4-phenylamino-quinazolin-6-yl-amides
View Patent ↗This invention provides quinazoline compounds of the formula: wherein: R 1 is halo; R 2 is H or halo; R 3 is a) C 1 -C 3 alkyl, optionally substituted by halo; or b) —(CH 2 ) n -morpholino, —(CH 2 ) n -piperidine, —(CH 2 ) n -piperazine, —(CH 2 ) n —-piperazine-N(C 1 -C 3 alkyl), —(CH 2 ) n -pyrrolidine, or —(CH 2 ) n -imidazole; n is 1 to 4; R 4 is —(CH 2 ) m -Het; Het is morpholine, piperidine, piperazine, piperazine-N(C 1 -C 3 alkyl), imidazole, pyrrolidine, azepane, 3,4-dihydro-2H-pyridine, or 3,6-dihydro-2H-pyridine, each optionally substituted by alkyl, halo, OH, NH 2 , NH(C 1 -C 3 alkyl) or N (C 1 -C 3 alkyl) 2 ; m is 1-3; and X is O, S or NH; or a pharmaceutically acceptable salt thereof, as well as processes and intermediate compounds for making them, useful pharmaceutical compositions and methods of using the compounds in the treatment of proliferative diseases.
1. A compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein:
R 3 is C 1 -C 3 straight or branched alkyl, optionally substituted by one or more halogens;
R 5 and R 6 are each independently selected from H, C 1 -C 3 alkyl, F, Br, I and Cl;
X O, S or NH; and
the dashed lines designated a and b each indicate an optional double bond, with the proviso that the optional double bond a and the optional double bond b may not both exist in one compound.
2. A compound according to claim 1 , wherein X is O and R 3 is C 1 -C 3 straight or branched alkyl optionally substituted by from 1 to 3 halogen atoms, or a pharmaceutically acceptable salt thereof.
3. A compound, which is selected from the following group of compounds:
4-Piperidin-1-yl-but-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]-amide;
4-Piperidin-1-yl-but-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-methylsulfanyl-quinazolin-6-yl]-amide;
4-Piperidin-1-yl-but-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-methylamino-quinazolin-6-yl]-amide;
4-Piperidin-1-yl-but-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-isopropoxy-quinazolin-6-yl]-amide;
4-Piperidin-1-yl-but-2-enoic acid [4(3-bromo-phenylamino)-7-methoxy-quinazolin-6-yl]-amide;
4-Piperidin-1-yl-but-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-ethoxy-quinazolin-6-yl]-amide;
4-Piperidin-1-yl-but-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-propoxy-quinazolin-6-yl]-amide;
4-(4-Fluoro-piperidin-1-yl)-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]-amide;
4-(3-Fluoro-piperidin-1-yl)-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]-amide;
4-(2-Fluoro-piperidin-1-yl)-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]-amide;
4-Piperidin-1-yl-but-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-trifluoromethoxy-quinazolin-6-yl]-amide;
4-Piperidin-1-yl-but-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-fluoromethoxy-quinazolin-6-yl]-amide;
4-Piperidin-1-yl-but-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-fluoroethoxy-quinazolin-6-yl]-amide;
4-Piperidin-1-yl-but-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-(2-fluoro-ethylsulfanyl)-quinazolin-6-yl]-amide;
4-Piperidin-1-yl-but-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-trifluoroethoxy-quinazolin-6-yl]-amide;
4-Piperidin-1 -yl-but-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-difluoroethoxy-quinazolin-6-yl]-amide;
4-(3,4-Dihydro-2H-pyridin-1 -yl)-but-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]amide;
4-(3,6-Dihydro-2H-pyridin-1 -yl)-but-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]amide;
4-(3,4-Dihydro-2H-pyridin-1-yl)-but-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-ethoxy-quinazolin-6-yl]amide;
4-(3,4-Dihydro-2H-pyridin-1-yl)-but-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-fluoroethoxy-quinazolin-6-yl]amide;
4-(3,6-Dihydro-2H-pyridin-1-yl)-but-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-fluoroethoxy-quinazolin-6-yl]amide; and
a pharmaceutically acceptable salt of any of the aforementioned compounds.
4. A pharmaceutical composition comprising:
a pharmaceutically effective amount of a compound as defined in claim 1 , or a pharmaceutically acceptable salt thereof; and
a pharmaceutically acceptable carrier.
5. A pharmaceutical composition comprising:
a pharmaceutically effective amount of 4-Piperidin-1-yl-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]-amide or a pharmaceutically acceptable salt thereof, and
a pharmaceutically acceptable carrier.
6. A compound which is 4-Piperidin-1-yl-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]-amide or a pharmaceutically acceptable salt thereof.
7. A compound which is selected from the following group of compounds:
4-Morpholin-4-yl-but-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]-amide;
4-Azepan-1-yl-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]-amide;
4-Piperidin-1-yl-but-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl]-amide;
4-Piperidin-1-yl-but-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-(2-piperidin-1-yl-ethoxy)-quinazolin-6-yl]-amide;
4-Piperazin-1-yl-but-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]amide;
4-(4-Methyl-piperazin-1-yl )-but-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]amide;
4-Imidazol-1-yl-but-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]amide;
4-Pyrrolidin-1-yl-but-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]amide;
5-Piperidin-1-yl-pent-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]-amide;
5-Piperidin-1-yl-pent-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-methylsulfanyl-quinazolin-6-yl]-amide;
5-Piperidin--yl-pent-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-methylamino-quinazolin-6-yl]-amide;
5-Piperidin-1-yl-pent-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-isopropoxy-quinazolin-6-yl]-amide;
5-Piperidin-1-yl-pent-2-enoic acid [4(3-bromo-phenylamino)-7-methoxy-quinazolin-6-yl]-amide;
5-Piperidin-1-yl-pent-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-ethoxy-quinazolin-6-yl]-amide;
5-Piperidin-1-yl-pent-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-propoxy-quinazolin-6-yl]-amide;
5-(4-Fluoro-piperidin-1-yl)-pent-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]-amide;
5-(3-Fluoro-piperidin-1-yl)-pent-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]-amide;
5-(2-Fluoro-piperidin-1-yl)-pent-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]-amide;
5-Morpholin-4-yl-pent-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]-amide;
5-Azepan-1-yl-pent-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]-amide;
5-Piperidin-1-yl-pent-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-trifluoromethoxy-quinazolin-6-yl]-amide;
5-Piperidin-1-yl-pent-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-fluoromethoxy-quinazolin-6-yl]-amide;
5-Piperidin-1-yl-pent-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-fluoroethoxy-quinazolin-6-yl]-amide;
5-Piperidin-1-yl-pent-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-(2-fluoro-ethylsulfanyl)-quinazolin-6-yl]-amide;
5-Piperidin-1-yl-pent-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-trifluoroethoxy-quinazolin-6-yl]-amide;
5-Piperidin-1-yl-pent-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-difluoroethoxy-quinazolin-6-yl]-amide;
5-Piperidin-1-yl-pent-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl]-amide;
5-Piperidin-1-yl-pent-2-enoic acid [4(3-chloro-4-fluoro-phenylamino)-7-(2-piperidin-1-yl-ethoxy)-quinazolin-6-yl]-amide;
6-Piperidin-1-yl-hex-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]-amide;
6-Piperidin-1-yl-hex-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-methylsulfanyl-quinazolin-6-yl]-amide;
6-Piperidin-1-yl-hex-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-methylamino-quinazolin-6-yl]-amide;
6-Piperidin-1-yl-hex-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-ethoxy-quinazolin-6-yl]-amide;
6-Piperidin-1-yl-hex-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-fluoroethoxy-quinazolin-6-yl]-amide; and
a pharmaceutically acceptable salt of any of the aforementioned compounds.
8. A compound which is
or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition comprising a compound which is
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.