Novel peptidic linkers and cryptophycin conjugates, their preparation and their therapeutic use

Abstract

wherein RCG1 represents a reactive chemical group being reactive towards a chemical group present on a polypeptide such as an antibody; P represents H, OH or an activated O; and L represents a specific linker. The disclosure also relates to cryptophycin payloads, as well as to cryptophycin conjugates, to compositions containing them and to their therapeutic use, especially as anticancer agents. The disclosure also relates to the process for preparing these conjugates.

1 . A Compound of formula (I):
   RCG1-L-P   (I)
   
       wherein
 RCG1 represents a reactive chemical group that is reactive towards a chemical group present on a polypeptide such as an antibody; 
 P represents a hydrogen atom, —OH or an activated O; 
 L represents a linker of formula (II): 
 
       
         
           
           
               
               
           
         
       
       wherein:
 L1 is of formula (III): 
 
       
         
           
           
               
               
           
         
       
       wherein:
 when P represents a hydrogen atom, then x=0 or 1 and y=1 and z=0; 
 when P represents —OH, then x=y=z=0; 
 when P represents an activated O, then x=1 and y=z=0, or x=y=z=1; 
 J 1 , J 2 , J 3  and J 4  are chosen, independently of each other, from CA 1  and N; 
 ALK represents a (C 1 -C 12 )alkylene group; 
 A 1 , A 2 , A 3 , A 4 , A 5 , and A 6  represent, independently of each other, a hydrogen atom or a (C 1 -C 6 )alkyl group; 
 (AA)w represents a sequence of w substituted amino acids (AA s ) or non-substituted amino acids (AA ns ) connected together via peptide bonds; 
 w represents an integer ranging from 1 to 12; 
 
       wherein:
 if (AA)w contains at least one substituted amino acid (AA s ), then L2 represents a single bond, a (C 1 -C 6 )alkyl group, a (C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group, a (C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i —O(C 1 -C 6 )alkyl group, a (CH 2 CH 2 O) i (C 1 -C 6 )alkyl group, a CH(SO 3 H)—(C 1 -C 6 )alkyl group, a (C 1 -C 6 )alkyl-CH(SO 3 H) group, a (C 1 -C 6 )alkyl-cyclohexyl group, a C(═O)—(C 1 -C 6 )alkyl group, a C(═O)—(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group, a C(═O)—(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i —O(C 1 -C 6 )alkyl group, a C(═O)—(CH 2 CH 2 O) i (C 1 -C 6 )alkyl group, a C(═O)—CH(SO 3 H)—(C 1 -C 6 )alkyl group, a C(═O)—(C 1 -C 6 )alkyl-CH(SO 3 H) group, a C(═O)—(C 1 -C 6 )alkyl-cyclohexyl group, a NA 8 -(C 1 -C 6 )alkyl group, a NA 8 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group, a NA 8 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i —O(C 1 -C 6 )alkyl group, a NA 8 -(CH 2 CH 2 O) i (C 1 -C 6 )alkyl group, a NA 8 -(C 1 -C 6 )alkyl-CH(SO 3 H) group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i —O(C 1 -C 6 )alkyl group, a C(═O)—NA 8 -(CH 2 CH 2 O) i (C 1 -C 6 )alkyl group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-CH(SO 3 H) group, a NA 7 -(C 1 -C 6 )alkyl group, a (C 1 -C 6 )alkyl-NA 7  group, a NA 7 -(CH 2 CH 2 O) i (C 1 -C 6 )alkyl group, a NA 7 -aryl group, a NA 7 -heteroaryl group, a (C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl group, a (C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group, a (C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl group, a (C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group, a (C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl group, a (C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group, a (C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i —NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—(C 1 -C 6 )alkyl-NA 7  group, a C(═O)—NA 7 -(CH 2 CH 2 O) i (C 1 -C 6 )alkyl group, a C(═O)—NA 7 -aryl group, a C(═O)—NA 7 -heteroaryl group, a C(═O)—(C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl group, a C(═O)—(C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group, a C(═O)—(C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—(C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group, a C(═O)—(C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—(C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group, a C(═O)—(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i —NA 7 -(C 1 -C 6 )alkyl group, a NA 8 -(C 1 -C 6 )alkyl-NA 7  group, a NA 8 -(C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl group, a NA 8 -(C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group, a NA 8 -(C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl group, a NA 8 -(C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group, a NA 8 -(C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl group, a NA 8 -(C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group, a NA 8 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i —NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-NA 7  group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group or a C(═O)—NA 8 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i —NA 7 -(C 1 -C 6 )alkyl group; 
 
       wherein:
 if (AA)w represents a sequence of w non-substituted amino acids (AA ns ), then L2 represents a NA 7 -(C 1 -C 6 )alkyl group, a (C 1 -C 6 )alkyl-NA 7  group, a NA 7 -(CH 2 CH 2 O) i (C 1 -C 6 )alkyl group, a NA 7 -aryl group, a NA 7 -heteroaryl group, a (C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl group, a (C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group, a (C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl group, a (C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group, a (C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl group, a (C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group, a (C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i —NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—(C 1 -C 6 )alkyl-NA 7  group, a C(═O)—NA 7 -(CH 2 CH 2 O) i (C 1 -C 6 )alkyl group, a C(═O)—NA 7 -aryl group, a C(═O)—NA 7 -heteroaryl group, a C(═O)—(C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl group, a C(═O)—(C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group, a C(═O)—(C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—(C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group, a C(═O)—(C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—(C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group, a C(═O)—(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i —NA 7 -(C 1 -C 6 )alkyl group, a NA 8 -(C 1 -C 6 )alkyl-NA 7  group, a NA 8 -(C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl group, a NA 8 -(C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group, a NA 8 -(C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl group, a NA 8 -(C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group, a NA 8 -(C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl group, a NA 8 -(C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group, a NA 8 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i —NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-NA 7  group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group or a C(═O)—NA 8 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i —NA 7 -(C 1 -C 6 )alkyl group; 
 A 7  represents a straight or branched, saturated or unsaturated, optionally substituted C 1 -C 160  hydrocarbon chain wherein optionally at least one methylene unit is independently replaced by —NHC(═O)—, —N(alkyl)C(═O)—, —C(═O)NH—, —C(═O)N(alkyl)-, —OC(═O)—, —C(═O)O—, —OC(═O)O—, —CH(OH)—, —CH(SO 3 H)—, —O—, —C(═O)—, —S(═O)—, —S(═O) 2 —, —NHS(═O) 2 —, —N(alkyl)S(═O) 2 —, —S(═O) 2 NH—, —S(═O) 2 N(alkyl)-, —P(═O)(OH)—, —P(═O)(OH)O—, —O—P(═O)(OH)—, —O—P(═O)(OH)—O— or a heterocycloalkyl group optionally substituted with at least one substituent, identical or different, chosen from —OH, —Oalkyl, -alkyl, a halogen atom, —NH 2 , —NHalkyl, and —N(alkyl) 2 , wherein —CH(SO 3 H)— is optionally the alkali metal salt; 
 A 8  represents a hydrogen atom or a (C 1 -C 6 )alkyl group; and 
 i represents an integer ranging from 1 to 50. 
 
     
     
         2 . The compound of formula (I) according to  claim 1 , wherein the sequence (AA)w of non-substituted amino acids (AA ns ) is selected from the following list: Gly-Gly, Phe-Lys, Val-Lys, Val-AcLys, Val-Cit, Phe-Phe-Lys, D-Phe-Phe-Lys, Gly-Phe-Lys, Ala-Lys, Val-Ala, Phe-Cit, Phe-Gly, Leu-Cit, Ile-Cit, Trp-Cit, Phe-Ala, Ala-Phe, Gly-Gly-Gly, Gly-Ala-Phe, Gly-Phe-Gly, Gly-Val-Cit, Gly-Phe-Leu-Cit, Gly-Phe-Leu-Gly, and Ala-Leu-Ala-Leu. 
     
     
         3 . The compound of formula (I) according to  claim 1 , wherein said substituted amino acids (AA s ) have the formula (VI): 
       
         
           
           
               
               
           
         
       
       wherein:
 T represents a saturated or unsaturated, linear or branched, (C 1 -C 8 ) trivalent alkyl group; 
 U group represents a single bond, —NHC(═O)—, —N(alkyl)C(═O)—, —C(═O)NH—, —C(═O)N(alkyl)-, —NHC(═O)NH—, —NHC(═NH)NH—, —OC(═O)—, —C(═O)O—, —OC(═O)O—, —S—, —Se—, —O—, —NH—, —N(alkyl)-, —C(═O)—, —OP(═O)—, —S(═O)—, —S(═O) 2 —, —NHS(═O) 2 —, —N(alkyl)S(═O) 2 —, —S(═O) 2 NH—, —S(═O) 2 N(alkyl)-, —P(═O)(OH)—, —P(═O)(OH)O—, —O—P(═O)(OH)—, or —O—P(═O)(OH)—O; 
 A 9  represents a straight or branched, saturated or unsaturated, optionally substituted C 1 -C 160  hydrocarbon chain wherein optionally at least one methylene unit is independently replaced by —NH—C(═O)—, —N(alkyl)C(═O)—, —C(═O)NH—, —C(═O)N(alkyl)-, —NHC(═O)NH—, —NHC(═NH)NH—, —OC(═O)—, —C(═O)O—, —OC(═O)O—, —CH(OH)—, —CH(SO 3 H)—, —CH(Oalkyl)-, —CHF—, —CF 2 —, —S—, —Se—, —O—, —NH—, —N(alkyl)-, —N + H(alkyl)-, —N + (alkyl) 2 -, —C(═O)—, —OP(═O)—, —S(═O)—, —S(═O) 2 —, —NHS(═O) 2 —, —N(alkyl)S(═O) 2 —, —S(═O) 2 NH—, —S(═O) 2 N(alkyl)-, —P(═O)(OH)—, —P(═O)(OH)O—, —O—P(═O)(OH)—, —O—P(═O)(OH)—O— or a heterocycloalkyl group optionally substituted with at least one substituent, identical or different, chosen from —OH, —Oalkyl, -alkyl, a halogen atom, —NH 2 , —NHalkyl, and —N(alkyl) 2 ; and 
 
       wherein —CH(SO 3 H)— is optionally the alkali metal salt. 
     
     
         4 . The compound of  claim 3 , wherein
 T represents   
       
         
           
           
               
               
           
         
         U represents —NH—C(═O)—, or —C(═O)NH—; 
         A 9  represents —[(CH 2 ) 2 —O] b —CH 3 ; and 
       
       wherein b represents an integer ranging from 1 to 50. 
     
     
         5 . The compound of formula (I) according to  claim 1 , wherein the sequence (AA s )w containing at least one substituted amino acid (AA s ), is selected from the list: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         6 . The compound of formula (I) according to  claim 1 , wherein (AA)w contains at least one substituted amino acid (AA s ) and L2 represents a (C 1 -C 6 )alkyl group, a —C(═O)—(C 1 -C 6 )alkyl group, or a (C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl group;
 wherein A 7  is a —C(═O)—(CH 2 ) 2 —C(═O)—NH—(CH 2 ) 2 —SO 3 H group; and
 wherein —CH(SO 3 H)— is optionally the alkali metal salt. 
 
 
     
     
         7 . The compound of formula (I) according to  claim 1 , wherein (AA)w contains w non-substituted amino acid (AA ns ) and L2 represents a (C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl group wherein A 7  represents a —C(═O)—[(CH 2 ) 2 —O] a —CH 3  group, a —C(═O)—(CH 2 )—C(═O)—NH—(CH 2 ) 2 —SO 3 H group,
 a —C(═O)—(CH 2 ) 2 —C(═O)—NH—[(CH 2 ) 2 —O] a —(CH 2 ) 2 —C(═O)—NH—(CH 2 ) 2 —SO 3 H group; 
 wherein “a” represents an integer ranging from 1 to 50; and
 wherein —CH(SO 3 H)— is optionally the alkali metal salt. 
 
 
     
     
         8 . The compound of formula (I) according to  claim 1 , wherein A 7  represents a —C(═O)—[(CH 2 ) 2 —O] 4 —CH 3  group,
 a —C(═O)—[(CH 2 ) 2 —O] 7 —CH 3  group, a —C(═O)—[(CH 2 ) 2 —O] 24 —CH 3  group; 
 a —C(═O)—(CH 2 ) 2 —C(═O)—NH—(CH 2 ) 2 —SO 3 H group, 
 a —C(═O)—(CH 22 —C(═O)—NH—[(CH 2 ) 2 —O—] 4 —(CH 2 ) 2 —C(═O)—NH—(CH 2 ) 2 —SO 3 H group; and
 wherein —CH(SO 3 H)— is optionally the alkali metal salt. 
 
 
     
     
         9 . The compound of formula (I) according to  claim 1 , wherein (AA)w contains at least one substituted amino acid up (AA s ) optionally a w non-substituted amino acid (AA ns ) and L2 represents: a NA 7 -(C 1 -C 6 )alkyl group, a (C 1 -C 6 )alkyl-NA 7  group, a NA 7 -(CH 2 CH 2 O) i (C 1 -C 6 )alkyl group, a NA 7 -aryl group, a NA 7 -heteroaryl group, a (C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl group, a (C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group, a (C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl group, a (C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group, a (C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl group, a (C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group, a (C 1 -C 6 )alkyl-(OCH 2 CH) i -NA 7 -(CH 2 CH 2 O) i (C 1 -C 6 )alkyl group, a C(═O)—NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—(C 1 -C 6 )alkyl-NA 7  group, a C(═O)—NA 7 -(CH 2 CH 2 O) i (C 1 -C 6 )alkyl group, a C(═O)—NA 7 -aryl group, a C(═O)—NA 7 -heteroaryl group, a C(═O)—(C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl group, a C(═O)—(C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group, a C(═O)—(C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—(C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group, a C(═O)—(C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—(C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group, a C(═O)—(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i —NA 7 -(C 1 -C 6 )alkyl group, a NA 8 -(C 1 -C 6 )alkyl-NA 7  group, a NA 8 -(C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl group, a NA 8 -(C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group, a NA 8 -(C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl group, a NA 8 -(C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group, a NA 8 -(C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl group, a NA 8 -(C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group, a NA 8 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i —NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-NA 7  group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i  group or a C(═O)—NA 8 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i —NA 7 -(C 1 -C 6 )alkyl group. 
     
     
         10 . The compound of formula (I) according to  claim 1 , wherein (AA)w contains at least one substituted amino acid (AA s ) optionally a w non-substituted amino acid (AA ns ) and L2 represents: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of formula (I) according to  claim 1 , wherein (AA)w contains at least one substituted amino acid (AA s ) optionally a w non-substituted amino acid (AA ns ) and L2 comprises an A 7  representing a C(═O)—[(CH 2 ) 2 —O] 4 —CH 3  group, a C(═O)—[(CH 2 ) 2 —O] 7 —CH 3  group, a C(═O)—[(CH 2 ) 2 —O] 24 —CH 3  group, a C(═O)—(CH 2 ) 2 —C(═O)—NH—(CH 2 ) 2 —SO 3 H group, a C(═O)—(CH 2 ) 2 —C(═O)—NH—[(CH 2 ) 2 —O] 4 —(CH 2 ) 2 —C(═O)—NH—(CH 2 ) 2 —SO 3 H group; and
 wherein —CH(SO 3 H)— is optionally the alkali metal salt. 
 
     
     
         12 . The compound of formula (I) according to  claim 1 , wherein L is selected from the following list: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         13 . The compound of formula (I) according to  claim 1 , wherein RCG1 is selected from a R a Z a —C(═O) reactive group wherein Z a  represents a single bond, —O— or —NH—, and R a  represents a hydrogen atom, a (C 1 -C 6 )alkyl group, a (C 3 -C 7 )cycloalkyl group, an alkenyl group, an aryl group, a heteroaryl group or a (C 3 -C 7 )heterocycloalkyl group, the aryl group, the heteroaryl group and/or the (C 3 -C 7 )heterocycloalkyl group being optionally substituted by 1 to 5 groups selected from a halogen atom, an alkyl group, an alkoxy group, a hydroxyl group, an oxo group, a nitro group and a cyano group; or wherein RCG1 is selected from a maleimido 
       
         
           
           
               
               
           
         
       
       group, a haloacetamido, 
       
         
           
           
               
               
           
         
       
       Cl—; N 3 —; HO—, HS—, 
       
         
           
           
               
               
           
         
       
       H 2 N—, HC≡C— group or an activated C≡C group, an O-alkyl hydroxylamine, or a Pictet-Spengler reaction substrate; and 
       wherein R 21  represents a hydrogen atom or (C 1 -C 6 )alkyl group. 
     
     
         14 . A Cryptophycin payload of formula (IV): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  represents a (C 1 -C 6 )alkyl group; 
 R 2  and R 3  represent, independently of each other, a hydrogen atom or a (C 1 -C 6 )alkyl group; 
 or alternatively R 2  and R 3  form together with the carbon atom to which they are attached, a (C 3 -C 6 )cycloalkyl or a (C 3 -C 6 )heterocycloalkyl group; 
 R 4  and R 5  represent, independently of each other, a hydrogen atom, a (C 1 -C 6 )alkyl group, a (C 1 -C 6 )alkyl-NH(R 12 ) group, a (C 1 -C 6 )alkyl-OH group, a (C 1 -C 6 )alkyl-SH group, or a (C 1 -C 6 )alkyl-CO 2 H group; 
 or alternatively R 4  and R 5  form together with the carbon atom to which they are attached a (C 3 -C 6 )cycloalkyl or a (C 3 -C 6 )heterocycloalkyl group; 
 X represents O or N(R 6 ); 
 R 6  represents a hydrogen atom or a (C 1 -C 6 )alkyl group; 
 R 7  and R 5  represent, independently of each other, a hydrogen atom, a (C 1 -C 6 )alkyl group, a (C 1 -C 6 )alkyl-CO 2 H group or a (C 1 -C 6 )alkyl-N(C 1 -C 6 )alkyl 2  group; 
 or alternatively R 7  and R 8  form together with the carbon atom to which they are attached a (C 3 -C 6 )cycloalkyl group or a (C 3 -C 6 )heterocycloalkyl group; 
 R 9  represents at least one substituent of the phenyl nucleus chosen, each independently of each other, a hydrogen atom, —OH, (C 1 -C 4 )alkoxy, a halogen atom, —NH 2 , —NH(C 1 -C 6 )alkyl or —N(C 1 -C 6 )alkyl 2  or —NH(C 1 -C 6 )cycloalkyl or (C 3 -C 6 )heterocycloalkyl group; 
 R 10  represents at least one substituent of the phenyl nucleus chosen from a hydrogen atom and a (C 1 -C 4 )alkyl group; 
 Y represents NR 11 —(C 1 -C 6 )alkyl-, —O—(C 1 -C 6 )alkyl-, or —S—(C 1 -C 6 )alkyl-; 
 R 11  and R 12  represent, independently of each other, a hydrogen atom or (C 1 -C 6 )alkyl; 
 n represents an integer ranging from 1 to 6; 
 L is defined as in formula (I) according to  claim 1  and represents a linker of formula (II) as defined in  claim 1 ; and 
 RCG1 represents a reactive chemical group present at the end of the linker L, RCG1 being reactive towards a chemical group present on a polypeptide such as an antibody. 
 
     
     
         15 . The Cryptophycin payload of formula (IV) according to  claim 14 , having the following structure: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , n, RCG 1 , X, Y and L are as defined in formula (IV) according to  claim 14 . 
 
     
     
         16 . The Cryptophycin payload of formula (IV) according to  claim 14  which are selected from the following list: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         17 . A conjugate of formula (V): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , n, X, Y and L are as defined in formula (IV) according to  claim 14 ; 
 G represents the product of reaction between RCG1 as defined in  claim 13 , a reactive chemical group present at the end of the linker L of formula (II) as defined in  claim 1 , and RCG2, an orthogonal reactive chemical group present on a polypeptide such as the antibody (Ab); and 
 Ab represents an antibody. 
 
     
     
         18 . The conjugate of formula (V) according to  claim 17 , having the following structure: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , n, X, Y, L, G, RCG1, RCG2 and Ab are as in formula (V) according to  claim 17 . 
 
     
     
         19 . The conjugate of formula (V) according to  claim 17 , wherein RCG2 is selected from an ε-amino groups of lysines borne by the side chains of the lysine residues that are present at the surface of an antibody, an α-amino groups of N-terminal amino acids of antibody heavy and light chains, the saccharide groups of the hinge region, the thiols of cysteines generated by reducing intra-chain disulfide bonds or the thiols of engineered cysteines, the) amide groups borne by the side chains of some glutamine residues that are present at the surface of an antibody, and aldehyde groups introduced using formylglycine generating enzyme. 
     
     
         20 . The conjugate of formula (V) according to  claim 17 , wherein:
 when RCG1 represents a N-hydroxysuccinimidyl ester, RCG2 represents a NH 2  group, or when RCG1 represents a maleimido function, a haloacetamido function, a chlorine atom or an activated disulfide, RCG2 represents a —SH group, or when RCG1 represents a N 3  group, RCG2 represents a C≡CH group or an activated C≡C group such as a cyclooctyne moiety, or when RCG1 represents a OH or NH 2  group, RCG2 represents a carboxylic acid or amide function, or when RCG1 represents a SH group, RCG2 represents a maleimido function, a haloacetamido function or an activated disulfide function, or when RCG1 represents a C≡CH group or an activated C≡C group, RCG2 represents a N 3  group, or when RCG1 represents a O-alkyl hydroxylamine function or a Pictet-Spengler reaction substrate, RCG2 represents an aldehyde or ketone function.   
     
     
         21 . The conjugate of formula (V) according to  claim 17 , wherein G is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         22 . The conjugate of formula (V) according to claim 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein Ab represents an antibody. 
     
     
         23 . A process for preparing a conjugate of formula (V) as defined in  claim 17  comprising at least the steps of:
 (i) placing in contact and leaving to react: an optionally buffered aqueous solution of an antibody, optionally modified by means of a modifying agent, and a solution of a cryptophycin payload of formula (IV), wherein the chemical group RCG1 of the cryptophycin payload of formula (IV) is reactive towards the chemical group RCG2 present on the polypeptide so as to attach the cryptophycin payload of formula (IV) to the antibody by formation of a covalent bond; and 
 (ii) optionally separating the conjugate formed in step (i) from the cryptophycin payload of formula (IV) and from the unreacted antibody and from any aggregates that may have formed. 
 
     
     
         24 . A medicament, wherein the medicament comprises a conjugate of formula (V). 
     
     
         25 . A pharmaceutical composition, wherein the composition comprises a conjugate of formula (III) and a pharmaceutically acceptable excipient. 
     
     
         26 . (canceled) 
     
     
         27 . A method of treating cancer in a patient in need thereof, comprising administering a therapeutically effect amount of a compound of formula (V).