Activators of human pyruvate kinase

Abstract

Disclosed are pyruvate kinase M2 activators which are compounds of Formula (I), including those of Formula (II), wherein A 1 , A 2 , L, R, R 1 to R 3 , X 1 to X 3 , k, n, and m are as defined herein, that are useful in treating a number of diseases that are treatable by the activation of PKM2, for example, cancer. A 1 -NR-L-A 2 (I).

1 . A compound of the formula for:
   R″—NR-L-R′;
   wherein R is H or C 1 -C 4  alkyl;   wherein L is SO 2  or CO;   wherein R′ is a fused bicyclic ring, wherein one ring of the bicyclic ring is phenyl which is linked to the NR-L moiety at the nitrogen atom or the sulfur atom when L is SO 2  or the carbon atom when L is CO and the other ring of the bicyclic ring is an aryl, a heteroaryl, a cyclyl, or a heterocyclyl, wherein R′ is optionally substituted on one or both rings with one or more substituents selected from the group consisting of aryl, heteroaryl, cyclyl, alkyl, alkoxyl, halogen, NH 2 , NH—(C 1 -C 4 )alkyl, N—(C 1 -C 4 )alkyl-(C 1 -C 4 )alkyl, (C 1 -C 4 )alkyl-CO—, and heterocyclyl, each of which other than halogen and NH 2  is further optionally substituted with one or more substituents selected from the group consisting of NH 2 , OH, NH—(C 1 -C 4 )alkyl and N—(C 1 -C 4 )alkyl-(C 1 -C 4 )alkyl; and   wherein R″ is phenyl, benzyl, or heteroaryl, which is optionally substituted with one or more substituents selected from the group consisting of halogen, C 1 -C 4  alkyl, C 1 -C 4  alkoxyl, cyano, alkylenedioxy, aryl, heteroaryl, benzyl, B(OH) 2 , and C 1 -C 4  alkyl substituted with one or more halogens, or is phenyl optionally fused with an aryl, a heteroaryl, a cyclyl, or a heterocyclyl, each of which is optionally substituted with one or more substituents selected from the group consisting of halogen, C 1 -C 4  alkyl, C 1 -C 4  alkoxyl, alkylenedioxy, aryl, heteroaryl, benzyl, and C 1 -C 4  alkyl substituted with one or more halogens; and   with the proviso that the compound is not   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . (canceled) 
     
     
         3 . The compound or salt of  claim 1 , wherein the phenyl ring of the bicyclic ring of R′ is fused with an aryl, a heteroaryl, a cyclyl, or a heterocyclyl, each of which is optionally substituted with one or more substituents selected from the group consisting of aryl, heteroaryl, cyclyl, alkyl, alkoxyl, halogen, NH 2 , NH—(C 1 -C 4 )alkyl, N—(C 1 -C 4 )alkyl-(C 1 -C 4 )alkyl, (C 1 -C 4 )alkyl-OC—, and heterocyclyl, each of which other than halogen and NH 2  is further optionally substituted with one or more substituents selected from the group consisting of NH 2 , OH, NH—(C 1 -C 4 )alkyl and N—(C 1 -C 4 )alkyl-(C 1 -C 4 )alkyl. 
     
     
         4 . The compound or salt of  claim 1 , wherein the cyclyl or heterocyclyl of R′ or R″ is a five-membered, six-membered, or seven-membered ring. 
     
     
         5 . The compound or salt of  claim 1 , wherein the heterocyclyl contains one or two heteroatoms. 
     
     
         6 . The compound or salt of  claim 1 , wherein R is methyl or H. 
     
     
         7 . The compound or salt of  claim 1 , wherein R′ is 
       
         
           
           
               
               
           
         
         wherein X 1  and X 2  are each individually O, N-acetyl, NR 6 , or CR 7 R 8 ; 
         wherein any CH 2 —CH 2  moiety within the ring containing X 1  and X 2  is optionally replaced with a CH═CH moiety; 
         wherein any NH—CH 2  moiety within the ring containing X 1  and X 2  is optionally replaced with a N═CH moiety; 
         wherein any methylene of the ring containing X 1  and X 2  is optionally replaced by a carbonyl; 
         wherein n and m are each individually 0, 1, or 2, and wherein n+m is 0 to 2; 
         wherein each R 1  is individually H, halogen, alkyl, alkoxyl, NH 2 , NH—(C 1 -C 4 )alkyl, N—(C 1 -C 4 )alkyl-(C 1 -C 4 )alkyl, aryl, heteroaryl, cyclyl, or heterocyclyl, each of which other than halogen and NH 2  is further optionally substituted with one or more substituents selected from the group consisting of NH 2 , OH, NH—(C 1 -C 4 )alkyl and N—(C 1 -C 4 )alkyl-(C 1 -C 4 )alkyl; 
         wherein R 6  is H, alkyl, alkylcarboxy, aryl, heteroaryl, cyclyl, or heterocyclyl, each of which is further optionally substituted with one or more substituents selected from the group consisting of NH 2 , OH, NH—(C 1 -C 4 )alkyl and N—(C 1 -C 4 )alkyl-(C 1 -C 4 )alkyl; and 
         wherein R 7  and R 8  are each individually H, halogen, alkyl, alkoxyl, NH 2 , NH—(C 1 -C 4 )alkyl, N—(C 1 -C 4 )alkyl-(C 1 -C 4 )alkyl, aryl, heteroaryl, cyclyl, or heterocyclyl, each of which other than halogen and NH 2  is further optionally substituted with one or more substituents selected from the group consisting of NH 2 , OH, NH—(C 1 -C 4 )alkyl and N—(C 1 -C 4 )alkyl-(C 1 -C 4 )alkyl. 
       
     
     
         8 . The compound or salt of  claim 7 , wherein one R 1  is at the ortho position relative to the carbon attached to the NR-L moiety. 
     
     
         9 . The compound or salt of  claim 7 , wherein one R 1  is H, F, Cl, Br, methyl, N(Me) 2 , NHMe, 1-piperidinyl, 2-(dimethylamino)ethyl)(methyl)amino, pyrrolidin-1-yl, 3-(dimethylamino)pyrrolidin-1-yl, 2-hydroxy-2-methylpropylamino, isopropylamino, diethylamino, 1-hydroxypropan-2-ylamino, 2-hydroxyethylamino, or phenyl. 
     
     
         10 . The compound or salt of  claim 1 , wherein R′ is substituted with one or more substituents selected from the group consisting of methyl and acetyl. 
     
     
         11 . The compound or salt of  claim 1 , wherein R′ is 3,4-dihydroquinolin-2(1H)-onyl, indolin-2-onyl, 4,5-dihydro-1H-benzo[b]azepin-2(3H)-onyl, 2H-benzo[b][1,4]oxazin-3(4H)-onyl, 4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, 1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-onyl, 1-(indolin-1-yl)ethanonyl, 1-methyl-1H-indolyl, 1-acetyl-2-methylindolinyl, 6-chloro-2-oxoindolinyl, 3,3-dichloro-2-oxoindolinyl, 7-((2-(dimethylamino)ethyl)(methyl)amino)-2-oxo-1,2,3,4-tetrahydroquinolinyl, 2-oxo-7-(pyrrolidin-1-yl)-1,2,3,4-tetrahydroquinolinyl, 7-(3-(dimethylamino)pyrrolidin-1-yl)-2-oxo-1,2,3,4-tetrahydroquinolinyl, 7-(2-hydroxy-2-methylpropylamino)-2-oxo-1,2,3,4-tetrahydroquinolinyl, 7-(isopropylamino)-2-oxo-1,2,3,4-tetrahydroquinolinyl, 7-(diethylamino)-2-oxo-1,2,3,4-tetrahydroquinolinyl, 7-(2-hydroxyethylamino)-2-oxo-1,2,3,4-tetrahydroquinolinyl, 7-(1-hydroxypropan-2-ylamino)-2-oxo-1,2,3,4-tetrahydroquinolinyl, (S)-7-(1-hydroxypropan-2-ylamino)-2-oxo-1,2,3,4-tetrahydroquinolinyl, or (R)-7-(1-hydroxypropan-2-ylamino)-2-oxo-1,2,3,4-tetrahydroquinolinyl. 
     
     
         12 . The compound or salt of  claim 1 , wherein R″ is 
       
         
           
           
               
               
           
         
         wherein X 3  is N or CH wherein when X 3  is N, the NR-L moiety is linked to a C of the ring containing X 3 ; 
         wherein R 2  and R 3  are each individually H, halogen, C 1 -C 4  alkyl, C 1 -C 4  alkoxyl, cyano, B(OH) 2 , phenyl, C 1 -C 4  alkyl substituted with one or more halogens, or taken together form alkylenedioxyl. 
       
     
     
         13 . The compound or salt of  claim 12 , wherein R 2  and R 3  are each individually H, F, Cl, Br, methyl, methoxy, cyano, trifluoromethyl, phenyl, B(OH) 2 , or taken together form alkylenedioxyl. 
     
     
         14 . The compound or salt of  claim 1 , wherein R″ is 3,4-dimethylphenyl, 3-chlorophenyl, meta-tolyl, 3-methoxyphenyl, 3-fluorophenyl, 3-trifluoromethylphenyl, biphenyl-3-yl, pyridine-3-yl, 4-chlorophenyl, para-tolyl, 4-methoxyphenyl, 4-fluorophenyl, ortho-tolyl, 2-methoxyphenyl, 2-fluorophenyl, naphthalen-2-yl, naphthalen-1-yl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, benzyl, 3-chloro-4-methylphenyl, 3,4-dichlorophenyl, 5-chloro-2-methylphenyl, 3-cyanophenyl, 3-chloro-2-methylphenyl, 3-phenylboronic acid, 4-fluoro-3-methylphenyl, 3-fluoro-4-methylphenyl, 4-chloro-3-methylphenyl, or 3-chloro-4-fluorophenyl. 
     
     
         15 . The compound or salt of  claim 1 , wherein the compound of formula (I) is a compound of formula (II): 
       
         
           
           
               
               
           
         
         wherein X 1  and X 2  are each individually O, N-acetyl, NR 6 , or CR 7 R 8 ; 
         wherein X 3  is N or CH wherein when X 3  is N, the NR-L moiety is linked to a C of the ring containing X 3 ; 
         wherein any CH 2 —CH 2  moiety within the ring containing X 1  and X 2  is optionally replaced with a CH═CH moiety; 
         wherein any NH—CH 2  moiety within the ring containing X 1  and X 2  is optionally replaced with a N═CH moiety; 
         wherein any methylene of the ring containing X 1  and X 2  is optionally replaced by a carbonyl; 
         wherein n and m are each individually 0, 1, or 2, and wherein n+m is 0 to 2; 
         wherein k is 0 or 1; 
         wherein R 1  is H, halogen, alkyl, alkoxyl, NH 2 , NH—(C 1 -C 4 )alkyl, N—(C 1 -C 4 )alkyl-(C 1 -C 4 )alkyl, aryl, heteroaryl, cyclyl, or heterocyclyl, each of which other than halogen and NH 2  is further optionally substituted with one or more substituents selected from the group consisting of NH 2 , OH, NH—(C 1 -C 4 )alkyl and N—(C 1 -C 4 )alkyl-(C 1 -C 4 )alkyl; 
         wherein R 2  and R 3  are each individually H, halogen, C 1 -C 4  alkyl, C 1 -C 4  alkoxyl, cyano, B(OH) 2 , phenyl, C 1 -C 4  alkyl substituted with one or more halogens, or taken together form alkylenedioxy or phenyl fused to a CH:CH moiety of the ring containing X 3 ; 
         wherein R 6  is H, alkyl, alkylcarboxy, aryl, heteroaryl, cyclyl, or heterocyclyl, each of which is further optionally substituted with one or more substituents selected from the group consisting of NH 2 , OH, NH—(C 1 -C 4 )alkyl and N—(C 1 -C 4 )alkyl-(C 1 -C 4 )alkyl; and 
         wherein R 7  and R 8  are each individually H, halogen, alkyl, alkoxyl, NH 2 , NH—(C 1 -C 4 )alkyl, N—(C 1 -C 4 )alkyl-(C 1 -C 4 )alkyl, aryl, heteroaryl, cyclyl, or heterocyclyl, each of which other than halogen and NH 2  is further optionally substituted with one or more substituents selected from the group consisting of NH 2 , OH, NH—(C 1 -C 4 )alkyl and N—(C 1 -C 4 )alkyl-(C 1 -C 4 )alkyl. 
       
     
     
         16 . The compound or salt of  claim 15 , wherein R 1  is H, F, Cl, Br, methyl, N(Me) 2 , NHMe, 1-piperidinyl, 2-(dimethylamino)ethyl)(methyl)amino, pyrrolidin-1-yl, 3-(dimethylamino)pyrrolidin-1-yl, 2-hydroxy-2-methylpropylamino, isopropylamino, diethylamino, 1-hydroxypropan-2-ylamino, 2-hydroxyethylamino, or phenyl. 
     
     
         17 . The compound or salt of  claim 15 , wherein 
       
         
           
           
               
               
           
         
       
       is substituted with one or more substituents selected from the group consisting of methyl and acetyl. 
     
     
         18 . The compound or salt of  claim 15 , wherein 
       
         
           
           
               
               
           
         
       
       is 3,4-dihydroquinolin-2(1H)-onyl, indolin-2-onyl, 4,5-dihydro-1H-benzo[b]azepin-2(3H)-onyl, 2H-benzo[b][1,4]oxazin-3(4H)-onyl, 4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, 1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-onyl, 1-(indolin-1-yl)ethanonyl, 1-methyl-1H-indolyl, 1-acetyl-2-methylindolinyl, 6-chloro-2-oxoindoline, 3,3-dichloro-2-oxoindolinyl, 7-((2-(dimethylamino)ethyl)(methyl)amino)-2-oxo-1,2,3,4-tetrahydroquinolinyl, 2-oxo-7-(pyrrolidin-1-yl)-1,2,3,4-tetrahydroquinolinyl, 7-(3-(dimethylamino)pyrrolidin-1-yl)-2-oxo-1,2,3,4-tetrahydroquinolinyl, 7-(2-hydroxy-2-methylpropylamino)-2-oxo-1,2,3,4-tetrahydroquinolinyl, 7-(isopropylamino)-2-oxo-1,2,3,4-tetrahydroquinolinyl, 7-(diethylamino)-2-oxo-1,2,3,4-tetrahydroquinolinyl, 7-(2-hydroxyethylamino)-2-oxo-1,2,3,4-tetrahydroquinolinyl, 7-(1-hydroxypropan-2-ylamino)-2-oxo-1,2,3,4-tetrahydroquinolinyl, (S)-7-(1-hydroxypropan-2-ylamino)-2-oxo-1,2,3,4-tetrahydroquinolinyl, or (R)-7-(1-hydroxypropan-2-ylamino)-2-oxo-1,2,3,4-tetrahydroquinolinyl. 
     
     
         19 . The compound or salt of  claim 15 , wherein R 2  and R 3  are each individually H, F, Cl, Br, methyl, methoxy, cyano, trifluoromethyl, phenyl, B(OH) 2 , or taken together form alkylenedioxyl or phenyl fused to a CH:CH moiety of the ring containing X 3 . 
     
     
         20 . The compound or salt of  claim 15 , wherein 
       
         
           
           
               
               
           
         
       
       is 3,4-dimethylphenyl, 3-chlorophenyl, meta-tolyl, 3-methoxyphenyl, 3-fluorophenyl, 3-trifluoromethylphenyl, biphenyl-3-yl, pyridin-3-yl, 4-chlorophenyl, para-tolyl, 4-methoxyphenyl, 4-fluorophenyl, ortho-tolyl, 2-methoxyphenyl, 2-fluorophenyl, naphthalen-2-yl, naphthalen-1-yl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, benzyl, 3-chloro-4-methylphenyl, 3,4-dichlorophenyl, 5-chloro-2-methylphenyl, 3-cyanophenyl, 3-chloro-2-methylphenyl, 3-phenylboronic acid, 4-fluoro-3-methylphenyl, 3-fluoro-4-methylphenyl, 4-chloro-3-methylphenyl, or 3-chloro-4-fluorophenyl. 
     
     
         21 . The compound or salt of  claim 1 , wherein the compound is
 N-(3,4-dimethylphenyl)-2-oxoindoline-5-sulfonamide,   N-(3,4-dimethylphenyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-7-sulfonamide,   N-(3,4-dimethylphenyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonamide,   N-(3,4-dimethylphenyl)-4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonamide,   N-(3,4-dimethylphenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide,   N-(3,4-di methylphenyl)-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazo le-5-sulfonamide,   1-acetyl-N-(3,4-dimethylphenyl)indoline-5-sulfonamide,   N-(3,4-dimethylphenyl)-1-methyl-1H-indole-5-sulfonamide,   N-(3-chlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   2-oxo-N-m-tolyl-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   N-(3-methoxyphenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   N-(3-fluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   2-oxo-N-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   N-(biphenyl-3-yl)-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   2-oxo-N-(pyridin-3-yl)-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   N-(4-chlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   2-oxo-N-p-tolyl-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   N-(4-methoxyphenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   N-(4-fluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   2-oxo-N-o-tolyl-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   N-(2-methoxyphenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   N-(2-fluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   N-(naphthalen-2-yl)-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   N-(naphthalen-1-yl)-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   N-benzyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   N-(3,4-dimethylphenyl)-7-fluoro-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   7-(dimethylamino)-N-(3,4-dimethylphenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   N-(3,4-dimethylphenyl)-7-(methylamino)-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   N-(3,4-dimethylphenyl)-2-oxo-7-(piperidin-1-yl)-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   6-chloro-N-(3,4-dimethylphenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-7-sulfonamide,   6-(dimethylamino)-N-(3,4-dimethylphenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-7-sulfonamide,   6-chloro-N-(3,4-dimethylphenyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide,   6-bromo-N-(3,4-dimethylphenyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide,   N-(3,4-dimethylphenyl)-6-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide,   N-(3,4-dimethylphenyl)-3-oxo-6-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide,   N-(3,4-dimethylphenyl)-N-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   N-(3,4-dimethylphenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-6-carboxamide,   N-(3-chloro-4-methylphenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   N-(3,4-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   6-chloro-N-(5-chloro-2-methylphenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-7-sulfonamide,   N-(3-cyanophenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   1-acetyl-N-(3,4-dimethylphenyl)-2-methylindoline-5-sulfonamide,   N-(5-chloro-2-methylphenyl)-7-fluoro-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   6-chloro-N-(3-chloro-4-methylphenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-7-sulfonamide,   N-(3-chloro-2-methylphenyl)-7-fluoro-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   N-(3-chloro-4-methylphenyl)-7-fluoro-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   3-(2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamido)phenylboronic acid,   N-(4-fluoro-3-methylphenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   N-(3,4-dichlorophenyl)-7-fluoro-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   N-(3-fluoro-4-methylphenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   N-(4-chloro-3-methylphenyl)-7-fluoro-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   6-chloro-N-(3,4-dimethylphenyl)-2-oxoindoline-5-sulfonamide,   N-(4-chloro-3-methylphenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   6-chloro-N-(3-chloro-2-methylphenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-7-sulfonamide,   3,3-dichloro-N-(3,4-dimethylphenyl)-2-oxoindoline-5-sulfonamide,   7-((2-(dimethylamino)ethyl)(methyl)amino)-N-(3,4-dimethylphenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   N-(3,4-dimethylphenyl)-2-oxo-7-(pyrrolidin-1-yl)-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   7-(3-(dimethylamino)pyrrolidin-1-yl)-N-(3,4-dimethylphenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   N-(3,4-dimethylphenyl)-7-(2-hydroxy-2-methylpropylamino)-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   N-(3,4-dimethylphenyl)-7-(isopropylamino)-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   7-(diethylamino)-N-(3,4-dimethylphenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   N-(3,4-dimethylphenyl)-7-(1-hydroxypropan-2-ylamino)-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   (S)—N-(3,4-dimethylphenyl)-7-(1-hydroxypropan-2-ylamino)-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   (R)—N-(3,4-dimethylphenyl)-7-(1-hydroxypropan-2-ylamino)-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   N-(3,4-dimethylphenyl)-7-(2-hydroxyethylamino)-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   (S)—N-(3-chloro-4-methylphenyl)-7-(1-hydroxypropan-2-ylamino)-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide,   (S)—N-(4-fluoro-3-methylphenyl)-7-(1-hydroxypropan-2-ylamino)-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide, or   (S)—N-(3-chloro-4-fluorophenyl)-7-(1-hydroxypropan-2-ylamino)-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide.   
     
     
         22 . A pharmaceutical composition comprising a compound or salt according to  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         23 .- 27 . (canceled) 
     
     
         28 . A method of treating a disease responsive to activation of human PK-M2 comprising administering to a patient in need thereof a therapeutically effective amount of a compound or salt according to  claim 1 . 
     
     
         29 . The method according to  claim 28 , wherein the disease responsive to activation of human PK-M2 is cancer. 
     
     
         30 . The method according to  claim 29 , wherein the cancer is leukemia, polycythemia vera, lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, sarcoma, or carcinoma. 
     
     
         31 . The method according to  claim 29 , wherein the cancer is acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's disease, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, malignant mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, alveolar rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, intrahepatic bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung cancer, small cell lung carcinoma, urinary bladder cancer, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, meningioma, melanoma, neuroblastoma, and retinoblastoma, bone cancer, brain cancer, cancer of the anus, cancer of the anal canal, cancer of the anorectum, cancer of the eye, cancer of the joints, cancer of the neck, cancer of the gallbladder, cancer of the pleura, cancer of the nose, cancer of the nasal cavity, cancer of the middle ear, cancer of the oral cavity, cancer of the vulva, esophageal cancer, gastrointestinal carcinoid tumor, hypopharynx cancer, kidney cancer, larynx cancer, liver cancer, nasopharynx cancer, non-small cell lung cancer, peritoneum cancer, omentum cancer, mesentery cancer, pharynx cancer, rectal cancer, renal cancer, small intestine cancer, soft tissue cancer, stomach cancer, thyroid cancer, or ureter cancer. 
     
     
         32 . The method according to  claim 31 , wherein the cancer is liver cancer.