Therapeutically active compositions and their methods of use

Abstract

Provided are compounds of formula (I), wherein X, Y, Z, W, V, R 2 , R 3 and m are defined as in the description. Their pharmaceutical compositions and their uses for treating cancers are also provided.

We claim: 
     
         1 . A compound having Structural Formula I 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 X is N; 
 Y is —N(R 5 )— or —CH(R 5 )—; 
 Z is —O—, —S—, —C(R) 2 — or N(R 7 ); 
 W is C(R 1 )(R 1 ) or N(R 7 ); provided that Z and W are not both N(R 7 ) at the same time; 
 V is N or C(R); 
 each R is independently selected from hydrogen, methyl or CF 3 ; 
 each R 1  is independently selected from hydrogen, alkoxy, or alkyl optionally substituted with OH or SH; 
 
       or two R 1  are taken together with the carbon atom to which they are bound to form a 3-7 membered cycloalkyl, or a 4-7 membered saturated heterocyclyl ring wherein said cycloalkyl or heterocyclyl is optionally substituted with methyl, halo or CF 3 ;
 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 single substituent selected from methyl, CF 3  or fluoro; 
 each R 3  is independently selected from —(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 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 5  is selected from: C 1 -C 4  alkyl, —C(O)—(C 1 -C 4  alkyl), —C(O)—(C 0 -C 2  alkylene)-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)-C(O)N(R 6 )—(C 1 -C 6  alkyl), —C(O)—(C 0 -C 2  alkylene)-C(O)—(C 1 -C 6  alkyl), —C(O)—(C 0 -C 2  alkylene)-N(R 6 )C(O)O—(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 4  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 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, —OH or CO 2 H;
 each R 6  is independently selected from hydrogen and methyl; 
 Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl; and Q is optionally substituted with up to 3 substituents independently selected from C 1 -C 4  alkyl optionally substituted by —OH, C 1 -C 4  alkoxy, —(C 1 -C 4  alkylene)-OC(O)O—(C 1 -C 4  alkyl), —C(O)O—(C 1 -C 4  alkyl), —CN, fluoro, chloro, and bromo; 
 
       each R 7  is independently -G-L-M;
 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, —NR 8 —, —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; 
 
       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; and
 m is 0, 1, 2 or 3. 
 
     
     
         2 . The compound of  claim 1 , wherein:
 X is N;   Y is —N(R 5 )— or —CH(R 5 )—;   Z is —O—, —S—, —C(R) 2 — or N(R 7 );   W is C(R 1 )(R 1 ) or N(R 7 ); provided that (1) when Z is —C(R) 2 —, then W is not C(R 1 )(R 1 ); and (2) Z and W are not both N(R 7 ) at the same time;   V is N or C(R);   each R is independently selected from hydrogen, methyl or CF 3 ;   each R 1  is independently selected from hydrogen, alkoxy, or alkyl optionally substituted with OH or SH;   or two R 1  are taken together with the carbon atom to which they are bound to form a 3-7 membered cycloalkyl, or a 4-7 membered saturated heterocyclyl ring wherein said cycloalkyl or heterocyclyl is optionally substituted with methyl, halo or CF 3 ;   R 2  is selected from phenyl, a 3-7 membered cycloalkyl, or C 2 -C 4  alkyl, wherein the phenyl or cycloalkyl is optionally substituted with a single substituent selected from methyl, CF 3  or fluoro;   each R 3  is independently selected from —C 1 -C 4  alkyl optionally substituted with halo, —(C 1 -C 4  alkyl)-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), 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 5  is selected from: —C(O)—(C 1 -C 4  alkyl), —C(O)—(C 0 -C 2  alkylene)-Q, —C(O)—(C 0 -C 2  alkylene)-N(R 6 )—(C 0 -C 2  alkylene)-Q, —C(O)—O—(C 1 -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 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; and 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;   each R 7  is independently -G-L-M;   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, —NR 8 —, —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;   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; and   m is 0, 1, 2 or 3.   
     
     
         3 . The compound of  claim 1 , wherein each R 1  is the same and is selected from methyl and hydrogen. 
     
     
         4 . The compound of  claim 1 , wherein Z is —O—. 
     
     
         5 . The compound of  claim 1 , wherein Z is —C(CH 3 ) 2 — and each R 1  is hydrogen. 
     
     
         6 . The compound of  claim 1 , wherein Z is —CH 2 —. 
     
     
         7 . The compound of  claim 1 , wherein Z is —N(R 7 )—. 
     
     
         8 . The compound of  claim 1 , wherein Y is —N(R 5 )—. 
     
     
         9 . The compound of  claim 1 , wherein R 2  is selected from phenyl optionally substituted with a single fluoro or a single methyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl optionally substituted with a single methyl, isopropyl, ethyl and methyl. 
     
     
         10 . The compound of  claim 9 , wherein R 2  is selected from cyclohexyl, cyclobutyl, cyclopropyl, ethyl and isopropyl. 
     
     
         11 . The compound of  claim 10 , wherein R 2  is cyclohexyl; Z is —O—; and each R 1  is hydrogen. 
     
     
         12 . The compound of  claim 10 , wherein R 2  is selected from cyclobutyl, cyclopropyl, ethyl and isopropyl; Z is —O—; and each R 1  is methyl. 
     
     
         13 . The compound of  claim 1 , wherein R 5  is selected from —C(O)—(C 1 -C 4  alkyl), —C(O)—(CH 2 ) 0-2 -Q, —C(O)—(CH 2 ) 1-2 —O—(CH 2 ) 0-2 -Q, —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)-C(O)—O—(C 1 -C 4  alkyl), —C(O)—(CH 2 ) 0-2 —N(R 6 )—(C 2 -C 6  alkenyl), —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 —C(O)—O—(C 1 -C 4  alkyl), and —C(O)—(CH 2 ) 1-2 —S—(C 1 -C 4  alkyl). 
     
     
         14 . The compound of  claim 1 , wherein R 5  is —C(O)—(C 0 -C 2  alkylene)-C(O)N(R 6 )—(C 1 -C 6  alkyl), —C(O)—(C 0 -C 2  alkylene)-C(O)—(C 1 -C 6  alkyl), —C(O)—(C 0 -C 2  alkylene)-N(R 6 )C(O)O—(C 1 -C 6  alkyl). 
     
     
         15 . The compound of  claim 1 , wherein each R 7  is independently selected from: 
       
         
           
           
               
               
           
         
       
     
     
         16 . The compound of  claim 1 , wherein R 7  is independently selected from 
       
         
           
           
               
               
           
         
       
       —C(O)—CH 3 , —SO 2 CH 3  and —CH 2 CH 2 OH. 
     
     
         17 . A pharmaceutical composition comprising a compound of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         18 . The composition of  claim 17 , further comprising a second therapeutic agent. 
     
     
         19 . 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 α-ketoglutarate to R(−)-2-hydroxyglutarate in a patient, comprising the step of administering to the patient in need thereof a composition of claim  30 . 
     
     
         20 . The method of  claim 19 , wherein the IDH1 mutation is an IDH1 R132H mutation. 
     
     
         21 . The method of  claim 20 , wherein the cancer is selected from glioma (glioblastoma), acute myelogenous leukemia, sarcoma, melanoma, non-small cell lung cancer, cholangiocarcinomas, chondrosarcoma, myelodysplastic syndromes (MDS), myeloproliferative neoplasm (MPN), or colon cancer. 
     
     
         22 . The method of  claim 19 , further comprising administering to the patient in need thereof a second therapeutic agent.