Novel 7-methoxy-4-phenoxyquinoline-6-formamide compound and application thereof

Abstract

The invention belongs to the field of medicines, and particularly relates to a novel 7-methoxy-4-phenoxyquinoline-6-formamide compound and an application thereof. The novel 7-methoxy-4-phenoxyquinoline-6-formamide compound provided by the invention has a structure as shown in a general formula (I), and has a strong effect of inhibiting c-Met kinase; the invention relates to a 7-methoxy-4-phenoxyquinoline-6-formamide compound, and provides application of the novel 7-methoxy-4-phenoxyquinoline-6-formamide compound and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof in preparation of drugs for treating and / or preventing diseases caused by abnormal high expression of c-Met kinase, especially application in preparation of drugs for treating and / or preventing cancers, as well as application of the novel 7-methoxy-4-phenoxyquinoline-6-formamide compound and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof in preparation of drugs for treating and / or preventing diseases caused by abnormal high expression of c-Met kinase. The compound provided by the invention is especially suitable for preparing medicines for treating and / or preventing gastric cancer, lung cancer and prostate cancer. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the technical field of medicines, and in particular to a novel 7-methoxy-4-phenoxyquinoline-6-carboxamide compound. Background Art

[0002] Cancer, also known as malignant tumor, is caused by malignant cell proliferation and is invasive and metastatic. Cancer is a genetic abnormality disease caused by the long-term combined action of multiple factors. When the body is affected by chemical, physical, viral and other carcinogens in the environment, and / or due to its own genetic, endocrine, gender, age and other factors, a series of genetic abnormalities may occur, forming malignant tumors. Cancer is one of the major diseases that seriously affect human health and threaten human life. Cancer has become the second largest "killer" threatening human health, second only to cardiovascular and cerebrovascular diseases, and its mortality rate even exceeds that of cardiovascular and cerebrovascular diseases, ranking first among all diseases, so the research on anti-tumor drugs is of great significance.

[0003] In recent years, with the development of molecular biology technology, molecular targeted therapy for malignant tumors has attracted more and more attention. Compared with traditional tumor treatment methods, molecular targeted therapy can simultaneously achieve the advantages of orientation and positioning, reduce the dosage of drugs, reduce toxic and side effects, and improve the efficacy. It has become a hot spot in modern anticancer drugs. Studies have found that the overexpression of receptor tyrosine kinases (RTKs) in tumor cells is closely related to the occurrence, development and metastasis of various malignant tumors. Inhibiting the activity of RTKs can effectively inhibit tumors. c-Met is a prototype member of the Ron subfamily of the tyrosine kinase receptor family. It is the only known high-affinity receptor for hepatocyte growth factor (HGF). Under normal physiological conditions, HGF binds to c-Met kinase, which can cause a series of biological effects, such as promoting the separation of epithelial cells, promoting the mitosis of the placenta, regulating the development and structure formation of the lungs, kidneys and breasts, etc. However, abnormal HGF / c-Met activity is closely related to tumor occurrence, division, angiogenesis, invasiveness, metastasis and drug resistance, and is abnormally highly expressed in a variety of tumor tissues, such as lung cancer, gastric cancer, breast cancer, colon cancer, prostate cancer, pancreatic cancer, ovarian cancer, etc. Receptor tyrosine kinase c-Met is highly expressed and abnormally activated in most cancers. Inhibition of c-Met kinase can inhibit a series of abnormal physiological processes such as tumor occurrence, development and metastasis. Therefore, c-Met kinase has become an important target for anti-tumor targeted therapy. Quinoline compounds are commonly used heterocyclic compounds in medicinal chemistry research and have been widely studied in c-Met kinase inhibitors. Cabozantinib, which has a 4-phenoxyquinoline core, is the first small molecule c-Met kinase inhibitor approved for marketing, and has a strong inhibitory effect on kinases such as VEGFR-2, c-Kit and Flt-3. Cabozantinib's analogue Foretinib has now entered the Phase III clinical research stage. Clinical studies have shown that it exhibits significant inhibitory effects on a variety of human tumor cell lines. Another 4-phenoxyquinoline compound, Pamufetinib (TAS-115), is currently in the Phase III clinical stage. It is a compound that can inhibit c-Met and VEGFR-2, and has significant anti-tumor activity and good tolerability. At present, the main problems in the research of c-Met inhibitors are as follows: large toxic and side effects in clinical application, unsatisfactory clinical treatment effects and pharmacokinetic parameters, and low oral bioavailability. Therefore, the development of novel, safe and effective new c-Met kinase inhibitors is still a key area of ​​anti-tumor drug research at home and abroad. Summary of the invention

[0004] The purpose of the present invention is to design and synthesize a series of novel 7-methoxy-4-phenoxyquinoline-6-carboxamide compounds. In vitro activity screening shows that the compounds have anti-tumor activity.

[0005] The present invention provides a novel 7-methoxy-4-phenoxyquinoline-6-carboxamide compound represented by general formula (I) and a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.

[0006]

[0007] in:

[0008] R1 is selected from hydrogen, C1-C 10 Alkyl, C3-C7 cycloalkyl or C1-C4 alkoxy;

[0009] X is selected from 1-4 identical or different substituents of the following: hydrogen, halogen, C1-C6 alkyl, or C1-C4 alkoxy;

[0010] Ar is selected from C6-C 10 Aryl or 5-10 membered heteroaryl; wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Ar is substituted by 1-3 identical or different R2;

[0011] R2 is selected from hydrogen, halogen, hydroxyl, nitro, ester, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkyl substituted by hydroxyl, amino or halogenated, C1-C6 alkoxy substituted by hydroxyl, amino or halogenated, and amino substituted by mono- or di-C1-C6 alkyl.

[0012] Furthermore, the above-mentioned novel 7-methoxy-4-phenoxyquinoline-6-carboxamide compound and its pharmaceutically acceptable salt, hydrate, solvate or prodrug, wherein:

[0013] R1 is selected from hydrogen, C1-C 10 Alkyl, C3-C7 cycloalkyl, or halogenated C1-C4 alkyl;

[0014] X is selected from 1 to 4 identical or different substituents of the following: hydrogen or halogen;

[0015] Ar is selected from phenyl, naphthyl, or 5-10 membered heteroaryl; wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Ar is substituted by 1-3 identical or different R2;

[0016] R2 is selected from hydrogen, halogen, hydroxyl, nitro, ester, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfonyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy and amino substituted by mono- or di-C1-C6 alkyl.

[0017] Furthermore, the above-mentioned novel 7-methoxy-4-phenoxyquinoline-6-carboxamide compound and its pharmaceutically acceptable salt, hydrate, solvate or prodrug, wherein:

[0018] R1 is selected from hydrogen, methyl, ethyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

[0019] X is selected from 1-2 identical or different substituents of the following: hydrogen, fluorine, or chlorine;

[0020] Ar is selected from phenyl or 5-6 membered heteroaryl; wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Ar is substituted by 1-3 identical or different R2;

[0021] R2 is selected from hydrogen, halogen, hydroxy, nitro, amino, cyano, methyl, C1-C6 alkoxy, trifluoromethyl, trifluoromethoxy, C1-C6 alkylsulfonyl and amino substituted by mono- or di-C1-C6 alkyl.

[0022] Furthermore, the above-mentioned novel 7-methoxy-4-phenoxyquinoline-6-carboxamide compound and its pharmaceutically acceptable salt, hydrate, solvate or prodrug, wherein:

[0023] R1 is selected from hydrogen, methyl, ethyl, or cyclopropyl;

[0024] X is selected from 1-2 identical or different substituents of the following: hydrogen, or fluorine;

[0025] Ar is phenyl, and Ar is substituted by 1-3 identical or different R2;

[0026] R2 is selected from hydrogen, halogen, hydroxy, methoxy, nitro, trifluoromethyl, trifluoromethoxy, methanesulfonyl or dimethylamino.

[0027] Furthermore, the above-mentioned novel 7-methoxy-4-phenoxyquinoline-6-carboxamide compound and its pharmaceutically acceptable salt, hydrate, solvate or prodrug have the following structural formula, but these compounds do not imply any limitation to the present invention:

[0028]

[0029]

[0030] A pharmaceutical composition comprises the above-mentioned novel 7-methoxy-4-phenoxyquinoline-6-carboxamide compound and its pharmaceutically acceptable salt, hydrate, solvate or prodrug as an active ingredient and a pharmaceutically acceptable excipient.

[0031] Use of any one of the above-mentioned novel 7-methoxy-4-phenoxyquinoline-6-carboxamide compounds and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof or the above-mentioned pharmaceutical composition in the preparation of drugs for treating and / or preventing diseases caused by abnormally high expression of c-Met kinase.

[0032] Use of any one of the above-mentioned novel 7-methoxy-4-phenoxyquinoline-6-carboxamide compounds and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof as well as the above-mentioned pharmaceutical compositions in the preparation of drugs for treating and / or preventing proliferative diseases.

[0033] Use of any one of the above-mentioned novel 7-methoxy-4-phenoxyquinoline-6-carboxamide compounds and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof as well as the above-mentioned pharmaceutical compositions in the preparation of drugs for treating and / or preventing cancer.

[0034] Furthermore, any one of the above-mentioned novel 7-methoxy-4-phenoxyquinoline-6-carboxamide compounds and their pharmaceutically acceptable salts, hydrates, solvates or prodrugs or the above-mentioned pharmaceutical compositions are used in the preparation of drugs for treating and / or preventing gastric cancer, lung cancer and prostate cancer.

[0035] Moreover, according to some common methods in the field to which the present invention belongs, the novel 7-methoxy-4-phenoxyquinoline-6-carboxamide compounds and configurational isomers shown in the general formula (I) of the present invention can form pharmaceutically acceptable salts with acids. Pharmaceutically acceptable addition salts include inorganic acid and organic acid addition salts, and salts with the following acids are 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.

[0036] In addition, the present invention also includes prodrugs of the derivatives of the present invention. Prodrugs of the derivatives of the present invention are derivatives of general formula I, which may have weak activity or even no activity themselves, but after administration, they are converted into the corresponding biologically active form under physiological conditions (e.g., by metabolism, solvolysis or other means).

[0037] In the present invention, "halogen" refers to fluorine, chlorine, bromine or iodine; "alkyl" refers to a straight-chain or branched alkyl; "alkylene" refers to a straight-chain or branched alkylene; "cycloalkyl" refers to a substituted or unsubstituted cycloalkyl; "aryl" refers to a phenyl group with no substituent or with a substituent; "heteroaryl" refers to a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, and S, and the ring system is aromatic, such as imidazolyl, pyridyl, pyrazolyl, (1,2 ,3)- and (1,2,4)-triazolyl, furanyl, thienyl, pyrrolyl, thiazolyl, benzothiazolyl, oxazolyl, isoxazolyl, naphthyl, quinolyl, isoquinolyl, benzimidazolyl and benzoxazolyl, etc.; "saturated or partially saturated heterocyclic group" refers to a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, S, such as pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, pyrazolidinyl, imidazolidinyl and thiazolinyl, etc.

[0038] The beneficial effects of the present invention are:

[0039] 1. Through in vitro inhibition of the activity of human gastric cancer cells MKN-45 and AGS, human lung adenocarcinoma cell line A549 and human prostate cancer cell line PC-3, the compounds of the present invention have a significant inhibitory effect on the above tumor cells, and are particularly useful for preparing drugs for the treatment and / or prevention of gastric cancer, lung cancer and prostate cancer.

[0040] 2. Through the c-Met kinase test, it was found that the compounds of the present invention have significant inhibitory c-Met kinase activity, and are particularly useful for preparing drugs for treating and / or preventing diseases caused by abnormally high expression of c-Met kinase, and in particular for preparing drugs for treating and / or preventing cancer.

[0041] 3. A novel 7-methoxy-4-phenoxyquinoline-6-carboxamide compound of the present invention has a novel chemical structure, and most of the compounds have significant inhibitory activity on c-Met kinase in in vitro biological activity studies and have strong anti-proliferative activity on the tested cells. The compound can be used for the treatment and prevention of cancer. DETAILED DESCRIPTION

[0042] The examples and preparation examples provided below further illustrate and illustrate the compounds of the present invention and their preparation methods. It should be understood that the scope of the following examples and preparation examples does not limit the scope of the present invention in any way. The following examples are intended to illustrate but not to limit the scope of the present invention. The nuclear magnetic resonance hydrogen spectrum of the compound was measured by Bruker ARX-600, and the mass spectrum was measured by Agilent6460QQQ; all reagents used were analytically pure or chemically pure.

[0043] The following synthetic routes describe the preparation of compounds of formula (I) of the present invention, all of which are prepared by the following synthetic routes, by methods well known to those of ordinary skill in the field of organic chemistry, or are commercially available. All final derivatives of the present invention are prepared by the following synthetic routes or by methods similar thereto, which are well known to those of ordinary skill in the field of organic chemistry. All variable factors used in the following synthetic routes are as defined below or as defined in the claims.

[0044]

[0045] Example 1: Preparation of Compound 1

[0046]

[0047] Step A: Synthesis of 4-(3-chloro-4-nitrophenoxy)-7-methoxyquinoline-6-carboxamide

[0048] 4-Chloro-7-methoxyquinoline-6-carboxamide (20 g, 84.51 mmol) and 3-chloro-4-nitrophenol (18.2 g, 126.77 mmol) were added to 100 mL of chlorobenzene and reacted at 140°C for 30 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in an appropriate amount of dichloromethane and washed three times with K2CO3 solution and saturated brine, respectively. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to obtain a brown solid. Column chromatography was performed to obtain 19.80 g of a light yellow solid product, 4-(3-chloro-4-nitrophenoxy)-7-methoxyquinoline-6-carboxamide. MS (ESI) m / z: 374.10 [M+H] + .

[0049] Step B: Synthesis of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide

[0050] 4-(3-chloro-4-nitrophenoxy)-7-methoxyquinoline-6-carboxamide (19 g, 50.84 mmol), iron powder (17.03 g, 305.02 mmol), acetic acid (45.80 g, 762.67 mmol) were added to 200 mL of ethanol, and then 20 mL of water was added. The mixture was heated under reflux for 12 h. After the reaction was completed, the mixture was filtered while hot, and the filtrate was evaporated under reduced pressure to remove the solvent to obtain a crude product. The crude product was subjected to column chromatography to obtain 9.90 g of a light yellow solid product, 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide. MS (ESI) m / z: 344.10 [M+H] + .

[0051] Step C: Synthesis of phenyl (4-((6-carbamoyl-7-methoxyquinolin-4-yl)oxy)-2-chlorophenyl)carbamate

[0052] 4-(4-Amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (8 g, 23.27 mmol) and triethylamine (7.10 g, 70.16 mmol) were added to 60 mL of dry THF, and a solution of phenyl chloroformate (4.40 g, 28.10 mmol) in 20 mL of dry THF was added dropwise at 0°C-5°C. After the addition was completed, the mixture was reacted at room temperature for 3 h, and the solvent was evaporated under reduced pressure. The residue was dissolved in 60 mL of dichloromethane, washed 4 times with appropriate amount of water, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain 7.60 g of a pale yellow solid crude product (phenyl 4-((6-carbamoyl-7-methoxyquinolin-4-yl)oxy)-2-chlorophenyl)carbamate, which was directly used in the next step reaction.

[0053] Step D: Synthesis of 4-(3-chloro-4-(hydrazinocarboxamido)phenoxy)-7-methoxyquinoline-6-carboxamide

[0054] Dissolve (4-((6-carbamoyl-7-methoxyquinolin-4-yl)oxy)-2-chlorophenyl)carbamic acid phenyl ester (7.5 g, 16.17 mmol) in 50 mL of 1,4-dioxane, slowly add 20 mL of 80% hydrazine hydrate, reflux and react overnight. After the reaction is completed, cool to below 10°C, filter out the precipitate, wash with water, and vacuum dry to obtain 4.60 g of light yellow solid 4-(3-chloro-4-(hydrazinocarboxamido)phenoxy)-7-methoxyquinoline-6-carboxamide. 1 H NMR(600MHz,DMSO-d6)δ9.19(s,1H),8.82–8.61(m,2H),8.43(s,1H),7.97(s,1H),7.86(s,1H),7.74(s ,1H),7.62–7.45(m,2H),7.28(dd,J=9.0,2.7Hz,1H),6.55(d,J=5.2Hz,1H),4.74(s,2H),4.04(s,3H).

[0055] Step E: Preparation of Compound 1

[0056] 4-(3-chloro-4-(hydrazinocarboxamido)phenoxy)-7-methoxyquinoline-6-carboxamide (0.20 g, 0.50 mmol) and 4-fluorobenzaldehyde (75 mg, 0.60 mmol) were added to 5 mL of ethanol, and an appropriate amount of glacial acetic acid was added. The mixture was refluxed for 5-8 hours. After the reaction was completed, the mixture was cooled to room temperature, the precipitate was filtered out, and dried to obtain 0.15 g of Example 1 compound (Compound 1) as a white solid. 1HNMR(600MHz,DMSO-d6)δ11.18(s,1H),8.98(s,1H),8.70(s,2H),8.26(d,J=8.6Hz,1H),8.02(s,1H),7 .90(s,1H),7.86–7.72(m,3H),7.64(s,1H),7.54(s,1H),7.42–7.25(m,3H),6.58(s,1H),4.05(s,3H).

[0057] Example 2: Preparation of Compound 2

[0058]

[0059] The 4-fluorobenzaldehyde in step E of Example 1 was replaced by 4-chlorobenzaldehyde, and the remaining steps were the same as those of Example 1 to obtain compound 2. 1 H NMR (600MHz, DMSO-d6) δ11.15(s,1H),8.91(s,1H),8.63(d,J=10.0Hz,2H),8.16(d,J=8.5Hz,1H),7.94(s,1H),7.82(s,1 H),7.71(s,3H),7.57(s,1H),7.47(s,3H),7.28(d,J=8.4Hz,1H),6.51(s,1H),3.98(s,3H); MS(ESI)m / z(%):524.1[M+H] + .

[0060] Example 3: Preparation of Compound 3

[0061]

[0062] The 4-fluorobenzaldehyde in step E of Example 1 was replaced by 4-dimethylaminobenzaldehyde, and the remaining steps were the same as those of Example 1 to obtain compound 3. 1 H NMR (600MHz, DMSO-d6) δ10.90(s,1H),8.99(s,1H),8.70(s,2H),8.39(d,J=8.7Hz,1H),7.89(s,2H),7.79(s,1H),7.63(s,1H),7 .60–7.46(m,3H),7.34(d,J=8.7Hz,1H),6.77(d,J=7.9Hz,2H),6.58(s,1H),4.05(s,3H),2.97(s,6H);MS(ESI)m / z:533.2[M+H] + .

[0063] Example 4: Preparation of Compound 4

[0064]

[0065] The 4-fluorobenzaldehyde in step E of Example 1 was replaced by 3,4-difluorobenzaldehyde, and the remaining steps were the same as those of Example 1 to obtain compound 4. 1 H NMR(600MHz,DMSO-d6)δ11.22(s,1H),9.01(s,1H),8.71(s,1H),8.68(s,1H),8.10(d,J=8.0Hz,1H),8.02– 7.72(m,4H),7.70–7.46(m,4H),7.35(d,J=8.6Hz,1H),6.57(s,1H),4.04(s,3H); MS(ESI)m / z:526.1[M+H] + .

[0066] Example 5: Preparation of Compound 5

[0067]

[0068] The 4-fluorobenzaldehyde in step E of Example 1 was replaced by 2-chloro-4-fluorobenzaldehyde, and the remaining steps were the same as those of Example 1 to obtain compound 5. 1 H NMR (600MHz, DMSO-d6) δ11.32(s,1H),8.98(s,1H),8.81–8.58(m,2H),8.34(s,1H),8.18(d,J=6.6Hz,2H) ,7.88(s,1H),7.77(s,1H),7.63(s,1H),7.59–7.47(m,2H),7.44–7.27(m,2H),6.58(s,1H),4.05(s,3H).

[0069] Example 6: Preparation of Compound 6

[0070]

[0071] The 4-fluorobenzaldehyde in step E of example 1 was replaced by 4-bromobenzaldehyde, and the remaining steps were the same as those of example 1 to obtain compound 6. 1 H NMR (600MHz, DMSO-d6) δ11.22(s,1H),8.98(s,1H),8.69(s,2H),8.23(d,J=8.3Hz,1H),7.99(s,1 H),7.88(s,1H),7.82–7.60(m,6H),7.54(s,1H),7.35(d,J=7.8Hz,1H),6.58(s,1H),4.05(s,3H).

[0072] Example 7: Preparation of Compound 7

[0073]

[0074] The 4-fluorobenzaldehyde in step E of Example 1 was replaced by 3,4,5-trimethoxybenzaldehyde, and the remaining steps were the same as those of Example 1 to obtain compound 7. 1 H NMR (600MHz, DMSO-d6) δ11.24(s,1H),9.07(s,1H),8.70(s,2H),8.33(d,J=8.3Hz,1H),7.94(s,1H),7.88(s,1H),7.78(s,1H),7.65( s,1H),7.54(s,1H),7.36(d,J=8.7Hz,1H),7.09(s,2H),6.57(s,1H),4.05(s,3H),3.84(s,6H),3.71(s,3H); MS(ESI)m / z:580.1[M+H] + .

[0075] Example 8: Preparation of Compound 8

[0076]

[0077] The 4-fluorobenzaldehyde in step E of Example 1 was replaced by 4-trifluoromethoxybenzaldehyde, and the remaining steps were the same as those of Example 1 to obtain compound 8. 1 H NMR (600MHz, DMSO-d6) δ11.35(s,1H),9.02(s,1H),8.70(d,J=5.4Hz,2H),8.22(d,J=8.6Hz,1H),8.09(s,1H),7.99(d,J =7.2Hz,2H),7.89(s,1H),7.85–7.73(m,3H),7.65(s,1H),7.54(s,1H),7.36(d,J=8.6Hz,1H),6.59(s,1H),4.05(s,3H).

[0078] Example 9: Preparation of Compound 9

[0079]

[0080] The 4-fluorobenzaldehyde in step E of example 1 was replaced by 3-hydroxy-4-methoxybenzaldehyde, and the remaining steps were the same as those of example 1 to obtain compound 9. 1H NMR (600MHz, DMSO-d6) δ11.00(s,1H),9.35(s,1H),8.97(s,1H),8.69(s,2H),8.38(d,J=7.7Hz,1H),7.88(s,2H),7.77(s,1H),7.65(s,1H), 7.54(s,1H),7.35(d,J=7.3Hz,1H),7.24(s,1H),7.06(s,1H),6.99(s,1H),6.59(s,1H),4.05(s,3H),3.81(s,3H);MS(ESI)m / z:536.1[M+H] + .

[0081] Example 10: Preparation of Compound 10

[0082]

[0083] The 4-fluorobenzaldehyde in step E of example 1 was replaced by 3-hydroxy-4-methoxybenzaldehyde, and the remaining steps were the same as those of example 1 to obtain compound 10. 1 H NMR (600MHz, DMSO-d6) δ11.09(s,1H),9.05(s,1H),8.70(s,2H),8.34(d,J=8. 7Hz,1H),7.94(s,1H),7.89(s,1H),7.78(s,1H),7.64(s,1H),7.54(s,1H),7. 42(s,1H),7.35(d,J=8.4Hz,1H),7.20(d,J=7.5Hz,1H),7.03(d,J=7.9Hz,1H) ,6.57(s,1H),4.05(s,3H),3.82(s,3H),3.81(s,3H); MS(ESI)m / z:550.2[M+H] + .

[0084] Example 11: Preparation of Compound 11

[0085]

[0086] The 4-fluorobenzaldehyde in step E of example 1 was replaced by 2,3-dichlorobenzaldehyde, and the remaining steps were the same as those of example 1 to obtain compound 11. 1H NMR (600MHz, DMSO-d6) δ11.40(s,1H),8.98(s,1H),8.83–8.62(m,2H),8.41(s,1H),8.18(d,J=8.8Hz,1H),8.09(d,J=7.8Hz,1H),7.86(s,1H), 7.75(s,1H),7.69(d,J=7.7Hz,1H),7.62(s,1H),7.54(s,1H),7.47(t,J =7.9Hz,1H),7.35(d,J=7.8Hz,1H),6.59(d,J=5.0Hz,1H),4.05(s,3H).

[0087] Example 12: Preparation of Compound 12

[0088]

[0089] The 4-fluorobenzaldehyde in step E of example 1 was replaced by 4-methylsulfonylbenzaldehyde, and the remaining steps were the same as in example 1 to obtain compound 12. 1 H NMR (600MHz, DMSO-d6) δ11.37(s,1H),9.03(s,1H),8.84–8.58(m,2H),8.20(d,J=8.9Hz,1H),8.10(s,1H),8.06–7.96(m,4H),7.87(s ,1H),7.75(s,1H),7.64(d,J=2.5Hz,1H),7.54(s,1H),7.35(dd,J=8.9,2.4Hz,1H),6.59(d,J=5.2Hz,1H),4.05(s,3H),3.26(s,3H).

[0090] Example 13: Preparation of Compound 13

[0091]

[0092] The 4-fluorobenzaldehyde in step E of Example 1 was replaced by 2,4-dihydroxybenzaldehyde, and the remaining steps were the same as those of Example 1 to obtain compound 13. 1H NMR(600MHz,DMSO-d6)δ10.83(s,1H),9.97(s,1H),9.78(s,1H),8.89(s,1H),8.78–8.56(m,2H),8.34(d,J=9.0Hz,1H),8.22(s,1H),7.87(s,1H) ,7.75(s,1H),7.67–7.45(m,3H),7.33(dd,J=9.0,2.7Hz,1H),6.58(d,J= 5.2Hz,1H),6.43–6.24(m,2H),4.05(s,3H); MS(ESI)m / z(%):522.1[M+H] + .

[0093] Example 14: Preparation of Compound 14

[0094]

[0095] The 4-fluorobenzaldehyde in step E of example 1 was replaced by 2-chloro-5-nitrobenzaldehyde, and the remaining steps were the same as those of example 1 to obtain compound 14. 1 H NMR (600MHz, DMSO-d6) δ11.53(s,1H),9.16(s,1H),8.87(s,1H),8.69(dd,J=11.7,6.9Hz,2H),8.38(s,1H),8.20(d,J=8.9Hz,2 H),7.92–7.80(m,2H),7.75(s,1H),7.66(s,1H),7.53(s,1H),7.36(dd,J=8.8,2.1Hz,1H),6.59(d,J=5.1Hz,1H),4.05(s,3H).

[0096] Example 15: Preparation of Compound 15

[0097]

[0098] The 4-fluorobenzaldehyde in step E of Example 1 was replaced by 4-nitrobenzaldehyde, and the remaining steps were the same as in Example 1 to obtain compound 15. MS (ESI) m / z: 535.2 [M+H] + .

[0099] Example 16: Preparation of Compound 16

[0100]

[0101] The 3-chloro-4-nitrophenol in step A of Example 1 was replaced by 4-nitrophenol, and the 4-fluorobenzaldehyde in step E of Example 1 was replaced by benzaldehyde. The remaining steps were the same as in Example 1 to obtain compound 16. MS (ESI) m / z: 456.2 [M+H] + .

[0102] Example 17: Preparation of Compound 17

[0103]

[0104] The 3-chloro-4-nitrophenol in step A of Example 1 was replaced by 4-nitrophenol, and the remaining steps were the same as in Example 1 to obtain compound 17. MS (ESI) m / z: 474.2 [M+H] + .

[0105] Example 18: Preparation of Compound 18

[0106]

[0107] The 3-chloro-4-nitrophenol in step A of Example 1 was replaced by 4-nitrophenol, and the 4-fluorobenzaldehyde in step E of Example 1 was replaced by 4-methoxybenzaldehyde. The remaining steps were the same as in Example 1 to obtain compound 18. MS (ESI) m / z: 486.2 [M+H] + .

[0108] Example 19: Preparation of Compound 19

[0109]

[0110] The 3-chloro-4-nitrophenol in step A of Example 1 was replaced by 4-nitrophenol, and the 4-fluorobenzaldehyde in step E of Example 1 was replaced by 4-hydroxybenzaldehyde. The remaining steps were the same as in Example 1 to obtain compound 19. MS (ESI) m / z: 472.2 [M+H] + .

[0111] Example 20: Preparation of Compound 20

[0112]

[0113] The 3-chloro-4-nitrophenol in step A of Example 1 was replaced by 2-fluoro-4-nitrophenol, and the remaining steps were the same as in Example 1 to obtain compound 20. MS (ESI) m / z: 491.1 [M+H] + .

[0114] Example 21: Preparation of Compound 21

[0115]

[0116] The 3-chloro-4-nitrophenol in step A of Example 1 was replaced by 2-fluoro-4-nitrophenol, and the 4-fluorobenzaldehyde in step E of Example 1 was replaced by 4-methoxybenzaldehyde. The remaining steps were the same as in Example 1 to obtain compound 21. MS (ESI) m / z: 503.2 [M+H] + .

[0117] Example 22: Preparation of Compound 22

[0118]

[0119] The 3-chloro-4-nitrophenol in step A of Example 1 was replaced by 2-fluoro-4-nitrophenol, and the 4-fluorobenzaldehyde in step E of Example 1 was replaced by 4-hydroxybenzaldehyde. The remaining steps were the same as in Example 1 to obtain compound 22. MS (ESI) m / z: 490.1 [M+H] + .

[0120] Example 23: Preparation of Compound 23

[0121]

[0122] The 3-chloro-4-nitrophenol in step A of Example 1 was replaced with 2-fluoro-4-nitrophenol, and the 4-fluorobenzaldehyde in step E of Example 1 was replaced with 4-methylsulfonylbenzaldehyde. The remaining steps were the same as in Example 1 to obtain compound 23. MS (ESI) m / z: 552.1 [M+H] + .

[0123] Example 24: Preparation of Compound 24

[0124]

[0125] The 3-chloro-4-nitrophenol in step A of Example 1 was replaced with 2-fluoro-4-nitrophenol, and the 4-fluorobenzaldehyde in step E of Example 1 was replaced with 3-hydroxy-4-methoxybenzaldehyde. The remaining steps were the same as those in Example 1 to obtain compound 24. MS (ESI) m / z: 520.2 [M+H] + .

[0126] Embodiment 25

[0127] In vitro anti-tumor cell activity

[0128] Compounds 1-24 were subjected to in vitro inhibitory activity tests on human gastric cancer cells MKN-4, human lung adenocarcinoma cell line A549 and human prostate cancer cells PC-3 and c-Met kinase activity screening.

[0129] In vitro tumor cell inhibition activity test

[0130] (1) After the cells have recovered and been passaged 2-3 times to stabilize, use trypsin solution (0.25%) to digest them from the bottom of the culture bottle. Pour the cell digestion solution into a centrifuge tube, and then add culture medium to terminate the digestion. Centrifuge the centrifuge tube at 800r / min for 10min, discard the supernatant and add 5mL culture medium. Mix the cells by blowing, and take 10μL of the cell suspension and add it to the cell counting plate for counting. Adjust the cell concentration to 10 4 100 μL of cell suspension was added to all wells except well A1 which was a blank well without cells. The 96-well plate was placed in an incubator and cultured for 24 h.

[0131] (2) Dissolve the test sample in 50 μL of dimethyl sulfoxide, then add an appropriate amount of culture medium to dissolve the sample into a 2 mg / mL solution. Then dilute the sample to 50, 10, 2, 0.4, and 0.08 μg / mL in a 24-well plate.

[0132] Each concentration was added to 3 wells, of which the growth of cells in the two rows and two columns around was greatly affected by the environment, and only the blank cell wells were used. The 96-well plate was placed in an incubator and cultured for 72 hours.

[0133] (3) The drug-containing culture medium in the 96-well plate was discarded, and the cells were rinsed twice with phosphate buffer solution (PBS). 100 μL of MTT (tetrazolium) (0.5 mg / mL) was added to each well and placed in the incubator for 4 hours. The MTT solution was discarded and 100 μL of dimethyl sulfoxide was added. The surviving cells were shaken on a magnetic oscillator to fully dissolve the formazan reaction product of MTT, and the result was measured in an ELISA instrument. The IC value of the drug can be calculated by the Bliss method. 50 The results of the inhibition of the activity of the compounds in the examples on human gastric cancer cell line MKN-45, human lung adenocarcinoma cell line A549 and human prostate cancer cell line PC-3 are shown in Table 2.

[0134] In vitro inhibition of c-Met enzyme activity test

[0135] The assay used to measure c-Met kinase activity is based on an enzyme-linked immunosorbent assay (ELISA). The specific procedure is:

[0136] Example compounds, 50 pM c-Met (His-tagged recombinant human Met (amino acid 974-terminal), expressed by baculovirus) and 5 μM ATP were incubated in assay buffer (25 mM MOPS, pH 7.4, 5 mM MgCl2, 0.5 mM MnCl2, 100 μM sodium orthovanadate, 0.01% Triton X-100, 1 mM DTT, final DMSO concentration 1% (v / v)) on 0.25 mg / mL PGT-coated plates at room temperature for 20 minutes. The reaction mixture was removed by washing and the phosphorylated polymer substrate was detected with 0.2 μg / mL phosphotyrosine-specific monoclonal antibody (PY20) conjugated to horseradish peroxidase (HRP). After the color development was stopped by the addition of 1 M phosphoric acid, the color of the developed substrate (TMB) was quantified by spectrophotometry at 450 nm. The inhibition data of the example compounds on c-Met kinase are shown in Table 2.

[0137] The results of c-Met kinase activity in human gastric cancer cell line MKN-45, human lung adenocarcinoma cell line A549, and human prostate cancer cell line PC-3 are shown in Table 2. The IC 50 ≦1μM, expressed as A, 1.0μM﹤IC 50 ≦10.0μM, represented by B, 10.0μM﹤IC 50 ≦100.0μM, indicated by C, ND indicates not tested

[0138] Table 2 Compounds inhibit the activity of three tumor cell lines MKN-45, A549 and PC-3 and c-Met kinase

[0139]

[0140]

[0141] It can be clearly seen from the test results in Table 2 that the novel 7-methoxy-4-phenoxyquinoline-6-carboxamide compounds of the general formula (I) to be protected by the present invention have good in vitro anti-tumor activity against tumor cell lines and c-Met kinase in vitro. This type of compound has a good prospect for the development and application of anti-tumor drugs.

[0142] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of equivalent transformations. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations. Any modification, equivalent replacement or improvement made within the technical concept of the present invention is included in the protection scope of the present invention.

Claims

1. A novel 7-methoxy-4-phenoxyquinoline-6-carboxamide compound, characterized in that: The structure is shown in formula (I), in: R1 is selected from hydrogen, C1-C 10 Alkyl, C3-C7 cycloalkyl or C1-C4 alkoxy; X is selected from 1-4 identical or different substituents of the following: hydrogen, halogen, C1-C6 alkyl, or C1-C4 alkoxy; Ar is selected from C6-C 10 Aryl or 5-10 membered heteroaryl; wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Ar is substituted by 1-3 identical or different R2; R2 is selected from hydrogen, halogen, hydroxyl, nitro, ester, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkyl substituted by hydroxyl, amino or halogenated, C1-C6 alkoxy substituted by hydroxyl, amino or halogenated, and amino substituted by mono- or di-C1-C6 alkyl.

2. A novel 7-methoxy-4-phenoxyquinoline-6-carboxamide compound according to claim 1, characterized in that: R1 is selected from hydrogen, C1-C 10 Alkyl, C3-C7 cycloalkyl, or halogenated C1-C4 alkyl; X is selected from 1 to 4 identical or different substituents of the following: hydrogen or halogen; Ar is selected from phenyl, naphthyl, or 5-10 membered heteroaryl; wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Ar is substituted by 1-3 identical or different R2; R2 is selected from hydrogen, halogen, hydroxyl, nitro, ester, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfonyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy and amino substituted by mono- or di-C1-C6 alkyl.

3. A novel 7-methoxy-4-phenoxyquinoline-6-carboxamide compound according to claim 2, characterized in that: R1 is selected from hydrogen, methyl, ethyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; X is selected from 1-2 identical or different substituents of the following: hydrogen, fluorine or chlorine; Ar is selected from phenyl or 5-6 membered heteroaryl; wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Ar is substituted by 1-3 identical or different R2; R2 is selected from hydrogen, halogen, hydroxy, nitro, amino, cyano, methyl, C1-C6 alkoxy, trifluoromethyl, trifluoromethoxy, C1-C6 alkylsulfonyl and amino substituted by mono- or di-C1-C6 alkyl.

4. A novel 7-methoxy-4-phenoxyquinoline-6-carboxamide compound according to claim 3, characterized in that: R1 is selected from hydrogen, methyl, ethyl, or cyclopropyl; X is selected from 1-2 identical or different substituents of the following: hydrogen or fluorine; Ar is phenyl, and Ar is substituted by 1-3 identical or different R2; R2 is selected from hydrogen, halogen, hydroxy, methoxy, nitro, trifluoromethyl, trifluoromethoxy, methanesulfonyl or dimethylamino.

5. A novel 7-methoxy-4-phenoxyquinoline-6-carboxamide compound according to claim 1, characterized in that: It has the following structural formula:

6. A pharmaceutical composition, characterized in that The invention comprises a novel 7-methoxy-4-phenoxyquinoline-6-carboxamide compound as claimed in any one of claims 1 to 5 and a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof as an active ingredient and a pharmaceutically acceptable excipient.

7. Use of a novel 7-methoxy-4-phenoxyquinoline-6-carboxamide compound according to any one of claims 1 to 5 or a pharmaceutical composition according to claim 6 in the preparation of a drug for treating a disease caused by abnormally high expression of c-Met kinase.

8. Use of a novel 7-methoxy-4-phenoxyquinoline-6-carboxamide compound according to any one of claims 1 to 5 or a pharmaceutical composition according to claim 6 in the preparation of a drug for treating and / or preventing a proliferative disease.

9. Use of a novel 7-methoxy-4-phenoxyquinoline-6-carboxamide compound according to any one of claims 1 to 5 or a pharmaceutical composition according to claim 6 in the preparation of a drug for treating and / or preventing cancer.

10. Use of a novel 7-methoxy-4-phenoxyquinoline-6-carboxamide compound according to any one of claims 1 to 5 or a pharmaceutical composition according to claim 6 in the preparation of a drug for treating and / or preventing gastric cancer, lung cancer and prostate cancer.

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