A novel quinoline compound containing 6-oxo-1-substituted phenyl-1,6-dihydropyridazine-3-carboxamide and application thereof

Abstract

The application belongs to the field of medicine, and particularly relates to a novel quinoline compound containing 6-oxo-1-substituted phenyl-1,6-dihydropyridazine-3-carboxamide and application thereof. The novel quinoline compound containing 6-oxo-1-substituted phenyl-1,6-dihydropyridazine-3-carboxamide has a structure of general formula (I). The application also relates to the compound of general formula (I) having a strong inhibitory effect on c-Met kinase, and further relates to the use of the compound and a pharmaceutically acceptable salt thereof in the preparation of a drug for treating and / or preventing a disease caused by abnormally high expression of c-Met kinase, in particular, in the preparation of 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, colon cancer, lung cancer, gastrointestinal stromal tumor and imatinib-resistant human gastrointestinal stromal tumor.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a novel quinoline compound containing 6-oxo-1-substituted phenyl-1,6-dihydropyridazine-3-carboxamide, its pharmaceutically acceptable salt, and a pharmaceutical composition containing said compound. This invention also relates to the use of this type of compound and its pharmaceutically acceptable salt in the preparation of remedies for diseases caused by abnormally high expression of c-Met kinase, particularly in the preparation of remedies for treating and / or preventing cancer. Background Technology

[0002] Malignant tumors have become a serious public health problem worldwide, with extremely high morbidity and mortality rates that are increasing year by year. According to a report released by the National Cancer Center of China in 2022, as of 2016, approximately 4.064 million new cancer cases were diagnosed in China, and it is estimated that by 2040, more than 30 million people worldwide will have cancer, and cancer deaths will exceed 16 million. With the rapid development of tumor-related sciences such as tumor genomics, the mechanisms of malignant tumor development are gradually being elucidated. The focus of anti-tumor drug development is shifting from traditional cytotoxic anti-tumor drugs to the research of novel targeted anti-tumor drugs. In recent years, it has become increasingly clear that the transformation of normal cells into cancerous cells, the unlimited proliferation and metastasis of cancer cells, are closely related to various physiological processes within tumor cells, such as signal transduction, cell cycle regulation, and angiogenesis. Dysregulation of signal transduction pathways is a significant reason for the loss of normal cell regulation and unlimited proliferation. Therefore, molecular targeted therapy for tumors, targeting specific tumor-related molecules and key kinases in signaling pathways, is receiving increasing attention from scientists, bringing hope to cancer patients. Compared to traditional cancer treatments, these small-molecule inhibitors that target abnormal signaling molecules and pathways are like "laser guidance," often possessing unique advantages such as directional and localized targeting. They also offer significant benefits, including high efficacy, low dosage, and minimal side effects, greatly improving treatment outcomes.

[0003] Protein tyrosine kinases (PTKs) play a crucial role in tumor cells, participating in signal transduction, cell cycle regulation, and apoptosis induction. Hepatocyte growth factor (HGF) is a multifunctional growth factor involved in pathophysiological activities such as embryogenesis, wound healing, and tumor invasion. c-Met is a transmembrane protein and a high-affinity receptor for HGF; the HGF / c-Met pathway plays a vital role in tumorigenesis and development. Abnormally active HGF / c-Met is closely related to tumorigenesis, division, angiogenesis, invasiveness, metastasis, and drug resistance. c-Met kinase is abnormally highly expressed in various tumor tissues, including lung cancer, gastric cancer, and colon cancer. Located at the intersection of numerous signal transduction pathways leading to tumor formation and metastasis, c-Met kinase can be targeted to simultaneously interfere with multiple signaling pathways, achieving a "one-shot-multiple-effects" approach. Once the abnormally activated HGF / c-Met signaling pathway in tumor cells is blocked, tumor cells will inevitably exhibit a series of changes, including morphological alterations, slowed proliferation, decreased tumorigenicity, and weakened invasiveness. Therefore, c-Met kinase has become a crucial target for targeted anti-tumor therapy. Small molecule inhibitors targeting c-Met kinase have become an important direction in anti-tumor drug research in recent years, and have achieved phased results in tumor treatment. 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, approved by the US FDA in November 2012 for the treatment of unresectable malignant locally advanced or metastatic medullary thyroid carcinoma (MTC). In April 2016, the FDA approved cabozantinib as a second-line treatment for advanced renal cell carcinoma. In December 2017, the FDA approved cabozantinib tablets for expanded indications in the treatment of advanced renal cell carcinoma (RCC), as it also has strong inhibitory effects on kinases such as VEGFR-2, c-Kit, and Flt-3. Foretinib, obtained by replacing the 7-methoxy group of its quinoline ring 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 pyridazine structures possess broad biological activities, often exhibiting antitumor, antibacterial, anti-inflammatory, and antihypertensive properties, thus attracting significant attention from chemists and pharmacologists. In the application of antitumor drugs, pyridazine structural units are frequently introduced into anticancer drugs as antitumor pharmacophores.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

[0004] Based on a summary of the structure-activity relationship of Type II small molecule c-Met kinase inhibitors and analysis of the three-dimensional structure of c-Met proteins, the inventors designed and synthesized a series of novel quinoline compounds containing 6-oxo-1-substituted phenyl-1,6-dihydropyridazine-3-carboxamide. In vitro activity screening showed that these compounds possess antitumor activity. This invention relates to novel quinoline compounds containing 6-oxo-1-substituted phenyl-1,6-dihydropyridazine-3-carboxamide as c-Met inhibitors, which have not been previously reported in the literature.

[0005] The technical solution adopted in this invention is: a novel quinoline compound containing 6-oxo-1-substituted phenyl-1,6-dihydropyridazine-3-carboxamide and its pharmaceutically acceptable salt, the structural formula of which is 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 4 carbons, or alkoxy group containing 1 to 4 carbons;

[0009] R1 is an alkyl group containing 1-6 carbons or selected from the following groups:

[0010]

[0011] R2 is selected from hydrogen, alkyl groups containing 1-6 carbons, cycloalkyl groups containing 3-6 carbons, or alkoxy groups containing 1-6 carbons;

[0012] R3 is selected from cycloalkyl, 3-10-membered heterocycle, 6-10-membered aryl, 5-10-membered heteroaryl, 6-10-membered arylmethyl, 5-10-membered heteroarylmethyl, 6-10-membered arylethyl or 5-10-membered heteroarylethyl, wherein the heterocycle or heteroaryl contains 1-3 heteroatoms selected from N, O or S; the cycloalkyl, 3-10-membered heterocycle, 6-10-membered aryl or 5-10-membered heteroaryl may optionally be replaced by 1-3 identical or different R4s;

[0013] R4 is hydrogen, hydroxyl, halogen, nitro, amino, cyano, alkyl containing 1-6 carbons, alkenyl containing 2-6 carbons, alkynyl containing 2-6 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, alkylsulfinyl containing 1-6 carbons, sulfonyl, alkyl acyl containing 1-6 carbons, carbamoyl, or carbamoyl substituted with one or two alkyl groups containing 1-6 carbons.

[0014] Furthermore, the above-mentioned novel quinoline compound containing 6-oxo-1-substituted phenyl-1,6-dihydropyridazine-3-carboxamide and its pharmaceutically acceptable salt,

[0015] X is selected from 1 to 4 identical or different substituents of the following: hydrogen or halogen;

[0016] R1 is methyl, ethyl, propyl, or selected from the following groups:

[0017]

[0018] R2 is selected from hydrogen, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, or propoxy.

[0019] R3 is selected from cycloalkyl, 3-10-membered heterocycle, 6-10-membered aryl, 5-10-membered heteroaryl, 6-10-membered arylmethyl, 5-10-membered heteroarylmethyl, 6-10-membered arylethyl or 5-10-membered heteroarylethyl, wherein the heterocycle or heteroaryl contains 1-3 heteroatoms selected from N, O or S; the cycloalkyl, 3-10-membered heterocycle, 6-10-membered aryl or 5-10-membered heteroaryl may optionally be replaced by 1-3 identical or different R4s;

[0020] R4 is hydrogen, hydroxyl, halogen, nitro, amino, cyano, alkyl containing 1-6 carbons, alkenyl containing 2-6 carbons, alkynyl containing 2-6 carbons, alkoxy containing 1-6 carbons, or an amino group substituted with one or two alkyl groups containing 1-6 carbons.

[0021] Preferably, the above-mentioned novel quinoline compound containing 6-oxo-1-substituted phenyl-1,6-dihydropyridazine-3-carboxamide and its pharmaceutically acceptable salt are...

[0022] X is selected from 1-2 identical or different substituents of the following: hydrogen or fluorine;

[0023] R1 is a methoxy group or selected from the following groups:

[0024]

[0025] R2 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, methoxy, or ethoxy.

[0026] R3 is selected from cyclopentyl, cyclohexyl, phenyl, pyridyl, thiophene, furan, naphthyl, quinolinyl, indole, phenylmethyl, phenylethyl, pyridylmethyl, or pyridylethyl, wherein the cyclopentyl, cyclohexyl, phenyl, pyridyl, thiophene, furan, naphthyl, quinolinyl, or indole may optionally be replaced by 1 to 3 identical or different R4s;

[0027] R4 is hydrogen, hydroxyl, halogen, nitro, amino, cyano, alkyl containing 1-6 carbons, or alkoxy containing 1-6 carbons.

[0028] Furthermore, the novel quinoline compounds containing 6-oxo-1-substituted phenyl-1,6-dihydropyridazine-3-carboxamide and their pharmaceutically acceptable salts, wherein the compounds of general formula (I) have structural formulas including, but not limited to, the following:

[0029]

[0030]

[0031]

[0032] The following synthetic route describes the preparation of novel quinoline compounds of general formula (I) containing 6-oxo-1-substituted phenyl-1,6-dihydropyridazine-3-carboxamide, 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 as defined below or in the claims.

[0033] Novel quinoline compounds containing 6-oxo-1-substituted phenyl-1,6-dihydropyridazine-3-carboxamide according to general formula (I) of the present invention can all be prepared according to the method of route 1.

[0034]

[0035] According to the compound of general formula (I) of the present invention, when R1 is an alkyl group, intermediate M can be prepared by the method shown in route 2, and other substituents are as defined in the claims, wherein M-1 represents a class of substructures of intermediate M;

[0036]

[0037] According to the compound of general formula (I) of the present invention, when R1 is a group with the following characteristics...

[0038]

[0039] Intermediate M can be prepared by the method shown in Route 3, in which R5 and R6 together with the nitrogen atoms to which they are attached form 4-morpholinyl, 1-piperidinyl, 4-methyl-1-piperidinyl, 4-methyl-1-piperazinyl and 1-pyrrolidinyl, wherein M-2 represents a class of substructures of intermediate M;

[0040]

[0041] When R5 and R6, together with the nitrogen atom to which they are attached, form a 4-morpholino group, i.e., R1 in general formula (I) is... When the group is present, intermediate M-2 can be prepared by reacting morpholine with chloroquinoline compound (k) via a similar route 3;

[0042] When R5 and R6 together with the nitrogen atom to which they are attached form a 1-piperidinyl group, i.e., R1 in general formula (I) is... When the group is present, intermediate M-2 can be prepared by reacting hexahydropyridine with chloroquinoline compound (k) via a similar route 3;

[0043] When R5 and R6 together with the nitrogen atom to which they are attached form a 4-methyl-1-piperidinyl group, i.e., R1 in general formula (I) is... When the group is present, intermediate M-2 can be prepared by reacting 4-methylpiperidine with chloroquinoline compound (k) via a similar route 3;

[0044] When R5 and R6 together with the nitrogen atom to which they are attached form a 4-methyl-1-piperazinyl group, i.e., R1 in general formula (I) is... When the group is present, intermediate M-2 can be prepared by reacting 1-methylpiperazine with chloroquinoline compound (k) via a similar route 3;

[0045] When R5 and R6 together with the nitrogen atom to which they are attached form a 1-pyrroloalkyl group, i.e., R1 in general formula (I) is... When the group is present, intermediate M-2 can be prepared by reacting tetrahydropyrrole with chloroquinoline compound (k) via a similar route 3;

[0046] The substituents R1, R2, R3, and X of all intermediates in the above three routes are as defined in the claims.

[0047] A pharmaceutical composition comprising any one of the above-mentioned novel quinoline compounds containing 6-oxo-1-substituted phenyl-1,6-dihydropyridazine-3-carboxamide and its pharmaceutically acceptable salt as an active ingredient and a pharmaceutically acceptable excipient.

[0048] The use of any of the above-mentioned novel quinoline compounds containing 6-oxo-1-substituted phenyl-1,6-dihydropyridazine-3-carboxamide, their pharmaceutically acceptable salts, or the above-mentioned pharmaceutical compositions in the preparation of medicaments for the treatment and / or prevention of diseases caused by abnormally high expression of c-Met kinase.

[0049] The use of any of the above-mentioned novel quinoline compounds containing 6-oxo-1-substituted phenyl-1,6-dihydropyridazine-3-carboxamide, their pharmaceutically acceptable salts, or the above-mentioned pharmaceutical compositions in the preparation of medicaments for the treatment and / or prevention of proliferative diseases.

[0050] The use of any of the above-mentioned novel quinoline compounds containing 6-oxo-1-substituted phenyl-1,6-dihydropyridazine-3-carboxamide, their pharmaceutically acceptable salts, or the above-mentioned pharmaceutical compositions in the preparation of medicaments for the treatment and / or prevention of cancer.

[0051] Furthermore, the use of any of the above-mentioned novel quinoline compounds containing 6-oxo-1-substituted phenyl-1,6-dihydropyridazine-3-carboxamide, their pharmaceutically acceptable salts, or the above-mentioned pharmaceutical compositions in the preparation of medicaments for the treatment and / or prevention of gastric cancer, colon cancer, lung cancer, gastrointestinal stromal tumors, and imatinib-resistant human gastrointestinal stromal tumors.

[0052] Furthermore, according to some common methods in the field to which this invention pertains, the novel quinoline compounds of general formula (I) of this invention, containing 6-oxo-1-substituted phenyl-1,6-dihydropyridazine-3-carboxamide, can react with acids to form pharmaceutically acceptable salts. Pharmaceutically acceptable addition salts include addition salts of inorganic and organic acids, 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.

[0053] 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, S, such as pyrroleyl, morpholinyl, piperazine, piperidinyl, pyrazolyl, imidazolyl and thiazolyl, etc. This represents the junction of substituents.

[0054] The beneficial effects of this invention are:

[0055] 1. Through in vitro inhibition assays of human gastric cancer cell line MKN45, human colon cancer cell line HT-29, human lung adenocarcinoma A549, human lung cancer cell line H460, human gastrointestinal stromal tumor cell line GIST882, and imatinib-resistant human gastrointestinal stromal tumor cell line GIST1210, 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 cancer, colon cancer, lung cancer, gastrointestinal stromal tumors, and imatinib-resistant human gastrointestinal stromal tumors.

[0056] 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, and are particularly useful in the preparation of medicaments for treating and / or preventing diseases caused by abnormally high expression of c-Met kinase, especially in the preparation of medicaments for treating and / or preventing cancer.

[0057] 3. The quinoline compounds of the present invention containing 6-oxo-1-substituted phenyl-1,6-dihydropyridazine-3-carboxamide have novel chemical structures. Most of the 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

[0058] The examples and preparation methods 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 and preparation methods 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 or ARX-600, and the mass spectrometry was performed using an Agilent 6460QQQ; all reagents used were analytical grade or chemically pure.

[0059] Example 1: Synthesis of N-phenyl-1-[4-(6,7-dimethoxyquinoline-4-oxy)phenyl]-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (Compound 1)

[0060]

[0061] Step 1: Synthesis of 4,5-dimethoxy-2-nitroacetophenone

[0062]

[0063] 120.0 g (0.67 mol) of 3,4-dimethoxyacetophenone was added to 600 mL of dichloromethane and stirred until completely dissolved. The mixture was cooled to -10 °C, and fuming nitric acid (157.4 g (2.50 mol)) was slowly added dropwise. After the addition was complete, the mixture was reacted at -5 °C for 1 h. The reaction solution was poured into 500 mL of ice water, and then 300 mL of dichloromethane was added for extraction. The organic layer was collected and washed with water until the aqueous layer was colorless. The mixture was then washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the dichloromethane was removed by vacuum distillation of the filtrate. The dried product yielded 139.0 g of a pale yellow solid, 4,5-dimethoxy-2-nitroacetophenone. MS (ESI), m / z: 226.00 [M+H] + 248.00 [M+Na] + .

[0064] Step 2: Synthesis of 1-(4,5-dimethoxy-2-nitro)phenyl-3-dimethylamino-2-ene-1-propanone

[0065]

[0066] 113.0 g (0.50 mol) of 4,5-dimethoxy-2-nitroacetophenone was added to 280 mL of toluene, followed by DMF-DMA (179.4 g, 1.50 mol). The mixture was refluxed for 15 h. The reaction solution was cooled to 25 °C with stirring for 4 h to allow crystallization, resulting in a large amount of solid precipitation. The solid was filtered and dried to obtain 113.5 g of a yellow solid, 1-(4,5-dimethoxy-2-nitro)phenyl-3-dimethylamino-2-ene-1-propanone. MS (ESI), m / z: 281.00 [M+H]+ 302.90[M+Na] + .

[0067] Step 3: Synthesis of 4-hydroxy-6,7-dimethoxyquinoline

[0068]

[0069] 1-(4,5-dimethoxy-2-nitro)phenyl-3-dimethylamino-2-ene-1-propanone (108 g, 0.39 mol) was added to 650 mL of glacial acetic acid and stirred until dissolved. Iron powder (64.7 g, 1.16 mol) was slowly added, and the mixture was heated to 90 °C and reacted for 1 h. The reaction solution was cooled to 15 °C to crystallize for 3 h. The crystals were filtered to obtain a brownish-red solid, which was then added to 300 mL of anhydrous methanol and refluxed at 65 °C for 1 h. The mixture was filtered while hot, and the filtrate was evaporated under reduced pressure to dryness to obtain 60.4 g of a brownish-red solid, 4-hydroxy-6,7-dimethoxyquinoline. MS (ESI), m / z: 206.00 [M+H] + .

[0070] Step 4: Synthesis of 4-chloro-6,7-dimethoxyquinoline

[0071]

[0072] 4-Hydroxy-6,7-dimethoxyquinoline (96.5 g, 0.47 mol) was added to 700 mL of acetonitrile. Then, thionyl chloride (386 mL, 4 v / w) and DIPEA (121.6 g, 0.94 mol) were slowly added sequentially with stirring, and the mixture was refluxed for 3 h. The reaction solution was evaporated to dryness under reduced pressure to obtain a brown oily substance. The residue was added to 1.5 L of ice water and stirred vigorously. The pH was adjusted to 12-13 with 10% potassium hydroxide aqueous solution, and the temperature was controlled not to exceed 25 °C. A large amount of solid precipitated out. The solid was extracted with dichloromethane (200 mL × 2), and the organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain 90.8 g of brownish-yellow solid 4-chloro-6,7-dimethoxyquinoline. MS (ESI), m / z: 224.00 [M+H] + .

[0073] Step 5: Synthesis of 6,7-dimethoxy-4-[(4-nitrophenyl)oxy]quinoline

[0074]

[0075] 4-Chloro-6,7-dimethoxyquinoline (98.6 g, 0.44 mol) was added to chlorobenzene (986 mL, 10 v / w). p-Nitrophenol (153.3 g, 1.1 mol) and DIPEA (113.9 g, 0.88 mol) were added sequentially with stirring. After the additions were complete, the mixture was refluxed for 14 h. After the reaction was complete, the reaction solution was cooled to 10 °C with stirring, and crystals were stirred for 4 h. The crystals were obtained by filtration, yielding a yellow-green solid. The solid was dissolved in 600 mL of dichloromethane and washed with 10% sodium hydroxide aqueous solution until the aqueous layer was colorless. The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove dichloromethane, yielding a pale yellow solid of 6,7-dimethoxy-4-[(4-nitrophenyl)oxy]quinoline, 122.9 g. MS (ESI), m / z: 327.00 [M+H] + .

[0076] Step 6: Synthesis of 4-[(6,7-dimethoxy-4-quinolinyl)oxy]aniline

[0077]

[0078] Reduced iron powder (87.8 g, 1.57 mol) and 17 mL concentrated hydrochloric acid were added sequentially to 1300 mL of 90% ethanol. The mixture was heated to reflux, and 6,7-dimethoxy-4-[(4-nitrophenyl)oxy]quinoline (85.3 g, 0.26 mol) was slowly added. After the addition was complete, the mixture was refluxed for 2 h. The mixture was filtered while hot, and most of the solvent was removed by vacuum distillation of the filtrate. The filtrate was then added to 10% potassium carbonate aqueous solution (1 L), stirred for 5 h, filtered, and dried to obtain 64.6 g of yellowish-white solid 4-[(6,7-dimethoxy-4-quinolinyl)oxy]aniline. 1 H-NMR (400MHz, DMSO-d6): δ8.42(d,J=4.1Hz,1H),7.50(s,1H),7.36(s,1H,),6.92(d,J=7.3Hz,2H) ,6.66(d,J=7.3Hz,1H),6.36(d,J=4.1Hz,1H),5.16(s,2H),3.93(s,6H); MS(ESI),m / z:296.60[M+H] + .

[0079] Step 7: Synthesis of ethyl 2-{2-[4-(6,7-dimethoxyquinoline-4-oxy)phenyl]hydrazine}-3-oxobutyrate

[0080]

[0081] 26.00 g (87.74 mmol) of 4-[(6,7-dimethoxy-4-quinolinyl)oxy]aniline and 120.0 mL of water were added to a reaction flask, followed by 24.7 mL of concentrated hydrochloric acid. The reaction system temperature was controlled below 5 °C. NaNO2 solution was added dropwise to the reaction solution in portions. After the addition was complete, the mixture was stirred for 30 min to obtain a diazonium salt solution for later use. In a separate reaction flask, sodium acetate (21.60 g, 263.31 mmol), 120 mL of water, 200 mL of anhydrous ethanol, and ethyl acetoacetate (22.84 g, 175.48 mmol) were added sequentially. The mixture was stirred for 30 min, and the temperature of the mixture was controlled below 5 °C. A diazonium salt solution was slowly added dropwise to the reaction flask. After the addition was complete, the reaction was carried out for 2 h. The mixture was then filtered, the filter cake was washed three times with water, and dried under reduced pressure to obtain 21.81 g of ethyl 2-{2-[4-(6,7-dimethoxyquinoline-4-oxy)phenyl]hydrazine}-3-oxobutyrate. MS (ESI), m / z: 438.20 [M+H] + .

[0082] Step 8: Synthesis of ethyl 1-[4-(6,7-dimethoxyquinoline-4-oxy)phenyl]-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate

[0083]

[0084] Ethyl 2-{2-[4-(6,7-dimethoxyquinoline-4-oxy)phenyl]hydrazine}-3-oxobutyrate (11.00 g, 25.15 mmol) and ethoxyformylmethylenetriphenylphosphine (13.14 g, 37.72 mmol) were added to 150 mL of toluene and refluxed for 12 h. After the reaction was complete, about half of the solvent was evaporated under reduced pressure. The mixture was allowed to stand at room temperature, and the precipitated solid was filtered. The filter cake was washed three times with toluene and dried to give 8.58 g of ethyl 1-[4-(6,7-dimethoxyquinoline-4-oxy)phenyl]-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate, a pale yellow solid. MS (ESI), m / z: 462.20 [M+H] + .

[0085] Step 9: Synthesis of 1-[4-(6,7-dimethoxyquinoline-4-oxy)phenyl]-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid

[0086]

[0087] Ethyl 1-[4-(6,7-dimethoxyquinoline-4-oxy)phenyl]-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (7.00 g, 15.17 mmol), 80 mL tetrahydrofuran, 20 mL water, and sodium hydroxide (1.85 g, 46.25 mmol) were added to a reaction flask, and the mixture was heated to 50 °C and reacted for 6 h. The mixture was concentrated under reduced pressure to remove most of the tetrahydrofuran. 100 mL of water was added, and the mixture was extracted twice with 80 mL of ethyl acetate. The aqueous phase was collected, and the pH was adjusted to 5-6 with hydrochloric acid, resulting in the precipitation of a large amount of solid. The solid was filtered, and the filter cake was washed with water until neutral. The filter cake was then dried under vacuum to obtain 5.96 g of 1-[4-(6,7-dimethoxyquinoline-4-oxy)phenyl]-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid. MS (ESI) m / z: 432.10 [MH] — .

[0088] Step 10: Synthesis of N-phenyl-1-[4-(6,7-dimethoxyquinoline-4-oxy)phenyl]-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (Compound 1)

[0089]

[0090] Add 1-[4-(6,7-dimethoxyquinoline-4-oxy)phenyl]-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (1.20 mmol), aniline (1.00 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.20 mmol), N,N-diisopropylethylamine (1.20 mmol), 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 100 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 by vacuum distillation to obtain a crude product. The crude product was separated by silica gel column chromatography to obtain N-phenyl-1-[4-(6,7-dimethoxyquinoline-4-oxy)phenyl]-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 1). 1HNMR (600MHz, CDCl3) δ8.88 (s, 1H), 8.56 (d, J = 5.1Hz, 1H), 7.73 (d, J = 8.7Hz ,2H),7.62(d,J=8.0Hz,2H),7.53(s,1H),7.46(s,1H),7.37(t,J=7.8Hz,2H ),7.33(d,J=8.7Hz,2H),7.17(t,J=7.4Hz,1H),6.93(s,1H),6.66(d,J=5.2 Hz,1H),4.06(s,3H),4.05(s,3H),2.67(s,3H); MS(ESI),m / z:509.10[M+H] + .

[0091] By replacing appropriate raw materials and reagents, and following the preparation method of Example 1, Examples 2-15 (compounds 2-15) were finally obtained.

[0092] Example 2: Synthesis of N-cyclohexyl-1-[4-(6,7-dimethoxyquinoline-4-oxy)phenyl]-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (Compound 2)

[0093]

[0094] MS(ESI), m / z: 515.2 [M+H] + 537.20 [M+Na] + .

[0095] Example 3: Synthesis of N-(4-fluorophenyl)-1-[4-(6,7-dimethoxyquinoline-4-oxy)phenyl]-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 3)

[0096]

[0097] 1 H NMR (600MHz, CDCl3) δ8.83(s,1H),8.56(d,J=5.2Hz,1H),7.72(d,J=8.8Hz,2H),7.62-7.55(m,2H),7.53(s,1H),7.46(s,1H),7.33(d,J= 8.8Hz,2H),7.07(t,J=8.6Hz,2H),6.93(s,1H),6.65(d,J=5.2Hz,1H),4.06(s,3H),4.05(s,3H),2.67(s,3H); MS(ESI),m / z:527.10[M+H] + .

[0098] Example 4: Synthesis of N-(4-chlorophenyl)-1-[4-(6,7-dimethoxyquinoline-4-oxy)phenyl]-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 4)

[0099]

[0100] 1 H NMR (600MHz, CDCl3): δ8.93(s,1H),8.55(d,J=5.1Hz,1H),7.70(d,J=8.7Hz,2H),7.58(d,J=8.7Hz,2H),7.52(s,1H),7.4 5(s,1H),7.32(d,J=8.7Hz,4H),6.92(s,1H),6.64(d,J=5.2Hz,1H),4.05(s,6H),2.66(s,3H);MS(ESI)m / z:543.10[M+H] + .

[0101] Example 5: Synthesis of N-(4-methoxyphenyl)-1-[4-(6,7-dimethoxyquinoline-4-oxy)phenyl]-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 5)

[0102]

[0103] 1 H NMR (600MHz, CDCl3): δ8.79(s,1H),8.55(d,J=5.1Hz,1H),7.72(d,J=8.8Hz,2H),7.52(d,J=5.5Hz,2H),7.51(s,1H),7.44(s,1H),7.32(d,J= 8.8Hz,2H),6.91(dd,J=8.5,4.9Hz,3H),6.64(d,J=5.2Hz,1H),4.05(s,3H),4.05(s,3H),3.81(s,3H),2.66(s,3H); MS(ESI)m / z:539.20[M+H] + .

[0104] Example 6: Synthesis of N-benzyl-1-[4-(6,7-dimethoxyquinoline-4-oxy)phenyl]-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 6)

[0105]

[0106] MS(ESI) m / z: 523.20 [M+H]+ .

[0107] Example 7: Synthesis of N-phenylethyl-1-[4-(6,7-dimethoxyquinoline-4-oxy)phenyl]-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 7)

[0108]

[0109] MS(ESI) m / z: 537.20 [M+H] + .

[0110] Example 8: Synthesis of N-phenyl-1-[4-(6,7-dimethoxyquinoline-4-oxy)-3-fluorophenyl]-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 8)

[0111]

[0112] 1 H NMR (600MHz, CDCl3): δ8.87(s,1H),8.54(d,J=5.2Hz,1H),7.76-7.52(m,5H),7.50-7.31(m,4H),7.18(t,J=7.4 Hz,1H),6.93(s,1H),6.56(d,J=5.2Hz,1H),4.07(s,3H),4.05(s,3H),2.67(s,3H); MS(ESI)m / z):527.10[M+H] + .

[0113] Example 9: Synthesis of N-cyclohexyl-1-[4-(6,7-dimethoxyquinoline-4-oxy)-3-fluorophenyl]-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 9)

[0114]

[0115] MS(ESI) m / z: 533.20 [M+H] + .

[0116] Example 10: Synthesis of N-(4-fluorophenyl)-1-[4-(6,7-dimethoxyquinoline-4-oxy)-3-fluorophenyl]-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (Compound 10)

[0117]

[0118] 1H NMR (600MHz, CDCl3): δ8.95 (s, 1H), 8.52 (d, J = 5.2Hz, 1H), 7.74-7.50 (m, 5H), 7.42 (s, 1H), 7.38 (t, J = 8.5Hz, 1H), 7.07 (t,J=8.4Hz,2H),6.92(s,1H),6.53(d,J=5.2Hz,1H),4.06(s,3H),4.04(s,3H),2.65(s,3H); MS(ESI)m / z:545.10[M+H] + .

[0119] Example 11: Synthesis of N-(4-methoxyphenyl)-1-[4-(6,7-dimethoxyquinoline-4-oxy)-3-fluorophenyl]-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 11)

[0120]

[0121] 1 H NMR (600MHz, CDCl3): δ8.73(s,1H),8.54(d,J=5.2Hz,1H),7.74-7.63(m,1H),7.62-7.55(m,2H),7.52(d,J=8.5Hz,2H),7.45(s,1H),7.39 (t,J=8.5Hz,1H),7.02-6.82(m,3H),6.56(d,J=5.2Hz,1H),4.07(s,3H),4.06(s,3H),3.81(s,3H),2.66(s,3H); MS(ESI)m / z:557.10[M+H] + .

[0122] Example 12: Synthesis of N-(4-chlorophenyl)-1-[4-(6,7-dimethoxyquinoline-4-oxy)-3-fluorophenyl]-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 12)

[0123]

[0124] 1H NMR (600MHz, CDCl3): δ8.90 (s, 1H), 8.54 (d, J = 5.2Hz, 1H), 7.64 (dd, J = 10.6, 2.5Hz, 1H), 7.61-7.50 (m, 4H), 7.44 (s, 1H), 7.40 (t, J = 8. 5Hz,1H),7.34(d,J=8.5Hz,2H),6.93(s,1H),6.55(d,J=5.2Hz,1H),4.07(s,3H),4.05(s,3H),2.66(s,3H); MS(ESI)m / z:561.10[M+H] + .

[0125] Example 13: Synthesis of N-benzyl-1-[4-(6,7-dimethoxyquinoline-4-oxy)-3-fluorophenyl]-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 13)

[0126]

[0127] MS(ESI) m / z: 541.20 [M+H] + .

[0128] Example 14: Synthesis of N-(4-fluorobenzyl)-1-[4-(6,7-dimethoxyquinoline-4-oxy)-3-fluorophenyl]-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 14)

[0129]

[0130] MS(ESI) m / z: 559.20 [M+H] + .

[0131] Example 15: Synthesis of N-phenylethyl-1-[4-(6,7-dimethoxyquinoline-4-oxy)-3-fluorophenyl]-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 15)

[0132]

[0133] MS (ESI) m / z (%): 555.20 [M+H] + .

[0134] Example 16: Synthesis of N-phenyl-1-{3-fluoro-4-[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-oxy]phenyl}-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 16)

[0135]

[0136] Step 1: Synthesis of 4-(3-chloropropoxy)-3-methoxyacetophenone

[0137]

[0138] 3-Methoxy-4-hydroxyacetophenone (498 g, 3.0 mol) and anhydrous potassium carbonate (579.8 g, 4.2 mol) were added to 2500 mL of N,N-dimethylformamide. 1-Bromo-3-chloropropane (660.5 g, 4.2 mol) was slowly added dropwise at room temperature. After the addition was complete, the reaction was allowed to proceed at room temperature for 20 h. After the reaction was complete, the mixture was filtered. The filter cake was washed with an appropriate amount of N,N-dimethylformamide, and the filtrates were combined. The filtrate was slowly poured into 15 L of ice water while stirring vigorously, resulting in the precipitation of a large amount of white solid. This solid was filtered, and the filter cake was washed three times with copious amounts of water. The filter cake was then dried under vacuum at 40 °C for 48 h to obtain 672.8 g of white powder 4-(3-chloropropoxy)-3-methoxyacetophenone. MS (ESI) m / z: 265.10 [M+Na] + .

[0139] Step 2: Synthesis of 4-(3-chloropropoxy)-3-methoxy-2-nitroacetophenone

[0140]

[0141] 4-(3-chloropropoxy)-3-methoxyacetophenone (400 g, 1.65 mol) was added to 2000 mL of dichloromethane and stirred until dissolved. The solution was then cooled to -10 °C, and fuming nitric acid (310 g, 4.92 mol) was slowly added dropwise. After the addition was complete, the reaction mixture was kept at this temperature for 4 h. After the reaction was complete, the reaction solution was poured into 1000 mL of ice water for extraction. The organic layer was collected and washed with saturated brine until the aqueous layer was neutral. The solution was then dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 410.2 g of a yellow solid, 4-(3-chloropropoxy)-3-methoxy-2-nitroacetophenone. MS (ESI), m / z: 288.10 [M+H] + 310.00 [M+Na] + .

[0142] Step 3: Synthesis of 1-[4-(3-chloropropoxy)-5-methoxy-2-nitrophenyl]-3-(dimethylamino)propyl-2-en-1-one

[0143]

[0144] 300 g (1.04 mol) of 4-(3-chloropropoxy)-3-methoxy-2-nitroacetophenone was added to 1500 mL of toluene and heated to 110 °C until completely dissolved. Then, 621.3 g (5.21 mol) of N,N-dimethylformamide dimethyl acetal (DMF-DMA) was added, and the mixture was refluxed for 16 h. After the reaction was complete, the reaction solution was cooled to approximately 0 °C, and a solid precipitated. The solid was filtered, and the filter cake was dried to obtain 264.7 g of a yellow solid, 1-[4-(3-chloropropoxy)-5-methoxy-2-nitrophenyl]-3-(dimethylamino)propyl-2-en-1-one. ESI-MS [M+H] + (m / z): 343.1, 365.10 [M+Na] + .

[0145] Step 4: Synthesis of 7-(3-chloropropoxy)-6-methoxy-4(1H)-quinolinone

[0146]

[0147] 250 g (0.73 mol) of 1-[4-(3-chloropropoxy)-5-methoxy-2-nitrophenyl]-3-(dimethylamino)propyl-2-en-1-one was added to 2000 mL of glacial acetic acid. The mixture was heated to 40 °C, and after 1-[4-(3-chloropropoxy)-5-methoxy-2-nitrophenyl]-3-(dimethylamino)propyl-2-en-1-one was completely dissolved, iron powder (203.65 g (3.65 mol) was slowly added in portions. The mixture was heated to 80 °C and stirred for 2 h. After the reaction was complete, the reaction solution was filtered while hot, and the filtrate was collected. Upon cooling, a large amount of solid precipitated out. This solid was then filtered to obtain a yellowish-brown solid. The filter cake was dissolved in glacial acetic acid and stirred at 80°C for about 30 minutes. The mixture was then filtered again while hot, and the filtrate was collected. Upon cooling, a solid precipitated. This filtrate was filtered, and the filter cake was washed with water until neutral. After drying, 138.7 g of solid 7-(3-chloropropoxy)-6-methoxy-4(1H)-quinolinone was obtained. MS (ESI) m / z: 268.10 [M+H] + .

[0148] Step 5: Synthesis of 6-methoxy-7-[4-(3-morpholinopropoxy)]-4(1H)-quinolinone

[0149]

[0150] 121 g (0.45 mol) of 7-(3-chloropropoxy)-6-methoxy-4(1H)-quinolinone and 196.9 g (2.26 mol) of morpholine were added to 900 mL of acetonitrile, and the mixture was heated under reflux for 8 h. After the reaction was complete, most of the solvent was evaporated, and the residue was placed in a cold trap to precipitate a solid. The solid was filtered, washed with ethyl acetate, and yielded 126.6 g of solid 6-methoxy-7-[4-(3-morpholinopropoxy)]-4(1H)-quinolinone. ESI-MS (m / z): 319.2 [M+H] + .

[0151] Step 6: Synthesis of 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline

[0152]

[0153] 105.0 g (0.33 mol) of 6-methoxy-7-[4-(3-morpholinopropoxy)]-4(1H)-quinoline and 260 mL of phosphorus oxychloride were added to 550 mL of acetonitrile, and the mixture was refluxed for 6 h. After the reaction was complete, most of the solvent was removed by evaporation under reduced pressure. The residue was added to a large amount of ice-water mixture, and the pH was adjusted to 10 with 10% potassium hydroxide solution. The mixture was extracted with CH2Cl2 (200 mL * 3), and the organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. After cooling, 83.6 g of a grayish-white solid, 4-chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline, was obtained. MS (ESI) m / z: 337.10 [M+H] + .

[0154] Step 7: Synthesis of 4-(2-fluoro-4-nitrophenoxy)-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline

[0155]

[0156] 4-Chloro-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline (81.0 g, 0.24 mol) and 2-fluoro-4-nitrophenol (57.00 g, 0.36 mol) were added to 400 mL of dry chlorobenzene, and the reaction mixture was heated to 145 °C for 30 h. After the reaction was complete, the solvent was evaporated to obtain a gray solid. This solid was dissolved in dichloromethane, washed with saturated potassium carbonate solution, and the organic layer was collected, dried, and the solvent was evaporated to obtain a solid product, 4-(2-fluoro-4-nitrophenoxy)-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline, 78.1 g. MS (ESI) m / z: 458.20 [M+H] + .

[0157] Step 8: Synthesis of 3-fluoro-4-{6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline-4-oxy}aniline

[0158]

[0159] Iron powder (53.00 g, 0.95 mol) and 15 mL concentrated hydrochloric acid were added to 1400 mL of 90% ethanol and stirred for 15 min. Then, 4-(2-fluoro-4-nitrophenoxy)-6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline (73.0 g, 0.16 mol) was added in portions to the reaction solution. After the addition was complete, the mixture was refluxed for 3 h. After the reaction was complete, the mixture was filtered while hot, and the filtrate was collected. Most of the solvent was removed by evaporation under reduced pressure. An appropriate amount of water was added, and the pH of the resulting solution was adjusted to 10 with 10% NaOH aqueous solution. A solid precipitated, which was filtered, washed with water, and dried to obtain a yellow solid crude product. The crude product was recrystallized from 90% ethanol aqueous solution to obtain 51.3 g of 3-fluoro-4-{6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline-4-oxy}aniline. MS (ESI) m / z: 428.20 [M+H] + .

[0160] Step 9: Synthesis of ethyl 2-[2-(3-fluoro-4-{6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline-4-oxy})phenyl)hydrazine]-3-oxobutyrate

[0161]

[0162] Add 15.00 g (35.09 mmol) of 3-fluoro-4-{6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline-4-oxy}aniline and 60 mL of water to a reaction flask, followed by 18 mL of concentrated hydrochloric acid. Maintain the reaction temperature below 5 °C. Add 15 mL of an aqueous solution of NaNO2 (2.91 g, 42.11 mmol) dropwise to the reaction solution. After the addition is complete, stir the reaction mixture for 30 min to obtain a diazonium salt solution. In another reaction flask, add sodium acetate (17.27 g, 210.54 mmol), 60 mL of water, 60 mL of anhydrous ethanol, and ethyl acetoacetate (4.80 g, 36.84 mmol) sequentially. Stir for 30 min, maintaining the temperature of the mixture below 5 °C. Slowly add the diazonium salt solution dropwise to the reaction flask. After the addition is complete, react for 3 h. The mixture was filtered, the filter cake was washed three times with water, and dried under reduced pressure to obtain 15.20 g of ethyl 2-[2-(3-fluoro-4-{6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline-4-oxy})phenyl)hydrazine]-3-oxobutyrate. MS (ESI), m / z: 569.20 [M+H] + .

[0163] Step 10: Synthesis of ethyl 1-(3-fluoro-4-{6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline-4-oxy})phenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate

[0164]

[0165] Ethyl 2-[2-(3-fluoro-4-{6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline-4-oxy})phenyl)hydrazine]-3-oxobutyrate (10.00 g, 17.60 mmol) and ethoxyformylmethylenetriphenylphosphine (9.20 g, 26.40 mmol) were added to 80 mL of toluene and refluxed for 12 h. After the reaction was complete, about half of the solvent was evaporated under reduced pressure. The mixture was allowed to stand at room temperature, and the precipitated solid was filtered. The filter cake was washed three times with toluene and dried to give 8.40 g of a pale yellow solid, 1-(3-fluoro-4-{6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline-4-oxy})phenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate. MS (ESI), m / z: 593.20 [M+H] + .

[0166] Step 11: Synthesis of 1-(3-fluoro-4-{6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline-4-oxy})phenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid

[0167]

[0168] Add ethyl 1-(3-fluoro-4-{6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline-4-oxy})phenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate (6.60 g, 11.14 mmol), 60 mL tetrahydrofuran, 15 mL water, and sodium hydroxide (1.34 g, 33.41 mmol) to the reaction flask, and heat to 50 °C for 8 h. Most of the tetrahydrofuran was removed by vacuum concentration. 100 mL of water was added, and the mixture was extracted twice with 80 mL of ethyl acetate. The aqueous phase was collected, and the pH was adjusted to 5-6 with hydrochloric acid, resulting in the precipitation of a large amount of solid. The solid was filtered, and the filter cake was washed with water until neutral. The filter cake was then dried under vacuum to obtain 4.70 g of 1-(3-fluoro-4-{6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline-4-oxy})phenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid. MS (ESI) m / z: 563.20 [MH] — .

[0169] Step 12: Synthesis of N-phenyl-1-{3-fluoro-4-[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-oxy]phenyl}-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 16)

[0170]

[0171] Add 1-(3-fluoro-4-{6-methoxy-7-[4-(3-morpholinopropoxy)]quinoline-4-oxy})phenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (1.20 mmol), aniline (1.00 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.20 mmol), N,N-diisopropylethylamine (1.20 mmol), 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 100 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 by vacuum distillation to obtain a crude product. The crude product was separated by silica gel column chromatography to obtain N-phenyl-1-{3-fluoro-4-[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-oxy]phenyl}-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 16). 1 H NMR (600MHz, CDCl3): δ8.83 (s, 1H), 8.54 (d, J = 5.2Hz, 1H), 7.77-7.60 (m, 3H), 7.60-7 .52(m,2H),7.46(s,1H),7.39(m,3H),7.18(t,J=7.4Hz,1H),6.93(s,1H),6.55(d,J= 5.2Hz,1H),4.28(t,J=6.7Hz,2H),4.04(d,J=7.0Hz,3H),3.82-3.63(m,4H),2.67(s, 3H),2.58(t,J=7.2Hz,2H),2.49(s,4H),2.19-2.08(m,2H); MS(ESI)m / z:640.20[M+H] + .

[0172] By replacing appropriate raw materials and reagents, and following the preparation method of Example 16, Examples 17-52 (compounds 17-52) were finally obtained.

[0173] Example 17: Synthesis of N-cyclohexyl-1-{3-fluoro-4-[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-oxy]phenyl}-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 17)

[0174]

[0175] 1 H NMR (600MHz, CDCl3) δ8.54 (d, J = 5.2Hz, 1H), 7.67-7.59 (m, 1H), 7.58-7.51 (m, 2H), 7.46 (s, 1H), 7.37 ( t,J=8.5Hz,1H),6.88(s,1H),6.79(d,J=8.0Hz,1H),6.55(d,J=5.2Hz,1H),4.29(t,J=6.6Hz,2H),4.0 5(s,3H),3.94-3.82(m,1H),3.73(t,J=4.5Hz,4H),2.66-2.55(m,5H),2.50(s,4H),2.18-2.10(m,2H) ,2.05-1.96(m,2H),1.79-1.73(m,2H),1.47-1.36(m,2H),1.32-1.13(m,4H); MS(ESI)m / z:646.3[M+H] + 668.3 [M+Na] + .

[0176] Example 18: Synthesis of N-(4-fluorophenyl)-1-{3-fluoro-4-[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-oxy]phenyl}-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 18)

[0177]

[0178] 1H NMR (600MHz, CDCl3) δ8.78 (s, 1H), 8.54 (d, J = 4.8Hz, 1H), 7.66 (dd, J = 10.6, 2.2Hz, 1H), 7.62-7.51(m,4H),7.46(s,1H),7.40(t,J=8.5Hz,1H),7.08(t,J=8.6Hz,2H),6.94(s,1H ),6.55(d,J=5.2Hz,1H),4.29(t,J=6.5Hz,2H),4.05(s,3H),3.73(t,J=4.3Hz,4H),2.67 (s,3H),2.59(t,J=6.8Hz,2H),2.50(s,4H),2.20-2.09(m,2H);MS(ESI)m / z:658.2[M+H] + 680.3 [M+Na] + .

[0179] Example 19: Synthesis of N-(2,4-difluorophenyl)-1-{3-fluoro-4-[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-oxy]phenyl}-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 19)

[0180]

[0181] 1 H NMR (600MHz, CDCl3): δ9.00 (s, 1H), 8.54 (d, J = 5.2Hz, 1H), 8.39-8.21 (m, 1H), 7.70 (dd, J = 10.6 ,2.2Hz,1H),7.59(d,J=8.4Hz,1H),7.56(s,1H),7.47(s,1H),7.40(t,J=8.5Hz,1H),7.02-6.8 4(m,3H),6.56(d,J=5.1Hz,1H),4.29(t,J=6.6Hz,2H),4.05(s,3H),3.73(t,J=4.3Hz,4H),2.6 8(s,3H),2.58(t,J=7.1Hz,2H),2.49(s,5H),2.14(p,J=6.7Hz,2H); MS(ESI)m / z:676.20[M+H] + .

[0182] Example 20: Synthesis of N-(4-methoxyphenyl)-1-{3-fluoro-4-[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-oxy]phenyl}-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (Compound 20)

[0183]

[0184] 1 H NMR (600MHz, CDCl3): δ8.68(s,1H),8.54(d,J=5.2Hz,1H),7.67(dd,J=10.6,2.5Hz,1H),7.61- 7.55(m,2H),7.54-7.49(m,2H),7.46(s,1H),7.40(t,J=8.5Hz,1H),6.99-6.88(m,3H),6.55(d, J=5.3Hz,1H),4.29(t,J=6.7Hz,2H),4.05(s,3H),3.82(s,3H),3.73(t,J=4.7Hz,4H),2.67(d, J=1.3Hz,3H),2.58(t,J=7.1Hz,2H),2.49(s,4H),2.19-2.08(m,2H); MS(ESI)m / z:670.20[M+H] + 692.2[M+Na] + .

[0185] Example 21: Synthesis of N-(4-methylphenyl)-1-{3-fluoro-4-[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-oxy]phenyl}-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 21)

[0186]

[0187] 1 H NMR (600MHz, CDCl3): δ8.82 (s, 1H), 8.53 (d, J = 5.3Hz, 1H), 7.66 (dd, J = 10.7, 2.5Hz, 1H), 7.60-7. 54(m,2H),7.50(d,J=8.3Hz,2H),7.45(s,1H),7.39(t,J=8.5Hz,1H),7.18(d,J=8.1Hz,2H),6.92( s,1H),6.55(d,J=5.2Hz,1H),4.28(t,J=6.6Hz,2H),4.04(s,3H),3.73(t,J=4.6Hz,4H),2.66(s, 3H),2.58(t,J=7.1Hz,2H),2.49(s,4H),2.34(s,3H),2.18-2.09(m,2H); MS(ESI)m / z:654.2[M+H] + 676.2 [M+Na] + .

[0188] Example 22: Synthesis of N-(4-chlorophenyl)-1-{3-fluoro-4-[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-oxy]phenyl}-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 22)

[0189]

[0190] 1 H NMR (600MHz, CDCl3): δ8.94(s,1H),8.52(d,J=5.0Hz,1H),7.63(d,J=10.5Hz,1H),7.59(d ,J=8.6Hz,2H),7.56-7.49(m,2H),7.44(s,1H),7.39(t,J=8.5Hz,1H),7.33(d,J=8.6Hz,2H ),6.93(s,1H),6.53(d,J=5.0Hz,1H),4.27(t,J=6.5Hz,2H),4.04(s,3H),3.73(s,4H),2.6 6(s,3H),2.58(t,J=7.0Hz,2H),2.49(s,4H),2.20-2.07(m,2H); MS(ESI)m / z:674.20[M+H] + .

[0191] Example 23: Synthesis of N-(3-fluorophenyl)-1-{3-fluoro-4-[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-oxy]phenyl}-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 23)

[0192]

[0193] 1H NMR (600MHz, CDCl3): δ8.87(s,1H),8.54(d,J=5.0Hz,1H),7.65(d,J=8.8Hz,1H),7.60(d,J=10.7Hz, 1H),7.57-7.51(m,2H),7.46(s,1H),7.40(t,J=8.5Hz,1H),7.32(dd,J=14.5,7.9Hz,1H),7.25(s,1H) ,6.95(s,1H),6.88(t,J=7.4Hz,1H),6.56(d,J=5.1Hz,1H),4.28(t,J=6.5Hz,2H),4.05(s,3H),3.73 (s,4H),2.68(s,3H),2.59(t,J=6.9Hz,2H),2.50(s,4H),2.19-2.09(m,2H);MS(ESI)m / z:658.2[M+H] + 680.2 [M+Na] + .

[0194] Example 24: Synthesis of N-(2-fluorophenyl)-1-{3-fluoro-4-[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-oxy]phenyl}-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 24)

[0195]

[0196] 1 H NMR (600MHz, CDCl3): δ9.13 (s, 1H), 8.55 (d, J = 5.2Hz, 1H), 8.37 (t, J = 7.9Hz, 1H), 7.72 (dd, J = 10.7, 2.1Hz, 1H),7.60(d,J=8.1Hz,1H),7.58-7.54(m,1H),7.46(d,J=4.4Hz,1H),7.40(t,J=8.5Hz,1H),7.20(t,J=7.2H z,1H),7.17-7.06(m,2H),6.95(s,1H),6.57(d,J=5.2Hz,1H),4.29(t,J=6.6Hz,2H),4.05(s,4H),3.74(t, J=4.3Hz,5H),2.68(s,3H),2.59(t,J=7.1Hz,3H),2.51(s,5H),2.17-2.12(m,2H); MS(ESI)m / z:658.2[M+H] + 680.2 [M+Na] + .

[0197] Example 25: Synthesis of N-benzyl-1-{3-fluoro-4-[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-oxy]phenyl}-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (Compound 25)

[0198]

[0199] 1 H NMR (600MHz, CDCl3) δ8.51(d,J=5.2Hz,1H),7.59(dd,J=10.7,2.4Hz,1H),7.54(s,1H),7. 50(d,J=8.7Hz,1H),7.45(s,1H),7.40-7.29(m,7H),6.90(d,J=0.9Hz,1H),6.52(d,J=5.2H z,1H),4.61(d,J=6.0Hz,2H),4.28(t,J=6.6Hz,2H),4.03(s,3H),3.73(t,J=4.5Hz,4H),2. 64(s,3H),2.59(t,J=7.1Hz,2H),2.50(s,4H),2.17-2.10(m,2H);MS(ESI)m / z:654.2[M+H] + 676.3 [M+Na] + .

[0200] Example 26: Synthesis of N-(4-fluorobenzyl)-1-{3-fluoro-4-[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-oxy]phenyl}-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 26)

[0201]

[0202] MS(ESI) m / z: 672.2 [M+H] + 694.2 [M+Na] + .

[0203] Example 27: Synthesis of N-phenylethyl-1-{3-fluoro-4-[6-methoxy-7-(3-morpholinopropoxy)quinoline-4-oxy]phenyl}-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 27)

[0204]

[0205] 1H NMR (600MHz, CDCl3) δ8.46 (d, J = 5.2Hz, 1H), 7.61-7.45 (m, 2H), 7.44-7.34 (m, 2H), 7.25-7.2 2(m,2H),7.19(s,1H),7.18-7.13(m,3H),6.93(t,J=5.3Hz,1H),6.80(s,1H),6.44(d,J=5.2 Hz,1H),4.22(t,J=6.6Hz,2H),3.98(s,3H),3.66(t,J=4.4Hz,4H),3.63-3.56(m,2H),2.85( t,J=6.8Hz,2H),2.59-2.49(m,5H),2.43(s,4H),2.12-2.05(m,2H); MS(ESI)m / z:668.3[M+H] + 690.2 [M+Na] + .

[0206] Example 28: Synthesis of N-phenyl-1-(3-fluoro-4-{6-methoxy-7-[3-(1-piperidinyl)propoxy]quinoline-4-oxy}phenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 28)

[0207]

[0208] MS(ESI) m / z: 672.2 [M+H] + 694.2 [M+Na] + .

[0209] Example 29: Synthesis of N-(4-fluorophenyl)-1-(3-fluoro-4-{6-methoxy-7-[3-(1-piperidinyl)propoxy]quinoline-4-oxy}phenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 29)

[0210]

[0211] MS(ESI) m / z: 656.2 [M+H] + 678.3 [M+Na] + .

[0212] Example 30: Synthesis of N-(4-fluorophenyl)-1-(3-fluoro-4-{6-methoxy-7-[3-(1-piperidinyl)propoxy]quinoline-4-oxy}phenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 30)

[0213]

[0214] MS(ESI) m / z: 656.2 [M+H] + 678.3 [M+Na] + .

[0215] Example 31: Synthesis of N-phenyl-1-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-1-piperidinyl)propoxy]quinoline-4-oxy}phenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 31)

[0216]

[0217] 1 H NMR (600MHz, CDCl3) δ8.80(s,1H),8.55(d,J=5.2Hz,1H),7.67(dd,J=10.6,2.4Hz,1H),7.62(d,J =7.7Hz,2H),7.59-7.53(m,2H),7.47-7.34(m,4H),7.18(t,J=7.4Hz,1H),6.94(s,1H),6.56(d,J= 5.2Hz,1H),4.27(t,J=6.1Hz,2H),4.04(s,3H),3.24(s,2H),2.91(s,2H),2.68(s,3H),2.35(s,4H ),1.75(d,J=10.7Hz,2H),1.56(d,J=42.8Hz,3H),0.99(d,J=6.0Hz,3H); MS(ESI)m / z:652.3[M+H] + 674.3 [M+Na] + .

[0218] Example 32: Synthesis of N-cyclohexyl-1-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-1-piperidinyl)propoxy]quinoline-4-oxy}phenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 32)

[0219]

[0220] 1H NMR (600MHz, CDCl3) δ8.54(d,J=5.2Hz,1H),7.62(dd,J=10.7,2.3Hz,1H),7.57-7.49(m,2H),7.44(s,1H),7.37(t,J=8 .5Hz,1H),6.88(s,1H),6.80(d,J=8.2Hz,1H),6.55(d,J=5.2Hz,1H),4.27(t,J=6.5Hz,2H),4.04(s,3H),3.94-3.84(m, 1H),3.05(d,J=9.9Hz,2H),2.69(s,2H),2.60(s,3H),2.27-2.18(m,2H),2.11(s,2H),2.00(d,J=9.5Hz,2H),1.81-1.7 2(m,2H),1.67(t,J=12.5Hz,3H),1.50-1.32(m,5H),1.29-1.18(m,3H),0.95(d,J=6.1Hz,3H); MS(ESI)m / z:658.2[M+H] + 680.2 [M+Na] + .

[0221] Example 33: Synthesis of N-(4-fluorophenyl)-1-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-1-piperidinyl)propoxy]quinoline-4-oxy}phenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 33)

[0222]

[0223] 1H NMR (600MHz, CDCl3) δ8.91 (s, 1H), 8.52 (d, J = 5.2Hz, 1H), 7.64 (dd, J = 10.6, 2.5Hz, 1H), 7.62-7.57 (m, 2H), 7.56 -7.52(m,2H),7.43(s,1H),7.38(t,J=8.5Hz,1H),7.07(t,J=8.6Hz,2H),6.93(s,1H),6.53(d,J=5.2Hz,1H),4. 24(t,J=6.6Hz,2H),4.04(s,3H),2.97(d,J=11.3Hz,2H),2.66(s,3H),2.62-2.56(m,2H),2.22-2.10(m,2H),2. 01(t,J=11.2Hz,2H),1.64(d,J=12.8Hz,2H),1.33-1.22(m,3H),0.93(d,J=6.4Hz,3H); MS(ESI)m / z:670.3[M+H] + 692.2[M+Na] + .

[0224] Example 34: Synthesis of N-(2,4-difluorophenyl)-1-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-1-piperidinyl)propoxy]quinoline-4-oxy}phenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 34)

[0225]

[0226] 1 H NMR(600MHz, CDCl3)δ9.01(s,1H),8.56(s,1H),8.30(m,1H),7.75-7.35(m ,5H),7.14-6.73(m,3H),6.56(d,J=5.1Hz,1H),4.27(t,J=6.1Hz,2H),4.0 4(s,3H),2.99(s,2H),2.65(br,5H),2.19(s,2H),2.04(s,2H),1.66(d,J= 11.8Hz,2H),1.36(br,3H),0.94(d,J=6.0Hz,3H); MS(ESI)m / z:688.3[M+H] + .

[0227] Example 35: Synthesis of N-(4-methoxyphenyl)-1-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-1-piperidinyl)propoxy]quinoline-4-oxy}phenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 35)

[0228]

[0229] 1 H NMR (600MHz, CDCl3) δ8.74(s,1H),8.53(d,J=5.2Hz,1H),7.66(dd,J=10.6,2.2Hz,1H),7.62-7.48(m,4 H),7.44(s,1H),7.39(t,J=8.5Hz,1H),7.07-6.80(m,3H),6.54(d,J=5.1Hz,1H),4.25(t,J=6.4Hz,2H) ,4.04(s,3H),3.81(s,3H),3.06(d,J=10.3Hz,2H),2.69(br,2H),2.66(s,3H),2.25-2.17(m,2H),2.12 (t,J=10.5Hz,2H),1.67(d,J=12.6Hz,2H),1.39(m,3H),0.95(d,J=6.1Hz,3H); MS(ESI)m / z:682.2[M+H] + .

[0230] Example 36: Synthesis of N-(4-methylphenyl)-1-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-1-piperidinyl)propoxy]quinoline-4-oxy}phenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 36)

[0231]

[0232] 1H NMR (600MHz, CDCl3) δ8.75 (s, 1H), 8.54 (d, J = 5.2Hz, 1H), 7.66 (dd, J = 10.6, 2.0Hz, 1H), 7.61-7.53 (m, 2H), 7.50 (d, J = 8. 2Hz,2H),7.45(s,1H),7.39(t,J=8.5Hz,1H),7.18(d,J=8.2Hz,2H),6.93(s,1H),6.55(d,J=5.1Hz,1H),4.26(t,J=6.7H z,2H),4.04(s,3H),2.93(d,J=10.5Hz,2H),2.67(s,3H),2.56(t,J=6.9Hz,2H),2.34(s,3H),2.20-2.11(m,2H),1.97(t ,J=10.9Hz,2H),1.63(d,J=12.4Hz,2H),1.37(s,1H),1.31-1.22(m,2H),0.93(d,J=6.4Hz,3H); MS(ESI)m / z:666.3[M+H] + .

[0233] Example 37: Synthesis of N-(4-chlorophenyl)-1-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-1-piperidinyl)propoxy]quinoline-4-oxy}phenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 37)

[0234]

[0235] 1 H NMR (600MHz, CDCl3) δ9.11-8.74(m,1H),8.52(d,J=5.1Hz,1H),7.64(dd,J=10.5,2.0Hz,1H),7.59(d,J=8.7 Hz,2H),7.54(d,J=5.5Hz,2H),7.43(s,1H),7.39(t,J=8.5Hz,1H),7.34(d,J=8.7Hz,2H),6.93(s,1H),6.54( d,J=5.1Hz,1H),4.25(t,J=6.5Hz,2H),4.04(s,3H),3.01(d,J=9.6Hz,2H),2.75-2.57(m,5H),2.24-2.14(m, 2H),2.06(s,2H),1.66(d,J=12.1Hz,2H),1.46-1.31(m,3H),0.94(d,J=6.1Hz,3H); MS(ESI)m / z:686.2[M+H] + .

[0236] Example 38: Synthesis of N-(3-fluorophenyl)-1-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-1-piperidinyl)propoxy]quinoline-4-oxy}phenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 38)

[0237]

[0238] 1 H NMR (600MHz, CDCl3) δ8.88(s,1H),8.54(d,J=5.2Hz,1H),7.65(dd,J=10.5,2.0Hz,1H),7.60(d,J=10.6Hz,1H ),7.54(d,J=5.5Hz,2H),7.44(s,1H),7.40(t,J=8.5Hz,1H),7.35-7.29(m,1H),7.02-6.92(m,1H),6.88(t,J= 7.4Hz,1H),6.55(d,J=5.1Hz,1H),4.26(t,J=6.5Hz,2H),4.04(s,3H),3.00(s,2H),2.78-2.50(m,5H),2.19(s ,2H),2.06(s,2H),1.66(d,J=12.0Hz,2H),1.50-1.20(m,4H),0.94(d,J=6.1Hz,3H); MS(ESI)m / z:670.3[M+H] + .

[0239] Example 39: Synthesis of N-(2-fluorophenyl)-1-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-1-piperidinyl)propoxy]quinoline-4-oxy}phenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 39)

[0240]

[0241] 1H NMR (600MHz, CDCl3) δ9.13 (s, 1H), 8.54 (d, J = 5.1Hz, 1H), 8.37 (t, J = 7.8Hz, 1H), 7.72 (d, J = 9.2Hz, 1H), 7.60 (d, J = 8.7Hz, 1H),7.55(s,1H),7.45(s,1H),7.40(t,J=8.5Hz,1H),7.20(t,J=6.9Hz,1H),7.13(dd,J=10.8,4.2Hz,2H),6.95(s,1H),6 .56(d,J=5.0Hz,1H),4.26(t,J=6.5Hz,2H),4.04(s,3H),2.98(d,J=10.0Hz,2H),2.68(s,3H),2.61(s,2H),2.25-2.11(m ,2H),2.02(t,J=10.6Hz,2H),1.65(d,J=12.3Hz,2H),1.36-1.11(m,3H),0.94(d,J=6.3Hz,3H); MS(ESI)m / z:670.3[M+H] + .

[0242] Example 40: Synthesis of N-benzyl-1-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-1-piperidinyl)propoxy]quinoline-4-oxy}phenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 40)

[0243]

[0244] 1 H NMR (600MHz, CDCl3) δ8.51(d,J=5.2Hz,1H),7.59(dd,J=10.7,2.3Hz,1H),7.53(s,1H),7.49(d,J=8.7Hz,1H ),7.43(s,1H),7.41-7.27(m,7H),6.90(s,1H),6.51(d,J=5.2Hz,1H),4.61(d,J=6.0Hz,2H),4.25(t,J=6.6H z,2H),4.03(s,3H),3.01(d,J=10.9Hz,2H),2.72-2.59(m,5H),2.26-2.14(m,2H),2.07(t,J=11.3Hz,2H),1 .66(d,J=12.8Hz,2H),1.47-1.37(m,1H),1.36-1.28(m,2H),0.94(d,J=6.4Hz,3H); MS(ESI)m / z:666.3[M+H] + .

[0245] Example 41: Synthesis of N-(4-fluorobenzyl)-1-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-1-piperidinyl)propoxy]quinoline-4-oxy}phenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 41)

[0246]

[0247] MS(ESI) m / z: 684.3 [M+H] + .

[0248] Example 42: Synthesis of N-phenylethyl-1-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-1-piperidinyl)propoxy]quinoline-4-oxy}phenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 42)

[0249]

[0250] 11 H NMR (600MHz, CDCl3) δ8.53 (d, J = 5.1Hz, 1H), 7.64-7.52 (m, 2H), 7.51-7.40 (m, 2H), 7.38-7.29 (m, 3H), 7. 23(d,J=7.3Hz,3H),7.01(br,1H),6.87(s,1H),6.51(d,J=5.1Hz,1H),4.27(t,J=6.3Hz,2H),4.05(s,3H ),3.68(dd,J=12.9,6.5Hz,2H),3.09(d,J=7.8Hz,2H),2.92(t,J=6.7Hz,2H),2.74(s,2H),2.60(s,3H), 2.32-2.08(m,4H),1.70(d,J=10.3Hz,2H),1.43(s,3H),0.96(d,J=5.0Hz,3H); MS(ESI)m / z:680.3[M+H] + .

[0251] Example 43: Synthesis of N-phenyl-1-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]quinoline-4-oxy}phenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 43)

[0252]

[0253] MS(ESI) m / z: 653.3 [M+H]+ .

[0254] Example 44: Synthesis of N-(4-fluorophenyl)-1-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]quinoline-4-oxy}phenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 44)

[0255]

[0256] MS(ESI) m / z: 671.3 [M+H] + 693.2 [M+Na] + .

[0257] Example 45: Synthesis of N-(2-fluorophenyl)-1-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]quinoline-4-oxy}phenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 45)

[0258]

[0259] MS(ESI) m / z: 671.3 [M+H] + 693.2 [M+Na] + .

[0260] Example 46: Synthesis of N-benzyl-1-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]quinoline-4-oxy}phenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 46)

[0261]

[0262] MS(ESI) m / z: 667.3 [M+H] + 689.3 [M+Na] + .

[0263] Example 47: Synthesis of N-phenylethyl-1-(3-fluoro-4-{6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]quinoline-4-oxy}phenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 47)

[0264]

[0265] MS(ESI) m / z: 681.3 [M+H] + 703.3 [M+Na] +.

[0266] Example 48: Synthesis of N-phenyl-1-(3-fluoro-4-{6-methoxy-7-[3-(1-tetrahydropyrrolyl)propoxy]quinoline-4-oxy}phenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 48)

[0267]

[0268] MS(ESI) m / z: 624.2 [M+H] + 646.3 [M+Na] + .

[0269] Example 49: Synthesis of N-(4-fluorophenyl)-1-(3-fluoro-4-{6-methoxy-7-[3-(1-tetrahydropyrrolyl)propoxy]quinoline-4-oxy}phenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (compound 49)

[0270]

[0271] MS(ESI) m / z: 641.2 [M+H] + 663.3 [M+Na] + .

[0272] Example 50: Synthesis of N-(2-fluorophenyl)-1-(3-fluoro-4-{6-methoxy-7-[3-(1-tetrahydropyrrolyl)propoxy]quinoline-4-oxy}phenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (Compound 50)

[0273]

[0274] MS(ESI) m / z: 641.2 [M+H] + 663.3 [M+Na] + .

[0275] Example 51: Synthesis of N-benzyl-1-(3-fluoro-4-{6-methoxy-7-[3-(1-tetrahydropyrrolyl)propoxy]quinoline-4-oxy}phenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (Compound 51)

[0276]

[0277] MS(ESI) m / z: 638.3 [M+H] + 660.2 [M+Na] + .

[0278] Example 52: Synthesis of N-(4-fluorobenzyl)-1-(3-fluoro-4-{6-methoxy-7-[3-(1-tetrahydropyrrolyl)propoxy]quinoline-4-oxy}phenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (Compound 52)

[0279]

[0280] MS(ESI) m / z: 656.2 [M+H] + 678.3 [M+Na] + .

[0281] Example 53 In vitro antitumor cell activity

[0282] Partial synthesis of novel quinoline compounds containing 6-oxo-1-substituted phenyl-1,6-dihydropyridazine-3-carboxamide according to the present invention formula (I) was screened in vitro for inhibitory activity against human gastric cancer cell line MKN45, human colon cancer cell line HT-29, human lung adenocarcinoma A549, human lung cancer cell line H460, human gastrointestinal stromal tumor cell line GIST882, and imatinib-resistant human gastrointestinal stromal tumor cell line GIST1210.

[0283] (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, followed by the addition of culture medium to terminate 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 is a blank well with no cells, 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 hours.

[0284] (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 in a 24-well plate to 20, 4, 0.8, 0.16, 0.032 μg / mL.

[0285] 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.

[0286] (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, incubate for 4 hours, then 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, then place the plate in a microplate reader to measure the results. The IC50 of the drug can be determined using the Bliss method. 50 The inhibitory activity of the compound on human lung adenocarcinoma A549, human gastric cancer cell line MKN45, human lung cancer cells H460, human liver cancer cells HepG2, human chronic myeloid leukemia cells K562, human gastrointestinal stromal tumor cells GIST882, imatinib-resistant human gastrointestinal stromal tumor cells GIST1210, and human colon cancer cells HCT116 is shown in Table 1. 50 ≤1.0μM, denoted by A, 1.0μM <IC 50 ≤10.0μM, denoted by B, 10.0μM <IC 50 ≤100.0μM, denoted by C.

[0287] Table 1. Inhibitory activity of the compounds against five tumor cell lines: MKN45, HT-29, A549, H460, GIST882, and GIST1210.

[0288]

[0289]

[0290] Example 54 c-Met enzyme activity assay

[0291] 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 added to a 0.25 mg / mL PGT-coated plate and incubated for 20 minutes 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 washed away, and the phosphorylated polymer substrate was detected using a 0.2 μg / mL phosphotyrosine-specific monoclonal antibody (PY20) conjugated with horseradish peroxidase (HRP). After stopping the color development with 1 M phosphate, the color of the substrate (TMB) was quantified spectrophotometrically at 450 nm.

[0292] The results of the compounds inhibiting c-Met kinase activity at a concentration of 1.0 μM are shown in Table 2. In Table 2, inhibition rate ≥50% is represented by A, inhibition rate <50% is represented by B, and untested is represented by ND.

[0293] Table 2 Inhibitory activity of compounds against c-Met kinase

[0294]

[0295]

[0296] The experimental results clearly demonstrate that the novel quinoline compounds of general formula (I) containing 6-oxo-1-substituted phenyl-1,6-dihydropyridazine-3-carboxamide, which are the subject of this invention, exhibit excellent in vitro antitumor activity. These compounds show promising potential for the development and application of antitumor drugs.

[0297] 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 quinoline compound containing 6-oxo-1-substituted phenyl-1,6-dihydropyridazine-3-carboxamide and its pharmaceutically acceptable salt, characterized in that, The structural formula is shown in general formula (I): (I); in: X is selected from 1 to 4 identical or different substituents of the following: hydrogen, halogen, alkyl group containing 1 to 4 carbons, or alkoxy group containing 1 to 4 carbons; R1 is an alkyl group containing 1-6 carbons or selected from the following groups: or ; R2 is selected from hydrogen, alkyl groups containing 1-6 carbons, cycloalkyl groups containing 3-6 carbons, or alkoxy groups containing 1-6 carbons; R3 is selected from cycloalkyl groups containing 3-10 carbons, 3-10 membered heterocycles, 6-10 membered aryl groups, 6-10 membered arylmethyl groups, 5-10 membered heteroarylmethyl groups, 6-10 membered arylethyl groups, or 5-10 membered heteroarylethyl groups; wherein the heterocycle or heteroaryl group contains 1-3 heteroatoms selected from N, O, or S; the cycloalkyl group containing 3-10 carbons, 3-10 membered heterocycle, or 6-10 membered aryl group may optionally be replaced by 1-3 identical or different R4 groups; R4 is hydrogen, hydroxyl, halogen, nitro, amino, cyano, alkyl containing 1-6 carbons, alkenyl containing 2-6 carbons, alkynyl containing 2-6 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, alkylsulfinyl containing 1-6 carbons, sulfonyl, alkyl acyl containing 1-6 carbons, carbamoyl, or carbamoyl substituted with one or two alkyl groups containing 1-6 carbons.

2. The quinoline compound containing 6-oxo-1-substituted phenyl-1,6-dihydropyridazine-3-carboxamide and its pharmaceutically acceptable salt according to claim 1, characterized in that, X is selected from 1 to 4 identical or different substituents of the following: hydrogen or halogen; R1 is methyl, ethyl, propyl, or selected from the following groups: or ; R2 is selected from hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, or propoxy; R3 is selected from cycloalkyl groups containing 3-10 carbons, 3-10 membered heterocycles, 6-10 membered aryl groups, 6-10 membered arylmethyl groups, 5-10 membered heteroarylmethyl groups, 6-10 membered arylethyl groups, or 5-10 membered heteroarylethyl groups; wherein the heterocycle or heteroaryl group contains 1-3 heteroatoms selected from N, O, or S; the cycloalkyl group containing 3-10 carbons, 3-10 membered heterocycle, or 6-10 membered aryl group may optionally be replaced by 1-3 identical or different R4 groups; R4 is hydrogen, hydroxyl, halogen, nitro, amino, cyano, alkyl containing 1-6 carbons, alkenyl containing 2-6 carbons, alkynyl containing 2-6 carbons, alkoxy containing 1-6 carbons, or an amino group substituted with one or two alkyl groups containing 1-6 carbons.

3. A quinoline compound containing 6-oxo-1-substituted phenyl-1,6-dihydropyridazine-3-carboxamide 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 or fluorine; R1 is methyl or selected from the following groups: or ; R2 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, methoxy, or ethoxy. R3 is selected from cyclopentyl, cyclohexyl, phenyl, pyridyl, thiophene, furan, naphthyl, quinolinyl, indole, phenylmethyl, phenylethyl, pyridylmethyl, or pyridylethyl, wherein the cyclopentyl, cyclohexyl, phenyl, pyridyl, thiophene, furan, naphthyl, quinolinyl, or indole may optionally be replaced by 1 to 3 identical or different R4s; R4 is hydrogen, hydroxyl, halogen, nitro, amino, cyano, alkyl containing 1-6 carbons, or alkoxy containing 1-6 carbons.

4. A quinoline compound containing 6-oxo-1-substituted phenyl-1,6-dihydropyridazine-3-carboxamide and its pharmaceutically acceptable salt, as described in claim 1, is characterized in that... The compounds of general formula (I) are selected from the following compounds:

5. A pharmaceutical composition, characterized in that, A quinoline compound containing 6-oxo-1-substituted phenyl-1,6-dihydropyridazine-3-carboxamide as described in any one of claims 1-4, and a pharmaceutically acceptable salt thereof, is included as an active ingredient and a pharmaceutically acceptable excipient.

6. The use of the quinoline compound containing 6-oxo-1-substituted phenyl-1,6-dihydropyridazine-3-carboxamide as described in any one of claims 1-4, and its pharmaceutically acceptable salt, or the pharmaceutical composition of claim 5, 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 the quinoline compound containing 6-oxo-1-substituted phenyl-1,6-dihydropyridazine-3-carboxamide as described in any one of claims 1-4, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 5, in the preparation of a medicament for the treatment and / or prevention of proliferative diseases.

8. The use of the quinoline compound containing 6-oxo-1-substituted phenyl-1,6-dihydropyridazine-3-carboxamide as described in any one of claims 1-4, and its pharmaceutically acceptable salt, or the pharmaceutical composition of claim 5, 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 are stomach cancer, colon cancer, lung cancer, and gastrointestinal stromal tumors.

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