Pyruvate kinase m2 modulators, therapeutic compositions and related methods of use

Abstract

Compositions comprising compounds that modulate pyruvate kinase M2 (PKM2) are described herein. Also described herein are methods of using the compounds that modulate PKM2 in the treatment of cancer.

1 . A compound selected from formula (II): 
       
         
           
           
               
               
           
         
       
       wherein
 A, B, D and E are each independently selected from H, —SO 2 —NR 4 R 5  and R 3 ; wherein at least one of A, B, D, or E is —SO 2 —NR 4 R 5 ; 
 Y 1 , Y 2 , Y 3  and Y 4  are each independently selected from N and CR 1 , wherein at least one of Y 1 , Y 2 , Y 3  and Y 4  are N; 
 each R 4  is independently selected from C 1-8  alkyl, aryl and heteroaryl, each of which is substituted with n occurrences of R 2 ; 
 each R 5  is independently hydrogen or C 1-8  alkyl; 
 each R 1  is independently selected from hydrogen, C 1-8  alkyl, C 1-8  terminal alkynyl, C 1-8  alkoxy, halogen, haloalkyl and haloalkoxy; 
 each R 2  is independently selected from halo, haloalkyl, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alknynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyano, —OR a , —COOR b  and —CONR c R c′ ; wherein two R 2 , together with the carbons to which they are attached, may form an optionally substituted ring, each of which can be further substituted; 
 each R 3  is independently selected from C 1-8  alkyl, —OR a , halogen, haloalkyl, haloalkoxy and optionally substituted heteroaryl; 
 each R a  is independently selected from alkyl, haloalkyl, optionally substituted heteroaryl and optionally substituted heterocyclyl; 
 each R b  is independently alkyl; and 
 each R c  is independently selected from hydrogen and alkyl; and 
 n is 0, 1, 2 or 3. 
 
     
     
         2 . A compound selected from formula (VI): 
       
         
           
           
               
               
           
         
       
       wherein
 A, B and E are each independently selected from H, —SO 2 —NR 4 R 5  and R 3 ; wherein at least one of A, B or E is —SO 2 —NR 4 R 5 ; 
 Y 1 , Y 2 , Y 3  and Y 4  are each independently selected from N and CR 1 , wherein at least one of Y 1 , Y 2 , Y 3  and Y 4  are N; 
 each R 4  is independently selected from C 1-8  alkyl, aryl and heteroaryl, each of which is substituted with n occurrences of R 2 ; 
 each R 5  is independently hydrogen or C 1-8  alkyl; 
 each R 1  is independently selected from hydrogen, C 1-8  alkyl, C 1-8  terminal alkynyl, C 1-8  alkoxy, halogen, haloalkyl and haloalkoxy; 
 each R 2  is independently selected from halo, haloalkyl, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alknynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyano, —OR a , —COOR b  and —CONR c R c′ ; wherein two R 2 , together with the carbons to which they are attached, may form an optionally substituted ring, each of which can be further substituted; 
 each R 3  is independently selected from C 1-8  alkyl, —OR a , halogen, haloalkyl, haloalkoxy and optionally substituted heteroaryl; 
 each R a  is independently selected from alkyl, haloalkyl, optionally substituted heteroaryl and optionally substituted heterocyclyl; 
 each R b  is independently alkyl; and 
 each R c  is independently selected from hydrogen and alkyl; and 
 n is 0, 1, 2 or 3.