A novel 7-methoxy-4-phenoxy quinoline-6-carboxamide compound and application thereof

Abstract

The application belongs to the field of medicine, and particularly relates to a novel 7-methoxy-4-phenoxy quinoline-6-carboxamide compound and application thereof. The novel 7-methoxy-4-phenoxy quinoline-6-carboxamide compound provided by the application has a structure of general formula (I), has a strong inhibitory effect on c-Met kinase, and provides a use of a novel 7-methoxy-4-phenoxy quinoline-6-carboxamide compound and a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof in preparing a drug for treating and / or preventing a disease caused by abnormally high expression of c-Met kinase, in particular, in preparing a drug for treating and / or preventing cancer. The compound of the application is particularly suitable for preparing a drug for treating and / or preventing gastric cancer, lung cancer and prostate cancer.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical technology, and in particular to a novel 7-methoxy-4-phenoxyquinoline-6-carboxamide compound. BACKGROUND

[0002] Cancer, also known as malignant tumor, is caused by cell malignant proliferation, and has invasiveness and metastasis. Cancer is a genetic abnormality disease caused by long-term joint action of various factors. When the body is affected by chemical, physical, viral and other carcinogens in the environment, and / or due to the action of its own genetic, endocrine, gender, age and other factors, a series of genetic abnormalities can occur, and malignant tumor can be formed. 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 after cardiovascular and cerebrovascular diseases in terms of incidence rate, and its mortality rate even exceeds that of cardiovascular and cerebrovascular diseases, ranking first among all diseases, so the research of antitumor drugs has great significance.

[0003] In recent years, with the development of molecular biology technology, the molecular targeted therapy of malignant tumor has been paid more and more attention. Compared with the traditional tumor treatment method, the molecular targeted therapy can achieve the advantages of targeting and positioning, reduce the dosage of drugs, reduce the toxic side effects, and improve the curative effect, and has become the hotspot of modern anticancer drugs. Studies have found that the overexpression of receptor tyrosine kinase (RTKs) in tumor cells is closely related to the occurrence, development and metastasis of various malignant tumors, and inhibiting the activity of RTKs can effectively inhibit tumors. c-Met is a prototype member of the Ron subfamily of tyrosine kinase receptors, and it is the only known high-affinity receptor for hepatocyte growth factor (HGF). Under normal physiological conditions, after HGF binds to c-Met kinase, a series of biological effects can be caused, such as promoting the separation of epithelial cells, promoting mitosis of placenta, regulating the development and structure formation of lung, kidney and breast, 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 various tumor tissues, such as lung cancer, gastric cancer, breast cancer, colon cancer, prostate cancer, pancreatic cancer, ovarian cancer, etc. The receptor tyrosine kinase c-Met is highly expressed and abnormally activated in most cancers. Inhibiting c-Met kinase can achieve inhibition of 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 drug chemistry research, and are widely studied in c-Met kinase inhibitors. Cabozantinib with 4-phenoxyquinoline mother nucleus is the first approved small molecule c-Met kinase inhibitor, and has strong inhibitory effect on VEGFR-2, c-Kit and Flt-3 kinases. The analog Foretinib of Cabozantinib has entered the phase III clinical research stage, and clinical studies have shown that it has a significant inhibitory effect on the proliferation of various human tumor cell lines. Another 4-phenoxyquinoline compound Pamufetinib (TAS-115) is currently in the phase III clinical stage, and is a compound capable of inhibiting c-Met and VEGFR-2, which has significant anti-tumor activity and good tolerability. At present, the main problems existing in the research of c-Met inhibitors are as follows: the clinical application has large toxic side effects, the clinical treatment effect and pharmacokinetic parameters are not ideal, and the oral bioavailability is low. Therefore, the development of new c-Met kinase inhibitors with novel structure, safety and effectiveness is still the focus of the research field of anti-tumor drugs at home and abroad. SUMMARY

[0004] The purpose of the present application is to design and synthesize a series of new 7-methoxy-4-phenoxyquinoline-6-carboxamide compounds. Through in vitro activity screening, it is shown that the compounds have anti-tumor activity.

[0005] This invention provides a novel 7-methoxy-4-phenoxyquinoline-6-carboxamide compound having the general formula (I) and its pharmaceutically acceptable salt, hydrate, solvate, or prodrug.

[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 to 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 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 atoms;

[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 with hydroxyl or amino or halogenated, C1-C6 alkoxy substituted with hydroxyl or amino or halogenated, and amino substituted with mono- or bis-C1-C6 alkyl.

[0012] Furthermore, the aforementioned 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 1 to 4 or fewer: hydrogen or halogen;

[0015] Ar is selected from phenyl, naphthyl, or 5-10 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 atoms;

[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 groups substituted with mono- or bis-C1-C6 alkyl groups.

[0017] Further, the novel 7-methoxy-4-phenoxyquinoline-6-carboxamide compound and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof described above, wherein,

[0018] R1is selected from hydrogen, methyl, ethyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

[0019] X is selected from 1-2 same or different substituents of 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 with 1-3 same or different R2;

[0021] R2is selected from hydrogen, halogen, hydroxyl, nitro, amino, cyano, methyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, C1-C6alkylsulfonyl and amino substituted with mono or di C1-C6alkyl.

[0022] Further, the novel 7-methoxy-4-phenoxyquinoline-6-carboxamide compound and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof described above, wherein,

[0023] R1is selected from hydrogen, methyl, ethyl, or cyclopropyl;

[0024] X is selected from 1-2 same or different substituents of hydrogen, or fluorine;

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

[0026] R2is selected from hydrogen, halogen, hydroxyl, methoxy, nitro, trifluoromethyl, trifluoromethoxy, methylsulfonyl or dimethylamino.

[0027] Further, the novel 7-methoxy-4-phenoxyquinoline-6-carboxamide compound and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof described above, have the following structural formula, but these compounds do not mean any limitation on the present application:

[0028]

[0029]

[0030] A pharmaceutical composition comprising the novel 7-methoxy-4-phenoxyquinoline-6-carboxamide compound and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof described above as an active ingredient and a pharmaceutically acceptable excipient.

[0031] Use of any one of the novel 7-methoxy-4-phenoxyquinoline-6-carboxamides and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, or the pharmaceutical composition thereof, as described above, for the preparation of a medicament for the treatment and / or prevention of diseases caused by abnormally high expression of c-Met kinase.

[0032] Use of any one of the novel 7-methoxy-4-phenoxyquinoline-6-carboxamides and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, or the pharmaceutical composition thereof, as described above, for the preparation of a medicament for the treatment and / or prevention of proliferative diseases.

[0033] Use of any one of the novel 7-methoxy-4-phenoxyquinoline-6-carboxamides and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, or the pharmaceutical composition thereof, as described above, for the preparation of a medicament for the treatment and / or prevention of cancer.

[0034] Further, use of any one of the novel 7-methoxy-4-phenoxyquinoline-6-carboxamides and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, or the pharmaceutical composition thereof, as described above, for the preparation of a medicament for the treatment and / or prevention of gastric cancer, lung cancer and prostate cancer.

[0035] Further, the novel 7-methoxy-4-phenoxyquinoline-6-carboxamides and configurational isomers according to the present application can form pharmaceutically acceptable salts with acids in accordance with some of the usual methods in the field to which the present application pertains. The pharmaceutically acceptable addition salts include inorganic acid and organic acid addition salts, and the 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, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid and the like.

[0036] In addition, the present application also includes prodrugs of the derivatives of the present application. The prodrugs of the derivatives of the present application are derivatives of the general formula I, which themselves can have weak activity or even no activity, but are converted into the corresponding biologically active forms under physiological conditions (for example, by metabolism, solvolysis or another means) after administration.

[0037] In the present application, "halogen" refers to fluorine, chlorine, bromine or iodine; "alkyl" refers to straight chain or branched alkyl; "alkylene" refers to straight chain or branched alkylene; "cycloalkyl" refers to substituted or unsubstituted cycloalkyl; "aryl" refers to unsubstituted or substituted phenyl; "heteroaryl" refers to monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, 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, quinolinyl, isoquinolinyl, benzimidazolyl and benzoxazolyl, etc.; "saturated or partially saturated heterocyclyl" refers to monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, S, such as pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, pyrazolidinyl, imidazolidinyl and thiazolidinyl, etc.

[0038] The present application has the following advantages:

[0039] 1. The present application has significant inhibitory effect on the above-mentioned tumor cells through in vitro inhibition of human gastric cancer cell MKN-45, AGS, human lung adenocarcinoma cell line A549 and human prostate cancer cell PC-3, and is particularly used for preparing drugs for treating and / or preventing gastric cancer, lung cancer and prostate cancer.

[0040] 2. The present application has significant inhibitory effect on c-Met kinase activity through c-Met kinase test, and is particularly used for preparing drugs for treating and / or preventing diseases caused by abnormally high expression of c-Met kinase, and particularly used for preparing drugs for treating and / or preventing cancer.

[0041] 3. The present application provides a novel 7-methoxy-4-phenoxyquinoline-6-carboxamide compound having novel chemical structure, most of which have significant inhibitory activity on c-Met kinase and strong anti-proliferation activity on tested cells in in vitro biological activity study. The compound can be used for treating and preventing cancer. DETAILED DESCRIPTION

[0042] The examples and preparation examples provided below further illustrate and exemplify the compounds of the present application and methods for preparing them. It is to be understood that the scope of the application is not to be limited in any way by the examples and preparation examples that follow. The following examples are intended to be illustrative of the present application and are not intended to limit the scope of the present application. The nuclear magnetic resonance hydrogen spectrum of the compound is determined by Bruker ARX-600, and the mass spectrum is determined by Agilent6460QQQ; the reagents used are analytical pure or chemical pure.

[0043] The following synthetic routes describe the preparation of the compounds of general formula (I) of the present application, all starting materials are prepared by the following synthetic routes, by methods well known to one of ordinary skill in the art of organic chemistry or are commercially available. All final derivatives of the present application are prepared by the following synthetic routes or by methods analogous thereto, which are well known to one of ordinary skill in the art of organic chemistry. All variable factors applied in the following synthetic routes are 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 into 100 mL chlorobenzene, reacted at 140 °C for 30 h. Cooled to room temperature, concentrated under reduced pressure, the residue was dissolved with appropriate amount of dichloromethane, washed with K2CO3 solution, saturated brine for 3 times respectively, separated the organic phase, dried over anhydrous sodium sulfate, filtered, evaporated the solvent to get brown solid, column chromatography to get the light yellow solid product 4-(3-chloro-4-nitrophenoxy)-7-methoxyquinoline-6-carboxamide 19.80 g. 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 into 200 mL ethanol, 20 mL water was added, heated to reflux for 12 h, after the reaction was completed, filtered hot, the filtrate was evaporated under reduced pressure to remove the solvent to get the crude product, the crude product was column chromatography to get the light yellow solid product 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide 9.90 g. MS (ESI) m / z: 344.10 [M+H] + .

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

[0052] To 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (8 g, 23.27 mmol), triethylamine (7.10 g, 70.16 mmol) was added into 60 mL dry THF, dropwise added phenyl chloroformate (4.40 g, 28.10 mmol) in 20 mL dry THF at 0-5 °C, after addition, the reaction was carried out at room temperature for 3 h, the solvent was evaporated under reduced pressure, the residue was dissolved in 60 mL dichloromethane, washed with water for 4 times, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give a light yellow solid crude product (4-((6-carbamoyl-7-methoxyquinolin-4-yl)oxy)-2-chlorophenyl)phenylcarbamate 7.60 g, which was used directly in the next step.

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

[0054] To (4-((6-carbamoyl-7-methoxyquinolin-4-yl)oxy)-2-chlorophenyl)phenylcarbamate (7.5 g, 16.17 mmol) was dissolved in 50 mL 1,4-dioxane, 80% hydrazine hydrate 20 mL was slowly added, the reaction was carried out at reflux overnight, after the reaction was completed, it was cooled to below 10 °C, the precipitate was filtered, washed with water, and dried under vacuum to give a light yellow solid 4-(3-chloro-4-(hydrazinecarboxamido)phenoxy)-7-methoxyquinoline-6-carboxamide 4.60 g. 1 H NMR (600 MHz, DMSO-d6) δ 9.19 (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, 2.7 Hz, 1H), 6.55 (d, J = 5.2 Hz, 1H), 4.74 (s, 2H), 4.04 (s, 3H).

[0055] Step E: Preparation of Compound 1

[0056] To 4-(3-chloro-4-(hydrazinecarboxamido)phenoxy)-7-methoxyquinoline-6- carboxamide (0.20 g, 0.50 mmol) and 4-fluorobenzaldehyde (75 mg, 0.60 mmol) was added into 5 mL ethanol, appropriate amount of glacial acetic acid was added, the reaction was carried out at reflux for 5-8 h, after the reaction was completed, it was cooled to room temperature, the precipitate was filtered and dried to give a white solid compound of Example 1 (Compound 1) 0.15 g. 1H NMR (600 MHz, DMSO-d6) δ 11.18 (s, 1H), 8.98 (s, 1H), 8.70 (s, 2H), 8.26 (d, J = 8.6 Hz, 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] Compound 2 was prepared by replacing 4-fluorobenzaldehyde in Example 1, Step E with 4-chlorobenzaldehyde, and following the remaining steps of Example 1. 1 H NMR (600 MHz, DMSO-d6) δ 11.18 (s, 1H), 8.98 (s, 1H), 8.70 (s, 2H), 8.26 (d, J = 8.6 Hz, 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). + .

[0060] Example 3: Preparation of Compound 3

[0061]

[0062] Compound 3 was prepared by replacing 4-fluorobenzaldehyde in Example 1, Step E with 4-dimethylaminobenzaldehyde, and following the remaining steps of Example 1. 1 H NMR (600 MHz, DMSO-d6) δ 11.18 (s, 1H), 8.98 (s, 1H), 8.70 (s, 2H), 8.26 (d, J = 8.6 Hz, 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). + .

[0063] Example 4: Preparation of Compound 4

[0064]

[0065] Replace 4-fluorobenzaldehyde in step E of example 1 with 3,4-difluorobenzaldehyde, and the rest of the steps are the same as example 1 to obtain compound 4. 1 H NMR (600 MHz, DMSO-d6) δ 11.22 (s, 1H), 9.01 (s, 1H), 8.71 (s, 1H), 8.68 (s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 8.02 - 7.72 (m, 4H), 7.70 - 7.46 (m, 4H), 7.35 (d, J = 8.6 Hz, 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] Replace 4-fluorobenzaldehyde in step E of example 1 with 2-chloro-4-fluorobenzaldehyde, and the rest of the steps are the same as example 1 to obtain compound 5. 1 H NMR (600 MHz, DMSO-d6) δ 11.32 (s, 1H), 8.98 (s, 1H), 8.81 - 8.58 (m, 2H), 8.34 (s, 1H), 8.18 (d, J = 6.6 Hz, 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] Replace 4-fluorobenzaldehyde in step E of example 1 with 4-bromobenzaldehyde, and the rest of the steps are the same as example 1 to obtain compound 6. 1 H NMR (600 MHz, DMSO-d6) δ 11.22 (s, 1H), 8.98 (s, 1H), 8.69 (s, 2H), 8.23 (d, J = 8.3 Hz, 1H), 7.99 (s, 1H), 7.88 (s, 1H), 7.82 - 7.60 (m, 6H), 7.54 (s, 1H), 7.35 (d, J = 7.8 Hz, 1H), 6.58 (s, 1H), 4.05 (s, 3H).

[0072] Example 7: Preparation of compound 7

[0073]

[0074] The 4-fluorobenzaldehyde in Example 1 step E was replaced with 3,4,5- trimethoxybenzaldehyde, and the remaining steps were the same as Example 1 to give compound 7. 1 H NMR (600 MHz, DMSO-d6) δ 11.24 (s, 1H), 9.07 (s, 1H), 8.70 (s, 2H), 8.33 (d, J = 8.3 Hz, 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 = 8.7 Hz, 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 Example 1 step E was replaced with 4- trifluoromethoxybenzaldehyde, and the remaining steps were the same as Example 1 to give compound 8. 1 H NMR (600 MHz, DMSO-d6) δ 11.35 (s, 1H), 9.02 (s, 1H), 8.70 (d, J = 5.4 Hz, 2H), 8.22 (d, J = 8.6 Hz, 1H), 8.09 (s, 1H), 7.99 (d, J = 7.2 Hz, 2H), 7.89 (s, 1H), 7.85 - 7.73 (m, 3H), 7.65 (s, 1H), 7.54 (s, 1H), 7.36 (d, J = 8.6 Hz, 1H), 6.59 (s, 1H), 4.05 (s, 3H).

[0078] Example 9: Preparation of compound 9

[0079]

[0080] The 4-fluorobenzaldehyde in Example 1 step E was replaced with 3-hydroxy-4- methoxybenzaldehyde, and the remaining steps were the same as Example 1 to give compound 9. 1H NMR (600 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.35 (s, 1H), 8.97 (s, 1H), 8.69 (s, 2H), 8.38 (d, J = 7.7 Hz, 1H), 7.88 (s, 2H), 7.77 (s, 1H), 7.65 (s, 1H), 7.54 (s, 1H), 7.35 (d, J = 7.3 Hz, 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] Replace 4-fluorobenzaldehyde in step E of example 1 with 3-hydroxy-4- methoxybenzaldehyde, and the rest of the steps are the same as example 1 to give compound 10. 1 H NMR (600 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.35 (s, 1H), 8.97 (s, 1H), 8.69 (s, 2H), 8.38 (d, J = 7.7 Hz, 1H), 7.88 (s, 2H), 7.77 (s, 1H), 7.65 (s, 1H), 7.54 (s, 1H), 7.35 (d, J = 7.3 Hz, 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] + .

[0084] Example 11: Preparation of compound 11

[0085]

[0086] Replace 4-fluorobenzaldehyde in step E of example 1 with 2,3-dichlorobenzaldehyde, and the rest of the steps are the same as example 1 to give compound 11. 1H NMR (600 MHz, DMSO-d6) δ 11.40 (s, 1H), 8.98 (s, 1H), 8.83 - 8.62 (m, 2H), 8.41 (s, 1H), 8.18 (d, J = 8.8 Hz, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.86 (s, 1H), 7.75 (s, 1H), 7.69 (d, J = 7.7 Hz, 1H), 7.62 (s, 1H), 7.54 (s, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 6.59 (d, J = 5.0 Hz, 1H), 4.05 (s, 3H).

[0087] Example 12: Preparation of compound 12

[0088]

[0089] Replace 4-fluorobenzaldehyde in step E of example 1 with 4-methanesulfonylbenzaldehyde, and the rest of the steps are the same as example 1 to give compound 12. 1 H NMR (600 MHz, DMSO-d6) δ 11.40 (s, 1H), 8.98 (s, 1H), 8.83 - 8.62 (m, 2H), 8.41 (s, 1H), 8.18 (d, J = 8.8 Hz, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.86 (s, 1H), 7.75 (s, 1H), 7.69 (d, J = 7.7 Hz, 1H), 7.62 (s, 1H), 7.54 (s, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 6.59 (d, J = 5.0 Hz, 1H), 4.05 (s, 3H).

[0090] Example 13: Preparation of compound 13

[0091]

[0092] Replace 4-fluorobenzaldehyde in step E of example 1 with 2,4-dihydroxybenzaldehyde, and the rest of the steps are the same as example 1 to give compound 13. 1H NMR (600 MHz, DMSO-d6) δ 10.83 (s, 1H), 9.97 (s, 1H), 9.78 (s, 1H), 8.89 (s, 1H), 8.78 - 8.56 (m, 2H), 8.34 (d, J = 9.0 Hz, 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, 2.7 Hz, 1H), 6.58 (d, J = 5.2 Hz, 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] Replace 4-fluorobenzaldehyde in step E of example 1 with 2-chloro-5-nitrobenzaldehyde, and the rest of the steps are the same as example 1 to give compound 14. 1 H NMR (600 MHz, DMSO-d6) δ 11.53 (s, 1H), 9.16 (s, 1H), 8.87 (s, 1H), 8.69 (dd, J = 11.7, 6.9 Hz, 2H), 8.38 (s, 1H), 8.20 (d, J = 8.9 Hz, 2H), 7.92 - 7.80 (m, 2H), 7.75 (s, 1H), 7.66 (s, 1H), 7.53 (s, 1H), 7.36 (dd, J = 8.8, 2.1 Hz, 1H), 6.59 (d, J = 5.1 Hz, 1H), 4.05 (s, 3H).

[0096] Example 15: Preparation of compound 15

[0097]

[0098] Replace 4-fluorobenzaldehyde in step E of example 1 with 4-nitrobenzaldehyde, and the rest of the steps are the same as example 1 to give compound 15. MS (ESI) m / z: 535.2 [M+H] + .

[0099] Example 16: Preparation of compound 16

[0100]

[0101] Replace 3-chloro-4-nitrophenol in Step A of Example 1 with 4-nitrophenol, replace 4-fluorobenzaldehyde in Step E of Example 1 with 4-methoxybenzaldehyde, and the remaining steps are the same as Example 1 to obtain compound 18. MS (ESI) m / z: 486.2 [M+H] + .

[0102] Example 17: Preparation of compound 17

[0103]

[0104] Replace 3-chloro-4-nitrophenol in Step A of Example 1 with 4-nitrophenol, and the remaining steps are the same as Example 1 to obtain compound 17. MS (ESI) m / z: 474.2 [M+H] + .

[0105] Example 18: Preparation of compound 18

[0106]

[0107] Replace 3-chloro-4-nitrophenol in Step A of Example 1 with 4-nitrophenol, replace 4-fluorobenzaldehyde in Step E of Example 1 with 4-methoxybenzaldehyde, and the remaining steps are the same as Example 1 to obtain compound 18. MS (ESI) m / z: 486.2 [M+H] + .

[0108] Example 19: Preparation of compound 19

[0109]

[0110] Replace 3-chloro-4-nitrophenol in Step A of Example 1 with 4-nitrophenol, replace 4-fluorobenzaldehyde in Step E of Example 1 with 4-hydroxybenzaldehyde, and the remaining steps are the same as Example 1 to obtain compound 19. MS (ESI) m / z: 472.2 [M+H] + .

[0111] Example 20: Preparation of compound 20

[0112]

[0113] Replace 3-chloro-4-nitrophenol in Step A of Example 1 with 2-fluoro-4-nitrophenol, and the remaining steps are the same as Example 1 to obtain compound 20. MS (ESI) m / z: 491.1 [M+H] + .

[0114] Example 21: Preparation of compound 21

[0115]

[0116] Replace 3-chloro-4-nitrophenol in Step A of Example 1 with 2-fluoro-4-nitrophenol, replace 4-fluorobenzaldehyde in Step E of Example 1 with 4-methoxybenzaldehyde, and the remaining steps are the same as Example 1 to obtain Compound 21. MS (ESI) m / z: 503.2 [M+H] + .

[0117] Example 22: Preparation of Compound 22

[0118]

[0119] Replace 3-chloro-4-nitrophenol in Step A of Example 1 with 2-fluoro-4-nitrophenol, replace 4-fluorobenzaldehyde in Step E of Example 1 with 4-hydroxybenzaldehyde, and the remaining steps are the same as Example 1 to obtain Compound 22. MS (ESI) m / z: 490.1 [M+H] + .

[0120] Example 23: Preparation of Compound 23

[0121]

[0122] Replace 3-chloro-4-nitrophenol in Step A of Example 1 with 2-fluoro-4-nitrophenol, replace 4-fluorobenzaldehyde in Step E of Example 1 with 4-methanesulfonylbenzaldehyde, and the remaining steps are the same as Example 1 to obtain Compound 23. MS (ESI) m / z: 552.1 [M+H] + .

[0123] Example 24: Preparation of Compound 24

[0124]

[0125] Replace 3-chloro-4-nitrophenol in Step A of Example 1 with 2-fluoro-4-nitrophenol, replace 4-fluorobenzaldehyde in Step E of Example 1 with 3-hydroxy-4-methoxybenzaldehyde, and the remaining steps are the same as Example 1 to obtain Compound 24. MS (ESI) m / z: 520.2 [M+H] + .

[0126] Example 25

[0127] In vitro anti-tumor cell activity

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

[0129] In vitro tumor cell inhibition activity test

[0130] (1) After the cells were recovered and subcultured 2-3 times stably, they were digested from the bottom of the culture bottle with trypsin solution (0.25%). After the cell digestion solution was poured into a centrifuge tube, culture solution was added to terminate the digestion. The centrifuge tube was centrifuged at 800 r / min for 10 min, and after the supernatant was discarded, 5 mL of culture solution was added, the cells were mixed by blowing, 10 μL of the cell suspension was taken and added to a cell counting plate for counting, and the cell concentration was adjusted to 10 4 cells / well. Except that 100 μL of cell suspension was added to the 96-well plate except for the blank well in Al, the rest were added to the 96-well plate. The 96-well plate was placed in an incubator for 24 h.

[0131] (2) The test sample was dissolved with 50 μL of dimethyl sulfoxide, and then an appropriate amount of culture solution was added to dissolve the sample into a 2 mg / mL drug solution, and then the sample was diluted into 50, 10, 2, 0.4, 0.08 μg / mL in a 24-well plate.

[0132] Three wells were added for each concentration, and the cell growth in the surrounding two rows and two columns was greatly affected by the environment, and was only used for blank cell wells. The 96-well plate was placed in an incubator for 72 h.

[0133] (3) The drug-containing culture solution in the 96-well plate was discarded, and the cells were washed twice with phosphate buffer solution (PBS), 100 μL of MTT (tetrazolium) (0.5 mg / mL) was added to each well, and then the plate was placed in an incubator for 4 h. After the MTT solution was discarded, 100 μL of dimethyl sulfoxide was added. The survival cells were fully dissolved with MTT reaction product formazan under magnetic shaking, and the results were measured in an enzyme marker instrument. The IC 50 value of the drug can be obtained by Bliss method. The results of the activity of the compound of the example in inhibiting human gastric cancer cells MKN-45, human lung adenocarcinoma cell line A549 and human prostate cancer cells PC-3 are shown in Table 1.

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

[0135] The test for measuring c-Met kinase activity is based on enzyme-linked immunosorbent assay (ELISA). The specific operation is as follows:

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

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

[0138] Table 1: Inhibition of MKN-45, A549 and PC-3 tumor cell lines and c-Met kinase activity by compounds

[0139]

[0140]

[0141] As can be clearly seen from the results of the experiments in Table 1, the novel 7-methoxy-4-phenoxyquinoline-6-carboxamide compounds of general formula (I) to be protected by the present application have good in vitro anti-tumor activity on tumor cell lines and c-Met kinase. The compounds have good prospects for development and application as anti-tumor drugs.

[0142] The preferred embodiments of the present application are described in detail above, but the present application is not limited to the specific details of the above-described embodiments, and various equivalent modifications can be made to the technical solutions of the present application within the technical concept of the present application. In order to avoid unnecessary repetition, the present application will not be described again for various possible combinations. Any modification, equivalent replacement or improvement made within the technical concept of the present application is included in the protection scope of the present application.

Claims

1. A 7-methoxy-4-phenoxyquinoline-6-carboxamide compound, characterized in that, The structure is shown in equation (Ⅰ). in: R1 is selected from hydrogen; X is selected from 1 to 4 identical or different substituents of the following: hydrogen, halogen, C1-C6 alkyl, or C1-C4 alkoxy; Ar is selected from phenyl; and Ar is substituted by 1-3 identical or different R2 groups; R2 is selected from hydrogen, halogen, hydroxyl, nitro, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfonyl, C1-C6 alkyl substituted with hydroxyl or amino or halogenated, C1-C6 alkoxy substituted with hydroxyl or amino or halogenated, and amino substituted with mono- or bis-C1-C6 alkyl.

2. The 7-methoxy-4-phenoxyquinoline-6-carboxamide compound according to claim 1, characterized in that, R1 is selected from hydrogen; X is selected from 1 to 4 identical or different substituents of 1 to 4 or fewer: hydrogen or halogen; Ar is selected from phenyl; and Ar is substituted by 1-3 identical or different R2 groups; R2 is selected from hydrogen, halogen, hydroxyl, nitro, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfonyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, and amino groups substituted with mono- or bis-C1-C6 alkyl groups.

3. A 7-methoxy-4-phenoxyquinoline-6-carboxamide compound according to claim 2, characterized in that, R1 is selected from hydrogen; X is selected from 1-2 identical or different substituents of the following: hydrogen, fluorine, or chlorine; Ar is selected from phenyl; and Ar is substituted by 1-3 identical or different R2 groups; R2 is selected from hydrogen, halogen, hydroxyl, nitro, amino, cyano, methyl, C1-C6 alkoxy, trifluoromethyl, trifluoromethoxy, C1-C6 alkylsulfonyl, and amino groups substituted with mono- or bis-C1-C6 alkyl groups.

4. A 7-methoxy-4-phenoxyquinoline-6-carboxamide compound according to claim 3, characterized in that, R1 is selected from hydrogen; 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 R2s; R2 is selected from hydrogen, halogen, hydroxyl, methoxy, nitro, trifluoromethyl, trifluoromethoxy, methanesulfonyl, or dimethylamino.

5. A 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 active ingredient comprises a 7-methoxy-4-phenoxyquinoline-6-carboxamide compound as described in any one of claims 1-5, and a pharmaceutically acceptable salt thereof, as well as a pharmaceutically acceptable excipient.

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

8. The use of a 7-methoxy-4-phenoxyquinoline-6-carboxamide compound according to any one of claims 1-5 or the pharmaceutical composition according to claim 6 in the preparation of a medicament for treating and / or preventing cancer.

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

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