Inhibitors of histone deacetylase

Abstract

The invention provides compounds and methods for treating cell proliferative diseases. The invention provides new inhibitors of histone deacetylase enzymatic activity, compositions of the compounds comprising the inhibitors and a pharmaceutically acceptable carrier, excipient, or diluent, and methods of using the compounds to inhibit cellular proliferation in vitro and therapeutically.

1 . A compound of the following formula: 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salt thereof, wherein
 Ar is aryl or heteroaryl, each of which is optionally substituted with from 1 to 3 substituents. 
 
     
     
         2 . The compound of  claim 1  wherein Ar is aryl or pyridinyl. 
     
     
         3 . The compound of  claim 1  wherein Ar is phenyl. 
     
     
         4 . The compound of  claim 1  wherein Ar is substituted with 1-3 substituents selected from the group consisting of halo, C 1 -C 6 -hydrocarbyl optionally substituted with halo, C 1 -C 6 -hydrocarbyloxy optionally substituted with halo. 
     
     
         5 . The compound of  claim 1  wherein Ar is selected from one of the following: 
       
         
           
           
               
               
           
         
       
     
     
         6 . A compound of the following formula: 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salt thereof, wherein
 X is —N(R 1 )—, —O—, or —S—; or X is a nitrogen-containing heterocyclyl in which a nitrogen is covalently bound to the adjacent carbonyl in structure V and is optionally substituted with from 1 to 3 substituents; and 
 R and R 1  independently are —H, or optionally substituted a) C 1 -C 6 -hydrocarbyl or b) R 2 -L-, wherein R 2  is aryl or heteroaryl, L is C 0 -C 6 -hydrocarbyl-L 1 -C 0 -C 6 -hydrocarbyl, and L 1  is a covalent bond, —O—, —S—, or —NH—. 
 
     
     
         7 . The compound according to  claim 6  wherein X is —NH—, —O—, morphilin-4-yl, piperidin-1-yl, piperizin-1-yl, or pyrrolidin-1-yl. 
     
     
         8 . The compound according to  claim 6  wherein X is —N(R 1 )— wherein R 1  is optionally substituted methyl or ethyl. 
     
     
         9 . The compound according to  claim 6  wherein X is —N(R 1 )— wherein R 1  is cyanoethyl or pyridinylmethyl. 
     
     
         10 . The compound according to  claim 6  wherein X is —N(R 1 )— wherein R is R 2 -L- wherein R 2  is phenyl, pyridinyl, indyl, or indolyl and L is a covalent bond, methyl, ethyl, or oxyethyl. 
     
     
         11 . The compound according to  claim 6  wherein the combination of R—X— is selected from the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         12 . A compound of formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein Ar 1  is aryl or heteroaryl optionally substituted with from 1-3 substituents independently selected from —NO 2 , CH 3 O—, and morpholinyl (e.g., morpholin-4-yl). 
     
     
         13 . The compound according to  claim 12  wherein Ar 1  is aryl optionally substituted with from 1-3 substituents independently selected from —NO 2 , CH 3 O—, and morpholinyl (e.g., morpholin-4-yl). 
     
     
         14 . The compound according to  claim 12  wherein Ar 1  is phenyl optionally substituted with from 1-3 substituents independently selected from —NO 2 , CH 3 O—, and morpholinyl (e.g., morpholin-4-yl). 
     
     
         15 . The compound according to  claim 12  selected from: 
       
         
           
           
               
               
           
         
       
     
     
         16 . A composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier, excipient, or diluent. 
     
     
         17 . A method of inhibiting histone deacetylase in a cell, comprising contacting a cell in which inhibition of histone deacetylase is desired with an inhibitor of histone deacetylase according to  claim 1 . 
     
     
         18 . A method of treating a mammal suffering from a cell proliferative disease or condition a therapeutically effective amount of a composition according to  claim 16 . 
     
     
         19 . The method according to  claim 18  wherein the mammal is a human.