Pyrrolopyrazinone inhibitors of kinases

1. A compound having formula (I)

wherein

R 1a , R 1b , and R 1c are independently hydrogen, hydroxy, nitro, halogen, cyano, trifluoromethyl, trifluoromethoxy, C 1-4 -alkyl, —OR a , or —NR b R c ;

X is heteroaryl, which is optionally substituted with one or more R 5 ;

n is 0, 1, 2, or 3; provided that when n is 1, 2, or 3, m is 0;

m is 0, 1, 2, or 3; provided that when m is 1, 2, or 3, n is 0;

Y is a bond, —O—, —C(O)—, —C(O)O—, —OC(O)—, —NR e —, —NR e C(O)—, —C(O)NR e —, —NR e C(O)NR e —, —SO 2 NR e —, or —NR e SO 2 —;

Z is C 3-8 -cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the C 3-8 -cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, are optionally substituted with one or more R 6 ;

R 5 is selected from the group consisting of C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, aryl, heterocyclyl, halogen, 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, and 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, —OR g , —C(O)R g , —C(O)OR g , —OC(O)R g , —NR h R i , —NR h C(O)R g , —NHSO 2 R g , —NHC(O)NHR h , and —C(O)NR h R i ; and wherein (b) the R 5 aryl and 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 -allynyl, aryl, heterocyclyl, halogen, cyano, nitro, oxo —OR j , —C(O)R j , —C(O)OR j , —OC(O)R j , —NR k R l , —NR k C(O)R j , —NHC(O)NHR k , —NHSO 2 R j , —C(O)NR k R l , —SR j , —S(O)R j , —SO 2 R j , —SO 2 NR k NR l , —CF 3 , —CF 2 CF 3 , —OCF 3 , and —OCF 2 CF 3 ;

R 6 is selected from the group consisting of C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, aryl, heterocyclyl, halogen, 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 6 C 1-8 -alkyl, C 2-8 -alkenyl, and 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, —OR g , —C(O)R g , —C(O)OR g , —OC(O)R g , —NR h R i , —NR h C(O)R g , —NHSO 2 R g , —NHC(O)NHR h , and —C(O)NR h R i ; and wherein (b) the R 6 aryl and 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 j , —C(O)R j , —C(O)OR j , —OC(O)R j , —NR k R l , —NR k C(O)R j , —NHC(O)NHR k , —NHSO 2 R j , —C(O)NR k R l , —SR j , —S(O)R j , —SO 2 R j , —SO 2 NR k NR l , —CF 3 , —CF 2 CF 3 , —OCF 3 , and —OCF 2 CF 3 ;

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 -allynyl, 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, hydroxy, C 1-8 -alkoxy, —NH 2 , —NH(C 1-8 -alkyl), —O(C 1-8 -alkyl)NH 2 , 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 -allynyl, 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, hydroxy, C 1-8 -alkoxy, —NH 2 , —NH(C 1-8 -alkyl), and —N(C 1-8 -allyl) 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, aryl-(C 1-8 -alkyl)-, heterocyclyl, C 3-8 -cycloalkyl, halogen, cyano, hydroxy, C 1-8 -alkoxy, —NH 2 , —NH(C 1-8 -alkyl), and —N(C 1-8 -alkyl) 2 ; wherein the aryl, aryl-(C 1-8 -alkyl)-, heterocyclyl, and C 3-8 -cycloalkyl, alone or as part of another group, 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, 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, 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, hydroxy, C 1-8 -alkoxy, —NH 2 , —NH(C 1-8 -alkyl), and —N(C 1-8 -alkyl) 2 ;

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, hydroxy, C 1-8 -alkoxy, —NH 2 , —NH(C 1-8 -alkyl), and —N(C 1-8 -alkyl) 2 ;

R j , 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, hydroxy, C 1-8 -alkoxy, —NH 2 , —NH(C 1-8 -alkyl), and —N(C 1-8 -alkyl) 2 ;

R k and R l , 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, 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, 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 R 1a , R 1b , and R 1c are hydrogen.

3. The compound of claim 1 , wherein Y is a bond, n is 1 or 2 and m is 0.

4. The compound of claim 1 , wherein Y is —C(O)—, n is 0 and m is 0.

5. The compound of claim 1 , wherein Z is aryl.

6. The compound of claim 1 , wherein Z is phenyl.

7. The compound of claim 1 , wherein X is

and p is 0, 1, or 2.

8. The compound of claim 1 , wherein R 1a , R 1b , and R 1c are hydrogen, Y is a bond, and n is 1 and m is 0.

9. The compound of claim 1 , wherein R 1a , R 1b , and R 1c are hydrogen, Y is —C(O)—, and n is 0 and m is 0.

10. The compound of claim 1 , wherein R 1a , R 1b , and R 1c are hydrogen, Y is a bond, n is 1 and m is 0, Z is aryl which is substituted with one or more R 6 , and X is

11. The compound of claim 1 , wherein R 1a , R 1b , and R 1c are hydrogen, Y is —C(O)—, n is 0 and m is 0, Z is aryl which is substituted with one or more R 6 , and X is

12. The compound of claim 1 which is

2-fluoro-5-{[1-oxo-7-(pyridin-4-yl)-1,2-dihydropyrrolo[1,2-a]pyrazin-4-yl]methyl}benzonitrile;

2-fluoro-5-{[1-oxo-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1,2-dihydropyrrolo[1,2-a]pyrazin-4-yl]methyl}benzonitrile;

2-fluoro-5-{[1-oxo-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1,2-dihydropyrrolo[1,2-a]pyrazin-4-yl]methyl}benzoic acid;

ethyl 3-{[1-oxo-7-(pyridin-4-yl)-1,2-dihydropyrrolo[1,2-a]pyrazin-4-yl]methyl}benzoate;

3-{[1-oxo-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1,2-dihydropyrrolo[1,2-a]pyrazin-4-yl]methyl}benzoic acid;

ethyl 3-{[1-oxo-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1,2-dihydropyrrolo[1,2-a]pyrazin-4-yl]methyl}benzoate;

3-{[1-oxo-7-(pyridin-4-yl)-1,2-dihydropyrrolo[1,2-a]pyrazin-4-yl]methyl}benzoic acid;

ethyl 3-{[1-oxo-7-(pyridin-3-yl)-1,2-dihydropyrrolo[1,2-a]pyrazin-4-yl]methyl}benzoate;

ethyl 3-{[1-oxo-7-(1H-pyrazol-4-yl)-1,2-dihydropyrrolo[1,2-a]pyrazin-4-yl]methyl}benzoate;

3-{[1-oxo-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1,2-dihydropyrrolo[1,2-a]pyrazin-4-yl]methyl}benzamide;

3-{[1-oxo-7-(5H-pyrrolo[2,3-b]pyrazin-7-yl)-1,2-dihydropyrrolo[1,2-a]pyrazin-4-yl]methyl}benzoic acid;

ethyl 3-{[1-oxo-7-(5H-pyrrolo[2,3-b]pyrazin-7-yl)-1,2-dihydropyrrolo[1,2-a]pyrazin-4-yl]methyl}benzoate;

3-{[1-oxo-7-(1H-pyrazol-4-yl)-1,2-dihydropyrrolo[1,2-a]pyrazin-4-yl]methyl}benzamide;

4-(3-nitrobenzyl)-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[1,2-a]pyrazin-1(2H)-one;

4-(4-nitrobenzyl)-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[1,2-a]pyrazin-1(2H)-one;

4-{[1-oxo-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1,2-dihydropyrrolo[1,2-a]pyrazin-4-yl]methyl}benzonitrile;

N-(4-{[1-oxo-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1,2-dihydropyrrolo[1,2-a]pyrazin-4-yl]methyl}phenyl)isonicotinamide;

N-(4-{[1-oxo-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1,2-dihydropyrrolo[1,2-a]pyrazin-4-yl]methyl}phenyl)cyclobutanecarboxamide;

4-{3-[cyclobutyl(methyl)amino]benzyl}-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[1,2-a]pyrazin-1(2H)-one;

N-(4-{[1-oxo-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1,2-dihydropyrrolo[1,2-a]pyrazin-4-yl]methyl}phenyl)cyclopropanecarboxamide;

N-(3-{[1-oxo-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1,2-dihydropyrrolo[1,2-a]pyrazin-4-yl]methyl}phenyl)methanesulfonamide;

4-(3-aminobenzyl)-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[1,2-a]pyrazin-1(2H)-one;

4-(4-aminobenzyl)-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[1,2-a]pyrazin-1(2H)-one;

4-{4-[(pyridin-2-ylmethyl)amino]benzyl}-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[1,2-a]pyrazin-1(2H)-one;

4-{4-[(cyclobutylamino)methyl]benzyl}-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[1,2-a]pyrazin-1(2H)-one;

N-(4-{[1-oxo-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1,2-dihydropyrrolo[1,2-a]pyrazin-4-yl]methyl}phenyl)-2-furamide;

4-[3-(dicyclobutylamino)benzyl]-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[1,2-a]pyrazin-1(2H)-one;

N-(4-{[1-oxo-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1,2-dihydropyrrolo[1,2-a]pyrazin-4-yl]methyl}phenyl)nicotinamide;

N-(4-{[1-oxo-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1,2-dihydropyrrolo[1,2-a]pyrazin-4-yl]methyl}benzyl)cyclopropanesulfonamide;

4-{4-[(dicyclobutylamino)methyl]benzyl}-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[1,2-a]pyrazin-1(2H)-one;

N-(4-{[1-oxo-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1,2-dihydropyrrolo[1,2-a]pyrazin-4-yl]methyl}benzyl)methanesulfonamide;

4-{4-[(1-isopropylpiperidin-4-yl)amino]benzyl}-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[1,2-a]pyrazin-1(2H)-one;

N 2 ,N 2 -dimethyl-N-(3-{[1-oxo-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1,2-dihydropyrrolo[1,2-a]pyrazin-4-yl]methyl}phenyl)glycinamide;

N 2 ,N 2 -dimethyl-N-(4-{[1-oxo-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1,2-dihydropyrrolo[1,2-a]pyrazin-4-yl]methyl}benzyl)glycinamide;

4-[4-(pentan-3-ylamino)benzyl]-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[1,2-a]pyrazin-1(2H)-one;

4-{4-[(dimethylamino)methyl]benzyl}-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[1,2-a]pyrazin-1(2H)-one;

4-[4-(aminomethyl)benzyl]-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[1,2-a]pyrazin-1(2H)-one;

N-(4-{[1-oxo-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1,2-dihydropyrrolo[1,2-a]pyrazin-4-yl]methyl}phenyl)methanesulfonamide;

4-{4-[(1-cyclopropylethyl)amino]benzyl}-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[1,2-a]pyrazin-1(2H)-one;

1-methyl-N-(4-{[1-oxo-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1,2-dihydropyrrolo[1,2-a]pyrazin-4-yl]methyl}phenyl)piperidine-3-carboxamide;

4-[3-(dimethylamino)benzyl]-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[1,2-a]pyrazin-1(2H)-one;

N-(4-{[1-oxo-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1,2-dihydropyrrolo[1,2-a]pyrazin-4-yl]methyl}phenyl)benzamide;

N-(4-{[1-oxo-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1,2-dihydropyrrolo[1,2-a]pyrazin-4-yl]carbonyl}phenyl)methanesulfonamide;

4-(4-{[(4-aminocyclohexyl)amino]methyl}benzyl)-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[1,2-a]pyrazin-1(2H)-one; or

N-(4-{[1-oxo-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1,2-dihydropyrrolo[1,2-a]pyrazin-4-yl]methyl}benzyl)acetamide.

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