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 . A compound of the formula: 
       A) 
       
         
           
           
               
               
           
         
       
       Wherein:
 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, —O—R 2a , —NH—R 2a , —S—CN, —S—R 2a , —S—CH 2 —R 2a  or —SO 2 —R 2a ; 
 R 2a  is C 1 -C 8  alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; 
 and 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; or 
 
       B) 
       
         
           
           
               
               
           
         
       
       wherein:
 R 4  and R 5  are independently hydrogen, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl or are taken together to form a 5-7 membered, optionally substituted, heteroaryl or heterocycloalkyl, provided that no more than one of R 4  and R 5  is hydrogen; 
 And R 6  is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; or 
 
       C) 
       
         
           
           
               
               
           
         
       
       Wherein
 R 7  is CH 2 —CO—R 7a ; —CH 2 —NH—SO 2 —R 7a ; 
 and R 7a  is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; or 
 
       D) 
       
         
           
           
               
               
           
         
       
       Wherein
 R 8  is —CO—R 8a ; —CO—NH—(CH 2 ) n —R 8a ; —CO—CH 2 —R 8a , —NH—CO—NH—R 8a ; —NH—SO 2 —NH—R 8a ; or —NH—CO—R 8a ; —NH—SO 2 —R 8a    
 and R 8a  is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; or 
 
       E) 
       
         
           
           
               
               
           
         
       
       wherein
 R 9  is hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkeynyl, C 2 -C 6  alkynyl, —NH 2 , —NHR 9a , 
 —NR 9a R 9b , —COH, —COR 9a , —COOH, or —COOR 9a ; 
 R 9a  and R 9b  are independently C 1 -C 6  alkyl, C 2 -C 6  alkeynyl, C 2 -C 6  alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl 
 
       W is
 —R 10 , 
 —CO—R 10 , 
 —CO—(CH 2 ) n —R 10 , 
 —CO—NH—R 10 , 
 —CO—NH—(CH 2 ) n —R 10 , 
 —CO—NH—CO—NH—(CH 2 ) n —R 10 , 
 —CO—NH—SO—NH—(CH 2 ) n —R 10 , 
 —SO—(CH 2 ) n —R 10 , 
 —SO—NH—(CH 2 ) n —R 10 , 
 —SO—NH—CO—NH—(CH 2 ) n —R 10 , 
 —SO—NH—SO—NH—(CH 2 ) n —R 10 , or 
 the group 
 
       
         
           
           
               
               
           
         
         wherein * represents the point of attachment; 
         R 10  is Z or substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; 
         R 12  is Z or hydrogen, C 1 -C 6  alkyl or —(CH 2 ) n —R 12a , 
         R 12a  is Z or substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; or 
       
       F) 
       
         
           
           
               
               
           
         
       
       wherein
 R 13  is C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, or C 1 -C 6  alkoxy, 
 and R 14  is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl wherein R 14  may be further substituted by Z; or 
 
       G) 
       
         
           
           
               
               
           
         
       
       wherein
 R 15  is hydrogen, hydroxyl, halogen, —CO—(CH 2 ) n —R 15a , —CO—NH—(CH 2 ) n —R 15a , —CO—NH—CO—NH—(CH 2 ) n —R 15a , —CO—NH—SO—NH—(CH 2 ) n —R 15a , NH—CO—(CH 2 ) n —R 15a , NH—CO—NH—(CH 2 ) n —R 15a , —SO—(CH 2 ) n —R 15a , —SO—NH—(CH 2 ) n —R 15a , —SO—NH—CO—NH—(CH 2 ) n —R 15a , —SO—NH—SO—NH—(CH 2 ) n —R 15a , or —NH—SO 2 —R 15a ; alkyl C 1 -C 8 —R15a 
 R 15a  is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; 
 and R 16  is hydrogen, halogen, hydroxyl or substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; or 
 
       H) 
       
         
           
           
               
               
           
         
       
       wherein
 X is O or S; 
 R 17  is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl, wherein R 17  may be further substituted by Z; 
 R 18  is hydrogen, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, or C 1 -C 6  alkoxy, wherein R 18  may be further substituted by Z; 
 and R 19  is hydrogen, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, or C 1 -C 6  alkoxy wherein R 19  may be further substituted by Z; or 
 
       I) 
       
         
           
           
               
               
           
         
       
       wherein
 Y 1  is N, NH, CH or CH 2 ; 
 Y 2  is O, S, or NH; 
 ---- represents an optional double bond; 
 R 20  is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl, wherein R 20  may be further substituted by Z; 
 R 21  represents ═S, ═NH, —NHR 21a , —CHR 21a , ═NR 21a , or ═CCO—R 21a ; and 
 R 21a  is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl, wherein R 21a  may be further substituted by Z; 
 
       or 
       J) 
       
         
           
           
               
               
           
         
       
       wherein
 R 22  is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl wherein R 22  may be further substituted by Z; 
 R 23  is 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 wherein R 23  may be further substituted by Z; and 
 R 24  is 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 wherein R 24  may be further substituted by Z; or 
 
       K) 
       
         
           
           
               
               
           
         
       
       wherein
 R 25  is —CO—R 25a ; —CO—NH—(CH 2 ) n —R 25a ; —CO—CH 2 —R 25a , —NH—CO—NH—R 25a ; —NH—SO 2 —NH—R 25a ; or —NH—CO—R 25a ; —NH—SO 2 —R 25a    
 R 25a  is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl wherein R 22  may be further substituted by Z; or 
 
       L) 
       
         
           
           
               
               
           
         
       
       wherein
 R 26  is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl wherein R 22  may be further substituted by Z; or
 and wherein 
 in each of formulas A-L: 
 each occurrence of n is independently an integer from 0-4; 
 each occurrence of m is independently an integer from 0-3; 
 each occurrence of p is independently an integer from 0-2; 
 each occurrence of q is independently an integer from 0-1; 
 each occurrence of Z, 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, 
 
 
       or M)
 a compound having the formula
   T 1 L-T 2  u Q-T 2  
 
 wherein: 
 T 1  represents a compound of the formula A-L; 
 
 each T 2  independently represents another compound of the formula A-L which may be the same or different from T 1 ;
 each Q represents a direct bond, a C 1 -C 8  alkylene linker, a C 2 -C 8  alkenylene linker, a C 2 -C 8  alkynylene linker, an amide linker, or a sulfonamide linker formed by joining together a Z, Z′, or Z″ moiety of T 1  with a Z, Z′, or Z″ moiety of each subsequent T 2 ; and 
 u represents an integer from 0-5 
 or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof. 
 
 
     
     
         2 . The compound according to  claim 1  having the formula:
   T 1 L-T 2  u Q-T 2  
 
 wherein: 
 T 1  represents a compound of the formula A-L; 
 each T 2  independently represents another compound of the formula A-L which may be the same or different from T 1 ; 
 each Q represents a direct bond, a C 1 -C 8  alkylene linker, a C 2 -C 8  alkenylene linker, or a C 2 -C 8  alkynylene linker formed by joining together a Z, Z′, or Z″ moiety of T 1  with a Z, Z′, or Z″ moiety of each subsequent T 2 ; and 
 u represents an integer from 0-5 
 or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof. 
 
     
     
         3 . The compound according to  claim 2 , wherein u is 0 and Q is a direct bond. 
     
     
         4 . The compound according to  claim 2 , wherein u is 0 and Q is a C 1 -C 8  alkylene linker. 
     
     
         5 . The compound according to  claim 2 , wherein u is 1 and each Q is independently a direct bond or a C 1 -C 8  alkylene linker. 
     
     
         6 . A pharmaceutical composition comprising a compound according to  claim 1  or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof and a pharmaceutically acceptable diluent or carrier. 
     
     
         7 . The pharmaceutical composition of  claim 6  wherein the compound is present in a therapeutically effective amount. 
     
     
         8 . The pharmaceutical composition of  claim 6  further comprising at least one further active compound. 
     
     
         9 . The pharmaceutical composition of  claim 8 , wherein the further active compound is a death receptor stimulant, an HDAC inhibitor, a proteasome inhibitor, a BCL-2 family inhibitor, a kinase inhibitor, a mitotic inhibitor, a nucleoside analog, an anti-cancer monoclonal antibody, a corticosteroid, a DNA-damaging agent, or an antimetabolite 
     
     
         10 . A packaged pharmaceutical composition comprising a container, the pharmaceutical composition of  claim 6  and instructions for using the pharmaceutical composition to treat a disease or condition in a mammal. 
     
     
         11 . A method of selectively modulating MCL-1 in cells comprising contacting a cell with one or more compounds of  claim 1 , thereby regulating MCL-1 in said cell. 
     
     
         12 . A method for modulating apoptotic cell death in a cell comprising contacting a cell with one or more compounds of  claim 1 , thereby regulating apoptotic cell death in said cell. 
     
     
         13 . A method for modulating autophagy in a cell comprising contacting a cell with one or more compounds of  claim 1 , thereby regulating autophagy in said cell. 
     
     
         14 . A method for modulating necrotic cell death in a cell comprising contacting a cell with one or more compounds of  claim 1 , thereby regulating necrotic cell death in said cell. 
     
     
         15 . A method for modulating metabolism in a cell comprising contacting a cell with one or more compounds of  claim 1 , thereby regulating energy production and consumption to effect cell viability in said cell. 
     
     
         16 . A method for modulating cell division in a cell comprising contacting a cell with one or more compounds of  claim 1 , thereby regulating proliferation in said cell. 
     
     
         17 .- 19 . (canceled) 
     
     
         20 . A method for modulating multimerization of MCL-1 in a cell comprising contacting said cell with one or more compounds of  claim 1 , thereby regulating multimerization of MCL-1 in said cell. 
     
     
         21 . A method of treating a hyperproliferative disorder in a mammal comprising administering to a mammal in need thereof, a therapeutically effective amount of one or more compounds of  claim 1 . 
     
     
         22 . The method of  claim 14  wherein the hyperproliferative disorder is cancer. 
     
     
         23 . The method of  claim 15  wherein the hyperproliferative disorder is refractory cancer. 
     
     
         24 .- 36 . (canceled)