Hydrophobically tagged small molecules as inducers of protein degradation

Abstract

Also provided are pharmaceutical compositions comprising a compound of Formula (I) or (II) and methods of using such compounds for treating proliferative diseases.

What is claimed is: 
     
         1 - 39 . (canceled) 
     
     
         40 . A compound of Formula (II): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein:
 Ring A is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 L 1  represents a linker selected from the group consisting of substituted and unsubstituted alkylene; substituted and unsubstituted alkenylene; substituted and unsubstituted alkynylene; substituted and unsubstituted heteroalkylene; substituted and unsubstituted heteroalkenylene; substituted and unsubstituted heteroalkynylene; substituted and unsubstituted heterocyclylene; substituted and unsubstituted carbocyclylene; substituted and unsubstituted arylene; substituted and unsubstituted heteroarylene; and combinations thereof; 
 R H  represents a hydrophobic group selected from the group consisting of substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroarylalkyl, substituted and unsubstituted carbocycylalkyl, and substituted and unsubstituted heterocyclylalkyl 
 L 2  represents a bond or a linker selected from the group consisting of substituted and unsubstituted alkylene; substituted and unsubstituted alkenylene; substituted and unsubstituted alkynylene; substituted and unsubstituted heteroalkylene; substituted and unsubstituted heteroalkenylene; substituted and unsubstituted heteroalkynylene; substituted and unsubstituted heterocyclylene; substituted and unsubstituted carbocyclylene; substituted and unsubstituted arylene; substituted and unsubstituted heteroarylene; and combinations thereof; and 
 R D  is of formula: 
 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein:
 R D1  is hydrogen, halogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —CN, —NO 2 , —OR D1a , —N(R D1a ) 2 , —SR D1a , —CH 2 OR D1a , —CH 2 N(R D1a ) 2 , —CH 2 SR D1a , —C(═O)R D1a , —C(═O)OR D1a , —C(═O)SR D1a , —C(═O)N(R D1a ) 2 , —C(═S)R D1a , —C(═S)OR D1a , —C(═S)SR D1a , —C(═S)N(R D1a ) 2 , —C(═NR D1a )R D1a , —C(═NR D1a )OR D1a , —C(═NR D1a )SR D1a , or —C(═NR D1a )N(R D1a ) 2 , wherein each occurrence of R D1a  is independently hydrogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R D1a  groups are joined to form an substituted or unsubstituted heterocyclic ring; 
 R D2  is hydrogen, halogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —CN, —NO 2 , —OR D2a , —N(R D2a ) 2 , —SR D2a , —CH 2 OR D2a , —CH 2 N(R D2a ) 2 , —CH 2 SR D2a , —C(═O)R D2a , —C(═O)OR D2a , —C(═O)SR D2a , —C(═O)N(R D2a ) 2 , —C(═S)R D2a , —C(═S)OR D2a , —C(═S)SR D2a , —C(═S)N(R D2a ) 2 , —C(═NR D2a )R D2a , —C(═NR D2a )OR D2a , —C(═NR D2a )SR D2a , and —C(═NR D2a )N(R D2a ) 2 , wherein each occurrence of R D2a  is independently hydrogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, or two R D2a  groups are joined to form an substituted or unsubstituted heterocyclic ring; 
 R D3  is hydrogen, halogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR D3a , —N(R D3a ) 2 , —SR D3a , —CH 2 OR D3a , —CH 2 N(R D3a ) 2 , —CH 2 SR D3a , —C(═O)R D3a , —C(═O)OR D3a , —C(═O)SR D3a , —C(═O)N(R D3a ) 2 , —C(═S)R D3a , —C(═S)OR D3a , —C(═S)SR D3a , —C(═S)N(R D3a ) 2 , —C(═NR D3a )R D3a , —C(═NR D3a )OR D3a , —C(═NR D3a )SR D3a , or —C(═NR D3a )N(R D3a ) 2  wherein each occurrence of R D3a  is independently hydrogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R D3a  groups are joined to form an substituted or unsubstituted heterocyclic ring; 
 optionally R D1  and R D3 , or R D2  and R D3 , or R D1  and R D2  are joined to form an substituted or unsubstituted carbocyclic or substituted or unsubstituted heterocyclic ring; 
 R D4  is a leaving group selected from the group consisting of —Br, —Cl, —I, and —OS(═O) w R D4a , wherein w is 1 or 2, and R D4a  is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 each occurrence of R B  is independently hydrogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group, or two R B  groups are joined to form an substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; 
 each occurrence of R C  is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR C1 , —N(R C1 ) 2 , —SR C1 , —C(═O)R C1 , —C(═O)OR C1 , —C(═O)SR C1 , —C(═O)N(R C1 ) 2 , —NR C1 C(═O)R C1 , —NR C1 C(═O)OR C1 , —NR C1 C(═O)SR C1 , or —NR C1 C(═O)N(R C1 ) 2 , wherein each occurrence of R C1  is independently hydrogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R C1  groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; 
 a is 0, 1, 2, 3, or 4; and 
 b is 0 or 1. 
 
       
     
     
         41 . The compound of  claim 40  of Formula (II-a): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         42 . The compound of  claim 40  of Formula (II-b): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         43 . The compound of  claim 40 , wherein Ring A is a substituted or unsubstituted phenyl. 
     
     
         44 . The compound of  claim 40 , wherein Ring A is a substituted or unsubstituted 5- to 6-membered heteroaryl ring. 
     
     
         45 . The compound of  claim 40 , wherein Ring A is a substituted or unsubstituted C 3 -C 8  carbocyclyl ring. 
     
     
         46 . The compound of  claim 40 , wherein Ring A is a substituted or unsubstituted 3- to 8-membered heterocyclyl ring. 
     
     
         47 . The compound of  claim 40  of Formula (II-c): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein:
 each occurrence of R A  is, independently, hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR A1 , —N(R A1 ) 2 , —SR A1 , —C(═O)R A1 , or —C(═O)OR A1  wherein each occurrence of R A1  is independently hydrogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R A1  groups are joined to form an substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; and 
 c is 0 or 1. 
 
       
     
     
         48 . The compound of  claim 40  of Formula (II-d): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein:
 each occurrence of R A  is, independently, hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR A1 , —N(R A1 ) 2 , —SR A1 , —C(═O)R A1 , or —C(═O)OR A1  wherein each occurrence of R A1  is independently hydrogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R A1  groups are joined to form an substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; and 
 c is 0 or 1. 
 
       
     
     
         49 . The compound of  claim 40  of Formula (II-e): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein:
 each occurrence of R A  is, independently, hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR A1 , —N(R A1 ) 2 , —SR A1 , —C(═O)R A1 , or —C(═O)OR A1  wherein each occurrence of R A1  is independently hydrogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R A1  groups are joined to form an substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; 
 c is 0 or 1; and 
 d is 0, 1, 2, 3, 4, or 5. 
 
       
     
     
         50 . The compound of  claim 40  of Formula (II-f): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein:
 each occurrence of R A  is, independently, hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR A1 , —N(R A1 ) 2 , —SR A1 , —C(═O)R A1 , or —C(═O)OR A1  wherein each occurrence of R A1  is independently hydrogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R A1  groups are joined to form an substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; and 
 c is 0 or 1. 
 
       
     
     
         51 . The compound of  claim 40 , wherein L 1  represents a linker 4 to 20 consecutive covalently bonded atoms in length, inclusive. 
     
     
         52 . The compound of  claim 40 , wherein L 1  represents a linker 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive covalently bonded atoms in length. 
     
     
         53 . The compound of  claim 40 , wherein L 1  represents a linker consisting of a combination of one or more groups of the formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein:
 each instance of n is independently an integer between 1 to 10, inclusive; 
 each instance of m is independently 0, 1 or 2; 
 each instance of Q is independently —NR W1 —; —NR W1 —NR W1 —; —O—NR W1 —; —NR W1 —O—; —S—; or —O—; 
 each instance of W is independently O, S, or NR W1 ; 
 each instance of G 1  and G 2  are independently N or CH; 
 each instance of R W1  is independently hydrogen; substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; a nitrogen protecting group if attached to a nitrogen atom, or an oxygen protecting group if attached to an oxygen atom; 
 each instance of R W2  is independently hydrogen; substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; or two R W2  groups are joined to form a 5-6 membered ring; and 
 each instance of R W3  is independently hydrogen; halogen; substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl, or two R W3  groups are joined to form a 3-6 membered ring; 
 or R W1  and R W3  are joined to form a 5-6 membered heterocyclic ring. 
 
       
     
     
         54 . The compound of  claim 40 , wherein R H  is a group of formula: 
       
         
           
           
               
               
           
         
         wherein each occurrence of R H1 , R H2 , and R H3  is independently halogen, alkyl, haloalkyl, alkoxy, or dialkylamino; and p and q are independently 0, 1, 2, or 3. 
       
     
     
         55 . The compound of  claim 40 , wherein R H  is a group of formula: 
       
         
           
           
               
               
           
         
         wherein each occurrence of R H1  and R H2  is independently halogen, alkyl, haloalkyl, alkoxy, or dialkylamino; and p and q are independently 0, 1, 2, or 3. 
       
     
     
         56 . The compound of  claim 52 , wherein -L 1 -R H  represents a group of the formula: 
       
         
           
           
               
               
           
         
         wherein each instance of G 1  and G 2  are independently N or CH. 
       
     
     
         57 . The compound of  claim 52 , wherein -L 1 -R H  represents a group of the formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein each instance of G 1  and G 2  are independently N or CH. 
       
     
     
         58 . A pharmaceutical composition comprising a compound of  claim 40 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         59 . A method of treating a cancer associated with aberrant activity of a Her3 protein kinase, the method comprising administering a compound of  claim 40  or pharmaceutical composition thereof to a subject in need thereof in an amount sufficient to reduce Her3 protein kinase activity.