Therapeutically active compositions and their methods of use

Abstract

Compounds and compositions comprising compounds that activate pyruvate kinase M2 (PKM2) are described herein. Also described herein are methods of using the compounds that activate PKM2 in the treatment of cancer.

1 . A compound of formula (I), 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 X and Y are each independently selected from O and N(-L-R 1 ); 
 Q is C(O), SO 2 , or —(CH 2 ) h —; 
 each L is independently selected from a bond, —C(O)—, —(CR a R b ) m —, —C(O)N(R c )— or —C(O)O—; 
 D and D 1  are each independently selected from a bond, O and N(R c ), provided that D and D 1  are not both a bond; 
 A is aryl or heteroaryl, each of which is substituted with 0-3 occurrences of R d ; and D-Q-D 1 -A is not OCH 2 -phenyl; 
 each R 1  is independently selected from hydrogen, C 1-4  alkyl, halo C 1-4 alkyl, alkyl-O-alkylene, C 3-10  cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; wherein each alkyl-O-alkylene, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl is substituted with 0-3 occurrences of R f  and each alkyl and haloalkyl is substituted with 0-3 occurrences of R g ; 
 each R a  and each R b  are independently selected from hydrogen, C 1-4  alkyl, or R a  and R b  bound to the same carbon atom are taken together with the carbon atom to form a cycloalkyl; 
 each R c  is independently selected from hydrogen and C 1-4  alkyl; 
 each R d  is independently selected from halo, halo C 1-4  alkyl, C 1-4  alkyl, nitro, cyano, —OH and —O(C 1-4  alkyl), or two R d , attached to the same or adjacent carbon atoms, taken together with the atom(s) to which they are attached form an optionally substituted heterocyclyl; 
 each R f  is independently selected from halo, halo C 1-4 alkyl, C 1-4  alkyl, nitro, cyano, —OH and —O(C 1-4  alkyl), or two R f , attached to the same or adjacent carbon atoms, taken together with the atoms to which they are attached form an optionally substituted heterocyclyl; 
 each R g  is independently selected from nitro, cyano, —OH, —O(C 1-4  alkyl) or two R g , attached to the same or adjacent carbon atoms, taken together with the atoms to which they are attached form an optionally substituted heterocyclyl; 
 each R 2  is independently selected from halo, halo C 1-4  alkyl, C 1-4  alkyl, C 1-4  alkoxy and hydroxyl; 
 h is 1, 2 or 3; 
 each m is independently 1, 2 or 3; and 
 each n is independently 0, 1, 2 or 3; 
 provided that the compound is not 2-chloro-N-(1,4-dihydro-2-oxo-2H-3,1-benzoxazin-7-yl)-5-[[(1-methylethyl)amino]sulfonyl]-benzamide; 
 4-[2-oxo-7-(phenylmethoxy)-2H-1,3-benzoxazin-3(4H)-yl], Benzoic methyl ester; 
 2-chloro-5-[[(1-methylethyl)amino]sulfonyl]-N-(1,2,3,4-tetrahydro-2-oxo-7-quinazolinyl)-benzamide; or 
 2-chloro-5-[[(1-methylethyl)amino]sulfonyl]-N-(1,2,3,4-tetrahydro-3-methyl-2-oxo-7-quinazolinyl)-benzamide. 
 
     
     
         2 . The compound of  claim 1 , wherein the compound is a compound of formula (Ia): 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1 , selected from any one of the compounds below: 
       
         
           
           
               
               
           
         
       
     
     
         4 . A compound of formula (II): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 X and Y are each independently selected from O and N-L-R 1 ; 
 Q is C(O), SO 2 , or —(CH 2 ) h —; 
 each L is independently selected from a bond, —C(O)—, —(CR a R b ) m —, —C(O)NR c — or —C(O)O—; 
 D and D 1  are each independently selected from a bond, O and NR c , provided that D and D 1  are not both a bond; 
 A is aryl or heteroaryl, each of which is substituted with 0-3 occurrences of R d ; 
 each R 1  is independently selected from hydrogen, C 1-4  alkyl, haloC 1-4  alkyl, alkyl-O-alkylene, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; wherein each alkyl-O-alkylene, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl is substituted with 0-3 occurrences of R f  and each alkyl and haloalkyl is substituted with 0-3 occurrences of R g ; 
 each R a  and each R b  are independently selected from hydrogen, C 1-4  alkyl, or R a  and R b  bound to the same carbon atom are taken together with the carbon atom to form a cycloalkyl; 
 each R c  is independently selected from hydrogen and C 1-4  alkyl; 
 each R d  is independently selected from halo, halo C 1-4  alkyl, C 1-4  alkyl, nitro, cyano, —OH and —O(C 1-4  alkyl), or two R d , attached to the same or adjacent carbon atoms, taken together with the atoms to which they are attached form an optionally substituted heterocyclyl; 
 each R f  is independently selected from halo, halo C 1-4  alkyl, C 1-4  alkyl, nitro, cyano, —OH and —O(C 1-4  alkyl), or two R f , attached to the same or adjacent carbon atoms, taken together with the atoms to which they are attached form an optionally substituted heterocyclyl; 
 each R g  is independently selected from nitro, cyano, —OH, —O(C 1-4  alkyl) or two R g , attached to the same or adjacent carbon atoms, taken together with the atoms to which they are attached form an optionally substituted heterocyclyl; 
 each R 2  is independently selected from halo, halo C 1-4  alkyl, C 1-4  alkyl, C 1-4  alkoxy and hydroxyl; 
 h is 1, 2 or 3; 
 each m is independently 1, 2 or 3; and 
 each n is independently 0, 1, 2 or 3; provided that
 1) D-Q-D 1 -A is not i) O-benzyl, ii) NHSO 2 -2-thiophenyl, iii) NHC(O)— optionally substituted phenyl, or iv) NHSO 2 -optionally substituted phenyl; and 
 2) the compound is not: 
 
 i) N-(2,6-dimethylphenyl)-1,2,3,4-tetrahydro-1,3-dimethyl-2-oxo-6-Quinazolinesulfonamide; 
 ii) N-[2-[[[(1S)-2-cyclohexyl-1-methylethyl]amino]methyl]phenyl]-1,4-dihydro-2-oxo-2H-3,1-Benzoxazine-6-sulfonamide; or 
 iii) N-[2-[[[(1S)-2-cyclopentyl-1-methylethyl]amino]methyl]phenyl]-1,4-dihydro-2-oxo-2H-3,1-Benzoxazine-6-sulfonamide. 
 
     
     
         5 . The compound of  claim 4 , wherein the compound is a compound of formula (IIa): 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 4 , selected from any one of the compounds below: 
       
         
           
           
               
               
           
         
       
     
     
         7 . A compound of formula (III): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 X and Y are each independently selected from O and N—R 1 ; 
 Q is C(O), SO 2 , or —(CH 2 ) h —; 
 L 1  and L 2  are each independently selected from a bond, —O—, C(O)—, —C(O)O—, —OC(O)—, —C(O)NR c —, —NR c C(O)—, —S—, —SO— and —SO 2 —;
 D and D 1  are each independently selected from a bond, 0 and NR c , provided that D and D 1  are not both a bond; 
 
 A is aryl or heteroaryl, each of which is substituted with 0-3 occurrences of R f ; 
 each R 1  is independently selected from hydrogen or C 1-4  alkyl, wherein each C 1-4  alkyl is substituted with 0-3 occurrences of R f ; 
 R a  and R b  are each independently selected from hydrogen, C 1-4  alkyl, haloC 1-4  alkyl, alkyl-O-alkylene, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; wherein each alkyl-O-alkylene, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl is substituted with 0-3 occurrences of R f  and each alkyl and haloalkyl is substituted with 0-3 occurrences of R g ; or 
 one of R a  or R b  is taken together with R 1  and the atoms to which they are respectively attached to form an optionally substituted five-membered heterocylyl; 
 each R c  is independently selected from hydrogen and C 1-4  alkyl; 
 each R d  is independently selected from halo, halo C 1-4  alkyl, C 1-4  alkyl, nitro, —NR c R c , —NHCH(NR c R c )NR c R c , —NHC(═NR c R c )NR c R c , —C(O)NR c R c , cyano, —SR c  and —OR c , or two R d , attached to the same or adjacent carbon atoms, taken together with the atoms to which they are attached form an optionally substituted heterocyclyl; 
 each R f  is independently selected from halo, halo C 1-4  alkyl, C 1-4  alkyl, nitro, cyano, —OH and —O(C 1-4  alkyl), or two R f , attached to the same or adjacent carbon atoms, taken together with the atoms to which they are attached form an optionally substituted heterocyclyl; 
 each R g  is independently selected from nitro, cyano, —OH, —O(C 1-4  alkyl) or two R g , attached to the same or adjacent carbon atoms, taken together with the atoms to which they are attached form an optionally substituted heterocyclyl; 
 each R 2  is independently selected from halo, halo C 1-4  alkyl, C 1-4  alkyl, C 1-4  alkoxy and hydroxyl; 
 h is 1, 2 or 3; and 
 n is 0, 1, 2 or 3; provided that
 1) D-Q-D 1 -A is not —SO 3 -phenyl or —SO 3 -p-methylphenyl; 
 2) when Y is NR c , then Q is not C(O); 
 3) when Y is NH, D-Q-D 1 - is not SO 2 NR c  or NR c SO 2 ; and 
 4) the compound is not: 
 
 i) N-(3-fluoro-2-methylphenyl)-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazine-6-sulfonamide; 
 ii) methyl 4,5-dimethoxy-2-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonamido)-phenethylcarbamate; 
 iii) 1-(difluoromethyl)-N-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-6-yl)-5-methyl-1H-pyrazole-4-sulfonamide; 
 iv) N-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-6-yl)-4-fluoro-3-methyl-benzenesulfonamide; 
 v) 7-chloro-N-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-6-yl)-2,3-dihydro-1,4-benzodioxin-6-sulfonamide; 
 vi) N-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-6-yl)-1,5-dimethyl-1H-pyrazole-4-sulfonamide; 
 vii) N-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-6-yl)-2-fluoro-5-methyl-benzenesulfonamide; or 
 viii) 5-chloro-N-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-6-yl)-2,4-dimethoxy-benzenesulfonamide. 
 
     
     
         8 . The compound of  claim 7 , wherein the compound is a compound of formula (IIIa): 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 7 , selected from any one of the compounds below: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         10 . A compound of formula (IV): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 X and Y are each independently selected from O and N—R 1 ; 
 Q is C(O), SO 2 , or —(CH 2 ) h —; 
 L 1  and L 2  are each independently selected from a bond, —O—, C(O)—, —C(O)O—, —OC(O)—, —C(O)NR c —, —NR c C(O)—, —S—, —SO— and —SO 2 —;
 D and D 1  are each independently selected from a bond, O and NR c , provided that D and D 1  are not both a bond; 
 
 A is aryl or heteroaryl, each of which is substituted with 0-3 occurrences of R d ; 
 each R 1  is independently selected from hydrogen or C 1-4  alkyl; wherein each C 1-4  alkyl is substituted with 0-3 occurrences of R f ; 
 R a  and R b  are each independently selected from hydrogen, C 1-4  alkyl, haloC 1-4  alkyl, alkyl-O-alkylene, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocycloalkyl; 
 wherein each alkyl-O-alkylene, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl is substituted with 0-3 occurrences of R f  and each alkyl and haloalkyl is substituted with 0-3 occurrences of R g ; or 
 one of R a  or R b  is taken together with a Y—R 1  or X—R 1  and the atoms to which they are respectively attached to form an optionally substituted five-membered heterocyclyl; 
 each R c  is independently selected from hydrogen and C 1-4  alkyl; 
 each R d  is independently selected from halo, halo C 1-4  alkyl, C 1-4  alkyl, nitro, —NR c R c , —NHCH(NR c R c )NR c R c , —NHC(═NR c R c )NR c R c , —C(O)NR c R c , cyano, —SR c  and —OR c , or two R d , attached to the same or adjacent carbon atoms, taken together with the atoms to which they are attached form an optionally substituted heterocyclyl; 
 each R f  is independently selected from halo, halo C 1-4  alkyl, C 1-4  alkyl, nitro, cyano, —OH and —O(C 1-4  alkyl), or two R f , attached to the same or adjacent carbon atoms, taken together with the atoms to which they are attached form an optionally substituted heterocyclyl; 
 each R g  is independently selected from nitro, cyano, —OH, —O(C 1-4  alkyl) or two R g , attached to the same or adjacent carbon atoms, taken together with the atoms to which they are attached form an optionally substituted heterocyclyl; 
 each R 2  is independently selected from halo, halo C 1-4  alkyl, C 1-4  alkyl, C 1-4  alkoxy and hydroxyl; 
 h is 1, 2 or 3; and 
 n is 0, 1, 2 or 3; provided that: 
 1) D-Q-D 1 -A is not O-benzyl; 
 2) when Y is O, X is not N—R 1 ; and 
 3) the compound of formula (IV) is not: 
 (E)-N-(3,3-dimethyl-2-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-4-(3,3,3-trifluoroprop-1-en-1-yl)benzamide; 
 (E)-N-(3,3-dimethyl-2-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-N-methyl-4-(3,3,3-trifluoroprop-1-en-1-yl)benzamide; 
 3-[2-(4-bromophenyl)-2-oxoethyl]-3,4-dihydro-6-methyl-2H-1,4-benzoxazin-2-one; or 
 4-[[(3,4-dihydro-2-oxo-2H-1,4-benzoxazin-6-yl)amino]sulfonyl]-5-methyl-2-furancarboxylic acid ethyl ester. 
 
     
     
         11 . The compound of  claim 10 , wherein the compound is a compound of formula (IVa): 
       
         
           
           
               
               
           
         
       
     
     
         12 . The compound of  claim 10 , selected from any one of the compounds below: 
       
         
           
           
               
               
           
         
       
     
     
         13 . A pharmaceutical composition comprising a compound of  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         14 . A method of modulating PKM2 activity in a subject in need thereof, the method comprising administering to said subject a compound of  claim 1  or a pharmaceutical composition of  claim 13 . 
     
     
         15 . A method of treating a cancer associated with PKM2 activity in a subject in need thereof, the method comprising administering to the subject a compound of  claim 1  or a pharmaceutical composition of  claim 13 . 
     
     
         16 . A pharmaceutical composition comprising a compound of  claim 4  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         17 . A method of modulating PKM2 activity in a subject in need thereof, the method comprising administering to said subject a compound of  claim 4  or a pharmaceutical composition of  claim 16 . 
     
     
         18 . A method of treating a cancer associated with PKM2 activity in a subject in need thereof, the method comprising administering to the subject a compound of  claim 4  or a pharmaceutical composition of  claim 16 . 
     
     
         19 . A pharmaceutical composition comprising a compound of  claim 7  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         20 . A method of modulating PKM2 activity in a subject in need thereof, the method comprising administering to said subject a compound of  claim 7  or a pharmaceutical composition of  claim 19 . 
     
     
         21 . A method of treating a cancer associated with PKM2 activity in a subject in need thereof, the method comprising administering to the subject a compound of  claim 7  or a pharmaceutical composition of  claim 19 . 
     
     
         22 . A pharmaceutical composition comprising a compound of  claim 10  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         23 . A method of modulating PKM2 activity in a subject in need thereof, the method comprising administering to said subject a compound of  claim 10  or a pharmaceutical composition of  claim 22 . 
     
     
         24 . A method of treating a cancer associated with PKM2 activity in a subject in need thereof, the method comprising administering to the subject a compound of  claim 10  or a pharmaceutical composition of  claim 22 .