IRE-1alpha INHIBITORS

Abstract

The invention provides compounds which directly inhibit IRE-1α activity in vitro, prodrugs, and pharmaceutically acceptable salts thereof. Such compounds and prodrugs are useful for treating diseases associated with the unfolded protein response and can be used as single agents or in combination therapies.

1 - 9 . (canceled) 
     
     
         10 . A compound of formula (2b): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein 
         R3 is hydrogen or —CN; 
         R6 is 
       
       
         
           
           
               
               
           
         
         Het is a five-membered heteroaryl containing 1, 2, or 3 heteroatoms atoms selected from N, S, and O and optionally substituted with alkyl, provided that Het is not unsubstituted 
       
       
         
           
           
               
               
           
         
         R24 is —OH or 
       
       
         
           
           
               
               
           
         
         R9 and R10 independently are alkyl; or 
         R9 and R10, together with the atoms to which they are attached, form a 4-, 5-, 6-, or 7-membered heteroaryl or heterocycle containing 1 or 2 heteroatoms selected from N, O and S, optionally substituted with alkyl; 
         or R9 is hydrogen and R10 is 
       
       
         
           
           
               
               
           
         
         wherein n is 0, 1, 2, or 3; and 
         R25 is C1-C3 alkoxy or a 5- or 6-membered heteroaryl or heterocycle having one or two heteroatoms selected from N, O, and S and optionally substituted with alkyl, with the proviso that when Het is 
       
       
         
           
           
               
               
           
         
         then R24 is not —OH, 
       
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 10 , wherein Het is thienyl optionally substituted with alkyl. 
     
     
         12 . A pharmaceutical composition, comprising the compound of  claim 10 , and a pharmaceutically acceptable vehicle. 
     
     
         13 . A method of treating a disease associated with the unfolded protein response, comprising administering to a patient in need thereof an effective amount of the compound of  claim 10 . 
     
     
         14 . A compound of formula (3f): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein 
         R6 is 
       
       
         
           
           
               
               
           
         
         in which R30 is hydrogen or halogen; one of R28 and R29 is hydrogen and the other is 
       
       
         
           
           
               
               
           
         
         R31 is —OH or 
       
       
         
           
           
               
               
           
         
         R9 and R10 independently are hydrogen, methyl, benzyl, or 
       
       
         
           
           
               
               
           
         
         or R9 and R10, together with the nitrogen to which they are attached, form a 6-membered saturated heterocycle, optionally substituted with C1-C3 alkyl, provided that either (1) R30 and R28 are not both hydrogen; or (2) R30 and R29 are not both hydrogen. 
       
     
     
         15 . A pharmaceutical composition, comprising the compound of  claim 14 , and a pharmaceutically acceptable vehicle. 
     
     
         16 . A method of treating a disease associated with the unfolded protein response, comprising administering to a patient in need thereof an effective amount of the compound of  claim 15 .