Compounds and methods for the targeted degradation of androgen receptor

Abstract

The present disclosure relates to bifunctional compounds, which find utility to degrade and (inhibit) Androgen Receptor. In particular, the present disclosure is directed to compounds, which contain on one end a cereblon ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds Androgen Receptor, such that Androgen Receptor is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of Androgen Receptor. The present disclosure exhibits a broad range of pharmacological activities associated with compounds according to the present disclosure, consistent with the degradation/inhibition of Androgen Receptor.

What is claimed is: 
     
         1 . A compound having the structure:
   CLM-L-ABM,   wherein:
 (a) CLM is a cereblon E3 ubiquitin ligase binding moiety; 
 (b) L is a chemical linker group that is covalently bound to the PTM and the CLM and has the chemical structure -(A L ) q -, wherein:
 q is greater than or equal to 1; 
 each A L  is selected from the group consisting of CR L1 R L2 , O, NR L3 , CONR L3 , CO, C 3-11  cycloalkyl optionally substituted with 1-6 R L1  and/or R L2  groups, and C 3-11  heterocyclyl optionally substituted with 1-6 R L1  and/or R L2  groups; and 
 R L1 , R L2 , R L3 , R L4  and R L5  are, each independently, H, halo, C 1-8 alkyl, OC 1-8 alkyl, NHC 1-8 alkyl, OH, or NH 2 ; and 
 
 (c) ABM is an androgen receptor (AR) binding moiety having the structure: 
   
       
         
           
           
               
               
           
         
         
           wherein:
 W 1  is aryl or heteroaryl, each independently substituted by 1 or more: H; halo; hydroxyl; nitro; CN; C≡CH; CF 3 ; linear or branched C 1-6  alkyl optionally substituted by 1 or more halo or C 1-6  alkoxyl; or linear or branched C 1-6  alkoxyl optionally substituted by 1 or more halo; 
 Y 1  and Y 2  are each independently O or S; 
 R 1 , R 2 , R Y1 , and R Y2  are each independently: H; halogen; C 1-6  alkoxy, linear or branched C 1-6  alkyl optionally substituted by 1 or more halo; or R 1  and R 2  together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms; 
 W 2  is aryl or heteroaryl, each optionally substituted by 1-10 R W2 ; 
 each R W2  is independently: H; halo; C 1-6  alkyl optionally substituted by 1 or more F; C 3-6  cycloalkyl; C 4-6  cycloheteroalkyl; OH; NH 2 ; NR Y1 R Y2 ; CN; or OC 1-3 alkyl optionally substituted by 1 or more —F; and
    is the point of attachment of the ABM to the chemical linker group (L). 
 
 
         
       
     
     
         2 . The bifunctional compound according to  claim 1 , wherein W 1  is: 
       
         
           
           
               
               
           
         
       
       each R 22  is independently halo, H, linear or branched C 1-6  alkyl optionally substituted by 1 or more halo, or cyano; and 
       each R 23  is independently H, halo, CF 3 , linear or branched C 1-6  alkyl, C 1-6  alkoxy, or cyano. 
     
     
         3 . The compound of  claim 1 , wherein at least one of: 
       W 1  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       and 
       W 2  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , wherein at least one of: 
       W 1  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       and 
       W 2  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The bifunctional compound according to  claim 1 , wherein the ABM has the chemical structure: 
       
         
           
           
               
               
           
         
       
       wherein:
 W 1  is 
 
       
         
           
           
               
               
           
         
         each R 22  is independently H or —CN; 
         each R 23  is independently H, halo, or —CF 3 ; 
         Y 1 , Y 2  are each independently O or S; 
         R 1 , R 2 , are each independently H or a methyl group; and 
         W 2  is aryl or heteroaryl, each optionally substituted by 1, 2 or 3 R W2 ; and 
         each R W2  is independently H, halo, C 1-6  alkyl optionally substituted by 1 or more F, C 3-6  cycloalkyl, C 4-6  cycloheteroalkyl, or OC 1-3 alkyl optionally substituted by 1 or more —F. 
       
     
     
         6 . The bifunctional compound according to  claim 1 , wherein the ABM is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         7 . The bifunctional compound according to  claim 1 , wherein the chemical linker group (L) has the chemical structure: 
       
         
           
           
               
               
           
         
         wherein m, n, o, p, q, and r are each independently 0, 1, 2, 3, 4, 5, or 6. 
       
     
     
         8 . The bifunctional compound according to  claim 1 , wherein linker (L) comprises a group represented by a general structure selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 1 , wherein the chemical linker group (L) is a substituted or unsubstituted polyethylene glycol group having 1 to 10 ethylene glycol units (e.g., 1 to 8 ethylene glycol units or 1 to 6 ethylene glycol units). 
     
     
         10 . The compound of  claim 1 , wherein the CLM comprises a chemical group derived from an amide or a thioamide that binds to the cereblon E3 ubiquitin ligase. 
     
     
         11 . The compound of  claim 1 , wherein the CLM comprises a chemical group derived from an imide or a thioimide that binds to the cereblon E3 ubiquitin ligase. 
     
     
         12 . The compound of  claim 1 , wherein the CLM comprises an amide or a thioamide derived moiety. 
     
     
         13 . The compound of  claim 1 , wherein the CLM comprises an imide or a thioimide derived moiety. 
     
     
         14 . A compound having the structure: 
       
         
           
           
               
               
           
         
         wherein:
 CLM is a thalidomide analog comprising a substituted glutaramide moiety; 
 L is a chemical linker group that is covalently bound to the PTM and the CLM and has the chemical structure -(A L ) q -, wherein:
 q is greater than or equal to 1; 
 each A L  is selected from the group consisting of CR L1 R L2 , O, NR L3 , CONR L3 , CO, C 3-11  cycloalkyl optionally substituted with 1-6 R L1  and/or R L2  groups, and C 3-11  heterocyclyl optionally substituted with 1-6 R L1  and/or RU groups, where R L1  and R, together with the carbon they are linked optionally form a cycloalkyl and/or heterocyclyl group; and 
 R L1 , R L2 , R L3 , R L4  and R L5  are, each independently, H, halo, C 1-8 alkyl, OC 1-8 alkyl, NHC 1-8 alkyl, OH, or NH 2 ; 
 
 W 1  is aryl or heteroaryl, each independently substituted by 1 or more: H; halo; hydroxyl; nitro; CN; C═CH; CF 3 ; linear or branched C1.6 alkyl optionally substituted by 1 or more halo or C 1-6  alkoxyl; or linear or branched C 1-6  alkoxyl optionally substituted by 1 or more halo; 
 Y 1  and Y 2  are each independently O or S; 
 R 1 , R 2 , R Y1 , and R Y2  are each independently: H; halogen; C 1-6  alkoxy, linear or branched C 1-6  alkyl optionally substituted by 1 or more halo; or R 1  and R 2  together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms; 
 W 2  is aryl or heteroaryl, each optionally substituted by 1-10 R W2 ; and 
 each R W2  is independently: H; halo; C 1-6  alkyl optionally substituted by 1 or more F; C 3-6  cycloalkyl; C 4-6 cycloheteroalkyl; OH; NH 2 ; NR Y1 R Y2 ; CN; or OC 1-3 alkyl optionally substituted by 1 or more —F. 
 
       
     
     
         15 . The compound of  claim 14 , wherein the linker comprises at least one group selected from an optionally substituted: 
       
         
           
           
               
               
           
         
       
       or a combination thereof,
 wherein m, and n are each independently 0, 1, 2, 3, 4, 5, or 6. 
 
     
     
         16 . A composition comprising an effective amount of a bifunctional compound of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         17 . The composition of  claim 16 , wherein the composition further comprises at least one bioactive agent. 
     
     
         18 . The composition of  claim 17 , wherein the bioactive agent is an anti-cancer agent. 
     
     
         19 . A method for treating a disease or disorder in a subject, the method comprising administering a composition comprising a pharmaceutically acceptable carrier and an effective amount of at least one compound of  claim 1 , wherein the compound is effective in treating or ameliorating at least one symptom of the disease or disorder. 
     
     
         20 . The method according to  claim 19 , wherein the disease or disorder is associated with androgen receptor accumulation and aggregation. 
     
     
         21 . The method according to  claim 19 , wherein the disease or disorder is cancer or a neoplasia associated with androgen receptor accumulation and aggregation. 
     
     
         22 . The method according to  claim 19 , wherein the disease or disorder is prostate cancer. 
     
     
         23 . The method according to  claim 19 , wherein the disease or disorder is Kennedy's Disease. 
     
     
         24 . A compound having the structure: 
       
         
           
           
               
               
           
         
         wherein:
 CLM is a cereblon E3 ubiquitin ligase binding moiety; 
 L is a chemical linker group that is covalently bound to the PTM and the CLM and has the chemical structure 
 
       
       
         
           
           
               
               
           
         
         
           W 1  is an aryl or heteroaryl substituted with CN and optionally substituted with CF 3 ; 
           R 1  and R 2  are each a C1 alkyl, or R 1  and R 2 , together with the atom to which they are attached, form a 4 membered cycloalkyl; and 
           W 2  is aryl substituted with an ethyl.