Small molecules

Abstract

Compounds having the general structure A-L-B are presented wherein A and B are independently an E3 ubiquitin ligase protein binding ligand compound of formula 1A or 1B. Pharmaceutical compositions comprising these compounds and methods of use are also presented.

1 . A compound having the structure:
   A-L-B   wherein A and B are independently an E3 ubiquitin ligase protein binding ligand compound of formula 1A or 1B and at least one of A or B is the compound of formula 1B:   
       
         
           
           
               
               
           
         
         wherein L is a linking group which is directly bonded to the compound of formula 1A at R 1  or R 2 , and/or directly bonded to the compound of formula 1B at R 3  or R 4  and wherein L is —R 5 —[O(CH 2 ) m ] n —R 6 —, wherein m and n are independently 0 to 10, and R 5  and R 6  are independently selected from the group: covalent bond, C1-C10 alkylene, —OR 7 —, C1-C10 polyether, or —O—; 
         wherein R 1  is selected from either the group: (1) a covalent bond, or C1-C5 alkylene when L is bonded to the compound of formula 1A at R 1 , or the group (2) H, NH 2 , C1-C5 alkyl, or C(CN)C 2 H 4  when L is bonded to the compound of formula 1A at R 2 ; 
         wherein R 2 , R 3 , and R 4  are independently selected from the group: a covalent bond, H, NH 2 , C1-C5 alkyl, C(CN)C 2 H 4 ; 
         wherein X and Y are independently selected from the group: H, OH or halogen; and 
         wherein R 7  is C1-C5 alkylene, 
         or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof. 
       
     
     
         2 . A compound according to  claim 1 , wherein X is H or halogen. 
     
     
         3 . A compound according to  claim 1 , wherein Y is OH. 
     
     
         4 . A compound according to  claim 1 , wherein either A or B is a compound according to formula 1A, wherein A has the formula 1C: 
       
         
           
           
               
               
           
         
       
     
     
         5 . A compound according to  claim 1 , wherein A is a compound of formula 1A and B is a compound of formula 1B. 
     
     
         6 . A compound according to  claim 1 , wherein L is connected to A via R 1  of formula 1A. 
     
     
         7 . A compound according to  claim 1 , wherein L is connected to B via R 1  of formula 1A. 
     
     
         8 . A compound according to  claim 1 , wherein R 5  is a chemical bond, R 6  is a chemical bond, m is 2 and n is 3, 4 or 5. 
     
     
         9 . A compound according to  claim 8 , wherein n is 5. 
     
     
         10 . A compound according to  claim 1 , wherein the linker L is a linear chain of 12-20 atoms in length. 
     
     
         11 . A compound according to  claim 10 , wherein the linker chain comprises carbon and/or oxygen atoms. 
     
     
         12 . A compound according to  claim 11 , wherein the linker chain comprises alkylene groups and/or ether groups and/or polyether groups. 
     
     
         13 . A pharmaceutical composition comprising one or more compounds according to  claim 1  and a pharmaceutically acceptable vehicle or diluent therefor. 
     
     
         14 . A method of use of a compound according to  claim 1  for the treatment of at least one of anaemia due to chronic kidney disease, anaemia due to cancer chemotherapy, ischemia, ischemic reperfusion injuries, myocardial infarction, stroke, acute lung injury, intestinal inflammation, wound healing and post-transplantation complications, mitochondrial respiratory chain dysfunctions and oncological conditions treatable by enhancing T-cell responses. 
     
     
         15 . A method of regulating activity of a target protein in a subject comprising administering to said subject an effective amount of a compound according to  claim 1 . 
     
     
         16 . The method according to  claim 15 , wherein the target protein is an E3 ubiquitin ligase protein.