Pyrrolopyrazine inhibitors of kinases

1. A compound having formula (I)

wherein

R 1a and R 1b are each hydrogen

X is N or CR 2 ;

R 2 is hydrogen or C 1-4 -alkyl;

Y is NR 3 R 4 or NR 6 C(O)R 7 ;

R 3 is C 1-8 -alkyl, C 2-8 -alkenyl, C 3-8 -cycloalkyl, heterocycloalkyl, aryl, or heteroaryl-, wherein (a) the R 3 C 1-8 -alkyl and C 2-8 -alkenyl are optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, oxo, —OR a , —C(O)R a , —C(O)OR a , —OC(O)R a , —NR b R c , —NR b C(O)R a , —NHC(O)NHR b , —C(O)NR b R c , —NHSO 2 R a , —SO 2 NR b NR c , and benzyl; and (b) the R 3 C 3-8 -cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R 5 ;

R 4 is hydrogen or C 1-8 -alkyl; wherein the C 1-8 -alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, oxo, —OR a , —C(O)R a , —C(O)OR a , —OC(O)R a , —NR b R c , —NR b C(O)R a , —NHC(O)NHR b , —C(O)NR b R c , —NHSO 2 R a , and —SO 2 NR b NR c ;

or R 3 and R 4 can be joined together to form a 4-7 membered heterocycloalkyl ring; wherein the heterocycloalkyl ring is optionally substituted with one or more R 5 ;

R 5 is selected from the group consisting of C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, aryl, heterocyclyl, halogen, oxo, cyano, nitro, —OR d , —C(O)R d , —C(O)OR d , —OC(O)R d , —NR e R f , —NR e C(O)R d , —NHC(O)NHR e , —NHSO 2 R d , —C(O)NR e R f , —SR d , —S(O)R d , —SO 2 R d , —SO 2 NR e NR f , —B(OH) 2 , —CF 3 , —CF 2 CF 3 , —OCF 3 , and —OCF 2 CF 3 wherein (a) the R 5 C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, substituents are optionally substituted with one or more substituents selected from the group consisting of aryl, heterocyclyl, C 3-8 -cycloalkyl, halogen, cyano, nitro, oxo, —OR d , —C(O)R d , —C(O)OR d , —OC(O)R d , —NR e R f , —NR e C(O)R d , —NHC(O)NHR e , —C(O)NR e R f ; and wherein (b) the R 5 aryl or heterocyclyl substituents are optionally substituted with one or more substituents independently selected from the group consisting of C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, aryl, heterocyclyl, halogen, cyano, nitro, oxo —OR g , —C(O)R g , —C(O)OR g , —OC(O)R g , —NR h R i , —NR h C(O)R g , —NHC(O)NHR h , —NHSO 2 R g , —C(O)NR h R i , —SR g , —S(O)R g , —SO 2 R g , —SO 2 NR h NR i , —CF 3 , —CF 2 CF 3 , —OCF 3 , and —OCF 2 CF 3 ;

R 6 is hydrogen or C 1-8 -alkyl;

R 7 is hydrogen, C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-(C 1-8 -alkyl)-, heterocycloalkyl, heterocycloalkyl-(C 1-8 -alkyl)-, aryl, aryl-(C 1-8 -alkyl)-, heteroaryl-, or heteroaryl-(C 1-8 -alkyl)-, wherein (a) the R 7 C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl substituents, alone or as part of another group, are optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, oxo, —OR a , —C(O)R a , —C(O)OR a , —OC(O)R a , —NR b R c , —NR b C(O)R a , —NHC(O)NHR b , —C(O)NR b R c , —NHSO 2 R a , —SO 2 NR b NR c , and benzyl; and (b) the R 7 C 3-8 -cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, alone or as part of another group, are optionally substituted with one or more R 5 ;

R a , at each occurrence, is selected from the group consisting of hydrogen, C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, aryl, heterocyclyl, and C 3-8 -cycloalkyl, wherein the C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, aryl, heterocyclyl, and C 3-8 -cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of C 1-8 -alkyl, aryl, heterocyclyl, C 3-8 -cycloalkyl, halogen, cyano, oxo, hydroxy, C 1-8 -alkoxy, —NH 2 , —NH(C 1-8 -alkyl), and —N(C 1-8 -alkyl) 2 ;

R b and R c , at each occurrence, are independently selected from the group consisting of hydrogen, C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, aryl, heterocyclyl, and C 3-8 -cycloalkyl, and optionally, R b and R c can be joined together to form a 4-7 membered heterocycloalkyl ring, wherein the C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, aryl, heterocyclyl, C 3-8 -cycloalkyl, and 4-7 membered heterocycloalkyl ring are optionally substituted with one or more substituents independently selected from the group consisting of C 1-8 -alkyl, aryl, heterocyclyl, C 3-8 -cycloalkyl, halogen, cyano, oxo, hydroxy, C 1-8 -alkoxy, —NH 2 , —NH(C 1-8 -alkyl), and —N(C 1-8 -alkyl) 2 ;

R d , at each occurrence, is selected from the group consisting of hydrogen, C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, aryl, heterocyclyl, and C 3-8 -cycloalkyl, wherein the C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, aryl, heterocyclyl, and C 3-8 -cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of C 1-8 -alkyl, aryl, heterocyclyl, C 3-8 -cycloalkyl, halogen, cyano, oxo, hydroxy, C 1-8 -alkoxy, —NH 2 , —NH(C 1-8 -alkyl), and —N(C 1-8 -alkyl) 2 ;

R e and R f , at each occurrence, are independently selected from the group consisting of hydrogen, C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, aryl, heterocyclyl, and C 3-8 -cycloalkyl, and optionally, R e and R f can be joined together to form a 4-7 membered heterocycloalkyl ring, wherein the C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, aryl, heterocyclyl, C 3-8 -cycloalkyl, and 4-7 membered heterocycloalkyl ring are optionally substituted with one or more substituents independently selected from the group consisting of C 1-8 -alkyl, aryl, heterocyclyl, C 3-8 -cycloalkyl, halogen, cyano, oxo, hydroxy, C 1-8 -alkoxy, —NH 2 , —NH(C 1-8 -alkyl), and —N(C 1-8 -alkyl) 2 ;

R g , at each occurrence, is selected from the group consisting of hydrogen, C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, aryl, heterocyclyl, and C 3-8 -cycloalkyl, wherein the C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, aryl, heterocyclyl, and C 3-8 -cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of C 1-8 -alkyl, aryl, heterocyclyl, C 3-8 -cycloalkyl, halogen, cyano, oxo, hydroxy, C 1-8 -alkoxy, —NH 2 , —NH(C 1-8 -alkyl), and —N(C 1-8 -alkyl) 2 ; and

R h and R i , at each occurrence, are independently selected from the group consisting of hydrogen, C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, aryl, heterocyclyl, and C 3-8 -cycloalkyl, and optionally, R h and R i can be joined together to form a 4-7 membered heterocycloalkyl ring, wherein the C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, aryl, heterocyclyl, C 3-8 -cycloalkyl, and 4-7 membered heterocycloalkyl ring are optionally substituted with one or more substituents independently selected from the group consisting of C 1-8 -alkyl, aryl, heterocyclyl, C 3-8 -cycloalkyl, halogen, cyano, oxo, hydroxy, C 1-8 -alkoxy, —NH 2 , —NH(C 1-8 -alkyl), and —N(C 1-8 -alkyl) 2 ;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein Y is NR 3 R 4 .

3. The compound of claim 2 , wherein R 4 is hydrogen or methyl.

4. The compound of claim 1 , wherein X is CR 2 and R 2 is hydrogen.

5. The compound of claim 1 , wherein Y is NR 6 C(O)R 7 .

6. The compound of claim 1 , wherein R 1a and R 1b are hydrogen, X is CR 2 , R 2 is hydrogen, Y is NR 3 R 4 , wherein R 3 is C 1-8 -alkyl, wherein the C 1-8 -alkyl is optionally substituted with one or two substituents independently selected from the group consisting of oxo, —OR a , —NR b R c , —NR b C(O)R a , and benzyl, wherein R 4 is hydrogen, and wherein R a , R b , and R c are independently selected from the group consisting of hydrogen, C 1-8 -alkyl, phenyl, C 3-8 -cycloalkyl, 4-7-membered heterocycloalkyl, and pyridyl.

7. The compound of claim 1 , wherein R 1a and R 1b are hydrogen, X is CR 2 , R 2 is hydrogen, Y is NR 3 R 4 , wherein R 3 is C 3-8 -cycloalkyl, wherein the C 3-8 -cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of C 1-8 -alkyl, oxo, cyano, halogen, —OR d , —NR e R f , —NR e C(O)R d , and —NHSO 2 R d , wherein R 4 is hydrogen, and wherein R d , R e , and R f are independently selected from the group consisting hydrogen, C 1-8 -alkyl, phenyl, C 3-8 -cycloalkyl, 4-7-membered heterocycloalkyl, and pyridyl.

8. The compound of claim 1 , wherein R 1a and R 1b are hydrogen, X is CR 2 , R 2 is hydrogen, Y is NR 3 R 4 , wherein R 3 is heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of C 1-8 -alkyl, oxo, cyano, halogen, —OR d , —NR e R f , —NR e C(O)R d , and —NHSO 2 R d , wherein R d , R e , and R f are independently selected from the group consisting of hydrogen, C 1-8 -alkyl, phenyl, C 3-8 -cycloalkyl, 4-7-membered heterocycloalkyl, and pyridyl, and wherein R 4 is hydrogen.

9. The compound of claim 1 , wherein R 1a and R 1b are hydrogen, X is CR 2 , R 2 is hydrogen, Y is NR 3 R 4 , wherein R 3 and R 4 are joined together to form a 4-7 membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or two substituents selected from the group consisting of C 1-8 -alkyl, oxo, cyano, halogen, —OR d , —NR e R f , —NR e C(O)R d , and, —NHSO 2 R d , wherein R d , R e , and R f are independently selected from the group consisting of hydrogen, C 1-8 -alkyl, phenyl, C 3-8 -cycloalkyl, 4-7-membered heterocycloalkyl, and pyridyl.

10. The compound of claim 1 which is

6-chloro-N-cyclohexyl-4-(5H-pyrrolo[3,2-b]pyrazin-7-yl)pyridin-2-amine;

Trans 4-(6-chloro-4-(5H-pyrrolo[3,2-b]pyrazin-7-yl)pyridin-2-ylamino)cyclohexanol;

6-chloro-N-(piperidin-3-yl)-4-(5H-pyrrolo[2,3-b]pyrazin-7-yl)pyridin-2-amine;

6-chloro-N-(1-ethylpiperidin-3-yl)-4-(5H-pyrrolo[2,3-b]pyrazin-7-yl)pyridin-2-amine;

(3-(6-chloro-4-(5H-pyrrolo[2,3-b]pyrazin-7-yl)pyridin-2-ylamino)piperidin-1-yl)(cyclopropyl)methanone;

6-chloro-N-(1-(methylsulfonyl)piperidin-3-yl)-4-(5H-pyrrolo[2,3-b]pyrazin-7-yl)pyridin-2-amine;

Trans N 1 -(6-chloro-4-(5H-pyrrolo[2,3-b]pyrazin-7-yl)pyridin-2-yl)cyclohexane-1,4-diamine;

N-(trans-4-(6-chloro-4-(5H-pyrrolo[2,3-b]pyrazin-7-yl)pyridin-2-ylamino)cyclohexyl)cyclopropanecarboxamide;

trans-N 1 -(6-chloro-4-(5H-pyrrolo[2,3-b]pyrazin-7-yl)pyridin-2-yl)-N 4 ,N 4 -dimethylcyclohexane-1,4-diamine;

N-(3-(6-chloro-4-(5H-pyrrolo[2,3-b]pyrazin-7-yl)pyridin-2-ylamino)cyclohexyl)cyclopropanecarboxamide;

N 1 -(6-chloro-4-(5H-pyrrolo[2,3-b]pyrazin-7-yl)pyridin-2-yl)-N 3 ,N 3 -dimethylcyclohexane-1,3-diamine;

N-(3-(6-chloro-4-(5H-pyrrolo[2,3-b]pyrazin-7-yl)pyridin-2-ylamino)cyclohexyl)methanesulfonamide;

N-(6-chloro-4-(5H-pyrrolo[2,3-b]pyrazin-7-yl)pyridin-2-yl)pentanamide;

N-(6-chloro-4-(5H-pyrrolo[2,3-b]pyrazin-7-yl)pyridin-2-yl)nicotinamide;

N-(6-chloro-4-(5H-pyrrolo[2,3-b]pyrazin-7-yl)pyridin-2-yl)piperidine-4-carboxamide;

N-(6-chloro-4-(5H-pyrrolo[2,3-b]pyrazin-7-yl)pyridin-2-yl)benzamide;

N 1 -(6-chloro-4-(5H-pyrrolo[2,3-b]pyrazin-7-yl)pyridin-2-yl)-2,2-dimethylpropane-1,3-diamine;

N-(trans 4-(6-chloro-4-(5H-pyrrolo[3,2-b]pyrazin-7-yl)pyridin-2-ylamino)cyclohexyl)-5-oxopyrrolidine-2-carboxamide;

4-chloro-N-cyclohexyl-6-(5H-pyrrolo[3,2-b]pyrazin-7-yl)pyrimidin-2-amine;

N-(trans 4-((6-chloro-4-(5H-pyrrolo[2,3-b]pyrazin-7-yl)pyridin-2-yl)(ethyl)amino)cyclohexyl)cyclopropanecarboxamide;

N-(3-(6-chloro-4-(5H-pyrrolo[2,3-b]pyrazin-7-yl)pyridin-2-ylamino)cyclohexyl)-2-(dimethylamino)acetamide;

N-(3-((6-chloro-4-(5H-pyrrolo[2,3-b]pyrazin-7-yl)pyridin-2-yl)(ethyl)amino)cyclohexyl)-2-(dimethylamino)acetamide; or

N-(3-(6-chloro-4-(5H-pyrrolo[2,3-b]pyrazin-7-yl)pyridin-2-ylamino)cyclohexyl)furan-2-sulfonamide.

11. A pharmaceutical composition comprising a compound of claim 1 , or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.