HK1193809A - Novel rock inhibitors - Google Patents

Description

Novel ROCK inhibitors

Technical Field

The present invention relates to novel kinase inhibitors, more particularly ROCK inhibitors, compositions, especially medicaments, comprising such inhibitors and the use of said inhibitors in the treatment and prevention of disease. In particular, the present invention relates to novel ROCK inhibitors, compositions, in particular pharmaceuticals, comprising such inhibitors, and the use of the inhibitors in the treatment and prevention of disease.

Background

The serine/threonine protein kinase ROCK consists of two isoforms, ROCK I and ROCK II, in humans. ROCK I encodes on chromosome 18, while ROCK II (also known as Rho-kinase) is located on chromosome 12. Both have a molecular weight of approximately 160 kDa. They have 65% overall homology and 95% homology in their kinase domain. Despite their sequence similarity, the tissue distribution differs. The highest level of ROCK I expression was observed in cardiac, lung and skeletal tissues, whereas ROCK II was predominantly expressed in brain. Recent data show that there is partial functional redundancy in both isoforms, ROCK I is more involved in immunological events, while ROCK II is involved in smooth muscle function. The term ROCK denotes ROCK I (ROK-. beta., p160ROCK or Rho-kinase. beta.) and ROCK II (ROCK-. alpha. or Rho-kinase. alpha.).

ROCK activity has been shown to be enhanced by GTPase RhoA, a member of the Rho (Ras homolog) GTP-binding protein. RhoA in the active GTP-bound state interacts with the Rho-binding domain (RBD) of ROCK located at the self-inhibiting carboxy terminal ring. Upon binding, the interaction between the ROCK negative regulatory domain and the kinase domain is disrupted. This process allows the kinase to adopt an open conformation that is completely active. This open conformation is also caused by the binding of a lipid activator (e.g., arachidonic acid) to the PH domain of the kinase carboxy-terminal domain. Another activation mechanism during apoptosis is also described and involves carboxy-terminal cleavage of ROCK I and II by caspases-3 and-2 (or granzyme B), respectively.

ROCK plays an important role in various cellular functions, such as smooth muscle contraction, actin cytoskeletal organization, platelet activation, down regulation of myosin phosphatase cell adhesion, migration of aortic smooth muscle cells, proliferation, survival and thrombin-induced responses, cardiomyocyte hypertrophy, bronchial smooth muscle contraction, smooth muscle contraction and non-muscle cytoskeletal reorganization, activation of volume-regulated anion channels, neurite retraction, wound healing, cellular transformation and gene expression. ROCK also plays a role in many signaling pathways involved in autoimmunity and inflammation. ROCK has been shown to play a role in the activation of NF- κ B, a key molecule responsible for the production of TNF and other inflammatory cytokines. ROCK inhibitors have been reported to counteract the production of TNF-alpha and IL-6 factors in Lipopolysaccharide (LPS) -stimulated THP-1 macrophages. ROCK inhibitors therefore provide a beneficial therapy for the treatment of autoimmune diseases, inflammatory diseases and oxidative stress.

ROCK also plays an important role in many critical cellular processes involved in angiogenesis. These processes include formation of tension fibers, Endothelial Cell (EC) polarity, EC adhesion, EC motility, cytokinesis and apoptosis. Previous studies have shown that Rho-signaling is required for Vascular Endothelial Growth Factor (VEGF) -dependent capillary formation in vitro and angiogenesis in vivo. This suggests that Rho/ROCK inhibition may be a new approach to the treatment of angiogenesis-related disorders such as neovascularization of the cornea or age-related macular degeneration.

In conclusion, ROCK is a major regulatory point for smooth muscle cell function and is a key signaling component of the inflammatory process of various inflammatory cells and the process of fibrosis and remodeling of many diseased organs. Furthermore, ROCK has been implicated in a variety of diseases and disorders, including: eye diseases; respiratory diseases; cardiovascular and vascular diseases; inflammatory diseases; neurological and central nervous system disorders; proliferative diseases; renal disease; sexual dysfunction; blood diseases; bone disease; diabetes mellitus; benign prostatic hyperplasia, transplant rejection, liver disease, systemic lupus erythematosus, spasticity, hypertension, chronic obstructive bladder disease, premature labor, infection, allergy, obesity, pancreatic disease, and AIDS.

ROCK appears to be a relatively safe target as evidenced by gene knockout models and extensive academic research. The data from these knockout mice was combined with post-market monitoring studies of Fasudil (Fasudil), a moderately potent ROCK inhibitor for the treatment of cerebral vasospasm following subarachnoid hemorrhage, indicating that ROCK is a true and significant drug target.

ROCK inhibitors are useful as therapeutic agents for the treatment of disorders involving the ROCK pathway. Therefore, there is a strong need to develop a ROCK inhibitor that can be used to treat a variety of diseases or disorders associated with ROCK activation, particularly in view of the current inadequacies of most of these diseases. Some non-limiting examples are glaucoma, asthma and chronic obstructive pulmonary disease.

Glaucoma is a neurodegenerative disease that is the second leading cause of irreversible blindness. The disease is characterized by elevated intraocular pressure (IOP) and progressive retinal ganglion cell apoptosis, resulting in irreversible visual field loss. Current treatments for this disease are directed to the reduction of IOP, which is the major, but not the only, risk factor for glaucoma. Since current treatments only control and fail to cure the disease and further cause irritating, local and systemic side effects, improved therapies are needed. In addition, other positive effects, such as anti-inflammatory and neuroregenerative components of ROCK inhibitors, are highly preferred. Reference ROCK inhibitors (such as Y-27632) cause alterations in cell morphology and decrease the tonofibrosis, focal adhesion and MLC phosphorylation of cultured human TM cells; they dilate human trabecular meshwork cultured in vitro, dilate human Schlemm's ductal endothelial cells in vitro, and when applied topically to animals will significantly increase trabecular efflux, resulting in a substantial decrease in intraocular pressure.

Allergic asthma is a chronic inflammatory disease of the respiratory tract caused by the non-adaptive immune response of genetically susceptible people to ubiquitous environmental proteins. Despite the rather successful treatment, the prevalence of allergic asthma is increased by the inability of these therapies to cure; the situation is still exacerbated and there are more and more non-responders. New, highly effective, palliative hormone therapies are necessary to address all the factors of the disease.

Age-related macular degeneration (AMD) is the leading cause of vision loss in the elderly population. Wet or neovascular AMD can lead to rapid, destructive vision loss due to Choroidal Neovascularization (CNV), macular edema, and photoreceptor cell death. Now, anti-Vascular Endothelial Growth Factor (VEGF) therapy constitutes the first line therapy for active CNV in wet AMD. VEGF promotes angiogenesis and vascular permeability and plays an important role in CNV formation. Different drugs have been developed aimed at blocking VEGF or its receptors. In addition to neovascularization, the pathogenesis of AMD also includes inflammation and scarring. A recent preclinical study showed that anti-VEGF treatment is limited to a reduction in angiogenesis and may even lead to inflammation and scarring. Another major concern is that anti-VEGF can cause significant systemic side effects (due to regression of blood vessels) and neurodegeneration, as well as local side effects. Therefore, alternative treatment modalities are needed. Previous studies have shown that pharmacological inhibition of ROCK1 and ROCK2 by Y-27632 strongly disrupts angiogenesis and that ROCK-inhibition reduces inflammation and scarring. Thus, ROCK-inhibitors may be an attractive and improved alternative to anti-VEGF therapy for the treatment of wet AMD.

Chronic Obstructive Pulmonary Disease (COPD) is a group of diseases characterized by irreversible airway limitation, which is associated with abnormal inflammatory responses, bronchoconstriction, and remodeling and damage of lung tissue. It is one of the leading causes of death in the world, with steadily increasing prevalence. As current therapies are inadequate, new treatments are urgently needed. Current treatments are mainly based on bronchodilators, since glucocorticoids have limited or no effect at all. ROCK inhibitors may provide a new therapeutic strategy for COPD. Reference ROCK inhibitors (such as Y-2)7632) Can relax isolated human bronchus preparation, inhibit increase of respiratory tract resistance of anesthetized animals, enhance relaxation of beta-agonist in vitro and in vivo, and bring about rapid bronchiectasis after inhalation. In addition, ROCK inhibitors block H₂O₂Induced airway smooth muscle contraction (clinical marker of oxidative stress). Associated with airway inflammation, ROCK inhibitors can counteract the anti-inflammatory-agent-mediated enhancement of transendothelial permeability, maintain the barrier integrity of vascular endothelium, inhibit the influx of eosinophils following ovalbumin challenge in vivo, prevent the formation of pulmonary edema and neutrophil migration, inhibit the HR of methacholine and 5-hydroxytryptamine in the airway of allergic mice, and block the release of TNF induced by LPS. With respect to respiratory fibrosis and remodeling, ROCK inhibitors block respiratory smooth muscle cell-induced migration. In vitro evidence of the role of ROCK in respiratory remodeling can be found in human lung cancer cell lines, bovine airway smooth muscle cells, and human respiratory smooth muscle. In vivo evidence of ROCK for fibrosis is generally generated in mice (where partial deletion of ROCK causes attenuated myocardial fibrosis). Attenuation of myocardial fibrosis by Y-27632 for myocardial infarction and fasudil for congestive heart failure in a chronic hypertensive rat model brought additional indications to the importance of ROCK for remodeling. Finally, ROCK inhibitors increase apoptotic cell loss from smooth muscle cells.

There are several known types of ROCK inhibitors. The current focus is on the use of tumors and cardiovascular diseases. To date, the outstanding therapeutic potential of ROCK inhibitors has been limited to a limited range. The reason for this is the fact that ROCK is a potent and widespread biochemical regulator, and that systemic inhibition of ROCK can bring about a powerful biological effect, but is also considered as a side effect in the treatment of most diseases. Indeed, the medical use of ROCK inhibitors for the treatment of diseases with strong anti-inflammatory components is hampered by the critical role of ROCK in regulating the tonic phase (tonicity) of smooth muscle cell contraction. Systemically available ROCK inhibitors induce a significant drop in blood pressure. Therefore, there is a high demand for ROCK inhibitors of different properties.

To develop a targeted specific treatment of disease by modulating smooth muscle function and/or inflammatory processes and/or remodeling, it is highly desirable that ROCK inhibitors be able to target organs to avoid significant amounts of drug from entering other organs. Therefore, topical application or external application is desirable. Generally, topically applied drugs have been used to treat respiratory, ocular, sexual dysfunction and skin disorders. In addition, local injection/infiltration into diseased tissue further expands the potential medical use of locally applied ROCK inhibitors. These topical applications can allow high concentrations of the drug to reach the target tissue if certain conditions are met. Furthermore, the incorporation of ROCK inhibitors into implants and stents can further expand the medical applications for the local treatment of cardiovascular diseases, such as atherosclerosis, coronary heart disease and heart failure.

Although direct topical application is a priority in medical practice, the level of drug entering the systemic circulation remains a concern. For example, local delivery by inhalation to treat respiratory diseases poses a risk of systemic exposure, since large amounts of the drug are passed into the gastrointestinal tract and/or absorbed systemically through the lungs. For the treatment of locally delivered eye conditions, large amounts of drug enter the gastrointestinal tract and/or systemic circulation due to low corneal permeability, low fluid capacity, efficient drainage, and the presence of eyelid vessels. With respect to dermal drug delivery, topical injection and implantable medical devices, there is a serious risk of leakage into the systemic circulation. Thus, in addition to topical application, it is desirable that the compounds have additional properties that avoid significant systemic exposure.

Soft drugs (soft drugs) are biologically active compounds that are inactivated once they enter the systemic circulation. This inactivation involves a controlled conversion of the soft drug to a predictable metabolite that exhibits a significantly reduced, or preferably, negligible, functional activity. Inactivation may be effected in the liver, but preferably inactivation should occur in the blood. These compounds, once applied topically to the target tissue/organ, will exert their intended effect locally. They will inactivate very rapidly when they leak from the target tissue into the systemic circulation. Thus, the soft drug of choice is sufficiently stable in the target tissue/organ to exert the desired biological effect, but rapidly degrades in the blood to a biologically inactive compound. Thus, soft drugs may reduce the systemic exposure of the functionally active pharmaceutical compound. Furthermore, it is highly preferred that the soft drug of choice be retained at its biological target. This property will limit the number of daily applications and it is highly desirable to reduce the total loading of drugs and metabolites and in addition will also significantly improve patient compliance. Soft drugs should not be confused with prodrugs (produgs) which undergo controlled conversion to functionally active metabolites and whose purpose is generally to provide increased exposure of the functionally active compound.

Given the high potential for the production of undesirable side effects of ROCK inhibitors, it will be appreciated that soft drug regimens represent an attractive route to the preparation of ROCK inhibitors with improved performance; in particular ROCK inhibitors associated with reduced systemic exposure and therefore lower potential for unwanted side effects.

While soft drugs represent an attractive approach to inhibiting ROCK and treating ROCK-related diseases or disorders, the design and optimization of such compounds is not trivial. Successful soft drugs must retain strong on-target potency and functional efficacy. In addition, a successful soft drug should exhibit good stability at the intended site of action (e.g., eye or lung) so that a pharmacologically relevant concentration of the drug can reach the intended site of action and be maintained for an extended period of time (typically several hours). In addition, a successful soft drug should degrade rapidly upon entering the systemic circulation, thereby avoiding systemic exposure and the undesirable side effects associated with systemic exposure. Finally, the molecules resulting from the degradation of the soft drug should exhibit a significantly reduced, preferably negligible, functional activity. As a result, the design and optimization of molecules that successfully combine all of these aspects represents a significant technical problem. In view of the foregoing, there is a continuing need to design and develop soft ROCK inhibitors for the treatment of a wide range of disease states.

The compounds described herein are soft ROCK inhibitors and address the technical problem of successfully combining strong target and functional potency, good stability in target organs (e.g., without limitation, eye or lung), and rapid conversion to predictable, non-functional active substances (species) in blood. The compounds described herein and pharmaceutically acceptable compositions thereof are useful for treating or lessening the severity of various disorders or conditions associated with ROCK activation. More specifically, the compounds of the present invention are preferably used for the prevention and/or treatment of at least one disease or disorder involving ROCK, such as diseases associated with smooth muscle cell function, inflammation, fibrosis, excessive cell proliferation, excessive angiogenesis, hyperreactivity, barrier dysfunction (barrier dysfunction), neurodegeneration, and remodeling. For example, the compounds of the present invention are useful for the prevention and/or treatment of the following diseases and disorders:

eye diseases or disorders including, but not limited to, retinopathy, optic neuropathy, glaucoma and degenerative retinal diseases such as macular degeneration, proliferative vitreoretinopathy, proliferative diabetic retinopathy, retinitis pigmentosa and inflammatory eye diseases, glaucoma filtration surgery failure, dry eye, allergic conjunctivitis, posterior capsular opacification, corneal wound healing abnormalities and eye pain.

-respiratory diseases; including but not limited to pulmonary fibrosis, emphysema, chronic bronchitis, asthma, fibrosis, pneumonia, cystic fibrosis, Chronic Obstructive Pulmonary Disease (COPD); bronchitis and rhinitis and respiratory distress syndrome.

-throat, nose and ear diseases: including but not limited to sinus problems (sinus problems), hearing problems, dental pain, tonsillitis, ulcers and rhinitis.

-skin diseases: including but not limited to hyperkeratosis, parakeratosis, thickening of the stratum granulosum, thickening of the stratum spinosum, parakeratosis, edema of the stratum spinosum, and ulceration.

-intestinal disorders: including but not limited to Inflammatory Bowel Disease (IBD), inflammatory bowel disease, gastroenteritis, ileus, appendicitis, and crohn's disease.

Cardiovascular and vascular diseases: including but not limited to pulmonary hypertension and pulmonary vasoconstriction.

-inflammatory diseases: including but not limited to contact dermatitis, atopic dermatitis, psoriasis, rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease, crohn's disease, and ulcerative colitis.

-neurological diseases: including but not limited to neuropathic pain. The compounds of the present invention are therefore useful in the prevention of neurodegeneration and in the stimulation of nerve regeneration in various neurological disorders.

-proliferative diseases: cancers such as, but not limited to, breast, colon, intestine, skin, head and neck, nerve, uterus, kidney, lung, ovary, pancreas, prostate, or thyroid; giant lymph node hyperplasia; a sarcoma; malignant cell tumors (malignoma) and melanoma.

-renal diseases: including but not limited to renal fibrosis or renal insufficiency.

-sexual dysfunction: male and female sexual dysfunction due to defective vasoactive responses are intended to be included. The soft ROCK inhibitors of the present invention are also useful in the treatment of sexual dysfunction due to a variety of causes. For example, in one embodiment, soft ROCK inhibitors are useful for treating sexual dysfunction associated with hypogonadism, more specifically, associated with decreased androgen levels. In another embodiment, soft ROCK inhibitors may be used to treat sexual dysfunction associated with a variety of causes, including but not limited to bladder disease, hypertension, diabetes, or pelvic surgery. In addition, soft ROCK inhibitors are useful in the treatment of sexual dysfunction caused by the use of certain drugs, for example, drugs for the treatment of hypertension, depression or anxiety.

Bone diseases including but not limited to osteoporosis and osteoarthritis.

Furthermore, the compounds of the present invention are useful for the prevention and/or treatment of diseases and disorders such as benign prostatic hyperplasia, transplant rejection, spasticity, chronic obstructive bladder disease, and allergy.

Disclosure of Invention

We have surprisingly found that the compounds described herein are useful as inhibitors of ROCK, in particular as soft ROCK inhibitors. Compared to the prior art known ROCK inhibitors described for example in WO2008/077057, WO2010/065782, WO2009/158587, US2009/0325959, US2009/325960, Iwakubo et al (bioorg. med. chem.,2007,15, 350-. Compound inactivation may occur in the liver but is preferably achieved directly in the bloodstream by blood enzymes such as carboxylic ester hydrolases (ec3.1.1) such as cholinesterase, paraoxonase 1(PON1) or plasma proteins exhibiting pseudoesterase activity such as human serum albumin. The compounds of the present invention thus solve the technical problem of successfully combining target potency (inhibitory activity against ROCK) and functional potency, good stability in target organs and rapid conversion in blood to predictable non-functional active substances. Therefore, the compounds of the present invention can achieve the desired pharmacological effects by inhibiting ROCK at the intended site of action (e.g., eye or lung) while avoiding systemic inhibition of ROCK which would create the potential for side effects.

Carboxylic ester hydrolases (EC3.1.1) represent a large group of enzymes involved in the degradation of carboxylic esters to alcohols and carboxylic acids. Therefore, enzymes exhibiting this catalytic activity are of potential interest for the design of soft kinase inhibitors. Ec3.1.1 includes the following subclasses: EC3.1.1.1 carboxyl esterase, EC3.1.1.2 aryl esterase, EC3.1.1.3 triacylglycerol lipase, EC3.1.1.4 phospholipase A2, EC3.1.1.5 lysophospholipase, EC3.1.1.6 acetyl esterase, EC3.1.1.7 acetylcholinesterase, EC3.1.1.8 cholinesterase, EC3.1.1.10 tropine esterase, EC3.1.1.11 pectin esterase, EC3.1.1.13 sterol esterase, EC3.1.1.14 chlorophyllase, EC3.1.1.15L-arabinonolactonase, EC3.1.1.17 gluconolactonase, EC3.1.1.19 urolactonase, EC3.1.1.20 tannase, EC3.1.1.21 retinoyl palmitate esterase, EC3.1.1.22 hydroxybutyrate dimer hydrolase, EC3.1.1.23 acylglycerol lipase, EC3.1.1.243-oxoadipate enollactonase, 36, 4-lactonase, 893.1.26, EC3.37.37-hydroxy butyrate dimer hydrolase, EC3.1.6 acetyl esterase, acetyl-D-arabinogalacturonan esterase, acetyl-D-L-D-acetyl-esterase, acetyl-D-L-D-, EC3.1.1.35 dihydrocoumarin hydrolase, EC3.1.1.36 limonin-D-cyclo-lactonase, EC3.1.1.37 steroid-lactonase, EC3.1.1.38 triacetonenase, EC3.1.1.39 actinomycin lactonase, EC3.1.1.40 orcinol hydrolase, EC3.1.1.41 cephalosporin-C deacetylase, EC3.1.1.42 chlorogenic acid hydrolase, EC3.1.1.43 alpha-amino acid esterase, EC3.1.1.444-methyloxaloacetate esterase, EC3.1.1.45 carboxymethylbutenolide esterase, EC3.1.1.46 deoxycitric acid A-cyclo-lactonase, EC3.1.1.471-alkyl-2-acetylglycerophosphocholinesterase, EC3.1.1.48 fusanin-C ornithine esterase, EC3.1.1.49 erucic base esterase, EC3.1.1.50 wax ester hydrolase, EC3.1.1.51 pol-diester hydrolase, EC3.1.1.52 phosphatidylinositol deacylase, EC3.1.1.53O-acetyl esterase, EC3.1.1.54 acetyloxybutynin diacyl-diacetylesterase, EC3.1.1.55 acetylsalicylic acid deacetylase, EC3.1.1.56 methylumbelliferyl acetate deacetylase, EC3.1.1.572-pyrone-4, 6-dicarboxylate lactonase, EC3.1.1.58N-acetylgalactosaminyl glycan deacetylase, EC3.1.1.59 juvenile hormone esterase, EC3.1.1.60 bis (2-ethylhexyl) phthalate esterase, EC3.1.1.61 protein-glutamic acid methyl esterase, EC3.1.1.6311-cis-retinyl-palmitic acid hydrolase, EC3.1.1.64 all-trans-retinyl-palmitic acid hydrolase, EC3.1.1.65L-rhamnose-1, 4-lactonase, EC3.1.1.665- (3, 4-diacetoxybutynyl-1-ynyl) -2,2' -bithiophene deacetylase, EC3.1.1.67 fatty-acyl-ethyl-ester synthase, EC3.1.1.68 xylose (xylono) -1, 4-lactonase, EC3.1.1.70 cetroratate benzylesterase, EC3.1.1.71 acetylalkylglyceroacetylhydrolase, EC3.1.1.72 acetylxylan esterase, EC3.1.1.73 feruloyl esterase, EC3.1.1.74 cutinase, EC3.1.1.75 poly (3-hydroxybutyrate) depolymerase, EC3.1.1.76 poly (3-hydroxyoctanoate) depolymerase, EC3.1.1.77 acyloxyacyl hydrolase, EC3.1.1.78 polynam-aldehyde esterase, EC3.1.1.79 hormone-sensitive lipase, EC3.1.1.80 acetylajmaline esterase, EC3.1.1.81 population-quenching N-acyl-homoserine lactonase, EC3.1.1.82 pheophorbidase (pheophorbidase), EC3.1.1.83 monoterpene epsilon-lactonase, EC3.1.1.84 cocaine esterase, EC3.1.1.85 mannosylglycerate hydrolase.

An example of a carboxylic ester hydrolase is PON 1. PON1 is a Ca²⁺Dependent serogroup a esterases, which are synthesized in the liver and secreted in the blood and bind exclusively to High Density Lipoproteins (HDLs). In addition, it is capable of cleaving a unique subset of substrates comprising organophosphates, aryl esters, lactones, and cyclic carbonates. Thus, R of the compounds of the present invention (hereinafter generally represented by formula I) may be selected¹Substituents to include substituents selected from aryl esters, lactones, and cyclic carbonates, more specifically aryl esters and lactones.

Human Serum Albumin (HSA) is the major component of plasma, accounting for approximately 60% of all plasma proteins. HSA has been found to catalyze the hydrolysis of a variety of compounds such as aspirin, cinnamoyl imidazole, p-nitrophenyl acetate, organophosphate insecticides, fatty acid esters, or nicotinic esters. In addition to its primary reaction site, HSA exhibits a variety of non-specific catalytic sites. However, the catalytic efficiency of these sites is low and HSA is often not described as a true esterase but as a pseudoesterase, although its catalytic efficiency is low, HSA may still play an important role in the metabolism of drug-like compounds because of its high concentration in plasma.

One skilled in the art will appreciate that a significant technical problem in the design of soft drugs (including soft ROCK inhibitors) is the successful combination of strong target potency and functional activity, good stability in target organs and rapid degradation to non-functional active species in systemic circulation. To produce the desired effect in the target organ, the soft ROCK inhibitor should achieve a pharmacologically relevant concentration in the target organ and maintain that concentration over a long period of time (typically several hours). To avoid systemic inhibition of ROCK, which may lead to unwanted effects, soft ROCK inhibitors should degrade rapidly after entering the systemic circulation before they can accumulate pharmacologically relevant concentrations in the bloodstream or in non-target organs.

It will also be understood by those skilled in the art that the recognition (complementary interaction) between ROCK and a soft ROCK inhibitor will result in the inhibition of ROCK, although the inactivation of a soft ROCK inhibitor in the liver or bloodstream results from said soft ROCK inhibitor being recognized as a substrate by one or more liver or blood enzymes, such as a carboxylic ester hydrolase (ec 3.1.1). Since these 2 recognition processes involve separate macromolecules (ROCK and hydrolase) and thus separate ligand binding sites, the structural features that control such recognition processes are also independent of each other and are not necessarily compatible. It will therefore be appreciated that the inhibitory activity of chemical compounds against ROCK is never predictive of (un) stability in systemic circulation.

As discussed above, successful soft ROCK inhibitors need to exhibit both low stability in the systemic circulation and good stability in the target organ. One skilled in the art will appreciate that such differences in stability between different organs and fluids may result from different enzymes (particularly esterases) present in these tissues or fluids, from different expression levels ("concentrations") of the same enzyme, or from both. It will also be appreciated that each additional enzyme (including esterases) present in an organ or fluid represents a new ligand binding site with its own set of rules governing recognition as a substrate. Such rules are not necessarily compatible with each other, and generally result in most enzymes exhibiting a degree of substrate specificity. To achieve acceptable stability in the target organ, a successful soft ROCK inhibitor should therefore at least to some extent avoid recognition as a substrate by degradative enzymes (including carboxylic ester hydrolases) present in large amounts in the target organ. Again, it should be understood that the inhibitory activity of chemical compounds against ROCK is never predictive of (un) stability in the target organ. In addition, it is understood that different enzymes may be involved due to potential degradation mechanisms in the liver, bloodstream, and target organs; the (non-) stability in the liver or blood stream is by no means predictive of the (non-) stability in the target organ.

In view of the above, it will be appreciated that the design of soft ROCK inhibitors exhibiting appropriate activity and stability characteristics (profile) represents a significant technical problem to be solved. In particular, it will be appreciated that the inhibitory activity against ROCK and stability in the liver, bloodstream or target organ is governed by an independent set of structural rules, making the design of a successful soft ROCK inhibitor unclear.

It will also be understood by those skilled in the art that soft drugs and prodrugs represent opposite protocols in their concept and purpose, although both protocols involve controlled and predictable metabolism of the administered compound. In fact, soft drugs are chemical compounds with strong functional activity that undergo controlled metabolism to non-functional active substances and therefore to non-toxic substances. The purpose of soft drugs is to reduce systemic exposure to the functionally active compound and to direct the metabolism and elimination of the drug compound to predictable pathways, thereby producing non-functionally active, non-toxic metabolites. In contrast, a prodrug is a chemical compound that does not necessarily have functional activity, but undergoes controlled metabolism to the functionally active compound. The purpose of the prodrug is to increase exposure to the functionally active compound, for example because the prodrug exhibits higher cell permeability, higher bioavailability, or allows for sustained release of the functionally active compound that would otherwise be rapidly cleared from the bloodstream.

An asterisk as used herein indicates the point at which a monovalent or divalent group is attached to its associated structure and the structure of which the group forms a part, unless the context dictates otherwise.

Viewed from a first aspect the invention provides a compound of formula I or a stereoisomer, tautomer, racemate, salt, hydrate or solvate thereof,

wherein

X is oxygen, -NH-or a direct bond;

y is-NH-or a direct bond;

n is an integer of 0 to 4;

m is an integer of 0 to 4;

cy represents a divalent group consisting of saturated (poly) rings, including fused, bicyclic, spiro or bridged carbocyclic and heterocyclic rings; in particular from:

ar is selected from:

wherein

R²Is hydrogen or methyl;

R⁸is hydrogen, methyl, halogen or alkynyl;

R¹is optionally halogenated (halo) or C_1-6Alkyl-substituted aryl or heteroaryl; wherein said aryl or heteroaryl is substituted with a substituent selected from the group consisting of:

●-(CH₂)_p-C(=O)-OR²¹；

●-(CH₂)_p-C(=O)-NR³R⁴；

●-(CH₂)_p-C(=O)-SR²²；

●Het¹、-O-Het¹、-NH-Het¹or-S-Het¹(ii) a And

●-O-C_1-6alkyl, -NH-C_1-6Alkyl, -S-C_1-6Alkyl or-C_1-6An alkyl group; wherein said-O-C_1-6Alkyl, -NH-C_1-6Alkyl, -S-C_1-6Alkyl or-C_1-6Each alkyl group is independently substituted with a substituent selected from the group consisting of: -C (= O) -OR²¹、-C(=O)-NR³R⁴、Het¹、-O-Het¹、-NH-Het¹and-S-Het¹；

Wherein

p is an integer of 0 to 3

Het¹Selected from:

R²¹selected from: optionally substituted C_1-20Alkyl, optionally substituted C_1-20Alkenyl, optionally substituted C_1-20Alkynyl, optionally substituted C_3-15Cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl;

R²²is optionally substituted C_1-6An alkyl group;

R³selected from: het¹、C_1-20Alkyl, aryl or heteroaryl; wherein said C_1-20Alkyl, aryl or heteroaryl is substituted with 1,2 or 3 substituents each independently selected from: aryl, heteroaryl, - (CH)₂)_p-C(=O)-OR²¹、-Het¹、-NH-Het¹、-O-Het¹、-S-Het¹、-S-C_2-6Alkyl, -NH-C_2-6Alkyl and-O-C_2-6An alkyl group;

wherein said aryl, heteroaryl, -O-C_2-6Alkyl, -NH-C_2-6Alkyl or-S-C_2-6Each alkyl group is independently substituted with a substituent selected from the group consisting of: c (= O) -OR²¹、-Het¹、-O-Het¹、-NH-Het¹and-S-Het¹(ii) a And

R⁴selected from: hydrogen or C_1-6An alkyl group; or

R³And R⁴Together with the nitrogen atom to which they are attached form a heterocyclic ring substituted with one substituent selected from: c_1-20Alkyl, aryl or heteroaryl; wherein said C_1-20Alkyl, aryl or heteroaryl is substituted with 1,2 or 3 substituents each independently selected from: aryl, heteroaryl, -C (= O) -OR²¹、-Het¹、-O-Het¹、-S-Het¹、-S-C_2-6Alkyl, -NH-C_2-6Alkyl and-O-C_2-6An alkyl group;

wherein said-O-C_2-6Alkyl, -NH-C_2-6Alkyl or-S-C_2-6Each alkyl group is independently substituted with a substituent selected from the group consisting of: c (= O) -OR²¹、-Het¹、-O-Het¹、-NH-Het¹and-S-Het¹；

With the proviso that,

-R¹is not selected from-O-CH₂-C(=O)-OR²¹Substituted aryl or heteroaryl;

if R is¹Is phenyl, then the phenyl group may not be in the para position by- (CH)₂)_p-C(=O)-OR²¹Substitution; and is

-said compound of formula I is not

As can be seen from the above, since at least one is selected from the group consisting of-C (= O) -OR²¹、-C(=O)-SR²²And Het¹All compounds of formula I contain at least one ester, thioester, cyclic ester or cyclic carbonate group.

Viewed from another aspect the invention provides the use of a compound of the invention or a composition comprising such a compound for inhibiting the activity of at least one kinase in vitro or in vivo.

Viewed from a further aspect the invention provides the use of a compound of the invention, or a composition comprising such a compound, for inhibiting the activity of at least one ROCK kinase (e.g. ROCKII and/or ROCKI isoforms) in vitro or in vivo.

Viewed from a further aspect the invention provides a pharmaceutical and/or veterinary composition comprising a compound of the invention.

Viewed from a further aspect the invention provides a compound of the invention for use in human or veterinary medicine.

Viewed from another aspect the invention provides the use of a compound of the invention in the manufacture of a medicament for the prevention and/or treatment of at least one disease and/or disorder selected from: eye diseases; respiratory diseases; throat, nose and ear diseases; intestinal disease; cardiovascular and vascular diseases; inflammatory diseases; neurological and central nervous system disorders; proliferative diseases; renal disease; sexual dysfunction; bone disease; benign prostatic hyperplasia, transplant rejection, spasticity, chronic obstructive bladder disease, and allergies.

Drawings

With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of the various embodiments of the present invention only. They are presented to provide the most useful and readily understandable description of the principles and conceptual aspects of the invention. In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for a fundamental understanding of the invention. The description taken with the drawings making apparent to those skilled in the art how the several forms of the invention may be embodied in practice.

FIG. 1: concentration-response curves of compound 14 (filled squares) and its metabolite Met1 (filled circles) in MLC phosphorylation assays. The 95% confidence interval for compound 14 is shown.

FIG. 2: reduction of intraocular pressure over time with compound 14.

Detailed Description

The invention will now be further described. In the following paragraphs, the different aspects of the invention are defined in more detail. Each aspect so defined may also be combined with one or more of any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may also be combined with any other feature or features indicated as being preferred or advantageous.

An asterisk as used herein indicates the point at which a monovalent or divalent group is attached to its associated structure and the structure of which the group forms a part, unless the context dictates otherwise.

Undefined (racemic) asymmetric centers that may be present in the compounds of the present invention are interchangeably indicated by plotting either a wavy bond or a direct bond to reveal the undefined steric nature of the bond.

As already mentioned above, in a first aspect, the present invention provides compounds of formula I

Wherein Ar, X, Cy, Y, m, n and R¹Are as defined above, including stereoisomeric forms, solvates and pharmaceutically acceptable addition salts thereof.

When describing the compounds of the present invention, the terms used are to be construed according to the following definitions, unless the context dictates otherwise:

the term "alkyl" by itself or as part of another group denotes the formula C_xH_2x+1Wherein x is a number greater than or equal to 1. Generally, the alkyl groups of the present invention contain 1 to 20 carbon atoms. Alkyl groups may be straight or branched chain and may be substituted as indicated herein. When a carbon atom is followed by a subscript, that subscript refers to the number of carbon atoms that the named group may contain. Thus, for example, C_1-4Alkyl refers to alkyl groups having one to four carbon atoms. Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, butyl and isomers thereof (e.g., n-butyl, isobutyl and tert-butyl); pentyl and its isomers, hexyl and its isomers, heptyl and its isomers, octyl and its isomers, nonyl and its isomers; decyl and isomers thereof. C₁-C₆Alkyl includes all straight, branched, or cyclic alkyl groups having 1 to 6 carbon atoms, and thus includes methyl, ethyl, n-propyl, isopropyl, butyl, and isomers thereof (e.g., n-butyl, isobutyl, and tert-butyl); pentyl and its isomers, hexyl and its isomers, cyclopentyl, 2-, 3-, or 4-methylcyclopentyl, cyclopentylmethylene (cyclopentylmethyl)methyl) and cyclohexyl.

The term "optionally substituted alkyl" denotes an alkyl group optionally substituted at any available point of attachment by one or more substituents (e.g. 1 to 4 substituents, such as 1,2,3 or 4 substituents or 1 to 2 substituents; especially 1 substituent). Non-limiting examples of such substituents include: halo, hydroxy, oxo, carbonyl, nitro, amino, amido, oxime, imino, azido, hydrazino, cyano, aryl, heteroaryl, cycloalkyl, heterocyclyl, acyl, alkylamino, alkoxy, haloalkoxy, haloalkyl, thiol, alkylthio, carboxylic acid, acylamino, alkyl ester, carbamate, thioamido, urea, sulfonamido, and the like. Preferably, such substituents are selected from halo, hydroxy, nitro, amino, cyano, aryl (especially phenyl), cycloalkyl, heterocyclyl (especially pyrrolidine, tetrahydrofuran (oxolane), tetrahydrothiophene (thiolane) or Het as described hereinafter¹(ii) a More particularly pyrrolidine or tetrahydrofuran) and alkoxy groups. More preferably, said substituents are selected from hydroxyl, aryl (especially phenyl), cycloalkyl, heterocyclyl (especially pyrrolidine, tetrahydrofuran, tetrahydrothiophene or Het) as described hereinafter¹(ii) a More particularly pyrrolidine or tetrahydrofuran) and alkoxy groups.

The term "alkenyl" as used herein, unless otherwise specified, refers to a straight, cyclic or branched chain hydrocarbon group containing at least one carbon-carbon double bond. Examples of alkenyl groups include ethenyl, E-and Z-propenyl, isopropenyl, E-and Z-butenyl, E-and Z-isobutenyl, E-and Z-pentenyl, E-and Z-hexenyl, E-, E, Z-, Z, E-, Z-hexadienyl, and the like. Optionally substituted alkenyl denotes alkenyl optionally having one or more (e.g. 1,2,3 or 4) substituents selected from those defined above for substituted alkyl.

The term "alkynyl" as used herein, unless otherwise specified, refers to a straight or branched chain hydrocarbon radical containing at least one carbon-carbon triple bond. Examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Optionally substituted alkynyl denotes alkynyl optionally bearing one or more (e.g. 1,2,3 or 4) substituents selected from those defined above for substituted alkyl.

The term "cycloalkyl" by itself or as part of another substituent is a cyclic alkyl group, that is, a monovalent, saturated or unsaturated hydrocarbon group having 1,2 or 3 cyclic structures. Cycloalkyl includes all saturated or partially saturated (containing 1 or 2 double bonds) hydrocarbon groups containing 1 to 3 rings, including monocyclic, bicyclic, and polycyclic alkyl groups. Cycloalkyl groups may contain 3 or more carbon atoms in the ring, while 3 to 15 atoms are generally included according to the invention. Further rings of the polycyclic cycloalkyl group may be fused, bridged and/or added through one or more spiro atoms. Cycloalkyl groups may also be considered to be a subset of homocyclic rings (homocyclic rings) as discussed below. Examples of cycloalkyl groups include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, adamantyl, bicyclo (2.2.1) heptanyl and cyclodecyl, with cyclopropyl, cyclopentyl, cyclohexyl, adamantyl and bicyclo (2.2.1) heptanyl being particularly preferred. "optionally substituted cycloalkyl" means cycloalkyl optionally having one or more substituents (e.g., 1-3 substituents, such as 1,2,3, or 4 substituents) selected from those defined above for substituted alkyl. When the prefix "ene" is used in conjunction with a cyclic group, also referred to hereinafter as "cycloalkylene", this means that the cyclic group as defined herein has two single bonds as points of attachment to other groups. Cycloalkylene groups of the present invention preferably contain the same number of carbon atoms as their cycloalkyl residue counterparts.

If an alkyl group is defined as divalent, i.e., two single bonds are attached to two other groups, they will be referred to as "alkylene" groups. Non-limiting examples of alkylene groups include methylene, ethylene, methylmethylene, trimethylene, propylene, tetramethylene, ethylethylene, 1, 2-dimethylethylene, pentamethylene, and hexamethylene. Similarly, if an alkenyl group as defined above and an alkynyl group as defined below are divalent, i.e., have a single bond attached to two other groups, they will be referred to as "alkenylene" and "alkynylene," respectively.

In general, the alkylene groups of the present invention preferably contain the same number of carbon atoms as their alkyl counterparts. If an alkylene or cycloalkylene diradical (bicadic) group is present, it will be attached to the molecular structure of which it forms a part, either through a common carbon atom or through different carbon atoms, of which common carbon atoms are preferred. To illustrate this, the asterisk nomenclature of the present invention, C, is used₃Alkylene may be, for example, -CH₂CH₂CH₂-*、*-CH(-CH₂CH₃) -CH₂CH(-CH₃) - *. Likewise, C₃The cycloalkylene group may be

If cycloalkylene is present, it is preferably C₃-C₆Cycloalkylene, more preferably C₃Cycloalkylene (i.e. cyclopropylene) groups, in which the moieties are attached through a common carbon atom. Cycloalkylene and alkylene diradicals in the compounds of the invention may be, but preferably are not, substituted.

The term "heterocyclyl" or "heterocycle" as used herein by itself or as part of another group refers to a non-aromatic, fully saturated or partially unsaturated cyclic group (e.g., a 3 to 13 membered monocyclic, or 7 to 17 membered bicyclic, or 10 to 20 membered tricyclic ring system, or containing 3 to 10 ring atoms in total) in which at least one heteroatom in at least one carbon atom-containing ring must be present. For each ring containing a heteroatom in the heterocyclic group, there may be 1,2,3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be attached to any heteroatom or carbon atom of the ring or ring system, as valency permits. The rings of the polycyclic heterocycle may be fused, bridged and/or added through one or more spiro atoms. Optionally substituted heterocycle means a heterocycle optionally having one or more substituents (e.g., 1 to 4 substituents, or such as 1,2,3, or 4) selected from those defined for substituted aryl.

Exemplary heterocyclic groups include piperidinyl, azetidinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, succinimidyl, 3H-indolyl, isoindolinyl, chromenyl, isochroman, xanthyl, 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 4H-quinolizinyl, 4 aH-carbazolyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, pyranyl, dihydro-2H-pyranyl, 4H-pyranyl, 3, 4-dihydro-2H-pyranyl, phthalazinyl, oxetanyl, thietanyl, 3-dioxocyclopentylpentyl, oxazanyl, and the like, 1, 3-dioxanyl, 2, 5-dioxoimidazolidinyl (dioxozolidinyl), 2, 4-piperidinonyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl (oxypyrrolidinyl), 2-oxazepinyl (2-oxoazepinyl), indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, thiomorpholinyl (thiomorpholinyl), thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1, 3-dioxolyl, 1, 4-oxathiacyclohexyl, 1, 4-dithianyl, 1,3, 5-trioxepanyl (trioxanyl), 6H-1,2, 5-thiadiazinyl, 2H-1,5, 2-dithiazinyl, 2H-oxocyclooctatrienyl (oxocinninyl), 1H-pyrrolizinyl, Tetrahydro-1, 1-dioxothienyl, N-formylpiperazinyl and morpholinyl.

The term "aryl" as used herein means a polyunsaturated aromatic hydrocarbon group containing a single ring (i.e., phenyl) or multiple aromatic rings fused together (e.g., naphthalene or anthracene) or covalently bonded, typically containing from 6 to 10 atoms; wherein at least one ring is aromatic. The aromatic ring may optionally contain one to three additional rings (cycloalkyl, heterocyclyl or heteroaryl) fused thereto. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic ring systems enumerated herein. Non-limiting examples of aryl groups include phenyl, biphenyl, biphenylene, 5-or 6-tetrahydronaphthyl (tetralinyl), 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-azulenyl, 1-or 2-naphthyl, 1-, 2-, or 3-indenyl, 1-, 2-, or 9-anthryl, 1-2-, 3-, 4-, or 5-acenaphthenyl (acenaphthenyl), 3-, 4-, or 5-dihydroacenaphthenyl (acenaphthenyl), 1-, 2-, 3-, 4-, or 10-phenanthrenyl, 1-or 2-pentalenyl, 1,2-, 3-, or 4-fluorenyl, 4-or 5-dihydroindenyl, tetralinyl, and the like, 5-, 6-, 7-, or 8-tetrahydronaphthyl, 1,2,3, 4-tetrahydronaphthyl, 1, 4-dihydronaphthyl, diphenylo [ a, d ] cycloheptenyl, and 1-, 2-, 3-, 4-, or 5-pyrenyl.

The aryl ring may be optionally substituted with one or more substituents. "optionally substituted aryl" means an aryl group optionally having one or more substituents (e.g., 1-5 substituents, e.g., 1,2,3, or 4) at any available point of attachment. Non-limiting examples of such substituents are selected from: halogen, hydroxy, oxo, nitro, amino, hydrazine, aminocarbonyl, azido, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkylalkyl, alkylamino, alkoxy, -SO₂-NH₂Aryl, heteroaryl, aralkyl, haloalkyl, haloalkoxy, alkoxycarbonyl, alkylaminocarbonyl, heteroarylalkyl, alkylsulfonamide, heterocyclyl, alkylcarbonylaminoalkyl, aryloxy, alkylcarbonyl, acyl, arylcarbonyl, aminocarbonyl, alkylsulfoxide, -SO₂R^aAlkyl thio, carboxyl, etc., wherein R^aIs an alkyl or cycloalkyl group. Preferably, such substituents are selected from: halogen, hydroxy, nitro, amino, cyano, alkyl (especially C)_1-6An alkyl group; more particularly methyl), alkylamino, alkoxy and haloalkyl.

If a carbon atom of an aryl group is replaced by a heteroatom, the resulting ring is referred to herein as a heteroaryl ring.

The term "heteroaryl" as used herein by itself or as part of another group refers to, but is not limited to, an aromatic ring or ring system of 5 to 12 carbon atoms, wherein 1 to 3 rings are fused together or covalently bonded, typically 5 to 8 atoms; at least one of which is aromatic, wherein one or more of the carbon atoms within one or more of these rings may be replaced by oxygen, nitrogen or sulfur atoms, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatoms may optionally be quaternized. These rings may be fused to aryl, cycloalkyl, heteroaryl or heterocyclyl rings. Non-limiting examples of these heteroaryl groups include: pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazinyl, dioxadienyl, thiazinyl, triazinyl, imidazo [2,1-b ] [1,3] thiazolyl, thieno [3,2-b ] furyl, thieno [3,2-b ] thienyl, thieno [2,3-d ] [1,3] thiazolyl, thieno [2,3-d ] imidazolyl, tetrazolo [1,5-a ] pyridyl, indolyl, indolizinyl, isoindolyl, benzofuryl, benzopyranyl, 1(4H) -benzopyranyl, 1(2H) -benzopyranyl, 3, 4-dihydro-1 (2H) -benzopyranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, indazolyl, benzimidazolyl, 1, 3-benzoxazolyl, 1, 2-benzisoxazolyl, 2, 1-benzisoxazolyl, 1, 3-benzothiazolyl, 1, 2-benzisothiazolyl, 2, 1-benzisothiazolyl, benzotriazolyl, 1,2, 3-benzoxadiazolyl, 2,1, 3-benzoxadiazolyl, 1,2, 3-benzothiadiazolyl, 2,1, 3-benzothiadiazolyl, thienopyridyl, purinyl, imidazo [1,2-a ] pyridyl, 6-oxo-pyridazin-1 (6H) -yl, 2-oxopyridin-1 (2H) -yl, 6-oxo-pyridazin-1 (6H) -yl, 2-oxopyridin-1 (2H) -yl, 1, 3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, 7-azaindolyl, 6-azaindolyl, 5-azaindolyl, 4-azaindolyl.

The term "pyrrolyl" (also known as oxazolyl) as used herein includes pyrrol-1-yl, pyrrol-2-yl and pyrrol-3-yl. The term "furyl" (also referred to as "furyl") as used herein includes furan-2-yl and furan-3-yl (also referred to as furan-2-yl and furan-3-yl). The term "thienyl" (also referred to as "thienyl") as used herein includes thien-2-yl and thien-3-yl (also referred to as thien-2-yl and thien-3-yl). The term "pyrazolyl" (also known as 1H-pyrazolyl and 1, 2-oxadiazolyl) as used herein includes pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl and pyrazol-5-yl. The term "imidazolyl" as used herein includes imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, and imidazol-5-yl. The term "oxazolyl" (also referred to as 1, 3-oxazolyl) as used herein includes oxazol-2-yl; oxazol-4-yl and oxazol-5-yl. The term "isoxazolyl" (also known as 1, 2-oxazolyl) as used herein includes isoxazol-3-yl, isoxazol-4-yl and isoxazol-5-yl. The term "thiazolyl" (also known as 1, 3-thiazolyl) as used herein includes thiazol-2-yl, thiazol-4-yl and thiazol-5-yl (also known as 2-thiazolyl, 4-thiazolyl and 5-thiazolyl). The term "isothiazolyl" (also known as 1, 2-thiazolyl) as used herein includes isothiazol-3-yl, isothiazol-4-yl and isothiazol-5-yl. The term "triazolyl" as used herein includes 1H-triazolyl and 4H-1,2, 4-triazolyl, and "1H-triazolyl" includes 1H-1,2, 3-triazol-1-yl, 1H-1,2, 3-triazol-4-yl, 1H-1,2, 3-triazol-5-yl, 1H-1,2, 4-triazol-1-yl, 1H-1,2, 4-triazol-3-yl and 1H-1,2, 4-triazol-5-yl. "4H-1, 2, 4-triazolyl" includes 4H-1,2, 4-triazol-4-yl and 4H-1,2, 4-triazol-3-yl. The term "oxadiazol" as used herein includes 1,2, 3-oxadiazol-4-yl, 1,2, 3-oxadiazol-5-yl, 1,2, 4-oxadiazol-3-yl, 1,2, 4-oxadiazol-5-yl, 1,2, 5-oxadiazol-3-yl and 1,3, 4-oxadiazol-2-yl. The term "thiadiazolyl" as used herein includes 1,2, 3-thiadiazol-4-yl, 1,2, 3-thiadiazol-5-yl, 1,2, 4-thiadiazol-3-yl, 1,2, 4-thiadiazol-5-yl, 1,2, 5-thiadiazol-3-yl (also known as furazan-3-yl) and 1,3, 4-thiadiazol-2-yl. The term "tetrazolyl" as used herein includes 1H-tetrazol-1-yl, 1H-tetrazol-5-yl, 2H-tetrazol-2-yl and 2H-tetrazol-5-yl. The term "oxatriazolyl" as used herein includes 1,2,3, 4-oxatriazol-5-yl and 1,2,3, 5-oxatriazol-4-yl. The term "thiatriazolyl" as used herein includes 1,2,3, 4-thiatriazol-5-yl and 1,2,3, 5-thiatriazol-4-yl. The term "pyridyl" (also referred to as "pyridyl") as used herein includes pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl (also referred to as 2-pyridyl, 3-pyridyl, and 4-pyridyl). The term "pyrimidinyl" as used herein includes pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl and pyrimidin-6-yl. The term "pyrazinyl" as used herein includes pyrazin-2-yl and pyrazin-3-yl. The term "pyridazinyl" as used herein includes pyridazin-3-yl and pyridazin-4-yl. The term "oxazinyl" (also referred to as "1, 4-oxazinyl") as used herein includes 1, 4-oxazin-4-yl and 1, 4-oxazin-5-yl. The term "dioxadienyl" (also referred to as "1, 4-dioxadienyl") as used herein includes 1, 4-dioxadien-2-yl and 1, 4-dioxadien-3-yl. The term "thiazinyl" (also referred to as "1, 4-thiazinyl") as used herein includes 1, 4-thiazin-2-yl, 1, 4-thiazin-3-yl, 1, 4-thiazin-4-yl, 1, 4-thiazin-5-yl, and 1, 4-thiazin-6-yl. The term "triazinyl group" as used herein includes 1,3, 5-triazin-2-yl, 1,2, 4-triazin-3-yl, 1,2, 4-triazin-5-yl, 1,2, 4-triazin-6-yl, 1,2, 3-triazin-4-yl and 1,2, 3-triazin-5-yl. The term "imidazo [2,1-b ] [1,3] thiazolyl" as used herein includes imidazo [2,1-b ] [1,3] thiazol-2-yl, imidazo [2,1-b ] [1,3] thiazol-3-yl, imidazo [2,1-b ] [1,3] thiazol-5-yl and imidazo [2,1-b ] [1,3] thiazol-6-yl. The term "thieno [3,2-b ] furyl" as used herein includes thieno [3,2-b ] furan-2-yl, thieno [3,2-b ] furan-3-yl, thieno [3,2-b ] furan-4-yl, and thieno [3,2-b ] furan-5-yl. The term "thieno [3,2-b ] thiophenyl" as used herein includes thieno [3,2-b ] thiophen-2-yl, thieno [3,2-b ] thiophen-3-yl, thieno [3,2-b ] thiophen-5-yl and thieno [3,2-b ] thiophen-6-yl. The term "thieno [2,3-d ] [1,3] thiazolyl" as used herein includes thieno [2,3-d ] [1,3] thiazol-2-yl, thieno [2,3-d ] [1,3] thiazol-5-yl and thieno [2,3-d ] [1,3] thiazol-6-yl. The term "thieno [2,3-d ] imidazolyl" as used herein includes thieno [2,3-d ] imidazol-2-yl, thieno [2,3-d ] imidazol-4-yl, and thieno [2,3-d ] imidazol-5-yl. The term "tetrazolo [1,5-a ] pyridyl" as used herein includes tetrazolo [1,5-a ] pyridin-5-yl, tetrazolo [1,5-a ] pyridin-6-yl, tetrazolo [1,5-a ] pyridin-7-yl and tetrazolo [1,5-a ] pyridin-8-yl. The term "indolyl" as used herein includes indol-1-yl, indol-2-yl, indol-3-yl, -indol-4-yl, indol-5-yl, indol-6-yl and indol-7-yl. The term "indolizinyl" as used herein includes indolizin-1-yl, indolizin-2-yl, indolizin-3-yl, indolizin-5-yl, indolizin-6-yl, indolizin-7-yl and indolizin-8-yl. The term "isoindolyl" as used herein includes isoindol-1-yl, isoindol-2-yl, isoindol-3-yl, isoindol-4-yl, isoindol-5-yl, isoindol-6-yl, and isoindol-7-yl. The term "benzofuranyl" (also referred to as benzo [ b ] furanyl) as used herein includes benzofuran-2-yl, benzofuran-3-yl, benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl and benzofuran-7-yl. The term "isobenzofuranyl" (also referred to as benzo [ c ] furanyl) as used herein includes isobenzofuran-1-yl, isobenzofuran-3-yl, isobenzofuran-4-yl, isobenzofuran-5-yl, isobenzofuran-6-yl and isobenzofuran-7-yl. The term "benzothienyl" (also referred to as benzo [ b ] thienyl) as used herein includes 2-benzo [ b ] thienyl, 3-benzo [ b ] thienyl, 4-benzo [ b ] thienyl, 5-benzo [ b ] thienyl, 6-benzo [ b ] thienyl and 7-benzo [ b ] thienyl (also referred to as benzothien-2-yl, benzothien-3-yl, benzothien-4-yl, benzothien-5-yl, benzothien-6-yl and benzothien-7-yl). The term "isobenzothiophenyl" (also referred to as benzo [ c ] thiophenyl) as used herein includes isobenzothiophen-1-yl, isobenzothiophen-3-yl, isobenzothiophen-4-yl, isobenzothiophen-5-yl, isobenzothiophen-6-yl and isobenzothiophen-7-yl. The term "indazolyl" (also referred to as 1H-indazolyl or 2-azaindolyl) as used herein includes 1H-indazol-1-yl, 1H-indazol-3-yl, 1H-indazol-4-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indazol-7-yl, 2H-indazol-2-yl, 2H-indazol-3-yl, 2H-indazol-4-yl, 2H-indazol-5-yl, 2H-indazol-6-yl and 2H-indazol-7-yl. The term "benzimidazolyl" as used herein includes benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl and benzimidazol-7-yl. The term "1, 3-benzoxazolyl" as used herein includes 1, 3-benzoxazol-2-yl, 1, 3-benzoxazol-4-yl, 1, 3-benzoxazol-5-yl, 1, 3-benzoxazol-6-yl and 1, 3-benzoxazol-7-yl. The term "1, 2-benzisoxazol-yl" as used herein includes 1, 2-benzisoxazol-3-yl, 1, 2-benzisoxazol-4-yl, 1, 2-benzisoxazol-5-yl, 1, 2-benzisoxazol-6-yl, and 1, 2-benzisoxazol-7-yl. The term "2, 1-benzisoxazol-yl" as used herein includes 2, 1-benzisoxazol-3-yl, 2, 1-benzisoxazol-4-yl, 2, 1-benzisoxazol-5-yl, 2, 1-benzisoxazol-6-yl, and 2, 1-benzisoxazol-7-yl. The term "1, 3-benzothiazolyl" as used herein includes 1, 3-benzothiazol-2-yl, 1, 3-benzothiazol-4-yl, 1, 3-benzothiazol-5-yl, 1, 3-benzothiazol-6-yl, and 1, 3-benzothiazol-7-yl. The term "1, 2-benzisothiazolyl" as used herein includes 1, 2-benzisothiazol-3-yl, 1, 2-benzisothiazol-4-yl, 1, 2-benzisothiazol-5-yl, 1, 2-benzisothiazol-6-yl and 1, 2-benzisothiazol-7-yl. The term "2, 1-benzisothiazolyl" as used herein includes 2, 1-benzisothiazol-3-yl, 2, 1-benzisothiazol-4-yl, 2, 1-benzisothiazol-5-yl, 2, 1-benzisothiazol-6-yl and 2, 1-benzisothiazol-7-yl. The term "benzotriazol-yl" as used herein includes benzotriazol-1-yl, benzotriazol 4-yl, benzotriazol-5-yl, benzotriazol-6-yl and benzotriazol-7-yl. The term "1, 2, 3-benzoxadiazolyl" as used herein includes 1,2, 3-benzoxadiazol-4-yl, 1,2, 3-benzoxadiazol-5-yl, 1,2, 3-benzoxadiazol-6-yl and 1,2, 3-benzoxadiazol-7-yl. The term "2, 1, 3-benzoxadiazolyl" as used herein includes 2,1, 3-benzoxadiazol-4-yl, 2,1, 3-benzoxadiazol-5-yl, 2,1, 3-benzoxadiazol-6-yl and 2,1, 3-benzoxadiazol-7-yl. The term "1, 2, 3-benzothiadiazol-yl" as used herein includes 1,2, 3-benzothiadiazol-4-yl, 1,2, 3-benzothiadiazol-5-yl, 1,2, 3-benzothiadiazol-6-yl, and 1,2, 3-benzothiadiazol-7-yl. The term "2, 1, 3-benzothiadiazolyl" as used herein includes 2,1, 3-benzothiadiazol-4-yl, 2,1, 3-benzothiadiazol-5-yl, 2,1, 3-benzothiadiazol-6-yl, and 2,1, 3-benzothiadiazol-7-yl. The term "thienopyridyl" as used herein includes thieno [2,3-b ] pyridyl, thieno [2,3-c ] pyridyl, thieno [3,2-c ] pyridyl and thieno [3,2-b ] pyridyl. The term "purinyl" as used herein includes purin-2-yl, purin-6-yl, purin-7-yl and purin-8-yl. The term "imidazo [1,2-a ] pyridyl" as used herein includes imidazo [1,2-a ] pyridin-2-yl, imidazo [1,2-a ] pyridin-3-yl, imidazo [1,2-a ] pyridin-4-yl, imidazo [1,2-a ] pyridin-5-yl, imidazo [1,2-a ] pyridin-6-yl and imidazo [1,2-a ] pyridin-7-yl. The term "1, 3-benzodioxolyl" as used herein includes 1, 3-benzodioxol-4-yl, 1, 3-benzodioxol-5-yl, 1, 3-benzodioxol-6-yl and 1, 3-benzodioxol-7-yl. The term "quinolyl" as used herein includes quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl and quinolin-8-yl. The term "isoquinolinyl" as used herein includes isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl and isoquinolin-8-yl. The term "cinnolin-based" as used herein includes cinnolin-3-yl, cinnolin-4-yl, cinnolin-5-yl, cinnolin-6-yl, cinnolin-7-yl and cinnolin-8-yl. The term "quinazolinyl" as used herein includes quinazolin-2-yl, quinazolin-4-yl, quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl and quinazolin-8-yl. The term "quinoxalinyl" as used herein includes quinoxalin-2-yl, quinoxalin-5-yl and quinoxalin-6-yl. The term "7-azaindolyl" as used herein denotes 1H-pyrrolo [2,3-b ] pyridinyl, and includes 7-azaindol-1-yl, 7-azaindol-2-yl, 7-azaindol-3-yl, 7-azaindol-4-yl, 7-azaindol-5-yl, 7-azaindol-6-yl. The term "6-azaindolyl" as used herein denotes 1H-pyrrolo [2,3-c ] pyridinyl, and includes 6-azaindol-1-yl, 6-azaindol-2-yl, 6-azaindol-3-yl, 6-azaindol-4-yl, 6-azaindol-5-yl, 6-azaindol-7-yl. The term "5-azaindolyl" as used herein denotes 1H-pyrrolo [3,2-c ] pyridinyl, and includes 5-azaindol-1-yl, 5-azaindol-2-yl, 5-azaindol-3-yl, 5-azaindol-4-yl, 5-azaindol-6-yl, 5-azaindol-7-yl. The term "4-azaindolyl" as used herein denotes 1H-pyrrolo [3,2-b ] pyridinyl, and includes 4-azaindol-1-yl, 4-azaindol-2-yl, 4-azaindol-3-yl, 4-azaindol-5-yl, 4-azaindol-6-yl, 4-azaindol-7-yl.

For example, non-limiting examples of heteroaryl groups can be 2-or 3-furyl, 2-or 3-thienyl, 1-, 2-or 3-pyrrolyl, 1-, 2-, 4-or 5-imidazolyl, 1-, 3-, 4-or 5-pyrazolyl, 3-, 4-or 5-isoxazolyl, 2-, 4-or 5-oxazolyl, 3-, 4-or 5-isothiazolyl, 2-, 4-or 5-thiazolyl, 1,2, 3-triazol-1-, -4-or-5-yl, 1,2, 4-triazol-1-, -3-, -4-or-5-yl, 2-, 4-triazol-1-, -3-, -4-or-5-yl, and, 1H-tetrazol-1-or-5-yl, 2H-tetrazol-2-or-5-yl, 1,2, 3-oxadiazol-4-or-5-yl, 1,2, 4-oxadiazol-3-or-5-yl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazol, 1,2, 3-thiadiazol-4-or-5-yl, 1,2, 4-thiadiazol-3-or-5-yl, 1,2, 5-thiadiazol-3-or-4-yl, 1,3, 4-thiadiazolyl, 1-or 5-tetrazolyl, 2-, 3-or 4-pyridyl, 3-or 4-pyridazinyl, 2-, 4-, 5-or 6-pyrimidinyl, 2-, 3-, 4-, 5-6-2H-thiopyranyl, 2-, 3-or 4-4H-thiopyranyl, 4-azaindol-1-, 2-, 3-, 5-or 7-yl, 5-azaindol-1-, or 2-, 3-, 4-, 6-or 7-yl, 6-azaindol-1, 2-, 3-, 4-, 5-or 7-yl, 7-azaindol-1-, 2-, 3-, 4, 5-or 6-yl, 2-, 4-, 5-, or 6-yl, 3-, 4-, 5-, 6-or 7-benzofuranyl, 1-, 3-, 4-or 5-isobenzofuranyl, 2-, 3-, 4-, 5-, 6-or 7-benzothienyl, 1-, 3-, 4-or 5-isobenzothienyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-indolyl, 2-or 3-pyrazinyl, 1, 4-oxazin-2-or-3-yl, 1, 4-dioxin-2-or-3-yl, 1, 4-thiazin-2-or-3-yl, 1,2, 3-triazinyl, p-tolyl-N-methyl-phenyl, p-tolyl-phenyl, p-phenyl, 1,2, 4-triazinyl, 1,3, 5-triazin-2-, -4-or-6-yl, thieno [2,3-b ] furan-2-, -3-, -4-or-5-yl, benzimidazol-1-yl, -2-yl, -4-yl, -5-yl, -6-yl or-7-yl, 1-, 3-, 4-, 5-, 6-or 7-benzopyrazolyl, 3-, 4-, 5-, 6-or 7-benzisoxazolyl, 2-, 4-, 5-, 6-or 7-benzoxazolyl, 3-, 4-, 5-, 6-or 7-benzisothiazolyl, 1, 3-benzothiazol-2-yl, -4-yl, -5-yl, -6-yl or-7-yl, 1, 3-benzodioxol-4-yl, -5-yl, -6-yl or-7-yl, benzotriazol-1-yl, -4-yl, -5-yl, -6-yl or-7-yl, 1-, 2-thianthryl, 3-, 4-or 5-isobenzofuranyl, 1-, 2-, 3-, 4-or 9-xanthenyl, 1-, 2-, 3-or 4-thioxanthyl (phenoxathiinyl), 2-, 3-pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-or 8-indolizinyl, 2-, 3-, 4-or 5-isoindolyl, 1H-indazol-1-yl, 3-yl, -4-yl, -5-yl, -6-yl or-7-yl, 2H-indazol-2-yl, 3-yl, -4-yl, -5-yl, -6-yl or-7-yl, imidazo [2,1-b ] [1,3] thiazol-2-yl, imidazo [2,1-b ] [1,3] thiazol-3-yl, imidazo [2,1-b ] [1,3] thiazol-yl, 1-b ] [1,3] thiazol-5-yl or imidazo [2,1-b ] [1,3] thiazol-6-yl, imidazo [1,2-a ] pyridin-2-yl, imidazo [1,2-a ] pyridin-3-yl, imidazo [1,2-a ] pyridin-4-yl, imidazo [1,2-a ] pyridin-5-yl, imidazo [1,2-a ] pyridin-6-yl or imidazo [1,2-a ] pyridin-7-yl, tetrazolo [1,5-a ] pyridin-5-yl, tetrazolo [1,5-a ] pyridin-6-yl, tetrazolo [1,5-a ] pyridin-7-yl, Or a tetrazolo [1,5-a ] pyridin-8-yl, 2-, 6-, 7-or 8-purinyl, 4-, 5-or 6-phthalazinyl, 2-, 3-or 4-naphthyridinyl, 2-, 5-or 6-quinoxalinyl, 2-, 4-, 5-, 6-, 7-or 8-quinazolinyl, 1-, 2-, 3-or 4-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl (quinolyl), 2-, 4-, 5-, 6-, 7-or 8-quinazolinyl, 1-, 3-, 4-, 5-, (meth) acrylic acid or methacrylic acid, 6-, 7-or 8-isoquinolinyl (isoquinolinyl), 3-, 4-, 5-, 6-, 7-or 8-cinnolinyl, 2-, 4-, 6-or 7-pteridinyl, 1-, 2-, 3-, 4-or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-or 9-carbolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-or 10-phenanthridinyl, 1-, 2-, 3-or 4-acridinyl, 1-, 2-, 3-, 4-, 5-), 6-, 7-, 8-or 9-perimidine, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-or 10- (1,7) phenanthroline, 1-or 2-phenazine, 1-, 2-, 3-, 4-, or 10-phenothiazinyl, 3-or 4-furazanyl, 1-, 2-, 3-, 4-, or 10-phenoxazinyl, or further substituted derivatives thereof.

"optionally substituted heteroaryl" means heteroaryl (e.g., 1-4 substituents, e.g., 1,2,3, or 4) optionally having one or more substituents selected from those defined above for substituted aryl.

The term "oxo" as used herein denotes the group = O.

The term "alkoxy" as used herein means having the formula-OR^bWherein R is^bIs an alkyl group. Preferably, alkoxy is C₁-C₁₀Alkoxy radical, C₁-C₆Alkoxy or C₁-C₄An alkoxy group. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy. If the oxygen atom of an alkoxy group is substituted with sulfur, the resulting group is referred to as thioalkoxy. "haloalkoxy" is an alkoxy group in which one or more hydrogen atoms of the alkyl group are replaced by a halogen. Non-limiting examples of suitable haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2, 2-trifluoroethoxy, 1,2, 2-tetrafluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2, 2-difluoroethoxy, 2,2, 2-trichloroethoxy; trichloromethoxy, 2-bromoethoxy, pentafluoroethyl, 3,3, 3-trichloropropoxy, 4,4, 4-trichlorobutoxy.

The term "aryloxy" as used herein denotes the group-O-aryl, wherein aryl is as defined above.

The term "arylcarbonyl" or "aroyl" as used herein denotes the group-c (o) -aryl, wherein aryl is as defined above.

The term "cycloalkylalkyl" by itself or as part of another substituent means a group having one of the foregoing cycloalkyl groups attached to one of the foregoing alkyl chains. Examples of such cycloalkylalkyl residues include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1-cyclopentylethyl, 1-cyclohexylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, cyclobutylpropyl, cyclopentylpropyl, 3-cyclopentylbutyl, cyclohexylbutyl and the like.

The term "heterocyclyl-alkyl" by itself or as part of another substituent denotes a group having one of the aforementioned heterocyclyl groups attached to one of the aforementioned alkyl groups, i.e. the group-R^d-R^cWherein R is^dIs alkylene or alkylene substituted by alkyl, and R^cIs a heterocyclic group.

The term "carboxy" or "carboxyl group" or "hydroxycarbonyl" by itself or as part of another substituent denotes the group-CO₂H. Thus, carboxyalkyl is-CO with at least one substituent₂H is an alkyl group as defined above.

The term "alkoxycarbonyl" by itself OR as part of another substituent means a carboxyl group attached to an alkyl residue, i.e., -C (= O) OR is formed^eWherein R is^eAs defined above for alkyl.

The term "alkylcarbonyloxy" by itself or as part of another substituent means-O-C (= O) R^eWherein R is^eAs defined above for alkyl.

The term "alkylcarbonylamino" by itself or as part of another substituent, denotes a group of formula-NH (C = O) R or-NR '(C = O) R, wherein R and R' are each independently alkyl or substituted alkyl.

The term "thiocarbonyl" by itself or as part of another substituent means the group-C (= S) -.

The term "alkoxy" by itself or as part of another substituent means a group consisting of an oxygen atom attached to an optionally substituted straight or branched chain alkyl, cycloalkyl, aralkyl or cycloalkylalkyl group. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, hexyloxy, and the like.

The term "halo" or "halogen" as a group or part of a group is a generic term for fluorine, chlorine, bromine or iodine.

The term "haloalkyl", employed alone or in combination, denotes an alkyl residue having the meaning as defined above wherein one or more hydrogens are replaced by a halogen as defined above. Non-limiting examples of such haloalkyl residues include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1, 1-trifluoroethyl, and the like.

The term "haloaryl", alone or in combination, denotes an aryl residue having the meaning as defined above, wherein one or more hydrogens are replaced by halogens as defined above.

The term "haloalkoxy", alone or in combination, signifies a group of formula-O-alkyl, wherein alkyl is substituted with 1,2 or 3 halogen atoms. For example, "haloalkoxy" includes-OCF₃、-OCHF₂、-OCH₂F、-O-CF₂-CF₃、-O-CH₂-CF₃、-O-CH₂-CHF₂and-O-CH₂-CH₂F。

Whenever the term "substituted" is used in the present invention, it is intended to indicate that in the expression using "substituted by … …" one or more hydrogens on an atom are replaced with a group selected from the indicated group, provided that the normal valency of the indicated atom is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that: it is robust enough to withstand isolation from the reaction mixture to useful purity levels, and formulation into a therapeutic agent.

As used herein, terms such as "alkyl, aryl or cycloalkyl, each optionally substituted with … …" or "alkyl, aryl or cycloalkyl, optionally substituted with … …" refer to optionally substituted alkyl, optionally substituted aryl and optionally substituted cycloalkyl.

As described herein, some compounds of the present invention may contain one or more asymmetric carbon atoms as chiral centers, which may result in different optically isomeric forms (e.g., enantiomers or diastereomers). The present invention includes all possible configurations of these optically isomeric forms, as well as mixtures thereof.

More generally, from the foregoing, it will be apparent to the skilled artisan that the compounds of the invention may exist in different isomeric and/or tautomeric forms, including, but not limited to, geometric isomers, conformational isomers, E/Z-isomers, stereochemical isomers (i.e., enantiomers and diastereomers), and isomers of the same substituent corresponding to different positions of a ring in the compounds of the invention. All such possible isomers, tautomers and mixtures thereof are intended to be within the scope of the invention.

Whenever the term "compounds of the invention" or similar terms are used in the present invention, it is intended to include compounds of formula I and any subset thereof. This term also refers to the compounds shown in tables 1 to 11, their derivatives, N-oxides, salts, solvates, hydrates, stereoisomeric forms, racemic mixtures, tautomeric forms, optical isomers, analogs, prodrugs, esters and metabolites, and their quaternized nitrogen analogs. The N-oxide form of the compound is intended to include compounds that: in which one or more nitrogen atoms are oxidized to the so-called N-oxide.

As used in the specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. By way of example, "a compound" means one compound or more than one compound.

The terms described above and other terms used in the specification are well understood by those skilled in the art.

The term "ROCK" as used herein means either or both of the ROCK-I or ROCK-II isoforms. The terms "ROCK-I", "ROCK 1", or any of their synonyms accepted in the art, include known naturally occurring or biologically engineered mutants and constructs of ROCK-I. The terms "ROCK-2", "ROCK 2", or any of their synonyms accepted in the art, include known naturally occurring or biologically engineered mutants and constructs of ROCK-II.

Whenever used in this document, the terms "soft inhibitor", "soft kinase inhibitor", "soft ROCK inhibitor" or similar terms refer to a compound having inhibitory properties on ROCK which is stable in the target organ after systemic circulation, but which is rapidly converted to a predictable non-functional active substance. This inactivation process may occur in the liver, but is preferentially achieved in the blood.

The term "target organ" as used herein means an organ (e.g., eye), organ portion (e.g., cornea, retina) or tissue in which inhibition of ROCK is expected to produce a beneficial effect.

The term "functionally active substance" or "functionally active compound" as used herein denotes a compound which: which exhibit significant in vivo activity, and/or exhibit significant activity in cellular assays, which activity is a physiologically relevant exhibit (readouts) recognized in the art as cellular ROCK activity. An example of such a cellular assay isThe myosin light chain phosphorylation assay described by et al in Biochemical and Biophysical Research Communications374(2008) 356-360, which has been used to evaluate the cellular activity of the compounds of the invention (see example, section c.1.2). The term "non-functionally active substance" or "non-functionally active compound" as used herein denotes such a compound: it shows a significantly reduced, preferably negligible, activity in the same in vivo or cellular representation of ROCK activity.

The term "esterase" as used herein includes all enzymes exhibiting carboxylic ester hydrolase (EC3.1.1) activity. This definition includes enzymes that exhibit additional hydrolytic activity on substrates other than carboxylic acid esters. For example; paraoxonase 1(PON1) exhibited aryl dialkyl phosphatase activity (EC3.1.8.1, also known as paraoxonase activity and hence the name) and diisopropyl-fluorophosphatase activity (EC3.1.8.2), but also exhibited arylesterase activity (ec3.1.1.2) and lactonase activity. Thus, PON1 is considered an esterase. The term "pseudoesterase" as used herein denotes a protein which: it exhibits a certain degree of carboxylate hydrolase activity, but has low catalytic efficiency for carboxylic esters. Some proteins called pseudoesterases (such as serum albumin) actually lack the actual catalytic site.

In another embodiment, the present invention provides a compound of formula I

Wherein

X is oxygen, -NH-or a direct bond; in particular oxygen or-NH-; more particularly-NH-;

y is-NH-or a direct bond;

n is an integer of 0 to 4;

m is an integer of 0 to 4;

cy is selected from:

ar is selected from:

R²is hydrogen or methyl; in particular hydrogen;

R⁸is hydrogen, methyl, halogen or alkynyl; in particular hydrogen or methyl; more particularly hydrogen;

R¹is optionally halogenated or C_1-6An alkyl-substituted aryl or heteroaryl, wherein the aryl or heteroaryl is substituted with a substituent selected from the group consisting of:

●-(CH₂)_p-C(=O)-OR²¹；

●-(CH₂)_p-C(=O)-NR³R⁴；

●-(CH₂)_p-C(=O)-SR²²；

●Het¹、-O-Het¹、-NH-Het¹or-S-Het¹(ii) a And

●-O-C_1-6alkyl, -NH-C_1-6Alkyl, -S-C_1-6Alkyl or-C_1-6An alkyl group; wherein said-O-C_1-6Alkyl, -NH-C_1-6Alkyl, -S-C_1-6Alkyl or-C_1-6Each alkyl group is independently substituted with a substituent selected from the group consisting of: -C (= O) -OR²¹、-C(=O)-NR³R⁴、Het¹、-O-Het¹、-NH-Het¹and-S-Het¹；

Wherein

p is an integer of 0 to 3

Het¹Selected from:

in particular Het¹Selected from:

more specifically Het¹Selected from:

R²¹selected from: optionally substituted C_1-20Alkyl, optionally substituted C_1-20Alkenyl, optionally substituted C_1-20Alkynyl, optionally substituted C_3-15Cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl; specifically, R²¹Selected from optionally substituted C_1-20Alkyl and optionally substituted aryl; more particularly from aryl and optionally substituted C_1-20An alkyl group;

R²²is optionally substituted C_1-6An alkyl group; specifically, R²²Is C_1-6An alkyl group;

R³selected from: het¹、C_1-20Alkyl, aryl or heteroaryl; wherein said C_1-20Alkyl, aryl or heteroaryl is substituted with 1,2 or 3 substituents each independently selected from: aryl, heteroaryl, - (CH)₂)_p-C(=O)-OR²¹、-Het¹、-NH-Het¹、-O-Het¹、-S-Het¹、-S-C_2-6Alkyl, -NH-C_2-6Alkyl and-O-C_2-6An alkyl group;

wherein said aryl, heteroaryl, -O-C_2-6Alkyl, -NH-C_2-6Alkyl or-S-C_2-6Each alkyl group is independently substituted with a substituent selected from the group consisting of: c (= O) -OR²¹、-Het¹、-O-Het¹、-NH-Het¹and-S-Het¹；

Specifically, R³Selected from: het¹、C_1-20Alkyl, aryl or heteroaryl; wherein said C_1-20Alkyl, aryl or heteroaryl is substituted with 1,2 or 3 substituents each independently selected from: - (CH)₂)_p-C(=O)-OR²¹、-Het¹、-NH-Het¹、-O-Het¹and-S-Het¹；

More specifically, R³Selected from: het¹、C_1-20An alkyl or aryl group; wherein said C_1-20Alkyl or aryl is substituted with 1,2 or 3 (preferably 1) substituents each independently selected from: - (CH)₂)_p-C(=O)-OR²¹、-Het¹and-S-Het¹；

And is

R⁴Selected from: hydrogen or C_1-6An alkyl group; in particular hydrogen; or

R³And R⁴Together with the nitrogen atom to which they are attached form a heterocyclic ring substituted with one substituent selected from: c_1-20Alkyl, aryl or heteroaryl; wherein said C_1-20Alkyl, aryl or heteroaryl is substituted with 1,2 or 3 substituents each independently selected from: aryl, heteroaryl, -C (= O) -OR²¹、-Het¹、-O-Het¹、-S-Het¹、-S-C_2-6Alkyl, -NH-C_2-6Alkyl and-O-C_2-6An alkyl group;

wherein said-O-C_2-6Alkyl, -NH-C_2-6Alkyl or-S-C_2-6Each alkyl group is independently substituted with a substituent selected from the group consisting of: c (= O) -OR²¹、-Het¹、-O-Het¹、-NH-Het¹and-S-Het¹；

With the proviso that,

-R¹is not selected from-O-CH₂-C(=O)-OR²¹Substituted aryl or heteroaryl;

if R is¹Is phenyl, then the phenyl group may not be in the para position by- (CH)₂)_p-C(=O)-OR²¹Substitution; and is

-said compound of formula I is not

In a preferred embodiment, the present invention provides compounds of formula I

Wherein X, Y, n, m, Cy and Ar are as defined above, and wherein R is¹Is aryl or heteroaryl; in particular aryl or any heteroaryl other than indolyl; more particularly phenyl, pyrrolyl or thienyl, substituted with a substituent selected from the group consisting of:

●-(CH₂)_p-C(=O)-OR²¹；

●-(CH₂)_p-C(=O)-NR³R⁴；

●-(CH₂)_p-C(=O)-SR²²；

●Het¹、-O-Het¹、-NH-Het¹or-S-Het¹(ii) a And

●-O-C_1-6alkyl, -NH-C_1-6Alkyl, -S-C_1-6Alkyl, -C_1-6An alkyl group; wherein said-O-C_1-6Alkyl, -NH-C_1-6Alkyl, -S-C_1-6Alkyl or-C_1-6Each alkyl group is independently substituted with a substituent selected from the group consisting of: -C (= O) -OR²¹、-C(=O)-NR³R⁴、、-Het¹、-O-Het¹、-NH-Het¹and-S-Het¹；

Wherein

p、Het¹、R²¹、R²²、R³And R⁴As defined above, in the above-mentioned manner,

with the proviso that,

-R¹is not selected from-O-CH₂-C(=O)-OR²¹Substituted byAryl or heteroaryl;

if R is¹Is phenyl, then the phenyl group may not be in the para position by- (CH)₂)_p-C(=O)-OR²¹Substitution; and is

-said compound of formula I is not

In an even further embodiment, the present invention provides a compound of formula I

Wherein X, Y, n, m, Cy and Ar are as defined above, and wherein R is¹Is aryl or heteroaryl; more particularly phenyl, pyrrolyl or thienyl, substituted with a substituent selected from the group consisting of:

　●-(CH₂)_p-C(=O)-OR²¹

　●-(CH₂)_p-C(=O)-NR³R⁴

　●-(CH₂)_p-C(=O)-SR²²

　●-O-C_1-6an alkyl group; -NH-C_1-6An alkyl group; -S-C_1-6An alkyl group; -C_1-6An alkyl group; wherein said-O-C_1-6An alkyl group; -NH-C_1-6An alkyl group; -S-C_1-6An alkyl group; or-C_1-6Each alkyl group is independently substituted with a substituent selected from the group consisting of: -C (= O) -OR²¹；-C(=O)-NR³R⁴；Het¹；-O-Het¹；-NH-Het¹and-S-Het¹；

Wherein p and R²¹、R²²、R³、R⁴And Het¹As defined above;

with the proviso that,

-R¹is not selected from-O-CH₂-C(=O)-OR²¹Substituted aryl or heteroaryl;

if R is¹Is phenyl, then the phenyl group may not be in the para position by- (CH)₂)_p-C(=O)-OR²¹Substitution; and is

-said compound of formula I is not

In another embodiment, the present invention provides a compound of formula I

Wherein X, Y, n and m are as defined above, and wherein

Cy represents a divalent group selected from:

in particular selected from:

ar is selected from:

in particular selected from:

wherein R is¹、R²¹、R²²、R³、R⁴And Het¹As defined above;

with the proviso that,

-R¹is not selected from-O-CH₂-C(=O)-OR²¹Substituted aryl or heteroaryl;

if R is¹Is phenyl, then the phenyl group may not be in the para position by- (CH)₂)_p-C(=O)-OR²¹Substitution; and is

-said compound of formula I is not

In another embodiment, the present invention provides a compound of formula I, wherein one or more of the following limitations apply:

● X is oxygen, -NH-, or a direct bond; in particular oxygen or-NH-; more particularly-NH-;

● Y is-NH-or a direct bond; in particular-NH-;

● n is an integer from 0 to 4; in particular 0 or 1;

● m is an integer from 0 to 4; in particular 0 or 1; more particularly 0;

● Cy represents a divalent group consisting of saturated (poly) rings, including fused, bicyclic, spiro or bridged carbocyclic and heterocyclic rings;

● Cy is selected from:

in particular selected from:

● Ar is selected from:

in particular selected from:

●R²is hydrogen or methyl; in particular hydrogen;

●R⁸is hydrogen, methyl, halogen or alkynyl; in particular hydrogen or methyl; more particularly hydrogen;

●R¹is optionally halogenated or C_1-6An alkyl-substituted aryl or heteroaryl, wherein the aryl or heteroaryl is substituted with a substituent selected from the group consisting of:

　●-(CH₂)_p-C(=O)-OR²¹；

　●-(CH₂)_p-C(=O)-NR³R⁴；

　●-(CH₂)_p-C(=O)-SR²²；

　●Het¹、-O-Het¹、-NH-Het¹or-S-Het¹(ii) a And

　●-O-C_1-6alkyl, -NH-C_1-6Alkyl, -S-C_1-6Alkyl or-C_1-6An alkyl group; wherein said-O-C_1-6Alkyl, -NH-C_1-6Alkyl, -S-C_1-6Alkyl or-C_1-6Each alkyl group is independently substituted with a substituent selected from the group consisting of: -C (= O) -OR²¹、-C(=O)-NR³R⁴、Het¹、-O-Het¹、-NH-Het¹and-S-Het¹；

In particular, the substituents are selected from:

　●-(CH₂)_p-C(=O)-OR²¹；

　●-(CH₂)_p-C(=O)-NR³R⁴；

　●-(CH₂)_p-C(=O)-SR²²(ii) a And

　●-O-C_1-6alkyl, -NH-C_1-6Alkyl, -S-C_1-6Alkyl or-C_1-6An alkyl group; wherein said-O-C_1-6Alkyl, -NH-C_1-6Alkyl, -S-C_1-6Alkyl or-C_1-6Each alkyl group is independently substituted with a substituent selected from the group consisting of: -C (= O) -OR²¹、-C(=O)-NR³R⁴、-Het¹、-O-Het¹、-NH-Het¹and-S-Het¹(ii) a In particular by-C (= O) -NR³R⁴substituted-O-C_1-6An alkyl group;

●R¹is aryl or heteroaryl; in particular aryl, pyrrolyl or thienyl; more particularly phenyl, pyrrolyl or thienyl, substituted with a substituent selected from the group consisting of:

　●-(CH₂)_p-C(=O)-OR²¹；

　●-(CH₂)_p-C(=O)-NR³R⁴；

　●-(CH₂)_p-C(=O)-SR²²；

　●Het¹、-O-Het¹、-NH-Het¹or-S-Het¹(ii) a And

　●-O-C_1-6alkyl, -NH-C_1-6Alkyl, -S-C_1-6Alkyl or-C_1-6An alkyl group; wherein said-O-C_1-6Alkyl, -NH-C_1-6Alkyl, -S-C_1-6Alkyl or-C_1-6Each alkyl group is independently substituted with a substituent selected from the group consisting of: -C (= O) -OR²¹、-C(=O)-NR³R⁴、Het¹、-O-Het¹、-NH-Het¹and-S-Het¹；

In particular, the substituents are selected from:

　●-(CH₂)_p-C(=O)-OR²¹；

　●-(CH₂)_p-C(=O)-NR³R⁴；

　●-(CH₂)_p-C(=O)-SR²²(ii) a And

　●-O-C_1-6alkyl, -NH-C_1-6Alkyl, -S-C_1-6Alkyl or-C_1-6An alkyl group; wherein said-O-C_1-6Alkyl, -NH-C_1-6Alkyl, -S-C_1-6Alkyl or-C_1-6Each alkyl group is independently substituted with a substituent selected from the group consisting of: -C (= O) -OR²¹、-C(=O)-NR³R⁴、Het¹、-O-Het¹、-NH-Het¹and-S-Het¹(ii) a In particular by-C (= O) -NR³R⁴substituted-O-C_1-6An alkyl group;

● p is an integer from 0 to 3; in particular 0 or 1;

●Het¹selected from:

in particular Het¹Selected from:

more specifically Het¹Selected from:

●R²¹selected from: optionally substituted C_1-20Alkyl, optionally substituted C_1-20Alkenyl, optionally substituted C_1-20Alkynyl, optionally substituted C_3-15Cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl; is in particular selected from optionally substituted C_1-20Alkyl and optionally substituted aryl; more particularly from aryl and optionally substituted C_1-20An alkyl group;

●R²¹is selected from C_1-20An alkyl or aryl group; wherein said C_1-20The alkyl or aryl group is optionally substituted with one or more groups selected from the group consisting of: halo, hydroxy, cyano, C_1-6Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and alkoxy; more particularly optionally substituted with one group selected from the group consisting of: cycloalkyl, aryl, hydroxy, alkoxy, and heterocyclyl;

●R²¹selected from aryl and C_1-20An alkyl group; wherein said C_1-20Alkyl is optionally substituted with: halo, hydroxy, cyano, C_1-6Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or alkoxy; more specifically by cycloalkyl, phenyl, hydroxy, alkoxy and heterocyclyl;

●R²²is optionally substituted C_1-6An alkyl group; in particular C_1-6An alkyl group;

●R³selected from: het¹、C_1-20Alkyl, aryl or heteroaryl; wherein said C_1-20Alkyl, aryl or heteroaryl is substituted with 1,2 or 3 substituents each independently selected from: aryl, heteroaryl, - (CH)₂)_p-C(=O)-OR²¹、-Het¹、-NH-Het¹、-O-Het¹、-S-Het¹、-S-C_2-6Alkyl, -NH-C_2-6Alkyl and-O-C_2-6An alkyl group;

wherein said aryl, heteroaryl, -O-C_2-6Alkyl, -NH-C_2-6Alkyl or-S-C_2-6Each alkyl group is independently substituted with a substituent selected from the group consisting of: c (= O) -OR²¹、-Het¹、-O-Het¹、-NH-Het¹and-S-Het¹;

Specifically, R³Selected from: het¹、C_1-20Alkyl, aryl or heteroaryl; wherein said C_1-20Alkyl, aryl or heteroaryl is substituted with 1,2 or 3 substituents each independently selected from: - (CH)₂)_p-C(=O)-OR²¹、-Het¹、-NH-Het¹、-O-Het¹and-S-Het¹；

More specifically, R³Selected from: het¹、C_1-20An alkyl or aryl group; wherein said C_1-20Alkyl or aryl is substituted with 1,2 or 3 (preferably 1) substituents each independently selected from: - (CH)₂)_p-C(=O)-OR²¹、-Het¹and-S-Het¹；

Even more specifically, R³Selected from: het¹、C_1-20Alkyl or phenyl; wherein said C_1-20Alkyl or phenyl is substituted with 1,2 or 3 (preferably 1) substituents each independently selected from: - (CH)₂)_p-C(=O)-OR²¹、-Het¹and-S-Het¹；

●R⁴Selected from: hydrogen or C_1-6An alkyl group; in particularHydrogen;

●R³and R⁴Together with the nitrogen atom to which they are attached form a heterocyclic ring substituted with one substituent selected from: c_1-20Alkyl, aryl or heteroaryl; wherein said C_1-20Alkyl, aryl or heteroaryl is substituted with 1,2 or 3 substituents each independently selected from: aryl, heteroaryl, -C (= O) -OR²¹、-Het¹、-O-Het¹、-S-Het¹、-S-C_2-6Alkyl, -NH-C_2-6Alkyl and-O-C_2-6An alkyl group;

wherein said-O-C_2-6Alkyl, -NH-C_2-6Alkyl or-S-C_2-6Each alkyl group is independently substituted with a substituent selected from the group consisting of: c (= O) -OR²¹、-Het¹、-O-Het¹、-NH-Het¹and-S-Het¹；

●R³And R⁴May not form a heterocyclic ring together with the nitrogen atom to which they are attached;

●R¹is not selected from-O-CH₂-C(=O)-OR²¹Substituted aryl or heteroaryl;

●R¹is not selected from indolyl;

● if R¹Is phenyl, then the phenyl group may not be in the para position by- (CH)₂)_p-C(=O)-OR²¹Substitution;

● if R¹Is phenyl, then said phenyl is substituted in the meta position; specifically, the phenyl group is substituted at the meta position with a substituent selected from the group consisting of:

　●-(CH₂)_p-C(=O)-OR²¹；

　●-(CH₂)_p-C(=O)-NR³R⁴；

　●-(CH₂)_p-C(=O)-SR²²；

　●Het¹、-O-Het¹、-NH-Het¹or-S-Het¹(ii) a And

　●-O-C_1-6alkyl, -NH-C_1-6Alkyl, -S-C_1-6Alkyl or-C_1-6An alkyl group; wherein said-O-C_1-6Alkyl, -NH-C_1-6Alkyl, -S-C_1-6Alkyl or-C_1-6Each alkyl group is independently substituted with a substituent selected from the group consisting of: -C (= O) -OR²¹、-C(=O)-NR³R⁴、Het¹、-O-Het¹、-NH-Het¹and-S-Het¹；

In particular, the substituents are selected from:

　●-(CH₂)_p-C(=O)-OR²¹；

　●-(CH₂)_p-C(=O)-NR³R⁴；

　●-(CH₂)_p-C(=O)-SR²²(ii) a And

　●-O-C_1-6alkyl, -NH-C_1-6Alkyl, -S-C_1-6Alkyl or-C_1-6An alkyl group; wherein said-O-C_1-6Alkyl, -NH-C_1-6Alkyl, -S-C_1-6Alkyl or-C_1-6Each alkyl group is independently substituted with a substituent selected from the group consisting of: -C (= O) -OR²¹、-C(=O)-NR³R⁴、Het¹、-O-Het¹、-NH-Het¹and-S-Het¹In particular by-C (= O) -NR³R⁴substituted-O-C_1-6An alkyl group;

● the compound of formula I is not

The compounds of the present invention may be prepared according to the reaction schemes provided in the examples below, but those skilled in the art will appreciate that these are merely exemplary of the present invention and that the compounds of the present invention may be prepared according to any standard synthetic procedure commonly used by those skilled in organic chemistry.

In a preferred embodiment, the compounds of the invention are useful as kinase inhibitors, more particularly to provide inhibition of at least one ROCK kinase (selected from ROCK i and ROCK ii), especially soft ROCK inhibitors.

The present invention further provides the use of a compound as defined above or a composition comprising said compound as a human or veterinary drug, in particular for the prevention and/or treatment of at least one disease or disorder involving ROCK, such as diseases associated with smooth muscle cell function, inflammation, fibrosis, excessive cell proliferation, excessive angiogenesis, hyperreactivity, barrier dysfunction, neurodegeneration, and remodeling.

In another embodiment, the present invention provides the use of a compound as defined above or a composition comprising said compound for the prevention and/or treatment of at least one disease or disorder selected from: eye diseases; respiratory diseases; throat, nose and ear diseases; intestinal disease; cardiovascular and vascular diseases; inflammatory diseases; neurological and central nervous system disorders; proliferative diseases; renal disease; sexual dysfunction; bone disease; benign prostatic hyperplasia, transplant rejection, spasticity, hypertension, chronic obstructive bladder disease, and allergies.

In a preferred embodiment, the present invention provides the use of a compound or a composition comprising said compound as defined above for the prevention and/or treatment of eye diseases including, but not limited to, retinopathy, optic neuropathy, glaucoma and degenerative retinal diseases such as age-related macular degeneration, retinitis pigmentosa and inflammatory eye diseases and/or for the prevention, treatment and/or alleviation of complications and/or symptoms associated therewith.

In another preferred embodiment, the present invention provides the use of a compound or a composition comprising said compound as defined above for the prevention and/or treatment of a respiratory disease including, but not limited to, pulmonary fibrosis, emphysema, chronic bronchitis, asthma, fibrosis, pneumonia, cystic fibrosis, Chronic Obstructive Pulmonary Disease (COPD); bronchitis and rhinitis and respiratory distress syndrome.

In another embodiment, the present invention provides the use of a compound or a composition comprising said compound as defined above for the prevention and/or treatment of cardiovascular diseases and vascular diseases including but not limited to pulmonary hypertension and pulmonary vasoconstriction, and/or for the prevention, treatment and/or alleviation of complications and/or symptoms associated therewith.

In another embodiment, the present invention provides the use of a compound as defined above or a composition comprising said compound for the prevention and/or treatment of disorders of the larynx, nose and ears including but not limited to sinus problems, hearing problems, dental pain, tonsillitis, ulcers and rhinitis.

In another embodiment, the present invention provides the use of a compound as defined above or a composition comprising said compound for the prevention and/or treatment of skin diseases including, but not limited to, hyperkeratosis, parakeratosis, stratum granulosum thickening, stratum spinosum thickening, dyskeratosis, edema of the stratum spinosum and ulcer formation.

In another embodiment, the invention provides the use of a compound as defined above or a composition comprising said compound for the prevention and/or treatment of bowel diseases including, but not limited to, Inflammatory Bowel Disease (IBD), colitis, gastroenteritis, ileus, ileitis, appendicitis and crohn's disease.

In another embodiment, the invention provides the use of a compound or composition comprising said compound as defined above for the prevention and/or treatment of inflammatory diseases including, but not limited to, contact dermatitis, atopic dermatitis, psoriasis, rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease, crohn's disease and ulcerative colitis and/or for the prevention, treatment and/or alleviation of the complications and/or symptoms and/or inflammatory responses associated therewith.

In another embodiment, the present invention provides the use of a compound or a composition comprising said compound as defined above for the prevention, treatment and/or management of neurological diseases and central nervous system diseases, including but not limited to neuropathic pain. The compounds of the present invention are therefore suitable for the prevention of neurodegeneration and the stimulation of nerve regeneration in various neurological diseases and/or for the prevention, treatment and/or alleviation of complications and/or symptoms associated therewith.

In another embodiment, the invention provides the use of a compound or composition comprising said compound as defined above for the prevention and/or treatment of proliferative diseases including, but not limited to, cancers of the breast, colon, intestine, skin, head and neck, nerves, uterus, kidney, lung, ovary, pancreas, prostate or thyroid gland; giant lymph node hyperplasia; a sarcoma; malignant cell tumors; and melanoma.

In another embodiment, the present invention provides the use of a compound or composition comprising said compound as defined above for the prevention and/or treatment of renal diseases including, but not limited to, renal fibrosis or renal dysfunction and/or the use for the prevention, treatment and/or alleviation of complications and/or symptoms and/or inflammatory reactions associated therewith.

In another embodiment, the present invention provides the use of a compound or a composition comprising said compound as defined above for the prevention and/or treatment of sexual dysfunction including, but not limited to, hypogonadism, bladder disease, hypertension, diabetes or pelvic surgery and/or for the treatment of sexual dysfunction associated with treatment with certain drugs, such as drugs for the treatment of hypertension, depression or anxiety.

In another embodiment, the present invention provides the use of a compound or a composition comprising said compound as defined above for the prevention and/or treatment of bone diseases including, but not limited to, osteoporosis and osteoarthritis and/or for the prevention, treatment and/or alleviation of complications and/or symptoms and/or inflammatory reactions associated therewith.

In another embodiment, the invention provides the use of a compound or a composition comprising said compound as defined above for the prevention and/or treatment of and/or for the prevention, treatment and/or alleviation of complications and/or symptoms associated with diseases and disorders such as benign prostatic hyperplasia, transplant rejection, spasticity, chronic obstructive bladder disease and allergy.

In a preferred embodiment, the present invention provides the use of a compound as defined above or a composition comprising said compound for the prevention and/or treatment of glaucoma, macular degeneration (including age-related macular degeneration), asthma, sexual dysfunction or COPD.

Method of treatment

The present invention further provides a method for the prevention and/or treatment of at least one disease or disorder selected from the group consisting of: eye diseases; respiratory diseases; throat, nose and ear diseases; intestinal disease; cardiovascular and vascular diseases; inflammatory diseases; neurological and central nervous system disorders; proliferative diseases; renal disease; sexual dysfunction; bone disease; benign prostatic hyperplasia; transplant rejection; spasm; hypertension; chronic obstructive bladder disease and allergies; the method comprises the following steps: administering to a subject in need thereof a therapeutically effective amount of a compound or composition as defined herein.

In a preferred embodiment, the present invention provides a method for preventing and/or treating eye diseases including, but not limited to, retinopathy, optic neuropathy, glaucoma, and degenerative retinal diseases such as age-related macular degeneration, retinitis pigmentosa, and inflammatory eye diseases; the method comprises the following steps: administering to a subject in need thereof a therapeutically effective amount of a compound or composition as defined herein.

In another preferred embodiment, the present invention provides a method for preventing and/or treating respiratory diseases including, but not limited to, pulmonary fibrosis, pulmonary emphysema, chronic bronchitis, asthma, fibrosis, pneumonia, cystic fibrosis, Chronic Obstructive Pulmonary Disease (COPD) bronchitis, rhinitis, and respiratory distress syndrome; the method comprises the following steps: administering to a subject in need thereof a therapeutically effective amount of a compound or composition as defined herein.

In another embodiment, the present invention provides a method for the prevention and/or treatment of cardiovascular and vascular diseases including, but not limited to, pulmonary hypertension and pulmonary vasoconstriction; the method comprises the following steps: administering to a subject in need thereof a therapeutically effective amount of a compound or composition as defined herein.

In another embodiment, the present invention provides a method for the prevention and/or treatment of inflammatory diseases including, but not limited to, contact dermatitis, atopic dermatitis, psoriasis, rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease, crohn's disease, and ulcerative colitis; the method comprises the following steps: administering to a subject in need thereof a therapeutically effective amount of a compound or composition as defined herein.

In another embodiment, the present invention provides a method for preventing and/or treating diseases of the throat, nose and ears including, but not limited to, sinus problems, hearing problems, dental pain, tonsillitis, ulcers and rhinitis; the method comprises the following steps: administering to a subject in need thereof a therapeutically effective amount of a compound or composition as defined herein.

In another embodiment, the present invention provides a method for preventing and/or treating skin diseases including, but not limited to, hyperkeratosis, parakeratosis, stratum granulosum thickening, stratum spinosum thickening, parakeratosis, stratum spinosum edema, and ulcer formation; the method comprises the following steps: administering to a subject in need thereof a therapeutically effective amount of a compound or composition as defined herein.

In another embodiment, the invention provides a method for preventing and/or treating bowel diseases including, but not limited to, Inflammatory Bowel Disease (IBD), colitis, gastroenteritis, ileus, ileitis, appendicitis, and crohn's disease; the method comprises the following steps: administering to a subject in need thereof a therapeutically effective amount of a compound or composition as defined herein.

In another embodiment, the present invention provides a method for preventing and/or treating neurological and central nervous system diseases, including but not limited to neuropathic pain. The compounds of the invention are therefore suitable for the prevention of neurodegeneration and for the stimulation of nerve regeneration in different neurological disorders; the method comprises the following steps: administering to a subject in need thereof a therapeutically effective amount of a compound or composition as defined herein.

In another embodiment, the invention provides a method for preventing and/or treating a proliferative disease including, but not limited to, cancer of the breast, colon, intestine, skin, head and neck, nerve, uterus, kidney, lung, liver, ovary, pancreas, prostate or thyroid; giant lymph node hyperplasia; a sarcoma; malignant cell tumors; and melanoma; the method comprises the following steps: administering to a subject in need thereof a therapeutically effective amount of a compound or composition as defined herein.

In another embodiment, the present invention provides a method for the prevention and/or treatment of renal diseases including, but not limited to, renal fibrosis or renal dysfunction; the method comprises the following steps: administering to a subject in need thereof a therapeutically effective amount of a compound or composition as defined herein.

In another embodiment, the invention provides a method for the prevention and/or treatment of sexual dysfunction including, but not limited to, hypogonadism, bladder disease, hypertension, diabetes or pelvic surgery, and/or for the treatment of sexual dysfunction associated with treatment with certain drugs, such as drugs used to treat hypertension, depression or anxiety; the method comprises the following steps: administering to a subject in need thereof a therapeutically effective amount of a compound or composition as defined herein.

In another embodiment, the present invention provides a method for preventing and/or treating bone diseases including, but not limited to, osteoporosis and osteoarthritis; the method comprises the following steps: administering to a subject in need thereof a therapeutically effective amount of a compound or composition as defined herein.

In another embodiment, the present invention provides a method for the prevention and/or treatment of diseases and disorders such as benign prostatic hyperplasia, transplant rejection, spasticity, chronic obstructive bladder disease, and allergy; the method comprises the following steps: administering to a subject in need thereof a therapeutically effective amount of a compound or composition as defined herein.

In a preferred embodiment, the present invention provides a method for preventing and/or treating glaucoma, degenerative retinal disease, age-related macular degeneration, retinopathy, asthma, sexual dysfunction or COPD; the method comprises the following steps: administering to a subject in need thereof a therapeutically effective amount of a compound or composition as defined herein.

In the present invention, it is particularly preferred that the IC in the ROCK inhibition assay described hereinafter can be less than 10. mu.M, preferably less than 1. mu.M, more preferably less than 0.1. mu.M₅₀A compound of formula I or any subset thereof that value inhibits ROCK.

Said inhibition may occur in vitro and/or in vivo, and when occurring in vivo, is preferably performed in a selective manner as defined above.

The term "ROCK-mediated disorder" or "disease" as used herein refers to any disease or other deleterious condition known to function. The term "ROCK-mediated disorder" or "disease" also refers to a disease or disorder in which remission by a ROCK inhibitor is achieved. Accordingly, another embodiment of the present invention relates to the treatment or lessening the severity of one or more diseases in which ROCK acts.

In terms of pharmaceutical use, the compounds of the invention may be used as free acids or bases, and/or in the form of pharmaceutically acceptable acid addition and/or base addition salts (e.g. as obtained by non-toxic organic or inorganic acids or bases), hydrates, solvates and/or complexes, and/or in the form of pro-drugs or pro-drugs of esters. The term "solvate" as used herein, unless otherwise indicated, refers to any combination of a compound of the present invention with a suitable inorganic solvent (e.g., hydrate) or organic solvent (e.g., without limitation, alcohols, ketones, esters, and the like). The skilled person will be aware of such salts, hydrates, solvates and the like and their preparation; references to salts, hydrates, solvates and the like may be found in US-A-6,372,778, US-A-6,369,086, US-A-6,369,087 and US-A-6,372,733.

Pharmaceutically acceptable salts of the compounds according to the invention, i.e. in the form of water, oil-soluble or dispersible products, include the conventional non-toxic salts or the quaternary ammonium salts formed, for example, from inorganic or organic acids or bases. Examples of such acid addition salts include: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalene-sulfonate, nicotinate, oxalate, palmitate (palmoate), pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucosamine, and salts with amino acids such as arginine, lysine, and the like. In addition, basic nitrogen-containing groups may be quaternized with agents such as: lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides such as benzyl and phenethyl-bromide and the like. Other pharmaceutically acceptable salts include the sulfate ethanolate and sulfate salts.

Generally, for pharmaceutical use, the compounds of the invention may be formulated as a pharmaceutical formulation or composition comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and optionally one or more other pharmaceutically active compounds.

By way of non-limiting example, such formulations may be in a form suitable for oral administration, parenteral administration (such as by intramuscular or subcutaneous injection), intravitreal injection, topical administration (including ophthalmic), inhalation administration, by dermal patch, by implant, by suppository and the like. Such suitable forms of administration (which may be solid, semi-solid or liquid, depending on the mode of administration) as well as methods for their preparation and carriers, diluents and adjuvants for their preparation are well known to the skilled worker; see, for example, US-A-6,372,778, US-A-6,369,086, US-A-6,369,087 and US-A-6,372,733, and standard manuals such as the latest version of Remington's Pharmaceutical Sciences.

Some preferred, but non-limiting examples of such formulations include tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, creams, lotions, soft and hard gelatin capsules, suppositories, eye drops, sterile injectable solutions, and sterile packaged powders (which typically need to be reconstituted prior to use) for rapid bolus administration and/or continuous administration, and may be formulated with carriers, excipients, and diluents that are inherently suitable for use in such formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia, calcium phosphate, acacia, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl-propylhydroxybenzoate, polyvinylpyrrolidone, sodium chloride, talc, magnesium stearate, edible oils, vegetable oils and mineral oils or suitable mixtures thereof. The formulations may optionally contain other pharmaceutically active substances, which may or may not act synergistically with the compounds of the present invention, and other substances conventionally used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, disintegrating agents, bulking agents, fillers, preservatives, sweetening agents, flavoring agents, flow control agents, mold release agents, and the like.

In addition, co-solvents such as alcohols may improve the solubility and/or stability of the compounds. In preparing aqueous compositions, it will be more appropriate to add salts of the compounds of the invention because of their higher water solubility.

For pain treatment, the compounds of the present invention may be used topically. For topical administration, sprays, ointments or transdermal patches or other forms of compounds suitable for topical, transdermal and/or intradermal administration may be beneficial.

For ophthalmic applications, solutions, gels, tablets, and the like will typically employ a physiological saline solution, gel, or excipient as the primary vehicle. Ophthalmic formulations are best prepared at a comfortable pH using an appropriate buffer system.

More specifically, the compositions can be formulated into pharmaceutical formulations comprising a therapeutically effective amount of particles comprised of a solid dispersion of the compound of the present invention and one or more pharmaceutically acceptable water-soluble polymers.

The term "solid dispersion" means a solid (rather than a liquid or gaseous) system comprising at least two components, one of which is capable of more or less uniformly dispersing into the other component or components. Such solid dispersions will be referred to as "solid solutions" when the components are dispersed such that the system is uniform in chemical and physical properties or homogeneous throughout or consists of a thermodynamically defined single phase. Solid solutions are a preferred physical system because the components are generally bioavailable to the organism to which they are administered.

It may be further convenient to formulate the compound in the form of nanoparticles having surface modifiers adsorbed on their surface sufficient to maintain an effective average particle size of less than 1000 nm. Suitable surface-modifying agents are preferably selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products, and surfactants. Preferred surface modifying agents include nonionic and anionic surfactants.

Another interesting way of formulating the compounds of the present invention comprises a pharmaceutical composition wherein the compounds are incorporated in a hydrophilic polymer and this mixture is then applied as a film coating on a number of beads, resulting in a composition with good bioavailability which is easy to prepare and suitable for the preparation of pharmaceutical dosage forms for oral use. Materials suitable for use as cores in beads may take a variety of forms, provided that the material is pharmaceutically acceptable and has the appropriate size and hardness. Examples of such materials are polymers, inorganic substances, organic substances, saccharides and derivatives thereof.

The formulations may be prepared in a manner known per se, which generally involves mixing at least one compound of the invention with one or more pharmaceutically acceptable carriers, if necessary under sterile conditions, in combination with other pharmaceutically active compounds. Reference is again made to standard manuals, such as the latest edition of Remington's Pharmaceutical Sciences.

The pharmaceutical preparations of the present invention are preferably in unit dosage form or suitably packaged, e.g. in a box, blister, vial, bottle, sachet, ampoule or any other suitable single or multi-dose holder or container (with suitable label); optionally plus one or more brochures containing product information and/or instructions for use. In general, the unit dose will contain from 1 to 1000mg, and usually from 5 to 500mg, of at least one compound of the invention, such as about 10, 25, 50, 100, 200, 300 or 400mg per unit dose.

The compounds may be administered by a variety of routes including oral, rectal, ocular, transdermal or intranasal routes depending primarily on the particular formulation used and the condition to be treated or prevented (e.g., eye drops for the treatment of ocular diseases or dry powder inhalers for the treatment of pulmonary diseases). At least one compound of the present invention is typically administered in an "effective amount," that is, any amount of a compound of formula I, or any subset thereof, that is sufficient, upon appropriate administration, to achieve the desired therapeutic or prophylactic effect in the individual to which it is administered. Generally, depending on the condition to be prevented or treated and the route of administration, the effective amount will generally be from 0.001 to 1000mg, more often from 0.1 to 500mg, for example from 1 to 250mg, per kg of patient body weight per day, such as about 5,10, 20, 50, 100, 150, 200 or 250mg per kg of patient body weight per day, in a single daily dose, divided into one or more daily doses, or administered substantially continuously, for example by implantable medical devices or sustained release formulations. The treating physician will determine the amount to be administered, the route of administration and the further course of treatment, depending on factors such as age, sex, general condition of the patient and the nature and severity of the disease/condition. Reference is again made to US-A-6,372,778, US-A-6,369,086, US-A-6,369,087 and US-A-6,372,733, and the other prior art mentioned above, as well as standard manuals such as the latest version of Remington's Pharmaceutical Sciences.

According to the methods of the present invention, the pharmaceutical compositions may be administered separately at different times during the course of therapy or simultaneously in divided or single combination forms. Accordingly, the invention is to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.

For oral forms, the compositions of the invention may be mixed with suitable additives, such as excipients, stabilizers or inert diluents, and converted into suitable administration forms, such as tablets, coated tablets, hard capsules, aqueous, alcoholic or oily solutions, using customary means. Examples of suitable inert carriers are gum arabic, magnesium oxide, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. In this case, the preparation of the drug may be both dry and wet granules. Suitable oily excipients or solvents are vegetable or animal oils, such as sunflower oil or cod liver oil. Suitable solvents for the aqueous or alcoholic solution are water, ethanol, sugar solutions or mixtures thereof. Polyethylene glycol and polypropylene glycol are also suitable for further adjuvants in other application forms. As immediate release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.

When administered by nasal aerosol or inhalation, these compositions may be prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as aqueous salt solutions, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and employing fluorocarbons and/or other solubilizing or dispersing agents known in the art. Suitable pharmaceutical formulations for administration in aerosol or spray form include solutions, suspensions or emulsions of a compound of the invention or a physiologically tolerable salt thereof in a pharmaceutically acceptable solvent, for example ethanol or water, or mixtures of such solvents. The formulation may additionally contain other pharmaceutical adjuvants, such as surfactants, emulsifiers, stabilizers and propellants, if desired.

For injection, the compounds of the invention may be formulated as solutions, suspensions or emulsions with conventional materials, such as solubilizers, emulsifiers or other adjuvants, if desired. The compounds of the invention can also be lyophilized, and the lyophilized powders obtained used, for example, in the production of injectable preparations. Suitable solvents are, for example, water, physiological saline solutions or alcohols, such as ethanol, propanol, glycerol, furthermore sugar solutions, such as glucose solutions or mannitol solutions, or mixtures of the various solvents mentioned above. Injections or suspensions may be formulated according to techniques known in the art using suitable non-toxic parenterally acceptable diluents or solvents, for example mannitol, 1, 3-butanediol, water, ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting agents and suspending agents, for example sterile, non-irritating, non-volatile oils including synthetic mono-or diglycerides and fatty acids, including oleic acid.

When administered rectally by suppository means, these formulations may be prepared by mixing the compounds of the present invention with suitable non-irritating excipients, such as cocoa butter, synthetic glycerides or polyethylene glycols, which are solid at ordinary temperatures but liquefy and/or dissolve in the rectal cavity to release the drug.

In preferred embodiments, the compounds and compositions of the present invention are used topically, e.g., for topical or adsorptive and non-adsorptive applications.

The composition has value in the veterinary field for purposes including not only the prevention and/or treatment of disease in animals, but also the promotion of growth and/or their weight and/or the quantity and/or quality of meat or other products obtained from animals of economic importance such as cattle, pigs, sheep, chickens, fish, etc. Thus, in another aspect, the invention relates to a composition for veterinary use comprising at least one compound of the invention and at least one suitable carrier (i.e. a carrier suitable for animal use). The invention also relates to the use of the compounds of the invention for the preparation of such compositions.

The present invention will now be explained by the following synthetic examples and biological examples, but the examples do not limit the scope of the present invention in any way.

Examples

A. Physicochemical Properties of the Compound

A.1. Purity of the compound

Unless otherwise indicated, the purity of the compounds will be confirmed by liquid chromatography/mass spectrometry (LC/MS) as follows:

● HPLC system: waters2690 with photodiode array detector Waters 996; column: c18; gradient: from solvent A (H) within 3min₂O/formic acid 26.5nM)0% to solvent B (CH)₃CN/formic acid 17nM) 80%. Flow rate: 2.75 ml/min.

● mass spectrometer: micromass platform LC. Ionization: electric injection (polarity: negative and positive)

A.2. Configuration division:

the absolute configuration of the chiral center was partitioned using the Cahn-Ingold-Prelog system, where four groups on asymmetric carbons would be ranked according to a set of sequence rules. Reference is made to Cahn, Ingold, prelogAngew. chem. int. Ed. Engl.1966,5, 385-.

A.3. Stereochemistry:

it is known to the person skilled in the art that specific enantiomers (or diastereomers) can be obtained by different methods, such AS, but not limited to, Chiral resolution (e.g., salts with optically active acids or bases can be used to form diastereomeric salts, which can facilitate separation of optically active isomers of compounds of formula I or any subset thereof), asymmetric synthetic or preparative Chiral chromatography (using different columns, such AS Chiralcel OD-H (tri-3, 5-dimethylphenylcarbamate, 46 x 250 or 100 x 250mm,5 μm), Chiralcel OJ (tri-methylbenzoate, 46 x 250 or 100 x 250mm,5 μm), Chiralpak AD (tri-3, 5-dimethylphenylcarbamate, 46 x 250mm,10 μm) and Chiralpak AS (tri- (S) -1-phenylethylcarbamate, 46X 250mm,10 μm). Stereoisomers may be obtained from commercially available materials having known configurations (such compounds include, for example, amino acids), if convenient.

A.4. Name of molecule

Using software MDL ISIS^TM/Draw2.3 specifies the name of the molecule.

B. Synthesis of compounds

B.1. Intermediates

The compounds of the present invention may be prepared by methods well known to those skilled in the art and described in the synthetic and experimental procedures set forth below.

Intermediate 1:5- (piperidin-3-ylamino) -indazole-1-carboxylic acid tert-butyl ester

To a solution of 5-nitro-indazole (200g,1.2mol,1.0 eq) in THF (2L) was added DMAP (22g,0.18mol,0.15 eq)And TEA (248g,2.4mol,2.0 equiv). The reaction mixture was stirred at 30 ℃ for 20min, then Boc₂O (320g,1.5mol,1.2 eq.) was added to the reaction mixture in one portion. The reaction mixture was stirred at 30 ℃ for 16h, evaporated and the residue dissolved in DCM (2L). With aqueous HCl (0.5M) (1 L.times.3) and H₂The DCM solution was washed with O (1 L.times.3) over MgSO₄Dried and concentrated to dryness to give Boc protected 5-nitro-indazole (310g, 96%).

To a solution of tert-butyl 5-nitro-indazole-1-carboxylate (300g,1.1mol,1.0 eq) in THF (3L) in the presence of H₂The mixture was hydrogenated in the presence of (50psi) Pd/C (30g) as a catalyst at 40 ℃. The reaction mixture was stirred at 40 ℃ for 16 hours. TLC (PE: EA =4:1) indicated the reaction was complete. Absorption of H₂After that, the catalyst was filtered off and the filtrate was evaporated to give crude tert-butyl 5-amino-indazole-1-carboxylate (252g,95%) which was used in the next step without purification.

A mixture of 1-benzyl-piperidin-3-one hydrochloride (116g,0.52mol,1.2 equiv.) and TEA (43.5g,0.43mol,1.0 equiv.) in DCE (800ml) was stirred at 30 ℃ for 1 hour. Then, after 30min, 5-amino-indazole-1-carboxylic acid tert-butyl ester (100g,0.43mol,1.0 eq.) and CH₃COOH (25.8g,0.43mol,1.0 eq) was added in one portion to the reaction mixture NaBH (OAc)₃(273g,1.29mol,3.0 equiv.). The mixture was stirred at 30 ℃ for 16 hours. LC-MS indicated the reaction was complete. 1L of DCM is added to the reaction mixture and saturated NaHCO is used₃(800 ml. times.3) and H₂O (500ml x3) washed the organic layer over Na₂SO₄Dried and concentrated by rotary evaporator. Using DCM: CH₃OH =60:1 and the crude product was purified by column chromatography on silica gel to give 5- (1-benzyl-piperidin-3-ylamino) -indazole-1-carboxylic acid tert-butyl ester (131g, 75%).

The aforementioned compound (120g,0.3mol,1.0 equivalent) was dissolved in CH₃In OH (1.5L) and in the presence of H₂The mixture was hydrogenated in the presence of (50psi) using Pd/C (12g) as a catalyst at 40 ℃. The reaction mixture was stirred at 40 ℃ for 16 hours. TLC (DCM: CH)₃OH =10:1) indicates the end of the reaction. Suction deviceH collection₂After that, the catalyst was filtered off and the filtrate was evaporated to give the title product (90g,95%) which was used in the next step without purification.

Intermediate 2- [1- (3-carboxy-benzyl) -piperidin-3-ylamino ] -indazole-1-carboxylic acid tert-butyl ester (mixture of Boc-protected and Boc-deprotected compounds)

To a mixture of intermediate 1(20g,0.063mol,1.0 eq) and (3-formyl) -benzoic acid (11.4g,0.076mol,1.2 eq) and TEA (12.8g,0.126mol,2.0 eq) in DCE (200ml) was added NaBH (OAc)₃(26.8g,0.132mol,2.0 equiv.). The reaction mixture was stirred at 30 ℃ for 16 hours. TLC (DCM/CH)₃OH =10:1) indicates the end of the reaction. 80ml DCM were added and the organic layer was washed with saturated NaHCO₃(150mlx3) and H₂O (150mlx3) wash, then in Na₂SO₄Dried and concentrated by rotary evaporator. The crude product was purified by preparative HPLC to give a mixture of protected and deprotected intermediate 5 (15.2g, 54%).

Intermediate 3- [1- (3-carboxymethyl-benzyl) -piperidin-3-ylamino ] -indazole-1-carboxylic acid tert-butyl ester (mixture of Boc-protected and Boc-deprotected compounds)

M-tolyl-acetic acid (15g,0.1mol,1.0 equiv.) was added to anhydrous CCl at room temperature₄(150ml) solution NBS (18.3g,0.105mol,1.05 equiv.) and AIBN (0.8g,0.0049mol,0.05 equiv.) in anhydrous CCl₄(150ml) in water. The reaction mixture was refluxed for 16 hours, cooled to room temperature and filtered to give a yellow solid which was taken up with CCl₄Washed and dried to give the desired product (3-bromomethyl-phenyl) -acetic acid (18 g)79.3%)。

To a mixture of intermediate 1(20g,0.063mol,1.0 equiv.) and DIEA (16.3g,0.126mol,2.0 equiv.) in THF (200ml) was added (3-bromomethyl-phenyl) -acetic acid (17.4g,0.076mol,1.2 equiv.). The reaction mixture was stirred at 80 ℃ for 16 hours. TLC (DCM/CH)₃OH =10:1) indicates the end of the reaction. The solvent was evaporated and the residue was purified by preparative HPLC to give a mixture of protected and deprotected intermediate 3 (14g, 54%).

Intermediate 4 isoquinolin-5-yl-piperidin-3-yl-amine hydrochloride

At-15 ℃ isoquinoline (120g,0.929mol) in H₂SO₄KNO is added into the solution in (1L)₃(112.6g,1.115mol) (in portions). The mixture was stirred at room temperature for 2 hours. TLC (petroleum ether: ethyl acetate =2:1) indicated the reaction was complete. The mixture was added to water (3L) at 0 ℃. By adding NH₄OH, the mixture was adjusted to pH8 and filtered. The filter cake was washed with methyl tert-butyl ether (1L X2) and concentrated in vacuo to give 5-nitro-isoquinoline (160g,94%) as a yellow solid.

To 5-nitro-isoquinoline (150g,0.861mol) in EtOH/H at room temperature₂To a solution in O =4:1(5L), NH was added₄Cl (92.2g,1.723mol) and Fe (193g,3.445 mol). Then, the mixture was heated to 80 ℃ and stirred for 10 hours. TLC (petroleum ether: ethyl acetate =1:1) indicated the reaction was complete. The mixture was cooled to room temperature and filtered through a pad of Celite (Celite). The filter cake was washed with EtOH (2 L.times.2). The filtrate was concentrated in vacuo to remove most of the EtOH. The residue was extracted with EtOAc (500 ml. times.10). The combined layers were passed through Na₂SO₄Drying, filtration and concentration in vacuo gave 5-amino-isoquinoline (67g,54%) as a yellow solid.

To a solution of 5-amino-isoquinoline (47g,0.320mol) in CH₃To a solution in COOH (1800mL) were added tert-butyl 3-amino-piperidine-1-carboxylate (69.6g,0.376mol) and Na₂SO₄(267g,1.88 mol). The mixture was stirred at room temperature for 0.5 hour. Then, NaBH (OAc) was added stepwise to the mixture₃(84.6g,0.376 mol). The mixture was stirred at room temperature for 18 hours. By adding K₂CO₃The mixture was adjusted to pH8 and extracted with EtOAc (2L X3) (combined layers Na₂SO₄Drying, filtration and concentration in vacuo gave a crude product which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate =5:1) to give 3- (isoquinolin-5-ylamino) -piperidine-1-carboxylic acid tert-butyl ester (55g,53%) as a yellow oil.

To a solution of 3- (isoquinolin-5-ylamino) -piperidine-1-carboxylic acid tert-butyl ester (80g,0.244mol) in EtOAc (1000mL) at room temperature was added HCl-EtOAc (1000 mL). The mixture was stirred at room temperature for 2.5 hours. TLC (dichloromethane: methanol =10:1) indicated the reaction was complete. The reaction mixture was filtered. The filter cake was dried under vacuum to give the title compound (66g,100%) as a yellow solid.

Intermediate 5 3- [3- (isoquinolin-5-ylamino) -piperidin-1-ylmethyl ] -benzoic acid

To a solution of intermediate 4(10 g. times.2, 0.0379 mol. times.2) in DCE (400 mL. times.2) was added Et₃N (9.2 g.times.2, 0.0910 mol.times.2) and MgSO₄(20X 2,0.139mol X2) and stirred at 30 ℃ for 0.5 h. 3-formylbenzoic acid (6.26 g.times.2, 0.0417 mol. times.2) and AcOH (5.46 g.times.2, 0.0910 mol. times.2) were added. The reaction mixture was stirred at 30 ℃ for 0.5 hour. Addition of NaBH (OAc)₃(24.1 g. times.2, 0.1137 mol. times.2), and the reaction mixture was stirred at 30 ℃ overnight. TLC (dichloromethane: methanol =10:1) indicated the reaction was complete. The reaction mixture was filtered. By CH₂Cl₂The filter cake was washed, the filtrate was washed with brine, over Na₂SO₄Dried and concentrated in vacuo and purified by preparative HPLC to give intermediate 5(10.2g,37.2%) as a yellow solid.

Intermediate 6 3- [3- (isoquinolin-5-ylamino) -pyrrolidin-1-ylmethyl ] -benzoic acid

To a homogeneous solution of isoquinolin-5-amine (15g,104mmol) and tert-butyl 3-oxopyrrolidine-1-carboxylate (23.12g,125mmol,1.2 eq) in AcOH (300mL) at 0 deg.C was added NaBH (OAc) dropwise₃(44.1g,208mmol,2 equiv.) in AcOH (200 mL). The mixture was stirred at room temperature overnight and concentrated to dryness. Then, by adding saturated Na₂CO₃Aqueous solution, the residue was adjusted to pH10 and extracted with DCM (× 3). The combined organic layers were washed with Na₂SO₄Drying, filtration and concentration in vacuo gave the expected compound, which was used in the next step without further purification.

A solution of the aforementioned compound (104mmol) in diethyl ether (1L) was bubbled with HCl for 1 h. The suspension was stirred for 5h and the solvent was evaporated. The residue was then dissolved in water and the pH was adjusted to pH by addition of 5M NaOH>12. The aqueous layer was extracted with DCM (3X) and the combined organic layers were washed with Na₂SO₄Drying, filtration and concentration under vacuum gave the expected compound (20.5g,92%) as a brown powder.

To a suspension of the above compound (10g,46.9mmol) in anhydrous THF (100mL) was added 3-formylbenzoic acid (7.74g,51.6mmol,1.1 equiv.) and the mixture was stirred at 50 deg.C for 15 min. Then, NaBH (OAc)₃A white slurry solution (29.8g,141mmol,3 equivalents) in THF (60mL) was added to the mixture, stirred overnight at room temperature, and concentrated to dryness. Finally, the residue was purified by C18 column chromatography to give intermediate 6(8g,49%) as a brown powder.

Intermediate 7 5-bromo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole

To a suspension of 5-bromo-1H-indazole (2.5g,12.69mmol,1.0 equiv.) in DCM (10ml) was added dihydropyran (3.2g,38mmol,3.0 equiv.) and a catalytic amount of PTSA (12% in AcOH, 1.8ml,0.1 equiv.). The mixture was stirred overnight and neutralized by the addition of sodium bicarbonate. The organic layer was then washed sequentially with 10% citric acid and brine in Na₂SO₄Dried and concentrated under vacuum. The resulting residue was purified by chromatography on silica gel, eluting with DCM, to give the expected compound as a colourless liquid (3.57g, 82%).

Intermediate 8, 3- (2-amino-ethylsulfanyl) -dihydro-furan-2-one

To 3-bromo-dihydro-furan-2-one (2.49g,15.1mmol) and 2- (Boc-amino) ethanethiol (2.9g,16.5mmol) in CH₃To a solution in CN (40ml), K was added₂CO₃(4.14g,30 mmol. the mixture was stirred at 80 ℃ for 16h and the solvent was evaporated to dryness then the residue was purified by column chromatography (PE/EtOAc =4/1) to give the expected Boc protected intermediate 8(3.8g) as a colourless oil.

The previous compound (3.7g,14.16mmol) was dissolved in 10ml EtOAc. Then, 40mL of 4N HCl/EtOAc was added to the solution, which was then stirred at 25 ℃ for 2 h. The white solid was filtered and washed with PE to give the expected intermediate 8(2g),

intermediate 9:4- (2-amino-ethyl) - [1,3] dioxol-2-one

In a 100mL autoclave reactor, 60mL NH₃In CH₃A saturated solution in OH was added rapidly to 4-bromo-but-1-ene (3 mL). Then, the mixture was stirred in an autoclave at 90 ℃ for 16 hours. After the reaction, the solvent was concentrated in vacuo to give the hydrobromide salt of but-3-enamine (12g,95%) as a yellow powder.

In N₂Next, the above-mentioned compound (12g,0.08mol) is reacted with CH₂Cl₂Adding K into the suspension in (1L)₂CO₃(33g,0.24mol) in water (80 mL). The biphasic mixture was cooled to 0 ℃ and Cbz-Cl (22g,0.128mol) was added dropwise. After stirring at this temperature for 15min, the reaction mixture was stirred at room temperature for 14 h. After the reaction is completed, CH is added to the mixture₂Cl₂And water, passing the organic layer over anhydrous Na₂SO₄Dried, concentrated in vacuo, and purified by silica gel chromatography (petroleum ether/ethyl acetate =3:1) to give the corresponding Cbz-protected compound (12.2g,75%) as colorless oil.

At room temperature under N₂Next, the stirred above compound (12.2g,59.5mmol) was added to acetone/H₂To a solution in O (60mL/50mL), NMO (7.3g,62.5mmol) and OsO were added₄(303mg,1.2 mmol). Adding OsO₄After that, the color of the reaction solution became black. Then, the mixture was stirred at room temperature for 10 h. TLC (CH)₂Cl₂MeOH =10:1) indicated complete consumption of the starting material. The mixture was evaporated under vacuum. Water was added to the residue, and extracted with ethyl acetate. Subjecting the organic layer to anhydrous Na₂SO₄Dried, concentrated under vacuum and chromatographed on silica gel (CH)₂Cl₂MeOH =10:1) to give the corresponding diol (12g,85%) as a pale solid.

At-20 to-30 ℃ in N₂Next, to the diol (9g,37.66mmol) was addedCH₂Cl₂To the solution (200mL) was added triethylamine (15.2g,151 mmol). After a few minutes, triphosgene (5.5g,18.83mmol) was added dropwise to the mixture at this temperature and stirred at-20 to-30 ℃ for half an hour. The mixture was then stirred at room temperature for 15 h. TLC (CH)₂Cl₂MeOH =10:1) indicated almost complete consumption of starting material. Water was added to the mixture, and extracted with ethyl acetate. Subjecting the organic layer to anhydrous Na₂SO₄Dried, concentrated under vacuum and chromatographed on silica gel (CH)₂Cl₂Purification with/MeOH =10:1) gave the corresponding cyclized dioxolane (6.5g,55%) as a pale solid.

Intermediate 10 methyl 3- ((4-aminopiperidin-1-yl) methyl) benzoate

To piperidin-4-ylcarbamic acid tert-butyl ester (1.5g,7.48mmol,1.0 eq.) and K₂CO₃(1.55g,11.2mmol,1.5 equiv.) in CH₃To a solution in CN (10ml) was added methyl 3- (bromomethyl) benzoate (1.88g,8.22mmol,1.1 equiv). The mixture was stirred at rt overnight and diluted in AcOEt. The organic layer was then sequentially washed with saturated NaHCO₃Washed with brine and then Na₂SO₄Dried and concentrated under vacuum. The residue was purified by flash chromatography on silica gel, eluting with DCM/AcOEt (80/20 to 50/50), to give the expected Boc-protected intermediate 10(1.7g, 65%).

A solution of the foregoing compound in DCM was bubbled with HCl gas for 5min, and the reaction mixture was stirred at rt overnight. The precipitate was collected by filtration and washed with ether to give the hydrochloride salt of the expected intermediate 10 (1.5g,80%) as a white powder.

Intermediate 11 methyl 3- { [ (4-aminocyclohexyl) amino ] methyl } benzoate

A suspension of trans-4- (tert-butoxycarbonylamino) cyclohexylamine (0.50g,2.33mmol,1.0 eq) and methyl 3-formylbenzoate (0.41g,2.45mmol,1.05 eq) in THF (13ml) was stirred at 50 ℃ for 30 min. After cooling to room temperature, sodium triacetoxyborohydride (0.79g,3.73mmol,1.6 equiv.) was added and the reaction was stirred at ambient temperature until the reaction was complete.

By adding NaHCO₃Solution, quench reaction, extract with EtOAc (3 ×), and sequentially with saturated NaHCO₃The solution and brine washes. Organic fraction Na₂SO₄Dried and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) eluting with DCM/MeOH (99/1 to 91/9) to give Boc-protected intermediate (0.54g,64%) as a white powder.

A solution of the foregoing compound in DCM was bubbled with HCl gas for 5min, and the reaction mixture was stirred at rt for 3 h. The precipitate was collected by filtration and washed with ether to give the hydrochloride salt of the expected intermediate 11 (0.47g,93%) as a white powder.

Intermediate 12 propyl 3- ({3- [ (isoquinolin-5-yl) amino ] -8-azabicyclo [3.2.1] oct-8-yl } methyl) benzoate

To isoquinolin-5-amine (2.67g,18.5mmol) and 3-amino-8-azabicyclo [3.2.1] at 0 deg.C]To a homogeneous solution of tert-butyl octane-8-carboxylate (5g,125mmol,1.2 equiv.) in AcOH (60mL) was added NaBH (OAc) dropwise₃(7.84g,37mmol,2 equiv.) in AcOH (40 mL). The mixture was stirred at room temperature for 5 days and concentrated to dryness. Then, by adding saturated Na₂CO₃Aqueous solution, conditioning the residueTo pH10 and extracted with DCM (. times.3). The combined organic layers were washed with Na₂SO₄Dried, filtered and then concentrated in vacuo. The resulting residue was purified by flash chromatography (silica gel) eluting with DCM/MeOH (98/2) to give the expected compound (1.4g, 21%).

A solution of the foregoing compound (1.4g,3.96mmol) in diethyl ether (40mL) was bubbled with HCl for 5 min. The suspension was stirred for 5h and the solvent was evaporated. The residue was then dissolved in water and the pH adjusted to pH by addition of 5M NaOH>12. The aqueous layer was extracted with DCM (3X) and the combined organic layers were washed with Na₂SO₄Drying, filtration and concentration in vacuo gave the expected compound (900mg,90%) as a white powder.

To a suspension of the above compound (900mg,3.55mmol) in anhydrous THF (10mL) was added 3-formylbenzoic acid (587mg,3.91mmol,1.1 equiv.), and the mixture was stirred at 50 ℃ for 15 min. Then, NaBH (OAc)₃A white slurry solution (2.2g,10.66mmol,3 equiv.) in THF (6mL) was added to the mixture, stirred overnight at room temperature, and concentrated to dryness. Finally, the residue was purified by C18 column chromatography to give intermediate 12(670mg,49%) as a brown powder.

Intermediate 13 methyl 3- [ (3-aminopyrrolidin-1-yl) methyl ] benzoate

The Boc-protected intermediate (2.11g,63%) was prepared starting from t-butyl pyrrolidin-3-ylcarbamate (1.86g) using similar conditions as intermediate 10. Boc-deprotection of the previous compound with HCl gas in DCM gave the expected hydrochloride salt of intermediate 13 as a white powder (1.82g, 94%).

B.1. Compounds of the invention

General procedure for ester or thioester formation:

scheme A

To intermediate (200mg,1.0 eq) and TEA (3.0 eq) in CH₃To a mixture in CN (4ml) were added HOBT (0.4 equiv.), EDCI (1.5 equiv.) and the selected alcohol or thiol (1.5 equiv.). The reaction mixture was stirred at 30 ℃ for 16 hours, and the solvent was concentrated to dryness. The crude product was purified by preparative HPLC to give the expected compound.

Scheme B

To intermediate (200mg,1.0 eq) and TEA (3.0 eq) in CH₃To a mixture in CN (4ml) were added HOBT (0.4 equiv.), EDCI (1.5 equiv.) and the selected alcohol or thiol (1.5 equiv.). The reaction mixture was stirred at 30 ℃ for 16 hours, and the solvent was concentrated to dryness. The resulting crude product was dissolved in DCM/TFA =7:1(4ml), the reaction mixture was stirred at 30 ℃ for 16h and concentrated in vacuo. The residue was purified by preparative HPLC to give the expected compound.

Using this general procedure, the following compounds of the invention were prepared

General procedure for reductive amination

To a mixture of intermediate (200mg), selected aldehyde (1.2 equiv.) and TEA (100. mu.l) in DCM (4ml) was added NaBH (OAc)₃(1.5 equiv.). The reaction mixture was stirred at 30 ℃ for 16 hours and concentrated to dryness. The crude product was then dissolved in DCM/TFA =7:1(4 ml). The reaction mixture was stirred at 30 ℃ for 16h, concentrated, and the crude product was purified by preparative HPLC to give the expected compound.

Using this general procedure, the following compounds of the invention were prepared:

general procedure for amide formation

Scheme A

To intermediate (200mg,1.0 equiv.) and R-NH₂(2.0 equiv.) in CH₃To a mixture in CN (4ml) were added HOBT (0.4 eq) and EDCI (1.5 eq). The reaction mixture was stirred at 30 ℃ for 16 hours and concentrated to dryness. The crude product obtained was purified by preparative HPLC to give the expected compound.

Scheme B

To intermediate (200mg,1.0 eq) and R-NH2(2.0 eq) in CH₃To a mixture in CN (4ml) were added HOBT (0.4 eq) and EDCI (1.5 eq). The reaction mixture was stirred at 30 ℃ for 16 hours and concentrated to dryness. The resulting crude product was dissolved in DCM/TFA =7:1(4 ml). The reaction mixture was stirred at 30 ℃ for 16h, concentrated, and the crude product was purified by preparative HPLC to give the expected compound.

Scheme C

To a solution of intermediate (100mg,1.0 eq), R-NH2(1.5 eq) and triethylamine (3.0 eq) in DMF (2ml) was added HATU (1.0 eq). The reaction mixture was stirred at 30 ℃ overnight and concentrated in vacuo. The crude product obtained was purified by preparative HPLC to give the expected compound.

Scheme D

To intermediate (100mg,1.0 equiv.), R-NH₂To a solution of (2.0 equiv.) and triethylamine (10.0 equiv.) in DMF (2ml) was added HATU (1.5 equiv.). DMAP (1.0 eq) was then added to the mixture. The reaction mixture was stirred at 50 ℃ overnight and concentrated in vacuo. The crude product obtained was purified by preparative HPLC to give the expected compound.

Scheme E

To intermediate (100mg,1.0 equiv.), R-NH₂To a solution of (1.5 eq) and triethylamine (3.0 eq) in DMF (2ml) was added HATU (1.0 eq). The reaction mixture was stirred at 30 ℃ overnight and concentrated in vacuo. The crude product was dissolved in 4ml of TFA in DCM (1:4) and the reaction mixture was stirred at 30 ℃ for 4 h. The solvent was then concentrated under vacuum and the crude product was purified by preparative HPLC to give the expected compound.

Scheme F

To intermediate (100mg,1.0 equiv.), R-NH₂To a solution of (2.0 equiv.) and DIEA (6.0 equiv.) in DMF (1.5ml) was added HATU (1.5 equiv.). Then, HOBT (0.5 eq) was added to the mixture. The reaction mixture was stirred at 30 ℃ overnight. The solvent was then concentrated under vacuum and the crude product was purified by preparative HPLC to give the expected compound.

Scheme G

To intermediate (100mg,1.0 equiv.), R-NH₂To a solution of (2.0 equiv.) and DIEA (6.0 equiv.) in DMF (1.5ml) was added HATU (1.5 equiv.). Then, HOBT (0.5 eq) was added to the mixture. The reaction mixture was stirred at 30 ℃ overnight and concentrated in vacuo. The crude product was dissolved in 4ml of TFA in DCM (1:4) and the reaction mixture was stirred at 30 ℃ for 4 h. The solvent was then concentrated under vacuum and the crude product was purified by preparative HPLC to give the expected compoundA compound (I) is provided.

Example Compound 25

To a solution of intermediate 5(100mg,277umol,1.0 eq), methyl 4-aminobenzoate (554 μmol,2.0 eq) and DIEA (1662 μmol,6.0 eq) in DMF (1.5ml) was added HATU (157.9mg,415.5 μmol,1.5 eq). HOBT (138.5. mu. mol,0.5 eq.) was then added to the mixture. The reaction mixture was stirred at 30 ℃ overnight. The solvent was then evaporated in vacuo and the crude product was purified by preparative HPLC to give the TFA salt of the expected compound (30mg,17%) as a white powder. Retention time: 2.058 min. m/z (MH +) =495.2

Using the general procedure described above, the following compounds of the invention were prepared:

compound 53 (methyl 3- ({4- [ (isoquinolin-5-yl) amino ] piperidin-1-yl } methyl) benzoate)

To a solution of 5-bromoisoquinoline (419mg,2.01mmol,1.0 equiv.) in toluene (5ml) were added intermediate 10(500mg,2.01mmol,1.0 equiv.), palladium acetate (67.5mg,0.3mmol,0.15 equiv.), rac- (±) -BINAP (187.5mg,0.3mmol,0.15 equiv.), and cesium carbonate (2.35g,7.22mmol,3.6 equiv.). The reaction mixture was then degassed 3 times with nitrogen and stirred at 80 ℃ overnight. The mixture was diluted with AcOEt and washed with brine, Na₂SO₄Dried, filtered, and concentrated under vacuum. The crude product was purified by flash chromatography on C18 using CH₃CN/H₂O elution gave the title compound (144mg,19%) as a white powder.

The title compound was checked for purity and identity by liquid chromatography/mass spectrometry (LC/MS). HPLC system: shimadzu SIL-20A/20 AC. Column: luna C1850 × 2.1 mm; 5 μm. Gradient: 0'-0.5': mobile phase a (water, 10mM ammonium acetate) 100%; 0.5'-3.0': from 100% mobile phase a to 98% mobile phase B (acetonitrile); 3'-4': 2% mobile phase a and 98% mobile phase B. Flow rate: 0.6 ml/min. Mass spectrometry: applied Biosystems MDS SCIEX,3200Q Trap.

For the title compound: retention time: 3.65 min; m/z (MH +): 376.5.

compound 54 (methyl 3- [ ({4- [ (isoquinolin-5-yl) amino ] cyclohexyl } amino) methyl ] benzoate)

Compound 54 was synthesized (19mg,4% yield) by the reaction of 5-bromo-isoquinoline (250mg) with intermediate 11, hydrochloride salt (403mg), using the same procedure as compound 53. The title compound was checked for purity and identity by liquid chromatography/mass spectrometry using the same equipment and setup as compound 53. Retention time: 3.25 min. m/z (MH +) =390.4

Compound 55 methyl 3- ({3- [ (4-methylisoquinolin-5-yl) amino ] pyrrolidin-1-yl } methyl) benzoate

Compound 55(51mg,10% yield) was synthesized by the reaction of 5-bromo-4-methylisoquinoline (300mg) with intermediate 13(420mg) using the same procedure as compound 53. The title compound was checked for purity and identity by liquid chromatography/mass spectrometry using the same equipment and setup as compound 53. Retention time: 3.81 min. m/z (MH +) =376.4

Met1(3- ({3- [ (1H-indazol-5-yl) amino ] piperidin-1-yl } methyl) benzoic acid):

met1 does not represent a compound of the invention, but is a metabolite resulting from ester hydrolysis of compounds 7, 9, 10, 14, 16, 17, 18, 19 by a carboxylic ester hydrolase or pseudoesterase. In the laboratory, by saponifying compound 7 with LiOH, Met1 can be easily prepared; such methods are well known to those skilled in the art. Metabolites derived from other compounds of the invention can be readily prepared by saponification of LiOH.

Met1 the purpose here was to demonstrate the lack of functional activity of metabolites produced by ester hydrolysis of the compounds of the invention by carboxylic ester hydrolases or pseudoesterases. After preparation in the laboratory by saponification of the parent compound of the invention, Met1 or similar metabolites may be evaluated in a functional assay to confirm their lack of functional activity.

C. In vitro and in vivo assays

C.1.ROCK inhibitory Activity screening

C.1.1. Kinase inhibition (ROCKI and ROCKII)

The activity at the target on ROCK was measured in a biochemical assay using the following reagents: basic reaction buffer, 20mM Hepes (pH7.5),10mM MgCl₂,1mM EGTA,0.02%Brij35,0.02mg/ml BSA,0.1mM Na₃VO₄2mM DTT,1% DMSO. The required cofactors were added individually to each kinase reactant. The reaction procedure first involves the preparation of the peptide substrate in a freshly prepared reaction buffer. The required cofactor is then added to the substrate solution. ROCK (1nM final concentration) was then delivered to the substrate solution. After gentle mixing, a DMSO solution of the test compound was added to the enzyme. Then mixing the substrate mixture³³P-ATP (final specific activity 0.01. mu. Ci/. mu.l) was delivered into the reaction mixture to initiate the reaction. The kinase reaction was incubated at room temperature for 120 min. The reaction was then blotted (spotted) on P81 ion exchange paper (Whatman # 3698-915). The filter was washed thoroughly in 0.1% phosphoric acid. Then performing radiometric counting and subsequently determining IC₅₀The value is obtained.

The obtained IC is shown below₅₀Values (according to the above scheme): "+ + + +" refers to an IC of less than 0.1. mu.M₅₀And "+ +" refers to an IC of 0.1. mu.M to 1. mu.M₅₀(ii) a "+" means 1-10. mu.M IC₅₀And "ND" means "not yet determined".

C.1.2. Myosin light chain phosphorylation assay

The rat smooth muscle cell line A7r5 was used. Endogenous expression of ROCK results in constitutive phosphorylation of the regulatory myosin light chain at T18/S19. A7r5 cells were placed in DMEM supplemented with 10% FCS in multi-well cell culture plates. After overnight serum starvation, cells were incubated with compounds in serum-free medium.

Quantification of MLC-T18/S19 phosphorylation was assessed by ELISA in 96-well plates using a phspho-MLC-T18/S19 specific antibody and a second detection antibody. Raw data were converted to percent substrate phosphorylation relative to high control (set at 100%). EC was determined using GraphPad prism5.01 software using nonlinear regression curve fitting with varying slopes₅₀The value is obtained.

The obtained EC is shown below₅₀Values (according to the above scheme): "+ + + +" means an EC of less than 0.3. mu.M₅₀And "+ +" means an EC of 0.3. mu.M to 1. mu.M₅₀(ii) a "+" means an EC of 1-10. mu.M₅₀And "-" means>EC of 10. mu.M₅₀。

In addition to this data, figure 1 provides concentration-response curves for compound 14 and Met1, which Met1 is the predicted metabolite of compound 14 produced by ester hydrolysis of carboxylic ester hydrolases. As demonstrated at point C2, such hydrolysis will occur readily in plasma, but not in aqueous humor. Figure 1 further illustrates the important activity difference between compound 14 (which represents a functionally active compound) and its metabolite Met1 (which is a non-functionally active compound); and thus further confirmed the soft nature of compound 14.

C.2. Pharmacological characterization

C.2.1. Stability assay in human and/or mouse plasma

Compounds were incubated in rat (mouse or rabbit) or human plasma at a concentration of 1 μ M. Samples were taken at fixed time points and the residual compounds were determined by LC-MS/MS after protein precipitation. The half-life is expressed in minutes.

Compound numbering	t1/2 mouse plasma	t1/2 human plasma
			1	ND	49
2	ND	53
			3	ND	19
10	ND	<5
			14	ND	<5
15	ND	5
			17	ND	25
18	ND	26
			26	2.5	5
27	ND	4

Compound numbering	t1/2 mouse plasma	t1/2 human plasma
			28	2.2	<5
29	ND	<5
			31	ND	<5
32	ND	25
			33	ND	<4
36	ND	24
			40	ND	40
41	ND	10
			42	ND	<5
44	ND	<5

C.2.2. Stability to drug metabolizing enzymes in lung S9

A1 μ M solution of ROCK inhibitor was incubated with a reaction mixture containing lung S9 (from smokers) and cofactors NADPH, UDPGA, PAPS and GSH. At 0, 15, 30 and 60 minutes after incubation. The sample was collected. Negative control samples incubated with ROCK inhibitor and S9 fractions in the absence of cofactors were also run in parallel. The percentage of ROCK compound remaining at each time point, the metabolic half-life of the ROCK compound (expressed in minutes), and the metabolic half-life of the control compound were determined by using LC-MS/MS analysis.

Compound numbering	t1/2 human Lung S9
		26	>240
28	>240
		32	>240

C.2.3. Stability assay in Rabbit aqueous Room Water

The compounds were incubated in rabbit Aqueous Humor (AH) at a concentration of 1 μ M. Samples were taken at fixed time points and the residual compounds were then determined by LC-MS/MS after protein precipitation. The half-life is expressed in minutes.

C.2.4. Intraocular pressure (IOP) reduction in normotensive rabbits

A detailed example of the IOP lowering effect of the compounds of the present invention is provided herein for compound 14. Compound 14 was formulated here as a 0.3% solution (pH = 6.91) in water/PEG 4001: 1.

IOP was measured at 9h00 using a Tonolab tonometer on normotensive new zealand white rabbits (n =3) prior to compound administration.

At 9h30, a drop (50 μ Ι) of the formulated solution was applied to the right eye (OD) of the rabbit; simultaneously, one drop (50 μ l) of the vehicle solution was administered to the left eye (OS). IOP was then recorded at 1h intervals until 17 h. As can be seen in the table below, a significant IOP drop was observed after administration of compound 14, and was evident before 17 h. This drop was considered statistically significant (P.ltoreq.0.05) before the 14h time point, or 4.30h after administration, confirming sustained activity of Compound 14 in the eye.

A graphical representation of this data is provided in fig. 2.

C3 achievement of Soft ROCK inhibitors

The compounds of the invention are useful as soft ROCK inhibitors for the treatment of ROCK-related diseases. The examples disclosed hereinafter in points C3.1 and C3.2 relate to the treatment of eye diseases or lung diseases, but do not limit the scope of the invention in any way. A comparison is provided with the structurally related ROCK inhibitors disclosed in the prior art.

C3.1 Soft ROCK inhibitors for ocular diseases

The compounds of the invention are suitable as soft ROCK inhibitors for the treatment of ROCK-related eye diseases. They show good inhibitory potency on ROCK, functional activity in cellular assays, low stability in systemic circulation and good stability in the eye (as assessed by stability in aqueous humor). In addition, they are converted into predictable substances, exhibiting negligible functional activity.

Compounds 14 or 17 provide detailed examples of soft ROCK inhibitors for the treatment of ocular diseases. This example does not limit in any way the applicability of the other compounds of the invention for the treatment of ocular diseases.

Indeed, it will be apparent from the published data that compounds 14 or 17 combine the properties required for the treatment of ROCK-related eye diseases. As disclosed in point C1.1, compounds 14 and 17 have strong inhibitory activity against ROCK. As disclosed in point C1.4, they show functional activity in MLC phosphorylation assays. As disclosed in point c.2.1, they have a short half-life in plasma. As disclosed in point c.2.3, they have a significantly longer half-life in aqueous humor than in plasma. In addition, compounds 14 and 17 yield compound Met1 after ester hydrolysis of the esterase. As disclosed in point c.1.4, this predictable metabolite resulting from the rapid degradation of compound 14 or 17 in blood/plasma is not functionally active.

C3.2 Soft ROCK inhibitors for pulmonary diseases

The compounds of the invention are suitable as soft ROCK inhibitors for the treatment of ROCK-related lung diseases. They show good inhibitory potency against ROCK, functional activity in cellular assays, low stability in systemic circulation and good stability in the lung. In addition, they are converted into predictable substances, exhibiting negligible functional activity.

Compounds 26 or 28 provide detailed examples of soft ROCK inhibitors for the treatment of lung diseases. This example does not limit in any way the applicability of other compounds of the invention for treating pulmonary diseases.

Indeed, it will be apparent from the published data that compounds 26 or 28 combine the properties required for the treatment of ROCK-related lung disease. As disclosed in point C1.1, these compounds have a strong inhibitory activity on ROCK. As disclosed in point C1.4, they show functional activity in MLC phosphorylation assays. As disclosed in point c.2.1, they have a short half-life in plasma. As disclosed in point c.2.2, they have a significantly longer half-life in lung tissue (>240min) than in plasma.

C3.3 comparison with structurally related Compounds

Compared to the structurally similar prior art known ROCK inhibitors (described for example in WO2008/077057, WO2010/065782, WO2009/158587, US2009/0325960, US2009/0325959, Iwakubo et al (bioorg. Med. chem.,2007,15, 350-. Although the above documents disclose ROCK inhibitors that are structurally similar to the compounds of the present invention, none of these documents discuss the design, discovery, or potential advantages of soft ROCK inhibitors. In particular, no information is provided regarding the stability of the disclosed ROCK inhibitors in plasma, whole blood or potential target organs.

In view of the structural similarity between some of the compounds obtained from the above-mentioned documents and the compounds of the invention, a comparison is provided here with compounds 1.091 and 1.060 present in documents WO2008/077057, WO2009/158587, WO2010/065782, US2009/0325960 and US 2009/0325959. In particular, compounds 1.091 and 1.060 are cited as preferred compounds in document WO2008/077057 (see claim 6), which document places a large emphasis on the treatment of eye diseases. Compound 1.091 is further cited as a preferred compound in documents WO2009/158587 (see claim 5) and WO2010/065782 (see claim 15) which place a great deal of emphasis on the treatment of lung diseases, including COPD. Furthermore, compound 1.200 is a chirally pure isomer of compound 1.060, which is described as a racemate and is further described as a preferred compound in document WO 2010/065782. Given their potent activity and the preferred compounds for treating the pathological conditions discussed in this document, it should be understood that these compounds constitute appropriate references for comparison.

Compound (I)	14	26	32	1.091	1.060
						IC50ROCK2(nM)	3.4	1.9	25	2.4	7.0
IC50MLC-PP(nM)	240	400	160	110	ND

t1/2Blood plasma (min)	<5	<5	22	>120*	<5
						t1/2AH(min)	>120	ND	98	>120	<5
t1/2Lung S9(min)	9	>240	>240	>240	<5

From this data, it is understood that both the compounds of the present invention and the prior art compounds 1.091 and 1.060 show comparable activity at target (ROCK2) and function (MLC-PP). It will therefore be recognised that optimisation of the compounds of the invention to soft ROCK inhibitors does not compromise their functional activity in any way.

Compound 1.091 represents a typical non-soft ROCK inhibitor that is not recognized as a substrate by the carboxylic ester hydrolase. Therefore, the compound does not solve the following technical problems: provided are soft ROCK inhibitors having strong target and functional activity, good stability in target organs, and low stability in systemic circulation. More specifically, compound 1.091 did not degrade at a significant rate in any of the media tested (including plasma). Thus, the compounds do not readily degrade when entering the bloodstream, resulting in potential systemic exposure.

Compound 1.060 represents an example of an ester derivative designated as a preferred compound in the above document. Although this compound is disclosed in documents that emphasize the potential of ROCK inhibitors for the treatment of ocular diseases, we have hereby demonstrated that this compound exhibits very low stability (t) in all tested media, including aqueous humor(s)_1/2<5 min). Therefore, 1.060 is not possible to achieve and maintain pharmacologically relevant concentrations in aqueous humor over a prolonged period of time. Therefore, the compound does not solve the following technical problems: provided are soft ROCK inhibitors having strong target and functional activity, good stability in target organs, and low stability in systemic circulation. In particular, the very low stability of compound 1.060 in lung or aqueous humor makes it unsuitable for use in the treatment of lung or eye diseases.

It will therefore be appreciated that prior art compounds such as 1.060 or 1.091 do not solve the following technical problem: provided are ROCK inhibitors having strong target and functional activity, high stability in target organs, and low stability in systemic circulation. Therefore, the pharmacological properties of these compounds are different from those of the present invention (which represents a soft ROCK inhibitor).

Claims (24)

1. A compound of formula I or a stereoisomer, tautomer, racemate, salt, hydrate, or solvate thereof,

wherein

X is oxygen, -NH-or a direct bond;

y is-NH-or a direct bond;

n is an integer of 0 to 4;

m is an integer of 0 to 4;

cy represents a divalent group consisting of saturated (poly) rings, including fused, bicyclic, spiro or bridged carbocyclic and heterocyclic rings; in particular from:

ar is selected from:

R²is hydrogen or methyl;

R⁸is hydrogen, methyl, halogen or alkynyl;

R¹is optionally halogenated or C_1-6Alkyl-substituted aryl or heteroaryl; wherein said aryl or heteroaryl is substituted with a substituent selected from the group consisting of:

●-(CH₂)_p-C(=O)-OR²¹；

●-(CH₂)_p-C(=O)-NR³R⁴；

●-(CH₂)_p-C(=O)-SR²²；

●Het¹、-O-Het¹、-NH-Het¹or-S-Het¹(ii) a And

●-O-C_1-6alkyl, -NH-C_1-6Alkyl, -S-C_1-6Alkyl or-C_1-6An alkyl group; wherein said-O-C_1-6Alkyl, -NH-C_1-6Alkyl, -S-C_1-6Alkyl or-C_1-6Each alkyl group is independently substituted with a substituent selected from the group consisting of: -C (= O) -OR²¹、-C(=O)-NR³R⁴、Het¹、-O-Het¹、-NH-Het¹and-S-Het¹；

Wherein

p is an integer of 0 to 3

Het¹Selected from:

R²¹selected from: optionally substituted C_1-20Alkyl, optionally substituted C_1-20Alkenyl, optionally substituted C_1-20Alkynyl, optionally substituted C_3-15Cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl;

R²²is optionally substituted C_1-6An alkyl group;

R³selected from: het¹、C_1-20Alkyl, aryl or heteroaryl; wherein said C_1-20Alkyl, aryl or heteroaryl is substituted with 1,2 or 3 substituents each independently selected from: aryl, heteroaryl, - (CH)₂)_p-C(=O)-OR²¹、-Het¹、-NH-Het¹、-O-Het¹、-S-Het¹、-S-C_2-6Alkyl, -NH-C_2-6Alkyl and-O-C_2-6An alkyl group;

wherein said aryl, heteroaryl, -O-C_2-6Alkyl, -NH-C_2-6Alkyl or-S-C_2-6Each alkyl group is independently substituted with a substituent selected from the group consisting of: c (= O) -OR²¹、-Het¹、-O-Het¹、-NH-Het¹and-S-Het¹(ii) a And

R⁴selected from: hydrogen or C_1-6An alkyl group; or

R³And R⁴Together with the nitrogen atom to which they are attached form a heterocyclic ring substituted with one substituent selected from: c_1-20Alkyl, aryl or heteroaryl; wherein said C_1-20Alkyl, aryl or heteroaryl is substituted with 1,2 or 3 substituents each independently selected from: aryl, heteroaryl, -C (= O) -OR²¹、-Het¹、-O-Het¹、-S-Het¹、-S-C_2-6Alkyl, -NH-C_2-6Alkyl and-O-C_2-6An alkyl group;

wherein said-O-C_2-6Alkyl, -NH-C_2-6Alkyl or-S-C_2-6Each alkyl group is independently substituted with a substituent selected from the group consisting of: c (= O) -OR²¹、-Het¹、-O-Het¹、-NH-Het¹and-S-Het¹；

With the proviso that,

-R¹is not selected from-O-CH₂-C(=O)-OR²¹Substituted aryl or heteroaryl;

if R is¹Is phenyl, then the phenyl group may not be in the para position by- (CH)₂)_p-C(=O)-OR²¹Substitution; and is

-said compound of formula I is not

2. The compound of claim 1, wherein X is oxygen or NH; in particular NH.

3. A compound according to claim 1 or 2, wherein

X is oxygen, -NH-or a direct bond; in particular oxygen or-NH-; more particularly-NH-;

y is-NH-or a direct bond;

n is an integer of 0 to 4;

m is an integer of 0 to 4;

cy is selected from:

ar is selected from:

R²is hydrogen or methyl; in particular hydrogen;

R⁸is hydrogen, methyl, halogen or alkynyl; in particular hydrogen or methyl; more particularly hydrogen;

R¹is optionally halogenated or C_1-6An alkyl-substituted aryl or heteroaryl, wherein the aryl or heteroaryl is substituted with a substituent selected from the group consisting of:

●-(CH₂)_p-C(=O)-OR²¹；

●-(CH₂)_p-C(=O)-NR³R⁴；

●-(CH₂)_p-C(=O)-SR²²；

●Het¹、-O-Het¹、-NH-Het¹or-S-Het¹(ii) a And

●-O-C_1-6alkyl, -NH-C_1-6Alkyl, -S-C_1-6Alkyl or-C_1-6An alkyl group; wherein said-O-C_1-6Alkyl, -NH-C_1-6Alkyl, -S-C_1-6Alkyl or-C_1-6Each alkyl group is independently substituted with a substituent selected from the group consisting of: -C (= O) -OR²¹、-C(=O)-NR³R⁴、Het¹、-O-Het¹、-NH-Het¹and-S-Het¹；

Wherein

p is an integer of 0 to 3

Het¹Selected from:

in particular Het¹Selected from:

more specifically Het¹Selected from:

R²¹selected from: optionally substituted C_1-20Alkyl, optionally substituted C_1-20Alkenyl, optionally substituted C_1-20Alkynyl, optionally substituted C_3-15Cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl; specifically, R²¹Selected from optionally substituted C_1-20Alkyl and optionally substituted aryl; more particularly from aryl and optionally substituted C_1-20An alkyl group;

R²²is optionally substituted C_1-6An alkyl group; specifically, R²²Is C_1-6An alkyl group;

R³selected from: het¹、C_1-20Alkyl, aryl or heteroaryl; wherein said C_1-20Alkyl, aryl or heteroaryl is substituted with 1,2 or 3 substituents each independently selected from: aryl, heteroaryl, - (CH)₂)_p-C(=O)-OR²¹、-Het¹、-NH-Het¹、-O-Het¹、-S-Het¹、-S-C_2-6Alkyl, -NH-C_2-6Alkyl and-O-C_2-6An alkyl group;

wherein said aryl, heteroaryl, -O-C_2-6Alkyl, -NH-C_2-6Alkyl or-S-C_2-6Each alkyl group is independently substituted with a substituent selected from the group consisting of: c (= O) -OR²¹、-Het¹、-O-Het¹、-NH-Het¹and-S-Het¹；

Specifically, R³Selected from: het¹、C_1-20Alkyl, aryl or heteroaryl; wherein said C_1-20Alkyl, aryl or heteroaryl is substituted with 1,2 or 3 substituents each independently selected from: - (CH)₂)_p-C(=O)-OR²¹、-Het¹、-NH-Het¹、-O-Het¹and-S-Het¹；

More specifically, R³Selected from: het¹、C_1-20An alkyl or aryl group; wherein said C_1-20Alkyl or aryl is substituted with 1,2 or 3, preferably 1, substituents each independently selected from: - (CH)₂)_p-C(=O)-OR²¹、-Het¹and-S-Het¹；

And is

R⁴Selected from: hydrogen or C_1-6An alkyl group; in particular hydrogen; or

R³And R⁴Together with the nitrogen atom to which they are attached form a heterocyclic ring substituted with one substituent selected from: c_1-20Alkyl, aryl or heteroaryl; wherein said C_1-20Alkyl, aryl or heteroaryl is substituted with 1,2 or 3 substituents each independently selected from: aryl, heteroaryl, -C (= O) -OR²¹、-Het¹、-O-Het¹、-S-Het¹、-S-C_2-6Alkyl, -NH-C_2-6Alkyl and-O-C_2-6An alkyl group;

wherein said-O-C_2-6Alkyl, -NH-C_2-6Alkyl or-S-C_2-6Each alkyl group is independently substituted with a substituent selected from the group consisting of: c (= O) -OR²¹、-Het¹、-O-Het¹、-NH-Het¹and-S-Het¹；

With the proviso that,

-R¹is not selected from-O-CH₂-C(=O)-OR²¹Substituted aryl or heteroaryl;

if R is¹Is phenyl, then the phenyl group may not be in the para position by- (CH)₂)_p-C(=O)-OR²¹Substitution; and is

-said compound of formula I is not

4. A compound according to any one of claims 1-3, wherein

R¹Is aryl or heteroaryl; in particular aryl or any heteroaryl other than indolyl; more particularly phenyl, pyrrolyl or thienyl, substituted with a substituent selected from the group consisting of:

●-(CH₂)_p-C(=O)-OR²¹；

●-(CH₂)_p-C(=O)-NR³R⁴；

●-(CH₂)_p-C(=O)-SR²²；

●Het¹、-O-Het¹、-NH-Het¹or-S-Het¹(ii) a And

●-O-C_1-6alkyl, -NH-C_1-6Alkyl, -S-C_1-6Alkyl, -C_1-6An alkyl group; wherein said-O-C_1-6Alkyl, -NH-C_1-6Alkyl, -S-C_1-6Alkyl or-C_1-6Each alkyl group is independently substituted with a substituent selected from the group consisting of: -C (= O) -OR²¹、-C(=O)-NR³R⁴、-Het¹、-O-Het¹、-NH-Het¹and-S-Het¹。

5. The compound of any one of claims 1-4, wherein

R¹Is aryl or heteroaryl; more particularly phenyl, pyrrolyl or thienyl, substituted with a substituent selected from the group consisting of:

●-(CH₂)_p-C(=O)-OR²¹

●-(CH₂)_p-C(=O)-NR³R⁴

●-(CH₂)_p-C(=O)-SR²²

●-O-C_1-6an alkyl group; -NH-C_1-6An alkyl group; -S-C_1-6An alkyl group; -C_1-6An alkyl group; wherein said-O-C_1-6An alkyl group; -NH-C_1-6An alkyl group; -S-C_1-6An alkyl group; or-C_1-6Each alkyl group is independently substituted with a substituent selected from the group consisting of: -C (= O) -OR²¹；-C(=O)-NR³R⁴；Het¹；-O-Het¹；-NH-Het¹and-S-Het¹。

6. The compound of any one of claims 1-5, wherein

Cy represents a divalent group selected from:

in particular selected from:

ar is selected from:

in particular selected from:

7. the compound according to any one of claims 1-6, wherein one or more of the following limitations apply:

● X is oxygen, -NH-, or a direct bond; in particular oxygen or-NH-; more particularly-NH-;

● Y is-NH-or a direct bond; in particular-NH-;

● n is an integer from 0 to 4; in particular 0 or 1;

● m is an integer from 0 to 4; in particular 0 or 1;

● Cy represents a divalent group consisting of saturated (poly) rings, including fused, bicyclic, spiro or bridged carbocyclic and heterocyclic rings;

● Cy is selected from:

in particular selected from:

● Ar is selected from:

in particular selected from:

●R²is hydrogen or methyl; in particular hydrogen;

●R⁸is hydrogen, methyl, halogen or alkynyl; in particular hydrogen or methyl; more particularly hydrogen;

●R¹is optionally halogenated or C_1-6An alkyl-substituted aryl or heteroaryl, wherein the aryl or heteroaryl is substituted with a substituent selected from the group consisting of:

　●-(CH₂)_p-C(=O)-OR²¹；

　●-(CH₂)_p-C(=O)-NR³R⁴；

　●-(CH₂)_p-C(=O)-SR²²；

　●Het¹、-O-Het¹、-NH-Het¹or-S-Het¹(ii) a And

　●-O-C_1-6alkyl, -NH-C_1-6Alkyl, -S-C_1-6Alkyl or-C_1-6An alkyl group; wherein said-O-C_1-6Alkyl, -NH-C_1-6Alkyl, -S-C_1-6Alkyl or-C_1-6Each alkyl group is independently substituted with a substituent selected from the group consisting of: -C (= O) -OR²¹、-C(=O)-NR³R⁴、Het¹、-O-Het¹、-NH-Het¹and-S-Het¹；

In particular, the substituents are selected from:

　●-(CH₂)_p-C(=O)-OR²¹；

　●-(CH₂)_p-C(=O)-NR³R⁴；

　●-(CH₂)_p-C(=O)-SR²²(ii) a And

　●-O-C_1-6alkyl, -NH-C_1-6Alkyl, -S-C_1-6Alkyl or-C_1-6An alkyl group; wherein said-O-C_1-6Alkyl, -NH-C_1-6Alkyl, -S-C_1-6Alkyl or-C_1-6Each alkyl group is independently substituted with a substituent selected from the group consisting of: -C (= O) -OR²¹、-C(=O)-NR³R⁴、-Het¹、-O-Het¹、-NH-Het¹and-S-Het¹(ii) a In particular by-C (= O) -NR³R⁴substituted-O-C_1-6An alkyl group;

●R¹is aryl or heteroaryl; in particular aryl, pyrrolyl or thienyl; more particularly phenyl, pyrrolyl or thienyl, substituted with a substituent selected from the group consisting of:

　●-(CH₂)_p-C(=O)-OR²¹；

　●-(CH₂)_p-C(=O)-NR³R⁴；

　●-(CH₂)_p-C(=O)-SR²²；

　●Het¹、-O-Het¹、-NH-Het¹or-S-Het¹(ii) a And

　●-O-C_1-6alkyl, -NH-C_1-6Alkyl, -S-C_1-6Alkyl or-C_1-6An alkyl group; wherein said-O-C_1-6Alkyl, -NH-C_1-6Alkyl, -S-C_1-6Alkyl or-C_1-6Each alkyl group being independently substituted(ii) a substituent selected from: -C (= O) -OR²¹、-C(=O)-NR³R⁴、Het¹、-O-Het¹、-NH-Het¹and-S-Het¹；

In particular, the substituents are selected from:

　●-(CH₂)_p-C(=O)-OR²¹；

　●-(CH₂)_p-C(=O)-NR³R⁴；

　●-(CH₂)_p-C(=O)-SR²²(ii) a And

　●-O-C_1-6alkyl, -NH-C_1-6Alkyl, -S-C_1-6Alkyl or-C_1-6An alkyl group; wherein said-O-C_1-6Alkyl, -NH-C_1-6Alkyl, -S-C_1-6Alkyl or-C_1-6Each alkyl group is independently substituted with a substituent selected from the group consisting of: -C (= O) -OR²¹、-C(=O)-NR³R⁴、Het¹、-O-Het¹、-NH-Het¹and-S-Het¹(ii) a In particular by-C (= O) -NR³R⁴substituted-O-C_1-6An alkyl group;

● p is an integer from 0 to 3; in particular 0 or 1;

●Het¹selected from:

in particular Het¹Selected from:

more specifically Het¹Selected from:

●R²¹selected from: optionally, optionallySubstituted C_1-20Alkyl, optionally substituted C_1-20Alkenyl, optionally substituted C_1-20Alkynyl, optionally substituted C_3-15Cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl; is in particular selected from optionally substituted C_1-20Alkyl and optionally substituted aryl; more particularly from aryl and optionally substituted C_1-20An alkyl group;

●R²¹is selected from C_1-20An alkyl or aryl group; wherein said C_1-20The alkyl or aryl group is optionally substituted with one or more groups selected from the group consisting of: halo, hydroxy, cyano, C_1-6Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and alkoxy; more particularly optionally substituted with one group selected from the group consisting of: cycloalkyl, aryl, hydroxy, alkoxy, and heterocyclyl;

●R²¹selected from aryl and C_1-20An alkyl group; wherein said C_1-20Alkyl is optionally substituted with: halo, hydroxy, cyano, C_1-6Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or alkoxy; more specifically by cycloalkyl, phenyl, hydroxy, alkoxy and heterocyclyl;

●R²²is optionally substituted C_1-6An alkyl group; in particular C_1-6An alkyl group;

●R³selected from: het¹、C_1-20Alkyl, aryl or heteroaryl; wherein said C_1-20Alkyl, aryl or heteroaryl is substituted with 1,2 or 3 substituents each independently selected from: aryl, heteroaryl, - (CH)₂)_p-C(=O)-OR²¹、-Het¹、-NH-Het¹、-O-Het¹、-S-Het¹、-S-C_2-6Alkyl, -NH-C_2-6Alkyl and-O-C_2-6An alkyl group;

wherein said aryl, heteroaryl, -O-C_2-6Alkyl, -NH-C_2-6Alkyl or-S-C_2-6Each alkyl group is independently substituted with a substituent selected from the group consisting of: c (= O) -OR²¹、-Het¹、-O-Het¹、-NH-Het¹and-S-Het¹;

Specifically, R³Selected from: het¹、C_1-20Alkyl, aryl or heteroaryl; wherein said C_1-20Alkyl, aryl or heteroaryl is substituted with 1,2 or 3 substituents each independently selected from: - (CH)₂)_p-C(=O)-OR²¹、-Het¹、-NH-Het¹、-O-Het¹and-S-Het¹；

More specifically, R³Selected from: het¹、C_1-20An alkyl or aryl group; wherein said C_1-20Alkyl or aryl is substituted with 1,2 or 3, preferably 1, substituents each independently selected from: - (CH)₂)_p-C(=O)-OR²¹、-Het¹and-S-Het¹；

Even more specifically, R³Selected from: het¹、C_1-20Alkyl or phenyl; wherein said C_1-20Alkyl or phenyl is substituted with 1,2 or 3, preferably 1, substituents each independently selected from: - (CH)₂)_p-C(=O)-OR²¹、-Het¹and-S-Het¹；

●R⁴Selected from: hydrogen or C_1-6An alkyl group; in particular hydrogen;

●R³and R⁴Together with the nitrogen atom to which they are attached form a heterocyclic ring substituted with one substituent selected from: c_1-20Alkyl, aryl or heteroaryl; wherein said C_1-20Alkyl, aryl or heteroaryl is substituted with 1,2 or 3 substituents each independently selected from: aryl, heteroaryl, -C (= O) -OR²¹、-Het¹、-O-Het¹、-S-Het¹、-S-C_2-6Alkyl, -NH-C_2-6Alkyl and-O-C_2-6An alkyl group;

wherein said-O-C_2-6Alkyl, -NH-C_2-6Alkyl or-S-C_2-6Each alkyl group is independently substituted with a substituent selected from the group consisting of: c (= O) -OR²¹、-Het¹、-O-Het¹、-NH-Het¹and-S-Het¹；

●R³And R⁴May not form a heterocyclic ring together with the nitrogen atom to which they are attached;

●R¹is not selected from-O-CH₂-C(=O)-OR²¹Substituted aryl or heteroaryl;

●R¹is not selected from indolyl;

● if R¹Is phenyl, then the phenyl group may not be in the para position by- (CH)₂)_p-C(=O)-OR²¹Substitution;

● if R¹Is phenyl, then said phenyl is substituted in the meta position; specifically, the phenyl group is substituted at the meta position with a substituent selected from the group consisting of:

　●-(CH₂)_p-C(=O)-OR²¹；

　●-(CH₂)_p-C(=O)-NR³R⁴；

　●-(CH₂)_p-C(=O)-SR²²；

　●Het¹、-O-Het¹、-NH-Het¹or-S-Het¹(ii) a And

　●-O-C_1-6alkyl, -NH-C_1-6Alkyl, -S-C_1-6Alkyl or-C_1-6An alkyl group; wherein said-O-C_1-6Alkyl, -NH-C_1-6Alkyl, -S-C_1-6Alkyl or-C_1-6Each alkyl group is independently substituted with a substituent selected from the group consisting of: -C (= O) -OR²¹、-C(=O)-NR³R⁴、Het¹、-O-Het¹、-NH-Het¹and-S-Het¹；

In particular, the substituents are selected from:

　●-(CH₂)_p-C(=O)-OR²¹；

　●-(CH₂)_p-C(=O)-NR³R⁴；

　●-(CH₂)_p-C(=O)-SR²²(ii) a And

　●-O-C_1-6alkyl, -NH-C_1-6Alkyl, -S-C_1-6Alkyl radicalor-C_1-6An alkyl group; wherein said-O-C_1-6Alkyl, -NH-C_1-6Alkyl, -S-C_1-6Alkyl or-C_1-6Each alkyl group is independently substituted with a substituent selected from the group consisting of: -C (= O) -OR²¹、-C(=O)-NR³R⁴、Het¹、-O-Het¹、-NH-Het¹and-S-Het¹In particular by-C (= O) -NR³R⁴substituted-O-C_1-6An alkyl group;

● the compound of formula I is not

8. A compound as defined in any one of claims 1 to 7 for use as human or veterinary medicine.

9. A composition comprising a compound as defined in any one of claims 1 to 7 for use as a human or veterinary drug.

10. A compound as defined in any one of claims 1 to 8 or a composition as defined in claim 9 for use in the prevention and/or treatment of at least one disease or disorder in which ROCK is implicated, such as diseases associated with smooth muscle cell function, inflammation, fibrosis, excessive cell proliferation, excessive angiogenesis, hyperreactivity, barrier dysfunction, neurodegeneration and remodeling.

11. A compound as defined in any one of claims 1 to 8 or a composition as defined in claim 9 for use in the prevention and/or treatment of at least one disease or disorder selected from: eye diseases; respiratory diseases; throat, nose and ear diseases; intestinal diseases: skin diseases, cardiovascular diseases and vascular diseases; inflammatory diseases; neurological diseases; proliferative diseases; renal disease; sexual dysfunction; bone disease; benign prostatic hyperplasia; transplant rejection; spasm; chronic obstructive bladder disease; and allergies.

12. A compound as defined in any one of claims 1 to 8 or a composition as defined in claim 9 for use in the prevention and/or treatment of an eye disease selected from: retinopathy, optic neuropathy, glaucoma, inflammatory eye diseases and degenerative retinal diseases such as macular degeneration and retinitis pigmentosa; glaucoma is preferred.

13. A compound as defined in any one of claims 1 to 8 or a composition as defined in claim 9 for use in the prophylaxis and/or treatment of a respiratory disease selected from: pulmonary fibrosis, emphysema, chronic bronchitis, asthma, fibrosis, pneumonia, cystic fibrosis, Chronic Obstructive Pulmonary Disease (COPD), bronchitis rhinitis, and respiratory distress syndrome; asthma or COPD is preferred.

14. A compound as defined in any one of claims 1 to 8 or a composition as defined in claim 9 for use in the prevention and/or treatment of a disease of the throat, nose and ear selected from: sinus problems, hearing problems, toothache, tonsillitis, ulcers and rhinitis.

15. A compound as defined in any one of claims 1 to 8 or a composition as defined in claim 9 for use in the prevention and/or treatment of a skin disease selected from: hyperkeratosis, parakeratosis, thickening of the stratum granulosum, thickening of the stratum spinosum, dyskeratosis, edema of the stratum spinosum, and ulcer formation.

16. A compound as defined in any one of claims 1 to 8 or a composition as defined in claim 9 for use in the prevention and/or treatment of an intestinal disease selected from: inflammatory Bowel Disease (IBD), colitis, gastroenteritis, ileus, appendicitis, and Crohn's disease.

17. A compound as defined in any one of claims 1 to 8 or a composition as defined in claim 9 for use in the prevention and/or treatment of sexual dysfunction and/or for use in the treatment of sexual dysfunction associated with treatment with certain drugs, such as drugs for the treatment of hypertension, depression or anxiety, said sexual dysfunction being selected from: erectile dysfunction, hypogonadism, bladder disease, hypertension, pulmonary hypertension, or pelvic surgery.

18. A method for the prevention and/or treatment of at least one disease or disorder selected from the group consisting of: eye diseases; respiratory diseases; throat, nose and ear diseases; intestinal diseases: skin diseases; cardiovascular and vascular diseases; inflammatory diseases; neurological and central nervous system disorders; proliferative diseases; renal disease; sexual dysfunction; bone disease; benign prostatic hyperplasia; transplant rejection; spasm; chronic obstructive bladder disease; and allergies; the method comprises the following steps: administering to a subject in need thereof a therapeutically effective amount of a compound as defined in claims 1 to 8 or a composition as defined in claim 9.

19. A method for the prevention and/or treatment of an eye disease selected from the group consisting of: retinopathy, optic neuropathy, glaucoma, inflammatory eye diseases and degenerative retinal diseases such as macular degeneration and retinitis pigmentosa; preferably glaucoma; the method comprises the following steps: administering to a subject in need thereof a therapeutically effective amount of a compound as defined in claims 1 to 8 or a composition as defined in claim 9.

20. A method for the prevention and/or treatment of a respiratory disease selected from the group consisting of: pulmonary fibrosis, emphysema, chronic bronchitis, asthma, fibrosis, pneumonia, cystic fibrosis, Chronic Obstructive Pulmonary Disease (COPD), bronchitis rhinitis, and respiratory distress syndrome; preferably asthma or COPD; the method comprises the following steps: administering to a subject in need thereof a therapeutically effective amount of a compound as defined in claims 1 to 8 or a composition as defined in claim 9.

21. A method for the prevention and/or treatment of a disease of the throat, nose and ears selected from the group consisting of: sinus problems, hearing problems, toothache, tonsillitis, ulcers and rhinitis; the method comprises the following steps: administering to a subject in need thereof a therapeutically effective amount of a compound as defined in claims 1 to 8 or a composition as defined in claim 9.

22. Method for the prevention and/or treatment of a skin disease selected from the group consisting of: hyperkeratosis, parakeratosis, stratum granulosum thickening, stratum spinosum thickening, dyskeratosis, acanthocyte layer edema, and ulcer formation; the method comprises the following steps: administering to a subject in need thereof a therapeutically effective amount of a compound as defined in claims 1 to 8 or a composition as defined in claim 9.

23. A method for the prevention and/or treatment of an intestinal disease selected from the group consisting of: inflammatory Bowel Disease (IBD), colitis, gastroenteritis, ileus, appendicitis and crohn's disease; the method comprises the following steps: administering to a subject in need thereof a therapeutically effective amount of a compound as defined in claims 1 to 8 or a composition as defined in claim 9.

24. A method for the prevention and/or treatment of sexual dysfunction and/or for the treatment of sexual dysfunction associated with treatment with certain drugs, such as drugs for the treatment of hypertension, depression or anxiety, said sexual dysfunction being selected from: erectile dysfunction, hypogonadism, bladder disease, hypertension, diabetes or pelvic surgery; the method comprises the following steps: administering to a subject in need thereof a therapeutically effective amount of a compound as defined in claims 1 to 8 or a composition as defined in claim 9.