Urea derivatives as abl modulators

Abstract

The invention provides methods and compositions for treating conditions mediated by Bcr-Abl. The invention also provides methods of using the compounds and/or compositions in the treatment of a variety of diseases and unwanted conditions in subjects.

1 . A compound of Formula (VII): 
     
       
         
         
             
             
         
       
     
     wherein:
 each X is independently C, CR, N, NR, or O, wherein no more than three X's are a heteroatom, and no two adjacent ring atoms are O; and
 each R is independently H, halogen, alkyl, —OH, alkoxy, —OC(O)R d , —NO 2 , —N(R d ) 2 , —SR d , —S(O) h R d  where j is 1 or 2, —NR d C(O)R d , —C(O) 2 R d , —C(O)N(R d ) 2  or —C(O)R d , or two adjacent R's are taken together to form a aryl or heteroaryl, where 
 each R d  is independently H, alkyl, cycloalkyl, aryl or heteroaryl. 
 
 
   
   
       2 . The compound of  claim 1 , wherein the compound has Formula (VIII): 
     
       
         
         
             
             
         
       
     
   
   
       3 . The compound of  claim 1 , wherein the compound is selected from: 
     
       
         
         
             
             
         
       
     
   
   
       4 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable excipient. 
   
   
       5 . A method of modulating abl kinase comprising administering a a therapeutically effective amount of the compound of  claim 1 . 
   
   
       6 . A method of treating a disease mediated by abl kinase, wherein the method comprises administering a therapeutically effective amount of the compound of  claim 1 . 
   
   
       7 . The method of  claim 6 , wherein the disease is cancer. 
   
   
       8 . The method of  claim 6 , wherein the abl kinase has a T315I mutation. 
   
   
       9 . The method of  claim 6 , wherein the cancer is leukemia. 
   
   
       10 . The method of  claim 6 , wherein the cancer is chronic myeloid leukemia. 
   
   
       11 . The method of  claim 6 , wherein the cancer is STI571-resistant chronic myeloid leukemia.