Fused pyrazine compounds useful for the treatment of degenerative and inflammatory diseases

1. A compound according to formula I:

wherein

Z is CH;

R 1 is H or C 1 -C 6 alkyl;

R 2 is H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, or C 3 -C 7 cycloalkyl-C 1 -C 6 alkyl;

R 8 is cycloalkyl and

R 9 is aryl or heteroaryl;

wherein each of said R 1 , R 2 , R 8 and R 9 that is not H is independently optionally substituted by at least one of fluoro, chloro, bromo, W being C 1 -C 6 alkyl, carboxy, hydroxyl, carbamoyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, cyano, amino, aryl, 3-7-membered heterocycloalkyl, aralkyl, and heteroaryl, wherein said W is optionally substituted by at least one of fluoro, chloro, and bromo, and wherein said amino is optionally substituted by C 1 -C 6 alkyl;

alternatively, R 8 is optionally substituted with -L-R 8d ; wherein

L is a single bond, alkylene, heteroalkylene, —O—, —N(R 8e )—, —CO—, —CO 2 , —SO—, —SO 2 —, —CON(R 8e )—, —SO 2 N(R 8e )—, —N(R 8e )CO—, —N(R 8e )SO 2 , —N(R 8e )CON(R 8e )—, or —N(R 8e )SO 2 N(R 8e )—; and

R 8d is C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, aryl, 3-7-membered heterocycloalkyl, heteroaryl, amino, aralkyl, C 1 -C 6 heteroarylalkyl or C 1 -C 6 aminoalkyl; and

R 8e is H, C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl;

wherein each of said R 8d or R 8e that is not H is independently optionally substituted by at least one of fluoro, chloro, bromo, W being C 1 -C 6 alkyl, carboxy, hydroxyl, carbamoyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, cyano, and amino, wherein said W is optionally substituted by at least one of fluoro, chloro, and bromo, and wherein said amino is optionally substituted by C 1 -C 6 alkyl;

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

2. A compound according to claim 1 , wherein R 8 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; and said R 8 is optionally substituted by at least one of fluoro, chloro, bromo, W being C 1 -C 6 alkyl, carboxy, hydroxyl, carbamoyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, cyano, amino, aryl, 3-7-membered heterocycloalkyl, aralkyl, and heteroaryl, wherein said W is optionally substituted by at least one of fluoro, chloro, and bromo, and wherein said amino is optionally substituted by C 1 -C 6 alkyl.

3. A compound according to claim 1 , wherein the compound is according to formula IIa, IIb, IIc, IId, or IIe:

wherein

the subscript n is 0, 1, 2, 3, or 4; and

each R 8a is independently C 1 -C 6 alkyl, carbamoyl, carboxy, hydroxyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, or amino; and each said R 8a is optionally substituted by at least one of fluoro, chloro, bromo, W being C 1 -C 6 alkyl, hydroxyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, cyano, amino, aryl, 3-7-membered heterocycloalkyl, aralkyl, and heteroaryl, wherein said W is optionally substituted by at least one of fluoro, chloro, and bromo, and wherein said amino is optionally substituted by C 1 -C 6 alkyl;

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

4. A compound according to claim 1 , wherein R 8 is cyclopropyl, cyclohexyl, cyclobutyl, cyclopentyl, or cycloheptyl; and said R 8 is optionally substituted by at least one of W being C 1 -C 6 alkyl, carboxy, hydroxyl, carbamoyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, cyano, amino, aryl, 3-7-membered heterocycloalkyl, aralkyl, and heteroaryl, wherein said W is optionally substituted by at least one of fluoro, chloro, and bromo, and wherein said amino is optionally substituted by C 1 -C 6 alkyl.

5. A compound according to claim 1 , wherein

R 8 is cycloalkyl substituted with -L-R 8d .

6. A compound according to claim 1 , wherein R 9 is phenyl optionally substituted by at least one of fluoro, chloro, bromo, W being C 1 -C 6 alkyl, carboxy, hydroxyl, carbamoyl, carboxy, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, cyano, amino, aryl, 3-7-membered heterocycloalkyl, aralkyl, and heteroaryl, wherein said W is optionally substituted by at least one of fluoro, chloro, and bromo, and wherein said amino is optionally substituted by C 1 -C 6 alkyl.

7. A compound according to claim 1 , wherein R 9 is

8. A compound according to claim 1 , wherein the compound is according to formula VIa, VIb, VIc, VId, or VIe:

wherein

the subscript n is 0, 1, 2, 3, or 4;

each R 8a is independently C 1 -C 6 alkyl, carbamoyl, carboxy, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, or amino;

wherein each said R 8a is optionally substituted by at least one of fluoro, chloro, bromo, W being C 1 -C 6 alkyl, hydroxyl, C 1 -C 6 haloalkyl, cyano, amino, aryl, 3-7-membered heterocycloalkyl, aralkyl, and heteroaryl, wherein said W is optionally substituted by at least one of fluoro, chloro, and bromo, and wherein said amino is optionally substituted by C 1 -C 6 alkyl;

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 1 .

10. A compound according to the following formula:

wherein

Z is CH;

R 1 is H or C 1 -C 6 alkyl;

R 2 is H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or C 3 -C 7 cycloalkyl-C 1 -C 6 alkyl;

R 8 is cycloalkyl; and

R 9 is

wherein A 1 is N or CR 9a ; A 2 is N or CR 9a ; and A 3 is S, O, or NR 9a ; and each R 9a is independently H or C 1 -C 4 alkyl; and R 9b is CONH 2 , CONHMe, or CN; or

wherein A 1 is N or CR 9a ; A 2 is S, O, or NR 9a ; and A 3 is N or CR 9a ; and each R 9a is independently H or C 1 -C 4 alkyl; and R 9b is CONH 2 , CONHMe, or CN;

wherein each of said R 1 , R 2 , R 8 and R 9a that is not H is independently optionally substituted by at least one of fluoro, chloro, bromo, W being C 1 -C 6 alkyl, carboxy, hydroxyl, carbamoyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, cyano, amino, aryl, 3-7-membered heterocycloalkyl, aralkyl, and heteroaryl, wherein said W is optionally substituted by at least one of fluoro, chloro, and bromo, and wherein said amino is optionally substituted by C 1 -C 6 alkyl;

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

11. A compound according to formula IVa, IVb, IVc, IVd, or IVe:

wherein

Z is CH,

the subscript n is 0, 1, 2, 3, or 4;

each R 8a is independently C 1 -C 6 alkyl, carbamoyl, carboxy, C 1 -C 6 hydroxyalkyl, alkoxy, or amino;

wherein each said R 8a is optionally substituted by at least one of fluoro, chloro, bromo, W being C 1 -C 6 alkyl, hydroxyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, cyano, amino, aryl, 3-7-membered heterocycloalkyl, aralkyl, and heteroaryl, wherein said W is optionally substituted by at least one of fluoro, chloro, and bromo, and wherein said amino is optionally substituted by C 1 -C 6 alkyl;

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

12. A compound that is:

5-(8-(cyclohexylamino)imidazo[1,2-a]pyrazin-5-yl)isoindolin-1-one;

5-(8-(cyclobutylamino)imidazo[1,2-a]pyrazin-5-yl)isoindolin-1-one;

4-(8-(cyclobutylamino)imidazo[1,2-a]pyrazin-5-yl)furan-2-carboxamide;

4-(8-(cyclopentylamino)imidazo[1,2-a]pyrazin-5-yl)furan-2-carboxamide;

or a pharmaceutically acceptable salts, stereoisomers, and or tautomers thereof.