2-anilino-4-aminoalkyleneaminopyrimidines

Abstract

The present invention relates to 2-arylamino-4-(aminoalkylene)aminopyrimidines inhibitors which are inhibitors and therefore inhibit Protein Kinase C-alpha (PKC-α). The PKC-α inhibitors of the present invention are important for improving myocardial intracellular calcium cycling, resulting in improved myocardial contraction and relaxation performance and thereby slowing the progression of heart failure. The present invention further relates to compositions comprising said 2-arylamino-4-(aminoalkylene)amino-pyrimidines and to methods for controlling, abating, or otherwise slowing the progression of heart failure.

1 . A compound having the formula:  
     
       
         
         
             
             
         
       
       wherein R is a unit having the formula:  
       
         
           
           
               
               
           
         
       
       R 2  and R 3  are each independently chosen from:  
       i) hydrogen; or  
       ii) C 1 -C 4  substituted or unsubstituted linear, branched, or cyclic alkyl;  
       L is a linking unit having the formula:  
         —[C(R 4a R 4b )] n — 
       each R 4a  and R 4b  is independently chosen from:  
       i) hydrogen; or  
       ii) C 1 -C 4  linear, branched, or cyclic alkyl;  
       the index n is from 1 to 4; and  
       R 1  is substituted or unsubstituted aryl;  
       excluding the compounds N 2 -(4-chlorophenyl)-N 4 -[(2-diethylamino)ethyl]-pyrimidine-2,4-diamine, N 2 -(4-chlorophenyl)-N 4 -[(3-diethylamino)propyl]-pyrimidine-2,4-diamine, and N 2 -(4-methylphenyl)-N 4 -[(2-diethylamino)ethyl]-pyrimidine-2,4-diamine.  
     
   
   
       2 . A compound according to  claim 1  wherein R 7  and R 3  are each independently chosen from hydrogen, methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl.  
   
   
       3 . A compound according to  claim 1  wherein R is a unit chosen from —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NH(CH 2 CH 3 ), —N(CH 2 CH 3 ) 2 , —N(CH 3 )(CH 2 CH 3 ), —NH(CH 2 CH 2 CH 3 ), —N(CH 3 )(CH 2 CH 2 CH 3 ), —N(CH 2 CH 3 )(CH 2 CH 2 CH 3 ), and —N(CH 2 CH 2 CH 3 ) 2 .  
   
   
       4 . A compound according to  claim 3  wherein R is a unit chosen from —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NH(CH 2 CH 3 ), and —N(CH 2 CH 3 ) 2 .  
   
   
       5 . A compound according to  claim 1  wherein R 1  is a phenyl unit substituted with one or more units chosen from: 
 i) C 1 -C 4  linear, branched, or cyclic alkyl;    ii) halogen;    iii) —OR 6 ;    iv) —SO 2 N(R 6 ) 2 ;    v) —CH m X n ; wherein each X is independently F, Cl, Br, or I, m is from 0 to 2, m+n=3; and    vi) —NO 2 ;    each R 6  is independently hydrogen, C 1 -C 4  linear, branched, or cyclic alkyl, or phenyl.    
   
   
       6 . A compound according to  claim 5  wherein R 1  is chosen from 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 3-chloro-4-methylphenyl, 3-chloro-4-fluorophenyl, 3,4-difluorophenyl, 3-trifluoromethylphenyl, 3-trifluoromethyl-4-chlorophenyl, 3-methoxyphenyl, 3-methylphenyl, 3-ethylphenyl, and 3-isopropylphenyl.  
   
   
       7 . A compound according to  claim 5  wherein R 1  is chosen from 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenyl, 2,3,6-trifluorophenyl, 2,4,5-trifluorophenyl, 2,4,6-trifluorophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 2,3,4-trichlorophenyl, 2,3,5-trichlorophenyl, 2,3,6-trichlorophenyl, 2,4,5-trichlorophenyl, and 2,4,6-trichlorophenyl.  
   
   
       8 . A compound according to  claim 5  wherein R 1  is chosen from 2-methylphenyl, 4-methylphenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethyl-phenyl, 2,6-dimethylphenyl, 3,4-dimethyl-phenyl, 2,3,4-trimethylphenyl, 2,3,5-trimethyl-phenyl, 2,3,6-trimethylphenyl, 2,4,5-trimethylphenyl, 2,4,6-trimethylphenyl, 2-ethylphenyl, 4-ethylphenyl, 2,3-diethylphenyl, 2,4-diethylphenyl, 2,5-diethylphenyl, 2,6-diethylphenyl, 3,4-diethylphenyl, 2,3,4-triethylphenyl, 2,3,5-triethylphenyl, 2,3,6-triethylphenyl, 2,4,5-triethylphenyl, and 2,4,6-triethylphenyl.  
   
   
       9 . A compound according to  claim 5  wherein R 1  is chosen from 2-methoxyphenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2,3,4-trimethoxyphenyl, 2,3,5-trimethoxyphenyl, 2,3,6-trimethoxy-phenyl, 2,4,5-trimethoxyphenyl, 2,4,6-trimethoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2,3-dihydroxyphenyl, 2,4-dihydroxyphenyl, 2,5-dihydroxyphenyl, 2,6-dihydroxyphenyl, 3,4-dihydroxy-phenyl, 2,3,4-trihydroxyphenyl, 2,3,5-trihydroxy-phenyl, 2,3,6-trihydroxyphenyl, 2,4,5-trihydroxyphenyl, and 2,4,6-trihydroxyphenyl.  
   
   
       10 . A compound chosen from: 
 N 2 -(3-chlorophenyl)-N 4 -(3-(dimethylamino)propyl)pyrimidine-2,4-diamine;    N 2 -(3-chlorophenyl)-N 4 -(3-(diethylamino)propyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)propyl)-N 2 -(3-methoxyphenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)propyl)-N 2 -(3-methylphenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)propyl)-N 2 -(3-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine;    N 2 -(3-chlorophenyl)-N 4 -(3-(methylamino)propyl)pyrimidine-2,4-diamine;    N 4 -(3-amino)propyl)-N 2 -(3-chlorophenyl)pyrimidine-2,4-diamine;    N 2 -(3,4-difluorophenyl)-N 4 -(3-(dimethylamino)propyl)pyrimidine-2,4-diamine;    N 2 -(3-chloro-4-methylphenyl)-N 4 -(3-(dimethylamino)propyl)pyrimidine-2,4-diamine;    N 2 -(3,4-dichlorophenyl)-N 4 -(3-(dimethylamino)propyl)pyrimidine-2,4-diamine;    N 2 -(3-chloro-4-fluorophenyl)-N 4 -(3-(dimethylamino)propyl)pyrimidine-2,4-diamine;    N 2 -(4-chloro-3-(trifluoromethyl)phenyl)-N 4 -(3-(dimethylamino)propyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)propyl)-N 2 -(3-ethylphenyl)pyrimidine-2,4-diamine;    N 4 -[3-(dimethylamino)-2,2-dimethylpropyl]-N 2 -[3-(trifluoromethyl)phenyl]-pyrimidine-2,4-diamine;    N 2 -(3-chlorophenyl)-N 4 -(3-(dimethylamino)butyl)pyrimidine-2,4-diamine;    N 2 -(3-chlorophenyl)-N 4 -(2-(dimethylamino)ethyl)pyrimidine-2,4-diamine; and    N 4 -(3-aminopropyl)-N 2 -(3-chlorophenyl)-N 4 -methylpyrimidine-2,4-diamine.    
   
   
       11 . A compound chosen from: 
 N 4 -(3-(dimethylamino)propyl)-N 2 -(2-fluorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)propyl)-N 2 -(3-fluorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)propyl)-N 2 -(4-fluorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)propyl)-N 2 -(2,3-difluorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)propyl)-N 2 -(2,4-difluorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)propyl)-N 2 -(2,5-difluorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)propyl)-N 2 -(2,6-difluorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)propyl)-N 2 -(2-chlorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)propyl)-N 2 -(2,3-dichlorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)propyl)-N 2 -(2,4-dichlorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)propyl)-N 2 -(2,5-dichlorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)propyl)-N 2 -(2,6-dichlorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)propyl)-N 2 -(2-methylphenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)propyl)-N 2 -(4-methylphenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)propyl)-N 2 -(2,3-dimethylphenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)propyl)-N 2 -(2,4-dimethylphenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)propyl)-N 2 -(2,5-dimethylphenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)propyl)-N 2 -(2,6-dimethylphenyl)pyrimidine-2,4-diamine; and    N 4 -(3-(dimethylamino)propyl)-N 2 -(3,4-dimethylphenyl)pyrimidine-2,4-diamine.    
   
   
       12 . A compound chosen from: 
 N 2 -(3-chlorophenyl)-N 4 -(3-(dimethylamino)butyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)ethyl)-N 2 -(2-fluorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)ethyl)-N 2 -(3-fluorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)ethyl)-N 2 -(4-fluorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)ethyl)-N 2 -(2,3-difluorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)ethyl)-N 2 -(2,4-difluorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)ethyl)-N 2 -(2,5-difluorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)ethyl)-N 2 -(2,6-difluorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)ethyl)-N 2 -(2-chlorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)ethyl)-N 2 -(4-fluorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)ethyl)-N 2 -(2,3-dichlorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)ethyl)-N 2 -(2,4-dichlorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)ethyl)-N 2 -(2,5-dichlorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethyl)amino)ethyl)-N 2 -(2,6-dichlorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)ethyl)-N 2 -(2-methylphenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)ethyl)-N 2 -(3-methylphenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)ethyl)-N 2 -(4-methylphenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)ethyl)-N 2 -(2,3-dimethylphenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)ethyl)-N 2 -(2,4-dimethylphenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)ethyl)-N 2 -(2,5-dimethylphenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)ethyl)-N 2 -(2,6-dimethylphenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)ethyl)-N 2 -(3,4-dimethylphenyl)pyrimidine-2,4-diamine;    N 2 -(3-chlorophenyl)-N 4 -(3-(dimethylamino)butyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)butyl)-N 2 -(2-fluorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)butyl)-N 2 -(3-fluorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)butyl)-N 2 -(4-fluorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)butyl)-N 2 -(2,3-difluorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)butyl)-N 2 -(2,4-difluorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)butyl)-N 2 -(2,5-difluorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)butyl)-N 2 -(2,6-difluorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)butyl)-N 2 -(2-chlorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)butyl)-N 2 -(4-chlorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)butyl)-N 2 -(2,3-dichlorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)butyl)-N 2 -(2,4-dichlorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)butyl)-N 2 -(2,5-dichlorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)butyl)-N 2 -(2,6-dichlorophenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)butyl)-N 2 -(2-methylphenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)butyl)-N 2 -(4-methylphenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)butyl)-N 2 -(2,3-dimethylphenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)butyl)-N 2 -(2,4-dimethylphenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)butyl)-N 2 -(2,5-dimethylphenyl)pyrimidine-2,4-diamine;    N 4 -(3-(dimethylamino)butyl)-N 2 -(2,6-dimethylphenyl)pyrimidine-2,4-diamine; and    N 4 -(3-(dimethylamino)butyl)-N 2 -(3,4-dimethylphenyl)pyrimidine-2,4-diamine.    
   
   
       13 . A compound having the formula:  
     
       
         
         
             
             
         
       
       R 2  and R 3  are each independently chosen from:  
       i) hydrogen; or  
       ii) C 1 -C 4  linear or branched alkyl; and  
       R 5  is chosen from:  
       i) C 1 -C 4  linear, branched, or cyclic alkyl;  
       ii) halogen;  
       iii) —OR 6 ;  
       iv) —SO 2 N(R 6 ) 2 ;  
       v) —CH m X n ; wherein each X is independently F, Cl, Br, or I, m is from 0 to 2, m+n=3;  
       vi) —NO 2 ; and  
       vii) phenyl;  
       each R 6  is independently hydrogen, or C 1 -C 4  linear, branched, or cyclic alkyl;  
       excluding N 2 -(4-chlorophenyl)-N 4 -[(3-diethylamino)propyl]-pyrimidine-2,4-diamine.  
     
   
   
       14 . A compound according to  claim 13  wherein R 2  and R 3  are each independently hydrogen, methyl, and ethyl.  
   
   
       15 . A compound according to  claim 13  wherein R 5  is chosen from 3-chloro, 4-chloro, 3,4-dichloro, 3-chloro-4-methyl-, 3-chloro-4-fluoro, 3,4-difluoro, 3-trifluoro-methyl, 3-trifluoromethyl-4-chloro, 3-methoxy, 3-methyl, 3-ethyl, and 3-iso-propyl.  
   
   
       16 . A compound according to  claim 13  wherein R 5  is chosen from 2-fluoro, 3-fluoro, 4-fluoro, 2,3-difluoro, 2,4-difluoro, 2,5-difluoro, 2,6-difluoro, 2-chloro, 2,3-dichloro, 2,4-dichloro, 2,5-dichloro and, 2,6-dichloro.  
   
   
       17 . A compound according to  claim 13  wherein R 5  is chosen from 2-methoxy, 4-methoxy, 2,3-dimethoxy, 2,4-dimethoxy, 2,5-dimethoxy, 2,6-dimethoxy, 3,4-dimethoxy, 2-hydroxy, 3-hydroxy, 4-hydroxy, 2,3-dihydroxy, 2,4-dihydroxy, 2,5-dihydroxy, 2,6-dihydroxy, and 3,4-dihydroxy.  
   
   
       18 . A compound having the formula:  
     
       
         
         
             
             
         
       
       R 2  and R 3  are each independently chosen from:  
       i) hydrogen; or  
       ii) C 1 -C 4  linear or branched alkyl; and  
       R 5  is chosen from:  
       i) C 1 -C 4  linear, branched, or cyclic alkyl;  
       ii) halogen;  
       iii) —OR 6 ;  
       iv) —SO 2 N(R 6 ) 2 ;  
       v) —CH m X n ; wherein each X is independently F, Cl, Br, or I, m is from 0 to 2, m+n=3;  
       vi) —NO 2 ; and  
       vii) phenyl;  
       each R 6  is independently hydrogen, or C 1 -C 4  linear, branched, or cyclic alkyl; and  
       L is chosen from:  
       i) —CH 2 —, methylene;  
       ii) —CH 2 CH 2 —, ethylene;  
       iii) —CH(CH 3 )CH 2 —, 1-propylene;  
       iv) —CH 2 CH(CH 3 )—, 2-propylene;  
       v) —CH 2 CH 2 CH 2 CH 2 —, butylene.  
       vi) —CH(CH 3 )CH 2 Cl 2 —, 1-butylene;  
       vii) —CH 2 CH(CH 3 )CH 2 —, 2-butylene; and  
       viii) —CH 2 C(CH 3 ) 2 CH 2 % 2,2-dimethylpropylene;  
       excluding N 2 -(4-chlorophenyl)-N 4 -[(2-diethylamino)ethyl]-pyrimidine-2,4-diamine and N 2 -(4-methylphenyl)-N 4 -[(2-diethylamino)ethyl]-pyrimidine-2,4-diamine.  
     
   
   
       19 . A composition comprising: 
 A) a compound having the formula:                        wherein R is a unit having the formula:                          R 2  and R 3  are each independently chosen from:    i) hydrogen; or    ii) C 1 -C 4  linear, branched, or cyclic allyl;    L is a linking unit having the formula:      —[C(R 4a R 4b )] n —   each R 4a  and R 4b  is independently chosen from:    i) hydrogen; or    ii) C 1 -C 4  linear, branched, or cyclic alkyl;    the index n is from 1 to 4; and    R 1  is aryl; and      B) the balance carriers and excipients.    
   
   
       20 . A method for improving cardiac contraction/relaxation parameters in heart failure 
 patients comprising administering to a human suffering from acute heart failure a composition comprising a compound having the formula:                          wherein R is a unit having the formula:                          R 2  and R 3  are each independently chosen from:    i) hydrogen; or    ii) C 1 -C 4  linear, branched, or cyclic alkyl;    L is a linking unit having the formula:      —[C(R 4a R 4b )] n —   each R 4a  and R 4b  is independently chosen from:    i) hydrogen; or    ii) C 1 -C 4  linear, branched, or cyclic alkyl;    the index n is from 1 to 4; and    R 1  is aryl.    
   
   
       21 . A method for treating chronic or acute heart failure comprising administering to a human an effective amount of a composition comprising one or more of the PKC-α inhibitors having the formula:  
     
       
         
         
             
             
         
       
       wherein R is a unit having the formula:  
       
         
           
           
               
               
           
         
       
       R 2  and R 3  are each independently chosen from:  
       i) hydrogen; or  
       ii) C 1 -C 4  linear, branched, or cyclic alkyl;  
       L is a linking unit having the formula:  
         —[C(R 4a R 4b )] n — 
       each R 41  and R 4b  is independently chosen from:  
       i) hydrogen; or  
       ii) C 1 -C 4  linear, branched, or cyclic alkyl;  
       the index n is from 1 to 4; and  
       R 1  is aryl.  
     
   
   
       22 . The use of a compound in the manufacture of a medicament, said compound having the formula:  
     
       
         
         
             
             
         
       
       wherein R is a unit having the formula:  
       
         
           
           
               
               
           
         
       
       R 2  and R 3  are each independently chosen from:  
       i) hydrogen; or  
       ii) C 1 -C 4  linear, branched, or cyclic alkyl;  
       L is a linking unit having the formula:  
         —[C(R 4a R 4b )] n — 
       each R 4a  and R 4b  is independently chosen from:  
       i) hydrogen; or  
       ii) C 1 -C 4  linear, branched, or cyclic alkyl;  
       the index n is from 1 to 4; and  
       R 1  is aryl.  
     
   
   
       23 . A method for treating or preventing a disease or medical condition selected from diabetes, numerous forms of cancer, microalbinuria, endothelial dysfunction, cerebrovascular disease, stroke, coronary heart disease, cardiovascular disease and sequela (e.g. arrhythmia, sudden death, increased infarct size, congestive heart failure, angina), myocardial ischemic states, hypertension, lipid disorders, ischemia-reperfusion injury, atherosclerosis, peripheral artery/vascular disease, microvascular complications of diabetes (neuropathy, nephropathy, retinopathy), restenosis, renal disease, blood coagulation disorders, inflammatory diseases, cardiac hypertrophy, dilated cardiomyopathy, ischemic injury and suboptimal mitogen stimulation said method comprised of the steps of administering to a patient in need thereof a therapeutic amount of a compound according to  claim 1 .  
   
   
       24 . A method for treating acute heart failure comprising administering to a human an effective amount of a composition comprising one or more of the PKC-α inhibitors according to  claim 1 .  
   
   
       25 . A method for chronic heart failure comprising administering to a human an effective amount of a composition comprising one or more of the PKC-α inhibitors according to  claim 1 .  
   
   
       26 . A method of treating or preventing chronic or acute heart failure, said method comprised of the step of administering to a patient in need thereof a pharmaceutically acceptable amount of a compound according to  claim 1  or a therapeutically acceptable salt thereof in combination with a drug selected that acts on the renin-angiotensin-aldosterone system, a diuretic, digoxin or a β-adrenergic receptor blockers, natriuretic peptides and inotropic agents.  
   
   
       27 . The method of  claim 26  wherein the drug used in combination with a compound according to  claim 1  is a renin-angiotensin-aldosterone system selected from an ACEI, ARB, or aldosterone inhibitor.