A 4-phenoxyquinoline compound containing dihydropyridine amide and dihydropyridazine amide and application thereof

Abstract

The application belongs to the field of medicine, and particularly relates to a 4-phenoxy quinoline compound containing dihydropyridine amide and dihydropyridazine amide and application thereof. The 4-phenoxy quinoline compound containing dihydropyridine amide and dihydropyridazine amide and pharmaceutically acceptable salts thereof have the structure of general formula (I). The application also relates to the compounds of general formula (I) having a strong inhibitory effect on c-Met kinase, and further relates to the application of the compounds in the preparation of drugs for treating and / or preventing diseases caused by abnormally high expression of c-Met kinase, particularly in the preparation of drugs for treating and / or preventing cancer. The compounds of the application are particularly suitable for the preparation of drugs for treating and / or preventing gastric cancer and breast cancer.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a novel 4-phenoxyquinoline compound containing dihydropyridine amide and dihydropyridazinamide, its pharmaceutically acceptable salt, and a pharmaceutical composition containing the above compound. This invention also relates to the use of this type of compound and its pharmaceutically acceptable salt in the preparation of medicaments for treating diseases caused by abnormally high expression of c-Met kinase, particularly in the preparation of medicaments for treating and / or preventing cancer. Background Technology

[0002] With the rapid development of tumor-related sciences such as tumor genomics, the mechanisms of malignant tumor development are gradually being elucidated. Molecular targeted therapy for tumors, targeting specific tumor-related molecules and key kinases in signaling pathways, is receiving increasing attention from scientists. Compared to traditional tumor treatments, these small-molecule inhibitors targeting abnormal signaling molecules and pathways often possess unique advantages such as directionality and localization. They also offer significant benefits, including high efficacy, low dosage, and low toxicity, greatly improving treatment outcomes. c-Met, as a specific transmembrane receptor for hepatocyte growth factor (HGF), is a unique member of the RTK family. The binding of c-Met to HGF induces c-Met dimerization, leading to autophosphorylation of tyrosine residues in the intracellular region of c-Met, subsequently activating downstream signaling pathways. Finally, the signal is transferred to nuclear transcription mechanisms, regulating many essential cellular processes such as cell proliferation, motility, morphogenesis, and survival. c-Met is widely expressed in various cells and tissues. Its overexpression is associated with many cancers and promotes the transformation of normal cells into malignant cells. c-Met kinases are located at the intersection of numerous signal transduction pathways leading to tumor formation and metastasis. Targeting c-Met kinases allows for the simultaneous interference of multiple signaling pathways. Therefore, c-Met kinases have become a crucial target in the development of targeted anti-tumor drugs. 4-Phenoxyquinoline compounds are the most important representative compounds among Type II small molecule c-Met kinase inhibitors. Cabozantinib was the first approved 4-phenoxyquinoline small molecule c-Met kinase inhibitor. Developed by Exelixis Biopharmaceuticals, Cabozantinib is a broad-spectrum anti-tumor drug with strong inhibitory effects on kinases such as VEGFR-2, RET, AXL, TIE-2, c-Kit, and Flt-3. It was approved by the FDA in November 2012 for the treatment of unresectable malignant locally advanced or metastatic medullary thyroid carcinoma. Following its clinical development for anti-tumor purposes, the US FDA subsequently approved cabozantinib for the treatment of advanced renal cell carcinoma, hepatocellular carcinoma, and neuroendocrine tumors of the pancreas and extrapancreatic tumors. Foretinib, obtained by replacing the methoxy group at the 7-position of the quinoline ring in the cabozantinib molecule with a morpholinopropyl group, is also a multi-target small-molecule c-Met kinase inhibitor. It exhibits strong inhibitory activity against kinases such as VEGFR-2, Ron, FLT-3, c-Kit, PDGFRα, PDGFRβ, and Tie-2, and has entered Phase II / III clinical trials for the treatment of malignant tumors such as bone cancer and head / neck cancer. On the other hand, studies have shown that compounds containing pyridine or pyridazine structures in their molecular structure often possess broad biological activities, such as anti-tumor, antibacterial, and anti-inflammatory effects, thus attracting significant attention from chemists and pharmacologists. In the application of anti-tumor drugs, pyridine or pyridazine structural units are frequently introduced as anti-tumor pharmacophores into anticancer drugs.Currently, c-Met inhibitor research faces several challenges, including poor clinical efficacy, unsatisfactory pharmacokinetic parameters, low oral bioavailability, and significant toxic side effects. Therefore, developing novel, safe, and effective c-Met kinase inhibitors remains a key area of ​​research in anti-tumor drugs both domestically and internationally. Summary of the Invention

[0003] Based on a summary of the structure-activity relationship of 4-phenoxyquinoline Type II small molecule c-Met kinase inhibitors and analysis of the three-dimensional structure of Type II c-Met proteins, the inventors designed and synthesized a series of novel 4-phenoxyquinoline compounds containing dihydropyridine amide and dihydropyridazinamide. Pharmacological activity screening showed that these compounds possess antitumor activity. This invention relates to novel 4-phenoxyquinoline compounds containing dihydropyridine amide and dihydropyridazinamide as c-Met inhibitors, which have not been previously reported in the literature.

[0004] The technical solution adopted in this invention is:

[0005] A 4-phenoxyquinoline compound containing dihydropyridineamide and dihydropyridazinamide, and its pharmaceutically acceptable salt, has the structural formula shown in general formula (I):

[0006] ;

[0007] in:

[0008] X is selected from 1 to 4 identical or different substituents of the following: hydrogen, halogen, alkyl group containing 1 to 3 carbons, alkoxy group containing 1 to 3 carbons;

[0009] n is selected from 0, 1, 2, 3, 4; where n is 0, it means that N on the amide is directly connected to Ar;

[0010] R1 is an alkyl group containing 1-6 carbons or selected from the following groups:

[0011] ;

[0012] L is selected from the following groups:

[0013] ;

[0014] R2 is selected from hydrogen, alkyl groups containing 1-6 carbons, and cycloalkyl groups containing 3-6 carbons;

[0015] Ar is selected from cycloalkyl groups containing 3-10 carbons, 3-10 non-aromatic heterocyclic groups, 6-10 aryl groups, and 5-10 heteroaryl groups; wherein the heterocyclic group or heteroaryl group contains 1-3 heteroatoms selected from N, O, or S; the cycloalkyl group containing 3-10 carbons, 3-10 non-aromatic heterocyclic group, 6-10 aryl group, or 5-10 heteroaryl group may optionally be replaced by 1-3 identical or different R3 atoms;

[0016] R3 is hydrogen, halogen, nitro, amino, cyano, alkyl containing 1-6 carbons, alkoxy containing 1-6 carbons, alkylthio containing 1-6 carbons, alkyl containing 1-6 carbons optionally hydroxyl, amino, or halogenated, alkoxy containing 1-6 carbons optionally hydroxyl, amino, or halogenated, amino substituted with one or two alkyl groups containing 1-6 carbons, alkylamide containing 1-6 carbons, free or salt-forming or esterified or amidated carboxyl group containing 1-6 carbons, alkylsulfinyl group containing 1-6 carbons, alkylsulfonyl group containing 1-6 carbons, alkylacyl group containing 1-6 carbons, alkylcarbamoyl group containing 1-6 carbons, or carbamoyl group substituted with one or two alkyl groups containing 1-6 carbons.

[0017] Furthermore, the above-mentioned 4-phenoxyquinoline compound containing dihydropyridine amide and dihydropyridazinamide, and its pharmaceutically acceptable salt,

[0018] X is selected from 1 to 4 identical or different substituents of the following: hydrogen, halogen;

[0019] n is selected from 0, 1, 2, 3; where n is 0, it means that N on the amide is directly connected to Ar;

[0020] R1 is methyl, ethyl, n-propyl, isopropyl, or selected from the following groups:

[0021] ;

[0022] L is selected from the following groups:

[0023] ;

[0024] R2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0025] Ar is selected from cycloalkyl groups containing 3-10 carbons, 3-10 non-aromatic heterocyclic groups, 6-10 aryl groups, and 5-10 heteroaryl groups; wherein the heterocyclic group or heteroaryl group contains 1-3 heteroatoms selected from N, O, or S; the cycloalkyl group containing 3-10 carbons, 3-10 non-aromatic heterocyclic group, 6-10 aryl group, or 5-10 heteroaryl group may optionally be replaced by 1-3 identical or different R3 atoms;

[0026] R3 is hydrogen, halogen, nitro, amino, cyano, alkyl containing 1-6 carbons, alkoxy containing 1-6 carbons, optionally halogenated alkyl containing 1-6 carbons, optionally halogenated alkoxy containing 1-6 carbons, amino substituted with one or two alkyl containing 1-6 carbons, or alkylsulfonyl containing 1-6 carbons.

[0027] Preferably, the above-mentioned 4-phenoxyquinoline compound containing dihydropyridine amide and dihydropyridazinamide, and its pharmaceutically acceptable salt,

[0028] X is selected from 1-2 identical or different substituents of the following: hydrogen, fluorine;

[0029] n is selected from 0, 1, 2, 3; where n is 0, it means that N on the amide is directly connected to Ar;

[0030] R1 is methyl or selected from the following groups:

[0031] ;

[0032] L is selected from the following groups:

[0033] ;

[0034] R2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, and cyclopropyl;

[0035] Ar is selected from cyclopentyl, cyclohexyl, adamantyl, phenyl, pyridyl, thiophenyl, furanyl, naphthyl, quinolinyl, and indoleyl, wherein the cyclopentyl, cyclohexyl, phenyl, pyridyl, thiophenyl, furanyl, naphthyl, quinolinyl, and indoleyl may optionally be replaced by 1 to 3 identical or different R3s;

[0036] R3 is hydrogen, halogen, nitro, amino, cyano, alkyl containing 1-6 carbons, alkoxy containing 1-6 carbons, optionally halogenated alkyl containing 1-6 carbons, optionally halogenated alkoxy containing 1-6 carbons, amino substituted with one or two alkyl containing 1-6 carbons, or alkylsulfonyl containing 1-6 carbons.

[0037] More preferably, the above-mentioned 4-phenoxyquinoline compound containing dihydropyridine amide and dihydropyridazinamide, and its pharmaceutically acceptable salt, wherein the 4-phenoxyquinoline compound containing dihydropyridine amide and dihydropyridazinamide has the following structural formula:

[0038]

[0039]

[0040]

[0041]

[0042] .

[0043] The following synthetic routes describe the preparation of novel 4-phenoxyquinoline compounds of general formula (I) of this invention, containing dihydropyridine amides and dihydropyridazinamides, all of which are prepared by methods well known to those skilled in the art of organic chemistry or are commercially available, as described in these reaction formulas. All final derivatives of this invention are prepared by methods described in the following reaction formulas or by similar methods well known to those skilled in the art of organic chemistry. All variable factors used in these reaction formulas are defined below or above.

[0044] Novel 4-phenoxyquinoline compounds containing dihydropyridine amide and dihydropyridazinamide according to general formula (I) of the present invention can all be prepared according to the method of route 1, wherein the preparation method of the analog of the relevant intermediate a is obtained according to the method of patent CN 111440177 A;

[0045]

[0046] Route 1;

[0047] The substituents R1, X, L, Ar, and n of all intermediates in the above route are as defined above.

[0048] A pharmaceutical composition comprising, as an active ingredient and a pharmaceutically acceptable excipient, a 4-phenoxyquinoline compound containing dihydropyridine amide and dihydropyridazinamide as described in any one of the preceding claims, and a pharmaceutically acceptable salt thereof.

[0049] The use of any of the above-described 4-phenoxyquinoline compounds containing dihydropyridine amide and dihydropyridazinamide, or pharmaceutically acceptable salts thereof, or any of the above-described pharmaceutical compositions, in the preparation of medicaments for the treatment and / or prevention of diseases caused by abnormally high expression of c-Met kinase.

[0050] The use of any of the above-described 4-phenoxyquinoline compounds containing dihydropyridine amide and dihydropyridazinamide, or pharmaceutically acceptable salts thereof, or any of the above-described pharmaceutical compositions, in the preparation of medicaments for the treatment and / or prevention of proliferative diseases.

[0051] The use of any of the above-described 4-phenoxyquinoline compounds containing dihydropyridine amide and dihydropyridazinamide, or pharmaceutically acceptable salts thereof, or any of the above-described pharmaceutical compositions, in the preparation of medicaments for the treatment and / or prevention of cancer.

[0052] The use of any of the above-described 4-phenoxyquinoline compounds containing dihydropyridine amide and dihydropyridazinamide, or pharmaceutically acceptable salts thereof, or any of the above-described pharmaceutical compositions, in the preparation of medicaments for the treatment and / or prevention of gastric and breast cancer.

[0053] Furthermore, according to some common methods in the field to which this invention pertains, the novel 4-phenoxyquinoline compounds of general formula (I) of this invention, containing dihydropyridineamide and dihydropyridazinamide, can react with acids to form pharmaceutically acceptable salts. Pharmaceutically acceptable addition salts include inorganic acid and organic acid addition salts, with salts reacting with the following acids being 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, etc.

[0054] In this invention, "halogen" refers to fluorine, chlorine, bromine, or iodide; "alkyl" refers to a straight-chain or branched alkyl group; "cycloalkyl" refers to a substituted or unsubstituted cycloalkyl group; "aryl" refers to a monocyclic or polycyclic aromatic ring system of carbon atoms, such as phenyl or naphthyl; "heteroaryl" refers to a cyclic system containing one or more monocyclic or polycyclic heteroatoms selected from N, O, and S, wherein the cyclic system is aromatic, such as imidazolyl, pyridinyl, pyrazolyl, (1,2) (3)- and (1,2,4)-triazolyl, furanyl, thiophene, pyrroleyl, thiazolyl, benzothiazolyl, oxazolyl, isoxazolyl, naphthyl, quinolinyl, isoquinolinyl, benzimidazolyl, and benzoxazolyl, etc.; "heterocyclic group" refers to a monocyclic or polycyclic cyclic system containing one or more heteroatoms selected from N, O, and S, such as pyrroleyl, morpholinyl, piperazine, piperidinyl, pyrazolyl, imidazolyl, and thiazolyl, etc. "Represents the substituent connection point."

[0055] The beneficial effects of this invention are:

[0056] 1. Through in vitro inhibition assays of human gastric cancer cell lines MKN45 and AGS and human breast cancer cell line MCF-7, the compounds of the present invention have significant inhibitory effects on the above-mentioned tumor cells, and are particularly useful for the preparation of drugs for the treatment and / or prevention of gastric and breast cancer.

[0057] 2. Through c-Met enzyme activity testing, it was found that the compounds of the present invention have significant inhibitory effects on c-Met kinase activity, particularly for use in the preparation of medicaments for the treatment and / or prevention of diseases caused by abnormally high expression of c-Met kinase, especially for use in the preparation of medicaments for the treatment and / or prevention of cancer.

[0058] 3. The 4-phenoxyquinoline compounds of the present invention, containing dihydropyridine amide and dihydropyridazinamide, have novel chemical structures. Most of these compounds exhibit significant inhibitory activity against c-Met kinase in in vitro biological activity studies and strong anti-proliferative activity against the tested cells. These compounds can be used for the treatment and prevention of cancer. Detailed Implementation

[0059] The examples provided below further illustrate and demonstrate the compounds of the present invention and their preparation methods. It should be understood that the scope of the following examples does not limit the scope of the invention in any way. The examples are intended to illustrate, not limit, the scope of the invention. The proton NMR spectra of the compounds were determined using a Bruker ARX-400, Bruker ARX-500, or ARX-600, and the mass spectrometry was performed using an Agilent 6460 QQQ; all reagents used were analytical grade or chemically pure.

[0060] Example 1 Synthesis of N-phenyl-5-{4-[(6,7-dimethoxyquinoline-4-yl)oxy]phenyl}-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (Compound 1)

[0061] Step 1: Synthesis of 4-(4-bromophenoxy)-6,7-dimethoxyquinoline

[0062]

[0063] Weigh 10.00 g (44.71 mmol) of 4-chloro-6,7-dimethoxyquinoline and 23.00 g (132.94 mmol) of p-bromophenol. Add 100 mL of chlorobenzene and stir at 50 °C for half an hour. Then add N,N-diisopropylethylamine (11.56 g, 89.42 mmol) dropwise. After reflux for 16 h, the reaction is complete. Remove chlorobenzene under reduced pressure. Separate the residue by silica gel column chromatography to obtain 12.00 g of grayish-white solid 4-(4-bromophenoxy)-6,7-dimethoxyquinoline, with a yield of 74.5%. 1 H NMR (500 MHz, CDCl3) δ 8.51 (d, J = 4.9 Hz, 1H), 7.58 (d, J = 7.9 Hz, 2H), 7.51 (s, 1H), 7.44 (s, 1H), 7.08 (d, J = 7.9 Hz, 2H), 6.48 (d, J = 4.8 Hz, 1H), 4.05 (s, 3H), 4.04 (s, 3H).

[0064] Step 2: Synthesis of 6,7-dimethoxy-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenoxy]quinoline

[0065]

[0066] 4-(4-bromophenoxy)-6,7-dimethoxyquinoline (10.00 g, 16.70 mmol), pinacol diborate (10.36 g, 25.04 mmol), and potassium acetate (7.90 g, 49.92 mmol) were added to 50 mL of 1,4-dioxane. After bubbling under nitrogen for half an hour, bis(triphenylphosphine)ferrocene palladium dichloride (1.60 g, 2.28 mmol) was added. The mixture was stirred at 110 °C for 10 h under nitrogen protection. After the reaction was complete, the mixture was filtered, the filtrate was concentrated, extracted with dichloromethane, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 8.06 g of a grayish-white solid 6,7-dimethoxy-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenoxy]quinoline, with a yield of 68.8%.

[0067] Step 3: Synthesis of methyl 5-{4-[(6,7-dimethoxyquinoline-4-yl)oxy]phenyl}-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate

[0068]

[0069] 6,7-Dimethoxy-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenoxy]quinoline (4.00 g, 9.80 mmol), methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (2.80 g, 11.40 mmol), and cesium carbonate (6.40 g, 19.60 mmol) were added to 50 mL of N,N-dimethylformamide. After bubbling under nitrogen for half an hour, dichlorobis(triphenylphosphine)palladium (0.34 g, 0.48 mmol) was added. The reaction was carried out under nitrogen protection and stirred at 60 °C for 10 h. After the reaction was completed, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was extracted three times with dichloromethane after adding an appropriate amount of water. The organic phase was dried and then evaporated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to give 2.00 g of methyl 5-{4-[(6,7-dimethoxyquinoline-4-yl)oxy]phenyl}-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate, a white solid, with a yield of 45.6%. MS (ESI) m / z: 447.1 [M+H] + .

[0070] Step 4: Synthesis of 5-{4-[(6,7-dimethoxyquinoline-4-yl)oxy]phenyl}-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid

[0071]

[0072] 2.00 g (4.48 mmol) of methyl 5-{4-[(6,7-dimethoxyquinoline-4-yl)oxy]phenyl}-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid was added to 20 mL of methanol and 10 mL of water. Sodium hydroxide (0.52 g, 13.00 mmol) was then added to the mixture, and the mixture was stirred at 40 °C for 4 h. Methanol was removed under reduced pressure. A suitable amount of water was added to the mixture, and the resulting solution was adjusted to pH 3-4 with dilute hydrochloric acid. The mixture was filtered, and the filter cake was washed three times with water and dried to obtain 1.50 g of 5-{4-[(6,7-dimethoxyquinoline-4-yl)oxy]phenyl}-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid, with a yield of 78.9%. MS (ESI) m / z: 431.1 [MH] - .

[0073] Step 5: Synthesis of N-phenyl-5-{4-[(6,7-dimethoxyquinoline-4-yl)oxy]phenyl}-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (Compound 1)

[0074]

[0075] Add 1.20 mmol of 5-{4-[(6,7-dimethoxyquinoline-4-yl)oxy]phenyl}-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid, aniline, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, N,N-diisopropylethylamine, and 10 mL of N,N-dimethylformamide to a reaction flask. Stir at room temperature for 15 h until the reaction is complete. Pour the reaction solution into 50 mL of 10% sodium carbonate aqueous solution and extract three times with 50 mL of dichloromethane. Combine the organic phases, wash the organic phase three times with 10% sodium carbonate aqueous solution, and wash the organic layer twice with saturated brine. Separate the organic layer and dry it with anhydrous sodium sulfate. The product was filtered and dichloromethane was removed under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography to obtain N-phenyl-5-{4-[(6,7-dimethoxyquinoline-4-yl)oxy]phenyl}-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (compound 1). 1H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 8.74(d, J = 2.5 Hz, 1H), 8.53 (d, J = 2.3 Hz, 1H), 8.51 (d, J = 5.2 Hz, 1H), 7.79(d, J = 8.5 Hz, 2H), 7.73 (d, J = 7.9 Hz, 2H), 7.51 (s, 1H), 7.47 - 7.28 (m,5H), 7.12 (t, J = 7.3 Hz, 1H), 6.55 (d, J = 5.2 Hz, 1H), 3.96 (s, 3H), 3.94(s, 3H), 3.74(s, 3H); MS (ESI) m / z: 508.1 [M+H] + .

[0076] By replacing appropriate raw materials and reagents, and following the preparation method of Example 1, Example 2-71 (compound 2-71) was finally obtained.

[0077] Example 2 Synthesis of N-(4-fluorophenyl)-5-{4-[(6,7-dimethoxyquinoline-4-yl)oxy]phenyl}-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (compound 2)

[0078] By replacing aniline in step 5 of Example 1 with p-fluoroaniline, and following the same steps as in Example 1, compound 2 was obtained. 1 H NMR (500 MHz, DMSO-d6) δ 12.19 (s, 1H), 8.77 (d, J = 2.7 Hz, 1H), 8.645 (d,J = 2.7 Hz, 1H), 8.54 (d, J = 5.2 Hz, 1H), 7.92 - 7.70 (m, 4H), 7.52 (s, 1H), 7.47 - 7.33 (m, 3H), 7.22 (t, J = 8.8 Hz, 2H), 6.57 (d, J = 5.2 Hz, 1H), 3.96 (s, 3H), 3.97 (s, 3H), 3.84 (s, 3H); MS (ESI) m / z: 526.1 [M+H] + .

[0079] Example 3 Synthesis of N-benzyl-1-[4-(6,7-dimethoxyquinoline-4-oxy)phenyl]-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (Compound 3)

[0080] In Example 1, step 5, aniline was replaced with benzylamine, and the remaining steps were the same as in Example 1, to obtain compound 3. MS (ESI) m / z: 522.2 [M+H] + .

[0081] Example 4 Synthesis of N-(4-fluorobenzyl)-5-{4-[(6,7-dimethoxyquinoline-4-yl)oxy]phenyl}-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (compound 4)

[0082] In Example 1, step 5, aniline was replaced with 4-fluorobenzylamine, and the remaining steps were the same as in Example 1, to obtain compound 4. MS (ESI) m / z: 540.2 [M+H] + .

[0083] Example 5 Synthesis of N-(4-chlorophenyl)-5-{4-[(6,7-dimethoxyquinoline-4-yl)oxy]phenyl}-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (compound 5)

[0084] By replacing aniline in step 5 of Example 1 with p-chloroaniline, and following the same steps as in Example 1, compound 5 was obtained. 1 H NMR (500 MHz, DMSO-d6) δ 12.39 (s, 1H), 8.56 (d, J = 2.8 Hz, 1H), 8.66 (d,J = 2.8 Hz, 1H), 8.43 (d, J = 5.2 Hz, 1H), 7.90 - 7.72 (m, 4H), 7.52 (s, 1H),7.49 - 7.33 (m, 5H), 6.58 (d, J = 5.2 Hz, 1H), 3.88 (s, 3H), 3.93 (s, 3H),3.87 (s, 3H); MS (ESI) m / z: 542.0 [M+H] + .

[0085] Example 6 Synthesis of N-(4-methoxyphenyl)-5-{4-[(6,7-dimethoxyquinoline-4-yl)oxy]phenyl}-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (compound 6)

[0086] By replacing aniline in step 5 of Example 1 with p-methoxyaniline, and following the same steps as in Example 1, compound 6 was obtained. 1H NMR (500 MHz, DMSO-d6) δ 12.15 (s, 1H), 8.75 (d, J = 2.8 Hz, 1H), 8.63 (d, J = 2.7 Hz, 1H), 8.62 (d, J = 5.2 Hz, 1H), 7.89 (d, J = 8.6 Hz, 2H), 7.67(d, J = 9.0 Hz, 2H), 7.52 (s, 1H), 7.47 - 7.30 (m, 3H), 6.95 (d, J = 9.0 Hz,2H), 6.57 (d, J = 5.2 Hz, 1H), 3.96 (s, 3H), 3.84 (s, 3H), 3.77 (s, 3H), 3.75(s, 3H); MS (ESI) m / z: 538.1 [M+H] + .

[0087] Example 7 Synthesis of N-phenyl-5-{4-[(6,7-dimethoxyquinoline-4-yl)oxy]phenyl}-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 7)

[0088] In step 3 of Example 1, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate, and the remaining steps were the same as in Example 1, to obtain compound 7. 1 HNMR (500 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.56 (d, J = 25.3 Hz, 2H), 8.28 (s,1H), 7.95 (d, J = 6.4 Hz, 2H), 7.73 (d, J = 6.4 Hz, 2H), 7.62 - 7.25 (m, 6H),7.11 (s, 1H), 6.57 (s, 1H), 3.96 (s, 3H), 3.95 (s, 3H), 3.65 (s, 3H); MS(ESI) m / z: 508.1 [M+H] + MS (ESI) m / z: 508.1 [M+H] + .

[0089] Example 8 Synthesis of N-(4-fluorophenyl)-5-{4-[(6,7-dimethoxyquinoline-4-yl)oxy]phenyl}-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 8)

[0090] In Example 1, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate, and aniline in step 5 was replaced with p-fluoroaniline. The remaining steps were the same as in Example 1, and compound 8 was obtained. 1 H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.56 (d, J= 2.5 Hz, 1H), 8.52 (d, J = 5.2 Hz, 1H), 8.25 (d, J = 2.5 Hz, 1H), 7.76 (d, J= 8.7 Hz, 2H), 7.82 - 7.68 (m, 2H), 7.62 (s, 1H), 7.41 (s, 1H), 7.54 (d, J =8.7 Hz, 2H), 7.22 (dd, J = 12.3, 5.5 Hz, 2H), 6.53 (d, J = 5.2 Hz, 1H), 3.75(s, 3H), 3.94(s, 3H), 3.64 (s, 3H); MS (ESI) m / z: 526.1 [M+H] + .

[0091] Example 9 Synthesis of N-benzyl-5-{4-[(6,7-dimethoxyquinoline-4-yl)oxy]phenyl}-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 9)

[0092] In Example 1, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate in step 3, and aniline in step 5 was replaced with benzylamine. The remaining steps were the same as in Example 1, yielding compound 9. MS (ESI) m / z: 522.1 [M+H] + .

[0093] Example 10 Synthesis of N-(4-fluorobenzyl)-5-{4-[(6,7-dimethoxyquinoline-4-yl)oxy]phenyl}-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 10)

[0094] In Example 1, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate in step 3, and aniline in step 5 was replaced with 4-fluorobenzylamine. The remaining steps were the same as in Example 1, yielding compound 10. MS (ESI) m / z: 540.1 [M+H] + .

[0095] Example 11 Synthesis of N-(4-chlorobenzyl)-5-{4-[(6,7-dimethoxyquinoline-4-yl)oxy]phenyl}-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 11)

[0096] In Example 1, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate, and aniline in step 5 was replaced with 4-chloroaniline. The remaining steps were the same as in Example 1, and compound 11 was obtained. 1 H NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.56 (d, J= 2.4 Hz, 1H), 8.56 (d, J = 5.2 Hz, 1H), 8.25 (d, J = 2.4 Hz, 1H), 7.94 (d, J= 8.6 Hz, 2H), 7.76 (d, J = 8.9 Hz, 2H), 7.53 (s, 1H), 7.48 - 7.38 (m, 3H), 7.34 (d, J = 8.6 Hz, 2H), 6.56 (d, J = 5.2 Hz, 1H), 3.96 (s, 3H), 3.95 (s,3H), 3.65 (s,3H); MS (ESI) m / z: 542.0 [M+H] + .

[0097] Example 12 Synthesis of N-(4-methoxybenzyl)-5-{4-[(6,7-dimethoxyquinoline-4-yl)oxy]phenyl}-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 12)

[0098] In Example 1, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate, and aniline in step 5 was replaced with 4-chloroaniline. The remaining steps were the same as in Example 1, and compound 12 was obtained. 1H NMR (500 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.55 (dd, J= 10.2, 3.7 Hz, 2H), 8.27 (d, J = 2.3 Hz, 1H), 7.95 (d, J = 8.6 Hz, 2H), 7.62(d, J = 8.9 Hz, 2H), 7.53 (s, 1H), 7.42 (s, 1H), 7.34 (d, J = 8.6 Hz, 2H), 6.95 (d, J = 9.0 Hz, 2H), 6.56 (d, J = 5.2 Hz, 1H), 3.96 (s, 3H), 3.95 (s,3H), 3.75 (s,3H), 3.64 (s, 3H); MS (ESI) m / z: 538.1 [M+H] + .

[0099] Example 13 Synthesis of N-benzyl-5-{4-[(6,7-dimethoxyquinoline-4-yl)oxy]-3-fluorophenyl}-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 13)

[0100] In Example 1, p-bromophenol in step 1 was replaced with 2-fluoro-4-bromophenol, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate in step 3 was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate, and aniline in step 5 was replaced with benzylamine. The remaining steps were the same as in Example 1, yielding compound 13. MS (ESI) m / z: 540.1 [M+H] + .

[0101] Example 14 Synthesis of N-(4-fluorobenzyl)-5-{4-[(6,7-dimethoxyquinoline-4-yl)oxy]-3-fluorophenyl}-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 14)

[0102] In Example 1, p-bromophenol in step 1 was replaced with 2-fluoro-4-bromophenol, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate in step 3 was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate, and aniline in step 5 was replaced with 4-fluorobenzylamine. The remaining steps were the same as in Example 1, yielding compound 14. MS (ESI) m / z: 558.1 [M+H] + .

[0103] Example 15 Synthesis of N-(4-fluorophenyl)-5-{4-[(6,7-dimethoxyquinoline-4-yl)oxy]phenyl}-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 15)

[0104] In Example 1, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate in step 3, and aniline in step 5 was replaced with 4-fluoroaniline. The remaining steps were the same as in Example 1, yielding compound 15. MS (ESI) m / z: 527.2 [M+H] + .

[0105] Example 16 Synthesis of N-(4-fluorobenzyl)-5-{4-[(6,7-dimethoxyquinoline-4-yl)oxy]-3-fluorophenyl}-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 16)

[0106] In Example 1, p-bromophenol in step 1 was replaced with 2-fluoro-4-bromophenol, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate in step 3 was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate, and aniline in step 5 was replaced with 4-fluorobenzylamine. The remaining steps were the same as in Example 1, yielding compound 16. MS (ESI) m / z: 559.1 [M+H] + .

[0107] Example 17 Synthesis of N-phenyl-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl]oxy}phenyl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (compound 17)

[0108] In Example 1, step 1, 4-chloro-6,7-dimethoxyquinoline was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline, and the remaining steps were the same as in Example 1, to obtain compound 17. 1H NMR (500 MHz, CDCl3) δ12.03 (s, 1H), 8.94 (d, J = 2.0 Hz, 1H), 8.52 (d, J = 5.1 Hz, 1H), 7.79 (dd,J = 13.2, 5.0 Hz, 3H), 7.65 - 7.51 (m, 3H), 7.46 (s, 1H), 7.37 (t, J = 7.7Hz, 2H), 7.28 (d, J = 8.9 Hz, 2H), 7.13 (t, J = 7.2 Hz, 1H), 6.53 (d, J = 5.1Hz, 1H), 4.29 (t, J = 6.5 Hz, 2H), 4.03 (s, 3H), 3.84 - 3.58 (m, 7H), 2.59(dd, J = 29.6, 23.0 Hz, 6H), 2.20 - 2.07 (m, 2H); MS (ESI) m / z: 621.2 [M+H] + .

[0109] Example 18 Synthesis of N-(4-fluorophenyl)-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl]oxy}phenyl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (compound 18)

[0110] In Example 1, 4-chloro-6,7-dimethoxyquinoline in step 1 was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline, and aniline in step 5 was replaced with 4-fluoroaniline. The remaining steps were the same as in Example 1, and compound 18 was obtained. 1H NMR (500 MHz, CDCl3) δ 12.02 (s, 1H), 8.92 (d, J = 2.6 Hz, 1H), 8.52 (d, J= 5.2 Hz, 1H), 7.81 (d, J = 2.5 Hz, 1H), 7.74 (dd, J = 8.8, 4.8 Hz, 2H), 7.58(d, J = 8.5 Hz, 2H), 7.53 (s, 1H), 7.46 (s, 1H), 7.28 (d, J = 8.5 Hz, 2H), 7.05 (t, J = 8.6 Hz, 2H), 6.53 (d, J = 5.2 Hz, 1H), 4.29 (t, J = 6.6 Hz, 2H),4.03 (s, 3H), 3.83 - 3.70 (m, 7H), 2.70 - 2.44 (m, 6H), 2.21 - 2.09 (m, 2H);MS (ESI) m / z: 639.2 [M+H] + .

[0111] Example 19 Synthesis of N-benzyl-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl]oxy}phenyl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (compound 19)

[0112] In Example 1, 4-chloro-6,7-dimethoxyquinoline in step 1 was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline, and aniline in step 5 was replaced with benzylamine. The remaining steps were the same as in Example 1, yielding compound 19. MS (ESI) m / z: 635.2 [M+H] + .

[0113] Example 20 Synthesis of N-(4-fluorobenzyl)-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl]oxy}phenyl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (compound 20)

[0114] In Example 1, 4-chloro-6,7-dimethoxyquinoline in step 1 was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline, and aniline in step 5 was replaced with 4-fluorobenzylamine. The remaining steps were the same as in Example 1, yielding compound 20. MS (ESI) m / z: 653.2 [M+H] + .

[0115] Example 21 Synthesis of N-(4-chlorophenyl)-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl]oxy}phenyl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (compound 21)

[0116] In Example 1, 4-chloro-6,7-dimethoxyquinoline in step 1 was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline, and aniline in step 5 was replaced with 4-chloroaniline. The remaining steps were the same as in Example 1, and compound 21 was obtained. 1 H NMR (500 MHz, CDCl3) δ 12.09 (s, 1H), 8.91 (d, J = 2.6 Hz, 1H), 8.52 (d, J= 5.2 Hz, 1H), 7.81 (d, J = 2.5 Hz, 1H), 7.73 (d, J = 8.7 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H), 7.54 (s, 1H), 7.46 (s, 1H), 7.36 - 7.27 (m, 4H), 6.53 (d, J =5.2 Hz, 1H), 4.29 (t, J = 6.6 Hz, 2H), 4.03 (s, 3H), 3.83 - 3.69 (m, 7H),2.64 - 2.45 (m, 6H), 2.21 - 2.10 (m, 2H); MS (ESI) m / z: 655.2 [M+H] + .

[0117] Example 22 Synthesis of N-(4-methoxyphenyl)-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl]oxy}phenyl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (compound 22)

[0118] In Example 1, 4-chloro-6,7-dimethoxyquinoline in step 1 was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline, and aniline in step 5 was replaced with 4-methoxyaniline. The remaining steps were the same as in Example 1, and compound 22 was obtained. 1H NMR (500 MHz, CDCl3) δ 11.90 (s, 1H), 8.92 (d, J = 2.6 Hz, 1H), 8.52 (d,J = 5.2 Hz, 1H), 7.79 (d, J = 2.6 Hz, 1H), 7.70 (d, J = 8.9 Hz, 2H), 7.58 (d,J = 8.5 Hz, 2H), 7.54 (s, 1H), 7.46 (s, 1H), 7.35 - 7.26 (m, 2H), 6.91 (d, J= 8.9 Hz, 2H), 6.53 (d, J = 5.2 Hz, 1H), 4.29 (t, J = 6.5 Hz, 2H), 4.03 (s,3H), 3.87 - 3.70 (m, 10H), 2.59 (dd, J = 29.8, 22.6 Hz, 6H), 2.18 - 2.13 (m,2H).

[0119] Example 23 Synthesis of N-(4-fluorobenzyl)-5-[4-({6-methoxy-7-[3-(4-methyl-1-piperidinyl)propoxy]quinoline-4-yl}oxy)phenyl]-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (compound 23)

[0120] In Example 1, step 1, 4-chloro-6,7-dimethoxyquinoline was replaced with 4-chloro-6-methoxy-7-[3-(4-methyl-1-piperidinyl)propoxy]quinoline, and step 5, aniline was replaced with 4-fluorobenzylamine. The remaining steps were the same as in Example 1, yielding compound 23. MS (ESI) m / z: 665.2 [M+H] + .

[0121] Example 24 Synthesis of N-phenyl-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl]oxy}phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 24)

[0122] In Example 1, 4-chloro-6,7-dimethoxyquinoline in step 1 was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline, and methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate in step 3 was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate. The remaining steps were the same as in Example 1, and compound 24 was obtained. 1H NMR(400 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.75 (s, 1H), 8.47 (d, J = 4.2 Hz, 1H), 8.28 (s, 1H), 7.94 (d, J = 7.7 Hz, 2H), 7.79 (d, J = 7.4 Hz, 2H), 7.50 (s,1H), 7.46 - 7.19 (m, 5H), 7.09 (d, J = 6.7 Hz, 1H), 6.54 (d, J = 4.1 Hz, 1H), 4.19 (s, 2H), 3.93 (s, 3H), 3.71 - 3.54 (m, 7H), 2.49 - 2.23 (m, 6H), 2.09 -1.92 (m, 2H); MS (ESI) m / z: 621.2 [M+H] + .

[0123] Example 25 Synthesis of N-(4-fluorophenyl)-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl]oxy}phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 25)

[0124] In Example 1, 4-chloro-6,7-dimethoxyquinoline in step 1 was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate in step 3 was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate, and aniline in step 5 was replaced with 4-fluoroaniline. The remaining steps were the same as in Example 1, and compound 25 was obtained. 1H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.63 (d, J =2.1 Hz, 1H), 8.50 (d, J = 5.2 Hz, 1H), 8.27 (d, J = 2.2 Hz, 1H), 7.94 (d, J =8.5 Hz, 2H), 7.76 (dd, J = 8.8, 5.1 Hz, 2H), 7.51 (s, 1H), 7.40 (s, 1H), 7.33(d, J = 8.6 Hz, 2H), 7.20 (t, J = 8.8 Hz, 2H), 6.54 (d, J = 5.2 Hz, 1H), 4.20(t, J = 6.1 Hz, 2H), 3.94 (s, 3H), 3.78 - 3.55 (m, 7H), 2.50 - 2.18 (m, 6H), 2.12 - 1.92 (m, 2H).

[0125] Example 26 Synthesis of N-phenyl-5-[4-({6-methoxy-7-[3-(4-methyl-1-piperidinyl)propoxy]quinoline-4-yl}oxy)phenyl]-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 26)

[0126] In Example 1, step 1, 4-chloro-6,7-dimethoxyquinoline was replaced with 4-chloro-6-methoxy-7-[3-(4-methyl-1-piperidinyl)propoxy]quinoline, and step 3, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate, was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate. The remaining steps were the same as in Example 1, yielding compound 26. MS (ESI) m / z: 633.2 [M+H] + .

[0127] Example 27 Synthesis of N-(4-fluorophenyl)-5-[4-({6-methoxy-7-[3-(4-methyl-1-piperidinyl)propoxy]quinoline-4-yl}oxy)phenyl]-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 27)

[0128] In Example 1, step 1, 4-chloro-6,7-dimethoxyquinoline was replaced with 4-chloro-6-methoxy-7-[3-(4-methyl-1-piperidinyl)propoxy]quinoline; step 3, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate; and step 5, aniline was replaced with 4-fluoroaniline. The remaining steps were the same as in Example 1, yielding compound 27. MS (ESI) m / z: 651.2 [M+H] + .

[0129] Example 28 Synthesis of N-(4-fluorophenyl)-5-[4-({6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]quinoline-4-yl}oxy)phenyl]-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 28)

[0130] In Example 1, step 1, 4-chloro-6,7-dimethoxyquinoline was replaced with 4-chloro-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]quinoline; step 3, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate; and step 5, aniline was replaced with 4-fluoroaniline. The remaining steps were the same as in Example 1, yielding compound 28. MS (ESI) m / z: 652.2 [M+H] + .

[0131] Example 29 Synthesis of N-(4-chlorophenyl)-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl]oxy}phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 29)

[0132] In Example 1, 4-chloro-6,7-dimethoxyquinoline in step 1 was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate in step 3 was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate, and aniline in step 5 was replaced with 4-chloroaniline. The remaining steps were the same as in Example 1, and compound 29 was obtained. 1H NMR (500 MHz, CDCl3) δ 9.24 (s, 1H), 8.45 (d, J =5.3 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.64 (d, J =8.8 Hz, 2H), 7.61 - 7.53 (m, 3H), 7.36 (s, 1H), 7.29 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 8.6 Hz, 2H), 6.46 (d, J = 5.3 Hz, 1H), 4.14 (t, J = 6.5 Hz, 2H),4.01 (s, 3H), 3.77 - 3.62 (m, 7H), 2.52 (dd, J = 24.3, 17.0 Hz, 7H), 2.08 (d,J = 7.0 Hz, 2H); MS (ESI) m / z: 637.2 [M+H] + .

[0133] Example 30 Synthesis of N-(4-methoxyphenyl)-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl]oxy}phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 30)

[0134] In Example 1, 4-chloro-6,7-dimethoxyquinoline in step 1 was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate in step 3 was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate, and aniline in step 5 was replaced with 4-methoxyaniline. The remaining steps were the same as in Example 1, and compound 30 was obtained. 1H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.72 -8.43 (m, 2H), 8.27 (s, 1H), 7.95 (d, J = 7.9 Hz, 2H), 7.63 (d, J = 8.2 Hz,2H), 7.52 (s, 1H), 7.41 (s, 1H), 7.33 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.3Hz, 2H), 6.54 (d, J = 4.6 Hz, 1H), 4.19 (s, 2H), 3.93 (s, 3H), 3.79 - 3.53(m, 10H), 2.49 - 2.21(m, 6H), 2.13 - 1.87 (m, 2H); MS (ESI) m / z: 651.2 [M+H] + .

[0135] Example 31 Synthesis of N-(4-bromophenyl)-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl]oxy}phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 31)

[0136] In Example 1, 4-chloro-6,7-dimethoxyquinoline in step 1 was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate in step 3 was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate, and aniline in step 5 was replaced with 4-bromoaniline. The remaining steps were the same as in Example 1, and compound 31 was obtained. 1H NMR (400 MHz, CDCl3) δ 9.38 (s, 1H), 8.42 (d, J =5.3 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 2.1 Hz, 1H), 7.68 - 7.51(m, 5H), 7.41 (d, J = 8.6 Hz, 2H), 7.35 (s, 1H), 7.07 (d, J = 8.5 Hz, 2H), 6.44 (d, J = 5.3 Hz, 1H), 4.12 (t, J = 6.4 Hz, 2H), 4.00 (s, 3H), 3.80 - 3.69(m, 4H), 3.65(s, 3H), 2.54 (dd, J = 19.7, 12.5 Hz, 6H), 2.14 - 2.00 (m, 2H);MS (ESI) m / z: 699.1 [M+H] + .

[0137] Example 32 Synthesis of N-(3-fluorophenyl)-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl]oxy}phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 32)

[0138] In Example 1, 4-chloro-6,7-dimethoxyquinoline in step 1 was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate in step 3 was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate, and aniline in step 5 was replaced with 3-fluoroaniline. The remaining steps were the same as in Example 1, and compound 32 was obtained. 1H NMR (400 MHz, CDCl3) δ 9.07 (s, 1H), 8.48 (d, J =5.1 Hz, 1H), 8.33 (s, 1H), 8.04 (s, 1H), 7.62 (dd, J = 22.1, 13.9 Hz, 4H),7.47 - 7.36 (m, 2H), 7.31 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 8.3 Hz, 2H), 6.87(t, J = 7.6 Hz, 1H), 6.50 (d, J = 5.2 Hz, 1H), 4.19 (t, J = 6.2 Hz, 2H), 4.04(s, 3H), 3.83 - 3.62 (m, 7H), 2.79 - 2.47 (m, 6H), 2.15 - 2.06 (m, 2H); MS(ESI) m / z: 639.3 [M+H] + .

[0139] Example 33 Synthesis of N-(2-fluorophenyl)-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl]oxy}phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 33)

[0140] In Example 1, 4-chloro-6,7-dimethoxyquinoline in step 1 was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate in step 3 was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate, and aniline in step 5 was replaced with 2-fluoroaniline. The remaining steps were the same as in Example 1, and compound 33 was obtained. 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J = 5.3 Hz, 1H), 8.38 - 8.22 (m, 2H), 8.18 (s, 1H), 7.94 (d, J = 2.6 Hz, 1H), 7.79 (d, J = 8.6Hz, 2H), 7.55 (s, 1H), 7.44 (s, 1H), 7.27 - 7.05 (m, 5H), 6.56 (d, J = 5.3Hz, 1H), 4.26 (t, J = 6.6 Hz, 2H), 4.03 (s, 3H), 3.82 - 3.65 (m, 7H), 2.67 -2.46 (m, 6H), 2.20 - 2.09 (m, 2H); MS (ESI) m / z: 639.2 [M+H] + .

[0141] Example 34 Synthesis of N-(2-fluorophenyl)-5-[4-({6-methoxy-7-[3-(4-methyl-1-piperidinyl)propoxy]quinoline-4-yl}oxy)phenyl]-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 34)

[0142] In Example 1, step 1, 4-chloro-6,7-dimethoxyquinoline was replaced with 4-chloro-6-methoxy-7-[3-(4-methyl-1-piperidinyl)propoxy]quinoline; step 3, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate; and step 5, aniline was replaced with 2-fluoroaniline. The remaining steps were the same as in Example 1, yielding compound 34. MS (ESI) m / z: 651.3 [M+H] + .

[0143] Example 35 Synthesis of N-(2-fluorophenyl)-5-[4-({6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]quinoline-4-yl}oxy)phenyl]-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 35)

[0144] In Example 1, step 1, 4-chloro-6,7-dimethoxyquinoline was replaced with 4-chloro-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]quinoline; step 3, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate; and step 5, aniline was replaced with 2-fluoroaniline. The remaining steps were the same as in Example 1, yielding compound 35. MS (ESI) m / z: 652.2 [M+H] + .

[0145] Example 36 Synthesis of N-(3,4-dimethoxyphenyl)-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl]oxy}phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 36)

[0146] In Example 1, 4-chloro-6,7-dimethoxyquinoline in step 1 was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate in step 3 was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate, and aniline in step 5 was replaced with 3,4-dimethoxyaniline. The remaining steps were the same as in Example 1, and compound 36 was obtained. 1 H NMR (400 MHz, CDCl3) δ 8.91 (s, 1H), 8.48 (d, J = 5.2 Hz, 1H), 8.31 (d, J = 1.8 Hz, 1H), 8.06 (s, 1H), 7.65 (d, J = 8.4Hz, 2H), 7.56 (s, 1H), 7.47 (s, 1H), 7.41 (s, 1H), 7.12 (d, J = 8.4 Hz, 3H), 6.82 (d, J = 8.7 Hz, 1H), 6.49 (d, J = 5.3 Hz, 1H), 4.19 (t, J = 6.4 Hz, 2H),4.03 (s, 3H), 3.87 (s, 3H), 3.84 (s, 3H), 3.80 - 3.71 (m, 4H), 3.68 (s, 3H), 2.72 - 2.33 (m, 6H), 2.22 - 2.00 (m, 2H); MS (ESI) m / z: 681.3 [M+H] + .

[0147] Example 37 Synthesis of N-benzyl-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl]oxy}phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 37)

[0148] In Example 1, 4-chloro-6,7-dimethoxyquinoline in step 1 was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate in step 3 was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate, and aniline in step 5 was replaced with benzylamine. The remaining steps were the same as in Example 1, and compound 37 was obtained. 1 H NMR (400 MHz, CDCl3) δ 8.43 (d, J = 5.3 Hz, 1H), 8.21(d, J = 2.4 Hz, 1H), 7.85 (d, J = 2.4 Hz, 1H), 7.68 (d, J = 8.6 Hz, 2H), 7.54(s, 1H), 7.45 - 7.28 (m, 6H), 7.18 - 6.98 (m, 3H), 6.48 (d, J = 5.3 Hz, 1H), 4.63 (d, J = 5.6 Hz, 2H), 4.21 (t, J = 6.5 Hz, 2H), 4.01 (s, 3H), 3.80 - 3.71(m, 4H), 3.66 (s, 3H), 2.65 - 2.47 (m, 6H), 2.19 - 2.08 (m, 2H).

[0149] Example 38 Synthesis of N-benzyl-5-[4-({6-methoxy-7-[3-(4-methyl-1-piperidinyl)propoxy]quinoline-4-yl}oxy)phenyl]-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 38)

[0150] In Example 1, step 1, 4-chloro-6,7-dimethoxyquinoline was replaced with 4-chloro-6-methoxy-7-[3-(4-methyl-1-piperidinyl)propoxy]quinoline; step 3, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate; and step 5, aniline was replaced with benzylamine. The remaining steps were the same as in Example 1, yielding compound 38. MS (ESI) m / z: 647.3 [M+H] + .

[0151] Example 39 Synthesis of N-(4-fluorobenzyl)-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl]oxy}phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 39)

[0152] In Example 1, 4-chloro-6,7-dimethoxyquinoline in step 1 was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate in step 3 was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate, and aniline in step 5 was replaced with 4-fluorobenzylamine. The remaining steps were the same as in Example 1, and compound 39 was obtained. 1 H NMR (500 MHz, CDCl3) δ 8.42 (d, J = 5.3 Hz, 1H), 8.21 (d, J = 2.4 Hz, 1H), 7.87 (d, J = 2.5 Hz, 1H), 7.66 (d, J = 8.6 Hz, 2H), 7.54 (s, 1H), 7.38 (s, 1H), 7.31 (dd, J = 8.4, 5.4 Hz, 2H), 7.25 (t, J = 5.4Hz, 1H), 7.12 (d, J = 8.6 Hz, 2H), 7.00 (t, J = 8.6 Hz, 2H), 6.48 (d, J = 5.3Hz, 1H), 4.59 (d, J = 5.6 Hz, 2H), 4.19 (t, J = 6.5 Hz, 2H), 4.01 (s, 3H), 3.81 - 3.71 (m, 4H), 3.66 (s, 3H), 2.65 - 2.45 (m, 6H), 2.19 - 2.07 (m, 2H).

[0153] Example 40 Synthesis of N-(4-fluorobenzyl)-5-[4-({6-methoxy-7-[3-(4-methyl-1-piperidinyl)propoxy]quinoline-4-yl}oxy)phenyl]-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 40)

[0154] In Example 1, step 1, 4-chloro-6,7-dimethoxyquinoline was replaced with 4-chloro-6-methoxy-7-[3-(4-methyl-1-piperidinyl)propoxy]quinoline; step 3, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate; and step 5, aniline was replaced with 4-fluorobenzylamine. The remaining steps were the same as in Example 1, yielding compound 40. MS (ESI) m / z: 665.3 [M+H] + .

[0155] Example 41 Synthesis of N-(4-fluorobenzyl)-5-[4-({6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]quinoline-4-yl}oxy)phenyl]-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 41)

[0156] In Example 1, step 1, 4-chloro-6,7-dimethoxyquinoline was replaced with 4-chloro-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]quinoline; step 3, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate; and step 5, aniline was replaced with 4-fluorobenzylamine. The remaining steps were the same as in Example 1, yielding compound 41. MS (ESI) m / z: 666.3 [M+H] + .

[0157] Example 42 Synthesis of N-(4-chlorobenzyl)-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl]oxy}phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 42)

[0158] In Example 1, 4-chloro-6,7-dimethoxyquinoline in step 1 was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate in step 3 was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate, and aniline in step 5 was replaced with 4-chlorobenzylamine. The remaining steps were the same as in Example 1, and compound 42 was obtained. 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 4.8 Hz, 1H), 8.20 (s, 1H), 7.89 (s, 1H), 7.77 - 7.43 (m, 4H), 7.44 - 7.23 (m, 5H), 7.09 (d, J = 8.0 Hz, 2H), 6.46 (d, J = 4.7 Hz, 1H), 4.58 (d, J = 4.7 Hz, 2H), 4.16(t, J = 6.6 Hz, 2H), 4.00 (s, 3H), 3.83 - 3.42 (m, 7H), 2.78 - 2.40 (m, 6H),2.21 - 1.97 (m, 2H).

[0159] Example 43 Synthesis of N-(4-bromobenzyl)-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl]oxy}phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 43)

[0160] In Example 1, 4-chloro-6,7-dimethoxyquinoline in step 1 was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate in step 3 was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate, and aniline in step 5 was replaced with 4-bromobenzylamine. The remaining steps were the same as in Example 1, and compound 43 was obtained. 1 H NMR (400 MHz, CDCl3) δ 8.43 (d, J = 5.3 Hz, 1H), 8.20 (d, J = 2.5 Hz, 1H), 7.86 (d, J = 2.5 Hz, 1H), 7.69 (d, J = 8.6 Hz, 2H), 7.54 (s, 1H), 7.47 - 7.42 (m, 2H), 7.39 (s, 1H), 7.22 (d, J = 8.3 Hz, 2H), 7.18 - 7.09 (m, 3H), 6.50 (d, J = 5.3 Hz, 1H), 4.57 (d, J = 5.7 Hz, 2H), 4.21(t, J = 6.6 Hz, 2H), 4.02 (s, 3H), 3.80 - 3.63 (m, 7H), 2.64 - 2.50 (m, 6H), 2.21 - 2.09 (m, 2H).

[0161] Example 44 Synthesis of N-(2-fluorobenzyl)-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl]oxy}phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 44)

[0162] In Example 1, 4-chloro-6,7-dimethoxyquinoline in step 1 was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline; methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate in step 3 was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate; and aniline in step 5 was replaced with 2-fluorobenzylamine. The remaining steps were the same as in Example 1, yielding compound 44. MS (ESI) m / z: 653.2 [M+H] + .

[0163] Example 45 Synthesis of N-(2,4-difluorobenzyl)-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl]oxy}phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 45)

[0164] In Example 1, 4-chloro-6,7-dimethoxyquinoline in step 1 was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline; methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate in step 3 was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate; and aniline in step 5 was replaced with 2,4-difluorobenzylamine. The remaining steps were the same as in Example 1, yielding compound 45. MS (ESI) m / z: 671.2 [M+H] + .

[0165] Example 46 Synthesis of N-cyclohexyl-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl]oxy}phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 46)

[0166] In Example 1, 4-chloro-6,7-dimethoxyquinoline in step 1 was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline; methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate in step 3 was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate; and aniline in step 5 was replaced with cyclohexylamine. The remaining steps were the same as in Example 1, yielding compound 46. MS (ESI) m / z: 627.2 [M+H] + .

[0167] Example 47 Synthesis of N-cyclohexylmethyl-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl]oxy}phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 47)

[0168] In Example 1, 4-chloro-6,7-dimethoxyquinoline in step 1 was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate in step 3 was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate, and aniline in step 5 was replaced with cyclohexylmethylamine. The remaining steps were the same as in Example 1, and compound 47 was obtained. 1 H NMR (400 MHz, CDCl3) δ 8.49 (d, J = 5.2 Hz, 1H),8.14 (d, J = 2.4 Hz, 1H), 7.88 - 7.70 (m, 3H), 7.55 (s, 1H), 7.44 (s, 1H),7.20 (d, J = 8.5 Hz, 2H), 6.54 (d, J = 5.3 Hz, 1H), 6.31 (s, 1H), 4.27 (t, J= 6.5 Hz, 2H), 4.03 (s, 3H), 3.88 - 3.67 (m, 7H), 3.29 (t, J = 6.4 Hz, 2H),2.67 - 2.44 (m, 6H), 2.21 - 2.05 (m, 3H), 1.81 - 1.69 (m, 4H), 1.42 - 1.20 (m, 6H).

[0169] Example 48 Synthesis of N-cyclohexylmethyl-5-[4-({6-methoxy-7-[3-(4-methyl-1-piperidinyl)propoxy]quinoline-4-yl}oxy)phenyl]-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 48)

[0170] In Example 1, step 1, 4-chloro-6,7-dimethoxyquinoline was replaced with 4-chloro-6-methoxy-7-[3-(4-methyl-1-piperidinyl)propoxy]quinoline; step 3, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate; and step 5, aniline was replaced with cyclohexylmethylamine. The remaining steps were the same as in Example 1, yielding compound 48. MS (ESI) m / z: 653.3 [M+H]+ .

[0171] Example 49 Synthesis of N-(1-adamantylmethyl)-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl]oxy}phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 49)

[0172] In Example 1, 4-chloro-6,7-dimethoxyquinoline in step 1 was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate in step 3 was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate, and aniline in step 5 was replaced with 1-aminomethyladamantane. The remaining steps were the same as in Example 1, and compound 49 was obtained. 1 H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 5.2 Hz,1H), 8.15 (d, J = 1.9 Hz, 1H), 7.93 - 7.70 (m, 3H), 7.55 (s, 1H), 7.44 (s,1H), 7.21 (d, J = 8.5 Hz, 2H), 6.56 (d, J = 5.2 Hz, 1H), 6.28 (t, J = 5.4 Hz,1H), 4.27 (t, J = 6.4 Hz, 2H), 4.03 (s, 3H), 3.80 - 3.62 (m, 7H), 3.15 (d, J= 6.2 Hz, 2H), 2.69 - 2.45 (m, 6H), 2.23 - 2.10 (m, 2H), 2.00 (s, 3H), 1.78 -1.54 (m, 12H).

[0173] Example 50 Synthesis of N-phenylethyl-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl]oxy}phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (Compound 50)

[0174] In Example 1, 4-chloro-6,7-dimethoxyquinoline in step 1 was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate in step 3 was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate, and aniline in step 5 was replaced with phenethylamine. The remaining steps were the same as in Example 1, and compound 50 was obtained. 1H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 5.3 Hz, 1H), 8.12(d, J = 2.4 Hz, 1H), 7.81 - 7.68 (m, 3H), 7.55 (s, 1H), 7.44 (s, 1H), 7.32(t, J = 7.2 Hz, 2H), 7.27 - 7.06 (m, 5H), 6.81 - 6.43 (m, 2H), 4.26 (t, J =6.5 Hz, 2H), 4.03 (s, 3H), 3.86 - 3.61 (m, 9H), 2.94 (t, J = 7.0 Hz, 2H),2.70 - 2.44 (m, 6H), 2.26 - 2.09 (m, 2H); MS (ESI) m / z: 649.3 [M+H] + .

[0175] Example 51 Synthesis of N-(4-fluorophenylethyl)-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl]oxy}phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 51)

[0176] In Example 1, 4-chloro-6,7-dimethoxyquinoline in step 1 was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate in step 3 was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate, and aniline in step 5 was replaced with 4-fluorophenylethylamine. The remaining steps were the same as in Example 1, and compound 51 was obtained. 1H NMR (500 MHz, CDCl3) δ 8.45 (d, J = 5.2 Hz, 1H), 8.11 (d, J = 1.7 Hz, 1H), 7.72 (dd, J = 11.8, 5.2 Hz, 3H), 7.55 (s, 1H), 7.43(s, 1H), 7.17 (d, J = 7.9 Hz, 4H), 6.99 (t, J = 8.5 Hz, 2H), 6.62 - 6.39 (m,2H), 4.26 (t, J = 6.5 Hz, 2H), 4.02 (s, 3H), 3.77 - 3.62 (m, 9H), 2.91 (t, J= 7.0 Hz, 2H), 2.63 - 2.43 (m, 6H), 2.21 - 2.07 (m, 2H); MS (ESI) m / z: 667.3[M+H] + .

[0177] Example 52 Synthesis of N-(4-fluorophenylethyl)-5-[4-({6-methoxy-7-[3-(4-methyl-1-piperidinyl)propoxy]quinoline-4-yl}oxy)phenyl]-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 52)

[0178] In Example 1, step 1, 4-chloro-6,7-dimethoxyquinoline was replaced with 4-chloro-6-methoxy-7-[3-(4-methyl-1-piperidinyl)propoxy]quinoline; step 3, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate; and step 5, aniline was replaced with 4-fluorophenylethylamine. The remaining steps were the same as in Example 1, yielding compound 52. MS (ESI) m / z: 679.3 [M+H] + .

[0179] Example 53 Synthesis of N-(4-fluorophenylethyl)-5-[4-({6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]quinoline-4-yl}oxy)phenyl]-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 53)

[0180] In Example 1, step 1, 4-chloro-6,7-dimethoxyquinoline was replaced with 4-chloro-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]quinoline; step 3, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate; and step 5, aniline was replaced with 4-fluorophenylethylamine. The remaining steps were the same as in Example 1, yielding compound 53. MS (ESI) m / z: 680.3 [M+H] + .

[0181] Example 54 Synthesis of N-(2-fluorophenylethyl)-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl]oxy}phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 54)

[0182] In Example 1, 4-chloro-6,7-dimethoxyquinoline in step 1 was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate in step 3 was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate, and aniline in step 5 was replaced with 2-fluorophenylethylamine. The remaining steps were the same as in Example 1, and compound 54 was obtained. 1 H NMR (500 MHz, CDCl3) δ 8.47 (d, J = 5.1 Hz, 1H), 8.09 (s, 1H), 7.75 (d, J = 8.9 Hz, 3H), 7.55 (s, 1H), 7.45 (s, 1H), 7.26 -7.15 (m, 4H), 7.10 (t, J = 7.3 Hz, 1H), 7.04 (t, J = 9.1 Hz, 1H), 6.54 (d, J= 5.1 Hz, 1H), 6.37 (s, 1H), 4.27 (t, J = 6.4 Hz, 2H), 4.02 (s, 3H), 3.81 -3.62 (m, 9H), 2.99 (t, J = 6.6 Hz, 2H), 2.70 - 2.47 (m, 6H), 2.25 - 2.10 (m,2H); MS (ESI) m / z: 667.3 [M+H] + .

[0183] Example 55 Synthesis of N-(4-methoxyphenethyl)-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl]oxy}phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 55)

[0184] In Example 1, 4-chloro-6,7-dimethoxyquinoline in step 1 was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate in step 3 was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate, and aniline in step 5 was replaced with 4-methoxyphenylethylamine. The remaining steps were the same as in Example 1, and compound 55 was obtained. 1 H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 5.3 Hz,1H), 8.10 (d, J = 2.5 Hz, 1H), 7.84 - 7.66 (m, 3H), 7.55 (s, 1H), 7.42 (s,1H), 7.24 - 7.07 (m, 4H), 6.85 (d, J = 8.6 Hz, 2H), 6.52 (d, J = 5.3 Hz, 1H), 6.41 (t, J = 5.6 Hz, 1H), 4.26 (t, J = 6.6 Hz, 2H), 4.03 (s, 3H), 3.77 (s,3H), 3.75 - 3.69 (m, 4H), 3.69 - 3.55 (m, 5H), 2.87 (t, J = 6.9 Hz, 2H), 2.63- 2.43 (m, 6H), 2.19 - 2.11 (m, 2H); MS (ESI) m / z: 679.3 [M+H] + .

[0185] Example 56 Synthesis of N-(4-chlorophenylethyl)-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl]oxy}phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 56)

[0186] In Example 1, 4-chloro-6,7-dimethoxyquinoline in step 1 was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate in step 3 was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate, and aniline in step 5 was replaced with 4-chlorophenylethylamine. The remaining steps were the same as in Example 1, and compound 56 was obtained. 1 H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 5.3 Hz, 1H), 8.11 (d, J = 2.5 Hz, 1H), 7.72 (dd, J = 12.6, 5.6 Hz, 3H), 7.55 (s, 1H), 7.42(s, 1H), 7.26 (d, J = 4.9 Hz, 2H), 7.20 - 7.09 (m, 4H), 6.52 (d, J = 5.3 Hz,2H), 4.25 (t, J = 6.6 Hz, 2H), 4.02 (s, 3H), 3.78 - 3.62 (m, 9H), 2.91 (t, J= 7.0 Hz, 2H), 2.62 - 2.48 (m, 6H), 2.18 - 2.08 (m, 2H).

[0187] Example 57 Synthesis of N-(3-phenylpropyl)-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl]oxy}phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 57)

[0188] In Example 1, 4-chloro-6,7-dimethoxyquinoline in step 1 was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate in step 3 was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate, and aniline in step 5 was replaced with 3-phenyl-1-propylamine. The remaining steps were the same as in Example 1, and compound 57 was obtained. 1H NMR (600 MHz, , CDCl3) δ 8.45 (d, J = 5.2 Hz,1H), 7.99 (d, J = 2.2 Hz, 1H), 7.71 (d, J = 8.5 Hz, 2H), 7.63 (d, J = 2.2Hz,1H), 7.53 (s, 1H), 7.42 (s, 1H), 7.25 - 7.22 (m, 2H), 7.17 (t, J = 7.8 Hz,4H), 7.11 (t, J = 7.2 Hz, 1H), 6.52 (d, J = 5.2 Hz, 1H), 6.28 (br, 1H), 4.24(t, J = 6.6 Hz, 2H), 4.00 (s, 3H), 3.79 - 3.69 (m, 4H), 3.63 (s, 3H), 3.54 -3.42 (m, 2H), 2.71 (t, J = 7.4 Hz, 2H), 2.59 (t, J = 7.1 Hz, 2H), 2.50 (br,4H), 2.17 - 2.07 (m, 2H), 2.00 - 1.88 (m, 2H); MS (ESI) m / z: 663.3 [M+H] + .

[0189] Example 58 Synthesis of N-[3-(4-chlorophenyl)propyl]-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl]oxy}phenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (compound 58)

[0190] In Example 1, 4-chloro-6,7-dimethoxyquinoline in step 1 was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline; methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate in step 3 was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate; and aniline in step 5 was replaced with 3-(4-chlorophenyl)propylamine. The remaining steps were the same as in Example 1, yielding compound 58. MS (ESI) m / z: 697.3 [M+H] + .

[0191] Example 59 Synthesis of N-(3-phenylpropyl)-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl]oxy}phenyl)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 59)

[0192] In Example 1, 4-chloro-6,7-dimethoxyquinoline in step 1 was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline, and methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate in step 3 was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate. The remaining steps were the same as in Example 1, and compound 59 was obtained. 1 H NMR(400 MHz, CDCl3) δ 8.96 (s, 1H), 8.55 (d, J = 5.2 Hz, 1H), 8.28 (s, 1H), 8.03(d, J = 8.7 Hz, 2H), 7.72 (d, J = 7.9 Hz, 2H), 7.53 (s, 1H), 7.47 (s, 1H), 7.42 (t, J = 7.8 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.20 (t, J = 7.4 Hz, 1H), 6.62 (d, J = 5.2 Hz, 1H), 4.29 (t, J = 6.5 Hz, 2H), 4.03 (s, 3H), 4.00 (s,3H), 3.88 - 3.60 (m, 4H), 2.92 - 2.44 (m, 6H), 2.34 - 2.10 (m, 2H); MS (ESI)m / z: 622.3 [M+H] + .

[0193] Example 60 Synthesis of N-(4-fluorophenyl)-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl]oxy}phenyl)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (Compound 60)

[0194] In Example 1, 4-chloro-6,7-dimethoxyquinoline in step 1 was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate in step 3 was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate, and aniline in step 5 was replaced with 4-fluoroaniline. The remaining steps were the same as in Example 1, and compound 60 was obtained. 1H NMR (400 MHz, CDCl3) δ 8.94 (s, 1H), 8.55 (d, J =5.2 Hz, 1H), 8.26 (s, 1H), 8.03 (d, J = 8.6 Hz, 2H), 7.80 - 7.62 (m, 2H),7.53 (s, 1H), 7.48 (s, 1H), 7.29 (d, J = 8.7 Hz, 2H), 7.11 (t, J = 8.6 Hz,2H), 6.62 (d, J = 5.2 Hz, 1H), 4.30 (t, J = 6.5 Hz, 2H), 4.03 (s, 3H), 4.00(s, 3H), 3.87 - 3.65 (m, 4H), 2.77 - 2.41 (m, 6H), 2.31 - 2.09 (m, 2H); MS(ESI) m / z: 640.3 [M+H] + .

[0195] Example 61 Synthesis of N-(4-fluorophenyl)-5-[4-({6-methoxy-7-[3-(4-methyl-1-piperidinyl)propoxy]quinoline-4-yl}oxy)phenyl]-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 61)

[0196] In Example 1, step 1, 4-chloro-6,7-dimethoxyquinoline was replaced with 4-chloro-6-methoxy-7-[3-(4-methyl-1-piperidinyl)propoxy]quinoline; step 3, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate; and step 5, aniline was replaced with 4-fluoroaniline. The remaining steps were the same as in Example 1, yielding compound 61. MS (ESI) m / z: 652.3 [M+H] + .

[0197] Example 62 Synthesis of N-(4-methoxyphenyl)-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl]oxy}phenyl)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 62)

[0198] In Example 1, 4-chloro-6,7-dimethoxyquinoline in step 1 was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate in step 3 was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate, and aniline in step 5 was replaced with 4-methoxyaniline. The remaining steps were the same as in Example 1, and compound 62 was obtained. 1 H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 8.55 (d, J= 5.2 Hz, 1H), 8.28 (s, 1H), 8.04 (d, J = 8.7 Hz, 2H), 7.63 (d, J = 8.9 Hz, 2H), 7.54 (s, 1H), 7.50 (s, 1H), 7.30 (d, J = 9.3 Hz, 2H), 6.96 (d, J = 8.9Hz, 2H), 6.62 (d, J = 5.3 Hz, 1H), 4.30 (t, J = 6.5 Hz, 2H), 4.04 (s, 3H),4.00 (s, 3H), 3.85 (s, 3H), 3.84 - 3.66 (m, 4H), 2.84 - 2.47 (m, 6H), 2.35 -2.13 (m, 2H); MS (ESI) m / z: 652.2 [M+H] + .

[0199] Example 63 Synthesis of N-(4-chlorophenyl)-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl]oxy}phenyl)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 63)

[0200] In Example 1, 4-chloro-6,7-dimethoxyquinoline in step 1 was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate in step 3 was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate, and aniline in step 5 was replaced with 4-chloroaniline. The remaining steps were the same as in Example 1, and compound 63 was obtained. 1H NMR (400 MHz, CDCl3) δ 8.97 (s, 1H), 8.55 (d, J =5.3 Hz, 1H), 8.26 (s, 1H), 8.03 (d, J = 8.7 Hz, 2H), 7.68 (d, J = 8.8 Hz, 2H), 7.52 (s, 1H), 7.48 (s, 1H), 7.38 (d, J = 8.8 Hz, 2H), 7.30 (d, J = 8.9Hz, 2H), 6.62 (d, J = 5.3 Hz, 1H), 4.30 (t, J = 6.6 Hz, 2H), 4.03 (s, 3H),4.00 (s, 3H), 3.89 - 3.66 (m, 4H), 2.87 - 2.40 (m, 6H), 2.34 - 2.07 (m, 2H);MS (ESI) m / z: 656.2 [M+H] + .

[0201] Example 64 Synthesis of N-(4-bromophenyl)-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl]oxy}phenyl)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 64)

[0202] In Example 1, 4-chloro-6,7-dimethoxyquinoline in step 1 was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate in step 3 was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate, and aniline in step 5 was replaced with 4-bromoaniline. The remaining steps were the same as in Example 1, and compound 64 was obtained. 1H NMR (400 MHz, CDCl3) δ 8.97 (s, 1H), 8.54 (d, J =5.1 Hz, 1H), 8.25 (s, 1H), 8.03 (d, J = 8.7 Hz, 2H), 7.63 (d, J = 8.8 Hz,2H), 7.60 - 7.50 (m, 3H), 7.47 (s, 1H), 7.29 (d, J = 8.6 Hz, 2H), 6.61 (d, J= 5.2 Hz, 1H), 4.29 (t, J = 6.6 Hz, 2H), 4.03 (s, 3H), 3.99 (s, 3H), 3.87 -3.65 (m, 4H), 2.61 (dd, J = 24.8, 17.7 Hz, 6H), 2.29 - 2.09 (m, 2H); MS (ESI)m / z: 700.1 [M+H] + .

[0203] Example 65 Synthesis of N-(3,4-dimethoxyphenyl)-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl]oxy}phenyl)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 65)

[0204] In Example 1, 4-chloro-6,7-dimethoxyquinoline in step 1 was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate in step 3 was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate, and aniline in step 5 was replaced with 3,4-dimethoxyaniline. The remaining steps were the same as in Example 1, and compound 65 was obtained. 1H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 8.54 (d, J = 5.2 Hz, 1H), 8.27 (s, 1H), 8.03 (d, J = 8.6 Hz, 1H), 7.50 (d, J =20.1 Hz, 2H), 7.29 (d, J = 8.2 Hz, 1H), 7.11 (dd, J = 8.6, 1.9 Hz, 1H), 6.89(d, J = 8.6 Hz, 1H), 6.62 (d, J = 5.2 Hz, 1H), 4.29 (t, J = 6.5 Hz, 1H), 4.03(s, 1H), 4.00 (s, 1H), 3.95 (s, 1H), 3.91 (s, 1H), 3.85 - 3.63 (m, 2H), 2.80- 2.45 (m, 3H), 2.29 - 2.07 (m, 1H); MS (ESI) m / z: 682.3 [M+H] + .

[0205] Example 66 Synthesis of N-benzyl-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl]oxy}phenyl)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 66)

[0206] In Example 1, step 1, 4-chloro-6,7-dimethoxyquinoline was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline; step 3, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate; and step 5, aniline was replaced with benzylamine. The remaining steps were the same as in Example 1, yielding compound 66. MS (ESI) m / z: 636.3 [M+H] + .

[0207] Example 67 Synthesis of N-(4-fluorobenzyl)-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl]oxy}phenyl)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 67)

[0208] In Example 1, 4-chloro-6,7-dimethoxyquinoline in step 1 was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate in step 3 was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate, and aniline in step 5 was replaced with 4-fluorobenzylamine. The remaining steps were the same as in Example 1, and compound 67 was obtained. 1 H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 5.2 Hz, 1H),8.21 (s, 1H), 8.00 (d, J = 8.7 Hz, 2H), 7.58 - 7.48 (m, 2H), 7.45 (s, 1H),7.40 - 7.27 (m, 4H), 7.12 - 7.00 (m, 2H), 6.60 (d, J = 5.3 Hz, 1H), 4.63 (d,J = 6.1 Hz, 2H), 4.29 (t, J = 6.6 Hz, 2H), 4.03 (s, 3H), 3.90 (d, J = 2.4 Hz,3H), 3.79 - 3.71 (m, 4H), 2.70 - 2.55 (m, 6H), 2.22 - 2.12 (m, 2H).

[0209] Example 68 Synthesis of N-(4-fluorobenzyl)-5-[4-({6-methoxy-7-[3-(4-methyl-1-piperidinyl)propoxy]quinoline-4-yl}oxy)phenyl]-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 68)

[0210] In Example 1, step 1, 4-chloro-6,7-dimethoxyquinoline was replaced with 4-chloro-6-methoxy-7-[3-(4-methyl-1-piperidinyl)propoxy]quinoline; step 3, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate; and step 5, aniline was replaced with 4-fluorobenzylamine. The remaining steps were the same as in Example 1, yielding compound 68. MS (ESI) m / z: 666.3 [M+H] + .

[0211] Example 69 Synthesis of N-(4-fluorophenylethyl)-5-(4-{[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl]oxy}phenyl)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 69)

[0212] In Example 1, 4-chloro-6,7-dimethoxyquinoline in step 1 was replaced with 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate in step 3 was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate, and aniline in step 5 was replaced with 4-fluorophenylethylamine. The remaining steps were the same as in Example 1, and compound 69 was obtained. 1 H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 5.2 Hz, 1H),8.17 (s, 1H), 8.00 (d, J = 8.7 Hz, 2H), 7.52 (s, 1H), 7.46 (s, 1H), 7.34 -7.20 (m, 5H), 7.03 (t, J = 8.7 Hz, 2H), 6.60 (d, J = 5.2 Hz, 1H), 4.29 (t, J= 6.6 Hz, 2H), 4.03 (s, 3H), 3.89 (s, 3H), 3.80 - 3.64 (m, 6H), 2.92 (t, J =7.1 Hz, 2H), 2.66 - 2.50 (m, 6H), 2.24 - 2.10 (m, 2H).

[0213] Example 70 Synthesis of N-phenylethyl-5-[4-({6-methoxy-7-[3-(4-methyl-1-piperidinyl)propoxy]quinoline-4-yl}oxy)phenyl]-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 70)

[0214] In Example 1, step 1, 4-chloro-6,7-dimethoxyquinoline was replaced with 4-chloro-6-methoxy-7-[3-(4-methyl-1-piperidinyl)propoxy]quinoline; step 3, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate; and step 5, aniline was replaced with phenethylamine. The remaining steps were the same as in Example 1, yielding compound 70. MS (ESI) m / z: 662.3 [M+H] + .

[0215] Example 71 Synthesis of N-(4-fluorophenylethyl)-5-[4-({6-methoxy-7-[3-(4-methyl-1-piperidinyl)propoxy]quinolin-4-yl}oxy)phenyl]-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 71)

[0216] In Example 1, step 1, 4-chloro-6,7-dimethoxyquinoline was replaced with 4-chloro-6-methoxy-7-[3-(4-methyl-1-piperidinyl)propoxy]quinoline; step 3, methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate was replaced with methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate; and step 5, aniline was replaced with 4-fluorophenylethylamine. The remaining steps were the same as in Example 1, yielding compound 71. MS (ESI) m / z: 680.3 [M+H] + .

[0217] Example 72 In vitro antitumor cell activity

[0218] Partially synthesized novel 4-phenoxyquinoline compounds containing dihydropyridine amide and dihydropyridazine amide according to the present invention formula (I) were screened in vitro for their inhibitory activity against human gastric cancer cell lines MKN45, AGS, and human breast cancer cell line MCF-7.

[0219] (1) After cell resuscitation and stabilization through 2-3 passages, digest the cells from the bottom of the culture flask using trypsin solution (0.25%). Pour the cell digestion solution into a centrifuge tube, then add culture medium to stop the digestion. Centrifuge the tube at 800 rpm for 10 min, discard the supernatant, add 5 mL of culture medium, mix the cells by pipetting, and add 10 μL of the cell suspension to a cell counting chamber for counting. Adjust the cell concentration to 102. 4 Cells / well. Except for well A1, which was a blank well with no cells added, 100 μL of cell suspension was added to all other wells of the 96-well plate. The 96-well plate was then incubated in an incubator for 24 h.

[0220] (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, and then dilute the sample into solutions of different concentrations in a 24-well plate.

[0221] Add cells to 3 wells for each concentration. The two outer rows and two columns of cells are more susceptible to environmental influences and are used as blank cells. Incubate the 96-well plate in an incubator for 72 hours.

[0222] (3) Discard the drug-containing culture medium in the 96-well plate, wash the cells twice with phosphate-buffered saline (PBS), add 100 μL of MTT (tetrazazole) (0.5 mg / mL) to each well, and incubate for 4 h. Discard the MTT solution and add 100 μL of dimethyl sulfoxide. Shake on a magnetic oscillator to fully dissolve the surviving cells and the MTT reaction product formazan, and then measure the results using a microplate reader. The IC50 of the drug can be determined using the Bliss method. 50Values. The inhibitory activity of the compound on human gastric cancer cell lines MKN45 and AGS and human breast cancer cell line MCF-7 is shown in Table 1. The IC50 values ​​in Table 1 are... 50 ≤1.0 μM, denoted by A, 1.0 μM < IC 50 ≤10.0μM, denoted by B, 10.0μM<IC 50 ≤100.0μM, indicated by C; untested, indicated by ND.

[0223] Table 1. Inhibitory activity of the compounds against three tumor cell lines: MKN45, AGS, and MCF-7.

[0224]

[0225]

[0226]

[0227] Example 73 c-Met enzyme activity assay

[0228] The assay used to measure c-Met kinase activity was based on enzyme-linked immunosorbent assay (ELISA). Specifically, at room temperature, the example compound, 50 pM c-Met (His-labeled recombinant human Met (amino acid 974-terminus), expressed via baculovirus), and 5 µM ATP were incubated for 20 minutes in a 0.25 mg / mL PGT-coated plate in test 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), and finally 1% DMSO (v / v). The reaction mixture was removed by washing, and the phosphorylated polymer substrate was detected using a 0.2 µg / mL phosphotyrosine-specific monoclonal antibody (PY20) conjugated with horseradish peroxidase (HRP). After terminating the color development with 1M phosphate, the color of the substrate (TMB) was quantified by spectrophotometry at 450 nm. The results of the compound's inhibition of c-Met kinase activity at a concentration of 5.0 μM are shown in Table 2. In Table 2, inhibition rates ≥50% are represented by A, 50% < inhibition rate ≤0 by B, and not tested by ND.

[0229] Table 2. Inhibitory activity of compounds against c-Met kinase

[0230]

[0231]

[0232] The experimental results clearly demonstrate that the novel 4-phenoxyquinoline compounds of general formula (I) protected by this invention, containing dihydropyridine amide and dihydropyridazine amide, exhibit excellent in vitro antitumor activity. These compounds show promising potential for the development and application of antitumor drugs.

[0233] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details of the above embodiments. Within the scope of the technical concept of the present invention, various equivalent transformations can be made to the technical solutions of the present invention. To avoid unnecessary repetition, the present invention will not describe the various possible combinations separately. Any modifications, equivalent substitutions, or improvements made within the scope of the technical concept of the present invention are included within the protection scope of the present invention.

Claims

1. A 4-phenoxyquinoline compound containing dihydropyridineamide and dihydropyridazinamide, and a pharmaceutically acceptable salt thereof, characterized in that, The structural formulas of the 4-phenoxyquinoline compounds containing dihydropyridine amide and dihydropyridazinamide, and their pharmaceutically acceptable salts, are shown in general formula (I): ； in: X is selected from 1 to 4 identical or different substituents of the following: hydrogen, halogen, alkyl group containing 1 to 3 carbons, alkoxy group containing 1 to 3 carbons; n is selected from 0, 1, 2, 3, 4; where n is 0, it means that N on the amide is directly connected to Ar; R1 is an alkyl group containing 1-6 carbons or selected from the following groups: ； L is selected from the following groups: ； R2 is selected from hydrogen, alkyl groups containing 1-6 carbons, and cycloalkyl groups containing 3-6 carbons; Ar is selected from cycloalkyl groups containing 3-10 carbons, 3-10 non-aromatic heterocyclic groups, 6-10 aryl groups, and 5-10 heteroaryl groups; wherein the heterocyclic group or heteroaryl group contains 1-3 heteroatoms selected from N, O, or S; the cycloalkyl group containing 3-10 carbons, 3-10 non-aromatic heterocyclic group, 6-10 aryl group, or 5-10 heteroaryl group may optionally be replaced by 1-3 identical or different R3 atoms; R3 is hydrogen, halogen, nitro, amino, cyano, alkyl containing 1-6 carbons, alkoxy containing 1-6 carbons, alkylthio containing 1-6 carbons, alkyl containing 1-6 carbons optionally hydroxyl, amino, or halogenated, alkoxy containing 1-6 carbons optionally hydroxyl, amino, or halogenated, amino substituted with one or two alkyl groups containing 1-6 carbons, alkylamide containing 1-6 carbons, free or salt-forming or esterified or amidated carboxyl group containing 1-6 carbons, alkylsulfinyl group containing 1-6 carbons, alkylsulfonyl group containing 1-6 carbons, alkylacyl group containing 1-6 carbons, alkylcarbamoyl group containing 1-6 carbons, or carbamoyl group substituted with one or two alkyl groups containing 1-6 carbons.

2. A 4-phenoxyquinoline compound containing dihydropyridine amide and dihydropyridazinamide, and its pharmaceutically acceptable salt, as described in claim 1, characterized in that... X is selected from 1 to 4 identical or different substituents of the following: hydrogen, halogen; n is selected from 0, 1, 2, 3; where n is 0, it means that N on the amide is directly connected to Ar; R1 is methyl, ethyl, n-propyl, isopropyl, or selected from the following groups: ； L is selected from the following groups: ； R2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Ar is selected from cycloalkyl groups containing 3-10 carbons, 3-10 non-aromatic heterocyclic groups, 6-10 aryl groups, and 5-10 heteroaryl groups; wherein the heterocyclic group or heteroaryl group contains 1-3 heteroatoms selected from N, O, or S; the cycloalkyl group containing 3-10 carbons, 3-10 non-aromatic heterocyclic group, 6-10 aryl group, or 5-10 heteroaryl group may optionally be replaced by 1-3 identical or different R3 atoms; R3 is hydrogen, halogen, nitro, amino, cyano, alkyl containing 1-6 carbons, alkoxy containing 1-6 carbons, optionally halogenated alkyl containing 1-6 carbons, optionally halogenated alkoxy containing 1-6 carbons, amino substituted with one or two alkyl containing 1-6 carbons, or alkylsulfonyl containing 1-6 carbons.

3. A 4-phenoxyquinoline compound containing dihydropyridine amide and dihydropyridazinamide, and its pharmaceutically acceptable salt, as described in claim 2, is characterized in that... X is selected from 1-2 identical or different substituents of the following: hydrogen, fluorine; n is selected from 0, 1, 2, 3; where n is 0, it means that N on the amide is directly connected to Ar; R1 is methyl or selected from the following groups: ； L is selected from the following groups: ； R2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, and cyclopropyl; Ar is selected from cyclopentyl, cyclohexyl, adamantyl, phenyl, pyridyl, thiophenyl, furanyl, naphthyl, quinolinyl, and indoleyl, wherein the cyclopentyl, cyclohexyl, phenyl, pyridyl, thiophenyl, furanyl, naphthyl, quinolinyl, and indoleyl may optionally be replaced by 1 to 3 identical or different R3s; R3 is hydrogen, halogen, nitro, amino, cyano, alkyl containing 1-6 carbons, alkoxy containing 1-6 carbons, optionally halogenated alkyl containing 1-6 carbons, optionally halogenated alkoxy containing 1-6 carbons, amino substituted with one or two alkyl containing 1-6 carbons, or alkylsulfonyl containing 1-6 carbons.

4. A 4-phenoxyquinoline compound containing dihydropyridine amide and dihydropyridazinamide, and its pharmaceutically acceptable salt, as described in claim 3, is characterized in that... The 4-phenoxyquinoline compounds containing dihydropyridine amide and dihydropyridazinamide have the following structural formula: 。 5. A pharmaceutical composition, characterized in that, The active ingredient and the pharmaceutically acceptable excipient comprise a 4-phenoxyquinoline compound containing dihydropyridine amide and dihydropyridazinamide as described in any one of claims 1-4.

6. The use of a 4-phenoxyquinoline compound containing dihydropyridineamide and dihydropyridazinamide, or a pharmaceutically acceptable salt thereof, as described in any one of claims 1-4, in the preparation of a medicament for treating and / or preventing diseases caused by abnormally high expression of c-Met kinase.

7. The use of a 4-phenoxyquinoline compound containing dihydropyridine amide and dihydropyridazinamide, or a pharmaceutically acceptable salt thereof, as described in any one of claims 1-4, in the preparation of a medicament for treating and / or preventing proliferative diseases.

8. The use of a 4-phenoxyquinoline compound containing dihydropyridine amide and dihydropyridazinamide, or a pharmaceutically acceptable salt thereof, as described in any one of claims 1-4, in the preparation of a medicament for treating and / or preventing cancer.

9. The application according to claim 8, characterized in that, The cancers mentioned include stomach cancer and breast cancer.

Images