Therapeutic compounds and compositions

Abstract

Compounds and 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.

What is claimed is: 
     
         1 . A compound of formula I or a pharmaceutically acceptable salt thereof, wherein: 
       
         
           
           
               
               
           
         
         W, X, Y and Z are each independently selected from CH or N; 
         D and D 1  are independently selected from a bond or NR b ; 
         A is optionally substituted bicyclic heteroaryl; 
         L is a bond, —C(O)—, —(CR c R c ) m —, —OC(O)—, —(CR c R c ) m —OC(O)—, —(CR c R c ) m —C(O)—, —NR b C(S)—, or —NR b C(O)—; 
         R 1  is selected from alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; each of which is substituted with 0-5 occurrences of R d ; 
         each R 3  is independently selected from halo, haloalkyl, alkyl, hydroxyl and —OR a  or two adjacent R 3  taken together with the carbon atoms to which they are attached form an optionally substituted cyclyl; 
         each R a  is independently selected from alkyl, acyl, hydroxyalkyl and haloalkyl; 
         each R b  is independently selected from hydrogen and alkyl; 
         each R c  is independently selected from hydrogen, halo, alkyl, alkoxy and halo alkoxy or two R c  taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl; 
         each R d  is independently selected from halo, haloalkyl, haloalkoxy, alkyl, alkynyl, nitro, cyano, hydroxyl, —C(O)R a , —OC(O)R a , —C(O)OR a , —SR a , —NR a R b  and —OR a , or two R d  taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl; 
         n is 0, 1, or 2; 
         m is 1, 2 or 3; and 
         h is 1 and g is 2, or g is 1 and h is 2. 
       
     
     
         2 . The compound of  claim 1 , wherein W, X, Y and Z are CH. 
     
     
         3 . The compound of  claim 2 , wherein D is NR b  and D 1  is a bond. 
     
     
         4 . The compound of  claim 3 , wherein R b  is H, methyl or ethyl. 
     
     
         5 . The compound of  claim 1 , wherein L is a bond, —(CR c R c ) m —, —NR b C(O)—, —(CR c R c ) m —C(O)—, —C(O)—, or —O(CO)—. 
     
     
         6 . The compound of  claim 5 , wherein L is a bond. 
     
     
         7 . The compound of  claim 6 , wherein R 1  is alkyl, aryl or heteroaryl substituted with 0-5 occurrences of R d . 
     
     
         8 . The compound of  claim 7 , wherein L is —(CR c R c ) m —. 
     
     
         9 . The compound of  claim 8 , wherein R 1  is cycloalkyl, aryl, heteroaryl or heterocyclyl substituted with 0-5 occurrences of R d . 
     
     
         10 . The compound of  claim 5 , wherein L is —NR b C(O)— and R b  is hydrogen. 
     
     
         11 . The compound of  claim 10 , wherein R 1  is aryl substituted with 0-5 occurrences of R d . 
     
     
         12 . The compound of  claim 5 , wherein L is —(CR c R c ) m —C(O)—. 
     
     
         13 . The compound of  claim 12 , wherein R 1  is cycloalkyl, aryl or heteroaryl substituted with 0-5 occurrencs of R d . 
     
     
         14 . The compound of  claim 5 , wherein L is —C(O)—. 
     
     
         15 . The compound of  claim 14 , wherein R 1  is aryl, alkyl, or heteroaryl substituted with 0-5 occurrencs of R d . 
     
     
         16 . The compound of  claim 5 , wherein L is —OC(O)—. 
     
     
         17 . The compound of  claim 16 , wherein R 1  is alkyl, aryl or heterocyclyl substituted with 0-5 occurrences of R d . 
     
     
         18 . The compound of  claim 5 , wherein L is —(CR c R c ) m —OC(O)—. 
     
     
         19 . The compound of  claim 18 , wherein R 1  is heterocyclyl or cycloalkyl substituted with 0-5 occurrences of R d . 
     
     
         20 . The compound of  claim 5 , wherein n is 0. 
     
     
         21 . The compound of  claim 5 , wherein n is 1 and R 3  is CH 3 , CH 2 CH 3 , OCH 3 , OCH 2 CH 3 , OH, F, Cl, or CF 3 . 
     
     
         22 . A pharmaceutical composition comprising a compound  claim 1 . 
     
     
         23 . The pharmaceutical composition of  claim 22 , wherein the compound is a compound of formula (Id): 
       
         
           
           
               
               
           
         
       
     
     
         24 . The compound of  claim 1 , wherein the compound is selected from the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         25 . A method of modulating PKM2 activity in a subject in need thereof, the method comprising administering to said subject a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, wherein: 
       
         
           
           
               
               
           
         
         W, X, Y and Z are each independently selected from CH or N; 
         D and D 1  are independently selected from a bond or NR b ; 
         A is optionally substituted bicyclic heteroaryl; 
         L is a bond, —C(O)—, —(CR c R c ) m —, —OC(O)—, —(CR c R c ) m —OC(O)—, —(CR c R c ) m —C(O)—, —NR b C(S)—, or —NR b C(O)—; 
         R 1  is selected from alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; each of which is substituted with 0-5 occurrences of R d ; 
         each R 3  is independently selected from halo, haloalkyl, alkyl, hydroxyl and —OR a  or two adjacent R 3  taken together with the carbon atoms to which they are attached form an optionally substituted cyclyl; 
         each R a  is independently selected from alkyl, acyl, hydroxyalkyl and haloalkyl; 
         each R b  is independently selected from hydrogen and alkyl; 
         each R c  is independently selected from hydrogen, halo, alkyl, alkoxy and halo alkoxy or two R c  taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl; 
         each R d  is independently selected from halo, haloalkyl, haloalkoxy, alkyl, alkynyl, nitro, cyano, hydroxyl, —C(O)R a , —OC(O)R a , —C(O)OR a , —SR a , —NR a R b  and —OR a , or two R d  taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl; 
         n is 0, 1, or 2; 
         m is 1, 2 or 3; 
         h is 0, 1, 2; and 
         g is 0, 1 or 2. 
       
     
     
         26 . A method of treating a cancer associated with PKM2 activity in a subject in need thereof, the method comprising administering to a subject a pharmaceutical composition  claim 22 .