Bi-functional compounds and methods for targeted ubiquitination of androgen receptor

Abstract

The present invention relates to bi-functional compounds which function to recruit endogenous proteins to an E3 ubiquitin ligase for degradation, and methods for using same. More specifically, the present disclosure provides specific proteolysis targeting chimera (PROTAC) molecules which find utility as modulators of targeted ubiquitinization of a variety of polypeptides and other proteins, in particular the androgen receptor of a slice variant of AR which lacks the LBD, labelled as AR-V7, which are then degraded and/or otherwise inhibited by the compounds as described herein.

1 . A compound having a chemical structure:
   ARB-Link-E3LB   wherein ARB is an AR binding moiety that does not bind to a ligand binding domain, E3LB is an E3 ligase binding moiety, and Link is a linker coupling the AR binding moiety to the E3 ligase binding moiety; and   wherein the E3LB moiety is a structure selected from the group consisting of:   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein in the E3LB moiety:
 X is CH 2 , N, or O; 
 D is a bond, aryl, or heteroaryl, wherein said aryl or heteroaryl is optionally substituted by 1 or more halo, hydroxyl, nitro, CN, C 1-6  alkyl or C 1-6  alkoxyl; 
 R 10  is independently optionally substituted alkyl or optionally substituted cycloalkyl (e.g., cyclohexyl), wherein said optional substituents are selected from OH, halo, and NH 2 ; 
 R 11  is independently optionally substituted alkyl or optionally substituted cycloalkyl, wherein said optional substituents are selected from alkyl, halogen, and OH; 
 R 12  and R 13  are independently hydrogen, optionally substituted alkyl (e.g., methyl), and optionally substituted cycloalkyl; 
 R 20  is selected is: 
 
       
         
           
           
               
               
           
         
       
       wherein B is aryl (e.g. phenyl);
 R 21  is independently aryl (e.g., phenyl) or heteroaryl, optionally substituted by mono-, di- or tri-substituted halogen (e.g., F or Cl); 
 R 22  is independently aryl (e.g., phenyl) or heteroaryl optionally substituted by mono-, di-, or tri-substituted halogen (e.g., F or Cl); 
 R 23  is selected from alkyl, substituted alkyl, cycloalkyl, and substituted cycloalkyl, 
 R 24  is H or alkyl; and 
 E is para-substituted aryl (e.g., phenyl) optionally substituted by —OCH 3 , —OCH 2 CH 3 , or halogen; 
 and wherein the AR binding moiety is: 
 
       
         
           
           
               
               
           
         
         wherein in the AR binding moiety:
 A is 3-7 membered alicyclic with 0-4 heteroatoms (e.g., morpholinyl) optionally substituted by 1 or more halo, hydroxyl, or C 1-6  alkyl; 
 B is aryl (e.g., phenyl), optionally substituted by 1 or more halo, hydroxyl, CN, OC 1-3  alkyl, CF 3 , or C 1-6  alkyl optionally substituted by 1 or more halo; 
 R 1  is each independently selected from H, OH, CONH 2 , CN, NH 2 , OCH 3 , CHF 2 , CH 2 F, CF 3 , halo, and C 1-6  alkyl optionally substituted by 1 or more halo; and 
 wherein the linker (“L”) is a chemical structure represented by -A q -, in which q is an integer greater than 1, and A is independently selected from the group consisting of a bond, CR L1 R L2 , O, NR L3 , CONR L3 , CO, C 3-11  cycloalkyl, and heteroaryl (optionally substituted with 0-6 R L1  and/or R L2  groups), wherein R L1 , R L2 , and R L3  are each independently selected from the group consisting of H, halo, and C 1-8  alkyl. 
 
       
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . The compound of  claim 1 , wherein the linker comprises a structure selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . The compound according to  claim 1 , wherein the compound is selected from the group consisting of:
 (S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N—((S)-1-((2-(2-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)ethoxy)ethoxy)ethyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)pyrrolidine-2-carboxamide,   (S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N—((S)-1-((4-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)butyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)pyrrolidine-2-carboxamide,   (S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N—((S)-1-((6-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)hexyl)amino)-1-oxo-3,3-diphenylpropan-2-yl)pyrrolidine-2-carboxamide,   (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-(4-((2-(2-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)ethoxy)ethoxy)ethyl)carbamoyl)-2-methoxyphenyl)-5-neopentylpyrrolidine-2-carboxamide,   (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-(4-((4-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)butyl)carbamoyl)-2-methoxyphenyl)-5-neopentylpyrrolidine-2-carboxamide,   (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-(4-((6-(2-(2,3-difluoro-6-(2-morpholinothiazol-4-yl)phenoxy)acetamido)hexyl)carbamoyl)-2-methoxyphenyl)-5-neopentylpyrrolidine-2-carboxamide,   and   N-(6-((S)-2-((S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)pyrrolidine-2-carboxamido)-3,3-diphenylpropanamido)hexyl)-2-morpholinobenzo[d]thiazole-4-carboxamide.   
     
     
         11 . A pharmaceutical composition, comprising:
 an effective amount of the compound of  claim 1 , and   a pharmaceutically acceptable carrier, additive and/or excipient   
     
     
         12 . The pharmaceutical composition of  claim 11 , further comprising at least one additional anticancer agent. 
     
     
         13 . A method for treating a disease state or condition in a patient wherein dysregulated protein activity is responsible for said disease or condition, said method comprising administering an effective amount of the compound according to  claim 1 . 
     
     
         14 . The compound according to  claim 1 , wherein the AR binding moiety is: 
       
         
           
           
               
               
           
         
         wherein A is: 
       
       
         
           
           
               
               
           
         
         B is: 
       
       
         
           
           
               
               
           
         
       
       and
 R 1  is each independently selected from H, halo, and C 1-6  alkyl optionally substituted by 1 or more halo. 
 
     
     
         15 . The compound according to  claim 1 , wherein the linker comprises a chemical structure represented by -A q -, in which q is an integer greater than 1, and A is independently selected from the group consisting of a bond, CR L1 R L2 , O, NR L3 , and CONR L3 , wherein R L1  and R L2 , are each independently selected from the group consisting of H and C 1-8  alkyl, and wherein R L3  is H. 
     
     
         16 . The compound according to  claim 1 , wherein the E3LB moiety is a structure selected 
       
         
           
           
               
               
           
         
       
     
     
         17 . The compound according to  claim 1 , wherein the E3LB moiety is: 
       
         
           
           
               
               
           
         
       
     
     
         18 . The compound according to  claim 17 , wherein in the E3LB moiety,
 R 10  is optionally substituted cycloalkyl (e.g., cyclohexyl);   R 12  and R 13  are independently optionally substituted alkyl (e.g., methyl); and   R 20  is:   
       
         
           
           
               
               
           
         
       
       wherein B is phenyl. 
     
     
         19 . The compound according to  claim 1 , wherein the E3LB moiety is 
       
         
           
           
               
               
           
         
       
     
     
         20 . The compound according to  claim 19 , wherein in the E3LB moiety:
 R 21  is aryl substituted by mono-, di- or tri-substituted halogen (e.g., F or Cl);   R 22  is aryl substituted by mono-, di-, or tri-substituted halogen (e.g., F or Cl);   R 23  is selected from alkyl;   R 24  is H; and   E is para-substituted phenyl substituted by —OCH 3 .