Quinazoline derivative, preparation method therefor, intermediate, composition and application thereof

摘要

Disclosed are as represented by Formula (I) a quinazoline derivative and a pharmaceutical acceptable salt thereof, or, an enantiomer, a non-enantiomer, a tautomer, a racemate, a solvate, a metabolic precursor, or a prodrug of both. Also disclosed are a preparation method therefor, an intermediate, a pharmaceutical composition having the quinazoline derivative, and an application thereof. The quinazoline derivative of the present invention is provided with improved anti-tumor activity.;

主权项

1. A compound selected from the group consisting of:
a quinazoline derivative, a pharmaceutically acceptable salt thereof, a racemate of the quinazoline derivative or a pharmaceutically acceptable salt thereof, a solvate of the quinazoline derivative or a pharmaceutically acceptable salt thereof, and a prodrug of the quinazoline derivative or a pharmaceutically acceptable salt thereof, wherein the quinazoline derivative is selected from the group consisting of: N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(dimethylamino)-2-fluorobut-2-enamide (compound 1); (Z)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(dimethylamino)-2-fluorobut-2-enamide (compound 2-1); (E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(dimethylamino)-2-fluorobut-2-enamide (compound 2-2); N-(4-((3-chloro-4-fluorophenyl)amino)-7-(2-methoxy)ethoxyquinazolin-6-yl)-4-(dimethylamino)-2-fluorobut-2-enamide (compound 3-1); N-(4-((3-chloro-4-fluorophenyl)amino)-7-ethoxyquinazolin-6-yl)-4-(dimethylamino)-2-fluorobut-2-enamide (compound 3-2); N-(4-((3-chloro-4-fluorophenyl)amino)-7-(2-methoxyethoxy)quinazolin-6-yl)-2-fluoro-4-morpholinobut-2-enamide (compound 3-3); N-(4-((3-chloro-4-fluorophenyl)amino)-7-((3R)-tetrahydrofuran-3-yloxy)quinazolin-6-yl)-4-(dimethylamino)-2-fluorobut-2-enamide (compound 3-4); N-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-6-yl)-4-(dimethylamino)-2-fluorobut-2-enamide (compound 3-5); N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(diethylamino)-2-fluorobut-2-enamide (compound 3-6); N-(4-((3-chloro-4-fluorophenyl)amino)-7-(2-methoxyethoxy)quinazolin-6-yl)-2-fluoro-4-(4-methylpiperazin-1-yl)but-2-enamide (compound 3-7); N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-4-((2-methoxyethyl)(methyl)amino)but-2-enamide (compound 3-8); N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-4-(4-methylpiperazin-1-yl)but-2-enamide (compound 3-9); N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-4-(methyl)(tetrahydrofuran-3-yl)amino)but-2-enamide (compound 3-10); N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(2-(dimethylamino)ethoxy)-2-fluorobut-2-enamide (compound 3-11); N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidine-2(S)-yl)acrylamide (compound 3-12); N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)-4-(dimethylamino)-2-fluorobut-2-enamide (compound 3-13); N-(4-(4-((3-fluorobenzyloxy)-3-chlorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(dimethylamino)-2-fluorobut-2-enamide (compound 3-14); N-(4-(1-(3-fluorobenzyl)-1H-indazol-5-ylamino)-7-methoxyquinazolin-6-yl)-4-(dimethylamino)-2-fluorobut-2-enamide (compound 3-15); 4-(dimethylamino)-N-(4-((3-ethynylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluorobut-2-enamide (compound 3-16); N-(4-((2,4-dichloro-5-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-4-(dimethylamino)-2-fluorobut-2-enamide (compound 3-17); N-(4-((5-chlorobenzo[d][1,3]dioxol-4-yl)amino)-7-methoxyquinazolin-6-yl)-4-(dimethylamino)-2-fluorobut-2-enamide (compound 3-18); N-(4-((4-chloro-3-(trifluoromethyl)phenyl)amino)-7-methoxyquinazolin-6-yl)-4-(dimethylamino)-2-fluorobut-2-enamide (compound 3-19); N-(4-((3-bromophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(dimethylamino)-2-fluorobut-2-enamide (compound 3-20); N-(4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(dimethylamino)-2-fluorobut-2-enamide (compound 3-21); N-(4-((4-bromo-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(dimethylamino)-2-fluorobut-2-enamide (compound 3-22); N-(4-((3-chloro-2,4-difluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(dimethylamino)-2-fluorobut-2-enamide (compound 3-23); N-(4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(dimethylamino)-2-fluorobut-2-enamide (compound 3-24); N-(4-((4-bromo-3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(dimethylamino)-2-fluorobut-2-enamide (compound 3-25); (Z)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)-4-(dimethylamino)-2-fluorobut-2-enamide (compound 4-1); (E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)-4-(dimethylamino)-2-fluorobut-2-enamide (compound 4-2); N-(4-((3-chloro-4-fluorophenyl)amino)-7-(3-morpholinopropoxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 5); N-(4-((3-chloro-2,4-difluorophenyl)amino)-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 6); N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-4-(piperidin-1-yl)but-2-enamide (compound 7); (Z)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-4-(piperidin-1-yl)but-2-enamide (compound 8-1); (E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-4-(piperidin-1-yl)but-2-enamide (compound 8-2); N-(4-((3-chloro-4-(pyridin-2-ylmethoxyl)phenyl)amino)-7-ethoxyquinazolin-6-yl)-4-(dimethylamino)-2-fluorobut-2-enamide (compound 9); (S)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-(tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-2-fluoro-4-morpholinobut-2-enamide (compound 10); (S)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-4-(dimethylamino)-2-fluorobut-2-enamide (compound 11); N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-4-morpholinobut-2-enamide (compound 12); N-(4-((3-bromophenyl)amino)-7-ethoxyquinazolin-6-yl)-2-fluoro-4-(piperidin-1-yl)but-2-enamide (compound 13); N-(4-((3-chloro-4-fluorophenyl)amino)-7-(2-methoxyethoxy)quinazolin-6-yl)-2-fluoro-4-(piperidin-1-yl)but-2-enamide (compound 14); N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)-2-fluoro-4-(piperidin-1-yl)but-2-enamide (compound 15); N-(4-((3-bromophenyl)amino)-7-ethoxyquinazolin-6-yl)-4-(dimethylamino)-2-fluorobut-2-enamide (compound 16); N-(4-((3-bromophenyl)amino)-7-ethoxyquinazolin-6-yl)-2-fluoro-4-morpholinobut-2-enamide (compound 17); N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-4-(pyrrolidin-1-yl)but-2-enamide (compound 18); (Z)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)-4-(dimethylamino)-2-fluorobut-2-enamide (compound 19-1); (E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)-4-(dimethylamino)-2-fluorobut-2-enamide (compound 19-2); (S,Z)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-2-fluoro-4-morpholinobut-2-enamide (compound 20-1); (S,E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-2-fluoro-4-morpholinobut-2-enamide (compound 20-2); (S,Z)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-4-(dimethylamino)-2-fluorobut-2-enamide (compound 21-1); (S,E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-4-(dimethylamino)-2-fluorobut-2-enamide (compound 21-2); (Z)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-4-morpholinobut-2-enamide (compound 22-1); (E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-4-morpholinobut-2-enamide (compound 22-2); N-[4-(4-bromo-2-fluorophenylamino)-7-(3-morpholinopropoxy)quinazolin-6-yl]-2-fluoroacrylamide (compound 23); N-[4-((3-chloro-2,4-difluorophenyl)amino)-7-(3-morpholinopropoxy)quinazolin-6-yl]-2-fluoroacrylamide (compound 24); N-[4-(3-ethynylphenylamino)-7-(3-morpholinopropoxy)quinazolin-6-yl]-2-fluoroacrylamide (compound 25); N-[4-((3-chloro-2-fluorophenyl)amino)-7-(3-morpholinopropoxy)quinazolin-6-yl]-2-fluoroacrylamide (compound 26); N-[4-((2,4-dichloro-5-methoxyphenyl)amino)-7-(3-morpholinopropoxy)quinazolin-6-yl]-2-fluoroacrylamide (compound 27); N-[4-((3-bromophenyl)amino)-7-(3-morpholinopropoxy)quinazolin-6-yl]-2-fluoroacrylamide (compound 28); N-[4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)-7-(3-morpholinopropoxy)quinazolin-6-yl]-2-fluoroacrylamide (compound 29); N-[4-((3,4-dichloro-2-fluorophenyl)amino)-7-(3-morpholinopropoxy)quinazolin-6-yl]-2-fluoroacrylamide (compound 30); N-[4-((2,4-difluorophenyl)amino)-7-(3-morpholinopropoxy)quinazolin-6-yl]-2-fluoroacrylamide (compound 31); 2-fluoro-N-(7-(3-morpholinopropoxy)-4-((2,3,4-trifluorophenyl)amino)quinazolin-6-yl]acrylamide (compound 32); N-[4-((2,4-dichlorophenyl)amino)-7-(3-morpholinopropoxy)quinazolin-6-yl]-2-fluoroacrylamide (compound 33); 2-chloro-N-(4-((3-chloro-2,4-difluorophenyl)amino)-7-(3-morpholinopropoxy)quinazolin-6-yl)acrylamide (compound 34); 2-chloro-N-(4-((3-chloro-4-fluorophenyl)amino)-7-(3-morpholinopropoxy)quinazolin-6-yl)acrylamide (compound 35); N-(4-((2,4-difluoro-3-methoxyphenyl)amino)-7-(3-morpholinopropoxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 36); N-(4-((4-chloro-3-methoxyphenyl)amino)-7-(3-morpholinopropoxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 37); N-(4-((4-bromo-3-chloro-2-fluorophenyl)amino)-7-(3-morpholinopropoxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 38); N-(4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)-2-fluoroacrylamide (compound 39); N-(4-((3-chloro-4-fluorophenyl)amino)-7-(3-(piperidine-1-yl)propoxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 40); 2-chloro-N-(4-((3-chloro-4-fluorophenyl)amino)-7-(3-morpholinopropoxy)quinazolin-6-yl)acrylamide (compound 41); N-(4-((3-chloro-4-fluorophenyl)amino)-7-(3-(dimethylamino)propoxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 42); N-(4-((3-chloro-4-fluorophenyl)amino)-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 43); N-(4-((3-chloro-4-fluorophenyl)amino)-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 44); (R)-N-(4-((3-chloro-2,4-difluorophenyl)amino)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 45); (R)-N-(4-((3-chloro-2,4-difluorophenyl)amino)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 46); N-(4-((3-chloro-2,4-difluorophenyl)amino)-7-(cyclobutylmethoxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 47); N-(4-((3-chloro-2,4-difluorophenyl)amino)-7-(cyclopropylmethoxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 48); N-(4-((3-chloro-4-fluorophenyl)amino)-7-((1-methylpiperidin-4-yl)oxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 49); (R)-N-(4-((3-chloro-2,4-difluorophenyl)amino)-7-((1-methylpyrrolidin-3-yl)oxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 50); (S)-N-(4-((3-chloro-2,4-difluorophenyl)amino)-7-((1-methylpyrrolidin-3-yl)oxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 51); N-(4-((3-bromophenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoroacrylamide (compound 52); N-(4-((3-bromophenyl)amino)-7-ethoxyquinazolin-6-yl)-2-fluoroacrylamide (compound 53); 2-fluoro-N-(7-methoxy-4-((3-(trifluoromethyl)phenyl)amino)quinazolin-6-yl)acrylamide (compound 54); N-(7-ethoxy-4-((3-(trifluoromethyl)phenyl)amino)quinazolin-6-yl)-2-fluoroacrylamide (compound 55); N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoroacrylamide (compound 56); 2-chloro-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)acrylamide (compound 57); 2-chloro-N-(7-ethoxy-4-((3-(trifluoromethyl)phenyl)amino)quinazolin-6-yl)acrylamide (compound 58); N-(4-((3-bromophenyl)amino)-7-ethoxyquinazolin-6-yl)-2-chloroacrylamide (compound 59); 2-chloro-N-(4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)acrylamide (compound 60); N-(4-((3-chloro-4-(cyclopropylbenzyloxy)phenyl)amino)-7-(3-morpholinopropoxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 61); 2-chloro-N-(4-((3-chloro-4-(cyclopropylbenzyloxy)phenyl)amino)-7-(3-morpholinopropoxy)quinazolin-6-yl)acrylamide (compound 62); (R)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-((1-methylpyrrolidin-3-yl)oxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 63); (S)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-((1-methylpyrrolidin-3-yl)oxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 64); (R)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-((4-methylmorpholin-3-yl)methoxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 65); (R)-2-chloro-N-(4-((3-chloro-4-fluorophenyl)amino)-7-((4-methylmorpholin-3-yl)methoxy)quinazolin-6-yl)acrylamide (compound 66); N-(4-((3-chloro-4-fluorophenyl)amino)-7-(2-(piperidin-1-yl)ethoxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 67); 2-chloro-N-(4-((3-chloro-4-fluorophenyl)amino)-7-(2-(piperidin-1-yl)ethoxy)quinazolin-6-yl)acrylamide (compound 68); 2-chloro-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinazolin-6-yl)acrylamide (compound 69); 2-chloro-N-(4-((3-chloro-4-(cyclopropylmethoxy)phenyl)amino)-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-6-yl)acrylamide (compound 70); N-(4-((3-chloro-4-(cyclopropylmethoxy)phenyl)amino)-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 71); (S)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-((4-methylmorpholin-3-yl)methoxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 72); (S)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-((1-methylpiperidin-3-yl)methoxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 73); (R)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-((1-methylpiperidin-3-yl)methoxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 74); (S)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-((4-methylmorpholin-2-yl)methoxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 75); (R)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-((4-methylmorpholin-2-yl)methoxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 76); N-(4-((3-chloro-4-fluorophenyl)amino)-7-(2-(1-methylpiperidin-4-yl)ethoxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 77); N-(4-((3-chloro-4-fluorophenyl)amino)-7-(2-(4-methylpiperazin-1-yl)ethoxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 78); N-(4-((3-chloro-4-fluorophenyl)amino)-7-(2-morpholinoethoxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 79); (R)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-(2-(1-methylpyrrolidin-2-yl)ethoxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 80); (S)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-(2-(1-methylpyrrolidin-2-yl)ethoxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 81); (R)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-(2-(1-methylpiperidin-2-yl)ethoxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 82); (S)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-(2-(1-methylpiperidin-2-yl)ethoxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 83); (R)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-(2-(1-methylpiperidin-3-yl)ethoxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 84); (S)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-(2-(1-methylpiperidin-3-yl)ethoxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 85); N-(4-((3-chloro-4-fluorophenyl)amino)-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 86); N-(4-((3-bromophenyl)amino)-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-6-yl)-2-fluoroacrylamide (compound 87); and (S)-2-chloro-N-(4-((3-chloro-4-fluorophenyl)amino)-7-(4-methylmorpholin-3-yl)methoxy)quinazolin-6-yl)acrylamide (compound 88).