Pyrimidine hydroxy amide compounds as histone deacetylase inhibitors

Abstract

Provided herein are compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds to treat or prevent diseases or disorders associated with HDAC activity, particularly diseases or disorders that involve activity of HDAC1, HDAC2, and/or HDAC6. Also provided herein are methods for inhibiting migration of a neuroblastoma cell, inducing maturation of a neuroblastoma cell, and altering cell cycle progression of a neuroblastoma cell comprising administering to the cell a therapeutically effective amount of a HDAC1, HDAC2, and/or HDAC6 selective inhibitor or a pharmaceutically acceptable salt thereof.

1 . A method of selectively inhibiting the activity of HDAC1, HDAC2, and HDAC6 over other HDACs in a subject in need thereof comprising administering to the subject a compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein, 
         R x  is selected from the group consisting of C 1-6 -alkyl, C 1-6 -alkoxy, halo, —OH, —C(O)R 1 , —CO 2 R 1 , —C(O)N(R 1 ) 2 , aryl, —C(S)N(R 1 ) 2 , and S(O) 2 R 1 , wherein aryl may be optionally substituted by one or more groups selected from C 1-6 -alkyl, C 1-6 -alkoxy, —OH, halo, and haloalkyl; 
         R y  is selected from the group consisting of H, C 1-6 -alkyl, C 1-6 -alkoxy, halo, —OH, —C(O)R 1 , —CO 2 R 1 , and —C(O)N(R 1 ) 2 ; 
         R z  is selected from the group consisting of C 1-6 -alkyl, C 1-6 -alkenyl, C 1-6 -alkynyl, C 3-8 -cycloalkyl, C 3-7 -heterocycloalkyl, aryl, and heteroaryl, each of which may be optionally substituted by C 1-6 -alkyl, C 1-6 -alkoxy, halo, or —OH; and 
         each R 1  is, independently for each occurrence, selected from the group consisting of H, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 3-7 -heterocycloalkyl, aryl, heteroaryl, C 1-6 -alkyl-cycloalkyl, C 1-6 -alkyl-heterocycloalkyl, C 1-6 -alkyl-aryl, and C 1-6 -alkyl-heteroaryl, wherein C 3-8 -cycloalkyl, C 3-7 -heterocycloalkyl, aryl, heteroaryl, C 1-6 -alkyl-cycloalkyl, C 1-6 -alkyl-heterocycloalkyl, C 1-6 -alkyl-aryl, and C 1-6 -alkyl-heteroaryl may be optionally substituted by one or more groups selected from C 1-6 -alkyl, C 1-6 -alkoxy, —OH, halo, and haloalkyl. 
       
     
     
         2 . The method of  claim 1 , wherein the compound of Formula I has the structure of Formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein, 
         R x  is independently selected from the group consisting of aryl, —C(O)R 1 , —CO 2 R 1 , —C(O)N(R 1 ) 2 , —C(S)N(R 1 ) 2 , and S(O) 2 R 1 ; 
         R y  is selected from the group consisting of H, C 1-6 -alkyl, or, halo; and 
         R z  is selected from the group consisting of C 1-6 -alkyl, C 3-8 -cycloalkyl, C 3-7 -heterocycloalkyl, aryl, and heteroaryl. 
       
     
     
         3 . The method of  claim 1 , wherein R z  is C 1-6 -alkyl or aryl. 
     
     
         4 . The method of  claim 1 , wherein R z  is isopropyl or methyl. 
     
     
         5 . The method of  claim 1 , wherein R z  is phenyl. 
     
     
         6 . The method of  claim 1 , wherein R x  is —C(O)NHR 1 . 
     
     
         7 . The method of  claim 1 , wherein R x  is —C(O)R 1  or —CO 2 R 1 . 
     
     
         8 . The method of  claim 1 , wherein R x  is —C(S)NHR 1  or S(O) 2 R 1 . 
     
     
         9 . The method of  claim 1 , wherein at least one of R 1  is selected from the group consisting of C 1-6 -alkyl, aryl, C 1-6 -alkyl-aryl and C 1-6 -alkyl-heteroaryl, wherein aryl, C 1-6 -alkyl-aryl and C 1-6 -alkyl-heteroaryl may be optionally substituted by one or more groups selected from C 1-6 -alkyl, C 1-6 -alkoxy, —OH, halo, and haloalkyl. 
     
     
         10 . The method of  claim 1 , wherein at least one of R 1  is —CH 3 , —CH 2 CH 3 , phenyl, —CH 2 -phenyl, or —CH 2 -indolyl, wherein phenyl, —CH 2 -phenyl, or —CH 2 -indolyl may be optionally substituted by one or more groups selected from C 1-6 -alkyl or halo. 
     
     
         11 . The method of  claim 1 , wherein at least one of R 1  is phenyl, and wherein phenyl is optionally substituted by one or more groups selected from C 1-6 -alkyl, C 1-6 -alkoxy, halo, and haloalkyl. 
     
     
         12 . The method of  claim 1 , wherein R y  is H. 
     
     
         13 . The method of  claim 1 , wherein the compound of Formula I is, selected from the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof. 
       
     
     
         14 - 32 . (canceled) 
     
     
         33 . A method for inhibiting migration of a neuroblastoma cell comprising administering to the cell a therapeutically effective amount of a HDAC1, HDAC2, and/or HDAC6 selective inhibitor or a pharmaceutically acceptable salt thereof. 
     
     
         34 . (canceled) 
     
     
         35 . (canceled) 
     
     
         36 . A method for decreasing viability and survival of a neuroblastoma cell comprising administering to the cell a therapeutically effective amount of a HDAC1, HDAC2, and/or HDAC6 selective inhibitor or a pharmaceutically acceptable salt thereof. 
     
     
         37 . A method for inducing differentiation of a neuroblastoma cell comprising administering to the cell a therapeutically effective amount of a HDAC1, HDAC2, and/or HDAC6 selective inhibitor or a pharmaceutically acceptable salt thereof. 
     
     
         38 . (canceled) 
     
     
         39 . (canceled) 
     
     
         40 . The method of  claim 33 , wherein the inhibitor is selected from the group consisting of a compound of Formula I, Formula II, Formula III, Compound 001, Compound X, Compound Y, or any of the compounds in Table 1. 
     
     
         41 . (canceled) 
     
     
         42 . A method for treating neuroblastoma in a subject comprising administering to the subject a therapeutically effective amount of
 Compound 001, having the structure:   
       
         
           
           
               
               
           
         
         
           or a pharmaceutically acceptable salt thereof; 
         
         Compound X, having the structure: 
       
       
         
           
           
               
               
           
         
         
           or a pharmaceutically acceptable salt thereof; or 
         
         Compound Y, having the structure: 
       
       
         
           
           
               
               
           
         
         
           or a pharmaceutically acceptable salt thereof. 
         
       
     
     
         43 . The method of  claim 36 , wherein the inhibitor is selected from the group consisting of a compound of Formula I, Formula II, Formula III, Compound 001, Compound X, Compound Y, or any of the compounds in Table 1. 
     
     
         44 . The method of  claim 37 , wherein the inhibitor is selected from the group consisting of a compound of Formula I, Formula II, Formula III, Compound 001, Compound X, Compound Y, or any of the compounds in Table 1.