1,2,4-triazine-6-carboxamide kinase inhibitors

1. A compound of Formula (I):

or a tautomer or a pharmaceutically acceptable salt thereof, wherein

T is X 1 where X 1 is monocyclic heteroaryl comprising 1-4 heteroatoms selected from S, O and N, wherein heteroaryl are optionally substituted with 1 to 5 R 1 ;

each 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 2 ) 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-W, where n is 0, 1, 2, 3, 4, 5, or 6 and j is 1, 2, 3, 4, 5, or 6;

L 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 ) z — where b is 0, 1, 2, 3, 4, or 5 and z is 1, 2, 3, 4, or 5;

W is selected from the group consisting of aryl, monocyclic or bicyclic heteroaryl comprising 1-4 heteroatoms selected from S, O and N, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl comprising 1-4 heteroatoms selected from S, O and N, each optionally substituted with 1 to 3 R 2 ;

each 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 ) m 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 2 ) 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 is (CH 2 ) v (X 2 ), wherein

v is 0, 1, 2, or 3;

X 2 is selected from the group consisting of CH 2 CH 3 , (CH 2 ) 3 NH 2 , C 3-8 cycloalkyl, 3-8 membered heterocyclyl comprising 1-4 heteroatoms selected from S, O and N, aryl, and monocyclic or bicyclic heteroaryl comprising 1-4 heteroatoms selected from S, 0 and N, wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted with 1 to 3 R 10 ;

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 10c , (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 2 ) q SO 2 NR 10b R 10c , (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)3-8 membered heterocyclyl comprising 1-4 heteroatoms selected from S, O and N, aryl, monocyclic or bicyclic heteroaryl comprising 1-4 heteroatoms selected from S, O and N, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl comprising 1-4 heteroatoms selected from S, O and N, where 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 11d is 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 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 10d is selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, and haloC 1-8 alkyl.

2. A compound of claim 1 or a tautomer or a pharmaceutically acceptable salt thereof, wherein at least one R 1 is -L-W.

3. A compound of Formula (Ib) or a tautomer or a pharmaceutically acceptable salt thereof

wherein

HET is monocyclic heteroaryl comprising 1-4 heteroatoms selected from S, O and N, optionally substituted with 1 to 3 R 1 ; and

B 1 is selected from the group consisting of CO—NR a R b , phenyl, monocyclic or bicyclic heteroaryl comprising 1-4 heteroatoms selected from S, O and N, and 3-8 membered heterocyclyl comprising 1-4 heteroatoms selected from S, O and N, wherein 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; and wherein

each 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 2 ) 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-W, where n is 0, 1, 2, 3, 4, 5, or 6 and j is 1, 2, 3, 4, 5, or 6;

L 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 ) z — where b is 0, 1, 2, 3, 4, or 5 and z is 1, 2, 3, 4, or 5;

W is selected from the group consisting of aryl, monocyclic or bicyclic heteroaryl comprising 1-4 heteroatoms selected from S, O and N, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl comprising 1-4 heteroatoms selected from S, O and N, each optionally substituted with 1 to 3 R 2 ;

each 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 ) m 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 2 ) 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 is (CH 2 ) v (X 2 ), wherein

v is 0, 1, 2, or 3;

X 2 is selected from the group consisting of CH 2 CH 3 , (CH 2 ) 3 NH 2 , C 3-8 cycloalkyl, 3-8 membered heterocyclyl comprising 1-4 heteroatoms selected from S, O and N, aryl, and monocyclic or bicyclic heteroaryl comprising 1-4 heteroatoms selected from S, 0 and N, wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted with 1 to 3 R 10 ;

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 10c , (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 2 ) q SO 2 NR 10b R 10c , (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)3-8 membered heterocyclyl comprising 1-4 heteroatoms selected from S, O and N, aryl, monocyclic or bicyclic heteroaryl comprising 1-4 heteroatoms selected from S, O and N, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl comprising 1-4 heteroatoms selected from S, O and N, where 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 11d is 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 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; and

R 10d is selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, and haloC 1-8 alkyl.

4. A compound of claim 1 or 3 or a tautomer or a pharmaceutically acceptable salt thereof, wherein W or B 1 is substituted with 1 to 3 R 2 .

5. A compound of claim 3 or a tautomer or a pharmaceutically acceptable salt thereof wherein R 1 and R 2 are independently selected from the group consisting of halo, C 1-8 alkyl, haloC 1-8 alkyl, cyano, oxo, OH, O(C 1-8 alkyl), and O(haloC 1-8 alkyl).

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

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

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

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

8. A compound of claim 1 or 3 one a tautomer or a pharmaceutically acceptable salt thereof, wherein W or B 1 is selected from the group consisting of

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

9. A compound or a tautomer or a pharmaceutically acceptable salt thereof having a structure selected from

3-(((1R,2S)-2-aminocyclohexyl)amino)-5-((5-fluoropyridin-3-yl)amino)-1,2,4-triazine-6-carboxamide,

3-(((1R,2S)-2-aminocyclohexyl)amino)-5-((6-(dimethylcarbamoyl)pyridin-3-yl)amino)-1,2,4-triazine-6-carboxamide,

3-(((1R,2S)-2-aminocyclohexyl)amino)-5-((6-(azetidine-1-carbonyl)pyridin-3-yl)amino)-1,2,4-triazine-6-carboxamide,

3-(((1R,2S)-2-aminocyclohexyl)amino)-5-((6-fluoropyridin-3-yl)amino)-1,2,4-triazine-6-carboxamide,

3-(((1R,2S)-2-aminocyclohexyl)amino)-5-((2-methoxypyridin-4-yl)amino)-1,2,4-triazine-6-carboxamide,

3-(((1R,2S)-2-aminocyclohexyl)amino)-5-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazine-6-carboxamide,

3-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-5-((1-methyl-1H-pyrazol-4-yl)amino)-1,2,4-triazine-6-carboxamide,

3-(((1R,2S)-2-aminocyclohexyl)amino)-5-(pyridin-3-ylamino)-1,2,4-triazine-6-carboxamide,

3-(((1R,2S)-2-aminocyclohexyl)amino)-5-((3-methylisothiazol-5-yl)amino)-1,2,4-triazine-6-carboxamide,

3-(((1R,2S)-2-aminocyclohexyl)amino)-5-((5-(4-fluorophenyl)isoxazol-3-yl)amino)-1,2,4-triazine-6-carboxamide,

3-(((1R,2S)-2-aminocyclohexyl)amino)-5-(thiazol-5-ylamino)-1,2,4-triazine-6-carboxamide,

3-(((1R,2S)-2-aminocyclohexyl)amino)-5-((3-phenyl-1,2,4-oxadiazol-5-yl)amino)-1,2,4-triazine-6-carboxamide,

3-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-5-((3-methylisothiazol-5-yl)amino)-1,2,4-triazine-6-carboxamide,

3-(((1R,2S)-2-aminocyclohexyl)amino)-5-(thiazol-5-ylamino)-1,2,4-triazine-6-carboxamide.

10. A composition comprising a compound of claim 1 or a tautomer or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier or diluent.

11. 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 .

12. The compound 3-(((1R,2S)-2-aminocyclohexyl)amino)-5-((3-methylisothiazol-5-yl)amino)-1,2,4-triazine-6-carboxamide or a pharmaceutically acceptable salt thereof.