Inhibitors of JAK

1. A method for inhibiting JAK or a signal transduction pathway mediated at least in part by JAK activity comprising the step of contacting a cell with 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. The method of claim 1 wherein said JAK is selected from the group consisting of JAK1, JAK2, and JAK3.

3. The method of claim 1 , wherein said JAK is JAK1 or JAK3.

4. The method of claim 1 , wherein said JAK is JAK3.

5. A method for treating a condition or disorder mediated at least in part by JAK activity selected from the group consisting of organ transplants, asthma, COPD, systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, Crohn's disease, Type I diabetes and psoriasis in a subject comprising the step of administering to a subject in need of such treatment a therapeutically effective amount of a 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.

6. The method of claim 5 wherein the compound has 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.

7. The method of claim 5 wherein the compound has 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.

8. The method of claim 5 wherein the compound has 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.

9. The method of claim 5 wherein the compound has 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.

10. The method of claim 5 wherein the compound has 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 ; and q is 0, 1, 2 or 3.

11. The method of claim 5 wherein the compound has 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.

12. The method of claim 5 wherein the compound has 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.

13. The method of claim 5 wherein the compound is 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.

14. The method of claim 5 wherein the compound is 2-(4-chloro-3-(pyrrolidine-1-carboxamido)phenylamino)-4-(2-fluorobenzylamino)pyrimidine-5 -carboxamide or a pharmaceutically acceptable salt thereof.