Pyrimidine kinase inhibitors

Abstract

Compounds that selectively inhibit inappropriate kinase activities and methods for their preparation are disclosed. In one embodiment, the compounds are represented by Formula I, As selective inhibitors of inappropriate kinase activities, the compounds of the present invention are useful in the treatment of conditions associated with such activity, including, but not limited to, inflammatory and autoimmune responses, diabetes, asthma, psoriasis, inflammatory bowel disease, transplantation rejection, and tumor metastasis. Also disclosed are methods of inhibiting inappropriate kinase activities and methods of treating conditions associated with such activities.

1 . A compound, or a salt thereof, represented by Formula I,  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1  is chosen from —H, C 1  to C 20  hydrocarbon, aminocarbonylalkyl, alkoxyalkyl, substituted arylalkyl, heteroaryl, heteroarylalkyl, heterocyclylalkyl, and substituted heterocyclylalkyl;  
 R 2  is chosen from halogen, C 1  to C 20  hydrocarbon, hydroxy, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl,  
                     
 wherein  
 R 5  is chosen from —H, alkyl and substituted alkyl;  
 R 6  is chosen from a direct bond, alkyl, aryl, and heteroaryl; and  
 R 7  is chosen from —H, acyl, alkyl, substituted alkyl, alkoxycarbonyl, amidine, aryl, arylalkyl, heterocyclyl, heteroaryl, substituted heteroaryl, substituted aryloxy, heteroarylsulfonamido, dialkylsulfonamido,  
                     
 wherein  
 R 8  is chosen from —H and alkyl; and  
 R 9  is chosen from —H alkyl, substituted alkyl, aryl, heteroaryl, alkylcarbonyl and arylcarbonyl;  
 R 3  is chosen from a direct bond,  
                     
 wherein the left hand bond is the point of attachment to the ring and the right hand bond is the point of attachment to R 4 ;  
 R 4  is chosen from —H, halogen, alkyl, heterocyclyl, alkylamino, aminocarbonyl,  
                     
 wherein  
 R 10  is chosen from —H, —OH, alkyl, cycloalkyl and substituted cycloalkyl;  
 R 11  is chosen from alkyl, —H, —OH, —COOH, aryl, heteroaryl, substituted heteroaryl, aryl substituted alkyl, cycloalkyl, substituted cycloalkyl, alkoxy, aminocarbonyl, aminocarbonylalkyl,  
                     
 R 12  is chosen from alkyl and aryl;  
 R 13  is chosen from —H and aryl;  
 R 14  is chosen from aryl, substituted aryl, heteroaryl, substituted alkyl, aryl substituted alkyl and alkoxy substituted alkyl;  
 R 15  is chosen from —H, alkyl, aryl, substituted aryl and substituted alkyl;  
 R 16  is chosen from aryl, substituted aryl, heteroaryl, carboxyl, alkoxy, substituted alkyl, cycloalkyl, substituted cycloalkyl, aminocarbonyl, substituted aminocarbonyl, heterocyclyl and  
                     
 R 17  is chosen from alkyl and dialkylamino; and  
 R 18  is chosen from C 1  to C 20  hydrocarbon, substituted C 1  to C 20  hydrocarbon and heteroaryl;  
 Y is chosen from —H and lower alkyl, or Y and R 1  taken together with the attached N, may be chosen from heterocyclyl, substituted heterocyclyl, heteroaryl and substituted heteroaryl; and wherein two of X, X 1  and X 2  are —N═, and the other is —C(H)═.  
 
   
   
       2 - 3 . (canceled)  
   
   
       4 . A compound, or salt thereof, according to  claim 1 , wherein: 
 R 1  is chosen from C 1  to C 20  hydrocarbon and substituted arylalkyl;    R 2  is                          wherein 
 R 5  and R 7  are each —H and  
 R 6  is chosen from substituted aryl and heteroaryl;  
   R 3  is chosen from                          and    R 4  is —C(O)NHR 15 , wherein R 15  is substituted aryl.    
   
   
       5 . A compound, or salt thereof, according to  claim 1 , wherein: 
 R 1  is chosen from C 1  to C 20  hydrocarbon, aminocarbonylalkyl, heteroarylalkyl and substituted arylalkyl;    R 2  is chosen from                          wherein 
 R 5  is chosen from —H and substituted alkyl; and  
 R 7  is chosen from —H, —C(O)NR 8 R 9 , —C(NH)NR 8 R 9  and —NR 8 R 9  wherein 
 R 8  is —H; and  
 R 9  is chosen from —H, alkyl, aryl and arylcarbonyl;  
 
   R 3  is chosen from                          R 4  is —H.    
   
   
       6 . A compound, or salt thereof, according to  claim 1 , wherein: 
 R 2  is                        R 5  is chosen from —H and alkyl; and    R 7  is chosen from heterocyclyl, substituted heteroaryl, —H, aryl, heteroaryl, substituted alkyl and —NR 8 R 9  wherein 
 R 8  is alkyl; and  
 R 9  is substituted alkyl;  
     R 3  is chosen from                          R 4  is chosen from —C(S)NHR 12 , —C(O)NHR 15  and —C(O)(CH 2 ) 0-2 R 16  wherein 
 R 12  is aryl;  
 R 15  is substituted aryl; and  
 R 16  is chosen from substituted aryl and heteroaryl.  
   
   
   
       7 . A compound, or salt thereof, according to  claim 1 , wherein: 
 R 1  is chosen from C 1  to C 20  hydrocarbon, aminocarbonylalkyl, substituted arylalkyl, heteroarylalkyl, heterocyclylalkyl, and substituted heterocyclylalkyl;    R 2  is chosen from                          wherein 
 R 5  is —H; and  
 R 7  is chosen from —H, heteroaryl, substituted heteroaryl, and —NR 8 R 9  wherein 
 R 9  is chosen from alkyl carbonyl and substituted alkyl;  
 
   R 3  is chosen from                          R 4  is chosen from —H and —C(O)(CH 2 ) 0-2 R 16 .    
   
   
       8 . A compound, or salt thereof, according to  claim 1 , wherein: 
 R 1  is chosen from C 1  to C 20  hydrocarbon, alkoxyalkyl, substituted arylalkyl, heteroarylalkyl, and substituted heterocyclalkyl;    R 2  is chosen from                        R 5  is chosen from —H and alkyl; and    R 7  is chosen from —H, heterocyclyl, substituted alkyl, heteroarylsulfonamido, dialkylsulfonamido,                          —NR 8 R 9  wherein 
 R 9  is chosen from alkylcarbonyl, alkyl, substituted alkyl, aryl and arylcarbonyl;  
     R 3  is chosen from a direct bond,                          R 4  is chosen from —H,                          —C(S)NHR 12 , —CHR 13 R 14 , —(O)NHR 15  and —C(O)(CH 2 ) 0-2 R 16  wherein 
 R 10  is —H;  
 R 11  is —H;  
 R 12  is alkyl;  
 R 13  is —H;  
 R 14  is chosen from heteroaryl, substituted aryl and alkoxy substituted alkyl;  
 R 15  is chosen from aryl and substituted aryl; and  
 R 16  is substituted aryl.  
   
   
   
       9 . A compound, or salt thereof, according to  claim 1 , wherein; 
 R 14  is chosen from aryl, substituted aryl, heteroaryl, substituted alkyl and aryl substituted alkyl.    
   
   
       10 . A compound, or salt thereof, according to  claim 1 , wherein: 
 R 1  is heteroaryl;    R 2  is chosen from halogen and                          R 3  is chosen from a direct bond,                          R 4  is chosen from —C(O)(CH 2 ) 0-2 R 16  and                          
   
   
       11 - 14 . (canceled)  
   
   
       15 . A pharmaceutical composition comprising as a therapeutic agent, a compound, or a prodrug or salt thereof, according to  claim 1 , and a pharmaceutically acceptable carrier.  
   
   
       16 - 18 . (canceled)  
   
   
       19 . A compound, or salt thereof, according to  claim 1 , wherein X is —C(H)═, and X 1  and X 2  are each —N═.  
   
   
       20 . A compound, or salt thereof, according to  claim 1 , wherein X 1  is —C(H)═, and X and X 2  are each —N═.  
   
   
       21 . A compound, or salt thereof, according to  claim 1 , wherein X 2  is —C(H)═, and X and X 1  are each —N═.  
   
   
       22 . A compound, or a salt thereof, according to  claim 1  wherein 
 R 1  is chosen from C 1  to C 20  hydrocarbon, heteroaryl, heteroarylalkyl, heterocyclylalkyl, and substituted heterocyclylalkyl.    
   
   
       23 . A compound, or a salt thereof, according to  claim 1  wherein 
 R 3  is chosen from a direct bond; and    R 4  is                        wherein    R 10  is —H; and    R 11  is chosen from heteroaryl, substituted heteroaryl and cycloalkyl.      
   
   
       24 . A compound, or a salt thereof, according to  claim 1  wherein 
 R 1  is chosen from heteroaryl, heteroarylalkyl, heterocyclylalkyl, and substituted heterocyclylalkyl;    R 3  is chosen from a direct bond; and    R 4  is                        wherein    R 10  is —H; and    R 11  is chosen from heteroaryl and substituted heteroaryl.      
   
   
       25 . A compound, or a salt thereof, according to  claim 1  wherein 
 R 1  is chosen from C 1  to C 20  hydrocarbon, alkoxyalkyl, heteroarylalkyl, heterocyclylalkyl, and substituted heterocyclylalkyl;    R 2  is chosen from substituted heteroaryl,                          wherein    R 5  is chosen from H and alkyl;    R 6  is a direct bond; and    R 7  is chosen from heteroaryl and substituted heteroaryl    R 3  is chosen from a direct bond, and                          wherein the left hand bond is the point of attachment to the ring and the right hand bond is the point of attachment to R 4 ;    R 4  is chosen from halogen, alkyl, heterocyclyl, alkylamino,                          —C(O)NHR 15      wherein    R 10  is chosen from H, alkyl and cycloalkyl;    R 11  is chosen from H, C 1  to C 20  hydrocarbon and cycloalkyl; and    R 15  is chosen from H and lower alkyl; and    Y is chosen from —H and lower alkyl.    
   
   
       26 . A compound, or a salt thereof, according to any of claims  1 ,  19 ,  20 , or  21 , wherein 
 R 1  is chosen from —H, C 1  to C 20  hydrocarbon, aminocarbonylalkyl, alkoxyalkyl, substituted arylalkyl, heteroaryl, heteroarylalkyl, heterocyclylalkyl, and substituted heterocyclylalkyl;    R 2  is chosen from halogen, C 1  to C 20  hydrocarbon, hydroxy, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl,                          wherein 
 R 5  is chosen from —H, alkyl and substituted alkyl;  
 R 6  is chosen from a direct bond, alkyl, aryl, and heteroaryl; and  
 R 7  is chosen from —H, acyl, alkyl, substituted alkyl, alkoxycarbonyl, amidine, aryl, arylalkyl, heterocyclyl, heteroaryl, substituted heteroaryl, and substituted aryloxy;  
   R 3  is chosen from a direct bond,                          wherein the left hand bond is the point of attachment to the ring and the right hand bond is the point of attachment to R 4 ;    R 4  is chosen from —H, halogen, alkyl, heterocyclyl, alkylamino, aminocarbonyl,                          wherein 
 R 10  is chosen from —H, —OH, alkyl, cycloalkyl and substituted cycloalkyl;  
 R 11  is chosen from —H, —OH, —COOH, aryl, heteroaryl, substituted heteroaryl, aryl substituted alkyl, cycloalkyl, substituted cycloalkyl, alkoxy, amonicarbonyl, and aminocarbonylalkyl; and  
   Y is chosen from —H and lower alkyl.