CN107474039B - 含三氮唑酮和咪唑的4-苯氧基取代喹啉类化合物及其应用 - Google Patents
含三氮唑酮和咪唑的4-苯氧基取代喹啉类化合物及其应用 Download PDFInfo
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- CN107474039B CN107474039B CN201610402784.XA CN201610402784A CN107474039B CN 107474039 B CN107474039 B CN 107474039B CN 201610402784 A CN201610402784 A CN 201610402784A CN 107474039 B CN107474039 B CN 107474039B
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- phenyl
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- carboxamide
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- -1 quinoline compound Chemical class 0.000 title claims description 184
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 title abstract description 12
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 14
- 239000003814 drug Substances 0.000 claims abstract description 13
- 201000010099 disease Diseases 0.000 claims abstract description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 25
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 238000006467 substitution reaction Methods 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 10
- 201000011510 cancer Diseases 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 8
- 206010009944 Colon cancer Diseases 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 208000029742 colonic neoplasm Diseases 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 claims description 5
- 238000011282 treatment Methods 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 3
- GDAAOSMDKDUBQC-UHFFFAOYSA-N 4-ethyl-N-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-5-oxo-1-[2-(trifluoromethoxy)phenyl]-1,2,4-triazole-3-carboxamide Chemical compound FC=1C=C(C=CC=1OC1=CC=NC2=CC(=C(C=C12)OC)OCCCN1CCN(CC1)C)NC(=O)C1=NN(C(N1CC)=O)C1=C(C=CC=C1)OC(F)(F)F GDAAOSMDKDUBQC-UHFFFAOYSA-N 0.000 claims description 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- DUKYCWIYUCFSDB-UHFFFAOYSA-N 1-(2,4-dichlorophenyl)-N-[3-fluoro-4-[6-methoxy-7-(3-piperidin-1-ylpropoxy)quinolin-4-yl]oxyphenyl]-4-methyl-5-oxo-1,2,4-triazole-3-carboxamide Chemical compound COc1cc2c(Oc3ccc(NC(=O)c4nn(-c5ccc(Cl)cc5Cl)c(=O)n4C)cc3F)ccnc2cc1OCCCN1CCCCC1 DUKYCWIYUCFSDB-UHFFFAOYSA-N 0.000 claims description 2
- RQOGWUAWGPJRDH-UHFFFAOYSA-N 1-(2,4-dichlorophenyl)-N-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-4-methyl-5-oxo-1,2,4-triazole-3-carboxamide Chemical compound FC=1C=C(C=CC=1OC1=CC=NC2=CC(=C(C=C12)OC)OCCCN1CCN(CC1)C)NC(=O)C1=NN(C(N1C)=O)C1=C(C=C(C=C1)Cl)Cl RQOGWUAWGPJRDH-UHFFFAOYSA-N 0.000 claims description 2
- RYHKILSQQOEOMU-UHFFFAOYSA-N 1-(2,4-dichlorophenyl)-N-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperidin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-4-methyl-5-oxo-1,2,4-triazole-3-carboxamide Chemical compound COc1cc2c(Oc3ccc(NC(=O)c4nn(-c5ccc(Cl)cc5Cl)c(=O)n4C)cc3F)ccnc2cc1OCCCN1CCC(C)CC1 RYHKILSQQOEOMU-UHFFFAOYSA-N 0.000 claims description 2
- BTHYGIKOOPUHTB-UHFFFAOYSA-N 1-(2-chlorophenyl)-4-cyclopropyl-N-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperidin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-5-oxo-1,2,4-triazole-3-carboxamide Chemical compound FC=1C=C(C=CC=1OC1=CC=NC2=CC(=C(C=C12)OC)OCCCN1CCC(CC1)C)NC(=O)C1=NN(C(N1C1CC1)=O)C1=C(C=CC=C1)Cl BTHYGIKOOPUHTB-UHFFFAOYSA-N 0.000 claims description 2
- BCUJXUWWYDJJDA-UHFFFAOYSA-N 1-(2-chlorophenyl)-N-[3-fluoro-4-[6-methoxy-7-(3-piperidin-1-ylpropoxy)quinolin-4-yl]oxyphenyl]-4-methyl-5-oxo-1,2,4-triazole-3-carboxamide Chemical compound COc1cc2c(Oc3ccc(NC(=O)c4nn(-c5ccccc5Cl)c(=O)n4C)cc3F)ccnc2cc1OCCCN1CCCCC1 BCUJXUWWYDJJDA-UHFFFAOYSA-N 0.000 claims description 2
- CZMWQUYUCFZBNA-UHFFFAOYSA-N 1-(2-chlorophenyl)-N-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-4-methyl-5-oxo-1,2,4-triazole-3-carboxamide Chemical compound FC=1C=C(C=CC=1OC1=CC=NC2=CC(=C(C=C12)OC)OCCCN1CCN(CC1)C)NC(=O)C1=NN(C(N1C)=O)C1=C(C=CC=C1)Cl CZMWQUYUCFZBNA-UHFFFAOYSA-N 0.000 claims description 2
- APXHWMWOIKYTMT-UHFFFAOYSA-N 1-(2-chlorophenyl)-N-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperidin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-4-methyl-5-oxo-1,2,4-triazole-3-carboxamide Chemical compound COc1cc2c(Oc3ccc(NC(=O)c4nn(-c5ccccc5Cl)c(=O)n4C)cc3F)ccnc2cc1OCCCN1CCC(C)CC1 APXHWMWOIKYTMT-UHFFFAOYSA-N 0.000 claims description 2
- XSROTVPYABCKDE-UHFFFAOYSA-N 1-[4-(difluoromethoxy)phenyl]-N-[3-fluoro-4-[6-methoxy-7-(3-piperidin-1-ylpropoxy)quinolin-4-yl]oxyphenyl]-4-methyl-5-oxo-1,2,4-triazole-3-carboxamide Chemical compound COc1cc2c(Oc3ccc(NC(=O)c4nn(-c5ccc(OC(F)F)cc5)c(=O)n4C)cc3F)ccnc2cc1OCCCN1CCCCC1 XSROTVPYABCKDE-UHFFFAOYSA-N 0.000 claims description 2
- SQPRGWQZNCMSJQ-UHFFFAOYSA-N 1-[4-(difluoromethoxy)phenyl]-N-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-4-methyl-5-oxo-1,2,4-triazole-3-carboxamide Chemical compound FC=1C=C(C=CC=1OC1=CC=NC2=CC(=C(C=C12)OC)OCCCN1CCN(CC1)C)NC(=O)C1=NN(C(N1C)=O)C1=CC=C(C=C1)OC(F)F SQPRGWQZNCMSJQ-UHFFFAOYSA-N 0.000 claims description 2
- RHHHJBZJHVAZLP-UHFFFAOYSA-N 1-[4-(difluoromethoxy)phenyl]-N-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperidin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-4-methyl-5-oxo-1,2,4-triazole-3-carboxamide Chemical compound COc1cc2c(Oc3ccc(NC(=O)c4nn(-c5ccc(OC(F)F)cc5)c(=O)n4C)cc3F)ccnc2cc1OCCCN1CCC(C)CC1 RHHHJBZJHVAZLP-UHFFFAOYSA-N 0.000 claims description 2
- VLJFLBCGOVWHRX-UHFFFAOYSA-N 4-cyclopropyl-N-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperidin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-5-oxo-1-[2-(trifluoromethoxy)phenyl]-1,2,4-triazole-3-carboxamide Chemical compound COc1cc2c(Oc3ccc(NC(=O)c4nn(-c5ccccc5OC(F)(F)F)c(=O)n4C4CC4)cc3F)ccnc2cc1OCCCN1CCC(C)CC1 VLJFLBCGOVWHRX-UHFFFAOYSA-N 0.000 claims description 2
- FGYNGDRCKUXMHU-UHFFFAOYSA-N 4-ethyl-N-[3-fluoro-4-[6-methoxy-7-(3-piperidin-1-ylpropoxy)quinolin-4-yl]oxyphenyl]-5-oxo-1-[2-(trifluoromethoxy)phenyl]-1,2,4-triazole-3-carboxamide Chemical compound CCn1c(nn(-c2ccccc2OC(F)(F)F)c1=O)C(=O)Nc1ccc(Oc2ccnc3cc(OCCCN4CCCCC4)c(OC)cc23)c(F)c1 FGYNGDRCKUXMHU-UHFFFAOYSA-N 0.000 claims description 2
- VGASWFVJNDNMJE-UHFFFAOYSA-N 4-ethyl-N-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperidin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-5-oxo-1-[2-(trifluoromethoxy)phenyl]-1,2,4-triazole-3-carboxamide Chemical compound CCn1c(nn(-c2ccccc2OC(F)(F)F)c1=O)C(=O)Nc1ccc(Oc2ccnc3cc(OCCCN4CCC(C)CC4)c(OC)cc23)c(F)c1 VGASWFVJNDNMJE-UHFFFAOYSA-N 0.000 claims description 2
- WYSPAHZPJHPKBV-UHFFFAOYSA-N N-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-(4-fluorophenyl)-4-methyl-5-oxo-1,2,4-triazole-3-carboxamide Chemical compound COc1cc2c(Oc3ccc(NC(=O)c4nn(-c5ccc(F)cc5)c(=O)n4C)cc3F)ccnc2cc1OCCCN1CCOCC1 WYSPAHZPJHPKBV-UHFFFAOYSA-N 0.000 claims description 2
- LTEBJIWTTURLAU-UHFFFAOYSA-N N-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-4-methyl-5-oxo-1-phenyl-1,2,4-triazole-3-carboxamide Chemical compound COc1cc2c(Oc3ccc(NC(=O)c4nn(-c5ccccc5)c(=O)n4C)cc3F)ccnc2cc1OCCCN1CCOCC1 LTEBJIWTTURLAU-UHFFFAOYSA-N 0.000 claims description 2
- TVPGMCBTNKBCNT-UHFFFAOYSA-N N-[3-fluoro-4-[6-methoxy-7-(3-piperidin-1-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-(2-fluorophenyl)-4-methyl-5-oxo-1,2,4-triazole-3-carboxamide Chemical compound COc1cc2c(Oc3ccc(NC(=O)c4nn(-c5ccccc5F)c(=O)n4C)cc3F)ccnc2cc1OCCCN1CCCCC1 TVPGMCBTNKBCNT-UHFFFAOYSA-N 0.000 claims description 2
- ZMFRNGFIWUJETF-UHFFFAOYSA-N N-[3-fluoro-4-[6-methoxy-7-(3-piperidin-1-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-(3-fluorophenyl)-4-methyl-5-oxo-1,2,4-triazole-3-carboxamide Chemical compound FC=1C=C(C=CC=1OC1=CC=NC2=CC(=C(C=C12)OC)OCCCN1CCCCC1)NC(=O)C1=NN(C(N1C)=O)C1=CC(=CC=C1)F ZMFRNGFIWUJETF-UHFFFAOYSA-N 0.000 claims description 2
- AZRVYURRCFBWQG-UHFFFAOYSA-N N-[3-fluoro-4-[6-methoxy-7-(3-piperidin-1-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-(4-fluorophenyl)-4-methyl-5-oxo-1,2,4-triazole-3-carboxamide Chemical compound COc1cc2c(Oc3ccc(NC(=O)c4nn(-c5ccc(F)cc5)c(=O)n4C)cc3F)ccnc2cc1OCCCN1CCCCC1 AZRVYURRCFBWQG-UHFFFAOYSA-N 0.000 claims description 2
- UHBPJDFRRQBFJT-UHFFFAOYSA-N N-[3-fluoro-4-[6-methoxy-7-(3-piperidin-1-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-(4-methoxyphenyl)-4-methyl-5-oxo-1,2,4-triazole-3-carboxamide Chemical compound COc1ccc(cc1)-n1nc(C(=O)Nc2ccc(Oc3ccnc4cc(OCCCN5CCCCC5)c(OC)cc34)c(F)c2)n(C)c1=O UHBPJDFRRQBFJT-UHFFFAOYSA-N 0.000 claims description 2
- FDXGMMFFRNDLOU-UHFFFAOYSA-N N-[3-fluoro-4-[6-methoxy-7-(3-piperidin-1-ylpropoxy)quinolin-4-yl]oxyphenyl]-4-methyl-5-oxo-1-[2-(trifluoromethoxy)phenyl]-1,2,4-triazole-3-carboxamide Chemical compound COc1cc2c(Oc3ccc(NC(=O)c4nn(-c5ccccc5OC(F)(F)F)c(=O)n4C)cc3F)ccnc2cc1OCCCN1CCCCC1 FDXGMMFFRNDLOU-UHFFFAOYSA-N 0.000 claims description 2
- NTMGHJWPNWUGDK-UHFFFAOYSA-N N-[3-fluoro-4-[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-(4-fluorophenyl)-4-methyl-5-oxo-1,2,4-triazole-3-carboxamide Chemical compound FC=1C=C(C=CC=1OC1=CC=NC2=CC(=C(C=C12)OC)OCCCN1CCCC1)NC(=O)C1=NN(C(N1C)=O)C1=CC=C(C=C1)F NTMGHJWPNWUGDK-UHFFFAOYSA-N 0.000 claims description 2
- JQSSIIALXXZFOR-UHFFFAOYSA-N N-[3-fluoro-4-[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinolin-4-yl]oxyphenyl]-4-methyl-5-oxo-1-phenyl-1,2,4-triazole-3-carboxamide Chemical compound COc1cc2c(Oc3ccc(NC(=O)c4nn(-c5ccccc5)c(=O)n4C)cc3F)ccnc2cc1OCCCN1CCCC1 JQSSIIALXXZFOR-UHFFFAOYSA-N 0.000 claims description 2
- WDAHGVLBPINGHW-UHFFFAOYSA-N N-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-1-(2-fluorophenyl)-4-methyl-5-oxo-1,2,4-triazole-3-carboxamide Chemical compound FC=1C=C(C=CC=1OC1=CC=NC2=CC(=C(C=C12)OC)OCCCN1CCN(CC1)C)NC(=O)C1=NN(C(N1C)=O)C1=C(C=CC=C1)F WDAHGVLBPINGHW-UHFFFAOYSA-N 0.000 claims description 2
- FDRIIYJUHIRODA-UHFFFAOYSA-N N-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-1-(3-fluorophenyl)-4-methyl-5-oxo-1,2,4-triazole-3-carboxamide Chemical compound FC=1C=C(C=CC=1OC1=CC=NC2=CC(=C(C=C12)OC)OCCCN1CCN(CC1)C)NC(=O)C1=NN(C(N1C)=O)C1=CC(=CC=C1)F FDRIIYJUHIRODA-UHFFFAOYSA-N 0.000 claims description 2
- RCVBRHXARSKFDV-UHFFFAOYSA-N N-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-1-(4-fluorophenyl)-4-methyl-5-oxo-1,2,4-triazole-3-carboxamide Chemical compound FC=1C=C(C=CC=1OC1=CC=NC2=CC(=C(C=C12)OC)OCCCN1CCN(CC1)C)NC(=O)C1=NN(C(N1C)=O)C1=CC=C(C=C1)F RCVBRHXARSKFDV-UHFFFAOYSA-N 0.000 claims description 2
- RIFHAFVNJRPWHI-UHFFFAOYSA-N N-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-1-(4-methoxyphenyl)-4-methyl-5-oxo-1,2,4-triazole-3-carboxamide Chemical compound FC=1C=C(C=CC=1OC1=CC=NC2=CC(=C(C=C12)OC)OCCCN1CCN(CC1)C)NC(=O)C1=NN(C(N1C)=O)C1=CC=C(C=C1)OC RIFHAFVNJRPWHI-UHFFFAOYSA-N 0.000 claims description 2
- WFFPPXWNLYXDOI-UHFFFAOYSA-N N-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-4-methyl-5-oxo-1-[2-(trifluoromethoxy)phenyl]-1,2,4-triazole-3-carboxamide Chemical compound FC=1C=C(C=CC=1OC1=CC=NC2=CC(=C(C=C12)OC)OCCCN1CCN(CC1)C)NC(=O)C1=NN(C(N1C)=O)C1=C(C=CC=C1)OC(F)(F)F WFFPPXWNLYXDOI-UHFFFAOYSA-N 0.000 claims description 2
- GDKGAWJKDBKJKB-UHFFFAOYSA-N N-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-4-methyl-5-oxo-1-phenyl-1,2,4-triazole-3-carboxamide Chemical compound FC=1C=C(C=CC=1OC1=CC=NC2=CC(=C(C=C12)OC)OCCCN1CCN(CC1)C)NC(=O)C1=NN(C(N1C)=O)C1=CC=CC=C1 GDKGAWJKDBKJKB-UHFFFAOYSA-N 0.000 claims description 2
- CMSBGVWDSKOQSH-UHFFFAOYSA-N N-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperidin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-1-(2-fluorophenyl)-4-methyl-5-oxo-1,2,4-triazole-3-carboxamide Chemical compound FC=1C=C(C=CC=1OC1=CC=NC2=CC(=C(C=C12)OC)OCCCN1CCC(CC1)C)NC(=O)C1=NN(C(N1C)=O)C1=C(C=CC=C1)F CMSBGVWDSKOQSH-UHFFFAOYSA-N 0.000 claims description 2
- NQGXFZLPORCWQH-UHFFFAOYSA-N N-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperidin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-1-(3-fluorophenyl)-4-methyl-5-oxo-1,2,4-triazole-3-carboxamide Chemical compound COc1cc2c(Oc3ccc(NC(=O)c4nn(-c5cccc(F)c5)c(=O)n4C)cc3F)ccnc2cc1OCCCN1CCC(C)CC1 NQGXFZLPORCWQH-UHFFFAOYSA-N 0.000 claims description 2
- JLZOCGXZEQATSB-UHFFFAOYSA-N N-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperidin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-1-(4-fluorophenyl)-4-methyl-5-oxo-1,2,4-triazole-3-carboxamide Chemical compound COc1cc2c(Oc3ccc(NC(=O)c4nn(-c5ccc(F)cc5)c(=O)n4C)cc3F)ccnc2cc1OCCCN1CCC(C)CC1 JLZOCGXZEQATSB-UHFFFAOYSA-N 0.000 claims description 2
- NOUYMHOJCIZCKZ-UHFFFAOYSA-N N-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperidin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-1-(4-methoxyphenyl)-4-methyl-5-oxo-1,2,4-triazole-3-carboxamide Chemical compound COc1ccc(cc1)-n1nc(C(=O)Nc2ccc(Oc3ccnc4cc(OCCCN5CCC(C)CC5)c(OC)cc34)c(F)c2)n(C)c1=O NOUYMHOJCIZCKZ-UHFFFAOYSA-N 0.000 claims description 2
- GLMXLUNKPYQLNV-UHFFFAOYSA-N N-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperidin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-4-methyl-5-oxo-1-[2-(trifluoromethoxy)phenyl]-1,2,4-triazole-3-carboxamide Chemical compound COc1cc2c(Oc3ccc(NC(=O)c4nn(-c5ccccc5OC(F)(F)F)c(=O)n4C)cc3F)ccnc2cc1OCCCN1CCC(C)CC1 GLMXLUNKPYQLNV-UHFFFAOYSA-N 0.000 claims description 2
- KXUZFTDEUDVDPG-UHFFFAOYSA-N N-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperidin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]-4-methyl-5-oxo-1-phenyl-1,2,4-triazole-3-carboxamide Chemical compound C1(=CC=CC=C1)N1N=C(N(C1=O)C)C(=O)NC1=CC(=C(C=C1)OC1=CC=NC2=CC(=C(C=C12)OC)OCCCN1CCC(CC1)C)F KXUZFTDEUDVDPG-UHFFFAOYSA-N 0.000 claims description 2
- 125000005257 alkyl acyl group Chemical group 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 2
- 238000011321 prophylaxis Methods 0.000 claims 2
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 210000004072 lung Anatomy 0.000 claims 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 230000002062 proliferating effect Effects 0.000 claims 1
- 210000002784 stomach Anatomy 0.000 claims 1
- 229940002612 prodrug Drugs 0.000 abstract description 12
- 239000000651 prodrug Substances 0.000 abstract description 12
- 230000000694 effects Effects 0.000 abstract description 10
- 150000004677 hydrates Chemical class 0.000 abstract description 10
- 239000012453 solvate Substances 0.000 abstract description 10
- 229940079593 drug Drugs 0.000 abstract description 8
- 230000002401 inhibitory effect Effects 0.000 abstract description 6
- 125000001424 substituent group Chemical group 0.000 abstract description 5
- 102000001253 Protein Kinase Human genes 0.000 abstract description 4
- 229940027991 antiseptic and disinfectant quinoline derivative Drugs 0.000 abstract description 4
- 108060006633 protein kinase Proteins 0.000 abstract description 4
- 230000002159 abnormal effect Effects 0.000 abstract description 2
- 125000002943 quinolinyl group Chemical class N1=C(C=CC2=CC=CC=C12)* 0.000 abstract description 2
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Classifications
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- 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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及通式Ⅰ所示的含三氮唑酮和咪唑的喹啉类衍生物及其药学上可接受的盐、水合物、溶剂化物或前药，其中取代基Ar、R1、R2、L、n具有在说明书中给出的含义。本发明还涉及通式Ⅰ的化合物具有强的抑制c‑Met激酶的作用，并且还涉及该类化合物及其药学上可接受的盐、水合物、溶剂化物或前药在制备治疗和/或预防由于c‑Met激酶异常高表达所引起疾病的药物中的用途，特别是在制备治疗和/或预防癌症的药物中的用途。
Description
技术领域
本发明涉及新的含1,2,4-三氮唑酮和咪唑的4-苯氧基取代喹啉类化合物及其药学上可接受的盐、水合物、溶剂化物或其前药，它们的制备方法以及含有所述化合物的药物组合物。本发明还涉及该类化合物及其药学上可接受的盐、水合物、溶剂化物或其前药在制备治疗由于c-Met激酶异常高表达所引起疾病的药物中的用途，特别是在制备治疗和/或预防癌症的药物中的用途。
技术背景
癌症，亦称为恶性肿瘤，为由控制细胞生长增殖机制失常而引起的疾病。《2014世界癌症报告》指出，仅2012当年就有1400万人被诊断患癌，报告还预测，到2025年，全球每年新增患癌病例将增至1900万。中国作为最大的发展中国家，癌症在2012年的发病人数几乎占了全球一半，高居第一位。因此，寻找切实有效的癌症治疗手段和方法迫在眉睫。近年来，随着肿瘤药理学、分子生物学及相关学科的飞速发展，恶性肿瘤细胞内信号转导途径、细胞周期的调控、细胞凋亡的诱导和抑制、血管生成以及细胞与细胞外基质的相互作用等各种基本过程正在被逐步阐明，一系列与肿瘤发生、发展密切相关的关键分子及靶点相继被发现。如表皮生长因子受体(EGFR)、血管内皮细胞生长因子受体(VEGFR)等具有酪氨酸激酶活性的分子靶点。研究表明，近80％的致癌基因都含有酪氨酸激酶编码。抑制酪氨酸激酶受体可以有效控制下游信号的磷酸化，从而抑制肿瘤细胞的生长。因此，以酪氨酸激酶为靶点的新药开发成为国内外抗肿瘤药物经久不衰的研究课题。
科学研究发现，受体酪氨酸激酶c-Met在绝大部分的癌症及部分肿瘤中高表达并异常激活，在肿瘤发生发展、侵袭转移、化疗抗性等各个环节均发挥关键作用。c-Met激酶作为肿瘤信号网络通路中的关键节点蛋白，因可以与细胞表面其他激酶、受体相互作用而备受关注，c-Met激酶抑制剂已成为医药界研究的前沿热点。研究表明，肿瘤细胞中异常活化的HGF/c-Met信号通路被阻断时，肿瘤细胞就会出现细胞形态改变、增殖减缓、成瘤性降低、侵袭能力下降等一系列的变化，因而c-Met已成为抗肿瘤转移治疗的一个极有希望的新靶点。近年来，各国学者已经陆续发现许多对HGF/c-Met蛋白具有拮抗作用的化合物，这些化合物作用于HGF/c-Met信号通路的各个环节。目前以HGF/c-Met为靶点的肿瘤分子靶向治疗药物，包括HGF/c-Met拮抗剂、c-Met小分子抑制剂、c-Met的反义核酸分子和c-Met的抗体。
Foretinib属于4-苯氧基喹啉类化合物，由葛兰素史克公司研发。它是一种可口服的c-Met和VEGFR/KDR激酶抑制剂，其对c-Met激酶和KDR激酶的IC50值分别为0.4和0.8nM，目前已进入Ⅲ期临床研究阶段。临床研究表明，Foretinib对多种人肿瘤细胞株(人肺癌细胞、人胃癌细胞等)表现出显著的抑制增殖作用。
本发明人在参考文献的基础上，设计并合成了一系列新的含有1,2,4-三氮唑酮及咪唑结构的喹啉类衍生物。经过体外活性筛选，表明该类化合物具有抗肿瘤活性。
发明内容
本发明涉及通式Ⅰ所示的喹啉类化合物及其药学上可接受的盐、水合物、溶剂化物或前药，
其中：
n为1-6之间的整数；
R1和R2相同或不同，分别独立地选自氢、C1-C10烷基，C3-C7环烷基，它们可以任选被1-3个相同或不同的R3取代；
或R1和R2与和它们所连接的氮原子一起形成5-10元杂环基，所述杂环基除了与R1和R2连接的氮原子外，任选含有0-4个选自N、O和S的杂原子，所述杂环基可以含有1或2个碳碳双键或叁键，还可以任选被1-3个相同或不同的R3取代；
R3为H、C1-C6烷基、C1-C4烷氧基、卤素、羟基、氰基、C1-C4羧基、C1-C4酯基；
L为
R4为氢、C1-C6烷基、C3-C6环烷基、任选被羟基或卤素取代的C1-C6烷基；
Ar为C6-C10芳基或5-10元杂芳基，其中，所述杂芳基含有1-3个选自N、O或S的杂原子，并且Ar任选1-3个相同或不同的R5取代；
R5为氢、羟基、卤素、硝基、氨基、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C1-C6烷基硫基、任选被羟基、氨基或卤代的C1-C6烷基或C1-C6烷氧基、被单或二C1-C6烷基取代的氨基、C1-C6烷基酰氨基、游离的、成盐的、酯化的和酰胺化的羧基、C1-C6烷基亚磺酰基、磺酰基、C1-C6烷基酰基、氨基甲酰基、被单或二C1-C6烷基取代的氨基甲酰基。
本发明优选涉及通式Ⅰ所示的喹啉类化合物及其药学上可接受的盐、水合物、溶剂化物或前药，其中，
n为1-6之间的整数；
R1和R2相同或不同，分别独立地选自氢、C1-C4烷基、C3-C4环烷基，它们可以任选被1-3个相同或不同的R3取代；
或R1和R2与和它们所连接的氮原子一起形成5-6元杂环基，所述杂环基除了与R1和R2连接的氮原子外，任选含有0-4个选自N、O和S的杂原子，所述杂环基可以含有1或2个碳碳双键或叁键，任选被1-3个相同或不同的R3取代；
R3为H、C1-C4烷基、C1-C4烷氧基、卤素、羟基、氰基；
L为
R4为氢、C1-C6烷基、C3-C6环烷基；
Ar为C6-C10芳基或5-10元杂芳基，其中，所述杂芳基含有1-3个选自N、O或S的杂原子，并且Ar任选1-3个相同或不同的R5取代；
R5为氢、羟基、卤素、硝基、氨基、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C1-C6烷基硫基、任选被羟基、氨基或卤代的C1-C6烷基或C1-C6烷氧基、被单或二C1-C6烷基取代的氨基、C1-C6烷基酰氨基、游离的、成盐的、酯化的和酰胺化的羧基、C1-C6烷基亚磺酰基、磺酰基、C1-C6烷基酰基、氨基甲酰基、被单或二C1-C6烷基取代的氨基甲酰基。
本发明优选涉及通式Ⅰ所示的喹啉类化合物及其药学上可接受的盐、水合物、溶剂化物或前药，其中，
n为3；
R1和R2相同或不同，分别独立地选自氢、C1-C4烷基、C3-C4环烷基，它们可以任选被1-3个相同或不同的R3取代；
或R1和R2与和它们所连接的氮原子一起形成5-6元杂环基，所述杂环基除了与R1和R2连接的氮原子外，任选含有0-4个选自N、O和S的杂原子，所述杂环基可以含有1或2个碳碳双键或叁键，任选被1-3个相同或不同的R3取代；
R3为H、C1-C4烷基、C1-C4烷氧基、卤素、羟基、氰基；
L为
R4为氢、C1-C6烷基、C3-C6环烷基；Ar为苯基、萘基、5-10元杂芳基，其中，所述杂芳基含有1-3个选自N、O或S的杂原子，并且Ar任选1-3个相同或不同的R5取代。
R5为氢或为羟基、卤素、硝基、氨基、氰基、C1-C6烷基、C1-C6烷氧基、任选被卤代的C1-C6烷基或C1-C6烷氧基、C1-C6烷基酰氨基、磺酰基、(C1-C6)烷基酰基、氨基甲酰基。本发明还优选涉及通式Ⅰ所示的喹啉类化合物及其药学上可接受的盐、水合物、溶剂化物或前药，其中，
n为3；
R1和R2与和它们所连接的氮原子一起形成5-6元杂环基，所述杂环基除了与R1和R2连接的氮原子外，任选含有0-4个选自N、O和S的杂原子，所述杂环基任选被1-3个相同或不同的R3取代；
R3为H、C1-C4烷基、卤素；
L为
R4为甲基、乙基、环丙基；
Ar为苯基、5-6元杂芳基，其中，所述杂芳基含有1-3个选自N、O或S的杂原子，并且Ar任选1-3个相同或不同的R5取代；
本发明还特别优选涉及通式Ⅰ所示的喹啉类化合物及其药学上可接受的盐、水合物、溶剂化物或前药，其中，
Ar为苯基，吡啶基，并且Ar任选1-3个相同或不同的R5取代；
R5为氢或为卤素、三氟甲氧基、三氟甲基、二氟甲氧基、甲基、甲氧基。
本发明非常特别优选的下列通式Ⅰ的衍生物，包括其药学上可接受的盐、水合物、溶剂化物或前药，但这些化合物并不意味着对本发明的任何限制：
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-苯基-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-苯基-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-苯基-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-苯基-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-苯基-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(N，N-二甲基)丙氧基]喹啉-4-氧基]苯基]-1-苯基-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(N，N-二乙基)丙氧基]喹啉-4-氧基]苯基]-1-苯基-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(4-氟苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(4-氟苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(4-氟苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(4-氟苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(4-氟苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氟苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氟苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氟苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氟苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氟苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氟苯基)-4-乙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氟苯基)-4-乙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氟苯基)-4-乙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氟苯基)-4-乙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氟苯基)-4-环丙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氟苯基)-4-乙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(3-氟苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(3-氟苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(3-氟苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(3-氟苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(3-氟苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(4-二氟甲氧基苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(4-二氟甲氧基苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(4-二氟甲氧基苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(4-二氟甲氧基苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(4-二氟甲氧基苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(4-甲氧基苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(4-甲氧基苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(4-甲氧基苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氯苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氯苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氯苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氯苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氯苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氯苯基)-4-环丙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(N，N-二乙基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基苯基)-4-乙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基苯基)-4-乙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基)-4-乙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基苯基)-4-乙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基苯基)-4-乙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基苯基)-4-环丙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基苯基)-4-环丙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基)-4-环丙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基苯基)-4-乙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基苯基)-4-乙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲基苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲基苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲基苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2,4-二氯苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2,4-二氯苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(2,4-二氯苯基)-4-环丙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(2,4-二氯苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(2,4-二氯苯基)-4-乙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(4-吡啶基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(4-吡啶基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(4-吡啶基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(4-氟苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(4-氟苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(4-氟苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(4-氟苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(4-氟苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(4-氯苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(4-氯苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(4-氯苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(4-氯苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(4-氯苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(4-甲氧基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(4-甲氧基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(4-甲氧基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(4-甲氧基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(4-甲氧基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2,6-二甲基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2,6-二甲基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(2,6-二甲基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(2,6-二甲基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(2,6-二甲基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2,6-二氟苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2,6-二氟苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(2,6-二氟苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(2,6-二氟苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(2,6-二氟苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(3-三氟甲基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(3-三氟甲基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(3-三氟甲基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(3-三氟甲基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(3-三氟甲基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氟苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氟苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氟苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氟苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氟苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氯苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氯苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氯苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氯苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氯苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氯苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氯苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氯苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氯苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氯苯基)-1H-咪唑-3-甲酰胺
而且，按照本发明所属领域的一些通常方法，本发明中上式Ⅰ喹啉类衍生物可以与酸生成药学上可接受的盐。可药用加成盐包括无机酸和有机酸加成盐，与下列酸加成的盐是特别优选的：盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、三氟乙酸、马来酸、柠檬酸、富马酸、草酸、酒石酸、苯甲酸等。
此外，本发明还包括本发明衍生物的前药。本发明衍生物的前药是通式Ⅰ的衍生物，它们自身可能具有较弱的活性甚至没有活性，但是在给药后，在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。
本发明中“卤素是指氟、氯、溴或碘代；“烷基”是指直链或支链的烷基；“环烷基”是指取代或未取代的环烷基；“芳基”是指单环或多环的碳原子芳香环系，如苯基、萘基等；“杂芳基”是指含有一个或多个选自N、O、S杂原子的单环或多环的环状体系，环状体系是芳香性的，如咪唑基、吡啶基、吡唑基、(1,2,3)-和(1,2,4)-三唑基、呋喃基、噻吩基、吡咯基、噻唑基、苯并噻唑基、噁唑基、异噁唑基、萘基、喹啉基、异喹啉基、苯并咪唑基和苯并噁唑基等；“杂环基”是指含有一个或多个选自N、O、S的杂原子的单环或多环的环状体系，如吡咯烷基、吗啉基、哌嗪基、哌啶基、吡唑烷基、咪唑烷基和噻唑啉基等。
通过体外抑制结肠癌细胞HT-29、肺癌细胞H460、人肺腺癌细胞细胞株A549和人胃癌细胞MKN-45活性试验，本发明化合物对结肠癌细胞、肺癌细胞以及人胃癌细胞具有显著抑制作用，特别用于制备治疗和/或预防结肠癌、肺癌和胃癌的药物。
通过对c-Met酶活性测试发现，本发明化合物具有显著的抑制c-Met激酶活性，对c-Met高表达的肺癌、结肠癌细胞以及胃癌细胞等有较强的抑制作用，特别用于制备治疗和/或预防胃癌的药物。
下文中提供的实施例和制备例进一步阐明和举例说明本发明化合物及其制备方法。应当理解，下述实例和制备例的范围并不以任何方式限制本发明的范围。
下面的合成路线(路线1)描述了本发明的式Ⅰ衍生物的制备，所有的原料都是通过这些路线中描述的方式、通过有机化学领域普通技术人员熟知的方法制备的或者可商购。本发明的全部最终衍生物都是通过这些路线中描述的方法或通过与其类似的方法制备的，这些方法是有机化学领域普通技术人员熟知的。这些路线中应用的全部可变因数如下文的定义或如权利要求中的定义。
按照本发明的式Ⅰ衍生物，均可按照路线1的方法由相应的中间体Q和相应的M通过缩合反应制备得到；
M的合成路线如路线2所示，其他取代基如权利要求中所定义；
按照本发明通式Ⅰ化合物，中间体Q可通过如路线3所示的方法制备，其他取代基如权利要求中所定义。
当R3为甲基，中间体Q的制备可由甲胺水溶液与氯代苯腙(h)经类似路线3制得；
当R3为乙基，中间体Q的制备可由乙胺水溶液与氯代苯腙(h)经类似路线3制得；
当R3为环丙基，中间体Q的制备可由环丙胺与氯代苯腙(h)经类似路线3制得；
按照本发明通式Ⅰ化合物，中间体Q也可通过如路线4所示的方法制备，其他取代基如权利要求中所定义。
以上四条路线中所有中间体的取代基R1、R2、R4、Ar、n如权利要求中所定义。
具体实施方式：
实施例旨在阐述而不是限制本发明的范围。化合物的核磁共振氢谱用BrukerARX-400或者ARX-600测定，质谱用Agilent 1100LC/MSD测定；所用试剂均为分析纯或化学纯.
制备通法
步骤A 1-(4-(3-氯丙氧基)-3-甲氧基)苯乙酮(a)
将3-甲氧基-4-羟基苯乙酮(249g，1.5mol)和无水碳酸钾(579.6g，2.1mol)加入到1250mL丙酮中，控温25℃以下缓慢滴加1-溴-3-氯丙烷(661.3g，4.2mol)/丙酮(1200mL)，滴毕，与室温搅拌过夜。反应完毕后，抽滤，滤饼用100mL丙酮淋洗，合并滤饼，将滤液缓慢倒入15L冰水中，同时剧烈搅拌，析出大量白色固体，抽滤，滤饼于40℃真空干燥48h，得白色粉末695.5g，收率92.5％，ESI-MS[M+H](m/z):242.7。
步骤B 1-(4-(3-氯丙氧基)-5-甲氧基-2-硝基)苯乙酮(b)
将中间体Ⅱ(200g，0.82mol)加入至CH2Cl2(5v/w，1000mL)中，充分搅拌使中间体Ⅱ全部溶解，然后将反应液冷却至-20℃后，缓缓滴加发烟硝酸(130g，2.06mol)，控制滴加速度保持反应液温度低于-10℃，滴加完毕后在-10～-20℃反应2h。反应完毕后，将反应液倒入冰水中，收集有机层，有机层用饱和食盐水洗涤，直至水层为中性，无水硫酸钠干燥。蒸干溶剂，得黄色固体210g，收率89％，ESI-MS[M+H](m/z):287.7。
步骤C (E)-1-(4-(3-氯丙氧基)-5-甲氧基-2-硝基苯基)-3-(二甲氨基)丙基-2-烯-1-酮(c)
将中间体Ⅲ(200g，0.695moL)加入至甲苯(5v/w，1000mL)中，加热至110℃使中间体Ⅲ完全溶解，再加入N,N-二甲基甲酰胺二甲基缩醛(DMF-DMA)(414.2g，3.476mol)，加热回流反应16h。反应完毕后，将反应液冷却至室温后放入冷阱中搅拌，析出固体，抽滤，滤饼干燥后得黄色固体180g，收率75.8％，ESI-MS[M+H](m/z):342.8。
步骤D 7-(3-氯丙氧基)-6-甲氧基-4(1H)-喹啉酮(d)
将中间体Ⅳ(150g，0.44mol)加至冰乙酸(8v/w，1200mL)中，升温至40℃，待中间体Ⅳ完全溶解后，分批缓慢加入铁粉(123.1g，2.20mol)升温至80℃机械搅拌反应2h。反应完毕后，反应液趁热抽滤，收集滤液，滤液冷却后有大量固体析出，抽滤，得土黄色固体。将滤饼溶解在冰乙酸中，于80℃下搅拌约30min，再次趁热抽滤，收集滤液，滤液冷却后有固体析出，抽滤，滤饼水洗至中性，干燥后得固体79g，收率65％，ESI-MS[M+H](m/z):267.7。
步骤E 6-(甲氧基)-7-(3-(1-吡咯烷基)丙氧基)-4(1H)-喹啉酮(e)
将中间体Ⅴ(62g，0.232mol)、四氢吡咯(98.6g，1.38mol)加入至乙腈(620mL)中，加热回流8h。反应完毕后，蒸去大部分溶剂，将残余液置于冷阱中，析出固体，抽滤，乙酸乙酯洗涤，得固体68.5g，收率95.5％，ESI-MS[M+H](m/z):302.4。
步骤F 4-氯-6-甲氧基-7-(3-(1-吡咯烷基)丙氧基)喹啉(f)
将中间体Ⅵ(64g，0.19mol)、三氯氧磷(5v/w，315mL)加入至乙腈(5v/w，315mL)中，升温至85℃回流反应6h。反应完毕后，减压蒸干，得灰色粘稠固体，将其加入到大量的冰水混合液中，用10％氢氧化钾溶液调pH至10。用CH2Cl2萃取(200mL*3)，收集有机层，无水硫酸钠干燥，蒸干溶剂，冷却得灰白色固体58g，收率87％，ESI-MS[M+H](m/z):320.8。
步骤G 4-(2-氟-4-硝基苯氧基)-6-甲氧基-7-(3-(1-吡咯烷基)丙氧基)喹啉(g)
将2-氟-4-硝基苯酚(36.73g，0.234mol)加入至干燥的氯苯(5v/w，250mL)中，加热至145℃，向反应液中加入中间体Ⅶ(62.5g，0.2mol)，此温度下反应20h。反应完毕后，蒸干溶剂，得灰色固体，将此固体溶于二氯甲烷中，用饱和碳酸钾溶液洗涤，收集有机层，干燥，蒸干溶剂，用乙醇重结晶，得固体50.15g，收率70.9％，ESI-MS[M+H](m/z):441.5。
步骤H 3-氟-4-(6-甲氧基-7-(3-(1-吡咯烷基)丙氧基)喹啉-4-氧基)苯胺(M)
将铁粉(61.42g，1.1mol)、6mL浓盐酸加入至90％乙醇(25v/w，1210.5mL)中，升温至80℃搅拌15min，然后向反应液中分批加入中间体Ⅷ(49.5g，0.11mol)，加毕，回流反应2h。反应完毕后，趁热抽滤，收集滤液，蒸干溶剂，得到黄色固体44g，收率95％，ESI-MS[M+H](m/z):411.4。
步骤I 2-氯-2-(2-邻甲基苯腙基)乙酸乙酯(h)
取邻甲基苯胺6.86g(63.4mmol)，加入在20mL乙醇，7mL水和13mL浓盐酸(158mmol)，使之溶解，该溶液冷却到-5℃以下，滴加15mL水溶解的4.69g(69.7mmol)亚硝酸钠溶液，滴加过程中保持温度低于5℃，滴毕，搅拌0.5h。降温到0℃以下，滴加90mL水溶解的15.6g(190.1mmol)无水乙酸钠，滴毕，加入2-氯乙酰乙酸乙酯10.87g(63.38mmol)。室温搅拌4h，过滤，滤饼冷乙醇打浆，过滤，干燥得淡黄色产物9.3g，产率72％。ESI-MS[M+H](m/z):241。
步骤J 2-甲氨基-2-(2-邻甲基苯腙基)乙酸乙酯(i)
取中间体h 8.4g(34.9mmol)，溶于50mL四氢呋喃中，冰浴下滴加40％甲胺水溶液8.3g g(105mmol)，滴毕，保温搅拌5h，蒸发除去THF，加入水200mL，析出固体，过滤，干燥，得黄色产物7.0g，产率85％。ESI-MS[M+H](m/z):236。
步骤K 4-甲基-5-氧代-1-(2-甲基苯基)-4,5-二氢-1H-1,2,4-三氮唑-3-甲酸乙酯(j)
取中间体i4.70g(20.0mmol)、碳酸钾6.0g(60.0mmol)，加入二氧六环20mL，冰浴下滴加20mL二氧六环溶解的对硝基氯甲酸苯酯6.0g(30.0mmol)，滴毕升至室温反应2h，继续回流反应6h，抽滤，滤饼二氧六环洗涤后弃去。滤液蒸干，用二氯甲烷溶解，饱和碳酸氢钠溶液洗涤三次，饱和氯化钠溶液洗涤一次，有机相无水硫酸钠干燥后蒸干。柱层析分离得灰白色产物2.2g，产率42％。ESI-MS[M+H](m/z):262。
步骤L 4-甲基-5-氧代-1-(2-甲基苯基)-4,5-二氢-1H-1,2,4-三氮唑-3-甲酸(Q-1)
取中间体j2.0g(7.65mmol)，溶于32mL四氢呋喃中，加入水8mL，搅拌下加入一水合氢氧化锂643mg(15.31mmol)，室温搅拌反应，30min反应完毕。减压蒸发除去THF，加入30mL水，乙酸乙酯萃取二次，水相用6mol/L盐酸调教pH 2，析出类白色固体，抽滤，滤饼水洗，干燥，得产物1.4g，产率78％。ESI-MS[M-H](m/z):232.08。
步骤M N-甲酰基苯胺的制备(k)
取苯胺9.31g(100.0mmol)，二水合甲酸钠2.08g(20.0mmol)，无水甲酸50ml，回流反应14h，反应完毕。减压蒸发除去溶剂，剩余物加入乙酸乙酯150ml，水洗三次，有机相干燥，减压浓缩得白色产物11.3g，产率93.3％。ESI-MS，120[M-1]。
步骤N 苯基异腈的制备(l)
取中间体k6.06g(50.0mmol)，用40ml THF溶解，加入三乙胺20.25g(200.0mmol)，控制反应温度0℃以下，滴加三氯氧磷10.0g(65.0mmol)和20mlTHF的混合液。保持0℃3h，升至室温反应1h，将反应液慢慢倒入冰水中，析出固体，过滤，干燥得淡黄色固体产物4.1g。产率79.5％。
步骤O 1-苯基-1H-咪唑-4-羧酸乙酯的制备(m)
取中间体l5.16g(50.0mmol)，异氰酸乙酯7.92g(70.0mmol)，氧化亚铜1.00g(7.0mmol)，一水邻菲罗啉1.98g(10.0mmol)，加入30ml THF溶解，回流反应4h，反应完毕。减压蒸发除去溶剂。加入乙酸乙酯100ml回流，趁热滤除不溶物。滤液减压蒸发至约15-20ml，冷却，析出固体，过滤，滤饼冷乙酸乙酯洗涤，得白色固体产物6.38g，产率59％。ESI-MS[M+Na](m/z):239。
步骤P 1-苯基-1H-咪唑-4-甲酸的制备(Q-2)
取中间体m 2.0g(9.25mmol)，溶于30mL四氢呋喃中，加入水8mL，搅拌下加入一水合氢氧化锂777mg(18.50mmol)，搅拌回流反应，2h反应完毕。减压蒸发除去THF，加入30mL水，乙酸乙酯萃取二次，水相用6mol/L盐酸调教pH 2，析出类白色固体，抽滤，滤饼水洗，干燥，得产物1.4g，产率80.44％。ESI-MS[M-H](m/z):187.1。
步骤R N-[3-氟-4-[6-甲氧基-7-[3-(取代氨基)丙氧基]喹啉-4-氧基]苯基]-1-取代芳香基-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺和N-[3-氟-4-[6-甲氧基-7-[3-(取代氨基)丙氧基]喹啉-4-氧基]苯基]-1-取代芳香基-1H-咪唑-3-甲酰胺的合成通法
在反应瓶中加入中间体Q(Q-1或Q-2)1.20mmol，中间体M 1.00mmol，HATU1.20mmol，三乙胺1.20mmol，15ml DMF，室温搅拌4.5h反应完毕。反应液倒入100mL 20％的碳酸钾水溶液，分别用50mL二氯甲烷萃取三次，合并有机相，有机相用20％的碳酸钾水溶液洗涤三次，饱和食盐水洗涤有机层两次，分出有机层用无水硫酸钠干燥。过滤，减压蒸去二氯甲烷，柱层析分离得产物。
按照制备通法，分别制得实施例1–124化合物(见表一)。
表一：
体外抗肿瘤细胞活性
对按照本发明的上式Ⅰ的含三氮唑酮的喹啉类衍生物进行了体外抑制人结肠癌细胞HT-29、人肺癌细胞H460、人胃癌细胞MKN-45、人肺腺癌A549活性筛选。
(1)细胞复苏并传代2-3次稳定后，用胰蛋白酶溶液(0.25％)使其从培养瓶底部消化下来。将细胞消化液倒入离心管中后，之后加入培养液以终止消化。将离心管在800r/min下离心10min，弃去上清液后加入5mL培养液，吹打混匀细胞，吸取10μL细胞混悬液加入细胞计数板中计数，调整细胞浓度为104个/孔。96孔板中除A1孔为空白孔不加细胞外，其余皆加入100μL细胞混悬液。将96孔板放入培养箱中培养24h。
(2)用50μL二甲基亚砜溶解受试样品，然后加入适量培养液，使样品溶解成2mg/mL药液，然后在24孔板中将样品稀释为20,4,0.8,0.16,0.032μg/mL。
每个浓度加入3孔，其中周围两行两列细胞长势受环境影响较大，只和为空白细胞孔使用。将96孔板放入培养箱中培养72h。
(3)将96孔板中带药培养液弃去，用磷酸缓冲溶液(PBS)将细胞冲洗两遍，在每孔中加入MTT(四氮唑)(0.5mg/mL)100μL放入培养箱中4h后，弃去MTT溶液，加入二甲基亚砜100μL。在磁力振荡器上振荡使存活细胞与MTT反应产物甲臜充分溶解，放入酶标仪中测定结果。通过Bliss法可求出药物IC50值。
化合物的抑制结肠癌细胞HT-29、肺癌细胞H460、人胃癌细胞MKN-45和人肺腺癌A549活性结果，以foretinib为阳性对照(见表二)。
表二
c-Met酶活性试验
用于测量c-Met激酶活性的试验基于酶联免疫吸附试验(ELISA)。具体操作是：
室温下，在0.25mg/mL PGT包被的板上，将实施例化合物、50pM c-Met(His-标记的重组人Met(氨基酸974-末端)，通过杆状病毒表达)和5μM ATP在试验缓冲液中(25mM MOPS,PH 7.4,5mM MgCl2,0.5raM MnCl2,100μM原钒酸钠，0.01％Triton X-100，1mM DTT，最后DMSO浓度1％(v/v))温育20分钟。通过冲洗除去反应混合物并用0.2μg/mL缀合辣根过氧化物酶(HRP)的磷酸酪氨酸特异性单克隆抗体(PY20)检测磷酸化聚合物底物。加入1M磷酸终止显色后，于450nm处通过分光光度法定量显色的底物(TMB)的颜色。实施例化合物及阳性对照药(foretinib)对c-Met激酶的抑制数据(见表三)。
表三：
从上述试验结果可以清楚地看出，本发明所要保护的通式Ⅰ的化合物具有良好的体外抗肿瘤活性，相当或优于对照药foretinib。
尽管已经通过特定实施方案描述了本发明，但修改和等价变化对于精通此领域的技术人员而言是显见的，且它们都包含在本发明范围之内。
Claims (11)
1.通式Ⅰ的化合物或药学上可接受的盐，
其中：
n为1-6之间的整数；
R1和R2与和它们所连接的氮原子一起形成1-哌啶基、4-吗啉基、4-甲基-1-哌嗪基、4-甲基-1-哌啶基；
L为
R4为氢、C1-C6烷基、C3-C6环烷基、任选被羟基或卤素取代的C1-C6烷基；
Ar为苯基，吡啶基，并且Ar任选1-3个相同或不同的R5取代；
R5为氢、羟基、卤素、硝基、氨基、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C1-C6烷基硫基、任选被羟基、氨基或卤代的C1-C6烷基或C1-C6烷氧基、被单或二C1-C6烷基取代的氨基、C1-C6烷基酰氨基、C1-C6烷基亚磺酰基、C1-C6烷基酰基、氨基甲酰基、被单或二C1-C6烷基取代的氨基甲酰基。
2.权利要求1的通式Ⅰ的化合物或药学上可接受的盐，其中，
R4为甲基、乙基、环丙基。
3.权利要求1的通式Ⅰ的化合物或药学上可接受的盐，其中，
R5为氢或为羟基、卤素、硝基、氨基、氰基、C1-C6烷基、C1-C6烷氧基、任选被卤代的C1-C6烷基或C1-C6烷氧基、C1-C6烷基酰氨基、(C1-C6)烷基酰基、氨基甲酰基。
4.权利要求1或2或3的通式Ⅰ的化合物或药学上可接受的盐，
其中，
R5为氢或为卤素、三氟甲氧基、三氟甲基、二氟甲氧基、甲基、甲氧基。
5.权利要求1-3任何一项的通式Ⅰ的化合物或药学上可接受的盐，
其中，n为3。
6.权利要求4的通式Ⅰ的化合物或药学上可接受的盐，
其中，n为3。
7.下列化合物或药学上可接受的盐：
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-苯基-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-苯基-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-苯基-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-苯基-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-苯基-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(N，N-二甲基)丙氧基]喹啉-4-氧基]苯基]-1-苯基-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(N，N-二乙基)丙氧基]喹啉-4-氧基]苯基]-1-苯基-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(4-氟苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(4-氟苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(4-氟苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(4-氟苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(4-氟苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氟苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氟苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氟苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氟苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氟苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氟苯基)-4-乙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氟苯基)-4-乙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氟苯基)-4-乙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氟苯基)-4-乙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氟苯基)-4-环丙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氟苯基)-4-乙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(3-氟苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(3-氟苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(3-氟苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(3-氟苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(3-氟苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(4-二氟甲氧基苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(4-二氟甲氧基苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(4-二氟甲氧基苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(4-二氟甲氧基苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(4-二氟甲氧基苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(4-甲氧基苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(4-甲氧基苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(4-甲氧基苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氯苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氯苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氯苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氯苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氯苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氯苯基)-4-环丙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(N，N-二乙基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基苯基)-4-乙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基苯基)-4-乙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基)-4-乙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基苯基)-4-乙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基苯基)-4-乙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基苯基)-4-环丙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基苯基)-4-环丙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基)-4-环丙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基苯基)-4-乙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基苯基)-4-乙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲基苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲基苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲基苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2,4-二氯苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2,4-二氯苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(2,4-二氯苯基)-4-环丙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(2,4-二氯苯基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(2,4-二氯苯基)-4-乙基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(4-吡啶基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(4-吡啶基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(4-吡啶基)-4-甲基-5-氧代-4,5-二氢-1H-1,2,4-三氮唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(4-氟苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(4-氟苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(4-氟苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(4-氟苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(4-氟苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(4-氯苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(4-氯苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(4-氯苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(4-氯苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(4-氯苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(4-甲氧基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(4-甲氧基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(4-甲氧基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(4-甲氧基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(4-甲氧基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2,6-二甲基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2,6-二甲基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(2,6-二甲基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(2,6-二甲基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(2,6-二甲基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2,6-二氟苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2,6-二氟苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(2,6-二氟苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(2,6-二氟苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(2,6-二氟苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲氧基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(2-三氟甲基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(3-三氟甲基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(3-三氟甲基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(3-三氟甲基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(3-三氟甲基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(3-三氟甲基苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氟苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氟苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氟苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氟苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氟苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氯苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氯苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氯苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氯苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氯苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氯苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌啶基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氯苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-吗啉基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氯苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(4-甲基-1-哌嗪基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氯苯基)-1H-咪唑-3-甲酰胺
N-[3-氟-4-[6-甲氧基-7-[3-(1-吡咯烷基)丙氧基]喹啉-4-氧基]苯基]-1-(2-氯苯基)-1H-咪唑-3-甲酰胺。
8.一种药用组合物，包含权利要求1-7中任何一项的化合物或药学上可接受的盐作为活性成分以及药学上可接受的赋形剂。
9.权利要求1-7中任何一项的化合物或药学上可接受的盐或权利要求8所述的药物组合物在制备治疗和/或预防增生性疾病药物中的应用。
10.权利要求1-7中任何一项的化合物或药学上可接受的盐或权利要求8所述的药物组合物在制备治疗和/或预防癌症的药物中的应用。
11.权利要求1-7中任何一项的化合物或药学上可接受的盐或权利要求8所述的药物组合物在制备治疗和/或预防肺癌、胃癌、结肠癌药物中的应用。
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| CN104072480A (zh) * | 2013-03-27 | 2014-10-01 | 沈阳药科大学 | 喹啉类化合物及其制备方法和应用 |
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