Nicotinamides as JAK kinase modulators

1. A compound having the formula:

or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof

wherein:

each X 1 or X 2 is independently H or halogen;

D 1 is selected from the group consisting of:

-L 1 -phenyl, wherein the phenyl is further optionally substituted with from 1 to 3 substituents, R 1 , independently selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy, halo, hydroxy, C 1-8 alkylsulfonyl, C 3-8 cycloalkylsulfonyl, C 1-8 dialkylaminoaminocarbonyl, C 1-8 alkylcarbonyl, C 1-8 alkoxyC 1-8 alkylcarbonyl, C 1-8 alkoxycarbonyl, heterocyclyl, heterocyclylC 1-8 alkyl, heterocyclylcarbonyl, aryl and heteroaryl, wherein the aryl is further optionally substituted with halo;

L 1 is selected from the group consisting of a bond, —C(R) 2 —, and CH 2 CH 2 ;

each R is independently selected from the group consisting of hydrogen, C 1-8 alkyl, and alkoxyC 1-8 alkyl;

and wherein the moiety:

is selected from the group consisting of:

and the wavy line indicates the point of attachment to the rest of the molecule;

provided that when D 1 is 2,6-difluorobenzyl, then R 3 is not 2-(pyrrolidin-1-yl)ethanoxy.

2. The compound of claim 1 , wherein D 1 is selected from the group consisting of:

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

3. A compound of claim 1 selected from the group consisting of:

(S)-4-(benzylamino)-6-(4-(3-(methylcarbamoyl)piperidin-1-yl)phenylamino)nicotinamide; (R)-4-(benzylamino)-6-(4-(3-(methylcarbamoyl)piperidin-1-yl)phenylamino)nicotinamide; 4-(benzylamino)-6-(4-(dimethylcarbamoyl)phenylamino)-N,N-dimethylnicotinamide; 6-(4-(azetidine-1-carbonyl)phenylamino)-4-(benzylamino)nicotinamide; 6-(4-(azetidin-1-ylsulfonyl)phenylamino)-4-(benzylamino)nicotinamide; tert-butyl 4-(4-(5-carbamoyl-4-(3-fluorobenzylamino)pyridin-2-ylamino)phenyl)piperidine-1-carboxylate; 4-(4-(5-carbamoyl-4-(3-fluorobenzylamino)pyridin-2-ylamino)phenyl)-1,1-dimethylpiperidinium formate; 4-(2,5-difluorobenzylamino)-6-(4-(dimethylcarbamoyl)phenylamino)nicotinamide; 6-(4-(azetidine-1-carbonyl)phenylamino)-4-(2,5-difluorobenzylamino)nicotinamide; 4-(2,5-difluorobenzylamino)-6-(4-(N,N-dimethylsulfamoyl)phenylamino)nicotinamide; 4-(2,6-difluorobenzylamino)-6-(4-(dimethylcarbamoyl)phenylamino)nicotinamide; 4-(2,6-difluorobenzylamino)-6-(4-(N,N-dimethylsulfamoyl)phenylamino)nicotinamide; 6-(4-(azetidine-1-carbonyl)phenylamino)-4-(2,6-difluorobenzylamino)nicotinamide; 4-(2-fluorobenzylamino)-6-(4-(1-methylpiperidin-4-yl)phenylamino)nicotinamide; 4-(2-fluorobenzylamino)-6-(4-(1-isopropylpiperidin-4-yl)phenylamino)nicotinamide; 6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-4-(2-fluorobenzylamino)nicotinamide; 6-(4-(1-(ethylsulfonyl)piperidin-4-yl)phenylamino)-4-(2-fluorobenzylamino)nicotinamide; 6-(4-(1-(cyclopropylsulfonyl)piperidin-4-yl)phenylamino)-4-(2-fluorobenzylamino)nicotinamide; 6-(4-(1-(dimethylcarbamoyl)piperidin-4-yl)phenylamino)-4-(2-fluorobenzylamino)nicotinamide; 6-(4-(1-acetylpiperidin-4-yl)phenylamino)-4-(2-fluorobenzylamino)nicotinamide; 4-(2-fluorobenzylamino)-6-(4-(1-(2-methoxyacetyl)piperidin-4-yl)phenylamino)nicotinamide; 6-(4-(1-(2-cyanoacetyl)piperidin-4-yl)phenylamino)-4-(2-fluorobenzylamino)nicotinamide; 6-(4-(1-(1-cyanocyclopropanecarbonyl)piperidin-4-yl)phenylamino)-4-(2-fluorobenzylamino)nicotinamide; 4-(2-fluorobenzylamino)-6-(4-(1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-4-yl)phenylamino)nicotinamide.

4. A compound of claim 1 selected from the group consisting of: 4-(3-fluorobenzylamino)-6-(4-(1-propionylpiperidin-4-yl)phenylamino)nicotinamide; 4-(3,4-difluorobenzylamino)-6-(4-(1-propionylpiperidin-4-yl)phenylamino)nicotinamide; 4-(2,5-difluorobenzylamino)-6-(4-(1-propionylpiperidin-4-yl)phenylamino)nicotinamide; 4-(2 fluorobenzylamino)-6-(4-isopropylphenylamino)nicotinamide; 4-(3,5-difluorobenzylamino)-6-(4-(1-propionylpiperidin-4-yl)phenylamino)nicotinamide; 4-(2,3-difluorobenzylamino)-6-(4-(1-propionylpiperidin-4-yl)phenylamino)nicotinamide; 4-(benzylamino)-6-(4-(1-propionylpiperidin-4-yl)phenylamino)nicotinamide; (R)-4-(1-phenylethylamino)-6-(4-(1-propionylpiperidin-4-yl)phenylamino)nicotinamide; 4-(2,6-difluorobenzylamino)-6-(4-(1-propionylpiperidin-4-yl)phenylamino)nicotinamide; 6-(4-(azetidin-3-yl)phenylamino)-4-(2,3-difluorobenzylamino)nicotinamide; 6-(4-(azetidin-3-yl)phenylamino)-4-(2,5-difluorobenzylamino)nicotinamide; 6-(4-(1-(cyanomethyl)piperidin-4-yl)phenylamino)-4-(2,3-difluorobenzylamino)nicotinamide; 4-(2,3-difluorobenzylamino)-6-(4-(1-(2,2-difluoroethyl)piperidin-4-yl)phenylamino)nicotinamide; 4-(2,3-difluorobenzylamino)-6-(4-(1-(2-fluoroethyl)piperidin-4-yl)phenylamino)nicotinamide; 6-(4-(1-(cyanomethyl)piperidin-4-yl)phenylamino)-4-(2,5-difluorobenzylamino)nicotinamide; 6-(4-(1-(cyanomethyl)azetidin-3-yl)phenylamino)-4-(2,3-difluorobenzylamino)nicotinamide; 6-(4-(1-(cyanomethyl)azetidin-3-yl)phenylamino)-4-(2,5-difluorobenzylamino)nicotinamide; 4-(3-(1H-imidazol-1-yl)benzylamino)-6-(4-(dimethylcarbamoyl)phenylamino)nicotinamide; 4-(benzylamino)-6-(4-(dimethylcarbamoyl)phenylamino)nicotinamide; (S)-6-(4-(dimethylcarbamoyl)phenylamino)-4-(2-methoxy-1-phenylethylamino)nicotinamide; (S)-6-(4-(azetidine-1-carbonyl)phenylamino)-4-(2-methoxy-1-phenylethylamino)nicotinamide; 6-(4-(1H-imidazol-4-yl)phenylamino)-4-(benzylamino)nicotinamide; 6-(4-(1H-pyrazol-1-yl)phenylamino)-4-(benzylamino)nicotinamide; 6-(4-(1,2,4-triazol-3-yl)phenylamino)-4-(benzylamino)nicotinamide; 6-(4-(1 acetylazetidin-3-yl)phenylamino)-4-(benzylamino)nicotinamide; 6-(4-(azetidin-3-yl)phenylamino)-4-(benzylamino)nicotinamide; 4-(benzylamino)-6-(4-(1-propionylazetidin-3-yl)phenylamino)nicotinamide; methyl 3-(4-(4-(benzylamino)-5-carbamoylpyridin-2-ylamino)phenyl)azetidine-1-carboxylate; 4-(benzylamino)-6-(4-(1-(methylsulfonyl)azetidin-3-yl)phenylamino)nicotinamide; 4-(benzylamino)-6-(4-(1-(2-methoxyacetyl)azetidin-3-yl)phenylamino)nicotinamide; 4-(benzylamino)-6-(4-(1-(dimethylcarbamoyl)azetidin-3-yl)phenylamino)nicotinamide; 4-(benzylamino)-6-(4-(1-(pyrrolidine-1-carbonyl)azetidin-3-yl)phenylamino)nicotinamide; 4-(benzylamino)-6-(4-(1-(N,N-dimethylsulfamoyl)azetidin-3-yl)phenylamino)nicotinamide; 4-(benzylamino)-6-(4-(2-(methylamino)-2-oxoethyl)phenylamino)nicotinamide; 4-(benzylamino)-6-(4-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)phenylamino)nicotinamide; 4-(benzylamino)-6-(4-(3-(dimethylcarbamoyl)azetidin-1-yl)-3-fluorophenylamino)nicotinamide; 4-(benzylamino)-6-(4-(4-(dimethylcarbamoyl)piperidin-1-yl)phenylamino)nicotinamide; 4-(benzylamino)-6-(4-(methylsulfonylmethyl)phenylamino)nicotinamide; 6-(4-(dimethylcarbamoyl)phenylamino)-4-(3-(pyridine-4-yl)benzylamino)nicotinamide; 6-(4-(dimethylcarbamoyl)phenylamino)-4-(3-(pyridine-3-yl)benzylamino)nicotinamide; 6-(4-(1-propionylpiperidin-4-yl)phenylamino)-4-(3-(pyridine-3-yl)benzylamino)nicotinamide; 6-(4-((N,N-dimethylsulfamoyl)methyl)phenylamino)-4-(3-(pyridine-4-yl)benzylamino)nicotinamide 6-(4-(methylsulfonylmethyl)phenylamino)-4-(3-(pyridine-4-yl)benzylamino)nicotinamide; 6-(4-(4-(dimethylcarbamoyl)piperidin-1-yl)phenylamino)-4-(3-(pyridine-4-yl)benzylamino)nicotinamide; 6-(4-(1-propionylpiperidin-4-yl)phenylamino)-4-(3-(pyridine-4-yl)benzylamino)nicotinamide; 6-(4-(dimethylcarbamoyl)phenylamino)-4-(3-(pyridine-2-yl)benzylamino)nicotinamide; 4-(3-(1H-pyrazol-1-yl)benzylamino)-6-(4-(dimethylcarbamoyl)phenylamino)nicotinamide; 6-(4-(dimethylcarbamoyl)phenylamino)-4-(3-(pyrimidine-5-yl)benzylamino)nicotinamide; 6-(4-(1-propionylpiperazin-4-yl)phenylamino)-4-(3-(pyridine-4-yl)benzylamino)nicotinamide; 6-(4-(dimethylcarbamoyl)phenylamino)-4-(3-(thiazol-4-yl)benzylamino)nicotinamide; 6-(4-(dimethylcarbamoyl)phenylamino)-4-(3-(pyrazin-2-yl)benzylamino)nicotinamide; 4-(benzylamino)-6-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)nicotinamide; 4-(2,3-difluorobenzylamino)-6-(4-(4-propionylpiperazin-1-yl)phenylamino)nicotinamide; 4-(2,3-difluorobenzylamino)-6-(4-(1-(1,3-difluoropropan-2-yl)piperidin-4-yl)phenylamino)nicotinamide; 4-(2,3-difluorobenzylamino)-6-(4-(1-(2-(dimethylamino)acetyl)piperidin-4-yl)phenylamino)nicotinamide; (R)-4-(2,3-difluorobenzylamino)-6-(4-(1-(1-methylpyrrolidine-2-carbonyl)piperidin-4-yl)phenylamino)nicotinamide; (S)-4-(2,3-difluorobenzylamino)-6-(4-(1-(1-methylpyrrolidine-2-carbonyl)piperidin-4-yl)phenylamino)nicotinamide; (R)-6-(4-(1-(1-acetylpyrrolidine-2-carbonyl)piperidin-4-yl)phenylamino)-4-(2,3-difluorobenzylamino)nicotinamide; (S)-6-(4-(1-(1-acetylpyrrolidine-2-carbonyl)piperidin-4-yl)phenylamino)-4-(2,3-difluorobenzylamino)nicotinamide; 4-(2,5-difluorobenzylamino)-6-(4-(1-formylpiperidin-4-yl)phenylamino)nicotinamide; 4-(2,3-difluorobenzylamino)-6-(4-(1-formylazetidin-3-yl)phenylamino)nicotinamide; 4-(2,5-difluorobenzylamino)-6-(4-(1-formylazetidin-3-yl)phenylamino)nicotinamide; 4-(2,3-difluorobenzylamino)-6-(4-(1-(2-fluoroethyl)azetidin-3-yl)phenylamino)nicotinamide; 4-(2,3-difluorobenzylamino)-6-(4-(1-(pyridin-2-yl)piperidin-4-yl)phenylamino)nicotinamide; and 4-(2,3)-difluorobenzylamino)-6-(4-(1-pyridin-2-yl)azetidin-3-yl)phenylamino)nicotinamide.

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

6. A kit comprising a composition of claim 5 , packaging and instructions for use.

7. The compound of claim 1 , wherein the moiety:

is selected from the group consisting of:

8. A compound of claim 1 selected from the group consisting of:

4-(benzylamino)-6-((4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)amino)nicotinamide; 4-((2-fluorobenzyl)amino)-6-((4-(1-propionylpiperidin-4-yl)phenyl)amino)nicotinamide; 4-((2,3-difluorobenzyl)amino)-6-((4-(4-propionylpiperazin-1-yl)phenyl)amino)nicotinamide; 4-(benzylamino)-6-((4-(4-(pyridin-2-yl)piperazin-1-yl)phenyl)amino)nicotinamide; 6-((4-(1H-imidazol-4-yl)phenyl)amino)-4-(benzylamino)nicotinamide; 4-((3,5-difluorobenzyl)amino)-6-((4-(1-propionylpiperidin-4-yl)phenyl)amino)nicotinamide; 4-(benzylamino)-6-((4-(1-propionylazetidin-3-yl)phenyl)amino)nicotinamide; 4-((2,3-difluorobenzyl)amino)-6-((4-(1-(2,2-difluoroethyl)piperidin-4-yl)phenyl)amino)nicotinamide; and 4-((2,3-difluorobenzyl)amino)-6-((4-(1-(2-fluoroethyl)piperidin-4-yl)phenyl)amino)nicotinamide.

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

10. A method for treating a condition or disorder mediated at least in part by JAK kinase activity in a subject comprising the step of administering to a subject in need of such treatment a therapeutically effective amount of a composition of claim 5 .