Small-molecule hsp90 inhibitors

Abstract

Purine scaffold Hsp90 inhibitors are useful in therapeutic applications and as radioimaging ligands.

1 - 35 . (canceled) 
     
     
         36 . A method of preparing a compound of formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         the method comprising reacting a compound of formula IN-1: 
       
       
         
           
           
               
               
           
         
         with NHR 1 R 2  in the presence of a base; 
         wherein:
 X 3  is hydrogen or halogen; 
 X 1 X 1  is a C 1  to C 10  alkyl, alkenyl, or alkynyl group, wherein the alkyl, alkenyl, or alkynyl group includes a nitrogen atom; 
 the linker is CH2 or S; 
 X 2  is halogen, alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, pyrollyl, optionally substituted aryloxy, alkylamino, dialkylamino, carbamyl, amido, alkylamido dialkylamido, acylamino, alkylsulfonylamido, trihalomethoxy, trihalocarbon, thioalkyl, COO-alkyl, NH 2 , OH, CN, SO 2 X 7 , NO 2 , NO, C═SR 2a , NHSO 2 X 7 , or C═OR 2a , where X 7  is F, NH 2 , alkyl or H, and R 2a  is alkyl, NH 2 , NH-alkyl or O-alkyl; 
 R 1  and R 2  are each independently hydrogen or a C 1  to C 10  alkyl, alkenyl, or alkynyl group; 
 n is 1 or 2; 
 m is 0, 1, or 2; and 
 the halo group is Cl, Br, or I. 
 
       
     
     
         37 . The method of  claim 36 , further comprising the step of preparing the compound of formula IN-1 by reacting a compound of formula IN-2: 
       
         
           
           
               
               
           
         
         with Halo-(CH 2 ) p —OH, 
         wherein:
 p is 1, 2, or 3; 
 the halo group is Cl, Br, or I. 
 
       
     
     
         38 . The method of  claim 37 , further comprising the step of preparing the compound of formula IN-2 by reacting a compound of formula IN-3: 
       
         
           
           
               
               
           
         
         with a compound of formula IN-4: 
       
       
         
           
           
               
               
           
         
         in the presence of a transition metal catalyst and a base; 
         wherein the halo group is Cl, Br, or I. 
       
     
     
         39 . The method of  claim 38 , further comprising the step of preparing the compound of formula IN-3 by reacting a compound of formula IN-8: 
       
         
           
           
               
               
           
         
         with CS 2 . 
       
     
     
         40 . The method of  claim 37 , further comprising the step of preparing the compound of formula IN-2 by reacting a compound of formula IN-5: 
       
         
           
           
               
               
           
         
         with a compound of formula IN-6: 
       
       
         
           
           
               
               
           
         
         wherein the halo group is Cl, Br, or I. 
       
     
     
         41 . The method of  claim 37 , wherein the reaction is carried out in the presence of PPh 3  and an azodicarboxylate. 
     
     
         42 . The method  claim 37 , wherein X 3  is F in the compound of formula IN-2, and further comprising the step of preparing the compound of formula IN-2 by reacting a compound of formula IN-7: 
       
         
           
           
               
               
           
         
         with a fluorine source. 
       
     
     
         43 . The method of  claim 42 , wherein the step of preparing the compound of formula IN-2 comprises HF-pyridine and a nitrite salt. 
     
     
         44 . The method of  claim 42 , wherein the linker is CH 2  in the compound of formula IN-7, and further comprising the step of preparing the compound of formula IN-7 by reacting a compound of formula IN-9: 
       
         
           
           
               
               
           
         
         with a base. 
       
     
     
         45 . The method of  claim 44 , further comprising the step of preparing the compound of formula IN-9 by reacting a compound of formula IN-10: 
       
         
           
           
               
               
           
         
         with a compound of formula IN-11: