Methods of treating cancer

Abstract

The present invention relates to methods of treating cancer by administering the EZH2 inhibitor compounds and pharmaceutical compositions to subjects in need thereof. The present invention also relates to the use of such compounds for research or other non-therapeutic purposes.

1 . A method comprising administering to a subject having an INI1-negative sarcoma a therapeutically effective amount of a compound being of Formula (V) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 R 2 , R 4  and R 12  are each, independently C 1-6  alkyl; 
 R 6  is C 6 -C 10  aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more -Q 2 -T 2 , wherein Q 2  is a bond or C 1 -C 3  alkyl linker optionally substituted with halo, cyano, hydroxyl or C 1 -C 6  alkoxy, and T 2  is H, halo, cyano, —OR a , —NR a R b , —(NR a R b R c ) + A − , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —NR b C(O)R a , —NR b C(O)OR a , —S(O) 2 R a , —S(O) 2 NR a R b , or R S2 , in which each of R a , R b , and R c , independently is H or R S3 , A −  is a pharmaceutically acceptable anion, each of R S2  and R S3 , independently, is C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R a  and R b , together with the N atom to which they are attached, form a 4 to 12-membered heterocycloalkyl ring having 0 or 1 additional heteroatom, and each of R S2 , R S3 , and the 4 to 12-membered heterocycloalkyl ring formed by R a  and R b , is optionally substituted with one or more -Q 3 -T 3 , wherein Q 3  is a bond or C 1 -C 3  alkyl linker each optionally substituted with halo, cyano, hydroxyl or C 1 -C 6  alkoxy, and T 3  is selected from the group consisting of halo, cyano, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, OR d , COOR d , —S(O) 2 R d , —NR d R e , and —C(O)NR d R e , each of R d  and R e  independently being H or C 1 -C 6  alkyl, or -Q 3 -T 3  is oxo; or any two neighboring -Q 2 -T 2 , together with the atoms to which they are attached form a 5- or 6-membered ring optionally containing 1-4 heteroatoms selected from N, O and S and optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—C 1 -C 6  alkyl, cyano, C 1 -C 6  alkoxyl, amino, mono-C 1 -C 6  alkylamino, di-C 1 -C 6  alkylamino, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl; 
 R 7  is -Q 4 -T 4 , in which Q 4  is a bond, C 1 -C 4  alkyl linker, or C 2 -C 4  alkenyl linker, each linker optionally substituted with halo, cyano, hydroxyl or C 1 -C 6  alkoxy, and T 4  is H, halo, cyano, NR f R g , —OR f , —C(O)R f , —C(O)OR f , —C(O)NR f R g , —C(O)NR f OR g , —NR f C(O)R g , —S(O) 2 R f , or R S4 , in which each of R f  and R g , independently is H or R S5 , each of R S4  and R S5 , independently is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and each of R S4  and R S5  is optionally substituted with one or more -Q 5 -T 5 , wherein Q 5  is a bond, C(O), C(O)NR k , NR k C(O), S(O) 2 , or C 1 -C 3  alkyl linker, R k  being H or C 1 -C 6  alkyl, and T 5  is H, halo, C 1 -C 6  alkyl, hydroxyl, cyano, C 1 -C 6  alkoxyl, amino, mono-C 1 -C 6  alkylamino, di-C 1 -C 6  alkylamino, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, or S(O) q R q  in which q is 0, 1, or 2 and R q  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and T 5  is optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 6  alkyl, hydroxyl, cyano, C 1 -C 6  alkoxyl, amino, mono-C 1 -C 6  alkylamino, di-C 1 -C 6  alkylamino, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl except when T 5  is H, halo, hydroxyl, or cyano; or -Q 5 -T 5  is oxo; and 
 R 8  is H, halo, hydroxyl, COOH, cyano, R S6 , OR S6 , or COOR S6 , in which R S6  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, 4 to 12-membered heterocycloalkyl, amino, mono-C 1 -C 6  alkylamino, or di-C 1 -C 6  alkylamino, and R S6  is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—C 1 -C 6  alkyl, cyano, C 1 -C 6  alkoxyl, amino, mono-C 1 -C 6  alkylamino, and di-C 1 -C 6  alkylamino; or R 7  and R 8 , together with the N atom to which they are attached, form a 4 to 11-membered heterocycloalkyl ring having 0 to 2 additional heteroatoms, and the 4 to 11-membered heterocycloalkyl ring formed by R 7  and R 8  is optionally substituted with one or more -Q 6 -T 6 , wherein Q 6  is a bond, C(O), C(O)NR m , NR m C(O), S(O) 2 , or C 1 -C 3  alkyl linker, R m  being H or C 1 -C 6  alkyl, and T 6  is H, halo, C 1 -C 6  alkyl, hydroxyl, cyano, C 1 -C 6  alkoxyl, amino, mono-C 1 -C 6  alkylamino, di-C 1 -C 6  alkylamino, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, or S(O) p R p  in which p is 0, 1, or 2 and R p  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and T 6  is optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 6  alkyl, hydroxyl, cyano, C 1 -C 6  alkoxyl, amino, mono-C 1 -C 6  alkylamino, di-C 1 -C 6  alkylamino, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl except when T 6  is H, halo, hydroxyl, or cyano; or -Q 6 -T 6  is oxo. 
 
     
     
         2 . The method of  claim 1 , wherein R 6  is C 6 -C 10  aryl or 5- or 6-membered heteroaryl, each of which is optionally, independently substituted with one or more -Q 2 -T 2 , wherein Q 2  is a bond or C 1 -C 3  alkyl linker, and T 2  is H, halo, cyano, —OR a , —NR a R b , —(NR a R b R c ) + A − , —C(O)NR a R b , —NR b C(O)R a , —S(O) 2 R a , or R S2 , in which each of R a  and R b , independently is H or R S3 , each of R S2  and R S3 , independently, is C 1 -C 6  alkyl, or R a  and R b , together with the N atom to which they are attached, form a 4 to 7-membered heterocycloalkyl ring having 0 or 1 additional heteroatom, and each of R S2 , R S3 , and the 4 to 7-membered heterocycloalkyl ring formed by R a  and R b , is optionally, independently substituted with one or more -Q 3 -T 3 , wherein Q 3  is a bond or C 1 -C 3  alkyl linker and T 3  is selected from the group consisting of halo, C 1 -C 6  alkyl, 4 to 7-membered heterocycloalkyl, OR d , —S(O) 2 R d , and —NR d R e , each of R d  and R e  independently being H or C 1 -C 6  alkyl, or -Q 3 -T 3  is oxo; or any two neighboring -Q 2 -T 2 , together with the atoms to which they are attached form a 5- or 6-membered ring optionally containing 1-4 heteroatoms selected from N, O and S. 
     
     
         3 . The method of  claim 1 , wherein the compound is of Formula (VI) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein Q 2  is a bond or methyl linker, T 2  is H, halo, —OR a , —NR a R b , —(NR a R b R c ) + A − , or —S(O) 2 NR a R b , R 7  is piperidinyl, tetrahydropyran, cyclopentyl, or cyclohexyl, each optionally substituted with one -Q 5 -T 5  and R 8  is ethyl. 
     
     
         4 . The method of  claim 1 , wherein the compound is of Formula (VIa) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 each of R a  and R b , independently is H or R S3 , R S3  being C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R a  and R b , together with the N atom to which they are attached, form a 4 to 12-membered heterocycloalkyl ring having 0 or 1 additional heteroatom, and each of R S3  and the 4 to 12-membered heterocycloalkyl ring formed by R a  and R b , is optionally substituted with one or more -Q 3 -T 3 , wherein Q 3  is a bond or C 1 -C 3  alkyl linker each optionally substituted with halo, cyano, hydroxyl or C 1 -C 6  alkoxy, and T 3  is selected from the group consisting of halo, cyano, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, OR d , COOR d , —S(O) 2 R d , —NR d R e , and —C(O)NR d R e , each of R d  and R e  independently being H or C 1 -C 6  alkyl, or -Q 3 -T 3  is oxo; 
 R 7  is -Q 4 -T 4 , in which Q 4  is a bond, C 1 -C 4  alkyl linker, or C 2 -C 4  alkenyl linker, each linker optionally substituted with halo, cyano, hydroxyl or C 1 -C 6  alkoxy, and T 4  is H, halo, cyano, NR f R g , —OR f , —C(O)R f , —C(O)OR f , —C(O)NR f R g , —C(O)NR f OR g , —NR f C(O)R g , —S(O) 2 R f , or R S4 , in which each of R f  and R g , independently is H or R S5 , each of R S4  and R S5 , independently is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 7-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and each of R S4  and R S5  is optionally substituted with one or more -Q 5 -T 5 , wherein Q 5  is a bond, C(O), C(O)NR k , NR k C(O), S(O) 2 , or C 1 -C 3  alkyl linker, R k  being H or C 1 -C 6  alkyl, and T 5  is H, halo, C 1 -C 6  alkyl, hydroxyl, cyano, C 1 -C 6  alkoxyl, amino, mono-C 1 -C 6  alkylamino, di-C 1 -C 6  alkylamino, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 7-membered heterocycloalkyl, 5- or 6-membered heteroaryl, or S(O) q R q  in which q is 0, 1, or 2 and R q  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10  aryl, 4 to 7-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and T 5  is optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 6  alkyl, hydroxyl, cyano, C 1 -C 6  alkoxyl, amino, mono-C 1 -C 6  alkylamino, di-C 1 -C 6  alkylamino, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 7-membered heterocycloalkyl, and 5- or 6-membered heteroaryl except when T 5  is H, halo, hydroxyl, or cyano; or -Q 5 -T 5  is oxo; provided that R 7  is not H; and 
 R 8  is H, halo, hydroxyl, COOH, cyano, R S6 , OR S6 , or COOR S6 , in which R S6  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, amino, mono-C 1 -C 6  alkylamino, or di-C 1 -C 6  alkylamino, and R S6  is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—C 1 -C 6  alkyl, cyano, C 1 -C 6  alkoxyl, amino, mono-C 1 -C 6  alkylamino, and di-C 1 -C 6  alkylamino; or R 7  and R 8 , together with the N atom to which they are attached, form a 4 to 11-membered heterocycloalkyl ring which has 0 to 2 additional heteroatoms and is optionally substituted with one or more -Q 6 -T 6 , wherein Q 6  is a bond, C(O), C(O)NR m , NR m C(O), S(O) 2 , or C 1 -C 3  alkyl linker, R m  being H or C 1 -C 6  alkyl, and T 6  is H, halo, C 1 -C 6  alkyl, hydroxyl, cyano, C 1 -C 6  alkoxyl, amino, mono-C 1 -C 6  alkylamino, di-C 1 -C 6  alkylamino, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 7-membered heterocycloalkyl, 5- or 6-membered heteroaryl, or S(O) p R p  in which p is 0, 1, or 2 and R p  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 7-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and T 6  is optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 6  alkyl, hydroxyl, cyano, C 1 -C 6  alkoxyl, amino, mono-C 1 -C 6  alkylamino, di-C 1 -C 6  alkylamino, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 7-membered heterocycloalkyl, and 5- or 6-membered heteroaryl except when T 6  is H, halo, hydroxyl, or cyano; or -Q 6 -T 6  is oxo. 
 
     
     
         5 . The method of  claim 4 , wherein R a  and R b , together with the N atom to which they are attached, form a 4 to 7-membered heterocycloalkyl ring having 0 or 1 additional heteroatoms to the N atom and the ring is optionally substituted with one or more -Q 3 -T 3 , wherein the heterocycloalkyl is azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, or morpholinyl. 
     
     
         6 . The method of  claim 5 , wherein R 7  is C 3 -C 8  cycloalkyl or 4 to 7-membered heterocycloalkyl, each optionally substituted with one or more -Q 5 -T 5 . 
     
     
         7 . The method of  claim 6 , wherein R 7  is piperidinyl, tetrahydropyran, tetrahydro-2H-thiopyranyl, cyclopentyl, cyclohexyl, pyrrolidinyl, or cycloheptyl, each optionally substituted with one or more -Q 5 -T 5 . 
     
     
         8 . The method of  claim 7 , wherein R 8  is H or C 1 -C 6  alkyl which is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—C 1 -C 6  alkyl, cyano, C 1 -C 6  alkoxyl, amino, mono-C 1 -C 6  alkylamino, and di-C 1 -C 6  alkylamino. 
     
     
         9 . The method of  claim 1 , wherein the subject has a deletion of INI1. 
     
     
         10 . The method of  claim 1 , wherein the INI1-negative sarcoma is resistant or refractory to at least one prior therapy. 
     
     
         11 . The method of  claim 1 , wherein the compound is administered orally. 
     
     
         12 . The method of  claim 11 , wherein the compound is administered in an amount of from about 0.1 mg/day to about 10 g/day. 
     
     
         13 . The method of  claim 11 , wherein the compound is administered in an amount of from about 0.1 mg/day to about 3 g/day. 
     
     
         14 . The method of  claim 11 , wherein the compound is administered in an amount of from about 0.1 mg/day to about 1 g/day. 
     
     
         15 . The method of  claim 11 , wherein the compound is administered twice daily. 
     
     
         16 . A method comprising administering to a subject having an INI1-negative sarcoma a therapeutically effective amount of a compound being 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         17 . The method of  claim 16 , wherein the subject has a deletion of INI1. 
     
     
         18 . The method of  claim 16 , wherein the INI1-negative sarcoma is resistant or refractory to at least one prior therapy. 
     
     
         19 . The method of  claim 16 , wherein the pharmaceutically acceptable salt is a hydrobromic acid salt. 
     
     
         20 . The method of  claim 16 , wherein the pharmaceutically acceptable salt is a hydrochloric acid salt. 
     
     
         21 . The method of  claim 16 , wherein the compound is administered orally. 
     
     
         22 . The method of  claim 21 , wherein the compound is administered in an amount of from about 0.1 mg/day to about 10 g/day. 
     
     
         23 . The method of  claim 21 , wherein the compound is administered in an amount of from about 0.1 mg/day to about 3 g/day. 
     
     
         24 . The method of  claim 21 , wherein the compound is administered in an amount of from about 0.1 mg/day to about 1 g/day. 
     
     
         25 . The method of  claim 21 , wherein the compound is administered twice daily.