Small molecules for the modulation of mcl-1 and methods of modulating cell death, cell division, cell differentiation and methods of treating disorders

Abstract

This invention relates to compounds which selectively bind to the survival protein MCL-1 with high affinity and selectivity, pharmaceutical compositions containing such compounds and the use of those compounds or compositions for modulating MCL-1 activity and for treating hyperproliferative disorders, angiogenesis disorders, cell cycle regulation disorders, autophagy regulation disorders, inflammatory disorders, and/or infectious disorders and/or for enhancing cellular engraftment and/or wound repair, as a sole agent or in combination with other active ingredients.

1 - 36 . (canceled) 
     
     
         37 . A compound of the formula (A): 
       
         
           
           
               
               
           
         
         wherein
 n is an integer from 0-4; 
 q is an integer from 0-1; 
 X is ═O or —O—R 3 ; 
 R 1  is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, —S—R 2a , —SO 2 —R 2a ; 
 R 2  is hydrogen, halogen, —NH—R 2a , —NH—R 2a , —S—CN, —S—R 2a , —S—CH 2 —R 2a  or —SO 2 —R 2a ; 
 each occurrence of R 2a  is independently C 1 -C 8  alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; 
 R 3  is hydrogen, C 1 -C 8  alkyl substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; and 
 each occurrence of Z and Z′ is independently halogen, hydroxyl, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, or C 1 -C 6  alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl. 
 
       
     
     
         38 . The compound of  claim 37 , wherein n is 0. 
     
     
         39 . The compound of  claim 37 , wherein q is 0. 
     
     
         40 . The compound of  claim 37 , wherein X is ═O. 
     
     
         41 . The compound of  claim 37 , wherein R 1  is —SO 2 —R 2a , in which R 2a  is substituted aryl. 
     
     
         42 . The compound of  claim 41 , wherein R 2a  is 4-methylphenyl. 
     
     
         43 . The compound of  claim 37 , wherein R 2  is —S—R 2a  in which R 2a  is unsubstituted heteroaryl. 
     
     
         44 . The compound of  claim 43 , wherein R 2a  is 1,2,4-triazolyl. 
     
     
         45 . The compound of  claim 37 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         46 . A pharmaceutical composition comprising the compound of  claim 37  or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof and a pharmaceutically acceptable diluent or carrier. 
     
     
         47 . A method of selectively modulating MCL-1 in a cell, comprising contacting the cell with one or more compounds of  claim 37 , thereby regulating MCL-1 in the cell. 
     
     
         48 . A method for modulating apoptotic cell death in a cell, comprising contacting the cell with one or more compounds of  claim 37 , thereby regulating apoptotic cell death in the cell. 
     
     
         49 . A method for modulating autophagy in a cell, comprising contacting the cell with one or more compounds of  claim 37 , thereby regulating autophagy in the cell. 
     
     
         50 . A method for modulating necrotic cell death in a cell, comprising contacting the cell with one or more compounds of  claim 37 , thereby regulating necrotic cell death in the cell. 
     
     
         51 . A method for modulating metabolism in a cell, comprising contacting the cell with one or more compounds of  claim 37 , thereby regulating energy production and consumption to effect cell viability in the cell. 
     
     
         52 . A method for modulating cell division in a cell, comprising contacting the cell with one or more compounds of  claim 37 , thereby regulating proliferation in the cell. 
     
     
         53 . A method for modulating transcription in a cell, comprising contacting the cell with one or more compounds of  claim 37 , thereby regulating transcription in the cell. 
     
     
         54 . A method for modulating RNA processing in a cell, comprising contacting the cell with one or more compounds of  claim 37 , thereby regulating RNA processing in the cell. 
     
     
         55 . A method for modulating differentiation in a stem or progenitor cell, comprising contacting the stem or progenitor cell with one or more compounds of  claim 37 , thereby regulating the lineage and phenotype in the cell. 
     
     
         56 . A method for modulating multimerization of MCL-1 in a cell, comprising contacting the cell with one or more compounds of  claim 37 , thereby regulating multimerization of MCL-1 in the cell. 
     
     
         57 . A method of treating a hyperproliferative disorder in a mammal, comprising administering to the mammal in need thereof a therapeutically effective amount of one or more compounds of  claim 37 . 
     
     
         58 . The method of  claim 57 , wherein the hyperproliferative disorder is cancer. 
     
     
         59 . A method of treating an angiogenesis disorder in a mammal, comprising administering to the mammal in need thereof a therapeutically effective amount of one or more compounds of  claim 37 . 
     
     
         60 . A method of treating an inflammatory disease or disorder in a mammal, comprising administering to the mammal in need thereof a therapeutically effective amount of one or more compounds of  claim 37 . 
     
     
         61 . A method of treating an infectious disease or disorder in a mammal, comprising administering to the mammal in need thereof a therapeutically effective amount of one or more compounds of  claim 37 . 
     
     
         62 . A method of treating a cell cycle regulation disease or disorder in a mammal, comprising administering to the mammal in need thereof a therapeutically effective amount of one or more compounds of  claim 37 . 
     
     
         63 . A method of treating an autophagy regulation or disorder in a mammal, comprising administering to the mammal in need thereof a therapeutically effective amount of one or more compounds of  claim 37 . 
     
     
         64 . A method of treating an autoimmune disease or disorder in a mammal, comprising administering to the mammal in need thereof a therapeutically effective amount of one or more compounds of  claim 37 .