Carbamic acid compounds comprising an amide linkage as hdac inhibitors

Abstract

This invention pertains to certain active carbamic acid compounds which inhibit HDAC activity and which have the following formula: wherein: A is a C 5-20 heteroaryl or C 5-20 carboaryl group and is optionally substituted; Q 1 is a C 2-7 alkylene group having a backbone of at least 2 carbon atoms, and is optionally substituted; J is —N(R 1 )C(═O)— or —C(═O)N(R 1 )—; R 1 is hydrogen, C 1-7 alkyl, C 3-20 heterocyclyl, or C 5-20 aryl; and, Q 2 is C 1-7 alkylene, C 5-20 arylene, C 5-20 arylene-C 1-7 alkylene, or C 1-7 alkylene-C 5-20 arylene having a backbone of at least 3 carbon atoms, and is optionally substituted; and pharmaceutically acceptable salts thereof. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit HDAC, and, e.g., to treat proliferative conditions, such as cancer and psoriasis.

1 . A compound selected from compounds of the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 A is a C 5-20 heteroaryl or C 5-20 carboaryl group and is optionally substituted; 
 Q 1  is a C 2-7 alkylene group having a backbone of at least 2 carbon atoms, and is optionally substituted; 
 J is: 
 
       
         
           
           
               
               
           
         
         R 1  is hydrogen, C 1-7 alkyl, C 3-20 heterocyclyl, or C 5-20 aryl; 
         Q 2  is C 1-7 alkylene, C 5-20 arylene, C 5-20 arylene-C 1-7 alkylene, or C 1-7 alkylene-C 5-20 arylene having a backbone of at least 3 carbon atoms, and is optionally substituted; 
         and pharmaceutically acceptable salts thereof. 
       
     
     
         2 . A compound according to  claim 1 , wherein J is —C(═O)NR 1 —. 
     
     
         3 . A compound according to  claim 1 , wherein J is —NR 1 C(═O)—. 
     
     
         4 . A compound according to  claim 1 , wherein Q 1  is a saturated aliphatic C 2-7 alkylene group. 
     
     
         5 . A compound according to  claim 1 , wherein Q 1  is a saturated alicyclic C 3-7 alkylene group. 
     
     
         6 . A compound according to  claim 1 , wherein Q 1  is a partially unsaturated aliphatic C 2-7 alkylene group. 
     
     
         7 . A compound according to  claim 1 , wherein Q 1  is optionally substituted with one or more groups selected from: halo, hydroxy, ether, C 5-20 aryl, acyl, amido, and oxo. 
     
     
         8 . A compound according to  claim 1 , wherein Q 1  is optionally substituted with one or more groups selected from: —F, —Cl, —Br, —I, —OH, —OMe, —OEt, —OPr, -Ph, and ═O. 
     
     
         9 . A compound according to  claim 1 , wherein Q 1  is: —CH═CH—, —CH 2 CH═CH—, —CH═CH—CH═CH—, or —CH═CHC(CH 3 )═CH—. 
     
     
         10 . A compound according to  claim 1 , wherein Q 2  is a saturated aliphatic C 3-10 alkylene group having a backbone of at least 3 carbon atoms. 
     
     
         11 . A compound according to  claim 1 , wherein Q 2  is a saturated linear C 3-10 alkylene group having a backbone of at least 3 carbon atoms. 
     
     
         12 . A compound according to  claim 1 , wherein Q 2  is: —(CH 2 ) 4 —, —(CH 2 ) 5 —, or —(CH 2 ) 6 —. 
     
     
         13 . A compound according to  claim 1 , wherein Q 2  is phenylene-C 1-7 alkylene having a backbone of at least 3 carbon atoms, and is optionally substituted. 
     
     
         14 . A compound according to  claim 1 , wherein Q 2  is phenylene-meta-C 1-7 alkylene or phenylene-para-C 1-7 alkylene, has a backbone of at least 3 carbon atoms, and is optionally substituted. 
     
     
         15 . A compound according to  claim 1 , wherein Q 2  is: 
       
         
           
           
               
               
           
         
       
     
     
         16 . A compound according to  claim 1 , wherein A is phenyl, pyridyl, furanyl, indolyl, pyrrolyl, imidazolyl, naphthyl, quinolinyl, benzimidazolyl, benzothiofuranyl, fluorenyl, acridinyl, or carbazolyl, and is optionally substituted. 
     
     
         17 . A compound according to  claim 1 , wherein A is phenyl and is optionally substituted. 
     
     
         18 . A compound according to  claim 1 , wherein A is phenyl optionally substituted with one or more of the following groups: fluoro, chloro, bromo, iodo, methyl, ethyl, isopropyl, t-butyl, cyano, trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy, trifluoromethoxy, phenoxy, methylthio, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, amido, acetamido, acetyl, nitro, sulfonamido, and phenyl. 
     
     
         19 . A compound according to  claim 1 , wherein R 1  is hydrogen or C 1-7 alkyl. 
     
     
         20 . A compound according to  claim 1 , wherein R 1  is —H. 
     
     
         21 . A composition comprising a compound according to  claim 1 , and a pharmaceutically acceptable carrier or diluent. 
     
     
         22 . A method inhibiting HDAC in a cell comprising said cell with an effective amount of a compound according to  claim 1 . 
     
     
         23 . A method of treatment of a condition mediated by HDAC comprising administering to a subject suffering from a condition mediated by HDAC a therapeutically-effective amount of a compound according to  claim 1 . 
     
     
         24 . A method of treatment of a proliferative condition comprising administering to a subject suffering from a proliferative condition a therapeutically-effective amount of a compound according to  claim 1 . 
     
     
         25 . A method of treatment of cancer comprising administering to a subject suffering from cancer a therapeutically-effective amount of a compound according to  claim 1 . 
     
     
         26 . A method of treatment of psoriasis comprising administering to a subject suffering from psoriasis a therapeutically-effective amount of a compound according to  claim 1 .