Kinase inhibitor scaffolds and methods for their preparation

Abstract

General methods for the solution phase as well as solid phase synthesis of various substituted heteroaryls has been demonstrated. These substituted heteroaryls can be further elaborated by aromatic substitution with amines at elevated temperature or by anilines, boronic acids and phenols via palladium catalyzed cross-coupling reactions.

1 . A compound having the following Formula:  
     
       
         
         
             
             
         
       
       wherein  
       R is selected from the group consisting of a 5- or 6-membered heteroaryl and a 9- or 10-membered 6,5- or 6,6-fused heteroaryl, containing from 1-4 nitrogen atoms, optionally substituted with 1-2 groups independently selected from the group consisting of hydrogen, C 1-6 alkyl, aryl, C 1-6 alkylaryl, C 3-8 cycloalkyl, heterocycle, heteroaryl, C 1-6 alkylhydroxy, C 1-6 alkoxy and NR 4 R 4 ;  
       R 1  is a member selected from the group consisting of phenyl and benzyl, substituted on the aromatic ring with from 1-4 substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylhydroxy, C 1-6 alkylamine, C 1-6 aminoalkyl, halo and heterocycle;  
       L is selected from the group consisting of —O—, —NR 2 — and a bond;  
       each R 2  is independently a member selected from the group consisting of hydrogen and C 1-4 alkyl;  
       R 3  is independently a member selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, halogen and alkoxy groups; or  
       R 2  and R 3  taken together form a 3-8 membered heterocyclic ring containing from 1-2 heteroatoms selected from the group consisting of N and O, optionally substituted with 1-2 members independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkylhydroxy, C 1-4 alkoxy and C 1-4 alkylamine;  
       R 4 , if present, is a member selected from the group consisting of optionally substituted alkyl, optionally substituted heteroalkyl and acyl groups; and  
       all pharmaceutically acceptable salts, hydrates, solvates, isomers and prodrugs thereof.  
     
   
   
       2 . A compound of  claim 1 , wherein R is a 6-membered aromatic ring containing 2 nitrogen atoms.  
   
   
       3 . A compound of  claim 1 , wherein R is a 6,5-fused aromatic ring containing from 1-4 nitrogen atoms.  
   
   
       4 . A compound of  claim 1 , wherein R is a 6,6-fused aromatic ring containing from 1-4 nitrogen atoms.  
   
   
       5 . A compound of  claim 1 , wherein R is a member selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
   
   
       6 . A compound of  claim 1 , wherein R is a member selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
   
   
       7 . A compound of  claim 1 , wherein R is a member selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
   
   
       8 . A compound of  claim 1 , wherein R is the following structure:  
     
       
         
         
             
             
         
       
     
   
   
       9 . A compound of  claim 1 , wherein: 
 R is a 2,6,9-substituted purine, substituted with a member selected from the group consisting of:                          R 1  is a phenyl substituted with morpholine;    L-R 3  is a member selected from the group consisting of-.                          R 4  is not present.    
   
   
       10 . A compound of  claim 1 , wherein R 1  is  
     
       
         
         
             
             
         
       
     
   
   
       11 . A compound of  claim 1 , wherein L and R 3  taken together are selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       12 . A compound of  claim 1 , wherein R 4 , when present, is isopropyl.  
   
   
       13 . A compound of  claim 1 , wherein R 2  is H or Me.  
   
   
       14 . A compound of  claim 1 , selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       15 . A compound of  claim 1 , selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
   
   
       16 . A pharmaceutical composition comprising a compound according to  claim 1 , and a pharmaceutically acceptable carrier.