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.

What is claimed is: 
     
         1 . A compound of formula (IVc) 
       
         
           
           
               
               
           
         
         wherein 
         R 1 , R 2 , R 3 , R 4 , R 5 , and R 6  are independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -aryl and —SO 2 -heteroaryl; or R 1  and R 2  together form an oxo group; or R 3  and R 4  together form an oxo group; or R 5  and R 6  together form an oxo group; 
         R 7 , R 8 , R 9 , and R 10  are independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -aryl and —SO 2 -heteroaryl; or R 7  and R 8  together form an oxo group; or R 9  and R 10  together form an oxo group; 
         R 11  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; 
         R 20  is selected from hydrogen, alkyl, and substituted alkyl; 
         Y 1  and Y 2  are independently selected from hydrogen and alkyl; and 
         R 12  is selected from hydrogen and halogen; 
         R 13  and R 16  are hydrogen; 
         R 14  is —O-Alk-OR 25 , where Alk is an optionally substituted alkylene group and R 25  is selected from hydrogen and an optionally substituted alkyl group; 
         R 15  is a substituted heterocyclyl; 
         or a salt or stereoisomer thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein R 12  is hydrogen. 
     
     
         3 . The compound of  claim 1 , wherein R 12  is fluoro. 
     
     
         4 . The compound of  claim 1 , wherein R 25  is hydrogen. 
     
     
         5 . The compound of  claim 1 , wherein R 25  is an optionally substituted alkyl group. 
     
     
         6 . The compound of  claim 1 , wherein Alk is a substituted alkylene group. 
     
     
         7 . The compound of  claim 1 , wherein Alk is an ethylene moiety. 
     
     
         8 . The compound of  claim 1 , wherein Alk is a substituted ethylene moiety. 
     
     
         9 . The compound of  claim 1 , wherein R 15  is an optionally substituted tetrazolone. 
     
     
         10 . The compound of  claim 1 , wherein R 15  is of the formula 
       
         
           
           
               
               
           
         
       
       wherein R 26  is hydrogen, haloalkyl or alkyl. 
     
     
         11 . The compound of  claim 1 , wherein R 1  and R 2  are hydrogen. 
     
     
         12 . The compound of  claim 1 , wherein R 3  and R 4  are hydrogen. 
     
     
         13 . The compound of  claim 1 , wherein R 5  and R 6  are hydrogen. 
     
     
         14 . The compound of  claim 1 , wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 6  are hydrogen. 
     
     
         15 . The compound of  claim 1 , wherein R 7 , R 8 , R 9 , and R 10  are independently selected from hydrogen, alkyl, substituted alkyl, and halogen. 
     
     
         16 . The compound of  claim 1 , wherein R 7  and R 8  are methyl. 
     
     
         17 . The compound of  claim 1 , wherein R 9  and R 10  are hydrogen. 
     
     
         18 . The compound of  claim 1 , wherein R 11  is selected from alkoxy, substituted alkoxy, cyano, halogen, acyl, aminoacyl, and nitro. 
     
     
         19 . The compound of  claim 1 , wherein R 11  is fluoro or cyano. 
     
     
         20 . The compound of  claim 1 , wherein R 20  is hydrogen. 
     
     
         21 . The compound of  claim 1 , wherein Y 1  and Y 2  are hydrogen. 
     
     
         22 . The compound of  claim 1 , wherein the formula is 
       
         
           
           
               
               
           
         
         wherein H 1  and H 2  are hydrogen with cis relative configuration. 
       
     
     
         23 . The compound of  claim 22 , wherein the compound is optically active. 
     
     
         24 . The compound of  claim 23 , having an enantiomeric excess of 90% or more. 
     
     
         25 . The compound of  claim 23 , wherein the enantiomeric excess is 95% or more. 
     
     
         26 . The compound of  claim 23 , wherein the enantiomeric excess is 99% or more. 
     
     
         27 . The compound of  claim 1 , wherein the compound is selected from:
 Compound 77: 1-(2-(2-hydroxyethoxy)-5-(4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-5-fluoropyrimidin-2-ylamino)-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-one;   Compound 78: 4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-2-(4-(2-hydroxyethoxy)-2-fluoro-5-(4,5-dihydro-4-methyl-5-oxotetrazol-1-yl)phenylamino)pyrimidine-5-carbonitrile;   Compound 79: 4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-2-(4-((S)-2-hydroxypropoxy)-2-fluoro-5-(4,5-dihydro-4-methyl-5-oxotetrazol-1-yl)phenylamino)pyrimidine-5-carbonitrile;   Compound 80: 4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-2-(4-(2-hydroxy-2-methylpropoxy)-2-fluoro-5-(4,5-dihydro-4-methyl-5-oxotetrazol-1-yl)phenylamino)pyrimidine-5-carbonitrile;   Compound 81: 1-(2-((S)-2-hydroxypropoxy)-5-(4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-5-fluoropyrimidin-2-ylamino)-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-one;   Compound 82: 1-(5-(4-((7R,8aS)-5,5-dimethyloctahydroindolizin-7-ylamino)-5-fluoropyrimidin-2-ylamino)-4-fluoro-2-((R)-2-hydroxypropoxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   Compound 83: 4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-2-(4-(1-hydroxy-2-methylpropan-2-yloxy)-3-(4,5-dihydro-4-methyl-5-oxotetrazol-1-yl)phenylamino)pyrimidine-5-carbonitrile;   Compound 84: 4-((7R,8aS)-5,5-dimethyloctahydroindolizin-7-ylamino)-2-(2-fluoro-4-(1-hydroxy-2-methylpropan-2-yloxy)-5-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenylamino)pyrimidine-5-carbonitrile;   Compound 85: 1-(5-(4-((7R,8aS)-5,5-dimethyloctahydroindolizin-7-ylamino)-5-fluoropyrimidin-2-ylamino)-4-fluoro-2-(1-hydroxy-2-methylpropan-2-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   Compound 86: 1-(5-(4-((7R,8aS)-5,5-dimethyloctahydroindolizin-7-ylamino)-5-fluoropyrimidin-2-ylamino)-2-(1-hydroxy-2-methylpropan-2-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one;   Compound 87: 1-(5-(4-((7R,8aS)-5,5-dimethyloctahydroindolizin-7-ylamino)-5-fluoropyrimidin-2-ylamino)-4-fluoro-2-(2-hydroxy-2-methylpropoxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one; and   Compound 90: 4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-2-(4-((R)-2-hydroxypropoxy)-2-fluoro-5-(4,5-dihydro-4-methyl-5-oxotetrazol-1-yl)phenylamino)pyrimindine-5-carbonitrile.   
     
     
         28 . A compound selected from:
 Compound 88: 1-(5-(4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-5-fluoropyrimidin-2-ylamino)-4-fluoro-2-(oxetan-3-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one; and   Compound 89: 1-(5-(4-((7R,8aS)-5,5-dimethyloctahydroindolizin-7-ylamino)-5-fluoropyrimidin-2-ylamino)-4-fluoro-2-hydroxyphenyl)-4-methyl-1H-tetrazol-5(4H)-one.   
     
     
         29 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         30 . 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 .