Compositions and methods for modulating interaction between polypeptides

Abstract

The present invention is based, in part, on assays we conducted that revealed compounds that may be used to treat or prevent diseases characterized by an abnormal or undesirable association of one protein with another.

1 . A pharmaceutical composition comprising a compound of Formula II: 
       
         
           
           
               
               
           
         
         wherein,
 Z is O or S; 
 Y is O, NR 25  or CR 26 R 27 ; 
 each R 21  and R 22  is, independently, halo, hydroxy, nitro, cyano, amino, amido, or alkyl; 
 
         R 23  is alkyl, cyclyl, aryl, heteroaryl, cyclylalkyl, arylalkyl, or heteroarylalkyl, or when taken together with R 24  and the nitrogen to which it is attached forms a ring; wherein R 23  is optionally substituted with 1-3 R 28 .
 R 24  is H, alkyl, or when taken together with R 23  and the nitrogen to which it is attached forms a ring; wherein R 24  is optionally substituted with 1-3 R 28 . 
 R 25  is H or alkyl; 
 each R 26  and R 27  is independently H or alkyl; 
 each R 28  is independently halo, hydroxy, nitro, cyano, amino, amido, or alkyl; 
 each p and q are independently an integer from 0-4. 
 
       
     
     
         2 . The composition of  claim 1 , wherein Z is O. 
     
     
         3 . The composition of  claim 1 , wherein Y is NR 25 . 
     
     
         4 . The composition of  claim 1 , wherein R 25  is H. 
     
     
         5 . The composition of  claim 1 , wherein Y is CR 26 R 27 . 
     
     
         6 . The composition of  claim 1 , wherein each R 21  and R 22  is independently halo or hydroxy. 
     
     
         7 - 9 . (canceled) 
     
     
         10 . The composition of  claim 1 , wherein
 R 22  is halo; and   q is 1.   
     
     
         11 . The composition of  claim 10 , wherein p is 0. 
     
     
         12 . The composition of  claim 10 , wherein R 22  is bromo. 
     
     
         13 - 24 . (canceled) 
     
     
         25 . A pharmaceutical composition comprising:
 4-Bromo-N-(4-bromo-phenyl)-3-cyclohexylsulfamoyl-benzamide;   N-(4-Bromo-phenyl)-3-(4-bromo-phenylsulfamoyl)-benzamide;   3-(4-Bromo-phenylsulfamoyl)-N-phenyl-benzamide;   4-Bromo-3-cyclohexylsulfamoyl-N-phenyl-benzamide;   N-(4-Bromo-phenyl)-3-cyclohexylsulfamoyl-benzamide; or   1-[3-(Azepane-1-sulfonyl)-2-bromo-phenyl]-2-(3-hydroxy-phenyl)-ethanone.   
     
     
         26 - 28 . (canceled) 
     
     
         29 . A method of treating a subject who has been diagnosed as having, or who is at risk of developing, a disorder characterized by an undesirable association of proteins, the method comprising identifying the subject and administering to the subject a therapeutically effective amount of the pharmaceutical composition of  claim 1 . 
     
     
         30 . The method of  claim 29 , wherein the subject has been diagnosed as having, or is at risk of developing, Huntington's disease. 
     
     
         31 . The method of  claim 29 , wherein the subject has been diagnosed as having, or is at risk of developing, Parkinson's disease. 
     
     
         32 . The method of  claim 29 , wherein the subject has been diagnosed as having, or is at risk of developing, spinal and bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, spinocerebellar ataxia type 1 (SCA1), SCA2, SCA6, SCAT, Machado-Joseph disease (MJD/SCA3), breast cancer, amyloidosis, myeloma, Creutzfeldt-Jakob disease, kuru, cystic fibrosis, neuroblastoma, carcinoma, or alpha-1-antitrypsin deficiency disease. 
     
     
         33 . A pharmaceutical composition comprising:
 (a) a compound Formula I:   
       
         
           
           
               
               
           
         
         X is C(O) or a bond; 
         each R 11  and R 12  is, independently, halo, nitro, amino, hydroxy, alkoxy, alkyl, alkenyl, alkynyl, cyclyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, NR 15 C(O)R 14 , or C(O)NR 15 R 16 , each of which is optionally substituted with 1-4 R 17 ; 
         R 13  is H, alkyl, alkenyl, alkynyl, amino, hydroxy, aryl, arylalkyl, arylamino, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, cyclyl, cyclylalkyl, aminoalkyl, hydroxyalkyl, or alkoxyalkyl, each of which is optionally substituted with 1-4 R 18 ; 
         R 14  is H, alkyl, alkenyl, alkynyl, cyclyl, heterocyclyl, aryl, or heteroaryl; 
         each of R 15  and R 16  is, independently, H, hydroxy, alkoxy, alkyl, alkenyl, alkynyl, cyclyl, heterocyclyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl; 
         each R 17  is, independently, halo, alkyl, alkoxy, or hydroxy; 
         each R 18  is, independently, halo, alkyl, amino, hydroxy, C(O)NR 15 R 16 , NR 15 C(O)R 14 , or hydroxyalkyl; and 
         m and n are each, independently, an integer from 0 to 3; 
         (b) a compound of Formula III: 
       
       
         
           
           
               
               
           
         
         A is N or CR 32 ; 
         B is N or CH; 
         R 31  is H or NR 33 R 34 , wherein R 31  is optionally substituted with 1-3 R 35 ; 
         R 32  is H or NR 33 R 34 , wherein R 32  is optionally substituted with 1-3 R 35 ; 
         R 33  is H, alkyl, or taken together with R 34  and the nitrogen to which it is attached forms a heterocyclyl ring; 
         R 34  is H, alkyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl or taken together with R 33  and the nitrogen to which it is attached to form a heterocyclyl ring; 
         each R 35  is, independently, halo, hydroxy, amino, nitro, alkyl, aryl, arylacyl, arylalkyl, heteroaryl, heteroarylacyl, heteroarylalkyl, cyclylacyl, heterocyclylacyl, or alkylacyl; 
         R 35  is optionally substituted with 1-4 R 36 ; and 
         each R 36  is, independently, halo, alkyl, nitro, amino or hydroxy; 
       
       or
 (c) a compound of Formula IV: 
 
       
         
           
           
               
               
           
         
         D is O, S, or NH; 
         E is O or NH; 
         R 41  is halo, alkyl, amino, hydroxy, or alkoxy; 
         R 42  is alkyl, arylalkyl, cyclyl, or cyclylalkyl; 
         R 43  is alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cyclyl, cyclylalkyl, heterocyclyl, or heterocyclylalkyl, where R 43  is optionally substituted with 1-4 R 45 ; 
         R 44  is alkyl, cyclyl, cyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, where R 44  is optionally substituted with 1-4 R 46 ; 
         each R 45  is independently halo, alkyl, amino, amido, hydroxy, alkoxy, nitro, cyano, thio, alkylthio, sulfonyl, or sulfonamidyl; and 
         each R 46  is independently halo, alkyl, amino, amido, hydroxy, alkoxy, nitro, cyano, thio, alkylthio, sulfonyl, or sulfonamidyl.