CN106496116A - Quinolines containing double aryl urea structures and application thereof - Google Patents

Abstract

The present invention relates to quinoline compounds containing bisaryl urea structure represented by general formula I and their pharmaceutically acceptable salts and pharmaceutical compositions with the compound as active ingredients in the preparation for the treatment and/or prevention of FLT3 Application in medicine for diseases caused by abnormal expression of kinases, wherein the substituents R ₁ , R ₂ , Ar, X, Y, Z, and n have the meanings given in the specification.

Description

Quinoline compounds containing bisaryl urea structure and uses thereof

technical field

The present invention relates to a quinoline compound containing a bisaryl urea structure and its use, in particular to a quinoline compound and a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing the compound in the preparation of the compound for treatment and/or prevention The application of the medicine in diseases caused by the abnormal expression of FLT3 kinase.

Background technique

The research on kinase target drugs has become an important direction in the research and development of anticancer drugs. Among the currently discovered kinase target drugs, protein kinases are known to be the most studied class. Due to mutation or rearrangement of protein kinases, it can cause disturbance or abnormality in the signal transduction process, resulting in abnormal cell growth, differentiation, metabolism and biological behavior, and thus can induce a variety of tumors.

Protein kinases (Protein Kinases, PKs) are enzymes that catalyze hydroxyl phosphorylation on tyrosine, serine and threonine residues of proteins through the terminal phosphate transfer of ATP, mainly including protein tyrosine kinases (Proteintyrosine kinases) kinase, PTK) and serine-threonine kinase (Serine-threonine kinase, STK). Through signal transduction pathways, these enzymes regulate cell growth, differentiation and proliferation, etc. PTKs convert growth factor receptors to their active forms by binding to growth factor ligands, which interact with proteins on the inner surface of cell membranes. This leads to the phosphorylation of tyrosine residues of receptors and other proteins and to the formation of complexes with various cytoplasmic signaling molecules in the cell, thereby affecting many aspects such as cell division (proliferation), cell differentiation, cell growth, metabolism, etc. a cellular response.

Growth factor receptors with PTK activity are called receptor tyrosine kinases (Receptor tyrosine kinase, RTK), which include a large family of transmembrane receptors with diverse biological activities. Fms-like tyrosine kinase (Fms liketyosine kinase 3, hereinafter Flt-3) is a receptor-type protein tyrosine kinase (PTK) belonging to the platelet-derived growth factor receptor (PDGFR) family. It consists of five immunoglobulin-like domains at the N' end of the cell, a transmembrane domain, a juxtamembrane (JM) intracellular domain, two kinase domains separated by a kinase insertion domain, and A C'-terminal domain constitutes, and its extracellular domain is highly glycosylated. The FLT3 gene is located on chromosome 13q12, with a total length of about 100kb and 24 exons, encoding 993 amino acids. After FLT3 binds to its receptor, receptor dimerization occurs, and the tyrosine residues in the kinase domain autophosphorylate, which further catalyzes the phosphorylation of substrate proteins. Many important signal transduction proteins such as signal transducers and transcription Activator 5 (signal transducer and activator of transcription 5, STAT5), phosphoinositide 3-kinase (PI3K), phospholipase C-γ (phospholipase C gamma, PLC-γ), RAS, mitogen-activated protein kinase (mitogen-activated protein kinase, MAPK), extracellular signal-regulated kinase (extra cellularly-responsive kinase, ERK), src homologous and collagen factor (src homologous and collagen gene, SHC) and Src family tyrosine kinases are activated, thereby Mediates a series of signal transduction, leading to cell proliferation and differentiation.

In hematological malignancies, high levels of FLT3 are expressed, or FLT3 mutations cause uncontrolled induction of the FLT3 receptor and downstream molecular pathways. Hematological malignancies include leukemia, lymphoma (non-Hodgkin lymphoma), Hodgkin's disease (also known as Hodgkin lymphoma), and myeloma - eg, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic neutrophil leukemia (CNL), acute undifferentiated leukemia (AUL), Anaplastic large cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T-cell ALL, AML with myeloid trilineage dysplasia (AML/TMDS) , mixed lineage leukemia (MLL), myelodysplastic syndromes (MDSs), myeloproliferative disorders (MPD), multiple myeloma, (MM), and myeloid sarcoma (Kottaridis, P.D., R.E. Gale et al. (2003). "Flt3mutations and leukaemia." Br J Haematol 122(4):523-38). Myeloid sarcoma is also associated with FLT3 mutations (Ansari-Lari, Ali et al. FLT3 mutations in myeloid sarcoma. British Journal of Haematology. 2004 Sep. 126(6):785-91).

FLT3 mutations have been detected in about 30% of patients with acute myeloid leukemia and a small number of patients with acute lymphoblastic leukemia or myelodysplastic syndrome. Patients with FLT3 mutations tend to have a poorer prognosis, with shorter remission times and lower disease-free survival. There are two known types of activating mutations of FLT3. One is a 4-40 amino acid duplication within the juxtamembrane region of the receptor (ITD mutation) (25-30% of patients) and the other is a point mutation in the kinase domain (5-7% of patients). Most of these mutations involve short tandem repeats of amino acids in the juxtamembrane domain of the receptor, resulting in tyrosine kinase activity. Expression of mutant FLT3 receptors in murine bone marrow cells causes fatal myelodysplastic syndrome, and preliminary studies (Blood. strong phenotype.

Foretinib (GSK1363089, XL880) belongs to quinoline compounds and is an oral c-Met and VEGFR/KDR kinase inhibitor. Its IC ₅₀ values for c-Met kinase and VEGFR kinase are 0.4 and 0.8nM respectively. Entered the phase II clinical research stage (WO2010036831A1).

On the basis of references, the present inventors designed and synthesized a series of new quinoline derivatives containing bisaryl urea structure. After in vitro activity screening, it is shown that this type of compound has a good inhibitory effect on c-Met kinase, and the later activity screening data shows that this type of compound has a good inhibitory activity on FLT3 kinase.

Contents of the invention

The present invention relates to quinoline compounds containing bisaryl urea structure represented by general formula I and their pharmaceutically acceptable salts,

in,

X is O, S, NH, _NCH3 ;

Y is optionally 1-2 of the following substituents: halogen, halogenated C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyl, cyano, nitro;

Z is O, S;

n is an integer between 1-6;

R ₁ and R ₂ are the same or different, each independently selected from hydrogen, (C ₁ -C ₁₀ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, (C ₂ -C ₁₀ ) alkenyl or (C ₂ -C ₁₀ ) alkynyl, which can be optionally substituted by 1-3 identical or different R ₃ ;

Or R ₁ and R ₂ form a 5-10 membered heterocyclic group or a 5-10 membered heteroaryl group together with the nitrogen atom to which they are attached, and the heterocyclic group and heteroaryl group are not connected to R ₁ and R ₂ In addition to the nitrogen atom, it contains 1-4 heteroatoms selected from N, O or S, except for the nitrogen atom to which R1 and R2 are connected, the heterocyclic group can optionally include _1-2 carbon-carbon _double bonds or a triple bond, the heterocyclyl and heteroaryl are optionally substituted by 1-3 identical or different R ₃ ;

R ₃ are independently selected from H, (C ₆ -C ₁₀ ) aryl, 5-10 membered heteroaryl, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, said The heteroaryl group contains 1-3 heteroatoms selected from N, O or S, and R ₃ is optionally substituted by 1-3 identical or different R ₄ ;

Ar is (C ₆ -C ₁₀ )aryl, 5-10 membered heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Ar is optionally 1-3 The same or different R ₄ substitutions;

R ₄ is H, hydroxyl, halogen, nitro, amino, cyano, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkyl or (C ₁ -C ₆ )alkoxy optionally substituted by hydroxyl, amino or halogen, by 1-2 (C ₁ -C ₆ ) alkyl substituted amino group, (C ₁ -C ₆ ) alkyl amido group, free, salified, esterified and amidated carboxyl group, (C ₁ -C ₆ ) alkyl sulfinyl group, (C ₁ -C ₆ )alkylsulfonyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkylacyl, carbamoyl, by 1-2 (C ₁ -C ₆ )alkyl substituted carbamoyl, (C ₁ -C ₃ )alkylenedioxy, allyl.

The present invention preferably shows quinoline compounds containing bisaryl urea structure shown in general formula I and their pharmaceutically acceptable salts, wherein

n is an integer between 1-3;

R ₁ and R ₂ are the same or different, independently selected from hydrogen, (C1-C6) alkyl, (C3-C5) cycloalkyl, (C2-C6) alkenyl and (C2-C6) alkynyl, which Can be optionally substituted by 1-3 identical or different R ₃ ;

Or R ₁ and R ₂ form _a 5-10 _membered heterocyclic group together with the nitrogen atom they are connected to, and the heterocyclic group optionally contains 1-4 optional A heteroatom from N, O or S, except the nitrogen atom to which R and R are connected, the heterocyclic group optionally includes _1-2 carbon _- carbon double bonds or triple bonds, and the heterocyclic group optionally Substituted by 1-3 identical or different R ₃ .

The present invention preferably shows quinoline compounds containing bisaryl urea structure shown in general formula I and their pharmaceutically acceptable salts, wherein

X is O, S;

Y is halogen, halogenated C ₁ -C ₄ alkyl;

The present invention preferably shows quinoline compounds containing bisaryl urea structure shown in general formula I and their pharmaceutically acceptable salts, wherein

X is O;

n is 2, 3;

R ₁ and R ₂ are the same or different, each independently selected from hydrogen, (C ₁ -C ₄ ) alkyl, (C ₃ -C ₅ ) cycloalkyl;

Or R ₁ and R ₂ form _a 5-6 membered heterocyclic group together with the nitrogen atom they are connected to, and the heterocyclic group optionally contains _1-2 optional A heteroatom from N, O and S, said heterocyclyl is optionally substituted by 1-3 identical or different R ₃ ;

R ₃ is H, (C ₁ -C ₄ )alkyl.

The present invention is more preferably quinoline compounds containing bisaryl urea structure shown in general formula I and their pharmaceutically acceptable salts, wherein

Y is F;

n is 2, 3;

Ar is phenyl, and Ar is optionally substituted by 1-3 identical or different R ₄ ; R ₄ is H, halogen, hydroxyl, nitro, cyano, halo (C ₁ -C ₄ ) alkyl, halo (C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )alkoxy, allyl, dimethylamino, methylsulfonyl.

R ₁ and R ₂ form dimethylamino, diethylamino, 1-piperidinyl, 4-morpholinyl, 4-methyl-1-piperazinyl, 1-piperazine together with the nitrogen atom to which they are attached Base, 4-methyl-1-piperidinyl, 1-pyrrolidinyl, 4-thiomorpholinyl. Preferred are 1-piperidinyl, 4-morpholinyl, 4-methyl-1-piperazinyl, 4-methyl-1-piperidinyl, and 1-pyrrolidinyl.

According to some common methods in the field of the present invention, the quinoline derivatives of general formula I in the present invention can form pharmaceutically acceptable salts with acids. Pharmaceutically acceptable addition salts include inorganic and organic acid addition salts, the addition salts with the following acids being particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid , Benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, etc.

Furthermore, the present invention also includes prodrugs of the derivatives of the present invention. The prodrugs of the derivatives of the present invention are derivatives of the general formula I, which themselves may have weak activity or even no activity, but after administration, are destroyed under physiological conditions (for example, by metabolism, solvolysis or otherwise) into the corresponding biologically active form.

In the present invention, "halogen" refers to fluorine, chlorine, bromine or iodo; "alkyl" refers to a linear or branched alkyl group; "alkylene" refers to a linear or branched alkylene group; " "Cycloalkyl" means a substituted or unsubstituted cycloalkyl group.

According to the present invention, the particularly preferred quinoline compounds of the above formula I containing a bisaryl urea structure include:

1-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl-3-(3-(trifluoromethyl base) phenyl) urea;

1-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl-3-(2-(trifluoromethyl base) phenylurea;

1-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl-3-(4-(trifluoromethyl base) phenyl) urea;

1-(3,4-difluorophenyl)-3-(3-fluoro-4-((6-methoxy-7-(3-morpholinepropoxy)quinolin-4-yl)oxy ) phenyl) urea;

1-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl-3-(3-fluorophenyl) urea;

1-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl-3-(4-methoxybenzene base) urea

1-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl -3-(4-methoxyphenyl)urea;

1-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl-3-(3-methoxybenzene base) urea;

1-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl -3-(3-methoxyphenyl)urea;

1-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl-3-(4-fluorophenyl) urea;

1-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin)-1-yl)propoxy)quinolin-4-yl)oxy)benzene Base-3-(4-fluorophenyl)urea;

1-(3-bromophenyl)-3-(3-fluoro-4-((6-methoxy-7-(3-morpholinepropoxy)quinolin-4-yl)oxy)phenyl ) urea;

1-(3-bromophenyl)-3-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin)-1-yl)propoxy)quinone (Phenyl-4-yl)oxy)phenyl)urea;

1-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl-3-(4-methylphenyl ) urea;

1-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl -3-(4-methylphenyl)urea;

1-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl-3-(3-nitrophenyl ) urea;

1-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl -3-(3-nitrophenyl)urea;

1-(4-chlorophenyl)-3-(3-fluoro-4-((6-methoxy-7-(3-morpholinepropoxy)quinolin-4-yl)oxy)phenyl ) urea;

1-(4-chlorophenyl)-3-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin)-1-yl)propoxy)quinone (Phenyl-4-yl)oxy)phenyl)urea

1-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl -3-(3-(trifluoromethyl)phenyl)urea;

1-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl -3-(2-methylphenyl)urea;

1-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl -3-(2-methylphenyl)urea;

1-(3-fluoro-4-((6-methoxy-7-(3-(tetrahydropyrrol-1-yl)propoxy)quinolin-4-yl)oxy)phenyl-3- (2-methylphenyl)urea;

1-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl-3-(3-methylphenyl ) urea;

1-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl -3-(3-methylphenyl)urea;

1-(3-fluoro-4-((6-methoxy-7-(3-(tetrahydropyrrol-1-yl)propoxy)quinolin-4-yl)oxy)phenyl-3- (3-methylphenyl)urea;

1-(4-ethylphenyl)-3-(3-fluoro-4-((6-methoxy-7-(3-morpholinepropoxy)quinolin-4-yl)oxy)benzene base) urea;

1-(4-ethylphenyl)-3-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin)-1-yl)propoxy) Quinolin-4-yl)oxy)phenyl)urea;

1-(4-ethylphenyl)-3-(3-fluoro-4-((6-methoxy-7-(3-(tetrahydropyrrol-1-yl)propoxy)quinoline-4 -yl)oxy)phenyl)urea;

1-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl-3-(4-isopropylbenzene base) urea;

1-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl -3-(4-isopropylphenyl)urea;

1-(3-fluoro-4-((6-methoxy-7-(3-(tetrahydropyrrol-1-yl)propoxy)quinolin-4-yl)oxy)phenyl-3- (4-isopropylphenyl)urea;

1-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl -3-(4-trifluoromethylphenyl)urea;

1-(3-fluoro-4-((6-methoxy-7-(3-(tetrahydropyrrol-1-yl)propoxy)quinolin-4-yl)oxy)phenyl-3- (4-(trifluoromethyl)phenyl)urea;

1-(3-fluoro-4-((6-methoxy-7-(3-(tetrahydropyrrol-1-yl)propoxy)quinolin-4-yl)oxy)phenyl-3- (4-methylphenyl)urea;

1-(3,4-Dimethylphenyl)-3-(3-fluoro-4-((6-methoxy-7-(3-morpholinepropoxy)quinolin-4-yl)oxy base) phenyl) urea;

1-(3,4-Dimethylphenyl)-3-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin)-1-yl)propane Oxy)quinolin-4-yl)oxy)phenyl)urea;

1-(3,4-Dimethylphenyl)-3-(3-fluoro-4-((6-methoxy-7-(3-(tetrahydropyrrol-1-yl)propoxy)quinone (Phenyl-4-yl)oxy)phenyl)urea;

The active compound of the present invention or its pharmaceutically acceptable salts and solvates thereof can be used alone as the only antineoplastic drug, or can be combined with existing marketed antineoplastic drugs (such as platinum drug cisplatin, camptothecin drug iritinib) Kang, vinblastine drug navelbine, deoxycytidine drug gemcitabine, etoposide, paclitaxel, etc.) in combination. Combination therapy is achieved by simultaneous, sequential or spaced administration of the individual therapeutic components.

The Examples and Preparations provided hereinafter further illustrate and illustrate the compounds of the present invention and methods for their preparation. It should be understood that the scope of the following examples and preparations does not limit the scope of the invention in any way.

Synthetic Scheme A below describes the preparation of compounds of formula I of the present invention. All starting materials are prepared by the method described in Scheme A, by methods well known to those of ordinary skill in the art of organic chemistry or are commercially available. All final compounds of the present invention are prepared by the methods described in this scheme or by methods analogous thereto, which methods are well known to those of ordinary skill in the art of organic chemistry. All variables applicable in these synthetic routes are as defined below or as defined in the claims.

detailed description:

The compounds of the present invention and their preparation will be better understood in connection with the following examples, which are intended to illustrate rather than limit the scope of the invention.

Example 1 1-(3-fluoro-4-((6-methoxy-7-(3-morpholine propoxy) quinoline-4-yl)oxy)phenyl-3-(3-( Trifluoromethyl)phenyl)urea

Step A: Preparation of 4-(3-chloropropoxy)-3-methoxyacetophenone (A ₁ )

Dissolve 3-methoxy-4-hydroxyacetophenone (16.6g, 0.1mol) in 100mL acetone, add anhydrous potassium carbonate (19.3g, 0.14mol), stir at room temperature for 0.5h, drop 1- Bromo-3-chloropropane (21.9g, 0.14mol), control the temperature below 25°C during the dropwise addition. After dropping, the reaction was stirred at 25°C for about 20h. After the reaction was completed, it was filtered with suction, and the filtrate was slowly poured into 200 mL of ice water. After stirring for 15 minutes, it was filtered with suction, and the filter cake was dried to obtain 22.2 g of a white solid, with a yield of 91.3%.

Step B: Preparation of 2-nitro-4-(3-chloropropoxy)-5-methoxyacetophenone (A ₂ )

Intermediate A ₁ (12.1g, 0.05mol) was dissolved in 50mL of dichloromethane, stirred until completely dissolved, cooled to -20°C, and fuming nitric acid (8.46mL, 0.18mol) was slowly added dropwise to control the reaction solution The temperature does not exceed -15°C. After dropping, the reaction was continued at -15°C for 8h. After the reaction is complete, slowly pour the reaction solution into 100 mL of ice-water mixture while vigorously stirring to collect the dichloromethane layer, wash the dichloromethane layer with water four times, wash with saturated saline four times, collect the organic layer, and anhydrous sodium sulfate Dry and evaporate to dryness to obtain a red oily substance, which is beaten with petroleum ether to obtain 12.4 g of a light yellow solid with a yield of 86.7%.

Step C: 1-{4-[(3-Chloropropyl)oxy]-5-methoxy-2-nitro}phenyl-3-dimethylamino-2-ene-1-propanone (A ₃ ) preparation

Intermediate A ₂ (14.35 g, 0.05 mol) was dissolved in 100 mL of toluene. After complete dissolution, DMF-DMA (16.6 mL, 0.125 mol) was added, and the temperature was raised to 113° C. for 10 h under reflux. After the reaction was completed, the reaction solution was fully cooled, and a large amount of yellow solid was precipitated, which was suction filtered to obtain 13.1 g of yellow powder with a yield of 76.8%.

Step D: Preparation of 6-methoxy-7-[(3-chloropropyl)oxy]-4-hydroxyquinoline (A ₄ )

Intermediate A ₃ (6.9g, 0.02mol) was added to 50mL of glacial acetic acid, stirred and dissolved at room temperature, then reduced iron powder (14g, 0.06mol) was added in batches at 40°C, and reacted at 80°C for 2h. Suction filtration while it is hot, collect the filtrate, put the filter cake in glacial acetic acid at 80°C and stir for 0.5h, suction filtration while it is hot, combine the filtrates, cool down, a large amount of gray-yellow solid precipitates, suction filtration, wash the filter cake with a large amount of water until the pH is close to neutral 4.43 g of yellow solid was obtained, and the yield was 83.1%.

Step E: Preparation of 6-methoxy-7-[(3-morpholinopropyl)oxy]-4-hydroxyquinoline (A _5-1 )

Intermediate A ₄ (5.34 g, 0.02 mol) and morpholine (0.08 mol) were added to 80 mL of acetonitrile, heated to 80° C. and refluxed for about 12 h. After the reaction was completed, the reaction solution was fully cooled to precipitate a solid, filtered with suction, and the filtrate was evaporated to dryness to obtain a black oily substance. Add 100 mL of ethyl acetate, stir at room temperature for 1.5 h, filter with suction, and merge with the filter cake to obtain 6.02 g of a powdery solid. The rate is 95.2%.

Step F: Preparation of 4-chloro-6-methoxy-7-[(3-morpholinopropyl)oxy]quinoline (A _6-1 )

Add the dried intermediate A _5-1 (0.05mol) into 50mL of acetonitrile, stir well at room temperature for 5-10min to obtain a suspension, then quickly add phosphorus oxychloride (5V/m) at one time, after the addition is complete, heat up to 80 ° C reflux reaction for 5h. After the reaction is complete, cool the reaction solution, evaporate most of the solvent to obtain a black oily liquid, slowly pour the black oily liquid into 200mL of ice-water mixture under vigorous stirring to obtain a clear light brown solution, and control the temperature at no more than 25°C When the pH was adjusted to 12 with potassium hydroxide, a large amount of solids were precipitated. After stirring for 0.5 h, the mixture was filtered with suction to obtain 14.3 g of off-white solid powder with a yield of 85.4%.

Step G: 4-(2-Fluoro-4-nitro-1-phenoxy)-6-methoxy-7-[(3-morpholinopropyl)oxy]quinoline (A _7-1 ) preparation of

The fully dried intermediate A _6-1 (0.02mol) and 2-fluoro-4-nitrophenol (0.03mol) were added to 50mL of dry chlorobenzene, and the temperature was raised to 135°C for about 8h. After the reaction was completed, the reaction liquid was cooled, and a large amount of yellow solid was precipitated, filtered with suction, and the filter cake was dissolved in an appropriate amount of dichloromethane, washed repeatedly with saturated aqueous sodium carbonate solution for 6-7 times, the organic layer was dried, evaporated to dryness to obtain a black oil, added After beating with isopropyl ether, a large amount of yellow solid was precipitated. After stirring for 1 h, it was suction filtered and dried to obtain 8.23 g of yellow solid powder, with a yield of 90.4%.

Step H: Preparation of 3-fluoro-4-{6-methoxy-7-[(3-substituted aminopropyl)oxy]quinoline-4-oxy}aniline (A _8-1 )

Iron powder (0.06mol) and concentrated hydrochloric acid (0.002mol) were added to 20mL of 90% ethanol, stirred at reflux for 30min, intermediate A _7-1 (0.01mol) was added in batches after slightly lowering the temperature, and the temperature was raised to reflux for about 1h. After the reaction is complete, cool the reaction solution to about 50°C, add activated carbon, heat and reflux for 30 minutes, pad diatomaceous earth and suction filter while it is hot, concentrate the filtrate to one-third volume, cool to room temperature, and adjust with 5% NaOH solution under stirring. After the pH reached 12, 100 mL of water was added, and a large amount of yellow-white solid precipitated out. After stirring for 1 h, the mixture was suction-filtered to obtain 3.6 g of off-white solid powder, with a yield of 85.5%.

Step J: 1-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl-3-(3-( Preparation of trifluoromethyl)phenyl)urea

1 mmol of intermediate A _8-1 was dissolved in 10 mL of dichloromethane, and 1.2 mmol of 3-trifluoromethylphenyl isocyanate was slowly added dropwise, and the reaction system was stirred overnight at room temperature after the dropping. The resulting solid was filtered with suction, and the filter cake was washed with dichloromethane to obtain 0.51 g of the target compound as a light yellow solid with a yield of 83.1%.

MS(ESI)m/z(%):615.3[M+H] ⁺ ; H NMR(400MHz,DMSO)δ9.32(d,2H),8.48(d,1H),8.03(s,1H),7.77 (dd,1H),7.62(d,1H),7.58–7.51(m,2H),7.46–7.37(m,2H),7.37–7.26(m,2H),6.46(s,1H),4.20(t ,2H),3.96(s,3H),3.60(t,4H),3.35(s,3H),2.40(s,3H),2.08–1.92(m,2H).

The preparation method of the compound of embodiment 2-embodiment 38 is the same as that of embodiment 1.

Example 2 1-(3-fluoro-4-((6-methoxy-7-(3-morpholinepropoxy)quinolin-4-yl)oxy)phenyl-3-(2-( Trifluoromethyl)phenylurea

MS (ESI) m/z (%): 615.2[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO) δ9.69 (s, 1H), 8.32 (d, 2H), 7.62 (dd, 9H), 6.44(s,1H),4.20(t,2H),3.96(s,3H),3.60(t,4H),3.35(s,3H),2.40(s,3H),2.08–1.92(m,2H) .

Example 3 1-(3-fluoro-4-((6-methoxy-7-(3-morpholinepropoxy)quinolin-4-yl)oxy)phenyl-3-(4-( Trifluoromethyl)phenyl)urea

MS(ESI)m/z(%):615.2[M+H] ⁺ ; ^1H NMR(400MHz,DMSO)δ8.63–8.51(m,1H),8.38–8.30(m,1H),8.19–8.10 (m,1H),7.52–7.45(m,1H),7.48–7.40(m,1H),7.39–7.32(m,1H),7.34–7.28(m,1H),7.28–7.19(m,1H) ,6.95–6.81(m,1H),4.20(t,2H),3.96(s,3H),3.60(t,4H),3.35(s,3H),2.40(s,3H),2.08–1.92(m, 2H).

Example 4 1-(3,4-difluorophenyl)-3-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl )oxy)phenyl)urea

MS (ESI) m/z (%): 583.3 [M+H] ⁺ ; ¹ H NMR (400MHz, DMSO) δ11.22 (s, 1H), 9.95 (d, 1H), 7.51 (ddd, 5H), 4.38(s,1H),4.17–3.94(m,3H),3.51(s,3H),3.13(s,1H),2.52(s,2H),2.40(s,1H).

Example 5 1-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl-3-(3-fluoro Phenyl)urea

MS(ESI)m/z(%):565.3[M+H] ⁺ ; ^1H NMR(400MHz,DMSO)δ9.22(d,1H),8.47(s,1H),8.04–6.97(m,4H ),6.63(d,1H),4.20(t,2H),3.96(s,3H),3.60(t,4H),3.35(s,3H),2.40(s,3H),2.08–1.92(m, 2H).

Example 6 1-(3-fluoro-4-((6-methoxy-7-(3-morpholinepropoxy)quinolin-4-yl)oxy)phenyl-3-(4-methyl Oxyphenyl)urea

MS (ESI) m/z (%): 577.3[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO) δ9.32 (d, 2H), 8.48 (d, 1H), 8.03 (s, 1H), 7.77(dd,1H),7.62(d,1H),7.58–7.51(m,2H),7.46–7.37(m,2H),7.37–7.26(m,2H),6.46(s,1H),δ4. 14(t,1H),4.05–3.95(m,1H),3.88(s,1H),3.75–3.54(m,2H),2.80(q,1H),2.52–2.39(m,1H),2.39– 2.29(m,1H),1.89(ddt,1H).

Example 7 1-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy )phenyl-3-(4-methoxyphenyl)urea

MS (ESI) m/z (%): 589.3[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO) δ9.34 (s, 1H), 8.91 (s, 1H), 8.48 (d, 1H), 7.77(dd,1H),7.55(s,1H),7.40(s,2H),7.38(dd,5H),7.39–7.34(m,2H),7.28–7.23(m,1H),7.31–7.20( m,1H),6.89(d,2H),6.45(d,J=4.8Hz,1H),4.19(t,3H),3.96(s,3H),3.73(s,3H),2.94(d,2H ),2.51(dd,2H),2.29–1.82(m,7H),2.06–1.94(m,4H),1.60(d,2H),1.45–1.28(m,2H),0.89(d,3H).

Example 8 1-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl-3-(3-methyl Oxyphenyl)urea

MS (ESI) m/z (%): 577.2[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO) δ9.34 (s, 1H), 8.91 (s, 1H), 8.48 (d, 1H), 7.77(dd,1H),7.55(s,1H),7.40(s,2H),7.38(dd,5H),7.39–7.34(m,2H),7.28–7.23(m,1H),7.31–7.20( m,1H),6.89(d,2H),6.45(d,1H),δ4.14(t,1H),4.05–3.95(m,1H),3.88(s,1H),3.75–3.54(m, 2H), 2.80(q,1H), 2.52–2.39(m,1H), 2.39–2.29(m,1H), 1.89(ddt,1H).

Example 9 1-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy )phenyl-3-(3-methoxyphenyl)urea

MS (ESI) m/z (%): 589.3[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO) δ9.60 (s, 1H), 9.27 (s, 1H), 8.51 (d, 1H), 7.77(d,1H),7.58(s,1H),7.47(s,1H),7.40(t,1H),7.26(d,1H),7.18(dd,2H),6.96(d,1H),6.57 (d,1H),6.51(d,1H),4.27(s,2H),3.98(s,3H),3.74(s,3H),3.53(d,2H),3.23(s,2H),2.94( d,2H),2.30(s,2H),1.81(d,2H),1.62(s,1H),1.53–1.34(m,2H),0.94(d,3H).

Example 10 1-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl-3-(4-fluoro Phenyl)urea

MS(ESI)m/z(%):565.2[M+H] ⁺ ; ^1H NMR(400MHz,DMSO)δ9.19(d,1H),9.01–8.91(m,1H),8.51–8.43(m ,1H),7.74(dd,1H),7.61–7.20(m,7H),7.14(dd,2H),6.46(d,1H),4.29–4.17(m,2H),3.96(d,3H), 3.61(d,4H),2.66(s,2H),2.32(s,2H),1.99(d,2H).

Example 11 1-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin)-1-yl)propoxy)quinolin-4-yl)oxy base) phenyl-3-(4-fluorophenyl) urea

MS (ESI) m/z (%): 577.3[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO) δ9.57 (s, 1H), 9.29 (s, 1H), 8.53 (d, 1H), 7.77(dd,1H),7.59(s,1H),7.48(t,3H),7.40(t,1H),7.27(d,1H),7.14(t,2H),6.53(d,1H),4.28 (t,2H),3.98(s,3H),3.53(d,2H),3.23(s,2H),3.01–2.88(m,2H),2.35–2.24(m,2H),1.81(d,2H ),1.63(s,1H),1.44(dd,2H),0.94(d,3H).

Example 12 1-(3-bromophenyl)-3-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy ) phenyl) urea

MS (ESI) m/z (%): 625.1[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO) δ9.13 (d, 2H), 8.50 (s, 1H), 7.88 (s, 1H), 7.77(d,1H),7.56(s,1H),7.48–7.13(m,5H),6.47(s,1H),4.34–4.13(m,2H),3.98(s,3H),3.62(s, 3H), 2.55(s,2H), 2.42(s,4H), 2.02(s,2H).

Example 13 1-(3-bromophenyl)-3-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin)-1-yl)propoxy Base) quinolin-4-yl) oxy) phenyl) urea

MS (ESI) m/z (%): 637.2[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO) δ9.25 (s, 1H), 9.14 (s, 1H), 9.05 (s, 1H), 8.48(d,1H),7.85(d,2H),7.75(d,1H),7.54(s,1H),7.40(d,2H),7.17(t,3H),6.45(d,1H),4.20 (s,2H),3.96(s,3H),2.54(s,2H),2.49–2.44(m,2H),2.01(d,2H),1.63(s,2H),1.39(s,1H), 1.18(t,2H),0.90(d,3H).

Example 14 1-(3-fluoro-4-((6-methoxy-7-(3-morpholinepropoxy)quinolin-4-yl)oxy)phenyl-3-(4-methyl phenyl)urea

MS (ESI) m/z (%): 561.2[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO) δ9.03 (s, 1H), 8.73 (s, 1H), 8.47 (d, 1H), 7.75(dd,1H),7.53(s,1H),7.37(dd,4H),7.25(dd,1H),7.11(d,2H),6.44(d,1H),4.20(t,2H),3.95 (s,3H),3.60(s,4H),2.37(d,4H),2.25(s,3H),2.04–1.95(m,2H),1.23(s,1H).

Example 15 1-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy )phenyl-3-(4-methylphenyl)urea

MS (ESI) m/z (%): 573.2[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO) δ9.63 (s, 1H), 9.45 (s, 1H), 9.04 (s, 1H), 8.49(d,1H),7.76(dd,1H),7.57(s,1H),7.45(s,1H),7.37(dd,3H),7.27–7.22(m,1H),7.10(d,2H) ,6.48(d,1H),4.27(t,2H),3.97(s,3H),3.58–3.46(m,2H),3.23(d,2H),2.94(dt,2H),2.28(d,2H ),2.25(s,3H),1.81(dd,2H),1.51–1.35(m,2H),0.94(d,3H).

Example 16 1-(3-fluoro-4-((6-methoxy-7-(3-morpholinepropoxy)quinolin-4-yl)oxy)phenyl-3-(3-nitro phenyl)urea

MS (ESI) m/z (%): 592.2[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO) δ8.76 (s, 1H), 8.55 (d, 1H), 8.34 (s, 1H), 8.28(t,1H),8.10(dt,1H),7.74(dt,1H),7.48(t,1H),7.33(dt,2H),7.20(s,1H),7.07(s,1H),6.91 –6.86(m,2H),4.12(t,2H),3.98(s,3H),3.67(t,4H),2.65–2.60(m,4H),2.40(t,2H),1.91(ddd,2H ).

Example 17 1-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy ) phenyl-3-(3-nitrophenyl) urea

MS (ESI) m/z (%): 604.3[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO) δ9.42 (s, 1H), 9.28 (s, 1H), 8.57 (d, 1H), 8.48(d,1H),7.86(dd,1H),7.81–7.72(m,1H),7.59(t,1H),7.54(s,1H),7.47–7.37(m,1H),7.32(d, 1H), 6.45(d, 1H), 4.19(t, 1H), 3.96(s, 1H), 2.86(s, 1H), 2.04–1.90(m, 1H), 1.58(d, 1H), 1.32(s ,1H),1.14(dd,1H),0.89(d,1H),0.89(d,1H).

Example 18 1-(4-chlorophenyl)-3-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy ) phenyl) urea

MS (ESI) m/z (%): 581.2[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO) δ9.03 (d, 2H), 8.48 (s, 1H), 7.75 (d, 1H), 7.61–7.22(m,9H),6.45(s,1H),4.21(s,2H),3.96(s,3H),3.60(s,4H),2.40(s,4H),1.99(s,2H) ,1.77(s,1H).

Example 19 1-(4-chlorophenyl)-3-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin)-1-yl)propoxy Base) quinolin-4-yl) oxy) phenyl) urea

MS (ESI) m/z (%): 593.2[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO) δ9.20 (s, 1H), 9.07 (s, 1H), 8.47 (d, 1H), 7.75(dd,1H),7.58–7.48(m,3H),7.44–7.31(m,4H),7.27(d,1H),6.44(d,1H),4.19(t,2H),3.95(s, 3H), 2.90(s, 2H), 2.00(s, 4H), 1.60(s, 2H), 1.36(s, 1H), 1.18(s, 2H), 0.90(d, 3H).

Example 20 1-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy )phenyl-3-(3-(trifluoromethyl)phenyl)urea

MS (ESI) m/z (%): 627.3[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO) δ9.57 (s, 2H), 8.49 (d, 1H), 8.02 (s, 1H), 7.77(d,1H),7.62(d,1H),7.58–7.49(m,2H),7.46–7.37(m,2H),7.31(dd,2H),6.47(d,1H),4.25(s, 2H), 3.97(s, 3H), 2.20(s, 2H), 1.75(s, 2H), 1.56(s, 1H), 1.36(s, 2H), 0.93(d, 3H).

Example 21 1-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy )phenyl-3-(2-methylphenyl)urea)

MS (ESI) m/z (%): 561.3[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO) δ9.40 (s, 1H), 8.48 (d, 1H), 8.07 (s, 1H), 7.87–7.71(m,3H),7.54(s,1H),7.46–7.32(m,2H),7.24(d,1H),7.15–7.10(m,1H),6.96(dt,2H),6.45( d,1H),4.21(t,2H),3.96(s,3H),3.60(s,4H),3.32(s,3H),2.26(s,6H),1.99(s,2H).

Example 22 1-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy )phenyl-3-(2-methylphenyl)urea

MS(ESI)m/z(%):573.3[M+H] ⁺ ; ^1H NMR(400MHz,DMSO)δ9.89(s,1H),9.63(s,1H),8.64–8.28(m,2H ),7.79(s,2H),7.65–6.86(m,8H),6.49(s,1H),4.28(s,2H),3.97(s,2H),3.52(s,2H),3.27(d, 5H), 2.93(s, 2H), 2.28(s, 4H), 1.80(s, 2H), 1.52(d, 3H), 0.93(s, 3H).

Example 23 1-(3-fluoro-4-((6-methoxy-7-(3-(tetrahydropyrrol-1-yl)propoxy)quinolin-4-yl)oxy)phenyl -3-(2-Methylphenyl)urea

MS (ESI) m/z (%): 547.3 [M+H] ⁺ ; ¹ H NMR (400MHz, DMSO) δ10.15 (s, 1H), 9.35 (s, 1H), 8.97 (s, 1H), 8.51(d,1H),7.77(dd,1H),7.58(s,1H),7.46(s,1H),7.39(t,1H),7.30(s,1H),7.26(d,2H),7.17 (t,1H),6.81(d,1H),6.50(d,1H),4.28(t,3H),3.97(s,4H),3.74(s,2H),3.55(d,3H),3.12( s,2H),2.29(s,6H),1.76(s,1H).

Example 24 1-(3-fluoro-4-((6-methoxy-7-(3-morpholinepropoxy)quinolin-4-yl)oxy)phenyl-3-(3-methyl phenyl)urea

MS (ESI) m/z (%): 561.3[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO) δ10.15 (s, 1H), 9.35 (s, 1H), 8.97 (s, 1H), 8.51(d,1H),7.77(dd,1H),7.58(s,1H),7.46(s,1H),7.39(t,1H),7.30(s,1H),7.26(d,2H),7.17 (t,1H),6.81(d,1H),6.50(d,1H),4.28(t,3H),3.97(s,4H),3.74(s,2H),3.55(d,3H),3.12( s,2H),2.29(s,6H),1.76(s,1H).

Example 25 1-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy )phenyl-3-(3-methylphenyl)urea

MS (ESI) m/z (%): 573.3[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO) δ9.61 (d, 1H), 9.11 (s, 1H), 8.51 (s, 1H), 7.78(s,1H),7.51(d,1H),7.28(s,1H),6.82(s,1H),6.49(s,1H),4.28(s,1H),3.98(s,1H),3.55 (s,1H),2.95(s,1H),2.30(s,1H),1.80(s,1H),1.52(d,1H),0.94(s,1H).

Example 26 1-(3-fluoro-4-((6-methoxy-7-(3-(tetrahydropyrrol-1-yl)propoxy)quinolin-4-yl)oxy)phenyl -3-(3-Methylphenyl)urea

MS (ESI) m/z (%): 545.3[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO) δ9.36 (s, 1H), 8.97 (s, 1H), 8.49 (d, 1H), 7.76(dd,1H),7.57(s,1H),7.45(s,1H),7.38(t,1H),7.26(dd,3H),7.16(dd,1H),6.81(d,1H),6.47 (d,1H),4.28(t,2H),3.96(d,3H),3.60(t,2H),3.07(s,2H),2.51(s,14H),2.35–2.16(m,5H), 1.96(d,4H),1.83–1.70(m,1H).

Example 27 1-(4-ethylphenyl)-3-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy base) phenyl) urea

MS (ESI) m/z (%): 575.3[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO) δ9.00 (s, 1H), 8.70 (s, 1H), 8.47 (d, 1H), 7.75(dd,1H),7.54(s,1H),7.44–7.31(m,4H),7.25(dd,1H),7.14(d,2H),6.44(d,1H),4.21(t,2H) ,3.96(s,3H),3.60(s,4H),2.55(dd,5H),2.40(s,4H),1.99(s,2H),1.17(t,3H).

Example 28 1-(4-ethylphenyl)-3-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin)-1-yl)propane Oxy)quinolin-4-yl)oxy)phenyl)urea

MS (ESI) m/z (%): 587.3[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO) δ9.25 (s, 1H), 8.89 (s, 1H), 8.49 (d, 1H), 7.75(d,1H),7.57(s,1H),7.45(s,1H),7.37(d,3H),7.25(d,1H),7.13(d,2H),6.48(d,1H),4.27 (t,2H),3.97(s,3H),3.54(d,2H),3.25(s,2H),2.95(d,2H),2.27(s,2H),1.82(d,2H),1.62( s,1H),1.38(d,2H),1.16(t,3H),0.94(d,3H).

Example 29 1-(4-ethylphenyl)-3-(3-fluoro-4-((6-methoxy-7-(3-(tetrahydropyrrol-1-yl)propoxy)quinone (Phenyl-4-yl)oxy)phenyl)urea

MS (ESI) m/z (%): 558.3[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO) δ9.42 (s, 1H), 9.03 (s, 1H), 8.48 (d, 1H), 7.76(dd,1H),7.56(s,1H),7.43(s,1H),7.37(dd,3H),7.24(dd,1H),7.13(d,2H),6.46(d,1H),4.26 (t,2H),3.97(s,3H),3.32(s,4H),2.55(d,2H),2.27–2.14(m,2H),1.93(s,4H),1.16(t,4H).

Example 30 1-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl-3-(4-iso Propylphenyl)urea

MS (ESI) m/z (%): 589.3 [M+H] ⁺ ; ¹ H NMR (400MHz, DMSO) δ8.48 (d, 1H), 7.54 (s, 1H), 7.44 (s, 1H), 7.07(t,1H),6.56(dd,1H),6.47(dd,1H),6.43(d,1H),4.26(t,2H),3.96(s,4H),3.33(s,4H),2.28 (s,2H).

Example 31 1-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy )phenyl-3-(4-isopropylphenyl)urea

MS(ESI)m/z(%):601.3[M+H]+; 1H NMR(400MHz,DMSO)δ9.75(s,1H),8.47(d,1H),7.54(s,1H),7.43 (s,1H),7.07(t,1H),6.55(d,1H),6.44(dd,2H),5.51(s,2H),4.25(s,2H),3.92(s,4H),3.51( d,2H),3.22(s,3H),2.93(d,2H),2.28(s,2H),1.99(s,1H),1.79(d,3H),1.62(s,1H),1.43(d ,2H), 1.17(d,1H),0.93(d,4H).

Example 32 1-(3-fluoro-4-((6-methoxy-7-(3-(tetrahydropyrrol-1-yl)propoxy)quinolin-4-yl)oxy)phenyl -3-(4-Isopropylphenyl)urea

MS (ESI) m/z (%): 573.3 [M+H] ⁺ ; ¹ H NMR (400MHz, DMSO) δ8.59 (d, 1H), 7.61 (s, 1H), 7.53 (s, 1H), 7.09(s,1H),6.59(d,1H),6.56(d,1H),6.49(dd,1H),4.30(t,2H),3.99(s,3H),3.60(d,2H),3.08 –2.96(m,2H),2.31–2.24(m,2H),2.03(s,2H),1.89(d,2H).

Example 33 1-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy )phenyl-3-(4-trifluoromethylphenyl)urea

MS (ESI) m/z (%): 627.3[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO) δ9.49 (d, 1H), 9.30 (s, 1H), 8.49 (d, 1H), 7.76(d,1H),7.67(d,2H),7.57(s,1H),7.48–7.37(m,1H),7.29(d,1H),6.48(d,1H),4.32–4.21(m, 1H),3.97(s,2H),3.54(d,1H),3.24(s,1H),2.95(s,1H),2.27(s,1H),1.82(d,1H),1.63(s,1H ),1.44–1.33(m,1H),0.94(d,1H).

Example 34 1-(3-fluoro-4-((6-methoxy-7-(3-(tetrahydropyrrol-1-yl)propoxy)quinolin-4-yl)oxy)phenyl -3-(4-(Trifluoromethyl)phenyl)urea

MS (ESI) m/z (%): 599.3[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO) δ9.81 (s, 1H), 9.48 (d, 2H), 8.49 (d, 1H), 7.78(d,1H),7.67(d,4H),7.57(s,1H),7.45(s,1H),7.40(d,1H),7.29(dd,1H),6.48(d,1H),4.27 (t,2H),3.97(s,4H),3.63(s,2H),3.06(s,2H),2.24(dt,3H),1.97(d,5H).

Example 35 1-(3-fluoro-4-((6-methoxy-7-(3-(tetrahydropyrrol-1-yl)propoxy)quinolin-4-yl)oxy)phenyl -3-(4-Methylphenyl)urea

MS (ESI) m/z (%): 545.3[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO) δ9.05 (s, 1H), 8.72 (s, 1H), 8.47 (d, 1H), 7.75(dd,1H),7.54(s,1H),7.40(s,1H),7.34(d,3H),7.24(d,1H),7.10(d,3H),6.45(d,1H),4.22 (t,2H),3.96(s,3H),2.66(s,5H),2.24(d,4H),2.04(s,2H),1.76(s,4H).

Example 36 1-(3,4-Dimethylphenyl)-3-(3-fluoro-4-((6-methoxy-7-(3-morpholinepropoxy)quinoline-4- base)oxy)phenyl)urea

MS (ESI) m/z (%): 575.3[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO) δ9.18 (s, 1H), 8.76 (s, 1H), 8.48 (d, 1H), 7.76(dd,1H),7.55(s,1H),7.43(s,1H),7.37(t,1H),7.23(d,2H),7.19(dd,1H),7.04(d,1H),6.46 (d,1H),4.25(s,3H),3.96(s,4H),3.66(s,3H),3.32(s,7H),2.17(dd,8H).

Example 37 1-(3,4-Dimethylphenyl)-3-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidine)-1- base) propoxy) quinolin-4-yl) oxy) phenyl) urea

MS (ESI) m/z (%): 587.3[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO) δ9.27 (s, 1H), 8.82 (s, 1H), 8.50 (d, 1H), 7.76(d,1H),7.57(s,1H),7.45(s,1H),7.41–7.32(m,1H),7.24(s,2H),7.19(d,1H),7.04(d,1H) ,6.46(d,1H),4.27(s,2H),3.97(s,3H),3.54(d,2H),3.24(s,3H),2.94(s,2H),2.21(t,8H), 1.82(d,2H),1.62(s,1H),1.40(d,2H),0.94(d,3H).

Example 38 1-(3,4-Dimethylphenyl)-3-(3-fluoro-4-((6-methoxy-7-(3-(tetrahydropyrrol-1-yl)propoxy) Base) quinolin-4-yl) oxy) phenyl) urea

MS (ESI) m/z (%): 559.3[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO) δ9.38 (s, 1H), 8.91 (s, 1H), 8.49 (d, 1H), 7.76(d,1H),7.56(s,1H),7.44(s,1H),7.38(d,1H),7.24(s,2H),7.18(s,1H),7.04(d,1H),6.47 (d,1H),4.27(t,2H),3.97(s,3H),3.61(s,1H),3.06(s,1H),2.20(t,8H),1.97(s,3H).

Pharmacological research on the product of the present invention

The in vitro biological activity of the quinoline derivatives of the above formula I of the present invention was evaluated by an in vitro activity inhibition test on the leukemia cell line MV4-11.

Experimental Materials:

MV4-11, IMDM (Hyclone, SH30228.01B, China), FBS (Gibco, 10099-141, Australia), 96-well plate (Cornng, 3599, America), MTT (Sigma, M2128, America).

experimental method:

Inoculate 90 μL of MV4-11 cells at 1×10 ⁴ /well in a 96-well plate, use DMSO to prepare the compound to be tested into a 10 mM stock solution, and dilute the compounds in IMDM (containing 10% FBS) under sterile conditions To 10 times the preset concentration, add 10 μL to a 96-well plate, incubate in a 37°C CO ₂ incubator for 48 hours, add 10 μL MTT to each well and continue to incubate for 4 hours, then add 100 μL SDS-isopropanol-HCl to each well The triplicate was left overnight, and the absorbance at a wavelength of 570nM was measured using a multifunctional microplate reader. The inhibitory activity of the compounds on cell MV4-11 was calculated.

Calculation formula:

Single-dose cell proliferation inhibition rate=(blank solvent control group-drug action group)/blank solvent control group*100%

IC ₅₀ calculation formula

The assay results of some compounds of the present invention are as follows:

Compound name IC ₅₀ (nM) Example 14 3.22 Example 15 1.11 Example 21 7.84 Example 22 5.56 Example 23 289 Example 24 91.0 Example 25 14.4 Example 26 0.43 Example 28 0.93 Example 29 0.35 Example 32 0.37 Example 34 0.98 Example 35 0.47 AC220 0.84

Claims (10)

1. Quinoline compounds containing bisaryl urea structure of general formula I and their pharmaceutically acceptable salts, in, X is O, S, NH, _NCH3 ; Y is optionally 1-2 of the following substituents: halogen, halogenated C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyl, cyano, nitro; Z is O, S; n is an integer between 1-6; R ₁ and R ₂ are the same or different, each independently selected from hydrogen, (C ₁ -C ₁₀ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, (C ₂ -C ₁₀ ) alkenyl or (C ₂ -C ₁₀ ) alkynyl, which can be optionally substituted by 1-3 identical or different R ₃ ; Or R ₁ and R ₂ form a 5-10 membered heterocyclic group or a 5-10 membered heteroaryl group together with the nitrogen atom to which they are attached, and the heterocyclic group and heteroaryl group are not connected to R ₁ and R ₂ In addition to the nitrogen atom, it contains 1-4 heteroatoms selected from N, O or S, except for the nitrogen atom to which R and R are connected, the heterocyclic group optionally includes _1-2 carbon-carbon _double bonds or Triple bond, the heterocyclyl and heteroaryl are optionally substituted by 1-3 identical or different _R3 ; R ₃ are independently selected from H, (C ₆ -C ₁₀ ) aryl, 5-10 membered heteroaryl, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, said The heteroaryl group contains 1-3 heteroatoms selected from N, O or S, and R ₃ is optionally substituted by 1-3 identical or different R ₄ ; Ar is (C ₆ -C ₁₀ )aryl, 5-10 membered heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Ar is optionally 1-3 The same or different R ₄ substitutions; R ₄ is H, hydroxyl, halogen, nitro, amino, cyano, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkyl or (C ₁ -C ₆ )alkoxy optionally substituted by hydroxyl, amino or halogen, by 1-2 (C ₁ -C ₆ ) alkyl substituted amino group, (C ₁ -C ₆ ) alkyl amido group, free, salified, esterified and amidated carboxyl group, (C ₁ -C ₆ ) alkyl sulfinyl group, (C ₁ -C ₆ )alkylsulfonyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkylacyl, carbamoyl, by 1-2 (C ₁ -C ₆ )alkyl substituted carbamoyl, (C ₁ -C ₃ )alkylenedioxy, allyl. 2. The compound of general formula I of claim 1 and their pharmaceutically acceptable salts, wherein n is an integer between 1-3; R ₁ and R ₂ are the same or different, each independently selected from hydrogen, (C1-C6) alkyl, (C3-C5) cycloalkyl, (C2-C6) alkenyl or (C2-C6) alkynyl, which Can be optionally substituted by 1-3 identical or different R ₃ ; Or R ₁ and R ₂ form _a 5-10 _membered heterocyclic group together with the nitrogen atom they are connected to, and the heterocyclic group optionally contains 1-4 optional A heteroatom selected from N, O and S, the heterocyclic group is optionally substituted by 1-3 identical or different R ₃ . 3. The compound of general formula I and their pharmaceutically acceptable salts according to claim 1 or 2, wherein n is 2, 3; R ₁ and R ₂ are the same or different, each independently selected from hydrogen, (C ₁ -C ₄ ) alkyl, (C ₃ -C ₅ ) cycloalkyl; Or R ₁ and R ₂ form _a 5-6 membered heterocyclic group together with the nitrogen atom they are connected to, and the heterocyclic group optionally contains _1-2 optional A heteroatom from N, O and S, said heterocyclyl is optionally substituted by 1-3 identical or different R ₃ ; R ₃ is H, (C ₁ -C ₄ )alkyl. 4. The compound of general formula I and their pharmaceutically acceptable salts according to any one of claims 1-3, wherein Y is F; n is 2, 3; R ₁ and R ₂ form dimethylamino, diethylamino, 1-piperidinyl, 4-morpholinyl, 4-methyl-1-piperazinyl, 1-piperazine together with the nitrogen atom to which they are attached Base, 4-methyl-1-piperidinyl, 1-pyrrolidinyl, 4-thiomorpholinyl. 5. The compound of general formula I and their pharmaceutically acceptable salts according to any one of claims 1-4, wherein Ar is phenyl, naphthyl, quinolinyl, isoquinolyl, quinazolinyl, indolyl, pyridyl, furyl, thienyl, pyrrolyl, pyrimidinyl, preferably phenyl; and Ar is optionally 1-3 identical or different R ₄ substitutions, R ₄ is preferably halogen, hydroxyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, allyl, dimethylamino, methylsulfonyl. 6. The compound of general formula I and their pharmaceutically acceptable salts according to any one of claims 1-5, wherein R ₁ and R ₂ form 1-piperidinyl, 4-morpholinyl, 4-methyl-1-piperazinyl, 4-methyl-1-piperidinyl, 1 - pyrrolidinyl. 7. Quinoline compounds containing bisaryl urea structure and their pharmaceutically acceptable salts, selected from: 1-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl-3-(3-(trifluoromethyl base) phenyl) urea; 1-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl-3-(2-(trifluoromethyl base) phenylurea; 1-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl-3-(4-(trifluoromethyl base) phenyl) urea; 1-(3,4-difluorophenyl)-3-(3-fluoro-4-((6-methoxy-7-(3-morpholinepropoxy)quinolin-4-yl)oxy ) phenyl) urea; 1-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl-3-(3-fluorophenyl) urea; 1-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl-3-(4-methoxybenzene base) urea 1-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl -3-(4-methoxyphenyl)urea; 1-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl-3-(3-methoxybenzene base) urea; 1-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl -3-(3-methoxyphenyl)urea; 1-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl-3-(4-fluorophenyl) urea; 1-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin)-1-yl)propoxy)quinolin-4-yl)oxy)benzene Base-3-(4-fluorophenyl)urea; 1-(3-bromophenyl)-3-(3-fluoro-4-((6-methoxy-7-(3-morpholinepropoxy)quinolin-4-yl)oxy)phenyl ) urea; 1-(3-bromophenyl)-3-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin)-1-yl)propoxy)quinone (Phenyl-4-yl)oxy)phenyl)urea; 1-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl-3-(4-methylphenyl ) urea; 1-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl -3-(4-methylphenyl)urea; 1-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl-3-(3-nitrophenyl ) urea; 1-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl -3-(3-nitrophenyl)urea; 1-(4-chlorophenyl)-3-(3-fluoro-4-((6-methoxy-7-(3-morpholinepropoxy)quinolin-4-yl)oxy)phenyl ) urea; 1-(4-chlorophenyl)-3-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin)-1-yl)propoxy)quinone (Phenyl-4-yl)oxy)phenyl)urea 1-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl -3-(3-(trifluoromethyl)phenyl)urea; 1-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl -3-(2-methylphenyl)urea; 1-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl -3-(2-methylphenyl)urea; 1-(3-fluoro-4-((6-methoxy-7-(3-(tetrahydropyrrol-1-yl)propoxy)quinolin-4-yl)oxy)phenyl-3- (2-methylphenyl)urea; 1-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl-3-(3-methylphenyl ) urea; 1-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl -3-(3-methylphenyl)urea; 1-(3-fluoro-4-((6-methoxy-7-(3-(tetrahydropyrrol-1-yl)propoxy)quinolin-4-yl)oxy)phenyl-3- (3-methylphenyl)urea; 1-(4-ethylphenyl)-3-(3-fluoro-4-((6-methoxy-7-(3-morpholinepropoxy)quinolin-4-yl)oxy)benzene base) urea; 1-(4-ethylphenyl)-3-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin)-1-yl)propoxy) Quinolin-4-yl)oxy)phenyl)urea; 1-(4-ethylphenyl)-3-(3-fluoro-4-((6-methoxy-7-(3-(tetrahydropyrrol-1-yl)propoxy)quinoline-4 -yl)oxy)phenyl)urea; 1-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl-3-(4-isopropylbenzene base) urea; 1-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl -3-(4-isopropylphenyl)urea; 1-(3-fluoro-4-((6-methoxy-7-(3-(tetrahydropyrrol-1-yl)propoxy)quinolin-4-yl)oxy)phenyl-3- (4-isopropylphenyl)urea; 1-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl -3-(4-trifluoromethylphenyl)urea; 1-(3-fluoro-4-((6-methoxy-7-(3-(tetrahydropyrrol-1-yl)propoxy)quinolin-4-yl)oxy)phenyl-3- (4-(trifluoromethyl)phenyl)urea; 1-(3-fluoro-4-((6-methoxy-7-(3-(tetrahydropyrrol-1-yl)propoxy)quinolin-4-yl)oxy)phenyl-3- (4-methylphenyl)urea; 1-(3,4-Dimethylphenyl)-3-(3-fluoro-4-((6-methoxy-7-(3-morpholinepropoxy)quinolin-4-yl)oxy base) phenyl) urea; 1-(3,4-Dimethylphenyl)-3-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin)-1-yl)propane Oxy)quinolin-4-yl)oxy)phenyl)urea; 1-(3,4-Dimethylphenyl)-3-(3-fluoro-4-((6-methoxy-7-(3-(tetrahydropyrrol-1-yl)propoxy)quinone phen-4-yl)oxy)phenyl)urea. 8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 and a pharmaceutically acceptable salt thereof as an active ingredient. 9. Application of the compound of any one of claims 1-7 and the pharmaceutically acceptable salt thereof or the composition described in claim 8 in the preparation of medicines for the treatment and/or prevention of diseases caused by the abnormal expression of FLT3 kinase . 10. The compound of any one in claim 1-7 and pharmaceutically acceptable salt thereof or the composition described in claim 8 in the medicine of preparation treatment and/or prevention acute myelogenous leukemia, chronic myelogenous leukemia application.