Methods to induce targeted protein degradation through bifunctional molecules

Abstract

The present application provides bifunctional compounds which act as protein degradation inducing moieties. The present application also relates to methods for the targeted degradation of endogenous proteins through the use of the bifunctional compounds that link a cereblon-binding moiety to a ligand that is capable of binding to the targeted protein which can be utilized in the treatment of proliferative disorders. The present application also provides methods for making compounds of the application and intermediates thereof.

We claim: 
     
         1 . A compound selected from: 
       
         
           
           
               
               
           
         
         or an enantiomer, diastereomer, stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:
 Y is a bond, (CH 2 ) 1-6 , (CH 2 ) 0-6 —O, (CH 2 ) 0-6 —C(O)NR 2 ′, (CH 2 ) 0-6 —NR 2 ′C(O), (CH 2 ) 0-6 —NH, or (CH 2 ) 0-6 —NR 2 ; 
 X is C(O) or C(R 3 ) 2 ; 
 X 1 -X 2  is C(R 3 )═N or C(R 3 ) 2 —C(R 3 ) 2 ; 
 each R 1  is independently halogen, OH, C 1 -C 6  alkyl, or C 1 -C 6  alkoxy; 
 R 2  is C 1 -C 6  alkyl, C(O)—C 1 -C 6  alkyl, or C(O)—C 3 -C 6  cycloalkyl; 
 R 2 ′ is H or C 1 -C 6  alkyl; 
 each R 3  is independently H or C 1 -C 3  alkyl; 
 R 5  is H, deuterium, C 1 -C 3  alkyl, F, or Cl; 
 m is 0, 1, 2 or 3; 
 n is 1 or 2; 
 the Linker is 3 
 
       
       
         
           
           
               
               
           
         
         
           each W is independently absent, CH 2 , O, S, NH or NR 5 ; 
           Z is absent, CH 2 , O, NH or NR 5 ; 
           Q is absent or —CH 2 C(O)NH—; 
           p1 is selected from 0, 1, 2, 3, 4, 5, and 6; 
           p2 is selected from 0, 1, 2, 3, 4, 5, and 6; 
           p3 is selected from 1, 2, 3, 4, and 5; 
           the Targeting Ligand is selected from: 
         
       
       
         
           
           
               
               
           
         
         
           wherein: 
           T 7  is CH 2  or CH 2 CH 2 ; 
           Rg 1  is C(O)Rg 5  or (CH 2 ) 1-3 Rg 6 ; 
           nn10 is 0, 1, 2, or 3; 
           nn11 is 0, 1, 2, or 3; 
           each Rg 2  is independently C 1 -C 3  alkyl, C 1 -C 3  alkoxy, CN, or halogen; 
           Rg 3  is C(O)NRg 4 L, OL, NRg 4 L, L, O—(CH 2 ) 1-3 —C(O)NRg 4 L, or NHC(O)—(CH 2 ) 1-3 —C(O)NRg 4 L; 
           Rg 4  is H or C 1 -C 3  alkyl; 
           Rg 5  is C 1 -C 6  alkyl; 
           Rg 6  is phenyl optionally substituted with C 1 -C 3  alkyl, C 1 -C 3  alkoxy, CN, or halogen; and 
           L is the attachment point to the Linker. 
         
       
     
     
         2 . The compound of  claim 1 , wherein T 7  is CH 2 . 
     
     
         3 . The compound of  claim 1 , wherein Rg 1  is C(O)Rg 5 . 
     
     
         4 . The compound of  claim 1 , wherein Rg 2  is C 1 -C 3  alkoxy. 
     
     
         5 . The compound of  claim 1 , wherein the compound is Formula I. 
     
     
         6 . The compound of  claim 5 , wherein X is C(O). 
     
     
         7 . The compound of  claim 5 , wherein X is C(R 3 ) 2 . 
     
     
         8 . The compound of  claim 1 , wherein the compound is Formula II. 
     
     
         9 . The compound of  claim 1 , wherein R 3  and R 5  are H. 
     
     
         10 . The compound of  claim 1 , wherein each R 1  is independently selected from F, Cl, OH, methyl, ethyl, propyl, methoxy, ethoxy and propoxy. 
     
     
         11 . The compound of  claim 1 , wherein m is 0. 
     
     
         12 . The compound of  claim 1 , wherein n is 1. 
     
     
         13 . The compound of  claim 1 , wherein the Linker has 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 chain atoms. 
     
     
         14 . The compound of  claim 1 , wherein at least one W is O or CH 2 . 
     
     
         15 . The compound of  claim 1 , wherein Q is —CH 2 C(O)NH—. 
     
     
         16 . The compound of  claim 5 , wherein T 7  is CH 2 . 
     
     
         17 . The compound of  claim 16 , wherein Rg 1  is C(O)Rg 5 . 
     
     
         18 . The compound of  claim 17 , wherein Rg 2  is C 1 -C 3  alkoxy. 
     
     
         19 . A method for treating a patient with a medical disorder mediated by FKBP12, comprising administering a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. 
     
     
         20 . A pharmaceutical composition comprising a compound of  claim 1  or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.