Therapeutic compounds and compositions

Abstract

Compounds of general formula (I) and compositions comprising compounds of general formula (I) that modulate pyruvate kinase are described herein. Also described herein are methods of using the compounds that modulate pyruvate kinase in the treatment of diseases.

What is claimed is: 
     
         1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 A is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted, and the aryl or heteroaryl is optionally fused to an optionally substituted carbocyclyl or an optionally substituted heterocyclyl; 
 X is selected from —NH—S(O) 2 —, —S(O) 2 —NH—, —NH—S(O) 2 —CH 2 —, —CH 2 —S(O)—NH—, —NH—S(O)—CH 2 —, —NH—S(O)—, —S(O)—NH—, or —CH 2 —S(O) 2 —NH—; 
 Y is C(H) or N; provided that no more than two Y groups are N; 
 R 1a  is hydroxyl, —CH 2 OH, —CHO, —CO 2 H, —N(R 10a ) 2 , —CO 2 —C 1-6  alkyl, —OP(═O)(OH) 2 , or —OCO 2 —CH 2 —OP(═O)(OH) 2 ; 
 R 1b  is C 1-8  alkyl optionally substituted with one to four R 5  groups; C 1-8  alkenyl optionally substituted with one to four R 5  groups; cycloalkyl; heterocycle; aryl; heteroaryl; cycloalkylalkyl; cycloalkylalkenyl; heterocyclylalkyl; heterocyclylalkenyl; aralkyl; aralkenyl; heteroaralkyl; heteroaralkenyl; or —OH, with the proviso that when R 1a  is OH, R 1b  is not OH; wherein each cycloalkyl, heterocycle, aryl, heteroaryl, cycloalkylalkyl, cycloalkylalkenyl, heterocyclylalkyl, heterocyclylalkenyl, aralkyl, aralkenyl, heteroaralkyl, or heteroaralkenyl is optionally substituted; 
 each R 2  is independently selected from halo, alkyl, CN, OH, and alkoxy, wherein said alkyl or alkoxy is optionally substituted with one to four R 5  groups; or 
 two adjacent R 2  groups are taken together with the ring atoms they are attached to form a 5- or 6-membered carbocyclic, aryl, heterocyclic or heteroaryl ring; 
 each R 4  is independently selected from halo, alkyl, alkoxy, haloalkyl, haloalkoxy and hydroxyl; 
 each R 5  is independently selected from halo, OH, C 1-6  alkoxy, CN, NH 2 , —SO 2 —C 1-6  alkyl, —NH(C 1-6  alkyl), and —N(C 1-6  alkyl) 2 ; 
 each R 10a  is independently selected from hydrogen or C 1-6  alkyl; 
 n is 0, 1, 2 or 3; and 
 m is 0, 1 or 2; provided that a compound of Formula (I) is not the following: 
 (1) 4-[[4-hydroxy-4-(4-methylphenyl)-1-piperidinyl]carbonyl]-N-2-thiazolyl-benzenesulfonamide; 
 (2) 4-[[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]carbonyl]-N-2-thiazolyl-benzenesulfonamide; 
 (3) 4-[[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]carbonyl]-N-2-thiazolyl-benzenesulfonamide; 
 (4) 4-[[4-(2-fluoro-5-methylphenyl)-4-hydroxy-1-piperidinyl]carbonyl]-N-2-thiazolyl-benzenesulfonamide; 
 (5) 4-phenyl-1-[4-[(phenylamino)sulfonyl]benzoyl]-4-piperidinecarboxylic acid methyl ester; 
 (6) 1-[4-[[(2-methylphenyl)amino]sulfonyl]benzoyl]-4-phenyl-4-piperidinecarboxylic acid methyl ester; or 
 (7) N-(4-fluorophenyl)-4-[[4-hydroxy-4-(methoxymethyl)-1-piperidinyl]carbonyl]-benzenesulfonamide. 
 
     
     
         2 . The compound of  claim 1 , wherein the compound is a compound of Formula (Ia): 
       
         
           
           
               
               
           
         
       
     
     
         3 . A compound of Formula (Ib): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 A is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted, and the aryl or heteroaryl is fused to an optionally substituted carbocyclyl or an optionally substituted heterocyclyl; 
 R 1b  is C 1-8  alkyl optionally substituted with one to four R 5  groups; C 1-8  alkenyl optionally substituted with one to four R 5  groups; cycloalkyl; heterocycle; aryl; heteroaryl; cycloalkylalkyl; cycloalkylalkenyl; heterocyclylalkyl; heterocyclylalkenyl; aralkyl; aralkenyl; heteroaralkyl; heteroaralkenyl; or —OH, with the proviso that when R 1a  is OH, R 1b  is not OH; wherein each cycloalkyl, heterocycle, aryl, heteroaryl, cycloalkylalkyl, cycloalkylalkenyl, heterocyclylalkyl, heterocyclylalkenyl, aralkyl, aralkenyl, heteroaralkyl, or heteroaralkenyl is optionally substituted; 
 each R 2  is independently selected from halo, alkyl, CN, OH, and alkoxy, wherein said alkyl or alkoxy is optionally substituted with one to four R 5  groups; or 
 two adjacent R 2  groups are taken together with the ring atoms they are attached to form a 5- or 6-membered carbocyclic, aryl, heterocyclic or heteroaryl ring; 
 each R 4  is independently selected from halo, alkyl, alkoxy, haloalkyl, haloalkoxy and hydroxyl; 
 each R 5  is independently selected from halo, OH, C 1-6  alkoxy, CN, NH 2 , —SO 2 —C 1-6  alkyl, —NH(C 1-6  alkyl), and —N(C 1-6  alkyl) 2 ; 
 n is 0, 1, 2 or 3; and 
 m is 0, 1 or 2. 
 
     
     
         4 . The compound of  claim 3 , wherein A is: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 3 , wherein the compound is a compound of Formula (II): 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 3 , wherein the compound is a compound of Formula (III): 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 3 , wherein the compound is a compound of Formula (IV): 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 3 , wherein R 1b  is C 1-8  alkyl optionally substituted with one to four R 5  groups; aryl; heteroaryl; aralkyl; or heteroaralkyl; wherein each aryl; heteroaryl; aralkyl; or heteroaralkyl; is optionally substituted. 
     
     
         9 . The compound of  claim 8 , wherein each aryl; heteroaryl; aralkyl; or heteroaralkyl is optionally substituted with halo, C 1-6  alkyl, —OH, C 1-6  alkoxy, —CN, —NH 2 , —SO 2 —C 1-6  alkyl, —NH(C 1-6  alkyl), —N(C 1-6  alkyl) 2 , aryl, haloalkyl, or haloalkoxy. 
     
     
         10 . The compound of  claim 3 , wherein R 1b  is C 1-8  alkyl optionally substituted with one to four R 5  groups. 
     
     
         11 . The compound of  claim 3 , wherein R 5  is fluoro, —OH, or —SO 2 —CH 3 . 
     
     
         12 . The compound of  claim 3 , wherein R 1b  is phenyl, optionally substituted with chloro, fluoro, bromo, methyl, ethyl, —CN, difluoromethyl, trifluoromethyl, —OCF 3 , —SO 2 —CH 3 , or —OCH 3 . 
     
     
         13 . The compound of  claim 1 , wherein the compound of Formula (I) is selected from Compounds 100-529 of Table 1. 
     
     
         14 . A pharmaceutical composition comprising a compound of  claim 1  or a pharmaceutical acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         15 . A method of modulating PKM2 activity in a subject in need thereof, the method comprising administering to said subject a pharmaceutical composition of  claim 14 . 
     
     
         16 . A method of treating a cancer associated with PKM2 activity in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition of  claim 14 . 
     
     
         17 . Use of a pharmaceutical composition of  claim 14  in the manufacture of a medicament for modulating PKM2 activity. 
     
     
         18 . Use of a pharmaceutical composition of  claim 14  in the manufacture of a medicament for treating a cancer associated with PKM2 activity. 
     
     
         19 . A method for increasing the lifetime of the red blood cells (RBCS) in need thereof comprising contacting blood with an effective amount of (1) a compound of  claim 1  or a pharmaceutically acceptable salt thereof; or (2) a composition of  claim 14 . 
     
     
         20 . The method of  claim 19 , wherein the compound is added directly to whole blood or packed cells extracorporeally. 
     
     
         21 . The method of  claim 19 , wherein the pharmaceutical composition is administered to a subject in need thereof. 
     
     
         22 . A method for regulating 2,3-diphosphoglycerate levels in blood in need thereof comprising contacting blood an effective amount of (1) a compound of  claim 1 ; or (2) a composition of  claim 14 . 
     
     
         23 . A method for treating hereditary non-spherocytic haemolytic anemia comprising administering to a subject in need thereof a therapeutically effective amount of an effective amount of (1) a compound of  claim 1 ; or (2) a pharmaceutically acceptable composition of  claim 14 . 
     
     
         24 . A method for treating sickle cell anemia comprising administering to a subject in need thereof a therapeutically effective amount of an effective amount of (1) a compound of  claim 1 ; or (2) a pharmaceutically acceptable composition of  claim 14 .