Modulators of methyl modifying enzymes, compositions and uses thereof

Abstract

Agents having the structural Formula (II) for modulating histone methyl modifying enzymes, compositions and uses thereof for instance as anti-cancer agents are provided herein.

1 . A compound having the structural Formula (II): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         A is CH or N; 
         R 1a  is selected from —C 1 -C 2  alkyl and —O—(C 1 -C 2  alkyl), wherein R 1a  is optionally substituted with one or more fluoro; 
         R 4a  is selected from —(C 1 -C 3  alkylene)-O—(C 1 -C 2  alkyl), 1-substituted-pipieridin-4-yl, C 3 -C 6  cycloalkyl optionally substituted with one or more fluoro, and tetrahydropyranyl; and 
         R 13  is selected from hydrogen, halo, phenyl, pyridinyl, and —O—(C 1 -C 4  alkyl). 
       
     
     
         2 . The compound of  claim 1 , wherein R 1a  is selected from —OCH 3 , —CH 3 , —OCHF 2 , and —CH 2 CH 3 . 
     
     
         3 . The compound of  claim 1  or  2 , wherein the 1-substituted-pipieridin-4-yl is a 1-halo(C 1 -C 3 )alkyl-piperidin-4-yl. 
     
     
         4 . The compound of any one of  claims 1  to  3 , wherein R 4a  is selected from —CH 2 OCH 3 , —CH(CH 3 )OCH 3 , 4,4-difluorocyclohexyl, cyclopropyl, tetrayhyrdopyran-4-yl, 1-(t-butoxycarbonyl)-piperidin-4-yl, 1-(isobutoxycarbonyl)-piperidin-4-yl, 1-(isopropoxycarbonyl)-piperidin-4-yl, 1-(2-fluoroethyl)-piperidin-4-yl, 1-(2,2-difluoroethyl)-piperidin-4-yl, 1-(2,2,2-trifluoroethyl)-piperidin-4-yl, 1-(2-hydroxyisobutyl)-piperidin-4-yl, 1-(hydroxyisopropylcarbonyl)-piperidin-4-yl, 1-(ethoxycarbonylmethyl)-piperidin-4-yl, 1-(isopropylcarbonyl)-piperidin-4-yl, 1-methylpiperidin-4-yl, 1-(methylsulfonyl)-piperidin-4-yl, 1-(ethylsulfonyl)-piperidin-4-yl, 1-(isopropylsulfonyl)-piperidin-4-yl, 1-(phenyl)-piperidin-4-yl, 1-(oxetan-3-yl)piperidin-4-yl, 1-(pyridin-2-yl)-piperidin-4-yl, and 1-(pyrimidin-2-yl)-piperidin-4-yl. 
     
     
         5 . The compound of any one of  claims 1  to  4 , wherein R 13  is selected from hydrogen, chloro, fluoro, —OCH(CH 3 ) 2 , phenyl, and pyridin-2-yl. 
     
     
         6 . The compound of  claim 1 , wherein the compound is N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide, or a pharmaceutically acceptable salt thereof. 
     
     
         7 . The compound of  claim 6 , wherein the compound is R—N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide, or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The compound of  claim 1 , wherein the compound is 1-(1-(1-(2,2-difluoroethyl)piperidin-4-yl)ethyl)-N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1H-indole-3-carboxamide, or a pharmaceutically acceptable salt thereof. 
     
     
         9 . The compound of  claim 8 , wherein the compound is R-1-(1-(1-(2,2-difluoroethyl)piperidin-4-yl)ethyl)-N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1H-indole-3-carboxamide, or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The compound of  claim 1 , wherein the compound is N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(1-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)ethyl)-2-methyl-1H-indole-3-carboxamide, or a pharmaceutically acceptable salt thereof. 
     
     
         11 . The compound of  claim 10 , wherein the compound is R—N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(1-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)ethyl)-2-methyl-1H-indole-3-carboxamide, or a pharmaceutically acceptable salt thereof. 
     
     
         12 . The compound of  claim 1 , wherein the compound is 1-(1-(1-ethylpiperidin-4-yl)ethyl)-N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1H-indole-3-carboxamide, or a pharmaceutically acceptable salt thereof. 
     
     
         13 . The compound of  claim 12 , wherein the compound is R-1-(1-(1-ethylpiperidin-4-yl)ethyl)-N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1H-indole-3-carboxamide, or a pharmaceutically acceptable salt thereof. 
     
     
         14 . A pharmaceutical composition comprising a compound of any one of  claims 1  to  13 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. 
     
     
         15 . Use of a compound of any one of  claims 1  to  13 , or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating a disease or disorder associated with cellular proliferation. 
     
     
         16 . The use of  claim 15 , wherein the disease is cancer. 
     
     
         17 . The use of  claim 16 , wherein the cancer is selected from breast cancer, prostate cancer, colon cancer, renal cell carcinoma, glioblastoma multiforme cancer, bladder cancer, melanoma, bronchial cancer, lymphoma, and liver cancer.