Substituted pyrazines as inhibitors of kinase activity

1. A compound of formula I:

wherein

Q is NR 3 ;

W is substituted phenyl,

wherein the phenyl may be substituted with 1 to 3 substituents independently selected from substituted or unsubstituted C 1-4 alkyl, OH, NO 2 , NR 7 R 8 , halogen, CF 3 , OCF 3 , CN, SO 2 C 1-4 alkyl, OC 1-4 alkyl, substituted or unsubstituted C 1-4 alkyl OH, C 1-4 alkylOC 1-4 alkyl, C 1-4 alkyl NR 7 R 8 , CONR 7 R 8 , COR 9 , CO 2 R 9 , C 3-8 cycloalkyl, aryl or heterocyclyl, wherein the cycloalkyl, aryl or heterocyclyl may be substituted 1 or 2 times with substituted or unsubstituted C 1-4 alkyl;

the unsaturated heterocyclyl is substituted with 1 or 2 substituents independently selected from substituted or unsubstituted C 1-4 alkyl, OH, NO 2 , NR 7 R 8 , halogen, CF 3 , CO 2 R 9 , OC 1-4 alkyl, COR 9 , SO 2 , C 1-4 alkyl and a saturated or unsaturated 5 or 6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O and S;

X is NHCO, NHCH 2 , N(CH 3 )CO, N(CH 2 CH 3 )CO, NHSO 2 , NHCH(CH 3 ), NHCONH, N(CH 3 )CH(CF 3 ) or NR 9 , wherein X is attached through the nitrogen atom to the adjacent ring bearing Z 1 , Z 2 , Z 3 and Z 4 ;

each of Z 1 , Z 2 , Z 3 or Z 4 is independently selected from N and CR 1 provided that no more than two of Z 1 , Z 2 , Z 3 or Z 4 are N and wherein both Z 2 and Z 3 are CH and Z 4 is CH or C(CH 3 ) or

one of Z 2 or Z 3 is N and Z 4 is CH;

each R 1 is independently selected from H, halogen, CF 3 , OCF 3 , substituted or unsubstituted C 1-4 alkyl and substituted or unsubstituted OC 1-4 alkyl;

R 2 and R 17 are independently selected from H, substituted or unsubstituted C 1-4 alkyl, CF 3 , substituted or unsubstituted C 1-4 alkylOH and substituted or unsubstituted C 1-4 alkylOC 1-4 alkyl; or

R 2 and R 17 together with the carbon atom to which they are attached form a substituted or unsubstituted C 3-8 cycloalkyl or substituted or unsubstituted 3 to 8 membered saturated heterocyclyl;

R 3 is selected from H and substituted or unsubstituted C 1-4 alkyl;

A and Y are N;

R 4 and R 5 are independently selected from H, substituted or unsubstituted C 1-4 alkyl, CF 3 , halogen and NR 9 R 10 ;

R 6 is selected from H, halogen, OR 11 , NR 12 R 13 , substituted or unsubstituted C 1-4 alkyl, substituted or unsubstituted C 1-4 alkylOH, CO 2 R 9 , and CONR 7 R 8 , S(O) n R 14 and aryl or 5 to 7 membered heterocyclyl having from 1 to 3 heteroatoms selected from N, O, S, SO and SO 2 , wherein the aryl or heterocyclyl may be substituted with 1 to 3 substituents independently selected from substituted or unsubstituted C 1-4 alkyl, OH, NR 15 R 16 , halogen, CF 3 , OCF 3 , CN, substituted or unsubstituted OC 1-4 alkyl, substituted or unsubstituted OC 2-4 alkyleneOH, OC 2-4 alkyleneNR 7 R 8 , substituted or unsubstituted C 1-4 alkyleneOH, substituted or unsubstituted C 1-4 alkyleneOC 1-4 alkyl, substituted or unsubstituted C 1-4 alkyleneNR 7 R 8 , CONR 7 R 8 , CO 2 R 9 , NR 7 COR 9 , NR 7 SO 2 C 1-4 alkyl, N(SO 2 C 1-4 alkyl) 2 , NR 7 CONR 8 C 1-4 alkyl, SO 2 NR 9 R 10 , OP(O)(OR 7 ) 2 , SO 2 C 1-4 alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heterocyclyl;

n is 0, 1 or 2;

R 7 and R 8 are independently selected from H, substituted or unsubstituted C 1-4 alkyl, substituted or unsubstituted C 1-4 alkyleneOH, C 1-4 alkylene OC 1-4 alkyl, C 1-4 alkylene NR 15 R 16 , COC 1-4 alkyl and substituted or unsubstituted aryl; or

R 7 and R 8 together with the nitrogen to which they are attached form a 5 to 7 membered heterocyclyl which contains 1 or 2 heteroatoms selected from N, O, S, SO and SO 2 which may be substituted with H, C 1-4 alkyl, OR 9 or NR 9 R 10 ;

R 9 and R 10 are independently selected from H and substituted or unsubstituted C 1-4 alkyl;

R 11 is independently selected from H, substituted or unsubstituted C 1-4 alkyl, substituted or unsubstituted C 2-4 alkyleneOH and substituted or unsubstituted C 2-4 alkylene NR 7 R 8 ;

R 12 and R 13 are independently selected from H, substituted or unsubstituted C 1-4 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 2-4 alkyleneOH, COC 1-4 alkyl, COaryl and COheterocyclyl; or

R 12 and R 13 together with the nitrogen to which they are attached form a 5 to 7 membered heterocyclyl which contains 1 or 2 heteroatoms selected from N, O, S, SO and SO 2 and may be substituted with substituted or unsubstituted C 1-4 alkyl, OR 9 or NR 9 R 10 ;

R 14 is selected from aryl and a 5 to 7 membered heterocyclyl having from 1 to 3 heteroatoms selected from N, O, S, SO and SO 2 , wherein the aryl or heterocyclyl may be substituted with 1 to 3 substituents selected from substituted or unsubstituted C 1-4 alkyl, OH, NR 15 R 16 , halogen, CF 3 , OCF 3 , CN, OC 1-4 alkyl, OC 2-4 alkyleneOH, C 1-4 alkylene OH, C 1-4 alkyleneOC 1-4 alkyl, C 1-4 alkyleneNR 15 R 16 , CONR 15 R 16 , CO 2 R 9 , NR 7 SO 2 CH 3 , N(SO 2 CH 3 ) 2 , NR 7 CONR 8 C 1-4 alkyl, SO 2 NR 15 R 16 , OP(O)(OR 7 ) 2 , substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl; and

R 15 and R 16 are independently selected from H, substituted or unsubstituted C 1-4 alkyl, substituted or unsubstituted C 1-4 alkylOH, substituted or unsubstituted C 1-4 alkylOC 1-4 alkyl, COC 1-4 alkyl and S(O)CH 3 ; or

R 15 and R 16 together with the nitrogen to which they are attached form a 5 to 6 membered heterocyclyl which contains 1 or 2 heteroatoms selected from N, O and S which may be substituted with substituted or unsubstituted C 1-4 alkyl, OR 9 or NR 9 R 10 ,

wherein the term “substituted or unsubstituted” refers to a group that may or may not be further substituted with one or more groups selected from C 1-4 alkyl, nitro, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heterocyclyl, halo, hydroxy, C 1-4 alkoxy, aryloxy, carboxy, amino, arylacyl, heterocyclylacyl, acylamino, acyloxy, OP(O)(OH) 2 , arylsulfonyl and cyano; and

pharmaceutically acceptable salts, stereoisomers and/or tautomers thereof.

2. The compound according to claim 1 , wherein the compound of formula I has the formula Ia

3. The compound according to claim 1 , wherein one of R 2 and R 17 is H and the other is H or C 1-4 alkyl.

4. The compound according to claim 1 , wherein both R 4 and R 5 are hydrogen.

5. The compound according to claim 1 , wherein in the substituted phenyl of W, one of the substituents is meta to the atom attached to X.

6. The compound according to claim 1 , wherein the methylene substituted with R 2 and R 17 is of S chirality.

7. The compound according to claim 1 , wherein the compound of formula I has the formula Ib

8. The compound according to claim 7 , wherein R 6 is H, halogen, CO 2 R 9 , CONR 7 R 8 or phenyl, saturated or unsaturated 5 or 6 membered heterocyclyl containing 1 to 2 heteroatoms selected from N, O and S or a condensed heterocyclyl containing 1 or 2 oxygen atoms, wherein the phenyl or heterocyclyl may be substituted with 1 or 2 substituents independently selected from OC 1-4 alkyl, OH, NR 7 CONR 8 , NR 15 R 16 , SO 2 NR 9 R 10 , OP(O)(OH) 2 , CO 2 R 9 , C 1-4 alkylOH, C 1-4 alkyleneNR 15 R 16 or substituted or unsubstituted 6 membered heterocyclyl containing 1 or 2 heteroatoms selected from N and O.

9. A pharmaceutical composition comprising the compound of formula I according to claim 1 and a pharmaceutically acceptable carrier.

10. A method of inhibiting a kinase in a cell comprising contacting the cell with the compound of formula I according to claim 1 .

11. A method of control of macrophage populations comprising contacting the macrophage population with the compound of formula I according to claim 1 .