Reverse amide compounds as protein deacetylase inhibitors and methods of use thereof

Abstract

The present invention relates to novel “reverse amide” compounds comprising a zinc chelator group, and the use of such compounds in the inhibition of HDAC6 and in the treatment of various diseases, disorders or conditions related to HDAC6.

What is claimed: 
     
         1 - 21 . (canceled) 
     
     
         22 . A compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, ester or prodrug thereof, 
       
       wherein,
 Z is N; 
 ring A is aryl or heteroaryl, wherein aryl or heteroaryl may be optionally substituted with halo; 
 ring B is aryl or heteroaryl, wherein aryl or heteroaryl may be optionally substituted by alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, haloalkyl, halo, alkoxy, OH, NH 2 , NHR″, CN, N 3 , or NO 2 ; 
 R 1  is H, alkyl, haloalkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, carbocyclic, C(O)—R 2 , or C(O)O—R 2 , each of which may be optionally substituted with OH, halo, alkyl, or alkoxy; 
 R is H or alkyl; 
 R″ is H or alkyl; 
 each R 2  is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and 
 n is 3, 4, 5, 6, 7, or 8. 
 
     
     
         23 . The compound of  claim 22 , wherein ring A is phenyl, naphthyl, anthracenyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, imidazolyl, oxazolyl, furyl, thienyl, thiazolyl, triazolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, or 5,6,7,8-tetrahydroisoquinoline; each of which may be optionally substituted with halo. 
     
     
         24 . The compound of  claim 22 , wherein R 1  is H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, phenyl, naphthyl, pyridinyl, OH or OCH 3 ; each of which may be optionally substituted with OH, halo, alkyl, or alkoxy. 
     
     
         25 . The compound of  claim 22 , wherein the carbonyl and the Z group attached to ring A are disposed para to each other. 
     
     
         26 . The compound of  claim 22 , wherein the carbonyl and Z group attached to ring A are disposed meta to each other. 
     
     
         27 . The compound of  claim 22 , wherein the carbonyl and the Z group attached to ring A are disposed ortho to each other. 
     
     
         28 . The compound of  claim 22 , which is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
       
       wherein,
 each of X 1 , X 2 , X 3 , or X 4  is independently N, CR′, O, S; wherein up to three of X 1 , X 2 , X 3 , or X 4  may be N; 
 ring B is aryl or heteroaryl; wherein aryl or heteroaryl may be optionally substituted with alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, haloalkyl, halo, alkoxy, OH, NH 2 , NHR″, CN, N 3 , or NO 2 . 
 R 1  is H, alkyl, haloalkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, carbocyclic, C(O)—R 2 , or C(O)O—R 2 , each of which may be optionally substituted by OH, halo, alkyl, or alkoxy; 
 R is H or alkyl; 
 each R′ is independently H, alkyl, halo, OH, NH 2 , NHR″, haloalkyl, CN, N 3 , or NO 2 ; 
 R″ is H or alkyl; and 
 R 2  is alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. 
 
     
     
         29 . The compound of  claim 28 , wherein ring B is phenyl, pyridinyl, pyrimidinyl, or pyrazinyl; wherein phenyl, pyridinyl, pyrimidinyl, or pyrazinyl may be optionally substituted with alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, haloalkyl, halo, OH, NH 2 , NHR″, CN, N 3 , or NO 2 . 
     
     
         30 . The compound of  claim 28 , wherein X 1 , X 2 , X 3 , and X 4  are all CR′. 
     
     
         31 . The compound of  claim 28 , wherein X 2  and X 3 , are N and X 1  and X 4  are CR′. 
     
     
         32 . The compound of  claim 28 , wherein R 1  is H, alkyl, aryl, arylalkyl, or heteroaryl, each of which may be optionally substituted by OH, halo, alkyl, or alkoxy. 
     
     
         33 . The compound of  claim 22 , which is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
       
       wherein,
 ring B is aryl or heteroaryl each of which may be optionally substituted by alkyl, aryl, aralkyl, haloalkyl, halo, OH, NH 2 , CN, or NO 2 ; 
 R 1  is H, alkyl, haloalkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, carbocyclic, C(O)—R 2 , or C(O)O—R 2 , each of which may be optionally substituted by OH, halo, alkyl, or alkoxy; and 
 R is H or alkyl. 
 
     
     
         34 . The compound of  claim 33 , wherein ring B is phenyl, pyridinyl, pyrimidinyl, or pyrazinyl; each of which may be optionally substituted by alkyl, aryl, aralkyl, haloalkyl, halo, OH, NH 2 , CN, or NO 2 . 
     
     
         35 . The compound of  claim 33 , wherein R 1  is H, alkyl, aryl, arylalkyl, heteroaryl, C(O)—R 2 , or C(O)O—R 2  each of which may be optionally substituted by OH, halo, alkyl, or alkoxy. 
     
     
         36 . The compound of  claim 22 , which is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
       
       wherein,
 ring B is aryl or heteroaryl, wherein aryl or heteroaryl may be optionally substituted by alkyl, aryl, aralkyl, haloalkyl, halo, OH, NH 2 , CN, or NO 2 ; 
 R 1  is H, alkyl, haloalkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted by OH, halo, or alkyl; and 
 R is H or alkyl. 
 
     
     
         37 . The compound of  claim 36 , wherein ring B is phenyl, pyridinyl, pyrimidinyl, or pyrazinyl; each of which may be optionally substituted by alkyl, aryl, aralkyl, haloalkyl, halo, OH, NH 2 , CN, or NO 2 . 
     
     
         38 . The compound of  claim 36 , wherein R 1  is H, alkyl, aryl, arylalkyl, or heteroaryl, each of which may be optionally substituted by OH, halo, or alkyl. 
     
     
         39 . The compound of  claim 22 , selected from the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts thereof. 
     
     
         40 . A pharmaceutical composition comprising a compound of  claim 22 , or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. 
     
     
         41 . A method of selectively inhibiting HDAC6 over other HDACs in a subject, comprising administering a compound of  claim 22  or a pharmaceutically acceptable salt thereof. 
     
     
         42 . A method of treating a disease mediated by HDAC6 in a subject comprising administering to the subject a compound of  claim 22 . 
     
     
         43 . A method of treating a subject suffering from or susceptible to multiple myeloma comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 22  to thereby treat the subject suffering from or susceptible to multiple myeloma.