Protein kinase c inhibitors and uses thereof

Abstract

This disclosure concerns compounds which are useful as inhibitors of protein kinase C (PKC) and are thus useful for treating a variety of diseases and disorders that are mediated or sustained through the activity of PKC. This disclosure also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.

1 . A compound of the formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         R 5  is selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; 
         Y 1  and Y 2  are independently selected from hydrogen, alkyl, and acyl; 
         R 1  is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, acyl, and oxy radical; 
         R a  and R b  are independently selected from hydrogen and alkyl; 
         R c  and R d  are independently selected from hydrogen and alkyl; 
         Q is selected from N and CR 7b ; 
         R 6a , R 6b , R 7b  and R 8  are independently selected from hydrogen, alkyl, substituted alkyl, halogen, cyano, hydroxyl, alkoxy, substituted alkoxy, amino, substituted amino, acylamino, aminocarbonyloxy, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkoxycarbonylamino, aminocarbonylamino, acyl, carboxyl, carboxyl ester, aminoacyl, sulfonyl, sulfonylamino, aminosulfonyl, and —O-alk-A; 
         alk is a bond, alkylene or substituted alkylene; 
         A is selected from aryl, cycloalkyl, heteroaryl, and heterocyclyl; 
         wherein the A ring can be substituted or unsubstituted; 
         R 7y  is selected from hydrogen, alkyl, cycloalkyl, and substituted alkyl; 
         or a salt or stereoisomer thereof. 
       
     
     
         2 . The compound of  claim 1  having the formula (VIII): 
       
         
           
           
               
               
           
         
         wherein 
         R 5  is selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; 
         Y 1  is selected from hydrogen and alkyl; 
         R 1  is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, acyl, and oxy radical; 
         R a  and R b  are independently selected from hydrogen and alkyl; 
         R c  and R d  are independently selected from hydrogen and alkyl; 
         Q is selected from N and CR 7b ; 
         R 7b  and R 8  are independently selected from hydrogen, alkyl, substituted alkyl, halogen, cyano, hydroxyl, alkoxy, substituted alkoxy, amino, substituted amino, acylamino, aminocarbonyloxy, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkoxycarbonylamino, aminocarbonylamino, acyl, carboxyl, carboxyl ester, aminoacyl, sulfonyl, sulfonylamino, aminosulfonyl, and —O-alk-A; 
         alk, if present, is alkyl or substituted alkyl; 
         A is selected from aryl, cycloalkyl, heteroaryl, and heterocyclyl; 
         wherein the A ring can be substituted or unsubstituted; 
         R 7y  is selected from hydrogen, alkyl, and substituted alkyl; 
         or a salt or stereoisomer thereof. 
       
     
     
         3 . The compound of  claim 1 , wherein R 5  is cyano, halogen, acyl, aminoacyl, or nitro. 
     
     
         4 . The compound of  claim 1 , wherein R 5  is fluoro. 
     
     
         5 . The compound of  claim 1 , wherein R 5  is cyano. 
     
     
         6 . The compound of  claim 1 , wherein Y 1  is hydrogen. 
     
     
         7 . The compound of  claim 1 , wherein Y 2  is hydrogen. 
     
     
         8 . The compound of  claim 1 , wherein R 1  is hydrogen. 
     
     
         9 . The compound of  claim 1 , wherein R 1  is alkyl. 
     
     
         10 . The compound of  claim 1 , wherein R a  and R b  are both alkyl. 
     
     
         11 . The compound of  claim 1 , wherein R c  and R d  are both alkyl. 
     
     
         12 . The compound of  claim 1 , wherein Q is CR 7b . 
     
     
         13 . The compound of  claim 1 , wherein Q is N. 
     
     
         14 . The compound of  claim 1 , wherein R 6a , R 6b , R 7b  and R 8  are independently selected from hydrogen, alkyl, substituted alkyl, halogen, cyano, hydroxyl, alkoxy, substituted alkoxy, amino, substituted amino, acylamino, aminocarbonyloxy, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, cycloalkyl, substituted cycloalkyl, and —O-alk-A. 
     
     
         15 . The compound of  claim 1 , wherein R 7b  and R 8  are independently selected from hydrogen, alkyl, substituted alkyl, halogen, cyano, hydroxyl, alkoxy, substituted alkoxy, amino, substituted amino, acylamino, aminocarbonyloxy, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, cycloalkyl, substituted cycloalkyl, and —O-alk-A. 
     
     
         16 . The compound of  claim 1 , wherein R 6a , R 6b , R 7b  and R 8  are independently selected from hydrogen, alkyl, substituted alkyl, halogen, cyano, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, acyl, carboxyl, carboxyl ester, aminoacyl, and —O-alk-A. 
     
     
         17 . The compound of  claim 1 , wherein at least one of R 6a , R 6b , R 7b  and R 8  is alkyl or substituted alkyl. 
     
     
         18 . The compound of  claim 1 , wherein at least one of R 6a , R 6b , R 7b  and R 8  is halogen. 
     
     
         19 . The compound of  claim 1 , wherein at least one of R 6a , R 6b , R 7b  and R 8  is alkoxy, substituted alkoxy, or —O-alk-A. 
     
     
         20 . The compound of  claim 1 , wherein at least one of R 6a , R 6b , R 7b  and R 8  is cyano, acyl, carboxyl, carboxyl ester, or aminoacyl. 
     
     
         21 . The compound of  claim 1 , wherein at least one of R 6a , R 6b , R 7b  and R 8  is cycloalkyl or substituted cycloalkyl. 
     
     
         22 . The compound of  claim 1 , wherein R 6a  is selected from hydrogen, alkyl, substituted alkyl, and halogen. 
     
     
         23 . The compound of  claim 1 , wherein R 6b  is selected from hydrogen, alkyl, substituted alkyl, and halogen. 
     
     
         24 . The compound of  claim 1 , wherein R 7b  is selected from hydrogen, alkyl, and substituted alkyl. 
     
     
         25 . The compound of  claim 1 , wherein R 7b  is selected from hydrogen, alkyl, substituted alkyl, halogen, cyano, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, acyl, carboxyl, carboxyl ester, aminoacyl, and —O-alk-A. 
     
     
         26 . The compound of  claim 1 , wherein R 7b  is hydrogen. 
     
     
         27 . The compound of  claim 1 , wherein R 8  is selected from hydrogen, alkyl, substituted alkyl, halogen, alkoxy, substituted alkoxy, cycloalkyl, and substituted cycloalkyl. 
     
     
         28 . The compound of  claim 1 , wherein R 8  is selected from hydrogen, alkyl, substituted alkyl, halogen, alkoxy, substituted alkoxy. 
     
     
         29 . The compound of  claim 1 , wherein R 8  is halogen. 
     
     
         30 . The compound of  claim 1 , wherein any of R 7b  or R 8  is selected from hydrogen, alkyl, substituted alkyl, halogen, cyano, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, acyl, carboxyl, carboxyl ester, aminoacyl, and —O-alk-A. 
     
     
         31 . The compound of  claim 1 , wherein at least one of R 7b  or R 8  is cycloalkyl, or substituted cycloalkyl. 
     
     
         32 . The compound of  claim 1 , wherein at least one of R 7b  or R 8  is alkoxy, substituted alkoxy, or —O-alk-A. 
     
     
         33 . The compound of  claim 1 , wherein at least one of R 7b  or R 8  is alkyl, substituted alkyl, or halogen. 
     
     
         34 . The compound of  claim 1 , wherein R 7y  is hydrogen. 
     
     
         35 . The compound of  claim 1 , wherein R 7y  is alkyl. 
     
     
         36 . The compound of  claim 1 , wherein R 7y  is methyl. 
     
     
         37 . The compound of  claim 1 , wherein R 7y  is substituted alkyl. 
     
     
         38 . The compound of  claim 1 , wherein the compound selected from:
 I-1: 5-Fluoro-N2-{4-fluoro-[3-(4-H)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-N4-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pyrimidinediamine;   I-2: 5-Fluoro-N2-{4-fluoro-[3-(4-H)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine;   I-3: 5-Fluoro-N2-{4-fluoro-[3-(4-methyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-N4-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pyrimidinediamine;   I-4: 5-Fluoro-N2-{4-fluoro-[3-(4-isopropyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine;   I-5: 5-Fluoro-N2-{4-fluoro-[3-(4-isopropyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-N4-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pyrimidinediamine;   I-6: 5-Fluoro-N2-{4-fluoro-3-[4-(2-fluoroethyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine;   I-7: 5-Fluoro-N2-{4-fluoro-3-[4-(2-fluoroethyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine;   I-8: 5-Fluoro-N2-{4-methyl-[3-(4-methyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-N4-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pyrimidinediamine;   I-9: 5-Fluoro-N2-{4-methyl-[3-(4-methyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine;   I-10: 5-Fluoro-N2-{4-isopropoxy-[3-(4-methyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-N4-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pyrimidinediamine;   I-11: 5-Fluoro-N2-{4-isopropoxy-[3-(4-methyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine;   I-12: 5-Fluoro-N2-[3-(4-methyl)-1,2,3,4-tetrazol-5-one-1-yl]phenyl-N4-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pyrimidinediamine;   I-13: 5-Fluoro-N2-[3-(4-methyl)-1,2,3,4-tetrazol-5-one-1-yl]phenyl-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine;   I-14: 1-(2-cyclopropyl-4-fluoro-5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-15: 2-(4-cyclopropyl-2-fluoro-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenylamino)-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidine-5-carbonitrile;   I-16: 1-{2-Cyclopropyl-4-fluoro-5-[5-fluoro-4-(1,2,2,6,6-pentamethyl-piperidin-4-ylamino)-pyrimidin-2-ylamino]-phenyl}-4-methyl-1,4-dihydro-tetrazol-5-one;   I-17: 2-[4-Cyclopropyl-2-fluoro-5-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-phenylamino]-4-(1,2,2,6,6-pentamethyl-piperidin-4-ylamino)-pyrimidine-5-carbonitrile;   I-18: 1-(5-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-(1,1,1-trifluoro-2-methylpropan-2-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-19: 1-(5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-(1,1,1-trifluoro-2-methylpropan-2-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-20: 1-(5-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-(oxetan-3-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-21: 1-(5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-(oxetan-3-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-22: 1-(3-fluoro-5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-23: 1-(3-fluoro-5-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-24: 1-(3-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-5-(oxetan-3-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-25: 1-(3-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-5-(oxetan-3-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-26: 1-(5-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-(tetrahydro-2H-pyran-4-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-27: 1-(5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-(tetrahydro-2H-pyran-4-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-28: 1-(5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-((3-methyloxetan-3-yl)methoxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-29: 1-(2-chloro-5-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-30: 1-(2-chloro-5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-31: 1-(3-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-5-methoxyphenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-32: 1-(3-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-5-methoxyphenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-33: 1-(2-cyclopropyl-5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-34: 1-(2-cyclopropyl-5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-35: 1-(3-cyclopropyl-5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-36: 1-(3-cyclopropyl-5-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-37: 1-(3-chloro-5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-38: 1-(2-chloro-5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-3-(trifluoromethyl)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-39: 1-(2-cyclopropyl-5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-3-(trifluoromethyl)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-40: 1-(2-cyclopropyl-5-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-3-(trifluoromethyl)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-41: 2-(4-cyclopropyl-3-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)-5-(trifluoromethyl)phenylamino)-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidine-5-carbonitrile;   I-42: 2-(4-cyclopropyl-3-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)-5-(trifluoromethyl)phenylamino)-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidine-5-carbonitrile;   I-43: 1-(3-cyclopropyl-2-fluoro-5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-44: 2-(3-cyclopropyl-4-fluoro-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenylamino)-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidine-5-carbonitrile;   I-45: 1-(5-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2,3-dimethylphenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-46: 1-(5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2,3-dimethylphenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-47: 1-(3-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-5-(trifluoromethyl)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-48: 1-(3-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-5-(trifluoromethyl)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-49: 3-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)benzonitrile;   I-50: 3-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)benzonitrile;   I-51: 1-(5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-isopropoxy-3-(trifluoromethyl)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-52: 1-(5-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-isopropoxy-3-(trifluoromethyl)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-53: 1-(5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-methyl-3-(trifluoromethyl)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-54: 1-(5-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-methyl-3-(trifluoromethyl)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-55: 1-(3-chloro-5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-methylphenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-56: 1-(3-chloro-5-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-methylphenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-57: 2-(4-cyclopropyl-3-fluoro-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenylamino)-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidine-5-carboxamide;   I-58: 4-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)benzonitrile;   I-59: 1-(2-cyclopropyl-3-fluoro-5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-60: methyl 5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-methyl-3-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)benzoate;   I-61: 5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-methyl-3-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)benzoic acid;   I-62: 2-(4-cyclopropyl-3-fluoro-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenylamino)-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidine-5-carbonitrile;   I-63: methyl 5-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-methyl-3-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)benzoate;   I-64: 5-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-N,2-dimethyl-3-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)benzamide;   I-65: 5-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-methyl-3-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)benzoic acid;   I-66: 1-(2,6-difluoro-3-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-67: 1-(2,6-difluoro-3-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-68: 1-(2-chloro-4-fluoro-5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-69: 1-(2-chloro-4-fluoro-5-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-70: 1-(4-fluoro-5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-(1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-71: 1-(4-fluoro-3-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-72: 1-(2-cyclopropyl-4-fluoro-5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-(trideuteromethyl)-1H-tetrazol-5(4H)-one;   I-73: N2-{4-Cyclopropyl-6-fluoro-[3-(4-isopropyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine;   I-74: N2-{4-Cyclopropyl-6-fluoro-3-(1,2,3,4-tetrazol-5-one-1-yl)}phenyl-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine, formate salt;   I-75: N2-{4-Cyclopropyl-6-fluoro-[3-(4-methyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine, citrate salt;   I-76: N2-{4-Cyclopropyl-6-fluoro-[3-(4-methyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine, maleate salt;   I-77: N2-{4-Cyclopropyl-6-fluoro-[3-(4-methyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine, fumarate salt;   I-78: N2-{4-Cyclopropyl-6-fluoro-[3-(4-methyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine, L-tartarate salt;   I-79: N2-{4-Cyclopropyl-6-fluoro-[3-(4-methyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine, hydrogen sulfate salt;   I-80: N2-{4-Cyclopropyl-6-fluoro-[3-(4-methyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine, hydrogen chloride salt;   I-81: N2-{4-Cyclopropyl-6-fluoro-[3-(4-methyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine, benzoate salt;   I-82: N2-{4-Cyclopropyl-6-fluoro-[3-(4-methyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine, tosylate salt;   I-83: N2-{4-Cyclopropyl-6-fluoro-[3-(4-methyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine, besylate salt;   I-84: N2-{4-Cyclopropyl-6-fluoro-[3-(4-methyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine, mesylate salt;   I-85: N2-{4-Cyclopropyl-6-fluoro-[3-(4-methyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine, acetate salt;   I-86: N2-(4-fluoro-2-methoxy-3-(4-methyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)phenyl)-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidine-2,4-diamine; and   I-87: N2-(4-fluoro-2-methoxy-3-(4-methyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)phenyl)-5-fluoro-N4-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyrimidine-2,4-diamine;   or a solvate, prodrug, or a pharmaceutically acceptable salt thereof.   
     
     
         39 . The compound of  claim 1 , wherein the compound selected from:
 I-1: 5-Fluoro-N2-{4-fluoro-[3-(4-H)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-N4-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pyrimidinediamine;   I-2: 5-Fluoro-N2-{4-fluoro-[3-(4-H)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine;   I-3: 5-Fluoro-N2-{4-fluoro-[3-(4-methyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-N4-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pyrimidinediamine;   I-4: 5-Fluoro-N2-{4-fluoro-[3-(4-isopropyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine;   I-5: 5-Fluoro-N2-{4-fluoro-[3-(4-isopropyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-N4-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pyrimidinediamine;   I-6: 5-Fluoro-N2-{4-fluoro-3-[4-(2-fluoroethyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine;   I-7: 5-Fluoro-N2-{4-fluoro-3-[4-(2-fluoroethyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine;   I-8: 5-Fluoro-N2-{4-methyl-[3-(4-methyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-N4-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pyrimidinediamine;   I-9: 5-Fluoro-N2-{4-methyl-[3-(4-methyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine;   I-10: 5-Fluoro-N2-{4-isopropoxy-[3-(4-methyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-N4-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pyrimidinediamine;   I-11: 5-Fluoro-N2-{4-isopropoxy-[3-(4-methyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine;   I-12: 5-Fluoro-N2-[3-(4-methyl)-1,2,3,4-tetrazol-5-one-1-yl]phenyl-N4-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pyrimidinediamine; and   I-13: 5-Fluoro-N2-[3-(4-methyl)-1,2,3,4-tetrazol-5-one-1-yl]phenyl-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine;   or a solvate, prodrug, or a pharmaceutically acceptable salt thereof.   
     
     
         40 . The compound of  claim 1 , wherein the compound selected from:
 I-14: 1-(2-cyclopropyl-4-fluoro-5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-15: 2-(4-cyclopropyl-2-fluoro-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenylamino)-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidine-5-carbonitrile;   I-16: 1-{2-Cyclopropyl-4-fluoro-5-[5-fluoro-4-(1,2,2,6,6-pentamethyl-piperidin-4-ylamino)-pyrimidin-2-ylamino]-phenyl}-4-methyl-1,4-dihydro-tetrazol-5-one; and   I-17: 2-[4-Cyclopropyl-2-fluoro-5-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-phenylamino]-4-(1,2,2,6,6-pentamethyl-piperidin-4-ylamino)-pyrimidine-5-carbonitrile;   or a solvate, prodrug, or a pharmaceutically acceptable salt thereof.   
     
     
         41 . The compound of  claim 1 , wherein the compound is 1-(2-cyclopropyl-4-fluoro-5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one (1-14). 
     
     
         42 . The compound of  claim 1 , wherein the compound selected from:
 I-18: 1-(5-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-(1,1,1-trifluoro-2-methylpropan-2-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-19: 1-(5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-(1,1,1-trifluoro-2-methylpropan-2-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-20: 1-(5-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-(oxetan-3-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-21: 1-(5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-(oxetan-3-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-22: 1-(3-fluoro-5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-23: 1-(3-fluoro-5-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-24: 1-(3-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-5-(oxetan-3-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-25: 1-(3-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-5-(oxetan-3-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-26: 1-(5-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-(tetrahydro-2H-pyran-4-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-27: 1-(5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-(tetrahydro-2H-pyran-4-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-28: 1-(5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-((3-methyloxetan-3-yl)methoxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-29: 1-(2-chloro-5-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-30: 1-(2-chloro-5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-31: 1-(3-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-5-methoxyphenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-32: 1-(3-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-5-methoxyphenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-33: 1-(2-cyclopropyl-5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-34: 1-(2-cyclopropyl-5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-35: 1-(3-cyclopropyl-5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-36: 1-(3-cyclopropyl-5-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-37: 1-(3-chloro-5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-38: 1-(2-chloro-5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-3-(trifluoromethyl)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-39: 1-(2-cyclopropyl-5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-3-(trifluoromethyl)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-40: 1-(2-cyclopropyl-5-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-3-(trifluoromethyl)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-41: 2-(4-cyclopropyl-3-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)-5-(trifluoromethyl)phenylamino)-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidine-5-carbonitrile;   I-42: 2-(4-cyclopropyl-3-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)-5-(trifluoromethyl)phenylamino)-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidine-5-carbonitrile;   I-43: 1-(3-cyclopropyl-2-fluoro-5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-44: 2-(3-cyclopropyl-4-fluoro-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenylamino)-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidine-5-carbonitrile;   I-45: 1-(5-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2,3-dimethylphenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-46: 1-(5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2,3-dimethylphenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-47: 1-(3-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-5-(trifluoromethyl)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-48: 1-(3-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-5-(trifluoromethyl)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-49: 3-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)benzonitrile;   I-50: 3-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)benzonitrile;   I-51: 1-(5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-isopropoxy-3-(trifluoromethyl)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-52: 1-(5-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-isopropoxy-3-(trifluoromethyl)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-53: 1-(5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-methyl-3-(trifluoromethyl)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-54: 1-(5-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-methyl-3-(trifluoromethyl)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-55: 1-(3-chloro-5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-methylphenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-56: 1-(3-chloro-5-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-methylphenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-57: 2-(4-cyclopropyl-3-fluoro-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenylamino)-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidine-5-carboxamide;   I-58: 4-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)benzonitrile;   I-59: 1-(2-cyclopropyl-3-fluoro-5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-60: methyl 5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-methyl-3-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)benzoate;   I-61: 5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-methyl-3-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)benzoic acid;   I-62: 2-(4-cyclopropyl-3-fluoro-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenylamino)-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidine-5-carbonitrile;   I-63: methyl 5-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-methyl-3-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)benzoate;   I-64: 5-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-N,2-dimethyl-3-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)benzamide;   I-65: 5-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-methyl-3-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)benzoic acid;   I-66: 1-(2,6-difluoro-3-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-67: 1-(2,6-difluoro-3-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-68: 1-(2-chloro-4-fluoro-5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one; and   I-69: 1-(2-chloro-4-fluoro-5-(5-fluoro-4-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   or a solvate, prodrug, or a pharmaceutically acceptable salt thereof.   
     
     
         43 . The compound of  claim 1 , wherein the compound selected from
 I-70: 1-(4-fluoro-5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)-2-(1S,2S)-2-(trifluoromethyl)cyclopropyl)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-71: 1-(4-fluoro-3-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   I-72: 1-(2-cyclopropyl-4-fluoro-5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-(trideuteromethyl)-1H-tetrazol-5(4H)-one;   I-73: N2-{4-Cyclopropyl-6-fluoro-[3-(4-isopropyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine;   I-74: N2-{4-Cyclopropyl-6-fluoro-3-(1,2,3,4-tetrazol-5-one-1-yl)}phenyl-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine, formate salt;   I-75: N2-{4-Cyclopropyl-6-fluoro-[3-(4-methyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine, citrate salt;   I-76: N2-{4-Cyclopropyl-6-fluoro-[3-(4-methyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine, maleate salt;   I-77: N2-{4-Cyclopropyl-6-fluoro-[3-(4-methyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine, fumarate salt;   I-78: N2-{4-Cyclopropyl-6-fluoro-[3-(4-methyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine, L-tartarate salt;   I-79: N2-{4-Cyclopropyl-6-fluoro-[3-(4-methyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine, hydrogen sulfate salt;   I-80: N2-{4-Cyclopropyl-6-fluoro-[3-(4-methyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine, hydrogen chloride salt;   I-81: N2-{4-Cyclopropyl-6-fluoro-[3-(4-methyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine, benzoate salt;   I-82: N2-{4-Cyclopropyl-6-fluoro-[3-(4-methyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine, tosylate salt;   I-83: N2-{4-Cyclopropyl-6-fluoro-[3-(4-methyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine, besylate salt;   I-84: N2-{4-Cyclopropyl-6-fluoro-[3-(4-methyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine, mesylate salt;   I-85: N2-{4-Cyclopropyl-6-fluoro-[3-(4-methyl)-1,2,3,4-tetrazol-5-one-1-yl]}phenyl-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)-2,4-pyrimidinediamine, acetate salt;   I-86: N2-(4-fluoro-2-methoxy-3-(4-methyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)phenyl)-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidine-2,4-diamine; and   I-87: N2-(4-fluoro-2-methoxy-3-(4-methyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)phenyl)-5-fluoro-N4-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyrimidine-2,4-diamine.   
     
     
         44 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         45 . A method of inhibiting a protein kinase C (PKC) activity in a biological sample or a patient, which method comprises contacting the biological sample or administering to the patient a compound of  claim 1 . 
     
     
         46 . The method of  claim 45 , wherein the inhibition of PKC results in treatment of a disease or disorder that is mediated or sustained through the activity of a PKC activity. 
     
     
         47 . The method of  claim 46 , wherein the disease or disorder is associated with activation of T cells. 
     
     
         48 . The method of  claim 46 , wherein the disease or disorder is an inflammatory disease. 
     
     
         49 . The method of  claim 46 , wherein the disease or disorder is an autoimmune disease. 
     
     
         50 . The method of  claim 46 , wherein the disease or disorder is an ocular disease or disorder involving inflammatory and/or neovascular events. 
     
     
         51 . The method of  claim 46 , wherein the disease or disorder is selected from atherosclerosis, vascular occlusion due to vascular injury, angioplasty, restenosis, obesity, syndrome X, impaired glucose tolerance, polycystic ovary syndrome, hypertension, heart failure, chronic obstructive pulmonary disease, CNS diseases, Alzheimer disease, amyotrophic lateral sclerosis, bipolar disease, cancer, infectious disease, AIDS, septic shock, adult respiratory distress syndrome, ischemia/reperfusion injury, myocardial infarction, stroke, gut ischemia, renal failure, hemorrhage shock, and traumatic shock, and traumatic brain injury. 
     
     
         52 . The method of  claim 46 , wherein the disease or disorder is selected from T-cell mediated acute or chronic inflammatory diseases or disorders or autoimmune diseases, rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, diabetes type I or II and the disorders associated therewith, transplant rejection, graft versus host disease, respiratory diseases, asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury, cutaneous manifestations of immunologically-mediated disorders or illnesses, inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, allergic contact dermatitis, irritant contact dermatitis and further eczematous dermatitises, seborrhoeic dermatitis, inflammatory eye diseases, Sjoegren's syndrome, keratoconjunctivitis, uveitis, inflammatory bowel disease, Crohn's disease or ulcerative colitis, Guillain-Barre syndrome, and allergies. 
     
     
         53 . A method of studying a biological sample known to comprise PKC, the method comprising:
 (a) contacting the biological sample with a compound of  claim 1 ; and   (b) determining the PKC activity inhibiting effects caused by the compound on the biologic sample.   
     
     
         54 . The method of  claim 53 , wherein the determination step is performed using an assay of inhibition of PKC activity.