CN105017217A - Pyrazolone-containing quinoline compound and preparation method and application thereof - Google Patents
Pyrazolone-containing quinoline compound and preparation method and application thereof Download PDFInfo
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- CN105017217A CN105017217A CN201410154172.4A CN201410154172A CN105017217A CN 105017217 A CN105017217 A CN 105017217A CN 201410154172 A CN201410154172 A CN 201410154172A CN 105017217 A CN105017217 A CN 105017217A
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- isophthalic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
The invention relates to a pyrazolone-containing quinoline compound as shown in the general formula (I) and its pharmaceutically acceptable salt, hydrate, solvate and prodrug, wherein substituent groups Ar, R1, R2, R3, X, Y and n are as defined in the specification. The invention also relates to the strong effect of the compound as shown in the general formula (I) in inhibiting c-Met tyrosine kinase and also relates to an application of the compound and its pharmaceutically acceptable salt, hydrate, solvate or prodrug in the preparation of drugs for treating and/or preventing diseases caused by abnormal high expression of c-Met kinase, especially to an application of the compound and its pharmaceutically acceptable salt, hydrate, solvate or prodrug in the preparation of drugs for treating and/or preventing cancer.
Description
Technical field
The present invention relates to new for the quinolines of pyrazolone and the preparation method of pharmacy acceptable salt, hydrate, solvate or its prodrug thereof and the pharmaceutical composition containing described compound, and preparing the purposes treated and/or prevented in the medicine of the cancer of c-Met high expression level.
Technical background
Protein kinase represent a class cellular function retentive control and various cytopathic regulation and control mid-term vital role protein.Respond approach by conditioning signal, protein kinase controls the metabolism of cell, the carrying out of cell division cycle, cell proliferation and apoptosis, differentiation and survival.Have human kinase group in 500 at present, wherein reach 150 kinds more than disease-relateds various with the mankind, as inflammatory diseases, cardiovascular disorder, metabolism class disease, nerve degenerative diseases and cancer.
Malignant tumour is a kind of frequently-occurring disease and common disease of serious harm human health.In China, due to the develop rapidly of economy, incident industrial pollution is more and more serious, and the life and health of people is subject to grave danger.Have data to show, annual new cancer cases 2,000,000 people of China, because number of cancer deaths is 1,400,000; In the urban of China's Mainland, malignant tumour surmounts cardiovascular and cerebrovascular diseases, becomes first cause of death.The Crack cause of cancer is various, and " the cancer village " that formed because of environmental pollution just increases year by year in China's Mainland.According to data, the quantity in Cancer in China village, more than 247, contains 27 provinces of China's Mainland.
C-Met is the heterodimer transmembrane receptor of being encoded by proto-oncogene Met, is one of tyrosine kinase receptor family member, and wide expression in multiple human normal tissue, but presents abnormal high expression level, sudden change or activity change in many tumor tissues.The sustained activation of c-Met, by the adhesion between destruction tumour cell, promotion cell movement and tumor neovasculature generation, makes tumour cell be easy to enter blood circulation and obtains the ability of Invasion and Metastasis.Due to the point of crossing that c-M et is the many paths causing tumour to be formed and shift; thus; be that target can relatively easily realize disturbing while many paths with c-Met; once the HGF/c-Met signal path of abnormal activation is blocked in tumour cell, tumour cell just there will be cellular form change, proliferation slowed down, Tumor formation reduce, a series of change of degradation under invasive ability.Thus c-Met has become a novel targets extremely likely of anti metastasis treatment.
C-Met kinases is extensively present in epithelium, plays an important role in fetal development and wound healing, and c-Met kinases has become an important target spot of antitumor drug research.LIU L, et a1.J.Med.Chem.2008,51 (13): 3688-3691; DANGELOND, et a1.J.Med.Chem.2008,51 (18): 5766-5779; KUNG P P, et al.Eur.J.Med.Chem.2008, the synthesis of some quinolines of the bibliographical informations such as 43 (6): 1321-1329 and pharmacology activity research thereof, there is lasting c-Met stimulation, process LAN or variation in the human malignancies of extensive existence, comprises mammary cancer, liver cancer, lung cancer, ovarian cancer, kidney, thyroid carcinoma, colorectal carcinoma, glioblastoma, prostate cancer etc.C-Met involves atherosclerosis and pulmonary fibrosis equally, by the interaction of mesenchyma stroma of tumors, comprise HGF/c-Met approach, the invasive growth speed of these cancer cells is thoroughly improve, research also shows to have obvious restraining effect containing the c-Met kinase inhibitor of quinoline structure to proliferative disease, especially in the nonsmall-cell lung cancer of c-Met high expression level and the treatment of small cell lung cancer, has all given play to good effect.
The Foretinib (Fig.1) of bibliographical information belongs to quinolines, it is a kind of oral c-Met and VEGFR/KDR kinase inhibitor, the name of compound is called N-[the fluoro-4-of 3-[[6-methoxyl group-7-[[3-(morpholine-4-base) propyl group] oxygen] quinolyl-4] oxygen] phenyl]-N'-(4-fluorophenyl) cyclopropane-1,1-diformamide, it is to c-Met kinases and the kinase whose IC of KDR
50value is respectively 0.4 and 0.8nM, has entered II phase clinical investigation phase at present.Clinical study shows, Foretinib shows significant Inhibit proliferaton effect to various human tumor cell line (human lung carcinoma cell, gastric carcinoma cells etc.).
The present inventor has carried out extensive research to quinolines, by modifying multiple structural points and transform, has synthesized the quinoline derivatives of a series of novel structure.By In Vitro Anti human tumor cell line, active and c-Met kinase activity shaker test, finds that this compounds has c-Met kinase inhibitory activity and anti-tumor activity.
Summary of the invention
The present invention relates to the quinolines containing pyrazolone shown in formula I and pharmacy acceptable salt, hydrate, solvate or prodrug,
Wherein,
X is O, S;
Y is H, halogen;
N is the integer between 2-6;
R
1and R
2identical or different, be separately selected from hydrogen, C
1-C
10alkyl, C
3-C
7cycloalkyl, C
2-C
10thiazolinyl and C
2-C
10alkynyl, they can optionally by the individual identical or different R of 1-3
4replace;
Or R
1and R
2form 5-10 unit's heterocyclic radical or 5-10 unit heteroaryl together with the nitrogen-atoms connected with them, described heterocyclic radical and heteroaryl except with R
1and R
2outside the nitrogen-atoms connected, the optional heteroatoms being selected from N, O and S containing 1-4, except R
1and R
2outside the nitrogen-atoms connected, described heterocyclyl comprises 1 or 2 carbon-carbon double bond or three key, and described heterocyclic radical and heteroaryl are optionally by the individual identical or different R of 1-3
4replace;
R
4for benzyl, C
1-C
4alkyl, C
1-C
4alkoxyl group, halogen, hydroxyl, carboxyl, ester group;
R
3for H, C
1-C
4alkyl, C
3-C
6cycloalkyl, C
1-C
4alkoxyl group, optionally by the C of halo
1-C
4alkyl;
Ar is C
6-C
10aryl, 5-10 unit heteroaryl, wherein, described heteroaryl contains the heteroatoms that 1-3 is selected from N, O or S, and the R that the optional 1-3 of Ar identical or different
5replace;
R
5for hydroxyl, halogen, nitro, amino, cyano group, C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
1-C
6alkoxyl group, C
1-C
6alkyl sulfenyl, optionally by the C of hydroxyl, amino or halo
1-C
6alkyl or C
1-C
6alkoxyl group, coverlet or two C
1-C
6amino, C that alkyl replaces
1-C
6alkyl amido, free, salify, esterification with amidated carboxyl, C
1-C
6alkyl sulphinyl, alkylsulfonyl, C
1-C
6alkyl acyl, formamyl, coverlet or two C
1-C
6formamyl, C that alkyl replaces
1-C
3alkylenedioxy group.
The present invention preferably relates to the quinolines containing pyrazolone shown in formula I and pharmacy acceptable salt, hydrate, solvate or prodrug,
Wherein,
X is O;
Y is H, F;
N is the integer between 2-4;
R
1and R
2identical or different, be separately selected from hydrogen, C
1-C
6alkyl, C
3-C
6cycloalkyl, they can optionally by the individual identical or different R of 1-3
4replace;
Or R
1and R
2form 5-10 unit heterocyclic radical together with the nitrogen-atoms connected with them, described heterocyclic radical except with R
1and R
2outside the nitrogen-atoms connected, the optional heteroatoms being selected from N, O and S containing 1-4, except R
1and R
2outside the nitrogen-atoms connected, described heterocyclyl comprises 1 or 2 carbon-carbon double bond or three key, optionally by the individual identical or different R of 1-3
4replace;
R
4for benzyl, C
1-C
4alkyl, C
1-C
4alkoxyl group, halogen, hydroxyl, carboxyl, ester group;
R
3for H, C
1-C
4alkyl, C
3-C
6cycloalkyl, C
1-C
4alkoxyl group, by the C of fluoro
1-C
4alkyl;
Ar is C
6-C
10aryl, 5-10 unit heteroaryl, wherein, described heteroaryl contains the heteroatoms that 1-3 is selected from N, O or S, and the R that the optional 1-3 of Ar identical or different
5replace;
R
5for hydroxyl, halogen, nitro, amino, cyano group, C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
1-C
6alkoxyl group, C
1-C
6alkyl sulfenyl, optionally by the C of hydroxyl, amino or halo
1-C
6alkyl or C
1-C
6alkoxyl group, coverlet or two C
1-C
6amino, C that alkyl replaces
1-C
6alkyl amido, free, salify, esterification with amidated carboxyl, C
1-C
6alkyl sulphinyl, alkylsulfonyl, C
1-C
6alkyl acyl, formamyl, coverlet or two C
1-C
6formamyl, C that alkyl replaces
1-C
3alkylenedioxy group.
The present invention also preferably relates to the quinolines containing pyrazolone shown in formula I and pharmacy acceptable salt, hydrate, solvate or prodrug,
Wherein,
X is O;
Y is F, its position of substitution by phenyl ring with X the ortho position of company's carbon atom;
N is the integer between 2-4;
R
1and R
2identical or different, be separately selected from hydrogen, C
1-C
6alkyl, C
3-C
6cycloalkyl, they can optionally by the individual identical or different R of 1-3
4replace;
Or R
1and R
2form 5-10 unit heterocyclic radical together with the nitrogen-atoms connected with them, described heterocyclic radical except with R
1and R
2outside the nitrogen-atoms connected, the optional heteroatoms being selected from N, O and S containing 1-4, except R
1and R
2outside the nitrogen-atoms connected, described heterocyclyl comprises 1 or 2 carbon-carbon double bond or three key, optionally by the individual identical or different R of 1-3
4replace;
R
4for benzyl, C
1-C
4alkyl, C
1-C
4alkoxyl group, halogen, hydroxyl, carboxyl, ester group;
R
3for H, C
1-C
4alkyl, C
3-C
6cycloalkyl, by the C of fluoro
1-C
4alkyl;
Ar is C
6-C
10aryl, 5-10 unit heteroaryl, wherein, described heteroaryl contains the heteroatoms that 1-3 is selected from N, O or S, and the R that the optional 1-3 of Ar identical or different
5replace;
R
5for hydroxyl, halogen, nitro, amino, cyano group, C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
1-C
6alkoxyl group, C
1-C
6alkyl sulfenyl, optionally by the C of hydroxyl, amino or halo
1-C
6alkyl or C
1-C
6alkoxyl group, coverlet or two C
1-C
6amino, C that alkyl replaces
1-C
6alkyl amido, free, salify, esterification with amidated carboxyl, C
1-C
6alkyl sulphinyl, alkylsulfonyl, C
1-C
6alkyl acyl, formamyl, coverlet or two C
1-C
6formamyl, C that alkyl replaces
1-C
3alkylenedioxy group.
The present invention particularly preferably relates to the quinolines containing pyrazolone shown in formula I and pharmacy acceptable salt, hydrate, solvate or prodrug,
Wherein,
X is O;
Y is F, its position of substitution by phenyl ring with X the ortho position of company's carbon atom;
N is the integer between 2-4;
R
1and R
2form 5-6 unit saturated heterocyclyl together with the nitrogen-atoms connected with them, described saturated heterocyclyl except with R
1and R
2outside the nitrogen-atoms connected, the optional heteroatoms being selected from N, O and S containing 1-4, optionally by the individual identical or different R of 1-3
4replace;
R
3for H, C
1-C
4alkyl, C
3-C
6cycloalkyl, trifluoromethyl;
R
4for C
1-C
4alkyl;
Ar is phenyl, naphthyl, quinolyl, pyridyl, furyl, thienyl, pyrryl, and the R that the optional 1-3 of Ar identical or different
5replace;
R
5for halogen, C
1-C
4alkyl, C
1-C
4alkoxyl group, C
1-C
4alkyl sulfenyl, optionally by the C of halo
1-C
4alkyl or C
1-C
4alkoxyl group, coverlet or two C
1-C
4amino, C that alkyl replaces
1-C
6alkyl acyl, formamyl, coverlet or two C
1-C
6the formamyl that alkyl replaces, coverlet or two C
1-C
6alkylsulfonyl, C that alkyl replaces
1-C
3alkylenedioxy group.
The present invention also particularly preferably relates to the quinolines containing pyrazolone shown in formula I and pharmacy acceptable salt, hydrate, solvate or prodrug,
Wherein,
X is O;
Y is F, its position of substitution by phenyl ring with X the ortho position of company's carbon atom;
N is the integer between 2-4;
R
1and R
2piperidino, 4-morpholinyl, 4-methyl isophthalic acid-piperazinyl, 4-methyl isophthalic acid-piperidyl, 1-pyrrolidyl is formed together with the nitrogen-atoms connected with them;
R
3for methyl, ethyl, cyclopropyl, trifluoromethyl;
Ar is phenyl, and the R that the optional 1-3 of Ar identical or different
5replace;
R
5for halogen, C
1-C
4alkyl, C
1-C
4alkoxyl group, C
1-C
4alkyl sulfenyl, optionally by the C of halo
1-C
4alkyl or C
1-C
4alkoxyl group, coverlet or two C
1-C
4amino, C that alkyl replaces
1-C
6alkyl acyl, formamyl, coverlet or two C
1-C
6the formamyl that alkyl replaces, coverlet or two C
1-C
6alkylsulfonyl, C that alkyl replaces
1-C
3alkylenedioxy group.
The present invention more particularly preferably relates to the quinolines containing pyrazolone shown in formula I and pharmacy acceptable salt, hydrate, solvate or prodrug,
Wherein,
X is O;
Y is F, its position of substitution by phenyl ring with X the ortho position of company's carbon atom;
N is 3;
R
3for methyl;
R
1and R
2piperidino, 4-morpholinyl, 4-methyl isophthalic acid-piperazinyl, 4-methyl isophthalic acid-piperidyl, 1-pyrrolidyl is formed together with the nitrogen-atoms connected with them;
Ar is phenyl, and the individual identical or different R of optional 1-3
5replace;
R
5for fluorine, chlorine, bromine, methyl, methoxyl group, trifluoromethyl, trifluoromethoxy, N-methyl carboxamido, N-methyl methanesulfonamido, methoxymethylene, methylthio group, N, N-dimethylamino and C
1-C
3methylenedioxy.
Generalformulaⅰcompound of the present invention and the preferred following compound of pharmacy acceptable salt, hydrate, solvate or prodrug thereof, but these compounds do not mean that any limitation of the invention:
(Z)-4-((the fluoro-4-of 3-(6-methoxyl group-7-(3-(1-pyrrolidyl) propoxy-) quinoline-4-oxygen base) phenyl amino) methylene radical)-1-(4-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-5 (4H)-one;
(Z)-4-((the fluoro-4-of 3-(6-methoxyl group-7-(3-(piperidino) propoxy-) quinoline-4-oxygen base) phenyl amino) methylene radical)-1-(4-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-5 (4H)-one;
(Z)-4-((the fluoro-4-of 3-(6-methoxyl group-7-(3-(4-morpholinyl) propoxy-) quinoline-4-oxygen base) phenyl amino) methylene radical)-1-(4-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-5 (4H)-one;
(Z)-4-((the fluoro-4-of 3-(6-methoxyl group-7-(3-(4-methyl isophthalic acid-piperazinyl) propoxy-) quinoline-4-oxygen base) phenyl amino) methylene radical)-1-(4-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-5 (4H)-one;
(Z)-4-((the fluoro-4-of 3-(6-methoxyl group-7-(3-(4-methyl isophthalic acid-piperidyl) propoxy-) quinoline-4-oxygen base) phenyl amino) methylene radical)-1-(4-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-5 (4H)-one;
(Z)-4-((the fluoro-4-of 3-(6-methoxyl group-7-(3-(4-morpholinyl) propoxy-) quinoline-4-oxygen base) phenyl amino) methylene radical)-1-phenyl-3-methyl isophthalic acid H-pyrazoles-5 (4H)-one;
(Z)-4-((the fluoro-4-of 3-(6-methoxyl group-7-(3-(piperidino) propoxy-) quinoline-4-oxygen base) phenyl amino) methylene radical)-1-(4-fluorophenyl)-3-methyl isophthalic acid H-pyrazoles-5 (4H)-one;
(Z)-4-((the fluoro-4-of 3-(6-methoxyl group-7-(3-(4-methyl isophthalic acid-piperidyl) propoxy-) quinoline-4-oxygen base) phenyl amino) methylene radical)-1-(4-bromophenyl)-3-methyl isophthalic acid H-pyrazoles-5 (4H)-one;
(Z)-4-((the fluoro-4-of 3-(6-methoxyl group-7-(3-(4-methyl isophthalic acid-piperazinyl) propoxy-) quinoline-4-oxygen base) phenyl amino) methylene radical)-1-(4-p-methoxy-phenyl)-3-methyl isophthalic acid H-pyrazoles-5 (4H)-one;
(Z)-4-((the fluoro-4-of 3-(6-methoxyl group-7-(3-(1-pyrrolidyl) propoxy-) quinoline-4-oxygen base) phenyl amino) methylene radical)-1-(2-trifluoromethyl)-3-methyl isophthalic acid H-pyrazoles-5 (4H)-one;
(Z)-4-((the fluoro-4-of 3-(6-methoxyl group-7-(3-(4-morpholinyl) propoxy-) quinoline-4-oxygen base) phenyl amino) methylene radical)-1-(2-Trifluoromethoxyphen-l)-3-methyl isophthalic acid H-pyrazoles-5 (4H)-one;
(Z)-4-((the fluoro-4-of 3-(6-methoxyl group-7-(3-(1-pyrrolidyl) propoxy-) quinoline-4-oxygen base) phenyl amino) methylene radical)-1-(3H-pyrroles-3-base)-3-ethyl-1H-pyrazoles-5 (4H)-one;
(Z)-4-((the fluoro-4-of 3-(6-methoxyl group-7-(3-(piperidino) propoxy-) quinoline-4-oxygen base) phenyl amino) methylene radical)-1-(2-furyl)-3-ethyl-1H-pyrazoles-5 (4H)-one;
(Z)-4-((the fluoro-4-of 3-(6-methoxyl group-7-(3-(4-morpholinyl) propoxy-) quinoline-4-oxygen base) phenyl amino) methylene radical)-1-(2-thienyl)-3-ethyl-1H-pyrazoles-5 (4H)-one;
(Z)-4-((the fluoro-4-of 3-(6-methoxyl group-7-(3-(4-methyl isophthalic acid-piperazinyl) propoxy-) quinoline-4-oxygen base) phenyl amino) methylene radical)-1-(3-pyridyl)-3-ethyl-1H-pyrazoles-5 (4H)-one;
(Z)-3-(3-ethyl-4-((the fluoro-4-of 3-(6-methoxyl group-7-(3-(4-methyl isophthalic acid-piperidyl) propoxy-) quinoline-4-oxygen base) phenyl amino) methylene radical)-5-oxo-4,5-dihydro-1 h-pyrazole-1-base)-N-methylbenzene Toluidrin;
(Z)-4-((the fluoro-4-of 3-(6-methoxyl group-7-(3-(4-morpholinyl) propoxy-) quinoline-4-oxygen base) phenyl amino) methylene radical)-1-(3,4-difluorophenyl)-3-methyl isophthalic acid H-pyrazoles-5 (4H)-one.
And according to some usual methods in field belonging to the present invention, the quinoline derivatives of formula I of the present invention can generate its pharmacy acceptable salt with acid.Acid can comprise mineral acid or organic acid, and the salt formed with following acid is particularly preferred: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, ethyl sulfonic acid, toluenesulphonic acids, Phenylsulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, toxilic acid, citric acid, fumaric acid, Tartaric acid, Phenylsulfonic acid, phenylformic acid or tosic acid etc.
In addition, the present invention also comprises the prodrug of the compounds of this invention.According to the present invention, prodrug is the derivative of generalformulaⅰcompound, they self may have more weak activity or even not have activity, but upon administration, (such as by metabolism, solvolysis or other mode) is converted to corresponding biologically active form in physiological conditions.
Unless otherwise noted, term used herein " halo " refers to fluoro, chloro, bromo or iodo, " alkyl " refers to the alkyl of straight or branched, " cycloalkyl " refers to substituted or unsubstituted cycloalkyl, " thiazolinyl " refers to the thiazolinyl of straight or branched, " alkynyl " refers to the alkynyl of straight or branched, " aryl " refers to a hydrogen atom in removing aromatic hydrocarbons and the organic group that obtains, as phenyl, naphthyl, 5-10 unit heteroaryl comprises and is selected from N containing one or more, the heteroatoms of O and S, wherein the ring-type system of each heteroaryl can be monocycle or many rings, ring-type system is aromaticity, altogether containing 5-10 atom, such as imidazolyl can be enumerated, pyridyl, pyrimidyl, pyrazolyl, (1, 2, 3)-and (1, 2, 4)-triazolyl, pyrazinyl, tetrazyl, furyl, thienyl, isoxazolyl, oxazolyl, pyrazolyl, pyrryl, thiazolyl, benzothienyl, benzofuryl, benzimidazolyl-, benzothiazolyl, indyl, quinolyl etc., 5-10 unit heterocyclic radical comprises containing one or more heteroatoms being selected from N, O and S, wherein the ring-type system of each heteroaryl can be monocycle or many rings, but be nonaromatic, ring-type system is altogether containing 5-10 atom, optionally can comprise 1 or 2 carbon-carbon double bond or carbon-carbon triple bond, such as pyrrolidyl, morpholinyl, piperazinyl, piperidyl, thiazolinyl etc. can be enumerated.
The compound that the invention still further relates to formula I has the strong kinase whose effect of suppression c-Met, and relate to this compounds and pharmacy acceptable salt, the purposes of hydrate in the medicine of preparation treatment disease caused by c-Met kinases overexpression, particularly preparing the purposes treated and/or prevented in the medicine of cancer.
Synthetic route 1-3 describes the preparation of generalformulaⅰcompound of the present invention below, and all raw materials are all methods by describing in these routes, prepared by the method known by organic chemistry filed those of ordinary skill or commercially available.Whole finalization compound of the present invention is all method by describing in these routes or is prepared by similar method, and these methods are that organic chemistry filed those of ordinary skill is known.The whole variable factors applied in these routes are as definition hereafter or as the definition in claim.According to type I compound of the present invention, all can be got by substitution reaction preparation by corresponding intermediate A and corresponding intermediate B according to the method for route 1.
According to type I compound of the present invention, when X is O, the preparation method of intermediate A is as route 2, and other substituting groups as defined in the claims.
When X is S, the preparation of compd A can be substituted with the fluoro-4-nitro thiophenol of 2-by the intermediate VII in route 2, the two-step reaction that reduces obtains.
When Y is H, the preparation of compd A can be substituted with 4-nitrophenols by the intermediate VII in route 2, the two-step reaction that reduces obtains.
According to generalformulaⅰcompound of the present invention, the preparation method of intermediate B as shown in Scheme 3, works as R
3during for methyl, the preparation method of intermediate B is as route 3, and other substituting groups as defined in the claims.
Work as R
3during for ethyl, the preparation of compd B can be substituted by the intermediate a in route 3 and propionyl ethyl acetate, cyclization, hydrolysis, chlorination obtain.
Work as R
3during for cyclopropyl, the preparation of compd B can be substituted by the intermediate a in route 3 and ring propionyl ethyl acetate, cyclization, hydrolysis, chlorination obtain.
Work as R
3during for trifluoromethyl, the preparation of compd B can by the intermediate a in route 3 and trifluoroacetic ethyl acetoacetate be substituted, cyclization, hydrolysis, chlorination obtain.
The substituent R of all intermediates in above three routes
1, R
2, R
3, R
4, Ar as defined in the claims.
Embodiment:
Embodiment is intended to set forth instead of limit the scope of the invention.The proton nmr spectra of compound measures with Bruker ARX-400, and mass spectrum Agilent1100LC/MSD measures; Agents useful for same is analytical pure or chemical pure.
The logical method of preparation
Steps A 1-(4-(3-chlorine propoxy-)-3-methoxyl group) methyl phenyl ketone (II)
By 3-methoxyl group-4-hydroxyacetophenone (249g, 1.5mol) with Anhydrous potassium carbonate (579.6g, 2.1mol) join in 1250mL acetone, temperature control less than 25 DEG C slowly drips the bromo-3-chloropropane of 1-(661.3g, 4.2mol)/acetone (1200mL), drip and finish, with stirred overnight at room temperature.After completion of the reaction, suction filtration, filter cake 100mL acetone drip washing, merges filter cake, filtrate is slowly poured in 15L frozen water, vigorous stirring, separates out a large amount of white solid, suction filtration simultaneously, filter cake is in 40 DEG C of vacuum-drying 48h, obtain white powder 695.5g, yield 92.5%, ESI-MS [M+H] (m/z): 242.70.
Step B 1-(4-(3-chlorine propoxy-)-5-methoxyl group-2-nitro) methyl phenyl ketone (III)
Intermediate II (200g, 0.82mol) is added to CH
2cl
2in (5v/w, 1000mL), fully stir and intermediate II is all dissolved, then, after reaction solution being cooled to-20 DEG C, nitrosonitric acid (130g, 2.06mol) is slowly dripped, controlling rate of addition keeps reacting liquid temperature lower than-10 DEG C, at-10 ~-20 DEG C of reaction 2h after dropwising.After completion of the reaction, reaction solution is poured in frozen water, collected organic layer, organic layer saturated common salt water washing, until water layer is neutral, anhydrous sodium sulfate drying.Solvent evaporated, obtains yellow solid 210g, yield 89%, ESI-MS [M+H] (m/z): 287.70.
Step C (E)-1-(4-(3-chlorine propoxy-)-5-methoxyl group-2-nitrophenyl)-3-(dimethylamino) propyl group-2-alkene-1-ketone (IV)
Intermediate III (200g, 0.695moL) is added in toluene (5v/w, 1000mL), being heated to 110 DEG C makes intermediate III dissolve completely, then adds DMF dimethylacetal (DMF-DMA) (414.2g, 3.476mol), heating reflux reaction 16h.After completion of the reaction, put into cold-trap after reaction solution being cooled to room temperature and stir, separate out solid, suction filtration, obtain yellow solid 180g after filtration cakes torrefaction, yield 75.8%, ESI-MS [M+H] (m/z): 342.77.
Step D 7-(3-chlorine propoxy-)-6-methoxyl group-4 (1H)-quinolinone (V)
Intermediate IV (150g, 0.44mol) is added in glacial acetic acid (8v/w, 1200mL), is warming up to 40 DEG C, after intermediate IV dissolves completely, slowly add iron powder (123.1g, 2.20mol) in batches and be warming up to 80 DEG C of mechanic whirl-nett reaction 2h.After completion of the reaction, reacting liquor while hot suction filtration, collects filtrate, and have a large amount of solid to separate out after filtrate cooling, suction filtration, obtains khaki color solid.Filter cake is dissolved in glacial acetic acid, stir about 30min at 80 DEG C, again suction filtration while hot, collects filtrate, have solid to separate out after filtrate cooling, suction filtration, filter cake is washed to neutrality, solid 79g is obtained, yield 65%, ESI-MS [M+H] (m/z): 267.71 after drying.
Step e 6-(methoxyl group)-7-(3-(1-pyrrolidyl) propoxy-)-4 (1H)-quinolinones (VI)
Intermediate V (62g, 0.232mol), Pyrrolidine (98.6g, 1.38mol) are added in acetonitrile (620mL), reflux 8h.After completion of the reaction, boil off most of solvent, residual solution is placed in cold-trap, separate out solid, suction filtration, ethyl acetate is washed, and obtains solid 68.5g, yield 95.5%, ESI-MS [M+H] (m/z): 302.37.
The chloro-6-methoxyl group of step F 4--7-(3-(1-pyrrolidyl) propoxy-) quinoline (VII)
Intermediate VI (64g, 0.19mol), phosphorus oxychloride (5v/w, 315mL) are added in acetonitrile (5v/w, 315mL), are warming up to 85 DEG C of back flow reaction 6h.After completion of the reaction, evaporated under reduced pressure, obtains grey sticky solid, is joined in a large amount of frozen water mixed solutions, adjusts pH to 10 with 10% potassium hydroxide solution.Use CH
2cl
2extraction (200mL*3), collected organic layer, anhydrous sodium sulfate drying, solvent evaporated, cools to obtain pale solid 58g, yield 87%, ESI-MS [M+H] (m/z): 320.81.
Step G 4-(the fluoro-4-nitrophenoxy of 2-)-6-methoxyl group-7-(3-(1-pyrrolidyl) propoxy-) quinoline (VIII)
2-fluoro-4-nitrophenol (36.73g, 0.234mol) is added in dry chlorobenzene (5v/w, 250mL), is heated to 145 DEG C, in reaction solution, adds intermediate VII (62.5g, 0.2mol), at this temperature, react 20h.After completion of the reaction, solvent evaporated, obtains gray solid, is dissolved in methylene dichloride by this solid, use saturated potassium carbonate solution washing, collected organic layer, dry, solvent evaporated, with ethyl alcohol recrystallization, obtain solid 50.15g, yield 70.9%, ESI-MS [M+H] (m/z): 441.45.
The fluoro-4-of step H 3-(6-methoxyl group-7-(3-(1-pyrrolidyl) propoxy-) quinoline-4-oxygen base) aniline (A)
Iron powder (61.42g, 1.1mol), 6mL concentrated hydrochloric acid are added in 90% ethanol (25v/w, 1210.5mL), are warming up to 80 DEG C and stir 15min, then in reaction solution, add intermediate VIII (49.5g, 0.11mol) in batches, finish, back flow reaction 2h.After completion of the reaction, suction filtration while hot, collect filtrate, solvent evaporated, obtains yellow solid 44g, yield 95%, ESI-MS [M+H] (m/z): 411.47.
Step I 4-chlorophenylhydxazine hydrochloride (a)
4-chloroaniline (12.75g, 0.1mol) is added in the aqueous solution of 30mL concentrated hydrochloric acid, after cryosel bath is cooled to-5 DEG C, 15mL Sodium Nitrite (7.59g is dripped in reaction solution, 0.11mol) the aqueous solution, controls rate of addition, makes temperature of reaction between-5 ~ 0 DEG C.Drip and finish, in 0-5 DEG C of reaction 30min, for subsequent use.S-WAT (37.44g, 0.36mol) is joined in 100mL water, then the diazonium salt solution of above-mentioned preparation is slowly instilled, keep temperature of reaction below 20 DEG C.Drip and finish, after reacting 30min at ambient temperature, be warming up to back flow reaction 3h.After completion of the reaction, stop heating, non-shock chilling separates out solid, suction filtration, and filter cake ethyl acetate is washed, dry, obtains off-white color solid 8g, yield 85%, ESI-MS [M+H] (m/z): 179.05.
Step J 1-(4-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-5 (4H)-one (b)
By intermediate a(5g, 0.028mol) join in the Glacial acetic acid of 20mL with methyl aceto acetate (4.3g, 0.034mol), be warming up to 90 DEG C of reaction 4h.React complete, oily matter is obtained after concentrating under reduced pressure Glacial acetic acid, 30mL ethyl acetate and 30mL saturated sodium bicarbonate aqueous solution extracting and demixing is added in oily matter, water layer uses the extraction into ethyl acetate of 30mL again, merge organic layer solution again with the washing of 50mL saturated sodium bicarbonate aqueous solution, 50mL saturated common salt water washing organic layer, anhydrous sodium sulfate drying.Suction filtration, concentrates and obtains oily liquids, with ether solidification, obtains faint yellow solid powder 4g, yield 85%, ESI-MS [M+H] (m/z): 208.64.
Step K (Z)-1-(4-chloro-phenyl-)-4-((dimethylamino) methylene radical)-3-methyl isophthalic acid H-pyrazoles-5 (4H)-one (B)
By intermediate b(4g, 0.019mol) be dissolved in 20mL DMF dimethylacetal (DMF-DMA), at 50 DEG C, react 2h.Carrying out along with reaction has solid and separates out, and reacts complete.Separate out solid after non-shock chilling, suction filtration, obtain yellow solid 3g, yield 90%, ESI-MS [M+H] (m/z): 263.72.
Step L (Z)-4-((the fluoro-4-of 3-(6-methoxyl group-7-(3-(1-pyrrolidyl) propoxy-) quinoline-4-oxygen base) phenyl amino) methylene radical)-1-(4-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-5 (4H)-one (embodiment 1)
Intermediate A (0.1g, 0.24mmol) and intermediate B (0.15g, 0.57mmol) are joined in the glacial acetic acid solution of 10mL, at 90 DEG C, reacts 3h.React complete, oily matter is obtained after concentrating under reduced pressure Glacial acetic acid, 20mL methylene dichloride and 20mL saturated sodium bicarbonate aqueous solution extracting and demixing is added in oily matter, water layer uses dichloromethane extraction again, merge organic layer solution again to wash with saturated sodium bicarbonate aqueous solution, saturated common salt water washing organic layer, anhydrous sodium sulfate drying.Suction filtration, concentrates and obtains oily liquids, use column chromatography separation and purification, obtain faint yellow solid powder 0.08g, yield 75%, ESI-MS [M+H] (m/z): 630.11.
According to the logical method of preparation, respectively obtained embodiment 1 – 74 compound (see table one).
Table one:
Extracorporeal anti-tumor cytoactive
Vitro inhibition colon cancer cell HT-29, lung carcinoma cell H460, gastric carcinoma cells MKN-45 screening active ingredients have been carried out to the quinoline derivatives containing pyrazolone according to above formula I of the present invention.
(1) cell recovery and go down to posterity 2-3 time stable after, make it digest bottom culturing bottle with trypsin solution (0.25%).Cell dissociation buffer is poured into after in centrifuge tube, add nutrient solution afterwards to stop digestion.By centrifuge tube centrifugal 10min under 800r/min, add 5mL nutrient solution after abandoning supernatant, piping and druming mixing cell, draws 10 μ L cell suspensions and adds in cell counting count board and count, and adjustment cell concn is 10
4individual/hole.Except A1 hole is that blank well does not add extracellular in 96 orifice plates, all the other all add 100 μ L cell suspensions.96 orifice plates are put into incubator and cultivates 24h.
(2) with 50 μ L dmso solution given the test agent, then add appropriate nutrient solution, make sample dissolution become 2mg/mL liquid, be then 20,4 by diluted sample in 24 orifice plates, 0.8,0.16,0.032 μ g/mL.
Each concentration adds 3 holes, and wherein around two row two row cell growing ways are affected by environment comparatively large, only and be the use of blanc cell hole.96 orifice plates are put into incubator and cultivates 72h.
(3) will medicine nutrient solution in 96 orifice plates, be with to discard, with phosphate buffer solution (PBS), cell is rinsed twice, after adding MTT (tetrazole) (0.5mg/mL) 100 in every hole μ L putting into incubator 4h, discard MTT solution, add dimethyl sulfoxide (DMSO) 100 μ L.On magnetic force vibrator, vibration makes survivaling cell and MTT reaction product formazan fully dissolve, and puts into microplate reader measurement result.Medicine IC can be obtained by Bliss method
50value.
Suppression colon cancer cell HT-29, the lung carcinoma cell H460 of compound and gastric carcinoma cells MKN-45 Activity Results take foretinib as positive control (see table two).
Table two
C-Met enzymic activity is tested
For measuring the test of c-Met kinase activity based on enzyme linked immunosorbent assay (ELISA).Concrete operations are:
Under room temperature, on the plate of 0.25mg/mL PGT bag quilt, by embodiment compound, 50pM c-Met (the recombinant human Met (amino acid 974-end) of His-mark, pass through baculovirus expression) and 5 μMs of ATP (25mM MOPS in test damping fluid, PH7.4,5mM MgCl
2, 0.5raM MnCl
2, 100 μMs of sodium orthovanadates, 0.01%Triton X-100,1mM DTT, last DMSO concentration 1% (v/v)) and incubation 20 minutes.Also phosphorylated polymer substrate is detected with the Tyrosine O-phosphate monoclonal antibody specific (PY20) that 0.2 μ g/mL puts together horseradish peroxidase (HRP) by rinsing removing reaction mixture.After adding 1M phosphoric acid color development stopping, in 450nm place by the color of the substrate (TMB) of spectrophotometry quantitative chromogenic.Embodiment compound and positive control drug (foretinib) are to the kinase whose suppression data (see table three) of c-Met.
Table three:
Can clearly be seen that from above-mentioned test-results, the compound of the claimed formula I of the present invention has good anti tumor activity in vitro, quite or be better than contrast medicine foretinib.
Although describe the present invention by particular, amendment and equivalent variations are obvious for the technician being proficient in this field, and they are included within the scope of the invention.
Claims (11)
1. the compound of formula I and pharmacy acceptable salt, hydrate, solvate or prodrug,
Wherein,
X is O, S;
Y is H, halogen;
N is the integer between 2-6;
R
1and R
2identical or different, be separately selected from hydrogen, C
1-C
10alkyl, C
3-C
7cycloalkyl, C
2-C
10thiazolinyl and C
2-C
10alkynyl, they can optionally by the individual identical or different R of 1-3
4replace;
Or R
1and R
2form 5-10 unit's heterocyclic radical or 5-10 unit heteroaryl together with the nitrogen-atoms connected with them, described heterocyclic radical and heteroaryl except with R
1and R
2outside the nitrogen-atoms connected, the optional heteroatoms being selected from N, O and S containing 1-4, except R
1and R
2outside the nitrogen-atoms connected, described heterocyclyl comprises 1 or 2 carbon-carbon double bond or three key, and described heterocyclic radical and heteroaryl are optionally by the individual identical or different R of 1-3
4replace;
R
4for benzyl, C
1-C
4alkyl, C
1-C
4alkoxyl group, halogen, hydroxyl, carboxyl, ester group;
R
3for hydrogen, C
1-C
4alkyl, C
3-C
6cycloalkyl, C
1-C
4alkoxyl group, optionally by the C of halo
1-C
4alkyl;
Ar is C
6-C
10aryl, 5-10 unit heteroaryl, wherein, described heteroaryl contains the heteroatoms that 1-3 is selected from N, O or S, and the R that the optional 1-3 of Ar identical or different
5replace;
R
5for hydroxyl, halogen, nitro, amino, cyano group, C
1-C
6alkyl, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
1-C
6alkoxyl group, C
1-C
6alkyl sulfenyl, optionally by the C of hydroxyl, amino or halo
1-C
6alkyl or C
1-C
6alkoxyl group, coverlet or two C
1-C
6amino, C that alkyl replaces
1-C
6alkyl amido, free, salify, esterification with amidated carboxyl, C
1-C
6alkyl sulphinyl, alkylsulfonyl, C
1-C
6alkyl acyl, formamyl, coverlet or two C
1-C
6formamyl, C that alkyl replaces
1-C
3alkylenedioxy group.
2. the compound of the formula I of claim 1 and pharmacy acceptable salt, hydrate, solvate or prodrug,
Wherein,
X is O;
Y is H, F;
R
1and R
2identical or different, be separately selected from hydrogen, C
1-C
6alkyl, C
3-C
6cycloalkyl, they can optionally by the individual identical or different R of 1-3
4replace;
Or R
1and R
2form 5-10 unit heterocyclic radical together with the nitrogen-atoms connected with them, described heterocyclic radical except with R
1and R
2outside the nitrogen-atoms connected, the optional heteroatoms being selected from N, O and S containing 1-4, except R
1and R
2outside the nitrogen-atoms connected, described heterocyclyl comprises 1 or 2 carbon-carbon double bond or three key, and described heterocyclyl is by the individual identical or different R of 1-3
4replace;
R
3for H, C
1-C
4alkyl, C
3-C
6cycloalkyl, C
1-C
4alkoxyl group, by the C of fluoro
1-C
4alkyl;
Ar is phenyl, naphthyl, 5-10 unit heteroaryl, and wherein, described heteroaryl contains the heteroatoms that 1-3 is selected from N, O or S, and the R that the optional 1-3 of Ar identical or different
5replace.
3. the compound of formula I according to claim 2 and pharmacy acceptable salt, hydrate, solvate or prodrug, the position of substitution of F by phenyl ring with X the ortho position of company's carbon atom.
4. the wherein n of claim 1-3 described in any one is the integer between 2-4, and preferred n is 3.
5. the compound of the formula I of claim 1-4 described in any one and pharmacy acceptable salt, hydrate, solvate or prodrug, wherein, R
1and R
2form 5-6 unit heterocyclic radical together with the nitrogen-atoms connected with them, described heterocyclic radical except with R
1and R
2outside the nitrogen-atoms connected, the optional heteroatoms being selected from N, O and S containing 1-3, described heterocyclyl is by the individual identical or different R of 1-3
4replace;
R
4for C
1-C
4alkyl;
R
3for H, C
1-C
4alkyl, C
3-C
6cycloalkyl, trifluoromethyl;
Ar is phenyl, naphthyl, quinolyl, pyridyl, furyl, thienyl, pyrryl, and the R that the optional 1-3 of Ar identical or different
5replace.
6. the compound of the formula I of claim 1-5 described in any one and pharmacy acceptable salt, hydrate, solvate or prodrug,
Wherein,
R
1and R
2piperidino, 4-morpholinyl, 4-methyl isophthalic acid-piperazinyl, 4-methyl isophthalic acid-piperidyl, 1-pyrrolidyl is formed together with the nitrogen-atoms connected with them;
R
3for methyl, ethyl, cyclopropyl, trifluoromethyl;
Ar is phenyl, naphthyl, quinolyl, pyridyl, furyl, thienyl, pyrryl, and the R that the optional 1-3 of Ar identical or different
5replace;
R
5for halogen, C
1-C
4alkyl, C
1-C
4alkoxyl group, C
1-C
6alkyl sulfenyl, optionally by the C of halo
1-C
4alkyl or C
1-C
4alkoxyl group, coverlet or two C
1-C
6amino, C that alkyl replaces
1-C
6alkyl acyl, formamyl, coverlet or two C
1-C
6the formamyl that alkyl replaces, coverlet or two C
1-C
6alkylsulfonyl, C that alkyl replaces
1-C
3methylenedioxy, preferred fluorine, chlorine, bromine, methyl, methoxyl group, trifluoromethyl, trifluoromethoxy, N-methyl carboxamido, N-methyl methanesulfonamido, methoxymethylene, methylthio group, N, N-dimethylamino and C
1-C
3methylenedioxy.
7. the compound of following formula I and pharmacy acceptable salt, solvate or prodrug:
(Z)-4-((the fluoro-4-of 3-(6-methoxyl group-7-(3-(1-pyrrolidyl) propoxy-) quinoline-4-oxygen base) phenyl amino) methylene radical)-1-(4-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-5 (4H)-one;
(Z)-4-((the fluoro-4-of 3-(6-methoxyl group-7-(3-(piperidino) propoxy-) quinoline-4-oxygen base) phenyl amino) methylene radical)-1-(4-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-5 (4H)-one;
(Z)-4-((the fluoro-4-of 3-(6-methoxyl group-7-(3-(4-morpholinyl) propoxy-) quinoline-4-oxygen base) phenyl amino) methylene radical)-1-(4-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-5 (4H)-one;
(Z)-4-((the fluoro-4-of 3-(6-methoxyl group-7-(3-(4-methyl isophthalic acid-piperazinyl) propoxy-) quinoline-4-oxygen base) phenyl amino) methylene radical)-1-(4-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-5 (4H)-one;
(Z)-4-((the fluoro-4-of 3-(6-methoxyl group-7-(3-(4-methyl isophthalic acid-piperidyl) propoxy-) quinoline-4-oxygen base) phenyl amino) methylene radical)-1-(4-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-5 (4H)-one;
(Z)-4-((the fluoro-4-of 3-(6-methoxyl group-7-(3-(4-morpholinyl) propoxy-) quinoline-4-oxygen base) phenyl amino) methylene radical)-1-phenyl-3-methyl isophthalic acid H-pyrazoles-5 (4H)-one;
(Z)-4-((the fluoro-4-of 3-(6-methoxyl group-7-(3-(piperidino) propoxy-) quinoline-4-oxygen base) phenyl amino) methylene radical)-1-(4-fluorophenyl)-3-methyl isophthalic acid H-pyrazoles-5 (4H)-one;
(Z)-4-((the fluoro-4-of 3-(6-methoxyl group-7-(3-(4-methyl isophthalic acid-piperidyl) propoxy-) quinoline-4-oxygen base) phenyl amino) methylene radical)-1-(4-bromophenyl)-3-methyl isophthalic acid H-pyrazoles-5 (4H)-one;
(Z)-4-((the fluoro-4-of 3-(6-methoxyl group-7-(3-(4-methyl isophthalic acid-piperazinyl) propoxy-) quinoline-4-oxygen base) phenyl amino) methylene radical)-1-(4-p-methoxy-phenyl)-3-methyl isophthalic acid H-pyrazoles-5 (4H)-one;
(Z)-4-((the fluoro-4-of 3-(6-methoxyl group-7-(3-(1-pyrrolidyl) propoxy-) quinoline-4-oxygen base) phenyl amino) methylene radical)-1-(2-trifluoromethyl)-3-methyl isophthalic acid H-pyrazoles-5 (4H)-one;
(Z)-4-((the fluoro-4-of 3-(6-methoxyl group-7-(3-(4-morpholinyl) propoxy-) quinoline-4-oxygen base) phenyl amino) methylene radical)-1-(2-Trifluoromethoxyphen-l)-3-methyl isophthalic acid H-pyrazoles-5 (4H)-one;
(Z)-4-((the fluoro-4-of 3-(6-methoxyl group-7-(3-(1-pyrrolidyl) propoxy-) quinoline-4-oxygen base) phenyl amino) methylene radical)-1-(3H-pyrroles-3-base)-3-ethyl-1H-pyrazoles-5 (4H)-one;
(Z)-4-((the fluoro-4-of 3-(6-methoxyl group-7-(3-(piperidino) propoxy-) quinoline-4-oxygen base) phenyl amino) methylene radical)-1-(2-furyl)-3-ethyl-1H-pyrazoles-5 (4H)-one;
(Z)-4-((the fluoro-4-of 3-(6-methoxyl group-7-(3-(4-morpholinyl) propoxy-) quinoline-4-oxygen base) phenyl amino) methylene radical)-1-(2-thienyl)-3-ethyl-1H-pyrazoles-5 (4H)-one;
(Z)-4-((the fluoro-4-of 3-(6-methoxyl group-7-(3-(4-methyl isophthalic acid-piperazinyl) propoxy-) quinoline-4-oxygen base) phenyl amino) methylene radical)-1-(3-pyridyl)-3-ethyl-1H-pyrazoles-5 (4H)-one;
(Z)-3-(3-ethyl-4-((the fluoro-4-of 3-(6-methoxyl group-7-(3-(4-methyl isophthalic acid-piperidyl) propoxy-) quinoline-4-oxygen base) phenyl amino) methylene radical)-5-oxo-4,5-dihydro-1 h-pyrazole-1-base)-N-methylbenzene Toluidrin;
(Z)-4-((the fluoro-4-of 3-(6-methoxyl group-7-(3-(4-morpholinyl) propoxy-) quinoline-4-oxygen base) phenyl amino) methylene radical)-1-(3,4-difluorophenyl)-3-methyl isophthalic acid H-pyrazoles-5 (4H)-one.
8. a pharmaceutical composition, to comprise in claim 1-7 any one compound and pharmacy acceptable salt, hydrate, solvate or prodrug as activeconstituents and pharmaceutically acceptable excipient.
9. in claim 1-7, any one compound and pharmacy acceptable salt, solvate or prodrug or composition according to claim 8 are preparing the application treated and/or prevented in the medicine of the proliferative disease of c-Met high expression level.
10. apply as claimed in claim 9, it is characterized in that, described proliferative disease is metastatic carcinoma, colorectal carcinoma, bladder cancer, mammary cancer, adenocarcinoma of stomach, carcinoma of the pancreas, glioblastoma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis.
In 11. claim 1-7, any one compound and pharmacy acceptable salt, solvate or prodrug or composition according to claim 8 are preparing the application treated and/or prevented in the lung-cancer medicament of liver cancer, cancer of the stomach, colorectal carcinoma, mammary cancer, c-Met high expression level.
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| CN110642837A (en) * | 2019-11-07 | 2020-01-03 | 江西科技师范大学 | Pyridine amide compound containing triazole or quinolinone structure and application thereof |
| CN112996865A (en) * | 2018-11-08 | 2021-06-18 | 联合利华知识产权控股有限公司 | Surface treatment method |
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Cited By (4)
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| CN107573340A (en) * | 2017-10-23 | 2018-01-12 | 江西科技师范大学 | The preparation and application of the miscellaneous pyridine compounds and their of the virtue of 2 carbamyl 4 |
| CN107573340B (en) * | 2017-10-23 | 2020-11-24 | 江西科技师范大学 | Preparation and application of 2-carbamoyl-4-aryl hetero pyridine compound |
| CN112996865A (en) * | 2018-11-08 | 2021-06-18 | 联合利华知识产权控股有限公司 | Surface treatment method |
| CN110642837A (en) * | 2019-11-07 | 2020-01-03 | 江西科技师范大学 | Pyridine amide compound containing triazole or quinolinone structure and application thereof |
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Application publication date: 20151104 |