Inhibitors of JAK

1. A compound having the formula I:

or a tautomer or pharmaceutically acceptable salt thereof,

wherein:

Y 1 is N or CR 1c ;

R 1a is benzyl, optionally substituted with from 1 to 3 substituents selected from the group consisting of C 2-8 alkenyl, C 2-8 alkynyl, amino, hydroxy, halogen, C 1-8 heteroalkyl, cyano, C 3-8 cycloalkyl, aryl, haloaryl, C 1-8 alkylaryl, and C 1-8 alkoxyaryl, heteroaryl, C 3-8 heterocyclyl and C 3-8 heterocyclylcarbonyl;

R 1b is H or C 1-8 alkyl;

R 1c is H, C 1-8 alkyl or halogen;

R 2 is H, C 1-8 alkyl, C 1-8 heteroalkyl, heterocyclylC 1-8 alkoxy, halogen or heterocyclyl;

R 3 is H or C 1-8 alkyl or C 3-8 cycloalkyl;

R 4 is selected from the group consisting amino, C 1-8 alkyl, aminoC 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 heteroalkyl, C 3-8 cycloalkyl, aryl, heteroaryl and C 3-8 heterocyclyl; and

m is 0, 1, 2 or 3.

2. A compound having the formula I:

or a tautomer or pharmaceutically acceptable salt thereof,

wherein:

Y 1 is N or CR 1c ;

R 1a is benzyl, optionally substituted with from 1 to 3 substituents selected from the group consisting of C 2-8 alkenyl, C 2-8 alkynyl, amino, hydroxy, halogen, C 1-8 heteroalkyl, cyano, C 3-8 cycloalkyl, aryl, haloaryl, C 1-8 alkylaryl, C 1-8 alkoxyaryl, heteroaryl, C 3-8 heterocyclyl and C 3-8 heterocyclylcarbonyl;

R 1b is H or C 1-8 alkyl;

R 1c is H, C 1-8 alkyl or halogen;

R 2 is H, C 1-8 alkyl, C 1-8 alkoxy or halogen;

R 3 is H or C 1-8 alkyl;

R 4 is selected from the group consisting amino, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 heteroalkyl, C 3-8 cycloalkyl, aryl, heteroaryl and C 3-8 heterocyclyl; and

m is 0, 1, 2 or 3.

3. The compound of claim 1 wherein Y 1 is N.

4. The compound of claim 1 wherein Y 1 is CH.

5. The compound of claim 1 having the formula Ia:

or a tautomer or pharmaceutically acceptable salt thereof,

wherein:

R 1a is benzyl, optionally substituted with from 1 to 3 substituents selected from the group consisting of C 2-8 alkenyl, C 2-8 alkynyl, amino, hydroxy, halogen, C 1-8 heteroalkyl, cyano, C 3-8 cycloalkyl, aryl, haloaryl, C 1-8 alkylaryl, C 1-8 alkoxyaryl, heteroaryl, C 3-8 heterocyclyl and C 3-8 heterocyclylcarbonyl;

R 1b is H or C 1-8 alkyl;

R 2 is H, C 1-8 alkyl, C 1-8 alkoxy or halogen;

R 3 is H or C 1-8 alkyl;

R 4 is selected from the group consisting C 1-8 alkyl, C 1-8 heteroalkyl, C 3-8 cycloalkyl, and amino; and

m is 0, 1, 2 or 3.

6. The compound of claim 1 wherein R 3 is H.

7. The compound of claim 1 having the formula (Ib):

or a tautomer or pharmaceutically acceptable salt thereof,

wherein:

R 1 is benzyl, optionally substituted with from 1 to 3 substituents selected from the group consisting of C 2-8 alkynyl, hydroxy, halogen, C 1-8 alkoxy, cyano, aminocarbonyl, C 3-8 cycloalkyl, aryl, haloaryl, C 1-8 alkylaryl, C 1-8 alkoxyaryl, heteroaryl, and heterocyclyl,

heterocyclylcarbonyl;

R 2a is H, C 1-8 alkyl, C 1-8 alkoxy or halogen;

R 2b is H, C 1-8 alkyl, C 1-8 alkoxy or halogen; and

R 4 is selected from the group consisting C 1-8 alkyl, C 1-8 alkoxyC 1-8 alkylene, C 3-8 cycloalkyl, C 1-8 alkoxy, and amino.

8. The compound of claim 7 wherein R 1 is benzyl, optionally substituted with from 1 to 3 substituents selected from the group consisting of C 2-8 alkynyl, hydroxy, halogen, C 1-8 alkoxy, cyano, aminocarbonyl, C 3-8 cycloalkyl, aryl, haloaryl, heteroaryl, heterocyclyl, and heterocyclylcarbonyl.

9. The compound of claim 7 wherein R 1 is benzyl, substituted with from 1 to 3 substituents selected from the group consisting of C 2-8 alkynyl, hydroxy, halogen, C 1-8 alkoxy, cyano, aminocarbonyl and C 3-8 cycloalkyl.

10. The compound of claim 7 wherein R 1 is benzyl, substituted with from 1 to 3 substituents selected from the group consisting of aryl, haloaryl, C 1-8 alkylaryl, C 1-8 alkoxyaryl, heteroaryl, heterocyclyl and heterocyclylcarbonyl.

11. The compound of claim 1 wherein R 2a is H, methyl, methoxy, fluoro or chloro and R 2b is H, methyl, methoxy, fluoro or chloro.

12. A compound having the formula (Ic):

or a tautomer or pharmaceutically acceptable salt thereof,

wherein:

Y 2 is —CH or —CH—CH—;

R 5 is H, C 1-8 alkyl or hydroxyC 1-8 alkylene; and

R 6 is benzyl, optionally substituted with from 1 to 3 substituents selected from the group consisting of C 2-8 alkynyl, hydroxy, halogen, C 1-8 alkoxy, cyano, aminocarbonyl, C 3-8 cyclopropyl, aryl, haloaryl, C 1-8 alkylaryl, C 1-8 alkoxyaryl, heteroaryl, heterocyclyl and heterocyclylcarbonyl.

13. The compound of claim 12 wherein R 5 is selected from the group consisting of CH 3 ; and

R 6 is Ph or

R 8 is selected from the group consisting of C 1-8 alkyl, halogen, C 1-8 alkoxy, or may be taken together to form a heterocyclic ring; and

q is 0, 1, 2 or 3; the wavy line indicates the point of attachment to the rest of the molecule.

14. The compound of claim 1 having the formula (Id):

or a tautomer or pharmaceutically acceptable salt thereof,

wherein:

R 5 is C 1-8 alkyl or hydroxyC 1-8 alkylene; or may be taken together with R 8 to form a cyclic ring;

R 7 is C 1-8 alkyl, hydroxy or C 1-8 alkoxy;

R 8 is selected from the group consisting of C 1-8 alkyl, halogen and C 1-8 alkoxy, or may be taken together to form a heterocyclic ring; and

p is 0,1,2, or 3;andqis-0,1, 2 or 3.

15. The compound of claim 1 having the formula (Ie):

or a tautomer or pharmaceutically acceptable salt thereof,

wherein:

R 5 is C 1-8 alkyl or hydroxyC 1-8 alkylene; or may be taken together with R 8a or R 8b to form a cyclic ring;

R 8a is H, halogen, or may be taken together with R 5 to form 5-6 membered carbocyclic ring;

R 8b is H, halogen or, or may be taken together with R 8a to form a heterocyclic ring;

R 8c is H, C 1-8 alkyl, halogen or C 1-8 alkoxy, or may be taken together with R 8b to form a heterocyclic ring;

R 8d is H; and

R 8e is H, halogen or may be taken together with R 5 to form 5-6 membered carbocyclic ring.

16. The compound of claim 1 wherein R 2 is selected from the group consisting of: H and C 1-8 alkyl.

17. The compound of claim 1 wherein R 4 is selected from the group consisting of: C 1-8 alkyl and C 3-8 cycloalkyl.

18. The compound of claim 1 wherein R 5 is selected from the group consisting of: H and C 1-8 alkyl.

19. The compound of claim 1 wherein having formula (Ii):

or a tautomer or pharmaceutically acceptable salt thereof,

wherein:

R 5 is H or C 1-8 alkyl;

R 4 is C 1-8 alkyl or heterocyclyl.

20. The compound of claim 1 wherein R 4 is selected from the group consisting of —CH 3 , —CH 2 CH 3 , —NH 2 , —NHCH 3 , —NCH 2 CH 3 , —N(CH 3 ) 2 , —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —CH 2 OCH 3 , —CH 2 CONH 2 , cPr, and cBu.

21. The compound of claim 1 wherein:

R 4 has the formula:

wherein R 12 is selected from the group consisting of H and OH,

r is 0 or 1; and

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

22. The compound of claim 1 wherein:

R 4 has the formula:

wherein R 12 is selected from the group consisting of H and OH; and

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

23. The compound of claim 1 selected from the group consisting of: methyl 3-(5-carbamoyl-4-(2,2,2-trifluoroethylamino)pyrimidin-2-ylamino)phenylcarbamate; 2-(3-(cyclopropanecarboxamido)phenylamino)-4-(2,2,2-trifluoroethylamino)pyrimidine-5-carboxamide; 2-(3-(2-methoxyacetamido)phenylamino)-4-(2,2,2-trifluoroethylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(2,2,2-trifluoroethylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(methylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(ethylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(prop-2-ynylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(isopropylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(cyclopropylmethylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(tert-butylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(2-methoxyethylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(cyclopentylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(3-methoxypropylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(benzylamino)pyrimidine-5-carboxamide; methyl 5-(5-carbamoyl-4-(2,2,2-trifluoroethylamino)pyrimidin-2-ylamino)-2-chlorophenylcarbamate; 4-(cyclopentylamino)-2-(3-(cyclopropanecarboxamido)phenylamino)pyrimidine-5-carboxamide; 2-(3-(cyclobutanecarboxamido)phenylamino)-4-(cyclopentylamino)pyrimidine-5-carboxamide; 4-(cyclopentylamino)-2-(3-propionamidophenylamino)pyrimidine-5-carboxamide; 4-(cyclopentylamino)-2-(3-(2-methoxyacetamido)phenylamino)pyrimidine-5-carboxamide; methyl 3-(5-carbamoyl-4-(cyclopentylamino)pyrimidin-2-ylamino)phenylcarbamate; ethyl 3-(5-carbamoyl-4-(cyclopentylamino)pyrimidin-2-ylamino)phenylcarbamate; methyl 5-(5-carbamoyl-4-(cyclopentylamino)pyrimidin-2-ylamino)-2-chlorophenylcarbamate; 4-(benzylamino)-2-(3-(cyclopropanecarboxamido)phenylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(3-(cyclobutanecarboxamido)phenylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(3-propionamidophenylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(3-(2-methoxyacetamido)phenylamino)pyrimidine-5-carboxamide; methyl 3-(4-(benzylamino)-5-carbamoylpyrimidin-2-ylamino)phenylcarbamate; ethyl 3-(4-(benzylamino)-5-carbamoylpyrimidin-2-ylamino)phenylcarbamate; methyl 5-(4-(benzylamino)-5-carbamoylpyrimidin-2-ylamino)-2-chlorophenylcarbamate; 4-(cyclopentylamino)-2-(3-ureidophenylamino)pyrimidine-5-carboxamide; 4-(cyclopentylamino)-2-(3-(3-methylureido)phenylamino)pyrimidine-5-carboxamide; 4-(cyclopentylamino)-2-(3-(3,3-dimethylureido)phenylamino)pyrimidine-5-carboxamide; 4-(cyclopentylamino)-2-(3-(3-ethylureido)phenylamino)pyrimidine-5-carboxamide; 4-(cyclopentylamino)-2-(3-(pyrrolidine-1-carboxamido)phenylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(3-ureidophenylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(3-(3-methylureido)phenylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(3-(pyrrolidine-1-carboxamido)phenylamino)pyrimidine-5-carboxamide; isopropyl 3-(4-(benzylamino)-5-carbamoylpyrimidin-2-ylamino)phenylcarbamate; (S)-2-(3-(2-methoxyacetamido)phenylamino)-4-(1-phenylethylamino)pyrimidine-5-carboxamide; 2-(3-(2-methoxyacetamido)phenylamino)-4-(4-methylbenzylamino)pyrimidine-5-carboxamide; 2-(3-(2-methoxyacetamido)phenylamino)-4-(4-methoxybenzylamino)pyrimidine-5-carboxamide; 4-(4-chlorobenzylamino)-2-(3-(2-methoxyacetamido)phenylamino)pyrimidine-5-carboxamide; 4-(3,4-dichlorobenzylamino)-2-(3-(2-methoxyacetamido)phenylamino)pyrimidine-5-carboxamide; (R)-2-(3-(2-methoxyacetamido)phenylamino)-4-(1-phenylethylamino)pyrimidine-5-carboxamide; (S)-2-(3-acetamidophenylamino)-4-(2-hydroxy-2-phenylethylamino)pyrimidine-5-carboxamide; (R)-2-(3-acetamidophenylamino)-4-(2-hydroxy-2-phenylethylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(2-amino-2-oxoethylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(2-phenylcyclopropylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(cyclohexylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-((trans)-2-hydroxycyclopentylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(benzyl(methyl)amino)pyrimidine-5-carboxamide; 4-(cyclobutylamino)-2-(3-(2-methoxyacetamido)phenylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(cyclobutylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(phenethylamino)pyrimidine-5-carboxamide; 4-(isopropylamino)-2-(3-(2-methoxyacetamido)phenylamino)pyrimidine-5-carboxamide; 2-(3-(2-methoxyacetamido)phenylamino)-4-(2,3,6-trifluorobenzylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(2,3,6-trifluorobenzylamino)pyrimidine-5-carboxamide; (S)-2-(3-acetamidophenylamino)-4-(2-phenylpropylamino)pyrimidine-5-carboxamide; (S)-2-(3-acetamidophenylamino)-4-(1-hydroxy-3-(1H-imidazol-5-yl)propan-2-ylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(3-amino-3-oxopropylamino)pyrimidine-5-carboxamide; (R)-2-(3-acetamidophenylamino)-4-(1-hydroxy-4-methylpentan-2-ylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(2-(pyrrolidin-1-yl)ethylamino)pyrimidine-5-carboxamide; (S)-2-(3-acetamidophenylamino)-4-(1-phenylethylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(2-oxo-2-(pyrrolidin-1-yl)ethylamino)pyrimidine-5-carboxamide; (R)-2-(3-acetamidophenylamino)-4-(piperidin-3-ylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(4-methylbenzylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(4-methoxybenzylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(4-chlorobenzylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(3,4-dichlorobenzylamino)pyrimidine-5-carboxamide; (R)-2-(3-acetamidophenylamino)-4-(1-phenylethylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(2-(methylamino)-2-oxoethylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-((2S,3S)-1-hydroxy-3-methylpentan-2-ylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(cyanomethylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(tetrahydro-2H-pyran-4-ylamino)pyrimidine-5-carboxamide; (S)-2-(3-acetamidophenylamino)-4-(1-hydroxy-3-phenylpropan-2-ylamino)pyrimidine-5-carboxamide; 4-(isopropylamino)-2-(3-(N-methylacetamido)phenylamino)pyrimidine-5-carboxamide; 4-(cyclopentylamino)-2-(3-(N-methylacetamido)phenylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(3-(N-methylacetamido)phenylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(2-morpholinoethylamino)pyrimidine-5-carboxamide; (R)-2-(3-acetamidophenylamino)-4-(2-phenylpropylamino)pyrimidine-5-carboxamide; (S)-2-(3-acetamidophenylamino)-4-(2-hydroxypropylamino)pyrimidine-5-carboxamide; (R)-2-(3-acetamidophenylamino)-4-(2,3-dihydroxypropylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(2-methoxy-2-phenylethylamino)pyrimidine-5-carboxamide; (S)-2-(3-acetamidophenylamino)-4-(1-amino-1-oxopropan-2-ylamino)pyrimidine-5-carboxamide; (R)-2-(3-(2-methoxy-N-methylacetamido)phenylamino)-4-(1-phenylethylamino)pyrimidine-5-carboxamide; (R)-2-(3-(N-methylacetamido)phenylamino)-4-(1-phenylethylamino)pyrimidine-5-carboxamide; 4-(isopropylamino)-2-(3-(2-methoxy-N-methylacetamido)phenylamino)pyrimidine-5-carboxamide; 4-(cyclopentylamino)-2-(3-(2-methoxy-N-methylacetamido)phenylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(3-(2-methoxy-N-methylacetamido)phenylamino)pyrimidine-5-carboxamide; (R)-2-(3-acetamidophenylamino)-4-(1-amino-1-oxopropan-2-ylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(2,3-dihydro-1H-inden-2-ylamino)pyrimidine-5-carboxamide; (S)-2-(3-acetamidophenylamino)-4-(2-hydroxy-1-phenylethylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(3-fluorobenzylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(2,3-difluorobenzylamino)pyrimidine-5-carboxamide; (S)-2-(3-acetamidophenylamino)-4-(2,3-dihydro-1H-inden-1-ylamino)pyrimidine-5-carboxamide; (R)-2-(3-acetamidophenylamino)-4-(2,3-dihydro-1H-inden-1-ylamino)pyrimidine-5-carboxamide; (R)-2-(3-acetamidophenylamino)-4-(2-hydroxy-1-phenylethylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(benzo[d][1,3]dioxol-5-ylmethylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(2-fluorobenzylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(3-chlorobenzylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(2,5-difluorobenzylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(4-fluorobenzylamino)pyrimidine-5-carboxamide; 4-(4-fluorobenzylamino)-2-(3-(2-methoxyacetamido)phenylamino)pyrimidine-5-carboxamide; and (R)-4-(1-phenylethylamino)-2-(3-(pyrrolidine-1-carboxamido)phenylamino)pyrimidine-5-carboxamide; 2-(3-acetamido-4-chlorophenylamino)-4-(benzylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(4-chloro-3-(2-methoxyacetamido)phenylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(4-chloro-3-(3-cyclobutylureido)phenylamino)pyrimidine-5-carboxamide; (R)-2-(3-acetamido-4-chlorophenylamino)-4-(1-phenylethylamino)pyrimidine-5-carboxamide; (R)-2-(4-chloro-3-(2-methoxyacetamido)phenylamino)-4-(1-phenylethylamino)pyrimidine-5-carboxamide; (R)-2-(4-chloro-3-(cyclopropanecarboxamido)phenylamino)-4-(1-phenylethylamino)pyrimidine-5-carboxamide; (R)-2-(4-chloro-3-(3-cyclobutylureido)phenylamino)-4-(1-phenylethylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(benzylamino)-N-methylpyrimidine-5-carboxamide; 4-(benzylamino)-2-(3-(2-methoxyacetamido)phenylamino)-N-methylpyrimidine-5-carboxamide; methoxyacetamido)phenylamino)-N-methylpyrimidine-5-carboxamide; benzyl 3-((2-(3-acetamidophenylamino)-5-carbamoylpyrimidin-4-ylamino)methyl)piperidine-1-carboxylate; and 6-(3-acetamidophenylamino)-4-(benzylamino)nicotinamide.

24. A composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable carrier or diluent.

25. A kit comprising a composition of claim 24 , packaging and instructions for use.

26. A compound of claim 1 that is 2-(4-chloro-3-(pyrrolidine-1-carboxamido)phenylamino)-4-(2-fluorobenzylamino)pyrimidine-5-carboxamide or a pharmaceutically acceptable salt thereof.

27. A composition comprising a compound of claim 26 in combination with a pharmaceutically acceptable carrier or diluent.