Bicyclic dihydropyridone kinase inhibitors

1. A compound of Formula (I):

or a tautomer or a pharmaceutically acceptable salt thereof, wherein

G 1 is N and G 2 is N

L 1 is selected from the group consisting of a bond, NH, O, and S;

Z 1 is selected from the group consisting of aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted with 1 to 5 R 1 ;

R 1 is independently selected from the group consisting of halo, C 1-8 alkyl, C 2-8 alkenyl, haloC 1-8 alkyl, (CH 2 ) n SR 1a , (CH 2 ) n OR 1a , O(CH 2 ) j OR 1a , (CH 2 ) n NR 1b R 1c , (CH 2 ) n COR 1e , (CH 2 ) n CONR 1b R 1c , (CH 2 ) n NR 1b COR 1e , (CH 2 ) n CONR 1b (OR 1a ), (CH 2 ) n CO 2 R 1a , O(CH 2 ) n CO 2 R 1a , (CH 2 ) n NR 1b CO 2 R 1a , (CH) n SO 2 NR 1b R 1c , (CH 2 ) n NR 1b SO 2 R 1e , (CH 2 ) n SOR 1e , (CH 2 ) n SO 2 R 1e , oxo, (CH 2 ) n CN, N 3 , NO 2 , and -L 2 -W, where n is 0, 1, 2, 3, 4, 5, or 6 and j is 1, 2, 3, 4, 5, or 6;

L 2 is selected from the group consisting of

—O(CH 2 ) b —, —SO—, —SO 2 —, —CO—, —NR 1d —, —CONR 1d (CH 2 ) b —, —NR 1d CO—NR 1d SO 2 —, —SO 2 NR 1d —, a bond, and —(CH 2 ) e — where b is 0, 1, 2, 3, 4, or 5 and e is 1, 2, 3, 4, or 5;

W is selected from the group consisting of aryl, heteroaryl, cycloalkyl, and heterocyclyl each optionally substituted with 1 to 3 R 2 ;

R 2 is independently selected from the group consisting of halo, C 1-8 alkyl, C 2-8 alkenyl, haloC 1-8 alkyl, (CH 2 ) m SR 2a , (CH 2 ) m OR 2a , O(CH 2 ) k OR 2a , (CH 2 ) m NR 2b R 2c , (CH 2 )—COR 2e , (CH 2 ) m CONR 2b R 2c , (CH 2 ) m NR 2b COR 2e , (CH 2 ) m CONR 2b (OR 2a ), (CH 2 ) m CO 2 R 2a , O(CH 2 ) m CO 2 R 2a , (CH 2 ) m NR 2b CO 2 R 2a , (CH) m SO 2 NR 2b R 2c , (CH 2 ) m NR 2b SO 2 R 2e , (CH 2 ) m SOR 2e , (CH 2 ) m SO 2 R 2e , oxo, (CH 2 ) m CN, N 3 , and NO 2 , where m is 0, 1, 2, 3, 4, 5, or 6 and k is 1, 2, 3, 4, 5, or 6;

R 1a , R 1b , R 1c , R 1d , R 2a , R 2b , and R 2c are independently selected from the group consisting of H, C 1-8 alkyl, C 2-8 alkenyl, and haloC 1-8 alkyl;

R 1e and R 2e are independently selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, and haloC 1-8 alkyl;

Y 1 is

or (CH 2 ) v (Y 2 ), wherein

v is 0, 1, 2, or 3;

Y 2 is selected from the group consisting of CH 2 CH 3 , (CH 2 ) 3 NH 2 , cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1 to 3 R 10 ;

R 4 is selected from the group consisting of H, halo, C 1-8 alkyl, C 2-8 alkenyl, haloC 1-8 alkyl, (CH 2 ) p SR 4a , (CH 2 ) p SOR 4a , (CH 2 ) p SO 2 R 4a , (CH 2 ) p OR 4a , (CH 2 ) p NR 4b R 4c , (CH 2 ) f CONR 4b R 4c , (CH 2 ) p NR 4b COR 4d , (CH 2 ) f CO 2 R 4a , (CH 2 ) p NR 4b CO 2 R 4a , (CH 2 ) f cycloalkyl, (CH 2 ) p (O)cycloalkyl, (CH 2 ) p (S)cycloalkyl, (CH) p SO 2 NR 4b R 4c , (CH 2 ) p NHcycloalkyl, (CH 2 ) f CN, (CH 2 ) f (aryl), (CH 2 ) f (heteroaryl), (CH 2 ) f (aryl)(heteroaryl), (CH 2 ) f (heterocyclyl), (CH 2 ) p (O)(CH 2 ) f (aryl), (CH 2 ) p (O)(CH 2 ) f (heteroaryl), (CH 2 ) p (O)(CH 2 ) f C 3-8 cycloalkyl, and (CH 2 ) p (O)(CH 2 ) f (heterocyclyl), where the aryl, heteroaryl, cycloalkyl, and heterocyclyl are each optionally substituted with 1 to 3 R 11a , f is 0, 1, 2, 3, 4, 5, or 6, and p is 1, 2, 3, 4, 5, or 6; or R 4 and R 5 together form ═O or a 3 to 8 membered carbocyclic or heterocyclic ring optionally substituted with 1 to 3 R 11a ;

R 5 is selected from the group consisting of H and C 1-8 alkyl; or R 5 is joined to the adjacent nitrogen atom to form a 4 to 6 membered heterocyclic ring optionally substituted with 1 to 3 R 11a ;

R 6 is selected from the group consisting of H, C 1-8 alkyl, OH, O(C 1-8 alkyl), CO 2 R 6a , CO(NR 6a R 6b ), and C 3-8 cycloalkyl; or R 6 together with R 7 and the atoms to which they are attached to form a heterocyclyl ring optionally substituted with 1 to 3 R 11b ;

R 7 is selected from the group consisting of H, C 1-8 alkyl, and cycloalkyl;

R 8 is selected from the group consisting of H, C 1-8 alkyl, (CH 2 )—NR 8b R 8c , (CH 2 ) g CONR 8b R 8c , (CH 2 ) g CO(CH 2 ) u NR 8b R 8c , (CH 2 ) g CO 2 R 8a , (CH 2 ) u OR 8a , CH(C 1-8 alkyl)OR 8a , (CH 2 ) g cycloalkyl, (CH 2 ) g heterocyclyl, (CH 2 ) g aryl, (CH 2 ) g heteroaryl, and (CH 2 ) u (O)(aryl), where the aryl, cycloalkyl, heteroaryl, and heterocyclyl are each optionally substituted with 1 to 3 R 11c , g is 0, 1, 2, 3, 4, 5, or 6 and u is 1, 2, 3, 4, 5, or 6; or R 8 together with R 9 and the atoms to which they are attached to form ═O, ═S, or a cycloalkyl or heterocyclyl ring optionally substituted with R 11c ;

R 9 is H or C 1-8 alkyl;

R 10 is independently selected from the group consisting of halo, C 1-8 alkyl, C 2-8 alkenyl, haloC 1-8 alkyl, (CH 2 ) q SR 10a , (CH 2 ) q OR 10a , (CH 2 ) q NR 10b R 10a , (CH 2 ) q COR 10d , (CH 2 ) q CONR 10b R 10c , (CH 2 ) q NR 10b COR 10d , (CH 2 ) q CONR 10b (OR 10a ), (CH 2 ) q CO 2 R 10a , O(CH 2 ) q CO 2 R 10a , (CH 2 ) q NR 10b CO 2 R 10a , (CH) q SO 2 NR 10b R 10a , (CH 2 ) q NR 10b SO 2 R 10d , (CH 2 ) q SOR 10d , (CH 2 ) q SO 2 R 10d , OXO, (CH 2 ) q CN, N 3 , N═CH 2 , NO 2 , C(O)heterocyclyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl, where the aryl, cycloalkyl, heteroaryl, and heterocyclyl are each optionally substituted with 1 to 3 R 11d and q is 0, 1, 2, 3, 4, 5, or 6;

R 11a , R 11b , R 11c , and R 11d are independently selected from the group consisting of halo, C 1-8 alkyl, haloC 1-8 alkyl, OH, C 1-8 alkoxy, haloC 1-8 alkoxy, C(O)C 1-8 alkyl, CO 2 C 1-8 alkyl, and SO 2 C 1-8 alkyl;

R 4a , R 4b , R 4c , R 6a , R 6b , R 8a , R 8b , R 8c , R 10a , R 10b , and R 10c are independently selected from the group consisting of H, C 1-8 alkyl, C 2-8 alkenyl, and haloC 1-8 alkyl;

R 4d and R 10d are independently selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, and haloC 1-8 alkyl; and

the wavy line indicates the point of attachment to the rest of the molecule.

2. A compound of claim 1 or a tautomer or a pharmaceutically acceptable salt thereof, wherein Z 1 is a five-membered heteroaryl ring optionally substituted with 1 to 3 R 1 .

3. A compound of claim 2 or a tautomer or a pharmaceutically acceptable salt thereof, wherein Z 1 is selected from the group consisting of

and wherein Z 1 is optionally substituted with 1 to 3 R 1 .

4. A compound of claim 1 , wherein at least one R 1 is C 1-3 alkyl.

5. A compound of claim 1 having Formula (II)

or a tautomer or a pharmaceutically acceptable salt thereof.

6. A compound of claim 5 , or a tautomer or a pharmaceutically acceptable salt thereof, wherein Z 1 is selected from the group consisting of:

and phenyl;

and wherein Z 1 is optionally substituted with 1 to 3 R 1 .

7. A compound of claim 5 or a tautomer or a pharmaceutically acceptable salt thereof wherein Z 1 is phenyl substituted with 1 to 5 R 1 .

8. A compound of claim 7 or a tautomer or a pharmaceutically acceptable salt thereof wherein at least one of R 1 is selected from the group consisting of halo, C 1-8 alkyl, cyano, and haloC 1-8 alkoxy.

9. A compound of claim 5 of Formula (IIa)

or a tautomer or a pharmaceutically acceptable salt thereof wherein

Ph is phenylene optionally substituted with 1 to 3 R 1 ;

B 1 is selected from the group consisting of CO—NR a R b , phenyl, heteroaryl, and heterocyclyl, wherein the phenyl, heteroaryl, and heterocyclyl are each optionally substituted with 1 to 3 R 2 , and R a and R b together form a four to six membered heterocyclic ring optionally substituted with one to three groups independently selected from halo, C 1-8 alkyl, and haloC 1-8 alkyl.

10. A compound of claim 9 or a tautomer or a pharmaceutically acceptable salt thereof wherein B 1 is heteroaryl or heterocyclyl, each optionally substituted with 1 to 3 R 2 .

11. A compound of claim 9 or a tautomer or a pharmaceutically acceptable salt thereof, wherein B 1 is selected from the group consisting of

where the wavy line indicates the point of attachment to the rest of the molecule and wherein B 1 is optionally substituted with 1 to 3 R 2 .

12. A compound of claim 1 or a tautomer or a pharmaceutically acceptable salt thereof wherein L 1 is a bond, and Z 1 is selected from the group consisting of:

where the wavy line indicates the point of attachment to the rest of the molecule.

13. A compound of claim 1 or a tautomer or a pharmaceutically acceptable salt thereof, wherein Y 1 is (CH 2 ) v (Y 2 ) wherein v is 0 and Y 2 is cycloalkyl or heterocycloalkyl each optionally substituted with 1 to 3 R 10 .

14. A compound of claim 13 or a tautomer or a pharmaceutically acceptable salt thereof, wherein Y 2 is tetrahydropyranyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each optionally substituted with 1 to 3 R 10 .

15. A compound of claim 13 or a tautomer or a pharmaceutically acceptable salt thereof, wherein Y 1 is

optionally substituted with 1 to 2 halo and where the wavy line indicates the point of attachment to the rest of the molecule.

16. A compound or a tautomer or a pharmaceutically acceptable salt thereof selected from the group consisting of:

STRUCTURE

NAME

2-(((1R,2S)-2- aminocyclohexyl)amino)- 4-(m-tolylamino)-7,8- dihydropyrido[4,3- d]pyrimidin-5(6H)-one

2-(((1R,2S)-2- aminocyclohexyl)amino)- 4-((1-methyl-1H-pyrazol- 4-yl)amino)-7,8- dihydropyrido[4,3- d]pyrimidin-5(6H)-one

2-(((1R,2S)-2- aminocyclohexyl)amino)- 4-(1-methyl-1H-pyrazol- 4-yl)-7,8- dihydropyrido[4,3- d]pyrimidin-5(6H)-one

2-(((1R,2S)-2- aminocyclohexyl)amino)- 4-((3-(pyrimidin-2- yl)phenyl)amino)- 7,8-dihydropyrido[4,3- d]pyrimidin-5(6H)-one

2-(((1R,2S)-2- aminocyclohexyl)amino)- 4-(quinolin-6-ylamino)- 7,8-dihydropyrido[4,3- d]pyrimidin-5(6H)-one

4-((3-(2H-1,2,3-triazol-2- yl)phenyl)amino)-2- (((1R,2S)- 2-aminocyclohexyl) amino)- 7,8-dihydropyrido[4,3- d]pyrimidin-5(6H)-one

2-(((1R,2S)-2- aminocyclohexyl)amino)- 4-((4-methoxy-3- (trifluoromethyl)phenyl) amino)- 7,8-dihydropyrido[4,3- d]pyrimidin-5(6H)-one

2-(((1R,2S)-2- aminocyclohexyl)amino)- 4-(1-methyl-1H-pyrazol- 4-yl)-7,8- dihydropyrido[4,3- d]pyrimidin-5(6H)-one

2-(cyclopentylamino)-4- (m-tolylamino)-7,8- dihydropyrido[4,3- d]pyrimidin-5(6H)-one

2-((3-aminotetrahydro- 2H-pyran-4-yl)amino)- 4-(m-tolylamino)-7,8- dihydropyrido[4,3- d]pyrimidin-5(6H)-one

2-(cyclopropylamino)-4- (m-tolylamino)-7,8- dihydropyrido[4,3- d]pyrimidin-5(6H)-one.

17. A pharmaceutical composition comprising a compound of claim 1 or a tautomer or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier or excipient.

18. A method for inhibiting Syk or JAK kinase or a signal transduction pathway mediated at least in part by Syk kinase activity comprising contacting a cell with a compound of claim 1 .