Sulfonamide-containing linkage systems for drug conjugates

Abstract

Sulfonamide-containing linkage systems for release of payload compounds from an attached targeting moiety in drug conjugates. The conjugates have the formula of [(P)-(L)]m-(T), wherein (P) is a payload compound, (L) is a linker, (T) is a targeting moiety and m is an integer from 1- to 10. Also provided are pharmaceutical compositions comprising such conjugates and there use in treating cancer.

1 .- 13 . (canceled) 
     
     
         14 . A conjugate having the following structure (I):
   [(P) o -(L)] m -(T)   (Ia)
   wherein:   (L) is a linker;   (T) is a targeting moiety that specifically binds to a target antigen;   m is between 1 and 10;   o is between 1 and 20, and   (P) is a compound of Formula XId:   
       
         
           
           
               
               
           
         
         wherein: 
         R 2  is —R″—NH—; 
         R″ is selected from optionally substituted alkyl, optionally substituted alkylamino, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl, and 
         R 4  and R 5  are each independently selected from: H and C 1 -C 6  alkyl. 
       
     
     
         15 . The conjugate according to  claim 14 , wherein R 2  is selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4-aminophenyl, 3-aminophenyl, 4-(1-aminocyclopropyl)benzyl, 4-(1-aminocyclopropyl)phenyl, 2-aminophenyl, 4′-amino-[1,1′-biphenyl]-4-yl, 4-amino-2-ethylphenyl, 4-amino-3-(trifluoromethoxy)phenyl, 4-amino-2,3-dimethylphenyl, 4-amino-5,6,7,8-tetrahydronaphthalen-1-yl, 4-amino-3-methylphenyl, 4-amino-3-fluorophenyl, 4-amino-3-ethylphenyl and 4-amino-3-(trifluoromethyl)phenyl. 
     
     
         16 . The conjugate according to  claim 14 , wherein R 2  is selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4-aminophenyl, 4-(1-aminocyclopropyl)benzyl and 4-(1-aminocyclopropyl)phenyl. 
     
     
         17 . The conjugate according to  claim 14 , wherein R 4  and R 5  are each C 1 -C 6  alkyl. 
     
     
         18 . The conjugate according to  claim 14 , wherein R 4  and R 5  are each methyl. 
     
     
         19 . The conjugate according to  claim 14 , wherein:
 R 2  is selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4-aminophenyl, 3-aminophenyl, 4-(1-aminocyclopropyl)benzyl, 4-(1-aminocyclopropyl)phenyl, 2-aminophenyl, 4′-amino-[1,1′-biphenyl]-4-yl, 4-amino-2-ethylphenyl, 4-amino-2,3-dimethylphenyl, 4-amino-5,6,7,8-tetrahydronaphthalen-1-yl, 4-amino-3-methylphenyl, 4-amino-3-fluorophenyl, 4-amino-3-ethylphenyl and 4-amino-3-(trifluoromethyl)phenyl, and   R 4  and R 5  are each C 1 -C 6  alkyl.   
     
     
         20 . The conjugate according to  claim 14 , wherein o is 1. 
     
     
         21 . The conjugate according to  claim 14 , wherein (L)-(T) has structure (III): 
       
         
           
           
               
               
           
         
         wherein: 
         each AA is independently an amino acid; 
         x is an integer from 0 to 25; 
         (L′) is the remaining portion of linker (L) or is absent; 
         the —NH— group bonded to R″ in —R″—NH— forms a junction peptide bond (JPB) with (AA) 1  in structure (III), and 
         wherein (AA) 1 -(AA) x  taken together comprises an amino acid sequence that facilitates cleavage of the JPB. 
       
     
     
         22 . The conjugate according to  claim 21 , wherein (L′) comprises a stretcher moiety and -(AA) 1 -(AA) x -(L′)-(T) has one of the structures (VII) or (VIII): 
       
         
           
           
               
               
           
         
         wherein: 
         L″ is a remaining portion of linker (L) or is absent, and 
         (S) is the stretcher moiety. 
       
     
     
         23 . The conjugate according to  claim 21 , wherein L′ comprises one or more alkyloxy units. 
     
     
         24 . The conjugate according to  claim 21 , wherein (AA) 1 -(AA) x  is a dipeptide, a tripeptide, a tetrapeptide or a pentapeptide. 
     
     
         25 . The conjugate according to  claim 21 , wherein:
 R 2  is selected from: 4-aminobenzyl, 4-(aminomethyl)benzyl, 4-(aminomethyl)phenyl, 4-aminophenyl, 3-aminophenyl, 4-(1-aminocyclopropyl)benzyl, 4-(1-aminocyclopropyl)phenyl, 2-aminophenyl, 4′-amino-[1,1′-biphenyl]-4-yl, 4-amino-2-ethylphenyl, 4-amino-2,3-dimethylphenyl, 4-amino-5,6,7,8-tetrahydronaphthalen-1-yl, 4-amino-3-methylphenyl, 4-amino-3-fluorophenyl, 4-amino-3-ethylphenyl and 4-amino-3-(trifluoromethyl)phenyl, and   R 4  and R 5  are each C 1 -C 6  alkyl.   
     
     
         26 . The conjugate according to  claim 14 , wherein (T) is an antibody or antigen-binding fragment. 
     
     
         27 . The conjugate according to  claim 26 , wherein the antibody or antigen-binding antibody fragment specifically binds a cancer cell antigen. 
     
     
         28 . The conjugate according to  claim 25 , wherein (T) is an antibody or antigen-binding fragment. 
     
     
         29 . The conjugate according to  claim 28 , wherein the antibody or antigen-binding antibody fragment specifically binds a cancer cell antigen. 
     
     
         30 . A pharmaceutical composition comprising a conjugate according to  claim 14  and a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         31 . A method of treating cancer in a mammal comprising administering to a mammal in need thereof an effective amount of a conjugate according to  claim 14 . 
     
     
         32 . A method of inhibiting tumor growth in a mammal comprising administering to a mammal in need thereof an effective amount of a conjugate according to  claim 14 . 
     
     
         33 . A conjugate having the following structure (I):
   [(P) o -(L)] m -(T)   (Ia)
   wherein:   (L) is a linker;   (T) is an antibody or antigen-binding antibody fragment;   m is between 1 and 10;   o is between 1 and 20;   (P) is a compound of Formula XId:   
       
         
           
           
               
               
           
         
         wherein: 
         R 2  is —R″—NH—; 
         R″ is selected from optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted aryl; 
         R 4  and R 5  are each methyl, and 
         (L)-(T) has structure (III): 
       
       
         
           
           
               
               
           
         
         wherein: 
         each AA is independently an amino acid; 
         (AA) 1 -(AA) x  is a dipeptide, a tripeptide, a tetrapeptide or a pentapeptide; 
         (L′) is the remaining portion of linker (L), 
         the —NH— group bonded to R″ in —R″—NH— forms a junction peptide bond (JPB) with (AA) 1  in structure (III), and 
         wherein (AA) 1 -(AA) x  taken together comprises an amino acid sequence that facilitates cleavage of the JPB.