Nicotinamides as jak kinase modulators

Abstract

The present invention is directed to compounds of formula I and pharmaceutically acceptable salts, esters, and prodrugs thereof which are inhibitors of JAK kinase. The present invention is also directed to intermediates used in making such compounds, the preparation of such a compound, pharmaceutical compositions containing such a compound, methods of inhibition JAK kinase activity, methods of inhibition the platelet aggregation, and methods to prevent or treat a number of conditions mediated at least in part by JAK kinase activity, such as undesired thrombosis and Non Hodgkin's Lymphoma.

1 . A compound having the formula: 
       
         
           
           
               
               
           
         
       
       or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof, wherein:
 each Q 1  and Q 2  are selected from the group consisting of CX 1  or N; wherein one of Q 1  or Q 2  is N and one is CX 1 ; 
 each X 1  or X 2  is independently H or halogen; 
 D 1  is selected from the group consisting of:
 (a) C 1-8 alkyl, C 1-8 alkenyl, or C 1-8 alkynyl; 
 (b) -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; 
 (c) -L 1 -C 3-8 cycloalkyl, wherein the C 3-8 cycloalkyl 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; 
 (d) -L 1 -heteroaryl; wherein the heteroaryl 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; and 
 (e) -L 1 -heterocyclyl; wherein the heterocyclyl 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; 
 each R 2 , R 3 , and R 4  is independently selected from the group consisting of: 
 C 1-8 alkyl, cyano, halo, haloC 1-8 alkyl, cyanoC 1-8 alkyl, C 1-8 dialkylaminocarbonyl, C 1-8 alkylaminocarbonyl, C 1-8 alkylaminocarbonyl C 1-8 alkyl, haloC 1-8 alkylaminocarbonyl, haloC 1-8 alkylaminocarbonyl C 1-8 alkyl, haloC 1-8 alkyl(C 1-8 alkyl)aminocarbonyl, diC 1-8 alkylamino, C 1-8 alkoxy, hydroxyC 1-8 alkyl(C 1-8 alkyl)aminocarbonyl, C 1-8 alkoxyC 1-8 alkyl(C 1-8 alkyl)aminocarbonyl, C 1-8 dialkylaminocarbonylaminoC 1-8 alkyl, C 1-8 alkylcarbonylaminoC 1-8 alkyl, C 1-8 alkylsulfonylaminoC 1-8 alkyl, C 1-8 dialkylaminosulfonylaminoC 1-8 alkyl, C 1-8 dialkylaminosulfonylC 1-8 alkyl, C 1-8 alkylsulfonylC 1-8 alkyl, haloC 1-8 alkyl, C 1-8 alkylcarbonylamino, C 1-8 alkylsulfonylamino, C 1-8 dialkylaminosulfonyl(C 1-8 alkyl)amino, C 1-8 dialkylaminosulfonylamino, C 1-8 alkylcarbonyl(C 1-8 alkyl)amino, C 1-8 alkoxycarbonyl(C 1-8 alkyl)amino, C 1-8 alkoxyC 1-8 alkoxy, cyanoC 1-8 alkylC 1-8 alkoxy, C 1-8 dialkylaminocarbonylC 1-8 alkoxy, haloC 1-8 alkoxy, C 1-8 dialkylaminosulfonyl, C 1-8 alkylsulfonyl, heteroaryl, heterocycylcarbonyl, C 3-8 cycloalkylcarbonyl(C 1-8 alkyl)amino, C 3-8 cycloalkylcarbonylamino, heterocyclylsulfonyl, heterocyclylC 1-8 alkoxy, heterocyclylcarbonylamino, heterocyclylcarbonylC 1-8 alkoxy, heterocyclylalkyl, heterocyclyl; 
 or are combined to form a heteroaryl moiety is selected from the group consisting of: 
 
 
       
         
           
           
               
               
           
         
         
           optionally substituted with from 1 to 3 R 7  substituents independently selected from the group consisting of: C 1-8  alkyl and oxo; and the wavy line indicates the point of attachment to the rest of the molecule; 
           wherein heterocyclyl is optionally subustituted with 1 to 3 substituents, R 5 , independently selected from the group consisting of C 1-8 alkyl, halo, cyanoC 1-8 alkyl, haloC 1-8 alkyl, C 1-8 dialkylaminocarbonyl, C 1-8 alkylsulfonyl, C 1-8 alkoxycarbonyl, C 1-8 alkylcarbonyl, C 1-8 alkoxyC 1-8 alkylcarbonyl, formyl, heterocyclylcarbonyl, C 1-8 alkylheterocycylcarbonyl, C 1-8 alkylcarbonylheterocyclylcarbonyl, C 1-8 dialkylaminosulfonyl, heteraryl, oxo, cyanoC 1-8 alkylcarbonyl, cyanoC 3-8 cycloalkylcarbonyl, C 3-8 cycloalkylsulfonyl, C 3-8 cycloalkyl, C 1-8 dialkylaminoC 1-8 alkylcarbonyl, C 1-8 alkoxyC 1-8 alkyl, hydroxy, C 1-8 alkylsulfonyl, C 1-8 heteroalkyl, heterocyclylC 1-8 alkoxy, or heterocyclyl; and 
         
         R 6  is H or acyl. 
       
     
     
         2 . The compound of  claim 1  having formula: 
       
         
           
           
               
               
           
         
         or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof. 
       
     
     
         3 . The compound of  claim 1  having formula: 
       
         
           
           
               
               
           
         
         or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof. 
       
     
     
         4 . The compound of  claim 1  having formula: 
       
         
           
           
               
               
           
         
         or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof. 
       
     
     
         5 . The compound of  claim 1  having formula: 
       
         
           
           
               
               
           
         
         or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof. 
       
     
     
         6 . The compound of  claim 1 , wherein X 1  is H. 
     
     
         7 . The compound of  claim 1 , wherein X 1  is halogen. 
     
     
         8 . The compound of  claim 1 , wherein X 1  is F. 
     
     
         9 . The compound of  claim 1 , wherein D 1  is C 1-8 alkyl. 
     
     
         10 . The compound of  claim 1 , wherein D 1  is -L 1 -phenyl. 
     
     
         11 . The compound of  claim 1 , wherein D 1  is -L 1 -C 3-8 cycloalkyl. 
     
     
         12 . The compound of  claim 11  wherein D 1  is selected from the group consisting of cyclopentyl, cyclobutyl and cyclopropyl. 
     
     
         13 . The compound of  claim 1 , wherein D 1  is -L 1 -heteroaryl. 
     
     
         14 . The compound of  claim 13  wherein heteroaryl is selected from the group consisting of triazoyl, thiophenyl, thiazoyl, pyrazoyl, imidazoyl, pyridinyl, pyrimidyl, benzothiophenyl, indolyl, benzimidazoyl and benzodioxoyl. 
     
     
         15 . The compound  claim 1 , wherein D 1  is -L 1 -heterocyclyl. 
     
     
         16 . The compound of  claim 15  wherein heterocyclyl is selected from the group consisting of tetrahydropyranyl and piperidinyl. 
     
     
         17 . The compound of  claim 1 , wherein L 1  is a bond. 
     
     
         18 . The compound of  claim 1 , wherein L 1  is —C(R) 2 —. 
     
     
         19 . The compound of  claim 18 , wherein R is H. 
     
     
         20 . The compound of  claim 1 , 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. 
       
     
     
         21 . 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. 
       
     
     
         22 . 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. 
       
     
     
         23 . 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. 
       
     
     
         24 . 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. 
       
     
     
         25 . 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. 
       
     
     
         26 . The compound of  claim 1  wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
       or a tautomer or pharmaceutically acceptable salt thereof. 
     
     
         27 . The compound of  claim 1  wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
       or a tautomer or pharmaceutically acceptable salt thereof. 
     
     
         28 . The compound of  claim 1  wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
       or a tautomer or pharmaceutically acceptable salt thereof. 
     
     
         29 . A compound selected from the group consisting of: 6-(4-(4-acetylpiperazin-1-yl)phenylamino)-2-(cyclobutylamino)nicotinamide; 6-(4-(4-acetylpiperazin-1-yl)phenyl amino)-4-(benzylamino)nicotinamide; (S)-4-(benzylamino)-6-(4-(3-(methylcarbamoyl)piperidin-1-yl)phenylamino)nicotinamide; 6-(4-(4-acetylpiperazin-1-yl)-3-methylphenylamino)-4-(benzylamino)nicotinamide; and (R)-4-(benzylamino)-6-(4-(3-(methylcarbamoyl)piperidin-1-yl)phenylamino)nicotinamide; (-(benzylamino)-6-(3-morpholinophenylamino)nicotinamide; 6-(4-fluoro-3-(pyrrolidine-1-carboxamido)phenylamino)-4-(pyridin-3-ylmethylamino)nicotinamide; (-(4-(4-acetylpiperazin-1-yl)phenylamino)-4-(phenethylamino)nicotinamide; 4-(benzylamino)-6-(4-(dimethylcarbamoyl)phenylamino)-N,N-dimethylnicotinamide; 4-(cyclopentylmethylamino)-6-(4-methoxyphenylamino)nicotinamide; 6-(4-methoxyphenylamino)-4-(p-tolylamino)nicotinamide; 4,6-bis(4-methoxyphenylamino)nicotinamide; 4-((1-acetylpiperidin-4-yl)methylamino)-6-(4-methoxyphenylamino)nicotinamide; (S)-4-(1-acetylpiperidin-3-ylamino)-6-(4-methoxyphenylamino)nicotinamide; (R)-4-(1-acetylpiperidin-3-ylamino)-6-(4-methoxyphenylamino)nicotinamide; (S)-4-((1-acetylpiperidin-3-yl)methylamino)-6-(4-methoxyphenylamino)nicotinamide; 4-(benzylamino)-6-(4-(pyrrolidine-1-carbonyl)phenylamino)nicotinamide; 4-(benzylamino)-6-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide; 4-(cyclopentylmethylamino)-6-(4-(pyrrolidine-1-carbonyl)phenylamino)nicotinamide; 4-(cyclopentylmethylamino)-6-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide; 4-((1-acetylpiperidin-4-yl)methylamino)-6-(4-(pyrrolidine-1-carbonyl)phenylamino)nicotinamide; 4-((1-acetylpiperidin-4-yl)methylamino)-6-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide; 6-(3-(azetidine-1-carbonyl)phenylamino)-4-(benzylamino)nicotinamide; 6-(4-(azetidine-1-carbonyl)phenylamino)-4-(benzylamino)nicotinamide; 6-(4-(azetidin-1-ylsulfonyl)phenylamino)-4-(benzylamino)nicotinamide; 6-(4-(azetidine-1-carbonyl)phenylamino)-4-(cyclopentylmethylamino)nicotinamide; 6-(4-(azetidin-1-ylsulfonyl)phenylamino)-4-(cyclopentylmethylamino)nicotinamide; 4-((1-acetylpiperidin-4-yl)methylamino)-6-(4-(azetidine-1-carbonyl)phenylamino)nicotinamide; (S)-4-((1-(2-methoxyacetyl)piperidin-3-yl)methylamino)-6-(4-methoxyphenylamino)nicotinamide; (S)-methyl 3-((5-carbamoyl-2-(4-methoxyphenylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate; (S)-4-((1-(dimethylcarbamoyl)piperidin-3-yl)methylamino)-6-(4-methoxyphenylamino)nicotinamide; (R)-4-((1-acetylpiperidin-3-yl)methylamino)-6-(4-methoxyphenylamino)nicotinamide; (R)-4-((1-(2-methoxyacetyl)piperidin-3-yl)methylamino)-6-(4-methoxyphenylamino)nicotinamide; (R)-methyl 3-((5-carbamoyl-2-(4-methoxyphenylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate; (R)-6-(4-methoxyphenylamino)-4-((1-(methylsulfonyl)piperidin-3-yl)methylamino)nicotinamide; 4-(3-fluorobenzylamino)-6-(3-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)nicotinamide; (S)-4-(2-hydroxy-1-phenylethylamino)-6-(3-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)nicotinamide; 4-(pyridin-3-ylmethylamino)-6-(3-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)nicotinamide; 4-(3-fluorobenzylamino)-6-(3-methyl-4-(2-oxopyrrolidin-1-yl)phenylamino)nicotinamide; 6-(3-chloro-4-(2-oxopyrrolidin-1-yl)phenylamino)-4-(3-fluorobenzylamino)nicotinamide; 4-(3-fluorobenzylamino)-6-(4-(2-oxopiperidin-1-yl)phenylamino)nicotinamide; 4-(3-fluorobenzylamino)-6-(3-morpholinophenylamino)nicotinamide; (6) 4-(3-fluorobenzylamino)-6-(3-morpholinophenylamino)nicotinamide; 4-(3-fluorobenzylamino)-6-(4-morpholinophenylamino)nicotinamide; 4-(3-fluorobenzylamino)-6-(3-(piperidin-1-yl)phenylamino)nicotinamide; 4-(3-fluorobenzylamino)-6-(3-(piperidin-1-yl)phenylamino)nicotinamide; 4-(3-fluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide; 4-(2-fluorobenzylamino)-6-(4-(2-oxopiperidin-1-yl)phenylamino)nicotinamide; 4-(2-fluorobenzylamino)-6-(3-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)nicotinamide; 4-(2-fluorobenzylamino)-6-(4-morpholinophenylamino)nicotinamide; 4-(2-fluorobenzylamino)-6-(4-(piperidin-1-yl)phenylamino)nicotinamide; (S)-4-(2-hydroxy-1-phenylethylamino)-6-(4-(piperidin-1-yl)phenylamino)nicotinamide; (S)-4-(2-hydroxy-1-phenylethylamino)-6-(3-(piperidin-1-yl)phenylamino)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; (-(2-fluorobenzylamino)-6-(4-(1-propionylpiperidin-4-yl)phenylamino)nicotinamide; 4-(benzylamino)-6-(4-(2-morpholino-2-oxoethoxy)phenylamino)nicotinamide; 4-(benzylamino)-6-(4-(2-(piperidin-1-yl)ethoxy)phenylamino)nicotinamide; 4-(2,6-difluorobenzylamino)-6-(4-methoxyphenylamino)nicotinamide; 4-(2,5-difluorobenzylamino)-6-(4-methoxyphenylamino)nicotinamide; 4-(benzylamino)-6-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylamino)nicotinamide; 4-(benzylamino)-6-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylamino)nicotinamide; 4-(benzylamino)-6-(quinolin-6-ylamino)nicotinamide; 4-(benzylamino)-6-(quinolin-7-ylamino)nicotinamid; 4-(benzylamino)-6-(isoquinolin-6-ylamino)nicotinamide; 4-(benzylamino)-6-(isoquinolin-7-ylamino)nicotinamide; 6-(benzo[d]thiazol-6-ylamino)-4-(benzylamino)nicotinamid; 4-(3-fluorobenzylamino)-6-(4-methoxyphenylamino)nicotinamide; 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-(2-oxopiperidin-1-yl)phenylamino)nicotinamide; 4-(cyclopentylmethylamino)-6-(3-(dimethylcarbamoyl)phenylamino)nicotinamid; 4-(cyclopentylmethylamino)-6-(4-(dimethylcarbamoyl)phenylamino)nicotinamide; 4-(cyclopentylmethylamino)-6-(4-(N,N-dimethylsulfamoyl)phenylamino)nicotinamide; 4-(2,5-difluorobenzylamino)-6-(4-(N,N-dimethylsulfamoyl)phenylamino)nicotinamide; 6-(3-(azetidine-1-carbonyl)phenylamino)-4-(2,5-difluorobenzylamino)nicotinamide; 2-(4-(azetidin-1-ylsulfonyl)phenylamino)-4-(benzylamino)pyrimidine-5-carboxamide; 4-(2,3-difluorobenzylamino)-6-(4-methoxyphenylamino)nicotinamide; 4-(2,6-difluorobenzylamino)-6-(4-(dimethylcarbamoyl)phenylamino)nicotinamide; 4-(2,6-difluorobenzylamino)-6-(4-(2-oxopiperidin-1-yl)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-(piperidin-4-yl)phenylamino)nicotinamid; 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-(3-(1-cyclopentylpiperidin-4-yl)phenylamino)-4-(2-fluorobenzylamino)nicotinamide; 4-(2-fluorobenzylamino)-6-(4-(1-(methylsulfonyl)piperidin-4-yl)phenylamino)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-(2-fluorobenzylamino)-6-(3-(piperidin-4-yl)phenylamino)nicotinamide; Preparation of 4-(2-fluorobenzylamino)-6-(3-(1-(methylsulfonyl)piperidin-4-yl)phenylamino)nicotinamide; 6-(4-(4-acetylpiperazin-1-yl)phenylamino)-4-(thiophen-2-ylmethylamino)nicotinamide; 6-(4-(4-acetylpiperazin-1-yl)phenylamino)-4-((1s,4s)-4-hydroxycyclohexylamino)nicotinamide; 4-(1-phenylcyclopropylamino)-6-(4-(4-propionylpiperazin-1-yl)phenylamino)nicotinamide; 6-(4-morpholinophenylamino)-4-(1-phenylcyclopropylamino)-nicotinamide; 6-(4-(4-acetylpiperazin-1-yl)phenylamino)-4-(1-phenylcyclopropylamino)nicotinamide; 6-(4-(morpholinomethyl)phenylamino)-4-(1-phenylcyclopropylamino)nicotinamide; 6-(3-morpholinophenylamino)-4-(1-phenylcyclopropylamino)-nicotinamide; 6-(3-(morpholinomethyl)phenylamino)-4-(1-phenylcyclopropylamino)nicotinamide; 6-(4-(4-acetylpiperazin-1-yl)phenylamino)-4-(1-(2-fluorophenyl)cyclopropylamino)nicotinamide; 6-(4-(4,4-difluoropiperidin-1-yl)phenylamino)-4-(1-phenylcyclopropylamino)nicotinamide; 4-(1-phenylcyclopropylamino)-6-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)nicotinamide; 6-(4-(2-morpholino-2-oxoethoxy)phenylamino)-4-(1-phenylcyclopropylamino)nicotinamide; 6-(3-(2-morpholino-2-oxoethoxy)phenylamino)-4-(1-phenylcyclopropylamino)nicotinamide; 6-(3-acetamidophenylamino)-4-(1-phenylcyclopropylamino)nicotinamide; and 6-(4-chloro-3-(1-methylpiperidine-4-carboxamido)phenylamino)-4-(1-phenylcyclopropylamino)nicotinamide. 
     
     
         30 . A compound selected from the group consisting of: 6-(4-chloro-3-(1-methylpiperidine-4-carboxamido)phenylamino)-4-(1-phenylcyclopropylamino)nicotinamide; 6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)-4-(tetrahydro-2H-pyran-4-ylamino)nicotinamide; 4-((tetrahydro-2H-pyran-4-yl)methylamino)-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide; 4-((1-hydroxycyclopentyl)methylamino)-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide; 4-(2-fluorobenzylamino)-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide; 4-(3-fluorobenzylamino)-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide; 6-(4-(1-propionylpiperidin-4-yl)phenylamino)-4-((tetrahydro-2H-pyran-4-yl)methylamino)nicotinamide; 4-(3-fluorobenzylamino)-6-(4-(1-propionylpiperidin-4-yl)phenylamino)nicotinamide; 6-(4-(1-propionylpiperidin-4-yl)phenylamino)-4-(tetrahydro-2H-pyran-4-ylamino)nicotinamide; 4-(cyclopentylamino)-6-(4-(1-propionylpiperidin-4-yl)phenylamino)nicotinamide; difluorobenzylamino)-6-(4-(1-propionylpiperidin-4-yl)phenylamino)nicotinamide; difluorobenzylamino)-6-(4-(1-propionylpiperidin-4-yl)phenylamino)nicotinamide; 4-(cyclopentylamino)-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide; 6-(3-(tetrahydro-2H-pyran-4-yl)phenylamino)-4-(tetrahydro-2H-pyran-4-ylamino)nicotinamide; 4-(2-fluorobenzylamino)-6-(3-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide; 4-(cyclopropylmethylamino)-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide; 4-(cyclopentylmethylamino)-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide; 4-(neopentylamino)-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide; 4-(isobutylamino)-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide; 4-(cyclohexylamino)-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide; 4-(2-fluorobenzylamino)-6-(4-isopropylphenylamino)nicotinamide; 4-((1-(methylsulfonyl)piperidin-4-yl)methylamino)-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide; 4-((1-(ethylsulfonyl)piperidin-4-yl)methylamino)-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide; 4-((1-(ethylsulfonyl)piperidin-4-yl)methylamino)-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide; 4-(2-fluorobenzylamino)-6-(3-isopropylphenylamino)nicotinamide; 4-(1-(dimethylcarbamoyl)piperidin-4-ylamino)-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide; 4-(1-propionylpiperidin-4-ylamino)-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide; 4-(1-(methylsulfonyl)piperidin-4-ylamino)-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide; 4-(1-(ethylsulfonyl)piperidin-4-ylamino)-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide; (S)-4-(3,3-dimethylbutan-2-ylamino)-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide; (R)-4-(3,3-dimethylbutan-2-ylamino)-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide; 4-(pyrrolidin-1-yl)-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide; 4-(3-(dimethylamino)-2,2-dimethylpropylamino)-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide; 6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)-4-(thiazol-2-ylmethylamino)nicotinamide; 4-((1-methyl-1H-pyrazol-4-yl)methylamino)-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide; 4-(pyridin-2-ylmethylamino)-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide; 4-(pyrimidin-2-ylmethylamino)-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide; 4-(cyclopentylmethylamino)-6-(4-(1-propionylpiperidin-4-yl)phenylamino)nicotinamide; 6-(4-(1-propionylpiperidin-4-yl)phenylamino)-4-(thiazol-2-ylmethylamino)nicotinamide; 4-((1-methyl-1H-pyrazol-4-yl)methylamino)-6-(4-(1-propionylpiperidin-4-yl)phenylamino)nicotinamide; 6-(4-(1-propionylpiperidin-4-yl)phenylamino)-4-(pyridin-2-ylmethylamino)nicotinamide; 6-(4-(1-propionylpiperidin-4-yl)phenylamino)-4-(pyrimidin-2-ylmethylamino)nicotinamide; 4-(pyrimidin-4-ylmethylamino)-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide; 4-((1-methyl-1H-benzo[d]imidazol-2-yOmethylamino)-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide; 4-((1-methyl-1H-imidazol-2-yOmethylamino)-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide; 4-(prop-2-ynylamino)-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide; 4-(pyridin-3-ylmethylamino)-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide; (S)-4-(3-methylbutan-2-ylamino)-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide; 6-(4-(1-propionylpiperidin-4-yl)phenylamino)-4-(pyridin-3-ylmethylamino)nicotinamide; 4-((5-fluoropyridin-3-yl)methylamino)-6-(4-(1-propionylpiperidin-4-yl)phenylamino)nicotinamide; (R)-4-(3-methylbutan-2-ylamino)-6-(4-(1-propionylpiperidin-4-yl)phenylamino)nicotinamide; (R)-4-(3,3-dimethylbutan-2-ylamino)-6-(4-(1-propionylpiperidin-4-yl)phenylamino)nicotinamide; (R)-4-(1-cyclohexylethylamino)-6-(4-(1-propionylpiperidin-4-yl)phenylamino)nicotinamide; 4-(cyclohexylmethylamino)-6-(4-(1-propionylpiperidin-4-yl)phenylamino)nicotinamide; 4-((1-hydroxycyclopentyl)methylamino)-6-(4-(1-propionylpiperidin-4-yl)phenylamino)nicotinamide; 44(1-phenylcyclopropyl)methylamino)-6-(4-(1-propionylpiperidin-4-yl)phenylamino)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; 6-(4-(1-propionylpiperidin-4-yl)phenylamino)-4-(thiophen-2-ylmethylamino)nicotinamide; 4-(benzylamino)-6-(4-(1-propionylpiperidin-4-yl)phenylamino)nicotinamide; (R)-4-(1-phenylethylamino)-6-(4-(1-propionylpiperidin-4-yl)phenylamino)nicotinamide; 4-((1H-indol-4-yl)methylamino)-6-(4-(1-propionylpiperidin-4-yl)phenylamino)nicotinamide; 4-((1-(2-(piperidin-1-yl(ethyl)-1H-1,2,3-triazol-4-yl)methylamino)-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide; (R)-4-(1-cyclopropylethylamino)-6-(4-(1-propionylpiperidin-4-yl)phenylamino)nicotinamide; 4-(2,6-difluorobenzylamino)-6-(4-(1-propionylpiperidin-4-yl)phenylamino)nicotinamide; 4-(3-fluorobenzylamino)-6-(3-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide; 4-(2,3-difluorobenzylamino)-6-(3-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide; 4-(3,5-difluorobenzylamino)-6-(3-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide; 4-(2,5-difluorobenzylamino)-6-(3-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide; 4-((5-fluoropyridin-3-yl)methylamino)-6-(3-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide; 4-(2,3-difluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide; 4-((1H-indazol-4-yl)methylamino)-6-(4-(1-propionylpiperidin-4-yl)phenylamino)nicotinamide; 4-(benzo[b]thiophen-7-ylmethylamino)-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; 4-(2,5-difluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)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-((1H-indol-4-yl)methylamino)-6-(4-(1-(cyanomethyl)piperidin-4-yl)phenylamino)nicotinamide; 6-(3-acetamidophenylamino)-4-(thiophen-2-ylmethylamino)nicotinamide; 4-(3-(1H-imidazol-1-yl)benzylamino)-6-(4-(dimethylcarbamoyl)phenylamino)nicotinamide; 6-(4-(4-acetylpiperazin-1-yl)phenylamino)-4-(isopropylamino)nicotinamide; 6-(4-(4-acetylpiperazin-1-yl)phenylamino)-4-(isobutylamino)nicotinamide; 6-(4-(4-acetylpiperazin-1-yl)phenylamino)-4-(cyclopropylmethylamino)nicotinamide; 6-(4-(4-acetylpiperazin-1-yl)phenylamino)-4-(cyclopentylamino)nicotinamide; 6-(6-(4-acetylpiperazin-1-yl)pyridin-3-ylamino)-4-(isobutylamino)nicotinamide; 6-(4-(4-acetylpiperazin-1-yl)phenylamino)-4-(cyclobutylmethylamino)nicotinamide; 6-(4-(4-acetylpiperazin-1-yl)phenylamino)-4-(cyclopentylmethylamino)nicotinamide; 4-(benzylamino)-6-(3-(methylcarbamoyl)phenylamino)nicotinamide; 4-(benzylamino)-6-(3-(dimethylcarbamoyl)phenylamino)nicotinamide; 4-(benzylamino)-6-(4-(dimethylcarbamoyl)phenylamino)nicotinamide; 4-(benzylamino)-6-(3-(piperidine-1-carbonyl)phenylamino)nicotinamide; 4-(benzylamino)-6-(4-morpholinophenylamino)nicotinamide; 4-(benzylamino)-6-(3-chloro-4-morpholinophenylamino)nicotinamide; 6-(4-(4-acetylpiperazin-1-yl)phenylamino)-4-(4-fluorobenzylamino)nicotinamide; 6-(4-(4-acetylpiperazin-1-yl)phenylamino)-4-(2,3-dihydro-1H-inden-2-ylamino)nicotinamide; 6-(4-(4-acetylpiperazin-1-yl)phenylamino)-4-(benzo[d][1,3]dioxol-5-ylmethylamino)nicotinamide; (S)-6-(4-(4-acetylpiperazin-1-yl)phenylamino)-4-(2,3-dihydro-1H-inden-1-ylamino)nicotinamide; 6-(4-(4-acetylpiperazin-1-yl)phenylamino)-4-(2,3-difluorobenzylamino)nicotinamide; 6-(4-(4-acetylpiperazin-1-yl)phenylamino)-4-(3-chlorobenzylamino)nicotinamide; 6-(4-(4-acetylpiperazin-1-yl)phenylamino)-4-(2-fluorobenzylamino)nicotinamide; 6-(4-(4-acetylpiperazin-1-yl)phenylamino)-4-(2,4-difluorobenzylamino)nicotinamide; (S)-4-(2-methoxy-1-phenylethylamino)-6-(4-methoxyphenylamino)nicotinamide; (S)-4-(2-methoxy-1-phenylethylamino)-6-(3-morpholinophenylamino)nicotinamide; (S)-4-(2-methoxy-1-phenylethylamino)-6-(4-morpholinophenylamino)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; (R)-4-((1-acetylpiperidin-3-yl)methylamino)-6-(4-(pyrrolidine-1-carbonyl)phenylamino)nicotinamide; (R)-6-(4-(dimethylcarbamoyl)phenylamino)-4-((1-(2-methoxyacetyl)piperidin-3-yl)methylamino)nicotinamide; (R)-4-((1-(2-methoxyacetyl)piperidin-3-yl)methylamino)-6-(4-(pyrrolidine-1-carbonyl)phenylamino)nicotinamide; 4-(benzylamino)-6-(4-((N,N-dimethylsulfamoyl)(methyl)amino)phenylamino)nicotinamide; (R)-4-((1-acetylpiperidin-3-yl)methylamino)-6-(4-(N,N-dimethylsulfamoylamino)phenylamino)nicotinamide; (S)-6-(4-methoxyphenylamino)-4-(piperidin-3-ylmethylamino)nicotinamide; (R)-6-(4-methoxyphenylamino)-4-((1-propionylpiperidin-3-yl)methylamino)nicotinamide; 4-(benzylamino)-6-(4-(dimethylcarbamoyl)-3-(trifluoromethyl)phenylamino)nicotinamide; 4-(benzylamino)-6-(4-(dimethylcarbamoyl)-3-fluorophenylamino)nicotinamide; (R)-4-((1-acetylpiperidin-3-yl)methylamino)-6-(4-(dimethylcarbamoyl)-3-(trifluoromethyl)phenylamino)nicotinamide; (R)-4-((1-acetylpiperidin-3-yl)methylamino)-6-(4-(dimethylcarbamoyl)-3-fluorophenylamino)nicotinamide; 6-(4-(1H-imidazol-4-yl)phenylamino)-4-(benzylamino)nicotinamide; 6-(4-(1H-pyrazol-1-yl)phenylamino)-4-(benzylamino)nicotinamide; 6-(6-(1H-pyrazol-1-yl)pyridin-3-ylamino)-4-(benzylamino)nicotinamide; 4-(benzylamino)-6-(4-methoxy-3-methylphenylamino)nicotinamide; 4-(benzylamino)-6-(3,4,5-trimethoxyphenylamino)nicotinamide; 6-(4-(1H-1,2,4-triazol-3-yl)phenylamino)-4-(benzylamino)nicotinamide; 4-((1H-indol-7-yl)methylamino)-6-(4-methoxyphenylamino)nicotinamide; 4-((1H-indol-7-yl)methylamino)-6-(4-(dimethylcarbamoyl)-3-methylphenylamino)nicotinamide; 4-(benzo[b]thiophen-7-ylmethylamino)-6-(4-methoxyphenylamino)nicotinamide; 4-(benzo[b]thiophen-7-ylmethylamino)-6-(4-(dimethylcarbamoyl)-3-methylphenylamino)nicotinamide; 6-(4-methoxyphenylamino)-4-(pyrimidin-5-ylmethylamino)nicotinamide; 6-(4-(dimethylcarbamoyl)-3-methylphenylamino)-4-(pyrimidin-5-ylmethylamino)nicotinamide; 4-((1H-indol-7-yl)methylamino)-6-(4-(dimethylcarbamoyl)phenylamino)nicotinamide; (R)-4-((1-(ethylsulfonyl)piperidin-3-yl)methylamino)-6-(4-methoxyphenylamino)nicotinamide; (R)-6-(4-methoxyphenylamind)-4-((1-(pyrrolidine-1-carbonyl)piperidin-3-yl)methylamino)nicotinamide; (R)-4-((1-(dimethylcarbamoyOpiperidin-3-yl)methylamino)-6-(4-methoxyphenylamino)nicotinamide; (R)-4-((1-(cyclopropylsulfonyl)piperidin-3-yl)methylamino)-6-(4-methoxyphenylamino)nicotinamide; 4-(benzylamino)-6-(3,4-dimethoxyphenylamino)nicotinamide; 4-((1H-indol-4-yl)methylamino)-6-(4-methoxyphenylamino)nicotinamide; 4-((1H-indol-4-yl)methylamino)-6-(4-(dimethylcarbamoyl)-3-methylphenylamino)nicotinamide; 4-((5-fluoropyridin-3-yl)methylamino)-6-(4-methoxyphenylamino)nicotinamide; 6-(4-(dimethylcarbamoyl)-3-methylphenylamino)-4-((5-fluoropyridin-3-yl)methylamino)nicotinamide; 6-(4-methoxyphenylamino)-4-(pyrimidin-4-ylmethylamino)nicotinamide; 6-(4-(dimethylcarbamoyl)phenylamino)-4-(pyrimidin-4-ylmethylamino)nicotinamide; 6-(4-methoxyphenylamino)-4-(pyrimidin-2-ylmethylamino)nicotinamide; 6-(4-methoxyphenylamino)-4-(3-(methylsulfonyl)benzylamino)nicotinamide; 6-(4-(dimethylcarbamoyl)phenylamino)-4-(3-(methylsulfonyl)benzylamino)nicotinamide; 6-(4-methoxyphenylamino)-4-((1-methyl-1H-indol-4-yl)methylamino)nicotinamide; 6-(4-(dimethylcarbamoyl)phenylamino)-4-((1-methyl-1H-indol-4-yl)methylamino)nicotinamide; 4-((5-fluoropyridin-3-yl)methylamino)-6-(4-(trifluoromethyl)phenylamino)nicotinamide; 6-(3-fluorophenylamino)-4-((5-fluoropyridin-3-yl)methylamino)nicotinamide; 6-(3-chlorophenylamino)-4-((5-fluoropyridin-3-yl)methylamino)nicotinamide; 6-(4-cyanophenylamino)-4-((5-fluoropyridin-3-yl)methylamino)nicotinamide; 6-(4-(difluoromethoxy)phenylamino)-4-((5-fluoropyridin-3-yl)methylamino)nicotinamide; 4-((5-fluoropyridin-3-yl)methylamino)-6-(4-(trifluoromethoxy)phenylamino)nicotinamide; 4-((5-fluoropyridin-3-yl)methylamino)-6-(p-tolylamino)nicotinamide; 6-(4-(dimethylcarbamoyl)phenylamino)-4-((5-fluoropyridin-3-yl)methylamino)nicotinamide; 4-(5-fluoropyridin-3-yl)methylamino)-6-(4-(2,2,2-trifluoroethylcarbamoyl)phenylamino)nicotinami de; 4-((5-fluoropyridin-3-yl)methylamino)-6-(4-(methyl(2,2,2-trifluoroethyl)carbamoyl)phenylamino)nicotinamide; 4-((6-fluoropyridin-2-yl)methylamino)-6-(4-methoxyphenylamino)nicotinamide; 6-(4-(dimethylcarbamoyl)phenylamino)-4-((6-fluoropyridin-2-yl)methylamino)nicotinamide; 6-(4-methoxyphenylamino)-4-((1-methyl-1H-indol-7-yl)methylamino)nicotinamide; 6-(4-(dimethylcarbamoyl)phenylamino)-4-((1-methyl-1H-indol-7-yl)methylamino)nicotinamide; 4-((1H-indol-4-yl)methylamino)-6-(4-fluorophenylamino)nicotinamide; 4-((1H-indol-4-yl)methylamino)-6-(4-(methylsulfonyl)phenylamino)nicotinamide; 4-((1H-indol-4-yl)methylamino)-6-(4-(difluoromethoxy)phenylamino)nicotinamide; 4-((1H-indol-4-yl)methylamino)-6-(4-(trifluoromethoxy)phenylamino)nicotinamide; 4-((1H-indol-4-yl)methylamino)-6-(3,5-difluorophenylamino)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-(2-(dimethylamino)-2-oxoethyl)phenylamino)nicotinamide; 4-(benzylamino)-6-(4-(2-oxo-2-(pyrrolidin-1-yl)ethyl)phenylamino)nicotinamide; 4-(benzylamino)-6-(4-(2-morpholino-2-oxoethyl)phenylamino)nicotinamide; 4-(benzylamino)-6-(4-(3-(dimethylcarbamoyl)azetidin-1-yl)phenylamino)nicotinamide; 4-(benzylamino)-6-(3-chloro-4-methoxyphenylamino)nicotinamide; 6-(4-(1-acetylazetidin-3-yl)phenylamino)-4-(benzo[b]thiophen-7-ylmethylamino)nicotinamide; 6-(4-(1-acetylazetidin-3-yl)phenylamino)-4-((5-fluoropyridin-3-yl)methylamino)nicotinamide; 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-(benzo[b]thiophen-4-ylmethylamino)-6-(4-(4-(dimethylcarbamoyepiperidin-1-yl)phenylamino)nicotinamide; 4-((1H-indol-4-yl)methylamino)-6-(4-(4-(dimethylcarbamoyl)piperidin-1-yl)phenylamino)nicotinamide; 4-(benzo[b]thiophen-7-ylmethylamino)-6-(4-(methylsulfonylmethyl)phenylamino)nicotinamide; 4-(benzylamino)-6-(4-(methylsulfonylmethyl)phenylamino)nicotinamide; 4-((1H-indol-4-yl)methylamino)-6-(4-(methylsulfonylmethyl)phenylamino)nicotinamide; 4-(benzo[b]thiophen-7-ylmethylamino)-6-(4-(3-(dimethylcarbamoyl)azetidin-1-yl)-3-fluorophenylamino)nicotinamide; 4-(benzo[b]thiophen-7-ylmethylamino)-6-(4-(4-(dimethylcarbamoyl)piperidin-1-yl)phenylamino)nicotinamide; 4-(benzo[b]thiophen-7-ylmethylamino)-6-(3-chloro-4-(4-(dimethylcarbamoyDpiperidin-1-yl)phenylamino)nicotinamide; 6-(4-(acetamidomethyl)phenylamino)-4-(benzo[b]thiophen-7-ylmethylamino)nicotinamide; 4-(benzo[b]thiophen-7-ylmethylamino)-6-(4-(methylsulfonamidomethyl)phenylamino)nicotinamide; 4-(benzo[b]thiophen-7-ylmethylamino)-6-(4-(3,3-dimethylureido)methyl)phenylamino)nicotinamide; 4-(benzo[b]thiophen-7-ylmethylamino)-6-(4-((N,N-dimethylsulfamoylamino)methyl)phenylamino)nicotinamide; 4-((1H-indol-5-yl)methylamino)-6-(4-(1-propionylpiperidin-4-yl)phenylamino)nicotinamide; 4-((1H-indol-6-yl)methylamino)-6-(pyridin-3-ylamino)nicotinamide; 4-((1H-indol-6-yl)methylamino)-6-(4-(1-propionylpiperidin-4-yl)phenylamino)nicotinamide; 6-(4-(N-methylacetamido)phenylamino)-4-(1-phenylcyclopropylamino)nicotinamide; 4-(1-phenylcyclopropylamino)-6-(4-piperidin-1-yl)phenylamino) nicotinamide; 4-(1-phenylcyclopropylamino)-6-(3-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)nicotinamide; 6-(4-(4-(methylsufonly)piperazin-1-yl)phenylamino)-4-(1-phenylcyclopropylamino)nicotinamide; 6-(3-(2-(dimethylamino)-2-oxoethoxy)phenylamino)-4-(1-phenylcyclopropylamino)nicotinamide; 6-(4-(2-(dimethylamino)-2-oxoethoxy)phenylamino)-4-(1-phenylcyclopropylamino)nicotinamide; 4-(1-phenylcyclopropylamino)-6-(3-(piperazin-1-yl)phenylamino)nicotinamide; 6-(3-(4-acetylpiperazin-1-yl)phenylamino)-4-(1-phenylcyclopropylamino)nicotinamide; 6-(N-(3-(4-acetylpiperazin-1-yl)phenyl)acetamino)-4-(1-phenylcyclopropylamino)nicotinamide; 6-(5-(4-(methylsulfonyl)piperazin-1-yl)pyridin-2-ylamino)-4-(1-phenylcyclopropylamino)nicotinamide; 4-(1-(2,3-difluorophenyl)cyclopropylamino)-6-(4-(4-propionylpiperazin-1-yl)phenylamino)nicotinamide; 4-(1-phenylcyclopropylamino)-6-(4-(1-propionylpiperidin-4-yl)phenylamino)nicotinamide; 6-(4-(4-acetylpiperazin-1-yl)phenylamino-5-chloro-4-(3-fluorobenzylamino)nicotinamide; 5-chloro-4-(3-fluorobenzylamino)-6-(4-morpholinophenylamino)nicotinamide; 4-(3-fluorobenzylamino-6-(5-(morpholine-4-carbonyl)thiazol-2-ylamino)nicotinamide; 6-(4-(dimethylcarbamoyl)phenylamino)-4-(3-(pyridine-4-yl)benzylamino)nicotinamide; 6-(4-(methylsulfonyl)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-(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; 6-(4-(morpholinomethyl)phenylamino)-4-(3-(pyridin-4-yl)benzylamino)nicotinamide; 4-(benzylamino)-6-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)nicotinamide; 4-(benzylamino)-6-(4-(2-morpholinoethoxyl)phenylamino)nicotinamide; 4-(benzylamino)-6-(3-(2-morpholino-2-oxoethoxy)phenylamino)nicotinamide; 4-(benzylamino)-6-(4-(morpholinomethyl)phenylamino)nicotinamide; 4-(benzylamino)-6-(4-(2-methoxyethoxyl)phenylamino)nicotinamide; 4-(benzylamino)-6-(3-(2-methoxyethoxyl)phenylamino)nicotinamide; 2-(4-(azetidin-1-ylsulfonyl)phenylamino)-4-(benzylamino)pyrimidine-5-carboxamide; 4-(2,3-difluorobenzylamino)-6-(4-(4-propionylpiperazin-1-yl)phenylamino)nicotinamide; 4-(benzylamino)-6-(4-(dimethylcarbamoyl)-3-methoxyphenylamino)nicotinamide; 4-(benzylamino)-6-(3-chloro-4-(dimethylcarbamoyl)phenylamino)nicotinamide; 4-(benzylamino)-6-(4-(dimethylcarbamoyl)-3-methylphenylamino)nicotinamide; 6-(3-(azetidine-1-carbonyl)-4-fluorophenylamino)-4-(benzylamino)nicotinamide; 4-(benzylamino)-6-(4-(dimethylamino)-3-(dimethylcarbamoyl)phenylamino)nicotinamide; (R)-4-((1-acetylpiperidin-3-yl)methylamino)-6-(4-(dimethylcarbamoyl)-3-methoxyphenylamino)nicotinamide; (R)-4-((1-acetylpiperidin-3-yl)methylamino)-6-(3-chloro-4-(dimethylcarbamoyl)phenylamino)nicotinamide; (R)-4-((1-acetylpiperidin-3-yl)methylamino)-6-(4-(dimethylcarbamoyl)-3-methylphenylamino)nicotinamide; (R)-4-((1-acetylpiperidin-3-yl)methylamino)-6-(3-(azetidine-1-carbonyl)-4-fluorophenylamino)nicotinamide; (R)-4-((1-acetylpiperidin-3-yl)methylamino)-6-(3-(dimethylamino)-4-(dimethylcarbamoyl)phenylamino)nicotinamide; 4-(benzylamino)-6-(3-methyl-4-(pyrrolidine-1-carbonyl)phenylamino)nicotinamide; 4-(benzylamino)-6-(3-methyl-4-(morpholine-4-carbonyl)phenylamino)nicotinamide; 6-(4-(azetidine-1-carbonyl)-3-methylphenylamino)-4-(benzylamino)nicotinamide; 4-(benzylamino)-6-(4-(2-hydroxyethylcarbamoyl)-3-methylphenylamino)nicotinamide; 4-(benzylamino)-6-(4-(cyclopropyl(methyl)carbamoyl)-3-methylphenylamino)nicotinamide; 4-(benzylamino)-6-(4-(2,5-dihydro-1H-pyrrole-1-carbonyl)-3-methylphenylamino)nicotinamide; 4-(benzylamino)-6-(4-((2-hydroxyethyl)(methyl)carbamoyl)-3-methylphenylamino)nicotinamide; 4-(benzylamino)-6-(4-((2-methoxyethyl)(methyl)carbamoyl)-3-methylphenylamino)nicotinamide; 6-(4-(azetidine-1-carbonyl)-3-methylphenylamino)-4-(2,3-difluorobenzylamino)nicotinamide; 4-(2,3-difluorobenzylamino)-6-(3-methyl-4-(morpholine-4-carbonyl)phenylamino)nicotinamide; 4-(2,3-difluorobenzylamino)-6-(3-methyl-4-(pyrrolidine-1-carbonyl)phenylamino)nicotinamide; 6-(4-(azetidine-1-carbonyl)-3-methylphenylamino)-4-(benzo[b]thiophen-7-ylmethylamino)nicotinamide; 4-(benzo[b]thiophen-7-ylmethylamino)-6-(3-methyl-4-(pyrrolidine-1-carbonyl)phenylamino)nicotinamide; 4-(benzo[b]thiophen-7-ylmethylamino)-6-(3-methyl-4-(morpholine-4-carbonyl)phenylamino)nicotinamide; 4-((1H-indol-4-yl)methylamino)-6-(4-(azetidine-1-carbonyl)-3-methylphenylamino)nicotinamide; 4-((1H-indol-4-yl)methylamino)-6-(3-methyl-4-(pyrrolidine-1-carbonyl)phenylamino)nicotinamide; 4-((1H-indol-4-yl)methylamino)-6-(3-methyl-4-(morpholine-4-carbonyl)phenylamino)nicotinamide; 4-((1H-indol-7-yl)methylamino)-6-(4-(azetidine-1-carbonyl)-3-methylphenylamino)nicotinamide; 4-((1H-indol-7-yl)methylamino)-6-(3-methyl-4-(pyrrolidine-1-carbonyl)phenylamino)nicotinamide; methyl 4-(4-(benzo[b]thiophen-7-ylmethylamino)-5-carbamoylpyridin-2-ylamino)phenyl(methyl)carbamate; 4-(benzo[b]thiophen-7-ylmethylamino)-6-(4-(N-methylpropionamido)phenylamino)nicotinamide; 4-(benzo[b]thiophen-7-ylmethylamino)-6-(4-(N-methylcyclopropanecarboxamido)phenylamino)nicotinamide; 4-(benzo[b]thiophen-7-ylmethylamino)-6-(4-(N-methylacetamido)phenylamino)nicotinamide; 4-((1H-indol-4-yl)methylamino)-6-(4-(N-methylacetamido)phenylamino)nicotinamide; 4-((1H-indol-7-yl)methylamino)-6-(4-(N-methylacetamido)phenylamino)nicotinamide; 6-(4-acetamidophenylamino)-4-(benzo[b]thiophen-7-ylmethylamino)nicotinamide; 4-((1H-indol-4-yl)methylamino)-6-(4-acetamidophenylamino)nicotinamide; 4-((1H-indol-7-yl)methylamino)-6-(4-acetamidophenylamino)nicotinamide; methyl 4-(4-((1H-indol-4-yl)methylamino)-5-carbamoylpyridin-2-ylamino)phenyl(methyl)carbamate; 4-((1H-indol-4-yl)methylamino)-6-(4-(N-methylpropionamido)phenylamino)nicotinamide; 4-((1H-indol-4-yl)methylamino)-6-(4-(N-methylcyclopropanecarboxamido)phenylamino)nicotinamide; 4-((1H-indol-7-yl)methylamino)-6-(4-(N-methylpropionamido)phenylamino)nicotinamide; 4-((1H-indol-7-yl)methylamino)-6-(4-(N-methylcyclopropanecarboxamido)phenylamino)nicotinamide; methyl 4-(5-carbamoyl-4-((5-fluoropyridin-3-yl)methylamino)pyridin-2-ylamino)phenyl(methyl)carbamate; 4-((5-fluoropyridin-3-yl)methylamino)-6-(4-(N-methylpropionamido)phenylamino)nicotinamide; 4-((5-fluoropyridin-3-yl)methylamino)-6-(4-(N-methylcyclopropanecarboxamido)phenylamino)nicotinamide; methyl 4-(4-((1H-indol-7-yl)methylamino)-5-carbamoylpyridin-2-ylamino)phenyl(methyl)carbamate; 4-((5-fluoropyridin-3-yl)methylamino)-6-(4-(N-methylacetamido)phenylamino)nicotinamide; 6-(4-acetamidophenylamino)-4-((5-fluoropyridin-3-yl)methylamino)nicotinamide; 4-((6-fluoropyridin-2-yl)methylamino)-6-(4-(N-methylacetamido)phenylamino)nicotinamide; 6-(4-acetamidophenylamino)-4-((6-fluoropyridin-2-yl)methylamino)nicotinamide; methyl 4-(5-carbamoyl-4-((6-fluoropyridin-2-yl)methylamino)pyridin-2-ylamino)phenyl(methyl)carbamate; 4-((6-fluoropyridin-2-yl)methylamino)-6-(4-(N-methylpropionamido)phenylamino)nicotinamide; 4-((6-fluoropyridin-2-yl)methylamino)-6-(4-(N-methylcyclopropanecarboxamido)phenylamino)nicotinamide; 4-((6-fluoropyridin-2-yl)methylamino)-6-(4-(1-propionylazetidin-3-yl)phenylamino)nicotinamide; 4-(benzo[b]thiophen-7-ylmethylamino)-6-(4-(1-propionylazetidin-3-yl)phenylamino)nicotinamide; 4-((1H-indol-4-yl)methylamino)-6-(4-(1-propionylazetidin-3-yl)phenylamino)nicotinamide; 4-((6-fluoropyridin-2-yl)methylamino)-6-(4-(1-(2-methoxyacetyl)azetidin-3-yl)phenylamino)nicotinamide; 4-((1H-indol-4-yl)methylamino)-6-(4-(1-(2-methoxyacetyl)azetidin-3-yl)phenylamino)nicotinamide; 4-(benzo[b]thiophen-7-ylmethylamino)-6-(4-(1-(2-methoxyacetyl)azetidin-3-yl)phenylamino)nicotinamide; difluorobenzylamino)-6-(4-(1-(1,3-difluoropropan-2-yl)piperidin-4-yl)phenylamino)nicotinamide; 4-(2,3-difluorobenzylamino)-6-(4-(1-formylpiperidin-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-((1H-indol-4-yl)methylamino)-6-(4-(1-formylpiperidin-4-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; 4-(2,3-difluorobenzylamino)-6-(4-(1-(pyridin-2-yl)azetidin-3-yl)phenylamino)nicotinamide; 4-((1H-indol-4-yl)methylamino)-6-(4-(1-(pyridin-2-yl)piperidin-4-yl)phenylamino)nicotinamide. 
     
     
         31 . (canceled) 
     
     
         32 . (canceled) 
     
     
         33 . A composition comprising a compound of  claim 1  in combination with a pharmaceutically acceptable carrier or diluent. 
     
     
         34 . 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 . 
     
     
         35 . 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 33 . 
     
     
         36 . The method of  claim 35 , wherein said JAK kinase is selected from the group consisting of JAK1, JAK2, and JAK3. 
     
     
         37 . The method of  claim 36 , wherein said JAK kinase is JAK1, JAK3, or combinations thereof. 
     
     
         38 . The method of  claim 35 , wherein said JAK kinase is JAK3. 
     
     
         39 . The method of  claim 35 , wherein the condition or disorder is selected from the group consisting of cardiovascular disease, inflammatory disease, immune-related disease, autoimmune disease, sickle cell disease and cell proliferative disorder. 
     
     
         40 . The method of  claim 35 , wherein said inflammatory disease, immune-related disease, autoimmune disease is selected from the group consisting of organ transplants, osteoarthritis, irritable bowel disease (IBD), asthma, allergic conjunctivitis, uvetis, chronic obstructive pulmonary disease (COPD), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), Crohn's disease, Type I diabetes and psoriasis. 
     
     
         41 . The method of  claim 36 , wherein said sickle cell disease is selected from the group consisting of sickle cell anemia, sickle-hemoglobin C disease, sickle beta-plus thalassemia, and sickle beta-zero thalassemia. 
     
     
         42 . The method of  claim 35 , wherein said immune-related disease is selected from the group consisting of a T-cell mediated disease, an autoimmune disease, host versus graft rejection, graft versus host rejection, a Type IV hypersensitivity reaction and allograft rejection. 
     
     
         43 . A kit comprising a composition of  claim 33 , packaging and instructions for use.