Therapeutically active compositions and their methods of use

Abstract

Provided are compounds with the following structure, formula (I) pharmaceutically acceptable salts thereof, use of those compounds for treating cancer and pharmaceutical compositions comprising those compounds.

1 . A compound of Structural Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         Y is —N(R 5 )—, —N(R 5 )—CH 2 —, —CH 2 —N(R 5 )— or —CH(R 5 )—; 
         each R 1a  and R 1b  is independently hydrogen, —C 1 -C 4  alkyl, —N(R 7 )(C 1 -C 4  alkylene)-N(R 7 )(C 1 -C 4  alkyl), aryl, heteroaryl, heterocyclyl, —C(O)N(R 7 )-aryl, —N(R 7 )C(O)-aryl, —(C 1 -C 4  alkylene)-aryl, —(C 1 -C 4  alkylene)-heteroaryl, —O—(C 0 -C 4  alkylene)-aryl, —O—(C 0 -C 4  alkylene)-heteroaryl, —O—(C 0 -C 4  alkylene)-heterocyclyl, —O—(C 0 -C 4  alkylene)-carbocyclyl, —N(R 7 )-aryl, or —N(R 7 )-heteroaryl, —N(R 9 )-aryl, —N(R 9 )-heteroaryl, —O—(C 1 -C 4  alkeylene)-N(R 7 )C(O)O—(C 1 -C 4  alkylene)-aryl, —N(R 9 )—C(O)—(C 2 -C 4  alkenyl) wherein: 
         at least one of R 1a  and R 1b  is not hydrogen or methyl; 
         any alkylene moiety present in R 1a  or R 1b  is optionally substituted with OH or F; 
         each R 7  is independently selected from hydrogen and C 1 -C 4  alkyl; and 
         any aryl, heteroaryl, or heterocyclyl of R 1a  or R 1b  is optionally substituted with one or more substituents selected from -G-L-M, halo, —NO 2 , C 1 -C 6  alkyl, —C≡N, ═O, —CF 3  and —OCF 3 ; 
         G is a bond or a bivalent C 1 -C 6  saturated or unsaturated, straight or branched hydrocarbon chain wherein optionally one, two or three methylene units of the hydrocarbon chain are independently replaced by —NR 8 —, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO 2 —, —C(═S)—, —C(═NR 8 )—, —N═N—, or —C(═N 2 )—; 
         L is a covalent bond or a bivalent C 1-8  saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one, two, or three methylene units of L are optionally and independently replaced by cyclopropylene, —N(R 8 )C(O)—, —C(O)N(R 8 )—, —N(R 8 )SO 2 —, SO 2 N(R 8 )—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO 2 —, —C(═S)—, —C(═NR 8 )—, —N═N—, or —C(═N 2 )—; 
         M is E, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with at 1-4 groups independently selected from -D-E, oxo, NO 2 , halogen, CN, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl; 
         D is a covalent bond or a bivalent C 1 -C 6  saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of D are optionally and independently replaced by —NR 8 —, —S—, —O—, —C(O)—, —SO—, or —SO 2 —; 
         E is hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl, wherein said alkyl, alkenyl or alkynyl is optionally substituted with oxo, halogen, or CN; and 
         each R 8  is independently hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, —C 1 -C 6  alkoxy, —S(O) 2 —C 2 -C 4  alkenyl, or an optionally substituted group selected from phenyl, a 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         R 2  is selected from phenyl, a 3-7 membered cycloalkyl, C 2 -C 4  alkyl, or CF 3 , wherein the phenyl or cycloalkyl is optionally substituted with a substituent selected from methyl or fluoro; 
         each R 3  is independently selected from halo, —(C 1 -C 4  alkylene)-O—(C 1 -C 4  alkyl), —C 1 -C 4  fluoroalkyl, —C(O)—O—(C 1 -C 4  alkyl), -phenyl, -heteroaryl, C 3 -C 7  cycloalkyl, —CH 2 —N(C 1 -C 4  alkyl) 2 , C(O)—N—(C 1 -C 4  alkyl) 2 , —C(O)—NH—(C 1 -C 4  alkyl), —C 1 -C 4  alkyl optionally substituted with one or more halo or —OH, or two R 3 s are taken together to form a 3-8 saturated ring or a fused phenyl wherein said saturated ring or fused phenyl is optionally substituted with 1 to 2 methyl; 
         R 4  is selected from hydrogen, —CN, halo, C 1 -C 4  alkoxy, —CH 2 NH(C 1 -C 4  alkyl), C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, —(C 1 -C 4  alkyl)-O—(C 1 -C 4  alkyl), C 1 -C 4  fluoroalkyl, C(O)—N—(C 1 -C 4  alkyl) 2 , —C(O)—NH—(C 1 -C 4  alkyl), —C(O)—O—(C 1 -C 4  alkyl), —C(O)—OH, —S(O) 2 —(C 1 -C 4  alkyl), and a 5-membered heteroaryl; 
         R 5  is selected from: —C(O)—(C 1 -C 5  alkyl), —C(O)—(C 2 -C 6  alkenyl), —C(O)—(C 0 -C 2  alkylene)-Q, —C(O)—(C 1 -C 4  alkenylene)-Q, —C(O)—(C 0 -C 2  alkylene)-N(R 6 )—(C 0 -C 2  alkylene)-Q, —C(O)—O—(C 0 -C 2  alkylene)-Q, —C(O)—(C 1 -C 2  alkylene)-O—(C 0 -C 2  alkylene)-Q, —C(O)—C(O)-Q, —S(O) 2 -Q, —C(O)—(C 1 -C 4  alkylene)-O—C(O)—(C 1 -C 4  alkyl), —C(O)—(C 1 -C 4  alkylene)-C(O)—O—(C 1 -C 4  alkyl), —C(O)—N(R 6 )—(C 1 -C 4  alkylene)-O—C(O)—(C 1 -C 4  alkyl), —C(O)—N(R 6 )—(C 1 -C 4  alkylene)-C(O)—O—(C 1 -C 4  alkyl), —C(O)—(C 0 -C 2  alkylene)-N(R 6 )—(C 1 -C 6  alkyl), —C(O)—(C 0 -C 2  alkylene)N(R 6 )—(C 2 -C 6  alkynyl), —C(O)—(C 0 -C 2  alkylene)-N(R 6 )—(C 2 -C 6  alkenyl), —C(O)—(C 0 -C 2  alkylene)-N(R 6 )—(C 0 -C 2  alkylene)-O—(C 1 -C 4  alkyl), —C(O)—(C 1 -C 2  alkylene)-O—(C 1 -C 4  alkyl), —C(O)—(C 1 -C 2  alkylene)-C(O)C(O)N(R)(C 1 -C 4  alkyl), —C(O)—O—(C 1 -C 4  alkylene)-O—(C 1 -C 4  alkyl), —(C 0 -C 4  alkylene)-O—C(O)—(C 1 -C 4  alkyl), —(C 0 -C 4  alkylene)-C(O)—O—(C 1 -C 4  alkyl), —(C 0 -C 4  alkylene)-O—(C 1 -C 4  alkyl), —C(O)—(C 1 -C 2  alkylene)-S(O) 0-2 -(C 1 -C 4  alkyl), —S(O) 2 —(C 1 -C 4  alkyl), —C(O)—(C 1 -C 4  alkylene)-C(O)C(O)N(R 6 )(C 1 -C 6  alkyl), —C(O)—(C 1 -C 4  alkylene)-N(R 6 )S(O) 2 —(C 1 -C 6  alkyl), or —C(O)—(C 1 -C 4  alkylene)-N(R 6 )S(O) 2 Q, wherein: 
         any alkylene moiety present in R 5  is optionally substituted with OCH 3 , OH or F; 
         any terminal methyl moiety present in R 5  is optionally replaced with —CH 2 OH, CF 3 , CH 2 F, —CH 2 Cl, C(O)CH 3 , C(O)CF 3 , CN, —OCH 3 , —C(O)H, —OP(O)(OH) 2 , —OP(O)(C 1 -C 4  alkoxy) 2  or CO 2 H; 
         each R 6  is independently selected from hydrogen and methyl; 
         Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, wherein Q is optionally substituted with up to 3 substituents independently selected from C 1 -C 4  alkyl optionally substituted with OH, C 1 -C 4  alkoxy, —C(O)O—(C 1 -C 4  alkyl), —(C 1 -C 4  alkylene)-(C 1 -C 4  alkoxy), —CN, —OH, fluoro, chloro, and bromo; 
         R 9  is selected from aryl and heteroaryl, wherein each aryl or heteroaryl is optionally substituted with one or more substituents selected from -G-L-M, halo, C 1 -C 6  alkyl, —C≡N, ═O, —CF 3  and —OCF 3 ; and 
         m is 0, 1, 2 or 3. 
       
     
     
         2 . The compound of  claim 1 , wherein:
 Y is —N(R 5 )— or —CH(R 5 )—;   each R 1a  and R 1b  is independently hydrogen, —C 1 -C 4  alkyl, —N(R 7 )(C 1 -C 4  alkylene)-N(R 7 )(C 1 -C 4  alkyl), aryl, heteroaryl, heterocyclyl, —C(O)N(R 7 )-aryl, —N(R 7 )C(O)-aryl, —(C 1 -C 4  alkylene)-aryl, —(C 1 -C 4  alkylene)-heteroaryl, —O—(C 1 -C 4  alkylene)-aryl, —O—(C 1 -C 4  alkylene)-heteroaryl, —O—(C 1 -C 4  alkylene)-heterocyclyl, —N(R 7 )-aryl, or —N(R 7 )-heteroaryl, wherein:
 at least one of R 1a  and R 1b  is not hydrogen or methyl; 
 any alkylene moiety present in R 1a  or R 1b  is optionally substituted with OH or F; 
 each R 7  is independently selected from hydrogen and C 1 -C 4  alkyl; and 
 any aryl, heteroaryl, or hetercylyl of R 1a  or R 1b  is optionally substituted with one or more substituents selected from -G-L-M, halo, C 1 -C 6  alkyl, —C≡N, ═O, —CF 3  and —OCF 3 ; 
   G is a bond or a bivalent C 1 -C 6  saturated or unsaturated, straight or branched hydrocarbon chain wherein optionally one, two or three methylene units of the hydrocarbon chain are independently replaced by —NR 8 —, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO 2 —, —C(═S)—, —C(═NR 8 )—, —N═N—, or —C(═N 2 )—;   L is a covalent bond or a bivalent C 1-8  saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one, two, or three methylene units of L are optionally and independently replaced by cyclopropylene, —N(R 8 )C(O)—, —C(O)N(R 8 )—, —N(R 8 )SO 2 —, SO 2 N(R 8 )—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO 2 —, —C(═S)—, —C(═NR 8 )—, —N═N—, or —C(═N 2 )—;   M is E, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with at 1-4 groups independently selected from -D-E, oxo, NO 2 , halogen, CN, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl;   D is a covalent bond or a bivalent C 1 -C 6  saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of D are optionally and independently replaced by —NR 8 —, —S—, —O—, —C(O)—, —SO—, or —SO 2 —;   E is hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl, wherein said alkyl, alkenyl or alkynyl is optionally substituted with oxo, halogen, or CN; and   each R 8  is independently hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, or an optionally substituted group selected from phenyl, a 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;   R 2  is selected from phenyl, a 3-7 membered cycloalkyl, and C 2 -C 4  alkyl, wherein the phenyl or cycloalkyl is optionally substituted with a substituent selected from methyl or fluoro;   each R 3  is independently selected from —C 1 -C 4  alkyl, —(C 1 -C 4  alkyl)-O—(C 1 -C 4  fluoroalkyl, —C(O)—O—(C 1 -C 4  alkyl), -phenyl, -heteroaryl, C 3 -C 7  cycloalkyl, —CH 2 —N(C 1 -C 4  alkyl) 2 , C(O)—N—(C 1 -C 4  alkyl) 2 , and —C(O)—NH—(C 1 -C 4  alkyl), or   or two R 3 s are taken together to form a 3-8 saturated ring or a fused phenyl wherein said saturated ring or fused phenyl is optionally substituted with 1 to 2 methyl groups;   R 4  is selected from hydrogen, —CN, halo, C 1 -C 4  alkoxy, —CH 2 NH(C 1 -C 4  alkyl), C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, —(C 1 -C 4  alkyl)-O—(C 1 -C 4  alkyl), C 1 -C 4  fluoroalkyl, C(O)—N—(C 1 -C 4  alkyl) 2 , —C(O)—NH—(C 1 -C 4  alkyl), —C(O)—O—(C 1 -C 4  alkyl), —C(O)—OH, —S(O) 2 —(C 1 -C 4  alkyl), and a 5-membered heteroaryl;   R 5  is selected from: —C(O)—(C 1 -C 4 alkyl), —C(O)—(CH 2 ) 0-2 -Q, —C(O)—(CH 2 ) 0-2 —N(R 6 )—(CH 2 ) 0-2 -Q, —C(O)—O—(CH 2 ) 1-2 -Q, —C(O)—(CH 2 ) 1-2 —O—(CH 2 ) 0-2 -Q, —C(O)—C(O)-Q, —S(O) 2 -Q, —C(O)—(C 1 -C 4  alkylene)-O—C(O)—(C 1 -C 4  alkyl), —C(O)—(C 1 -C 4  alkylene)-C(O)—O—(C 1 -C 4  alkyl), —C(O)—N(R 6 )—(C 1 -C 4  alkylene)-O—C(O)—(C 1 -C 4  alkyl), —C(O)—N(R 6 )—(C 1 -C 4  alkylene)-C(O)—O—(C 1 -C 4  alkyl), —C(O)—(CH 2 ) 0-2 —N(R 6 )—(C 1 -C 6  alkyl), —C(O)—(CH 2 ) 0-2 —N(R 6 )—(C 2 -C 6  alkynyl), —C(O)—(CH 2 ) 0-2 —N(R 6 )—(C 2 -C 6  alkenyl), —C(O)—(CH 2 ) 0-2 —N(R 6 )—(CH 2 ) 0-2 —O—(C 1 -C 4  alkyl), —C(O)—(CH 2 ) 1-2 —O—(C 1 -C 4  alkyl), —C(O)—O—(C 1 -C 4  alkylene)-O—(C 1 -C 4  alkyl), —(CH 2 ) 0-4 —O—C(O)—(C 1 -C 4  alkyl), —(CH 2 ) 0-4 —C(O)—O—(C 1 -C 4  alkyl), —(CH 2 ) 0-4 —O—(C 1 -C 4  alkyl), —C(O)—(CH 2 ) 1-2 —S—(C 1 -C 4  alkyl), —S(O) 2 —(C 1 -C 4  alkyl), —C(O)—(C 1 -C 4  alkylene)-C(O)C(O)N(R 6 )(C 1 -C 6  alkyl), —C(O)—(C 1 -C 4  alkylene)-N(R 6 )S(O) 2 —(C 1 -C 6  alkyl), and —C(O)—(C 1 -C 4  alkylene)-N(R 6 )S(O) 2 Q, wherein:
 any alkylene moiety present in R 5  is optionally substituted with OH or F; 
 any terminal methyl moiety present in R 5  is optionally replaced with —CH 2 OH, CF 3 , —CH 2 F, —CH 2 Cl, C(O)CH 3 , or C(O)CF 3 ; 
   each R 6  is independently selected from hydrogen and methyl;   Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, wherein Q is optionally substituted with up to 3 substituents independently selected from C 1 -C 4  alkyl, C 1 -C 4  alkoxy, —CN, fluoro, chloro, and bromo; and   m is 0, 1, 2 or 3.   
     
     
         3 . The compound of  claim 1 , wherein R 4  is selected from —CN or C(O)—O—C 1 -C 4  alkyl. 
     
     
         4 . The compound of  claim 1 , wherein R 4  is 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 1 , wherein Y is —N(R 5 )—. 
     
     
         6 . The compound of  claim 6 , wherein R 5  is —C(O)—(C 1 -C 3  alkyl)-O—(C 1 -C 2  alkyl), —C(O)-Q, —C(O)—(C 1 -C 5  alkyl), —C(O)—(C 1 -C 2  alkylene)-Q, —C(O)—(C 2 -C 4  alkenyl), —C(O)O—(C 1 -C 4  alkyl), or —C(O)—(C 1 -C 4  alkenylene)-Q; wherein: any alkylene moiety present in R 5  is optionally substituted with OH; any terminal methyl moiety present in R 5  is optionally replaced with —OH, CF 3 , OCH 3 , —C(O)H, OP(O)(C 1 -C 4  alkoxy) 2 , or —OP(O)(OH) 2  (or a salt of —OP(O)(OH) 2 ). 
     
     
         7 . The compound of  claim 6 , wherein Q is cyclopropyl, cyclobutyl, oxetanyl, furanyl, azetidinonyl, pyrrolidinonyl, tetrahydrofuranyl, dihydrofuranonyl, or cyclopentyl, wherein each member of Q is optionally substituted with one substituent independently selected from C 1 -C 4  alkyl optionally substituted with OH, C 1 -C 4  alkoxy, alkylene)-(C 1 -C 4  alkoxy), and —OH. 
     
     
         8 . The compound of  claim 1 , wherein R 1a  is H and R 1b  is aryl, heteroaryl, heterocyclyl, alkylene)-aryl, alkylene)-heteroaryl, —O—(C 0 -C 4  alkylene)-aryl, —O—(C 0 -C 4  alkylene)-heteroaryl, —N(R 7 )-aryl, —N(R 7 )heteroaryl, —N(R 9 )-aryl, or —N(R 9 )-heteroaryl; wherein said aryl or heteroaryl is substituted with -G-L-M, CH 3 , or CN. 
     
     
         9 . The compound of  claim 8 , wherein aryl associated with R 1b  is phenyl. 
     
     
         10 . The compound of  claim 8 , wherein heteroaryl is associated with R 1b  pyridyl, pyrimidinyl, naphthyridinyl, quinolyl, isoquinolyl, isoxazolyl, benzoxazolyl, imidazopyrazinyl, benzothiazolyl, benzimidazolyl, pyrollopyridinyl, pyrazolopyridinyl, indolyl, indazolyl, imidazopyridinyl, quinoxalinyl, quinazolinyl, pyridazinyl or pyrazolyl. 
     
     
         11 . The compound of  claim 8 , wherein heterocyclyl is associated with R 1b  benzodioxole, pyridazinone, benzoxazolone, indolinone, N-methylindolinone, piperazinyl, N-methylisoquinolinone, tetrahydropyridinyl, dihydropyrrolyl and said phenyl, pyridyl, pyrimidinyl, naphthyridinyl, quinolyl, isoquinolyl, isoxazolyl, benzoxazolyl, imidazopyrazinyl, benzothiazolyl, benzimidazolyl, pyrollopyridinyl, pyrazolopyridinyl, indolyl, indazolyl, imidazopyridinyl, quinoxalinyl, quinazolinyl, pyridazinyl, pyrazolyl, benzodioxole, pyridazinone, benzoxazolone, indolinone, N-methylindolinone, piperazinyl, N-methylisoquinolinone, tetrahydropyridinyl, or dihydropyrrolyl 
     
     
         12 . The compound of  claim 9 , wherein aryl, heteroaryl or heterocyclyl associated with R 1b  is substituted with -G-L-M, —CF 3 , —OCF 3 , halo (e.g., fluoro, chloro or bromo), CH 3 , or CN. 
     
     
         13 . The compound of  claim 1 , wherein R 1a  is methyl and R 1b  is aryl, heteroaryl, heterocyclyl, —O—(C 0 -C 4  alkylene)-aryl, or —O—(C 0 -C 4  alkylene)-heteroaryl. 
     
     
         14 . The compound of  claim 13 , wherein R 1a  is methyl and R 1b  is aryl, heteroaryl, heterocyclyl, —O—(CH 2 )-aryl, —O—CH(CH 3 )-aryl, —O—(CH 2 )-heteroaryl or —O—CH(CH 3 )-heteroaryl. 
     
     
         15 . The compound of  claim 13 , wherein aryl associated with R 1b  is phenyl or naphthyl. 
     
     
         16 . The compound of  claim 13 , wherein heteroaryl associated with R 1b  is quinolinyl, pyrazolyl, isoquinolinyl, pyridyl, pyrimidinyl, indolyl, or pyrazolyl. 
     
     
         17 . The compound of  claim 13 , wherein heterocyclyl associated with R 1b  is tetrahydropyridinyl and said phenyl, pyridyl, pyrimidinyl, indolyl, or pyrazolyl. 
     
     
         18 . The compound of  claim 13 , wherein aryl, heteroaryl or heterocyclyl associated with R 1b  is substituted with -G-L-M, halo, CH 3 , or CN. 
     
     
         19 . The compound of  claim 8 , wherein -G-L-M: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 1 -C 4  alkoxy, tetrazolyl, morpholino, piperazinyl, pyrrolidinone, pyrazolyl, benzyl, —(CH 2 ) 1-4 —SH, —(CH 2 ) 1-4 —NH 2 , —NH 2 , —(CH 2 ) 1-4 —OH, —N(H)C(O)OCH(CH 3 ) 3 , —(CH 2 ) 1-4 —OCH 3 , —NH—(CH 2 ) 1-4 —OH, —C(O)—(C 1 -C 4  alkyl), —C(O)—(C 1 -C 4  alkenyl), —O—(CH 2 ) 1-4 —C(O)—O—(C 1 -C 4  alkyl), —C(O)NH 2 , —(CH 2 ) 1-4 C(O)CH 3 , —N(CH 3 )(CH 3 ), —NHC(O)(C 2 -C 4  alkenyl), —NHC(O)(C 2 -C 4  alkyl), —SO 2 (CH 2 ) 1-4 , —(CH 2 ) 1-4 —NHSO 2 Me, —NHSO 2 (CH 2 ) 1-4 , —O—SO 2 CF 3 , —SO 2 NH—(C 1 -C 4  alkyl), —SO 2 NH—(C 2 -C 4  alkenyl), SO 2 —NH 2  or —NHSO 2 Me 
       
     
     
         20 . A pharmaceutical composition comprising a compound of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         21 . The composition of  claim 20 , further comprising a second therapeutic agent. 
     
     
         22 . A method of treating a cancer characterized by the presence of an IDH1 mutation, wherein the IDH1 mutation result in a new ability of the enzyme to catalyze the NAPH-dependent reduction of a-ketoglutarate to R(−)-2-hydroxyglutarate in a patient, comprising the step of administering to the patient in need thereof a composition of  claim 20 . 
     
     
         23 . The method of  claim 22 , wherein the IDH1 mutation is an IDH1 R132H or IDH1 R132C mutation. 
     
     
         24 . The method of  claim 23 , wherein the cancer is selected from glioma (glioblastoma), acute myelogenous leukemia, sarcoma, melanoma, non-small cell lung cancer and cholangiocarcinomas, cholangiocarcinomas, chondrosarcoma, myelodysplastic syndromes (MDS), myeloproliferative neoplasm (MPN), or colon cancer. 
     
     
         25 . The method of  claim 22 , further comprising administering to the patient in need thereof a second therapeutic agent.