Cyclic vinylogous amides as bromodomain inhibitors
Cyclic vinylogous amides of Formula I are disclosed The compounds are useful for treating diseases that arise from inappropriate activity of proteins containing an acetyl-lysine. The compositions comprise a genus of cyclic vinylogous amides that are inhibitors of bromodomain.
1. A compound of formula 1
wherein:
U is (CH 2 ) n , where n=1, 2 or 3;
R 1 is selected from the group consisting of: (C 1 -C 10 )alkyl, substituted (C 1 -C 10 )alkyl, and nitrile;
Cy is a carbocycle or heterocycle;
R 11 and R 12 are independently selected from the group consisting of: H, (C 1 -C 10 )alkyl, (C 1 -C 10 )perfluoroalkyl, halogen, nitrile, hydroxy, (C 1 -C 10 )alkoxy, perfluoro(C 1 -C 10 )alkoxy, (C 1 -C 10 )alkylthio, amino, (C 1 -C 10 )alkylamino, (C 1 -C 10 )acylamino, aryl, heteroaryl, aminocarbonyl, carboxyl, and (C 1 -C 10 )alkoxycarbonyl; or
taken together, R 11 and R 12 may form a 5, 6,or 7-membered carbocycle or heterocycle wherein said carbocycle or heterocycle may be optionally substituted with R 2 ;
R 2 is selected from the group consisting of: halogen, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, hydroxy, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, carboxy, amino, (C 1 -C 4 )alkylamino and di(C 1 -C 4 )alkylamino;
Y is selected from
L and L′ are independently a bond or (CR 3 R 4 ) m where R 3 and R 4 are independently selected from the group consisting of H and (C 1 -C 4 )alkyl, and m is 1or 2;
R 10 is chosen from carbocycle and heterocycle, wherein said carbocycle or heterocycle is optionally substituted with R 7 and/or R 8 ;
R 20 is —C(═O)OR R 21 ;
R 21 is chosen from H and (C 1 -C 4 )alkyl;
R 5 and R 6 are independently selected from the group consisting of hydrogen, hydroxy, (C 1 -C 10 )hydrcarbyl, halo(C 1 -C 10 )hydrocarbyl, and (C 1 -C 10 )alkoxy;
R 7 and R 8 are independently selected from the group consisting of: hydroxy, halogen, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylthio, (C 1 -C 4 )alkylcarbonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cyano, oxo, (C 1 -C 4 )alkylsulfonyl, amino, (C 1 -C 4 )alkylamino, di(C 1 -C 4 )alkylamino, (C 1 -C 4 )acylamino, aminocarbonyl, carboxyl, and (C 1 -C 4 )alkoxycarbonyl, where each said alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, may be further optionally substituted with hydroxy, oxo, carboxy, carboxy(C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxycarbonyl, (C 1 -C 4 )alkoxycarbonyl(C 1 -C 4 )alkyl, amino, (C 1 -C 4 )alkylamino, di(C 1 -C 4 )alkylamino, amido, (C 1 -C 4 )alkylamido, di (C 1 -C 4 )alkylamido, halogen, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl;
or, taken together, R 5 and R 6 , or R 7 and R 8 may form a 5, 6, or 7-membered carbocycle or heterocycle, wherein said carbocycle or heterocycle is optionally substituted with R 9 ;
R 9 is selected from the group consisting of: halogen, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, hydroxy, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, amino, (C 1 -C 4 )alkylamino and di(C 1 -C 4 )alkylamino.
2. A compound according to claim 1 wherein Cy is aryl or heteroaryl.
3. A compound according to claim 2 wherein Cy is phenyl, having the formula:
4. A compound according to claim 3 wherein Y is chosen from
5. A compound according to claim 3 wherein R 11 is hydrogen and R 12 is halogen.
6. A compound according to claim 1 wherein U is —CH 2 CH 2 —.
7. A compound according to claim 1 wherein U is —CH 2 —.
8. A compound according to claim 1 wherein Y is
9. A compound according to claim 8 wherein L is —CH 2 —.
10. A compound according to claim 9 wherein R 10 is chosen from cyclohexyl, cyclopentyl, phenyl, naphthyl, thiophenyl, pyrrolyl, pyridinyl, and pyrimidinyl, each optionally substituted with R 7 and/or R 8 .
11. A compound according to claim 10 wherein R 7 is chosen from halogen, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy and aminocarbonyl.
12. A compound according to claim 1 wherein Y is
13. A compound according to claim 1 wherein Y is
14. A compound according to claim 1 wherein R 21 is hydrogen or methyl.
15. A compound according to claim 1 wherein R 10 is a phenyl, optionally substituted with R 7 and/or R 8 .
16. A compound according to claim 1 wherein L is a direct bond, L′ is a direct bond or CH 2 and R 21 is H.
17. A compound according to claim 16 wherein R 10 is chosen from cyclohexyl, cyclopentyl, phenyl, naphthyl, thiophenyl, pyrrolyl, pyridinyl, and pyrimidinyl, each optionally substituted with R 7 and/or R 8 .
18. A compound according to claim 17 wherein R 10 is
19. A compound according to claim 18 wherein R 7 is chosen from halogen, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy and aminocarbonyl.
20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 1 .