Substituted benzene compounds

Abstract

The present invention relates to substituted benzene compounds. The present invention also relates to pharmaceutical compositions containing these compounds and methods of treating cancer by administering these 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 compound of Formula III: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 R 801  is C 1-6  alkyl, C 2-6  alkenyl, C 3-8  cycloalkyl, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, phenyl or 5- or 6-membered heteroaryl, each of which is substituted with O—C 1-6  alkyl-R x  or NH—C 1-6  alkyl-R x , wherein R x  is hydroxyl, O—C 1-3  alkyl or NH—C 1-3  alkyl, and R x  is optionally further substituted with O—C 1-3  alkyl or NH—C 1-3  alkyl except when R x  is hydroxyl; and R 801  is optionally further substituted; 
 each of R 802  and R 803 , independently is H, halo, C 1-4  alkyl, C 1-6  alkoxyl or C 6 -C 10  aryloxy, each optionally substituted with one or more halo; 
 each of R 804  and R 805 , independently is C 1-4  alkyl; and 
 R 806  is -Q x -T x , wherein Q x  is a bond or C 1-4  alkyl linker, T x  is H, optionally substituted C 1-4  alkyl, optionally substituted C 3 -C 8  cycloalkyl or optionally substituted 4- to 14-membered heterocycloalkyl, provided that the compound is not 
 
       
         
           
           
               
               
           
         
       
     
     
         2 . The compound of  claim 1 , wherein Q x  is a bond or methyl linker, and T x  is tetrahydropyranyl, piperidinyl substituted by 1, 2, or 3 C 1-4  alkyl groups, or cyclohexyl substituted by N(C 1-4  alkyl) 2  wherein one or both of the C 1-4  alkyl is optionally substituted with C 1-6  alkoxy. 
     
     
         3 . The compound of  claim 1 , wherein (i) R 806  is cyclohexyl substituted by N(C 1-4  alkyl) 2 ; or (ii) R 806  is 
       
         
           
           
               
               
           
         
       
       or (iii) R 801  is phenyl or 5- or 6-membered heteroaryl substituted with O—C 1-6  alkyl-R x ; or (iv) R 802  is methyl or isopropyl and R 803  is methyl or methoxyl; or (v) R 804  is methyl. 
     
     
         4 - 5 . (canceled) 
     
     
         6 . The compound of  claim 1 , wherein the compound is of Formula IVa or IVb: 
       
         
           
           
               
               
           
         
       
       wherein Z′ is CH or N, and R 807  is C 2-3  alkyl-R x . 
     
     
         7 . The compound of  claim 6 , wherein R 807  is —CH 2 CH 2 OH, —CH 2 CH 2 OCH 3 , or —CH 2 CH 2 OCH 2 CH 2 OCH 3 . 
     
     
         8 - 9 . (canceled) 
     
     
         10 . A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein
 R 701  is H, F, OR 707 , NHR 707 , —(C≡C)—(CH 2 ) n7 —R 708 , phenyl, 5- or 6-membered heteroaryl, C 3-8  cycloalkyl, or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the phenyl, 5- or 6-membered heteroaryl, C 3-8  cycloalkyl or 4-7 membered heterocycloalkyl each independently is optionally substituted with one or more groups selected from halo, C 1-3  alkyl, OH, O—C 1-6  alkyl, NH—C 1-6  alkyl, and, C 1-3  alkyl substituted with C 3-8  cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein each of the O—C 1-6  alkyl and NH—C 1-6  alkyl is optionally substituted with hydroxyl, O—C 1-3  alkyl or NH—C 1-3  alkyl, each of the O—C 1-3  alkyl and NH—C 1-3  alkyl being optionally further substituted with O—C 1-3  alkyl or NH—C 1-3  alkyl; 
 each of R 702  and R 703 , independently is H, halo, C 1-4  alkyl, C 1-6  alkoxyl or C 6 -C 10  aryloxy, each optionally substituted with one or more halo; 
 each of R 704  and R 705 , independently is C 1-4  alkyl; 
 R 706  is cyclohexyl substituted by N(C 1-4  alkyl) 2  wherein one or both of the C 1-4  alkyl is substituted with C 1-6  alkoxy; or R 706  is tetrahydropyranyl; 
 R 707  is C 1-4  alkyl optionally substituted with one or more groups selected from hydroxyl, C 1-4  alkoxy, amino, mono- or di-C 1-4  alkylamino, C 3-8  cycloalkyl, and 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the C 3-8  cycloalkyl or 4-7 membered heterocycloalkyl each independently is further optionally substituted with C 1-3  alkyl; 
 R 708  is C 1-4  alkyl optionally substituted with one or more groups selected from OH, halo, and C 1-4  alkoxy, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, or O—C 1-6  alkyl, wherein the 4-7 membered heterocycloalkyl can be optionally further substituted with OH or C 1-6  alkyl; and 
 n 7  is 0, 1 or 2, provided that the compound is not 
 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 10 , wherein (i) R 706  is cyclohexyl substituted by N(C 1-4  alkyl) 2  wherein one of the C 1-4  alkyl is unsubstituted and the other is substituted with methoxy; or (ii) R 706  is 
       
         
           
           
               
               
           
         
       
       or (iii) R 702  is methyl or isopropyl and R 703  is methyl or methoxyl; or (iv) R 704  is methyl; or (v) R 701  is OR 707  and R 707  is C 1-3  alkyl optionally substituted with OCH 3  or morpholino; or (vi) R 701  is H or F; or (vii) R 701  is tetrahydropyranyl, phenyl, pyridyl, pyrimidyl, pyrazinyl, imidazolyl, or pyrazolyl, each of which is optionally substituted with methyl, methoxy, ethyl substituted with morpholine, or —OCH 2 CH 2 OCH 3 ; or (viii) R 708  is morpholine, piperidine, piperazine, pyrrolidine, diazepane, or azetidine, each of which is optionally substituted with OH or C 1-6  alkyl; or (ix) R 708  is morpholine; or (x) R 708  is piperazine substituted with C 1-6  alkyl; or (xi) R 708  is methyl, t-butyl or C(CH 3 ) 2 OH. 
     
     
         12 . (canceled) 
     
     
         13 . The compound of  claim 10 , wherein the compound is of Formula II: 
       
         
           
           
               
               
           
         
       
     
     
         14 - 22 . (canceled) 
     
     
         23 . A compound of Formula VI or VII: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof;
 wherein 
 n 5  is 0, 1, or 2; 
 n 6  is 1 or 2; 
 R 501  is C(H) or N; 
 R 502 , R 503 , R 504  and R 505  are, independently for each occurrence, C 1-4  alkyl; 
 R 506  is cyclohexyl substituted by N(C 1-4  alkyl) 2  or piperidine substituted by 1, 2, or 3 C 1-4  alkyl groups; 
 when R 501  is C(H), R 507  is morpholine; piperidine; diazepane; pyrrolidine; azetidine; O—C 1-6  alkyl; or O-heterocycle, wherein the heterocycle is a 4-7 membered heterocycle containing an oxygen or nitrogen, or both, and wherein the nitrogen can optionally be substituted with C 1-3  alkyl; wherein the piperidine, diazepane, pyrrolidine or azetidine groups can be optionally further substituted with OH, C 1-6  alkyl, or O—C 1-3  alkyl; 
 or when R 501  is C(H), R 507  can be piperazine optionally further substituted with C 1-6  alkyl, provided that R 506  is piperidine substituted by 1, 2, or 3 C 1-4  alkyl groups; 
 when R 501  is N, R 507  is morpholine; piperidine; piperazine; diazepane; pyrrolidine; 
 azetidine; O—C 1-6  alkyl; or O-heterocycle, wherein the heterocycle is a 4-7 membered heterocycle containing an oxygen or nitrogen, or both, and wherein the nitrogen can optionally be substituted with C 1-3  alkyl; wherein the piperidine, piperazine, diazepane, pyrrolidine or azetidine groups can be optionally further substituted with OH, C 1-6  alkyl, or O—C 1-3  alkyl; 
 R 602 , R 603 , R 604  and R 605  are, independently for each occurrence, C 1-4  alkyl; 
 R 606  is cyclohexyl substituted by N(C 1-4  alkyl) 2  or piperidine substituted by 1, 2, or 3 C 1-4  alkyl groups; and 
 R 607  is morpholine, piperidine, piperazine, pyrrolidine, diazepane, azetidine or O—C 1-6  alkyl, wherein the piperidine, diazepane or azetidine groups can be optionally further substituted with OH or C 1-6  alkyl. 
 
     
     
         24 . The compound of  claim 23 , wherein the compound is of Formula (VI), wherein (i) R 501  is C(H), and R 507  is piperidine; diazepane; pyrrolidine; azetidine; O—C 1-6  alkyl; or O-heterocycle, wherein the heterocycle is a 4-7 membered heterocycle containing an oxygen or nitrogen, or both, and wherein the nitrogen can optionally be substituted with C 1-3  alkyl; wherein the piperidine, diazepane, pyrrolidine or azetidine groups can be optionally further substituted with OH, C 1-6  alkyl, or O—C 1-3  alkyl; or (ii) R 501  is C(H) and R 507  is piperidine, diazepane, pyrrolidine, azetidine or O—C 1-6  alkyl, wherein the piperidine, diazepane, pyrrolidine or azetidine groups can be optionally further substituted with OH or C 1-6  alkyl; or (iii) R 501  is C(H), R 507  is piperazine optionally further substituted with C 1-6  alkyl, and R 506  is piperidine substituted by 1, 2, or 3 C 1-4  alkyl groups; or (iv) R 501  is N, and R 507  is morpholine, piperidine, piperazine, diazepane, pyrrolidine, azetidine or O—C 1-6  alkyl, wherein the piperidine, piperazine, diazepane, pyrrolidine or azetidine groups can be optionally further substituted with OH or C 1-6  alkyl. 
     
     
         25 - 27 . (canceled) 
     
     
         28 . The compound of  claim 23 , wherein the compound is of Formula (VI), wherein (i) R 502  is methyl or isopropyl, and R 503  is methyl; or (ii) R 502  is methyl or isopropyl, and R 503  is methyl; or (iii) R 504  is methyl; or (iv) R 505  is ethyl; or (v) R 506  is 
       
         
           
           
               
               
           
         
       
       or (vi) R 506  is 
       
         
           
           
               
               
           
         
       
     
     
         29 - 32 . (canceled) 
     
     
         33 . The compound of  claim 23 , wherein the compound is of Formula (VI), wherein (i) when R 501  is C(H), R 507  is piperidine or diazepane, which are substituted with OH or C 1-6  alkyl, or when R 501  is N, R 507  is piperidine, piperazine, or diazepane, which are optionally further substituted with OH or C 1-6  alkyl; or (ii) when R 501  is C(H), R 507  is piperidine substituted with C 1-6  alkyl, or when R 501  is N, R 507  is piperidine substituted with OH or piperazine substituted with C 1-6  alkyl; or (iii) when R 501  is N, R 507  is unsubstituted piperazine; or (iv) when R 501  is C(H) or N, R 507  is O—C 1-6  alkyl or O-heterocycle, and n 5  is 1; or (v) when R 501  is C(H), R 507  is unsubstituted piperazine and R 506  is piperidine substituted by 1, 2, or 3 C 1-4  alkyl groups; or (vi) n 5  is 0 or 1. 
     
     
         34 - 38 . (canceled) 
     
     
         39 . The compound of  claim 23 , being of Formula VII: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         40 . The compound of  claim 39 , wherein (i) R 602  is methyl or isopropyl and R 603  is methyl; or (ii) R 604  is methyl and R 605  is ethyl; or (iii) R 607  is piperidine or diazepane, each of which is substituted with OH or C 1-6  alkyl; or (iv) R 607  is piperidine substituted with OH; or (v) R 606  is 
       
         
           
           
               
               
           
         
       
       or (vi) R 606  is 
       
         
           
           
               
               
           
         
       
       or (vii) n 6  is 2. 
     
     
         41 - 47 . (canceled) 
     
     
         48 . A pharmaceutical composition comprising a compound of  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         49 . A method of treating an EZH2-mediated disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         50 . The method of  claim 49 , wherein the EZH2-mediated disorder is cancer. 
     
     
         51 . The method of  claim 50 , wherein the cancer is lymphoma, leukemia or melanoma. 
     
     
         52 . The method of  claim 50 , wherein the cancer is diffuse large B-cell lymphoma (DLBCL), non-Hodgkin's lymphoma (NHL), follicular lymphoma, chronic myelogenous leukemia (CML), acute myeloid leukemia, acute lymphocytic leukemia, mixed lineage leukemia, or myelodysplastic syndromes (MDS). 
     
     
         53 . The method of  claim 50 , wherein the cancer is malignant rhabdoid tumor or INI1-deficient tumor. 
     
     
         54 - 56 . (canceled)