Therapeutic compounds and methods of use thereof

Abstract

There are provided new heterobifuctional agents designed to mediated formation of protein-protein dimers and promote ubiqutination of a protein of the dimer. Also provided are methods of synthesizing the agents, pharmaceutical formulations including the agents, and methods of using the agents to treat, ameliorate or cure diseases characterized by protein over-expression or malfunction.

1 . A compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof: 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted aminylacylene, optionally substituted acylaminylene and optionally substituted acylene; 
         R 2  is selected from H, halogen and methyl; 
         R 3  and R 4  are independently selected from H and methyl; 
         R 5  is selected from H and methyl; 
         L is an optionally substituted linker having 2 to 18 atoms in the chain length; 
         X is a protein binding moiety; and 
         Z is N or CH. 
       
     
     
         2 . The compound of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
         wherein R 6  is H or C 1 -C 6  alkyl, e.g., methyl; 
         X 1 , X 2  and X 3  are independently selected from N and CH, and C-L 3 , such that when X 1  and X 3  are N, X 2  is C-L 3 ; and 
         L 3  is a linker. 
       
     
     
         3 . The compound of  claim 2 , wherein X 2  is N; and
 X 1  and X 3  are CH.   
     
     
         4 . The compound of  claim 2 , wherein X 2  is N;
 X 1  and X 3  are C-L 3  or CH; and the pyridyl moiety is attached at the 5-position of the oxindole ring.   
     
     
         5 . (canceled) 
     
     
         6 . The compound of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
         wherein L 4  is a linker; X 1 , X 2  and X 3  are independently selected from N and CH, and C-L 4 , such that when X 1  and X 3  are N, X 2  is C-L 4 . 
       
     
     
         7 . The compound of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
         wherein L 2  is a linker. 
       
     
     
         8 . The compound of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
         wherein L 1  is a linker. 
       
     
     
         9 . The compound of preceding  claim 1 , wherein X is: 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 1 , wherein X is: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
         in which L 2  is a linker. 
       
     
     
         12 . The compound of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
         in which L 1  is a linker. 
       
     
     
         13 . The compound of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
         in which L 5  is a linker. 
       
     
     
         14 . The compound of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
         wherein L 5  is a linker. 
       
     
     
         15 . The compound of  claim 1 , wherein R 1  is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         16 . The compound of preceding  claim 1 , wherein the linker is a member selected from: 
       
         
           
           
               
               
           
         
         wherein the index m is an integer from 1 to 6; and the index n is an integer from 1 to 18. 
       
     
     
         17 . The compound of  claim 1 , wherein R 1  is located at either a 5′ or 6′ position of the oxindole ring. 
     
     
         18 . The compound of  claim 1 , wherein R 1  is selected from optionally substituted phenylene, optionally substituted pyridinylene, optionally substituted pyrazolylene, optionally substituted aminylacylene, optionally substituted acylaminylene. 
     
     
         19 . The compound of  claim 1 , wherein the optional substituent at R 1  is selected from optionally substituted heterocyclyl, optionally substituted amino, optionally substituted aminoacyl, optionally substituted acylamino, optionally substituted aryl and optionally substituted heteroaryl. 
     
     
         20 . The compound of  claim 1 , wherein, R 1  is optionally substituted heteroarylene and R 2  is selected from H, halogen or methyl. 
     
     
         21 . The compound of  claim 1 , wherein the linker is selected from optionally substituted alkylene, optionally substituted heteroalkylene and optionally substituted cycloalkylene. 
     
     
         22 . The compound of  claim 1 , wherein the linker is selected from optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted cycloalkylene and optionally substituted heterocyclylene, each having 2 to 18 atoms in the chain length, and optionally substituted polyethoxy having 2 to 18 atoms in the chain length. 
     
     
         23 . The compound of  claim 1 , wherein X is selected from bromodomain-containing protein 4 (BRD4) binding moiety, transcriptional enhanced associate domain (TEAD) binding moiety, Polycomb Repressive Complex 2 (PRC2) binding moiety, focal adhesion kinase (FAK) binding moiety, BCR-ABL binding moiety, Hippo pathway protein binding moiety and transcription factor binding moiety. 
     
     
         24 . The compound according to  claim 1 , having a formula according to Table 1. 
     
     
         25 . A compound of Formula (XI) or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof: 
       
         
           
           
               
               
           
         
         wherein R 1′  is selected from optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aminoacyl, optionally substituted acylamino and optionally substituted acyl; 
         R 2  is selected from H, halogen and methyl; 
         R 3  and R 4  are independently selected from H and methyl; and 
         R 5  is selected from H and methyl; and 
         Z is selected from CH, and N, 
         wherein R 1′  is located at either a 5′ or 6′ position of the oxindole ring. 
       
     
     
         26 . The compound of Formula (XI) according to  claim 25 ,
 wherein R 1′  is selected from optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted pyrazolyl, optionally substituted indolyl, optionally substituted azaindolyl, optionally substituted aminoacyl, optionally substituted acylamino, optionally substituted heterocyclylacyl and optionally substituted piperidinyl.   
     
     
         27 . The compound of Formula (XI) according to  claim 25 , as represented by Formula (XI′) or (XII″): 
       
         
           
           
               
               
           
         
       
     
     
         28 . The compound of Formula (II) according to  claim 25 , as represented by Formulae (XI′a) or (XI″a): 
       
         
           
           
               
               
           
         
         wherein R 2 , R 3 , R 4  and R 5  are as defined herein, and 
         wherein R 6  is selected from optionally substituted amino, optionally substituted aminoacyl, and optionally substituted acylamino. 
       
     
     
         29 . The compound of Formulae (XI′a) or (XI″a) according to  claim 25 ,
 wherein R 6  is optionally substituted spirocycloalkyl. 
 
     
     
         30 . A compound of Formula (XII) or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof: 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , R 4  and R 5  are as defined herein; 
         wherein R 1  is located at either a 5′ or 6′ position of the oxindole ring; and 
         L is an optionally substituted linker having 2 to 18 atoms in the chain length. 
       
     
     
         31 . A pharmaceutical composition comprising an effective amount of compound of a compound of  claim 1  or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, optionally in combination with a pharmaceutically acceptable carrier, excipient or diluent. 
     
     
         32 . A method of inducing degradation of an overexpressed protein in a cell, including a step of contacting a compound of  claim 1  with the cell to induce degradation of the overexpressed protein in the cell. 
     
     
         33 . A method of treating a disease or condition associated with an overexpressed protein, comprising administering a compound of  claim 1  or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof in a patient in need thereof. 
     
     
         34 . The method according to  claim 32 , wherein the overexpressed protein is selected from BRD4, transcriptional enhanced associate domain (TEAD), Polycomb Repressive Complex 2 (PRC2), focal adhesion kinase (FAK), BCR-ABL, Hippo pathway protein and transcription factor. 
     
     
         35 . The method according to  claim 32 , wherein the disease or condition is selected from hyperplasia and cancer (such as multiple myeloma, glioblastoma, uveal melanoma, liposarcoma, hepatocellular carcinoma, midline carcinoma, acute myeloid leukemia, Burkitt lymphoma and prostate cancer) and a protein accumulation disease (such as Alzheimer's disease and amyotrophic lateral sclerosis). 
     
     
         36 . A compound of  claim 1  or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof for use as a medicament. 
     
     
         37 . A compound of  claim 1  or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof for use in the treatment of a disease or condition associated with an overexpressed protein. 
     
     
         38 . The compound according to  claim 36 , wherein the disease or condition is selected from hyperplasia and cancer (such as multiple myeloma, glioblastoma, uveal melanoma, liposarcoma, hepatocellular carcinoma, midline carcinoma, acute myeloid leukemia, Burkitt lymphoma and prostate cancer) and a protein accumulation disease (such as Alzheimer's disease and amyotrophic lateral sclerosis). 
     
     
         39 . (canceled) 
     
     
         40 . (canceled) 
     
     
         41 . A ternary complex comprising a first protein and a second protein interacting with a first moiety and a second moiety, respectively, of the compound of  claim 1 .