Releasable conjugates

Abstract

The present application provides compounds of Formula (B): or pharmaceutically acceptable salts thereof, wherein D is a residue of a biologically active drug, which underdo hydrolysis under physiological conditions to release the biologically active drug and which are useful in the treatment of disorders that could be beneficially treated with the drug.

What is claimed is: 
     
         1 . A compound of Formula (B) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         the aliphatic moiety is selected from a polymer, R, and a group selected from:
   polymer-L-(CH 2 ) m — and polymer-L-(CH 2 —CH 2 —O) p —(CH 2 ) m —;
 
 
         R is selected from optionally substituted C 1-6  alkyl, optionally substituted C 1-3  alkyl-O—(CH 2 —CH 2 —O) p —(CH 2 ) m —, and optionally substituted C 3-7  cycloalkyl; 
         L is a linking group; 
         m and p are each independently an integer from 1 to 10; 
         D is a residue of a biologically active drug; 
         Z 1  is selected from O, S, and N(R N ); 
         Z 3  is selected from O and N(R N ), or Z 3  is absent; 
         A is O or N, wherein when A is O then R 3  is absent; 
         R N  is selected from H and optionally substituted C 1-6  alkyl; 
         R 3  is selected from H and C 1-6  alkyl, or 
         R 3  and R 1 , together with A and the carbon atom to which R 1  is attached, form an optionally substituted 4 to 7 membered aliphatic heterocyclic ring; or 
         R 3  and R 2 , together with A, the carbon atom to which R 1  is attached, and the carbon atom to which R 2  is attached, form an optionally substituted 4 to 8 membered aliphatic heterocyclic ring; 
         M A  is a self-immolative group having any one of formulae (a)-(i): 
       
       
         
           
           
               
               
           
         
         wherein x denotes a point of attachment to Z 1  and y denotes a point of attachment to Z 3 ; 
         R 1  and R 2  are independently selected from the group consisting of hydrogen, optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl and optionally substituted 5- to 14-membered heteroaryl; 
         or R 1  and R 2  are joined together with the carbon atoms to which they are attached to form an optionally substituted C 3-7  cycloalkyl ring, an optionally substituted 4 to 7 membered aliphatic heterocyclic ring, an optionally substituted C 6-10  aryl or an optionally substituted 5- to 14-membered heteroaryl; 
         or R 1  and R 2  are joined together to form a ribose ring system; 
         R 7  and R 8  are independently selected from H and C 1-6  alkyl; and 
         E is a cleavable moiety.