.99 (m, 8H), 1.97-1.82 (m, 3H), 1.36(s, 9H)。

Separation of enantiomers:

170 mg of the title compound are separated by preparative HPLC on the chiral phase into the enantiomers (see example 257A and 258A) [ column: daicel Chiralpak OX-H, 5 μm,250 mm X20 mm, eluent n-heptane/isopropanol 82:18, flow rate: 30 ml/min, UV detection: 220 nm, temperature: RT ]. The combined target fractions were each concentrated on a rotary evaporator.

Example 257A

5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid tert-butyl ester(enantiomer 1)

In the enantiomeric separation described in example 256A, 82 mg (98% purity, ee value 98%) of the title compound were obtained as the earlier eluting enantiomer.

Chiral analytical HPLC [ column: daicel Chiralpak OX-H, 5 μm,250 mm x 4.6mm, eluent n-heptane/isopropanol 80:20, flow rate: 1 ml/min, UV detection: 220 nm, temperature: 30 deg.C]: R_t= 2.13min.

LC-MS (method 1) R_t= 2.65 min; MS (ESIpos): m/z = 652/654 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.49), 0.008 (0.47), 1.105(0.66), 1.120 (0.67), 1.364 (16.00), 1.887 (0.54), 2.071 (0.51), 2.097(0.69), 2.114 (0.87), 2.135 (0.66), 2.154 (1.54), 3.166 (0.53), 3.448 (0.62),3.478 (1.91), 7.059 (0.45), 7.081 (0.83), 7.104 (0.53), 7.698 (1.28), 7.707(0.88), 7.712 (0.77), 8.825 (0.44)。

Example 258A

5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid tert-butyl ester(enantiomer 2)

In the enantiomeric separation described in example 256A, 73 mg (98% purity, ee value 95%) of the title compound were obtained as the enantiomer which eluted later.

Chiral analytical HPLC [ column: daicel Chiralpak OX-H, 5 μm,250 mm x 4.6mm, eluent n-heptane/isopropanol 80:20, flow rate: 1 ml/min, UV detection: 220 nm, temperature: 30 deg.C]: R_t= 3.23min.

LC-MS (method 1) R_t= 2.65 min; MS (ESIpos): m/z = 652/654 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.50), 0.008 (0.51), 1.105(0.61), 1.120 (0.60), 1.364 (16.00), 1.888 (0.54), 2.072 (0.50), 2.097(0.68), 2.114 (0.86), 2.136 (0.64), 2.154 (1.50), 3.166 (0.52), 3.475 (1.28),3.504 (0.56), 7.059 (0.46), 7.081 (0.80), 7.104 (0.52), 7.698 (1.25), 7.707(0.84), 7.712 (0.75), 8.825 (0.43)。

Example 259A

5- [ ({ 6-bromo-2- (3-fluoropiperidin-1-yl) -3-methylquinolin-4-yl } carbonyl) amino]-4- (2, 6-difluorophenyl) pentanoic acid tert-butyl ester(mixture of diastereomers)

(+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2, 6-difluorophenyl) pentanoic acid tert-butyl ester (b-butyl ester)Racemic modification400 mg, 98% purity, 690 μmol, example 249A) initial charge in NMP (4.0 ml) and sequential addition of 3-fluoropiperidine hydrochloride (497 mg, 97% purity, 3.45 mmol) and DIPEA (600 μ l, 3.5 mmol). The vessel was closed and shaken overnight at 130 ℃. After cooling to room temperature, the reaction solution was purified by preparative HPLC (method 14). The product containing fractions were concentrated and dried in vacuo. The residue was dissolved in a small amount of dichloromethane and foamed under vacuum. 343 mg (100% purity, 78% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.60 min; MS (ESIpos): m/z = 634/636 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d ₆): δ [ppm]= 8.82 (t, 1H), 7.72-7.64 (m, 2H),7.61-7.43 (m, 1H), 7.41-7.30 (m, 1H), 7.08 (d, 2H), 4.98-4.76 (m, 1H), 3.82-3.63 (m, 2H), 3.56-3.30 (m, 3H), 3.24-3.02 (m, 2H), 2.23-1.72 (m, 10H), 1.70-1.57 (m, 1H), 1.36 (s, 9H)。

Example 260A

5- [ ({ 6-bromo-2- (3-ethylpiperidin-1-yl) -3-methylquinolin-4-yl } carbonyl) amino]-4- (2, 6-difluorophenyl)) Glutaric acid tert-butyl ester(mixture of diastereomers)

(+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2, 6-difluorophenyl) pentanoic acid tert-butyl ester (b-butyl ester)Racemic modification400 mg, 98% purity, 690 μmol, example 249A) initial charge in NMP (4.0 ml) and sequential addition of 3-ethylpiperidine (411 mg, 95% purity, 3.45 mmol) and DIPEA (600 μ l, 3.5 mmol). The vessel was closed and shaken overnight at 130 ℃. After cooling to room temperature, the reaction solution was purified by preparative HPLC (method 14). The product containing fractions were concentrated and dried in vacuo. The residue was dissolved in a small amount of dichloromethane and foamed under vacuum. 365 mg (100% purity, 82% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, DMSO-d ₆): δ [ppm]= 8.81 (t, 1H), 7.71-7.59 (m, 2H),7.56-7.42 (m, 1H), 7.42-7.29 (m, 1H), 7.08 (t, 2H), 3.80-3.64 (m, 2H), 3.57-3.42 (m, 3H), 2.83-2.69 (m, 1H), 2.48-2.36 (m, 1H), 2.24-1.99 (m, 6H), 1.98-1.81 (m, 2H), 1.81-1.70 (m, 1H), 1.68-1.48 (m, 2H),1.36 (s, 9H), 1.32-1.20(m, 2H), 1.16-1.00 (m, 1H), 0.97-0.83 (m, 3H)。

Example 261A

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 5-difluorophenyl) pentanoic acid tert-butyl ester(raceme)

(+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2, 5-difluorophenyl) pentanoic acid tert-butyl ester (b-butyl ester)Racemic modification300 mg, 528 μmol, example 226A) initial charge in NMP (4.0 ml) and sequential addition of piperidine (260 μ l,2.6 mmol) and DIPEA (460 ml, 2.6 mmol). The vessel was closed and shaken overnight at 130 ℃. After cooling to room temperature, the mixture is fractionated by preparative HPLC (method 14)The reaction solution was separated. The product containing fractions were concentrated and dried in vacuo. The residue was dissolved in a small amount of dichloromethane and foamed under vacuum. 265 mg (100% purity, 81% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.72 min; MS (ESIpos): m/z = 616/618 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d ₆): δ [ppm]= 8.81-8.67 (m, 1H), 7.73-7.58 (m,2H), 7.55-7.36 (m, 1H), 7.33-7.27 (m, 1H), 7.27-7.19 (m, 1H), 7.18-7.06 (m,1H), 3.76 – 3.56 (m, 2H), 3.40-3.33 (m, 1H), 3.19-3.07 (m, 4H), 2.16-2.07 (m,5H), 2.06-1.96 (m, 1H), 1.86-1.73 (m, 1H), 1.73 – 1.55 (m, 6H), 1.37 (s, 9H)。

Separation of enantiomers:

the title compound (268 mg) was separated by preparative HPLC on chiral phase into enantiomers (see intermediates 262 and 263) [ column: daicel Chiralpak OX-H, 5 μm,250 mm X20 mm, eluent n-heptane/ethanol 80:20, flow rate: 20 ml/min, UV detection: 210 nm, temperature: 23 ℃ C. The combined target fractions were each concentrated on a rotary evaporator. The respective residue was mixed with 2ml acetonitrile and 15 ml water and lyophilized.

Example 262A

5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 5-difluorophenyl) pentanoic acid tert-butyl ester(enantiomer 1))

In the enantiomeric separation described in example 261A, 82 mg (99% purity, ee value 100%) of the title compound was obtained as the earlier eluting enantiomer.

Chiral analytical HPLC [ column: daicel Chiralpak OX-3, 3 μm, 50mm x 4.6mm, eluent isohexane/ethanol 80:20, flow rate: 1 ml/min, UV detection: 220 nm, temperature: 25 deg.C]: R_t= 2.24min.

LC-MS (method 1) R_t= 2.74 min; MS (ESIpos): m/z = 616/618 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.46), 0.008 (0.40), 1.371(16.00), 1.607 (0.40), 1.670 (0.79), 2.079 (0.65), 2.096 (0.94), 2.115(1.18), 3.132 (1.05), 7.646 (1.28), 7.655 (0.84), 7.660 (0.76)。

Example 263A

5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 5-difluorophenyl) pentanoic acid tert-butyl ester(enantiomer 2)

In the enantiomeric separation described in example 261A, 90 mg (98% purity, ee value 97%) of the title compound were obtained as the enantiomer which eluted later.

Chiral analytical HPLC [ column: daicel Chiralpak OX-3, 3 μm, 50mm x 4.6mm, eluent isohexane/ethanol 80:20, flow rate: 1 ml/min, UV detection: 220 nm, temperature: 25 deg.C]: R_t= 2.60min.

LC-MS (method 1) R_t= 2.74 min; MS (ESIpos): m/z = 616/618 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.44), 1.372 (16.00), 1.605(0.43), 1.670 (0.83), 2.080 (0.67), 2.096 (0.97), 2.115 (1.24), 3.133 (1.10),7.646 (1.31), 7.655 (0.88), 7.660 (0.81), 8.740 (0.40)。

Example 264A

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 5-difluorophenyl) pentanoic acid tert-butyl ester(raceme)

(+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2, 5-difluorophenyl) pentanoic acid tert-butyl ester (b-butyl ester)Racemic modification300 mg, 528 μmol, example 226A) initial charge in NMP (4.0 ml) and sequential addition of pyrrolidine (220 μ l,2.6 mmol) and DIPEA (460 μ l,2.6 mmol). The vessel was closed and stirred at 130 ℃ overnight. After cooling to room temperature, the reaction solution was purified by preparative HPLC (method 14). The product containing fractions were concentrated and dried in vacuo. 245 mg (100% purity, 77% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.13 min; MS (ESIpos): m/z = 602/604 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d ₆): δ [ppm]= 8.69 (t, 1H), 7.56 (dd, 1H), 7.48(d, 1H), 7.44-7.18 (m, 3H), 7.17-7.08 (m, 1H), 3.73-3.50 (m, 6H), 3.39-3.33(m, 1H), 2.20-1.97 (m, 6H), 1.91-1.84 (m, 4H), 1.85-1.73 (m, 1H), 1. 37 (s,9H)。

Separation of enantiomers:

the title compound (173 mg) was separated by preparative HPLC on chiral phase into enantiomers (see examples 265A and 266A) [ column: daicel Chiralpak IC, 5 μm,250 mm. times.30 mm, eluent n-heptane/isopropanol 80:20, flow rate: 42.5 ml/min, UV detection: 260 nm, temperature: 25 ℃ C. The combined target fractions were concentrated in each case (25 ℃, 40 mbar).

Example 265A

5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 5-difluorophenyl) pentanoic acid tert-butyl ester(enantiomer 1)

In the enantiomeric separation described in example 264A, 83 mg (90% purity, with solvent, ee value 96%) of the title compound were obtained as the earlier eluting enantiomer.

Chiral analytical HPLC [ column: daicel Chiralpak IC, 5 μm,250 mm. times.4.6 mm, eluent n-heptane/isopropanol 80:20, flow rate: 1 ml/min, UV detection: 260 nm, temperature: 25 deg.C]: R_t=19.2 min.

LC-MS (method 1) R_t= 2.13 min; MS (ESIpos): m/z = 602/604 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.81), 0.008 (0.79), 1.236(0.96), 1.259 (0.72), 1.298 (0.54), 1.370 (16.00), 1.871 (1.18), 2.078(0.65), 2.095 (0.85), 2.115 (0.44), 2.142 (0.50), 2.523 (0.56), 3.565 (0.80),7.466 (0.63), 7.488 (1.07), 7.545 (0.55), 7.551 (0.50)。

Example 266A

5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 5-difluorophenyl) pentanoic acid tert-butyl ester(enantiomers)Isomer 2)

In the enantiomeric separation described in example 264A, 86 mg (90% purity, with solvent, ee value 96%) of the title compound were obtained as the later eluting enantiomer.

Chiral analytical HPLC [ column: daicel Chiralpak IC, 5 μm,250 mm. times.4.6 mm, eluent n-heptane/isopropanol 80:20, flow rate: 1 ml/min, UV detection: 260 nm, temperature: 25 deg.C]: R_t=23.1 min.

LC-MS (method 1) R_t= 2.13 min; MS (ESIpos): m/z = 602/604 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.66), 0.008 (0.62), 0.839(0.47), 1.235 (1.44), 1.259 (1.15), 1.298 (0.84), 1.352 (0.50), 1.370(16.00), 1.871 (1.21), 2.078 (0.67), 2.095 (0.87), 2.115 (0.46), 2.141(0.51), 2.523 (0.47), 3.567 (0.83), 7.466 (0.64), 7.488 (1.07), 7.545 (0.55),7.551 (0.51)。

Example 267A

(+/-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2, 5-difluorophenyl) pentanoic acid tert-butyl ester(raceme)

(+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2, 5-difluorophenyl) pentanoic acid tert-butyl ester (b-butyl ester)Racemic modification300 mg, 528 μmol, example 226A) was initially charged in NMP (4.0 ml) and 3, 3-difluoropiperidine hydrochloride (416 mg, 2.64 mmol) and DIPEA (460 μ l,2.6 mmol) were added successively. The vessel was closed, shaken overnight at 130 ℃ and shaken for a further 20 h at 140 ℃. After cooling to room temperature, the reaction solution was separated by preparative HPLC (method 14). The product containing fractions were concentrated and dried in vacuo. The residue was dissolved in a small amount of dichloromethane and foamed under vacuum. 253 mg (100% purity, 73% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.60 min; MS (ESIpos): m/z = 652/654 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d ₆): δ [ppm]= 8.75 (t, 1H), 7.74-7.67 (m, 2H),7.48 (br s, 1H), 7.39-7.20 (m, 2H), 7.17-7.09 (m, 1H), 3.78-3.56 (m, 2H),3.48 (t, 2H), 3.40-3.29 (m, 1H), 3.17 (br s, 2H), 2.20-1.97 (m, 8H), 1.92-1.75 (m, 3H), 1.39-1.29 (m, 9H)。

Separation of enantiomers:

the title compound (202 mg) was separated by preparative HPLC on chiral phase into enantiomers (see intermediates 268A and 269A) [ column: daicel Chiralpak OX-H, 5 μm,250 mm X30 mm, eluent n-heptane/ethanol 85:15, flow rate: 42.5 ml/min, UV detection: 220 nm, temperature: 20 ℃ C. The combined target compounds were each concentrated and the respective residue was dried in vacuo.

Example 268A

5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2, 5-difluorophenyl) pentanoic acid tert-butyl ester(enantiomer 1)

In the enantiomeric separation described in example 267A, 71 mg (99% purity, ee value 99%) of the title compound were obtained as the earlier eluting enantiomer.

Chiral analytical HPLC [ column: daicel Chiralpak OX-3, 3 μm, 50mm x 4.6mm, eluent isohexane/ethanol 80:20, flow rate: 1 ml/min, UV detection: 220 nm, temperature: 25 deg.C]: R_t= 1.10min.

LC-MS (method 1) R_t= 2.60 min; MS (ESIpos): m/z = 652/654 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.84), 0.008 (0.94), 1.358(0.70), 1.371 (16.00), 1.880 (0.44), 2.081 (0.90), 2.098 (1.18), 2.120(0.74), 2.134 (1.11), 3.164 (0.56), 3.475 (0.68), 7.697 (1.31), 7.704 (0.89),7.709 (0.81), 8.752 (0.43)。

Example 269A

5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2, 5-difluorophenyl) pentanoic acid tert-butyl ester(enantiomer 2)

In the enantiomeric separation described in example 267A, 71 mg (95% purity, ee value 93%) of the title compound were obtained as the enantiomer which eluted later.

LC-MS (method 1) R_t= 2.60 min; MS (ESIpos): m/z = 652/654 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.68), 0.008 (1.48), 1.372(16.00), 1.879 (0.41), 2.081 (0.84), 2.098 (1.10), 2.119 (0.69), 2.134(1.02), 3.165 (0.52), 3.475 (0.62), 7.697 (1.27), 7.704 (0.89), 7.709 (0.79),8.752 (0.41)。

Example 270A

5- [ ({ 6-bromo-2- (3-fluoropiperidin-1-yl) -3-methylquinolin-4-yl } carbonyl) amino]-4- (2, 5-difluorophenyl) pentanoic acid tert-butyl ester(mixture of diastereomers)

(+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2, 5-difluorophenyl) pentanoic acid tert-butyl ester (b-butyl ester)Racemic modification400 mg, 704 μmol, example 226A) were initially charged in NMP (4.5 ml) and 3-fluoropiperidine hydrochloride (492 mg, 3.52 mmol) and DIPEA (610 μ l, 3.5mmol) were added successively. The vessel was closed and shaken overnight at 130 ℃. After cooling to room temperature, the reaction solution was purified by preparative HPLC (method 14). The product containing fractions were concentrated and dried in vacuo. 293 mg (100% purity, 66% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.59 min; MS (ESIpos): m/z = 634/636 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d ₆): δ [ppm]= 8.75 (t, 1H), 7.71-7.64 (m, 2H),7.60-7.36 (m, 1H), 7.33-7.20 (m, 2H), 7.17-7.08 (m, 1H), 4.98-4.76 (m, 1H),3.77-3.57 (m, 2H), 3.50-3.35 (m, 2H), 3.23-3.14 (m,1H), 3.13-3.03 (m,1H), 2.16-1.87 (m, 8H), 1.86-1.73 (m, 2H), 1.71-1.57 (m,1H), 1.37 (s, 9H), 1H.

Example 271A

(+/-) -5- [ (tert-butoxycarbonyl) amino group]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(raceme)

To a mixture of tert-butyl (+/-) -5-amino-4- (2-chlorophenyl) pentanoate (6.57 g, 83% pure, 19.2 mmol, example 25A) in dichloromethane (40 ml) was added triethylamine (3.0 ml, 21.5 mmol) and di-tert-butyl dicarbonate (4.70 g, 21.5 mmol) (evolved gas) at room temperature, and the mixture was first stirred at room temperature and then allowed to stand for five days. The mixture was then mixed with dichloromethane (60 ml) and washed once with sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (100 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3 → 7:3, Isolera One). The combined target fractions were concentrated on a rotary evaporator at 20 ℃ and the residue was dried in vacuo. Two fractions of the title compound were obtained with slightly different purities: fraction 1: 4.33 g (100% purity, 59% of theory, see analysis) and fraction 2:1.66 g (94% purity, 21% of theory).

LC-MS (method 2) R_t= 1.26 min; MS (ESIpos): m/z = 384 [M+H]⁺

¹H-NMR (400 MHz,DMSO-d6) δ [ppm]: 1.333 (9.46), 1.353 (16.00), 1.398(0.17), 1.692 (0.21), 1.708 (0.24), 1.716 (0.21), 1.731 (0.18), 1.933 (0.16),1.947 (0.27), 1.957 (0.23), 1.976 (0.92), 1.999 (0.31), 2.012 (0.23), 3.038(0.18), 3.055 (0.25), 3.072 (0.28), 3.087 (0.19), 3.183 (0.25), 3.200 (0.23),3.335 (0.25), 3.352 (0.23), 3.363 (0.16), 6.843 (0.18), 6.857 (0.33), 6.871(0.17), 7.220 (0.26), 7.227 (0.32), 7.238 (0.32), 7.248 (0.27), 7.311 (0.94),7.320 (1.08), 7.395 (0.60), 7.415 (0.50)。

Separation of enantiomers:

two combined fractions (5.9 g) of the title compound were dissolved in ethanol (100 ml), filtered and separated into enantiomers on the chiral phase by preparative SFC (see examples 272A and 273A) [ column: daicel Chiralcel OX, 20 μm, 380 mm x 50mm, flow rate: 300 ml/min, injection: 1.2 ml, UV detection: 210 nm, temperature: 40 deg.C, eluent 90% carbon dioxide/10% ethanol, running time 10 min, and isocratic. The combined target fractions were each concentrated and dried in vacuo.

Example 272A

(+) -5- [ (tert-butoxycarbonyl) amino group]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(enantiomer 1)

In the enantiomeric separation described in example 271A, 2.59 g (99% purity, ee >99%) of the title compound were obtained as the earlier eluting enantiomer.

[α]_D ²⁰= 8.5 °, 589 nm, c = 0.41 g/100 ml, methanol

LC-MS (method 1) R_t= 2.42 min; MS (ESIpos): m/z = 384 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.332 (9.45), 1.352 (16.00), 1.691(0.22), 1.706 (0.24), 1.715 (0.21), 1.730 (0.18), 1.946 (0.27), 1.955 (0.24),1.975 (0.91), 2.011 (0.23), 3.037 (0.17), 3.054 (0.24), 3.071 (0.28), 3.086(0.19), 3.182 (0.25), 3.198 (0.23), 3.334 (0.28), 3.351 (0.24), 6.843 (0.19),6.857 (0.33), 6.871 (0.18), 7.219 (0.26), 7.227 (0.33), 7.238 (0.32), 7.247(0.27), 7.311 (0.98), 7.320 (1.08), 7.395 (0.60), 7.415 (0.51)。

Example 273A

(-) -5- [ (tert-butoxycarbonyl) amino group]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(enantiomer 2)

In the enantiomeric separation described in example 271A, 2.47 g (100% purity, ee >99%) of the title compound were obtained as the later eluting enantiomer.

[α]_D ²⁰= -8.2Degree, 589 nm, c = 0.65 g/100 ml, methanol

LC-MS (method 1) R_t= 2.42 min; MS (ESIpos): m/z = 384 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.33), 0.008 (0.34), 1.332(8.75), 1.352 (16.00), 1.691 (0.19), 1.706 (0.22), 1.715 (0.19), 1.730(0.16), 1.946 (0.22), 1.955 (0.20), 1.975 (0.81), 2.012 (0.21), 3.053 (0.22),3.071 (0.25), 3.086 (0.17), 3.162 (0.18), 3.175 (0.18), 3.181 (0.23), 3.198(0.20), 3.333 (0.28), 3.351 (0.22), 6.858 (0.30), 7.219 (0.23), 7.227 (0.30),7.238 (0.30), 7.248 (0.25), 7.311 (0.89), 7.320 (0.99), 7.396 (0.57), 7.415(0.48)。

Example 274A

(-) -5-amino-4- (2-chlorophenyl) pentanoic acid tert-butyl ester hydrochloride(enantiomer 1)

To a mixture of tert-butyl (+) -5- [ (tert-butoxycarbonyl) amino ] -4- (2-chlorophenyl) pentanoate (2.55 g, 6.64mmol, example 272A) in dioxane (13 ml) was slowly added dropwise a 4M solution of hydrogen chloride in dioxane (3.3 ml, 13.28 mmol) at room temperature and the mixture was stirred at room temperature for 22 h. Then, a 4M solution of hydrogen chloride in dioxane (830 μ l, 3.32 mmol) was again added dropwise, and the mixture was stirred at room temperature for another 1 hour. Then, a 4M solution of hydrogen chloride in dioxane (830 μ l, 3.32 mmol) was again added dropwise, and the mixture was stirred at room temperature for another 2 hours. The mixture was then concentrated and dichloromethane was repeatedly added, followed by concentration again. The residue was dried in vacuo. 2.29 g (67% purity, 72% of theory) of the title compound are obtained.

[α]_D ²⁰= 4.4 °, 589 nm, c = 0.72 g/100 ml, methanol

LC-MS (method 1) R_t= 1.14 min; MS (ESIpos): m/z = 284 [M+H]⁺

Example 275A

(+) -5-amino-4- (2-chlorophenyl) pentanoic acid tert-butyl esterEster hydrochloride(enantiomer 2)

To a mixture of (-) -tert-butyl 5- [ (tert-butoxycarbonyl) amino ] -4- (2-chlorophenyl) pentanoate (2.42 g, 6.30mmol, example 273A) in dioxane (12 ml) was slowly added dropwise a 4M solution of hydrogen chloride in dioxane (3.2 ml, 12.61 mmol) at room temperature and the mixture was stirred at room temperature for 22 h. Then, a 4M solution of hydrogen chloride in dioxane (790 μ l, 3.16 mmol) was again added dropwise, and the mixture was stirred at room temperature for another 1 hour. Then, a 4M solution of hydrogen chloride in dioxane (790 μ l, 3.16 mmol) was again added dropwise, and the mixture was stirred at room temperature for another 2 hours. The mixture was then concentrated and dichloromethane was repeatedly added, followed by concentration again. The residue was dried in vacuo. 2.15 g (68% purity, 73% of theory) of the title compound are obtained.

[α]_D ²⁰= 5.9 °, 589 nm, c = 0.66 g/100 ml, methanol

LC-MS (method 1) R_t= 1.12 min; MS (ESIpos): m/z = 284 [M+H]⁺

Example 276A

(+) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2-chlorophenyl) pentanoic acid tert-butyl ester(pair) Enantiomer 1)

[ structural formula see example 37A: (Racemic modification)]

To a suspension of (-) -5-amino-4- (2-chlorophenyl) pentanoic acid tert-butyl ester hydrochloride (2.25 g, 67% purity, 5.29mmol, example 274A) in dichloromethane (50 ml) was added DIPEA (2.3 ml, 13.22mmol) at room temperature. Then 6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (1.41 g, 4.41 mmol, example 3A) was added and the mixture was stirred at room temperature for 16 h. Then, water (100 ml) was added to the mixture, which was shaken. After phase separation, the aqueous phase was extracted once with dichloromethane (100 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (100 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3 → 7:3, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 2.26 g (100% purity, 91% of theory) of the title compound are obtained.

[α]_D ²⁰= 12.8 °, 589 nm, c = 0.59 g/100 ml, methanol

LC-MS (method 2) R_t= 1.33 min; MS (ESIpos): m/z = 565/567/569 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.157 (0.24), 1.175 (0.47), 1.193(0.24), 1.371 (16.00), 1.816 (0.18), 1.820 (0.18), 1.989 (0.88), 2.028(0.18), 2.033 (0.17), 2.045 (0.19), 2.051 (0.17), 2.065 (0.28), 2.077 (0.96),2.093 (0.81), 2.110 (0.29), 2.114 (0.28), 2.213 (0.28), 3.569 (0.16), 3.589(0.19), 3.713 (0.29), 4.021 (0.20), 4.039 (0.20), 7.279 (0.27), 7.297 (0.20),7.360 (0.17),7.378 (0.29), 7.396 (0.16), 7.448 (0.58), 7.451 (0.58), 7.468(0.48), 7.471 (0.48), 7.491 (0.44), 7.509 (0.33), 7.894 (2.14), 7.899 (1.08),8.847 (0.21), 8.861 (0.40), 8.874 (0.20)。

Example 277A

(-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2-chlorophenyl) pentanoic acid tert-butyl ester(pair) Enantiomer 2)

To a suspension of (+) -5-amino-4- (2-chlorophenyl) pentanoic acid tert-butyl ester hydrochloride (2.12 g, 68% purity, 5.08mmol, example 275A) in dichloromethane (50 ml) was added DIPEA (2.2ml, 12.70mmol) at room temperature. Then 6-bromo-2-chloro-3-methylquinoline-4-carbonyl chloride (1.35 g, 4.23 mmol, example 3A) was added and the mixture was stirred at room temperature for 16 h. Then, water (100 ml) was added to the mixture, which was shaken. After phase separation, the aqueous phase was extracted once with dichloromethane (100 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (100 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 97:3 → 7:3, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 2.21 g (99% purity, 91% of theory) of the title compound are obtained.

[α]_D ²⁰= 12.2 °, 589 nm, c = 0.43 g/100 ml, methanol

LC-MS (method 2) R_t= 1.33 min; MS (ESIpos): m/z = 565/567/569 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.24), 0.008 (0.21), 1.157(0.30), 1.175 (0.59), 1.193 (0.30), 1.371 (16.00), 1.815 (0.17), 1.989(1.13), 2.027 (0.17), 2.045 (0.18), 2.050 (0.16), 2.064 (0.27), 2.076 (0.96),2.092 (0.80), 2.109 (0.28), 2.210 (0.28), 3.588 (0.19), 3.712 (0.28), 4.021(0.26), 4.039 (0.26), 7.279 (0.27), 7.298 (0.19), 7.359 (0.17), 7.377 (0.29),7.396 (0.16), 7.448 (0.59), 7.451 (0.63), 7.468 (0.50), 7.470 (0.52), 7.491(0.44), 7.509 (0.33), 7.894 (2.22), 8.846 (0.20), 8.860 (0.39), 8.874 (0.20)。

Example 278A

(+) -5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]² H ₁₀) Piperidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(enantiomer 1)

To (+) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]To a solution of tert-butyl amino } -4- (2-chlorophenyl) valerate (283 mg, 0.5 mmol, example 276A) in NMP (2 ml) was added piperidine-D11 (148 μ l, 1.50mmol) and the mixture was stirred at 110 ℃ for 2 h. After cooling to room temperature, water (75ml) was added to the mixture, the solid present was filtered off and washed twice with water (4 ml each). Drying in vacuo gives 284 mg (92% purity, 83% of theory) of the title compound.

[α]_D ²⁰= 9.2 °, 589 nm, c = 0.39 g/100 ml, methanol

LC-MS (method 1) R_t= 2.79 min; MS (ESIpos): m/z = 624/626 [M+H]⁺

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.087 (1.47), 1.369 (16.00), 1.814(0.16), 2.055 (0.21), 2.075 (1.01), 2.085 (0.55), 2.099 (0.27), 2.104 (0.27),2.129 (1.02), 2.695 (0.24), 3.585 (0.18), 3.671 (0.28), 7.255 (0.18), 7.271(0.36), 7.285 (0.23), 7.356 (0.22), 7.371 (0.39), 7.385 (0.20), 7.440 (0.61),7.442 (0.58), 7.456 (0.53), 7.458 (0.48), 7.479 (0.49), 7.482 (0.50), 7.495(0.41), 7.624 (0.34), 7.641 (1.25), 7.651 (0.85), 7.655 (0.79), 7.669 (0.21),7.673 (0.23), 8.709 (0.23), 8.720 (0.41), 8.732 (0.19)。

Example 279A

(-) -5- [ ({ 6-bromo-3-methyl-2- [ (S))² H ₁₀) Piperidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(enantiomer 2)

To (-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]To a solution of tert-butyl amino } -4- (2-chlorophenyl) valerate (283 mg, 0.5 mmol, example 277A) in NMP (2 ml) was added piperidine-D11 (148 μ l, 1.50mmol) and the mixture was stirred at 110 ℃ for 4 h. After cooling to room temperature, water (75ml) was added to the mixture, the solid present was filtered off and washed twice with water (4 ml each). Drying in vacuo afforded 276 mg (100% purity, 88% of theory) of the title compound.

[α]_D ²⁰= 9.3 °, 589 nm, c = 0.33 g/100 ml, methanol

LC-MS (method 1) R_t= 2.78 min; MS (ESIpos): m/z = 624/626 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.087 (0.22), 1.369 (16.00), 1.807(0.17), 2.041 (0.18), 2.045 (0.16), 2.053 (0.21), 2.056 (0.23), 2.073 (1.08),2.083 (0.72), 2.095 (0.33), 2.098 (0.34), 2.126 (0.65), 2.695 (0.20), 3.585(0.20), 3.670 (0.22), 7.262 (0.16), 7.274 (0.33), 7.286 (0.21), 7.361 (0.21),7.373 (0.37), 7.385 (0.20), 7.444 (0.62), 7.446 (0.64), 7.458 (0.55), 7.459(0.55), 7.487 (0.49), 7.499 (0.40), 7.628 (0.47), 7.643 (1.32), 7.656 (0.76),7.660 (0.72), 7.671 (0.26), 7.674 (0.27), 8.734 (0.24), 8.744 (0.45), 8.753(0.23)。

Example 280A

(-) -5- [ ({ 6-bromo-3-methyl-2- [ (S))² H ₁₀) Piperidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(enantiomer 1)

To (-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- [2- (trifluoromethyl) phenyl]piperidine-Achatic acid tert-butyl valerate (234 mg, 391. mu. mol, example 39A) in NMP (1.6 ml)D11 (116 μ l,1.17 mmol) and the mixture was stirred at 110 ℃ for 4 h. After cooling to room temperature, water (75ml) was added to the mixture, the solid present was filtered off and washed twice with water (4 ml each). After drying in vacuo, 228 mg (86% purity, 97% of theory) of the title compound are obtained.

[α]_D ²⁰= 14.0 °, 589 nm, c = 0.48 g/100 ml, methanol

LC-MS (method 1) R_t= 2.80 min; MS (ESIpos): m/z = 658/660 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.346 (16.00), 1.889 (0.17), 1.903(0.18), 1.913 (0.17), 1.991 (0.23), 2.001 (0.18), 2.006 (0.26), 2.015 (0.21),2.022 (0.23), 2.034 (0.30), 2.049 (0.29), 2.116 (0.17), 2.128 (0.26), 2.140(0.30), 2.163 (0.54), 2.696 (0.21), 3.303 (0.21), 3.315 (0.26), 7.470 (0.21),7.483 (0.41), 7.495 (0.24), 7.640 (0.39), 7.655 (1.29), 7.665 (0.77), 7.669(0.70), 7.680 (0.22), 7.684 (0.24), 7.697 (0.18), 7.709 (0.43), 7.726 (0.60),7.739 (0.99), 7.752 (0.27), 8.790 (0.23), 8.800 (0.46), 8.809 (0.23)。

Example 281A

(+) -5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]² H ₁₀) Piperidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(enantiomer 2)

To (+) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- [2- (trifluoromethyl) phenyl]piperidine-Achatic acid tert-butyl valerate (234 mg, 391. mu. mol, example 40A) in NMP (1.6 ml)D11 (116 μ l,1.17 mmol) and the mixture was stirred at 110 ℃ for 4 h. After cooling to room temperature, water (75ml) was added to the mixture, the solid present was filtered off andwashed twice with water (4 ml each). After drying in vacuo, 221 mg (100% purity, 86% of theory) of the title compound are obtained.

[α]_D ²⁰= 13.9 °, 589 nm, c = 0.49 g/100 ml, methanol

LC-MS (method 1) R_t= 2.80 min; MS (ESIpos): m/z = 658/660 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.346 (16.00), 1.890 (0.18), 1.898(0.18), 1.905 (0.19), 1.913 (0.18), 1.991 (0.24), 2.001 (0.19), 2.006 (0.28),2.016 (0.22), 2.023 (0.25), 2.034 (0.32), 2.049 (0.31), 2.116 (0.19), 2.129(0.28), 2.140 (0.33), 2.163 (0.58), 3.303 (0.19), 3.314 (0.26), 3.322 (0.25),7.470 (0.23), 7.482 (0.45), 7.495 (0.27), 7.641 (0.40), 7.655 (1.33), 7.665(0.80), 7.669 (0.72), 7.680 (0.23), 7.683 (0.24), 7.696 (0.20), 7.709 (0.47),7.726 (0.64), 7.739 (1.05), 7.752 (0.29), 8.790 (0.25), 8.800 (0.49), 8.810(0.24)。

Example 282A

(+) -5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]² H ₁₀) Piperidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Glutaric acid tert-butyl ester(enantiomer 1)

To (+) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- [2- (trifluoromethoxy) phenyl group]piperidine-Achattacid was added to a solution of tert-butyl valerate (241 mg, 391. mu. mol, example 42A) in NMP (1.6 ml)D11 (116 μ l,1.17 mmol) and the mixture was stirred at 110 ℃ for 4 h. After cooling to room temperature, water (75ml) was added to the mixture, the solid present was filtered off and washed twice with water (4 ml each). After drying in vacuo, 211 mg (100% purity, 80% of theory) of the title compound are obtained.

[α]_D ²⁰= +12.4°, 589 nm, c = 0.45 g/100 ml, DMSO

LC-MS (method 1) R_t= 2.82 min; MS (ESIpos): m/z = 674/676 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.360 (16.00), 1.374 (0.22), 1.809(0.20), 1.824 (0.21), 2.038 (0.29), 2.052 (0.31), 2.055 (0.30), 2.065 (1.21),2.085 (0.35), 2.089 (0.32), 2.097 (0.18), 2.138 (0.38), 3.383 (0.27), 3.615(0.18), 3.626 (0.22), 3.636 (0.22), 3.648 (0.20), 3.659 (0.16), 7.352 (0.25),7.364 (0.40), 7.394 (0.18), 7.407 (0.67), 7.413 (0.58), 7.419 (0.65), 7.554(0.41), 7.564 (0.31), 7.569 (0.31), 7.637 (0.43), 7.652 (1.21), 7.665 (0.69),7.668 (0.64), 7.679 (0.23), 7.683 (0.23), 8.758 (0.21), 8.767 (0.40), 8.777(0.21)。

Example 283A

(-) -5- [ ({ 6-bromo-3-methyl-2- [ (S))² H ₁₀) Piperidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Glutaric acid tert-butyl ester(enantiomer 2)

To (-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- [2- (trifluoromethoxy) phenyl group]piperidine-Achattacid was added to a solution of tert-butyl valerate (241 mg, 391. mu. mol, example 43A) in NMP (1.6 ml)D11 (116 μ l,1.17 mmol) and the mixture was stirred at 110 ℃ for 4 h. After cooling to room temperature, water (75ml) was added to the mixture, the solid present was filtered off and washed twice with water (4 ml each). After drying in vacuo 196 mg (94% purity, 69% of theory) of the title compound are obtained.

[α]_D ²⁰= -11.9°, 589 nm, c = 0.49 g/100 ml, DMSO

LC-MS (method 1) R_t= 2.83 min; MS (ESIpos): m/z = 674/676 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.360 (16.00), 1.817 (1.14), 2.064(3.81), 2.137 (2.64), 2.694 (0.27), 3.635 (1.64), 7.362 (1.83), 7.410 (3.01),7.562 (1.69), 7.657 (2.27), 8.767 (1.34)。

Example 284A

(+) -5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]² H ₈) Pyrrolidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(enantiomer 1)

To (+) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]To a solution of tert-butyl amino } -4- (2-chlorophenyl) valerate (283 mg, 0.5 mmol, example 276A) in NMP (2 ml) was added pyrrolidine-2, 2,3,3,4,4,5,5-D8(150 μ l, 1.50mmol) and the mixture was stirred at 110 ℃ for 2 h. After cooling to room temperature, water (75ml) was added to the mixture, the solid present was filtered off and washed twice with water (4 ml each). After drying in vacuo, 254 mg (93% purity, 77% of theory) of the title compound are obtained.

[α]_D ²⁰= 9.0 °, 589 nm, c = 0.47 g/100 ml, methanol

LC-MS (method 1) R_t= 2.13 min; MS (ESIpos): m/z = 608/610 [M+H]⁺

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.085 (1.40), 1.334 (0.21), 1.367(16.00), 1.798 (0.21), 1.815 (0.28), 2.028 (0.20), 2.038 (0.23), 2.044(0.23), 2.052 (0.34), 2.073 (1.32), 2.083 (0.78), 2.097 (0.37), 2.103 (0.32),2.156 (0.92), 2.694 (0.20), 3.578 (0.30), 3.655(0.31), 7.250 (0.26), 7.266(0.49), 7.281 (0.32), 7.352 (0.34), 7.367 (0.56), 7.381 (0.34), 7.434 (0.82),7.449 (0.69), 7.468 (0.97), 7.474 (0.78), 7.486 (1.43), 7.545 (0.71), 7.549(0.68), 7.562 (0.47), 7.567 (0.44), 8.658 (0.31), 8.669 (0.50), 8.680 (0.26)。

Example 285A

(-) -5- [ ({ 6-bromo-3-methyl-2- [ (S))² H ₈) Pyrrolidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid tert-butyl ester(enantiomer 2)

To (-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]To a solution of tert-butyl amino } -4- (2-chlorophenyl) valerate (283 mg, 0.5 mmol, example 277A) in NMP (2 ml) was added pyrrolidine-2, 2,3,3,4,4,5,5-D8(150 μ l, 1.50mmol) and the mixture was stirred at 110 ℃ for 2 h. After cooling to room temperature, water (75ml) was added to the mixture, the solid present was filtered off and washed with waterTwice (4 ml each). After drying in vacuo 274 mg (100% purity, 90% of theory) of the title compound are obtained.

[α]_D ²⁰= 9.2 °, 589 nm, c = 0.37 g/100 ml, methanol

LC-MS (method 1) R_t= 2.11 min; MS (ESIpos): m/z = 608/610 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.085 (0.23), 1.367 (16.00), 1.809(0.17), 2.039 (0.17), 2.051 (0.20), 2.055 (0.24), 2.072 (0.92), 2.081 (0.59),2.093 (0.27), 2.098 (0.25), 2.152 (0.30), 2.162 (0.29), 2.175 (0.22), 2.694(0.25), 3.580 (0.19), 7.268 (0.25), 7.280 (0.18), 7.357 (0.18), 7.369 (0.29),7.381 (0.17), 7.437 (0.60), 7.439 (0.60), 7.451 (0.53), 7.452 (0.51), 7.471(0.89), 7.482 (0.51), 7.486 (1.32), 7.493 (0.39), 7.550 (0.57), 7.553 (0.53),7.564 (0.40), 7.568 (0.38), 8.686 (0.18), 8.695 (0.32), 8.703 (0.18)。

Example 286A

(-) -5- [ ({ 6-bromo-3-methyl-2- [ (S))² H ₈) Pyrrolidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(enantiomer 1)

To (-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- [2- (trifluoromethyl) phenyl]Pyrrolidine-2, 2,3,3,4,4,5,5-D8 (98 μ l,1.17 mmol) and the mixture was stirred at 110 ℃ for 3 h. After cooling to room temperature, water (75ml) was added to the mixture, and the solid present was filtered off and washed twice with water (4 ml each). After drying in vacuo, 218 mg (100% purity, 87% of theory) of the title compound are obtained.

[α]_D ²⁰= 13.1 °, 589 nm, c = 0.44 g/100 ml, methanol

LC-MS (method 1) R_t= 2.16 min; MS (ESIpos): m/z = 642/644 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.324 (0.18), 1.345 (16.00), 1.890(0.20), 1.898 (0.21), 1.904 (0.21), 1.913 (0.21), 1.987 (0.25), 1.997 (0.20),2.002 (0.28), 2.012 (0.21), 2.027 (0.24), 2.038 (0.33), 2.053 (0.33), 2.065(0.17), 2.103 (0.18), 2.113 (0.24), 2.125 (0.32), 2.136 (0.33), 2.148 (0.28),2.163 (0.25), 2.177 (0.27), 2.190 (0.23), 2.696 (0.25), 3.302 (0.24), 3.313(0.29), 7.465 (0.22), 7.478 (0.42), 7.484 (0.92), 7.499 (1.13), 7.559 (0.59),7.562 (0.58), 7.574 (0.41), 7.577 (0.41), 7.694 (0.20), 7.706 (0.48), 7.719(0.84), 7.736 (0.81), 7.750 (0.34), 8.746 (0.35)。

Example 287A

(+) -5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]² H ₈) Pyrrolidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Glutaric acid tert-butyl ester(enantiomer 2)

To (+) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- [2- (trifluoromethyl) phenyl]Pyrrolidine-2, 2,3,3,4,4,5,5-D8 (98 μ l,1.17 mmol) and the mixture was stirred at 110 ℃ for 3 h. After cooling to room temperature, water (75ml) was added to the mixture, the solid present was filtered off and washed twice with water (4 ml each). Drying in vacuo gives 239 mg (100% purity, 95% of theory) of the title compound.

[α]_D ²⁰= 14.1 °, 589 nm, c = 0.44 g/100 ml, methanol

LC-MS (method 1) R_t= 2.16 min; MS (ESIpos): m/z = 642/644 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.345 (16.00), 1.890 (0.16), 1.897(0.17), 1.904 (0.17), 1.913 (0.17), 1.987 (0.22), 1.997 (0.17), 2.002 (0.24),2.012 (0.18), 2.027 (0.21), 2.038 (0.30), 2.053 (0.30), 2.112 (0.19), 2.125(0.27), 2.136 (0.27), 2.144 (0.22), 2.148 (0.22), 2.159 (0.20), 2.176 (0.21),2.186 (0.18), 2.696 (0.17), 3.302 (0.19), 3.313 (0.23), 7.465 (0.18), 7.477(0.35), 7.484 (0.89), 7.499 (1.12), 7.559 (0.56), 7.562 (0.52), 7.573 (0.39),7.577 (0.37), 7.694 (0.17), 7.706 (0.41), 7.719 (0.73), 7.736 (0.68), 7.750(0.28), 8.736 (0.17), 8.745 (0.30)。

Example 288A

(+) -5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]² H ₈) Pyrrolidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Glutaric acid tert-butyl ester(enantiomer 1)

To (+) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- [2- (trifluoromethoxy) phenyl group]Pyrrolidine-2, 2,3,3,4,4,5,5-D8 (98 μ l,1.17 mmol), and the mixture was stirred at 110 ℃ for 2 h. After cooling to room temperature, water (75ml) was added to the mixture, the solid present was filtered off and washed twice with water (4 ml each). After drying in vacuo, 241 mg (98% purity, 91% of theory) of the title compound are obtained.

[α]_D ²⁰= 13.9 °, 589 nm, c = 0.46 g/100 ml, methanol

LC-MS (method 1) R_t= 2.22 min; MS (ESIpos): m/z = 658/660 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.358 (16.00), 1.372 (0.17), 1.806(0.22), 1.823 (0.20), 2.039 (0.27), 2.049 (0.34), 2.062 (1.24), 2.080 (0.32),2.084 (0.26), 2.16 (0.14), 3.369 (0.20), 3.381 (0.20), 3.61 (0.14), 3.65(0.15), 7.345 (0.26), 7.357 (0.41), 7.402 (0.47), 7.407 (0.47), 7.414 (0.50),7.478 (0.71), 7.493 (0.98), 7.550 (0.42), 7.557 (0.64), 7.561 (0.73), 7.565(0.37), 7.572 (0.36), 7.575 (0.33), 8.715 (0.25)。

Example 289A

(-) -5- [ ({ 6-bromo-3-methyl-2- [ (S))² H ₈) Pyrrolidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Glutaric acid tert-butyl ester(enantiomer 2)

To (-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- [2- (trifluoromethoxy) phenyl group]Pyrrolidine-2, 2,3,3,4,4,5,5-D8 (98 μ l,1.17 mmol) and the mixture was stirred at 110 ℃ for 3 h. After cooling to room temperature, water (75ml) was added to the mixture, the solid present was filtered off and washed twice with water (4 ml each). After drying in vacuo, 225 mg (100% purity, 88% of theory) of the title compound are obtained.

[α]_D ²⁰= 13.7 °, 589 nm, c = 0.43 g/100 ml, methanol

LC-MS (method 1) R_t= 2.24 min; MS (ESIpos): m/z = 658/660 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.359 (16.00), 1.807 (0.21), 1.824(0.20), 2.040 (0.26), 2.050 (0.33), 2.064 (1.21), 2.081 (0.31), 2.086 (0.25),2.16 (0.14), 3.383 (0.24), 3.61 (0.13), 3.65 (0.13), 7.345 (0.25), 7.355(0.33), 7.358 (0.41), 7.402 (0.47), 7.408 (0.47), 7.414 (0.49), 7.480 (0.71),7.495 (0.99), 7.550 (0.40), 7.553 (0.33), 7.558 (0.60), 7.562 (0.71), 7.565(0.38), 7.573 (0.35), 7.576 (0.33), 8.718 (0.24)。

Example 290A

5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]² H ₈) Pyrrolidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- (2-chloro-3, 6-difluorophenyl) pentanoic acid tert-butyl ester(enantiomer 1)

To (+) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Pyrrolidine-2, 2,3,3,4,4,5, 5-propanal was added to a solution of tert-butyl amino } -4- (2-chloro-3, 6-difluorophenyl) pentanoate (241 mg, 400 μmol, example 48A) in NMP (1.6 ml)D8 (100 μ l, 1.20 mmol) and the mixture was stirred at 110 ℃ for 20 h. After cooling to room temperature, water (100 ml) was added to the mixture, which was extracted twice with ethyl acetate (80 ml each). The combined organic phases are dried over sodium sulfateFiltered and concentrated and the residue purified by preparative HPLC (method 32). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. Two fractions were obtained: the resulting fraction 1 was 34 mg (100% purity) of (+) -5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]² H ₈) Pyrrolidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- (2-chloro-3, 6-difluorophenyl) pentanoic acid (see example 281, method B). Fraction 2 was obtained as 42 mg (93% purity, 15% of theory, see analysis) of the title compound.

LC-MS (method 1) R_t= 2.14 min; MS (ESIpos): m/z = 644/646 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.231 (0.25), 1.359 (16.00), 2.053(0.22), 2.061 (0.26), 2.074 (0.26), 2.084 (0.19), 2.139 (0.80), 2.151 (1.21),2.162 (0.89), 3.689 (0.28), 7.302 (0.28), 7.413 (0.24), 7.475 (1.03), 7.490(1.40), 7.558 (0.72), 7.562 (0.66), 7.573 (0.51), 7.576 (0.48), 8.786 (0.36)。

Example 291A

5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]² H ₈) Pyrrolidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- (2-chloro-3, 6-difluorophenyl) pentanoic acid tert-butyl ester(enantiomer 2)

To (-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Pyrrolidine-2, 2,3,3,4,4,5, 5-propanal was added to a solution of tert-butyl amino } -4- (2-chloro-3, 6-difluorophenyl) pentanoate (241 mg, 400 μmol, example 49A) in NMP (1.6 ml)D8 (100 μ l, 1.20 mmol) and the mixture was stirred at 110 ℃ for 20 h. After cooling to room temperature, water (100 ml) was added to the mixture, which was extracted twice with ethyl acetate (80 ml each). The combined organic phases were dried over sodium sulfate, filtered and concentrated and the residue was purified by preparative HPLC (method 32). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. Two fractions were obtained: the resulting fraction 1 was 55 mg (100% purity) of (-) -5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]² H ₈) Pyrrolidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- (2-chloro-3, 6-difluorophenyl) pentanoic acid as described in example 282. Fraction 2 obtained is 24 mg (100% purity, 9% of theory, seeAnalysis) of the title compound.

LC-MS (method 1) R_t= 2.09 min; MS (ESIpos): m/z = 644/646 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.231 (0.36), 1.359 (16.00), 1.962(0.21), 2.054 (0.30), 2.063 (0.36), 2.075 (0.36), 2.086 (0.28), 2.097 (0.23),2.141 (1.07), 2.152 (1.57), 3.692 (0.39), 3.751 (0.22), 7.301 (0.37), 7.412(0.33), 7.476 (0.97), 7.491 (1.32), 7.558 (0.76), 7.573 (0.56), 8.786 (0.47)。

Example 292A

(4R) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester(enantiomer 1)

[ structural formula see example 79A: (Racemic modification)]

To a solution of tert-butyl (+) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chlorophenyl) pentanoate (2.30 g, 4.06 mmol, example 276A) in NMP (34 ml) was added pyrrolidine (1.0ml, 12.18mmol) and the mixture was stirred at 100 ℃ for 17 h. After cooling to room temperature, the mixture was concentrated, and to the residue were added water (100 ml) and ethyl acetate (100 ml), which were shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (75 ml). The combined organic phases were washed once with saturated sodium chloride solution (150 ml), dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (50 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 93:7 → 6:4, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 2.19 g (100% purity, 90% of theory) of the title compound are obtained.

[α]_D ²⁰= 6.3 °, 589 nm, c = 0.45 g/100 ml, methanol

LC-MS (method 2) R_t= 1.08 min; MS (ESIpos): m/z = 600/602 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.175 (0.27), 1.367 (16.00), 1.794(0.16), 1.814 (0.23), 1.870 (1.42), 1.988 (0.49), 2.034 (0.17), 2.044 (0.23),2.051 (0.21), 2.072 (1.29), 2.083 (0.65), 2.100 (0.28), 2.107 (0.25), 2.158(0.97), 3.567 (1.19), 3.657 (0.32), 7.248 (0.18), 7.266 (0.42), 7.285 (0.31),7.349 (0.28), 7.368 (0.50), 7.386 (0.30), 7.432 (0.66), 7.434 (0.67), 7.452(0.54), 7.454 (0.54), 7.467 (0.78), 7.473 (0.61), 7.490 (1.36), 7.544 (0.64),7.550 (0.60), 7.567 (0.38), 7.572 (0.37), 8.657 (0.22), 8.671 (0.42), 8.685(0.22)。

The absolute configuration of this compound is determined by VCD spectroscopy (see Kuppens et al, "determination of absolute configuration of aqueous solution circular dichroism", Drug discovery today: Technologies 2004,1, 269-275 (2004); Stephens, P. J., "Vibrationalcircular dichroism spectroscopy: A new tool for the stereochemicalcharacterization of chiral molecules", Computational Medicinal Chemistry forDrug Discovery 2004, 699-725)。

thus, the title compound has the R configuration.

Example 293A

(-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester(enantiomer 2)

To a solution of (-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chlorophenyl) pentanoic acid tert-butyl ester (2.25 g, 3.97 mmol, example 277A) in NMP (34 ml) was added pyrrolidine (1.0ml, 11.92mmol) and the mixture was stirred at 100 ℃ for 17 h. After cooling to room temperature, the mixture was concentrated, and to the residue were added water (100 ml) and ethyl acetate (100 ml), which were shaken. After phase separation, the aqueous phase was extracted once with ethyl acetate (75 ml). The combined organic phases were washed once with saturated sodium chloride solution (150 ml), dried over sodium sulfate, filtered and concentrated, and the residue was dissolved in dichloromethane and purified by flash column chromatography (50 g silica gel Biotage Snap cartridge Ultra, cyclohexane/ethyl acetate gradient 93:7 → 6:4, Isolera One). The combined target fractions were concentrated and the residue was dried in vacuo. 2.14 g (98% purity, 88% of theory) of the title compound are obtained.

[α]_D ²⁰= -10.4°, 589 nm, c = 0.46 g/100 ml, methanol

LC-MS (method 2) R_t= 1.08 min; MS (ESIpos): m/z = 600/602 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.157 (0.18), 1.175 (0.36), 1.192(0.18), 1.367 (16.00), 1.814 (0.20), 1.870 (1.24), 1.988 (0.67), 2.044(0.20), 2.051 (0.18), 2.072 (1.15), 2.083 (0.57), 2.100 (0.24), 2.108 (0.22),2.158 (0.85), 3.311 (8.02), 3.657 (0.27), 7.248 (0.16), 7.266 (0.37), 7.286(0.27), 7.349 (0.25), 7.368 (0.45), 7.386 (0.27), 7.432 (0.64), 7.434 (0.64),7.451 (0.53), 7.454 (0.52), 7.467 (0.78), 7.473 (0.55), 7.476 (0.54), 7.490(1.36), 7.544 (0.64), 7.550 (0.59), 7.567 (0.37), 7.572 (0.36), 8.657 (0.20),8.671 (0.38), 8.686 (0.19)。

Example (b):

example 1

(+/-) -4- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -3- (2-chloro-6-fluorophenyl) butanoic acid(raceme)

To (+/-) -4- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -3- (2-chloro-6-fluorophenyl) butanoic acid tert-butyl ester (150 mg, 242 μmol,racemic modificationExample 53A) in dichloromethane (2.3 ml) TFA (370 μ l, 4.8 mmol) was added and the mixture was stirred at room temperature for 16 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 125 mg (98% purity, 90% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.13 min; MS (ESIpos): m/z = 562/564 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (3.57), 0.008 (2.96), 0.146(0.41), 1.611 (4.57), 1.676 (8.94), 2.072 (0.69), 2.150 (16.00), 2.327(0.68), 2.366 (0.48), 2.670 (0.79), 2.709 (0.98), 2.774 (1.22), 2.796 (3.04),2.812 (3.09), 2.835 (1.38), 2.851 (1.09), 3.153 (11.54), 3.711 (1.62), 3.816(1.22), 4.070 (2.46), 4.089 (3.00), 4.106 (2.39), 7.176 (1.51), 7.186 (1.95),7.200 (2.59), 7.208 (2.12), 7.227 (2.29), 7.303 (2.07), 7.315 (8.43), 7.323(9.04), 7.341 (2.19), 7.362 (0.73), 7.481 (0.59), 7.637 (3.03), 7.659(13.06), 7.669 (8.47), 7.673 (7.54), 7.691 (1.75), 7.695 (1.86), 8.799(2.25), 8.815 (4.44), 8.829 (2.18).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.21 (s, 1H), 8.81 (t, 1H), 7.68 (dd,1H), 7.66 (d, 1H), 7.48 (br. s, 1H), 7.37-7.29 (m, 2H), 7.24-7.16 (m, 1H),4.14-4.06 (m, 1H), 3.82 (br. s, 1H), 3.71 (br. s, 1H), 3.19-3.12 (m, 4H),2.89-2.62 (m, 2H), 2.15 (s, 3H), 1.74-1.52 (m, 6H)。

Separation of enantiomers:

the title compound (100 mg) was dissolved in isopropanol (2.5 ml) and separated by preparative HPLC on chiral phase into enantiomers (see examples 2 and 3) [ column: daicel Chiralpak ID, 5 μm,250 mm x20 mm, flow rate: 20 ml/min, injection: 0.06 ml, eluent 30% isopropanol/70% heptane, run time 15min, isocratic ]. The combined target fractions were concentrated and the residue was lyophilized. Followed by preparative HPLC on the achiral phase (acetonitrile/water gradient). The residue was again lyophilized.

Example 2

(-) -4- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -3- (2-chloro-6-fluorophenyl) butanoic acid(enantiomer 1)

In the enantiomeric separation described in example 1, 29 mg (ee value 99%) of the title compound was obtained as the earlier eluting enantiomer, previously purified. Followed by repurification by preparative HPLC (method 9). The combined target fractions were concentrated, the residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic phase was dried over sodium sulfate, filtered and concentrated, and the residue was lyophilized. 13 mg (98% purity, 13% of theory) of the repurified title compound are obtained.

[α]_D ²⁰= 16.9 °, 589 nm, c = 0.25 g/100 ml, methanol

LC-MS (method 1) R_t= 2.13 min; MS (ESIpos): m/z = 562/564 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.61), -0.008 (16.00), 0.008(13.21), 0.146 (1.69), 0.959 (0.44), 1.040 (0.73), 1.235 (2.64), 1.374(0.95), 1.607 (3.23), 1.673 (6.17), 2.150 (9.39), 2.327 (2.50), 2.366 (2.57),2.518 (10.06), 2.523 (8.00), 2.670 (3.23), 2.674 (2.50), 2.710 (3.38), 2.777(1.25), 3.140 (7.93), 3.510 (1.54), 3.689 (1.03), 3.819 (0.81), 4.076 (1.39),7.193 (1.47), 7.216 (1.17), 7.317 (5.06), 7.624 (1.91), 7.646 (8.22), 7.657(5.28), 7.661 (4.70), 7.684 (1.25), 8.900 (0.73)。

Example 3

(+) -4- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -3- (2-chloro-6-fluorophenyl) butanoic acid(enantiomer 2)

In the enantiomeric separation described in example 1, 26 mg (ee value 96%) of the title compound were obtained as the enantiomer which eluted later, previously purified. Followed by repurification by preparative HPLC (method 9). The combined target fractions were concentrated and the residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic phase was dried over sodium sulfate, filtered and concentrated, and the residue was lyophilized. 12 mg (98% purity, 12% of theory) of the repurified title compound are obtained.

[α]_D ²⁰= 15.6 °, 589 nm, c = 0.25 g/100 ml, methanol

LC-MS (method 1) R_t= 2.13 min; MS (ESIpos): m/z = 562/564 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (1.51), -0.008 (16.00), 0.008(12.20), 0.146 (1.58), 1.234 (2.73), 1.372 (1.87), 1.610 (1.72), 1.669(3.23), 2.149 (5.60), 2.327 (3.01), 2.366 (2.65), 2.523 (10.48), 2.669(3.23), 2.709 (3.30), 2.799 (1.00), 3.139 (4.23), 3.509 (0.93), 3.707 (0.86),4.084 (0.86), 7.198 (1.08), 7.321 (3.01), 7.625 (1.22), 7.647 (4.74), 7.658(3.09), 7.663 (2.58), 7.680 (1.00), 8.842 (0.57)。

Example 4

(+/-) -4- [ ({ 6-bromo-3-methyl-2- [ (2-phenylethyl) amino group]Quinolin-4-yl } carbonyl) amino]-3- (2-chloro-6-fluorophenyl) butanoic acid(raceme)

To (+/-) -4- [ ({ 6-bromo-3-methyl-2- [ (2-phenylethyl) amino group]Quinolin-4-yl } carbonyl) amino]-tert-butyl 3- (2-chloro-6-fluorophenyl) butyrate (150 mg, 229 μmol,racemic modificationExample 54A) in dichloromethane (2.2ml) TFA (350 μ l, 4.6 mmol) was added and the mixture was stirred at room temperature for 16 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 9). The combined target fractions were concentrated and the residue was dried in vacuo. 55 mg (98% purity, 39% of theory) of the title compound are obtained.

LC-MS (method 2) R_t= 0.92 min; MS (ESIpos): m/z = 598/600 [M+H]⁺

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 12.23 (br. s, 1H), 8.88 (br. s, 1H),8.02-7.06 (m, 11H), 4.07 (br. s, partial coverage, 1H), 3.93-3.63 (m, partial coverage, 4H),3.04-2.90 (m, 2H), 2.88-2.68 (m, 2H), 2.11-1.83 (m, 3H).

Example 5

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-5-fluorophenyl) pentanoic acid(raceme)

To (+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester (90 mg, 98% purity, 139 μmol,racemic modificationExample 55A) in dichloromethane (990 μ l) was added TFA (210 μ l,2.8 mmol) and the mixture was stirred at room temperatureStirring overnight. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 9). The combined target fractions were concentrated and the residue was combined with ethyl acetate and saturated aqueous sodium bicarbonate (20 ml each) and shaken. After phase separation, the aqueous phase was extracted twice with ethyl acetate (20 ml each). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was dried in vacuo. 45 mg (98% purity, 55% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.22 min; MS (ESIpos): m/z = 576/578 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.235 (2.02), 1.605 (3.36), 1.670(6.76), 1.768 (0.41), 1.782 (0.67), 1.804 (1.37), 1.824 (1.54), 1.835 (1.07),1.865 (0.45), 1.899 (0.47), 2.020 (1.25), 2.041 (2.87), 2.068 (2.26), 2.080(2.13), 2.090 (2.63), 2.101 (1.69), 2.128 (16.00), 2.160 (1.18), 2.176(0.61), 2.689 (0.94), 2.731 (0.90), 2.890 (1.03), 3.132 (8.80), 3.585 (1.45),3.689 (3.38), 7.124 (1.14), 7.144 (2.04), 7.159 (1.20), 7.165 (1.14), 7.385(2.26), 7.392 (2.36), 7.410 (2.44), 7.417 (2.40), 7.484 (2.83), 7.497 (2.85),7.506 (2.61), 7.519 (2.32), 7.622 (1.58), 7.644 (8.32), 7.651 (5.86), 7.655(5.07), 7.674 (1.01), 7.678 (1.08), 8.719 (1.55), 8.734 (2.96), 8.747 (1.48).

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 8.73 (t, 1H), 7.70-7.60(m, 2H), 7.50(dd, 1H), 7.46 (br. s, 1H, partial coverage), 7.40 (dd, 1H), 7.14(td, 1H), 3.78-3.51(m, 3H), 3.13 (br. s, 4H), 2.20-1.96 (m,6H), 1.91-1.75 (m,1H), 1.72-1.52(m, 6H).

Example 6

(-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-5-fluorophenyl) pentanoic acid(enantiomer 1)

To (-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester (230 mg, 98% purity, 356 μmol,enantiomer 1Example 56A) in dichloromethane (2.5 ml) TFA (550 μ l, 7) was added1mmol) and the mixture was stirred at room temperature overnight. Then, TFA (270 μ l, 3.6 mmol) was added again, and the mixture was stirred at room temperature overnight. The mixture was then concentrated and dichloromethane was repeatedly added, followed by concentration again. The residue was purified by preparative HPLC (method 8). The combined target fractions were concentrated and the residue was dried in vacuo. 165 mg (98% purity, ee 99%, 79% of theory) of the title compound are obtained.

[α]_D ²⁰= 18.7 °, 589 nm, c = 0.38 g/100 ml, methanol

LC-MS (method 1) R_t= 2.18 min; MS (ESIpos): m/z = 576/578 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.97), 0.008 (1.54), 1.604(2.79), 1.670 (5.48), 1.786 (0.53), 1.808 (1.09), 1.829 (1.31), 1.850 (0.77),2.012 (0.76), 2.023 (1.05), 2.041 (1.18), 2.055 (2.69), 2.082 (2.31), 2.095(2.27), 2.102 (2.81), 2.128 (16.00), 2.149 (2.04), 2.172 (0.75), 3.132(7.19), 3.590 (1.09), 3.692 (2.69), 7.119 (0.93), 7.126 (1.05), 7.140 (1.72),7.147 (1.83), 7.160 (1.06), 7.168 (1.05), 7.390 (2.22), 7.397 (2.22), 7.415(2.32), 7.422 (2.27), 7.457 (0.69), 7.485 (3.00), 7.499 (2.98), 7.508 (2.75),7.521 (2.53), 7.622 (1.66), 7.644 (8.81), 7.652 (5.93), 7.657 (5.03), 7.674(1.03), 7.679 (1.13), 8.711 (1.34), 8.726 (2.72), 8.740 (1.29), 12.066(0.66).

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 12.07 (br. s, 1H), 8.73 (t, 1H), 7.70-7.60(m, 2H), 7.50(dd, 1H), 7.46 (br. s, 1H, partial coverage), 7.41 (dd, 1H), 7.14(td, 1H), 3.74-3.64 (m, 2H), 3.63-3.54 (m,1H), 3.17-3.09 (m, 4H), 2.20-1.98(m, 6H), 1.89-1.76 (m,1H), 1.72-1.55 (m, 6H).

Example 7

(+) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-5-fluorophenyl) pentanoic acid(enantiomer 2)

To (+) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester (200 mg, 98% purity, 310 μmol,antipodeIsomer 2Example 57A) in dichloromethane (2.2ml) TFA (480 μ l, 6.2 mmol) was added and the mixture was stirred at room temperature overnight. Then, TFA (240. mu.l, 3.1mmol) was added again, and the mixture was stirred at room temperature overnight. The mixture was then concentrated and dichloromethane was repeatedly added, followed by concentration again. The residue was purified by preparative HPLC (method 8). The combined target fractions were concentrated and the residue was dried in vacuo. 150 mg (98% purity, ee 99%, theoretical 82%) of the title compound are obtained.

[α]_D ²⁰= 17.4 °, 589 nm, c = 0.35 g/100 ml, methanol

LC-MS (method 1) R_t= 2.18 min; MS (ESIpos): m/z = 576/578 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.88), 0.008 (1.49), 1.605(2.71), 1.670 (5.29), 1.786 (0.50), 1.809 (1.07), 1.830 (1.30), 1.850 (0.76),2.011 (0.75), 2.024 (0.98), 2.042 (1.13), 2.056 (2.63), 2.083 (2.20), 2.097(2.19), 2.103 (2.78), 2.128 (16.00), 2.150 (2.00), 2.173 (0.74), 3.134(6.98), 3.591 (1.11), 3.692 (2.69), 7.119 (0.86), 7.127 (1.00), 7.141 (1.66),7.147 (1.80), 7.161 (1.03), 7.168 (1.04), 7.390 (2.13), 7.398 (2.20), 7.416(2.28), 7.423 (2.26), 7.486 (2.99), 7.499 (2.96), 7.508 (2.77), 7.521 (2.58),7.624 (1.61), 7.646 (8.66), 7.654 (5.91), 7.658 (5.11), 7.676 (1.01), 7.681(1.11), 8.712 (1.32), 8.727 (2.75), 8.741 (1.30).

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 12.06 (br. s, 1H), 8.73 (t, 1H), 7.70-7.61 (m, 2H), 7.50(dd, 1H), 7.46 (br. s, 1H, partial coverage), 7.41 (dd, 1H), 7.14(td, 1H), 3.75-3.64 (m, 2H), 3.63-3.53 (m,1H), 3.19-3.08 (m, 4H), 2.21-1.98(m, 6H), 1.88-1.75 (m,1H), 1.72-1.52(m, 6H).

Example 8

(+/-) -5- ({ [ 6-bromo-2- (4, 4-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chloro-5-fluorophenyl) pentanoic acid(raceme)

To (+/-) -5- ({ [ 6-bromo-2- (4, 4-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester (19 mg, 72% purity, 20.4 μmol,racemic modificationExample 58A) was added to TFA (32 μ l, 410 μmol) in dichloromethane (140 μ l) solution, and the mixture was stirred at room temperature overnight. Then, TFA (32 μ l, 410 μmol) was added again, and the mixture was stirred at room temperature overnight again. The mixture was then concentrated and dichloromethane was repeatedly added, followed by concentration again. The residue was purified by preparative HPLC (method 10). The combined target fractions were concentrated and the residue was dried in vacuo. 8mg (98% purity, 61% of theory) of the title compound are obtained.

LC-MS (method 2) R_t= 1.14 min; MS (ESIpos): m/z = 612/614 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.242 (0.50), 1.789 (0.50), 1.811(1.11), 1.832 (1.34), 1.854 (0.80), 2.012 (0.86), 2.025 (1.09), 2.044 (1.23),2.058 (2.67), 2.085 (2.29), 2.105 (3.75), 2.119 (3.73), 2.134 (4.47), 2.167(16.00), 3.302 (5.23), 3.315 (7.55), 3.598 (1.20), 3.702 (2.68), 4.410(1.45), 6.962 (0.45), 7.090 (0.51), 7.121 (0.84), 7.128 (0.99), 7.148 (1.77),7.163 (1.04), 7.169 (1.00), 7.218 (0.48), 7.398 (2.06), 7.405 (2.18), 7.423(2.18), 7.430 (2.11), 7.486 (2.77), 7.499 (2.87), 7.508 (2.68), 7.521 (2.39),7.661 (1.50), 7.684 (7.74), 7.691 (5.10), 7.696 (4.49), 7.714 (0.99), 7.718(1.05), 8.736 (1.40), 8.750 (2.79), 8.764 (1.38).

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 8.75 (t, 1H), 7.73-7.63 (m, 2H), 7.50(dd, 1H), 7.46 (br. s, 1H, masked), 7.41 (dd, 1H), 7.15 (td,1H), 3.70 (br. s,2H), 3.60 (br. s, 1H), 3.38-3.24 (m, 4H), 2.24-1.97 (m, 10H), 1.89-1.74 (m, 1H).

Example 9

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (morpholin-4-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-5-fluorophenyl) pentanoic acid(raceme)

To (+/-) -5- ({ [ 6-bromo-3-methyl-2- (morpholin-4-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester (55 mg, 98% purity, 84.9 μmol,racemic modificationExample 59A) in dichloromethane (600 μ l) was added TFA (130 μ l, 1.7 mmol) and the mixture was stirred at room temperature overnight. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 9). The combined target fractions were concentrated and the residue was combined with ethyl acetate and saturated aqueous sodium bicarbonate (20 ml each) and shaken. After phase separation, the aqueous phase was extracted twice with ethyl acetate (20 ml each). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was dried in vacuo. 37 mg (98% purity, 74% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 1.89 min; MS (ESIpos): m/z = 578/580 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.061 (0.65), 0.854 (0.64), 1.175(0.42), 1.235 (4.42), 1.769 (0.44), 1.783 (0.75), 1.805 (1.56), 1.826 (1.77),1.837 (1.11), 1.847 (0.98), 1.866 (0.49), 1.988 (0.93), 2.005 (1.13), 2.019(1.47), 2.045 (3.35), 2.072 (2.85), 2.084 (2.55), 2.093 (3.17), 2.105 (1.88),2.123 (3.22), 2.151 (16.00), 2.690 (0.60), 2.890 (0.46), 3.175 (11.00), 3.184(8.56), 3.510 (0.50), 3.586 (1.72), 3.696 (3.93), 3.755 (9.55), 3.766(12.93), 3.777 (8.58), 7.119 (1.16), 7.125 (1.35), 7.140 (2.19), 7.146(2.28), 7.160 (1.31), 7.167 (1.25), 7.390 (2.73), 7.397 (2.79), 7.415 (2.82),7.423 (2.73), 7.485 (3.89), 7.499 (3.92), 7.507 (3.56), 7.521 (3.08), 7.659(1.54), 7.682 (12.34), 7.688 (7.12), 7.706 (0.79), 7.711 (0.94), 8.743(1.86), 8.757 (3.48), 8.771 (1.67).

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 12.03 (br. s, 1H), 8.76 (t, 1H), 7.73-7.63 (m, 2H), 7.50(dd, 1H), 7.46 (br. s, 1H, mask), 7.41 (dd, 1H), 7.14(td, 1H), 3.82-3.64 (m,6H), 3.59 (br. s, 1H), 3.20-3.12 (m, 4H), 2.21-1.95 (m,6H), 1.88-1.75 (m, 1H).

Example 10

(+/-) -5- ({ [ 6-bromo-2- (3, 6-dihydropyridin-1 (2H) -yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chloro-5-fluorophenyl) pentanoic acid(raceme)

To (+/-) -5- ({ [ 6-bromo-2- (3, 6-dihydropyridine-1 (2)H) -yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester (50 mg, 79.2 μmol,racemic modificationExample 60A) was added to a dichloromethane (580 μ l) solution of TFA (61 μ l, 790 μmol), and the mixture was stirred at room temperature for two days. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 25 mg (98% purity, 53% of theory) of the title compound are obtained.

LC-MS (method 2) R_t= 1.12 min; MS (ESIpos): m/z = 574/576 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.369 (0.42), 1.787 (0.60), 1.809(1.26), 1.829 (1.41), 1.841 (0.94), 1.870 (0.43), 1.989 (0.41), 2.010 (0.86),2.027 (1.19), 2.046 (2.98), 2.073 (2.55), 2.085 (2.25), 2.093 (2.89), 2.106(1.49), 2.124 (2.93), 2.141 (16.00), 2.163 (1.30), 2.180 (0.59), 2.304(2.87), 3.275 (3.32), 3.309 (3.34), 3.590 (1.31), 3.795 (5.16), 5.817 (0.94),5.843 (3.17), 5.863 (2.80), 5.889 (0.85), 7.117 (0.97), 7.124 (1.11), 7.139(1.80), 7.145 (1.90), 7.159 (1.09), 7.166 (1.06), 7.390 (2.34), 7.398 (2.37),7.416 (2.44), 7.423 (2.38), 7.484 (3.06), 7.497 (3.07), 7.506 (2.86), 7.519(2.63), 7.617 (2.21), 7.639 (8.00), 7.653 (5.10), 7.658 (4.43), 7.675 (1.38),7.680 (1.36), 8.731 (1.43), 8.745 (2.71), 8.759 (1.30).

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 12.15 (br. s, 1H), 8.75 (t, 1H), 7.69-7.61 (m, 2H), 7.50(dd, 1H), 7.46 (br. s, 1H, partial coverage), 7.41 (dd, 1H), 7.14(td, 1H), 5.92-5.79 (m, 2H),3.80 (br. s,2H), 3.75-3.65 (m, 2H), 3.59 (br.s, 1H), 3.35-3.22 (coverage, 2H), 2.30 (br. s,2H), 2.22-1.96 (m,6H), 1.90-1.73(m, 1H).

Example 11

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (thiomorpholin-4-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-5-fluorophenyl) pentanoic acid(raceme)

To (+/-) -5- ({ [ 6-bromo-3-methyl-2- (thiomorpholin-4-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester (55 mg, 84.5 μmol,racemic modificationExample 61A) was added to a dichloromethane (620 μ l) solution of TFA (65 μ l, 840 μmol), and the mixture was stirred at room temperature for two days. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 41 mg (98% purity, 80% of theory) of the title compound are obtained.

LC-MS (method 2) R_t= 1.10 min; MS (ESIpos): m/z = 594/596 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.05), 0.008 (0.98), 1.788(0.49), 1.810 (1.08), 1.820 (0.71), 1.831 (1.32), 1.852 (0.79), 2.011 (0.78),2.024 (1.04), 2.042 (1.18), 2.056 (2.70), 2.074 (0.77), 2.083 (2.28), 2.097(2.36), 2.103 (2.82), 2.131 (16.00), 2.149 (2.40), 2.172 (0.86), 2.189(0.44), 2.523 (0.52), 2.775 (6.19), 2.787 (7.27), 2.798 (6.78), 3.413 (6.57),3.419 (6.69), 3.426 (7.12), 3.436 (6.16), 3.590 (1.20), 3.695 (2.52), 7.120(0.86), 7.127 (1.01), 7.141 (1.67), 7.147 (1.76), 7.161 (1.04), 7.169 (1.00),7.393 (2.19), 7.401 (2.24), 7.418 (2.29), 7.426 (2.20), 7.485 (3.17), 7.499(3.20), 7.507 (2.93), 7.521 (2.65), 7.656 (1.27), 7.678 (9.12), 7.683 (6.85),7.687 (5.30), 7.705 (0.85), 7.709 (0.91), 8.720 (1.43), 8.734 (2.85), 8.748(1.36), 12.055 (0.73).

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 12.06 (br. s, 1H), 8.73 (t, 1H), 7.73-7.63 (m, 2H), 7.50(dd, 1H), 7.46 (br. s, 1H, partial coverage), 7.41 (dd, 1H), 7.14(td, 1H), 3.69 (br. s,2H), 3.59 (br. s, 1H), 3.46-3.39 (m, 4H), 2.83-2.75(m, 4H), 2.21-1.97 (m,6H), 1.89-1.75 (m, 1H).

Example 12

(+/-) -5- [ ({ 6-bromo-2- ], a salt thereof, and a salt thereofCis-alpha-carboxylic acid derivatives2, 6-dimethylmorpholin-4-yl]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chloro-5-fluorophenyl) pentanoic acid(raceme)

To (+/-) -5- [ ({ 6-bromo-2- ], solution of (+/-) -5- [ ({ 6-bromo-2- ]Cis-alpha-carboxylic acid derivatives2, 6-dimethylmorpholin-4-yl]-3-methylquinolin-4-yl } carbonyl) amino]-tert-butyl 4- (2-chloro-5-fluorophenyl) valerate (70 mg, 106 μmol,racemic modificationExample 62A) in dichloromethane (780 μ l) was added TFA (81 μ l,1.1 mmol) and the mixture was stirred at room temperature for two days. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 47 mg (98% purity, 71% of theory) of the title compound are obtained.

LC-MS (method 2) R_t= 1.10 min; MS (ESIpos): m/z = 606/608 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.134 (16.00), 1.149 (15.70), 1.793(0.43), 1.814 (0.86), 1.835 (1.00), 1.856 (0.57), 2.013 (0.68), 2.026 (0.87),2.045 (1.01), 2.057 (2.01), 2.084 (1.82), 2.098 (1.82), 2.104 (2.14), 2.119(1.55), 2.132 (2.14), 2.157 (11.42), 2.190 (0.41), 2.469 (1.68), 3.431(2.87), 3.462 (2.59), 3.589 (0.93), 3.693 (1.77), 3.756 (1.66), 3.776 (2.04),7.120 (0.71), 7.127 (0.80), 7.142 (1.27), 7.148 (1.30), 7.162 (0.75), 7.169(0.70), 7.391 (1.65), 7.398 (1.65), 7.416 (1.69), 7.423 (1.58), 7.486 (2.10),7.499 (2.07), 7.508 (1.83), 7.521 (1.63), 7.655 (0.55), 7.676 (9.58), 8.710(1.15), 8.725 (2.08), 8.739 (0.98), 12.063 (4.18).

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 12.06 (s, 1H), 8.72 (t, 1H), 7.72-7.63(m, 2H), 7.50(dd, 1H), 7.47 (br. s, 1H, partial coverage), 7.41 (dd, 1H), 7.14(td, 1H), 3.84-3.53 (m,5H), 3.45 (br. d, 2H), 2.53-2.45 (coverage, 2H), 2.21-1.97 (m,6H), 1.91-1.75 (m,1H), 1.15 (s, 3H), 1.13 (s, 3H).

Example 13

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-5-fluorophenyl) pentanoic acid(raceme)

To (+/-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester (63 mg, 102 μmol,racemic modificationExample 63A) was added to a dichloromethane (750 μ l) solution of TFA (78 μ l, 1.0 mmol), and the mixture was stirred at room temperature for two days. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 36 mg (98% purity, 62% of theory) of the title compound are obtained.

LC-MS (method 2) R_t= 0.77 min; MS (ESIpos): m/z = 562/564 [M+H]⁺

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 12.06 (br. s, 1H), 8.68 (t, 1H), 7.59-7.53 (m,1H), 7.50(dd, 2H), 7.40 (dd, 1H), 7.35 (br. s, partial coverage), 7.14(td, 1H), 3.68 (br. s,2H), 3.57 (br. s, 5H), 2.26-1.97 (m,6H), 1.94-1.74 (m, 5H).

Example 14

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (1, 2-oxazolidin-2-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-5-fluorophenyl) pentanoic acid(raceme)

To (+/-) -5- ({ [ 6-bromo-3-methyl-2- (1, 2-oxazolidin-2-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester (35 mg, 56.4 μmol,racemic modificationExample 64A) was added to TFA (43 μ l, 560 μmol) in dichloromethane (410 μ l) solution, and the mixture was stirred at room temperature for two days. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 24 mg (95% purity, 72% of theory) of the title compound are obtained.

LC-MS (method 2) R_t= 0.96 min; MS (ESIpos): m/z = 564/566 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.04), 0.008 (0.83), 1.134(1.33), 1.150 (1.34), 1.788 (0.58), 1.810 (1.36), 1.820 (0.87), 1.831 (1.64),1.853 (1.06), 1.873 (0.44), 1.989 (0.45), 2.010 (0.97), 2.023 (1.32), 2.041(1.43), 2.057 (3.36), 2.073 (2.58), 2.085 (2.55), 2.098 (2.36), 2.106 (2.63),2.120 (1.78), 2.134 (2.29), 2.138 (2.23), 2.156 (2.79), 2.179 (1.33), 2.209(10.75), 2.242 (4.23), 2.260 (5.79), 2.278 (4.24), 2.296 (1.31), 2.523(0.63), 3.432 (0.53), 3.463 (0.64), 3.658 (0.84), 3.693 (2.87), 3.706 (3.75),3.777 (2.81), 3.825 (4.26), 3.844 (7.14), 3.862 (3.86), 7.121 (0.95), 7.128(1.11), 7.142 (1.89), 7.149 (1.96), 7.163 (1.16), 7.170 (1.12), 7.394 (2.57),7.401 (2.60), 7.419 (2.65), 7.426 (2.51), 7.489 (3.30), 7.502 (3.52), 7.511(3.35), 7.525 (3.11), 7.677 (0.86), 7.712 (0.64), 7.733 (16.00), 7.759(0.50), 8.775 (1.61), 8.790 (3.19), 8.804 (1.53).

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 8.79 (t, 1H), 7.78-7.70 (m, 2H), 7.51(dd, 1H), 7.46 (br. s, 1H, masked), 7.41 (dd, 1H), 7.15 (td,1H), 3.84 (t, 2H),3.78 (br. s,2H), 3.74-3.67 (m, 2H), 3.65-3.55 (m,1H), 2.32-1.95 (m, 8H),1.90-1.74 (m, 1H).

Example 15

(+/-) -5- ({ [ 6-bromo-2- (2, 5-dihydro-1)H-pyrrol-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chloro-5-fluorophenyl) pentanoic acid(raceme)

To (+/-) -5- ({ [ 6-bromo-2- (2, 5-dihydro-1)H-pyrrol-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester (32 mg, 51.9 μmol,racemic modificationExample 65A) was added to TFA (40 μ l, 520 μmol) in dichloromethane (380 μ l) solution, and the mixture was stirred at room temperature for two days. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 20 mg (90% purity, 61% of theory) of the title compound are obtained.

LC-MS (method 2) R_t= 0.87 min; MS (ESIpos): m/z = 560/562 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.773 (0.50), 1.787 (0.88), 1.808(1.83), 1.819 (1.42), 1.829 (2.14), 1.840 (1.55), 1.851 (1.30), 1.870 (0.65),2.026 (1.76), 2.048 (4.09), 2.075 (3.34), 2.087 (3.15), 2.097 (3.64), 2.108(2.21), 2.128 (2.86), 2.145 (2.35), 2.169 (1.45), 2.188 (2.40), 2.247 (7.74),2.324 (0.57), 3.586 (1.76), 3.677 (2.88), 4.527 (3.34), 5.964 (16.00), 6.305(1.64), 6.311 (2.40), 6.316 (1.56), 7.141 (2.44), 7.256 (1.95), 7.262 (2.79),7.267 (1.88), 7.384 (3.11), 7.391 (3.20), 7.409 (3.34), 7.416 (3.32), 7.439(0.90), 7.446 (0.82), 7.474 (5.90), 7.479 (3.94), 7.496 (10.52), 7.501(4.70), 7.515 (3.18), 7.525 (0.90), 7.553 (4.95), 7.558 (4.50), 7.575 (2.94),7.580 (2.80), 7.880 (3.13), 8.688 (1.91), 8.702 (3.51), 8.716 (1.74), 8.886(0.68).

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 12.09 (br. s, 1H), 8.70 (t, 1H), 7.56(dd, 1H), 7.53-7.46 (m, 2H), 7.46 (wide, masked, 1H), 7.40 (dd, 1H), 7.18-7.10(m, 1H), 5.96 (s, 2H), 4.53 (br. s, 4H), 3.78-3.53 (m, 3H), 2.29-1.97 (m,6H), 1.88-1.72 (m, 1H).

Example 16

5- [ ({ 6-bromo-2- [ 3-hydroxypyrrolidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chloro-5-fluorophenyl) pentanoic acid(mixture of diastereomers)

To 5- [ ({ 6-bromo-2- [ 3-hydroxypyrrolidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-tert-butyl 4- (2-chloro-5-fluorophenyl) valerate (60 mg, 94.5 μmol,mixtures of diastereomersExample 66A) was added to TFA (73 μ l, 940 μmol) in dichloromethane (690 μ l) solution, and the mixture was stirred at room temperature for two days. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 50 mg (98% purity, 90% of theory) of the title compound are obtained.

LC-MS (method 2) R_t= 0.69 min; MS (ESIpos): m/z = 578/580 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.27), 0.008 (1.10), 1.772(0.54), 1.786 (0.97), 1.808 (2.80), 1.830 (3.88), 1.850 (3.12), 1.920 (1.78),1.938 (1.54), 1.988 (0.75), 2.023 (1.72), 2.040 (1.99), 2.053 (4.47), 2.081(3.66), 2.094 (3.39), 2.102 (4.12), 2.115 (3.02), 2.147 (16.00), 2.171(1.97), 2.189 (1.08), 2.327 (0.57), 2.523 (1.83), 2.669 (0.59), 2.710 (0.40),3.356 (2.29), 3.569 (2.21), 3.667 (3.45), 3.678 (3.50), 3.782 (2.75), 4.331(3.12), 4.898 (3.56), 4.905 (5.60), 4.912 (3.39), 7.130 (2.10), 7.138 (2.24),7.149 (2.13), 7.262 (0.51), 7.381 (2.88), 7.388 (3.99), 7.406 (2.94), 7.414(3.80), 7.466 (5.93), 7.480 (3.91), 7.488 (11.07), 7.500 (3.34), 7.514(3.02), 7.544 (5.14), 7.566 (2.99), 8.699 (3.26), 12.057 (4.53).

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 12.06 (br. s, 1H), 8.70 (br. t, 1H),7.58-7.53 (m,1H), 7.52-7.45 (m, 2H), 7.40 (br. dt, 1H), 7.34 (br. s, partial coverage, 1H), 7.19-7.09 (m,1H), 4.91 (t, 1H), 4.33 (br. s, 1H), 3.88-3.47 (m,7H), 2.19-1.78 (m, 9H).

Example 17

5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- (2-chloro-5-fluorophenyl) pentanoic acid(mixture of diastereomers)

To 5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-tert-butyl 4- (2-chloro-5-fluorophenyl) valerate (75 mg, 116 μmol,mixtures of diastereomersExample 67A) in dichloromethane (850 μ l) was added TFA (89 μ l, 1.2 mmol) and the mixture was stirred at room temperature for two days. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 12). The combined target fractions were concentrated, and the residue was mixed with ethyl acetate and saturated aqueous sodium bicarbonate solution (10 ml each) and shaken. After phase separation, the aqueous phase was extracted twice with ethyl acetate (10 ml each). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was lyophilized. 57 mg (98% purity, 82% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.34 min; MS (ESIpos): m/z = 590/592[M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.022 (0.66), -0.008 (1.50), 0.008(1.14), 0.920 (8.53), 0.936 (8.61), 0.963 (0.41), 1.077 (0.96), 1.099 (1.00),1.127 (0.40), 1.233 (1.61), 1.627 (0.77), 1.650 (0.89), 1.729 (1.77), 1.767(1.86), 1.783 (2.28), 1.791 (2.42), 1.801 (2.33), 1.823 (2.39), 2.001 (0.74),2.015 (1.13), 2.034 (2.73), 2.048 (0.97), 2.060 (2.13), 2.072 (1.97), 2.083(2.19), 2.093 (1.23), 2.115 (2.53), 2.131 (16.00), 2.153 (1.13), 2.169(0.45), 2.417 (0.53), 2.458 (0.99), 2.523 (0.79), 2.670 (0.67), 2.696 (0.88),2.710 (1.15), 3.432 (1.94), 3.459 (2.87), 3.487 (1.47), 3.579 (1.20), 3.686(2.45), 7.116 (0.84), 7.123 (0.97), 7.137 (1.62), 7.144 (1.72), 7.158 (0.99),7.165 (0.98), 7.381 (2.07), 7.389 (2.10), 7.407 (2.19), 7.414 (2.11), 7.456(0.62), 7.482 (2.69), 7.495 (2.67), 7.504 (2.47), 7.517 (2.35), 7.624 (0.93),7.647 (9.27), 7.654 (5.14), 7.672 (0.63), 7.676 (0.73), 8.719 (1.20), 8.733(2.27), 8.746 (1.13).

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 12.26 (br. s, 1H), 8.73 (t, 1H), 7.69-7.61 (m, 2H), 7.50(dd, 1H), 7.46 (br. s, partial coverage, 1H), 7.40 (dd, 1H), 7.14(td, 1H), 3.76-3.40 (m,5H), 2.80-2.61 (m,1H), 2.48-2.34 (m,1H), 2.20-1.95(m, 6H), 1.88-1.55 (m,5H), 1.17-1.01 (m,1H), 0.93 (d, 3H).

Example 18

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (4-methylpiperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-5-fluorophenyl) pentanoic acid(raceme)

To (+/-) -5- ({ [ 6-bromo-3-methyl-2- (4-methylpiperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-5-fluorophenyl) pentanoic acid tert-butyl ester (70 mg, 108 μmol,racemic modificationExample 68A) was added to a dichloromethane (790 μ l) solution of TFA (83 μ l,1.1 μmol), and the mixture was stirred at room temperature for two days. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 12). The combined target fractions were concentrated, and the residue was mixed with ethyl acetate and saturated aqueous sodium bicarbonate solution (10 ml each) and shaken. After phase separation, the aqueous phase was extracted twice with ethyl acetate (10 ml each). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was lyophilized. 35 mg (98% purity, 53% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.33 min; MS (ESIpos): m/z = 590/592 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.964 (10.37), 0.980 (10.93), 1.233(0.56), 1.256 (0.68), 1.286 (1.96), 1.315 (2.22), 1.345 (0.95), 1.552 (0.89),1.562 (1.05), 1.578 (0.95), 1.588 (0.80), 1.718 (2.85), 1.746 (2.59), 1.780(0.68), 1.802 (1.29), 1.821 (1.41), 1.833 (0.90), 1.844 (0.79), 1.863 (0.41),2.001 (0.79), 2.017 (1.16), 2.036 (3.01), 2.063 (2.22), 2.075 (2.05), 2.086(2.34), 2.097 (1.62), 2.119 (16.00), 2.156 (0.97), 2.173 (0.46), 2.730(1.03), 2.759 (2.00), 2.774 (2.10), 2.802 (1.10), 3.302 (2.59), 3.314 (2.67),3.508 (3.25), 3.540 (3.16), 3.580 (1.37), 3.688 (2.97), 7.116 (0.92), 7.123(1.05), 7.137 (1.77), 7.144 (1.90), 7.157 (1.08), 7.165 (1.08), 7.383 (2.21),7.390 (2.26), 7.408 (2.34), 7.415 (2.30), 7.457 (0.72), 7.482 (2.87), 7.495(2.84), 7.504 (2.61), 7.517 (2.39), 7.617 (1.88), 7.639 (8.36), 7.648 (5.27),7.653 (4.59), 7.671 (1.10), 7.676 (1.17), 8.719 (1.41), 8.734 (2.79), 8.748(1.35).

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 12.16 (br. s, 1H), 8.73 (t, 1H), 7.69-7.61 (m, 2H), 7.50(dd, 1H), 7.46 (br. s, partial coverage, 1H), 7.40 (dd, 1H), 7.14(td, 1H), 3.74-3.48 (m,5H), 2.82-2.69 (m, 2H), 2.19-1.96 (m,6H), 1.88-1.67(m, 3H), 1.63-1.50 (m,1H), 1.38-1.19 (m, 2H), 0.97 (d, 3H).

Example 19

5- [ ({ 6-bromo-2- [ 3-methoxypiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chloro-5-fluorophenyl) pentanoic acid(mixture of diastereomers)

To 5- [ ({ 6-bromo-2- [ 3-methoxypiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-tert-butyl 4- (2-chloro-5-fluorophenyl) valerate (65 mg, 98.0 μmol,mixtures of diastereomersExample 69A) to a dichloromethane (720 μ l) solution was added TFA (76 μ l, 980 μmol), and the mixture was stirred at room temperature for two days. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was dissolved in acetonitrile and passed throughPurification by preparative HPLC (method 12). The combined target fractions were concentrated, and the residue was mixed with ethyl acetate and saturated aqueous sodium bicarbonate solution (10 ml each) and shaken. After phase separation, the aqueous phase was extracted twice with ethyl acetate (10 ml each). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was lyophilized. 35 mg (98% purity, 57% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.04 min; MS (ESIpos): m/z = 606/608 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.400 (0.45), 1.806 (0.89), 1.817(0.65), 1.828 (0.90), 2.020 (0.80), 2.048 (1.24), 2.076 (0.89), 2.089 (0.77),2.097 (1.04), 2.131 (6.49), 2.732 (0.44), 2.845 (0.41), 2.861 (0.42), 3.301(16.00), 3.313 (7.33), 3.425 (0.66), 3.434 (0.65), 3.588 (1.07), 3.616(0.82), 3.694 (1.18), 7.123 (0.42), 7.138 (0.70), 7.144 (0.75), 7.158 (0.43),7.165 (0.42), 7.390 (0.84), 7.398 (0.87), 7.416 (0.89), 7.423 (0.87), 7.481(1.16), 7.495 (1.15), 7.503 (1.03), 7.517 (0.93), 7.633 (0.58), 7.656 (3.28),7.662 (2.19), 7.667 (1.89), 8.714 (0.52), 8.727 (1.00), 8.741 (0.50).

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 12.09 (br. s, 1H), 8.73 (t, 1H), 7.70-7.62 (m, 2H), 7.50(dd, 1H), 7.46 (br. s, partial coverage, 1H), 7.41 (dd, 1H), 7.14(td, 1H), 3.75-3.66 (m, 2H), 3.65-3.54 (m, 2H), 3.47-3.39 (m,1H), 3.30 (s, partial coverage, 3H), 2.93-2.80 (m,1H), 2.78-2.65 (m,1H), 2.18-1.96 (m,7H), 1.89-1.75 (m, 2H), 1.66-1.51 (m,1H), 1.46-1.32 (m,1H), 1H) In that respect

Example 20

5- [ ({ 6-bromo-2- [2- (hydroxymethyl) morpholin-4-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chloro-5-fluorophenyl) pentanoic acid(mixture of diastereomers)

To 5- [ ({ 6-bromo-2- [2- (hydroxymethyl) morpholin-4-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chloro-5-fluorophenyl)Tert-butyl valerate (35 mg, 52.6 μmol,mixtures of diastereomersExample 70A) was added to TFA (41 μ l, 530 μmol) in dichloromethane (390 μ l) solution, and the mixture was stirred at room temperature for two days. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 12). The combined target fractions were concentrated, and the residue was combined with ethyl acetate and saturated aqueous sodium bicarbonate (10 ml each) and shaken. After phase separation, the aqueous phase was extracted twice with ethyl acetate (10 ml each). The combined organic phases were dried over sodium sulfate, filtered and concentrated, and the residue was lyophilized. 26 mg (98% purity, 78% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 1.67 min; MS (ESIpos): m/z = 608/610 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.788 (0.65), 1.810 (1.36), 1.831(1.64), 1.852 (0.96), 1.871 (0.44), 1.991 (0.46), 2.011 (0.97), 2.024 (1.28),2.042 (1.48), 2.055 (3.21), 2.082 (2.67), 2.095 (2.49), 2.102 (3.16), 2.116(1.97), 2.131 (3.02), 2.157 (16.00), 2.189 (0.75), 2.643 (0.63), 2.670(1.36), 2.691 (1.24), 2.710 (0.74), 2.717 (0.78), 2.891 (1.17), 2.921 (0.67),3.385 (3.18), 3.415 (3.71), 3.428 (2.50), 3.490 (2.32), 3.502 (3.16), 3.517(3.57), 3.529 (2.32), 3.551 (2.26), 3.605 (2.21), 3.619 (2.39), 3.644 (1.89),3.659 (1.32), 3.688 (3.34), 3.710 (4.45), 3.739 (1.84), 3.909 (2.58), 3.936(2.02), 4.762 (0.56), 7.120 (1.03), 7.126 (1.19), 7.141 (2.03), 7.147 (2.14),7.161 (1.24), 7.168 (1.20), 7.394 (2.43), 7.401 (2.44), 7.419 (2.54), 7.426(2.41), 7.486 (3.59), 7.499 (3.61), 7.508 (3.33), 7.521 (2.98), 7.661 (0.94),7.683 (14.87), 7.706 (0.58), 7.710 (0.70), 8.743 (1.59), 8.756 (2.91), 8.770(1.45).

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 12.07 (br. s, 1H), 8.76 (t, 1H), 7.72-7.64 (m, 2H), 7.50(dd, 1H), 7.47 (br. s, partial coverage, 1H), 7.41 (dd, 1H), 7.14(td, 1H), 4.76 (br. s, 1H), 3.92 (br. d,1H), 3.78-3.36 (m, 9H), 2.97-2.80(m, 1H), 2.77-2.60 (m,1H), 2.21-1.95 (m,6H), 1.90-1.71 (m, 1H).

Example 21

5- [ ({ 6-bromo-2- [3- (hydroxymethyl) piperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chloro-5-fluorophenyl) pentanoic acid(mixture of diastereomers)

To 5- [ ({ 6-bromo-2- [3- (hydroxymethyl) piperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-tert-butyl 4- (2-chloro-5-fluorophenyl) valerate (63 mg, 95.0 μmol,mixtures of diastereomersExample 71A) was added to a dichloromethane (700 μ l) solution of TFA (73 μ l, 950 μmol), and the mixture was stirred at room temperature for two days. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 12). The combined target fractions were concentrated and the residue was lyophilized. 20 mg (98% purity, 34% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 1.80 min; MS (ESIpos): m/z = 606/608 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.089 (0.50), 1.117 (1.29), 1.140(1.38), 1.622 (1.10), 1.648 (1.20), 1.676 (0.84), 1.746 (5.89), 1.773 (5.29),1.812 (1.66), 1.833 (1.70), 1.857 (2.04), 1.871 (1.27), 1.885 (1.70), 1.904(1.40), 1.917 (1.31), 1.924 (1.32), 1.959 (0.47), 2.151 (16.00), 2.566(0.62), 2.723 (1.19), 2.747 (1.22), 2.776 (0.57), 3.336 (11.62), 3.450(2.50), 3.481 (3.01), 7.083 (1.12), 7.090 (1.27), 7.105 (2.10), 7.111 (2.23),7.125 (1.26), 7.132 (1.23), 7.298 (2.44), 7.305 (2.40), 7.323 (2.44), 7.330(2.25), 7.458 (3.55), 7.471 (3.44), 7.479 (3.00), 7.493 (2.57), 7.621 (1.06),7.643 (11.76), 7.672 (0.74), 8.997 (1.74).

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 9.00 (br. s, 1H), 7.69-7.60 (m,1H), 7.48 (dd, 1H), 7.43 (br. s, partial coverage, 1H), 7.31 (dd, 1H), 7.11 (td,1H), 4.63(br. s, 1H), 3.74-3.18 (m, partial coverage, 8H), 2.82-2.62 (m,1H), 2.15 (s, 3H),1.99-1.55 (m, 8H), 1.21-1.04 (m, 1H).

Example 22

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(raceme)

To (+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester (100 mg, 163 μmol,racemic modificationExample 72A) in dichloromethane (2.9 ml) was added TFA (130 μ l, 1.6 mmol) and the mixture was stirred at room temperature for 66 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated. The residue was repeatedly dissolved in dichloromethane and concentrated again, then dried in vacuo. 62 mg (100% purity, 68% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.18 min; MS (ESIpos): m/z = 558/560 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.58), -0.008 (7.08), 0.008(4.63), 0.146 (0.60), 1.235 (0.47), 1.370 (2.53), 1.605 (4.27), 1.670 (8.18),1.793 (0.89), 1.811 (1.74), 1.834 (2.19), 1.857 (1.16), 2.045 (4.22), 2.081(5.18), 2.089 (5.36), 2.103 (3.13), 2.130 (16.00), 2.159 (1.61), 2.327(0.92), 2.366 (0.92), 2.518 (4.78), 2.523 (4.22), 2.669 (1.05), 2.710 (0.87),3.119 (8.34), 3.132 (10.53), 3.591 (1.94), 3.674 (3.53), 5.754 (4.60), 7.257(1.83), 7.275 (3.80), 7.291 (2.79), 7.295 (2.66), 7.356 (2.55), 7.373 (4.60),7.391 (2.66), 7.441 (6.50), 7.444 (6.06), 7.461 (5.90), 7.464 (5.52), 7.479(5.92), 7.482 (5.83), 7.498 (4.36), 7.622 (2.73), 7.643 (12.72), 7.651(9.12), 7.656 (7.69), 7.673 (1.72), 7.678 (1.77), 8.707 (2.17), 8.722 (4.09),8.736 (1.92), 12.039 (6.06)。

Example 23

(-)-5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(enantiomer 1)

To (-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester (70 mg, 114 μmol,enantiomer 1Example 73A) in dichloromethane (2.0 ml) TFA (88 μ l,1.1 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 48mg (98% purity, ee 99%, theoretical 73%) of the title compound are obtained.

[α]_D ²⁰= 17.0 °, 589 nm, c = 0.27 g/100 ml, methanol

LC-MS (method 1) R_t= 2.19 min; MS (ESIpos): m/z = 558/560 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.060 (0.99), -0.008 (2.24), 0.008(1.64), 0.084 (0.74), 1.607 (4.12), 1.672 (7.98), 1.782 (0.53), 1.793 (0.79),1.812 (1.62), 1.835 (2.14), 1.858 (1.17), 2.014 (0.51), 2.035 (1.18), 2.046(4.07), 2.073 (4.15), 2.082 (4.75), 2.089 (5.01), 2.103 (2.60), 2.132(16.00), 2.159 (1.48), 2.327 (0.44), 2.366 (0.43), 2.523 (1.22), 2.670(0.41), 3.143 (10.38), 3.595 (3.12), 3.620 (2.84), 3.676 (7.44), 3.690(7.13), 7.257 (1.62), 7.275 (3.74), 7.292 (2.72), 7.295 (2.61), 7.356 (2.25),7.374 (4.12), 7.392 (2.14), 7.441 (5.77), 7.444 (5.50), 7.461 (5.08), 7.464(4.86), 7.480 (5.49), 7.482 (5.54), 7.499 (4.21), 7.630 (2.09), 7.652(11.83), 7.658 (8.30), 7.663 (7.08), 7.680 (1.37), 7.685 (1.52), 8.712(2.04), 8.726 (4.16), 8.740 (2.01).

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 12.02 (br. s, 1H), 8.73 (t, 1H), 7.71-7.62 (m, 2H), 7.54-7.42 (m, 3H), 7.37 (t, 1H), 7.31-7.24 (m,1H), 3.95-3.45(m, 3H, partial coverage), 3.19-3.08 (m, 4H), 2.20-2.01 (m,6H), 1.95-1.73 (m,1H), 1.72-1.49 (m, 6H).

Example 24

(+) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(enantiomer 2)

To (+) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester (70 mg, 114 μmol,enantiomer 2Example 74A) in dichloromethane (2.0 ml) TFA (88 μ l,1.1 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 43 mg (98% purity, ee 96%, 66% of theory) of the title compound are obtained.

[α]_D ²⁰= 8.1 °, 589 nm, c = 0.26 g/100 ml, methanol

LC-MS (method 1) R_t= 2.19 min; MS (ESIpos): m/z = 558/560 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.47), -0.008 (3.94), 0.008(4.07), 0.146 (0.50), 1.606 (3.77), 1.671 (7.49), 1.793 (0.66), 1.810 (1.47),1.834 (2.05), 1.857 (1.10), 2.024 (0.78), 2.044 (3.30), 2.077 (4.23), 2.086(4.55), 2.094 (2.58), 2.131 (16.00), 2.155 (1.53), 2.327 (0.52), 2.366(0.40), 2.523 (1.73), 2.670 (0.61), 2.710 (0.46), 3.133 (9.79), 3.591 (1.72),3.674 (3.17), 3.687 (2.47), 7.256 (1.53), 7.274 (3.55), 7.291 (2.47), 7.294(2.51), 7.355 (2.17), 7.374 (3.95), 7.392 (2.04), 7.441 (5.56), 7.444 (5.59),7.461 (4.94), 7.464 (4.94), 7.481 (5.29), 7.497 (3.95), 7.622 (2.32), 7.644(12.05), 7.651 (8.27), 7.656 (7.28), 7.673 (1.50), 7.678 (1.62), 8.712(1.84), 8.726 (3.79), 8.740 (1.84).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.05 (br. s, 1H), 8.73 (t, 1H), 7.69-7.61 (m, 2H), 7.53-7.42 (m, 3H), 7.37 (t, 1H), 7.31-7.23 (m, 1H), 3.76-3.62(m, 2H), 3.62-3.53 (m, 1H), 3.20-3.06 (m, 4H), 2.20-1.98 (m, 6H), 1.90-1.75(m, 1H), 1.72-1.50 (m, 6H)。

Example 25

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (thiomorpholin-4-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(raceme)

To (+) -5- ({ [ 6-bromo-3-methyl-2- (thiomorpholin-4-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester (70 mg, 111 μmol,racemic modificationExample 75A) in dichloromethane (810 μ l) TFA (85 μ l,1.1 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 58 mg (98% purity, 89% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.11 min; MS (ESIpos): m/z = 576/578 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.022 (0.68), 1.004 (2.17), 1.234(1.54), 1.394 (0.86), 1.809 (1.65), 1.831 (2.44), 1.854 (1.44), 2.037 (3.90),2.064 (5.65), 2.072 (5.19), 2.085 (3.39), 2.095 (2.40), 2.134 (16.00), 2.196(0.47), 2.327 (0.57), 2.670 (0.65), 2.710 (0.50), 2.787 (11.08), 2.798(10.38), 2.864 (0.71), 3.045 (0.42), 3.414 (11.05), 3.425 (11.71), 3.584(2.28), 3.676 (3.53), 7.255 (1.81), 7.273 (4.16), 7.293 (2.93), 7.353 (2.45),7.372 (4.50), 7.391 (2.36), 7.442 (6.27), 7.462 (5.42), 7.478 (5.58), 7.495(4.58), 7.655 (2.31), 7.677 (13.29), 7.681 (10.73), 7.686 (8.04), 7.704(1.13), 7.708 (1.41), 8.732 (2.04), 8.745 (3.71), 8.759 (1.92).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.01 (br. s, 1H), 8.75 (t, 1H), 7.73-7.64 (m, 2H), 7.58-7.42 (m, 3H), 7.37 (t, 1H), 7.28 (t, 1H), 3.78-3.63 (m,2H), 3.62-3.53 (m, 1H), 3.46-3.39 (m, 4H), 2.85-2.74 (m, 4H), 2.22-1.98 (m,6H), 1.92-1.74 (m, 1H)。

Separation of enantiomers:

the title compound (50 mg) was dissolved in methanol (50 ml) and separated into enantiomers on the chiral phase by preparative SFC (see examples 26 and 27) [ column: daicel Chiralpak ID, 5 μm,250 mm x20 mm, flow rate: 70 ml/min, injection: 0.40 ml, eluent 30% methanol/70% carbon dioxide, run time 7 min, isocratic. The combined target fractions were concentrated and the residue was lyophilized.

Example 26

(+) -5- ({ [ 6-bromo-3-methyl-2- (thiomorpholin-4-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(enantiomer 1)

In the enantiomeric separation described in example 25, 8mg (98% purity, ee value 99%) of the title compound were obtained as the earlier eluting enantiomer.

[α]_D ²⁰= 8.9 °, 589 nm, c = 0.30 g/100 ml, methanol

LC-MS (method 1) R_t= 2.08 min; MS (ESIpos): m/z = 576/578 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.02), 0.068 (1.62), 0.146(1.00), 0.940 (0.50), 0.955 (0.52), 1.139 (0.50), 1.157(0.52), 1.811 (1.54),1.835 (2.04), 1.857 (1.14), 2.042 (3.63), 2.076 (4.73), 2.083 (5.00), 2.133(16.00), 2.327 (1.22), 2.366 (1.12), 2.402 (0.95), 2.669 (1.42), 2.710(1.29), 2.788 (10.55), 3.425 (10.48), 3.587 (1.94), 3.677 (3.31), 7.256(1.72), 7.275 (3.73), 7.294 (2.66), 7.355 (2.26), 7.374 (4.08), 7.391 (2.24),7.443 (5.60), 7.463 (4.80), 7.481 (5.08), 7.499 (4.23), 7.655 (1.74), 7.677(11.84), 7.686 (7.42), 7.709 (1.39), 8.720 (1.84), 8.735 (3.66), 8.749(1.97), 12.054 (0.80).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.05 (br. s, 1H), 8.74 (t, 1H), 7.74-7.62 (m, 2H), 7.58-7.42 (m, 3H), 7.37 (t, 1H), 7.31-7.23 (m, 1H), 3.76-3.63(m, 2H), 3.62-3.54 (m, 1H), 3.47-3.38 (m, 4H), 2.83-2.74 (m, 4H), 2.19-1.99(m, 6H), 1.89-1.76 (m, 1H)。

Example 27

(-) -5- ({ [ 6-bromo-3-methyl-2- (thiomorpholin-4-yl) quinolin-4-yl]Carbonyl group } ammonia4- (2-chlorophenyl) pentanoic acid(enantiomer 2)

In the enantiomeric separation described in example 25, 8mg (98% purity, ee value 93%) of the title compound are obtained as the enantiomer which elutes later.

[α]_D ²⁰= 6.4 °, 589 nm, c = 0.25 g/100 ml, methanol

LC-MS (method 1) R_t= 2.08 min; MS (ESIpos): m/z = 576/578 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.15), 0.008 (8.73), 0.069(2.56), 0.146 (1.10), 1.812 (1.58), 1.834 (2.06), 1.859 (1.15), 2.043 (3.66),2.083 (5.02), 2.133 (16.00), 2.328 (1.39), 2.366 (0.98), 2.523 (6.60), 2.670(1.39), 2.709 (1.15), 2.786 (10.64), 3.425 (10.43), 3.588 (2.08), 3.677(3.35), 7.256 (1.77), 7.274 (3.85), 7.292 (2.63), 7.354 (2.37), 7.374 (4.14),7.391 (2.20), 7.441(6.07), 7.461 (5.33), 7.481 (5.14), 7.498 (4.21), 7.655(2.20), 7.677 (13.30), 7.686 (7.49), 7.709 (1.43), 8.734 (3.56), 12.050(0.84).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.05 (br. s, 1H), 8.73 (t, 1H), 7.73-7.63 (m, 2H), 7.59-7.41 (m, 3H), 7.37 (t, 1H), 7.31-7.22 (m, 1H), 3.76-3.63(m, 2H), 3.62-3.53 (m, 1H), 3.47-3.38 (m, 4H), 2.83-2.73 (m, 4H), 2.18-1.98(m, 6H), 1.89-1.74 (m, 1H)。

Example 28

(+/-) -5- ({ [ 6-bromo-2- (4, 4-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(raceme)

To (+/-) -5- ({ [ 6-bromo-2- (4, 4-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester (28 mg, 43.0 μmol,racemic modificationExample 76A) was added to a dichloromethane (320 μ l) solution of TFA (33 μ l, 430 μmol), and the mixture was stirred at room temperature overnight. The mixture was then concentrated and dichloromethane was added repeatedlyAlkane and the mixture was concentrated again. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 6 mg (98% purity, 23% of theory) of the title compound are obtained.

LC-MS (method 2) R_t= 1.13 min; MS (ESIpos): m/z = 594/596 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.57), -0.008 (8.43), 0.008(4.79), 0.146 (0.52), 1.234 (0.75), 1.810 (1.45), 1.831 (1.86), 1.854 (1.14),2.034 (3.35), 2.062 (5.16), 2.093 (2.83), 2.118 (5.33), 2.170 (16.00), 2.327(1.03), 2.366 (0.89), 2.523 (6.12), 2.669 (0.98), 2.710 (0.58), 3.586 (1.93),3.681 (3.12), 7.255 (1.54), 7.272 (3.22), 7.290 (2.24), 7.355 (2.13), 7.373(3.61), 7.391 (1.95), 7.440 (5.04), 7.459 (4.37), 7.481 (4.37), 7.499 (3.62),7.658 (2.37), 7.680 (10.19), 7.688 (6.97), 7.693 (5.96), 7.710 (1.28), 7.715(1.33), 8.771 (2.79).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.14 (br. s, 1H), 8.77 (t, 1H), 7.74-7.62 (m, 2H), 7.59-7.41 (m, 3H), 7.37 (t, 1H), 7.31-7.23 (m, 1H), 3.76-3.62(m, 2H), 3.62-3.53 (m, 1H), 2.24-1.97 (m, 11H), 1.89-1.75 (m, 1H)。

Example 29

(+/-) -5- ({ [ 6-bromo-2- (3, 6-dihydropyridine-1 (2))H) -yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(raceme)

To (+/-) -5- ({ [ 6-bromo-2- (3, 6-dihydropyridine-1 (2)H) -yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester (80 mg, 131. mu. mol,racemic modificationExample 77A) in dichloromethane (960. mu.l) TFA (100. mu.l, 1.3 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). Combining the target fractionsConcentrated and the residue was lyophilized. 65 mg (98% purity, 88% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.15 min; MS (ESIpos): m/z = 556/558 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.195 (1.62), 1.211 (1.64), 1.233(0.51), 1.242 (0.74), 1.257 (0.81), 1.272 (0.44), 1.800 (0.79), 1.819 (1.67),1.842 (2.17), 1.865 (1.23), 2.052 (3.96), 2.086 (5.33), 2.093 (5.55), 2.143(16.00), 2.303 (4.60), 3.271 (3.84), 3.596 (2.12), 3.680 (3.38), 3.796(7.68), 5.818 (1.47), 5.844 (4.74), 5.863 (4.13), 5.889 (1.26), 7.256 (1.75),7.274 (3.79), 7.293 (2.71), 7.357 (2.33), 7.376 (4.04), 7.394 (2.21), 7.442(5.66), 7.462 (5.13), 7.484 (5.68), 7.502 (4.18), 7.618 (2.71), 7.640 (9.36),7.653 (6.42), 7.657 (5.51), 7.675 (1.77), 7.680 (1.64), 8.721 (2.17), 8.735(3.91), 8.748 (1.96), 12.047 (4.68).

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 12.05 (s, 1H), 8.73 (t, 1H), 7.70-7.60(m, 2H), 7.57-7.41 (m, 3H), 7.37 (t, 1H), 7.28 (t, 1H), 5.93-5.79 (m, 2H),3.80 (br. s,2H), 3.73-3.63 (m, 2H), 3.63-3.54 (m,1H), 3.27 (br. s,2H, partial coverage), 2.30 (br. s,2H), 2.19-1.99 (m,6H), 1.91-1.72 (m, 1H).

Separation of enantiomers:

the title compound (60 mg) was dissolved in a mixture of isopropanol (3 ml), heptane (2 ml) and acetonitrile (1 ml) in an ultrasonic bath, filtered and separated into enantiomers by preparative HPLC on chiral phase (see examples 30 and 31) [ column: daicel Chiralcel OX-H, 5 μm,250 mm x20 mm, flow rate: 15 ml/min, detection: 220 nm, temperature: 35 ℃ and injection: 0.40 ml, eluent 80% heptane/20% isopropanol, run time 16 min, isocratic ]. The combined target fractions were concentrated and the respective residues were lyophilized in acetonitrile/water.

Example 30

5- ({ [ 6-bromo-2- (3, 6-dihydropyridin-1 (2H) -yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(enantiomer 1)

In the enantiomeric separation described in example 29, the title compound was obtained as a previously purified enantiomer (ee value 99%). Followed by repurification by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water. 22 mg (98% purity, 37% of theory) of the repurified title compound are obtained.

LC-MS (method 1) R_t= 2.15 min; MS (ESIpos): m/z = 556/558 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (1.15), 0.145 (1.01), 1.234(0.91), 1.836 (2.69), 1.859 (1.58), 2.044 (4.28), 2.072 (6.37), 2.143(16.00), 2.302 (4.72), 2.366 (1.79), 2.669 (1.95), 2.709 (1.62), 3.589(2.46), 3.677 (3.54), 3.796 (7.65), 5.844 (4.82), 5.863 (4.28), 7.253 (2.12),7.273 (4.35), 7.291 (3.03), 7.356 (2.86), 7.374 (4.65), 7.392 (2.49), 7.441(6.91), 7.461 (6.23), 7.481 (6.16), 7.498 (4.58), 7.617 (3.40), 7.639(11.59), 7.652 (7.07), 7.657 (6.27), 7.674 (2.19), 8.750 (3.57)。

Example 31

5- ({ [ 6-bromo-2- (3, 6-dihydropyridin-1 (2H) -yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(enantiomer 2)

In the enantiomeric separation described in example 29, the title compound was obtained as a previously purified enantiomer (ee value 99%) which eluted later. And then purified again by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water. 11 mg (98% purity, 18% of theory) of the repurified title compound are obtained.

LC-MS (method 1) R_t= 2.15 min; MS (ESIpos): m/z = 556/558 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (2.35), 0.146 (2.13), 0.936(2.03), 0.952 (2.03), 1.234 (6.29), 1.795 (2.13), 1.996 (4.48), 2.154(16.00), 2.327 (8.96), 2.366 (4.59), 2.670 (6.72), 2.709 (5.01), 3.545(3.09), 3.661 (4.16), 3.801 (10.77), 5.844 (6.61), 7.260 (4.05), 7.362(4.27), 7.429 (6.08), 7.450 (6.93), 7.615 (3.84), 7.637 (14.83), 7.650(10.03), 8.925 (1.71)。

Example 32

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (1, 2-oxaazacyclohex-2-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(raceme)

To (+) -5- ({ [ 6-bromo-3-methyl-2- (1, 2-oxaazacyclohex-2-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester (24 mg, 38.9 μmol,racemic modificationExample 78A) in dichloromethane (1.0ml) was added TFA (30 μ l, 390 μmol), and the mixture was stirred at room temperature overnight. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 12 mg (98% purity, 56% of theory) of the title compound are obtained.

LC-MS (method 2) R_t= 1.11 min; MS (ESIpos): m/z = 560/562 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (1.62), 1.172 (0.42), 1.189(0.42), 1.696 (3.60), 1.708 (2.94), 1.784 (0.42), 1.795 (0.61), 1.813 (1.31),1.836 (1.81), 1.868 (3.31), 1.883 (3.96), 1.897 (2.58), 2.046 (3.08), 2.081(3.58), 2.089 (3.69), 2.141 (10.12), 3.575 (3.73), 3.647 (0.92), 3.667(1.81), 3.681 (2.72), 3.695 (1.97), 3.723 (1.12), 4.041 (3.52), 4.054 (5.58),4.066 (3.45), 7.255 (1.27), 7.274 (2.96), 7.293 (2.11), 7.354 (1.73), 7.373(3.18), 7.391 (1.68), 7.445 (4.44), 7.465 (3.92), 7.478 (3.64), 7.497 (2.80),7.533 (0.87), 7.727 (16.00), 8.789 (1.61), 8.804 (3.12), 8.818 (1.54), 12.028(0.59).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.03 (br. s, 1H), 8.80 (t, 1H), 7.73(s, 2H), 7.53 (br. s, 1H), 7.47 (dd, 2H), 7.37 (t, 1H), 7.31-7.24 (m, 1H),4.05 (t, 2H), 3.80-3.47 (m, 5H), 2.21-1.98 (m, 6H), 1.94-1.77 (m, 3H), 1.75-1.64 (m, 2H)。

Example 33

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(raceme)

To (+) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester (380 mg, 632 μmol,racemic modificationExample 79A) in dichloromethane (4.6 ml) TFA (490. mu.l, 6.3 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 256 mg (98% purity, 73% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 1.43 min; MS (ESIpos): m/z = 544/546 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.19), 0.008 (1.14), 1.241(0.73), 1.256 (0.78), 1.271 (0.46), 1.785 (0.59), 1.796 (0.85), 1.814 (1.80),1.838 (3.17), 1.871 (12.01), 2.026 (1.00), 2.047 (3.97), 2.080 (4.63), 2.090(4.73), 2.111 (1.81), 2.119 (1.82), 2.138 (3.86), 2.161 (9.89), 3.322(16.00), 3.659 (2.60), 7.251 (1.67), 7.268 (3.84), 7.286 (2.77), 7.352(2.63), 7.370 (4.65), 7.389 (2.83), 7.435 (6.55), 7.437 (6.28), 7.455 (5.45),7.457 (5.19), 7.474 (6.87), 7.494 (8.62), 7.547 (4.32), 7.551 (4.10), 7.569(2.55),7.573 (2.43), 8.662 (1.99), 8.677 (3.85), 8.690 (1.92), 12.041(3.75).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.68 (t, 1H), 7.56 (dd, 1H), 7.52-7.40(m, 4H), 7.37 (t, 1H), 7.31-7.23 (m, 1H), 3.78-3.48 (m, 7H), 2.22-1.98 (m,6H), 1.93-1.75 (m, 5H)。

Separation of enantiomers:

the title compound (220 mg) was dissolved in methanol (15 ml), filtered and separated into enantiomers on the chiral phase by preparative SFC (see examples 34 and 35) [ column: daicel Chiralcel OX-H, 5 μm,250 mm x20 mm, flow rate: 80 ml/min, detection: 210 nm, temperature: injection at 40 ℃: 0.15 ml, eluent 35% methanol/65% carbon dioxide, running time 5min, isocratic. The combined target fractions were concentrated and the residue was lyophilized.

Example 34

(-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(enantiomer 1)

In the enantiomeric separation described in example 33, the title compound was obtained as a previously purified enantiomer eluting earlier (ee value 99%). Followed by repurification by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was dried in vacuo. 35 mg (98% purity) of the repurified title compound are obtained.

[α]_D ²⁰= 11.4 °, 589 nm, c = 0.30 g/100 ml, methanol

LC-MS (method 1) R_t= 1.49 min; MS (ESIpos): m/z = 544/546 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.811 (2.39), 1.835 (4.10), 1.871(16.00), 2.043 (5.13), 2.076 (6.19), 2.086 (6.23), 2.134 (4.98), 2.158(13.15), 2.286 (0.46), 2.328 (1.03), 2.366 (0.61), 2.670 (1.10), 2.710(0.68), 3.567 (13.61), 3.656 (3.65), 7.251 (2.39), 7.268 (5.05), 7.287(3.69), 7.352 (3.53), 7.370 (6.08), 7.388 (3.80), 7.435 (8.06), 7.455 (6.95),7.466 (9.27), 7.474 (6.88), 7.488 (14.78), 7.543 (7.22), 7.548 (6.31), 7.565(4.14), 7.570 (3.76), 8.661 (2.89), 8.676 (5.21), 8.690 (2.58), 12.038(0.57).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.04 (br. s, 1H), 8.68 (t, 1H), 7.55(dd, 1H), 7.52-7.40 (m, 4H), 7.37 (t, 1H), 7.31-7.23 (m, 1H), 3.77-3.48 (m,7H), 2.24-1.97 (m, 6H), 1.95-1.75 (m, 5H)。

The method B comprises the following steps:

to (-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester (2.11 g, 3.51 mmol,Enantiomer 2Example 293A) in dichloromethane (27 ml) TFA (6.0 ml, 77.24 mmol) was added and the mixture was left to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 1.44 g (100% purity, 75% of theory) of the title compound are obtained.

[α]_D ²⁰= 13.1 °, 589 nm, c = 0.32 g/100 ml, methanol

LC-MS (method 1) R_t= 1.44 min; MS (ESIpos): m/z = 544/546 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.795 (0.23), 1.814 (0.53), 1.837(0.93), 1.871 (3.68), 2.026 (0.28), 2.046 (1.18), 2.079 (1.39), 2.089 (1.41),2.110 (0.55), 2.118 (0.54), 2.137 (1.15), 2.160 (3.09), 3.316 (16.00), 3.658(0.81), 7.251 (0.50), 7.269 (1.13), 7.289 (0.82), 7.352 (0.77), 7.371 (1.38),7.389 (0.85), 7.437 (1.84), 7.457 (1.53), 7.469 (1.47), 7.477 (1.68), 7.491(2.55), 7.545 (1.30), 7.549 (1.32), 7.567 (0.78), 7.571 (0.80), 8.661 (0.60),8.675 (1.17), 8.689 (0.60), 12.039 (1.84)。

Example 35

(+) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(enantiomer 2)

The method A comprises the following steps:

in the enantiomeric separation described in example 33, the title compound was obtained as a previously purified enantiomer (ee value 93%) which eluted later. Followed by repurification by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was dried in vacuo. 37 mg (98% purity) of the repurified title compound are obtained.

[α]_D ²⁰= 11.4 °, 589 nm, c = 0.29 g/100 ml, methanol

LC-MS (method 1) R_t= 1.49 min; MS (ESIpos): m/z = 544/546 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.794 (1.17), 1.811 (2.44), 1.836(4.11), 1.872 (16.00), 2.045 (5.39), 2.078 (6.39), 2.088 (6.44), 2.117(2.50), 2.136 (5.11), 2.159 (13.11), 2.241 (0.50), 2.288 (0.50), 2.327(0.83), 2.366 (0.67), 2.670 (0.83), 2.710 (0.67), 3.570 (13.00), 3.656(3.56), 7.251 (2.33), 7.269 (5.06), 7.287 (3.61), 7.352 (3.56), 7.371 (6.17),7.389 (3.78), 7.435 (8.33), 7.437 (8.00), 7.455 (6.94), 7.457 (6.67), 7.473(8.39), 7.493 (11.33), 7.546 (5.61), 7.551 (5.22), 7.568 (3.33), 7.573(3.17), 8.661 (2.72), 8.676 (5.11), 8.689 (2.56), 12.040 (3.78).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.04 (br. s, 1H), 8.68 (t, 1H), 7.59-7.53 (m, 1H), 7.53-7.40 (m, 4H), 7.37 (t, 1H), 7.30-7.23 (m, 1H), 3.79-3.48(m, 7H), 2.21-2.00 (m, 6H), 1.92-1.77 (m, 5H)。

The method B comprises the following steps:

to (4R) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester (2.16 g, 3.59 mmol,enantiomer 1Example 292A) in dichloromethane (28 ml) TFA (6.1 ml, 79.07 mmol) was added and the mixture was left to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 1.37 g (100% purity, 70% of theory) of the title compound are obtained. For the starting compound, the R configuration was determined by VCD spectroscopy (see example 292A) and thus the title compound also has the R configuration.

[α]_D ²⁰= 11.3 °, 589 nm, c = 0.30 g/100 ml, methanol

LC-MS (method 1) R_t= 1.44 min; MS (ESIpos): m/z = 544/546 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.784 (0.16), 1.795 (0.23), 1.813(0.53), 1.837 (0.95), 1.870 (3.74), 2.026 (0.28), 2.046 (1.18), 2.079 (1.40),2.089 (1.42), 2.110 (0.56), 2.118 (0.55), 2.137 (1.18), 2.159 (3.13), 3.315(16.00), 3.658 (0.81), 7.249 (0.49), 7.268 (1.13), 7.287 (0.82), 7.352(0.77), 7.370 (1.38), 7.388 (0.85), 7.435 (1.80), 7.455 (1.49), 7.467 (1.84),7.475 (1.60), 7.489 (3.11), 7.543 (1.54), 7.548 (1.45), 7.565 (0.91), 7.570(0.88), 8.660 (0.62), 8.674 (1.23), 8.688 (0.62), 12.038 (2.54)。

Example 36

5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpyrrolidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(mixture of diastereomers)

To 5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpyrrolidin-1-yl)]Quinolin-4-yl } carbonyl) amino]Tert-butyl 4- (2-chlorophenyl) valerate (25 mg, 40.6. mu. mol,mixtures of diastereomersExample 80A) in dichloromethane (1.0ml) was added TFA (31 μ l,410 μmol), and the mixture was stirred at room temperature overnight. Then, TFA (31 μ l,410 μmol) was added again, and the mixture was stirred at room temperature for another 24 h. Then, TFA (31 μ l,410 μmol) was added again, and the mixture was stirred at 60 ℃ for another 6 h. Then, TFA (31 μ l,410 μmol) was added again, and the mixture was stirred at 60 ℃ for another 8 h. The mixture was then concentrated and dichloromethane was repeatedly added, followed by concentration again. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 7mg (98% purity, 31% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 1.59 min; MS (ESIpos): m/z = 560 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (0.99), -0.008 (14.17), 0.008(8.09), 0.062 (1.26), 0.146 (1.04), 1.059 (16.00), 1.075 (15.93), 1.235(1.80), 1.367 (2.66), 1.472 (1.69), 1.494 (2.37), 1.522 (1.83), 1.806 (2.03),1.827 (2.59), 1.851 (1.76), 2.029 (6.85), 2.057 (7.53), 2.114 (3.25), 2.159(12.03), 2.237 (2.23), 2.327 (1.40), 2.366 (0.95), 2.670 (1.78), 2.689(10.39), 2.709 (1.31), 2.731 (5.54), 2.890 (6.63), 3.209 (2.70), 3.230(4.30), 3.592 (4.55), 3.653 (6.72), 7.264 (3.47), 7.283 (2.64), 7.363 (4.26),7.372 (3.74), 7.433 (8.11), 7.460 (8.29), 7.482 (12.53), 7.539 (6.04), 7.561(3.58), 7.951 (0.86), 8.699 (3.61).

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 8.74-8.65 (m,1H), 7.59-7.51 (m,1H), 7.51-7.40 (m,4H), 7.40-7.33 (m,1H), 7.31-7.22 (m,1H), 3.76-3.52 (m,6H), 3.28-3.17 (m,1H, partial coverage), 2.29-1.97 (m, 8H), 1.90-1.76 (m,1H), 1.58-1.42(m, 1H), 1.07 (d, 3H).

Example 37

(+/-) -5- ({ [ 6-bromo-2- (3, 3-difluoropyrrolidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(raceme)

To (+/-) -5- ({ [ 6-bromo-2- (3, 3-difluoropyrrolidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester (30 mg, 47.1 μmol,racemic modificationExample 81A) was added to a dichloromethane (1.0ml) solution of TFA (36 μ l, 470 μmol), and the mixture was stirred at room temperature overnight. Then, TFA (31 μ l,410 μmol) was added again, and the mixture was stirred at room temperature for another 24 h. Then, TFA (31 μ l,410 μmol) was added again, and the mixture was stirred at 60 ℃ for another 6 h. Then, TFA (31 μ l,410 μmol) was added again, and the mixture was stirred at 60 ℃ for another 8 h. The mixture was then concentrated and dichloromethane was repeatedly added, followed by concentration again. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 12mg (98% purity, 44% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.11 min; MS (ESIpos): m/z = 580/582 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.00), -0.008 (8.49), 0.008(8.89), 0.049 (0.70), 0.063 (1.25), 0.146 (1.05), 0.943 (1.12), 0.960 (1.05),1.235 (0.75), 1.813 (2.12), 1.836 (3.07), 1.860 (1.72), 2.041 (5.02), 2.071(6.34), 2.082 (6.27), 2.104 (2.65), 2.130 (4.19), 2.165 (12.61), 2.327(1.40), 2.366 (0.92), 2.421 (1.70), 2.440 (3.49), 2.457 (4.82), 2.475 (7.21),2.523 (5.14), 2.669 (1.50), 2.689 (10.68), 2.709 (1.05), 2.731 (5.17), 2.890(6.34),3.584 (2.77), 3.671 (3.42), 3.781 (5.62), 3.965 (3.17), 7.253 (2.12),7.271 (4.89), 7.290 (3.59), 7.354 (3.10), 7.372 (5.57), 7.391 (3.17), 7.437(8.89), 7.440 (8.96), 7.457 (7.54), 7.460 (7.51), 7.480 (6.99), 7.497 (5.12),7.568 (8.01), 7.590 (16.00), 7.628 (8.79), 7.633 (8.11), 7.650 (4.27), 7.655(4.19), 7.952 (0.85), 8.699 (2.67), 8.712 (5.19), 8.726 (2.70).

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 12.04 (br. s, 1H), 8.71 (t, 1H), 7.64(dd, 1H), 7.58 (d, 1H), 7.52-7.42 (m, 3H), 7.37 (t, 1H), 7.31-7.23 (m,1H), 4.11-3.87 (m, 2H), 3.85-3.50 (m, 5H), 2.51-2.40 (m, 2H, mask), 2.23-1.96 (m,6H), 1.90-1.74 (m, 1H).

Example 38

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (1, 2-oxazolidin-2-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(raceme)

To (+) -5- ({ [ 6-bromo-3-methyl-2- (1, 2-oxazolidin-2-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester (110 mg, 182 μmol,racemic modificationExample 82A) in dichloromethane (1.3 ml) TFA (140 μ l, 1.8 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 80 mg (98% purity, 79% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 1.83 min; MS (ESIpos): m/z = 546/548 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.94), 0.008 (1.90), 1.782(0.41), 1.793 (0.66), 1.814 (1.34), 1.835 (1.71), 1.858 (0.99), 2.033 (0.92),2.045 (3.57), 2.073 (2.81), 2.081 (3.16), 2.093 (3.30), 2.121 (1.33), 2.129(1.23), 2.141 (2.11), 2.164 (1.10), 2.210 (7.16), 2.240 (4.55), 2.257 (5.85),2.276 (4.31), 2.294 (1.35), 3.604 (1.49), 3.651 (0.90), 3.670 (1.66), 3.684(2.28), 3.698 (2.02), 3.714 (1.56), 3.771 (3.06), 3.822 (4.25), 3.840 (7.28),3.859 (3.97), 7.257 (1.29), 7.275 (2.94), 7.293 (2.07), 7.356 (1.72), 7.375(3.14), 7.393 (1.64), 7.445 (4.53), 7.447 (4.50), 7.465 (3.83), 7.467 (3.73),7.486 (3.85), 7.502 (3.01), 7.707 (0.71), 7.729 (16.00), 7.756 (0.60), 8.767(1.66), 8.782 (3.27), 8.796 (1.64), 12.043 (3.12).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.04 (s, 1H), 8.78 (t, 1H), 7.78-7.69(m, 2H), 7.53 (br. s, 1H), 7.51-7.43 (m, 2H), 7.37 (t, 1H), 7.31-7.24 (m,1H), 3.84 (t, 2H), 3.81-3.52 (m, 5H), 2.31-1.99 (m, 8H), 1.90-1.74 (m, 1H)。

Separation of enantiomers:

the title compound (70 mg) was dissolved in a mixture of isopropanol (2 ml) and heptane (2 ml) and separated by preparative HPLC on the chiral phase into enantiomers (see examples 39 and 40) [ column: daicel Chiralpak ID, 5 μm,250 mm x 20 mm, flow rate: 15 ml/min, injection: 0.4 ml, eluent 50% isopropanol/50% (heptane + 0.2% TFA), run time 13 min, isocratic. The combined target fractions were concentrated and the residue was lyophilized.

Example 39

(-) -5- ({ [ 6-bromo-3-methyl-2- (1, 2-oxazolidin-2-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(enantiomer 1)

In the enantiomeric separation described in example 38, the title compound was obtained as a previously purified enantiomer eluting earlier (ee value 99%). And then purified again by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water. 39 mg (98% purity) of the repurified title compound are obtained.

[α]_D ²⁰= 8.0 °, 589 nm, c = 0.30 g/100 ml, methanol

LC-MS (method 2) R_t= 0.94 min; MS (ESIpos): m/z = 546/548 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.87), -0.008 (7.75), 0.008(6.54), 0.146 (0.84), 1.809 (1.24), 1.832 (1.61), 1.856 (0.90), 2.039 (2.88),2.073 (3.07), 2.084 (2.79), 2.133 (1.83), 2.209 (6.54), 2.240 (4.16), 2.257(5.49), 2.276 (4.09), 2.294 (1.27), 2.327 (1.27), 2.366 (1.27), 2.523 (3.57),2.669 (1.36), 2.710 (1.27), 3.600 (1.43), 3.667 (1.55), 3.682 (2.14), 3.697(1.86), 3.771 (2.82), 3.822 (4.09), 3.840 (6.98), 3.859 (3.88), 7.256 (1.27),7.274 (2.79), 7.292 (1.98), 7.355 (1.58), 7.374 (2.95), 7.392 (1.55), 7.444(4.43), 7.464 (3.78), 7.484 (3.53), 7.501 (2.79), 7.707 (0.68), 7.729(16.00), 8.777 (1.33), 8.791 (2.73), 8.805 (1.43)。

Example 40

(+) -5- ({ [ 6-bromo-3-methyl-2- (1, 2-oxazolidin-2-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(enantiomer 2)

In the enantiomeric separation described in example 38, the title compound was obtained as a previously purified enantiomer (ee value 97%) which eluted later. Followed by repurification by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water. 30 mg (98% purity) of the repurified title compound are obtained.

[α]_D ²⁰= 14.0 °, 589 nm, c = 0.25 g/100 ml, methanol

LC-MS (method 2) R_t= 0.94 min; MS (ESIpos): m/z = 546/548 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.52), 0.146 (0.52), 1.790(0.55), 1.808 (1.29), 1.831 (1.85), 1.854 (0.98), 2.014 (0.69), 2.036 (2.96),2.067 (3.48), 2.078 (3.21), 2.088 (2.20), 2.102 (1.35), 2.128 (2.06), 2.152(0.94), 2.211 (7.24), 2.240 (4.66), 2.258 (6.01), 2.276 (4.41), 2.294 (1.36),2.327 (0.74), 2.366 (0.66), 2.670 (0.77), 2.710 (0.69), 3.595 (1.54), 3.648(0.94), 3.667 (1.68), 3.681 (2.27), 3.695 (2.04), 3.712 (1.60), 3.732 (1.47),3.772 (3.13), 3.822 (4.34), 3.841 (7.47), 3.859 (4.08), 7.256 (1.29), 7.274(2.92), 7.294 (2.04), 7.355 (1.74), 7.373 (3.20), 7.392 (1.67), 7.446 (4.48),7.466 (3.78), 7.483 (3.92), 7.502 (3.00), 7.707 (0.67), 7.729 (16.00), 7.756(0.66), 8.784 (1.45), 8.799 (2.85), 8.812 (1.52)。

EXAMPLE 41

5- [ ({ 6-bromo-2- [ 3-methoxypyrrolidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(mixture of diastereomers)

To 5- ({ [ 6-bromo-2- (3-methoxypyrrolidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid butyl ester (30 mg, 47.5 μmol,mixtures of diastereomersExample 83A) in dichloromethane (1.0ml) was added TFA (37 μ l, 480 μmol), and the mixture was stirred at room temperature overnight. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 10 mg (98% purity, 37% of theory) of the title compound are obtained.

LC-MS (method 2) R_t= 0.80 min; MS (ESIpos): m/z= 574/576 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.41), 0.008 (1.36), 1.812(0.64), 1.834 (0.89), 1.858 (0.55), 1.954 (0.60), 2.018 (1.00), 2.040 (1.85),2.068 (2.03), 2.079 (1.86), 2.103 (0.85), 2.129 (1.23), 2.158 (3.82), 2.523(0.81), 3.199 (0.60), 3.245 (16.00), 3.417 (0.42), 3.511 (1.14), 3.551(0.87), 3.572 (0.89), 3.591 (0.88), 3.659 (0.88), 3.714 (0.98), 3.778 (0.79),3.807 (0.63), 4.017 (1.34), 7.245 (0.44), 7.263 (0.96), 7.275 (0.93), 7.293(0.63), 7.346 (0.69), 7.364 (1.23), 7.378 (1.10), 7.395 (0.66), 7.435 (2.45),7.437 (2.36), 7.455 (2.05), 7.457 (1.93), 7.478 (2.83), 7.500 (3.63), 7.556(1.97), 7.561 (1.29), 7.579 (1.19), 8.694 (1.08).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.05 (br. s, 1H), 8.69 (br. s, 1H),7.62-7.53 (m, 1H), 7.53-7.41 (m, 4H), 7.40-7.33 (m, 1H), 7.31-7.22 (m, 1H),4.02 (br. s, 1H), 3.84-3.46 (m, 7H), 3.24 (s, 3H), 2.22-1.77 (m, 9H)。

Example 42

(+/-) -5- ({ [ 6-bromo-2- (3, 3-dimethylpiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(raceme)

To (+/-) -5- ({ [ 6-bromo-2- (3, 3-dimethylpiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester (80 mg, 124 μmol,racemic modificationExample 84A) in dichloromethane (910 μ l) TFA (96 μ l,1.2 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 65 mg (98% purity, 87% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.43 min; MS (ESIpos): m/z = 586/588 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.007 (16.00), 1.377 (1.50), 1.386(2.45), 1.392 (2.05), 1.723 (2.48), 1.731 (2.30), 1.740 (1.95), 1.753 (1.20),1.762 (0.78), 1.818 (0.64), 1.829 (0.83), 1.839 (0.50), 1.919 (0.68), 1.929(0.67), 2.182 (3.52), 2.386 (0.52), 2.614 (0.58), 2.868 (3.61), 3.043 (1.14),3.476 (0.92), 3.635 (0.64), 7.232 (0.61), 7.244 (1.47), 7.256 (1.05), 7.339(0.71), 7.351 (1.38), 7.364 (0.79), 7.420 (2.16), 7.433 (2.83), 7.442 (1.31),7.632 (0.62), 7.646 (4.36), 7.668 (0.51), 9.138 (0.94).

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 9.14 (br. s, 1H), 7.69-7.60 (m, 2H),7.48 (br. s, 1H), 7.45-7.40 (m, 2H), 7.35 (t, 1H), 7.27-7.21 (m, 1H), 3.64(br. s, 2H), 3.52-3.44 (m, 1H), 3.04 (br. s, 2H), 2.87 (s, 2H), 2.18 (br. s,3H), 1.98-1.88 (m, 1H), 1.87-1.78 (m, 1H), 1.78-1.68 (m, 4H), 1.41-1.34 (m,2H), 1.01 (s, 6H)。

Separation of enantiomers:

the title compound (50 mg) was dissolved in methanol (25 ml) and separated into enantiomers on the chiral phase by preparative SFC (see examples 43 and 44) [ column: daicel Chiralpak AD, 5 μm,250 mm x 20 mm, flow rate: 80 ml/min, injection: 3 ml, eluent 25% isopropanol/75% carbon dioxide, run time 9 min, isocratic. The combined target fractions were concentrated and the residue was lyophilized.

Example 43

(-) -5- ({ [ 6-bromo-2- (3, 3-dimethylpiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(enantiomer 1)

In the enantiomeric separation described in example 42, 10 mg (98% purity, ee value 99%) of the title compound were obtained as the earlier eluting enantiomer.

[α]_D ²⁰= 12.0 °, 589 nm, c = 0.25 g/100 ml, methanol

LC-MS (method 1) R_t= 2.45 min; MS (ESIpos): m/z = 586/588 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.83), 0.008 (3.24), 1.004(16.00), 1.373 (1.13), 1.387 (1.81), 1.402 (1.39), 1.721 (1.36), 1.805(0.50), 1.827 (0.66), 1.850 (0.42), 2.024 (1.09), 2.054 (1.93), 2.070 (1.15),2.106 (0.65), 2.165 (5.23), 2.710 (0.41), 2.864 (4.18), 3.044 (1.53), 3.576(0.67), 3.669 (0.97), 7.253 (0.55), 7.272 (1.28), 7.289 (0.91), 7.353 (0.75),7.371 (1.38), 7.389 (0.74), 7.438 (1.91), 7.440 (1.92), 7.458 (1.75), 7.461(1.78), 7.475 (1.85), 7.491 (1.37), 7.628 (0.41), 7.650 (5.99), 7.655 (2.96),8.762 (0.98).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.15 (br. s, 1H), 8.76 (t, 1H), 7.70-7.61 (m, 2H), 7.58-7.41 (m, 3H), 7.37 (t, 1H), 7.30-7.24 (m, 1H), 3.75-3.62(m, 2H), 3.61-3.54 (m, 1H), 3.04 (br. s, 2H), 2.86 (s, 2H), 2.17 (s, 3H),2.13-1.97 (m, 3H), 1.90-1.77 (m, 1H), 1.76-1.65 (m, 2H), 1.45-1.32 (m, 2H),1.00 (s, 6H)。

Example 44

(+) -5- ({ [ 6-bromo-2- (3, 3-dimethylpiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(enantiomer 2)

In the enantiomeric separation described in example 42, 10 mg (98% purity, ee value 99%) of the title compound are obtained as the enantiomer which elutes later.

[α]_D ²⁰= 9.3 °, 589 nm, c = 0.25 g/100 ml, methanol

LC-MS (method 1) R_t= 2.45 min; MS (ESIpos): m/z = 586/588 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (3.58), 0.008 (3.59), 0.146(0.41), 1.004 (16.00), 1.372 (1.15), 1.386 (1.87), 1.401 (1.40), 1.720(1.37), 1.810 (0.50), 1.833 (0.71), 1.857 (0.42), 2.039 (1.14), 2.067 (1.73),2.122 (0.84), 2.163 (5.31), 2.327 (0.42), 2.669 (0.46), 2.863 (4.18), 3.044(1.59), 3.583 (0.66), 3.673 (1.01), 7.256 (0.55), 7.274 (1.29), 7.291 (0.94),7.355 (0.79), 7.373 (1.42), 7.393 (0.73), 7.440 (2.01), 7.442 (2.03), 7.460(1.83), 7.478 (1.90), 7.495 (1.41), 7.628 (0.41), 7.650 (6.13), 7.655 (3.12),7.678 (0.41), 8.737 (1.17).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.1 (br. s, 1H), 8.74 (t, 1H), 7.71-7.59 (m, 2H), 7.58-7.41 (m, 3H), 7.37 (t, 1H), 7.31-7.23 (m, 1H), 3.76-3.62(m, 2H), 3.62-3.53 (m, 1H), 3.04 (br. s, 2H), 2.86 (s, 2H), 2.16 (s, 3H),2.14-2.00 (m, 3H), 1.90-1.76 (m, 1H), 1.76-1.67 (m, 2H), 1.43-1.34 (m, 2H),1.00 (s, 6H)。

Example 45

5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(mixture of diastereomers)

To a solution of tert-butyl 5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl ] quinolin-4-yl } carbonyl) amino ] -4- (2-chlorophenyl) pentanoate (100 mg, 159 μmol, mixture of diastereomers, example 85A) in dichloromethane (1.2 ml) was added TFA (120 μ l, 1.6 mmol) and the mixture was stirred at room temperature overnight. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 82 mg (98% purity, 88% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.33 min; MS (ESIpos): m/z = 572/574 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.921 (4.93), 0.936 (4.95), 1.077(0.56), 1.107 (0.57), 1.625 (0.46), 1.654 (0.54), 1.730 (1.03), 1.761 (1.00),1.793 (1.35), 1.821 (1.21), 1.837 (1.07), 1.860 (0.44), 2.049 (1.51), 2.083(1.79), 2.091 (1.94), 2.135 (6.39), 2.160 (0.58), 2.431 (0.42), 2.501(16.00), 2.675 (0.41), 2.709 (0.64), 3.489 (3.11), 3.574 (1.10), 3.591(1.05), 3.677 (1.20), 7.255 (0.62), 7.274 (1.47), 7.292 (1.12), 7.355 (0.86),7.374 (1.53), 7.392 (0.80), 7.441 (2.18), 7.461 (1.95), 7.480 (2.10), 7.499(1.51), 7.626 (0.50), 7.648 (5.52), 8.704 (0.73), 8.719 (1.40), 8.732 (0.68).

H-NMR (400 MHz, DMSO-d6) delta [ ppm ]: 12.05 (br. s, 1H), 8.72 (t, 1H), 7.70-7.61 (m, 2H), 7.58-7.41 (m, 3H), 7.37 (t, 1H), 7.32-7.23 (m,1H), 3.82-3.26(m, 5H, partial coverage), 2.78-2.62 (m,1H), 2.48-2.38 (m,1H, partial coverage), 2.20-1.98(m, 6H), 1.90-1.54 (m, 5H), 1.17-1.01 (m,1H), 0.93 (d, 3H).

Example 46

(-) -5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(diastereomer 1)

To (-) -5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidine-1-radical]Quinolin-4-yl } carbonyl) amino]Tert-butyl 4- (2-chlorophenyl) valerate (185 mg, 294. mu. mol,diastereomer 1Example 86A) in dichloromethane (2.2 ml) was added TFA (230 μ l, 2.9 mmol) and the mixture was left to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water. 117 mg (98% purity, ee value) are obtained>99%, 68% of theory) of the title compound.

[α]_D ²⁰= 20.6 °, 589 nm, c = 0.35 g/100 ml, methanol

LC-MS (method 2) R_t= 1.20 min; MS (ESIpos): m/z = 572/574 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.52), 0.920 (13.64), 0.936(13.90), 1.048 (0.47), 1.077 (1.44), 1.106 (1.50), 1.128 (0.61), 1.234(0.50), 1.589 (0.44), 1.621 (1.24), 1.651 (1.47), 1.679 (0.69), 1.729 (2.53),1.765 (2.53), 1.791 (3.56), 1.821 (3.15), 1.837 (2.76), 1.861 (1.16), 2.016(0.54), 2.029 (0.87), 2.049 (3.74), 2.082 (4.70), 2.090 (5.03), 2.134(16.00), 2.160 (1.56), 2.186 (0.52), 2.419 (1.30), 2.447 (2.04), 2.476(1.42), 2.523 (0.75), 2.682 (1.18), 2.710 (2.27), 2.738 (1.14), 3.439 (2.24),3.460 (3.55), 3.486 (1.99), 3.577 (1.53), 3.593 (1.74), 3.680 (3.29), 7.256(1.62), 7.274 (3.82), 7.291 (2.89), 7.355 (2.22), 7.374 (4.05), 7.392 (2.09),7.441 (5.61), 7.443 (5.48), 7.461 (4.98), 7.463 (4.84), 7.482 (5.43), 7.498(4.02), 7.624 (1.48), 7.647 (14.26), 7.654 (7.96), 7.672 (0.97), 7.676(1.18), 8.700 (1.90), 8.715 (3.84), 8.729 (1.85), 12.043 (2.06).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.04 (br. s, 1H), 8.71 (t, 1H), 7.70-7.60 (m, 2H), 7.53-7.42 (m, 3H), 7.37 (t, 1H), 7.31-7.23 (m, 1H), 3.78-3.63(m, 2H), 3.63-3.52 (m, 1H), 3.51-3.38 (m, 2H), 2.71 (t, 1H), 2.45 (t, 1H),2.21-1.98 (m, 6H), 1.91-1.55 (m, 5H), 1.17-1.02 (m, 1H), 0.93 (d, 3H)。

Example 47

(+) -5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(diastereomer 2)

To (+) -5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]Tert-butyl 4- (2-chlorophenyl) valerate (185 mg, 294. mu. mol,diastereomer 2Example 87A) in dichloromethane (1.6ml) was added TFA (170 μ l, 2.2 mmol) and the mixture was left to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water. 117 mg (98% purity, ee value) are obtained>99%, 68% of theory) of the title compound.

[α]_D ²⁰= 24.9 °, 589 nm, c = 0.34 g/100 ml, methanol

LC-MS (method 2) R_t= 1.20 min; MS (ESIpos): m/z = 572/574 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.59), 0.008 (2.07), 0.921(13.42), 0.937 (13.48), 1.055 (0.46), 1.081 (1.40), 1.105 (1.43), 1.134(0.56), 1.623 (1.22), 1.653 (1.43), 1.682 (0.67), 1.732 (2.48), 1.766 (2.50),1.793 (3.54), 1.814 (2.99), 1.823 (3.07), 1.837 (2.80), 1.861 (1.12), 2.048(3.60), 2.083 (4.54), 2.091 (4.85), 2.136 (16.00), 2.160 (1.50), 2.432(1.28), 2.461 (2.09), 2.524 (0.99), 2.670 (0.41), 2.695 (1.08), 2.724 (1.92),2.752 (1.03), 3.448 (2.22), 3.471 (3.55), 3.497 (1.95), 3.577 (1.64), 3.593(1.85), 3.681 (3.38), 3.973 (1.31), 7.257 (1.61), 7.275 (3.65), 7.292 (2.61),7.295 (2.61), 7.357 (2.19), 7.375 (4.01), 7.394 (2.04), 7.441 (5.78), 7.444(5.83), 7.461 (5.09), 7.464 (5.09), 7.483 (5.41), 7.499 (3.99), 7.634 (1.40),7.657 (14.87), 7.663 (8.60), 7.680 (0.93), 7.685 (1.10), 8.706 (1.85), 8.720(3.73), 8.734 (1.82)。

Example 48

(+) -5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(diastereomer 3)

To (+) -5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]Tert-butyl 4- (2-chlorophenyl) valerate (150 mg, 238 μmol,diastereomer 3Example 88A) in dichloromethane (1.8 ml) TFA (180. mu.l, 2.4 mmol) was added and the mixture was left to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water. 102 mg (100% purity, ee value) are obtained>99%, 74% of theory) of the title compound.

[α]_D ²⁰= 7.5 °, 589 nm, c = 0.38 g/100 ml, methanol

LC-MS (method 2) R_t= 1.20 min; MS (ESIpos): m/z = 572/574 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.921 (11.56), 0.937 (11.71), 1.050(0.44), 1.077 (1.30), 1.106 (1.33), 1.128 (0.54), 1.234 (0.56), 1.626 (1.13),1.657 (1.35), 1.686 (0.66), 1.729 (2.37), 1.760 (2.30), 1.794 (2.97), 1.821(2.75), 1.836 (2.48), 1.860 (1.04), 2.048 (3.26), 2.083 (4.03), 2.090 (4.31),2.104 (2.16), 2.135 (16.00), 2.159 (1.29), 2.429 (1.25), 2.458 (1.97), 2.669(1.11), 2.697 (1.76), 2.726 (0.96), 3.434 (2.04), 3.461 (3.58), 3.492 (1.67),3.592 (1.60), 3.670 (2.24), 7.256 (1.35), 7.274 (3.19), 7.292 (2.26), 7.356(1.92), 7.374 (3.51), 7.392 (1.85), 7.441 (4.84), 7.461 (4.35), 7.480 (4.74),7.499 (3.41), 7.625 (1.11), 7.648 (12.30), 7.654 (6.45), 7.672 (0.76), 7.676(0.88), 8.703 (1.72), 8.717 (3.36), 8.731 (1.65), 12.052 (0.67)。

Example 49

(-) -5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(diastereomer 4)

To (-) -5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]Tert-butyl 4- (2-chlorophenyl) valerate (140 mg, 223 μmol,diastereomer 4Example 89A) in dichloromethane (1.6ml) was added TFA (170 μ l, 2.2 mmol) and the mixture was allowed to stand at room temperature for 30 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized in acetonitrile/water. 78 mg (97% purity, ee value) are obtained>99%, 59% of theory) of the title compound.

[α]_D ²⁰= 17.3 °, 436 nm, c = 0.38 g/100 ml, methanol

LC-MS (method 2) R_t= 1.20 min; MS (ESIpos): m/z = 572/574 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.921 (6.01), 0.936 (6.18), 1.077(0.69), 1.106 (0.70), 1.626 (0.59), 1.657 (0.70), 1.729 (1.24), 1.760 (1.21),1.792 (1.61), 1.812 (1.34), 1.820 (1.42), 1.834 (1.41), 1.858 (0.57), 2.045(1.68), 2.078 (2.14), 2.086 (2.32), 2.134 (8.43), 2.155 (0.82), 2.429 (0.64),2.500 (16.00), 2.669 (0.63), 2.698 (0.92), 2.726 (0.50), 3.433 (1.14), 3.461(1.93), 3.491 (0.91), 3.574 (0.74), 3.590 (0.85), 3.669 (1.16), 7.255 (0.73),7.273 (1.75), 7.292 (1.28), 7.355 (1.03), 7.374 (1.87), 7.392 (0.98), 7.441(2.63), 7.461 (2.35), 7.480 (2.52), 7.498 (1.77), 7.624 (0.61), 7.647 (6.71),7.675 (0.51), 8.705 (0.85), 8.719 (1.68), 8.733 (0.85)。

Example 50

(+/-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(raceme)

To (+/-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester (100 mg, 154 μmol,racemic modificationExample 90A) in dichloromethane (1.1ml) TFA (120 μ l, 1.5 mmol) was added and the mixture was left to stand at room temperature for 16 h. Then concentrating the mixture, anddichloromethane was added again and the mixture was concentrated again. The residue was dissolved in acetonitrile and purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 70mg (98% purity, 75% of theory) of the title compound are obtained.

LC-MS (method 2) R_t= 1.13 min; MS (ESIpos): m/z = 594/596 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.73), 0.008 (2.65), 1.795(0.82), 1.814 (1.76), 1.838 (2.35), 1.881 (4.53), 2.047 (5.28), 2.082 (7.13),2.091 (7.78), 2.150 (16.00), 2.225 (0.40), 2.327 (0.75), 2.366 (0.66), 2.670(0.74), 2.709 (0.63), 3.164 (5.24), 3.447 (3.36), 3.476 (6.42), 3.505 (3.20),3.593 (1.89), 3.686 (3.35), 7.256 (1.75), 7.275 (4.05), 7.293 (2.86), 7.358(2.48), 7.375 (4.44), 7.394 (2.29), 7.443 (6.36), 7.462 (5.35), 7.486 (5.22),7.502 (4.30), 7.673 (2.44), 7.695 (13.97), 7.700 (9.61), 7.705 (8.12), 7.723(1.34), 7.728 (1.56), 8.720 (2.31), 8.734 (4.37), 8.748 (2.09), 12.047(1.44).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.05 (br. s, 1H), 8.73 (t, 1H), 7.76-7.64 (m, 2H), 7.59-7.42 (m, 3H), 7.38 (t, 1H), 7.32-7.22 (m, 1H), 3.80-3.64(m, 2H), 3.63-3.54 (m, 1H), 3.48 (t, 2H), 3.23-3.07 (m, 2H), 2.20-2.00 (m,8H), 1.94-1.74 (m, 3H)。

Example 51

(-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(enantiomer 1)

To 5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester (660 mg, 1.01 mmol,enantiomer 1Example 91A) in dichloromethane (8.0 ml) TFA (1.6ml, 20 mmol) was added and the mixture was left to stand at room temperature for 18 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 479 mg (100% purity, ee value) are obtained>99%, 79% of theory) ofThe title compound.

[α]_D ²⁰= -17.6°, 589 nm, c = 0.39 g/100 ml, DMSO

LC-MS (method 2) R_t= 1.13 min; MS (ESIpos): m/z = 594/596 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.52), -0.008 (6.12), 0.008(4.60), 0.146 (0.48), 1.797 (0.95), 1.815 (1.92), 1.838 (2.60), 1.881 (4.78),2.048 (5.58), 2.083 (7.57), 2.092 (8.27), 2.150 (16.00), 2.327 (0.76), 2.366(0.59), 2.669 (0.62), 2.710 (0.52), 3.162 (5.51), 3.447 (3.52), 3.476 (6.45),3.504 (3.21), 3.596 (2.04), 3.686 (3.52), 7.258 (1.92), 7.276 (4.03), 7.296(2.81), 7.358 (2.54), 7.377 (4.41), 7.395 (2.25), 7.442 (6.36), 7.445 (6.48),7.462 (5.42), 7.465 (5.37), 7.486 (5.36), 7.503 (4.30), 7.673 (2.60), 7.695(13.64), 7.700 (10.23), 7.705 (8.55), 7.723 (1.42), 7.728 (1.67), 8.719(2.31), 8.734 (4.43), 8.748 (2.10), 12.048 (3.00)。

Example 52

(+) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(enantiomer 2)

To 5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester (620 mg, 952 μmol,enantiomer 2Example 92A) in dichloromethane (8.0 ml) TFA (1.5ml, 19 mmol) was added and the mixture was left to stand at room temperature for 18 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 397 mg (100% purity, ee 98%, 70% of theory) of the title compound are obtained.

[α]_D ²⁰= +12.1°, 589 nm, c = 0.37 g/100 ml, DMSO

LC-MS (method 2) R_t= 1.13 min; MS (ESIpos): m/z = 594/596 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (3.83), 0.008 (3.53), 0.146(0.41), 1.784 (0.53), 1.795 (0.82), 1.814 (1.73), 1.837 (2.38), 1.881 (4.61),2.013 (0.53), 2.047 (5.23), 2.082 (7.24), 2.090 (7.79), 2.110 (4.09), 2.150(16.00), 2.327 (0.51), 2.366 (0.50), 2.670 (0.53), 2.709 (0.51), 3.163(5.34), 3.447 (3.40), 3.476 (6.48), 3.504 (3.25), 3.594 (1.94), 3.685 (3.39),7.258 (1.69), 7.275 (3.92), 7.293 (2.77), 7.358 (2.34), 7.376 (4.30), 7.393(2.26), 7.442 (6.13), 7.445 (5.76), 7.462 (5.14), 7.465 (4.75), 7.486 (5.18),7.503 (4.26), 7.673 (2.10), 7.695 (13.05), 7.700 (9.57), 7.705 (8.01), 7.723(1.37), 7.728 (1.62), 8.720 (2.18), 8.734 (4.42), 8.748 (2.14), 12.051(1.27)。

Example 53

5- [ ({ 6-bromo-3-methyl-2- [3- (trifluoromethyl) piperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(mixture of diastereomers)

To 5- [ ({ 6-bromo-3-methyl-2- [3- (trifluoromethyl) piperidin-1-yl group)]Quinolin-4-yl } carbonyl) amino]Tert-butyl 4- (2-chlorophenyl) valerate (156 mg, 228 μmol,mixtures of diastereomersExample 93A) in dichloromethane (1.7ml) TFA (180 μ l, 2.3 mmol) was added and the mixture was stirred at room temperature for 16 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 89 mg (98% purity, 61% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.33 min; MS (ESIpos): m/z = 626/628 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.367 (0.99), 1.466 (0.45), 1.487(1.20), 1.496 (1.31), 1.517 (1.47), 1.525 (1.47), 1.547 (0.69), 1.555 (0.65),1.656 (1.14), 1.680 (1.14), 1.815 (3.30), 1.838 (2.92), 2.004 (1.84), 2.034(2.50), 2.048 (3.94), 2.083 (3.91), 2.092 (4.19), 2.140 (13.11), 2.753(1.91), 2.871 (1.12), 2.900 (1.56), 2.926 (0.80), 3.482 (1.80), 3.513 (1.67),3.599 (1.70), 3.686 (2.90), 3.713 (3.39), 3.742 (2.39), 7.255 (1.45), 7.274(3.31), 7.292 (2.33), 7.356 (2.00), 7.375 (3.62), 7.393 (1.90), 7.440 (4.78),7.459 (4.01), 7.487 (4.49), 7.506 (3.81), 7.668 (0.50), 7.689 (16.00), 8.714(1.66), 8.727 (3.04), 8.741 (1.61), 12.057 (0.83)。

Example 54

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (4-methylpiperazin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(raceme)

To (+/-) -5- ({ [ 6-bromo-3-methyl-2- (4-methylpiperazin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester (135 mg, 214 μmol,racemic modificationExample 94A) in dichloromethane (1.6ml) TFA (170 μ l, 2.1 mmol) was added and the mixture was stirred at room temperature for 16 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 115 mg (98% purity, 92% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 1.23 min; MS (ESIpos): m/z = 573/575 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.30), 0.008 (2.32), 1.784(0.56), 1.795 (0.95), 1.815 (1.86), 1.837 (2.38), 1.861 (1.34), 2.034 (1.33),2.046 (5.04), 2.082 (4.92), 2.092 (5.43), 2.104 (2.68), 2.143 (16.00), 2.236(0.40), 2.328 (0.48), 2.366 (0.50), 2.524 (3.16), 2.670 (0.68), 2.710 (0.66),2.923 (3.22), 3.599 (2.22), 3.650 (1.13), 3.670 (2.61), 3.684 (4.10), 3.699(3.14), 7.254 (1.94), 7.274 (4.49), 7.293 (3.29), 7.356 (2.73), 7.374 (4.99),7.392 (2.56), 7.441 (7.40), 7.444 (6.82), 7.461 (6.18), 7.464 (5.59), 7.484(5.88), 7.487 (5.82), 7.503 (4.97), 7.664 (2.93), 7.686 (13.99), 7.694(9.19), 7.699 (7.80), 7.717 (1.75), 7.721 (1.89), 8.719 (2.52), 8.734 (5.03),8.748 (2.36)。

Example 55

5- [ ({ 6-bromo-2- [ 3-hydroxypiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(mixture of diastereomers)

To 5- [ ({ 6-bromo-2- [ 3-hydroxypiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]Tert-butyl 4- (2-chlorophenyl) valerate (154 mg, 244. mu. mol,mixtures of diastereomersExample 95A) in dichloromethane (1.8 ml) was added TFA (190 μ l, 2.4 mmol) and the mixture was allowed to stand at room temperature for 16 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 55 mg (98% purity, 38% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 1.71 min; MS (ESIpos): m/z = 574/576 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (3.27), 0.008 (3.32), 0.146(0.42), 1.284 (0.43), 1.295 (0.55), 1.315 (1.31), 1.347 (1.48), 1.368 (0.70),1.378 (0.62), 1.576 (1.16), 1.604 (1.23), 1.775 (1.85), 1.783 (1.97), 1.795(1.76), 1.810 (2.61), 1.835 (2.19), 1.857 (1.20), 1.882 (0.40), 1.913 (1.55),1.922 (1.62), 1.944 (1.55), 2.044 (3.61), 2.078 (4.46), 2.086 (4.74), 2.133(16.00), 2.156 (1.71), 2.327 (0.48), 2.366 (0.49), 2.523 (1.40), 2.631(1.40), 2.664 (1.04), 2.710 (0.51), 2.745 (0.93), 2.775 (1.64), 2.804 (0.95),3.357 (2.61), 3.388 (1.92), 3.512 (2.02), 3.543 (1.94), 3.593 (1.70), 3.682(4.41), 4.864 (1.31), 7.256 (1.56), 7.274 (3.58), 7.294 (2.49), 7.355 (2.13),7.374 (3.85), 7.393 (2.01), 7.441 (5.79), 7.444 (5.77), 7.461 (5.11), 7.464(5.07), 7.481 (5.24), 7.501 (3.83), 7.619 (3.18), 7.642 (11.39), 7.654(7.20), 7.659 (6.40), 7.676 (1.90), 7.682 (1.95), 8.721 (1.91), 8.735 (3.83),8.749 (1.84)。

Example 56

5- [ ({2- [ 3-aminopiperidin-1-yl)]-6-bromo-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(mixture of diastereomers)

To 5- { [ (6-bromo-2- {3- [ (tert-butoxycarbonyl) amino group]Piperidin-1-yl } -3-methylquinolin-4-yl) carbonyl]Tert-butyl amino } -4- (2-chlorophenyl) valerate (162 mg, 222 μmol,mixtures of diastereomersExample 96A) in dichloromethane (1.6ml) TFA (170 μ l, 2.2 mmol) was added and the mixture was left to stand at room temperature for 16 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 38 mg (98% purity, 29% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 1.27 min; MS (ESIpos): m/z = 573/575 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.47), -0.008 (4.19), 0.008(4.66), 0.146 (0.47), 1.442 (1.31), 1.469 (1.48), 1.676 (1.39), 1.836 (4.04),1.859 (2.54), 1.961 (1.72), 1.985 (1.67), 2.043 (3.81), 2.074 (5.01), 2.081(5.07), 2.129 (2.81), 2.164 (16.00), 2.327 (0.88), 2.366 (0.73), 2.670(0.84), 2.710 (0.82), 2.875 (1.93), 3.228 (2.34), 3.303 (2.21), 3.578 (3.96),3.671 (3.59), 3.685 (3.79), 7.257 (1.85), 7.276 (4.22), 7.295 (2.95), 7.356(2.51), 7.375 (4.55), 7.393 (2.37), 7.444 (6.60), 7.463 (5.53), 7.484 (5.50),7.504 (4.53), 7.647 (4.15), 7.669 (12.29), 7.686 (7.15), 7.691 (6.32), 7.709(2.23), 7.713 (2.15), 8.751 (1.26), 8.765 (2.72), 8.782 (2.10)。

Example 57

(+/-) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(mixture of diastereomers)

To 5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]Tert-butyl 4- (2-chlorophenyl) valerate (157 mg, 244. mu. mol,mixtures of diastereomersExample 97A) in dichloromethane (1.8 ml) TFA (190 μ l, 2.4 mmol) was added and the mixture was left to stand at room temperature for 16 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 93 mg (98% purity, 64% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.43 min; MS (ESIpos): m/z = 586/588 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.890 (7.22), 0.909 (15.43), 0.927(7.98), 1.033 (0.70), 1.062 (1.77), 1.085 (1.79), 1.114 (0.79), 1.239 (1.58),1.256 (3.34), 1.274 (4.29), 1.291 (3.01), 1.563 (2.10), 1.598 (1.87), 1.631(1.58), 1.745 (2.50), 1.780 (2.02), 1.814 (2.13), 1.837 (3.69), 1.876 (2.18),2.049 (4.75), 2.080 (5.39), 2.093 (6.18), 2.124 (14.79), 2.163 (1.56), 2.367(0.47), 2.426 (1.73), 2.710 (1.27), 2.738 (1.77), 3.493 (3.77), 3.516 (3.09),3.596 (2.29), 3.678 (3.79), 7.252 (1.99), 7.271 (4.31), 7.290 (2.97), 7.354(2.63), 7.373 (4.57), 7.392 (2.44), 7.437 (6.02), 7.457 (5.32), 7.483 (6.32),7.502 (4.67), 7.624 (1.86), 7.647 (16.00), 7.676 (1.20), 8.699 (2.34), 8.713(4.23), 8.727 (2.09).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 11.86 (br. s, 1H), 8.71 (t, 1H), 7.71-7.59 (m, 2H), 7.56-7.42 (m, 3H), 7.37 (t, 1H), 7.27 (t, 1H), 3.78-3.43 (m,5H), 2.82-2.61 (m, 1H), 2.48-2.34(m, 1H), 2.21-1.97 (m, 6H), 1.94-1.69 (m,3H), 1.68-1.46 (m, 2H), 1.37-1.18 (m, 2H), 1.16-0.98 (m, 1H), 0.91 (t, 3H)。

Example 58

(+) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolineLin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(diastereomer 1)

To (+) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]Tert-butyl 4- (2-chlorophenyl) valerate (180 mg, 280. mu. mol,diastereomer 1Example 98A) in dichloromethane (2.4 ml) was added TFA (470 μ l, 6.2 mmol) and the mixture was left to stand at room temperature for 18 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 139 mg (100% purity, 85% of theory) of the title compound are obtained.

[α]_D ²⁰= 4.8 °, 589 nm, c = 0.42 g/100 ml, methanol

LC-MS (method 1) R_t= 2.45 min; MS (ESIpos): m/z = 586/588 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.892 (6.73), 0.910 (16.00), 0.929(8.30), 1.034 (0.54), 1.064 (1.47), 1.093 (1.52), 1.115 (0.67), 1.240 (1.18),1.257 (2.88), 1.275 (3.82), 1.292 (2.63), 1.563 (1.82), 1.598 (1.77), 1.629(1.43), 1.658 (0.62), 1.746 (2.07), 1.780 (1.69), 1.812 (1.62), 1.837 (2.98),1.855 (2.28), 1.876 (1.78), 2.025 (0.94), 2.046 (3.88), 2.080 (4.53), 2.091(5.07), 2.114 (11.74), 2.138 (3.29), 2.162 (1.21), 2.390 (0.94), 2.418(1.59), 2.445 (0.97), 2.713 (1.14), 2.742 (2.05), 2.772 (1.11), 3.475 (2.07),3.498 (3.51), 3.520 (2.33), 3.596 (1.74), 3.678 (3.39), 3.693 (2.66), 7.252(1.52), 7.271 (3.65), 7.289 (2.67), 7.353 (2.16), 7.372 (3.99), 7.390 (2.07),7.436 (5.20), 7.456 (4.37), 7.484 (5.31), 7.502 (4.33), 7.624 (1.33), 7.647(13.21), 7.676 (1.03), 8.697 (1.87), 8.711 (3.78), 8.725 (1.91), 12.043(4.25)。

Example 59

(-) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(diastereomer 2)

To (-) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinoline-4-yl } carbonyl) amino]Tert-butyl 4- (2-chlorophenyl) valerate (200 mg, 311. mu. mol,diastereomer 2Example 99A) in dichloromethane (2.6ml) was added TFA (530 μ l, 6.8 mmol) and the mixture was allowed to stand at room temperature for 18 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 143 mg (100% purity, 78% of theory) of the title compound are obtained.

[α]_D ²⁰= 26.0 °, 589 nm, c = 0.38 g/100 ml, methanol

LC-MS (method 1) R_t= 2.45 min; MS (ESIpos): m/z = 586/588 [M+H]⁺

Example 60

(-) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(diastereomer 3)

To (-) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]Tert-butyl 4- (2-chlorophenyl) valerate (420 mg, 650. mu. mol,diastereomer 3EXAMPLE 100A) in methylene chloride (5.5ml)To the solution was added TFA (1.1ml, 14 mmol), and the mixture was allowed to stand at room temperature for 18 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 348 mg (100% purity, 91% of theory) of the title compound are obtained.

[α]_D ²⁰= 5.1 °, 589 nm, c = 0.48 g/100 ml, methanol

LC-MS (method 1) R_t= 2.45 min; MS (ESIpos): m/z = 586/588 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.891 (6.76), 0.910 (16.00), 0.928(8.20), 1.034 (0.55), 1.063 (1.49), 1.085 (1.52), 1.093 (1.51), 1.114 (0.67),1.239 (1.17), 1.257 (2.87), 1.274 (3.81), 1.292 (2.60), 1.563 (1.83), 1.597(1.73), 1.629 (1.44), 1.660 (0.62), 1.745 (2.09), 1.779 (1.67), 1.812 (1.63),1.836 (3.03), 1.853 (2.24), 1.876 (1.77), 2.013 (0.54), 2.025 (0.97), 2.046(3.88), 2.080 (4.59), 2.090 (5.07), 2.114 (11.27), 2.138 (3.27), 2.162(1.16), 2.390 (0.94), 2.418 (1.57), 2.713 (1.09), 2.742 (1.95), 2.771 (1.06),3.474 (2.09), 3.498 (3.43),3.520 (2.33), 3.596 (1.71), 3.678 (3.31), 3.693(2.57), 7.252 (1.56), 7.271 (3.74), 7.289 (2.72), 7.353 (2.19), 7.372 (4.02),7.390 (2.08), 7.436 (5.26), 7.456 (4.43), 7.484 (5.27), 7.502 (4.30), 7.624(1.39), 7.647 (13.75), 7.676 (1.02), 8.697 (1.88), 8.712 (3.76), 8.726(1.87), 12.047 (1.45)。

Example 61

(+) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(diastereomer 4)

To (+) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-tert-butyl 4- (2-chlorophenyl) valerate (463 mg, 720. mu. mol,diastereomer 4Example 101A) in dichloromethane (6.1ml) TFA (1.2 ml, 16 mmol) was added and the mixture was left to stand at room temperature for 18 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. Removing residuesThe residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 360 mg (100% purity, 85% of theory) of the title compound are obtained.

[α]_D ²⁰= 27.7 °, 589 nm, c = 0.48 g/100 ml, methanol

LC-MS (method 1) R_t= 2.45 min; MS (ESIpos): m/z = 586/588 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.888 (5.59), 0.907 (13.71), 0.925(6.95), 1.033 (0.43), 1.062 (1.18), 1.084 (1.19), 1.092 (1.20), 1.113 (0.54),1.123 (0.48), 1.238 (0.87), 1.256 (2.08), 1.265 (1.91), 1.273 (2.87), 1.282(2.43), 1.290 (2.12), 1.300 (1.70), 1.317 (0.67), 1.557 (1.25), 1.565 (1.23),1.573 (1.20), 1.603 (1.20), 1.635 (1.16), 1.665 (0.50), 1.744 (1.64), 1.778(1.28), 1.793 (0.94), 1.814 (1.27), 1.836 (2.25), 1.854 (1.87), 1.876 (1.47),2.033 (0.90), 2.049 (3.07), 2.078 (2.80), 2.085 (3.19), 2.094 (3.73), 2.125(16.00), 2.139 (2.89), 2.163 (0.88), 2.402 (0.81), 2.430 (1.33), 2.458(0.81), 2.701 (0.82), 2.731 (1.48), 2.759 (0.82), 3.485 (2.59), 3.515 (2.44),3.599 (1.42), 3.624 (0.88), 3.642 (0.73), 3.662 (1.56), 3.676 (2.32), 7.253(1.31), 7.272 (3.02), 7.292 (2.12), 7.355 (1.80), 7.374 (3.28), 7.392 (1.70),7.440 (4.50), 7.460 (3.99), 7.483 (4.32), 7.501 (2.96), 7.624 (1.00), 7.647(12.31), 7.652 (6.71), 7.670 (0.66), 7.675 (0.81), 8.699 (1.53), 8.713(3.02), 8.727 (1.49), 12.053 (0.70)。

Example 62

5- [ ({ 6-bromo-2- [ 3-hydroxy-3-methylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(mixture of diastereomers)

To 5- [ ({ 6-bromo-2- [ 3-hydroxy-3-methylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]Tert-butyl 4- (2-chlorophenyl) valerate (148 mg, 229. mu. mol,diastereomer mixturesArticle (A)Example 102A) in dichloromethane (1.7ml) TFA (180 μ l, 2.3 mmol) was added and the mixture was left to stand at room temperature for 16 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 106 mg (98% purity, 77% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 1.83 min; MS (ESIpos): m/z = 588/560 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.69), 1.190 (16.00), 1.557(3.93), 1.570 (4.21), 1.613 (1.10), 1.627 (1.00), 1.796 (0.66), 1.814 (1.72),1.836 (2.49), 1.859 (1.71), 2.045 (2.66), 2.061 (1.71), 2.079 (3.37), 2.086(4.47), 2.134 (2.03), 2.165 (10.97), 2.855 (0.60), 3.021 (7.70), 3.075(3.50), 3.592 (1.35), 3.676 (2.23), 4.614 (1.55), 7.254 (1.18), 7.274 (2.80),7.292 (1.97), 7.356 (1.67), 7.374 (3.07), 7.392 (1.61), 7.441 (4.38), 7.461(3.98), 7.481 (4.14), 7.499 (2.92), 7.614 (2.20), 7.636 (7.81), 7.649 (5.05),7.654 (4.49), 7.671 (1.34), 7.676 (1.37), 8.712 (1.50), 8.727 (2.91), 8.741(1.39)。

Example 63

5- [ ({ 6-bromo-2- [3, 5-dimethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(mixture of diastereomers)

To 5- [ ({ 6-bromo-2- [3, 5-dimethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]Tert-butyl 4- (2-chlorophenyl) valerate (91 mg, 142 μmol,mixtures of diastereomersExample 103A) in dichloromethane (4.8 ml) TFA (110 μ l, 1.4 mmol) was added and the mixture was stirred at room temperature for 42 h. Then, TFA (105. mu.l, 0.7 mmol) was added again, and the mixture was stirred at room temperature for another 66 h. The mixture was then concentrated and dichloromethane was repeatedly added, followed by concentration again. The residue was first pre-treated by preparative HPLCPurification was performed first (method 6) and then by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 47 mg (100% purity, 57% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.42&2.44 min; MS (ESIpos): m/z = 586/586 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.718 (1.40), 0.748 (1.54), 0.778(0.50), 0.898 (15.75), 0.913 (16.00), 1.005 (3.11), 1.021 (3.17), 1.234(0.86), 1.424 (0.56), 1.437 (1.00), 1.451 (0.61), 1.808 (3.64), 1.839 (3.30),1.861 (1.10), 2.049 (3.42), 2.083 (3.96), 2.090 (4.17), 2.134 (11.83), 2.164(3.04), 2.266 (1.30), 2.294 (2.05), 2.323 (1.27), 2.848 (0.48), 3.116 (0.65),3.146 (0.56), 3.488 (2.66), 3.517 (2.54), 3.592 (1.54), 3.674 (2.27), 7.256(1.27), 7.274 (2.92), 7.292 (2.07), 7.356 (1.74), 7.375 (3.20), 7.393 (1.71),7.440 (4.43), 7.460 (4.05), 7.480 (4.37), 7.499 (3.07), 7.625 (0.76), 7.647(13.38), 7.673 (0.59), 8.692 (1.42), 8.705 (2.74), 12.049 (1.42)。

Example 64

5- [ ({ 6-bromo-2- [3- (difluoromethyl) piperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(mixture of diastereomers)

To 5- [ ({ 6-bromo-2- [3- (difluoromethyl) piperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-tert-butyl 4- (2-chlorophenyl) valerate (116 mg, 48% purity, 83.0 μmol,mixtures of diastereomersExample 104A) was added to TFA (64 μ l, 830 μmol) in dichloromethane (2.9 ml) solution, and the mixture was stirred at room temperature for 18 h. Then, TFA (64 μ l, 830 μmol) was added again, and the mixture was stirred at room temperature for another 24 h. Then, TFA (64 μ l, 830 μmol) was added again, and the mixture was stirred again at room temperature for 24 h. The mixture was then concentrated and dichloromethane was repeatedly added, followed by concentration again. The residue was purified by preparative HPLC (method)7). The combined target fractions were concentrated and the residue was lyophilized. 34 mg (93% purity, 63% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.19 min; MS (ESIpos): m/z = 608/610 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.13), -0.008 (16.00), 0.008(9.90), 0.146 (1.18), 1.235 (0.65), 1.397 (0.96), 1.427 (1.09), 1.664 (0.92),1.812 (2.31), 1.853 (2.49), 2.044 (2.96), 2.088 (3.57), 2.139 (9.68), 2.327(1.57), 2.366 (1.57), 2.523 (9.59), 2.669 (1.96), 2.710 (2.40), 2.838 (1.48),3.413 (1.57), 3.553 (2.18), 3.581 (2.75), 3.681 (2.44), 5.754 (0.70), 5.941(0.70), 6.083 (1.40), 6.096 (1.31), 6.237 (0.74), 7.257 (1.26), 7.274 (2.57),7.293 (1.87), 7.356 (1.61), 7.375 (2.92), 7.392 (1.66), 7.439 (4.40), 7.459(3.75), 7.485 (3.79), 7.502 (3.10), 7.677 (13.34), 8.734 (2.31), 12.043(1.13)。

Example 65

5- [ ({ 6-bromo-2- [ ((6-bromo-2-) ]3S) -3-fluoropyrrolidin-1-yl]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(Epimer mixture)

To 5- [ ({ 6-bromo-2- [ (6-bromo-2- [))3S) -3-fluoropyrrolidin-1-yl]-3-methylquinolin-4-yl } carbonyl) amino]Tert-butyl 4- (2-chlorophenyl) valerate (141 mg, 89% purity, 203 μmol, epimer mixture, example 105A) in dichloromethane (2.2 ml) was added TFA (160 μ l, 2.0 mmol) and the mixture was stirred at room temperature for 42 h. Then, TFA (80. mu.l, 1.0 mmol) was added again, and the mixture was stirred at room temperature for another 24 h. The mixture was then concentrated and dichloromethane was repeatedly added, followed by concentration again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 44 mg (94% purity, 36% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 1.75 min; MS (ESIpos): m/z = 562/564 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.50), -0.008 (4.85), 0.008(4.45), 0.146 (0.45), 1.235 (0.77), 1.797 (1.23), 1.818 (2.56), 1.838 (3.44),1.862 (1.98), 1.988 (0.79), 2.047 (7.30), 2.076 (7.77), 2.088 (7.95), 2.138(4.97), 2.176 (16.00), 2.327 (0.92), 2.366 (0.79), 2.669 (0.79), 2.709(0.74), 3.600 (6.02), 3.866 (2.36), 3.884 (2.32), 3.911 (2.23), 3.944 (1.37),4.013 (1.48), 4.046 (1.24), 5.330 (3.51), 5.464 (3.44), 5.754 (5.44), 7.245(1.57), 7.261 (4.38), 7.280 (5.05), 7.297 (2.40), 7.346 (2.58), 7.364 (5.51),7.382 (5.14), 7.401 (2.31), 7.437 (10.14), 7.440 (9.69), 7.457 (8.61), 7.459(8.00), 7.473 (5.24), 7.476 (5.21), 7.491 (5.14), 7.504 (8.41), 7.508 (7.91),7.526 (10.05), 7.530 (9.68), 7.574 (5.17), 7.579 (8.88), 7.585 (4.72), 7.596(2.97), 7.602 (5.05), 7.607 (2.72), 7.893 (1.57), 8.694 (4.86), 12.050(1.46)。

Example 66

5- [ ({ 6-bromo-2- [ ((6-bromo-2-) ]3R) -3-fluoropyrrolidin-1-yl]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(Epimer mixture)

To 5- [ ({ 6-bromo-2- [ (6-bromo-2- [))3R) -3-fluoropyrrolidin-1-yl]-3-methylquinolin-4-yl } carbonyl) amino]Tert-butyl 4- (2-chlorophenyl) valerate (120 mg, 96% purity, 187. mu. mol, epimer mixture, example 106A) in dichloromethane (2.4 ml) was added TFA (140. mu.l, 1.9 mmol) and the mixture was stirred at room temperature for 42 h. Then, TFA (80. mu.l, 1.0 mmol) was added again, and the mixture was stirred at room temperature for another 24 h. Then, TFA (80. mu.l, 1.0 mmol) was added again, and the mixture was stirred at room temperature for another 24 h. The mixture was then concentrated and dichloromethane was repeatedly added, followed by concentration again. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 86 mg (97% purity, 79% of theory) of the title compound are obtained。

LC-MS (method 1) R_t= 1.76 min; MS (ESIpos): m/z = 562/564 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.49), 0.146 (0.51), 1.798(1.12), 1.817 (2.38), 1.839 (3.22), 1.862 (1.84), 2.049 (7.23), 2.078 (7.50),2.089 (7.59), 2.121 (3.46), 2.139 (4.86), 2.176 (16.00), 2.327 (0.85), 2.366(0.67), 2.670 (0.79), 2.710 (0.70), 3.600 (5.99), 3.626 (4.79), 3.657 (4.00),3.867 (2.42), 3.883 (2.41), 3.912 (2.32), 3.945 (1.44), 4.012 (1.54), 4.046(1.33), 5.331 (3.59), 5.465 (3.56), 5.754 (6.66), 7.245 (1.53), 7.263 (4.27),7.280 (4.74), 7.297 (2.23), 7.326 (0.79), 7.346 (2.69), 7.364 (5.42), 7.383(4.83), 7.400 (2.08), 7.437 (9.28), 7.440 (9.14), 7.457 (7.78), 7.477 (5.10),7.492 (4.88), 7.504 (7.74), 7.508 (7.57), 7.526 (9.34), 7.530 (9.61), 7.574(4.77), 7.580 (8.37), 7.585 (4.71), 7.596 (2.81), 7.602 (4.80), 7.607 (2.77),8.693 (4.97), 12.045 (3.38)。

Separation of the epimer mixture:

the title compound (72 mg) was dissolved in methanol (12 ml) and separated by preparative SFC on the chiral phase into enantiomers/epimers (see examples 67 and 68) [ column: daicel Chiralcel OX-H, 5 μm,250 mm x30 mm, flow rate: 100 ml/min, injection: 1.0ml, eluent 20% methanol/80% carbon dioxide, running time 21 min, isocratic, UV detection 210 nm, temperature 40 deg.C ]. The combined target fractions were concentrated and the respective residue was lyophilized.

Example 67

(+) -5- [ ({ 6-bromo-2- [ (6-bromo-2- [))3R) -3-fluoropyrrolidin-1-yl]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(Epimers1)

In the enantiomeric separation described in example 66, 16 mg (100% purity, ee >99%) of the title compound were obtained as the epimer/enantiomer which eluted earlier.

[α]_D ²⁰= 22.1 °, 589 nm, c = 0.29 g/100 ml, methanol

LC-MS (method 1) R_t= 1.79 min; MS (ESIpos): m/z = 562/564 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.64), -0.008 (5.27), 0.008(5.32), 0.070 (0.55), 0.146 (0.62), 1.236 (0.44), 1.359 (1.61), 1.754 (0.54),1.819 (2.40), 1.840 (3.08), 1.865 (1.93), 2.025 (2.41), 2.051 (6.86), 2.078(7.50), 2.092 (6.21), 2.100 (4.56), 2.115 (3.52), 2.141 (5.17), 2.177(16.00), 2.295 (0.60), 2.327 (0.93), 2.670 (0.75), 2.994 (0.93), 3.207(0.79), 3.601 (5.46), 3.672 (4.92), 3.840 (1.34), 3.867 (2.43), 3.884 (2.44),3.913 (2.25), 3.946 (1.30), 4.023 (1.47), 4.047 (1.26), 5.331 (3.06), 5.466(3.06), 6.311 (0.64), 7.246 (2.55), 7.264 (5.98), 7.283 (4.16), 7.347 (3.88),7.366 (6.57), 7.384 (3.70), 7.437 (8.61), 7.440 (9.05), 7.457 (7.58), 7.460(7.75), 7.477 (7.69), 7.493 (5.77), 7.496 (5.99), 7.508 (8.92), 7.530(14.54), 7.580 (8.24), 7.585 (7.42), 7.602 (4.52), 7.608 (4.33), 7.879(0.83), 8.680 (2.80), 8.695 (5.16), 8.708 (2.51), 12.041 (3.60)。

Example 68

(+) -5- [ ({ 6-bromo-2- [ (6-bromo-2- [))3R) -3-fluoropyrrolidin-1-yl]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(Epimers2)

In the enantiomeric separation described in example 66, 14 mg (100% purity, ee >82%) of the title compound are obtained as the epimer/enantiomer which elutes later.

[α]_D ²⁰= 40.7 °, 589 nm, c = 0.30 g/100 ml, methanol

LC-MS (method 1) R_t= 1.79 min; MS (ESIpos): m/z = 562/564 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.09), -0.008 (9.27), 0.008(8.56), 0.069 (2.49), 0.146 (1.09), 1.235 (0.52), 1.359 (1.59), 1.754 (0.45),1.798 (1.61), 1.819 (2.89), 1.839 (3.82), 1.861 (2.49), 2.048 (7.89), 2.089(9.53), 2.136 (6.02), 2.174 (14.55), 2.327 (1.47), 2.366 (0.43), 2.670(1.33), 2.994 (0.52), 3.207 (1.14), 3.462 (0.47), 3.578 (4.81), 3.602 (6.35),3.627 (5.43), 3.640 (5.24), 3.703 (2.56), 3.857 (2.49), 3.876 (2.44), 3.903(2.23), 3.944 (1.37), 4.011 (1.49), 4.044 (1.23), 5.330 (3.56), 5.464 (3.51),6.305 (0.71), 6.310 (1.02), 6.316 (0.69), 7.260 (4.27), 7.280 (5.78), 7.298(3.93), 7.365 (4.76), 7.383 (6.42), 7.400 (3.96), 7.421 (1.75), 7.437(10.38), 7.440 (10.05), 7.457 (8.53), 7.460 (8.18), 7.486 (6.83), 7.504(13.27), 7.525 (16.00), 7.574 (8.23), 7.579 (8.63), 7.596 (4.62), 7.601(5.03), 7.879 (1.37), 8.675 (3.25), 8.689 (5.67), 8.703 (3.18), 9.688 (0.50),12.040 (7.44)。

Example 69

5- [ ({ 6-bromo-2- [ trans-3, 4-difluoropyrrolidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(mixture of diastereomers)

To 5- [ ({ 6-bromo-2- [ trans-3, 4-difluoropyrrolidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]Tert-butyl 4- (2-chlorophenyl) valerate (169 mg, 77% purity, 204 μmol,mixtures of diastereomersExample 107A) in dichloromethane (2.3 ml) TFA (160 μ l, 2.0 mmol) was added and the mixture was stirred at room temperature for 42 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 6). The combined target fractions were each concentrated and the respective residue was lyophilized. 8mg (100% purity, 7% of theory) of the first title compound and 57mg (98% purity, 47% of theory) of the second title compound are obtained.

The first batch was analyzed:

LC-MS (method 1) R_t= 1.96 min; MS (ESIpos): m/z = 580/582 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.235 (1.28), 1.258 (0.52), 1.372(6.58), 1.822 (1.87), 1.836 (3.94), 1.851 (4.34), 1.866 (2.51), 1.986 (0.72),2.065 (8.57), 2.083 (9.10), 2.108 (4.07), 2.130 (4.83), 2.141 (4.69), 2.162(3.43), 2.198 (16.00), 2.308 (0.51), 3.613 (3.36), 3.645 (3.02), 3.758(4.47), 4.101 (3.01), 4.175 (3.15), 5.378 (6.46), 5.468 (6.57), 5.743 (0.97),7.252 (2.23), 7.264 (4.72), 7.278 (4.83), 7.352 (2.93), 7.365 (5.53), 7.377(4.90), 7.441 (9.98), 7.454 (9.21), 7.477 (6.06), 7.490 (8.21), 7.501 (4.48),7.555 (5.84), 7.570 (8.53), 7.616 (6.75), 7.630 (4.65), 7.888 (1.25), 8.680(7.05), 12.012 (1.02)。

The second batch was analyzed:

LC-MS (method 1) R_t= 1.96 min; MS (ESIpos): m/z = 580/582 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.66), -0.008 (6.04), 0.008(5.65), 0.146 (0.64), 1.157 (0.68), 1.175 (1.34), 1.192 (0.75), 1.234 (0.57),1.367 (1.36), 1.801 (1.23), 1.819 (2.68), 1.842 (3.65), 1.865 (2.07), 1.988(2.50), 2.049 (6.83), 2.077 (7.97), 2.089 (8.19), 2.114 (3.09), 2.139 (3.90),2.192 (16.00), 2.304 (0.43), 2.327 (1.16), 2.366 (0.91), 2.523 (3.13), 2.670(1.02), 2.710 (1.00), 3.600 (3.25), 3.647 (2.77), 3.741 (3.54), 4.020 (0.79),4.038 (0.93), 4.074 (2.36), 4.100 (2.22), 4.183 (2.45), 5.354 (5.11), 5.360(5.45), 5.494 (5.49), 5.500 (5.36), 5.754 (2.75), 7.246 (1.66), 7.264 (4.63),7.282 (5.06), 7.301 (2.25), 7.348 (2.63), 7.366 (5.81), 7.385 (5.15), 7.403(2.16), 7.439 (10.44), 7.458 (8.76), 7.476 (5.56), 7.479 (5.83), 7.494(6.33), 7.509 (3.43), 7.544 (5.83), 7.548 (6.45), 7.566 (10.80), 7.571(11.57), 7.609 (5.56), 7.615 (9.74), 7.621 (5.65), 7.631 (3.13), 7.637(5.38), 7.643 (3.27), 7.893 (0.68), 8.688 (3.29), 8.702 (6.42), 8.716 (3.43),12.035 (0.98)。

Example 70

(+/-) -5- [ ({ 6-bromo-2- ], a salt thereof, and a salt thereofCis-alpha-carboxylic acid derivatives3, 4-difluoropyrrolidin-1-yl]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(raceme)

To (+/-) -5- [ ({ 6-bromo)-2-[Cis-alpha-carboxylic acid derivatives3, 4-difluoropyrrolidin-1-yl]-3-methylquinolin-4-yl } carbonyl) amino]Tert-butyl 4- (2-chlorophenyl) valerate (160 mg, 93% purity, 233 μmol,racemic modificationExample 108A) in dichloromethane (2.3 ml) TFA (180 μ l, 2.3 mmol) was added and the mixture was stirred at room temperature for 66 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 68 mg (93% purity, 47% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 1.93 min; MS (ESIpos): m/z = 580/582 [M+H]⁺

¹H-NMR (400 MHz,DMSO-d6) δ [ppm]: -0.149 (1.26), -0.008 (12.03), 0.008(11.85), 0.146 (1.32), 1.157 (0.60), 1.174 (1.32), 1.192 (0.60), 1.236(0.54), 1.368 (0.42), 1.797 (1.08), 1.816 (2.41), 1.839 (3.25), 1.862 (1.80),1.988 (2.47), 2.046 (5.95), 2.080 (7.04), 2.090 (7.22), 2.137 (6.02), 2.160(14.20), 2.297 (0.42), 2.327 (1.80), 2.366 (1.86), 2.523 (6.44), 2.669(2.11), 2.710 (2.05), 3.586 (2.89), 3.671 (3.55), 3.782 (3.19), 3.994 (2.53),4.021 (2.47), 5.298 (3.07), 5.311 (2.29), 5.324 (2.41), 5.333 (2.47), 5.426(2.65), 5.435 (2.77), 5.448 (2.41), 5.460 (3.07), 5.754 (7.10), 7.254 (2.35),7.271 (5.17), 7.290 (3.73), 7.356 (3.25), 7.374 (5.95), 7.392 (3.43), 7.438(9.32), 7.440 (9.44), 7.458 (7.70), 7.460 (7.58), 7.482 (7.46), 7.499 (5.53),7.541 (8.78), 7.563 (16.00), 7.609 (8.54), 7.614 (8.18), 7.631 (4.63), 7.636(4.69), 8.678 (3.13), 8.693 (6.38), 8.707 (3.13), 12.043 (7.52)。

Example 71

5- [ ({ 6-bromo-2- [ 3-fluoro-3-methylpyrrolidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(mixture of diastereomers)

To 5- [ ({ 6-bromo-2- [ 3-fluoro-3-methylpyrrolidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]Tert-butyl 4- (2-chlorophenyl) valerate (120 mg, 96% purity, 181 μmol,mixtures of diastereomersExample 109A) in dichloromethane (2.4 ml) TFA (140 μ l, 1.8 mmol) was added and the mixture was stirred at room temperature for 42 h. Then, TFA (70 μ l, 0.9 mmol) was added again, and the mixture was stirred at room temperature for another 24 h. The mixture was then concentrated and dichloromethane was repeatedly added, followed by concentration again. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 83 mg (100% purity, 79% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 1.89 min; MS (ESIpos): m/z = 576/578 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (2.03), 1.157 (4.22), 1.175(8.34), 1.192 (4.18), 1.541 (8.21), 1.593 (8.22), 1.817 (0.84), 1.839 (1.06),1.862 (0.58), 1.988 (16.00), 2.018 (0.92), 2.048 (2.34), 2.078 (2.77), 2.088(2.72), 2.114 (1.68), 2.134 (2.41), 2.170 (5.51), 2.327 (0.45), 2.523 (1.92),2.670 (0.43), 3.616 (1.97), 3.798 (0.72), 3.829 (0.51), 3.890 (0.85), 3.921(1.25), 3.947 (0.84), 4.003 (1.38), 4.021 (3.82), 4.038 (3.71), 4.056 (1.22),7.246 (0.61), 7.262 (1.49), 7.281 (1.62), 7.298 (0.74), 7.346 (1.01), 7.365(1.86), 7.382 (1.59), 7.401 (0.70), 7.437 (3.28), 7.457 (2.76), 7.474 (1.73),7.494 (3.00), 7.499 (2.45), 7.516 (3.28), 7.521 (3.10), 7.566 (1.68), 7.572(2.81), 7.578 (1.55), 7.589 (0.99), 7.594 (1.61), 7.600 (0.88), 8.692 (1.46),12.038 (3.86)。

Example 72

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (3,3,4, 4-tetrafluoropyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(raceme)

To (+/-) -5- ({ [ 6-bromo-3-methyl-2- (3,3,4, 4-tetrafluoropyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acidTert-butyl ester (69 mg, 9% purity, 9.49 μmol,racemic modificationExample 110A) was added to TFA (7.3 μ l, 95 μmol) in dichloromethane (910 μ l) solution, and the mixture was stirred at room temperature for 18 h. Then, TFA (7.3 μ l, 95 μmol) was added again, and the mixture was stirred at room temperature for another 48 h. The mixture was then concentrated, and dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 4 mg (100% purity, 68% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.21 min; MS (ESIpos): m/z = 616/618 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: -0.052 (0.83), 0.854 (0.54), 0.901(1.54), 0.911 (1.52), 1.236 (2.63), 1.262 (1.41), 1.300 (0.66), 1.338 (0.74),1.369 (1.41), 1.820 (1.99), 1.834 (4.21), 1.848 (4.54), 1.864 (2.58), 2.047(3.16), 2.060 (9.95), 2.078 (9.12), 2.083 (7.22), 2.092 (4.10), 2.099 (3.52),2.107 (3.71), 2.125 (4.63), 2.132 (5.17), 2.139 (6.68), 2.156 (4.33), 2.184(16.00), 2.256 (0.78), 2.313 (0.61), 2.383 (0.51), 2.611 (0.63), 3.512(0.66), 3.589 (4.04), 3.689 (4.56), 4.258 (10.47), 7.261 (3.41), 7.274(6.97), 7.286 (4.66), 7.360 (4.30), 7.373 (7.46), 7.385 (4.17), 7.443(11.50), 7.457 (10.28), 7.482 (9.64), 7.495 (8.17), 7.648 (9.39), 7.662(15.42), 7.697 (9.84), 7.712 (5.70), 7.888 (0.93), 8.680 (4.82), 8.689(8.49), 8.698 (4.46), 12.010 (4.14)。

Example 73

(+/-) -5- [ ({2- [ 3-azabicyclo [3.1.1 ] 1)]Hept-3-yl]-6-bromo-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(raceme)

To (+/-) -5- [ ({2- [ 3-azabicyclo [ 3.1.1.1)]Hept-3-yl]-6-bromo-3-methylquinolin-4-yl } carbonyl) amino]Tert-butyl 4- (2-chlorophenyl) valerate (63 mg, 100. mu. mol,racemic modificationMethylene chloride of example 111A)To the solution (2.5 ml) was added TFA (120. mu.l, 1.5 mmol), and the mixture was stirred at room temperature for 24 h. Then, TFA (7.3 μ l, 95 μmol) was added again, and the mixture was stirred at room temperature for another 48 h. The mixture was then concentrated and dichloromethane was repeatedly added, followed by concentration again. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 38 mg (100% purity, 66% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.07 min; MS (ESIpos): m/z = 570/572 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.04), -0.008 (9.81), 0.008(9.81), 0.146 (1.07), 1.235 (0.70), 1.369 (1.83), 1.426 (1.48), 1.439 (9.09),1.445 (8.32), 1.455 (8.53), 1.461 (9.55), 1.474 (1.76), 1.796 (1.00), 1.814(2.18), 1.838 (3.04), 1.861 (1.76), 1.885 (0.56), 2.046 (5.15), 2.076 (9.00),2.087 (12.29), 2.102 (8.74), 2.108 (8.81), 2.124 (4.50), 2.134 (4.24), 2.158(2.02), 2.195 (16.00), 2.274 (0.46), 2.300 (0.56), 2.327 (0.86), 2.366(0.93), 2.670 (0.83), 2.710 (0.93), 3.591 (2.83), 3.666 (3.99), 3.867 (3.83),7.253 (2.32), 7.272 (5.24), 7.291 (3.69), 7.354 (3.39), 7.373 (6.14), 7.391(3.73), 7.438 (8.74), 7.441 (8.70), 7.458 (7.05), 7.461 (6.91), 7.480 (6.61),7.498 (4.78), 7.524 (7.63), 7.546 (15.61), 7.581 (8.77), 7.587 (8.16), 7.603(4.20), 7.609 (4.20), 8.705 (2.81), 8.720 (5.43), 8.734 (2.81), 11.983(0.42)。

Example 74

(+/-) -5- [ ({2- [ 3-azabicyclo [3.2.1 ] C]Oct-3-yl]-6-bromo-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(raceme)

To (+/-) -5- [ ({2- [ 3-azabicyclo [ 3.2.1)]Oct-3-yl]-6-bromo-3-methylquinolin-4-yl } carbonyl) amino]Tert-butyl 4- (2-chlorophenyl) valerate (77 mg, 120. mu. mol,racemic modificationExample 112A) solution in dichloromethane (2.0 ml) T was addedFA (140. mu.l, 1.8 mmol) and the mixture was stirred at room temperature for 48 h. Then, TFA (140. mu.l, 1.8 mmol) was added again, and the mixture was stirred at room temperature for another 18 h. The mixture was then concentrated, and dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 38 mg (100% purity, 54% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.40 min; MS (ESIpos): m/z = 584/586 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.42), -0.008 (3.49), 0.008(3.22), 0.147 (0.42), 1.236 (0.97), 1.325 (1.08), 1.349 (4.20), 1.552(10.36), 1.652 (4.29), 1.664 (4.68), 1.702 (1.24), 1.749 (5.47), 1.768(5.29), 1.808 (2.02), 1.830 (2.75), 1.853 (1.69), 2.039 (4.17), 2.067 (6.22),2.074 (5.47), 2.088 (3.49), 2.097 (2.29), 2.123 (3.05), 2.146 (1.53), 2.182(16.00), 2.226 (0.73), 2.299 (7.19), 2.366 (0.81), 2.670 (0.80), 2.710(0.78), 2.890 (2.64), 2.907 (3.61), 2.934 (3.27), 3.133 (0.41), 3.583 (2.22),3.668 (3.76), 7.256 (2.02), 7.274 (4.53), 7.292 (3.24), 7.354 (2.83), 7.373(5.00), 7.391 (2.71), 7.443 (7.29), 7.445 (7.37), 7.466 (7.25), 7.475 (6.63),7.494 (4.54), 7.605 (4.66), 7.627 (14.17), 7.643 (8.36), 7.648 (7.56), 7.666(2.56), 7.671 (2.59), 8.734 (2.17), 8.748 (4.20), 8.762 (2.05)。

Example 75

(+/-) -5- ({ [ 6-bromo-2- (3, 3-difluoroazetidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(raceme)

To (+/-) -5- ({ [ 6-bromo-2- (3, 3-difluoroazetidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester (30 mg, 96% purity, 46.2 μmol,racemic modificationExample 113A) in dichloromethane (1.9ml) was added TFA (36 μ l, 460 μmol), and the mixture was mixedThe mixture was stirred at room temperature for 18 h. Then, TFA (36 μ l, 460 μmol) was added again, and the mixture was stirred at room temperature for another 24 h. Then, TFA (18 μ l, 230 μmol) was added again, and the mixture was stirred at room temperature for another 24 h. The mixture was then concentrated, and dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 18 mg (100% purity, 69% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.00 min; MS (ESIpos): m/z = 566/568 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.80), 0.008 (14.73), 0.146(1.67), 1.236 (1.47), 1.367 (1.27), 1.793 (1.20), 1.813 (2.47), 1.835 (3.20),1.858 (1.80), 2.041 (9.47), 2.066 (14.00), 2.085 (9.27), 2.113 (3.20), 2.133(3.93), 2.156 (1.80), 2.327 (2.40), 2.366 (2.07), 2.523 (8.00), 2.669 (2.73),2.710 (2.13), 3.585 (2.80), 3.673 (3.73), 4.581 (6.73), 4.613 (12.67), 4.644(6.60), 5.754 (9.53), 7.254 (2.20), 7.271 (5.00), 7.290 (3.53), 7.352 (3.00),7.371 (5.47), 7.389 (3.00), 7.438 (9.33), 7.458 (8.07), 7.476 (7.53), 7.493(5.67), 7.588 (7.87), 7.610 (16.00), 7.647 (8.87), 7.652 (7.80), 7.669(4.27), 7.674 (4.07), 8.693 (3.07), 8.707 (5.87), 8.722 (2.93), 12.045(3.13)。

Example 76

5- [ ({ 6-bromo-2- [ 3-cyanopiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(mixture of diastereomers)

To 5- [ ({ 6-bromo-2- [ 3-cyanopiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]Tert-butyl 4- (2-chlorophenyl) valerate (197 mg, 308 μmol,mixtures of diastereomersExample 114A) in dichloromethane (4.0ml) TFA (360 μ l, 4.6 mmol) was added and the mixture was stirred at room temperature overnight. The mixture is then concentrated, dichloromethane is repeatedly added and againThe mixture was concentrated. The residue was first previously purified by preparative HPLC (method 8) and then twice more purified by the same method. The combined target fractions were concentrated and the residue was lyophilized. 55 mg (95% purity, 29% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 1.97 min; MS (ESIpos): m/z = 583/585 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (3.11), 0.008 (3.20), 0.938(0.76), 0.955 (0.75), 1.488 (9.73), 1.656 (0.56), 1.667 (0.80), 1.719 (1.80),1.802 (2.69), 1.825 (3.97), 1.846 (2.65), 1.876 (4.02), 1.888 (5.87), 1.901(4.88), 2.003 (1.54), 2.015 (3.69), 2.041 (6.06), 2.063 (3.89), 2.073 (3.24),2.100 (2.40), 2.122 (1.26), 2.181 (16.00), 2.239 (0.56), 2.327 (0.59), 2.366(0.58), 2.523 (1.43), 2.665 (0.46), 2.670 (0.55), 2.710 (0.66), 2.756 (4.54),3.020 (2.08), 3.212 (2.91), 3.268 (4.82), 3.276 (4.72), 3.295 (4.84), 3.328(5.24), 3.441 (3.75), 3.456 (3.51), 3.473 (2.89), 3.487 (2.47), 3.580 (2.53),3.681 (3.48), 7.252 (1.84), 7.270 (4.21), 7.287 (2.95), 7.352 (2.53), 7.371(4.60), 7.389 (2.37), 7.436 (6.16), 7.440 (5.96), 7.456 (5.23), 7.459 (4.98),7.478 (5.40), 7.495 (4.41), 7.669 (1.98),7.691 (14.43), 7.694 (12.09), 7.699(8.72), 7.717 (1.14), 7.721 (1.37), 7.891 (0.91), 8.753 (2.20), 8.767 (4.21),8.781 (2.02)。

Example 77

(+/-) -5- ({ [ 6-bromo-2- (3, 6-dihydro-2)H-1, 2-oxazin-2-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(raceme)

To (+/-) -5- ({ [ 6-bromo-2- (3, 6-dihydro-2)H-1, 2-oxazin-2-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester (65 mg, 106 μmol,racemic modificationExample 115A) in dichloromethane (2.0 ml) TFA (160 μ l, 2.1 mmol) was added and the mixture was stirred at room temperature for 18 h. Then concentratingThe mixture was added dichloromethane repeatedly and the mixture was concentrated again. The residue was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 51 mg (97% purity, 83% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.09 min; MS (ESIpos): m/z = 558/560 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.935 (1.33), 0.952 (1.27), 1.066(1.35), 1.082 (1.38), 1.531 (8.69), 1.809 (1.67), 1.830 (1.32), 1.945 (1.75),1.972 (2.68), 1.992 (3.01), 2.006 (3.92), 2.033 (2.92), 2.187 (8.46), 2.327(0.72), 2.365 (0.70), 2.669 (0.84), 2.730 (4.10), 3.334 (2.23), 3.556 (1.91),3.673 (2.35), 4.069 (6.50), 4.505 (4.29), 5.990 (1.44), 6.015 (3.42), 6.049(2.99), 6.074 (1.24), 7.246 (1.38), 7.264 (3.21), 7.282 (2.18), 7.346 (1.76),7.365 (3.36), 7.384 (1.70), 7.436 (4.65), 7.459 (5.68), 7.481 (2.65), 7.548(0.84), 7.743 (15.75), 7.745 (16.00), 8.955 (2.23)。

Example 78

5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(mixture of diastereomers)

To 5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]Tert-butyl 4- (2-chlorophenyl) valerate (75 mg, 118 μmol,mixtures of diastereomersExample 116A) in dichloromethane (870 μ l) was added TFA (91 μ l,1.2 mmol) and the mixture was allowed to stand at room temperature for 16 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 56 mg (98% purity, 80% of theory) of the title compound are obtained.

LC-MS (method 2) R_t= 1.09 min; MS (ESIpos): m/z = 576/578 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.24), 0.008 (2.48), 1.642(1.63), 1.765 (0.52), 1.793 (1.91), 1.810 (3.01), 1.819 (2.66), 1.834 (3.26),1.858 (1.97), 1.900 (2.78), 1.920 (2.26), 1.950 (1.57), 1.982 (0.97), 2.011(0.73), 2.034 (1.27), 2.045 (4.21), 2.079 (5.00), 2.088 (5.22), 2.143(16.00), 2.217 (0.40), 2.327 (0.45), 2.366 (0.51), 2.523 (1.47), 2.669(0.48), 2.710 (0.56), 3.094 (1.88), 3.159 (2.00), 3.377 (2.00), 3.410 (1.07),3.434 (1.75), 3.465 (1.09), 3.593 (1.93), 3.679 (3.48), 4.816 (1.35), 4.936(1.31), 7.256 (1.72), 7.274 (4.01), 7.294 (2.80), 7.356 (2.44), 7.374 (4.45),7.393 (2.29), 7.441 (6.25), 7.444 (6.25), 7.461 (5.34), 7.464 (5.25), 7.484(5.69), 7.500 (4.68), 7.647 (2.48), 7.669 (13.43),7.675 (9.66), 7.680(8.33), 7.697 (1.60), 7.702 (1.84), 8.715 (2.20), 8.730 (4.40), 8.744 (2.14),12.062 (0.87)。

Example 79

5- [ ({ 6-bromo-3-methyl-2- [ 2-methylpyrrolidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(mixture of diastereomers)

Initial charge of (+/-) -2-methylpyrrolidine (9 mg, 100 μmol) was placed in the well of a 96-well MTP and (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl was added]Tert-butyl amino } -4- (2-chlorophenyl) valerate (57mg, 100. mu. mol,racemic modificationExample 37A) was added with DIPEA (50 μ l,287 μmol). The MTP was blocked with a gel film and shaken overnight at 120 ℃. Then, the solvent was removed in a centrifugal drier, and TFA (800 μ l, 10.4 mmol) was added to the residue. The MTP was blocked again with a gel film and shaken overnight at room temperature. Then, TFA was removed in a centrifugal drier and the residue was dissolved in DMF (600 μ l). The solution was filtered through a filter plate and the filtrate was purified by preparative HPLC-MS (method 17). Removal of the solvent and drying in vacuo gives 6 mg (100% purity, 11% of theory) of the title compound.

LC-MS (method 16) R_t= 0.95 min; MS (ESIpos): m/z = 558/560 [M+H]⁺

Example 80

(-) -5- [ ({ 6-bromo-3-methyl-2- [ (S))2S) -2-methylpyrrolidin-1-yl]Quinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(Epimers1)

To (-) -5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]2S) -2-methylpyrrolidin-1-yl]Quinolin-4-yl } carbonyl) amino]-tert-butyl 4- (2-chlorophenyl) valerate (135 mg, 220 μmol, epimer)1Example 118A) in dichloromethane (1.7ml) was added TFA (370 μ l, 4.8 mmol) and the mixture was left to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 56 mg (100% purity, 46% of theory) of the title compound are obtained.

[α]_D ²⁰= 33.3 °, 589 nm, c = 0.40 g/100 ml, methanol

LC-MS (method 1) R_t= 1.88 min; MS (ESIpos): m/z = 558/560 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.141 (15.77), 1.156 (16.00), 1.370(0.82), 1.512 (0.44), 1.539 (1.29), 1.557 (1.57), 1.579 (1.54), 1.606 (0.94),1.663 (1.38), 1.689 (1.45), 1.709 (0.94), 1.792 (0.79), 1.810 (1.53), 1.832(1.99), 1.854 (1.21), 1.896 (1.94), 2.041 (4.08), 2.097 (10.55), 2.127(4.78), 2.327 (0.46), 2.669 (0.44), 3.587 (2.86), 3.610 (1.84), 3.623 (2.08),3.691 (1.33), 3.716 (2.88), 3.732 (3.30), 3.756 (2.27), 4.360 (1.38), 4.375(2.28), 4.397 (2.15), 4.413 (1.32), 7.260 (1.69), 7.278 (3.73), 7.297 (2.73),7.362 (2.89), 7.381 (4.34), 7.398 (2.39), 7.436 (6.24), 7.455 (5.02), 7.481(4.21), 7.498 (8.03), 7.520 (9.92), 7.566 (5.37), 7.571 (4.99), 7.588 (2.85),7.594 (2.78), 8.688 (2.06), 8.702 (3.28)。

Example 81

(-) -5- [ ({ 6-bromo-3-methyl-2- [ (S))2S) -2-methylpyrrolidin-1-yl]Quinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(Epimers2)

To (-) -5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]2S) -2-methylpyrrolidin-1-yl]Quinolin-4-yl } carbonyl) amino]-tert-butyl 4- (2-chlorophenyl) valerate (130 mg, 211 μmol, epimer)2Example 119A) in dichloromethane (1.6ml) was added TFA (360 μ l, 4.7 mmol) and the mixture was left to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 71 mg (100% purity, 60% of theory) of the title compound are obtained.

[α]_D ²⁰= 9.2 °, 589 nm, c = 0.47 g/100 ml, methanol

LC-MS (method 1) R_t= 1.87 min; MS (ESIpos): m/z = 558/560 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.142 (15.85), 1.157 (16.00), 1.346(0.61), 1.511 (0.44), 1.540 (1.31), 1.556 (1.56), 1.563 (1.55), 1.579 (1.52),1.607 (0.99), 1.660 (1.32), 1.684 (1.35), 1.705 (0.86), 1.793 (0.68), 1.813(1.62), 1.835 (2.04), 1.859 (1.20), 1.897 (1.92), 1.912 (1.82), 2.021 (0.92),2.047 (4.11), 2.075 (5.50), 2.104 (14.49), 2.142 (4.74), 2.164 (2.34), 2.201(0.49), 3.611 (2.35), 3.661 (2.85), 3.678 (2.70), 3.695 (2.70), 3.712 (2.42),3.720 (2.96), 3.737 (2.63), 3.761 (1.12), 4.362 (1.27), 4.377 (2.15), 4.392(1.83), 4.399 (2.04), 4.414 (1.23), 7.242 (1.76), 7.260 (4.06), 7.279 (2.87),7.343 (2.51), 7.362 (4.68), 7.380 (2.49), 7.438 (6.32), 7.458 (5.90), 7.472(5.71), 7.491 (4.08), 7.503 (5.93), 7.525 (9.65), 7.573 (5.51), 7.579 (5.04),7.596 (2.97), 7.601 (2.83), 8.689 (2.01), 8.703 (3.73), 11.998 (0.66)。

Example 82

(+) -5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]2R) -2-methylpyrrolidin-1-yl]Quinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(Epimers1)

To (+) -5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]2R) -2-methylpyrrolidin-1-yl]Quinolin-4-yl } carbonyl) amino]-tert-butyl 4- (2-chlorophenyl) valerate (135 mg, 220 μmol, epimer)1Example 121A) in dichloromethane (1.6ml) was added TFA (360. mu.l, 4.7 mmol) and the mixture was left to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 66 mg (100% purity, 56% of theory) of the title compound are obtained.

[α]_D ²⁰= 10.3 °, 589 nm, c = 0.27 g/100 ml, methanol

LC-MS (method 1) R_t= 1.83 min; MS (ESIpos): m/z = 558/560 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.99), 0.008 (1.83), 0.069(0.74), 1.142 (15.94), 1.157 (16.00), 1.512 (0.42), 1.540 (1.20), 1.556(1.41), 1.563 (1.38), 1.579 (1.40), 1.591 (1.01), 1.607 (0.94), 1.659 (1.18),1.684 (1.19), 1.703 (0.76), 1.813 (1.41), 1.832 (1.75), 1.857 (1.04), 1.897(1.67), 1.911 (1.60), 2.014 (0.79), 2.041 (3.65), 2.068 (4.96), 2.103(12.77), 2.135 (4.21), 2.158 (2.42), 2.200 (0.41), 2.327 (0.42), 2.669(0.40), 3.616 (1.97), 3.661 (2.55), 3.676 (2.39), 3.695 (2.33), 3.712 (2.11),3.720 (2.73), 3.736 (2.47), 3.745 (1.54), 3.761 (1.03), 4.361 (1.20), 4.377(2.01), 4.392 (1.64), 4.399 (1.83), 4.414 (1.14), 7.242 (1.70), 7.260 (3.70),7.277 (2.72), 7.280 (2.68), 7.342 (2.47), 7.361 (4.37), 7.377 (2.29), 7.435(5.99), 7.438 (5.94), 7.455 (5.61), 7.458 (5.42), 7.469 (5.23), 7.473 (5.18),7.489 (3.79), 7.502 (6.11), 7.524 (10.25), 7.573 (6.05), 7.578 (5.39), 7.595(3.25), 7.601 (3.05), 8.693 (1.77), 8.708 (3.30)。

Example 83

(+) -5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]2R) -2-methylpyrrolidin-1-yl]Quinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(Epimers2)

To (+) -5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]2R) -2-methylpyrrolidin-1-yl]Quinolin-4-yl } carbonyl) amino]-tert-butyl 4- (2-chlorophenyl) valerate (130 mg, 211 μmol, epimer)2Example 122A) in dichloromethane (1.6ml) was added TFA (360 μ l, 4.7 mmol) and the mixture was left to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 67 mg (100% purity, 57% of theory) of the title compound are obtained.

[α]_D ²⁰= 32.3 °, 589 nm, c = 0.29 g/100 ml, methanol

LC-MS (method 1) R_t= 1.82 min; MS (ESIpos): m/z = 558/560 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.45), 0.008 (1.37), 0.070(1.15), 1.141 (15.90), 1.156 (16.00), 1.234 (0.48), 1.511 (0.49), 1.540(1.33), 1.556 (1.56), 1.563 (1.54), 1.578 (1.53), 1.591 (1.12), 1.607 (1.00),1.618 (0.48), 1.646 (0.89), 1.663 (1.38), 1.688 (1.40), 1.708 (0.86), 1.792(0.76), 1.810 (1.48), 1.832 (1.92), 1.854 (1.17), 1.879 (1.22), 1.895 (1.83),1.910 (1.71), 1.924 (1.44), 2.040 (3.92), 2.082 (7.77), 2.097 (9.79), 2.127(4.49), 2.149 (2.42), 3.551 (1.52), 3.586 (2.61), 3.609 (1.77), 3.623 (1.97),3.636 (1.06), 3.691 (1.34), 3.708 (1.88), 3.715 (2.78), 3.732 (3.09), 3.740(2.44), 3.756 (2.09), 4.360 (1.33), 4.375 (2.20), 4.382 (1.74), 4.391 (1.81),4.397 (2.08), 4.413 (1.27), 7.260 (1.62), 7.278 (3.41), 7.297 (2.41), 7.362(2.67), 7.381 (3.92), 7.399 (2.14), 7.435 (5.68), 7.438 (5.69), 7.455 (4.64),7.458 (4.55), 7.481 (3.87), 7.498 (7.60), 7.520 (9.64), 7.566 (5.08), 7.572(4.98), 7.588 (2.76), 7.594 (2.84), 8.688 (1.91), 8.703 (3.11), 8.715 (1.87)。

Example 84

(+/-) -5- ({ [ 6-bromo-2- (3, 4-dihydroisoquinoline-2 (1))H) -yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid (racemate)

1,2,3, 4-tetrahydroisoquinoline (13 mg, 100 μmol) was initially charged to the well of a 96-well MTP and (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl was added]Tert-butyl amino } -4- (2-chlorophenyl) valerate (57mg, 100. mu. mol,racemic modificationExample 37A) was added with DIPEA (50 μ l,287 μmol). The MTP was blocked with a gel film and shaken overnight at 120 ℃. Then, the solvent was removed in a centrifugal drier, and TFA (800 μ l, 10.4 mmol) was added to the residue. The MTP was blocked again with a gel film and shaken overnight at room temperature. Then, TFA was removed in a centrifugal drier and the residue was dissolved in DMF (600 μ l). The solution was filtered through a filter plate and the filtrate was purified by preparative HPLC-MS (method 17). Removal of the solvent and drying in vacuo gives 12mg (96% purity, 19% of theory) of the title compound.

LC-MS (method 16) R_t= 1.26 min; MS (ESIpos): m/z = 606/608 [M+H]⁺

Example 85

5- [ ({ 6-bromo-2- [ 3-carbamoylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(mixture of diastereomers)

From (+/-) -piperidine-3-carboxamide (13 mg, 100. mu. mol) and (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Tert-butyl amino } -4- (2-chlorophenyl) valerate (57mg, 100. mu. mol,racemic modificationExample 37A) was started in analogy to the preparation of (+/-) -5- ({ [ 6-bromo-2- (3, 4-dihydroisoquinoline-2 (1)H) -yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid (example)84) 11 mg (95% purity, 18% of theory) of the title compound are obtained.

LC-MS (method 16) R_t= 1.00 min; MS (ESIpos): m/z = 601/603 [M+H]⁺

Example 86

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (octahydro-2)H-isoindol-2-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(racemic or diastereomeric mixture)

From octahydro-1HIsoindole hydrochloride (13 mg, 100 μmol, molar based on free amine, stereochemical unknown) and (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Tert-butyl amino } -4- (2-chlorophenyl) valerate (57mg, 100. mu. mol,racemic modificationExample 37A) was started in analogy to the preparation of (+/-) -5- ({ [ 6-bromo-2- (3, 4-dihydroisoquinoline-2 (1)H) -yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid (example 84) to yield 8mg (100% purity, 13% of theory) of the title compound.

LC-MS (method 16) R_t= 0.95 min; MS (ESIpos): m/z = 598/600 [M+H]⁺

Example 87

(+/-) -5- ({ [ 6-bromo-2- (1, 1-thiomorpholin-4-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(raceme)

From thiomorpholine 1, 1-dioxide (14 mg, 100 μmol) and (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Tert-butyl amino } -4- (2-chlorophenyl) valerate (57mg, 100. mu. mol,racemic modificationExample 37A) was started in analogy to the preparation of (+/-) -5- ({ [ 6-bromo-2- (3, 4-dihydroisoquinoline-2 (1)H) -yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid (example 84) to yield 1 mg (100% purity, 2% of theory) of the title compoundThe title compound.

LC-MS (method 16) R_t= 1.08 min; MS (ESIpos): m/z = 608/610 [M+H]⁺

Example 88

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (4-oxoimidazolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(raceme)

From imidazolidin-4-one hydrochloride (9 mg, 100. mu. mol, molar amounts based on free amine) and (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Tert-butyl amino } -4- (2-chlorophenyl) valerate (57mg, 100. mu. mol,externally-applied medicine Rotary bodyExample 37A) was started in analogy to the preparation of (+/-) -5- ({ [ 6-bromo-2- (3, 4-dihydroisoquinoline-2 (1)H) -yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid (example 84) to yield 1.7 mg (100% purity, 3% of theory) of the title compound.

LC-MS (method 16) R_t= 1.00 min; MS (ESIpos): m/z = 559/561 [M+H]⁺

Example 89

5- [ ({ 6-bromo-3-methyl-2- [ 2-methylmorpholin-4-yl)]Quinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(mixture of diastereomers)

From (+/-) -2-methylmorpholine (10 mg, 100 μmol) and (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Tert-butyl amino } -4- (2-chlorophenyl) valerate (57mg, 100. mu. mol,racemic modificationExample 37A) was started in analogy to the preparation of (+/-) -5- ({ [ 6-bromo-2- (3, 4-dihydroisoquinoline-2 (1)H) -yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid (example 84) to yield 1.7 mg (100% purity, 3% of theory) of the title compound.

LC-MS (method 16) R_t= 1.14 min; MS (ESIpos): m/z = 574/576 [M+H]⁺

Example 90

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (1, 4-oxazepan-4-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(raceme)

From 1, 4-Oxazacycloheptane hydrochloride (10 mg, 100. mu. mol, molar amounts based on free amine) and (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Tert-butyl amino } -4- (2-chlorophenyl) valerate (57mg, 100. mu. mol,racemic modificationExample 37A) was started in analogy to the preparation of (+/-) -5- ({ [ 6-bromo-2- (3, 4-dihydroisoquinoline-2 (1)H) -yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid (example 84) to yield 3.4 mg (100% purity, 6% of theory) of the title compound.

LC-MS (method 16) R_t= 1.10 min; MS (ESIpos): m/z = 574/576 [M+H]⁺

Example 91

5- [ ({ 6-bromo-2- [ 3-isopropylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(mixture of diastereomers)

From (+/-) -3-isopropylpiperidine (13 mg, 100. mu. mol) and (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Tert-butyl amino } -4- (2-chlorophenyl) valerate (57mg, 100. mu. mol,racemic modificationExample 37A) was started in analogy to the preparation of (+/-) -5- ({ [ 6-bromo-2- (3, 4-dihydroisoquinoline-2 (1)H) -yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid (example 84) to yield 10 mg (99% purity, 16% of theory) of the title compound.

LC-MS (method 16) R_t= 1.28 min; MS (ESIpos): m/z = 600/602 [M+H]⁺

Example 92

(+/-) -5- ({ [ 6-bromo-2- (3-methoxyazetidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(raceme)

From 3-Methoxyazetidine hydrochloride (9 mg, 100. mu. mol, molar amounts based on free amine) and (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Tert-butyl amino } -4- (2-chlorophenyl) valerate (57mg, 100. mu. mol,racemic modificationExample 37A) was started in analogy to the preparation of (+/-) -5- ({ [ 6-bromo-2- (3, 4-dihydroisoquinoline-2 (1)H) -yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid (example 84) to yield 3.2 mg (100% purity, 7% of theory) of the title compound.

LC-MS (method 16) R_t= 0.88 min; MS (ESIpos): m/z = 560/562 [M+H]⁺

Example 93

5- [ ({ 6-bromo-2- [3- (methoxymethyl) piperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(mixture of diastereomers)

From (+/-) -3- (methoxymethyl) piperidine (13 mg, 100. mu. mol) and (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Tert-butyl amino } -4- (2-chlorophenyl) valerate (57mg, 100. mu. mol,racemic modificationExample 37A) was started in analogy to the preparation of (+/-) -5- ({ [ 6-bromo-2- (3, 4-dihydroisoquinoline-2 (1)H) -yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid (example 84) to yield 10 mg (100% purity, 16% of theory) of the title compound.

LC-MS (method 16) R_t= 1.18 min; MS (ESIpos): m/z = 602/604 [M+H]⁺

Example 94

(+/-) -5- [ ({ 6-bromo-3-methyl-2- [ (2-phenylethyl) amino group]Quinolin-4-yl } carbonyl) amino]-4-(2-chlorophenyl) pentanoic acid(raceme)

From 2-phenylethylamine (12 mg, 100. mu. mol) and (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Tert-butyl amino } -4- (2-chlorophenyl) valerate (57mg, 100. mu. mol,racemic modificationExample 37A) was started in analogy to the preparation of (+/-) -5- ({ [ 6-bromo-2- (3, 4-dihydroisoquinoline-2 (1)H) -yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid (example 84) to yield 8.5 mg (97% purity, 14% of theory) of the title compound.

LC-MS (method 16) R_t= 0.97 min; MS (ESIpos): m/z = 594/596 [M+H]⁺

Example 95

(+/-) -5- [ ({ 6-bromo-3-methyl-2- [ methyl (2-phenylethyl) amino)]Quinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(raceme)

FromN-methyl-2-phenylethylamine (14 mg, 100 μmol) and (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Tert-butyl amino } -4- (2-chlorophenyl) valerate (57mg, 100. mu. mol,racemic modificationExample 37A) was started in analogy to the preparation of (+/-) -5- ({ [ 6-bromo-2- (3, 4-dihydroisoquinoline-2 (1)H) -yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid (example 84) to yield 8mg (98% purity, 12% of theory) of the title compound.

LC-MS (method 16) R_t= 1.23 min; MS (ESIpos): m/z = 608/610 [M+H]⁺

Example 96

(+/-) -5- ({ [2- (benzylamino) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(raceme)

From 1-phenylmethylamine (11 mg, 100. mu. mol) and (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Tert-butyl amino } -4- (2-chlorophenyl) valerate (57mg, 100. mu. mol,racemic modificationExample 37A) was started in analogy to the preparation of (+/-) -5- ({ [ 6-bromo-2- (3, 4-dihydroisoquinoline-2 (1)H) -yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid (example 84) to yield 4 mg (94% purity, 6% of theory) of the title compound.

LC-MS (method 16) R_t= 1.04 min; MS (ESIpos): m/z = 580/582 [M+H]⁺

Example 97

(+/-) -5- ({ [ 6-bromo-2- (cyclobutylamino) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(raceme)

From cyclobutylamine hydrochloride (7 mg, 100. mu. mol, molar amounts based on free amine) and (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Tert-butyl amino } -4- (2-chlorophenyl) valerate (57mg, 100. mu. mol,racemic modificationExample 37A) was started in analogy to the preparation of (+/-) -5- ({ [ 6-bromo-2- (3, 4-dihydroisoquinoline-2 (1)H) -yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid (example 84) to yield 2mg (100% purity, 4% of theory) of the title compound.

LC-MS (method 16) R_t= 0.87 min; MS (ESIpos): m/z = 544/546 [M+H]⁺

Example 98

(+/-) -5- [ ({ 6-bromo-3-methyl-2- [ (3,3, 3-trifluoropropyl) amino group]Quinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(raceme)

From 3,3, 3-trifluoropropan-1-amine (11 mg, 100. mu. mol) and (+/-) -5- { [ (6-bromo-2-chloro)-3-methylquinolin-4-yl) carbonyl]Tert-butyl amino } -4- (2-chlorophenyl) valerate (57mg, 100. mu. mol,racemic modificationExample 37A) was started in analogy to the preparation of (+/-) -5- ({ [ 6-bromo-2- (3, 4-dihydroisoquinoline-2 (1)H) -yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid (example 84) to yield 1.5 mg (98% purity, 2% of theory) of the title compound.

LC-MS (method 16) R_t= 1.09 min; MS (ESIpos): m/z = 586/588 [M+H]⁺

Example 99

(+/-) -5- [ ({ 6-bromo-2- [ (cyclohexylmethyl) amino group]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(raceme)

From 1-cyclohexylmethylamine (11 mg, 100. mu. mol) and (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Tert-butyl amino } -4- (2-chlorophenyl) valerate (57mg, 100. mu. mol,racemic modificationExample 37A) was started in analogy to the preparation of (+/-) -5- ({ [ 6-bromo-2- (3, 4-dihydroisoquinoline-2 (1)H) -yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid (example 84) to yield 5 mg (98% purity, 9% of theory) of the title compound.

LC-MS (method 16) R_t= 0.96 min; MS (ESIpos): m/z = 586/588 [M+H]⁺

Example 100

(+/-) -5- [ ({ 6-bromo-2- [ (cyclopropylmethyl) amino group]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(raceme)

From 1-cyclopropylmethylamine hydrochloride (7 mg, 100. mu. mol, molar amounts based on free amine) and (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Tert-butyl amino } -4- (2-chlorophenyl) valerate (57mg, 100. mu. mol,externally-applied medicine Rotary bodyBeginning with example 37A), the process of example 37A),in analogy to the preparation of (+/-) -5- ({ [ 6-bromo-2- (3, 4-dihydroisoquinoline-2 (1))H) -yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid (example 84) to yield 1.7 mg (100% purity, 3% of theory) of the title compound.

LC-MS (method 16) R_t= 0.86 min; MS (ESIpos): m/z = 544/546 [M+H]⁺

Example 101

(+/-) -5- ({ [ 6-bromo-2- (butylamino) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(raceme)

From butan-1-amine (7.31 mg, 100. mu. mol) and (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Tert-butyl amino } -4- (2-chlorophenyl) valerate (57mg, 100. mu. mol,racemic modificationExample 37A) was started in analogy to the preparation of (+/-) -5- ({ [ 6-bromo-2- (3, 4-dihydroisoquinoline-2 (1)H) -yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid (example 84) to yield 1.7 mg (100% purity, 3% of theory) of the title compound.

LC-MS (method 16) R_t= 0.88 min; MS (ESIpos): m/z = 546/548 [M+H]⁺

Example 102

(+/-) -5- ({ [ 6-bromo-2- (isobutylamino) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(raceme)

From 2-methylpropan-1-amine (7 mg, 100. mu. mol) and (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Tert-butyl amino } -4- (2-chlorophenyl) valerate (57mg, 100. mu. mol,racemic modificationExample 37A) was started in analogy to the preparation of (+/-) -5- ({ [ 6-bromo-2- (3, 4-dihydroisoquinoline-2 (1)H) -yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid (example 84) to yield 1.6 mg (100% purity, 3% of theory) of the title compoundThe title compound.

LC-MS (method 16) R_t= 0.88 min; MS (ESIpos): m/z = 546/548 [M+H]⁺

Example 103

(+/-) -5- ({ [ 6-bromo-2- (cyclopentylamino) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(raceme)

From cyclopentylamine (8.5 mg, 100. mu. mol) and (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Tert-butyl amino } -4- (2-chlorophenyl) valerate (57mg, 100. mu. mol,racemic modificationExample 37A) was started in analogy to the preparation of (+/-) -5- ({ [ 6-bromo-2- (3, 4-dihydroisoquinoline-2 (1)H) -yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid (example 84) to yield 6 mg (98% purity, 10% of theory) of the title compound.

LC-MS (method 16) R_t= 0.89 min; MS (ESIpos): m/z = 558/560 [M+H]⁺

Example 104

(+/-) -5- [ ({ 6-bromo-2- [ (2-methoxyethyl) amino)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(raceme)

From 2-methoxyethylamine (7.5 mg, 100. mu. mol) and (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Tert-butyl amino } -4- (2-chlorophenyl) valerate (57mg, 100. mu. mol,racemic modificationExample 37A) was started in analogy to the preparation of (+/-) -5- ({ [ 6-bromo-2- (3, 4-dihydroisoquinoline-2 (1)H) -yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid (example 84) to yield 5 mg (100% purity, 10% of theory) of the title compound.

LC-MS (method 16) R_t= 0.83 min; MS (ESIpos): m/z = 548/550 [M+H]⁺

Example 105

(+/-) -5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(raceme)

From azepane (10 mg, 100. mu. mol) and (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Tert-butyl amino } -4- (2-chlorophenyl) valerate (57mg, 100. mu. mol,racemic modificationExample 37A) was started in analogy to the preparation of (+/-) -5- ({ [ 6-bromo-2- (3, 4-dihydroisoquinoline-2 (1)H) -yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid (example 84) to yield 9mg (100% purity, 15% of theory) of the title compound.

LC-MS (method 16) R_t= 1.14 min; MS (ESIpos): m/z = 572/574 [M+H]⁺

Example 106

(-) -5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(enantiomer 1)

To (-) -5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester (460 mg, 731 μmol,enantiomer 1Example 124A) in dichloromethane (5.6 ml) TFA (1.2 ml, 16 mmol) was added and the mixture was left to stand at room temperature for 22 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 353 mg (100% purity, 84% of theory) of the title compound are obtained.

[α]_D ²⁰= 11.0 °, 589 nm, c = 0.45 g/100 ml, methanol

LC-MS (method 1) R_t= 2.24 min; MS (ESIpos): m/z = 572/574 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.234 (0.92), 1.602 (13.71), 1.781(9.13), 1.838 (2.48), 1.861 (1.35), 1.885 (0.41), 2.015 (0.52), 2.027 (0.93),2.047 (3.94), 2.080 (5.20), 2.088 (5.61), 2.097 (3.42), 2.126 (16.00), 2.158(1.47), 2.188 (0.52), 3.488 (10.68), 3.503 (15.64), 3.517 (10.53), 3.575(1.79), 3.591 (2.07), 3.666 (2.69), 7.254 (1.70), 7.273 (4.00), 7.292 (2.84),7.355 (2.46), 7.374 (4.52), 7.392 (2.65), 7.440 (6.52), 7.460 (5.09), 7.481(5.13), 7.500 (3.64), 7.525 (5.49), 7.547 (10.22), 7.591 (5.50), 7.596(5.36), 7.613 (2.93), 7.618 (2.95), 8.684 (2.11), 8.698 (4.20), 8.712 (2.10),12.061 (0.74)。

Example 107

(+) -5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(enantiomer 2)

To (+) -5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester (460 mg, 731 μmol,enantiomer 2Example 125A) in dichloromethane (5.6 ml) TFA (1.2 ml, 16 mmol) was added and the mixture was left to stand at room temperature for 22 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 312 mg (100% purity, 74% of theory) of the title compound are obtained.

[α]_D ²⁰= 12.5 °, 589 nm, c = 0.50 g/100 ml, methanol

LC-MS (method 1) R_t= 2.25 min; MS (ESIpos): m/z = 572/574 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.602 (13.76), 1.780 (9.07), 1.839(2.47), 1.861 (1.35), 1.884 (0.43), 2.048 (3.93), 2.082 (5.18), 2.089 (5.61),2.126 (16.00), 2.159 (1.44), 2.188 (0.56), 3.488 (10.85), 3.503 (15.65),3.517 (10.64), 3.592 (2.07), 3.666 (2.71), 7.255 (1.73), 7.273 (4.04), 7.293(2.84), 7.355 (2.51), 7.374 (4.61), 7.392 (2.69), 7.438 (6.62), 7.441 (6.85),7.458 (5.22), 7.461 (5.35), 7.482 (5.16), 7.499 (3.67), 7.525 (5.79), 7.547(10.73), 7.591 (5.94), 7.596 (5.65), 7.613 (3.13), 7.618 (3.13), 8.684(2.16), 8.698 (4.31), 8.712 (2.14), 12.058 (0.92)。

Example 108

5- [ ({ 6-bromo-3-methyl-2- [ 2-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(mixture of diastereomers)

From (+/-) -2-methylpiperidine (10 mg, 100. mu. mol) and (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Tert-butyl amino } -4- (2-chlorophenyl) valerate (57mg, 100. mu. mol,racemic modificationExample 37A) was started in analogy to the preparation of (+/-) -5- ({ [ 6-bromo-2- (3, 4-dihydroisoquinoline-2 (1)H) -yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid (example 84) to yield 2mg (94% purity, 3% of theory) of the title compound.

LC-MS (method 16) R_t= 1.13 min; MS (ESIpos): m/z = 572/574 [M+H]⁺

Example 109

(+/-) -5- ({ [ 6-bromo-2- (ethylamino) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(raceme)

From ethylamine hydrochloride (5 mg, 100. mu. mol, molar amounts based on free amine) and (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Tert-butyl amino } -4- (2-chlorophenyl) valerate (57mg, 100. mu. mol,racemic modificationExample 37A) was started in analogy to the preparation of (+/-) -5- ({ [ 6-bromo-2- (3, 4-dihydroisoquinoline-2 (1)H) -yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid (example 84) to yield 1.8 mg (100% purity, 3% of theory) of the title compound.

LC-MS (method 16) R_t= 0.8 min; MS (ESIpos): m/z = 518/520 [M+H]⁺

Example 110

(+/-) -5- ({ [2- (5-Nitrogen)Hetero spiro [2.5 ]]Oct-5-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid(raceme)

From 5-azaspiro [2.5 ]]Octane hydrochloride (11 mg, 100. mu. mol, molar amounts based on free amine) and (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Tert-butyl amino } -4- (2-chlorophenyl) valerate (57mg, 100. mu. mol,racemic modificationExample 37A) was started in analogy to the preparation of (+/-) -5- ({ [ 6-bromo-2- (3, 4-dihydroisoquinoline-2 (1)H) -yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid (example 84) to yield 2.6 mg (100% purity, 4% of theory) of the title compound.

LC-MS (method 16) R_t= 1.23 min; MS (ESIpos): m/z = 584/586 [M+H]⁺

Example 111

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethyl) phenyl]Valeric acid(raceme)

To (+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethyl) phenyl]Tert-butyl valerate (85 mg, 131 μmol,racemic modificationExample 126A) in dichloromethane (1.5ml) TFA (200 μ l, 2.6 mmol) was added and the mixture was stirred at room temperature for 18 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 52 mg (100% purity, 67% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.23 min; MS (ESIpos): m/z = 592/594 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.611 (5.32), 1.679 (10.54), 1.897(1.82), 1.907 (1.73), 1.928 (2.08), 1.942 (1.97), 1.962 (1.64), 1.979 (2.69),1.992 (1.70), 2.003 (3.05), 2.023 (0.92), 2.040 (1.68), 2.055 (3.02), 2.078(3.08), 2.096 (1.81), 2.114 (3.33), 2.165 (16.00), 3.150 (13.69), 3.606(1.32), 3.623 (2.06), 3.639 (2.27), 3.684 (1.45), 3.700 (2.32), 3.716 (1.96),3.733 (1.31), 7.435 (1.23), 7.463 (2.79), 7.482 (4.90), 7.501 (3.01), 7.634(2.00), 7.656 (15.77), 7.664 (9.55), 7.687 (3.06), 7.707 (5.08), 7.724(11.45), 7.733 (8.28), 7.742 (6.88), 8.767 (2.49), 8.782 (4.97), 8.796(2.45), 12.044 (0.78)。

Example 112

(-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethyl) phenyl]Valeric acid(enantiomer 1)

To (-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethyl) phenyl]Tert-butyl valerate (225 mg, 347 μmol,enantiomer 1Example 127A) in dichloromethane (2.6ml) was added TFA (590 μ l, 7.6 mmol) and the mixture was allowed to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 142 mg (100% purity, 69% of theory) of the title compound are obtained.

[α]_D ²⁰= 20.5 °, 589 nm, c = 0.37 g/100 ml, methanol

LC-MS (method 1) R_t= 2.25 min; MS (ESIpos): m/z = 592/594 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.163 (1.22), 1.181 (2.62), 1.199(1.29), 1.614 (4.47), 1.681 (8.91), 1.897 (1.55), 1.907 (1.43), 1.928 (1.72),1.942 (1.72), 1.964 (1.35), 1.981 (2.37), 1.993 (1.47), 2.005 (2.77), 2.024(0.81), 2.041 (1.51), 2.055 (2.72), 2.078 (2.75), 2.096 (1.57), 2.114 (2.87),2.166 (13.61), 2.328 (0.45), 3.077 (0.70), 3.089 (0.80), 3.095 (0.79), 3.107(0.82), 3.160 (11.47), 3.324 (2.20), 3.345 (2.07), 3.589 (2.39), 3.605(2.50), 3.622 (2.85), 3.638 (2.83), 3.685 (1.74), 3.700 (2.38), 3.716 (2.02),3.733 (1.42), 7.432 (0.97), 7.464 (2.39), 7.483 (4.25), 7.501 (2.59), 7.643(1.56), 7.665 (16.00), 7.672 (8.78), 7.689 (2.46), 7.708 (4.46), 7.724(9.86), 7.734 (6.97), 7.742 (5.94), 8.769 (2.26), 8.784 (4.59), 8.799 (2.17)。

Example 113

(+) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethyl) phenyl]Valeric acid(enantiomer 2)

To (+) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethyl) phenyl]Tert-butyl valerate (230 mg, 355 μmol,enantiomer 2Example 128A) in dichloromethane (2.7ml) was added TFA (600 μ l, 7.8 mmol) and the mixture was left to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 158 mg (100% purity, 75% of theory) of the title compound are obtained.

[α]_D ²⁰= 22.7 °, 589 nm, c = 0.49 g/100 ml, methanol

LC-MS (method 1) R_t= 2.25 min; MS (ESIpos): m/z = 592/594 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.614 (4.61), 1.681 (9.03), 1.896(1.62), 1.907 (1.52), 1.928 (1.80), 1.942 (1.79), 1.963 (1.45), 1.980 (2.43),1.993 (1.57), 2.004 (2.84), 2.025 (0.92), 2.040 (1.60), 2.055 (2.81), 2.078(2.82), 2.096 (1.75), 2.113 (3.02), 2.165 (13.52), 2.328 (0.42), 3.160(11.56), 3.324 (2.39), 3.492 (2.62), 3.589 (1.71), 3.606 (1.97), 3.622(2.44), 3.639 (2.48), 3.684 (1.64), 3.699 (2.30), 3.716 (1.91), 3.732 (1.31),7.463 (2.54), 7.483 (4.26), 7.501 (2.53), 7.643 (1.92), 7.666 (16.00), 7.672(8.62), 7.689 (2.69), 7.694 (2.06), 7.708 (4.85), 7.724 (10.06), 7.734(7.01), 7.742 (5.89), 8.769 (2.40), 8.784 (4.53), 8.799 (2.10)。

Example 114

(+/-) -5- ({ [ 6-bromo)-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethyl) phenyl]Valeric acid(raceme)

To (+/-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethyl) phenyl]Tert-butyl valerate (85 mg, 134 μmol,racemic modificationExample 129A) in dichloromethane (1.5ml) TFA (210 μ l, 2.7 mmol) was added and the mixture was stirred at room temperature for 18 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 40 mg (100% purity, 52% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 1.54 min; MS (ESIpos): m/z = 578/580 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.879 (16.00), 1.924 (3.02), 1.951(2.34), 1.968 (2.79), 1.980 (1.68), 1.992 (2.98), 2.011 (1.08), 2.037 (1.55),2.053 (3.01), 2.076 (3.20), 2.093 (2.11), 2.113 (3.51), 2.181 (6.81), 2.281(0.57), 2.327 (0.41), 3.318 (6.26), 3.709 (2.16), 3.725 (1.96), 3.741 (1.48),7.341 (0.65), 7.434 (0.44), 7.457 (2.26), 7.477(11.20), 7.500 (13.68), 7.550(6.77), 7.555 (6.41), 7.572 (3.79), 7.578 (3.74), 7.685 (1.86), 7.705 (5.30),7.716 (8.48), 7.733 (10.38), 7.747 (2.43), 8.715 (2.47), 8.729 (4.76), 8.744(2.37)。

Example 115

(+) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethyl) phenyl]Valeric acid(enantiomer 1)

To (+) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethyl) phenyl]Tert-butyl valerate (160 mg, 252 μmol,enantiomer 1Example 130A) in dichloromethane (1.9ml) TFA (430 μ l, 5.5 mmol) was added and the mixture was allowed to stand at room temperaturePlacing for 22 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 73 mg (100% purity, 50% of theory) of the title compound are obtained.

[α]_D ²⁰= 18.9 °, 589 nm, c = 0.47 g/100 ml, methanol

LC-MS (method 1) R_t= 1.52 min; MS (ESIpos): m/z = 578/580 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.879 (16.00), 1.925 (2.74), 1.954(2.21), 1.971 (2.77), 1.984 (1.69), 1.996 (3.01), 2.014 (1.13), 2.041 (1.58),2.055 (3.04), 2.079 (3.17), 2.096 (2.13), 2.115 (3.52), 2.138 (2.71), 2.181(6.83), 2.281 (0.59), 2.328 (0.43), 3.583 (12.90), 3.693 (1.38), 3.709(2.16), 3.725 (1.92), 3.742 (1.48), 7.335 (0.61), 7.459 (2.16), 7.477(10.75), 7.500 (13.45), 7.551 (6.29), 7.556 (6.19), 7.573 (3.60), 7.578(3.64), 7.686 (1.82), 7.706 (5.20), 7.717 (8.11), 7.734 (10.70), 7.749(2.41), 8.711 (2.44), 8.726 (4.79), 8.741 (2.38), 12.044 (0.69)。

Example 116

(-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethyl) phenyl]Valeric acid(enantiomer 2)

To (-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethyl) phenyl]Tert-butyl valerate (170 mg, 268 μmol,enantiomer 2Example 131A) in dichloromethane (2.1ml) TFA (450 μ l, 5.9 mmol) was added and the mixture was left to stand at room temperature for 22 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 81 mg (100% purity, 52% of theory) of the title compound are obtained.

[α]_D ²⁰= 17.5 °, 589 nm, c = 0.41 g/100 ml, methanol

LC-MS (method 1) R_t= 1.52 min; MS (ESIpos): m/z = 578/580 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.236 (0.42), 1.885 (16.00), 1.935(2.55), 1.957 (2.22), 1.974 (2.98), 1.986 (1.84), 1.998 (3.37), 2.016 (1.29),2.041 (1.73), 2.056 (3.35), 2.080 (3.42), 2.097 (2.31), 2.115 (3.73), 2.137(2.74), 2.186 (6.71), 2.328 (0.54), 2.670 (0.46), 3.597 (11.63), 3.711(2.35), 3.727 (2.10), 3.744 (1.60), 7.246 (0.44), 7.334 (0.66), 7.459 (2.46),7.478 (5.04), 7.497 (4.57), 7.519 (2.99), 7.567 (3.96), 7.588 (2.35), 7.687(1.96), 7.706 (5.62), 7.717 (8.55), 7.734 (12.13), 7.750 (2.51), 8.719(2.21), 8.734 (4.05), 8.748 (2.14), 12.028 (1.34)。

Example 117

(+/-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethyl) phenyl]Valeric acid(raceme)

To (+/-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethyl) phenyl]Tert-butyl valerate (85 mg, 124 μmol,racemic modificationExample 132A) in dichloromethane (1.5ml) TFA (190 μ l, 2.5 mmol) was added and the mixture was stirred at room temperature for 18 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 46 mg (100% purity, 59% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.17 min; MS (ESIpos): m/z = 628/630 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.896 (6.19), 1.980 (2.25), 2.004(2.45), 2.055 (3.73), 2.078 (4.51), 2.114 (5.44), 2.136 (4.06), 2.185(12.02), 2.670 (0.22), 3.180 (6.09), 3.463 (3.22), 3.492 (5.91), 3.520(3.16), 3.648 (1.96), 3.710 (1.91), 7.465 (2.61), 7.483 (4.20), 7.501 (2.79),7.707 (16.00), 7.725 (9.34), 7.738 (8.33), 8.793 (3.72), 12.049 (0.53)。

Example 118

(-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethyl) phenyl]Valeric acid(enantiomer 1)

To (-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethyl) phenyl]Tert-butyl valerate (85 mg, 124 μmol,enantiomer 1Example 133A) to a dichloromethane (960 μ l) solution TFA (210 μ l, 2.7 mmol) was added and the mixture was left to stand at room temperature for 22 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 65 mg (100% purity, 83% of theory) of the title compound are obtained.

[α]_D ²⁰= 18.2 °, 589 nm, c = 0.49 g/100 ml, methanol

LC-MS (method 1) R_t= 2.19 min; MS (ESIpos): m/z = 628/630 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.899 (4.56), 1.946 (1.50), 1.953(1.22), 1.967 (1.16), 1.984 (1.98), 1.997 (1.22), 2.008 (2.30), 2.028 (0.88),2.043 (1.59), 2.057 (3.11), 2.065 (2.55), 2.081 (3.82), 2.099 (3.51), 2.118(4.18), 2.137 (2.87), 2.152 (2.34), 2.186 (10.54), 2.227 (0.62), 3.182(4.64), 3.464 (2.89), 3.493 (5.52), 3.522 (2.77), 3.617 (0.87), 3.634 (1.31),3.649 (1.45), 3.712 (1.41), 3.727 (1.22), 7.467 (2.12), 7.486 (3.75), 7.504(2.35), 7.685 (1.58), 7.692 (1.59), 7.708 (16.00), 7.713 (10.69), 7.727(7.64), 7.743 (7.02), 7.758 (1.87), 8.777 (1.83), 8.792 (3.78), 8.807 (1.84),12.035 (1.20)。

Example 119

(+) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethyl) phenyl]Valeric acid(enantiomer 2)

To (+) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylQuinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethyl) phenyl]Tert-butyl valerate (60 mg, 87.6 μmol,enantiomer 2Example 134A) in dichloromethane (670 μ l) was added TFA (150 μ l, 1.9 mmol) and the mixture was allowed to stand at room temperature for 22 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 38 mg (100% purity, 69% of theory) of the title compound are obtained.

[α]_D ²⁰= 18.9 °, 589 nm, c = 0.39 g/100 ml, methanol

LC-MS (method 1) R_t= 2.19 min; MS (ESIpos): m/z = 628/630 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.898 (4.75), 1.944 (1.51), 1.965(1.18), 1.982 (1.96), 1.995 (1.22), 2.006 (2.25), 2.026 (0.88), 2.041 (1.53),2.055 (3.13), 2.063 (2.55), 2.079 (3.69), 2.097 (3.46), 2.116 (4.22), 2.136(2.97), 2.150 (2.39), 2.185 (10.76), 2.225 (0.69), 3.180 (4.82), 3.463(2.94), 3.492 (5.61), 3.520 (2.84), 3.632 (1.38), 3.648 (1.51), 3.710 (1.47),3.726 (1.28), 7.466 (2.20), 7.485 (3.79), 7.503 (2.39), 7.684 (1.67), 7.691(1.73), 7.707 (16.00), 7.726 (7.79), 7.742 (6.86), 7.757 (1.83), 8.777(1.83), 8.791 (3.69), 8.806 (1.78), 12.037 (0.82)。

Example 120

(+/-) -5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethyl) phenyl]Valeric acid(raceme)

To (+/-) -5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethyl) phenyl]Tert-butyl valerate (85 mg, 128 μmol,racemic modificationExample 135A) in dichloromethane (1.5ml) TFA (200 μ l, 2.6 mmol) was added and the mixture was stirred at room temperature for 18 h. Then concentrating the mixture and repeatedly addingDichloromethane was added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 60 mg (100% purity, 77% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.28 min; MS (ESIpos): m/z = 606/608 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.610 (14.32), 1.791 (9.69), 1.899(1.71), 1.908 (1.60), 1.930 (2.04), 1.945 (1.85), 1.961 (1.78), 1.978 (2.56),1.990 (1.59), 2.002 (2.80), 2.011 (1.67), 2.041 (1.48), 2.056 (2.80), 2.079(3.00), 2.097 (1.87), 2.116 (3.51), 2.152 (11.34), 3.505 (10.82), 3.519(16.00), 3.533 (10.80), 3.609 (1.63), 3.624 (1.73), 3.705 (1.75), 3.720(1.56), 7.371 (0.83), 7.463 (2.07), 7.482 (4.24), 7.501 (2.63), 7.537 (5.32),7.559 (10.25), 7.599 (5.62), 7.604 (5.69), 7.622 (2.80), 7.626 (2.98), 7.689(1.75), 7.709 (4.73), 7.722 (8.25), 7.739 (9.99), 7.754 (2.31), 8.739 (2.25),8.754 (4.52), 8.769 (2.24), 12.037 (1.01)。

Example 121

(-) -5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethyl) phenyl]Valeric acid(enantiomer 1)

To (-) -5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethyl) phenyl]Tert-butyl valerate (70 mg, 106 μmol,enantiomer 1Example 136A) in dichloromethane (810 μ l) TFA (180 μ l, 2.3 mmol) was added and the mixture was allowed to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 44 mg (100% purity, 69% of theory) of the title compound are obtained.

[α]_D ²⁰= 17.2 °, 589 nm, c = 0.43 g/100 ml, methanol

LC-MS (method 1) R_t= 2.30 min; MS (ESIpos): m/z = 606/608 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.609 (14.30), 1.790(9.46), 1.896(1.66), 1.905 (1.58), 1.927 (2.05), 1.942 (1.89), 1.957 (1.86), 1.973 (2.51),1.986 (1.54), 1.997 (2.79), 2.007 (1.65), 2.037 (1.43), 2.052 (2.75), 2.075(2.90), 2.093 (1.79), 2.112 (3.33), 2.150 (11.02), 2.328 (0.44), 2.670(0.42), 3.504 (11.33), 3.518 (16.00), 3.533 (11.13), 3.607 (1.63), 3.621(1.70), 3.704 (1.72), 7.369 (0.84), 7.462 (2.12), 7.481 (4.20), 7.500 (2.62),7.536 (5.72), 7.558 (10.90), 7.599 (6.17), 7.604 (5.82), 7.621 (3.10), 7.626(3.06), 7.688 (1.73), 7.707 (4.75), 7.721 (8.19), 7.737 (9.36), 7.752 (2.20),8.740 (2.23), 8.755 (4.40), 8.770 (2.18), 12.042 (0.47)。

Example 122

(+) -5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethyl) phenyl]Valeric acid(enantiomer 2)

To (+) -5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethyl) phenyl]Tert-butyl valerate (65 mg, 98.1 μmol,enantiomer 2Example 137A) in dichloromethane (750 μ l) TFA (170 μ l, 2.2 mmol) was added and the mixture was allowed to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 44 mg (100% purity, 74% of theory) of the title compound are obtained.

[α]_D ²⁰= 16.9 °, 589 nm, c = 0.38 g/100 ml, methanol

LC-MS (method 1) R_t= 2.30 min; MS (ESIpos): m/z = 606/608 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.234 (0.46), 1.341 (0.42), 1.353(0.63), 1.371 (2.44), 1.609 (14.42), 1.790 (9.61), 1.896 (1.69), 1.906(1.59), 1.927 (2.08), 1.942 (1.89), 1.957 (1.81), 1.974(2.47), 1.987 (1.58),1.998 (2.65), 2.038 (1.46), 2.053 (2.67), 2.076 (2.81), 2.094 (1.80), 2.114(3.37), 2.151 (11.17), 3.504 (11.21), 3.518 (16.00), 3.533 (11.08), 3.608(1.66), 3.622 (1.72), 3.704 (1.75), 3.720 (1.56), 7.367 (0.82), 7.462 (2.06),7.481 (4.17), 7.499 (2.61), 7.536 (5.40), 7.558 (10.42), 7.599 (5.89), 7.604(5.66), 7.621 (2.99), 7.626 (2.99), 7.688 (1.66), 7.707 (4.67), 7.721 (8.20),7.737 (9.48), 7.752 (2.35), 8.740 (2.22), 8.755 (4.42), 8.770 (2.21)。

Example 123

5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Valeric acid(mixture of diastereomers)

To 5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Tert-butyl valerate (85 mg, 128 μmol,mixtures of diastereomersExample 138A) in dichloromethane (1.5ml) TFA (200 μ l, 2.6 mmol) was added and the mixture was stirred at room temperature for 18 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 55 mg (100% purity, 71% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.12 min; MS (ESIpos): m/z = 610/612 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.652 (1.93), 1.773 (0.54), 1.812(1.78), 1.829 (1.51), 1.908 (4.68), 1.928 (4.50), 1.943 (3.34), 1.952 (3.13),1.982 (3.45), 1.994 (2.44), 2.006 (3.39), 2.041 (1.73), 2.057 (2.96), 2.080(3.00), 2.097 (1.82), 2.116 (3.20), 2.140 (2.39), 2.178 (14.18), 3.084(1.27), 3.114 (2.24), 3.170 (2.37), 3.186 (2.31), 3.214 (1.29), 3.317(12.17), 3.395 (2.33), 3.428 (1.26), 3.452 (2.01), 3.480 (1.30), 3.613(1.25), 3.628 (1.89), 3.644 (2.09), 3.707 (1.99), 4.824 (1.57), 4.945 (1.58),7.465 (2.95), 7.484 (4.87), 7.502 (3.00), 7.658 (2.05), 7.681 (16.00), 7.688(10.91), 7.710 (6.16), 7.725 (10.19), 7.741 (8.20), 7.755 (2.49), 8.772(2.36), 8.787 (4.50), 8.801 (2.20), 12.043 (0.89)。

Example 124

5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Valeric acid(mixture of diastereomers)

To 5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Tert-butyl valerate (85 mg, 126 μmol,mixtures of diastereomersExample 139A) in dichloromethane (1.5ml) TFA (190 μ l, 2.5 mmol) was added and the mixture was stirred at room temperature for 18 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 45 mg (100% purity, 58% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.48 min; MS (ESIpos): m/z = 620/622 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.895 (6.54), 0.913 (16.00), 0.932(8.08), 1.042 (0.48), 1.070 (1.30), 1.092 (1.32), 1.099 (1.35), 1.121 (0.59),1.131 (0.54), 1.245 (1.03), 1.262 (2.36), 1.279 (3.38), 1.296 (2.77), 1.310(1.63),1.570 (1.54), 1.578 (1.49), 1.596 (1.25), 1.611 (1.37), 1.642 (1.23),1.752 (1.86), 1.785 (1.25), 1.853 (1.69), 1.892 (2.33), 1.926 (1.42), 1.939(1.34), 1.948 (1.17), 1.961 (1.05), 1.978 (1.80), 1.991 (1.10), 2.002 (2.03),2.019 (0.80), 2.041 (1.16), 2.056 (2.01), 2.079 (2.14), 2.097 (1.54), 2.115(3.36), 2.133 (4.50), 2.159 (7.40), 2.417 (0.90), 2.443 (1.33), 2.474 (0.85),2.721 (1.01), 2.749 (1.83), 2.778 (1.01), 3.513 (2.86), 3.534 (2.38), 3.614(1.11), 3.628 (1.30), 3.701 (0.98), 3.717 (1.62), 3.734 (1.43), 3.751 (0.99),3.767 (0.53), 7.462 (1.95), 7.481 (3.47), 7.499 (2.11), 7.635 (0.82), 7.657(15.46), 7.686 (1.56), 7.707 (3.81), 7.723 (5.27), 7.738 (7.56), 7.756(1.73), 8.753 (1.67), 8.768 (3.28), 8.782 (1.65), 12.055 (0.48)。

Example 125

5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Valeric acid(mixture of diastereomers)

To 5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Tert-butyl valerate (85 mg, 128 μmol,mixtures of diastereomersExample 140A) in dichloromethane (1.5ml) TFA (200 μ l, 2.6 mmol) was added and the mixture was stirred at room temperature for 18 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 66 mg (100% purity, 85% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.36 min; MS (ESIpos): m/z = 606/608 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.961 (11.43), 0.977 (11.69), 1.119(1.33), 1.142 (1.37), 1.170 (0.55), 1.668 (1.15), 1.698 (1.36), 1.772 (2.38),1.805 (2.36), 1.831 (3.01), 1.861 (1.82), 1.931 (1.31), 1.942 (1.22), 1.963(1.52), 1.977 (1.40), 1.995 (1.27), 2.012 (1.97), 2.025 (1.20), 2.036 (2.22),2.045 (1.32), 2.073 (1.16), 2.088 (2.19), 2.112 (2.28), 2.129 (1.30), 2.148(2.41), 2.202 (9.83), 2.362 (0.23), 2.401 (0.17), 2.472 (1.26), 2.724 (1.08),2.753 (1.97), 2.781 (1.07), 3.488 (2.15), 3.514 (3.81), 3.543 (1.91), 3.647(1.13), 3.663 (1.43), 3.678 (1.25), 3.745 (1.32), 7.468 (0.77), 7.498 (1.91),7.517 (3.49), 7.535 (2.12), 7.670 (0.83), 7.692 (16.00), 7.721 (1.57), 7.742(3.68), 7.758 (7.71), 7.770 (5.90), 8.795 (1.69), 8.809 (3.31), 8.824 (1.65),12.057 (0.39)。

Example 126

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethoxy) phenyl]Valeric acid(raceme)

To (+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethoxy) phenyl]Tert-butyl valerate (85 mg, 128 μmol,racemic modificationExample 141A) in dichloromethane (1.5ml) TFA (200 μ l, 2.6 mmol) was added and the mixture was stirred at room temperature for 18 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 58 mg (100% purity, 75% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.28 min; MS (ESIpos): m/z = 608/610 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.609 (5.45), 1.674 (10.79), 1.802(1.40), 1.816 (1.97), 1.826 (1.94), 1.836 (2.70), 1.860 (2.03), 1.888 (0.49),2.034 (0.85), 2.048 (3.13), 2.062 (3.86), 2.074 (15.09), 2.105 (2.80), 2.141(13.35), 2.223 (0.46), 3.142 (14.21), 3.358 (1.72), 3.378 (2.31), 3.389(2.71), 3.405 (2.55), 3.585 (0.80), 3.600 (1.32), 3.618 (2.89), 3.634 (3.97),3.644 (3.21), 3.659 (3.20), 3.677 (2.34), 3.693 (1.16), 3.711 (0.65), 7.362(4.71), 7.366 (4.18), 7.380 (1.52), 7.386 (2.11), 7.401 (8.29), 7.411 (6.88),7.418 (6.54), 7.423 (7.52), 7.436 (2.09), 7.462 (1.58), 7.548 (5.03), 7.554(3.43), 7.561 (4.22), 7.572 (3.66), 7.630 (2.79), 7.652 (16.00), 7.658(11.38), 7.663 (9.59), 7.680 (1.69), 7.685 (1.88), 8.732 (2.66), 8.746(5.24), 8.761 (2.61), 12.069 (0.60)。

Example 127

(-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoro) phenylMethoxy) phenyl]Valeric acid(enantiomer 1)

To (-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethoxy) phenyl]Tert-butyl valerate (90 mg, 135 μmol,enantiomer 1Example 142A) in dichloromethane (1.0ml) TFA (230 μ l, 3.0 mmol) was added and the mixture was left to stand at room temperature for 22 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 50 mg (100% purity, 61% of theory) of the title compound are obtained.

[α]_D ²⁰= 18.0 °, 589 nm, c = 0.49 g/100 ml, methanol

LC-MS (method 1) R_t= 2.29 min; MS (ESIpos): m/z = 608/610 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.609 (5.83), 1.674 (11.45), 1.803(1.47), 1.817 (2.13), 1.826 (2.21), 1.837 (2.80), 1.861 (2.09), 1.888 (0.51),2.051 (3.70), 2.077 (16.00), 2.107 (3.39), 2.140 (13.75), 2.222 (0.47), 3.142(14.84), 3.390 (2.52), 3.405 (2.42), 3.585 (0.89), 3.600 (1.48), 3.618(3.15), 3.634 (4.30), 3.648 (3.40), 3.659 (3.41), 3.677 (2.42), 3.693 (1.19),3.711 (0.64), 7.358 (3.80), 7.362 (4.85), 7.366 (4.34), 7.381 (1.93), 7.387(2.65), 7.401 (8.69), 7.412 (7.29), 7.418 (6.79), 7.424 (7.60), 7.436 (2.21),7.443 (1.73), 7.458 (1.58), 7.549 (5.35), 7.554 (3.69), 7.561 (4.42), 7.572(3.74), 7.630 (3.18), 7.651 (15.85), 7.658 (11.08), 7.663 (9.30), 7.680(1.75), 7.685 (1.89), 8.729 (2.97), 8.744 (5.43), 8.758 (2.65), 12.048(9.94)。

Example 128

(+) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethoxy) phenyl]Valeric acid(enantiomer 2)

To (+) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethoxy) phenyl]Tert-butyl valerate (80 mg, 120 μmol,enantiomer 2Example 143A) twoTo a solution of methyl chloride (930 μ l) was added TFA (200 μ l, 2.6 mmol), and the mixture was allowed to stand at room temperature for 22 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 45 mg (100% purity, 62% of theory) of the title compound are obtained.

[α]_D ²⁰= 18.6 °, 589 nm, c = 0.42 g/100 ml, methanol

LC-MS (method 1) R_t= 2.29 min; MS (ESIpos): m/z = 608/610 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.609 (5.47), 1.674 (10.78), 1.802(1.28), 1.815 (1.94), 1.825 (1.99), 1.836 (2.69), 1.860 (2.04), 1.887 (0.50),2.049 (3.08), 2.075 (15.31), 2.105 (2.79), 2.140 (13.35), 2.222 (0.46), 2.327(0.57), 2.670 (0.58), 3.142 (14.18), 3.390 (2.48), 3.403 (2.39), 3.585(0.80), 3.599 (1.32), 3.617 (2.90), 3.633 (3.99), 3.659 (3.26), 3.676 (2.36),3.693 (1.16), 3.709 (0.65), 7.362 (4.65), 7.380 (1.46), 7.387 (2.06), 7.401(8.36), 7.412 (6.83), 7.418 (6.44), 7.424 (7.64), 7.436 (2.15), 7.460 (1.59),7.548 (5.00), 7.561 (4.22), 7.572 (3.68), 7.629 (2.93), 7.651 (16.00), 7.658(10.68), 7.662 (9.54), 7.680 (1.74), 7.685 (1.95), 8.729 (2.66), 8.744(5.30), 8.758 (2.62), 12.050 (3.04)。

Example 129

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethoxy) phenyl]Valeric acid(raceme)

To (+/-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethoxy) phenyl]Tert-butyl valerate (85 mg, 131 μmol,racemic modificationExample 144A) in dichloromethane (1.5ml) TFA (200 μ l, 2.6 mmol) was added and the mixture was stirred at room temperature for 18 h. Then concentrating the mixture and repeatedly addingDichloromethane was added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 53 mg (100% purity, 68% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 1.60 min; MS (ESIpos): m/z = 594/596 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.22), 0.008 (1.27), 1.803(0.93), 1.816 (1.30), 1.825 (1.46), 1.837 (2.26), 1.875 (10.81), 2.032(0.74), 2.046 (2.32), 2.056 (1.86), 2.073 (10.27), 2.081 (6.67), 2.103(1.93), 2.115 (1.46), 2.125 (1.55), 2.161 (4.17), 3.315 (16.00), 3.356(0.63), 3.386 (1.60), 3.401 (1.57), 3.613 (2.82), 3.628 (1.60), 3.643 (1.41),3.660 (1.95), 3.677 (1.62), 3.694 (0.98), 3.712 (0.55), 7.337 (1.93), 7.341(2.10), 7.346 (2.33), 7.351 (2.89), 7.356 (3.69), 7.360 (3.24), 7.375 (1.47),7.381 (1.74), 7.398 (5.84), 7.407 (4.63), 7.415 (4.68), 7.432 (1.15), 7.473(5.13), 7.495 (8.79), 7.549 (6.82), 7.555 (6.12), 7.571 (4.26), 7.577 (2.97),8.680 (1.74), 8.695 (3.33), 8.709 (1.70), 12.049 (1.68)。

Example 130

(-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethoxy) phenyl]Valeric acid(enantiomer 1)

To (-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethoxy) phenyl]Tert-butyl valerate (140 mg, 215 μmol,enantiomer 1Example 145A) in dichloromethane (1.7ml) was added TFA (360 μ l, 4.7 mmol) and the mixture was left to stand at room temperature for 22 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 97 mg (100% purity, 76% of theory) of the title compound are obtained.

[α]_D ²⁰= 16.7 °, 589 nm, c = 0.41 g/100 ml, methanol

LC-MS (method 1) R_t= 1.58 min; MS (ESIpos): m/z = 594/596 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.825 (0.44), 1.836 (0.68), 1.875(3.31), 2.046 (0.70), 2.074 (2.84), 2.103 (0.59), 2.116 (0.44), 2.125 (0.47),2.162 (1.28), 3.313 (16.00), 3.386 (0.48), 3.401 (0.47), 3.612 (0.87), 3.628(0.48), 3.643 (0.43), 3.660 (0.59), 3.677 (0.50), 7.346 (0.74), 7.355 (1.15),7.359 (1.03), 7.375 (0.46), 7.381 (0.54), 7.398 (1.81), 7.407 (1.42), 7.415(1.45), 7.473 (1.56), 7.495 (2.67), 7.549 (2.09), 7.555 (1.90), 7.571 (1.31),7.577 (0.92), 8.679 (0.54), 8.694 (1.03), 8.709 (0.52), 12.043 (2.77)。

Example 131

(+) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethoxy) phenyl]Valeric acid(enantiomer 2)

To (+) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethoxy) phenyl]Tert-butyl valerate (130 mg, 200 μmol,enantiomer 2Example 146A) in dichloromethane (1.5ml) was added TFA (340 μ l,4.4 mmol) and the mixture was allowed to stand at room temperature for 22 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 94 mg (100% purity, 79% of theory) of the title compound are obtained.

[α]_D ²⁰= 48.5 °, 589 nm, c = 0.41 g/100 ml, methanol

LC-MS (method 1) R_t= 1.58 min; MS (ESIpos): m/z = 594/596 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (3.65), 1.815 (2.03), 1.825(2.29), 1.836 (3.45), 1.879 (16.00), 2.007 (0.46), 2.032 (1.10), 2.046(3.63), 2.055 (2.83), 2.074 (14.77), 2.102 (2.92), 2.124 (2.33), 2.163(6.20), 2.327 (0.57), 2.669 (0.50), 3.385 (2.83), 3.401 (2.67), 3.581(11.94), 3.612 (5.50), 3.628 (2.90), 3.644 (2.39), 3.661 (3.14), 3.678(2.59), 3.694 (1.61), 3.712 (0.91), 7.346 (3.62), 7.356 (5.66), 7.375 (2.23),7.381 (2.65), 7.398 (9.07), 7.407 (7.10), 7.416 (7.30), 7.433 (1.86), 7.482(2.36), 7.504 (3.73), 7.546 (6.03), 7.559 (7.96), 7.569 (5.48), 7.578 (3.09),8.685 (2.29), 8.699 (4.21), 8.713 (2.32), 12.044 (3.05)。

Example 132

(+/-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethoxy) phenyl]Valeric acid(raceme)

To (+/-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethoxy) phenyl]Tert-butyl valerate (85 mg, 121 μmol,racemic modificationExample 147A) in dichloromethane (1.5ml) TFA (190 μ l, 2.4 mmol) was added and the mixture was stirred at room temperature for 18 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 56 mg (100% purity, 72% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.21 min; MS (ESIpos): m/z = 644/646 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.805 (1.11), 1.818 (1.77), 1.828(1.91), 1.839 (2.54), 1.887 (5.28), 2.050 (4.05), 2.077 (16.00), 2.115(4.22), 2.159 (11.45), 2.245 (0.46), 3.174 (6.42), 3.360 (1.50), 3.391(2.46), 3.406 (2.34), 3.456 (3.91), 3.485 (7.30), 3.513 (3.66), 3.595 (0.77),3.610 (1.24), 3.628 (2.53), 3.644 (3.42), 3.657 (3.10), 3.672 (2.69), 3.689(1.99), 3.705 (1.05), 3.722 (0.56), 7.363 (4.21), 7.382(1.32), 7.388 (1.84),7.403 (7.29), 7.414 (6.03), 7.421 (5.78), 7.425 (6.39), 7.438 (1.46), 7.495(1.18), 7.553 (4.60), 7.566 (3.87), 7.576 (3.35), 7.680 (2.13), 7.702(14.18), 7.707 (10.77), 7.712 (8.50), 7.729 (1.33), 7.734 (1.48), 8.743(2.48), 8.758 (4.81), 8.772 (2.40), 12.069 (0.56)。

Example 133

(-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethoxy) phenyl]Valeric acid(enantiomer 1)

To (-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethoxy) phenyl]Tert-butyl valerate (115 mg, 164 μmol,enantiomer 1Example 148A) in dichloromethane (1.3 ml) TFA (280 μ l, 3.6 mmol) was added and the mixture was left to stand at room temperature for 22 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 92 mg (100% purity, 86% of theory) of the title compound are obtained.

[α]_D ²⁰= 15.9 °, 589 nm, c = 0.39 g/100 ml, methanol

LC-MS (method 2) R_t= 1.17 min; MS (ESIpos): m/z = 644/646 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.806 (0.97), 1.818 (1.67), 1.829(1.78), 1.840 (2.38), 1.887 (4.81), 2.054 (3.60), 2.080 (16.00), 2.093(6.95), 2.115 (3.93), 2.159 (10.72), 2.245 (0.45), 3.174 (5.85), 3.362(0.96), 3.392 (2.07), 3.407 (2.04), 3.456 (3.60), 3.485 (6.81), 3.513 (3.40),3.595 (0.68), 3.611 (1.12), 3.628 (2.37), 3.644 (3.21), 3.658 (2.83), 3.671(2.52), 3.689 (1.85), 3.704 (0.96), 3.722 (0.52), 7.364 (4.04), 7.368 (3.55),7.383 (1.21), 7.389 (1.74), 7.404 (6.92), 7.414 (5.86), 7.421 (5.49), 7.426(6.17), 7.439 (1.40), 7.494 (1.13), 7.554 (4.44), 7.559 (3.07), 7.566 (3.66),7.577 (3.23), 7.680 (2.15), 7.702 (14.00), 7.707 (10.50), 7.712 (8.41), 7.730(1.33), 7.734 (1.49), 8.741 (2.35), 8.755 (4.60), 8.770 (2.27), 12.052(2.47)。

Example 134

(+) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethoxy) phenyl]Valeric acid(enantiomer 2)

To (+) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethoxy) phenyl]Tert-butyl valerate (105 mg, 150 μmol,enantiomer 2Example 149A) in dichloromethane (1.2 ml) was added TFA (250 μ l, 3.3 mmol) and the mixture was allowed to stand at room temperature for 22 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 81 mg (99% purity, 83% of theory) of the title compound are obtained.

[α]_D ²⁰= 17.2 °, 589 nm, c = 0.42 g/100 ml, methanol

LC-MS (method 2) R_t= 1.17 min; MS (ESIpos): m/z = 644/646 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.53), 0.008 (1.48), 1.806(1.02), 1.819 (1.71), 1.829 (1.81), 1.840 (2.41), 1.887 (4.81), 2.053 (3.70),2.079 (16.00), 2.093 (6.81), 2.116 (3.90), 2.159 (10.73), 2.245 (0.44), 3.174(5.91), 3.392 (2.02), 3.406 (1.98), 3.456 (3.65), 3.485 (6.90), 3.513 (3.41),3.595 (0.67), 3.610 (1.11), 3.628 (2.38), 3.644 (3.22), 3.658 (2.82), 3.672(2.49), 3.689 (1.85), 3.704 (0.95), 3.722 (0.52), 7.354 (2.52), 7.359 (3.13),7.364 (4.16), 7.368 (3.61), 7.382 (1.24), 7.389 (1.78), 7.404 (7.08), 7.414(6.10), 7.421 (5.65), 7.426 (6.34), 7.439 (1.47), 7.496 (1.14), 7.554 (4.57),7.559 (3.07), 7.566 (3.74), 7.577 (3.32), 7.680 (2.29), 7.702 (14.75), 7.707(10.95), 7.712 (8.88), 7.729 (1.44), 7.734 (1.59), 8.741 (2.36), 8.756(4.69), 8.770 (2.33), 12.055 (2.70)。

Example 135

(+/-) -5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethoxy) phenyl]Valeric acid(raceme)

To (+/-) -5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethoxy) phenyl]Tert-butyl valerate (85 mg, 125 μmol,racemic modificationExample 150A) in dichloromethane (1.1ml) TFA (210 μ l, 2.8 mmol) was added and the mixture was left to stand at room temperature for 18 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 52 mg (100% purity, 67% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.34 min; MS (ESIpos): m/z = 622/624 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.234 (0.73), 1.605 (14.46), 1.784(9.83), 1.835 (2.54), 1.859 (1.84), 1.886 (0.52), 2.032 (0.83), 2.046 (2.81),2.073 (13.10), 2.124 (8.68), 2.215 (0.46), 2.327 (0.46), 2.669 (0.49), 3.357(1.19), 3.387 (2.23), 3.402 (2.13), 3.494 (11.26), 3.509 (16.00), 3.523(10.92), 3.571 (0.90), 3.586 (1.30), 3.604 (2.18), 3.618 (2.63), 3.635(1.81), 3.662 (2.15), 3.679 (1.80), 7.358 (4.37), 7.385 (2.48), 7.399 (7.73),7.410 (6.56), 7.417 (6.14), 7.421 (6.49), 7.434 (1.57), 7.531 (6.00), 7.553(13.64), 7.562 (4.00), 7.573 (3.14), 7.597 (6.11), 7.602 (5.59), 7.619(3.18), 7.625 (3.00), 8.702 (2.26), 8.717 (4.27), 8.731 (2.14), 12.058(0.97)。

Example 136

(-) -5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethoxy) phenyl]Valeric acid(enantiomer 1)

To (-) -5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethoxy) phenyl]Tert-butyl valerate (145 mg, 214 μmol,enantiomer 1Example 151A) in dichloromethane (1.6ml) was added TFA (360. mu.l, 4.7 mmol) and the mixture was allowed to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). Combining the target fractionsConcentrated and the residue was lyophilized. 75 mg (100% purity, 56% of theory) of the title compound are obtained.

[α]_D ²⁰= 16.5 °, 589 nm, c = 0.35 g/100 ml, methanol

LC-MS (method 1) R_t= 2.34 min; MS (ESIpos): m/z = 622/624 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.64), 0.008 (2.00), 1.371(0.52), 1.605 (14.32), 1.613 (12.24), 1.784 (9.58), 1.824 (2.16), 1.836(2.49), 1.860 (1.82), 1.887 (0.48), 2.032 (0.82), 2.046 (2.82), 2.061 (3.46),2.073 (12.90), 2.079 (9.89), 2.124 (8.41), 2.215 (0.43), 3.388 (2.27), 3.404(2.15), 3.495 (11.59), 3.509 (16.00), 3.524 (11.30), 3.571 (0.87), 3.586(1.27), 3.604 (2.17), 3.619 (2.60), 3.635 (1.74), 3.645 (1.58), 3.663 (2.15),3.679 (1.76), 3.694 (1.07), 3.714 (0.57), 7.353 (3.36), 7.358 (4.32), 7.362(3.85), 7.378 (1.75), 7.385 (2.43), 7.399 (7.64), 7.410 (6.64), 7.417 (6.07),7.421 (6.62), 7.435 (1.61), 7.532 (6.31), 7.554 (14.24), 7.562 (4.07), 7.573(3.33), 7.597 (6.38), 7.603 (5.95), 7.620 (3.35), 7.625 (3.23), 8.704 (2.31),8.718 (4.42), 8.732 (2.22), 12.060 (0.53)。

Example 137

(+) -5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethoxy) phenyl]Valeric acid(enantiomer 2)

To (+) -5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- [2- (trifluoromethoxy) phenyl]Tert-butyl valerate (140 mg, 206 μmol,enantiomer 2Example 152A) in dichloromethane (1.6ml) TFA (350 μ l, 4.5 mmol) was added and the mixture was left to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 88 mg (100% purity, 68% of theory) of the title compound are obtained.

[α]_D ²⁰= 16.9 °, 589 nm, c = 0.44 g/100 ml, methanol

LC-MS (method 1) R_t= 2.34 min; MS (ESIpos): m/z = 622/624 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.606 (14.31), 1.784 (9.86), 1.837(2.55), 1.861 (1.79), 1.888 (0.53), 2.049 (2.72), 2.076 (13.15), 2.125(8.84), 2.215 (0.47), 2.328 (0.42), 2.670 (0.44), 3.390 (2.07), 3.403 (2.07),3.495 (10.87), 3.510 (16.00), 3.524 (10.86), 3.572 (0.92), 3.587 (1.31),3.605 (2.21), 3.620 (2.66), 3.637 (1.81), 3.664 (2.19), 3.680 (1.85), 7.359(4.31), 7.385 (2.45), 7.400 (7.84), 7.410 (6.35), 7.422 (6.61), 7.435 (1.62),7.532 (5.57), 7.554 (13.16), 7.563 (3.91), 7.574 (3.13), 7.598 (5.67), 7.603(5.52), 7.620 (2.99), 7.625 (3.00), 8.701(2.25), 8.716 (4.35), 8.730 (2.19),12.046 (2.47)。

Example 138

5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Valeric acid(mixture of diastereomers)

To 5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Tert-butyl valerate (85 mg, 125 μmol,mixtures of diastereomersExample 153A) in dichloromethane (1.1ml) TFA (210 μ l, 2.7 mmol) was added and the mixture was left to stand at room temperature for 18 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 55 mg (100% purity, 71% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.18 min; MS (ESIpos): m/z = 626/628 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.06), 0.008 (2.52), 1.236(0.83), 1.646 (1.98), 1.768 (0.68), 1.815 (3.36), 1.826 (3.43), 1.837 (3.81),1.861 (2.67), 1.902 (3.30), 1.922 (2.78), 1.953 (1.96), 1.987 (1.15), 2.010(0.72), 2.050 (2.99), 2.077 (14.97), 2.104 (2.52), 2.153 (12.67), 2.328(0.48), 2.670 (0.45), 3.074 (1.28), 3.104 (2.25), 3.163 (2.42), 3.176 (2.36),3.208 (1.25), 3.350 (2.24), 3.387 (4.28), 3.411 (3.01), 3.438 (2.24), 3.472(1.37), 3.590 (0.69), 3.605 (1.17), 3.622 (2.52), 3.639 (3.61), 3.652 (3.10),3.680 (1.90), 4.820 (1.66), 4.939 (1.69), 7.362 (4.58), 7.366 (4.02), 7.381(1.37), 7.387 (1.93), 7.402 (7.98), 7.412 (6.54), 7.419 (6.20), 7.424 (7.11),7.437 (1.74), 7.474 (1.39), 7.551 (4.96), 7.563 (4.09), 7.574 (3.61), 7.654(2.68), 7.675 (16.00), 7.681 (11.09), 7.686 (9.41), 7.704 (1.75), 7.708(1.85), 8.736 (2.62), 8.750 (5.19), 8.765 (2.57), 12.057 (1.66)。

Example 139

5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Valeric acid(mixture of diastereomers)

To 5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Tert-butyl valerate (85 mg, 123 μmol,mixtures of diastereomersExample 154A) in dichloromethane (1.5ml) TFA (190 μ l, 2.5 mmol) was added and the mixture was stirred at room temperature for 18 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 60 mg (100% purity, 77% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.52 min; MS (ESIpos): m/z = 636/638 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.892 (6.52), 0.911 (16.00), 0.930(8.01), 1.039 (0.62), 1.059 (1.34), 1.067 (1.35), 1.090 (1.31), 1.097 (1.32),1.119 (0.60), 1.128 (0.53), 1.242 (1.02), 1.260 (2.47), 1.277 (3.35), 1.295(2.40), 1.564 (1.51), 1.573 (1.45), 1.590 (1.24), 1.601 (1.32), 1.635 (1.16),1.749 (1.81), 1.782 (1.45), 1.801 (0.96), 1.814 (1.34), 1.825 (1.40), 1.837(2.34), 1.858 (2.39), 1.884 (1.66), 2.051 (2.07), 2.078 (10.33), 2.109(4.06), 2.135 (5.81), 2.409 (0.86), 2.435 (1.21), 2.464 (0.70), 2.715 (0.95),2.745 (1.75), 2.775 (0.94), 3.363 (0.67), 3.393 (1.53), 3.406 (1.51), 3.495(2.71), 3.525 (2.53), 3.585 (0.64), 3.600 (1.01), 3.618 (1.79), 3.633 (2.24),3.649 (1.67), 3.660 (1.23), 3.677 (1.52), 3.695 (1.19), 7.357 (2.77), 7.385(1.24), 7.400 (5.23), 7.410 (4.34), 7.421 (4.73), 7.435 (1.32), 7.456 (0.83),7.554 (2.88), 7.566 (2.50), 7.576 (2.07), 7.631 (1.14), 7.654 (12.66), 7.682(0.77), 8.718 (1.71), 8.733 (3.25), 8.747 (1.66), 12.046 (0.84)。

Example 140

5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Valeric acid(mixture of diastereomers)

To 5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Tert-butyl valerate (85 mg, 125 μmol,mixtures of diastereomersExample 155A) in dichloromethane (1.1ml) TFA (210 μ l, 2.8 mmol) was added and the mixture was left to stand at room temperature for 18 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 56 mg (100% purity, 71% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.42 min; MS (ESIpos): m/z = 622/624 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.923 (14.04), 0.939 (14.42), 1.054(0.58), 1.080 (1.68), 1.109 (1.75), 1.132 (0.71), 1.235 (0.89), 1.628 (1.42),1.658 (1.67), 1.685 (0.79), 1.733 (3.00), 1.766 (3.19), 1.800 (3.96), 1.816(3.37), 1.825 (3.80), 1.835 (3.76), 1.860 (1.79), 1.888 (0.45), 2.050 (2.61),2.076 (13.15), 2.106 (2.82), 2.140 (8.43), 2.433 (1.30), 2.458 (2.15), 2.684(1.32), 2.713 (2.46), 2.742 (1.32), 3.358 (0.97), 3.389 (2.11), 3.404 (2.09),3.440 (2.69), 3.469 (4.76), 3.500 (2.26), 3.598 (1.01), 3.617 (1.92), 3.631(2.43), 3.647 (2.54), 3.665 (2.40), 3.682 (1.87), 3.698 (1.04), 3.716 (0.56),7.361 (3.79), 7.387 (1.64), 7.400 (6.96), 7.412 (5.56), 7.423 (6.36), 7.436(1.82), 7.550 (4.02), 7.563 (3.50), 7.573 (2.95), 7.631 (1.47), 7.654(16.00), 7.682 (1.06), 8.720 (2.23), 8.735 (4.29), 8.749 (2.17), 12.048(3.54)。

Example 141

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-3-fluorophenyl) pentanoic acid(raceme)

To (+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-3-fluorophenyl) pentanoic acid tert-butyl ester (172 mg, 272 μmol,racemic modificationExample 156A) in dichloromethane (4.0ml) TFA (310 μ l, 4.1 mmol) was added and the mixture was stirred at room temperature for 18 h. Then, TFA (155. mu.l, 2.05 mmol) was added again, and the mixture was stirred at room temperature for 26 h. The mixture was then concentrated and dichloromethane was repeatedly added, followed by concentration again. The residue was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 143 mg (100% purity, 91% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.19 min; MS (ESIpos): m/z = 576/578 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.606 (4.25), 1.672 (8.45), 1.790(0.50), 1.806 (0.96), 1.824 (1.50), 1.845 (1.97), 1.867 (1.12), 1.883 (0.52),2.020 (0.49), 2.039 (1.16), 2.063 (3.60), 2.075 (1.70), 2.090 (4.80), 2.100(8.16), 2.130 (16.00), 2.165 (1.21), 2.328 (0.48), 2.366 (0.44), 2.669(0.52), 2.709 (0.44), 3.135 (11.08), 3.616 (1.87), 3.697 (3.00), 7.288(1.68), 7.309 (3.78), 7.331 (2.61), 7.344 (2.90), 7.363 (4.95), 7.396 (2.49),7.411 (2.98), 7.416 (3.42), 7.430 (3.39), 7.450 (1.62), 7.624 (2.09), 7.646(11.69), 7.653 (7.79), 7.658 (6.74), 7.675 (1.30), 7.680 (1.47), 8.718(2.07), 8.732 (4.17), 8.746 (2.03), 12.059 (0.63)。

Separation of enantiomers:

the title compound (125 mg) was dissolved in methanol (20 ml) and separated by preparative SFC on chiral phase into enantiomers (see examples 142 and 143) [ column: daicel Chiralcel OX-H, 5 μm,250 mm x 20 mm, flow rate: 80 ml/min, detection: 210 nm, temperature: injection at 40 ℃: 1.0ml, eluent 17% ethanol/83% carbon dioxide, running time 13 min, isocratic. The combined target fractions were each concentrated and the respective residue was lyophilized.

Example 142

(-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-3-fluorophenyl) pentanoic acid(enantiomer 1)

In the enantiomeric separation described in example 141, 43 mg (100% purity, ee >99%) of the title compound were obtained as the earlier eluting enantiomer.

[α]_D ²⁰= 13.8 °, 589 nm, c = 0.37 g/100 ml, methanol

LC-MS (method 1) R_t= 2.20 min; MS (ESIpos): m/z = 576/578 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]:-0.008 (2.03), 0.008 (2.00), 1.596(3.88), 1.605 (4.29), 1.671 (8.19), 1.792 (0.54), 1.807 (1.05), 1.826 (1.62),1.833 (1.58), 1.846 (2.10), 1.868 (1.23), 1.884 (0.62), 2.021 (0.60), 2.040(1.29), 2.064 (3.77), 2.077 (1.88), 2.091 (4.95), 2.101 (8.41), 2.131(16.00), 2.166 (1.27), 2.182 (0.56), 3.121 (7.95), 3.134 (10.68), 3.617(1.89), 3.644 (1.14), 3.699 (2.96), 7.289 (1.83), 7.309 (3.92), 7.332 (2.80),7.346 (2.97), 7.364 (5.02), 7.397 (2.62), 7.411 (3.07), 7.416 (3.55), 7.430(3.51), 7.450 (1.68), 7.624 (2.18), 7.645 (11.92), 7.652 (7.95), 7.657(7.09), 7.674 (1.32), 7.679 (1.53), 8.719 (2.03), 8.733 (4.07), 8.747 (2.01),12.066 (5.30)。

Example 143

(+) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-3-fluorophenyl) pentanoic acid(enantiomer 2)

In the enantiomeric separation described in example 141, 37 mg (100% purity, ee value 95%) of the title compound were obtained as the enantiomer which eluted later.

[α]_D ²⁰= 13.4 °, 589 nm, c = 0.35 g/100 ml, methanol

LC-MS (method 1) R_t= 2.20 min; MS (ESIpos): m/z = 576/578 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.605 (4.31), 1.671 (8.37), 1.793(0.53), 1.808 (1.01), 1.827 (1.61), 1.834 (1.61), 1.847 (2.06), 1.869 (1.22),1.885 (0.62), 2.023 (0.56), 2.041 (1.26), 2.065 (3.63), 2.077 (1.87), 2.092(4.86), 2.102 (8.13), 2.131 (16.00), 2.167 (1.31), 2.183 (0.60), 3.134(10.81), 3.618 (1.95), 3.644 (1.18), 3.699 (3.03), 7.288 (1.74), 7.309(3.75), 7.331 (2.65), 7.346 (2.89), 7.364 (4.84), 7.397 (2.46), 7.411 (3.00),7.416 (3.41), 7.430 (3.37), 7.450 (1.67), 7.624 (1.92), 7.646 (10.90), 7.652(7.58), 7.657 (6.58), 7.675 (1.19), 7.679 (1.36), 8.719 (1.99), 8.734 (3.94),8.748 (1.97), 12.068 (3.84)。

Example 144

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (6-chloro-2, 3-difluorophenyl) pentanoic acid(raceme)

To (+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (6-chloro-2, 3-difluorophenyl) pentanoic acid tert-butyl ester (123 mg, 189 µmol,Racemic modificationExample 157A) in dichloromethane (3 ml) TFA (220 μ l, 2.8 mmol) was added and the mixture was stirred at room temperature for 18 h. Then, TFA (110. mu.l, 1.4 mmol) was added again, and the mixture was stirred at room temperature for 26 h. The mixture was then concentrated and dichloromethane was repeatedly added, followed by concentration again. The residue was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 124 mg (94% purity, 103% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.22 min; MS (ESIpos): m/z = 594/596 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.023 (0.44), -0.008 (2.46), 0.008(2.14), 1.234 (0.89), 1.367 (4.68), 1.606 (2.38), 1.656 (4.36), 1.671 (4.64),1.979 (0.61), 2.073 (2.70), 2.101 (1.76), 2.128 (2.50), 2.144 (16.00), 2.187(0.81), 2.327 (0.46), 2.332 (0.40), 2.347 (0.61), 2.366 (0.85), 2.670 (0.52),2.710 (0.85), 3.135 (6.17), 3.734 (0.97), 3.770 (1.43), 7.376 (1.80), 7.389(2.16), 7.412 (1.47), 7.433 (1.39), 7.456 (0.69), 7.626 (1.67), 7.648 (6.98),7.658 (4.62), 7.663 (4.00), 7.680 (1.01), 7.685 (1.05), 8.807 (1.03), 8.822(2.00), 8.835 (0.99)。

Separation of enantiomers:

the title compound (110 mg) was dissolved in methanol (15 ml) and separated into enantiomers on the chiral phase by preparative SFC (see examples 145 and 146) [ column: daicel Chiralpak AD, 5 μm,250 mm x 20 mm, flow rate: 80 ml/min, detection: 210 nm, temperature: injection at 40 ℃: 2.0 ml, eluent 30% isopropanol/70% carbon dioxide, run time 7 min, isocratic. The combined target fractions were each concentrated and the respective residue was lyophilized.

Example 145

(-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (6-chloro-2, 3-difluorophenyl) pentanoic acid(enantiomer 1)

In the enantiomeric separation described in example 144, 43 mg (100% purity, ee >99%) of the title compound were obtained as the earlier eluting enantiomer.

[α]_D ²⁰= 31.8 °, 589 nm, c = 0.41 g/100 ml, methanol

LC-MS (method 2) R_t= 1.13 min; MS (ESIpos): m/z = 594/596 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.069 (0.50), 1.367 (3.93), 1.606(2.74), 1.671 (5.29), 1.983 (0.77), 2.065 (1.26), 2.076 (1.30), 2.095 (1.33),2.110 (1.94), 2.144 (16.00), 2.172 (2.18), 2.195 (0.93), 2.434 (0.58), 3.135(6.96), 3.738 (1.19), 3.771 (1.70), 7.377 (2.00), 7.389 (2.43), 7.412 (1.72),7.434 (1.70), 7.456 (1.02), 7.486 (0.51), 7.626 (1.66), 7.648 (6.84), 7.658(4.26), 7.663 (4.01), 7.681 (0.93), 7.685 (1.02), 8.803 (1.17), 8.817 (2.27),8.831 (1.13)。

Example 146

(+) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (6-chloro-2, 3-difluorophenyl) pentanoic acid(enantiomer 2)

In the enantiomeric separation described in example 144, 31 mg (98% purity, ee >99%) of the title compound were obtained as the enantiomer which eluted later.

[α]_D ²⁰= 34.1 °, 589 nm, c = 0.40 g/100 ml, methanol

LC-MS (method 2) R_t= 1.14 min; MS (ESIpos): m/z = 594/596 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.37), 0.008 (0.74), 1.368(0.77), 1.596 (2.49), 1.606 (2.69), 1.671 (5.00), 1.982 (0.72), 2.067 (1.07),2.079 (1.22), 2.097 (1.31), 2.116 (2.21), 2.145 (16.00), 2.178 (2.09), 2.200(0.82), 3.122 (5.17), 3.135 (6.49), 3.739 (1.21), 3.771 (1.63), 7.355 (0.86),7.378 (2.03), 7.390 (2.38), 7.413 (1.64), 7.435 (1.43), 7.457 (0.74), 7.627(1.88), 7.649 (7.16), 7.659 (4.59), 7.664 (4.01), 7.681 (1.00), 7.686 (1.02),8.802 (1.22), 8.816 (2.19), 8.830 (1.05)。

Example 147

(+/-) -5- ({ [ 6-bromo-3-carboxylic acid methyl esterYl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (5-fluoro-2-methylphenyl) pentanoic acid(raceme)

To (+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (5-fluoro-2-methylphenyl) pentanoic acid tert-butyl ester (185 mg, 302 μmol,racemic modificationExample 158A) in dichloromethane (4 ml) TFA (350 μ l, 4.5 mmol) was added and the mixture was stirred at room temperature for 18 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. 149 mg (100% purity, 89% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.21 min; MS (ESIpos): m/z = 556/558 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.37), 0.008 (2.26), 1.606(3.10), 1.670 (6.11), 1.739 (0.41), 1.756 (0.83), 1.772 (0.96), 1.797 (1.23),1.828 (0.55), 1.993 (0.96), 2.006 (1.24), 2.023 (1.21), 2.043 (1.30), 2.063(4.89), 2.079 (5.98), 2.100 (10.78), 2.293 (16.00), 2.327 (0.60), 2.669(0.46), 3.135 (8.13), 3.460 (1.02), 3.473 (1.34), 3.493 (1.53), 3.507 (1.68),3.521 (1.03), 3.653 (1.00), 3.672 (1.51), 3.690 (1.34), 3.705 (1.15), 3.725(0.70), 6.921 (1.05), 6.928 (1.22), 6.942 (2.27), 6.949 (2.54), 6.963 (1.30),6.970 (1.35), 7.132 (2.32), 7.139 (2.36), 7.159 (2.39), 7.166 (2.29), 7.197(2.30), 7.213 (2.66), 7.218 (2.51), 7.234 (2.07), 7.439 (1.06), 7.626 (1.65),7.648 (9.38), 7.654 (6.97), 7.659 (5.99), 7.676 (1.07), 7.681 (1.21), 8.711(1.47), 8.726 (2.38), 8.740 (1.48)。

Separation of enantiomers:

the title compound (135 mg) was dissolved in methanol (20 ml) and separated into enantiomers on the chiral phase by preparative SFC (see examples 148 and 149) [ column: daicel Chiralcel OX-H, 5 μm,250 mm x 20 mm, flow rate: 80 ml/min, detection: 210 nm, temperature: injection at 40 ℃: 2.0 ml, eluent 30% ethanol/70% carbon dioxide, running time 8 min, isocratic. The combined target fractions were each concentrated and the respective residue was lyophilized.

Example 148

(-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (5-fluoro-2-methylphenyl) pentanoic acid(enantiomer 1)

In the enantiomeric separation described in example 147, 57mg (100% purity, ee >99%) of the title compound were obtained as the earlier eluting enantiomer.

[α]_D ²⁰= 13.8 °, 589 nm, c = 0.49 g/100 ml, methanol

LC-MS (method 2) R_t= 1.12 min; MS (ESIpos): m/z = 556/558 [M-H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.609 (3.14), 1.673 (6.11), 1.746(0.41), 1.764 (0.84), 1.780 (1.02), 1.788 (1.06), 1.798 (1.19), 1.803 (1.18),1.818 (1.00), 1.836 (0.56), 1.980 (0.44), 1.999 (1.06), 2.012 (1.31), 2.030(1.30), 2.049 (1.40), 2.062 (1.59), 2.075 (5.10), 2.091 (7.94), 2.103(10.32), 2.294 (16.00), 3.147 (7.87), 3.320 (1.45), 3.432 (0.41), 3.450(0.52), 3.463 (1.20), 3.476 (1.60), 3.496 (1.88), 3.510 (2.09), 3.524 (1.47),3.656 (1.37), 3.674 (1.84), 3.693 (1.62), 3.708 (1.41), 3.727 (0.90), 6.924(1.07), 6.930 (1.25), 6.945 (2.28), 6.951 (2.50), 6.966 (1.28), 6.972 (1.33),7.137 (2.34), 7.144 (2.41), 7.164 (2.39), 7.171 (2.32), 7.200 (2.34), 7.215(2.65), 7.220 (2.47), 7.236 (2.02), 7.444 (1.01), 7.638 (1.21), 7.660 (9.17),7.664 (7.93), 7.669 (5.88), 7.686 (0.75), 7.691 (0.88), 8.714 (1.52), 8.729(2.41), 8.743 (1.46)。

Example 149

(+) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (5-fluoro-2-methylphenyl) pentanoic acid(enantiomer 2)

In the enantiomeric separation described in example 147, 51 mg (100% purity, ee value 96%) of the title compound were obtained as the enantiomer which eluted later.

[α]_D ²⁰= 13.4 °, 589 nm, c = 0.37 g/100 ml, methanol

LC-MS (method 2) R_t= 1.13 min; MS (ESIpos):m/z = 556/558 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.34), 0.008 (1.21), 1.030(0.40), 1.046 (0.41), 1.609 (3.05), 1.673 (5.95), 1.745 (0.41), 1.763 (0.85),1.779 (1.01), 1.787 (1.04), 1.797 (1.17), 1.803 (1.15), 1.820 (1.02), 1.835(0.58), 1.979 (0.43), 1.999 (1.03), 2.012 (1.29), 2.030 (1.29), 2.049 (1.38),2.062 (1.54), 2.075 (5.05), 2.091 (7.75), 2.103 (10.14), 2.294 (16.00), 3.149(7.64), 3.319 (1.39), 3.450 (0.41), 3.463 (1.08), 3.476 (1.46), 3.496 (1.72),3.510 (1.90), 3.524 (1.28), 3.656 (1.43), 3.674 (1.91), 3.693 (1.69), 3.708(1.48), 3.727 (0.98), 6.923 (1.08), 6.930 (1.25), 6.944 (2.29), 6.951 (2.50),6.965 (1.28), 6.972 (1.31), 7.137 (2.34), 7.143 (2.38), 7.164 (2.38), 7.170(2.30), 7.199 (2.38), 7.215 (2.66), 7.220 (2.45), 7.236 (2.05), 7.443 (0.99),7.640 (1.11), 7.662 (9.23), 7.669 (5.86), 7.687 (0.70), 7.692 (0.82), 8.715(1.52), 8.730 (2.36), 8.744 (1.44)。

Example 150

(+/-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (5-fluoro-2-methylphenyl) pentanoic acid(raceme)

To (+/-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (5-fluoro-2-methylphenyl) pentanoic acid tert-butyl ester (263 mg, 406 μmol,racemic modificationExample 159A) in dichloromethane (4 ml) TFA (620 μ l, 8.1 mmol) was added and the mixture was stirred at room temperature for 18 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 6). Combining the target fractionsConcentrated and the residue was lyophilized. 211 mg (100% purity, 88% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.17 min; MS (ESIpos): m/z = 592/594 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.15), 0.008 (1.52), 1.763(0.87), 1.779 (1.10), 1.787 (1.11), 1.796 (1.27), 1.802 (1.23), 1.820 (1.00),1.835 (0.72), 1.880 (3.31), 1.976 (0.53), 1.996 (1.11), 2.009 (1.35), 2.027(1.46), 2.046 (2.40), 2.071 (6.38), 2.087 (8.11), 2.117 (10.60), 2.292(16.00), 2.322 (0.52), 2.327 (0.56), 2.524 (1.64), 3.164 (4.06), 3.449(2.71), 3.479 (5.41), 3.505 (3.74), 3.518 (2.18), 3.533 (1.13), 3.665 (1.08),3.683 (1.64), 3.702 (1.40), 3.716 (1.20), 3.736 (0.71), 6.924 (1.18), 6.931(1.33), 6.945 (2.41), 6.952 (2.57), 6.966 (1.34), 6.973 (1.35), 7.141 (2.55),7.147 (2.54), 7.167 (2.57), 7.174 (2.42), 7.200 (2.58), 7.215 (2.84), 7.221(2.58), 7.237 (2.16), 7.476 (0.90), 7.678 (1.75), 7.699 (10.07), 7.704(7.52), 7.709 (6.08), 7.727 (0.97), 7.731 (1.10), 8.722 (1.71), 8.736 (2.53),8.751 (1.53)。

Example 151

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid(raceme)

To (+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid tert-butyl ester (269 mg, 413 μmol,racemic modificationExample 160A) in dichloromethane (5 ml) TFA (480 μ l, 6.2 mmol) was added and the mixture was stirred at room temperature for 18 h. Then, TFA (240. mu.l, 3.1 mmol) was added again, and the mixture was stirred at room temperature for another 24 h. The mixture was then concentrated and dichloromethane was repeatedly added, followed by concentration again. The residue was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized. Obtain 221mg (100% purity, 90% of theory) of the title compound.

LC-MS (method 1) R_t= 2.19 min; MS (ESIpos): m/z = 594/596 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.84), 0.008 (2.84), 1.606(3.28), 1.673 (6.38), 1.980 (0.76), 2.073 (2.12), 2.095 (2.56), 2.122 (4.17),2.143 (16.00), 2.172 (1.53), 2.194 (0.58), 2.327 (0.55), 2.366 (0.54), 2.669(0.59), 2.710 (0.57), 3.137 (8.46), 3.722 (1.94), 7.267 (0.88), 7.278 (1.02),7.290 (1.81), 7.301 (1.87), 7.316 (1.43), 7.327 (1.33), 7.389 (1.13), 7.400(1.34), 7.410 (1.91), 7.421 (1.92), 7.433 (1.20), 7.444 (1.12), 7.629 (2.29),7.650 (9.72), 7.660 (6.52), 7.665 (5.84), 7.683 (1.37), 7.687 (1.47), 8.821(2.50)。

Separation of enantiomers:

the title compound (200 mg) was dissolved in methanol (20 ml) and separated into enantiomers on the chiral phase by preparative SFC (see examples 152 and 153) [ column: daicel Chiralcel OJ-H, 5 μm,250 mm x 20 mm, flow rate: 80 ml/min, detection: 210 nm, temperature: injection at 40 ℃: 0.5 ml, eluent 17% methanol/83% carbon dioxide, running time 5 min, isocratic. The combined target fractions were each concentrated and the respective residue was lyophilized.

Example 152

(-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid(enantiomer 1)

In the enantiomeric separation described in example 151, 70mg (99% purity, ee >99%) of the title compound was obtained as the earlier eluting enantiomer.

[α]_D ²⁰= 35.9 °, 589 nm, c = 0.45 g/100 ml, methanol

LC-MS (method 2) R_t= 1.12 min; MS (ESIpos): m/z = 594/596 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.78), 0.008 (0.73), 1.597(2.64), 1.607 (2.93), 1.673 (5.58), 1.980 (0.71), 2.073 (1.02), 2.082 (1.14),2.089 (1.23), 2.103 (2.10), 2.144 (16.00), 2.161 (3.72), 2.179 (1.26), 2.201(0.46), 3.125 (5.49), 3.137 (7.35), 3.726 (1.72), 7.268 (0.79), 7.279 (0.89),7.291 (1.58), 7.302 (1.63), 7.317 (1.24), 7.328 (1.14), 7.390 (1.02), 7.401(1.20), 7.411 (1.67), 7.422 (1.65), 7.433 (1.05), 7.445 (0.95), 7.629 (1.92),7.651 (8.28), 7.661 (5.32), 7.665 (4.77), 7.683 (1.12), 7.688 (1.20), 8.804(1.22), 8.819 (2.19), 12.101 (1.08)。

Example 153

(+) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid(enantiomer 2)

In the enantiomeric separation described in example 151, 67 mg (98% purity, ee value 99%) of the title compound was obtained as the enantiomer which eluted later.

[α]_D ²⁰= 36.3 °, 589 nm, c = 0.38 g/100 ml, methanol

LC-MS (method 2) R_t= 1.13 min; MS (ESIpos): m/z = 594/596 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.16), 0.008 (1.02), 1.607(2.99), 1.673 (5.69), 1.980 (0.73), 2.102 (2.13), 2.144 (16.00), 2.159(3.78), 2.178 (1.27), 2.201 (0.47), 3.125 (5.63), 3.137 (7.50), 3.725 (1.78),7.268 (0.83), 7.279 (0.95), 7.291 (1.66), 7.302 (1.69), 7.317 (1.28), 7.328(1.17), 7.390 (1.09), 7.401 (1.28), 7.411 (1.75), 7.422 (1.72), 7.433 (1.10),7.445 (0.99), 7.629 (2.00), 7.651 (8.50), 7.661 (5.45), 7.666 (4.83), 7.683(1.13), 7.688 (1.20), 8.804 (1.26), 8.818 (2.23), 12.101 (0.71)。

Example 154

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid(raceme)

To (+/-) -5- ({ [ 6-bromo-3-methyl)-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid tert-butyl ester (84 mg, 131 μmol,racemic modificationExample 161A) in dichloromethane (1.1ml) TFA (220 μ l, 2.9 mmol) was added and the mixture was left to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 24 mg (100% purity, 32% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 1.46 min; MS (ESIpos): m/z = 580/582 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.854 (0.47), 1.236 (2.28), 1.271(0.43), 1.873 (16.00), 1.969 (1.55), 2.091 (4.87), 2.118 (6.28), 2.131(8.95), 2.169 (15.24), 2.327 (0.58), 2.342 (0.50), 2.670 (0.47), 3.317(4.55), 3.713 (4.24), 7.261 (1.77), 7.273 (2.08), 7.285 (3.43), 7.296 (3.55),7.311 (2.67), 7.322 (2.43), 7.382 (2.28), 7.392 (2.69), 7.403 (3.45), 7.413(3.29), 7.436 (1.69), 7.471 (8.63), 7.493 (14.06), 7.551 (7.71), 7.556(7.15), 7.573 (4.50), 7.579 (4.32), 8.756 (2.66), 8.770 (4.44)。

Example 155

(+/-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid(raceme)

To (+/-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid tert-butyl ester (68 mg, 83% purity, 82.2 μmol,racemic modificationExample 162A) in dichloromethane (690 μ l) was added TFA (140 μ l, 1.8 mmol) and the mixture was allowed to stand at room temperature for 18 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. Obtain35 mg (100% purity, 67% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.14 min; MS (ESIpos): m/z = 630/632 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.30), 0.008 (1.39), 1.236(0.67), 1.885 (2.91), 1.980 (0.64), 2.082 (2.77), 2.100 (3.27), 2.106 (3.21),2.134 (4.76), 2.147 (4.55), 2.165 (16.00), 3.170 (3.69), 3.451 (2.24), 3.480(4.31), 3.509 (2.17), 3.736 (1.60), 7.271 (0.76), 7.282 (0.86), 7.295 (1.56),7.305 (1.62), 7.320 (1.22), 7.331 (1.11), 7.392 (0.94), 7.403 (1.13), 7.414(1.56), 7.425 (1.52), 7.436 (0.92), 7.447 (0.78), 7.680 (1.80), 7.702 (8.65),7.710 (5.87), 7.715 (5.09), 7.733 (1.08), 7.738 (1.16), 8.818 (1.29), 8.833(2.32), 12.100 (1.60)。

Example 156

5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chloro-3, 6-difluorophenyl) pentanoic acid(mixture of diastereomers)

To 5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-tert-butyl 4- (2-chloro-3, 6-difluorophenyl) pentanoate (85 mg, 127 μmol,mixtures of diastereomersExample 163A) in dichloromethane (1.1ml) was added TFA (220 μ l, 2.8 mmol) and the mixture was allowed to stand at room temperature for 18 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 51 mg (100% purity, 65% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.09 min; MS (ESIpos): m/z = 612/614 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.33), 1.235 (0.52), 1.647(1.14), 1.808 (1.08), 1.901 (1.96), 1.921 (1.82), 1.953 (1.67), 1.984 (1.23),2.099 (2.21), 2.127 (3.58), 2.139 (4.40), 2.157 (16.00), 2.198 (0.59), 3.100(1.31), 3.166 (1.35), 3.174 (1.35), 3.381 (1.62), 3.413 (0.83), 3.438 (1.26),3.467 (0.80), 3.728 (1.77), 4.820 (0.94), 4.938 (0.95), 7.268 (0.78), 7.279(0.90), 7.292 (1.63), 7.303 (1.69), 7.318 (1.28), 7.329 (1.18), 7.390 (0.96),7.411 (1.63), 7.422 (1.63), 7.445 (0.87), 7.653 (1.94), 7.676 (8.85), 7.684(5.74), 7.689 (5.25), 7.706 (1.15), 7.711 (1.24), 8.814 (1.27), 8.828 (2.28)。

Example 157

5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- (2-chloro-3, 6-difluorophenyl) pentanoic acid(mixture of diastereomers)

To 5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-tert-butyl 4- (2-chloro-3, 6-difluorophenyl) pentanoate (85 mg, 128 μmol,mixtures of diastereomersExample 164A) in dichloromethane (1.1ml) TFA (220 μ l, 2.8 mmol) was added and the mixture was left to stand at room temperature for 18 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 53 mg (100% purity, 69% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.33 min; MS (ESIpos): m/z = 608/610 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.922 (10.55), 0.938 (10.81), 1.051(0.41), 1.080 (1.22), 1.108 (1.27), 1.131 (0.52), 1.235 (0.49), 1.630 (0.96),1.657 (1.13), 1.732 (2.16), 1.765 (2.08), 1.793 (2.57), 1.824 (1.63), 1.983(0.80), 2.104 (2.45), 2.145 (16.00), 2.161 (4.62), 2.179 (1.52), 2.203(0.55), 2.461 (1.21), 2.679 (0.77), 2.711 (1.36), 2.741 (0.72), 3.436 (1.83),3.464 (3.30), 3.493 (1.55), 3.725 (1.98), 7.268 (0.89), 7.279 (1.01), 7.292(1.83), 7.303 (1.89), 7.317 (1.40), 7.329 (1.28), 7.390 (1.15), 7.401 (1.39),7.412 (1.93), 7.423 (1.91), 7.433 (1.23), 7.445 (1.09), 7.632 (1.57), 7.654(9.91), 7.658 (7.43), 7.663 (5.90), 7.681 (0.88), 7.685 (1.00), 8.796 (1.39),8.811 (2.45), 12.100 (2.08)。

Example 158

5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chloro-3, 6-difluorophenyl) pentanoic acid(mixture of diastereomers)

To 5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-tert-butyl 4- (2-chloro-3, 6-difluorophenyl) pentanoate (85 mg, 125 μmol,mixtures of diastereomersExample 165A) in dichloromethane (1.1ml) was added TFA (210 μ l, 2.8 mmol) and the mixture was allowed to stand at room temperature for 18 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 59 mg (100% purity, 76% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.44 min; MS (ESIpos): m/z = 622/624 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (2.12), 0.891 (5.97), 0.910(13.55), 0.928 (7.25), 1.038 (0.57), 1.066 (1.50), 1.088 (1.54), 1.096(1.54), 1.117 (0.72), 1.241 (1.46), 1.259 (3.18), 1.277 (4.17), 1.294 (2.81),1.566 (1.70), 1.600 (1.55), 1.633 (1.32), 1.748 (2.11), 1.781 (1.43), 1.847(1.75), 1.878 (1.71), 1.972 (0.97), 2.067 (1.41), 2.104 (3.81), 2.136(16.00), 2.162 (4.53), 2.181 (1.63), 2.203 (0.64), 2.327 (0.43), 2.423(1.35), 2.670 (0.43), 2.745 (1.52), 3.488 (3.26), 3.518 (3.03), 3.725 (2.52),7.266 (1.04), 7.277 (1.19), 7.290 (2.16), 7.300 (2.21), 7.315 (1.62), 7.326(1.46), 7.386 (1.42), 7.397 (1.68), 7.408 (2.33), 7.419 (2.32), 7.429 (1.44),7.441 (1.30), 7.631 (1.77), 7.653 (11.15), 7.684 (1.03), 8.794 (1.74), 8.809(3.01), 12.096 (8.21)。

Example 159

(+/-) -5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid(raceme)

To (+/-) -5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid tert-butyl ester (85 mg, 128 μmol,racemic modificationExample 166A) in dichloromethane (1.1ml) TFA (210 μ l, 2.8 mmol) was added and the mixture was left to stand at room temperature for 3.5 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 54 mg (100% purity, 69% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.22 min; MS (ESIpos): m/z = 608/610 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.603 (11.39), 1.781 (7.18), 1.972(0.89), 2.104 (2.93), 2.134 (16.00), 2.161 (4.26), 2.179 (1.62), 2.202(0.64), 3.492 (8.81), 3.506 (13.30), 3.521 (8.69), 3.722 (2.42), 7.267(1.00), 7.278 (1.15), 7.291 (2.00), 7.301 (2.10), 7.316 (1.57), 7.327 (1.47),7.388 (1.42), 7.400 (1.68), 7.410 (2.19), 7.421 (2.12), 7.444 (1.08), 7.531(4.68), 7.553 (8.36), 7.600 (4.67), 7.606 (4.40), 7.622 (2.52), 7.628 (2.47),8.792 (2.66), 12.101 (1.23)。

Example 160

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [ 2-fluoro-6- (trifluoromethyl) phenyl]Valeric acid(raceme)

To (+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [ 2-fluoro-6- (trifluoromethyl) phenyl]Tert-butyl valerate (55 mg, 82.5 μmol,racemic modificationExample 167A) in dichloromethane (1.1ml) was added TFA (610 μ l, 8.3 mmol) and the mixture was stirred at room temperature for 1.5 h. Then, the mixture was concentrated and the residue was dissolved in DMSO and purified by preparative HPLC (method 15). The combined target fractions were concentrated and the residue was dried in vacuo. 45 mg (100% purity, 89% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.21 min; MS (ESIpos): m/z = 610/612 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.21), -0.008 (15.78), 0.008(11.37), 0.146 (1.24), 1.234 (1.30), 1.340 (0.44), 1.611 (5.24), 1.677(10.32), 2.017 (1.79), 2.030 (3.50), 2.060 (4.14), 2.092 (2.65), 2.121(5.79), 2.136 (5.10), 2.167 (15.23), 2.268 (0.63), 2.327 (1.41), 2.366(0.44), 2.670 (1.41), 3.148 (13.24), 3.703 (1.54), 3.873 (1.46), 7.383(0.58), 7.562 (5.88), 7.571 (5.05), 7.577 (4.94), 7.587 (4.08), 7.595 (8.17),7.626 (5.79), 7.652 (16.00), 7.658 (11.67), 7.663 (9.57), 7.680 (1.57), 7.685(1.77), 8.808 (2.37), 8.824 (4.50), 8.839 (2.21), 12.075 (1.49).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]12.08 (br. s, 1H), 8.82 (t, 1H), 7.74-7.51 (m, 5H), 7.38 (br. s, 1H), 3.87 (br. s, 1H), 3.70 (br. s, 1H), 3.33-3.27(1H, masked, assumed), 3.20-3.10 (m,4H), 2.25-1.95 (m, 7H), 1.70-1.55 (m, 6H).

Example 161

(-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [ 2-fluoro-6- (trifluoromethyl) phenyl]Valeric acid(enantiomer 1)

To 5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [ 2-fluoro-6- (trifluoromethyl) phenyl]Tert-butyl valerate (85 mg, 128 μmol,enantiomer 1EXAMPLE 168A) in dichloromethane (1.7ml) TFA (950 μ l, 13 mmol) was added and the mixture was cooled at room temperatureStirring for 1 h. The mixture was then concentrated and the residue was dissolved in DMSO and purified by preparative HPLC (method 20). The combined target fractions were concentrated and the residue concerned was lyophilized. The lyophilizates were then dissolved in methanol and combined, and the mixture was dried under ambient conditions. The residue is then dried in vacuo to yield 63 mg (98% purity, 79% of theory) of the title compound.

[α]_D ²⁰= 40.1 °, 589 nm, c = 0.38 g/100 ml, methanol

LC-MS (method 1) R_t= 2.24 min; MS (ESIpos): m/z = 610/612 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.84), 0.146 (0.81), 1.612(5.48), 1.678 (10.55), 2.019 (1.74), 2.031 (3.64), 2.062 (4.46), 2.084(2.72), 2.122 (6.02), 2.137 (5.09), 2.167 (16.00), 2.268 (0.57), 2.327(1.29), 2.366 (0.72), 2.670 (1.38), 2.710 (0.81), 3.149 (13.62), 3.162(14.23), 3.174 (7.58), 3.511 (0.50), 3.694 (1.67), 3.877 (1.54), 4.076(1.83), 4.089 (1.77), 7.370 (0.63), 7.563 (5.36), 7.577 (5.14), 7.595 (7.85),7.627 (5.54), 7.652 (14.78), 7.684 (1.70), 8.806 (2.22), 8.821 (4.53), 8.836(2.38), 12.061 (1.47)。

Example 162

(+) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [ 2-fluoro-6- (trifluoromethyl) phenyl]Valeric acid(enantiomer 2)

To 5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [ 2-fluoro-6- (trifluoromethyl) phenyl]Tert-butyl valerate (93 mg, 140 μmol,enantiomer 2Example 169A) in dichloromethane (1.9ml) was added TFA (1.0ml, 14 mmol) and the mixture was stirred at room temperature for 1 h. The mixture was then concentrated and the residue was dissolved in DMSO and purified by preparative HPLC (method 20). The combined target fractions were concentrated and the residue concerned was lyophilized. The lyophilizates were then dissolved in methanol and combined, and the mixture was dried under ambient conditions. The residue is then dried in vacuo to yield 68 mg (98% purity, 78% of theory) of the title compound.

[α]_D ²⁰= 45.9 °, 589 nm, c = 0.45 g/100 ml, methanol

LC-MS (method 1) R_t= 2.21 min; MS (ESIpos): m/z = 610/612 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.70), -0.008 (5.63), 0.008(5.76), 0.146 (0.70), 1.613 (4.93), 1.679 (9.47), 2.019 (1.64), 2.032 (3.34),2.062 (4.01), 2.093 (2.39), 2.122 (5.44), 2.137 (4.54), 2.167 (14.53), 2.268(0.52), 2.327 (1.02), 2.366 (0.57), 2.670 (1.02), 2.710 (0.56), 3.149(12.27), 3.162 (10.30), 3.174 (4.19), 3.707 (1.42), 3.876 (1.33), 4.075(0.66), 4.089 (0.66), 7.370 (0.56), 7.563 (5.67), 7.572 (4.77), 7.578 (4.68),7.587 (3.90), 7.596 (8.06), 7.626 (5.40), 7.653 (16.00), 7.658 (11.01), 7.663(9.24), 7.681 (1.51), 7.685 (1.70), 8.807 (2.26), 8.822 (4.55), 8.837 (2.29),12.062 (1.62)。

Example 163

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [ 2-fluoro-6- (trifluoromethyl) phenyl]Valeric acid(raceme)

To (+/-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [ 2-fluoro-6- (trifluoromethyl) phenyl]Tert-butyl valerate (55 mg, 84.3 μmol,racemic modificationExample 170A) in dichloromethane (1.1ml) TFA (630 μ l, 8.4 mmol) was added and the mixture was stirred at room temperature for 1.5 h. Then, the mixture was concentrated and the residue was dissolved in DMSO and purified by preparative HPLC (method 15). The combined target fractions were concentrated and the residue was dried in vacuo. 41 mg (100% purity, 82% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 1.51 min; MS (ESIpos): m/z = 596/598 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.17), -0.008 (10.78), 0.008(13.42), 0.146 (1.33), 1.879 (16.00), 2.012 (2.39), 2.026 (3.42), 2.056(4.94), 2.085 (2.81), 2.118 (5.81), 2.125 (5.56), 2.154 (6.67), 2.171 (6.97),2.328 (2.11), 2.366 (0.53), 2.669 (1.75), 3.581 (11.19), 3.895 (1.53), 7.474(8.50), 7.496 (14.53), 7.549 (8.83), 7.555 (10.11), 7.571 (10.28), 7.577(8.56), 7.592 (8.33), 7.617 (5.47), 7.629 (3.89), 7.640 (2.44), 8.139 (1.83),8.748 (2.86), 8.763 (5.56), 8.778 (2.81), 12.088 (1.00).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]12.09 (br. s, 1H), 8.76 (t, 1H), 7.72-7.52 (m,4H), 7.51-7.39 (m,1H), 7.28 (br. s, 1H), 3.90 (br. s, 1H), 3.73-3.49 (m, 5H), 3.33-2.26 (1H, masked, assumed), 2.27-1.95 (m, 7H), 1.82-1.83 (m, 4H).

Example 164

(+) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [ 2-fluoro-6- (trifluoromethyl) phenyl]Valeric acid(enantiomer 1)

To 5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [ 2-fluoro-6- (trifluoromethyl) phenyl]Tert-butyl valerate (75 mg, 115 μmol,enantiomer 1Example 171A) in dichloromethane (1.5ml) TFA (850 μ l, 11 mmol) was added and the mixture was stirred at room temperature for 1 h. The mixture was then concentrated and the residue was dissolved in DMSO and purified by preparative HPLC (method 22). The combined target fractions were concentrated and the residue concerned was lyophilized. The lyophilizates were then dissolved in methanol and combined, and the mixture was dried under ambient conditions. The residue is then dried in vacuo to yield 55 mg (99% purity, 79% of theory) of the title compound.

[α]_D ²⁰= 38.1 °, 589 nm, c = 0.35 g/100 ml, methanol

LC-MS (method 1) R_t= 1.54 min; MS (ESIpos): m/z = 596/598 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.69), -0.008 (13.12), 0.146(1.65), 1.880 (16.00), 2.012 (2.46), 2.027 (3.61), 2.056 (5.18), 2.089(2.95), 2.118 (5.99), 2.125 (5.83), 2.154 (6.79), 2.176 (6.98), 2.328 (2.53),2.366 (1.42), 2.670 (2.30), 2.710 (1.50), 2.998 (0.42), 3.071 (2.07), 3.169(2.76), 3.581 (11.20), 3.926 (2.19), 4.072 (0.42), 4.154 (3.65), 7.431(0.58), 7.474 (7.60), 7.497 (13.47), 7.549 (8.02), 7.555 (9.63), 7.571(10.24), 7.577 (8.75), 7.592 (8.71), 7.617 (5.83), 7.629 (4.34), 7.676(1.96), 8.136 (1.23), 8.748 (2.95), 8.763 (5.76), 8.779 (2.88), 12.062(1.73)。

Example 165

(-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [ 2-fluoro-6- (trifluoromethyl) phenyl]Valeric acid(enantiomer 2)

To 5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [ 2-fluoro-6- (trifluoromethyl) phenyl]Tert-butyl valerate (79 mg, 121 μmol,enantiomer 2Example 172A) in dichloromethane (1.6ml) TFA (900 μ l, 12 mmol) was added and the mixture was stirred at room temperature for 1 h. The mixture was then concentrated and the residue was dissolved in DMSO and purified by preparative HPLC (method 21). The combined target fractions were concentrated and the residue concerned was lyophilized. The lyophilizates were then dissolved in methanol and combined, and the mixture was dried under ambient conditions. The residue is then dried in vacuo to yield 49 mg (97% pure, 66% of theory) of the title compound.

[α]_D ²⁰= 41.4 °, 589 nm, c = 0.35 g/100 ml, methanol

LC-MS (method 1) R_t= 1.53 min; MS (ESIpos): m/z = 596/598 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (1.29), -0.008 (10.93), 0.008(10.93), 0.146 (1.33), 1.879 (16.00), 2.012 (2.80), 2.026 (3.87), 2.056(5.56), 2.092 (3.20), 2.118 (6.40), 2.124 (6.22), 2.153 (6.98), 2.171 (7.07),2.293 (0.58), 2.327 (2.18), 2.366 (0.98), 2.669 (2.22), 2.709 (1.29), 3.162(0.62), 3.174 (0.71), 3.210 (0.58), 3.472 (0.93), 3.580 (11.02), 3.897(1.87), 7.393 (0.58), 7.409 (0.62), 7.432 (0.89), 7.474 (6.98), 7.496(12.49), 7.549 (7.78), 7.555 (9.56), 7.571 (10.22), 7.592 (8.93), 7.617(5.91), 7.628 (4.44), 7.640 (2.89), 8.748 (3.11), 8.763 (5.69), 8.778 (2.89),9.693 (0.44), 12.054 (6.53)。

Example 166

(+/-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- [ 2-fluoro-6- (trifluoromethyl) phenyl]Valeric acid(raceme)

To (+/-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- [ 2-fluoro-6- (trifluoromethyl) phenyl]Tert-butyl valerate (55 mg, 78.3 μmol,racemic modificationExample 173A) in dichloromethane (1.0ml) was added TFA (580 μ l, 7.8 mmol) and the mixture was stirred at room temperature for 1.5 h. Then, the mixture was concentrated and the residue was dissolved in DMSO and purified by preparative HPLC (method 15). The combined target fractions were concentrated and the residue was dried in vacuo. 50 mg (100% purity, 99% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.16 min; MS (ESIpos): m/z = 646/648 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.66), -0.008 (8.90), 0.008(6.39), 0.146 (0.64), 1.890 (5.53), 2.037 (4.19), 2.067 (7.01), 2.087 (6.21),2.099 (6.24), 2.122 (8.03), 2.137 (6.44), 2.155 (5.81), 2.188 (14.73), 2.293(0.54), 2.327 (0.78), 2.670 (0.80), 3.175 (6.37), 3.186 (5.71), 3.462 (4.30),3.491 (7.92), 3.520 (3.94), 3.699 (1.55), 3.891 (1.37), 7.420 (0.55), 7.566(5.81), 7.575 (5.24), 7.581 (5.08), 7.591 (4.30), 7.599 (7.83), 7.628 (5.37),7.638 (3.85), 7.652 (2.57), 7.681 (2.59), 7.704 (16.00), 7.707 (13.15), 7.712(9.58), 7.730 (1.41), 7.734 (1.57), 8.820 (2.64), 8.835 (4.85), 8.850 (2.43),12.072 (2.23).

¹H-NMR (400 MHz, DMSO-d ₆): δ [ppm]= 12.07 (br. s, 1H), 8.84 (t, 1H),7.77-7.52 (m, 5H), 7.52-7.17 (m, 1H), 4.01-3.81 (m, 1H), 3.81-3.61 (m, 1H),3.49 (t, 2H), 3.25-3.10 (m, 2H), 2.30-1.99 (m, 10H), 1.89 (br. s, 2H)。

Example 167

(-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- [ 2-fluoro-6- (trifluoromethyl) phenyl]Valeric acid(enantiomer 1)

To 5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- [ 2-fluoro-6- (trifluoromethyl) phenyl]Tert-butyl valerate (91 mg, 130 μmol,enantiomer 1Example 174A) in dichloromethane (1.7ml) was added TFA (960. mu.l, 13 mmol) and the mixture was stirred at room temperature for 1 h. The mixture was then concentrated and the residue was dissolved in DMSO and purified by preparative HPLC (method 19). The combined target fractions were concentrated and the residue concerned was lyophilized. The lyophilizates were then dissolved in methanol and combined, and the mixture was dried under ambient conditions. The residue is then dried in vacuo to yield 61 mg (97% purity, 71% of theory) of the title compound.

[α]_D ²⁰= 40.8 °, 589 nm, c = 0.34 g/100 ml, methanol

LC-MS (method 1) R_t= 2.16 min; MS (ESIpos): m/z = 646/648 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.45), 0.146 (0.47), 1.891(5.64), 2.038 (4.28), 2.068 (7.20), 2.088 (6.27), 2.099 (6.42), 2.123 (8.16),2.137 (6.54), 2.155 (5.94), 2.189 (15.09), 2.293 (0.57), 2.328 (0.70), 2.366(0.41), 2.670 (0.67), 2.710 (0.41), 3.163 (11.92), 3.175 (14.69), 3.462(4.32), 3.491 (8.03), 3.520 (4.01), 3.703 (1.56), 3.895 (1.38), 4.063 (1.08),4.076 (2.53), 4.089 (2.43), 4.102 (0.90), 7.422 (0.55), 7.566 (5.90), 7.575(5.37), 7.581 (5.29), 7.591 (4.40), 7.599 (7.94), 7.628 (5.40), 7.638 (3.92),7.651 (2.59), 7.681 (2.56), 7.703 (16.00), 7.712 (9.63), 7.730 (1.32), 7.734(1.55), 8.819 (2.73), 8.834 (5.02), 8.849 (2.47), 12.066 (3.48)。

Example 168

(+) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- [ 2-fluoro-6- (trifluoromethyl) phenyl]Valeric acid(enantiomer isomerization)Body 2)

To 5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- [ 2-fluoro-6- (trifluoromethyl) phenyl]Tert-butyl valerate (93 mg, 132 μmol,enantiomer 2Example 175A) in dichloromethane (1.8 ml) TFA (980 µ l, 13 mmol) was added and the mixture was stirred at room temperature for 1 h. The mixture was then concentrated and the residue was dissolved in DMSO and purified by preparative HPLC (method 19). The combined target fractions were concentrated and the residue concerned was lyophilized. The lyophilizates were then dissolved in methanol and combined, and the mixture was dried under ambient conditions. The residue is then dried in vacuo to yield 61 mg (98% purity, 70% of theory) of the title compound.

[α]_D ²⁰= 40.8 °, 589 nm, c = 0.34 g/100 ml, methanol

LC-MS (method 1) R_t= 2.16 min; MS (ESIpos): m/z = 646/648 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.31), 0.146 (1.38), 1.890(5.50), 2.034 (3.86), 2.067 (6.68), 2.086 (6.14), 2.097 (5.80), 2.121 (8.32),2.136 (6.41), 2.153 (5.43), 2.188 (15.23), 2.292 (0.50), 2.327 (1.78), 2.366(1.11), 2.670 (2.05), 2.710 (1.21), 3.162 (12.11), 3.175 (15.19), 3.462(4.33), 3.491 (8.18), 3.519 (4.13), 3.708 (1.54), 3.894 (1.44), 4.063 (0.97),4.074 (2.62), 4.088 (2.65), 4.100 (1.01), 7.424 (0.57), 7.566 (5.47), 7.575(5.03), 7.599 (8.02), 7.628 (5.27), 7.638 (3.89), 7.651 (2.58), 7.680 (2.11),7.703 (16.00), 7.734 (1.61), 8.821 (2.28), 8.837 (4.46), 8.851 (2.38), 12.068(1.31)。

Example 169

5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [ 2-fluoro-6- (trifluoromethyl) phenyl]Valeric acid(mixture of diastereomers)

To 5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [ 2-fluoro-6- (trifluoromethyl) phenyl]Tert-butyl valerate (55 mg, 80.3 μmol,mixtures of diastereomersExample 176A) in dichloromethane (1.1ml) TFA (600 μ l, 8.0 mmol) was added and the mixture was stirred at room temperature for 1.5 h. Then, the mixture was concentrated and the residue was dissolved in DMSO and purified by preparative HPLC (method 15). The combined target fractions were concentrated and the residue was dried in vacuo. 43 mg (100% purity, 85% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.11 min; MS (ESIpos): m/z = 628/630 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.05), -0.008 (8.09), 0.008(9.08), 0.146 (1.02), 1.654 (2.10), 1.811 (1.98), 1.907 (3.49), 1.927 (3.06),1.957 (2.29), 2.002 (1.61), 2.021 (2.10), 2.035 (4.08), 2.065 (5.07), 2.087(3.12), 2.123 (6.15), 2.137 (4.76), 2.156 (5.44), 2.181 (16.00), 2.286(0.59), 2.328 (1.33), 2.670 (1.36), 3.118 (2.38), 3.178 (2.53), 3.356 (2.47),3.392 (2.47), 3.424 (1.42), 3.449 (2.29), 3.482 (1.45), 3.705 (1.67), 3.888(1.51), 4.827 (1.70), 4.939 (1.76), 7.417 (0.65), 7.565 (6.15), 7.573 (5.50),7.589 (4.36), 7.597 (8.93), 7.627 (5.93), 7.636 (4.26), 7.652 (3.37), 7.677(15.14), 7.708 (1.64), 8.815 (2.44), 8.829 (4.76), 8.844 (2.44), 12.073(2.35).

¹H-NMR (400 MHz, DMSO-d ₆): δ [ppm]= 12.07 (br. s, 1H), 8.83 (t, 1H),7.73-7.54 (m, 5H), 7.52-7.26 (m,1H), 4.88 (br. d, 1H), 4.00-3.80 (m,1H), 3.77-3.60 (m,1H), 3.52-3.33 (m, 3H, partially covered, assumed), 3.25-3.03 (m, 2H),2.26-1.72 (m, 10H), 1.70-1.57 (m, 1H).

Example 170

5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [ 2-fluoro-6- (trifluoromethyl) phenyl]Valeric acid(mixture of diastereomers)

To 5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [ 2-fluoro-6- (trifluoromethyl) phenyl]Tert-butyl valerate (57mg, 82 μmol,mixtures of diastereomersExample 177A) in dichloromethane (1.1ml) was added TFA (610 μ l, 8.2 mmol) and the mixture was stirred at room temperature for 1.5 h. Then, the mixture was concentrated and the residue was dissolved in DMSO and purified by preparative HPLC (method 15). The combined target fractions were concentrated and the residue was dried in vacuo. 51 mg (100% purity, 97% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.46 min; MS (ESIpos): m/z = 638 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.26), -0.008 (16.00), 0.008(10.04), 0.146 (1.32), 0.896 (5.78), 0.914 (13.57), 0.933 (6.59), 1.071(1.05), 1.092 (1.14), 1.263 (2.01), 1.280 (2.73), 1.290 (2.22), 1.308 (1.53),1.574 (1.32), 1.640 (1.02), 1.753 (1.53), 1.853 (1.32), 1.882 (1.20), 2.031(1.92), 2.062 (2.58), 2.086 (1.74), 2.122 (3.69), 2.137 (4.58), 2.162 (6.14),2.327 (1.44), 2.669 (1.38), 2.710 (0.81), 2.739 (1.05), 3.512 (2.52), 3.688(0.84), 3.900 (0.84), 7.563 (3.09), 7.573 (2.85), 7.595 (4.28), 7.626 (2.67),7.654 (9.32), 7.657 (9.41), 7.680 (0.60), 8.813 (2.10), 12.069 (1.14).

¹H-NMR (400 MHz, DMSO-d ₆): δ [ppm]12.07 (br. s, 1H), 8.81 (t, 1H),7.70-7.52 (m, 5H), 7.51-7.19 (br. m,1H), 3.99-3.82 (m,1H), 3.76-3.62 (m,1H), 3.58-3.45 (m, 2H), 2.84-2.69 (m,1H), 2.50-2.37 (m,1H, partial cover), 2.24-1.99 (m, 8H), 1.93-1.82 (m,1H), 1.82-1.71 (m,1H), 1.70-1.49 (m, 2H), 1.38-1.20 (m, 2H), 1.08 (br. q, 1H), 0.91 (t, 3H).

Example 171

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2,3, 6-trichlorophenyl) pentanoic acid(raceme)

To (+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2,3, 6-trichlorophenyl) pentanoic acid tert-butyl ester (55 mg, 80.4 μmol,racemic modificationExample 178A) in dichloromethane (1.1ml) TFA (600 μ l, 8.0 mmol) was added and the mixture was stirred at room temperature for 1.5 h. Then, the mixture was concentrated and the residue was dissolved in DMSO and purified by preparative HPLC (method 15). The combined target fractions were concentrated and the residue was dried in vacuo. 49 mg (100% purity, 97% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.34 min; MS (ESIpos): m/z = 626/628/630 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.91), -0.008 (16.00), 0.008(14.22), 0.146 (1.95), 1.234 (0.51), 1.610 (3.52), 1.675 (6.66), 2.071(1.40), 2.085 (1.95), 2.099 (2.63), 2.120 (3.18), 2.136 (7.09), 2.155 (3.52),2.169 (14.39), 2.180 (3.35), 2.203 (1.49), 2.282 (1.40), 2.327 (2.55), 2.366(0.42), 2.670 (2.04), 2.710 (0.55), 3.140 (8.79), 3.807 (1.23), 4.065 (1.99),7.476 (2.50), 7.498 (3.56), 7.533 (3.18), 7.555 (5.43), 7.596 (3.78), 7.617(2.59), 7.630 (1.74), 7.635 (1.61), 7.652 (6.24), 7.657 (5.90), 7.661 (4.63),7.667 (5.94), 7.672 (3.01), 7.689 (1.57), 8.813 (2.25), 12.108 (1.10).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.10 (br. s, 1H), 8.92-8.69 (m, 1H),7.77-7.39 (m, 5H), 4.20-3.92 (m, 2H), 3.90-3.75 (m, 1H), 3.14 (br. s, 4H),2.32-2.22 (m, 1H), 2.21-2.01 (m, 6H), 1.67 (br. s, 4H), 1.65-1.55 (m, 2H)。

Example 172

(+) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2,3, 6-trichlorophenyl) pentanoic acid(enantiomer 1)

To 5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl under argon]Carbonyl } amino) -4- (2,3, 6-trichlorophenyl) pentanoic acid tert-butyl ester (92 mg, 95% purity, 128 μmol,enantiomer 1Example 179A) solution in dichloromethane (1.1ml)To which TFA (960. mu.l, 13 mmol) was added, and the mixture was stirred at room temperature for 2 h. Then, the mixture was concentrated and the residue was dissolved in DMSO and purified by preparative HPLC (method 15). The combined target fractions were concentrated and the residue was dried in vacuo. 68 mg (100% purity, 85% of theory) of the title compound are obtained.

[α]_D ²⁰= 31.4 °, 589 nm, c = 0.37 g/100 ml, methanol

LC-MS (method 1) R_t= 2.36 min; MS (ESIpos): m/z = 626/628/630 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.92), -0.008 (15.84), 0.146(1.96), 1.609 (3.95), 1.676 (7.70), 2.075 (1.68), 2.101 (3.23), 2.122 (4.27),2.136 (8.34), 2.169 (16.00), 2.183 (3.27), 2.206 (1.56), 2.230 (0.76), 2.282(1.56), 2.327 (2.91), 2.366 (1.52), 2.669 (2.31), 2.710 (1.52), 3.143(10.13), 3.808 (1.44), 4.057 (2.19), 7.477 (2.67), 7.498 (3.91), 7.533(3.47), 7.555 (5.79), 7.597 (4.27), 7.618 (2.99), 7.631 (1.76), 7.654 (6.46),7.658 (6.34), 7.668 (6.30), 7.691 (1.52), 8.808 (2.79), 12.101 (0.48)。

Example 173

(-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2,3, 6-trichlorophenyl) pentanoic acid(enantiomer 2)

To 5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl under argon]Carbonyl } amino) -4- (2,3, 6-trichlorophenyl) pentanoic acid tert-butyl ester (96 mg, 95% purity, 133 μmol,enantiomer 2Example 180A) in dichloromethane (1.1ml) TFA (1.0ml, 13 mmol) was added and the mixture was stirred at room temperature for 2 h. Then, the mixture was concentrated and the residue was dissolved in DMSO and purified by preparative HPLC (method 15). The combined target fractions were concentrated and the residue was dried in vacuo. 62 mg (100% purity, 74% of theory) of the title compound are obtained.

[α]_D ²⁰= 28.8 °, 589 nm, c = 0.35 g/100 ml, methanol

LC-MS (method 1) R_t= 2.36 min; MS (ESIpos): m/z = 626/628/630 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.14), 0.147 (1.14), 1.607(4.08), 1.675 (8.11), 2.072 (1.61), 2.086 (2.39), 2.099 (3.19), 2.120 (4.11),2.136 (8.64), 2.156 (4.33), 2.169 (16.00), 2.181 (3.50), 2.203 (1.67), 2.282(1.64), 2.327 (2.25), 2.367 (1.03), 2.669 (1.69), 2.710 (1.14), 3.141(10.56), 3.807 (1.42), 4.054 (2.42), 7.476 (2.58), 7.497 (3.81), 7.533(3.39), 7.555 (5.50), 7.598 (4.42), 7.618 (3.11), 7.629 (2.06), 7.651 (6.64),7.656 (6.81), 7.666 (6.50), 7.688 (1.56), 8.810 (2.67), 12.111 (1.14)。

Example 174

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2,3, 6-trichlorophenyl) pentanoic acid(raceme)

To (+/-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2,3, 6-trichlorophenyl) pentanoic acid tert-butyl ester (55 mg, 82.1 μmol,racemic modificationExample 181A) in dichloromethane (1.1ml) was added TFA (610 μ l, 8.2 mmol) and the mixture was stirred at room temperature for 1.5 h. Then, the mixture was concentrated and the residue was dissolved in DMSO and purified by preparative HPLC (method 15). The combined target fractions were concentrated and the residue was dried in vacuo. 41 mg (100% purity, 81% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 1.66 min; MS (ESIpos): m/z = 612/614/616 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (1.74), -0.008 (16.00), 0.146(1.82), 1.875 (15.55), 2.070 (2.64), 2.097 (4.97), 2.118 (5.12), 2.158(8.72), 2.194 (15.11), 2.277 (2.23), 2.327 (2.78), 2.669 (2.04), 3.573(11.14), 3.784 (2.12), 4.068 (3.34), 7.472 (8.09), 7.494 (13.07), 7.499(8.76), 7.522 (4.64), 7.544 (8.24), 7.552 (5.31), 7.558 (7.39), 7.580 (5.16),7.590 (5.79), 7.611 (3.56), 8.146 (2.26), 8.757 (4.08).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 12.06 (br. s, 1H), 8.76 (br. s, 1H),7.73-7.15 (m, 5H), 4.23-3.92 (m, 2H), 3.92-3.69 (m, 1H), 3.57 (br. s, 4H),2.39-2.02 (m, 7H), 1.88 (br. s, 4H)。

Example 175

To 5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl under argon]Carbonyl } amino) -4- (2,3, 6-trichlorophenyl) pentanoic acid tert-butyl ester (92 mg, 97% purity, 133 μmol,enantiomer 1Example 182A) in dichloromethane (1.1ml) TFA (990 μ l, 13 mmol) was added and the mixture was stirred at room temperature for 2 h. Then, the mixture was concentrated and the residue was dissolved in DMSO and purified by preparative HPLC (method 15). The combined target fractions were concentrated and the residue was dried in vacuo. 48 mg (100% purity, 59% of theory) of the title compound are obtained.

[α]_D ²⁰= 31.4 °, 589 nm, c = 0.37 g/100 ml, methanol

LC-MS (method 1) R_t= 1.63 min; MS (ESIpos): m/z = 612/614/616 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.80), -0.008 (15.65), 0.008(16.00), 0.147 (1.97), 1.875 (15.71), 2.067 (2.90), 2.096 (4.93), 2.108(5.22), 2.157 (8.64), 2.194 (15.19), 2.276 (2.38), 2.327 (4.81), 2.366(1.62), 2.669 (3.59), 2.710 (1.39), 3.576 (11.13), 3.785 (2.09), 4.057(3.36), 7.472 (9.10), 7.494 (14.03), 7.500 (8.93), 7.523 (5.28), 7.544(9.28), 7.552 (5.74), 7.558 (7.71), 7.580 (5.22), 7.590 (5.97), 7.611 (3.59),8.206 (1.74), 8.759 (4.00), 12.141 (0.93)。

Example 176

(-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2,3, 6-trichlorophenyl) pentanoic acid formate salt(enantiomer 2)

To 5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl under argon]Carbonyl } amino) -4- (2,3, 6-trichlorophenyl) pentanoic acid tert-butyl ester (98 mg, 94% purity, 138 μmol,enantiomer 2Example 183A) in dichloromethane (1.2 ml) TFA (1.0ml, 14 mmol) was added and the mixture was stirred at room temperature for 2 h. Then, the mixture was concentrated and the residue was dissolved in DMSO and purified by preparative HPLC (method 15). The combined target fractions were concentrated and the residue was dried in vacuo. 51 mg (100% purity, 56% of theory) of the title compound are obtained.

[α]_D ²⁰= 29.4 °, 589 nm, c = 0.36 g/100 ml, methanol

LC-MS (method 1) R_t= 1.65 min; MS (ESIpos): m/z = 612/614/616 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.68), -0.008 (6.08), 0.008(5.30), 0.146 (0.67), 1.876 (7.64), 2.070 (1.42), 2.085 (1.86), 2.097 (2.48),2.110 (2.55), 2.118 (2.55), 2.131 (2.05), 2.159 (4.35), 2.194 (7.61), 2.231(0.86), 2.281 (1.11), 2.305 (1.13), 2.327 (1.39), 2.366 (0.65), 2.670 (0.99),2.674 (0.75), 2.710 (0.62), 3.143 (0.56), 3.574 (5.49), 3.769 (0.86), 3.785(1.00), 3.800 (1.07), 4.034 (1.42), 4.069 (1.66), 4.085 (0.92), 4.102 (0.67),7.472 (4.33), 7.477 (2.93), 7.495 (7.02), 7.500 (4.41), 7.523 (2.67), 7.544(4.63), 7.552 (2.80), 7.558 (3.90), 7.564 (1.99), 7.574 (1.77), 7.580 (2.63),7.590 (2.85), 7.612 (1.83), 8.145 (16.00), 8.757 (2.02)。

Example 177

(+/-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2,3, 6-trichlorophenyl) pentanoic acid(raceme)

To (+/-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-Methyl quinolin-4-yl]Carbonyl } amino) -4- (2,3, 6-trichlorophenyl) pentanoic acid tert-butyl ester (56 mg, 77.8 μmol,racemic modificationExample 184A) in dichloromethane (1.0ml) TFA (580 μ l, 7.8 mmol) was added and the mixture was stirred at room temperature for 1.5 h. Then, the mixture was concentrated and the residue was dissolved in DMSO and purified by preparative HPLC (method 15). The combined target fractions were concentrated and the residue was dried in vacuo. 48 mg (100% purity, 93% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.25 min; MS (ESIpos): m/z = 662/664/666 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.885 (3.71), 2.103 (4.93), 2.116(5.04), 2.135 (3.96), 2.159 (9.28), 2.188 (16.00), 2.307 (1.63), 2.328(1.61), 2.670 (1.01), 3.174 (4.63), 3.453 (2.74), 3.483 (5.27), 3.511 (2.65),3.819 (1.27), 4.071 (2.16), 7.479 (2.26), 7.501 (3.20), 7.535 (3.02), 7.556(5.36), 7.599 (4.05), 7.620 (2.74), 7.681 (1.38), 7.703 (6.38), 7.709 (6.79),7.716 (6.35), 7.739 (1.34), 8.822 (2.49), 12.109 (1.24).

¹H-NMR (400 MHz, DMSO-d ₆): δ [ppm]= 12.10 (br. s, 1H), 8.95-8.67 (m,1H), 7.78-7.66 (m, 2H), 7.65-7.47 (m, 3H), 4.17-3.96 (m, 2H), 3.92-3.76 (m,1H), 3.48 (br. t, 2H), 3.17 (br. s, 2H), 2.19 (s, 9H), 1.94-1.82 (m, 2H)。

Example 178

(+) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2,3, 6-trichlorophenyl) pentanoic acid(enantiomer 1)

To 5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2,3, 6-trichlorophenyl) pentanoic acid tert-butyl ester (79 mg, 95% purity, 104 μmol,enantiomer 1Example 185A) to a dichloromethane (890. mu.l) solution TFA (780. mu.l, 10 mmol) was added and the mixture was stirred at room temperature for 1 h. The mixture was then concentrated and the residue was dissolved in DMSO and purified by preparative HPLC (method 19). The combined target fractions were concentrated and the residue concerned was lyophilized. Then, freeze-dryingThe materials were dissolved in methanol and combined and the mixture was dried at ambient conditions. The residue is then dried in vacuo to yield 49 mg (98% purity, 69% of theory) of the title compound.

[α]_D ²⁰= 30.4 °, 589 nm, c = 0.35 g/100 ml, methanol

LC-MS (method 1) R_t= 2.28 min; MS (ESIpos): m/z = 662/664/666 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.91), 0.146 (0.82), 1.886(3.76), 2.102 (4.96), 2.117 (5.16), 2.136 (4.03), 2.158 (9.41), 2.188(16.00), 2.229 (0.82), 2.307 (1.69), 2.328 (1.71), 2.366 (0.74), 2.669(1.07), 2.710 (0.60), 3.162 (13.82), 3.175 (14.53), 3.453 (2.72), 3.483(5.34), 3.512 (2.63), 3.819 (1.31), 3.833 (1.23), 4.062 (2.91), 4.076 (4.18),4.088 (3.40), 7.479 (2.31), 7.500 (3.29), 7.534 (2.87), 7.556 (5.16), 7.598(4.34), 7.620 (2.89), 7.685 (1.49), 7.703 (6.67), 7.709 (7.06), 7.716 (6.21),7.738 (1.33), 8.822 (2.47), 12.100 (1.47)。

Example 179

(-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2,3, 6-trichlorophenyl) pentanoic acid(enantiomer 2)

To 5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2,3, 6-trichlorophenyl) pentanoic acid tert-butyl ester (100 mg, 97% purity, 134 μmol,enantiomer 2Example 186A) in dichloromethane (1.2 ml) TFA (1.0ml, 13 mmol) was added and the mixture was stirred at room temperature for 1 h. The mixture was then concentrated and the residue was dissolved in DMSO and purified by preparative HPLC (method 19). The combined target fractions were concentrated and the residue concerned was lyophilized. The lyophilizates were then dissolved in methanol and combined, and the mixture was dried under ambient conditions. The residue is then dried in vacuo to yield 49 mg (98% purity, 69% of theory) of the title compound.

[α]_D ²⁰= 26.7 °, 589 nm, c = 0.36 g/100 ml, methanol

LC-MS (method 1) R_t= 2.25 min; MS (ESIpos): m/z = 662/664/666 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.65), -0.008 (5.21), 0.008(3.92), 0.146 (0.56), 1.884 (3.63), 2.065 (2.12), 2.078 (3.31), 2.103 (4.75),2.117 (4.92), 2.136 (3.88), 2.158 (9.19), 2.188 (16.00), 2.206 (1.67), 2.229(0.81), 2.279 (1.29), 2.307 (1.58), 2.327 (1.60), 2.366 (0.65), 2.670 (1.04),2.710 (0.56), 3.162 (6.10), 3.175 (6.79), 3.453 (2.73), 3.482 (5.23), 3.511(2.58), 3.802 (0.90), 3.817 (1.25), 3.833 (1.21), 4.048 (1.81), 4.074 (2.58),4.106 (0.85), 7.479 (2.23), 7.500 (3.19), 7.535 (2.83), 7.556 (5.19), 7.598(4.19), 7.620 (2.79), 7.680 (1.40), 7.685 (1.35), 7.703 (6.46), 7.709 (6.79),7.716 (6.08), 7.738 (1.33), 8.821 (2.46), 12.100 (2.10)。

Example 180

5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2,3, 6-trichlorophenyl) pentanoic acid(mixture of diastereomers)

To 5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-tert-butyl 4- (2,3, 6-trichlorophenyl) pentanoate (55 mg, 78.4 μmol,mixtures of diastereomersExample 187A) in dichloromethane (1.0ml) TFA (580 μ l, 7.8 mmol) was added and the mixture was stirred at room temperature for 1.5 h. Then, the mixture was concentrated and the residue was dissolved in DMSO and purified by preparative HPLC (method 15). The combined target fractions were concentrated and the residue was dried in vacuo. 46 mg (100% purity, 91% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.22 min; MS (ESIpos): m/z = 644/646/648 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.84), -0.008 (16.00), 0.008(15.66), 0.146 (1.80), 1.234 (0.68), 1.641 (1.24), 1.811 (1.24), 1.903(1.88), 2.072 (1.33), 2.100 (2.40), 2.112 (2.70), 2.153 (7.06), 2.182(12.62), 2.306 (1.37), 2.327 (2.52), 2.366 (0.81), 2.669 (1.84), 2.709(0.64), 3.105 (1.33), 3.171 (1.45), 3.385 (1.37), 3.441 (1.16), 3.472 (0.68),3.832 (0.98), 4.060 (1.71), 4.819 (0.98), 4.940 (0.94), 7.477 (2.05), 7.499(2.82), 7.533 (2.87), 7.555 (4.96), 7.597 (3.17), 7.617 (2.10), 7.654 (1.33),7.676 (5.48), 7.680 (5.18), 7.690 (5.39), 7.712 (1.28), 8.819 (1.97), 12.102(0.98)。

Example 181

5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2,3, 6-trichlorophenyl) pentanoic acid(mixture of diastereomers)

To 5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-tert-butyl 4- (2,3, 6-trichlorophenyl) pentanoate (55 mg, 77.3 μmol,mixtures of diastereomersExample 188A) in dichloromethane (1.0ml) was added TFA (570 μ l, 7.7 mmol) and the mixture was stirred at room temperature for 1.5 h. Then, the mixture was concentrated and the residue was dissolved in DMSO and purified by preparative HPLC (method 15). The combined target fractions were concentrated and the residue was dried in vacuo. 45 mg (100% purity, 89% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.58 min; MS (ESIpos): m/z = 654/656/658 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.89), -0.008 (16.00), 0.008(15.48), 0.146 (1.85), 0.893 (5.12), 0.912 (12.22), 0.930 (6.41), 1.068(1.29), 1.092 (1.25), 1.261 (2.41), 1.279 (3.14), 1.571 (1.42), 1.640 (1.20),1.751 (1.76), 1.850 (1.42), 1.880 (1.46), 2.073 (1.46), 2.127 (5.85), 2.154(11.44), 2.159 (9.81), 2.184 (2.37), 2.206 (1.29), 2.230 (0.82), 2.276(1.38), 2.327 (2.37), 2.366 (0.77), 2.426 (1.25), 2.669 (2.11), 2.710 (1.12),2.754 (1.16), 3.493 (2.80), 3.523 (2.62), 3.819 (1.08), 4.047 (1.76), 4.080(1.76), 7.475 (2.58), 7.497 (3.74), 7.527 (3.35), 7.549 (5.59), 7.590 (3.44),7.596 (3.61), 7.612 (2.37), 7.632 (1.25), 7.658 (8.82), 7.663 (6.24), 7.684(1.03), 8.802 (2.06), 12.107 (1.38)。

Example 182

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (difluoromethoxy) -6-fluorophenyl]Valeric acid(raceme)

To (+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (difluoromethoxy) -6-fluorophenyl]Tert-butyl valerate (85 mg, 128 μmol,racemic modificationExample 189A) in dichloromethane (1.1ml) TFA (220 μ l, 2.8 mmol) was added and the mixture was left to stand at room temperature for 3.5 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 52 mg (100% purity, 67% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.16 min; MS (ESIpos): m/z = 608/610 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.21), 1.608 (4.52), 1.673(8.82), 1.908 (0.41), 1.924 (0.72), 1.941 (1.34), 1.963 (1.75), 1.986 (1.24),2.004 (0.65), 2.036 (1.55), 2.055 (3.62), 2.093 (8.19), 2.134 (16.00), 3.139(11.63), 3.534 (1.87), 3.665 (0.84), 3.680 (1.39), 3.697 (2.25), 3.713(2.67), 3.728 (1.44), 3.745 (1.52), 3.762 (2.00), 3.781 (1.70), 3.794 (1.07),3.815 (0.62), 7.020 (4.00), 7.041 (4.62), 7.050 (3.53), 7.091 (2.63), 7.114(4.09), 7.138 (2.96), 7.234 (5.54), 7.359 (1.55), 7.380 (3.08), 7.397 (3.02),7.418 (4.11), 7.478 (0.95), 7.628 (2.91), 7.650 (13.17), 7.659 (8.54), 7.664(7.65), 7.681 (1.71), 7.686 (1.86), 8.775 (2.20), 8.790 (4.37), 8.805 (2.16),12.045 (0.54)。

Example 183

(-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (difluoromethoxy) -6-fluorophenyl]Valeric acid(enantiomer 1)

To (-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (difluoromethoxy) -6-fluorophenyl]Tert-butyl valerate (180 mg, 271 μmol,enantiomer 1Example 190A) in dichloromethane (2.1ml) TFA (460 μ l, 6.0 mmol) was added and the mixture was left to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 121 mg (100% purity, 73% of theory) of the title compound are obtained.

[α]_D ²⁰= 30.4 °, 589 nm, c = 0.33 g/100 ml, methanol

LC-MS (method 1) R_t= 2.15 min; MS (ESIpos): m/z = 608/610 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.66), 1.608 (4.73), 1.673(9.37), 1.921 (0.69), 1.939 (1.41), 1.959 (1.86), 1.984 (1.30), 2.003 (0.64),2.034 (1.58), 2.050 (3.83), 2.087 (8.86), 2.133 (16.00), 2.327 (0.43), 2.670(0.46), 3.137 (12.32), 3.532 (1.88), 3.663 (0.85), 3.678 (1.42), 3.696(2.33), 3.711 (2.76), 3.726 (1.49), 3.744 (1.58), 3.761 (2.09), 3.780 (1.82),3.793 (1.14), 3.814 (0.67), 7.020 (4.17), 7.040 (4.81), 7.049 (3.58), 7.091(2.74), 7.113 (4.27), 7.138 (3.06), 7.233 (5.70), 7.359 (1.62), 7.379 (3.26),7.396 (3.13), 7.417 (4.27), 7.474 (1.00), 7.626 (3.16), 7.648 (13.68), 7.658(8.84), 7.662 (8.24), 7.680 (1.79), 7.685 (2.02), 8.776 (2.26), 8.791 (4.44),8.805 (2.18), 12.067 (0.62)。

Example 184

(+) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (difluoromethoxy) -6-fluorophenyl]Valeric acid(enantiomer 2)

To (+) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- [2- (difluoromethoxy) -6-fluorophenyl]Glutaric acid tert-butyl esterButyl ester (145 mg, 218 μmol,enantiomer 2Example 191A) in dichloromethane (1.7ml) was added TFA (370 μ l, 4.8 mmol) and the mixture was left to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized. 95 mg (100% purity, 72% of theory) of the title compound are obtained.

[α]_D ²⁰= 29.9 °, 589 nm, c = 0.30 g/100 ml, methanol

LC-MS (method 1) R_t= 2.15 min; MS (ESIpos): m/z = 608/610 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.070 (0.53), 1.608 (4.56), 1.673(9.01), 1.921 (0.70), 1.939 (1.37), 1.959 (1.76), 1.984 (1.24), 2.000 (0.64),2.034 (1.52), 2.052 (3.62), 2.090 (8.27), 2.133 (16.00), 2.669 (0.44), 3.137(11.85), 3.532 (1.81), 3.664 (0.80), 3.678 (1.36),3.696 (2.21), 3.712(2.64), 3.727 (1.46), 3.744 (1.54), 3.763 (2.00), 3.781 (1.73), 3.815 (0.63),7.020 (4.01), 7.041 (4.64), 7.049 (3.41), 7.091 (2.61), 7.114 (4.15), 7.138(2.97), 7.234 (5.33), 7.359 (1.49), 7.380 (3.11), 7.397 (2.99), 7.417 (4.01),7.474 (0.98), 7.626 (2.92), 7.648 (12.70), 7.658 (7.83), 7.662 (7.47), 7.680(1.63), 7.684 (1.80), 8.775 (2.16), 8.789 (4.27), 8.804 (2.14), 12.053(1.06)。

Example 185

(-) -5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(diastereomer 1)

[ structural formula see example 78: (Mixtures of diastereomers)]

To (-) -5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]Tert-butyl 4- (2-chlorophenyl) valerate (470 mg, 742 μmol,diastereomer 1Example 192A) in dichloromethane (13 ml) TFA (1.3 ml, 16 mmol) was added and the mixture was left to stand at room temperature for 16 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. Will be provided withThe residue was purified by preparative HPLC (method 32). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 372 mg (100% purity, 68% of theory) of the title compound are obtained.

[α]_D ²⁰= 9.3 °, 589 nm, c = 0.35 g/100 ml, methanol

LC-MS (method 1) R_t= 2.06 min; MS (ESIpos): m/z = 576/578 [M+H]⁺

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.007 (1.49), 0.006 (1.24), 1.640(2.13), 1.775 (0.87), 1.793 (2.38), 1.801 (2.71), 1.818 (3.92), 1.835 (3.85),1.853 (2.01), 1.906 (3.85), 1.916 (2.80), 1.923 (3.08), 1.944 (1.86), 1.966(1.19), 1.973 (1.24), 1.990 (0.72), 2.022 (0.95), 2.032 (1.71), 2.049 (6.03),2.070 (5.11), 2.077 (5.53), 2.094 (4.64), 2.117 (3.43), 2.134 (7.30), 2.146(15.75), 3.067 (1.67), 3.087 (2.43), 3.161 (2.60), 3.175 (2.56), 3.196(1.61), 3.281 (1.64), 3.295 (2.57), 3.307 (3.21), 3.320 (3.36), 3.335 (2.14),3.389 (2.50), 3.410 (1.66), 3.415 (1.66), 3.436 (2.25), 3.457 (1.57), 3.595(2.39), 4.829 (1.80), 4.919 (1.56), 4.925 (1.81), 4.931 (1.50), 7.259 (2.37),7.273 (4.84), 7.287 (3.20), 7.289 (3.16), 7.358 (3.08), 7.373 (5.30), 7.387(2.77), 7.443 (8.03), 7.445 (8.07), 7.459 (6.96), 7.461 (6.79), 7.482 (6.24),7.485 (6.43), 7.498 (5.40), 7.500 (5.27), 7.651 (4.10), 7.669 (16.00), 7.676(11.40), 7.680 (9.95), 7.694 (2.38), 7.698 (2.47), 8.720 (3.02), 8.731(5.62), 8.743 (2.74)。

Example 186

(-) -5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(diastereomer 2)

To (-) -5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]Tert-butyl 4- (2-chlorophenyl) valerate (420 mg, 664. mu. mol,diastereomer 2Example 193A) in dichloromethane (12 ml) TFA (1.1ml, 15 mmol) was added and the mixture was left to stand at room temperature for 16 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. Will be provided withThe residue was purified by preparative HPLC (method 32). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 331 mg (100% purity, 86% of theory) of the title compound are obtained.

[α]_D ²⁰= 16.5 °, 589 nm, c = 0.43 g/100 ml, methanol

LC-MS (method 1) R_t= 2.06 min; MS (ESIpos): m/z = 576/578 [M+H]⁺

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.007 (1.47), 0.007 (1.09),1.644(1.88), 1.650 (1.80), 1.772 (0.62), 1.791 (2.00), 1.799 (2.22), 1.815 (3.30),1.833 (3.44), 1.851 (1.68), 1.905 (3.34), 1.922 (2.59), 1.943 (1.35), 1.949(1.32), 1.967 (1.01), 1.975 (1.02), 1.983 (0.67), 1.991 (0.54), 2.019 (0.68),2.029 (1.29), 2.038 (1.58), 2.046 (5.27), 2.066 (4.31), 2.073 (4.72), 2.090(4.20), 2.113 (2.61), 2.130 (5.56), 2.144 (12.88), 2.518 (0.57), 2.522(0.43), 3.073 (1.31), 3.094 (2.18), 3.108 (1.92), 3.150 (2.24), 3.163 (2.22),3.185 (1.32), 3.282 (1.40), 3.297 (2.20), 3.309 (2.83), 3.322 (3.01), 3.337(1.88), 3.385 (2.32), 3.406 (1.51), 3.411 (1.50), 3.427 (2.03), 3.432 (2.11),3.453 (1.48), 3.592 (2.08), 3.651 (1.20), 3.665 (2.13), 3.676 (2.72), 3.686(2.31), 4.820 (1.33), 4.826 (1.57), 4.915 (1.34), 4.921 (1.57), 4.927 (1.30),7.257 (1.94), 7.260 (2.01), 7.273 (4.31), 7.288 (2.95), 7.290 (2.80), 7.359(2.64), 7.374 (4.73), 7.388 (2.45), 7.442 (8.34), 7.445 (7.88), 7.458 (7.21),7.461 (6.59), 7.482 (5.70), 7.484 (5.71), 7.497 (4.85), 7.651 (3.74), 7.668(16.00), 7.675 (11.47), 7.679 (9.85), 7.693 (2.33), 7.697 (2.46), 8.720(2.73), 8.732 (5.23), 8.743 (2.55)。

Example 187

(+) -5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(diastereomer 3)

To (+) -5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]Tert-butyl 4- (2-chlorophenyl) valerate (580 mg, 916 μmol,diastereomer 3Example 194A) in methylene chloride (8 ml)To the solution was added TFA (1.4 ml, 18 mmol), and the mixture was allowed to stand at room temperature for 18 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 470mg (100% purity, ee value) are obtained>99%, 89% of theory) of the title compound.

[α]_D ²⁰= 10.0 °, 589 nm, c = 0.37 g/100 ml, methanol

LC-MS (method 1) R_t= 2.09 min; MS (ESIpos): m/z = 576/578 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (3.12), 0.008 (2.34), 1.641(1.61), 1.793 (1.81), 1.811 (2.86), 1.835 (3.14), 1.858 (1.83), 1.898 (2.57),1.917 (2.18), 1.948 (1.57), 1.982 (0.97), 2.012 (0.69), 2.045 (4.00), 2.079(4.65), 2.088 (4.76), 2.143 (16.00), 2.327 (0.60), 2.366 (0.43), 2.670(0.60), 3.060 (1.10), 3.093 (1.78), 3.158 (1.92), 3.175 (1.84), 3.202 (1.07),3.380 (1.98), 3.406 (1.07), 3.438 (1.66), 3.464 (1.06), 3.594 (1.82), 3.680(3.53), 4.817 (1.32), 4.937 (1.32), 7.256 (1.68), 7.274 (3.88), 7.291 (2.78),7.356 (2.33), 7.374 (4.34), 7.392 (2.23), 7.441 (6.24), 7.444 (5.85), 7.461(5.31), 7.464 (4.93), 7.484 (5.31), 7.500 (4.60), 7.647 (2.38), 7.668(13.37), 7.675 (9.32), 7.680 (8.01), 7.698 (1.56), 7.702 (1.76), 8.716(2.06), 8.730 (4.24), 8.745 (2.04), 12.062 (0.71)。

Example 188

(+) -5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(diastereomer 4)

To (+) -5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]Tert-butyl 4- (2-chlorophenyl) valerate (609 mg, 962. mu. mol,diastereomer 4Example 195A) in dichloromethane (8 ml) was added TFA (1.5ml, 19 mmol) and the mixture was allowed to stand at room temperature for 18 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 6). Will be combinedThe target fractions of (d) were concentrated and the residue was lyophilized from acetonitrile/water. 485 mg (100% purity, ee value) are obtained>95%, 87% of theory) of the title compound.

LC-MS (method 1) R_t= 2.09 min; MS (ESIpos): m/z = 576/578 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.646 (1.83), 1.765 (0.56), 1.792(1.99), 1.811 (3.13), 1.819 (2.79), 1.834 (3.36), 1.858 (2.09), 1.901 (2.96),1.921 (2.38), 1.948 (1.57), 1.983 (1.04), 2.011 (0.79), 2.045 (4.41), 2.080(5.20), 2.088 (5.48), 2.101 (2.64), 2.142 (16.00), 2.218 (0.42), 2.327(0.45), 2.366 (0.42), 2.670 (0.47), 2.710 (0.44), 3.068 (1.11), 3.100 (2.08),3.147 (2.16), 3.162 (2.10), 3.190 (1.11), 3.376 (2.35), 3.409 (1.20), 3.433(1.91), 3.461 (1.20), 3.593 (2.05), 3.645 (1.01), 3.664 (2.25), 3.678 (3.47),4.814 (1.44), 4.934 (1.43), 7.257 (1.79), 7.275 (4.15), 7.293 (2.91), 7.357(2.52), 7.375 (4.58), 7.394 (2.42), 7.441 (6.19), 7.444 (6.08), 7.461 (5.32),7.464 (5.20), 7.484 (5.92), 7.501 (4.82), 7.646 (2.35), 7.668 (13.36), 7.675(9.12), 7.679 (7.80), 7.697 (1.46), 7.702 (1.63), 8.716 (2.26), 8.730 (4.52),8.744 (2.19), 12.050 (0.58)。

Example 189

(+) -5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Valeric acid(diastereomer 1)

[ structural formula see example 123: (Mixtures of diastereomers)]

To (+) -5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Tert-butyl valerate (60 mg, 90 μmol,diastereomer 1Example 196A) was added to a solution of TFA (150 μ l, 2.0 mmol) in dichloromethane (690 μ l) and the mixture was allowed to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 43 mg (100% purity, 77% of theory) of the title compound are obtainedA compound (I) is provided.

[α]_D ²⁰= 15.8 °, 589 nm, c = 0.29 g/100 ml, methanol

LC-MS (method 1) R_t= 2.11 min; MS (ESIpos): m/z = 610/612 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.36), 0.069 (0.58), 1.652(1.85), 1.773 (0.52), 1.812 (1.73), 1.905 (4.46), 1.925 (4.44), 1.935 (3.90),1.957 (3.44), 1.974 (3.09), 1.987 (2.33), 1.998 (3.21), 2.036 (1.48), 2.051(2.71), 2.074 (2.78), 2.092 (1.69), 2.110 (2.91), 2.135 (2.12), 2.177(14.09), 2.328 (0.51), 2.670 (0.49), 3.113 (2.20), 3.169 (2.39), 3.187(2.31), 3.213 (1.42), 3.320 (11.51), 3.394 (2.51), 3.420 (1.33), 3.452(2.05), 3.479 (1.32), 3.627 (1.84), 3.643 (2.09), 3.702 (2.12), 3.718 (1.77),3.733 (1.19), 4.824 (1.57), 4.944 (1.56), 7.463 (2.86), 7.482 (4.75), 7.500(2.94), 7.658 (1.91), 7.680 (16.00), 7.687 (11.53), 7.706 (5.71), 7.724(10.67), 7.733 (7.57), 7.741 (6.70), 8.778 (2.25), 8.793 (4.51), 8.808(2.24)。

Example 190

(+) -5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Valeric acid(diastereomer 2)

To (+) -5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Tert-butyl valerate (60 mg, 90 μmol,diastereomer 2Example 197A) in dichloromethane (690 μ l) was added TFA (150 μ l, 2.0 mmol) and the mixture was allowed to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 38 mg (100% purity, 70% of theory) of the title compound are obtained.

[α]_D ²⁰= 21.1 °, 589 nm, c = 0.29 g/100 ml, methanol

LC-MS (method 1) R_t= 2.11 min; MS (ESIpos): m/z = 610/612 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.069 (0.92), 1.651 (1.87), 1.771(0.52), 1.811 (1.72), 1.903 (4.20), 1.923 (4.35), 1.952 (3.26), 1.968 (3.32),1.981 (2.34), 1.992 (3.53), 2.030 (1.48), 2.046 (2.71), 2.069 (2.78), 2.086(1.60), 2.105 (2.86), 2.131 (2.09), 2.177 (13.12), 2.327 (0.52), 2.670(0.49), 3.083 (1.26), 3.114 (2.23), 3.169 (2.41), 3.184 (2.37), 3.212 (1.51),3.309 (7.64), 3.322 (8.73), 3.338 (7.32), 3.395 (2.74), 3.420 (1.48), 3.452(2.14), 3.479 (1.38), 3.605 (1.26), 3.622 (1.90), 3.639 (2.06), 3.708 (2.01),3.724 (1.76), 3.741 (1.22), 4.824 (1.52), 4.944 (1.52), 7.463 (2.71), 7.482(4.63), 7.500 (2.86), 7.657 (1.95), 7.679 (16.00), 7.686 (11.33), 7.708(5.90), 7.723 (10.09), 7.734 (7.42), 7.739 (7.24), 8.784 (2.18), 8.799(4.37), 8.813 (2.19)。

Example 191

5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Valeric acid(diastereomer 3)

Reaction and isolation of the mixed fraction from example 196A (peak 1):

the mixed fraction described in example 196A (peak 1) was dissolved in dichloromethane (1.5ml), TFA (340 μ l,4.4 mmol) was added, and the mixture was allowed to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The product-containing fractions were collected (where material loss occurred), combined and concentrated, and the residue was lyophilized from acetonitrile/water. 45 mg (100% purity) of 5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl ] -3-methylquinolin-4-yl } carbonyl) amino ] -4- [2- (trifluoromethyl) phenyl ] pentanoic acid (diastereomer mixture) are obtained.

14 mg of this diastereoisomeric mixture was dissolved in a mixture of acetonitrile and methanol (8 ml) and purified by preparative SFC on the chiral phase (see examples 191 and 192) [ column: daicel Chiralcel OD-H, 5 μm,250 mm x 20 mm, flow rate: 80 ml/min, injection: 2.0 ml, 40 deg.C, UV detection 210 nm, eluent 80% carbon dioxide/20% ethanol, running time 6.5 min, isocratic. The combined target fractions were each concentrated and the respective residue was lyophilized.

(-) -5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Valeric acid(diastereomer 3)

In the diastereomer separation, 3mg (100% purity) of the title compound was obtained as the first eluting diastereomer.

LC-MS (method 1) R_t= 2.12 min; MS (ESIpos): m/z = 610/612 [M+H]⁺

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.007 (0.29), 0.006 (0.25), 0.069(0.38), 0.843 (0.31), 1.033 (0.89), 1.045 (0.90), 1.236 (0.47), 1.296 (0.21),1.483 (0.16), 1.498 (0.17), 1.652 (1.74), 1.813 (1.61), 1.829 (1.36), 1.907(4.05), 1.914 (4.49), 1.924 (3.83), 1.947 (2.99), 1.965 (2.07), 1.979 (3.03),1.989 (2.09), 1.998 (2.78), 2.007 (1.91), 2.045 (1.72), 2.057 (2.46), 2.076(2.68), 2.090 (1.44), 2.107 (2.78), 2.118 (1.61), 2.133 (2.08), 2.177(10.18), 2.215 (0.82), 2.359 (0.30), 2.363 (0.36), 2.432 (1.68), 2.637(0.45), 2.640 (0.34), 3.087 (1.24), 3.106 (1.94), 3.173 (2.21), 3.188 (2.24),3.208 (1.55), 3.229 (3.57), 3.396 (3.72), 3.422 (2.39), 3.448 (2.66), 3.469(1.89), 3.604 (1.48), 3.614 (1.57), 3.629 (1.80), 3.642 (1.90), 3.705 (1.90),3.717 (1.73), 3.922 (0.24), 3.933 (0.24), 3.962 (0.30), 3.985 (0.27), 4.836(1.52), 4.923 (1.82), 4.931 (1.65), 4.938 (1.32), 7.467 (2.66), 7.483 (4.72),7.497 (2.92), 7.662 (3.02), 7.679 (16.00), 7.685 (12.54), 7.689 (11.15),7.703 (3.21), 7.707 (6.31), 7.724 (9.33), 7.735 (6.85), 7.740 (6.75), 7.749(2.78), 7.826 (0.92), 8.777 (2.43), 8.789 (4.78), 8.801 (2.35)。

Example 192

5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Valeric acid(diastereomer 4)

In the diastereoisomeric separation described in example 191, 3mg (100% purity) of the title compound are obtained as the second eluting diastereomer.

LC-MS method 1) R_t= 2.12 min; MS (ESIpos): m/z = 610/612 [M+H]⁺

Example 193

(+) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Valeric acid(diastereomer 1)

[ structural formula see example 124: (Mixtures of diastereomers)]

To (+) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Tert-butyl valerate (45 mg, 67 μmol,diastereomer 1Example 198A) was added to TFA (110 μ l, 1.5 mmol) in dichloromethane (510 μ l) solution and the mixture was left to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 33 mg (100% purity, 81% of theory) of the title compound are obtained.

[α]_D ²⁰= 11.5 °, 436 nm, c = 0.44 g/100 ml, methanol

LC-MS (method 2) R_t= 1.28 min; MS (ESIpos): m/z = 620/622 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.895 (1.56), 0.913 (3.64), 0.932(1.85), 1.263 (0.63), 1.281 (0.82), 1.298 (0.59), 1.571 (0.42), 1.753 (0.48),1.887 (0.65), 1.921 (0.41), 1.965 (0.46), 1.989 (0.49), 2.049 (0.52), 2.072(0.57), 2.089 (0.48), 2.130 (1.77), 2.434 (0.42), 2.501 (16.00), 2.749(0.48), 3.511 (0.75), 3.532 (0.62), 3.716 (0.46), 3.732 (0.40), 7.459 (0.53),7.479 (0.88), 7.497 (0.53), 7.657 (3.86), 7.685 (0.50), 7.706 (0.96), 7.715(1.30), 7.735 (2.15), 7.754 (0.48), 8.778 (0.74)。

Example 194

(-) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Valeric acid(diastereomer 2)

To (-) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Tert-butyl valerate (40 mg, 59 μmol,diastereomer 2Example 199A) in dichloromethane (450 μ l) was added TFA (100 μ l, 1.3 mmol) and the mixture was allowed to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 33 mg (100% purity, 81% of theory) of the title compound are obtained.

[α]_D ²⁰= 42.9 °, 589 nm, c = 0.34 g/100 ml, methanol

LC-MS (method 2) R_t= 1.28 min; MS (ESIpos): m/z = 620/622 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.146 (0.17), 0.896 (6.44), 0.915(16.00), 0.934 (7.90), 1.060 (0.48), 1.087 (1.16), 1.113 (1.24), 1.139(0.55), 1.234 (0.82), 1.247 (1.07), 1.264 (2.26), 1.281 (3.55), 1.299 (3.26),1.315 (1.91), 1.333 (0.76), 1.578 (1.42), 1.618 (1.33), 1.651 (1.17), 1.763(1.74), 1.797 (1.17), 1.858 (1.58), 1.895 (2.34), 1.927 (1.27), 1.945 (1.22),1.967 (0.98), 1.985 (1.74), 1.997 (1.06), 2.008 (2.11), 2.025 (0.80), 2.041(1.12), 2.057 (2.00), 2.080 (2.04), 2.097 (1.20), 2.110 (2.27), 2.165(10.84), 2.328 (0.56), 2.367 (0.30), 2.671 (0.47), 2.711 (0.25), 2.779(0.72), 2.809 (1.32), 3.326 (1.42), 3.546 (2.56), 3.577 (2.59), 3.618 (1.37),3.634 (1.42), 3.724 (1.28), 4.333 (0.69), 7.415 (0.63), 7.465 (1.66), 7.484(3.16), 7.502 (2.03), 7.706 (10.33), 7.724 (6.22), 7.741 (8.10), 7.758(1.71), 8.778 (1.46), 8.792 (2.81), 8.807 (1.49)。

Example 195

5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Valeric acid(diastereomer 3)

To (-) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Tert-butyl valerate (55 mg, 81 μmol,diastereomer 3Example 200A) was added to TFA (138 μ l, 1.78 mmol) in dichloromethane (625 μ l) solution, and the mixture was left to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 33 mg (100% purity, 81% of theory) of the title compound are obtained.

LC-MS (method 2) R_t= 1.28 min; MS (ESIpos): m/z = 620/622 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.896 (6.71), 0.915 (16.00), 0.933(7.95), 1.060 (0.50), 1.089 (1.32), 1.118 (1.37), 1.140 (0.62), 1.233 (0.74),1.248 (1.12), 1.265 (2.52), 1.275 (2.32), 1.283 (3.35), 1.292 (2.79), 1.301(2.42), 1.310 (1.90), 1.344 (0.28), 1.580 (1.69), 1.606 (1.47), 1.616 (1.53),1.648 (1.30), 1.678 (0.58), 1.763 (1.92), 1.796 (1.31), 1.856 (1.82), 1.895(2.61), 1.920 (1.46), 1.927 (1.46), 1.943 (1.42), 1.965 (1.14), 1.982 (1.98),1.995 (1.20), 2.006 (2.34), 2.023 (1.04), 2.044 (1.28), 2.059 (2.27), 2.082(2.50), 2.137 (6.50), 2.328 (0.40), 2.367 (0.31), 2.671 (0.37), 2.711 (0.24),2.784 (0.87), 2.812 (1.60), 2.840 (0.89), 3.324 (1.56), 3.545 (2.89), 3.576(2.80), 3.609 (1.15), 3.626 (1.48), 3.643 (1.56), 3.708 (1.13), 3.725 (1.89),3.742 (1.68), 3.759 (1.21), 3.775 (0.66), 4.374 (0.60), 7.465 (2.03), 7.483(3.62), 7.502 (2.29), 7.690 (1.98), 7.710 (13.25), 7.728 (4.42), 7.739(8.10), 7.761 (2.15), 8.780 (1.62), 8.795 (3.23), 8.809 (1.68)。

Example 196

(+) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Valeric acid(diastereomer 4)

To (-) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Tert-butyl valerate (45 mg, 67 μmol,diastereomer 4Example 201A) in dichloromethane (512 μ l) was added TFA (113 μ l, 1.46 mmol) and the mixture was allowed to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 22 mg (100% purity, 54% of theory) of the title compound are obtained.

[α]_D ²⁰= 36.5 °, 589 nm, c = 0.44 g/100 ml, methanol

LC-MS (method 2) R_t= 1.28 min; MS (ESIpos): m/z = 620/622 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.895 (6.49), 0.914 (16.00), 0.933(7.87), 1.045 (0.48), 1.074 (1.22), 1.097 (1.27), 1.126 (0.56), 1.245 (1.11),1.262 (2.28), 1.279 (3.44), 1.296 (3.11), 1.312 (1.94), 1.330 (0.77), 1.572(1.42), 1.615 (1.37), 1.644 (1.20), 1.755 (1.80), 1.788 (1.19), 1.853 (1.63),1.894 (2.29), 1.926 (1.31), 1.942 (1.33), 1.965 (1.02), 1.982 (1.75), 1.994(1.19), 2.006 (2.13), 2.024 (0.84), 2.041 (1.16), 2.056 (2.06), 2.079 (2.04),2.097 (1.29), 2.110 (2.32), 2.159 (11.74), 2.328 (0.58), 2.367 (0.41), 2.429(1.18), 2.458 (1.97), 2.670 (0.49), 2.710 (0.42), 2.733 (0.86), 2.759 (1.56),2.790 (0.85), 3.325 (1.61), 3.522 (5.03), 3.543 (4.60), 3.595 (2.21), 3.614(2.34), 3.631 (2.17), 3.716 (1.56), 7.414 (0.69), 7.464 (1.69), 7.483 (3.14),7.501 (1.93), 7.643 (0.61), 7.665 (14.63), 7.690 (1.70), 7.709 (3.46), 7.723(6.19), 7.740 (7.10), 7.756 (1.65), 8.756 (1.60), 8.770 (3.12), 8.785 (1.58)。

Example 197

(+) -5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Valeric acid(diastereomer 1)

[ structural formula see example 125: (Mixtures of diastereomers)]

To (+) -5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Tert-butyl valerate (70 mg, 106 μmol,diastereomer 1Example 202A) in dichloromethane (810 μ l) TFA (180 μ l, 2.32 mmol) was added and the mixture was allowed to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 45 mg (100% purity, 70% of theory) of the title compound are obtained.

[α]_D ²⁰= 22.2 °, 589 nm, c = 0.27 g/100 ml, methanol

LC-MS (method 1) R_t= 2.34 min; MS (ESIpos): m/z = 606/608 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.18), -0.008 (1.58), 0.008(1.81), 0.069 (0.44), 0.146 (0.19), 0.927 (10.77), 0.943 (10.98), 0.984(0.16), 1.056 (0.36), 1.084 (1.12), 1.114 (1.17), 1.135 (0.48), 1.235 (0.33),1.633 (0.97), 1.663 (1.14), 1.691 (0.56), 1.737 (2.00), 1.771 (1.99), 1.797(2.53), 1.827 (1.55), 1.893 (1.08), 1.902 (1.01), 1.924 (1.40), 1.938 (1.28),1.952 (1.21), 1.968 (1.64), 1.981 (0.97), 1.992 (1.83), 2.001 (1.10), 2.032(0.90), 2.047 (1.77), 2.071 (1.84), 2.088 (1.01), 2.108 (1.88), 2.162 (8.48),2.328 (0.30), 2.367 (0.19), 2.436 (1.04), 2.465 (1.69), 2.670 (0.37), 2.691(0.96), 2.718 (1.71), 2.747 (0.94), 3.452 (1.85), 3.479 (3.26), 3.508 (1.63),3.608 (0.78), 3.625 (1.19), 3.641 (1.32), 3.696 (1.34), 3.712 (1.15), 3.729(0.76), 7.435 (0.73), 7.462 (1.67), 7.481 (2.99), 7.499 (1.81), 7.636 (0.90),7.657 (16.00), 7.661 (8.05), 7.684 (1.57), 7.707 (3.18), 7.722 (6.86), 7.732(4.91), 7.739 (4.39), 8.766 (1.46), 8.781 (2.92), 8.795 (1.44), 12.101(0.17)。

Example 198

(+) -5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Valeric acid(diastereomer 2)

To (+) -5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Tert-butyl valerate (70 mg, 106 μmol,diastereomer 2Example 203A) was added to a dichloromethane (810 μ l) solution of TFA (180 μ l, 2.3 mmol), and the mixture was allowed to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 47 mg (100% purity, 73% of theory) of the title compound are obtained.

[α]_D ²⁰= 11.7 °, 589 nm, c = 0.29 g/100 ml, methanol

LC-MS (method 1) R_t= 2.34 min; MS (ESIpos): m/z = 606/608 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.27), 0.008 (1.49), 0.069(0.30), 0.146 (0.17), 0.928 (11.12), 0.944 (11.35), 1.059 (0.37), 1.085(1.15), 1.115 (1.18), 1.136 (0.47), 1.235 (0.19), 1.635 (0.98), 1.665 (1.19),1.695 (0.56), 1.737 (2.01), 1.771 (1.99), 1.797 (2.48), 1.828 (1.54), 1.897(1.09), 1.907(1.03), 1.927 (1.25), 1.942 (1.18), 1.961 (1.04), 1.978 (1.67),1.990 (1.02), 2.002 (1.92), 2.011 (1.17), 2.039 (1.00), 2.053 (1.87), 2.076(1.89), 2.094 (1.09), 2.113 (1.91), 2.168 (10.24), 2.328 (0.43), 2.366(0.20), 2.438 (1.20), 2.468 (1.84), 2.670 (0.48), 2.689 (0.90), 2.718 (1.63),2.746 (0.89), 3.452 (1.81), 3.480 (3.20), 3.508 (1.54), 3.612 (1.12), 3.629(1.22), 3.707 (1.17), 3.723 (1.04), 7.424 (0.65), 7.465 (1.63), 7.483 (2.97),7.501 (1.79), 7.636 (0.89), 7.658 (16.00), 7.662 (7.92), 7.685 (1.30), 7.709(3.20), 7.724 (6.78), 7.735 (4.84), 7.741 (4.46), 8.760 (1.53), 8.775 (3.04),8.789 (1.47), 12.012 (0.45)。

Example 199

(-) -5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Valeric acid(diastereomer 3)

Reaction and isolation of the mixed fraction (Peak 1) from example 202A

The mixed fraction described in example 202A (peak 1) was dissolved in dichloromethane (1.8 ml), TFA (390 μ l,5.05 mmol) was added, and the mixture was allowed to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 106 mg (100% purity) of 5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl ] quinolin-4-yl } carbonyl) amino ] -4- [2- (trifluoromethyl) phenyl ] pentanoic acid (mixture of diastereomers) are obtained.

78 mg of this diastereoisomeric mixture are dissolved in a mixture of acetonitrile and methanol (8 ml) and purified by preparative SFC on the chiral phase (see examples 199 and 200) [ column: daicel Chiralcel OD-H, 5 μm,250 mm x 20 mm, flow rate: 80 ml/min, injection: 2.0 ml, 40 deg.C, UV detection 210 nm, eluent 80% carbon dioxide/20% ethanol, running time 6.5 min, isocratic. The combined target fractions were each concentrated and the respective residue was lyophilized.

In the diastereoisomeric separation, 24 mg (100% purity, ee >99%) of the title compound are obtained as the first eluting diastereoisomer.

LC-MS(method 2) R_t= 1.22 min; MS (ESIpos): m/z = 606/608 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.79), 0.008 (0.76), 0.069(0.28), 0.927 (10.81), 0.943 (10.94), 1.056 (0.42), 1.084 (1.13), 1.108(1.18), 1.136 (0.48), 1.237 (0.16), 1.633 (1.00), 1.663 (1.16), 1.737 (2.02),1.744 (1.93), 1.772 (2.02), 1.797 (2.51), 1.828 (1.59), 1.898 (1.22), 1.909(1.22), 1.929 (1.37), 1.942 (1.31), 1.963 (1.20), 1.979 (1.84), 1.992 (1.24),2.004 (2.13), 2.012 (1.20), 2.040 (1.15), 2.055 (2.08), 2.079 (2.19), 2.096(1.33), 2.114 (2.35), 2.162 (8.78), 2.328 (0.42), 2.366 (0.31), 2.436 (1.08),2.466 (1.74), 2.670 (0.48), 2.691 (0.94), 2.718 (1.67), 2.747 (0.93), 3.452(1.70), 3.479 (3.15), 3.509 (1.53), 3.628 (1.16), 3.644 (1.35), 3.697 (1.39),3.713 (1.17), 7.432 (0.80), 7.464 (1.77), 7.483 (3.21), 7.502 (1.99), 7.636(0.94), 7.658 (16.00), 7.662 (7.86), 7.685 (1.53), 7.709 (3.51), 7.724(6.91), 7.740 (5.40), 7.754 (1.76), 8.756 (1.54), 8.770 (3.12), 8.785 (1.54),12.030 (2.34)。

Example 200

(-) -5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Valeric acid(diastereomer 4)

In the diastereoisomeric separation described in example 199, 23mg (100% purity, ee >99%) of the title compound are obtained as the second eluting diastereoisomer.

LC-MS (method 2) R_t= 1.22 min; MS (ESIpos): m/z = 606/608 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.008 (0.84), 0.069 (0.29), 0.928(11.23), 0.944 (11.35), 1.085 (1.20), 1.115 (1.22), 1.136 (0.52), 1.634(1.04), 1.665 (1.28), 1.692 (0.64), 1.737 (2.13), 1.771 (2.10), 1.797 (2.59),1.828 (1.65), 1.897 (1.30), 1.909 (1.29), 1.929 (1.44), 1.943 (1.42), 1.963(1.22), 1.980 (1.93), 1.993 (1.27), 2.004 (2.23), 2.014 (1.33), 2.040 (1.25),2.055 (2.17), 2.078 (2.26), 2.096 (1.43), 2.114 (2.23), 2.168 (10.68), 2.255(0.24), 2.328 (0.50), 2.367 (0.27), 2.438 (1.21), 2.469 (1.90), 2.670 (0.59),2.690 (0.94), 2.718 (1.67), 2.746 (0.93), 3.453 (1.89), 3.480 (3.27), 3.509(1.63), 3.613 (1.27), 3.630 (1.33), 3.708 (1.29), 3.724 (1.16), 7.425 (0.71),7.465 (1.79), 7.484 (3.29), 7.502 (2.08), 7.636 (0.78), 7.658 (16.00), 7.662(8.26), 7.690 (1.53), 7.709 (3.65), 7.725 (7.44), 7.735 (5.58), 7.742 (5.23),8.758 (1.60), 8.773 (3.25), 8.788 (1.62), 12.029 (2.27)。

Example 201

(-) -5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Valeric acid(diastereomer 1)

[ structural formula see example 138: (Mixtures of diastereomers)]

To (-) -5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Tert-butyl valerate (70 mg, 101 μmol,diastereomer 1Example 204A) in dichloromethane (1.8 ml) was added TFA (172 μ l, 2.23 mmol) and the mixture was left to stand at room temperature for 16 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 40 mg (100% purity, 62% of theory) of the title compound are obtained.

[α]_D ²⁰= 20.0 °, 589 nm, c = 0.33 g/100 ml, methanol

LC-MS (method 1) R_t= 2.15 min; MS (ESIpos): m/z = 626/628 [M+H]⁺

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.007 (1.74), 0.006 (1.29), 0.117(0.17), 1.234 (0.48), 1.358 (0.18), 1.647 (2.01), 1.777 (0.83), 1.794 (1.85),1.807 (3.28), 1.815 (3.49), 1.825 (3.10), 1.833 (3.74), 1.851 (2.21), 1.910(3.53), 1.926 (2.82), 1.948 (1.55), 1.970 (1.09), 1.978 (1.12), 1.995 (0.62),2.010 (0.51), 2.031 (1.08), 2.042 (2.73), 2.068 (9.82), 2.072 (8.73), 2.093(2.44), 2.106 (1.59), 2.153 (8.47), 2.242 (0.33), 2.358 (0.31), 2.362 (0.41),2.519 (0.94), 2.523 (0.70), 2.632 (0.31), 2.636 (0.41), 2.639 (0.31), 3.079(1.46), 3.100 (2.29), 3.163 (2.39), 3.177 (2.41), 3.198 (1.53), 3.292 (1.73),3.305 (2.59), 3.318 (3.24), 3.331 (3.42), 3.345 (2.27), 3.390 (4.35), 3.395(4.39), 3.415 (2.52), 3.441 (2.30), 3.463 (1.61), 3.594 (1.07), 3.605 (1.65),3.620 (2.70), 3.632 (3.18), 3.645 (1.99), 3.656 (1.71), 3.670 (2.44), 3.684(2.05), 3.696 (1.26), 3.711 (0.70), 4.831 (1.64), 4.920 (1.40), 4.926 (1.64),4.932 (1.37), 7.343 (2.70), 7.347 (2.74), 7.351 (2.93), 7.355 (3.78), 7.359(4.72), 7.362 (3.77), 7.384 (1.38), 7.389 (2.08), 7.399 (6.05), 7.403 (8.73),7.410 (7.42), 7.417 (7.35), 7.431 (1.78), 7.468 (0.96), 7.550 (4.55), 7.554(3.30), 7.562 (3.39), 7.569 (3.42), 7.657 (3.58), 7.674 (16.00), 7.681(10.84), 7.685 (9.37), 7.699 (2.17), 7.703 (2.30), 8.746 (2.70), 8.757(4.94), 8.769 (2.51)。

Example 202

(-) -5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Valeric acid(diastereomer 2)

To (-) -5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Tert-butyl valerate (70 mg, 103 μmol,diastereomer 2Example 205A) in dichloromethane (1.8 ml) was added TFA (174 μ l, 2.26 mmol) and the mixture was left to stand at room temperature for 16 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 37 mg (100% purity, 58% of theory) of the title compound are obtained.

[α]_D ²⁰= 14.2 °, 589 nm, c = 0.33 g/100 ml, methanol

LC-MS (method 1) R_t= 2.15 min; MS (ESIpos): m/z = 626/628 [M+H]⁺

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.120 (0.23), -0.007 (2.56), 0.006(1.91), 0.070 (0.24), 0.117 (0.21), 1.234 (0.27), 1.249 (0.18), 1.365 (0.16),1.646 (1.97), 1.779 (0.86), 1.795 (1.89), 1.809 (3.39), 1.818 (3.31), 1.827(3.12), 1.835 (3.65), 1.854 (2.25), 1.910 (3.52), 1.920 (2.49), 1.927 (2.86),1.949 (1.66), 1.970 (1.11), 1.978 (1.13), 2.017 (0.45), 2.048 (2.62), 2.070(10.21), 2.096 (2.46), 2.154 (9.21), 2.240 (0.34), 2.362 (0.39), 2.519(0.85), 2.523 (0.58), 2.636 (0.37), 3.078 (1.46), 3.098 (2.24), 3.167 (2.44),3.181 (2.44), 3.202 (1.56), 3.290 (1.92), 3.304 (2.85), 3.316 (3.52), 3.329(3.62), 3.343 (2.38), 3.395 (4.37), 3.416 (2.57), 3.442 (2.19), 3.464 (1.51),3.599 (0.89), 3.611 (1.41), 3.625 (2.70), 3.638 (3.40),3.650 (3.29), 3.664(2.72), 3.678 (2.12), 3.690 (1.14), 3.705 (0.62), 4.826 (1.45), 4.832 (1.71),4.921 (1.45), 4.927 (1.72), 4.933 (1.42), 7.345 (2.69), 7.348 (2.70), 7.352(2.89), 7.356 (3.79), 7.360 (4.70), 7.363 (3.78), 7.384 (1.46), 7.389 (2.13),7.399 (6.05), 7.403 (8.97), 7.410 (7.38), 7.417 (7.59), 7.431 (1.73), 7.480(0.99), 7.551 (4.79), 7.555 (3.42), 7.563 (3.46), 7.570 (3.57), 7.658 (3.77),7.675 (16.00), 7.682 (10.74), 7.686 (9.28), 7.700 (2.17), 7.704 (2.26), 8.743(2.56), 8.755 (4.81), 8.766 (2.44), 12.171 (0.19)。

Example 203

(+) -5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Valeric acid(diastereomer 3)

To (+) -5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Tert-butyl valerate (64 mg, 92 μmol,diastereomer 3Example 206A) in dichloromethane (1.62 ml) TFA (156 μ l, 2.02 mmol) was added and the mixture was left to stand at room temperature for 16 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 38 mg (100% purity, 65% of theory) of the title compound are obtained.

[α]_D ²⁰= 14.9 °, 589 nm, c = 0.32 g/100 ml, methanol

LC-MS (method 1) R_t= 2.15 min; MS (ESIpos): m/z = 626/628 [M+H]⁺

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.007 (1.72), 0.006 (1.14), 0.070(0.25), 1.233 (0.53), 1.333 (0.22), 1.353 (0.39), 1.371 (0.25), 1.646 (2.02),1.779 (0.85), 1.795 (1.93), 1.809 (3.59), 1.819 (3.45), 1.827 (3.18), 1.835(3.82), 1.854 (2.40), 1.911 (3.61), 1.920 (2.55), 1.927 (2.93), 1.949 (1.71),1.971 (1.13), 1.978 (1.15), 2.015 (0.49), 2.036 (1.12), 2.047 (2.88), 2.069(10.49), 2.096 (2.64), 2.111 (1.57), 2.154 (9.53), 2.241 (0.34), 2.362(0.36), 2.519 (0.74), 2.522 (0.54), 2.636 (0.34), 3.078 (1.52), 3.099 (2.33),3.167 (2.56), 3.181 (2.58), 3.202 (1.69), 3.289 (1.77), 3.303 (2.69), 3.316(3.34), 3.329 (3.53), 3.343 (2.33), 3.395 (4.62), 3.416 (2.75), 3.442 (2.37),3.464 (1.65), 3.599 (0.94), 3.611 (1.50), 3.625 (2.85), 3.638 (3.63), 3.650(3.47), 3.664 (2.87), 3.678 (2.24), 3.690 (1.23), 3.705 (0.71), 4.832 (1.74),4.921 (1.49), 4.927 (1.76), 4.933 (1.46), 7.345 (2.68), 7.348 (2.69), 7.352(2.86), 7.357 (3.85), 7.360 (4.78), 7.384 (1.37), 7.389 (2.04), 7.399 (6.17),7.403 (9.14), 7.410 (7.53), 7.417 (7.95), 7.431 (1.82), 7.481 (1.02), 7.551(5.06), 7.555 (3.52), 7.563 (3.66), 7.570 (3.84), 7.658 (3.63), 7.675(16.00), 7.683 (10.62), 7.686 (9.13), 7.700 (2.21), 7.704 (2.30), 8.744(2.82), 8.756 (5.44), 8.767 (2.75)。

Example 204

(+) -5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Valeric acid(diastereomer 4)

To (+) -5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Tert-butyl valerate (64 mg, 94 μmol,diastereomer 4Example 207A) in dichloromethane (1.66 ml) TFA (159. mu.l, 2.06 mmol) was added and the mixture was allowed to stand at room temperature for 16 h. Then concentrating the mixture and repeatedly addingDichloromethane was added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 31 mg (100% purity, 53% of theory) of the title compound are obtained.

[α]_D ²⁰= 20.0 °, 589 nm, c = 0.35 g/100 ml, methanol

LC-MS (method 1) R_t= 2.15 min; MS (ESIpos): m/z = 626/628 [M+H]⁺

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.120 (0.20), -0.007 (2.68), 0.006(1.93), 0.117 (0.20), 1.131 (3.23), 1.235 (0.50), 1.353 (0.28), 1.386 (0.19),1.646 (2.21), 1.778 (0.95), 1.795 (2.07), 1.807 (3.59), 1.816 (3.73), 1.825(3.47), 1.833 (4.07), 1.852 (2.39), 1.910 (3.89), 1.926 (3.11), 1.947 (1.73),1.971 (1.24), 1.978 (1.26), 2.047 (2.74), 2.068 (11.03), 2.093 (2.58), 2.153(9.32), 2.242 (0.35), 2.362 (0.50), 2.636 (0.46), 3.080 (1.61), 3.099 (2.52),3.163 (2.63), 3.176 (2.67), 3.198 (1.69), 3.291 (2.30), 3.305 (3.33), 3.318(4.05), 3.331 (4.17), 3.345 (2.80), 3.390 (4.88), 3.415 (2.76), 3.441 (2.48),3.462 (1.70), 3.594 (1.14), 3.605 (1.76), 3.620 (2.90), 3.632 (3.47), 3.645(2.18), 3.656 (1.95), 3.670 (2.71), 3.683 (2.24), 3.696 (1.38), 3.711 (0.77),4.254 (0.23), 4.265 (0.19), 4.831 (1.80), 4.926 (1.80), 7.213 (0.24), 7.286(0.23), 7.302 (0.26), 7.344 (2.98), 7.347 (3.03), 7.351 (3.22), 7.355 (4.05),7.359 (4.92), 7.389 (2.26), 7.400 (6.52), 7.403 (9.12), 7.411 (7.68), 7.418(7.84), 7.432 (1.90), 7.473 (1.07), 7.551 (4.79), 7.562 (3.74), 7.569 (3.59),7.657 (3.65), 7.674 (16.00), 7.681 (10.76), 7.685 (9.35), 7.699 (2.19), 7.703(2.29), 8.745 (2.59), 8.756 (4.66), 8.768 (2.45), 12.196 (0.18)。

Example 205

(+) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Valeric acid(diastereomer 1)

[ structural formula see example 139: (Mixtures of diastereomers)]

To (+) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Tert-butyl valerate (45 mg, 65 μmol,diastereomer 1Example 208A) in dichloromethane (0.5 ml) was added TFA (110 μ l, 1.43 mmol) and the mixture was left to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 38 mg (100% purity, 92% of theory) of the title compound are obtained.

[α]_D ²⁰= 12.7 °, 436 nm, c = 0.30 g/100 ml, methanol

LC-MS (method 2) R_t= 1.31 min; MS (ESIpos): m/z = 636/638 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.893 (6.77), 0.911 (16.00), 0.930(8.24), 1.045 (0.61), 1.067 (1.37), 1.102 (1.47), 1.140 (0.77), 1.242 (1.36),1.260 (2.97), 1.278 (3.89), 1.296 (2.68), 1.567 (1.79), 1.603 (1.66), 1.636(1.39), 1.753 (2.05), 1.785 (1.75), 1.812 (1.58), 1.836 (2.59), 1.857 (2.73),1.882 (1.90), 1.909 (1.96), 2.051 (2.59), 2.077 (12.08), 2.111 (7.17), 2.229(0.46), 2.246 (0.53), 2.327 (0.72), 2.675 (0.63), 2.739 (1.08), 2.769 (1.95),2.799 (1.06), 3.390 (1.88), 3.510 (3.52), 3.540 (3.41), 3.567 (1.51), 3.584(1.48), 3.599 (1.93), 3.617 (2.79), 3.633 (3.32), 3.648 (2.34), 3.661 (2.48),3.678 (3.22), 3.696 (2.83), 3.711 (2.05), 3.731 (1.49), 7.355 (3.26), 7.385(1.48), 7.397 (5.85), 7.409 (4.92), 7.420 (5.18), 7.476 (1.21), 7.555 (3.56),7.567 (3.02), 7.578 (2.59), 7.674 (15.79), 8.734 (1.88), 8.749 (3.42), 8.763(1.76)。

Example 206

5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Valeric acid(diastereomer 2)

To (-) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl)Oxy) phenyl]Tert-butyl valerate (30 mg, 43 μmol,diastereomer 2Example 209A) was added to the TFA (73 μ l, 950 μmol) solution in dichloromethane (330 μ l), and the mixture was allowed to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 14 mg (100% purity, 50% of theory) of the title compound are obtained.

LC-MS (method 2) R_t= 1.31 min; MS (ESIpos): m/z = 636/638 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.069 (0.21), 0.894 (6.49), 0.913(16.00), 0.931 (8.01), 1.086 (1.30), 1.114 (1.33), 1.138 (0.60), 1.245(1.15), 1.262 (2.51), 1.280 (3.24), 1.291 (2.89), 1.298 (2.89), 1.309 (1.93),1.574 (1.48), 1.614 (1.40), 1.645 (1.26), 1.760 (1.81), 1.792 (1.65), 1.815(1.52), 1.838 (1.92), 1.858 (2.48), 1.885 (1.73), 1.909 (0.69), 2.054 (2.32),2.079 (10.90), 2.141 (9.25), 2.328 (0.48), 2.367 (0.29), 2.671 (0.47), 2.710(0.27), 2.803 (1.31), 3.406 (1.46), 3.536 (2.86), 3.566 (2.69), 3.603 (1.12),3.621 (1.93), 3.637 (2.39), 3.653 (1.91), 3.675 (1.73), 3.691 (1.41), 4.286(0.64), 7.358 (2.99), 7.387 (1.36), 7.401 (5.34), 7.412 (4.79), 7.419 (4.47),7.424 (5.17), 7.437 (1.59), 7.554 (3.13), 7.566 (2.68), 7.577 (2.30), 7.702(8.48), 8.747 (1.57), 8.762 (2.93)。

Example 207

(-) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Valeric acid(diastereomer 3)

To (-) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Tert-butyl valerate (45 mg, 65 μmol,diastereomer 3Example 210A) in dichloromethane (0.5 ml) was added TFA (110 μ l, 1.43 mmol) and the mixture was left to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue is led throughPurification by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 22 mg (100% purity, 53% of theory) of the title compound are obtained.

[α]_D ²⁰= 10.6 °, 436 nm, c = 0.35 g/100 ml, methanol

LC-MS (method 2) R_t= 1.31 min; MS (ESIpos): m/z = 636/638 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.893 (6.49), 0.912 (16.00), 0.930(7.83), 1.069 (1.16), 1.098 (1.20), 1.121 (0.54), 1.243 (1.11), 1.260 (2.52),1.278 (3.35), 1.296 (2.24), 1.564 (1.46), 1.602 (1.36), 1.634 (1.14), 1.751(1.72), 1.784 (1.42), 1.814 (1.24), 1.825 (1.32), 1.836 (2.15), 1.857 (2.26),1.883 (1.55), 2.050 (2.20), 2.077 (10.21), 2.109 (5.78), 2.328 (0.41), 2.367(0.34), 2.404 (0.80), 2.430 (1.31), 2.458 (0.96), 2.670 (0.35), 2.723 (0.91),2.755 (1.66), 2.783 (0.94), 3.409 (2.32), 3.498 (3.72), 3.528 (3.05), 3.584(0.97), 3.599 (1.25), 3.617 (1.88), 3.633 (2.25), 3.648 (1.36), 3.660 (1.49),3.677 (1.98), 3.696 (1.66), 3.712 (0.97), 3.730 (0.63), 7.355 (2.78), 7.384(1.19), 7.399 (4.88), 7.410 (4.38), 7.417 (3.92), 7.421 (4.57), 7.434 (1.17),7.472 (0.98), 7.555 (3.27), 7.560 (2.08), 7.567 (2.60), 7.578 (2.44), 7.637(1.08), 7.660 (13.23), 7.665 (7.07), 7.683 (0.77), 7.688 (0.90), 8.722(1.55), 8.736 (2.95), 8.750 (1.56), 12.021 (0.18)。

Example 208

(+) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Valeric acid(diastereomer 4)

To (+) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Tert-butyl valerate (50 mg, 72 μmol,diastereomer 4Example 211A) was added to a dichloromethane (550 μ l) solution of TFA (122 μ l, 1.60 mmol) and the mixture was allowed to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. Passing the residue throughPreparative HPLC purification (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 29 mg (100% purity, 64% of theory) of the title compound are obtained.

[α]_D ²⁰= 33.2 °, 589 nm, c = 0.33 g/100 ml, methanol

LC-MS (method 2) R_t= 1.31 min; MS (ESIpos): m/z = 636/638 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.893 (2.80), 0.911 (6.69), 0.930(3.44), 1.040 (0.22), 1.068 (0.60), 1.098 (0.62), 1.120 (0.28), 1.242 (0.50),1.260 (1.07), 1.277 (1.46), 1.288 (1.30), 1.306 (0.89), 1.323 (0.36), 1.565(0.68), 1.608 (0.66), 1.638 (0.61), 1.669 (0.27), 1.749 (0.86), 1.783 (0.69),1.813 (0.64), 1.825 (0.64), 1.837 (1.03), 1.857 (1.17), 1.883 (0.79), 2.052(0.97), 2.078 (4.80), 2.104 (0.89), 2.134 (4.71), 2.408 (0.49), 2.436 (0.80),2.501 (16.00), 2.711 (0.49), 2.743 (0.82), 2.772 (0.45), 3.391 (0.71), 3.405(0.71), 3.495 (1.33), 3.525 (1.23), 3.585 (0.29), 3.600 (0.45), 3.618 (0.88),3.633 (1.10), 3.650 (1.01), 3.668 (0.85), 3.686 (0.68), 3.702 (0.37), 3.721(0.20), 7.357 (1.35), 7.385 (0.60), 7.400 (2.46), 7.410 (2.05), 7.422 (2.29),7.435 (0.73), 7.551 (1.40), 7.564 (1.20), 7.574 (1.03), 7.630 (0.49), 7.653(5.71), 7.681 (0.35), 8.718 (0.80), 8.733 (1.55), 8.747 (0.78), 12.050(0.93)。

Example 209

(-) -5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Valeric acid(diastereomer 1)

[ structural formula see example 140: (Mixtures of diastereomers)]

To 5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Tert-butyl valerate (55 mg, 81 μmol,diastereomer 1Example 212A) in dichloromethane (620 μ l) was added TFA (140 μ l, 1.78 mmol) and the mixture was allowed to stand at room temperature for 24 h. The mixture is then concentrated and dichloromethane is repeatedly addedAnd the mixture was concentrated again. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 31 mg (100% purity, 62% of theory) of the title compound are obtained.

[α]_D ²⁰= 10.3 °, 589 nm, c = 0.32 g/100 ml, methanol

LC-MS (method 1) R_t= 2.38 min; MS (ESIpos): m/z = 622/624 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 0.926 (16.00), 0.936 (15.61), 1.064(0.58), 1.078 (1.42), 1.084 (1.41), 1.097 (1.41), 1.102 (1.47), 1.117 (0.60),1.123 (0.56), 1.231 (0.22), 1.613 (0.50), 1.634 (1.34), 1.654 (1.48), 1.675(0.64), 1.735 (2.32), 1.740 (2.10), 1.757 (2.38), 1.782 (1.39), 1.798 (2.50),1.805 (2.60), 1.814 (2.76), 1.821 (2.68), 1.828 (2.74), 1.844 (1.25), 1.863(0.27), 2.010 (0.25), 2.020 (0.39), 2.037 (0.85), 2.046 (2.13), 2.064 (6.16),2.069 (7.11), 2.090 (2.07), 2.101(1.52), 2.140 (3.50), 2.223 (0.26), 2.388(0.21), 2.438 (1.09), 2.457 (1.74), 2.476 (1.11), 2.616 (0.17), 2.685 (0.84),2.703 (1.42), 2.722 (0.81), 3.446 (3.21), 3.470 (3.69), 3.495 (2.02), 3.599(1.21), 3.611 (1.68), 3.621 (1.82), 3.671 (1.25), 7.349 (2.25), 7.362 (3.62),7.394 (1.37), 7.407 (4.92), 7.413 (4.94), 7.419 (5.18), 7.432 (1.39), 7.556(3.06), 7.567 (2.56), 7.572 (2.44), 7.641 (2.35), 7.655 (10.60), 7.661(6.80), 7.665 (6.00), 7.676 (1.43), 7.679 (1.49), 8.756 (2.07), 8.765 (3.88),8.775 (2.04)。

Example 210

(-) -5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Valeric acid(diastereomer 2)

To 5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Tert-butyl valerate (54 mg, 80 μmol,diastereomer 2Example 213A) in dichloromethane (612. mu.l) was added TFA (135. mu.l, 1.75 mmol) and the mixture was allowed to stand at room temperature for 24 h. Then concentrating and mixingDichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 32 mg (100% purity, 65% of theory) of the title compound are obtained.

[α]_D ²⁰= 21.8 °, 589 nm, c = 0.36 g/100 ml, methanol

LC-MS (method 1) R_t= 2.38 min; MS (ESIpos): m/z = 622/624 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 0.924 (16.00), 0.935 (15.74), 1.056(0.52), 1.063 (0.63), 1.076 (1.57), 1.082 (1.58), 1.096 (1.60), 1.100 (1.67),1.115 (0.68), 1.121 (0.63), 1.231 (0.24), 1.630 (1.33), 1.650 (1.46), 1.736(2.56), 1.741 (2.31), 1.758 (2.71), 1.777 (1.77), 1.783 (1.70), 1.803 (3.04),1.812 (3.22), 1.820 (3.18), 1.827 (3.32), 1.843 (1.39), 1.861 (0.33), 1.912(0.18), 2.015 (0.47), 2.033 (1.03), 2.042 (2.40), 2.060 (6.59), 2.068 (7.94),2.088 (2.88), 2.098 (2.41), 2.128 (2.87), 2.183 (1.04), 2.203 (0.44), 2.388(0.27), 2.448 (1.37), 2.616 (0.22), 2.689 (1.13), 2.707 (2.01), 2.727 (1.10),3.444 (3.52), 3.470 (3.91), 3.494 (2.73), 3.596 (0.97), 3.606 (1.40), 3.617(1.98), 3.627 (2.24), 3.637 (1.42), 3.668 (1.72), 3.679 (1.54), 7.349 (2.52),7.361 (4.01), 7.393 (1.55), 7.406 (5.60), 7.412 (5.50), 7.418 (5.79), 7.431(1.52), 7.482 (0.41), 7.539 (0.39), 7.557 (3.59), 7.568 (2.93), 7.572 (2.82),7.640 (3.18), 7.655 (13.58), 7.661 (7.95), 7.665 (7.00), 7.676 (1.83), 7.679(1.86), 7.691 (0.24), 7.694 (0.24), 8.756 (1.89), 8.765 (3.35), 8.774 (1.84)。

Example 211

(+) -5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Valeric acid(diastereomer 3)

To 5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Tert-butyl valerate (43 mg, 63 μmol,diastereomer 3Dichloromethane (490 μm) of example 214A)l) to the solution was added TFA (107 μ l, 1.39 mmol), and the mixture was allowed to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 32 mg (100% purity, 65% of theory) of the title compound are obtained.

[α]_D ²⁰= 28.2 °, 589 nm, c = 0.32 g/100 ml, methanol

LC-MS (method 1) R_t= 2.38 min; MS (ESIpos): m/z = 622/624 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 0.926 (16.00), 0.937 (15.62), 1.073(0.62), 1.087 (1.54), 1.092 (1.54), 1.111 (1.60), 1.126 (0.64), 1.132 (0.60),1.232 (0.37), 1.635 (1.27), 1.654 (1.37), 1.742 (2.59), 1.747 (2.38), 1.753(1.94), 1.764 (2.85), 1.770 (2.57), 1.782 (1.70), 1.788 (1.71), 1.802 (2.90),1.810 (2.73), 1.825 (3.13), 1.832 (3.13), 1.848 (1.67), 1.866 (0.40), 2.030(0.47), 2.048 (1.13), 2.057 (2.98), 2.075 (10.52), 2.082 (8.56), 2.096(3.00), 2.104 (2.18), 2.110 (2.35), 2.128 (2.72), 2.216 (0.36), 2.389 (0.23),2.478 (1.40), 2.617 (0.18), 2.720 (1.08), 2.739 (1.95), 2.759 (1.06), 3.394(1.70), 3.466 (1.91), 3.496 (2.75), 3.518 (2.09), 3.611 (1.33), 3.623 (1.95),3.633 (2.23), 3.643 (1.46), 3.673 (1.78), 3.684 (1.62), 4.021 (3.98), 7.351(2.40), 7.361 (3.19), 7.364 (4.04), 7.396 (1.42), 7.405 (3.71), 7.410 (5.53),7.415 (5.55), 7.422 (5.89), 7.434 (1.58), 7.562 (3.71), 7.573 (3.06), 7.577(3.13), 7.662 (2.25), 7.677 (12.80), 7.681 (8.38), 7.684 (7.38), 7.696(1.44), 7.699 (1.60), 8.763 (1.83), 8.773 (3.46), 8.783 (1.97)。

Example 212

(+) -5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Valeric acid(diastereomer 4)

To 5- [ ({ 6-bromo-3-methyl-2- [ 3-methylpiperidin-1-yl)]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Valeric acid tert-butyl ester (53 m)g, 78 µmol,Diastereomer 4Example 215A) was added to TFA (132 μ l, 1.72 mmol) in dichloromethane (600 μ l) solution, and the mixture was left to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 26 mg (100% purity, 53% of theory) of the title compound are obtained.

[α]_D ²⁰= 11.8 °, 589 nm, c = 0.34 g/100 ml, methanol

LC-MS (method 1) R_t= 2.38 min; MS (ESIpos): m/z = 622/624 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 0.925 (16.00), 0.936 (15.89), 1.064(0.59), 1.078 (1.47), 1.083 (1.49), 1.097 (1.49), 1.102 (1.57), 1.116 (0.65),1.123 (0.61), 1.230 (0.21), 1.613 (0.51), 1.634 (1.38), 1.655 (1.54), 1.675(0.66), 1.735 (2.39), 1.740 (2.19), 1.757 (2.49), 1.781 (1.46), 1.798 (2.63),1.804 (2.79), 1.813 (2.92), 1.821 (2.88), 1.828 (2.98), 1.843 (1.28), 1.862(0.30), 2.018 (0.36), 2.035 (0.83), 2.044 (2.11), 2.063 (6.09), 2.068 (7.27),2.086 (2.04), 2.089 (2.21), 2.099 (1.65), 2.140 (3.69), 2.222 (0.30), 2.388(0.20), 2.438 (1.12), 2.457 (1.81), 2.476 (1.13), 2.616 (0.20), 2.684 (0.89),2.704 (1.50), 2.722 (0.88), 3.447 (3.51), 3.470 (3.99), 3.495 (2.22), 3.599(1.31), 3.610 (1.79), 3.620 (1.95), 3.670 (1.33), 7.349 (2.41), 7.361 (3.73),7.393 (1.49), 7.407 (5.12), 7.412 (5.06), 7.419 (5.28), 7.431 (1.38), 7.556(3.17), 7.567 (2.64), 7.571 (2.47), 7.640 (2.43), 7.655 (10.78), 7.661(6.89), 7.664 (6.03), 7.676 (1.37), 7.679 (1.44), 8.756 (2.16), 8.766 (3.93),8.776 (2.02)。

Example 213

(-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (5-fluoro-2-methylphenyl) pentanoic acid(enantiomer 1)

[ structural formula see example 150: (Racemic modification)]

Is separated fromEnantiomer from example 150:

(+/-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (5-fluoro-2-methylphenyl) pentanoic acid (Racemic modification183 mg, 309 μmol, example 150) were separated into enantiomers on a chiral column by preparative SFC (see examples 213 and 214) [ column: daicel Chiralcel OX-H, 5 μm,250 mm x 20 mm, flow rate: 60 ml/min, UV detection: 230 nm, temperature: 25 deg.C, eluent 80% carbon dioxide/20% ethanol, isocratic]. The combined target fractions were each concentrated at 30 ℃/30 mbar.

In the diastereoisomeric separation, 90 mg (>99% purity, ee >97%) of the title compound was obtained as the earlier eluting enantiomer.

[α]_D ²⁰= 10.8 °, 589 nm, c = 0.46 g/100 ml, methanol

LC-MS (method 2) R_t= 1.12 min; MS (ESIpos): m/z = 592/594 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.17), 0.069 (0.30), 0.146(0.19), 1.235 (0.96), 1.745 (0.36), 1.763 (0.84), 1.779 (1.06), 1.797 (1.31),1.819 (1.05), 1.835 (0.71), 1.880 (3.50), 1.976 (0.55), 1.997 (1.12), 2.009(1.39), 2.028 (1.49), 2.046 (2.35), 2.072 (5.97), 2.088 (7.64), 2.117(11.26), 2.293 (16.00), 2.366 (0.29), 2.670 (0.41), 2.710 (0.21), 3.165(4.29), 3.450 (2.65), 3.479 (5.58), 3.506 (3.83), 3.533 (1.13), 3.665 (1.00),3.683 (1.61), 3.702 (1.43), 3.717 (1.21), 3.736 (0.69), 6.930 (1.26), 6.945(2.35), 6.951 (2.51), 6.966 (1.32), 6.972 (1.35), 7.141 (2.38), 7.147 (2.44),7.168 (2.44), 7.174 (2.35), 7.200 (2.42), 7.216 (2.84), 7.237 (2.08), 7.479(1.02), 7.677 (1.46), 7.699 (9.77), 7.708 (5.87), 7.731 (0.97), 8.722 (1.64),8.736(2.62), 8.749 (1.57), 12.074 (0.51)。

Example 214

(+)-5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (5-fluoro-2-methylphenyl) pentanoic acid(enantiomer 2)

In the enantiomeric separation described in example 213, 91 mg (>99% purity, ee >95%) of the title compound was obtained as the later eluting enantiomer.

[α]_D ²⁰= 15.6 °, 589 nm, c = 0.46 g/100 ml, methanol

LC-MS (method 2) R_t= 1.12 min; MS (ESIpos): m/z = 592/594 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.22), 0.069 (0.40), 0.146(0.25), 0.854 (0.28), 1.236 (1.91), 1.743 (0.33), 1.761 (0.79), 1.776 (1.03),1.795 (1.26), 1.817 (1.00), 1.833 (0.64), 1.880 (3.52), 1.974 (0.55), 1.995(1.09), 2.008 (1.35), 2.025 (1.40), 2.044 (2.36), 2.067 (5.71), 2.083 (7.36),2.117 (11.16), 2.292 (16.00), 2.327 (0.76), 2.366 (0.39), 2.669 (0.53), 2.710(0.36), 3.164 (4.38), 3.449 (2.80), 3.479 (5.80), 3.506 (3.89), 3.532 (1.17),3.665 (1.03), 3.683 (1.64), 3.701 (1.45), 3.717 (1.24), 3.736 (0.71), 6.924(1.15), 6.930 (1.27), 6.945 (2.41), 6.951 (2.58), 6.966 (1.37), 6.972 (1.37),7.140 (2.43), 7.146 (2.46), 7.167 (2.48), 7.173 (2.37), 7.199 (2.53), 7.215(2.93), 7.220 (2.73), 7.236 (2.18), 7.477 (1.00), 7.677 (1.54), 7.699(10.24), 7.704 (7.44), 7.708 (5.90), 7.727 (0.92), 7.731 (1.00), 8.724(1.65), 8.737 (2.63), 8.752 (1.58), 12.098 (0.31)。

Example 215

(+) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid(enantiomer 1)

[ structural formula see example 154: (Racemic modification)]

To a mixture of (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid tert-butyl ester (301 mg, 500 μmol, example 48A) in NMP (2.0 ml) was added pyrrolidine (125 μ l, 1.50 mmol) and the mixture was stirred at 110 ℃ for 2 h. After cooling to room temperature, the mixture was mixed with ethyl acetate (100ml) and washed once with water (100 ml). The aqueous phase was extracted once with ethyl acetate (100 ml). The combined organic phases were washed once with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated, and the residue was purified by preparative HPLC (method 33). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. The title compound is obtained directly (without the need for isolation of the tert-butyl ester and subsequent hydrolysis step) since the reactants used are apparently in already partially hydrolysed form. 27 mg (100% purity, 9% of theory) of the title compound are obtained.

[α]_D ²⁰= 25.1 °, 589 nm, c = 0.37 g/100 ml, methanol

LC-MS (method 1) R_t= 1.45 min; MS (ESIpos): m/z = 580/582 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.81), 1.020 (0.81), 1.029(0.43), 1.036 (0.81), 1.245 (0.78), 1.261 (0.79), 1.277 (0.42), 1.402 (0.68),1.838 (0.86), 1.898 (16.00), 1.938 (2.12), 2.066 (2.00), 2.077 (2.29), 2.102(4.07), 2.129 (6.46), 2.142 (7.04), 2.159 (7.73), 2.178 (7.47), 2.196(11.68), 2.328 (0.69), 2.367 (0.78), 2.667 (0.96), 2.686 (1.84), 2.695(8.17), 2.710 (0.72), 3.285 (2.20), 3.303 (3.04), 3.321 (2.14), 3.718 (7.64),3.816 (7.02), 7.266 (1.61), 7.277 (1.87), 7.290 (3.14), 7.301 (3.22), 7.315(2.42), 7.326 (2.20), 7.386 (2.00), 7.407 (3.05), 7.418 (2.99), 7.566 (1.86),7.588 (3.77), 7.615 (5.18), 7.635 (2.29), 8.817(3.70)。

Example 216

(-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid(enantiomer 2)

To a mixture of (-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid tert-butyl ester (301 mg, 500 μmol, example 49A) in NMP (2.0 ml) pyrrolidine (125 μ l, 1.50 mmol) was added and the mixture was stirred at 110 ℃ for 2 h. After cooling to room temperature, the mixture was mixed with ethyl acetate (100ml) and washed once with water (100 ml). The aqueous phase was extracted once with ethyl acetate (100 ml). The combined organic phases were washed once with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated, and the residue was purified by preparative HPLC (method 33). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. The title compound is obtained directly (without the need for isolation of the tert-butyl ester and subsequent hydrolysis step) since the reactants used are apparently in already partially hydrolysed form. 15 mg (100% purity, 5% of theory) of the title compound are obtained.

[α]_D ²⁰= 26.9 °, 589 nm, c = 0.32 g/100 ml, methanol

LC-MS (method 1) R_t= 1.45 min; MS (ESIpos): m/z = 580/582 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.024 (3.21), 0.853 (0.68), 1.120(0.42), 1.135 (0.88), 1.150 (0.46), 1.234 (8.39), 1.606 (0.89), 1.667 (1.32),1.689 (2.77), 1.713 (2.12), 1.872 (16.00), 1.919 (2.19), 1.938 (1.34), 1.987(2.25), 2.174 (10.50), 2.227 (1.01), 2.248 (0.88), 2.328 (0.52), 2.346(0.56), 2.366 (0.42), 2.670 (0.49), 2.694 (6.62), 2.710 (0.54), 3.285 (4.71),3.303 (8.01), 3.526 (6.69), 3.571 (9.55), 3.653 (3.61), 3.822 (1.24), 7.226(1.39), 7.236 (1.65), 7.249 (2.96), 7.258 (3.79), 7.274 (2.59), 7.279 (2.66),7.285 (2.57), 7.336 (2.05), 7.348 (2.38), 7.358 (3.09), 7.369 (2.96), 7.391(1.71), 7.466 (7.59), 7.488 (12.49), 7.544 (6.80), 7.549 (6.31), 7.566(3.94), 7.571 (3.80), 7.589 (0.63), 7.615 (0.53), 8.526 (0.60), 8.859 (0.49),8.938 (3.00)。

Example 217

(+) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid(enantiomer 1)

[ structural formula see example 155: (Racemic modification)]

To (+) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid tert-butyl ester (70 mg, 99 μmol,enantiomers ofBody 1Example 216A) in dichloromethane (1.8 ml) was added TFA (169. mu.l, 2.19 mmol) and the mixture was allowed to stand at room temperature for 16 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 18 mg (100% purity, 28% of theory) of the title compound are obtained.

[α]_D ²⁰= 33.1 °, 589 nm, c = 0.31 g/100 ml, methanol

LC-MS (method 1) R_t= 2.11 min; MS (ESIpos): m/z = 630/632 [M+H]⁺

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.007 (1.41), 0.006 (1.38), 0.071(0.81), 1.235 (0.63), 1.353 (0.24), 1.361 (0.68), 1.885 (4.28), 1.969 (0.95),2.070 (2.84), 2.097 (5.30), 2.111 (4.98), 2.122 (5.25), 2.165 (16.00), 2.292(0.18), 2.304 (0.18), 2.362 (0.41), 2.523 (0.97), 2.636 (0.39), 3.170 (5.56),3.317 (1.07), 3.457 (3.41), 3.480 (6.14), 3.503 (3.20), 3.727 (2.01), 7.274(1.01), 7.283 (1.19), 7.293 (2.09), 7.302 (2.18), 7.313 (1.54), 7.322 (1.36),7.411 (2.06), 7.419 (2.03), 7.683 (3.35), 7.701 (12.28), 7.711 (8.00), 7.715(7.27), 7.728 (2.00), 7.732 (2.13), 8.838 (2.94)。

Example 218

(-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid(enantiomer 2)

To (-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid tert-butyl ester (70 mg, 102 μmol,enantiomer 2Example 217A) in dichloromethane (1.8 ml) TFA (173 μ l, 2.24 mmol) was added and the mixture was left to stand at room temperature for 16 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 7). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 27 mg (100% purity, 42% of theory) of the title compound are obtained.

[α]_D ²⁰= 33.8 °, 589 nm, c = 0.34 g/100 ml, methanol

LC-MS (method 1) R_t= 2.11 min; MS (ESIpos): m/z = 630/632 [M+H]⁺

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.120 (0.21), -0.007 (2.56), 0.006(1.56), 0.069 (0.21), 0.117 (0.20), 1.234 (0.54), 1.353 (0.21), 1.361 (0.19),1.370 (0.20), 1.885 (4.23), 1.967 (0.93), 2.069 (2.85), 2.084 (4.22), 2.094(5.84), 2.114 (4.95), 2.127 (5.76), 2.164 (16.00), 2.304 (0.18), 2.358(0.39), 2.362 (0.50), 2.519 (1.30), 2.522 (0.91), 2.635 (0.48), 3.169 (5.45),3.314 (1.22), 3.457 (3.35), 3.480 (6.01), 3.503 (3.07), 3.730 (1.95), 7.274(1.09), 7.283 (1.25), 7.293 (2.14), 7.302 (2.17), 7.313 (1.56), 7.322 (1.38),7.411 (2.05), 7.419 (1.97), 7.683 (3.38),7.701 (12.40), 7.710 (8.28), 7.715(7.26), 7.728 (2.01), 7.732 (2.08), 8.826 (1.80), 8.837 (3.09)。

Example 219

(+) -5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid(enantiomer 1)

[ structural formula see example 159: (Racemic modification)]

To 5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid tert-butyl ester (35 mg, 49 μmol,enantiomer 1Example 218A) was added to TFA (83 μ l, 1.08 mmol) in dichloromethane (378 μ l) solution, and the mixture was allowed to stand at room temperature for 4 days. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 15 mg (100% purity, 51% of theory) of the title compound are obtained.

[α]_D ²⁰= 31.4 °, 589 nm, c = 0.38 g/100 ml, methanol

LC-MS (method 1) R_t= 2.21 min; MS (ESIpos): m/z = 608/610 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (0.18), 1.234 (0.71), 1.259(0.35), 1.298 (0.28), 1.360 (1.00), 1.602 (13.68), 1.781 (8.50), 1.891(0.92), 1.965 (1.10), 2.071 (3.58), 2.107 (7.74), 2.133 (15.66), 2.272(0.34), 2.327 (0.34), 2.366 (0.31), 2.669 (0.32), 2.710 (0.31), 3.318 (2.40),3.491 (10.92), 3.505 (16.00), 3.520 (10.56), 3.711 (2.90), 7.262 (1.06),7.273 (1.27), 7.285 (2.29), 7.296 (2.42), 7.311 (1.84), 7.322 (1.74), 7.384(1.63), 7.395 (1.94), 7.405 (2.60), 7.416 (2.58), 7.438 (1.37), 7.529 (5.55),7.551 (10.09), 7.599 (5.55), 7.604 (5.36), 7.621 (3.13), 7.626(3.13), 8.804(3.10)。

Example 220

5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid(enantiomer 2)

To 5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid tert-butyl ester (28 mg, 39 μmol,enantiomer 2Example 219A) was added to a dichloromethane (300 μ l) solution of TFA (66 μ l, 858 μmol), and the mixture was allowed to stand at room temperature for 4 days. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 6). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 9mg (100% purity, 39% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.21 min; MS (ESIpos): m/z = 608/610 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.235 (0.90), 1.259 (0.51), 1.298(0.35), 1.360 (0.94), 1.602 (13.49), 1.781 (8.38), 1.880 (2.79), 1.946(1.09), 2.055 (3.52), 2.085 (6.46), 2.132 (15.36), 2.274 (0.37), 2.326(0.42), 2.366 (0.38), 2.669 (0.41), 2.710 (0.34), 3.320 (1.46), 3.490(10.99), 3.505 (16.00), 3.519 (10.58), 3.703 (2.91), 7.259 (1.22), 7.270(1.40), 7.282 (2.43), 7.293 (2.56), 7.308 (1.90), 7.319 (1.76), 7.401 (2.69),7.412 (2.69), 7.528 (6.05), 7.551 (10.65), 7.598 (5.94), 7.603 (5.52), 7.620(3.18), 7.625 (3.14), 8.810 (3.11)。

Example 221

5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2,3, 6-trichlorophenyl) pentanoic acid(diastereomer 1)

[ structural formula see example 180: (Mixtures of diastereomers)]

To 5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-tert-butyl 4- (2,3, 6-trichlorophenyl) pentanoate (14 mg, 20 μmol,diastereomer 1Example 220A) was added to a dichloromethane (153 μ l) solution of TFA (34 μ l, 439 μmol), and the mixture was allowed to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 7mg (100% purity, 51% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.20 min; MS (ESIpos): m/z = 644/646/648 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: -0.024 (0.18), 0.852 (0.29), 0.923(0.20), 1.232 (1.22), 1.369 (0.28), 1.648 (2.02), 1.723 (1.34), 1.809 (1.91),1.910 (3.93), 1.924 (3.45), 2.040 (1.60), 2.154 (4.33), 2.183 (8.36), 2.299(0.27), 2.388 (0.31), 2.618 (0.25), 2.695 (0.22), 3.097 (2.45), 3.164 (2.36),3.330 (5.54), 3.413 (16.00), 3.765 (1.57), 4.002 (1.26), 4.100 (1.07), 4.839(1.36), 4.919 (1.34), 7.459 (1.70), 7.473 (1.94), 7.519 (2.29), 7.533 (3.23),7.573 (2.41), 7.658 (2.35), 7.673 (5.57), 7.689 (4.72), 7.704 (1.81), 8.972(1.67)。

Example 222

5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2,3, 6-trichlorophenyl) pentanoic acid(diastereomer 2)

To 5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2,3, 6-trichlorophenyl)) Tert-butyl valerate (17 mg, 24 μmol,diastereomer 2Example 220A) was added to TFA (41 μ l, 533 μmol) in dichloromethane (186 μ l) solution, and the mixture was left to stand at room temperature for 24 hours. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 7mg (100% purity, 51% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.20 min; MS (ESIpos): m/z = 644/646/648 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 0.854 (0.19), 1.233 (0.77), 1.645(1.59), 1.817 (1.51), 1.912 (2.83), 1.925 (2.37), 1.945 (1.40), 1.968 (0.93),2.060 (0.51), 2.073 (1.19), 2.083 (1.71), 2.097 (3.37), 2.108 (3.12), 2.114(3.29), 2.128 (2.50), 2.151 (3.80), 2.160 (4.09), 2.184 (16.00), 2.197(2.28), 2.214 (0.72), 2.290 (1.68), 2.301 (1.57), 2.389 (0.24), 2.617 (0.24),3.086 (1.75), 3.180 (1.65), 3.192 (1.74), 3.326 (1.77), 3.336 (1.90), 3.395(1.70), 3.415 (1.17), 3.434 (1.69), 3.453 (1.22), 3.805 (3.40), 3.816 (3.99),3.826 (4.27), 3.835 (4.43), 3.912 (6.65), 4.040 (3.28), 4.055 (3.16), 4.064(3.35), 4.073 (3.57), 4.079 (3.71), 4.088 (2.70), 4.098 (2.22), 4.113 (1.56),4.846 (1.43), 4.925 (1.41), 7.486 (1.89), 7.501 (2.34), 7.543 (2.74), 7.558(4.14), 7.605 (2.65), 7.619 (2.28), 7.666 (2.31), 7.671 (2.15), 7.680 (6.02),7.686 (5.41), 7.694 (3.96), 7.697 (4.31), 7.703 (3.05), 7.709 (1.79), 7.712(1.82), 7.718 (1.29), 8.838 (2.29), 8.848 (2.59)。

Example 223

5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2,3, 6-trichlorophenyl) pentanoic acid(diastereomer 3)

To 5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-tert-butyl 4- (2,3, 6-trichlorophenyl) pentanoate (32 mg, 46 μmol,diastereomer 3Example 220A) was added to a solution of TFA (77 μ l, 1.0 mmol),and the mixture was allowed to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 15 mg (100% purity, 52% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.20 min; MS (ESIpos): m/z = 644/646/648 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.232 (0.37), 1.244 (0.46), 1.255(0.44), 1.259 (0.38), 1.270 (0.31), 1.646 (1.40), 1.817 (1.34), 1.912 (2.53),1.926 (2.11), 1.944 (1.31), 1.968 (0.82), 2.009 (0.20), 2.060 (0.58), 2.074(1.12), 2.083 (1.63), 2.097 (3.20), 2.109 (2.88), 2.114 (3.11), 2.129 (2.31),2.151 (3.35), 2.160 (3.84), 2.184 (16.00), 2.197 (2.11), 2.214 (0.68), 2.289(1.54), 2.301 (1.44), 2.306 (1.31), 2.389 (0.24), 2.617 (0.21), 3.074 (1.12),3.089 (1.58), 3.185 (1.49), 3.197 (1.59), 3.214 (1.04), 3.320 (1.20), 3.330(1.56), 3.340 (1.66), 3.351 (0.95), 3.398 (1.52), 3.420 (1.00), 3.437 (1.49),3.456 (1.05), 3.806 (1.52), 3.817 (1.72), 3.827 (1.71), 3.834 (1.57), 4.040(4.13), 4.049 (4.31), 4.056 (4.60), 4.064 (5.06), 4.071 (5.46), 4.079 (5.82),4.088 (5.09), 4.099 (4.83), 4.113 (4.27), 4.847 (1.34), 4.926 (1.33), 7.028(0.27), 7.113 (0.32), 7.198 (0.28), 7.486 (1.95), 7.501 (2.41), 7.543 (3.07),7.558 (4.54), 7.605 (2.56), 7.619 (2.13), 7.668 (2.51), 7.674 (2.27), 7.683(6.65), 7.689 (5.63), 7.696 (4.24), 7.700 (4.26), 7.702 (3.33), 7.706 (2.72),7.711 (1.61), 7.715 (1.64), 7.717 (1.20), 7.721 (1.08), 8.835 (2.19), 8.846(2.41), 9.683 (0.16)。

Example 224

5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2,3, 6-trichlorophenyl) pentanoic acid(diastereomer 4)

To 5- [ ({ 6-bromo-2- [ 3-fluoropiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-tert-butyl 4- (2,3, 6-trichlorophenyl) pentanoate (27 mg, 38 μmol,diastereomer 4Example 220A) To a dichloromethane (296 μ l) solution, TFA (65 μ l, 846 μmol) was added, and the mixture was left to stand at room temperature for 24 hours. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. 9mg (100% purity, 36% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.20 min; MS (ESIpos): m/z = 644/646/648 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 0.841 (0.19), 0.853 (0.24), 0.913(0.21), 1.231 (0.86), 1.552 (0.61), 1.648 (2.28), 1.674 (0.65), 1.812 (2.09),1.825 (1.79), 1.910 (4.02), 1.924 (2.87), 1.947 (1.51), 1.970 (1.30), 2.061(1.95), 2.076 (2.56), 2.083 (3.02), 2.096 (3.15), 2.109 (2.63), 2.121 (2.60),2.145 (5.67), 2.166 (4.32), 2.180 (16.00), 2.278 (1.99), 2.389 (0.46), 2.616(0.26), 3.077 (1.94), 3.093 (2.84), 3.174 (2.89), 3.427 (5.68), 3.449 (3.64),3.783 (0.87), 3.791 (1.60), 3.802 (1.66), 3.812 (1.93), 3.822 (1.47), 4.054(1.96), 4.062 (1.76), 4.070 (1.68), 4.077 (1.98), 4.088 (1.51), 4.099 (1.29),4.109 (1.07), 4.124 (0.59), 4.839 (1.68), 4.919 (1.66), 7.484 (2.30), 7.498(2.76), 7.539 (4.21), 7.554 (6.01), 7.603 (3.12), 7.617 (2.69), 7.662 (3.82),7.667 (2.96), 7.677 (9.70), 7.682 (7.07), 7.690 (6.12), 7.694 (6.22), 7.700(3.79), 7.705 (2.38), 7.709 (2.46), 7.715 (1.52), 8.837 (2.65), 8.846 (3.25)。

Example 225

5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2, 5-difluorophenyl) pentanoic acid(mixture of diastereomers)

Coupling 5- [ ({ 6-bromo-2- (3-ethylpiperidin-1-yl) -3-methylquinolin-4-yl } carbonyl) amino]-tert-butyl 4- (2, 5-difluorophenyl) pentanoate (f)Mixtures of diastereomers56 mg, 86.9 μmol, Shi GaoExample 227A) was dissolved in dichloromethane (1.2 ml). At room temperature, TFA (650 μ l, 8.7 mmol) was added and the mixture was stirred at room temperature for 90 min. The volatile components were removed on a rotary evaporator. The residue was dissolved in a small amount of DMSO and purified by preparative HPLC (method 15). The target fractions were concentrated together by rotary evaporation and the residue was dried in vacuo. 48 mg (100% purity, 94% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.37 min; MS (ESIpos): m/z = 588/590 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (3.01), 0.890 (6.60), 0.908(16.00), 0.927 (8.11), 1.035 (0.56), 1.064 (1.36), 1.093 (1.40), 1.116(0.62), 1.238 (1.14), 1.256 (2.65), 1.275 (3.54), 1.292 (2.47), 1.560 (1.54),1.602 (1.47), 1.632 (1.31), 1.747 (1.98), 1.786 (1.98), 1.809 (1.45), 1.842(1.85), 1.877 (1.52), 2.002 (1.18), 2.015 (1.54), 2.034 (1.67), 2.054 (1.89),2.063 (1.63), 2.108 (12.92), 2.119 (6.84), 2.139 (2.27), 2.160 (0.71), 2.327(0.67), 2.422 (1.36), 2.670 (0.80), 2.709 (1.23), 2.737 (1.87), 2.766 (1.05),3.481 (2.87), 3.513 (2.74), 3.616 (1.09), 3.634 (1.63), 3.649 (2.32), 3.662(1.38), 3.677 (1.11), 3.696 (1.45), 7.122 (2.01), 7.143 (1.43), 7.198 (1.72),7.209 (1.78), 7.221 (2.79), 7.232 (2.72), 7.244 (1.31), 7.256 (1.20), 7.291(1.65), 7.300 (2.36), 7.315 (1.65), 7.426 (0.71),7.624 (1.40), 7.647(11.57), 7.654 (6.46), 7.677 (1.03), 8.729 (2.85), 12.061 (5.15)。

Example 226

(-) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2, 5-difluorophenyl) pentanoic acid(mixture of two diastereomers)

To 5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-tert-butyl 4- (2, 5-difluorophenyl) valerate (118 mg, 183 μmol,mixtures of two diastereomersExample 228A) in dichloromethane (1.4 ml) was added TFA (310 μ l, 4.03 mmol) and the mixture was left to stand at room temperature for 24 h. The mixture is then concentrated, dichloromethane is repeatedly added and the mixture is concentrated againAnd (4) condensing the mixture. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 88 mg (100% purity, 81% of theory) of the title compound are obtained.

[α]_D ²⁰= 32.2 °, 589 nm, c = 0.46 g/100 ml, methanol

LC-MS (method 1) R_t= 2.35 min; MS (ESIpos): m/z = 588/590 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: -0.021 (1.21), 0.839 (0.16), 0.851(0.32), 0.862 (0.18), 0.895 (7.27), 0.907 (16.00), 0.919 (8.17), 1.036(0.49), 1.042 (0.58), 1.057 (1.40), 1.062 (1.43), 1.076 (1.48), 1.081 (1.49),1.096 (0.64), 1.103 (0.57), 1.227 (2.36), 1.245 (1.25), 1.257 (2.57), 1.269(3.67), 1.280 (3.10), 1.292 (1.60), 1.551 (1.33), 1.556 (1.48), 1.574 (0.99),1.585 (0.77), 1.606 (1.26), 1.627 (1.34), 1.647 (0.55), 1.748 (2.00), 1.769(1.82), 1.775 (1.61), 1.791 (1.33), 1.805 (1.44), 1.814 (1.08), 1.829 (0.61),1.853 (1.68), 1.870 (1.64), 1.997 (0.58), 2.010 (1.28), 2.018 (1.73), 2.032(1.83), 2.041 (1.27), 2.053 (1.10), 2.064 (1.27), 2.073 (1.48), 2.078 (1.64),2.091 (4.12), 2.104 (7.92), 2.116 (7.21), 2.130 (3.21), 2.144 (1.34), 2.157(0.68), 2.414 (0.84), 2.714 (0.86), 2.733 (1.45), 2.752 (0.82), 3.494 (3.60),3.510 (2.68), 3.627 (1.33), 3.637 (1.69), 3.640 (1.59), 3.649 (2.00), 3.709(1.15), 7.127 (1.84), 7.140 (1.20), 7.211 (1.72), 7.219 (1.85), 7.226 (2.96),7.234 (2.92), 7.242 (1.44), 7.250 (1.30), 7.301 (1.79), 7.309 (2.30), 7.317(1.78), 7.448 (0.24), 7.635 (2.37), 7.649 (9.88), 7.657 (5.87), 7.672 (1.32),8.744 (1.47), 8.754 (2.67)。

Example 227

(+) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2, 5-difluorophenyl) pentanoic acid(diastereomer 1)

To 5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-tert-butyl 4- (2, 5-difluorophenyl) valerate (37 mg, 57 μmol,diastereomer 1Example 229A) twoTo a solution of methyl chloride (442 μ l), TFA (97 μ l, 1.26 mmol) was added, and the mixture was allowed to stand at room temperature for 24 hours. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 20 mg (100% purity, 60% of theory) of the title compound are obtained.

[α]_D ²⁰= 17.1 °, 589 nm, c = 0.31 g/100 ml, methanol

LC-MS (method 1) R_t= 2.38 min; MS (ESIpos): m/z = 588/590 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: -0.021 (1.57), 0.839 (0.20), 0.851(0.40), 0.862 (0.20), 0.895 (6.95), 0.908 (16.00), 0.920 (7.91), 1.036(0.39), 1.042 (0.45), 1.057 (1.08), 1.062 (1.11), 1.076 (1.14), 1.081 (1.15),1.096 (0.50), 1.103 (0.45), 1.228 (3.22), 1.245 (1.13), 1.256 (2.13),1.268(3.04), 1.280 (2.59), 1.292 (1.39), 1.539 (0.79), 1.545 (0.94), 1.550 (1.07),1.557 (1.21), 1.562 (1.04), 1.574 (0.82), 1.605 (0.92), 1.626 (0.99), 1.646(0.43), 1.747 (1.60), 1.752 (1.34), 1.764 (1.31), 1.769 (1.42), 1.774 (1.36),1.787 (1.08), 1.796 (1.06), 1.802 (1.15), 1.811 (0.88), 1.817 (0.65), 1.826(0.52), 1.854 (1.30), 1.862 (0.90), 1.870 (1.27), 1.993 (0.47), 2.006 (1.01),2.014 (1.35), 2.027 (1.49), 2.036 (0.99), 2.041 (1.03), 2.053 (1.23), 2.062(1.16), 2.079 (2.91), 2.094 (4.55), 2.108 (4.56), 2.121 (2.74), 2.135 (1.28),2.148 (0.71), 2.417 (0.69), 2.695 (0.28), 2.713 (0.72), 2.733 (1.24), 2.752(0.70), 3.478 (2.03), 3.495 (3.09), 3.511 (2.04), 3.612 (0.89), 3.621 (1.38),3.634 (1.50), 3.643 (1.98), 3.652 (1.12), 3.709 (1.00), 7.125 (1.33), 7.209(1.28), 7.217 (1.39), 7.225 (2.20), 7.232 (2.18), 7.240 (1.10), 7.247 (0.98),7.290 (1.07), 7.295 (1.34), 7.299 (1.42), 7.305 (1.91), 7.310 (1.40), 7.314(1.34), 7.320 (1.05), 7.499 (0.20), 7.634 (2.33), 7.649 (9.46), 7.656 (5.17),7.659 (4.64), 7.671 (1.16), 7.674 (1.22), 8.745 (1.67), 8.755 (2.75), 8.764(1.62)。

Example 228

(+) -5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-4- (2, 5-difluorophenyl) pentanoic acid(diastereomer 2)

To 5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]-tert-butyl 4- (2, 5-difluorophenyl) valerate (43 mg, 67 μmol,diastereomer 2Example 230A) was added to TFA (113 μ l, 1.47 mmol) in dichloromethane (513 μ l) solution and the mixture was allowed to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 25 mg (100% purity, 63% of theory) of the title compound are obtained.

[α]_D ²⁰= 47.3 °, 589 nm, c = 0.32 g/100 ml, methanol

LC-MS (method 1) R_t= 2.38 min; MS (ESIpos): m/z = 588/590 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: -0.022 (1.15), 0.852 (0.27), 0.895(6.90), 0.907 (16.00), 0.919 (7.82), 1.037 (0.38), 1.043 (0.44), 1.058(1.06), 1.063 (1.08), 1.077 (1.11), 1.083 (1.12), 1.097 (0.50), 1.104 (0.44),1.230 (2.23), 1.247 (0.91), 1.258 (1.89), 1.270 (2.65), 1.281 (2.16), 1.290(1.20), 1.557 (1.06), 1.586 (0.60), 1.606 (1.01), 1.628 (1.08), 1.648 (0.45),1.750 (1.53), 1.755 (1.31), 1.760 (1.16), 1.771 (1.65), 1.783 (1.27), 1.791(1.07), 1.799 (1.12), 1.807 (0.84), 1.813 (0.64), 1.822 (0.50), 1.855 (1.27),1.871 (1.24), 1.990 (0.41), 2.003 (0.94), 2.012 (1.23), 2.025 (1.35), 2.034(0.86), 2.038 (0.86), 2.046 (0.75), 2.055 (0.78), 2.064 (0.82), 2.082 (2.33),2.095 (4.70), 2.108 (7.35), 2.121 (2.98), 2.135 (1.06), 2.148 (0.51), 2.412(0.62), 2.730 (0.98), 3.491 (2.76), 3.509 (2.34), 3.614 (0.80), 3.623 (1.33),3.636 (1.50), 3.645 (2.05), 3.654 (1.10), 3.701 (0.84), 7.126 (1.43), 7.140(0.93), 7.210 (1.32), 7.217 (1.42), 7.225 (2.26), 7.233 (2.23), 7.240 (1.11),7.248 (1.00), 7.292 (1.09), 7.297 (1.34), 7.301 (1.40), 7.307 (1.90), 7.313(1.37), 7.317 (1.32), 7.322 (1.04), 7.632 (1.89), 7.647 (7.35), 7.654 (4.76),7.658 (4.23), 7.669 (1.08), 7.672 (1.12), 8.748 (1.37), 8.757 (2.29), 8.767(1.29)。

Example 229

(+/-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-methylphenyl) pentanoic acid(raceme)

To (+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl in NMP (2.6ml)]Amino } -4- (2-methylphenyl) pentanoic acid (A)Racemic modification500 mg, 86% pure, 0.88 mmol, example 234A) and 3, 3-difluoropiperidine hydrochloride (804 mg, 5.10 mmol) DIPEA (2.1ml, 12 mmol) was added and the mixture was stirred at 120 ℃ for 4 days. Then, the mixture was cooled to room temperature and the reaction mixture was added to 1M hydrochloric acid. The mixture was extracted with dichloromethane and the organic phase was dried over sodium sulfate and concentrated on a rotary evaporator. The residue was previously purified by column chromatography (Isolera, KP-Sil, eluent: dichloromethane/methanol, gradient: 0-40% methanol) and then repurified by preparative HPLC (method 27). 212 mg (99% purity, 42% of theory) of the title compound are obtained.

LC-MS (method 26) R_t= 0.80 min; MS (ESIpos): m/z = 574/576 [M+H]⁺

H-NMR (400 MHz, chloroform-d) delta [ ppm ]: 1.262 (1.33), 1.935 (1.64), 1.950(1.86), 1.957 (1.72), 1.967 (1.54), 1.974 (1.08), 1.985 (0.60), 1.991 (0.70),2.009 (0.48), 2.022 (0.57), 2.039 (0.67), 2.055 (1.10), 2.071 (1.05), 2.087(0.88), 2.106 (0.65), 2.121 (0.52), 2.142 (0.63), 2.155 (0.73), 2.173 (0.67),2.190 (0.41), 2.208 (0.49), 2.212 (0.57), 2.244 (16.00), 2.277 (2.20), 3 (3.73), 6342 (1.84), 84.3853), 2.46 (84.46), 8953), 854 (0.46), 2.46), 2.35 (38, 3.65), 3.410 (0.81),3.433 (1.79), 3.447 (0.50), 3.461 (2.58), 3.489 (1.35), 3.677 (0.49), 3.690(0.54), 3.699 (0.48), 3.711 (1.03), 3.725 (0.66), 3.732 (0.61), 3.746 (0.54),3.933 (0.69), 3.949 (1.16), 3.965 (0.97), 3.982 (0.92), 3.998 (0.46), 5.949(0.59), 5.963 (1.00), 5.977 (0.56), 7.114 (0.46), 7.122 (0.56), 7.127 (0.44),7.133 (1.21), 7.142 (1.42), 7.154 (1.65), 7.167 (2.44), 7.185 (0.96), 7.193(0.71), 7.199 (0.74), 7.204 (0.97), 7.208 (0.67), 7.219 (2.04), 7.223 (3.71),7.231 (3.85), 7.234 (3.60), 7.602 (1.21), 7.607 (1.30), 7.624 (2.59), 7.629(2.96), 7.659 (4.47), 7.682 (2.17), 7.692 (3.39), 7.697 (2.97).

Separation of enantiomers:

the title compound (197 mg) was dissolved in dichloromethane/methanol (1:1, 3.3 ml) and separated by preparative HPLC on the chiral phase into enantiomers (see examples 230 and 231) [ column: daicel Chiralpak IA, 5 μm,250 mm x30 mm, flow rate: 50 ml/min, detection: UV 254 nm, injection: 0.3 ml, eluent hexane +0.1 vol% TFA (80%)/isopropanol (20%), isocratic. The combined target fractions were each concentrated and the respective residue was lyophilized.

Example 230

(-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-methylphenyl) pentanoic acid(enantiomer 1)

In the enantiomeric separation described in example 229, 71 mg (98% purity, ee >99%) of the title compound was obtained as the earlier eluting enantiomer.

[α]_D ²⁰= 5.0 °, 589 nm, c = 0.34 g/100 ml, methanol

Example 231

(+) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-methylphenyl) pentanoic acid(enantiomer 2)

In the enantiomeric separation described in example 229, 85 mg (88% purity, ee value 87%) of the title compound were obtained as the enantiomer which eluted later.

[α]_D ²⁰= 7.8 °, 589 nm, c = 0.28 g/100 ml, methanol

Practice ofExample 232

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-methylphenyl) pentanoic acid(raceme)

(+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2-methylphenyl) pentanoic acid (A)Outer cover Racemic modification500 mg, 86% pure, 0.88 mmol, example 234A) in pyrrolidine (3.0 ml, 2.2 mmol) was stirred at 100 ℃ for 2 h. After cooling to room temperature, the reaction mixture was added to 1M hydrochloric acid, and the mixture was extracted with dichloromethane. The organic phase is dried over sodium sulfate and concentrated on a rotary evaporator. The residue was previously purified by column chromatography (Isolera, KP-Sil, eluent: dichloromethane/methanol, gradient: 0-40% methanol) and repurified by preparative HPLC (method 27). 375 mg (99% purity, 80% of theory) of the title compound are obtained.

LC-MS (method 26) R_t= 0.77 min; MS (ESIpos): m/z = 524/526 [M+H]⁺

H-NMR (400 MHz, chloroform-d) delta [ ppm ]: 0.084 (0.46), 0.087 (0.42), 0.838(0.57), 0.850 (0.55), 0.871 (0.52), 0.888 (0.83), 1.184 (0.44), 1.217 (0.82),1.262 (7.00), 1.391 (0.53), 1.918 (2.72), 1.927 (3.16), 1.935 (8.00), 1.942(3.26), 1.951 (3.35), 1.968 (1.08), 1.977 (0.98), 1.063987 (0.95), 1.993 (0.93),2.012 (0.96), 2.028 (0.87), 2.037 (0.70), 2.049 (0.87), 2.054 (0.66), 2.829 (0.63), 2.075 (0.38), 2.493 (0.23), 2.38.38), 2.38 (19), 2.493 (0.23), 2.38.38), 2.38, 1.927), 2.38 (2.38, 3671), 2.71 (19), 2.71,71), 2.186 (0.64), 2.199(0.90), 2.224 (15.03), 2.282 (0.60), 2.301 (2.74), 2.320 (3.62), 2.339(1.34), 2.368 (16.00), 2.385 (1.42), 2.392 (11.83), 2.518 (0.66), 2.535(0.58), 2.545 (0.67),2.560 (1.05), 2.567 (0.84), 2.574 (0.82), 2.582 (0.76),2.629 (3.84), 3.246 (0.40), 3.258 (0.54), 3.266 (0.45), 3.273 (0.42), 3.284(0.50), 3.292 (0.49), 3.297 (0.85), 3.325 (1.15), 3.352 (0.62), 3.401 (0.45),3.410 (0.84), 3.421 (1.22), 3.431 (0.88), 3.436 (0.94), 3.448 (0.68), 3.459(0.48), 3.586 (2.41), 3.602 (6.38), 3.618 (2.37), 3.671 (0.54), 3.684 (0.58),3.693 (0.54), 3.705 (0.95), 3.718 (0.69), 3.727 (0.59), 3.741 (0.56), 3.933(0.55), 3.949 (0.98), 3.966 (0.89), 3.983 (0.81), 3.999 (0.42), 5.785 (0.65),7.006 (0.54), 7.114 (0.46), 7.121 (0.50), 7.128 (0.52), 7.133 (1.29), 7.141(1.26), 7.146 (1.19), 7.154 (1.89), 7.166 (2.94), 7.181 (1.44), 7.193 (2.67),7.198 (2.32), 7.207 (4.20), 7.221 (2.42), 7.229 (3.00), 7.235 (4.04), 7.238(3.76), 7.249 (0.51), 7.507 (5.43), 7.528 (0.70), 7.576 (2.43), 7.579 (3.98).

Separation of enantiomers:

the title compound (360 mg) was dissolved in DMSO/dichloromethane/methanol (1:1:1, 6ml) and separated into enantiomers on the chiral phase by preparative SFC (see examples 233 and 234) [ column: chiralpak IG, 5 μm,250 mmx 30mm, flow rate: 100 ml/min, detection: MWD 220 nm, injection: 1.0ml, eluent 28% methanol/72% carbon dioxide, isocratic ]. The combined target fractions were each concentrated and the respective residue was lyophilized.

Example 233

(+) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-methylphenyl) pentanoic acid(enantiomer 1)

In the enantiomeric separation described in example 232, 190 mg (98% purity, ee value 98%) of the title compound were obtained as the earlier eluting enantiomer.

[α]_D ²⁰= 12.7 °, 589 nm, c = 0.27 g/100 ml, methanol

Example 234

(-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-methylphenyl) pentanoic acid(enantiomer 2)

In the enantiomeric separation described in example 232, 135 mg (96% purity, ee value 96%) of the title compound are obtained as the enantiomer which elutes later.

[α]_D ²⁰= -4.43°, 589 nm, c = 0.35 g/100 mlMethanol, methanol

Example 235

(+) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-methoxyphenyl) pentanoic acid(enantiomer 1)

Coupling 5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2-methoxyphenyl) pentanoic acid (A)Enantiomers of a compound Structure body 1200 mg, 85% purity, 336 μmol, example 241A) and piperidine (5.0 ml) were stirred at 100 ℃ for 2 h. After cooling to room temperature, the reaction mixture was added to 1M hydrochloric acid and extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated. The crude product was purified by preparative HPLC (method 28). 160 mg (99% purity, 85% of theory) of the title compound are obtained.

[α]_D ²⁰= 4.73 °, 589 nm, c = 0.36 g/100 ml, chloroform

LC-MS (method 25) R_t= 1.29 min; MS (ESIpos): m/z = 554/556 [M+H]⁺

H-NMR (400 MHz, chloroform-d) delta [ ppm ]: 1.643 (1.02), 1.653 (1.13), 1.711(2.01), 1.721 (2.28), 2.018 (0.40), 2.031 (0.46), 2.039 (0.46), 2.054 (0.43),2.131 (0.52), 2.144 (0.65), 2.151 (0.45), 2.165 (0.67), 2.189 (8.51), 2.279(0.84), 2.293 (1.56), 2.299 (0.99), 2.313 (1.58), 2.323 (0.57), 2.334 (0.69),3.173 (2.55), 3.447 (0.48), 3.460 (0.61), 3.472 (0.51), 3.551 (0.42), 3.709(0.51), 3. 3.815 (740), 3.3546), 3.58 (0.46), 3658), 3.946 (0.58), 3646.58), 3.946 (0.46), 3.946 (0.58), 5.824 (0.55),6.845 (1.50), 6.865 (1.54), 6.958 (0.68), 6.960 (0.70), 6.979 (1.59), 6.995(0.95), 6.998 (0.90), 7.210 (1.95), 7.212 (1.90), 7.230 (2.18), 7.251 (0.81),7.255 (0.63), 7.561 (0.88), 7.566 (1.02), 7.583 (1.45), 7.589 (1.81), 7.630(2.05), 7.635 (1.95), 7.664 (0.46).

Example 236

(-) -5- ({ [ 6-bromo-3-methyl-2-(piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-methoxyphenyl) pentanoic acid(enantiomer 2)

Coupling 5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2-methoxyphenyl) pentanoic acid (A)Enantiomers of a compound Structure body 2200 mg, 87% purity, 344 μmol, example 242A) and piperidine (5.0 ml) were stirred at 100 ℃ for 1.5 h, after cooling to room temperature, the reaction mixture was added to 1M hydrochloric acid and extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated. The crude product was purified by preparative HPLC (method 28). 166 mg (99% purity, 86% of theory) of the title compound are obtained.

[α]_D ²⁰= 2.58 °, 589 nm, c = 0.8 g/100 ml, chloroform.

LC-MS (method 25) R_t= 1.35 min; MS (ESIpos): m/z = 554/556 [M+H]⁺

H-NMR (400 MHz, chloroform-d) delta [ ppm ]: 1.036 (0.66), 1.194 (0.73), 1.261(0.62), 1.276 (16.00), 1.282 (1.00), 1.295 (0.60), 1.610 (0.44), 1.623(0.62), 1.638 (0.83), 1.650 (0.82), 1.707 (1.46), 1.717 (1.68), 1.745 (0.88),1.760 (0.72), 2.179 (6.04), 2.225 (0.48), 2.238 (0.80),2.258 (0.82), 2.299(0.42), 2.995 (0.57), 3.76), 3.023 (0.54), 3.148 (1.64), 3.162 (2.07),3.173 (1.50), 3.439 (0.43), 3.589 (0.76), 3.023 (0.48), 596 (1.11), 5.978), 5967.48 (0.11), 5.978 (1.11), 5.978 (1.48), 5.978 (1.48), 6.945 (0.50),6.962 (1.06), 6.963 (1.09), 6.980 (0.68), 6.982 (0.65), 7.199 (2.09), 7.218(2.39), 7.235 (0.57), 7.552 (0.71), 7.557 (0.73), 7.574 (1.23), 7.579 (1.51),7.625 (2.89), 7.628 (1.65), 7.634 (1.32), 7.646 (1.30).

Example 237

(+) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-methoxyphenyl) pentanoic acid(enantiomer 1)

Coupling 5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2-methoxyphenyl) pentanoic acid (A)Enantiomers of a compound Structure body 1200 mg, 85% purity, 336 μmol, example 241A) and pyrrolidine (1.5ml) were stirred at 100 ℃ for 2 h. After cooling to room temperature, the reaction mixture was added to 1M hydrochloric acid and extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated. The crude product was purified by preparative HPLC (method 28). 65 mg (99% purity, 35% of theory) of the title compound are obtained.

[α]_D ²⁰= 5.19 °, 589 nm, c = 0.24 g/100 ml, chloroform

LC-MS (method 25) R_t= 0.85 min; MS (ESIpos): m/z = 540/542 [M+H]⁺

(vi) NMR (400 MHz, chloroform-d) delta [ ppm ]: 1.914 (1.96), 1.923 (2.41), 1.930(5.41), 1.937 (2.38), 1.946 (2.04), 1.962 (0.41), 1.973 (0.52), 1.993 (0.40),2.007 (0.47), 2.015 (0.41), 2.019 (0.50), 2.028 (0.51), 2.032 (0.50), 2.043(0.45), 2.126 (0.75), 2.150 (4.86), 2.172 (0.56), 2.179 (0.40), 2.239 (0.55),2.272 (0.92), 2.285 (1.36), 2.292 (1.07), 2.304 (1.54), 2.324 (0.67), 2.374(0.50), 2.84 (0.38), 2.38), 36960.38 (38), 36961.36), 3665 (19), 36960.38), 36964.38), 3665 (0.38), 3638) (3665), 3.741 (16.00), 3.753(0.68), 3.828 (0.47), 3.841 (0.44), 3.896 (0.41), 3.911 (0.69), 3.926 (0.48),6.082 (0.69), 6.847 (1.55), 6.867 (1.61), 6.954 (0.76), 6.956 (0.75), 6.974(1.66), 6.991 (1.01), 6.993 (0.94), 7.211 (3.38), 7.230 (3.74), 7.249 (0.85),7.253 (0.61), 7.408 (0.72), 7.430 (1.91), 7.450 (1.96), 7.456 (2.06), 7.473(0.66), 7.478 (0.82), 7.528 (1.65).

Example 238

(-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-methoxyphenyl) pentanoic acid(enantiomer 2)

Coupling 5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2-methoxyphenyl) pentanoic acid (A)Enantiomers of a compound Structure body 2127 mg, 87% purity, 218 μmol, example 242A) and pyrrolidine (1.0ml) were stirred at 100 ℃ for 1.5 h. After cooling to room temperature, the reaction was mixedThe mixture was added to 1M hydrochloric acid and extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated. The crude product was purified by preparative HPLC (method 28). 24 mg (99% purity, 20% of theory) of the title compound are obtained.

To determine the optical rotation, a sample of the title compound was dissolved in dichloromethane and washed with water. The organic phase was concentrated, and the residue was dried and dissolved in chloroform to measure the optical rotation.

[α]_D ²⁰= 2.0 °, 589 nm, c = 0.33 g/100 ml, chloroform

LC-MS (method 25) R_t= 0.85 min; MS (ESIpos): m/z = 540/542 [M+H]⁺

H-NMR (400 MHz, chloroform-d) delta [ ppm ]: 1.260 (1.06), 1.649 (2.69), 1.790(1.96), 1.911 (2.71), 1.928 (7.02), 1.944 (3.21), 1.978 (0.87), 1.998 (0.87),2.016 (0.86), 2.035 (0.46), 2.085 (0.76), 2.099 (0.91), 2.118 (0.91), 2.139(0.64), 2.171 (6.76), 2.220 (1.98), 2.238 (1.97), 2.257 (0.91), 3.028 (2.58),3.042 (3.03), 3.056 (2.57), 3.423 (0.94), 3.435 (1.21), 3.448 (1.02), 3.568(3.20), 3.584 (7.25), 35638 (23.81), 36639 (1.81), 36638 (1.23), 36639), 3639.81), 3.638 (3.23), 3.81), 3.639 (3.23), 3681), 3.913 (0.97),3.931 (0.85), 6.149 (1.09), 6.827 (1.86), 6.848 (2.18), 6.935 (1.01), 6.953(2.11), 6.971 (1.26), 7.192 (1.35), 7.206 (3.26), 7.225 (2.36), 7.452 (0.52),7.476 (4.64), 7.504 (0.56), 7.551 (2.52).

Example 239

(+) -5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-methoxyphenyl) pentanoic acid(enantiomer 1)

Coupling 5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2-methoxyphenyl) pentanoic acid (A)Enantiomers of a compound Structure body 1200 mg, 85% purity, 336 μmol, example 241A) and azepane (1.5ml) were stirred at 100 ℃ for 2 h. Cooling to room temperatureAfter that, the reaction mixture was added to 1M hydrochloric acid and extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated. The crude product was purified by preparative HPLC (method 28). 65 mg (99% purity, 34% of theory) of the title compound are obtained.

To determine the optical rotation, a sample of the title compound was dissolved in dichloromethane and washed with water. The organic phase was concentrated, and the residue was dried and dissolved in methanol to measure the optical rotation.

[α]_D ²⁰= 11.0 °, 589 nm, c = 0.47 g/100 ml, methanol

LC-MS (method 25) R_t= 1.26 min; MS (ESIpos): m/z = 568/570 [M+H]⁺

H-NMR (400 MHz, chloroform-d) delta [ ppm ]: 1.261 (0.55), 1.654 (1.36), 1.660(2.71), 1.669 (3.59), 1.677 (3.06), 1.684 (2.08), 1.815 (2.31), 2.019 (0.45),2.032 (0.49), 2.041 (0.52), 2.055 (0.47), 2.066 (0.43), 2.130 (0.58), 2.144(0.76), 2.151 (0.58), 2.171 (7.20), 2.278 (0.94), 2.292 (1.65), 2.299 (1.06),2.313 (1.86), 2.332 (0.76), 2.632 (0.59), 3.446 (0.4653), 45 (0.68), 3.471(0.60), 2.65), 3.509 (24.821), 24. 3.715 (24. 3.715), 5842 (0. 3.715), 3.831.593), 599.58), 3.599, 3.58), 3.58, 3, 3.715, 3.845 (0.45), 3.922(0.49), 3.936 (0.88), 3.951 (0.55), 3.969 (0.59), 5.825 (0.48), 6.843 (1.57),6.863 (1.56), 6.956 (0.77), 6.958 (0.74), 6.977 (1.60), 6.993 (1.04), 7.210(2.73), 7.229 (3.12), 7.249 (0.85),7.253 (0.63), 7.523 (0.48), 7.528 (0.63),7.545 (1.76), 7.549 (1.96), 7.561 (0.89), 7.590 (1.96).

Example 240

(-) -5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-methoxyphenyl) pentanoic acid(enantiomer 2)

Coupling 5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2-methoxyphenyl) pentanoic acid (A)Enantiomers of a compound Structure body 270mg, 87% purity, 120. mu. mol, example 242A) and azepane (0.5 ml) were stirred at 100 ℃ for 1.5 h. After cooling to room temperature, the reaction mixture was added to 1M hydrochloric acid and diluted with diAnd (4) extracting methyl chloride. The organic phase was dried over sodium sulfate and concentrated. The crude product was purified by preparative HPLC (method 28). 58 mg (99% purity, 84% of theory) of the title compound are obtained.

[α]_D ²⁰= 8.8 °, 589 nm, c = 0.40 g/100 ml, methanol

LC-MS (method 25) R_t= 1.38 min; MS (ESIpos): m/z = 568/570 [M+H]⁺

¹H-NMR (400 MHz, chloroform-d) delta [ ppm [ (. sub.m. ])]: 1.287 (0.66), 1.430 (0.60), 1.435(0.60), 1.440 (0.59), 1.447 (0.68), 1.451 (0.68), 1.459 (0.66), 1.464 (0.82),1.475 (0.64), 1.480 (0.66), 1.487 (0.79), 1.589 (0.72), 1.620 (0.90), 1.671(2.26), 1.676 (2.27), 1.681 (2.15), 1.688 (2.69), 1.692 (2.40), 1.700 (2.08),1.706 (2.52), 1.710 (2.46), 1.715 (1.42), 1.722 (1.23), 1.728 (1.45), 1.739(0.58), 1.746 (0.66), 2.074 (9.60), 2.080 (9.89), 2.088 (10.03), 2.225(8.25), 2.392 (1.01), 2.413 (1.28), 2.427 (1.51), 2.449 (1.17), 2.463 (0.78),2.508 (1.34), 2.523 (1.47), 2.542 (1.59), 2.562 (3.91), 2.583 (5.23), 2.597(6.79), 2.607 (4.51), 2.618 (6.43), 2.636 (2.19), 2.653 (2.10), 2.673 (1.04),3.403 (1.36), 3.408 (1.53), 3.413 (1.92), 3.427 (2.90), 3.432 (3.63), 3.437(4.40), 3.442 (4.50), 3.448 (3.86), 3.453 (4.66), 3.460 (4.20), 3.467 (3.15),3.476 (2.60), 3.481 (1.25), 3.488 (1.49), 3.852 (1.68), 3.879 (2.23), 3.885(2.31), 3.915 (6.23), 3.930 (6.53), 3.944 (4.69), 3.966 (2.11), 4.116 (4.77),4.120 (4.83), 4.126 (4.65), 4.133 (5.54), 4.136 (5.90), 4.139 (5.58), 4.144(5.35), 4.150 (8.43), 4.154 (7.75), 4.160 (4.77), 4.166 (5.01), 4.173 (7.65),4.188 (0.85), 4.202 (1.00), 4.223 (0.87), 4.324 (0.95), 4.338 (1.27), 4.358(1.14), 4.372 (0.79), 6.547 (1.48), 7.235 (1.36), 7.251 (1.79), 7.292 (1.11),7.347 (1.00), 7.364 (1.59), 7.382 (2.13), 7.400 (1.78), 7.420 (0.70), 7.580(0.44), 7.585 (0.42), 7.599 (1.69), 7.604 (1.77), 7.609 (1.76), 7.620 (2.87),7.628 (2.62), 7.635 (3.96), 7.660 (12.32), 7.664 (11.67), 7.670 (10.66),7.677 (12.09), 7.680 (12.39), 7.683 (11.15), 7.688 (11.09), 7.694 (15.57),7.699 (14.56), 7.702 (2.63), 7.704 (10.36), 7.710 (10.63), 7.715 (12.08),7.717 (16.00), 7.931 (0.88), 7.936 (1.58), 7.942 (1.97), 7.948 (2.49), 7.954(2.68), 7.960 (2.75), 7.965 (3.65), 7.970 (3.52), 7.981 (3.59), 7.988 (3.08),7.995 (3.43), 8.001 (3.64), 8.015 (1.81), 8.031 (2.10), 8.049 (1.69)。

Example 241

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 6-dichlorophenyl) pentanoic acid(raceme)

The method A comprises the following steps:

(+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2, 6-dichlorophenyl) pentanoic acid (C:)Racemic modification45.0 mg, 72% purity, 59.5 μmol, example 246A) and piperidine (1.0ml, 180 μmol) were stirred at 100 ℃ for 1.5 h.

The method B comprises the following steps:

(+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2, 6-dichlorophenyl) pentanoic acid (C:)Racemic modification123 mg, 72% purity, 163 μmol, example 246A) and piperidine (50 μ l, 500 μmol) were stirred in 1-butanol (6 ml) at 100 ℃ for 8 h.

The combined reaction mixtures from method a and method B were added to 1M hydrochloric acid and extracted with dichloromethane. The organic phase is dried over sodium sulfate and concentrated on a rotary evaporator. The crude product was purified by preparative HPLC (ChromatorexC-18, 10 μm, 125 mm x30 mm, eluent A: water + 0.1% formic acid, eluent B: acetonitrile; gradient: 50-95% B). 69mg (97% purity, 50% of theory) of the title compound are obtained.

LC-MS (method 25) R_t= 1.39 min; MS (ESIpos): m/z = 592/594/596 [M+H]⁺

H-NMR (400 MHz, chloroform-d) delta [ ppm ]: 0.959 (0.56), 1.185 (1.50), 1.200(2.54), 1.205 (0.61), 1.219 (0.63), 1.370 (12.44), 1.561 (0.53), 1.604(1.80), 1.614 (1.57), 1.650 (3.36), 1.659 (3.52), 2.069 (0.76), 2.079 (0.72),2.085 (0.73), 2.088 (0.75), 2.102 (1.06), 2.113 (0.71), 2.121 (0.58), 2.133(1.46), 2.158 (16.00), 2.172 (1.46), 2.187 (1.38), 2.205 (1.47), 2.223(1.78), 2.242 (1.01), 2.264 (0.283), 2.313 (0.43), 2.43.58), 2.287 (0.61), 2.48 (19), 2.58), 2.48 (19), 2.61), 2.48 (19, 2.61), 2.378(0.60), 2.390 (0.61), 2.534 (1.04), 2.931 (0.65), 3.214 (4.22), 3.783 (3.91),3.991 (0.77), 4.006 (0.82), 4.019 (1.17), 4.033 (1.38), 4.045 (0.93), 4.059(0.85), 4.072 (0.85), 4.083 (0.65), 4.090 (0.95), 4.107 (0.60), 4.118 (0.79),4.133 (0.70), 6.816 (0.42), 6.836 (0.47), 7.049 (1.92), 7.070 (4.35), 7.089(2.79), 7.219 (2.59), 7.222 (3.11), 7.239 (2.35), 7.242 (2.40), 7.261 (0.43),7.273 (2.98), 7.277 (2.73), 7.294 (2.59), 7.297 (2.53), 7.317 (0.41), 7.527(1.62), 7.532 (1.85), 7.549 (2.11), 7.554 (2.61), 7.587 (2.49), 7.636 (3.49),7.658 (2.29).

Example 242

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-methylphenyl) pentanoic acid(raceme)

(+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2-methylphenyl) pentanoic acid (A)Outer cover Racemic modification500 mg, 86% pure, 0.88 mmol, example 234A) and piperidine (3.0 ml, 2.2 mmol) were stirred at 100 ℃ for 2 h. After cooling to room temperature, the reaction mixture was added to 1M hydrochloric acid and extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated. The crude product was previously purified by column chromatography (Isolera, KP-Sil, eluent: dichloromethane/methanol, gradient: 0-40% methanol) and repurified by preparative HPLC (method 27). 330 mg (99% purity, 69% of theory) of the title compound are obtained.

LC-MS (method 26) R_t= 0.82 min; MS (ESIpos): m/z = 538/540 [M+H]⁺

H-NMR (400 MHz, chloroform-d) delta [ ppm ]: 1.565 (0.89), 1.577 (0.89), 1.660(2.48), 1.672 (2.38), 1.689 (2.28), 1.704 (2.76), 1.716 (2.87), 1.885 (0.46),1.907 (0.57), 1.913 (0.68), 1.920 (0.65), 1.942 (0.49), 2.079 (0.56), 2.092(0.70), 2.111 (0.70), 2.130 (0.42), 2.180 (2.18), 2.198 (3.83), 2.207(16.00), 2.218 (1.80), 2.262 (0.53), 2.356 (14.53), 2.391 (4.38), 2.874(2.02), 2.888 (2.61), 2.902 (1.88), 2.145.37), 2.54 (145.54), 3637.54), 3637 (19.54), 3637 (19), 3637.54), 3637 (19.54), 3.652(0.46), 3.665 (0.52), 3.673 (0.45), 3.685 (1.01), 3.698 (0.61), 3.706 (0.58),3.720 (0.52), 3.913 (0.55), 3.929 (1.06), 3.945 (0.91), 3.962 (0.86), 3.979(0.43), 6.165 (0.58), 6.179 (1.00), 6.193 (0.56), 7.087 (0.47), 7.091 (0.49),7.107 (1.30), 7.111 (1.31), 7.122 (1.34), 7.126 (1.68), 7.141 (2.27), 7.155(0.79), 7.178 (0.74), 7.183 (0.61), 7.190 (1.05), 7.197 (1.99), 7.202 (1.60),7.205 (1.91), 7.217 (3.58), 7.221 (2.59), 7.237 (0.66), 7.554 (1.42), 7.559(1.49), 7.577 (2.49), 7.582 (2.70), 7.628 (4.42), 7.650 (2.37), 7.664 (3.39),7.669 (3.15).

Example 243

(+/-) -5- ({ [2- (azepan-1-yl) -6-bromo-3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-methylphenyl) pentanoic acid(raceme)

(+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2-methylphenyl) pentanoic acid (A)Outer cover Racemic modification500 mg, 86% pure, 0.88 mmol, example 234A) and azepane (3.0 ml, 2.2 mmol) were stirred at 100 ℃ for 2 h. After cooling to room temperature, the reaction mixture was added to 1M hydrochloric acid and extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated. The crude product was purified by preparative HPLC (method 27). 315 mg (99% purity, 64% of theory) ofThe title compound.

LC-MS (method 26) R_t= 0.87 min; MS (ESIpos): m/z = 552/554 [M+H]⁺

H-NMR (400 MHz, chloroform-d) delta [ ppm ]: 1.262 (0.44), 1.622 (0.65), 1.629(1.23), 1.637 (1.69), 1.652 (2.55), 1.657 (3.68), 1.665 (4.74), 1.674 (4.04),1.680 (2.70), 1.812 (3.00), 1.898 (0.58), 1.908 (0.52), 1.924 (0.51), 1.931(0.58), 1.942 (0.65), 1.965 (0.57), 2.111 (0.66), 2.125 (0.74), 2.144 (0.71),2.160 (0.48), 2.177 (0.48), 2.194 (16.00), 2.207 (0.84), 2.230 (2.25), 2.385 (3.63), 84 (1.71), 2.84 (1.68), 2.68 (15.68), 3.020 (0.72), 2.0352), 2.194 (15.87), 2.67), 2.84 (38.68), 2.68, 1.68), 2.68 (0.72), 2.68, 1.68, 1.65), 3.398 (0.58),3.406 (0.49), 3.486 (4.69), 3.501 (5.26), 3.515 (4.60), 3.551 (0.41), 3.648(0.50), 3.661 (0.57), 3.670 (0.49), 3.682 (1.07), 3.696 (0.67), 3.704 (0.61),3.717 (0.56), 3.907 (0.61), 3.923 (1.16), 3.940 (1.00), 3.957 (0.93), 3.973(0.47), 5.949 (0.63), 5.963 (1.10), 5.977 (0.62), 7.096 (0.45), 7.102 (0.49),7.116 (1.30), 7.122 (1.17), 7.129 (1.28), 7.136 (1.72), 7.148 (2.58), 7.165(0.88), 7.185 (0.51), 7.192 (0.68), 7.197 (0.67), 7.205 (2.43), 7.208 (2.22),7.215 (2.91), 7.219 (3.74), 7.222 (3.61), 7.234 (0.49), 7.519 (0.65), 7.523(0.61), 7.541 (3.29), 7.546 (3.86), 7.553 (5.15), 7.574 (0.96), 7.608 (0.42),7.616 (3.08), 7.620 (2.89).

Example 244

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid(raceme)

From (+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid tert-butyl esterRacemic modification55 mg, 89.2. mu. mol, example 250A) start, as for 5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]4- (2, 5-difluorophenyl) pentanoic acid (example 225) as describedReaction with TFA and product purification. 44 mg (100% purity, 88% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.10 min; MS (ESIpos): m/z = 560/562 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.65), -0.008 (5.92), 0.008(5.82), 0.146 (0.65), 1.607 (3.47), 1.671 (6.81), 1.873 (0.73), 1.888 (0.94),1.905 (1.25), 2.051 (1.10), 2.065 (1.33), 2.082 (1.41), 2.101 (1.80), 2.116(7.07), 2.135 (16.00), 2.327 (0.73), 2.669 (0.89), 3.133 (9.00), 3.489(1.25), 3.677 (0.84), 3.695 (1.88), 3.710 (3.03), 3.724 (2.17), 7.057 (3.63),7.079 (6.66), 7.102 (4.28), 7.322 (0.57), 7.340 (1.41), 7.359 (2.04), 7.378(1.31), 7.396 (0.55), 7.468 (0.63), 7.623 (2.35), 7.645 (9.74), 7.656 (6.19),7.661 (5.74), 7.678 (1.46), 7.683 (1.59), 8.798 (1.62), 8.813 (3.26), 8.827(1.67), 12.078 (4.36)。

Example 245

(+) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid(enantiomer 1)

Reacting 5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid tert-butyl esterEnantiomer 185 mg, 138 μmol, example 251A) in dichloromethane (1.8 ml). At room temperature, TFA (1.0ml, 14 mmol) was added and the mixture was stirred at room temperature for 1 h. The volatile components were removed on a rotary evaporator. The residue was dissolved in a small amount of DMSO and purified by preparative HPLC (method 31). The combined target fractions were concentrated and the residue was dried in vacuo. 64 mg (99% purity, 82% of theory) of the title compound are obtained.

[α]_D ²⁰= 40.8 °, 589 nm, c = 0.32 g/100 ml, methanol

LC-MS (method 1) R_t= 2.09 min; MS (ESIpos): m/z = 560/562 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.63), 0.008 (3.76), 0.146(0.46), 0.839 (0.69), 1.234 (0.67), 1.607 (3.61), 1.671 (6.99), 1.903 (1.28),2.051 (1.15), 2.064 (1.45), 2.081 (1.45), 2.116 (7.35), 2.135 (16.00), 2.327(1.49), 2.366 (0.97), 2.670 (1.49), 2.710 (0.92), 3.133 (9.28), 3.162 (1.97),3.175 (1.74), 3.496 (1.22), 3.677 (0.82), 3.695 (1.89), 3.710 (3.13), 3.725(2.14), 7.057 (3.84), 7.079 (7.06), 7.102 (4.58), 7.341 (1.47), 7.359 (2.10),7.378 (1.36), 7.477 (0.67), 7.623 (2.54), 7.645 (10.62), 7.656 (6.64), 7.661(6.07), 7.678 (1.72), 7.683 (1.72), 8.798 (1.66), 8.813 (3.38), 8.827 (1.76),12.080 (2.94)。

Example 246

(-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid(enantiomer 2)

From 5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid tert-butyl esterEnantiomer 263 mg, 102 μmol, example 252A) start as on 5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid tert-butyl esterEnantiomer 1Example 245) reactions and product purification. 48 mg (100% purity, 84% of theory) of the title compound are obtained.

[α]_D ²⁰= 46.7 °, 589 nm, c = 0.30 g/100 ml, methanol

LC-MS (method 1) R_t= 2.09 min; MS (ESIpos): m/z = 560/562 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.52), -0.008 (3.81), 0.008(3.85), 0.146 (0.46), 1.606 (3.56), 1.671 (7.01), 1.902 (1.29), 2.050 (1.14),2.063 (1.35), 2.081 (1.41), 2.115 (7.45), 2.135 (16.00), 2.327 (1.39), 2.366(0.73), 2.669 (1.60), 2.710 (0.92), 3.133 (9.32), 3.493 (1.29), 3.676 (0.87),3.694 (1.89), 3.710 (3.14), 3.724 (2.23), 7.057 (3.85), 7.079 (7.03), 7.101(4.51), 7.340 (1.48), 7.359 (2.10), 7.379 (1.37), 7.396 (0.60), 7.470 (0.67),7.623 (2.50), 7.645 (10.42), 7.656 (6.45), 7.661 (6.01), 7.678 (1.50), 7.683(1.64), 8.798 (1.69), 8.813 (3.39), 8.828 (1.75), 12.083 (2.29)。

Example 247

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid hydrogen formate salt(raceme)

From (+/-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid tert-butyl esterRacemic modification56 mg, 92.9. mu. mol, example 253A) as for 5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]The reaction and product purification were carried out as described for 4- (2, 5-difluorophenyl) pentanoic acid (example 225). 20 mg (100% purity, 36% of theory) of the title compound (formic acid present from the HPLC method) are obtained.

LC-MS (method 1) R_t= 1.39 min; MS (ESIpos): m/z = 546/548 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.79), 0.008 (16.00), 0.146(1.79), 1.872 (13.83), 2.061 (1.98), 2.079 (2.02), 2.114 (8.78), 2.129(7.73), 2.163 (9.28), 2.328 (2.17), 2.670 (2.10), 3.566 (8.93), 3.680 (2.52),3.695 (3.53), 3.709 (2.80), 7.050 (5.01), 7.072 (9.09), 7.095 (5.79), 7.354(2.87), 7.372 (2.14), 7.466 (7.03), 7.488 (11.61), 7.547 (6.21), 7.553(5.86), 7.570 (3.77), 7.575 (3.61), 8.137 (14.49), 8.750 (2.29), 8.765(4.50), 8.779 (2.29), 12.103 (0.50)。

Example 248

5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid(enantiomer 1)

From 5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid tert-butyl esterEnantiomer 154 mg, 89.6 μmol, example 254A) as for (+) -5- ({ [ 6-bromo-3-methyl)-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid (example 245) was subjected to the reaction with TFA and product purification. 20 mg (96% purity, 39% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 1.39 min; MS (ESIpos): m/z = 546/548 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.41), 0.146 (1.22), 1.141(5.31), 1.235 (3.97), 1.356 (1.09), 1.872 (13.06), 2.086 (16.00), 2.115(9.79), 2.130 (8.19), 2.165 (8.58), 2.328 (3.90), 2.366 (2.69), 2.669 (4.54),2.710 (3.14), 3.564 (8.13), 3.694 (3.65), 4.538 (0.83), 7.051 (4.99), 7.073(8.96), 7.095 (5.44), 7.354 (3.14), 7.466 (6.53), 7.489 (10.50), 7.548(5.63), 7.553 (5.31), 7.570 (3.39), 7.575 (3.14), 7.838 (0.96), 8.133 (5.63),8.750 (2.43), 8.765 (4.10), 12.071 (1.73)。

Example 249

(-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid(enantiomer 2)

From 5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid tert-butyl esterEnantiomer 247 mg, 78.0 μmol, example 255A) as for (+) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid (example 245) was subjected to the reaction with TFA and product purification. 33 mg (96% purity, 74% of theory) of the title compound are obtained.

[α]_D ²⁰= 41.1 °, 589 nm, c = 0.30 g/100 ml, methanol

LC-MS (method 1) R_t= 1.39 min; MS (ESIpos): m/z = 546/548 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.73), 0.146 (1.64), 1.147(0.95), 1.872 (16.00), 2.114 (10.29), 2.129 (9.25), 2.162 (10.64), 2.327(5.88), 2.366 (2.34), 2.669 (5.71), 2.710 (2.51), 3.565 (9.95), 3.693 (3.98),7.050 (5.79), 7.072 (10.81), 7.095 (6.40), 7.351 (3.11), 7.466 (8.13), 7.488(13.15), 7.547 (6.83), 7.553 (6.66), 7.575 (4.15), 8.134(10.90), 8.763(4.84), 12.069 (1.38)。

Example 250

(+/-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid(raceme)

From (+/-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid tert-butyl esterRacemic modification55 mg, 84.3. mu. mol, example 256A) start, as for 5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]Reaction with TFA and product purification as described for 4- (2, 5-difluorophenyl) pentanoic acid (example 225). 48 mg (100% purity, 95% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.07 min; MS (ESIpos): m/z = 596/598 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.57), -0.008 (4.89), 0.146(0.61), 1.234 (0.46), 1.890 (4.70), 2.064 (2.82), 2.082 (3.71), 2.101 (3.95),2.118 (8.92), 2.134 (9.20), 2.155 (16.00), 2.327 (0.69), 2.670 (0.74), 3.165(5.06), 3.448 (3.31), 3.477 (6.93), 3.505 (4.20), 3.686 (0.95), 3.704 (2.05),3.719 (3.23), 3.733 (2.39), 7.059 (4.20), 7.081 (7.65), 7.104 (4.95), 7.324(0.61), 7.343 (1.58), 7.361 (2.22), 7.379 (1.43), 7.398 (0.58), 7.511 (0.64),7.674 (2.48), 7.696 (11.37), 7.705 (7.37), 7.710 (6.84), 7.728 (1.50), 7.732(1.69), 8.814 (1.90), 8.828 (3.82), 8.842 (1.95), 12.091 (1.33)。

Example 251

(+) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid(enantiomer 1)

From 5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid tert-butyl esterEnantiomer 182 mg, 126 μmol, example 257A) as for (+) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid (example 245) was reacted with TFA as described. The product was purified by preparative HPLC (method 19). 48 mg (98% purity, 63% of theory) of the title compound are obtained.

[α]_D ²⁰= 44.1 °, 589 nm, c = 0.48 g/100 ml, methanol

LC-MS (method 1) R_t= 2.09 min; MS (ESIpos): m/z = 596/598 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (0.59), 0.146 (0.64), 1.889(4.78), 2.081 (3.71), 2.100 (3.95), 2.118 (8.73), 2.133 (9.08), 2.154(16.00), 2.365 (0.46), 2.709 (0.55), 3.162 (10.75), 3.174 (9.58), 3.446(3.22), 3.476 (6.83), 3.504 (4.20), 3.703 (2.08), 3.719 (3.25), 4.063 (0.59),4.075 (1.40), 4.087 (1.37), 7.058 (3.98), 7.080 (7.57), 7.103 (4.68), 7.342(1.63), 7.360 (2.24), 7.377 (1.44), 7.501 (0.70), 7.673 (2.24), 7.695(10.13), 7.705 (6.46), 7.731 (1.48), 8.812 (1.86), 8.827 (3.59), 8.841(1.87), 12.083 (1.83)。

Example 252

(-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid(enantiomer 2)

From 5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid tert-butyl esterEnantiomer 273 mg, 112 μmol, example 258A), e.g. on (+) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid (example 245) was reacted with TFA as described. The product was purified by preparative HPLC (method 19). 40 mg (98% purity, 59% of theory) of the title compound are obtained.

[α]_D ²⁰= 38.2 °, 589 nm, c = 0.37 g/100 ml, methanol

LC-MS (method 1) R_t= 2.06 min; MS (ESIpos): m/z = 596/598 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.890 (4.67), 2.065 (2.78), 2.082(3.62), 2.101 (3.76), 2.119 (8.55), 2.135 (9.19), 2.155 (16.00), 2.327(0.66), 2.670 (0.70), 2.710 (0.43), 3.162 (9.09), 3.175 (8.05), 3.447 (3.23),3.476 (6.83), 3.504 (4.13), 3.687 (0.97), 3.703 (2.09), 3.719 (3.30), 3.734(2.38), 4.062 (0.43), 4.075 (1.22), 4.088 (1.19), 4.102 (0.40), 7.059 (4.21),7.081 (7.74), 7.104 (4.91), 7.323 (0.64), 7.342 (1.64), 7.361 (2.27), 7.378(1.46), 7.398 (0.56), 7.511 (0.67), 7.674 (2.44), 7.696 (11.21), 7.705(6.99), 7.710 (6.16), 7.728 (1.40), 7.732 (1.46), 8.812 (1.93), 8.827 (3.80),8.841 (1.89), 12.081 (4.01)。

Example 253

5- [ ({ 6-bromo-2- (3-fluoropiperidin-1-yl) -3-methylquinolin-4-yl } carbonyl) amino]-4- (2, 6-difluorophenyl) pentanoic acid(mixture of diastereomers)

Starting from tert-butyl 5- [ ({ 6-bromo-2- (3-fluoropiperidin-1-yl) -3-methylquinolin-4-yl } carbonyl) amino ] -4- (2, 6-difluorophenyl) pentanoate (56 mg, 88 μmol, example 259A), the reaction with TFA and product purification were carried out as described for 5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl ] -3-methylquinolin-4-yl } carbonyl) amino ] -4- (2, 5-difluorophenyl) pentanoic acid (example 225). 44 mg (100% purity, 88% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.01 min; MS (ESIpos): m/z = 578/580 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.03), -0.008 (8.38), 0.008(8.14), 0.146 (0.93), 1.644 (1.51), 1.806 (1.39), 1.902 (3.86), 2.051 (1.37),2.064 (1.63), 2.082 (1.68), 2.116 (7.76), 2.132 (8.29), 2.150 (16.00), 2.328(1.27), 2.670 (1.27), 3.094 (1.82), 3.169 (1.75), 3.379 (1.96), 3.405 (1.08),3.437 (1.77), 3.470 (1.84), 3.714 (2.97), 4.817 (1.29), 4.937 (1.20), 7.057(4.38), 7.080 (7.98), 7.102 (5.17), 7.341 (1.68), 7.359 (2.32), 7.377 (1.49),7.491 (0.77), 7.648 (2.80), 7.670 (11.98), 7.680 (7.57), 7.684 (7.16), 7.702(1.77), 7.707 (1.80), 8.807 (1.82), 8.822 (3.74), 8.836 (1.96), 12.087(1.51)。

Example 254

5- [ ({ 6-bromo-2- (3-ethylpiperidin-1-yl) -3-methylquinolin-4-yl } carbonyl) amino]-4- (2, 6-difluorophenyl) pentanoic acid(mixture of diastereomers)

From 5- [ ({ 6-bromo-2- (3-ethylpiperidin-1-yl) -3-methylquinolin-4-yl } carbonyl) amino]-tert-butyl 4- (2, 6-difluorophenyl) pentanoate (f)Mixtures of diastereomers55 mg, 85.3. mu. mol, example 260A) start, as for 5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]Reaction with TFA and product purification as described for 4- (2, 5-difluorophenyl) pentanoic acid (example 225). This gives 48 mg (100% purity, 96% of theory) of the title compound.

LC-MS (method 1) R_t= 2.37 min; MS (ESIpos): m/z = 588/590 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.62), -0.008 (5.31), 0.008(4.88), 0.146 (0.62), 0.892 (5.28), 0.909 (12.18), 0.911 (12.13), 0.928(6.42), 1.035 (0.46), 1.065 (1.21), 1.086 (1.24), 1.116 (0.56), 1.240 (1.12),1.257 (2.48), 1.275 (3.28), 1.293 (2.31), 1.398 (0.50), 1.563 (1.35), 1.603(1.26), 1.632 (1.09), 1.747 (1.69), 1.780 (1.17), 1.854 (1.61), 1.887 (2.01),2.030 (0.44), 2.049 (1.06), 2.063 (1.30), 2.081 (1.38), 2.100 (1.76), 2.118(8.16), 2.132 (16.00), 2.150 (2.62), 2.327 (0.62), 2.396 (0.74), 2.423(1.15), 2.451 (0.74), 2.670 (0.71), 2.710 (0.96), 2.738 (1.43), 2.768 (0.80),3.493 (3.67), 3.515 (2.99), 3.679 (0.74), 3.696 (1.61), 3.712 (2.60), 3.726(1.88), 7.053 (3.55), 7.075 (6.48), 7.097 (4.26), 7.319 (0.53), 7.338 (1.33),7.357 (1.92), 7.376 (1.26), 7.394 (0.56), 7.473 (0.53), 7.625 (1.61), 7.647(9.98), 7.654 (6.34), 7.658 (5.28), 7.676 (0.99), 7.680 (1.02), 8.790 (1.48),8.805 (2.94), 8.819 (1.52), 12.082 (1.72)。

Example 255

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 5-difluorophenyl) pentanoic acid(raceme)

From (+/-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 5-difluorophenyl) pentanoic acid tert-butyl ester (Racemic modification56 mg, 90.8. mu. mol, example 261A) as for 5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]Reaction with TFA (reaction time: 45 min) and purification of the product were carried out as described for 4- (2, 5-difluorophenyl) pentanoic acid (example 225). This gives 49 mg (100% purity, 96% of theory) of the title compound.

LC-MS (method 1) R_t= 2.11 min; MS (ESIpos): m/z = 560/562 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (0.88), 0.146 (0.88), 1.371(0.59), 1.605 (4.49), 1.670 (8.78), 1.805 (1.66), 2.003 (1.56), 2.015 (2.05),2.035 (1.95), 2.054 (2.24), 2.090 (5.07), 2.117 (16.00), 2.327 (1.76), 2.366(0.54), 2.669 (1.95), 3.132 (11.56), 3.612 (1.46), 3.631 (2.10), 3.645(3.02), 3.695 (1.76), 7.127 (2.54), 7.204 (2.05), 7.215 (2.24), 7.227 (3.32),7.239 (3.32), 7.250 (1.61), 7.262 (1.46), 7.300 (3.12), 7.436 (1.02), 7.622(2.54), 7.644 (12.63), 7.653 (8.44), 7.658 (7.66), 7.680 (1.76), 8.723(2.15), 8.738 (3.90), 8.752 (2.10), 12.064 (1.46)。

Example 256

(-) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 5-difluorophenyl) pentanoic acid(enantiomer 1)

From 5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 5-difluorophenyl) pentanoic acid tert-butyl ester (Enantiomer 181 mg, 131. mu. mol, example 262A) as determined for (+) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quineLin-4-yl]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid (example 245) was reacted with TFA as described. The product was purified by preparative HPLC (method 20). 40 mg (98% purity, 59% of theory) of the title compound are obtained.

[α]_D ²⁰= 28.8 °, 589 nm, c = 0.32 g/100 ml, methanol

LC-MS (method 1) R_t= 2.10 min; MS (ESIpos): m/z = 560/562 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.04), 0.146 (0.87), 1.606(4.57), 1.670 (8.65), 1.807 (1.78), 2.003 (1.72), 2.016 (2.23), 2.035 (2.23),2.055 (2.53), 2.063 (2.20), 2.090 (5.31), 2.117 (16.00), 2.137 (3.69), 2.327(1.78), 2.366 (1.04), 2.669 (1.65), 2.710 (0.81), 3.132 (11.40), 3.162(5.70), 3.175 (5.54), 3.612 (1.49), 3.631 (2.07), 3.646 (2.98), 3.659 (1.68),3.694 (1.65), 4.062 (0.52), 4.075 (1.49), 4.088 (1.43), 4.100 (0.49), 7.127(2.49), 7.147 (1.68), 7.204 (2.23), 7.216 (2.36), 7.227 (3.47), 7.239 (3.43),7.250 (1.65), 7.262 (1.59), 7.278 (1.78), 7.287 (2.11), 7.293 (2.17), 7.301(3.01), 7.316 (2.11), 7.324 (1.68), 7.422 (0.94), 7.622 (2.66), 7.644(12.70), 7.653 (7.90), 7.658 (7.13), 7.675 (1.46), 7.680 (1.68), 8.724(2.17), 8.739 (3.92), 8.753 (2.14), 12.061 (2.36)。

Example 257

(+) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 5-difluorophenyl) pentanoic acid(enantiomer 2)

From 5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 5-difluorophenyl) pentanoic acid tert-butyl ester (Enantiomer 290 mg, 146. mu. mol, example 263A) as for (+) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid (example 245) was reacted with TFA as described. The product was purified by preparative HPLC (method 20). 69mg (97% purity, 82% of theory) of the title compound are obtained.

[α]_D ²⁰= 34.2 °, 589 nm, c = 0.33 g/100 ml, methanol

LC-MS (method 1) R_t= 2.11 min; MS (ESIpos): m/z = 560/562 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.51), -0.008 (4.19), 0.008(4.29), 0.146 (0.51), 1.605 (4.49), 1.670 (8.69), 1.750 (0.60), 1.773 (1.12),1.785 (1.50), 1.808 (1.80), 1.984 (0.65), 2.003 (1.58), 2.016 (2.12), 2.035(2.10), 2.055 (2.37), 2.063 (2.03), 2.091 (5.24), 2.117 (16.00), 2.137(3.73), 2.157 (1.03), 2.327 (0.70), 2.366 (0.41), 2.670 (0.81), 2.710 (0.49),3.132 (11.49), 3.162 (9.35), 3.175 (9.18), 3.195 (0.52), 3.599 (0.84), 3.612(1.50), 3.632 (2.10), 3.645 (3.04), 3.659 (1.77), 3.675 (1.35), 3.694 (1.74),3.712 (1.47), 4.062 (0.93), 4.075 (2.52), 4.088 (2.42), 4.101 (0.85), 7.105(1.19), 7.127 (2.47), 7.136 (2.01), 7.147 (1.69), 7.204 (2.06), 7.215 (2.25),7.227 (3.34), 7.239 (3.26), 7.250 (1.60), 7.262 (1.46), 7.278 (1.77), 7.286(2.06), 7.292 (2.15), 7.301 (3.04), 7.310 (2.10), 7.316 (2.07), 7.324 (1.68),7.422 (0.90), 7.622 (2.45), 7.644 (12.19), 7.653 (7.77), 7.657 (6.84), 7.675(1.47), 7.680 (1.60), 8.724 (2.17), 8.739 (3.97), 8.753 (2.14), 12.060(2.50)。

Example 258

(+/-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 5-difluorophenyl) pentanoic acid(raceme)

From (+/-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 5-difluorophenyl) pentanoic acid tert-butyl ester (Racemic modification55 mg, 91.3. mu. mol, example 264A) as for 5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]Reaction with TFA and product purification as described for 4- (2, 5-difluorophenyl) pentanoic acid (example 225). 29 mg (100% purity, 58% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 1.41 min; MS (ESIpos): m/z = 546/548 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.78), -0.008 (5.94), 0.008(6.57), 0.146 (0.78), 1.235 (0.57), 1.750 (0.63), 1.773 (1.30), 1.786 (1.77),1.806 (2.19), 1.830 (1.93), 1.871 (16.00), 1.981 (0.83), 2.001 (1.98),2.013(2.61), 2.033 (2.81), 2.052 (3.07), 2.060 (2.66), 2.088 (5.37), 2.102 (7.09),2.118 (8.44), 2.138 (9.07), 2.323 (0.99), 2.327 (1.25), 2.332 (0.94), 2.665(0.99), 2.670 (1.30), 2.674 (1.04), 2.710 (0.42), 3.566 (11.15), 3.597(3.80), 3.617 (3.28), 3.631 (4.12), 3.644 (2.35), 3.688 (2.08), 7.099 (1.41),7.120 (2.87), 7.140 (2.03), 7.196 (2.92), 7.208 (3.07), 7.219 (4.53), 7.231(4.59), 7.242 (2.40), 7.254 (2.24), 7.271 (2.55), 7.279 (2.92), 7.285 (3.13),7.294 (4.22), 7.303 (3.02), 7.309 (3.02), 7.317 (2.61), 7.465 (8.55), 7.488(14.59), 7.544 (7.35), 7.549 (6.98), 7.566 (4.33), 7.571 (4.27), 8.133(1.98), 8.678 (2.76), 8.693 (4.95), 8.707 (2.76), 12.057 (2.24)。

Example 259

(+) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 5-difluorophenyl) pentanoic acid(enantiomer 1)

From 5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 5-difluorophenyl) pentanoic acid tert-butyl ester (Enantiomer 180 mg, 133 μmol, example 265A), e.g. on (+) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid (example 245) was subjected to the reaction with TFA and product purification. 59 mg (100% purity, 81% of theory) of the title compound are obtained.

[α]_D ²⁰= 30.2 °, 589 nm, c = 0.30 g/100 ml, methanol

LC-MS (method 1) R_t= 1.42 min; MS (ESIpos): m/z = 546/548 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.42), -0.008 (10.42), 0.008(9.95), 0.146 (1.26), 1.148 (0.74), 1.806 (2.42), 1.871 (16.00), 2.001(2.11), 2.013 (2.68), 2.033 (2.95), 2.052 (3.21), 2.060 (2.74), 2.088 (5.53),2.101 (7.47), 2.118 (8.79), 2.137 (9.00), 2.327 (3.63), 2.332 (2.74), 2.366(1.95), 2.669 (4.11), 2.710 (2.11), 3.169 (0.74), 3.566 (10.89), 3.617(3.47), 3.631 (4.32), 3.645 (2.58), 3.685 (2.26), 7.119 (2.95), 7.196 (2.95),7.207 (3.16), 7.219 (4.68), 7.231 (4.74), 7.242 (2.58), 7.254 (2.37), 7.271(2.63), 7.285 (3.16), 7.294 (4.32), 7.303 (3.21), 7.317 (2.74), 7.466 (5.63),7.488 (9.68), 7.544 (5.95), 7.550 (5.58), 7.567 (3.53), 7.572 (3.58), 7.834(0.42), 8.133 (2.00), 8.679 (2.74), 8.693 (4.84), 8.707 (2.74), 12.057(2.84), 12.732 (0.58)。

Example 260

(-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 5-difluorophenyl) pentanoic acid(enantiomer 2)

From 5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 5-difluorophenyl) pentanoic acid tert-butyl ester (Enantiomer 283 mg, 138 μmol, example 266A), e.g. on (+) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid (example 245) was subjected to the reaction with TFA and product purification. 56 mg (100% purity, 74% of theory) of the title compound are obtained.

[α]_D ²⁰= 28.6 °, 589 nm, c = 0.30 g/100 ml, methanol

LC-MS (method 1) R_t= 1.42 min; MS (ESIpos): m/z = 546/548 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.11), -0.008 (8.91), 0.008(10.55), 0.146 (1.15), 1.147 (0.53), 1.806 (2.44), 1.871 (16.00), 2.001(1.99), 2.013 (2.61), 2.033 (2.75), 2.052 (3.10), 2.088 (5.50), 2.102 (7.31),2.118 (8.60), 2.138 (9.00), 2.327 (2.75), 2.366 (1.60), 2.669 (3.01), 2.710(1.68), 3.207 (0.58), 3.565 (11.21), 3.617 (3.28), 3.631 (4.08), 3.644(2.30), 3.686 (2.13), 7.120 (3.01), 7.196 (2.75), 7.208(3.06), 7.219 (4.43),7.231 (4.43), 7.242 (2.26), 7.254 (2.26), 7.271 (2.57), 7.285 (3.19), 7.294(4.21), 7.303 (3.06), 7.317 (2.48), 7.465 (7.40), 7.487 (12.59), 7.544(6.47), 7.549 (6.12), 7.566 (3.81), 7.571 (3.77), 8.132 (0.49), 8.678 (2.84),8.693 (4.92), 8.707 (2.57), 12.055 (6.43)。

Example 261

(+/-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2, 5-difluorophenyl) pentanoic acid(raceme)

From (+/-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2, 5-difluorophenyl) pentanoic acid tert-butyl ester (Racemic modification55 mg, 84.3. mu. mol, example 267A) as per 5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) amino]Reaction with TFA (reaction time: 40 min) and purification of the product were carried out as described for 4- (2, 5-difluorophenyl) pentanoic acid (example 225). 47 mg (100% purity, 93% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.07 min; MS (ESIpos): m/z = 596/598 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.53), -0.008 (4.53), 0.008(4.37), 0.146 (0.53), 1.372 (1.58), 1.788 (1.68), 1.811 (1.95), 1.881 (5.11),2.004 (1.84), 2.017 (2.37), 2.037 (2.95), 2.056 (4.21), 2.063 (3.89), 2.092(8.63), 2.106 (8.47), 2.119 (10.53), 2.136 (15.47), 2.327 (1.53), 2.366(0.42), 2.670 (1.63), 2.710 (0.53), 3.163 (6.42), 3.446 (4.05), 3.475 (7.63),3.504 (3.84), 3.622 (1.68), 3.641 (2.42), 3.655 (3.42), 3.670 (2.00), 3.701(1.79), 7.107 (1.21), 7.128 (2.79), 7.138 (2.26), 7.149 (1.95), 7.206(2.53),7.217 (2.74), 7.229 (4.11), 7.241 (4.16), 7.252 (2.00), 7.264 (1.84), 7.285(2.05), 7.292 (2.42), 7.298 (2.58), 7.307 (3.58), 7.316 (2.42), 7.322 (2.47),7.330 (2.16), 7.469 (0.89), 7.673 (2.89), 7.695 (16.00), 7.702 (10.95), 7.707(9.63), 7.724 (1.95), 7.729 (2.11), 8.739 (2.53), 8.754 (4.79), 8.768 (2.58),12.069 (1.58)。

Example 262

(-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2, 5-difluorophenyl) pentanoic acid(enantiomer 1)

From 5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2, 5-difluorophenyl) pentanoic acid tert-butyl ester (Enantiomer 155 mg, 84.3. mu. mol, example 268A) as for (+) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid (example 245) was reacted with TFA as described. The product was purified by preparative HPLC (method 20). 23mg (98% purity, 35% of theory) of the title compound are obtained.

[α]_D ²⁰= 30.7 °, 589 nm, c = 0.33 g/100 ml, methanol

LC-MS (method 1) R_t= 2.07 min; MS (ESIpos): m/z = 596/598 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.99), -0.008 (12.44), 0.146(0.96), 1.812 (2.13), 1.882 (5.42), 2.005 (2.03), 2.017 (2.55), 2.037 (3.26),2.057 (4.72), 2.093 (9.47), 2.109 (9.62), 2.119 (11.50), 2.136 (16.00), 2.327(1.24), 2.366 (0.72), 2.669 (1.46), 2.710 (0.82), 3.162 (13.03), 3.175(11.43), 3.446 (4.30), 3.475 (7.79), 3.504 (3.88), 3.540 (0.67), 3.622(1.83), 3.641 (2.65), 3.656 (3.59), 3.669 (2.28), 3.702 (2.08), 4.075 (1.63),4.088 (1.58), 7.128 (2.97), 7.149 (2.05), 7.206 (2.52), 7.217 (2.72), 7.229(4.06), 7.241 (4.03), 7.252 (2.05), 7.264 (1.85), 7.285 (2.23), 7.298 (2.74),7.307 (3.66), 7.316 (2.60), 7.322 (2.57), 7.330 (2.08), 7.474 (1.04), 7.673(2.99), 7.695 (15.06), 7.702 (10.51), 7.707 (9.15), 7.725 (1.76), 7.729(1.98), 8.739 (2.72), 8.753 (4.77), 8.768 (2.62), 12.065 (1.78)。

Example 263

(+) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2, 5-difluorophenyl) pentanoic acid(enantiomer 2)

From 5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2, 5-difluoroPhenyl) pentanoic acid tert-butyl ester (Enantiomer 271 mg, 95% purity, 103. mu. mol, example 269A) as for (+) -5- ({ [ 6-bromo-3-methyl-2- (piperidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2, 6-difluorophenyl) pentanoic acid (example 245) was reacted with TFA as described. The product was purified by preparative HPLC (method 20). 28 mg (99% purity, 45% of theory) of the title compound are obtained.

[α]_D ²⁰= 34.0 °, 589 nm, c = 0.33 g/100 ml, methanol

LC-MS (method 1) R_t= 2.06 min; MS (ESIpos): m/z = 596/598 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.62), 0.146 (0.69), 1.371(0.58), 1.754 (0.65), 1.790 (1.79), 1.810 (2.06), 1.881 (5.45), 2.004 (1.92),2.017 (2.47), 2.038 (3.17), 2.056 (4.63), 2.092 (9.35), 2.108 (9.58), 2.119(11.35), 2.136 (16.00), 2.327 (0.91), 2.366 (0.44), 2.669 (1.00), 2.709(0.49), 3.163 (7.70), 3.447 (4.16), 3.475 (7.62), 3.504 (3.78), 3.622 (1.83),3.642 (2.58), 3.655 (3.47), 3.669 (2.14), 3.703 (1.99), 7.128 (2.87), 7.148(1.86), 7.206 (2.42), 7.217 (2.60), 7.229 (3.79), 7.240 (3.68), 7.252 (1.83),7.263 (1.66), 7.285 (2.14), 7.298 (2.63), 7.307 (3.52), 7.316 (2.47), 7.329(1.86),7.467 (0.96), 7.673 (2.87), 7.695 (14.19), 7.702 (9.23), 7.706(8.04), 7.729 (1.64), 8.739 (2.76), 8.753 (4.69), 8.767 (2.46), 12.063(1.15)。

Example 264

5- [ ({ 6-bromo-2- (3-fluoropiperidin-1-yl) -3-methylquinolin-4-yl } carbonyl) amino]-4- (2, 5-difluorophenyl) pentanoic acid(mixture of diastereomers)

From 5- [ ({ 6-bromo-2- (3-fluoropiperidin-1-yl) -3-methylquinolin-4-yl } carbonyl) amino]-tert-butyl 4- (2, 5-difluorophenyl) pentanoate (f)Mixtures of diastereomers55 mg, 86.7. mu. mol, example 270A) as for 5- [ ({ 6-bromo-2- [ 3-ethylpiperidin-1-yl)]-3-methylquinolin-4-yl } carbonyl) Amino group]Reaction with TFA and product purification as described for 4- (2, 5-difluorophenyl) pentanoic acid (example 225). 43 mg (100% purity, 86% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 2.02 min; MS (ESIpos): m/z = 578/580 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.90), -0.008 (10.95), 0.008(6.96), 0.017 (0.58), 0.146 (0.90), 1.643 (2.02), 1.806 (3.83), 1.899 (3.35),1.948 (2.02), 1.983 (1.70), 2.003 (2.29), 2.016 (2.55), 2.035 (2.60), 2.055(2.82), 2.063 (2.39), 2.091 (6.01), 2.105 (7.44), 2.128 (14.41), 2.327(1.54), 2.523 (3.88), 2.665 (1.38), 2.670 (1.70), 2.711 (0.43), 3.094 (2.29),3.153 (2.39), 3.170 (2.34), 3.369 (3.99), 3.401 (1.75), 3.434 (2.29), 3.460(1.54), 3.540 (0.64), 3.618 (1.59), 3.636 (2.34), 3.650 (3.08), 3.700 (1.97),4.817 (1.70), 4.935 (1.70), 7.127 (2.92), 7.147 (1.97), 7.204 (2.76), 7.216(2.92), 7.227 (4.36), 7.239 (4.25), 7.251 (2.07), 7.262 (1.91), 7.281 (2.23),7.289 (2.60), 7.295 (2.71), 7.304 (3.72), 7.313 (2.66), 7.319 (2.50), 7.327(2.13), 7.450 (1.06), 7.647 (3.40), 7.669 (16.00), 7.676 (10.95), 7.681(9.51), 7.699 (1.97), 7.704 (2.13), 8.732 (2.71), 8.747 (4.73), 8.761 (2.50),12.068 (2.29)。

Example 265

(-) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2, 6-dichlorophenyl) pentanoic acid(enantiomer 1)

(+/-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Amino } -4- (2, 6-dichlorophenyl) pentanoic acid (C:)Racemic modificationA mixture of 401 mg, 72% purity, 5 μmol, example 246A), 3-difluoropiperidine hydrochloride (580 mg,3.68 mmol) and DIPEA (1.5ml, 8.8 mmol) in NMP (1.9ml) was stirred at 120 ℃ for 4 days. After cooling to room temperature, the reaction mixture was added to 1M hydrochloric acid and extracted with dichloromethane. The organic phase is dried over sodium sulfateAnd concentrated. The crude product was purified by column chromatography (Isolera, LiChroprep RP-18, eluent: water/acetonitrile, gradient: 20-100% acetonitrile). The product fractions (238 mg) were dissolved in dichloromethane/methanol (1:1, 5ml) and separated by preparative HPLC on the chiral phase into enantiomers [ column: daicel Chiralpak IA, 5 μm,250 mm x30 mm, flow rate: 50 ml/min, detection: UV 254 nm, injection: 1.0ml of eluent 70% hexane + 0.1% trifluoroacetic acid/30% isopropanol, isocratic]. The combined target fractions were each concentrated and the respective residue was lyophilized.

The title compound was obtained as the earlier eluting enantiomer (52 mg, 98% purity, ee > 99%).

[α]_D ²⁰= 10.2 °, 589 nm, c = 0.50 g/100 ml, chloroform

LC-MS (method 25) R_t= 1.37 min; MS (ESIpos): m/z = 628/630/632 [M+H]⁺

¹H-NMR (400 MHz, chloroform-d) delta [ ppm [ (. sub.m. ])]: 0.888 (0.45), 0.894 (0.47), 1.215(0.47), 1.226 (1.52), 1.241 (1.34), 1.263 (2.42), 1.286 (1.77), 1.304 (0.89),1.379 (4.12), 1.395 (4.07), 1.999 (2.53), 2.115 (1.08), 2.152 (2.73), 2.163(3.07), 2.180 (2.45), 2.244 (0.69), 2.310 (16.00), 2.331 (2.78), 2.436(0.45), 2.451 (0.79), 2.476 (0.98), 2.485 (0.84), 2.493 (0.84), 2.503 (1.20),3.048 (0.51), 3.538 (2.47), 3.709 (1.54), 3.737 (2.47), 3.761 (1.32), 3.848(0.43), 4.055 (0.46), 4.071 (0.96), 4.086 (1.16), 4.101 (1.99), 4.112 (1.96),4.231 (0.65), 4.247 (0.86), 4.260 (1.13), 4.273 (0.87), 6.758 (1.37), 7.152(2.35), 7.172 (5.73), 7.192 (3.52), 7.225 (0.51), 7.242 (0.74), 7.302 (0.56),7.321 (3.36), 7.324 (3.85), 7.341 (3.30), 7.344 (3.50), 7.352 (0.95), 7.364(4.49), 7.367 (3.81), 7.385 (3.43), 7.388 (2.99), 7.761 (2.77), 7.768 (3.04),7.790 (2.66), 7.859 (2.44), 7.881 (1.58), 8.350 (0.78)。

Example 266

(+) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2, 6-dichlorophenyl) pentanoic acid(enantiomer 2)

In the enantiomeric separation described in example 265, 50 mg (95% purity, ee value 98%) of the title compound are obtained as the enantiomer which elutes later.

[α]_D ²⁰= 14.8 °, 589 nm, c = 0.50 g/100 ml, chloroform

¹H-NMR (400 MHz, chloroform-d) delta [ ppm [ (. sub.m. ])]: 0.861 (0.55), 0.876 (0.59), 0.888(0.89), 0.894 (0.86), 0.901 (0.64), 0.913 (0.48), 1.199 (0.55), 1.215 (0.70),1.227 (1.84), 1.242 (1.70), 1.263 (4.61), 1.379 (3.69), 1.395 (3.79), 2.005(2.59), 2.164 (2.71), 2.179 (2.35), 2.315 (16.00), 2.342 (2.09), 2.478(1.02), 2.507 (1.24), 3.540 (2.34), 3.736 (2.05), 4.079 (1.03), 4.115 (2.36),4.228 (0.74), 4.242 (0.88), 4.256 (1.23), 4.268 (0.91), 6.702 (1.37), 7.154(2.59), 7.174 (6.12), 7.194 (3.69), 7.322 (3.68), 7.326 (4.24), 7.343 (3.18),7.345 (3.19), 7.367 (4.49), 7.370 (3.96), 7.386 (3.70), 7.390 (3.25), 7.529(0.51), 7.767 (3.80), 7.791 (3.05), 7.863 (2.27), 7.884 (1.87), 7.947 (0.79)。

Example 267

(+) -5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]² H ₁₀) Piperidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(enantiomer 1)

To (+) -5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]² H ₁₀) Piperidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]Tert-butyl 4- (2-chlorophenyl) valerate (262 mg, 419. mu. mol,enantiomer 1Example 278A) in dichloromethane (3.2 ml) was added TFA (711 μ l, 9.23 mmol) and the mixture was left to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 187 mg (100% purity, 79% of theory) of the title compound are obtained.

[α]_D ²⁰= +13.3°, 589 nm, c = 0.38 g/100 ml of methanol

LC-MS (method 1) R_t= 2.15 min; MS (ESIpos): m/z = 568/570 [M+H]⁺

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.021 (0.35), 1.232 (0.75), 1.540(0.53), 1.613 (0.41), 1.792 (0.63), 1.800 (0.99), 1.818 (2.03), 1.835 (2.41),1.853 (1.25), 1.873 (0.28), 2.024 (0.57), 2.036 (1.20), 2.041 (1.40), 2.052(5.86), 2.074 (4.33), 2.081 (4.40), 2.097 (4.07), 2.127 (15.83), 2.154(2.03), 2.196 (0.35), 2.363 (0.20), 2.636 (0.22), 3.078 (0.18), 3.086 (0.20),3.593 (2.03), 3.674 (3.19), 7.258 (1.99), 7.261 (2.01), 7.274 (4.38), 7.288(3.00), 7.291 (2.84), 7.359 (2.69), 7.374 (4.82), 7.388 (2.54), 7.443 (8.16),7.446 (7.64), 7.459 (7.24), 7.462 (6.59), 7.480 (6.24), 7.482 (6.15), 7.496(4.97), 7.623 (4.16), 7.640 (16.00), 7.650 (10.72), 7.654 (9.32), 7.667(2.58), 7.671 (2.69), 8.710 (2.72), 8.721 (5.30), 8.733 (2.56), 12.042(0.39)。

Example 268

(-) -5- [ ({ 6-bromo-3-methyl-2- [ (S))² H ₁₀) Piperidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(enantiomer 2)

To (-) -5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]² H ₁₀) Piperidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]Tert-butyl 4- (2-chlorophenyl) valerate (244 mg, 391 μmol,enantiomer 2Example 279A) in dichloromethane (3.0 ml) was added TFA (662 μ l, 8.59 mmol) and the mixture was left to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 180 mg (100% purity, 81% of theory) of the title compound are obtained.

[α]_D ²⁰= 11.1 °, 589 nm, c = 0.40 g/100 ml, methanol

LC-MS (method 1) R_t= 2.17 min; MS (ESIpos): m/z = 568/570 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.538 (0.58), 1.611 (0.46), 1.799(1.21), 1.814 (2.79), 1.828 (3.08), 1.843 (1.64), 2.028(0.83), 2.043 (1.96),2.053 (7.45), 2.071 (6.42), 2.076 (5.14), 2.087 (2.91), 2.092 (2.98), 2.099(3.62), 2.125 (13.11), 2.131 (11.82), 2.148 (3.42), 2.195 (0.42), 2.386(0.17), 2.613 (0.16), 3.074 (0.19), 3.081 (0.19), 3.592 (2.59), 3.673 (3.20),7.263 (2.39), 7.276 (5.09), 7.288 (3.29), 7.363 (3.08), 7.376 (5.48), 7.388(2.98), 7.448 (9.82), 7.461 (8.60), 7.488 (6.94), 7.500 (5.71), 7.626 (5.57),7.641 (16.00), 7.654 (9.27), 7.656 (8.85), 7.668 (3.13), 7.671 (3.26), 8.734(3.59), 8.744 (7.01), 8.753 (3.50), 12.078 (1.77)。

Example 269

(-) -5- [ ({ 6-bromo-3-methyl-2- [ (S))² H ₁₀) Piperidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Valeric acid(enantiomer 1)

To (-) -5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]² H ₁₀) Piperidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Tert-butyl valerate (231 mg, 352 μmol,enantiomer 1Example 280A) in dichloromethane (2.7ml) TFA (596 μ l, 7.74 mmol) was added and the mixture was left to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 166 mg (100% purity, 79% of theory) of the title compound are obtained.

[α]_D ²⁰= 19.1 °, 589 nm, c = 0.31 g/100 ml, methanol

LC-MS (method 1) R_t= 2.18 min; MS (ESIpos): m/z = 602/604 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 0.005 (0.22), 1.229 (0.23), 1.546(0.54), 1.620 (0.59), 1.876 (0.59), 1.885 (0.81), 1.892 (1.34), 1.900 (1.97),1.907 (1.66), 1.915 (1.99), 1.923 (1.82), 1.939 (1.08), 1.953 (1.49), 1.962(1.01), 1.969 (1.61), 1.980 (2.72), 1.989 (1.82), 1.996 (2.72), 2.005 (2.10),2.047 (2.24), 2.058 (3.02), 2.063 (2.06), 2.074 (3.61), 2.078 (1.32), 2.085(1.93), 2.101 (1.97), 2.116 (1.74), 2.125 (2.27), 2.139 (3.57), 2.162 (6.96),2.191 (1.27), 2.388 (0.17), 2.616 (0.17), 3.096 (0.32), 3.633 (1.56), 3.707(1.54), 7.471 (2.48), 7.484 (4.85), 7.497 (2.90), 7.639 (4.67), 7.654(16.00), 7.662 (9.66), 7.666 (8.77), 7.677 (2.62), 7.680 (2.72), 7.698(2.13), 7.711 (5.07), 7.724 (4.34), 7.729 (7.06), 7.741 (10.81), 7.753(3.07), 8.793 (3.05), 8.803 (6.14), 8.813 (3.01), 12.085 (0.33)。

Example 270

(+) -5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]² H ₁₀) Piperidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Valeric acid(enantiomer 2)

To (+) -5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]² H ₁₀) Piperidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Tert-butyl valerate (204 mg, 310 μmol,enantiomer 2Example 281A) in dichloromethane (2.4 ml) TFA (525 μ l, 6.82 mmol) was added and the mixture was left to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 157 mg (100% purity, 84% of theory) of the title compound are obtained.

[α]_D ²⁰= 19.1 °, 589 nm, c = 0.45 g/100 ml, methanol

LC-MS (method 1) R_t= 2.23 min; MS (ESIpos): m/z = 602/604 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.546 (0.56), 1.620 (0.64), 1.877(0.74), 1.892 (1.70), 1.900 (2.53), 1.907 (2.16), 1.915 (2.60), 1.923 (2.32),1.939 (1.35), 1.954 (1.73), 1.963 (1.23), 1.970 (1.91), 1.981 (3.42), 1.990(2.23), 1.997 (3.23), 2.006 (2.55), 2.048 (2.67), 2.059 (3.62), 2.074 (4.25),2.086 (2.28), 2.101 (2.44), 2.117 (2.22), 2.126 (3.06), 2.162 (9.18), 2.387(0.23), 2.614 (0.20), 3.096 (0.31), 3.632 (2.08), 3.705 (2.06), 7.472 (3.23),7.484 (6.23), 7.497 (3.72), 7.638 (4.69), 7.653 (16.00), 7.663 (10.11), 7.679(2.87), 7.698 (2.74), 7.711 (6.46), 7.729 (8.95), 7.742 (13.87), 7.753(3.91), 8.792 (3.69), 8.802 (7.25), 8.812 (3.62), 12.063 (7.55)。

Example 271

(+) -5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]² H ₁₀) Piperidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Valeric acid(enantiomer 1)

To (+) -5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]² H ₁₀) Piperidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Tert-butyl valerate (181 mg, 268 μmol,enantiomer 1Example 282A) in dichloromethane (2.1ml) TFA (460 μ l, 5.90 mmol) was added and the mixture was left to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 140 mg (100% purity, 84% of theory) of the title compound are obtained.

[α]_D ²⁰= 19.7 °, 589 nm, c = 0.33 g/100 ml, methanol

LC-MS (method 1) R_t= 2.28 min; MS (ESIpos): m/z = 618/620 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.231 (0.17), 1.543 (0.59), 1.615(0.66), 1.788 (0.36), 1.799 (0.68), 1.812 (2.24), 1.819 (2.71), 1.826 (2.26),1.834 (3.75), 1.849 (2.42), 1.867 (0.57), 2.031 (0.65), 2.048 (1.50), 2.057(4.09), 2.077 (16.00), 2.098 (4.42), 2.105 (3.31), 2.111 (3.54), 2.135(6.56), 2.219 (0.49), 2.388 (0.21), 2.616 (0.21), 3.089 (0.29), 3.393 (2.89),3.403 (2.82), 3.599 (1.13), 3.609 (1.93), 3.620 (3.25), 3.631 (3.89), 3.641(2.48), 3.664 (2.81), 3.674 (2.40), 7.282 (0.18), 7.352 (4.12), 7.364 (6.45),7.394 (2.55), 7.408 (8.73), 7.414 (8.57), 7.421 (8.95), 7.433 (2.43), 7.559(5.83), 7.569 (4.84), 7.573 (4.73), 7.634 (5.43), 7.649 (15.94), 7.661(9.19), 7.664 (9.30), 7.679 (3.24), 8.756 (3.78), 8.765 (7.15), 8.775 (3.68),12.083 (13.49)。

Example 272

(-) -5- [ ({ 6-bromo-3-methyl-2- [ (S))² H ₁₀) Piperidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Valeric acid(enantiomer 2)

To (-) -5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]² H ₁₀) Piperidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Tert-butyl valerate (215 mg, 320 μmol,enantiomer 2Example 283A) in dichloromethane (2.5 ml) was added TFA (540 μ l, 7.03 mmol) and the mixture was left to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 166 mg (100% purity, 84% of theory) of the title compound are obtained.

[α]_D ²⁰= 17.5 °, 589 nm, c = 0.36 g/100 ml, methanol

LC-MS (method 1) R_t= 2.23 min; MS (ESIpos): m/z = 618/620 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 0.005 (0.31), 1.230 (0.24), 1.543(0.56), 1.615 (0.58), 1.786 (0.29), 1.799 (0.52), 1.811 (1.78), 1.819 (2.11),1.826 (1.75), 1.833 (2.88), 1.849 (2.02), 1.866 (0.46), 2.030 (0.51), 2.035(0.44), 2.047 (1.22), 2.056 (3.38), 2.075 (11.92), 2.078 (11.58), 2.082(10.29), 2.097 (3.39), 2.105 (2.47), 2.110 (2.68), 2.135 (4.84), 2.219(0.43), 2.387 (0.17), 2.615 (0.17), 3.089 (0.30), 3.392 (2.55), 3.402 (2.34),3.598 (0.88), 3.608 (1.48), 3.620 (2.50), 3.630 (2.95), 3.641 (1.87), 3.652(1.45), 3.663 (2.07), 3.674 (1.76), 7.351 (3.20), 7.361 (4.27), 7.364 (5.30),7.394 (2.04), 7.403 (5.07), 7.408 (6.93), 7.414 (7.35), 7.420 (7.47), 7.423(5.23), 7.433 (1.99), 7.558 (4.77), 7.569 (3.85), 7.573 (3.74), 7.634 (5.48),7.649 (16.00), 7.661 (8.72), 7.664 (8.01), 7.676 (2.81), 7.679 (2.85), 8.756(3.09), 8.765 (5.88), 8.775 (3.00), 12.090 (0.88)。

Example 273

(+) -5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]² H ₁₀) Piperidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- (2-chloro-3, 6-difluorophenyl) pentanoic acid(enantiomer 1)

To (+) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Tert-butyl amino } -4- (2-chloro-3, 6-difluorophenyl) pentanoate (241 mg, 400 μmol,enantiomer 1Example 48A) to a solution of NMP (1.6ml) was added piperidine-D11 (120 μ l,1.20 mmol) and the mixture was stirred at 110 ℃ for 20 h. After cooling to room temperature, water (100ml) was added to the mixture, which was extracted twice with ethyl acetate (80 ml each). The combined organic phases were dried over sodium sulfate, filtered and concentrated and the residue was purified by preparative HPLC (method 32). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. The title compound was obtained directly (without isolation of the corresponding tert-butyl ester). 32 mg (100% purity, 13% of theory) of the title compound are obtained.

[α]_D ²⁰= 37.3 °, 589 nm, c = 0.30 g/100 ml, methanol

LC-MS (method 1) R_t= 2.12 min; MS (ESIpos): m/z = 604/606 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: -0.022 (0.32), 0.070 (0.18), 1.095(0.19), 1.106 (0.18), 1.228 (1.01), 1.312 (0.88), 1.343 (0.85), 1.353 (0.90),1.377 (0.85), 1.402 (0.51), 1.539 (0.67), 1.612 (0.55), 1.950 (1.96), 2.069(4.94), 2.084 (5.40), 2.135 (16.00), 2.388 (0.38), 2.616 (0.42), 2.694(0.48), 3.084 (0.84), 3.394 (4.23), 3.714 (4.00), 7.293 (3.51), 7.299 (3.54),7.309 (2.55), 7.413 (3.39), 7.632 (6.05), 7.646 (14.75), 7.661 (9.57), 7.665(8.43), 7.676 (3.85), 7.679 (3.58), 8.842 (4.13)。

Example 274

(-) -5- [ ({ 6-bromo-3-methyl-2- [ (S))² H ₁₀) Piperidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- (2-chloro-3, 6-difluorophenyl) pentanoic acid(enantiomer 2)

To (-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl]Tert-butyl amino } -4- (2-chloro-3, 6-difluorophenyl) pentanoate (241 mg, 400 μmol,enantiomer 2Example 49A) to a solution of NMP (1.6ml) was added piperidine-D11 (120 μ l,1.20 mmol) and the mixture was stirred at 110 ℃ for 20 h. After cooling to room temperature, water (100ml) was added to the mixture, which was extracted twice with ethyl acetate (80 ml each). The combined organic phases were dried over sodium sulfate, filtered and concentrated and the residue was purified by preparative HPLC (method 32). The combined target fractions were concentrated and the residue was lyophilized from acetonitrile/water. The title compound was obtained directly (without isolation of the corresponding tert-butyl ester). 42 mg (100% purity, 17% of theory) of the title compound are obtained.

[α]_D ²⁰= 29.2 °, 589 nm, c = 0.33 g/100 ml, methanol

LC-MS (method 1) R_t= 2.12 min; MS (ESIpos): m/z = 604/606 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: -0.022 (0.18), 0.072 (0.21), 1.228(1.00), 1.343 (0.66), 1.354 (0.71), 1.361 (0.75), 1.402 (0.20), 1.540 (0.68),1.613 (0.55), 1.954 (1.87), 2.071 (4.75), 2.088 (5.11), 2.135 (16.00), 2.388(0.30), 2.616 (0.35), 2.695 (0.50), 3.085 (0.78), 3.394 (3.81), 7.294 (3.41),7.300 (3.44), 7.310 (2.45), 7.413 (3.29), 7.632 (6.00), 7.647 (14.77), 7.662(9.74), 7.665 (8.27), 7.677 (3.79), 7.680 (3.41), 8.842 (4.09)。

Example 275

(+) -5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]² H ₈) Pyridine (II)Pyrrolidin-1-yl group]Quinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(enantiomer 1)

To (+) -5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]² H ₈) Pyrrolidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]Tert-butyl 4- (2-chlorophenyl) valerate (232 mg, 380. mu. mol,enantiomer 1Example 284A) in dichloromethane (2.9 ml) was added TFA (645 μ l, 8.37 mmol) and the mixture was left at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 170 mg (100% purity, 81% of theory) of the title compound are obtained.

[α]_D ²⁰= 12.8 °, 589 nm, c = 0.38 g/100 ml, methanol

LC-MS (method 1) R_t= 1.42 min; MS (ESIpos): m/z = 552/554 [M+H]⁺

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.232 (0.37), 1.792 (0.70), 1.800(1.02), 1.818 (2.38), 1.835 (2.71), 1.853 (1.37), 2.022 (0.70), 2.032 (1.39),2.041 (1.72), 2.049 (5.62), 2.070 (4.67), 2.072 (4.71), 2.076 (5.09), 2.093(4.12), 2.117 (2.81), 2.134 (4.96), 2.155 (9.05), 2.237 (0.36), 2.284 (0.43),2.362 (0.18), 2.636 (0.18), 3.587 (2.38), 3.654 (2.45), 7.254 (2.02), 7.269(4.23), 7.283 (2.85), 7.355 (2.96), 7.370 (5.05), 7.384 (2.96), 7.436 (8.59),7.439 (8.21), 7.452 (7.33), 7.455 (6.80), 7.468 (10.62), 7.475 (6.17), 7.477(6.21), 7.486 (16.00), 7.490 (5.16), 7.543 (7.85), 7.548 (7.12), 7.561(4.96), 7.566 (4.68), 8.663 (2.87), 8.674 (5.45), 8.686 (2.67)。

Example 276

(-) -5- [ ({ 6-bromo-3-methyl-2- [ (S))² H ₈) Pyrrolidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- (2-chlorophenyl) pentanoic acid(enantiomer 2)

To (-) -5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]² H ₈) Pyrrolidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]Tert-butyl 4- (2-chlorophenyl) valerate (236 mg, 388. mu. mol,enantiomer 2Example 285A) in dichloromethane (3.0 ml) TFA (657 μ l, 8.53 mmol) was added and the mixture was left to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 177 mg (100% purity, 83% of theory) of the title compound are obtained.

[α]_D ²⁰= 11.5 °, 589 nm, c = 0.48 g/100 ml, methanol

LC-MS (method 1) R_t= 1.43 min; MS (ESIpos): m/z = 552/554 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.800 (1.03), 1.815 (2.52), 1.829(2.74), 1.845 (1.38), 2.027 (0.69), 2.035 (1.39), 2.051 (6.12), 2.069 (5.24),2.088 (2.40), 2.099 (2.00), 2.117 (3.32), 2.132 (5.50), 2.148 (5.66), 2.238(0.37), 2.283 (0.33), 3.585 (2.21), 3.651 (2.02), 7.258 (1.88), 7.270 (3.56),7.282 (2.45), 7.360 (2.37), 7.372 (3.84), 7.384 (2.29), 7.441 (8.20), 7.455(7.11), 7.469 (8.21), 7.484 (16.00), 7.495 (4.67), 7.548 (5.71), 7.551(5.48), 7.562 (4.01), 7.565 (3.91), 8.686 (3.02), 8.695 (5.74), 8.704 (2.88),12.077 (1.33)。

Example 277

(-) -5- [ ({ 6-bromo-3-methyl-2- [ (S))² H ₈) Pyrrolidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Valeric acid(enantiomer 1)

To (-) -5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]² H ₈) Pyrrolidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Tert-butyl valerate (200 mg, 311 μmol,enantiomer 1Dichloromethane (2) from example 286A)4 ml) was added TFA (528 μ l, 6.85 mmol) and the mixture was left to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 151 mg (100% purity, 83% of theory) of the title compound are obtained.

[α]_D ²⁰= 18.0 °, 589 nm, c = 0.30 g/100 ml, methanol

LC-MS (method 1) R_t= 1.51 min; MS (ESIpos): m/z = 586/588 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.829 (0.40), 1.874 (0.82), 1.883(1.18), 1.890 (1.90), 1.898 (2.80), 1.905 (2.37), 1.913 (2.80), 1.920 (2.63),1.937 (1.64), 1.946 (2.11), 1.955 (1.34), 1.962 (2.15), 1.972 (3.71), 1.981(2.35), 1.989 (3.43), 1.997 (2.66), 2.049 (2.83), 2.059 (3.89), 2.075 (4.72),2.086 (2.77), 2.102 (3.03), 2.113 (2.77), 2.121 (3.45), 2.135 (4.67), 2.145(4.69), 2.159 (4.40), 2.169 (3.85), 2.178 (3.42), 2.278 (0.75), 2.387 (0.30),2.615 (0.24), 3.598 (2.01), 3.722 (2.08), 7.247 (0.41), 7.394 (0.44), 7.467(3.00), 7.480 (14.90), 7.495 (16.00), 7.555 (7.51), 7.558 (7.44), 7.570(5.29), 7.573 (5.31), 7.696 (2.72), 7.709 (6.63), 7.722 (12.22), 7.736(13.62), 7.751 (4.23), 8.737 (3.79), 8.746 (7.33), 8.756 (3.77), 12.063(3.78)。

Example 278

(+) -5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]² H ₈) Pyrrolidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Valeric acid(enantiomer 2)

To (+) -5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]² H ₈) Pyrrolidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Tert-butyl valerate (184 mg, 287 μmol,enantiomer 2Example 287A) in dichloromethane (2.2 ml) TFA (486 μ l, 6.32 mmol) was added and the mixture was left to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. Passing the residue throughPreparative HPLC purification (method 11). The combined target fractions were concentrated and the residue was lyophilized. 139 mg (100% purity, 82% of theory) of the title compound are obtained.

[α]_D ²⁰= 19.2 °, 589 nm, c = 0.30 g/100 ml, methanol

LC-MS (method 1) R_t= 1.47 min; MS (ESIpos): m/z = 586/588 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 0.005 (0.36), 1.232 (0.17), 1.830(0.45), 1.876 (0.97), 1.884 (1.37), 1.891 (2.25), 1.899 (3.28), 1.907 (2.78),1.914 (3.26), 1.922 (3.14), 1.938 (1.95), 1.948 (2.59), 1.957 (1.61), 1.964(2.69), 1.975 (4.42), 1.983 (2.89), 1.991 (4.33), 1.999 (3.30), 2.050 (3.56),2.061 (4.90), 2.066 (3.43), 2.077 (6.09), 2.088 (3.47), 2.104 (3.78), 2.114(3.37), 2.122 (4.01), 2.136 (5.33), 2.147 (5.35), 2.152 (5.03), 2.161 (5.04),2.170 (4.40), 2.180 (3.85), 2.281 (0.77), 2.387 (0.31), 2.616 (0.25), 3.325(4.10), 3.601 (2.25), 3.724 (2.31), 7.118 (0.19), 7.247 (0.51), 7.396 (0.52),7.467 (3.62), 7.483 (11.19), 7.498 (11.31), 7.557 (7.64), 7.561 (7.43), 7.572(5.45), 7.575 (5.28), 7.696 (3.26), 7.709 (7.80), 7.722 (14.33), 7.737(16.00), 7.751 (4.94), 8.739 (4.26), 8.748 (8.09), 8.758 (4.19), 12.062(8.04)。

Example 279

(+) -5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]² H ₈) Pyrrolidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl ]Valeric acid(enantiomer 1)

To (+) -5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]² H ₈) Pyrrolidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Tert-butyl valerate (221 mg, 335 μmol,enantiomer 1Example 288A) was added TFA (569 μ l, 7.38 mmol) to a dichloromethane (2.6 ml) solution and the mixture was left to stand at room temperature for 24 h. Then concentrating and mixingDichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 173 mg (100% purity, 86% of theory) of the title compound are obtained.

[α]_D ²⁰= 17.6 °, 589 nm, c = 0.44 g/100 ml, methanol

LC-MS (method 1) R_t= 1.52 min; MS (ESIpos): m/z = 602/604 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 0.005 (0.45), 1.232 (0.18), 1.371(0.16), 1.785 (0.41), 1.797 (0.70), 1.809 (2.46), 1.817 (2.57), 1.824 (2.21),1.832 (4.22), 1.847 (2.31), 1.863 (0.70), 2.025 (0.79), 2.043 (1.94), 2.052(4.74), 2.057 (2.57), 2.062 (4.02), 2.070 (16.00), 2.077 (11.82), 2.080(12.48), 2.095 (4.14), 2.099 (3.35), 2.110 (3.35), 2.128 (2.33), 2.154(2.44), 2.299 (0.39), 2.387 (0.29), 2.521 (0.34), 2.615 (0.27), 3.388 (2.82),3.539 (0.29), 3.576 (1.26), 3.586 (1.99), 3.597 (2.89), 3.608 (3.17), 3.618(1.85), 3.665 (2.28), 3.675 (2.12), 7.279 (0.39), 7.342 (3.44), 7.345 (4.50),7.355 (5.69), 7.357 (7.09), 7.360 (5.29), 7.389 (2.33), 7.404 (6.74), 7.409(7.73), 7.417 (7.25), 7.429 (2.39), 7.478 (5.56), 7.492 (7.70), 7.555(10.48), 7.566 (6.58), 7.570 (8.36), 8.707 (3.14), 8.716 (5.60), 8.726(3.03), 12.080 (6.24)。

Example 280

(-) -5- [ ({ 6-bromo-3-methyl-2- [ (S))² H ₈) Pyrrolidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethyl) phenyl]Valeric acid(enantiomer 2)

To (-) -5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]² H ₈) Pyrrolidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- [2- (trifluoromethoxy) phenyl]Tert-butyl valerate (188 mg, 286 μmol,enantiomer 2Example 289A) in dichloromethane (2.2 ml) TFA (484 μ l, 6.28 mmol) was added and the mixture was left to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC(method 11). The combined target fractions were concentrated and the residue was lyophilized. 140 mg (100% purity, 81% of theory) of the title compound are obtained.

[α]_D ²⁰= 14.4 °, 589 nm, c = 0.36 g/100 ml, methanol

LC-MS (method 1) R_t= 1.57 min; MS (ESIpos): m/z = 602/604 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.786 (0.41), 1.799 (0.79), 1.811(2.56), 1.819 (2.97), 1.833 (4.47), 1.848 (2.43), 1.865 (0.72), 2.026 (0.76),2.044 (1.92), 2.053 (4.55), 2.071 (16.00), 2.081 (13.66), 2.096 (4.73), 2.111(3.63), 2.130 (2.70), 2.156 (2.87), 2.298 (0.47), 2.386 (0.22), 2.614 (0.20),3.391 (3.10), 3.539 (0.31), 3.577 (1.37), 3.587 (2.26), 3.598 (3.23), 3.609(3.59), 3.619 (2.09), 3.666 (2.65), 3.676 (2.45), 7.278 (0.44), 7.345 (4.72),7.357 (7.31), 7.389 (2.62), 7.405 (7.34), 7.409 (8.25), 7.417 (7.84), 7.429(2.59), 7.477 (8.39), 7.492 (11.72), 7.556 (12.90), 7.570 (9.71), 8.707(3.63), 8.717 (6.58), 8.726 (3.55), 12.080 (13.05)。

Example 281

(+) -5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]² H ₈) Pyrrolidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- (2-chloro-3, 6-difluorophenyl) pentanoic acid(enantiomer 1)

The method A comprises the following steps:

to 5- [ ({ 6-bromo-3-methyl-2- [ ((6-bromo-3-) ]² H ₈) Pyrrolidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-tert-butyl 4- (2-chloro-3, 6-difluorophenyl) pentanoate (38 mg, 59 μmol,enantiomer 1Example 290A) was added to a dichloromethane (1.0ml) solution of TFA (100 μ l, 1.30 mmol), and the mixture was allowed to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilizedA compound (I) is provided. 9 mg (100% purity, 25% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 1.43 min; MS (ESIpos): m/z = 588/560 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: -0.022 (0.55), 1.232 (1.37), 1.825(0.38), 1.966 (2.96), 2.072 (4.00), 2.079 (4.99), 2.092 (5.37), 2.105 (8.11),2.128 (11.23), 2.139 (14.79), 2.151 (15.29), 2.160 (16.00), 2.171 (11.89),2.341 (0.60), 2.387 (0.49), 2.616 (0.55), 3.440 (0.93), 3.536 (0.44), 3.708(6.36), 7.301 (5.26), 7.415 (4.77), 7.478 (9.92), 7.493 (13.42), 7.560(10.14), 7.562 (9.70), 7.574 (7.34), 7.577 (7.07), 7.649 (0.55), 8.792(7.56), 12.132 (4.16)。

The method B comprises the following steps:

starting from (+) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid tert-butyl ester (241 mg, 400 μmol, example 48A) the title compound was obtained directly as fraction 1 (without isolation of the corresponding tert-butyl ester) (34 mg, 100% purity, 14% of theory) as described in example 290A.

[α]_D ²⁰= 41.9 °, 589 nm, c = 0.32 g/100 ml, methanol

LC-MS (method 1) R_t= 1.43 min; MS (ESIpos): m/z = 588/560 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 0.071 (0.24), 1.085 (0.75), 1.232(0.38), 1.357 (0.72), 1.368 (0.31), 1.825 (0.35), 1.956 (1.60), 2.081 (4.26),2.098 (4.30), 2.157 (7.33), 2.338 (0.36), 2.387 (0.36), 2.615 (0.42), 3.703(3.89), 7.297 (3.26), 7.410 (2.92), 7.473 (11.97), 7.488 (16.00), 7.555(7.89), 7.559 (7.36), 7.570 (5.57), 7.573 (5.29), 8.792 (4.04)。

Example 282

(-) -5- [ ({ 6-bromo-3-methyl-2- [ (S))² H ₈) Pyrrolidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-4- (2-chloro-3, 6-difluorophenyl) pentanoic acid(enantiomer 2)

The method A comprises the following steps:

to 5- [, ({ 6-bromo-3-methyl-2- [ ((S))² H ₈) Pyrrolidin-1-yl radical]Quinolin-4-yl } carbonyl) amino]-tert-butyl 4- (2-chloro-3, 6-difluorophenyl) pentanoate (20 mg, 31 μmol,enantiomer 2Example 291A) in dichloromethane (1.0ml) was added TFA (52 μ l, 682 μmol), and the mixture was left to stand at room temperature for 24 h. The mixture was then concentrated, dichloromethane was repeatedly added and the mixture was concentrated again. The residue was purified by preparative HPLC (method 11). The combined target fractions were concentrated and the residue was lyophilized. 7 mg (100% purity, 40% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 1.43 min; MS (ESIpos): m/z = 588/590 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: -0.023 (0.78), 0.841 (0.28), 0.853(0.58), 0.864 (0.25), 1.232 (2.98), 1.824 (0.24), 1.965 (1.80), 2.078 (2.77),2.090 (3.00), 2.104 (4.61), 2.126 (5.66), 2.136 (7.73), 2.149 (8.42), 2.158(9.21), 2.338 (0.40), 2.387 (0.34), 2.426 (0.43), 2.478 (0.57), 2.615 (0.40),2.655 (0.45), 3.507 (0.69), 3.709 (3.84), 6.739 (0.25), 7.302 (3.16), 7.410(2.83), 7.474 (11.76), 7.489 (16.00), 7.556 (7.66), 7.560 (7.21), 7.571(5.50), 7.575 (5.26), 8.791 (4.57), 12.136 (0.40)。

The method B comprises the following steps:

starting from (-) -5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl ] amino } -4- (2-chloro-3, 6-difluorophenyl) pentanoic acid tert-butyl ester (241 mg, 400 μmol, example 49A) as described in example 291A, the title compound was obtained directly (without isolation of the corresponding tert-butyl ester) as fraction 1 (55 mg, 100% purity, 23% of theory).

[α]_D ²⁰= 35.2 °, 589 nm, c = 0.34 g/100 ml, methanol

LC-MS (method 1) R_t= 1.40 min; MS (ESIpos): m/z = 588/590 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 0.071 (0.17), 1.231 (0.19), 1.357(0.26), 1.825 (0.27), 1.964 (1.63), 2.076 (2.62), 2.099 (4.96), 2.118 (4.75),2.130 (5.92), 2.153 (8.09), 2.339 (0.43), 2.387 (0.35), 2.615 (0.33), 3.708(3.65), 7.300 (3.01), 7.414 (2.67), 7.474 (11.71), 7.489 (16.00), 7.556(7.50), 7.560 (7.17), 7.571 (5.41), 7.574 (5.25), 8.790 (4.30)。

Example 283

(-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid hydrochloride(enantiomer 1)

To prepare the experiment, three different batches of (-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid (C:)Enantiomer 11.386 g in total, 2.54 mmol, example 34) were each dissolved in a few ml of methanol, the solutions were combined and the major part of the methanol was removed again on a rotary evaporator. The residue was then dissolved in dioxane (14 ml) and a 4M solution of hydrogen chloride in dioxane (3.2 ml, 12.72mmol) was added dropwise at room temperature. The mixture was allowed to stand at room temperature for 1 h. After this time, the solid formed is filtered off and dried in vacuo. Since the methyl ester corresponding to the title compound has also formed according to LC-MS due to the methanol used for the preparation of the experiment, the residue is first purified by preparative HPLC (method 32). The combined target fractions were concentrated and the residue was dried in vacuo. The residue (960mg) was then dissolved in dioxane (10 ml) and a 4M solution of hydrogen chloride in dioxane (3.2 ml, 12.72mmol) was added slowly at room temperature and the mixture was left to stand at room temperature for 2 h. The solid formed was then filtered off and the residue was lyophilized from acetonitrile/water. 603 mg (100% purity, 41% of theory) of the title compound are obtained.

[α]_D ²⁰= 17.0 °, 589 nm, c = 0.42 g/100 ml, methanol

LC-MS (method 1) R_t= 1.42 min; MS (ESIpos): m/z = 544/546 [M+H]⁺

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 0.006 (0.51), 1.699 (0.22), 1.797(0.88), 1.808 (1.38), 1.825 (2.64), 1.842 (2.97), 1.859 (1.76), 1.875 (0.81),1.971 (16.00), 2.016 (1.20), 2.054 (6.83), 2.075 (5.25), 2.084 (4.69), 2.092(3.14), 2.099 (3.96), 2.123 (3.41), 2.136 (3.36), 2.155 (1.81), 2.167 (1.04),2.258 (3.04), 2.457 (0.43), 2.637 (0.27), 3.391 (1.40), 3.567 (9.59), 3.589(5.02), 3.883 (6.69), 7.192 (0.27), 7.278 (3.55), 7.293 (2.99), 7.374 (3.48),7.429 (0.87), 7.443 (9.54), 7.445 (8.90), 7.459 (7.85), 7.462 (7.11), 7.492(5.89), 7.507 (4.80), 7.804 (2.56), 7.821 (2.63), 8.192 (0.78), 8.921 (3.10)。

Example 284

(+) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid hydrochloride(enantiomer 2)

The method A comprises the following steps:

to (+) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl under argon at room temperature]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid (200 mg, 367 μmol,enantiomer 2Example 35) was slowly added dropwise to a 4M solution of hydrogen chloride in dioxane (2ml) and the mixture was stirred at room temperature for 16 h. The solid formed is then filtered off and dried in vacuo. 195 mg (100% purity, 89% of theory) of the title compound are obtained.

Ion chromatography (method 34) mass ratio of chloride ions: 9.9 wt% (1.7 eq)

LC-MS (method 1) R_t= 1.49 min; MS (ESIpos): m/z = 544/546 [M+H]⁺

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.061 (0.36), -0.007 (1.38), 0.007(0.75), 1.085 (0.25), 1.368 (1.02), 1.799 (0.66), 1.809 (1.07), 1.827 (2.10),1.843 (2.36), 1.861 (1.33), 1.877 (0.54), 1.911 (0.37), 1.989 (13.81), 2.055(5.55), 2.076 (4.32), 2.085 (3.94), 2.093 (2.67), 2.099 (2.82), 2.123 (2.59),2.136 (2.33), 2.155 (1.09), 2.167 (0.49), 2.256 (2.66), 2.347 (2.35), 2.479(0.87), 2.639 (0.16), 3.567 (16.00), 3.586 (1.74), 3.950 (5.56), 5.329(0.39), 7.281 (2.32), 7.373 (2.16), 7.444 (8.14), 7.447 (7.62), 7.460 (6.83),7.463 (6.17), 7.495 (3.99), 7.510 (3.54), 7.850 (3.33), 7.868 (3.51), 8.371(2.22), 8.387 (2.08), 8.972 (2.46), 8.984 (4.49), 8.995 (2.33)。

A portion of the title compound was then lyophilized from acetonitrile/water and analyzed again:

ion chromatography (method 34) mass ratio of chloride ions: 4.6 wt% (0.8 eq)

LC-MS (method 1) R_t= 1.47 min; MS (ESIpos): m/z = 544/546 [M+H]⁺

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.061 (0.46), -0.007 (0.68), 0.007(0.49), 1.086 (0.47), 1.143 (0.19), 1.368 (1.75), 1.795 (0.91), 1.806 (1.50),1.824 (2.91), 1.840 (3.33), 1.858 (1.93), 1.874 (0.82), 1.962 (16.00), 2.015(1.18), 2.053 (7.92), 2.074 (5.96), 2.082 (5.25), 2.091 (3.40), 2.098 (4.54),2.118 (3.35), 2.123 (3.80), 2.135 (3.95), 2.153 (2.00), 2.165 (1.04), 2.248(3.53), 2.363 (0.78), 2.637 (0.43), 3.679 (5.00), 3.839 (5.70), 7.277 (4.13),7.292 (3.05), 7.361 (2.86), 7.375 (4.27), 7.389 (2.53), 7.442 (11.82), 7.445(10.93), 7.458 (9.93), 7.461 (8.79), 7.491 (6.84), 7.506 (5.46), 7.786(2.10), 8.063 (0.54), 8.875 (2.69)。

The method B comprises the following steps:

to (+) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl at room temperature]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid (3.31 g, 6.08 mmol,enantiomer 2Example 35) was slowly added dropwise to a solution of 4M hydrogen chloride in dioxane (33 ml), and the mixture was allowed to stand at room temperature for 4 h. The solid formed was then filtered off, dissolved in water/acetonitrile and lyophilized to obtain the first lyophilizate. The filtrate was left at room temperature overnight and the overnight formed precipitate was filtered off. The obtained precipitate was combined with the above lyophilizate, and the mixture was dissolved in water/acetonitrile and lyophilized to obtain a second lyophilizate. 3.21 g (100% purity, 91% of theory, ee value 99%) of the title compound are obtained.

Ion chromatography (method 34) mass ratio of chloride ions: 4.8 wt% (0.9 eq)

LC-MS (method 1) R_t= 1.47 min; MS (ESIpos): m/z = 544/546 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 0.005 (0.73), 1.799 (0.90), 1.808(1.47), 1.823 (3.13), 1.837 (3.31), 1.851 (1.89), 1.865 (0.77), 1.974(16.00), 2.021 (1.18), 2.045 (3.16), 2.056 (7.95), 2.074 (5.59), 2.081(4.92), 2.088 (2.71), 2.097 (3.16), 2.119 (3.61), 2.133 (3.29), 2.148 (1.72),2.159 (0.86), 2.235 (3.75), 2.335 (3.01), 3.389 (0.71), 3.567 (3.96), 3.589(3.99), 3.897 (5.37), 7.286 (3.18), 7.376 (2.64), 7.448 (10.89), 7.449(10.57), 7.461 (9.38), 7.463 (8.90), 7.500 (5.06), 7.512 (4.82), 7.824(2.61), 7.834 (2.66), 8.266 (0.69), 8.970 (3.38)。

The method C comprises the following steps:

to (+) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl at room temperature]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid tert-butyl ester (6.50 g, 10.82 mmol,enantiomer 1Example 292A) in dioxane (70ml) was slowly added dropwise a 4M solution of hydrogen chloride in dioxane (100 ml, 400 mmol) and the mixture was stirred at room temperature for 6 h. A further 4M hydrogen chloride in dioxane (40 ml, 40 mmol) was added dropwise and the mixture was stirred at room temperature for a further 16 h. Since 1-2% of the reaction was still present according to HPLC, the mixture was sonicated for 1 h. Diisopropyl ether (300 ml) was then added slowly to the mixture, the solid present was filtered off and washed successively with three portions of diisopropyl ether (50 ml each) and then dried under vacuum at 60 ℃. 6.18 g (100% purity, 89% of theory) of the title compound are obtained.

LC-MS (method 1) R_t= 1.42 min; MS (ESIpos): m/z = 544/546 [M+H]⁺

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.007 (1.43), 0.007 (0.81), 1.030(1.11), 1.042 (1.11), 1.086 (0.20), 1.368 (1.75), 1.595 (0.60), 1.797 (0.87),1.808 (1.42), 1.825 (2.76), 1.842 (3.11), 1.859 (1.78), 1.877 (0.74), 1.971(16.00), 2.016 (1.24), 2.047 (3.15), 2.055 (7.39), 2.076 (5.65), 2.084(5.03), 2.093 (3.33), 2.099 (4.13), 2.120 (3.19), 2.124 (3.52), 2.136 (3.47),2.155 (1.73), 2.167 (0.87), 2.251 (3.11), 2.457 (0.39), 2.637 (0.21), 3.567(3.96), 3.589 (2.60), 3.682 (3.45), 7.278 (3.61), 7.291 (2.86), 7.375 (3.60),7.443 (10.86), 7.446 (9.79), 7.459 (9.09), 7.462 (7.90), 7.493 (6.15), 7.508(5.00), 7.821 (2.31), 8.219 (0.58), 8.924 (2.84)。

Example 285

(-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid sodium salt(enantiomer 1)

To (-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl at room temperature]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid (125 mg, 229 mol,enantiomer 1Example 34) to a suspension in water (10 ml) 1M aqueous sodium hydroxide solution (229 μ l, 229 μmol) was added. The mixture was sonicated and mixed with THF (2ml) whereupon a solution was formed. After stirring at room temperature for 1 hour, the mixture was concentrated and the residue was lyophilized from acetonitrile/water. 110 mg (98% purity, 83% of theory) of the title compound are obtained.

Ion chromatography (method 34) mass ratio of sodium: 3.5 wt% (0.9 eq)

[α]_D ²⁰= 10.6 °, 589 nm, c = 0.36 g/100 ml, methanol

LC-MS (method 1) R_t= 1.45 min; MS (ESIpos): m/z = 544/546 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.355 (2.06), 1.695 (1.15), 1.707(2.06), 1.729 (4.57), 1.738(3.79), 1.753 (5.65), 1.768 (3.60), 1.782 (2.15),1.807 (3.30), 1.833 (4.04), 1.872 (16.00), 1.916 (2.99), 1.933 (3.03), 2.178(13.86), 2.256 (0.54), 2.267 (0.63), 2.710 (0.42), 3.465 (2.14), 3.480(3.21), 3.497 (2.73), 3.514 (1.48), 3.572 (12.27), 3.618 (3.97), 7.215(2.22), 7.233 (5.04), 7.251 (3.56), 7.325 (2.98), 7.343 (5.56), 7.361 (3.60),7.407 (8.57), 7.426 (8.75), 7.438 (4.80), 7.462 (6.70), 7.484 (11.36), 7.536(6.50), 7.541 (5.90), 7.558 (3.81), 7.564 (3.51), 9.051 (2.89)。

Example 286

(+) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid sodium salt(enantiomer 2)

To (+) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl at room temperature]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid (125 mg, 229. mu. mol,enantiomer 2Example 35) to a suspension in water (10 ml) 1M aqueous sodium hydroxide solution (229 μ l, 229 μmol) was added. The mixture was sonicated and mixed with THF (2ml) whereupon a solution was formed. After stirring at room temperature for 1 hour, the mixture was concentrated and the residue was lyophilized from acetonitrile/water. 129 mg (100% purity, 99% of theory, ee value) are obtained>99%) of the title compound.

Ion chromatography (method 34) mass ratio of sodium: 4.7 wt% (1.2 eq)

[α]_D ²⁰= 11.4 °, 589 nm, c = 0.31 g/100 ml, methanol

LC-MS (method 1) R_t= 1.41 min; MS (ESIpos): m/z = 544/546 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.354 (3.55), 1.366 (1.65), 1.701(1.24), 1.710 (2.34), 1.731 (5.80), 1.743 (5.24), 1.748 (5.40), 1.758 (4.03),1.770 (2.04), 1.823 (4.25), 1.832 (3.64), 1.841 (6.72), 1.867 (15.69), 1.907(3.02), 1.925 (3.71), 1.940 (2.01), 2.163 (6.98), 2.245 (0.69), 2.268 (0.64),3.489 (4.06), 3.567 (10.12), 3.600 (5.64), 3.611 (4.58), 7.223 (2.64), 7.236(5.49), 7.248 (3.68), 7.332 (3.31), 7.345 (5.80), 7.357 (3.71), 7.413(10.88), 7.426 (16.00), 7.439 (6.16), 7.466 (11.09), 7.481 (15.50), 7.542(7.81), 7.545 (7.58), 7.556 (5.65), 7.560 (5.53), 8.942 (3.81), 8.952 (7.12),8.961 (3.87)。

Example 287

(-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid potassium salt(enantiomer 1)

To (-) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl at room temperature]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid (125 mg, 229. mu. mol,enantiomer 1Example 34) to a suspension in water (10 ml) a 1M potassium tert-butoxide solution (229 μ l, 229 μmol) was added. The mixture was sonicated and mixed with THF (2ml) whereupon a solution was formed. After stirring at room temperature for 1 hour, the mixture was concentrated and the residue was lyophilized from acetonitrile/water. 110 mg (98% purity, 81% of theory) of the title compound are obtained.

Ion chromatography (method 34) mass ratio of potassium: 6.9 wt% (1.0 eq)

[α]_D ²⁰= 11.1 °, 589 nm, c = 0.50 g/100 ml, methanol

LC-MS (method 1) R_t= 1.45 min; MS (ESIpos): m/z = 544/546 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.299 (0.67), 1.612 (0.45), 1.694(2.98), 1.717 (3.05), 1.730 (2.65), 1.758 (2.16), 1.782 (2.10), 1.794 (1.32),1.863 (12.88), 1.947 (0.70), 2.184 (16.00), 2.227 (1.36), 2.237 (1.34), 2.709(0.40), 3.552 (11.72), 3.597 (2.67), 3.617 (2.06), 3.650 (0.84), 7.054(0.49), 7.137 (0.50), 7.181 (2.23), 7.200 (1.66), 7.223 (0.61), 7.289 (1.71),7.307 (3.07), 7.325 (1.86), 7.361 (2.90), 7.381 (2.64), 7.403 (4.69), 7.420(5.12), 7.442 (3.90), 7.482 (2.93), 7.503 (2.19)。

Example 288

(+) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid potassium salt(enantiomer 2)

To (+) -5- ({ [ 6-bromo-3-methyl-2- (pyrrolidin-1-yl) quinolin-4-yl at room temperature]Carbonyl } amino) -4- (2-chlorophenyl) pentanoic acid (125 mg, 229. mu. mol,enantiomer 2Example 35) to a suspension in water (10 ml) a 1M solution of potassium tert-butoxide in THF (229 μ l, 229 μmol) was added. The mixture was sonicated and mixed with THF (2ml) whereupon a solution was formed. After stirring at room temperature for 1 hour, concentrateThe mixture was mixed and the residue was lyophilized from acetonitrile/water. 137 mg (100% purity, "102%" theoretically, ee value) were obtained>99%) of the title compound.

Ion chromatography (method 34) mass ratio of potassium: 5.8 wt% (0.9 eq)

[α]_D ²⁰= 11.3 °, 589 nm, c = 0.31 g/100 ml, methanol

LC-MS (method 1) R_t= 1.41 min; MS (ESIpos): m/z = 544/546 [M+H]⁺

¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.109 (1.62), 1.354 (3.30), 1.366(1.60), 1.683 (1.38), 1.692 (2.50), 1.707 (5.61), 1.712 (5.58), 1.724 (5.74),1.733 (3.59), 1.748 (1.84), 1.758 (1.21), 1.764 (1.24), 1.781 (4.21), 1.790(2.78), 1.798 (5.09), 1.808 (3.45), 1.825 (2.13), 1.870 (13.58), 1.916(2.38), 2.182 (8.32), 2.263 (0.72), 3.438 (2.92), 3.450 (4.06), 3.461 (4.99),3.472 (4.00), 3.574 (10.43), 7.221 (2.77), 7.233 (5.99), 7.246 (3.94), 7.330(3.46), 7.342 (6.22), 7.354 (3.92), 7.410 (12.30), 7.417 (8.36), 7.423(11.97), 7.469 (11.20), 7.483 (16.00), 7.543 (7.97), 7.546 (7.69), 7.557(5.73), 7.561 (5.54), 9.146 (3.89), 9.155 (7.29), 9.164 (3.93)。

Example 289

(+) -5- ({ [ 6-bromo-2- (3, 3-difluoropiperidin-1-yl) -3-methylquinolin-4-yl]Carbonyl } amino) -4- (2-methoxyphenyl) pentanoic acid(enantiomer 1)

5- { [ (6-bromo-2-chloro-3-methylquinolin-4-yl) carbonyl in NMP (1.0ml)]Amino } -4- (2-methoxyphenyl) pentanoic acid (A)Enantiomer 1200 mg, 85% purity, 336 μmol, example 241A), 3-difluoropiperidine hydrochloride (312 mg, 1.98 mmol) and DIPEA (830 μ l, 4.7 mmol) were stirred at 120 ℃ for 4 days. After cooling to room temperature, the reaction mixture was added to 1M hydrochloric acid and extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated. The crude product was previously purified by column chromatography (Isolera, KP-Sil)Eluent dichloromethane/methanol, gradient 0-40% methanol) and repurification by preparative HPLC (method 27). 54 mg (99% purity, 27% of theory) are obtained.

[α]_D ²⁰= 6.7 °, 589 nm, c = 0.50 g/100 ml, chloroform

LC-MS (method 26) R_t= 0.80 min; MS (ESIpos): m/z = 590/592 [M+H]⁺

H-NMR (400 MHz, chloroform-d) delta [ ppm ]: 1.262 (0.43), 1.953 (1.11), 1.965(0.97), 1.981 (0.52), 2.025 (0.71), 2.038 (0.82), 2.057 (1.02), 2.072 (1.08),2.087 (0.84), 2.108 (0.48), 2.116 (0.44), 2.136 (0.57), 2.149 (0.66), 2.170(0.63), 2.191 (1.16), 2.213 (7.96), 2.287 (0.88), 2.301 (1.65), 2.307 (1.08),2.321 (1.76), 2.340 (0.84), 2.348 (0.58), 3.147 (1.27), 4 (1.19), 3.445(0.50), 3.459 (2.36), 3642 (1.42), 3643.7 (3.35), 3643 (0.7.35), 3643), 3.942(0.56), 3.957 (0.88), 3.971 (0.57), 3.989 (0.59), 5.786 (0.50), 5.800 (1.00),5.814 (0.52), 6.853 (1.55), 6.873 (1.58), 6.965 (0.71), 6.967 (0.71), 6.983(1.56), 6.985 (1.54), 7.001 (0.96), 7.216 (1.85), 7.220 (1.39), 7.224 (0.68),7.235 (1.67), 7.238 (1.56), 7.259 (0.89), 7.263 (0.94), 7.602 (0.82), 7.607(0.89), 7.624 (1.77), 7.630 (2.19), 7.649 (0.42), 7.659 (3.62), 7.671 (2.06),7.676 (1.81), 7.680 (1.92).

B. Pharmacological efficacy assessment

The pharmacological activity of the compounds of the invention may be demonstrated by in vitro and in vivo studies, as is known to those skilled in the art. The following application examples describe the biological effects of the compounds of the present invention, but the present invention is not limited to these examples.

Abbreviations and acronyms:

chemoattractant receptor homologous molecule expressed on T helper type 2 cells by CRTH2

DMEM Dulbecco's modified Eagle Medium

DMSO dimethyl sulfoxide

DP PGD2 receptor

EC₅₀Half maximal effective concentration

em. emission

EP PGE2 receptor

Ex excitation

Fa. Co (Source)

FCS fetal calf serum

FP PGF2 alpha receptor

HEPES 2- [4- (2-hydroxyethyl) piperazin-1-yl ] ethanesulfonic acid

IC₅₀Half maximal inhibitory concentration

IP PGI2 receptor

lite, documentation (reference)

MES 2-(N-morpholino) ethanesulfonic acid

Pen/Strep penicillin/streptomycin

PGD2 prostaglandin D2

PGE2 prostaglandin E2

PGF2 alpha prostaglandin F2 alpha

PGI2 prostaglandin I2

TC tissue culture

TP thromboxane A2 receptor

Tris Tris (hydroxymethyl) aminomethane

volume ratio v/v (of solution)

w/w (of solution) weight ratio.

B-1 in vitro assay for inhibition of human FP receptor Activity

To characterize the test substances for FP antagonism, PGF2 α -induced calcium flux in CHEM1 cells expressing FP (Millipore, HTS093C) was used.

Mu.l of complete medium [ DMEM F12, 10% FCS, 1.35mM sodium pyruvate, 20mM HEPES, 4mM Glutamax, 2% sodium bicarbonate, 1% Pen/Strep, 1% 100 Xnon-essential amino acids]3000 cells in a 384-well microtiter plate (Greiner, TC plate, black with a clear bottom) and at 33 deg.C/5% CO₂The mixture was incubated for 24 hours. Prior to measurement, 30. mu.l Fluo-8AM loading buffer [ calcium-free Taiwanese solution (130 mM NaCl, 5mM KCl, 20mM HEPES,1 mM MgCl)₂, 4.8 mM NaHCO₃, pH 7.4), 2 mM CaCl₂6.3 mM probenecid, 5 mu M Fluo-8AM, 0.0112% Pluronic]Replace the medium and add 5% CO at 37 deg.C/5%₂Incubate for 30 minutes. Test substances were prepared in DMSO at various concentrations as dose-response curves (starting concentration 10mM, dilution factor 3.16) and dosed at 1:50 with calcium-free Taiwanese solution, 2mM CaCl₂0.002% SmartBlock (CANDOR bioscience GmbH) was prediluted. Mu.l of the pre-diluted substance solution was added to the cells loaded with Fluo-8 and incubated at 37 ℃/5% CO₂The mixture was incubated for 10 minutes. By adding 40. mu.l of a solution in Ca-free Taiwanese, 2mM CaCl₂2nM PGF2 α in 0.002% SmartBlock (final concentration) activated the FP receptor and calcium flux was determined by measuring fluorescence in fluorescence-measuring instruments (FLIPR Tetra, molecular sieves) at excitation 470 nM/emission 525 nM for 120 seconds.

The ICs from this experiment for various embodiments of the present invention are listed in table 1A below₅₀Values (in part, average from multiple independent individual determinations):

TABLE 1

B-2 in vitro FP receptorsBinding inhibition assay

For the FP receptor binding assay, human recombinant prostanoid FP receptors were used, which were expressed in HEK293 cells in modified MES buffer, ph 6.0. The assay was performed commercially (Eurofins Panlabs, catalog No. 268510). The 80. mu.g of the membrane was treated with 1 nM³H]-PGF2 α was incubated at 25 ℃ for 60 minutes. The amount of membrane protein can vary from batch to batch and can be adjusted as needed. Nonspecific binding was determined in the presence of 1 μ M of lorprostenol. The membrane is filtered, washed, and then measured to determine [2 ]³H]Specific binding of PGF2 α. Substances were tested for inhibitory activity at a concentration of 10 μ M or in the form of a dose-effect curve [ literature: abramovitz et al,J. Biol. Chem.1994, 269 (4):2632]。

b-3 in vitro CRTH2 receptor binding inhibition assay

For this assay, human recombinant prostanoid CRTH2 receptor was used, which was expressed in CHO-K1 cells in modified Tris-HCl buffer, pH 7.4. The assay was performed commercially (Eurofins Panlabs, catalog No. 268030). The membrane was treated with 1 nM 2 to 4. mu.g³H]-PGD2 was incubated at 25 ℃ for 120 minutes. The amount of membrane protein can vary from batch to batch and can be adjusted as needed. Non-specific binding was determined in the presence of 1 μ M PGD 2. The membrane is filtered, washed, and then measured to determine [2 ]³H]Specific binding of PGD 2. Substances were tested for inhibitory activity at a concentration of 10 μ M or in the form of a dose-effect curve [ literature: the results of Sugimoto et al,J. Pharmacol. Exp. Ther.2003, 305(1): 347]。

b-4 in vitro DP receptor binding inhibition assay

For this assay, human recombinant prostanoid DP receptor was used, expressed in Chem-1 cells in modified HEPES buffer, pH 7.4. The assay was performed commercially (Eurofins Panlabs, catalog No. 268060). The membrane of 10. mu.g was treated with 2nM³H]-PGD2 was incubated at 25 ℃ for 120 minutes. The amount of membrane protein can vary from batch to batch and can be adjusted as needed. Non-specific binding was determined in the presence of 1 μ M PGD 2. The membrane is filtered, and then the filtrate is filtered,washed and then measured to determine [ [2 ] ]³H]Specific binding of PGD 2. Substances were tested for inhibitory activity at a concentration of 10 μ M or in the form of a dose-effect curve [ literature: the number of people in Wright et al,Br. J. Pharmacol.1998, 123 (7): 1317; Sharif et al,Br. J. Pharmacol.2000, 131 (6): 1025]。

b-5 in vitro EP1 receptor binding inhibition assay

For this assay, human recombinant prostanoid EP1 receptor was used, which was expressed in HEK293 cells in modified MES buffer, ph 6.0. The assay was performed commercially (Eurofins Panlabs, catalog No. 268110). The membrane of 14. mu.g was treated with 1 nM³H]PGE2 was incubated at 25 ℃ for 60 minutes. The amount of membrane protein can vary from batch to batch and can be adjusted as needed. Non-specific binding was determined in the presence of 10 μ M PGE 2. The membrane is filtered, washed, and then measured to determine [2 ]³H]Specific binding of PGE 2. Substances were tested for inhibitory activity at a concentration of 10 μ M or in the form of a dose-effect curve [ literature: abramovitz et al,Biochim. Biophys. Acta2000, 1483 (2): 285; Funk et al,J. Biol. Chem.1993, 268 (35): 26767]。

b-6 in vitro EP2 receptor binding inhibition assay

For this assay, human recombinant prostanoid EP2 receptor was used, which was expressed in HEK293 cells in modified MES/KOH buffer, pH 6.0. The assay was performed commercially (Eurofins Panlabs, catalog No. 268200). The membrane of 25 mg/ml was treated with 4 nM³H]PGE2 was incubated at 25 ℃ for 120 minutes. The amount of membrane protein can vary from batch to batch and can be adjusted as needed. Non-specific binding was determined in the presence of 10 μ M PGE 2. The membrane is filtered, washed, and then measured to determine [2 ]³H]Specific binding of PGE 2. Substances were tested for inhibitory activity at a concentration of 10 μ M or in the form of a dose-effect curve [ literature: the number of Bastien et al,J. Biol. Chem.1994, 269 (16):11873; Boie et al,Eur. J. Pharmacol.1997, 340 (2-3): 227]。

b-7 in vitro EP3 receptor binding inhibition assay

For this assay, human recombinant prostanoid EP3 receptor was used, which was expressed in HEK293 cells in modified MES buffer, ph 6.0. The assay was performed commercially (Eurofins Panlabs, catalog No. 268310). Mu.g of the membrane was treated with 0.5 nM [ sic ], [ solution ]³H]PGE2 was incubated at 25 ℃ for 120 minutes. The amount of membrane protein can vary from batch to batch and can be adjusted as needed. Non-specific binding was determined in the presence of 10 μ M PGE 2. The membrane is filtered, washed, and then measured to determine [2 ]³H]Specific binding of PGE 2. Substances were tested for inhibitory activity at a concentration of 10 μ M or in the form of a dose-effect curve [ literature: in the case of Schmidt et al,Eur. J. Biochem.1995, 228 (1): 23]。

b-8 in vitro EP4 receptor binding inhibition assay

For this assay, human recombinant prostanoid EP4 receptor was used, expressed in Chem-1 cells in modified MES buffer, pH 6.0. The assay was performed commercially (Eurofins Panlabs, catalog No. 268420). Mu.g of the membrane was treated with 1 nM³H]PGE2 was incubated at 25 ℃ for 120 minutes. The amount of membrane protein can vary from batch to batch and can be adjusted as needed. Non-specific binding was determined in the presence of 10 μ M PGE 2. The membrane is filtered, washed, and then measured to determine [2 ]³H]Specific binding of PGE 2. Substances were tested for inhibitory activity at a concentration of 10 μ M or in the form of a dose-effect curve [ literature: the result of Davis et al,Br. J. Pharmacol.2000, 130 (8): 1919]。

b-9 in vitro inhibition of IP receptor binding

For this assay, human recombinant prostanoid IP receptors were used, which were expressed in HEK293 cells in modified HEPES buffer, ph 6.0. The assay was performed commercially (Eurofins Panlabs, catalog No. 268600). The 15. mu.g of the membrane was treated with 5 nM³H]Iloprost was incubated at 25 ℃ for 60 minutes. The amount of membrane protein can vary from batch to batch and can be adjusted as needed. Non-specific binding was determined in the presence of 10 μ M iloprost. The membrane is filtered, washed, and then measured to determine [2 ]³H]Specific binding of iloprost. Substances were tested for inhibitory activity at a concentration of 10 μ M or in the form of a dose-effect curve [ literature: the Armstrong et al,Br. J. Pharmacol.1989, 97(3): 657; Boie et al,J. Biol. Chem.1994, 269 (16): 12173]。

b-10 in vitro TP receptor binding inhibition assay

For this assay, human recombinant prostanoid TP receptors were used, expressed in HEK-293 EBNA cells in modified Tris/HCl buffer, pH 7.4. The assay was performed commercially (Eurofins Panlabs, catalogue No. 285510). A film of 18.4. mu.g was treated with 5 nM [ mu ] m³H]-SQ-29,548 was incubated at 25 ℃ for 30 minutes. The amount of membrane protein can vary from batch to batch and can be adjusted as needed. Non-specific binding was determined in the presence of 1 μ M SQ-29,548. The membrane is filtered, washed, and then measured to determine [2 ]³H]Specific binding of SQ-29,548. Substances were tested for inhibitory activity at a concentration of 10 μ M or in the form of a dose-effect curve [ literature: the Saussy jr. et al,J. Biol. Chem.1986,261: 3025, Hedberg et al,J. Pharmacol. Exp. Ther.1988, 245: 786]。

b-11 in vitro test for DP agonism and antagonism

To characterize the test substances for DP agonism and antagonism, PGD 2-induced calcium flux in DP-expressing CHEM1 cells (Millipore, HTS091C) was used: mu.l of complete medium [ DMEM, 4.5G/l glucose, 10% heat-inactivated FCS, 1% 100 Xnon-essential amino acids, 10mM HEPES, 0.25 mg/ml Geneticin (G418), 100U/ml penicillin and streptomycin]3000 cells in a 384-well microtiter plate (Greiner, TC plate, black with a clear bottom) and at 37 deg.C/5% CO₂The mixture was incubated for 24 hours. Prior to measurement, the medium was replaced with 30. mu.l of calcium-dye-loading buffer (FLIPR calcium assay, Molecular Devices) and the incubation was carried out at 37 ℃/5% CO₂The mixture was incubated for 60 minutes. Test substances are prepared in DMSO at different concentrations as dose-response curves (starting concentration 10mM, dilution factor 3.16) and are diluted at 1:50 with, for example, calcium-free typhon solution (130 mM NaCl, 5mM KCl,20 mMHEPES, 1 mM MgCl₂, 4.8 mM NaHCO₃, pH 7.4)/2 mM CaCl₂pre-diluting. For measuring DP agonism, the fluorescence measuring instrument (FLIPR Tetra)^®Molecular Devices), 10 μ l of a pre-diluted substance solution was added to the calcium-dye loaded cells, and the calcium flux was determined by measuring fluorescence at excitation 470 nm/emission 525 nm for 120 seconds. The cells were then incubated at 37 ℃/5% CO₂The mixture was incubated for 10 minutes. To measure DP antagonism, at FLIPR Tetra^®By mixing 20 μ l ~ 76 nM (2 xEC)₅₀Final concentration) PGD2 was added to, for example, Ca-free Taiwanese solution/2 mM CaCl₂Activates the DP receptor and determines calcium flux by measuring fluorescence at excitation 470 nm/emission 525 nm for 120 seconds [ literature: t, Matsuoka et al (2000)Science287: 2013-2017, S. Narumiya and G.A. Fitzgerald (2001)J. Clin. Invest.108: 25-30]。

B-12 in vitro test for agonism and antagonism of EP1

To characterize the test substances for EP1 agonism and antagonism, PGE 2-induced calcium flux in CHEM1 cells expressing EP1 (Millipore, HTS099C) was used: mu.l of complete medium [ DMEM, 4.5G/l glucose, 10% heat-inactivated FCS, 1% 100 Xnon-essential amino acids, 10mM HEPES, 0.25 mg/ml Geneticin (G418), 100U/ml penicillin and streptomycin]3000 cells in a 384-well microtiter plate (Greiner, TC plate, black with a clear bottom) and at 37 deg.C/5% CO₂The mixture was incubated for 24 hours. Prior to measurement, the medium was replaced with 30. mu.l of calcium-dye-loading buffer (FLIPR calcium assay, Molecular Devices) and the incubation was carried out at 37 ℃/5% CO₂The mixture was incubated for 60 minutes. Test substances are prepared in DMSO at different concentrations as dose-response curves (starting concentration 10mM, dilution factor 3.16) and applied at a rate of 1:50, for example, in Ca-free Taiwanese (130 mM NaCl, 5mM KCl, 20mM HEPES,1 mM MgCl)₂, 4.8 mM NaHCO₃, pH 7.4)/2 mM CaCl₂Pre-diluting. To measure EP1 agonism, a fluorescence measuring instrument (FLIPR Tetra)^®Molecular Devices), 10. mu.l of a pre-diluted substance solution was added to the calcium-dye-loaded cellsAnd the calcium flux was determined by measuring fluorescence at excitation 470 nm/emission 525 nm for 120 seconds. The cells were then incubated at 37 ℃/5% CO₂The mixture was incubated for 10 minutes. To measure EP1 antagonism, at FLIPR Tetra^®By mixing 20 μ l ~ 6nM (2 xEC)₅₀Final concentration) PGE2 was added to, for example, Ca-free Taiwanese solution/2 mM CaCl₂To activate the EP1 receptor and to determine calcium flux by measuring fluorescence at excitation 470 nm/emission 525 nm for 120 seconds [ literature: y. Matsuoka et al (2005)Proc. Natl. Acad. Sci. USA102: 16066-J. Clin. Invest.108: 25-30, K. Watanabe et al (1999)Cancer Res.59: 5093-5096]。

B-13 in vitro test for agonism and antagonism of EP2

To characterize the test substances for EP2 agonism and antagonism, PGE 2-induced calcium flux in CHEM9 cells expressing EP2 (Millipore, HTS185C) was used: the cells were plated in 25. mu.l of plate medium [ DMEM,4.5 g/l glucose, 4mM glutamine, 10% heat-inactivated FCS, 1% 100 Xnon-essential amino acids, 10mM HEPES, 100U/ml penicillin and streptomycin]3000 cells in a 384-well microtiter plate (Greiner, TC plate, black with a clear bottom) and at 37 deg.C/5% CO₂The mixture was incubated for 24 hours. Prior to measurement, the medium was replaced with 30. mu.l of calcium-dye-loading buffer (FLIPR calcium assay, Molecular Devices) and the incubation was carried out at 37 ℃/5% CO₂The mixture was incubated for 60 minutes. Test substances are prepared in DMSO at different concentrations as dose-response curves (starting concentration 10mM, dilution factor 3.16) and at a ratio of 1:50 with, for example, calcium-free Taiwanese (130 mM NaCl, 5mM KCl, 20mM HEPES,1 mM MgCl)₂, 4.8 mM NaHCO₃, pH 7.4)/2 mM CaCl₂Pre-diluting. To measure EP2 agonism, a fluorescence measuring instrument (FLIPR Tetra)^®Molecular Devices), 10 μ l of a pre-diluted substance solution was added to the calcium-dye loaded cells, and the calcium flux was determined by measuring fluorescence at excitation 470 nm/emission 525 nm for 120 seconds. The cells were then incubated at 37 ℃/5% CO₂The mixture was incubated for 10 minutes. To measure EP2 antagonism, at FLIPR Tetra^®By mixing 20 μ l ~ 22nM (2 xEC)₅₀Final concentration) PGE2 was added to, for example, Ca-free Taiwanese solution/2 mM CaCl₂To activate the EP2 receptor and to determine calcium flux by measuring fluorescence at excitation 470 nm/emission 525 nm for 120 seconds [ literature: C.R. Kennedy et al (1999)Nat. Med.5: 217-220, S. Narumiya and G.A. Fitzgerald (2001)J. Clin. Invest.108: 25-30, N. Yang et al (2003)J. Clin. Invest.111: 727-735]。

B-14 in vitro test for agonistic and antagonistic action of EP3

To characterize the test substances against EP3 agonism and antagonism, PGE 2-induced calcium flux in CHEM1 cells expressing EP3 (splice variant 6) (Millipore, HTS092C) was used: the cells were plated in 25. mu.l plate medium [ DMEM,4.5 g/l glucose, 4mM glutamine, 10% heat-inactivated FCS, 1% 100 Xnon-essential amino acids, 10mM HEPES, 100U/ml penicillin and streptomycin]3000 cells in a 384-well microtiter plate (Greiner, TC plate, black with a clear bottom) and at 37 deg.C/5% CO₂The mixture was incubated for 24 hours. Prior to measurement, the medium was replaced with 30. mu.l of calcium-dye-loading buffer (FLIPR calcium assay, Molecular Devices) and the incubation was carried out at 37 ℃/5% CO₂The mixture was incubated for 60 minutes. Test substances are prepared in DMSO at different concentrations as dose-response curves (starting concentration 10mM, dilution factor 3.16) and applied at a rate of 1:50, for example, in Ca-free Taiwanese (130 mM NaCl, 5mM KCl, 20mM HEPES,1 mM MgCl)₂, 4.8 mM NaHCO₃, pH 7.4)/2 mM CaCl₂Pre-diluting. To measure EP3 agonism, a fluorescence measuring instrument (FLIPR Tetra)^®Molecular Devices), 10 μ l of a pre-diluted substance solution was added to the calcium-dye loaded cells, and the calcium flux was determined by measuring fluorescence at excitation 470 nm/emission 525 nm for 120 seconds. The cells were then incubated at 37 ℃/5% CO₂The mixture was incubated for 10 minutes. To measure EP3 antagonism, at FLIPR Tetra^®By mixing 20 μ l ~ 2nM (2 xEC)₅₀Final concentration) PGE2 was added to, for example, Ca-free Taiwanese solution/2 mM CaCl₂Activates the EP3 receptor and is detected by excitation at 470 nm/emission at 525 nmFluorescence was measured for 120 seconds to determine calcium flux [ literature: m, Kotani et al (1995)Mol. Pharmacol.48: 869-879; M. Kotani et al (1997)Genomics40: 425-434, T, Kunikata et al (2005)Nat. Immunol.6: 524-J. Clin. Invest.108: 25-30, F. Ushikubi et al (1998)Nature395: 281-284]。

B-15 in vitro test for agonism and antagonism of EP4

To characterize the test substances for EP4 agonism and antagonism, PGE 2-induced calcium flux in CHEM1 cells expressing EP4 (Millipore, HTS142C) was used: the cells were plated in 25. mu.l of plate medium [ DMEM,4.5 g/l glucose, 4mM glutamine, 10% heat-inactivated FCS, 1% 100 Xnon-essential amino acids, 10mM HEPES, 100U/ml penicillin and streptomycin]3000 cells in a 384-well microtiter plate (Greiner, TC plate, black with a clear bottom) and at 37 deg.C/5% CO₂The mixture was incubated for 24 hours. Prior to measurement, the medium was replaced with 30. mu.l of calcium-dye-loading buffer (FLIPR calcium assay, Molecular Devices) and the incubation was carried out at 37 ℃/5% CO₂The mixture was incubated for 60 minutes. Test substances are prepared in DMSO at different concentrations as dose-response curves (starting concentration 10mM, dilution factor 3.16) and at a ratio of 1:50 with, for example, calcium-free Taiwanese (130 mM NaCl, 5mM KCl, 20mM HEPES,1 mM MgCl)₂, 4.8 mM NaHCO₃, pH 7.4)/2 mM CaCl₂Pre-diluting. To measure EP4 agonism, a fluorescence measuring instrument (FLIPR Tetra)^®Molecular Devices), 10 μ l of a pre-diluted substance solution was added to the calcium-dye loaded cells, and the calcium flux was determined by measuring fluorescence at excitation 470 nm/emission 525 nm for 120 seconds. The cells were then incubated at 37 ℃/5% CO₂The mixture was incubated for 10 minutes. To measure EP4 antagonism, at FLIPR Tetra^®By mixing 20 μ l ~ 26nM (2 xEC)₅₀Final concentration) PGE2 was added to, for example, Ca-free Taiwanese solution/2 mM CaCl₂To activate the EP4 receptor and to determine calcium flux by measuring fluorescence at excitation 470 nm/emission 525 nm for 120 seconds [ literature: s, Narumiya and G.A. Fitzgerald (2001)J. Clin. Invest.108: 25-30; M.Nguyen et al (1997)Nature390: 78-81, K. Yoshida et al (2002)Proc. Natl. Acad. Sci. USA99: 4580-4585]。

B-16 in vitro test for agonism and antagonism of IP

To characterize the test substances for IP agonism and antagonism, iloprost-induced calcium flux in IP-expressing CHEM1 cells (Millipore, HTS131C) was used: the cells were plated in 25. mu.l of plate medium [ DMEM,4.5 g/l glucose, 4mM glutamine, 10% heat-inactivated FCS, 1% 100 Xnon-essential amino acids, 10mM HEPES, 100U/ml penicillin and streptomycin]3000 cells in a 384-well microtiter plate (Greiner, TC plate, black with a clear bottom) and at 37 deg.C/5% CO₂The mixture was incubated for 24 hours. Prior to measurement, the medium was replaced with 30. mu.l of calcium-dye-loading buffer (FLIPR calcium assay, Molecular Devices) and the incubation was carried out at 37 ℃/5% CO₂The mixture was incubated for 60 minutes. Test substances are prepared in DMSO at different concentrations as dose-response curves (starting concentration 10mM, dilution factor 3.16) and at a ratio of 1:50 with, for example, calcium-free Taiwanese (130 mM NaCl, 5mM KCl, 20mM HEPES,1 mM MgCl)₂, 4.8 mM NaHCO₃, pH 7.4)/2 mM CaCl₂Pre-diluting. For measuring IP agonism, in a fluorescence measuring instrument (FLIPR Tetra)^®Molecular Devices), 10 μ l of a pre-diluted substance solution was added to the calcium-dye loaded cells, and the calcium flux was determined by measuring fluorescence at excitation 470 nm/emission 525 nm for 120 seconds. The cells were then incubated at 37 ℃/5% CO₂The mixture was incubated for 10 minutes. To measure IP antagonism, at FLIPR Tetra^®By mixing 20 μ l ~ 106nM (2 xEC)₅₀Final concentration) iloprost to e.g. calcium-free Taiwanese solution/2 mM CaCl₂Activates the IP receptor and determines the calcium flux by measuring fluorescence at excitation 470 nm/emission 525 nm for 120 seconds [ literature: narumiya et al (1999)Physiol. Rev.79: 1193-Nature388: 678-682; Y, Cheng et al (2002)Science296: 539-541; C.H. Xiao et al (2001)Circulation104: 2210-2215; G. A. Fitzgerald (2004)N. Engl. J. Med.351:1709-1711]。

B-17 in vitro test for TP agonism and antagonism

To characterize the test substances for TP agonism and antagonism, U46619-induced calcium flux in TP-expressing CHEM1 cells (Millipore, HTS081C) was used: the cells were plated in 25. mu.l of plate medium [ DMEM, 10% heat-inactivated FCS, 1% 100 Xnon-essential amino acids, 10mM HEPES, 0.25 mg/ml geneticin (G418), 100U/ml penicillin and streptomycin]3000 cells in a 384-well microtiter plate (Greiner, TC plate, black with a clear bottom) and at 37 deg.C/5% CO₂The mixture was incubated for 24 hours. Prior to measurement, the medium was replaced with 30. mu.l of calcium-dye-loading buffer (FLIPR calcium assay, Molecular Devices) and the incubation was carried out at 37 ℃/5% CO₂The mixture was incubated for 60 minutes. Test substances are prepared in DMSO at different concentrations as dose-response curves (starting concentration 10mM, dilution factor 3.16) and at a ratio of 1:50 with, for example, calcium-free Taiwanese (130 mM NaCl, 5mM KCl, 20mM HEPES,1 mM MgCl)₂, 4.8 mM NaHCO₃, pH 7.4)/2 mM CaCl₂Pre-diluting. For measuring TP agonism, in a fluorescence measuring instrument (FLIPR Tetra)^®Molecular Devices), 10 μ l of a pre-diluted substance solution was added to the calcium-dye loaded cells, and the calcium flux was determined by measuring fluorescence at excitation 470 nm/emission 525 nm for 120 seconds. The cells were then incubated at 37 ℃/5% CO₂The mixture was incubated for 10 minutes. To measure TP antagonism, at FLIPR Tetra^®By mixing 20 μ l ~ 88nM (2 xEC)₅₀Final concentration) U46619 to, for example, Ca-free Tai liquor/2 mM CaCl₂Activates TP receptors and determines calcium flux by measuring fluorescence at excitation 470 nm/emission 525 nm for 120 seconds [ literature: s, Ali et al (1993)J. Biol. Chem.268: 17397-Biochem. Pharmacol.38: 2967-Nature349: 617-620]。

B-18 bleomycin induced pulmonary fibrosis animal model

Bleomycin-induced pulmonary fibrosis in mice or rats is a widely used animal model of pulmonary fibrosis.Bleomycin is a glycopeptide antibiotic used in oncology for the treatment of testicular, hodgkin and non-hodgkin tumors. It is eliminated by the kidney, has a half-life of about 3 hours, and acts as a cytostatic agent affecting the various stages of the division cycle [ Lazo et al,Cancer Chemother. Biol. Response Modif.15, 44-50(1994)]. The antitumor effect is attributed to the oxidative damage to DNA [ Hay et al, Arch. Toxicol.65, 81-94 (1991)]. In the face of bleomycin, lung tissue is compromised in a particular way, since here the so-called cysteine hydrolase, which leads to bleomycin inactivation in other tissues, is only present in small amounts. Following bleomycin administration, animals develop "Acute Respiratory Distress Syndrome (ARDS)" followed by pulmonary fibrosis.

Administration of bleomycin may be single or multiple intratracheal, inhalation, intravenous or intraperitoneal administration. From the day of the first bleomycin administration or 3-14 days after treatment, the animals are initially treated with the test substance (by gavage, by addition to feed or drinking water, by an osmotische minipump, by subcutaneous or intraperitoneal injection or by inhalation) for a period of 2-6 weeks. At the end of the study, bronchoalveolar lavages were performed to determine cell content and proinflammatory and profibrotic markers, and lung function measurements and histological evaluation of pulmonary fibrosis were performed.

B-19 DQ12 quartz-induced pulmonary fibrosis animal model

DQ12 quartz-induced pulmonary fibrosis in mice and rats is a widely used animal model of pulmonary fibrosis [ shimbiri et al,Exp. Lung Res.36, 292-301 (2010)]. DQ12 quartz is a quartz that has high activity due to breakage or grinding. Intratracheal or inhalational administration of DQ12 quartz resulted in pulmonary alveolar proteinosis followed by interstitial pulmonary fibrosis in mice and rats. Animals received single or multiple intratracheal or inhalation instillations of DQ12 quartz. Starting from the day of the first instillation of the silicate or 3 to 14 days after the treatment, the animals are treated with the test substance (by gavage, by addition to feed or drinking water, by a micro-osmotic pump, by subcutaneous or intraperitoneal injection or by inhalation) andand the time lasts for 3-12 weeks. At the end of the study, bronchoalveolar lavages were performed to determine cell content and proinflammatory and profibrotic markers, and lung function measurements and histological evaluation of pulmonary fibrosis were performed.

Animal model of B-20 DQ12 Quartz induced pulmonary inflammation

In mice and rats, intratracheal administration of DQ12 quartz resulted in inflammation in the lungs [ shimbi et al,Exp. Lung Res.36, 292-301 (2010)]. On the day of or one day after instillation of DQ12 quartz, animals are treated with the test substance for a period of 24 hours up to 7 days (by gavage, by addition to feed or drinking water, by use of a micro-osmotic pump, by subcutaneous or intraperitoneal injection or by inhalation). At the end of the experiment, bronchoalveolar lavages were performed to determine the cell content and the pro-inflammatory and pro-fibrotic markers.

₄Carbon tetrachloride (CCl) -induced liver fibrosis in mice

60C 57BL/6J mice (Charles River, male, 8 weeks old) were randomized and evenly divided into 4 groups (15 mice per group). Group 1 was used as an untreated healthy control group, while groups 2-4 were used as mice with liver fibrosis. Throughout the study period, 50 μ l CCl was injected intraperitoneally by three times a week (Monday, Wednesday, and Friday)₄Olive oil suspension (CCl)₄+ olive oil, 1 + 9 v/v) induces liver fibrosis. CCl₄Is the oldest and most widely used substance that initiates toxicity-induced liver fibrosis (Starkel and Leclercq,Best Pract. Res. Clin. Gastroenterol.2011,25,319-333). Group 2 warp CCl₄Treated mice were used as disease controls and received no further treatment, while group 3 was CCl treated₄Treated mice were first treated with vehicle and thus used as vehicle controls. Group 4 warp CCl₄The treated mice were treated with the compound of formula (I). Group 3 oral treatment with vehicle solution and group 4 oral treatment with compound of formula (I) started on day 1 and continued twice daily (morning and evening) throughout the study period of two weeks. At the end of the study, all animals were sacrificed under anesthesia and the liver was sacrificedRemoved and fixed in 4% buffered formaldehyde solution for subsequent histological processing and analysis. For this purpose, liver samples of all animals were embedded in paraffin and 3 μm thick paraffin sections were made. Thereafter, all liver sections were deparaffinized and stained with sirius red (Waldeck, germany) to determine liver fibrosis. Sirius red staining is a histological technique for collagen staining and thus fibrotic staining in tissues. A Carl Zeiss microscope (Axio Observer) connected to a computer was used to scan sirius red stained liver sections to generate corresponding images. The slices were scanned at 20x magnification and 4.8V light intensity. The resulting images were then converted to JPG format and the red-stained areas were quantified by ImageJ software (National Institute of Health, USA). Results are shown as sirius red% per area of liver.

Treatment with the compound of example 284 resulted in a significant reduction in the progression of fibrosis in a 2-week mouse liver fibrosis study (p < 0.01; mean ± SD using two-way ANOVA statistical analysis of Dunnett's post-hoc test) (see table 2).

TABLE 2

B-22 animal model of Unilateral Ureteral Obstruction (UUO) (renal fibrosis) in mice

Unilateral ureteral obstruction in mice and rats is a widely used animal model of interstitial renal fibrosis (Chevalier et al,Kidney Int.2009,75, 1145-1152). Permanent ureteral obstruction results in increased infiltration of inflammatory cells into the interstitium, tubular cell death, and irreversible loss of renal parenchyma due to the sustained accumulation of urine. After 5 to 7 days, interstitial fibrosis is caused by increased deposition of extracellular matrix proteins. Adult male C57B16J mice (Charles River Laboratories, Sulzfeld, germany) weighing 20-22g were anesthetized with isoflurane and then the ureters were ligated and cut under the ligature after opening the abdominal cavity. In SHAM operated control mice (SHAM), only the abdominal cavity was opened, and the ureters were not ligated. After operationAnimals in the substance group were initially treated with the compound from example 284 (10 and 30 mg/kg, oral (po), twice daily (bid)) for an additional 10 days. 10 days after UUO, animals were anesthetized and sacrificed by exsanguination. Thereafter, the kidneys were removed and renal fibrosis assessed based on expression of pro-inflammatory and pro-fibrotic markers and histological evaluation of renal tissue. The results are shown in tables 3 and 4.

Table 3:gene expression of proinflammatory and fibrosis markers in untreated and treated animals.

Table 4:immunohistochemically detectable staining for alpha SMA and histochemical staining for collagen (SR/FG)

UUO causes increased gene expression of pro-inflammatory and pro-fibrotic genes of the obstructive kidney (e.g., α SMA, collagen TGF-b, KC, MCP-1). Treatment with this material resulted in a dose-dependent decrease in the expression of SMA, Col1 α 1, Col4 α 1, TGF- β and KC. Gene expression of Col3 alpha 1, CTGF, MCP-1, IL-6 and IL 1-beta was not affected by treatment.

Histological staining showed elevated levels of alpha SMA and collagen (SR/FG) in the UUO kidney compared to sham operated mice. Treatment with 60 [ mg/kg ] of material resulted in a significant reduction in the positive area for alpha SMA. The collagen content of the obstructive kidney was not affected by the treatment.

B-23 silica-induced pulmonary fibrosis in mice: therapeutic chronic 30-day study with FP antagonists

Adult female C57Bl6J mice (Charles River Laboratories, Sulzfeld, Germany) weighing 18-20 g were anesthetized in a room containing isoflurane (3% v/v) and treated intratracheally with 2.5 mg of crystalline DQ12 silica dissolved in 70 μ L sterile phosphate buffered saline. Untreated control mice received the same volume of phosphate buffered saline. After treatment with silicaOn day 10, animals in the substance group were treated with the compound from example 35 for 20 days (10 and 30 mg/kg, oral (po), twice daily (bid)). 30 days after the silica instillation, animals were anesthetized by intraperitoneal injection of ketamine/medetomidine (50 mg/kg and 0.33 mg/kg) in combination with subcutaneous injection of Temgesic (0.06 mg/kg) and sacrificed by exsanguination. Thereafter, the trachea was cannulated and the lungs of the animals were lavaged 3 times with 0.5 ml of ice-cold phosphate buffered saline. Thereafter, the lungs were removed, weighed and snap frozen in dry ice. After homogenization of lung tissue, hydroxyproline was determined by HPLC [ paroi et al,Clin. Chem.1992,38407 + 411, column Phenomenex Synergi Hydro RP 4 μm 80A, 75X 4,6 mm, gradient eluent A, water (6 ml/l triethylamine, 3 ml/l acetic acid) pH 4.3, solvent B, acetonitrile, flow rate 1.3 ml/min. Data are mean ± SEM of 8-12 animals per group. Statistical analysis was performed using unpaired student's t-test. P value<0.05 was considered significant. The results are shown in table 5.

TABLE 5

The silica treatment resulted in a significant increase in hydroxyproline, a marker of collagen accumulation and fibrosis in the lungs of the silica-treated animals compared to the untreated control group. Treatment with the compound from example 35 (10 and 30 mg/kg po bid) resulted in a significant reduction in hydroxyproline formation and fibrosis in the treated group compared to the silica treated control.

B-24 Effect of FP antagonists on mechanical sensitivity (peripheral, mouse)

Injected and non-injected hind paws were examined multiple times for mechanical allodynia after injection by using the von Frey test.

By the up-down method (Chaplan et al,J. Neurosci. Meth.1994,5356-63) using 8 Semmes-Weinstein filaments (Stöting ©; Wood Dale, IL, USA) with different stiffness (0.04; 0.07; 0.16; 0.4; 1.0.4.0 and 8.0 g) to measure mechanical allodynia intact male ND4 mice (about 30g, 10 animals per group)Placed in each acrylic cell on the surface of a metal grid and allowed to acclimate for at least 15 minutes before testing. Each filament is pressed against the underside of the paw at right angles with sufficient force to cause it to bend slightly relative to the paw and remain there for about 6 seconds or until a positive response is recorded (paw is rapidly retracted). The test was started with 0.4 gram of filament. If the paw is not retracted, the next stronger stimulus is used. In the case of retracting the paw, the next weaker stimulus is used. This process was repeated until 4 responses were obtained after the initial change in response (no response after positive response or positive response after no response). If the animal did not respond after the strongest filament was reached or if the animal responded after the weakest filament was reached, the test was stopped at this point in time. The 50% response threshold (paw response threshold) was calculated using the following formula:

xf = value of last von Frey filament used (in logarithmic units)

k = table value of the positive/negative response pattern (see Chaplan et al,J. Neurosci. Meth.1994,5356-63, appendix 1, page 62)

δ = mean difference between stimuli (in logarithmic units).

The mean and standard deviation (SEM) of the measurements were determined for each paw of each treatment group at each time point.

Group design

IPL, intraplantar, PO, oral.

To evaluate the analgesic effect of FP antagonists on fluprostenol-induced mechanical sensitivity, test substances were administered 2 hours before and 8 and 22 hours after fluprostenol injection. Ipsilateral and contralateral "50% paw response thresholds" were examined before and 0.5, 2, 6 and 24 hours post-administration of fluprostenol.

C.Examples of pharmaceutical compositions

The compounds of the invention can be converted into pharmaceutical preparations in the following manner:

and (3) tablet preparation:

consists of the following components:

100mg of the compound according to the invention, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

Tablet weight 212 mg, diameter 8 mm, radius of curvature 12 mm.

Preparation of:

A mixture of the compound of the invention, lactose and starch was granulated using a 5% solution of PVP in water (m/m). After drying, the granules were mixed with magnesium stearate for 5 minutes. The mixture is compressed with a conventional tablet press (see above for tablet forms). As a standard value for pressing, a pressing force of 15 kN was used.

Orally administrable suspensions:

Consists of the following components:

1000 mg of a compound of the invention, 1000 mg of ethanol (96%), 400 mg of Rhodigel ® (xanthan gum, FMC Inc., Pennsylvania, USA) and 99 g of water.

10 ml of oral suspension corresponds to a single dose of 100mg of a compound of the invention.

Preparation:

rhodigel is suspended in ethanol and the compound of the invention is added to the suspension. Water was added with stirring. The mixture was stirred for about 6 h until the swelling of the Rhodigel was complete.

Orally administrable solution:

Consists of the following components:

500 mg of a compound of the invention, 2.5 g of polysorbate and 97 g of polyethylene glycol 400. 20 g of oral solution corresponds to a single dose of 100mg of the compound of the invention.

Preparation:

the compounds of the invention are suspended in a mixture of polyethylene glycol and polysorbate under agitation. The stirring process is continued until the compound of the invention is completely dissolved.

Intravenous solution:

The compounds of the invention are dissolved at a concentration below the saturation solubility in physiologically tolerated solvents (e.g., isotonic saline, 5% glucose solution, and/or 30% PEG 400 solution). The solution was sterile filtered and filled into sterile and pyrogen-free injection containers.

Claims

1. Compounds of formula (I) and their useN-oxides, salts, solvates,NSalts of oxides andNsolvates of oxides and salts

Wherein

Ar is a phenyl group or a pyridyl group,

wherein phenyl can be up to tetrasubstituted and pyridyl can be up to disubstituted and said phenyl or pyridyl can be in each case up to trisubstituted by fluorine, chlorine (C)₁-C₄) Alkyl, up to tetra-substituted by fluorine (C)₃-C₄) Cycloalkyl, (C) trisubstituted by fluorine up to₁-C₂) Alkoxy or (C) trisubstituted by fluorine at most₁-C₂) -alkylsulfanyl is substituted identically or differently, or wherein two substituents of the phenyl or pyridyl group, if bonded to adjacent ring atoms, are optionally bonded to each other to form together methylenedioxy or ethylenedioxy,

or

Wherein the phenyl group may be up to penta-substituted with fluorine,

y is a bond or a group of the formula

#¹−X−(CR^10AR^10B)_k−#²

Wherein

#¹Is a site of attachment to a carbon atom,

#²is the site of attachment to the carboxyl group,

x is a bond, -CH₂−、−O−、−S(=O)_m-or-N (R)¹¹) -, wherein

m is 0, 1 or 2, and

R¹¹is hydrogen or a methyl group, or a mixture thereof,

R^10Aand R^10BIndependently of one another, hydrogen, fluorine or methyl,

or

k is 1, 2, 3 or 4,

wherein cyclopropyl and cyclobutyl may be up to tetra-substituted by fluorine,

R⁶is-NR¹²R¹³

Wherein

R¹²Is hydrogen or (C)₁-C₃) -alkyl, and

R¹³is (C)₁-C₄) -alkyl or (C)₃-C₇) -a cycloalkyl group,

wherein the phenyl group may be up to trisubstituted by fluorine,

or

Is a saturated or partially unsaturated 4-to 8-membered monocyclic or 6-to 10-membered bicyclic heterocyclic ring which is linked via a nitrogen atom and which may contain a further ring member selected from N, O, S, SO and SO₂As ring members, identical or different heteroatoms,

wherein the 4-to 8-membered monocyclic and 6-to 10-membered bicyclic heterocycles can each be selected from (C) independently of one another by 1 to 3₁-C₄) -alkyl, hydroxy, oxo, (C)₁-C₃) -alkoxy, difluoromethoxy, trifluoromethoxy, cyano, amino, monomethylamino, dimethylamino, aminocarbonyl, monomethylaminocarbonyl, dimethylaminocarbonyl and additionally up to tetrasubstituted by fluorine,

R^7Aand R^7BIndependently of one another, is hydrogen or methyl,

or

R⁸is hydrogen, fluorine, methyl, trifluoromethyl, ethyl or hydroxy,

R⁹is hydrogen or methyl.

2. A compound of formula (I) according to claim 1 and salts, solvates and solvates of salts thereof, wherein

Ar is a phenyl group, and Ar is a phenyl group,

y is a bond or a group of the formula

#¹−(CH₂)_n−#²

Wherein

#¹Is a site of attachment to a carbon atom,

#²is the site of attachment to the carboxyl group,

n is 1, 2 or 3,

R¹is a bromine or acetylene group, and the compound is,

R²、R³and R⁴Each of which is a hydrogen atom,

R⁵is a chlorine or a methyl group, and the compound is,

and

R⁶is-NR¹²R¹³

Wherein

R¹²Is hydrogen or methyl, and

R¹³is (C)₁-C₄) -an alkyl group,

or

R^7A、R^7B、R⁸and R⁹Each is hydrogen.

3. A compound of formula (I) according to any one of claims 1 to 3, and salts, solvates and solvates of salts thereof, wherein

Ar is a phenyl group, and Ar is a phenyl group,

y is a radical of the formula

#¹−CH₂CH₂−#²

Wherein

#¹Is a site of attachment to a carbon atom,

#²is the site of attachment to the carboxyl group,

R¹is a bromine compound, and is,

R²、R³、R⁴each of which is a hydrogen atom,

R⁵is a methyl group, and the compound is,

R⁶is a radical of the formula

Wherein

#³Is the site of attachment to the rest of the molecule,

R¹⁴is a fluorine or a methyl group, and the compound is,

R¹⁵is a fluorine, a methyl or an ethyl radical,

R^7A、R^7B、R⁸and R⁹Each is hydrogen.

4. A process for the preparation of a compound of formula (I) as defined in claims 1 to 3, characterized in that a compound of formula (II) is reacted

and

t is an ester protecting group, especially (C)₁-C₄) -an alkyl group,

in the first step of the process, the first step,

[A] with amine compounds of the formula (III)

Wherein R is⁶With the definitions given above, it is possible to use,

and in a subsequent step(s),

and

t is an ester protecting group, especially (C)₁-C₄) -an alkyl group,

and the compounds of the formula (I) thus obtained

5. A compound as defined in any one of claims 1 to 3 for use in the treatment and/or prevention of a disease.

6. A compound as defined in any one of claims 1 to 3 for use in a method of treatment and/or prevention of idiopathic pulmonary fibrosis, pulmonary hypertension, bronchiolitis obliterans syndrome, inflammatory and fibrotic skin diseases and ocular diseases and fibrotic diseases of internal organs.

7. Use of a compound as defined in any one of claims 1 to 3 for the preparation of a medicament for the treatment and/or prevention of idiopathic pulmonary fibrosis, pulmonary hypertension, bronchiolitis obliterans syndrome, inflammatory and fibrotic skin diseases and ocular diseases and fibrotic diseases of internal organs.

8. A medicament comprising a compound as defined in any one of claims 1 to 3 and one or more inert, non-toxic, pharmaceutically suitable excipients.

9. A medicament comprising a compound as defined in any one of claims 1 to 3 and one or more further active ingredients selected from PDE 5 inhibitors, sGC activators, sGC stimulators, prostacyclin analogues, IP receptor agonists, endothelin antagonists, compounds inhibiting the signal transduction cascade and pirfenidone.

10. The medicament according to claim 8 or 9 for the treatment and/or prevention of idiopathic pulmonary fibrosis, pulmonary hypertension, bronchiolitis obliterans syndrome, inflammatory and fibrotic skin diseases and ocular diseases and fibrotic diseases of internal organs.

11. A method for the treatment and/or prophylaxis of idiopathic pulmonary fibrosis, pulmonary hypertension, bronchiolitis obliterans syndrome, inflammatory and fibrotic skin diseases and ocular diseases and fibrotic diseases of internal organs in humans and animals by administering an effective amount of at least one compound as defined in any of claims 1 to 3 or a medicament as defined in any of claims 8 to 10.