Maytansinoid derivatives, conjugates thereof, and methods of use

Abstract

Provided herein are maytansinoid derivatives, conjugates thereof, and methods of treating or preventing proliferative diseases with the same.

1 - 62 . (canceled) 
     
     
         63 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein:
 A is arylene or heteroarylene; 
 L is a linker; 
 BA is a binding agent; and 
 k is an integer from 1 to 30. 
 
       
     
     
         64 . The compound of  claim 63 , wherein
 BA is an antibody or antigen binding fragment thereof; and   k is an integer from 1-6.   
     
     
         65 . The compound of  claim 64 , wherein 
       
         
           
           
               
               
           
         
         R 1 , independently at each occurrence, is alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl, aralkyl, halo, haloalkyl, haloalkoxy, heteroaryl, heterocycloalkyl, hydroxyl, cyano, nitro, 
       
       
         
           
           
               
               
           
         
       
       or azido,
 R A  is alkyl or heteroalkyl; 
 n is an integer from 0 to 4; 
 m is an integer from 0 to 3; 
 p is an integer from 0 to 6; and 
 q is an integer from 0 to 5. 
 
     
     
         66 . The compound of  claim 65 , wherein
 A is:   
       
         
           
           
               
               
           
         
         R 1  is halo, haloalkyl, alkoxy, alkyl, 
       
       
         
           
           
               
               
           
         
       
       —OH, heterocycloalkyl, or 
       
         
           
           
               
               
           
         
       
       and R A  is alkyl. 
     
     
         67 . The compound of  claim 66 , wherein A is 
       
         
           
           
               
               
           
         
       
     
     
         68 . The compound of  claim 66 , wherein A is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       is the bond linking A to the N atom, and 
       
         
           
           
               
               
           
         
       
       is the bond linking A to the carbonyl. 
     
     
         69 . The compound of  claim 64 , wherein
 L is   
       
         
           
           
               
               
           
         
         SP is a spacer; 
       
       
         
           
           
               
               
           
         
       
       is one or more bonds to the binding agent;
 R AA1  is an amino acid side chain; and 
 R AA2  is an amino acid side chain. 
 
     
     
         70 . The compound of  claim 69 , wherein R AA1  is 
       
         
           
           
               
               
           
         
       
       and R AA2  is 
       
         
           
           
               
               
           
         
       
     
     
         71 . The compound of  claim 69 , wherein
 SP is   
       
         
           
           
               
               
           
         
       
       is a bond to the antibody or antigen binding fragment thereof, 
       
         
           
           
               
               
           
         
       
       is a bond to a cysteine on the antibody or antigen binding fragment thereof;
 b is an integer from 2 to 8. 
 R N  is a hydrogen atom or alkyl; and 
 R M  is alkyl. 
 
     
     
         72 . The compound of  claim 64 , wherein
 L is   
       
         
           
           
               
               
           
         
         wherein: 
       
       
         
           
           
               
               
           
         
       
       is a bond to the antibody or antigen binding fragment thereof; and 
       
         
           
           
               
               
           
         
       
       is a bond to a cysteine on the antibody or antigen binding fragment thereof. 
     
     
         73 . The compound of  claim 64 , wherein the compound is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein t is an integer from 1 to 6; 
         Ab is an antibody or antigen binding fragment thereof; 
           S  is a bond to a cysteine on said antibody or fragment thereof; and 
           N  is a bond to a lysine on said antibody or fragment thereof. 
       
     
     
         74 . The compound of  claim 64 , wherein the antibody, or antigen binding fragment thereof, binds PSMA, MUC16, or PRLR. 
     
     
         75 . A pharmaceutical composition comprising the compound of  claim 63  and a pharmaceutically acceptable diluent, excipient, or carrier. 
     
     
         76 . A method for killing tumor cells comprising contacting the tumor cells with a compound of  claim 63  or a pharmaceutical composition of  claim 75 . 
     
     
         77 . A method for treating cancer in a patient comprising administering to a patient having said cancer a compound of  claim 63  or a pharmaceutical composition of  claim 75 . 
     
     
         78 . A compound of Formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein A is arylene or heteroarylene. 
       
     
     
         79 . A pharmaceutical composition comprising the compound of  claim 78  and a pharmaceutically acceptable diluent, excipient, or carrier. 
     
     
         80 . A method for killing tumor cells comprising contacting the tumor cells with a compound of  claim 78  or a pharmaceutical composition of  claim 79 . 
     
     
         81 . A method for treating cancer in a patient having the cancer comprising administering a compound of  claim 78  or a pharmaceutical composition of  claim 79 . 
     
     
         82 . A compound of Formula P1: 
       
         
           
           
               
               
           
         
         wherein A is arylene or heteroarylene and RL is a reactive linker. 
       
     
     
         83 . A process for preparing a compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         A is arylene or heteroarylene; 
         L is a linker; 
         BA is a binding agent; and 
         k is an integer from 1 to 30 
         comprising contacting a compound of Formula P1 
       
       
         
           
           
               
               
           
         
         wherein A is arylene or heteroarylene and RL is a reactive linker 
         with a binding agent.