Small molecule ire1-alpha inhibitors

Abstract

Described herein are IRE1α inhibitors, compositions containing such inhibitors, and methods of treatment that include administration of such compounds. Exemplary compounds are provided throughout the application.

1 . (canceled) 
     
     
         2 . A method of treating cancer comprising: administering to a subject in need thereof a therapeutically effective amount of a compound of formula Ia: 
       
         
           
           
               
               
           
         
       
       wherein,
 A 1  is N, CH, or CR 1 ; A 2  is N, CH, or CR 1 ; A 3  is N, CH, or CR t ; A 4  is N, CH, or CR 1 ; A 5  is N, CH, or CR 1 ; A 6  is N, CH, or CR 1 ; A 7  is N, CH, or CR 1 ; 
 v is an integer of 0-2; 
 each R 1  is NH 2  or OH; provided that the number of R 1  on the A ring does not exceed 4; 
 B is selected from: 
 
       
         
           
           
               
               
           
         
         each R 2  is independently selected from H and optionally substituted C 1 -C 4  alkyl; 
         X 1  and X 2  are each independently CH 2  or NH; with the provision that X 1  and X 2  are not each CH 2 ; 
         R 3  is selected from H, halo, CF 3 , optionally substituted C 1 -C 4  alkyl, and optionally substituted heteroaryl; 
         D is a heterocyclyl ring containing at least one N atom; and 
         each R 4  is selected from H, optionally substituted C 1 -C 4  alkyl, optionally substituted C 1 -C 4  alkoxy, (optionally substituted C 1 -C 4  alkylene)-OH, hydroxy, optionally substituted aryl, and optionally substituted benzyl; or 
         a pharmaceutically acceptable salt thereof. 
       
     
     
         3 . The method of  claim 2 , wherein A 1  is CH or CR 1 ; A 2  is N; A 3  is CH or CR 1 ; A 4  is N, CH, or CR 1 ; A 5  is CH or CR 1 ; A 6  is CH or CR 1 ; and A 7  is CH or CR 1 . 
     
     
         4 . The method of  claim 2 , wherein B is 
       
         
           
           
               
               
           
         
       
       and each R 2  is independently H or methyl. 
     
     
         5 . The method of  claim 2 , wherein R 3  is selected from H, halo, and CF 3 . 
     
     
         6 . The method of  claim 2 , wherein D is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The method of  claim 2 , wherein v is 1; and R 4  is selected from H, optionally substituted C 1 -C 4  alkyl, (optionally substituted C 1 -C 4  alkylene)-OH, hydroxy, optionally substituted aryl, and optionally substituted benzyl. 
     
     
         8 . The method of  claim 2 , wherein the compound is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         9 . The method of  claim 2 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         10 . The method of  claim 2 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         11 . The method of  claim 2 , wherein the compound is a compound of formula Ib: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The method of  claim 2 , wherein the compound is a compound of formula Ic: