3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant idh

Abstract

The invention is directed to a formula (I): or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2a , R 2b and R 3 -R 7 are herein. The invention is also directed to compositions containing a compound of formula (I) and to the use of such compounds in the inhibition of mutant IDH proteins having a neomorphic activity. The invention is further directed to the use of a compound of formula (I) in the treatment of diseases or disorders associated with such mutant IDH proteins including, but not limited to, cell-proliferation disorders, such as cancer.

What is claimed is: 
     
         1 . A compound according to formula (I) 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is hydrogen, methyl or ethyl; 
 R 2a  is hydrogen, methyl or C 1-3  haloalkyl; 
 R 2b  is OH, halo, C 1-6  alkoxy, C 1-3  haloalkyl, NH 2 , NH(CH 3 ) or N(CH 3 ) 2 ; 
 R 3  and R 4  are each independently hydrogen, methyl or ethyl or R 3  and R 4  are joined together forming cyclopropyl, cyclobutyl or oxetanyl; 
 R 5  and R 6  are each independently hydrogen, deuterium, halo, —C(O)OCH 3 , C 1-3  alkyl or C 1-3  haloalkyl; 
 R 7  is 
 
       
         
           
           
               
               
           
         
         wherein:
 ring A is a 6 membered heteroaryl ring having one to three nitrogen atoms; 
 ring B is a 5 membered heteroaryl ring having one to four heteroatoms each independently selected from the group consisting of N, O and S; 
 X is N or CH; 
 each R 8  is independently hydrogen, halo, C 1-3  alkyl, C 1-3  haloalkyl, C 1-3  alkoxy or C 1-3  haloalkoxy; 
 n is 1 or 2; 
 R 9  is hydrogen, halo, C 1-3  haloalkyl, optionally substituted C 1-6  alkyl, optionally substituted C 3-6  cycloalkyl, optionally substituted aryl, optionally substituted 5 or 6 membered heterocyclic, optionally substituted heteroaryl, —OR 9a , —SO 2 R 9a , —C(O)NHR 9a , CH 2 R 9b  or CHCH 3 R 9b , provided that when X is N, R 9  is hydrogen, C 1-3  haloalkyl, optionally substituted C 1-6  alkyl, optionally substituted C 3-6  cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —SO 2 R 9a  or —C(O)NHR 9a , wherein:
 said C 1-6  alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of: OH, phenyl and phenoxy, and 
 Said C 3-6  cycloalkyl, 5 or 6 membered heterocyclic, aryl and heteroaryl are each optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, —NRR, C 1-6  alkyl, C 1-6  haloalkyl, C 1-3  alkoxy, and C 1-3  haloalkoxy; 
 
 R 9a  is optionally substituted C 1-6  alkyl, C 1-6  haloalkyl, optionally substituted C 3-6  cycloalkyl, optionally substituted phenyl, or optionally substituted heterocyclic, 
 wherein:
 said C 1-6  alkyl is optionally substituted with one C 3-6  cycloalkyl, 
 Said C 3-6  cycloalkyl and heterocyclic are each optionally substituted with one to three substituents each independently selected from the group consisting of: hydroxyl, CH 2 OH, —NRR, cyano, C 1-3  alkyl, C 1-3  haloalkyl, and C 1-3  alkoxy, and 
 Said phenyl is optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, —NRR, C 1-6  alkyl, C 1-6  haloalkyl, C 1-3  alkoxy, and C 1-3  haloalkoxy; 
 
 R 9b  is optionally substituted C 3-6  cycloalkyl, optionally substituted phenyl or optionally substituted heterocyclic,
 said C 3-6  cycloalkyl and heterocyclic are each optionally substituted with one to four substituents each independently selected from the group consisting of: hydroxyl, CH 2 OH, —NRR, —NRC(O)CH 3 , 4 to 6 membered heterocyclic, cyano, halo, C 1-3  alkyl, C 1-3  haloalkyl, and C 1-3  alkoxy, and 
 Said phenyl is optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, C 1-6  alkyl, Cl — 6 haloalkyl, C 1-3  alkoxy, and C 1-3  haloalkoxy; and 
 
 each R is independently selected from the group consisting of H, C 1-3  alkyl and C 3-6  cycloalkyl; or a pharmaceutically acceptable salt thereof. 
 
       
     
     
         2 . The compound according to  claim 1  wherein R 3  and R 4  are both hydrogen; or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The compound according to  claim 1  wherein R 1  is hydrogen; or a pharmaceutically acceptable salt thereof. 
     
     
         4 . The compound according to  claim 1  according to formula (II): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         5 . The compound according to  claim 1  wherein:
 R 5  is hydrogen or halo; and 
 R 6  is hydrogen, halo, methyl, CH 2 F, CHF 2 , or CF 3 ; or a pharmaceutically acceptable salt thereof. 
 
     
     
         6 . The compound according to  claim 5  wherein R 5  is hydrogen; or a pharmaceutically acceptable salt thereof. 
     
     
         7 . The compound according  claim 5  wherein R 6  is hydrogen; or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The compound according to  claim 5  wherein R 5  and R 6  are both hydrogen; or a pharmaceutically acceptable salt thereof. 
     
     
         9 . The compound according to  claim 1  wherein R 2a  is methyl; or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The compound according to  claim 1  wherein R 2b  is OH, fluoro, methoxy, t-butoxy, CHF 2 , CF 3 , NH 2  or NH(CH 3 ); or a pharmaceutically acceptable salt thereof. 
     
     
         11 . The compound according to  claim 1  having the following formula: 
       
         
           
           
               
               
           
         
         wherein R 2b  is OH, NH 2  or fluoro; or a pharmaceutically acceptable salt thereof. 
       
     
     
         12 . The compound according to  claim 1  according to formula (IV): 
       
         
           
           
               
               
           
         
       
       wherein R 2b  is OH or NH 2 ; or a pharmaceutically acceptable salt thereof. 
     
     
         13 . The compound according to  claim 12  wherein R 2b  is OH; or a pharmaceutically acceptable salt thereof. 
     
     
         14 . The compound according to  claim 12  wherein R 2b  is NH 2 ; or a pharmaceutically acceptable salt thereof. 
     
     
         15 . The compound according to  claim 1  according to formula (V): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         16 . The compound according to  claim 15  wherein R 2a  is methyl; or a pharmaceutically acceptable salt thereof. 
     
     
         17 . The compound according to  claim 1  wherein R 7  is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         18 . The compound according to  claim 1  wherein R 9  is hydrogen, halo, C 1-3  haloalkyl, optionally substituted C 1-6  alkyl or optionally substituted C 3-6  cycloalkyl; or a pharmaceutically acceptable salt thereof. 
     
     
         19 . The compound according to  claim 1  wherein R 9  is phenyl optionally substituted with one or two substituents each independently selected from the group consisting of: fluoro, chloro, bromo, cyano, methoxy, CH 2 OH, C 1-4  alkyl, C 1-4  haloalkyl and C 1-3  haloalkoxy; or a pharmaceutically acceptable salt thereof. 
     
     
         20 . The compound according to  claim 1  wherein R 9  is pyrazolyl, pyridinyl, indolyl or isoquinolinyl each of which is optionally substituted; or a pharmaceutically acceptable salt thereof. 
     
     
         21 . The compound according to  claim 1  wherein R 9  is CH 2 R 9b  wherein R 9b  is piperidinyl, piperazinyl or morpholinyl each of which is optionally substituted with one to three substituents each independently selected from the group consisting of: hydroxyl, halo, CH 2 OH, —NRR, cyano, C 1-3  alkyl, C 1-3  haloalkyl, and C 1-3  alkoxy. 
     
     
         22 . The compound according to  claim 1  according to formula (IV) 
       
         
           
           
               
               
           
         
         wherein: 
         R 2b  is OH; 
         R 5  is hydrogen or fluoro; 
         R 6  is hydrogen, chloro, methyl or CH 2 F; 
         R 7  is 
       
       
         
           
           
               
               
           
         
         R 8  is hydrogen, methyl or fluoro; 
         n is 1 or 2; and 
         R 9  is methylcyclopropyl, isobutoxy, phenyl optionally substituted with one or two substituents each independently selected from the group consisting of: fluoro, chloro, bromo, C 1-4  alkyl, CF 2 H and CF 3  or pyridinyl optionally substituted with one or two substituents each independently selected from the group consisting of: methyl, CF 3  and C(CH 3 ) 2 CF 3 ; or a pharmaceutically acceptable salt thereof. 
       
     
     
         23 . The compound according to  claim 22  wherein:
 R 5  is hydrogen and R 6  is chloro, methyl or CH 2 F or 
 R 6  is hydrogen and R 5  is fluoro; or a pharmaceutically acceptable salt thereof. 
 
     
     
         24 . The compound according to  claim 22  wherein R 5  and R 6  are both hydrogen; or a pharmaceutically acceptable salt thereof. 
     
     
         25 . The compound according to  claim 1  according to formula (V) 
       
         
           
           
               
               
           
         
       
       wherein:
 R 2b  is fluoro; 
 R 5  is hydrogen or fluoro; 
 R 6  is hydrogen; 
 R 7  is 
 
       
         
           
           
               
               
           
         
         R 8  is hydrogen or methyl; 
         n is 1; and 
         R 9  is phenyl optionally substituted with one chloro; or a pharmaceutically acceptable salt thereof. 
       
     
     
         26 . The compound according to  claim 1  selected from the group consisting of:
 (R)-4-((R)-1-hydroxy(R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-onethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one; 
 (R)-3-(2-(((S)-1-(5-(4-fluoro-3-methylphenyl)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; 
 (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyridin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one; 
 (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(6-(trifluoromethyl)-[2,3′-bipyridin]-6′-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one; 
 (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one; 
 (R)-3-(2-(((S)-1-(5-(4-fluoro-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; 
 (R)-3-(2-(((S)-1-(5-(4-chloro-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; 
 (R)-3-(2-(((S)-1-(5-(3,4-dichlorophenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; 
 (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one; 
 (R)-3-(2-(((S)-1-(5-(4-chloro-3-methylphenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; 
 (R)-3-(2-(((S)-1-(5-(3-chloro-5-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; 
 (R)-3-(2-(((S)-1-(5-(3,4-dichlorophenyl)pyrimidin-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; 
 (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one; 
 (R)-3-(5-fluoro-2-(((S)-1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; 
 (R)-3-(2-(((S)-1-(5-(2-fluoro-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; and 
 (R)-3-(2-(((S)-1-(2,5-difluoro-4-(2-methylpyridin-4-yl)phenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; or a pharmaceutically acceptable salt thereof. 
 
     
     
         27 . The compound according to  claim 1  selected from the group consisting of:
 (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; 
 (R)-3-(2-(((S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; 
 (R)-3-{2-[(S)-1-(5-Benzyl-[1,2,4]oxadiazol-3-yl)-ethylamino]-5-fluoro-pyrimidin-4-yl}-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one; 
 (R)-3-(2-{(S)-1-[3-(3,4-Dichloro-phenyl)-isoxazol-5-yl]-ethylamino}-pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one; 
 (R)-3-(2-{(S)-1-[3-(3,4-Dichloro-phenyl)-isoxazol-5-yl]-ethylamino}-5-fluoro-pyrimidin-4-yl)-4-((R)-1-hydroxy-ethyl)-oxazolidin-2-one; 
 (R)-3-(5-fluoro-2-(((S)-1-(3-(4-isopropylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; 
 (R)-4-((R)-1-hydroxyethyl)-3-(2-(((S)-1-(3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one; 
 (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)-4-methyloxazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; 
 (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)-4-methyloxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; 
 (R)-3-(2-(((S)-1-(4-(4-bromophenyl)thiazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; 
 (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; 
 (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; 
 (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; 
 (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)-6-(fluoromethyl)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; 
 (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; 
 (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; 
 (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)-6-methylpyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; 
 (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)-6-methylpyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; 
 (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl) ethyl)amino)-6-methylpyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; 
 (R)-3-(2-(((S)-1-(2-(4-(difluoromethyl)phenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; 
 (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; 
 (R)-3-(6-chloro-2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; and 
 (R)-3-(2-(((S)-1-(3-(3-(tert-butyl)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; or a pharmaceutically acceptable salt thereof. 
 
     
     
         28 . The compound according to  claim 1  selected from the group consisting of:
 (R)-3-(2-((S)-1-(2-fluoro-4-(1-methylcyclopropyl)phenyl)ethylamino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; 
 (R)-3-(5-fluoro-2-(((S)-1-(2-fluoro-4-isobutoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; and 
 (R)-3-(2-(((S)-1-(2-fluoro-4-isobutoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one; or a pharmaceutically acceptable salt thereof. 
 
     
     
         29 . The compound according to  claim 1  selected from the group consisting of:
 (R)-3-(6-chloro-2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one; 
 (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl) ethyl)amino)pyrimidin-4-yl)-4-((R)-1-methoxyethyl)oxazolidin-2-one; and 
 (S)-4-((R)-1-aminoethyl)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one; or a pharmaceutically acceptable salt thereof. 
 
     
     
         30 . The compound according to  claim 1  selected from the group consisting of:
 (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl) ethyl)amino)pyrimidin-4-yl)-4-((R)-1-fluoroethyl)oxazolidin-2-one; 
 (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl) ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one; 
 (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one; 
 (R)-3-(2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one; 
 (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-fluoroethyl)oxazolidin-2-one; 
 (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-2-methyl-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one; 
 (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-(4-fluorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one; 
 (R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-(fluoromethyl)oxazolidin-2-one; and 
 (S)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one; or a pharmaceutically acceptable salt thereof. 
 
     
     
         31 . A pharmaceutical composition comprising a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. 
     
     
         32 . A method for the treatment of a disease or disorder associated with a mutant IDH protein having a neomorphic activity comprising administration of a therapeutically effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, to subject in need of thereof. 
     
     
         33 . A method for the treatment of a disease or disorder associated with a mutant IDH protein having a neomorphic activity comprising administration of a therapeutically effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and another therapeutic agent to subject in need of thereof.