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; 
 h is 0, 1, 2; and 
 g is 0, 1 or 2. 
 
     
     
         2 . The compound of  claim 1 , wherein h is 1 and g is 1. 
     
     
         3 . The compound of  claim 2 , wherein W, X, Y and Z are CH. 
     
     
         4 . The compound of  claim 3 , wherein D is NR b  and D 1  is a bond. 
     
     
         5 . The compound of  claim 4 , wherein R b  is H, methyl or ethyl. 
     
     
         6 . The compound of any one of  claims 1 - 5 , 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)—. 
     
     
         7 . The compound of  claim 6 , wherein L is a bond. 
     
     
         8 . The compound of  claim 7 , wherein R 1  is alkyl, aryl or heteroaryl substituted with 0-5 occurrences of R d . 
     
     
         9 . The compound of  claim 6 , wherein L is —(CR c R c ) m —. 
     
     
         10 . The compound of  claim 9 , wherein R 1  is cycloalkyl, aryl, heteroaryl or heterocyclyl substituted with 0-5 occurrences of R d . 
     
     
         11 . The compound of  claim 6 , wherein L is —NR b C(O)— and R b  is hydrogen. 
     
     
         12 . The compound of  claim 11 , wherein R 1  is aryl substituted with 0-5 occurrences of R d . 
     
     
         13 . The compound of  claim 6 , wherein L is —(CR c R c ) m —C(O)—. 
     
     
         14 . The compound of  claim 13 , wherein R 1  is cycloalkyl, aryl or heteroaryl substituted with 0-5 occurrences of R d . 
     
     
         15 . The compound of  claim 6 , wherein L is —C(O)—. 
     
     
         16 . The compound of  claim 15 , wherein R 1  is aryl, alkyl, or heteroaryl substituted with 0-5 occurrences of R d . 
     
     
         17 . The compound of  claim 6 , wherein L is —OC(O)—. 
     
     
         18 . The compound of  claim 17 , wherein R 1  is alkyl, aryl or heterocyclyl substituted with 0-5 occurrences of R d . 
     
     
         19 . The compound of  claim 6 , wherein L is —(CR c R c ) m —OC(O)—. 
     
     
         20 . The compound of  claim 19 , wherein R 1  is heterocyclyl or cycloalkyl substituted with 0-5 occurrences of R d . 
     
     
         21 . The compound of any one of  claims 6 - 20 , wherein n is 0. 
     
     
         22 . The compound of any one of  claims 6 - 20 , 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 . 
     
     
         23 . A pharmaceutical composition comprising a compound 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 aryl or optionally substituted 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)— (wherein the point of the attachment to R 1  is on the left-hand side); 
         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 heterocyclyl; 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. 
       
     
     
         24 . The pharmaceutical composition of  claim 23 , wherein the compound is a compound of formula (Id): 
       
         
           
           
               
               
           
         
       
     
     
         25 . A pharmaceutical composition comprising a compound of any one of  claims 1 - 22 . 
     
     
         26 . A pharmaceutical composition comprising a compound represented in  FIG. 1  or pharmaceutically acceptable salt thereof. 
     
     
         27 . A method of modulating PKM2 activity in a subject in need thereof, the method comprising administering to said subject a pharmaceutical composition of any one of  claims 23 - 26 . 
     
     
         28 . 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 of any one of  claims 23 - 27 . 
     
     
         29 . 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; 
 for use as a medicament. 
 
     
     
         30 . A use of 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; 
 in the manufacture of a medicament for modulating PKM2 activity in a subject in need thereof or for treating cancer associated with PKM2 activity in a subject in need thereof.