The present disclosure relates to new peptidic linkers, to new cryptophycin payloads, to new cryptophycin conjugates, to compositions containing them and to their therapeutic use, such as for use as anticancer agents. The present disclosure also relates to the process for preparing these conjugates.

These linkers are enzymatically cleaved in the lysosome of cells, by enzymes such as Cathepsin B for example. Cathepsin B is a cysteine proteinase belonging to the papain family and one of the main lysosomal proteinases among mammals. It is involved in protein turnover and in the maintenance of cellular metabolism as well as in several other physiological or pathological processes, like for example tumoral progression. Its over-expression, both at the genetic and proteic levels, has been demonstrated in tumors, the increase of protein leading also to an increase of enzymatic activity. This was the basis of several prodrug approaches of chemotherapeutic agents (Int J Oncology 2013, 42, 373-383) but also of the conception of cleavable linkers for antibody-drug conjugates (ADC) (Bioconj Chem 2002, 13, 855-869). For ADC, one commonly used peptidic linker consists of the sequence Valine-Citrulline (ValCit) joined to the p-aminobenzylic alcohol self-immolative moeity (J Org Chem 2002, 67, 1866-1872), as examplified in WO2011/001052 with example 23. Associated to a cytotoxic drug, the subsequent construct is quite hydrophobic which can be challenging for achieving certain drug-to-antibody ratio (DAR), monomeric purity and ADC stability. Actually, despite extensive conjugation optimization, example 23 of WO2011/00152 couldn’t be successfully conjugated to provide an ADC with satisfactory DAR and monomeric purity, namely DAR > 2 and > 95% of monomers.

Since drugs used for ADC – like tubulin or DNA binders – are essentially hydrophobic, there was a need for more hydrophilic peptidic linkers to improve the solubility of the payload– a payload is a compound comprising the cytotoxic drug conjugated to a linker – and thus potentially its reactivity towards antibody conjugation and the stability of the subsequent ADC. Increasing payload solubility should allow to increase the DAR, the monomeric purityand ADC stability, especially in terms of aggregation propensity.

Summary of the disclosure

The disclosure relates to new peptidic compounds, chosen from compounds of formula (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 wherein an activated O is defined below.

■ 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;

■ J1, J2, J3 and J4 are chosen, independently of each other, from CA1 and N;

■ ALK represents a (C1-C12)alkylene group, for instance (C1-C6)alkylene, such as of the form -(CH2)n-, n being an integer ranging from 1 to 12 and for example ranging from 1 to 6;

■ A1, A2, A3, A4, A5, and A6 represent, independently of each other, a hydrogen atom or a (C1-C6)alkyl group, such as a hydrogen atom or a methyl group.

■ (AA)w represents a sequence of w substituted AAs or non-substituted amino acids AAns connected together via peptide bonds wherein substituted AAs or non-substituted AAns is defined below; ■ w represents an integer ranging from 1 to 12, for instance from 1 to 6, such as 2 or 3;

• if (AA)w contains at least one substituted amino acid AAs, then L2 represents a single bond, a (C1-C6)alkyl group, a (C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-(OCH2CH2)i-O(C1-C6)alkyl group, a (CH2CH2O)i(C1-C6)alkyl group, a CH(SO3H)-(C1-C6)alkyl group, a (C1-C6)alkyl-CH(SO3H) group, a (C1-C6)alkyl-cyclohexyl group, a C(=O)-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-(OCH2CH2)i-O(C1-C6)alkyl group, a C(=O)-(CH2CH2O)i(C1-C6)alkyl group, a C(=O)-CH(SO3H)-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-CH(SO3H) group, a C(=O)-(C1-C6)alkyl-cyclohexyl group, a NA8-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-(OCH2CH2)i-O(C1-C6)alkyl group, a NA8-(CH2CH2O)i(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-CH(SO3H) group, a C(=O)-NA8-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-(OCH2CH2)i-O(C1-C6)alkyl group, a C(=O)-NA8-(CH2CH2O)i(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-CH(SO3H) group, a NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7 group, a NA7-(CH2CH2O)i(C1-C6)alkyl group, a NA7-aryl group, a NA7-heteroaryl group, a (C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a C(=O)-NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7 group, a C(=O)-NA7-(CH2CH2O)i(C1-C6)alkyl group, a C(=O)-NA7-aryl group, a C(=O)-NA7-heteroaryl group, a C(=O)-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-(OCH2CH2)i-NA7- (C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7 group, a NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7 group, a C(=O)-NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group or a C(=O)-NA8-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group;

• if (AA)w represents a sequence of w non-substituted amino acids AAns, L2 represents a NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7 group, a NA7-(CH2CH2O)i(C1-C6)alkyl group, a NA7-aryl group, a NA7-heteroaryl group, a (C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a C(=O)-NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7 group, a C(=O)-NA7-(CH2CH2O)i(C1-C6)alkyl group, a C(=O)-NA7-aryl group, a C(=O)-NA7-heteroaryl group, a C(=O)-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7 group, a NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7 group, a C(=O)-NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group or a C(=O)-NA8-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group;

■ A7 representing a straight or branched, saturated or unsaturated, optionally substituted C1-C160 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(SO3H)-, -O- , -C(=O)-, -S(=O)-, -S(=O)2-, -NHS(=O)2-, -N(alkyl)S(=O)2-, -S(=O)2NH-, - SO2N(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, -NH2, -NHalkyl, and - N(alkyl)2;

being understood that each A7 comprising a SO3H function can be under salt forms such as alkali metal salts, for instance sodium salts (SO3- +Na);

■ A8 representing a hydrogen atom or a (C1-C6)alkyl group, for instance a hydrogen atom or a methyl group;

■ i representing an integer ranging from 1 to 50, for instance ranging from 1 to 35.

The disclosure further relates to cr to h cin a loads of formula (IV):

wherein:

■ R1 represents a (C1-C6)alkyl group;

■ R2 and R3 represent, independently of each other, a hydrogen atom or a (C1- C6)alkyl group;

or alternatively R2 and R3 form together with the carbon atom to which they are attached a (C3-C6)cycloalkyl or a (C3-C6)heterocycloalkyl group;

■ R4 and R5 represent, independently of each other, a hydrogen atom or a (C1- C6)alkyl group or a (C1-C6)alkyl-NH(R12) group or a (C1-C6)alkyl-OH group or a (C1- C6)alkyl-SH group or a (C1-C6)alkyl-CO2H group;

or alternatively R4 and R5 form together with the carbon atom to which they are attached a (C3-C6)cycloalkyl or a (C3-C6)heterocycloalkyl group;

■ X represents O or N(R6);

■ R6 represents a hydrogen atom or a (C1-C6)alkyl group;

■ R7 and R8 represent, independently of each other, a hydrogen atom or a (C1-C6)alkyl group or a (C1-C6)alkyl-CO2H group or a (C1-C6)alkyl-N(C1-C6)alkyl2 group; or alternatively R7 and R8 form together with the carbon atom to which they are attached a (C3-C6)cycloalkyl group or a (C3-C6)heterocycloalkyl group;

■ R9 represents at least one substituent of the phenyl nucleus chosen, independently of each other, from: a hydrogen atom, -OH, (C1-C4)alkoxy, a halogen atom, -NH2, -NH(C1-C6)alkyl, -N(C1-C6)alkyl2, -NH(C1-C6)cycloalkyl or (C3-C6)heterocycloalkyl;

■ R10 represents at least one substituent of the phenyl nucleus chosen from a hydrogen atom and a (C1-C4)alkyl group;

■ Y represents

■ -NR11-(C1-C6)alkyl-, such as -NR11-(CH2)n- like

■ -O-(C1-C6)alkyl-, such as -O-(CH2)n- like

■ -S-(C1-C6)alkyl-, such as -S-(CH2)n- like

Y being positioned in an ortho (o), meta (m) or para (p) position of the phenyl nucleus;

■ R11 and R12 represent, independently of each other, a hydrogen atom or (C1-C6)alkyl, such as a hydrogen atom or a methyl group;

■ n represents an integer ranging from 1 to 6.

■ L is defined as in formula (I) and represents a linker of formula (II);

■ RCG1 represents a reactive chemical group present at the end of the linker, RCG1 being reactive towards a chemical group present on a polypeptide such as an antibody.

The present disclosure further relates to conu ates of formula (V):

wherein:

■ R1, R2, R3, R4, R5, R6, R7, R8, R9 ,R10, R11 and R12 are as defined in formula (IV); ■ X, Y and L are as defined as in formula (IV);

■ G represents the product of reaction between RCG1, a reactive chemical group present at the end of the linker and RCG2, an orthogonal reactive chemical group present on the antibody (Ab);

■ Ab represents an antibody.

Each substituent R1 to R12 may also adopt one of the spatial configurations (e.g. R or S or alternatively Z or E) as described in the examples.

The compounds of formula (I), (II), (III), (IV) and (V) may contain at least one asymetric carbon atoms. They may therefore exist in the form of enantiomers or diastereoisomers. These enantiomers and diastereoisomers, and also mixtures thereof, including racemic mixtures, form part of this disclosure.

The compounds of formula (I), (II), (IV), including those that are illustrated, may exist in the form of bases or of acid-addition salts, for instance of pharmaceutically acceptable acids. For example, if these compounds comprise a SO3H function, they may exist in the form of SO3- alkali metal salts, such as of SO3- sodium salts (SO - 3 +Na).

Definitions

In the context of the present disclosure, certain terms have the following definitions: ■ alkenyl group: a hydrocarbon group obtained by removing one hydrogen atom from an alkene. The alkenyl group may be linear or branched. Examples that may

be mentioned include ethenyl (-CH=CH2, also named vinyl) and propenyl (-CH2-CH=CH2, also named allyl).

■ alkoxy group: a group -O-alkyl, in which the alkyl group is as defined below;

■ alkyl group: a linear or branched saturated aliphatic hydrocarbon-based group obtained by removing a hydrogen atom from an alkane. Examples that may be mentioned include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, 2,2-dimethylpropyl and hexyl groups;

■ alkylene group: a saturated divalent group of empirical formula -CnH2n-, obtained by removing two hydrogen atoms from an alkane. The alkylene group may be linear or branched. Examples that may be mentioned include methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-) and hexylene

(-CH2CH2CH2CH2CH2CH2-) groups or the following branched groups
,

;for instance, the alkylene group is of the formula -(CH2)n-, n representing an integer; in the ranges of values, the limits are included (e.g. a range of the type“n ranging from 1 to 6” or“ranging from1 to 6” includes limits 1 and 6);

■ antibody: an antibody with affinity for a biological target, such as a monoclonal antibody. The function of the antibody is to direct the biologically active compound as a cytotoxic compound towards the biological target. The antibody may be monoclonal, polyclonal or multispecific; it may also be an antibody fragment; it may also be a murine, chimeric, humanized or human antibody. An“antibody” may be a natural or conventional antibody in which two heavy chains are linked to each other by disulfide bonds and each heavy chain is linked to a light chain by a disulfide bond (also referred to as a“full-length antibody”). The terms“conventional (or full-length) antibody” refers both to an antibody comprising the signal peptide (or pro-peptide, if any), and to the mature form obtained upon secretion and proteolytic processing of the chain(s). There are two types of light chain, lambda (l) and kappa (k). There are five main heavy chain classes (or isotypes) which determine the functional activity of an antibody molecule: IgM, IgD, IgG, IgA and IgE. Each chain contains distinct sequence domains. The light chain includes two domains or regions, a variable domain (VL) and a constant domain (CL). The heavy chain includes four domains, a variable domain (VH) and three constant domains (CH1,

CH2 and CH3, collectively referred to as CH). The variable regions of both light (VL) and heavy (VH) chains determine binding recognition and specificity to the antigen. The constant region domains of the light (CL) and heavy (CH) chains confer important biological properties such as antibody chain association, secretion, trans-placental mobility, complement binding, and binding to Fc receptors (FcR). The Fv fragment is the N-terminal part of the Fab fragment of an immunoglobulin and consists of the variable portions of one light chain and one heavy chain. The specificity of the antibody resides in the structural complementarity between the antibody combining site and the antigenic determinant. Antibody combining sites are made up of residues that are primarily from the hypervariable or complementarity determining regions (CDRs). Occasionally, residues from nonhypervariable or framework regions (FR) influence the overall domain structure and hence the combining site. CDRs refer to amino acid sequences which together define the binding affinity and specificity of the natural Fv region of a native immunoglobulin binding site. The light and heavy chains of an immunoglobulin each have three CDRs, designated CDR1-L, CDR2-L, CDR3-L and CDR1-H, CDR2-H, CDR3-H, respectively. A conventional antibody antigen-binding site, therefore, includes six CDRs, comprising the CDR set from each of a heavy and a light chain V region.

As used herein, the term“antibody” denotes both conventional (full-length) antibodies and fragments thereof, as well as single domain antibodies and fragments thereof, such as variable heavy chain of single domain antibodies. Fragments of (conventional) antibodies typically comprise a portion of an intact antibody, such as the antigen binding region or variable region of the intact antibody, and retain the biological function of the conventional antibody. Examples of such fragments include Fv, Fab, F(ab')2, Fab', dsFv, (dsFv)2, scFv, sc(Fv)2, nanobodies and diabodies.

The function of the antibody is to direct the biologically active compound as a cytotoxic compound towards the biological target.

■ aryl group: a cyclic aromatic group containing ranging from 5 to 10 carbon atoms. Examples of aryl groups include phenyl, tolyl, xylyl, naphthyl;

■ biological target: an antigen (or group of antigens) for instance located at the surface of cancer cells or stromal cells associated with this tumour; these antigens may be, for example, a growth factor receptor, an oncogene product or a mutated “tumor suppressant” gene product, an angiogenesis-related molecule or an adhesion molecule;

■ conjugate: an antibody-drug conjugate or ADC, i.e. a polypeptide such as an antibody to which is covalently attached via a linker at least one molecule of a cytotoxic compound;

■ cycloalkyl group: a cyclic alkyl group comprising carbon atoms ranging from 3 and 6 engaged in the cyclic structure. Examples that may be mentioned include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups;

■ DAR (drug-to-antibody ratio): an average number of cytotoxic molecules attached via a linker to an antibody;

■ halogen: any of the four elements fluorine, chlorine, bromine and iodine;

■ heteroaryl group: an aryl group containing carbon atoms ranging from 2 to 10 and heteroatoms ranging from 1 to 5 such as nitrogen, oxygen or sulphur engaged in the ring and connected to the carbon atoms forming the ring. Examples of heteroaryl groups include pyridyl, pyrimidyl, thienyl, imidazolyl, triazolyl, indolyl, imidazo-pyridyl, pyrazolyl;

■ heterocycloalkyl group: a cycloalkyl group containing carbon atoms ranging from 2 to 8 and heteroatoms ranging from 1 to 3, such as nitrogen, oxygen or sulphur engaged in the ring and connected to the carbon atoms forming the ring. Examples include aziridinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, azetidinyl, oxetanyl and pyranyl;

■ linker: a group of atoms or a single bond that can covalently attach a cytotoxic compound to a polypeptide such as an antibody in order to form a conjugate;

■ payload: a cytotoxic compound to which is covalently attached a linker;

■ reactive chemical group: a group of atoms that can promote or undergo a chemical reaction;

Further, as stated throughout the present disclosure, a SO3H function can be under salt forms such as alkali metal salts, for instance sodium salts (SO3- +Na).

Abbreviations

ADC: antibody-drug conjugate; ALK: (C1-C12)alkylene group, for instance (C1-C6)alkylene, such as of the form -(CH2)n-, n being an integer ranging from 1 to 12 and for example ranging from 1 to 6; aq.: aqueous; Ar: argon ; AUC: area under the curve; BCN: (1α,8α,9β)-bicyclo[6.1.0]non-4-yne-9-methanol; CHCl3: chloroform; CH3CN: acetonitrile; CO2: carbon dioxide; CR: complete response; crypto denotes

the unit of formula
crypto for instance denoting a cryptophycin compound of an example, one of the D1-D8 cryptophycin compounds described in WO2011/001052 or one of the D1-D19 cryptophycin compounds below as described in PCT/EP2016/076603:

■ wherein W represents

■ (C1-C6)alkyl-NH(R11), such as (CH2)nNHR11; ■ (C1-C6)alkyl-OH, such as (CH2)nOH;

■ (C1-C6)alkyl-SH, such as (CH2)nSH;

■ CO2H or C(=O)NH2;

■ (C1-C6)alkyl-CO2H or (C1-C6)alkyl-C(=O)NH2; or

■ (C1-C6)alkyl-N3.

W is positioned in an ortho (o), meta (m) or para (p) position of the phenyl nucleus;

■ R11 represents, independently of each other, a hydrogen atom or a group (C1- C6)alkyl, for instance a hydrogen atom or a methyl group;

■ n represents an integer ranging from 1 to 6;

d: day; DAR : drug-to-antibody ratio (D1 refers to an ADC with a DAR of 1, D2 to an ADC with a DAR of 2, etc.); DBCO: dibenzylcyclooctyne; DCC: N,N’-dicyclohexylcarbodiimide; DCM: dichloromethane; DIEA: N,N-diisopropylethylamine; DMA: dimethylacetamide; DMAP : 4-(dimethylamino)pyridine; DMEM: Dulbecco's Modified Eagle Medium; DMEM/F12: Dulbecco's Modified Eagle Medium Nutrient Mixture F-12; DMF: dimethylformamide; DMSO: dimethylsulfoxide; DPBS: Dulbecco’s phosphate-buffered saline; DSC: N,N′-disuccinimidyl carbonate; EDC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide; EDTA: ethylenediaminetetraacetic acid; EEDQ: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; ELSD: evaporating light scattering detector; eq.: equivalent; ES: electrospray; EtOAc: ethyl acetate; Et2O: diethyl ether; Ex.: example; FCS: foetal calf serum; Fmoc: 9-fluorenylmethoxycarbonyl; GI: electroinductive group; h: hour; H2O: water; Hal: halogen; HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate; HCl: chlorohydric acid; HEPES: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; HIC: hydrophobic interaction chromatography; HOAt: 1-hydroxy-7-azabenzotriazole; HOBt: 1-hydroxy-benzotriazole; HPLC: high performance liquid chromtography; HRMS: high resolution mass spectrometry; IC50: median inhibitory concentration; i.e.: id est meaning that is; IEC: ion exchange chromatography; iPrOH: 2-propanol; iPr2O: diisopropyl ether; i.v.: intravenous; MeCN: acetonitrile; MeOH: methanol; MeTHF: 2-methyl-tetrahydrofuran; MFCO: 1-fluoro-2-cyclooctyne-1-carboxylic acid; MgSO4: magnesium sulfate; min: minute; MsCl: methanesulfonyl chloride; MTBE: methyl tert-butyl ether; MTD: maximum tolerated dose; NaH: sodium hydride; NaCl: sodium chloride; NaHCO3: sodium hydrogen carbonate; n.d.: not determined; NHS: N-hydroxysuccinimide; NMP: 1-methyl-2-pyrrolidone; NMR: nuclear magnetic resonance; PABA: para-aminobenzyl alcohol; PBS: phosphate-buffered saline; PEG: polyethylene glycol; PNGase F:

Peptide-N-Glycosidase F; ppm: parts per million; PR: partial response; QS: quantum satis meaning the amount what is needed; Q-Tof: quadrupole time-of-flight; quant.: quantitative yield; RCG: reactive chemical group; RT: room temperature; sat.: saturated; s.c.: subcutaneously; SCID: severe combined immunodeficiency; SEC: size exclusion chromatography; T3P: propylphosphonic anhydride; TBAF: tetrabutylammonium fluoride; TFA: trifluoroacetic acid; TFS: tumor-free survivor; THF: tetrahydrofuran; TLC: thin layer chromatography; t1/2: half-life; tR: retention time; UPLC: Ultra Performance Liquid Chromatography; UV: ultra-violet.

Figures

Figure 1: In vivo efficacy of Ex.6 against MDA-MB-231 xenograft in SCID mice Figure 2: In vivo efficacy of Ex.16, Ex.19, Ex.23 and Ex.32 against MDA-MB-231 xenograft in SCID mice at 2.5 mg/kg

Figure 3: In vivo efficacy of Ex.16, Ex.19, Ex.23 and Ex.32 against MDA-MB-231 xenograft in SCID mice at 1.25 mg/kg

Figure 4: In vivo efficacy of Ex.26 against MDA-MB-231 xenograft in SCID mice Figure 5: In vivo efficacy of Ex.29 against MDA-MB-231 xenograft in SCID mice Figure 6: In vivo efficacy of Ex.35 against MDA-MB-231 xenograft in SCID mice Figure 7: In vivo efficacy of Ex.41 against MDA-MB-231 xenograft in SCID mice

Detailed description of the present disclosure

The disclosure relates to new peptidic compounds, chosen from compounds 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;

■ L represents a linker of formula (II) as defined below;

■ P represents a hydrogen atom, -OH or an activated O.

Examples of activated O that may be mentioned include (O-NHS),

where cation represents for example sodium, potassium or cesium;

or,
group in which GI represents at least one electroinductive group such as -NO2 or a halogen atom (-Hal), for instance a

fluorine atom -F . They may be, for example, the following groups:

The linker L which is present in formula (I) is 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;

■ J1, J2, J3 and J4 are chosen, independently of each other, from CA1 and N;

■ ALK represents a (C1-C12)alkylene group, for instance (C1-C6)alkylene, such as of the form -(CH2)n-, n being an integer ranging from 1 to 12 and for example ranging from 1 to 6;

■ A1, A2, A3, A4, A5, and A6 represent, independently of each other, a hydrogen atom or a (C1-C6)alkyl group, such as a hydrogen atom or a methyl group.

■ (AA)w represents a sequence of w substituted AAs or non-substituted amino acids AAns connected together via peptide bonds wherein substituted AAs or non-substituted AAns is defined below; ■ w represents an integer ranging from 1 to 12, for instance from 1 to 6, such as 2 or 3;

• if (AA)w contains at least one substituted amino acid AAs, then L2 represents:

a single bond, a (C1-C6)alkyl group, a (C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-(OCH2CH2)i-O(C1-C6)alkyl group, a (CH2CH2O)i(C1-C6)alkyl group, a CH(SO3H)-(C1-C6)alkyl group, a (C1-C6)alkyl-CH(SO3H) group, a (C1-C6)alkyl-cyclohexyl group, a C(=O)-(C1-C6)alkyl group, a
group, a C(=O)-(C1-C6)alkyl-(OCH2CH2)i-O(C1-C6)alkyl group, a C(=O)- (CH2CH2O)i(C1-C6)alkyl group, a C(=O)-CH(SO3H)-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-CH(SO3H) group, a C(=O)-(C1-C6)alkyl-cyclohexyl group, a NA8-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-(OCH2CH2)i-O(C1-C6)alkyl group, a NA8-(CH2CH2O)i(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-CH(SO3H) group, a C(=O)-NA8-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-(OCH2CH2)i-O(C1-C6)alkyl group, a C(=O)-NA8-(CH2CH2O)i(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-CH(SO3H) group, a NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7 group, a NA7-(CH2CH2O)i(C1-C6)alkyl group, a NA7-aryl group, a NA7-heteroaryl group, a (C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl

group, a (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a C(=O)-NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7 group, a C(=O)-NA7-(CH2CH2O)i(C1-C6)alkyl group, a C(=O)-NA7-aryl group, a C(=O)-NA7-heteroaryl group, a C(=O)-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7 group, a NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7 group, a C(=O)-NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group or a C(=O)-NA8-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group;

• if (AA)w represents a sequence of w non-substituted amino acids AAns, then L2 represents:

a NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7 group, a NA7-(CH2CH2O)i(C1-C6)alkyl group, a NA7-aryl group, a NA7-heteroaryl group, a (C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a C(=O)-NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7 group, a C(=O)-NA7-(CH2CH2O)i(C1-C6)alkyl group, a C(=O)-NA7-aryl group, a C(=O)-NA7-heteroaryl group, a C(=O)-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a

C(=O)-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7 group, a NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7 group, a C(=O)-NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group or a C(=O)-NA8-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group;

■ A7 representing a straight or branched, saturated or unsaturated, optionally substituted C1-C160 hydrocarbon chain wherein optionally at least one methylene unit is independently replaced by -NHCO-, -N(alkyl)C(=O)-, -C(=O)NH-, - C(=O)N(alkyl)-, -OC(=O)-, -C(=O)O-, -OC(=O)O-, -CH(OH)-, -CH(SO3H)-, -O-, - C(=O)-, -S(=O)-, -S(=O)2-, -NHS(=O)2-, -N(alkyl)S(=O)2-, -S(=O)2NH-, - S(=O)2N(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, -NH2, - NHalkyl, and -N(alkyl)2; being understood that each A7 comprising a SO3H function can be under salt forms such as alkali metal salts, for instance sodium salts (SO - 3 +Na).

■ A8 representing a hydrogen atom or a (C1-C6)alkyl group, for instance a hydrogen atom or a methyl group;

■ i representing an integer ranging from1 to 50, such as ranging from 1 to 35.

According to a particular embodiment, the disclosure relates to compounds of formula (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;

■ J1, J2, J3 and J4 are chosen, independently of each other, from CA1 and N;

■ ALK represents a (C1-C12)alkylene group, for instance (C1-C6)alkylene, such as of the form -(CH2)n-, n being an integer ranging from 1 to 12 and for example ranging from 1 to 6;

■ A1, A2, A3, A4, A5, and A6 represent, independently of each other, a hydrogen atom or a (C1-C6)alkyl group, such as a hydrogen atom or a methyl group.

■ (AA)w represents a sequence of w substituted AAs or non-substituted amino acids AAns connected together via peptide bonds;

■ w represents an integer ranging from 1 to 12, for instance from 1 to 6, such as 2 or 3;

• if (AA)w contains at least one substituted amino acid AAs, then L2 represents a single bond, a (C1-C6)alkyl group, a (C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-(OCH2CH2)i-O(C1-C6)alkyl group, a (CH2CH2O)i(C1-C6)alkyl group, a CH(SO3H)-(C1-C6)alkyl group, a (C1-C6)alkyl-CH(SO3H) group, a (C1-C6)alkyl-cyclohexyl group, a C(=O)-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-(OCH2CH2)i-O(C1-C6)alkyl group, a C(=O)-(CH2CH2O)i(C1-C6)alkyl group, a C(=O)-CH(SO3H)-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-CH(SO3H) group, a C(=O)-(C1-C6)alkyl-cyclohexyl group, a NA8-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-(OCH2CH2)i-O(C1-C6)alkyl group, a NA8-(CH2CH2O)i(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-CH(SO3H) group, a C(=O)-NA8-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-(OCH2CH2)i-O(C1-C6)alkyl group, a C(=O)-NA8-(CH2CH2O)i(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-CH(SO3H) group, a NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7 group, a NA7-(CH2CH2O)i(C1-C6)alkyl group, a NA7-aryl group, a NA7-heteroaryl group, a (C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a C(=O)-NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7 group, a C(=O)-NA7-(CH2CH2O)i(C1-C6)alkyl group, a C(=O)-NA7-aryl group, a C(=O)-NA7-heteroaryl group, a C(=O)-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7 group, a NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7 group, a C(=O)-NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i

group, a C(=O)-NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group or a C(=O)-NA8-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group;

• if (AA)w represents a sequence of w non-substituted amino acids AAns, then L2 represents a NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7 group, a NA7-(CH2CH2O)i(C1-C6)alkyl group, a NA7-aryl group, a NA7-heteroaryl group, a (C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a C(=O)-NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7 group, a C(=O)-NA7-(CH2CH2O)i(C1-C6)alkyl group, a C(=O)-NA7-aryl group, a C(=O)-NA7-heteroaryl group, a C(=O)-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7 group, a NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7 group, a C(=O)-NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group or a C(=O)-NA8-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group;

■ A7 representing a straight or branched, saturated or unsaturated, optionally substituted C1-C160 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(SO3H)- , -O-, - C(=O)-, -S(=O)-, -S(=O)2-, -NHS(=O)2-, -N(alkyl)S(=O)2-, -S(=O)2NH-, -

S(=O)2N(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, -NH2, - NHalkyl, and -N(alkyl)2, being understood that each A7 comprising a SO3H function can be under salt forms such as alkali metal salts, for instance sodium salts (SO3- +Na);

■ A8 representing a hydrogen atom or a (C1-C6)alkyl group, for instance a hydrogen atom or a methyl group;

■ i representing an integer ranging from 1 to 50, for instance ranging from 1 to 35, ■ a non-substituted amino acid AAns denoting natural or non-natural amino acid, of configuration D or L, identical to or derived from: alanine (Ala), β-alanine, γ- aminobutyric acid, 2-amino-2-cyclohexylacetic acid, 2-amino-2-phenylacetic acid, arginine (Arg), asparagine (Asn), aspartic acid (Asp), citrulline (Cit), cysteine (Cys), α,α-dimethyl-γ-aminobutyric acid, β,β-dimethyl-γ-aminobutyric acid, glutamine (Gln), glutamic acid (Glu), glycine (Gly), homo-cysteine, selenocysteine, homo- selenocysteine, histidine (His), isoleucine (Ile), leucine (Leu), lysine (Lys), ε-acetyl- lysine (AcLys), methionine (Met), ornithine (Orn), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr), and valine (Val).

According to another particular embodiment, the disclosure relates to compounds of formula (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;

■ J1, J2, J3 and J4 are chosen, independently of each other, from CA1 and N;

■ ALK represents a (C1-C12)alkylene group, for instance (C1-C6)alkylene, such as of the form -(CH2)n-, n being an integer ranging from 1 to 12 and for example ranging from 1 to 6;

■ A1, A2, A3, A4, A5, and A6 represent, independently of each other, a hydrogen atom or a (C1-C6)alkyl group, such as a hydrogen atom or a methyl group.

■ (AA)w represents a sequence of w substituted AAs or non-substituted amino acids AAns connected together via peptide bonds; ■ w represents an integer ranging from 1 to 12, for instance from 1 to 6, such as 2 or 3;

• if (AA)w contains at least one substituted amino acid AAs, then L2 represents a single bond, a (C1-C6)alkyl group, a (C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-(OCH2CH2)i-O(C1-C6)alkyl group, a (CH2CH2O)i(C1-C6)alkyl group, a CH(SO3H)-(C1-C6)alkyl group, a (C1-C6)alkyl-CH(SO3H) group, a (C1-C6)alkyl-cyclohexyl group, a C(=O)-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-(OCH2CH2)i-O(C1-C6)alkyl group, a C(=O)-(CH2CH2O)i(C1-C6)alkyl group, a C(=O)-CH(SO3H)-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-CH(SO3H) group, a C(=O)-(C1-C6)alkyl-cyclohexyl group, a NA8-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-(OCH2CH2)i-O(C1-C6)alkyl group, a NA8-

(CH2CH2O)i(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-CH(SO3H) group, a C(=O)-NA8-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-(OCH2CH2)i-O(C1-C6)alkyl group, a C(=O)-NA8-(CH2CH2O)i(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-CH(SO3H) group, a NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7 group, a NA7-(CH2CH2O)i(C1-C6)alkyl group, a NA7-aryl group, a NA7-heteroaryl group, a (C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a C(=O)-NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7 group, a C(=O)-NA7-(CH2CH2O)i(C1-C6)alkyl group, a C(=O)-NA7-aryl group, a C(=O)-NA7-heteroaryl group, a C(=O)-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7 group, a NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7 group, a C(=O)-NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group or a C(=O)-NA8-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group;

• if (AA)w represents a sequence of w non-substituted amino acids AAns, then L2 represents a NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7 group, a NA7-(CH2CH2O)i(C1-C6)alkyl group, a NA7-aryl group, a NA7-heteroaryl group, a (C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-(OCH2CH2)i-NA7-(C1- C6)alkyl group, a C(=O)-NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7 group, a C(=O)-NA7-(CH2CH2O)i(C1-C6)alkyl group, a C(=O)-NA7-aryl group, a C(=O)-NA7-heteroaryl group, a C(=O)-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7 group, a NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7 group, a C(=O)-NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group or a C(=O)-NA8-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group;

■ A7 representing a straight or branched, saturated or unsaturated, optionally substituted C1-C160 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(SO3H)- , -O-, - C(=O)-, -S(=O)-, -S(=O)2-, -NHS(=O)2-, -N(alkyl)S(=O)2-, -S(=O)2NH-, - S(=O)2N(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, -NH2, - NHalkyl, and -N(alkyl)2, being understood that each A7 comprising a SO3H function can be under salt forms such as alkali metal salts, for instance sodium salts (SO - 3 +Na);

■ A8 representing a hydrogen atom or a (C1-C6)alkyl group, for instance a hydrogen atom or a methyl group;

■ i representing an integer ranging from 1 to 50, for instance ranging from 1 to 35, wherein said substituted amino acids AAs have the formula (VI):

wherein:

■ T represents a saturated or unsaturated, linear or branched, (C1-C8) trivalent

alkyl group, preferably T is

■ 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)2NH-, -S(=O)2N(alkyl)-, - P(=O)(OH)-, -P(=O)(OH)O-, -O-P(=O)(OH)-, or -O-P(=O)(OH)-O, such as U group represents -NH-C(=O)-, or -C(=O)NH-;

■ A9 represents a straight or branched, saturated or unsaturated, optionally substituted C1-C160 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(SO3H)-, -CH(Oalkyl)-, -CHF-, -CF2-, - 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)2NH-, -S(=O)2N(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, -NH2, - NHalkyl, and -N(alkyl)2, for instance A9 is–[(CH2)2-O]4-CH3, -[(CH2)2-O]24-CH3,

or -[(CH2)2-O)]4-(CH2)2-C(=O)-NH-(CH2)2-SO3H;

being understood that each A9 comprising a SO3H function can be under salt forms such as alkali metal salts, for instance sodium salts (SO3- +Na).

According to another particular embodiment, the disclosure relates to compounds of formula (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;

■ J1, J2, J3 and J4 are chosen, independently of each other, from CA1 and N;

■ ALK represents a (C1-C12)alkylene group, for instance (C1-C6)alkylene, such as of the form -(CH2)n-, n being an integer ranging from 1 to 12 and for example ranging from 1 to 6;

■ A1, A2, A3, A4, A5, and A6 represent, independently of each other, a hydrogen atom or a (C1-C6)alkyl group, such as a hydrogen atom or a methyl group.

■ (AA)w represents a sequence of w substituted AAs or non-substituted amino acids AAns connected together via peptide bonds; ■ w represents an integer ranging from 1 to 12, for instance from 1 to 6, such as 2 or 3;

• if (AA)w contains at least one substituted amino acid AAs, then L2 represents a single bond, a (C1-C6)alkyl group, a (C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-(OCH2CH2)i-O(C1-C6)alkyl group, a (CH2CH2O)i(C1-C6)alkyl group, a CH(SO3H)-(C1-C6)alkyl group, a (C1-C6)alkyl-CH(SO3H) group, a (C1-C6)alkyl-cyclohexyl group, a C(=O)-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-(OCH2CH2)i-O(C1-C6)alkyl group, a C(=O)-(CH2CH2O)i(C1-C6)alkyl group, a C(=O)-CH(SO3H)-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-CH(SO3H) group, a C(=O)-(C1-C6)alkyl-cyclohexyl group, a NA8-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-(OCH2CH2)i-O(C1-C6)alkyl group, a NA8-(CH2CH2O)i(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-CH(SO3H) group, a C(=O)-NA8-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-(OCH2CH2)i-O(C1-C6)alkyl group, a C(=O)-NA8-(CH2CH2O)i(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-CH(SO3H) group, a NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7 group, a NA7-(CH2CH2O)i(C1-C6)alkyl group, a NA7-aryl group, a NA7-heteroaryl group, a (C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a C(=O)-NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7 group, a C(=O)-NA7-(CH2CH2O)i(C1-C6)alkyl group, a C(=O)-NA7-aryl group, a C(=O)-NA7-heteroaryl group, a C(=O)-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7 group, a NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a NA8- (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7 group, a C(=O)-NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group or a C(=O)-NA8-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group;

• if (AA)w represents a sequence of w non-substituted amino acids AAns, then L2 represents a NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7 group, a NA7-(CH2CH2O)i(C1-C6)alkyl group, a NA7-aryl group, a NA7-heteroaryl group, a (C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a C(=O)-NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7 group, a C(=O)-NA7-(CH2CH2O)i(C1-C6)alkyl group, a C(=O)-NA7-aryl group, a C(=O)-NA7-heteroaryl group, a C(=O)-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7 group, a NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7 group, a C(=O)-NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group or a C(=O)-NA8-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group;

■ A7 representing a straight or branched, saturated or unsaturated, optionally substituted C1-C160 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(SO3H)- , -O-, - C(=O)-, -S(=O)-, -S(=O)2-, -NHS(=O)2-, -N(alkyl)S(=O)2-, -S(=O)2NH-, - S(=O)2N(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, -NH2, - NHalkyl, and -N(alkyl)2, being understood that each A7 comprising a SO3H function can be under salt forms such as alkali metal salts, for instance sodium salts (SO3- +Na);

■ A8 representing a hydrogen atom or a (C1-C6)alkyl group, for instance a hydrogen atom or a methyl group;

■ i representing an integer ranging from 1 to 50, for instance ranging from 1 to 35, wherein said substituted amino acids AAs have the formula (VI):

wherein:

■ T represents a saturated or unsaturated, linear or branched, (C1-C8) trivalent

alkyl group, preferably T is

■ 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)2NH-, -S(=O)2N(alkyl)-, - P(=O)(OH)-, -P(=O)(OH)O-, -O-P(=O)(OH)-, or -O-P(=O)(OH)-O, such as U group represents -NH-C(=O)-, or -C(=O)NH-;

■ A9 represents a straight or branched, saturated or unsaturated, optionally substituted C1-C160 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(=NH)NH-, -OC(=O)-, -C(=O)O-, -OC(=O)O-, -CH(OH)-, -CH(SO3H)-, -CH(Oalkyl)-, -CHF-, -CF2-, -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)2NH-, -S(=O)2N(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, -NH2, -NHalkyl, and - N(alkyl)2, for instance A9 is –[(CH2)2-O]4-CH3, -[(CH2)2-O]24-CH3,

or -[(CH2)2-O)]4-(CH2)2-C(=O)-NH-(CH2)2-SO3H;

being understood that each A9 comprising a SO3H function can be under salt forms such as alkali metal salts, for instance sodium salts (SO3- +Na).

According to another particular embodiment, the disclosure relates to compounds of formula (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;

■ J1, J2, J3 and J4 are chosen, independently of each other, from CA1 and N;

■ ALK represents a (C1-C12)alkylene group, for instance (C1-C6)alkylene, such as of the form -(CH2)n-, n being an integer ranging from 1 to 12 and for example ranging from 1 to 6;

■ A1, A2, A3, A4, A5, and A6 represent, independently of each other, a hydrogen atom or a (C1-C6)alkyl group, such as a hydrogen atom or a methyl group.

■ (AA)w represents a sequence of w substituted AAs or non-substituted amino acids AAns connected together via peptide bonds; ■ w represents an integer ranging from 1 to 12, for instance from 1 to 6, such as 2 or 3;

• if (AA)w contains at least one substituted amino acid AAs, then L2 represents a single bond, a (C1-C6)alkyl group, a (C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-(OCH2CH2)i-O(C1-C6)alkyl group, a (CH2CH2O)i(C1-C6)alkyl group, a CH(SO3H)-(C1-C6)alkyl group, a (C1-C6)alkyl-CH(SO3H) group, a (C1-C6)alkyl-cyclohexyl group, a C(=O)-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-(OCH2CH2)i-O(C1-C6)alkyl group, a C(=O)-(CH2CH2O)i(C1-C6)alkyl group, a C(=O)-CH(SO3H)-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-CH(SO3H) group, a C(=O)-(C1-C6)alkyl-cyclohexyl group, a NA8-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-(OCH2CH2)i-O(C1-C6)alkyl group, a NA8-

(CH2CH2O)i(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-CH(SO3H) group, a C(=O)-NA8-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-(OCH2CH2)i-O(C1-C6)alkyl group, a C(=O)-NA8-(CH2CH2O)i(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-CH(SO3H) group, a NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7 group, a NA7-(CH2CH2O)i(C1-C6)alkyl group, a NA7-aryl group, a NA7-heteroaryl group, a (C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a C(=O)-NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7 group, a C(=O)-NA7-(CH2CH2O)i(C1-C6)alkyl group, a C(=O)-NA7-aryl group, a C(=O)-NA7-heteroaryl group, a C(=O)-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7 group, a NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7 group, a C(=O)-NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group or a C(=O)-NA8-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group;

• if (AA)w represents a sequence of w non-substituted amino acids AAns, then L2 represents a NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7 group, a NA7-(CH2CH2O)i(C1-C6)alkyl group, a NA7-aryl group, a NA7-heteroaryl group, a (C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-(OCH2CH2)i-NA7-(C1- C6)alkyl group, a C(=O)-NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7 group, a C(=O)-NA7-(CH2CH2O)i(C1-C6)alkyl group, a C(=O)-NA7-aryl group, a C(=O)-NA7-heteroaryl group, a C(=O)-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7 group, a NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7 group, a C(=O)-NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group or a C(=O)-NA8-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group;

■ A7 representing a straight or branched, saturated or unsaturated, optionally substituted C1-C160 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(SO3H)- , -O-, - C(=O)-, -S(=O)-, -S(=O)2-, -NHS(=O)2-, -N(alkyl)S(=O)2-, -S(=O)2NH-, - S(=O)2N(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, -NH2, - NHalkyl, and -N(alkyl)2, being understood that each A7 comprising a SO3H function can be under salt forms such as alkali metal salts, for instance sodium salts (SO - 3 +Na);

■ A8 representing a hydrogen atom or a (C1-C6)alkyl group, for instance a hydrogen atom or a methyl group;

■ i representing an integer ranging from 1 to 50, for instance ranging from 1 to 35, wherein said substituted amino acids AAs have the formula (VI):

wherein:

■ T represents a saturated or unsaturated, linear or branched, (C1-C8) trivalent

alkyl group, preferably T is
;

■ 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)2NH-, -S(=O)2N(alkyl)-, - P(=O)(OH)-, -P(=O)(OH)O-, -O-P(=O)(OH)-, or -O-P(=O)(OH)-O, such as U group represents -NH-C(=O)-, or -C(=O)NH-;

■ A9 represents a straight or branched, saturated or unsaturated, optionally substituted C1-C160 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(=NH)NH-, -OC(=O)-, -C(=O)O-, -OC(=O)O-, -CH(OH)-, -CH(SO3H)-, -CH(Oalkyl)-, -CHF-, -CF2-, -S-, -Se-, -O-, -N(alkyl)-, - N+H(alkyl)-, -N+(alkyl)2-, -OP(=O)-, -S(=O)-, -S(=O)2-, -NHS(=O)2-, - N(alkyl)S(=O)2-, -S(=O)2NH-, -S(=O)2N(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, -NH2, -NHalkyl, and -N(alkyl)2, for

instance A9 is–[(CH2)2-O]4-CH3, -[(CH2)2-O]24-CH3,

or -[(CH2)2-O)]4-(CH2)2-C(=O)-NH-(CH2)2-SO3H;

being understood that each A9 comprising a SO3H function can be under salt forms such as alkali metal salts, for instance sodium salts (SO3- +Na).

According to another particular embodiment, the disclosure relates to compounds of formula (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;

■ J1, J2, J3 and J4 are chosen, independently of each other, from CA1 and N;

■ ALK represents a (C1-C12)alkylene group, for instance (C1-C6)alkylene, such as of the form -(CH2)n-, n being an integer ranging from 1 to 12 and for example ranging from 1 to 6;

Examples of RCG1 that may be mentioned include:

(i) a RaZa-C(=O)- reactive group for which:

Za represents a single bond, -O- or -NH, such as -O-, and

Ra represents a hydrogen atom, a (C1-C6)alkyl, a (C3-C7)cycloalkyl, an alkenyl, an aryl, a heteroaryl or a (C3-C7)heterocycloalkyl group. The aryl group, the heteroaryl group and/or the (C3-C7)heterocycloalkyl group may be substituted by 1 to 5 atoms/groups chosen from a halogen atom, such as a fluorine atom, an alkyl group, an alkoxy group, a hydroxyl group, an oxo group, a nitro group and a cyano group;

(ii) one of the following reactive groups: a maleimido group; a haloacetamido

group with R21 representing a hydrogen atom or a (C1-C6)alkyl group, such as Me; Cl-; N3-; HO-; HS-; an activated disulfide such as

; H2N-; HC■C- or an activated C■C such as a cyclooctyne

moiet for instance a DBCO-amine or MFCO

-alkyl hydroxylamine or a Pictet-Spengler reaction substrate such

described in Agarwal P., et al., Bioconjugate Chem 2013, 24, 846-851.

According to a particular embodiment, RCG1 may be:

(i) a RaZa-C(=O)- reactive group for which:

Za represents a single bond, -O- or -NH, such as -O-, and

Ra represents a hydrogen atom, a (C1-C6)alkyl, a (C3-C7)cycloalkyl, an alkenyl, an aryl, a heteroaryl or a (C3-C7)heterocycloalkyl group. The aryl group, the heteroaryl group and/or the (C3-C7)heterocycloalkyl group may be substituted by 1 to 5 atoms/groups chosen from a halogen atom, such as a fluorine atom, an alkyl group, an alkoxy group, a hydroxyl group, an oxo group, a nitro group and a cyano group;

C

(ii) one of the following reactive groups: a haloacetamido
group with R21 representing a hydrogen atom or a (C1-C6)alkyl group, such as Me; Cl-; N3-; HO-;

HS-; an activated disulfide such as
; H2N-; HC■C- or an activated C■C such as a cyclooctyne moiety for instance a DBCO-amine

y

hydroxylamine or a Pictet-Spengler reaction substrate such as

described in Agarwal P., et al., Bioconjugate Chem 2013, 24, 846-851.

For instance, RaZa- may represent HO-, CH3O-, CH2=CH-CH2O-,

NHS
), O where cation represents for example sodium, potassium

or cesium or
group in which

GI represents at least one electroinductive group such as -NO2 or a halogen atom, such as a fluorine atom (F). They may be, for example, the following groups:

Another type of RaZa-C(=O)- group is the following:
.

For instance, RCG1 may be chosen from one of those described in the examples that is to say chosen from the following groups:

The present disclosure further relates to cr to h cin a loads of formula (IV):

wherein:

■ R1 represents a (C1-C6)alkyl group,

■ R2 and R3 represent, independently of each other, a hydrogen atom or a (C1- C6)alkyl group;

or alternatively R2 and R3 form together with the carbon atom to which they are attached a (C3-C6)cycloalkyl or a (C3-C6)heterocycloalkyl group;

■ R4 and R5 represent, independently of each other, a hydrogen atom or a (C1- C6)alkyl group or a (C1-C6)alkyl-NH(R12) group or a (C1-C6)alkyl-OH group or a (C1- C6)alkyl-SH group or a (C1-C6)alkyl-C(=O)2H group;

or alternatively R4 and R5 form together with the carbon atom to which they are attached a (C3-C6)cycloalkyl or a (C3-C6)heterocycloalkyl group;

■ X represents O or N(R6);

■ R6 represents a hydrogen atom or a (C1-C6)alkyl group;

■ R7 and R8 represent, independently of each other, a hydrogen atom or a (C1-C6)alkyl group or a (C1-C6)alkyl-C(=O)2H group or a (C1-C6)alkyl-N(C1-C6)alkyl2 group;

or alternatively R7 and R8 form together with the carbon atom to which they are attached a (C3-C6)cycloalkyl group or a (C3-C6)heterocycloalkyl group;

■ R9 represents at least one substituent of the phenyl nucleus chosen, independently of each other, from: a hydrogen atom, -OH, (C1-C4)alkoxy, a halogen atom, -NH2, -NH(C1-C6)alkyl or -N(C1-C6)alkyl2 or -NH(C1-C6)cycloalkyl or (C3-C6)heterocycloalkyl group;

■ R10 represents at least one substituent of the phenyl nucleus chosen from a hydrogen atom and a (C1-C4)alkyl group;

■ Y represents

■ -NR11-(C1-C6)alkyl-, such as -NR11-(CH2)n- like

;

■ -O-(C1-C6)alkyl-, such as -O-(CH2)n- like

;

■ -S-(C1-C6)alkyl-, such as -S-(CH2)n- like

;

Y being positioned in an ortho (o), meta (m) or para (p) position of the phenyl nucleus;

■ R11 and R12 represent, independently of each other, a hydrogen atom or (C1-C6)alkyl, for instance a hydrogen atom or a methyl group;

■ n represents an integer ranging from 1 to 6;

■ L is defined as in formula (I) and represents a linker of formula (II) as defined in the present disclosure;

■ 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. RCG1 is defined above.

Each substituent R1 to R12 may also adopt one of the spatial configurations (e.g. R or S or alternatively Z or E) as described in the examples. The compounds of formula (IV) may contain at least one asymetric carbon atom. They may therefore exist in the form of enantiomers or diastereoisomers. These enantiomers and diastereoisomers, and also mixtures thereof, including racemic mixtures, form part of the disclosure.

As an example, the cryptophycin compound of formula (IV) may be one of the cryptophycin compounds of formula (I) described in WO2011/001052 (such as one of D1-D8) or in PCT/EP2016/076603, (such as one of D1-D19), as mentioned above.

Or the cryptophycin compound may be an equivalent unit described in one of the examples.

Among the compounds of formula (IV) that are subject matter of the disclosure, a group of compounds is composed of the compounds for which R1 represents a (C1-C6)alkyl, such as a methyl group.

Among the compounds of formula (IV) that are subject matter of the disclosure, a group of compounds is composed of the compounds for which each of R2 and R3 represents a hydrogen atom.

Among the compounds of formula (IV) that are subject matter of the disclosure, a group of compounds is composed of the compounds for which one of R2 and R3 represents a (C1-C6)alkyl, such as a methyl group, and the other one represents a hydrogen atom.

Among the compounds of formula (IV) that are subject matter of the disclosure, a group of compounds is composed of the compounds for which R2 and R3 form together with the carbon atom to which they are attached a (C3-C6)cycloalkyl group, such as a cyclopropyl group.

Among the compounds of formula (IV) that are subject matter of the disclosure, a group of compounds is composed of the compounds for which each of R4 and R5 represents a (C1-C6)alkyl, such as a methyl group.

Among the compounds of formula (IV) that are subject matter of the disclosure, a group of compounds is composed of the compounds for which X represents an oxygen atom, that is to say O.

Among the compounds of formula (IV) that are subject matter of the disclosure, a group of compounds is composed of the compounds for which X represents NH.

Among the compounds of formula (IV) that are subject matter of the disclosure, a group of compounds is composed of the compounds for which R7 and R8 represent independently of each other an hydrogen atom or a (C1-C6)alkyl group, such as an isobutyl group or a neopentyl group.

Among the compounds of formula (IV) that are subject matter of the disclosure, a group of compounds is composed of the compounds for which R9 represents two substituents selected from a methoxy group and a chlorine atom, such as the two R9 substituents are 3-Cl and 4-methoxy.For instance, the phenyl nucleus comprises two substituents in positions 3 and 4 on the phenyl nucleus.

Among the compounds of formula (IV) that are subject matter of the disclosure, a group of compounds is composed of the compounds for which R10 represents a hydrogen atom.

Among the compounds of formula (IV) that are subject matter of the disclosure, a group of compounds is composed of the compounds for which Y is positioned in the para position of the phenyl nucleus.

Among the compounds of formula (IV) that are subject matter of the disclosure, a group of compounds is composed of the compounds for which Y represents NR11-(C1-C6)alkyl, such as NR11-(C1-C3)alkyl, for instance NH-CH2.

Among the compounds of formula (IV) that are subject matter of the disclosure, a group of compounds is composed of the compounds for which L of formula (II) comprises at least one substituted amino acid AAs in the sequence of w amino acids (AA)w, L1 and L2 are as defined in formula (II).

Among the compounds of formula (IV) that are subject matter of the disclosure, a group of compounds is composed of the compounds for which L of formula (II) comprises a sequence of w non-substituted amino-acid AAns, L1 and L2 are as defined in formula (II) .

Among the compounds of formula (IV) that are subject matter of the disclosure, a group of compounds is composed of the compounds for which (AA)w in L of formula (II) contains at least one substituted amino acid AAs and L2 represents:

- a (C1-C6)alkyl group, such as a (CH2)3 group;

- a C(=O)-(C1-C6)alkyl group, such as a C(=O)-(CH2)3 group; or

- a (C1-C6)alkyl-NA7-(C1-C6)alkyl group, such as a (CH2)2-NA7-(CH2)2 group in which A7 is as defined above.

Among the compounds of formula (IV) that are subject matter of the disclosure, a group of compounds is composed of the compounds for which (AA)w in L of formula (II) contains at least one substituted amino acid AAs and L2 represents:

- a (C1-C6)alkyl group, such as a (CH2)3 group;

- a C(=O)-(C1-C6)alkyl group, such as a C(=O)-(CH2)3 group; or

- a (C1-C6)alkyl-NA7-(C1-C6)alkyl group, such as a (CH2)2-NA7-(CH2)2 group in which A7 is a -C(=O)-(CH2)2-C(=O)-NH-(CH2)2-SO3H group;

being understood that each A7 comprising a SO3H function can be under salt forms such as alkali metal salts, for instance sodium salts (SO3- +Na).

Among the compounds of formula (IV) that are subject matter of the disclosure, a group of compounds is composed of the compounds for which (AA)w in L of formula (II) contains w non-substituted amino acid AAns and L2 represents:

a (C1-C6)alkyl-NA7-(C1-C6)alkyl group, such as a (CH2)2-NA7-(CH2)2 group in which A7 is as defined above.

Among the compounds of formula (IV) that are subject matter of the disclosure, a group of compounds is composed of the compounds for which (AA)w in L of formula (II) contains w non-substituted amino acid AAns and L2 represents:

a (C1-C6)alkyl-NA7-(C1-C6)alkyl group, such as a (CH2)2-NA7-(CH2)2 group in which A7 represents:

- a C(=O)-[(CH2)2-O]a-CH3 group wherein“a” represents an integer ranging from 1 to 50, for instance ranging from 1 to 24, such as 4, 7 and 24, for example A7 is a C(=O)-[(CH2)2-O]4-CH3 group, a C(=O)-[(CH2)2-O]7-CH3 group, or a C(=O)-[(CH2)2-O]24-CH3 group;

- a -C(=O)-(CH2)2-C(=O)-NH-(CH2)2-SO3H group; or

- a C(=O)-(CH2)2-C(=O)-NH-[(CH2)2-O]a-(CH2)2-C(=O)-NH-(CH2)2-SO3H group wherein“a” represents an integer ranging from 1 to 50, such as ranging from 1 to 24, for example 4, such as A7 is -C(=O)-(CH2)2-C(=O)-NH-[(CH2)2-O]4-(CH2)2-C(=O)-NH-(CH2)2-SO3H group;

being understood that each A7 comprising a SO3H function can be under salt forms such as alkali metal salts, for instance sodium salts (SO3- +Na);

Among the compounds of formula (IV) that are subject matter of the disclosure, a group of compounds is composed of the compounds for which (AA)w in L of formula (II) contains at least one substituted amino acid AAs and/or w non-substituted amino acid AAns and L2 represents:

a NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7 group, a NA7-(CH2CH2O)i(C1-C6)alkyl group, a NA7-aryl group, a NA7-heteroaryl group, a (C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a C(=O)-NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7 group, a C(=O)-NA7-(CH2CH2O)i(C1-C6)alkyl group, a C(=O)-NA7-aryl group, a C(=O)-NA7-heteroaryl group, a C(=O)-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a NA8-

(C1-C6)alkyl-NA7 group, a NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7 group, a C(=O)-NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group or a C(=O)-NA8-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group; wherein i, A7 and A8 are as defined above.

Among the compounds of formula (IV) that are subject matter of the disclosure, a preferred group of compounds is composed of the compounds for which (AA)w in L of formula (II) contains at least one substituted amino acid AAs and/or w non-substituted amino acid AAns and L2 represents:

a NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7 group, a NA7-(CH2CH2O)i(C1-C6)alkyl group, a NA7-aryl group, a NA7-heteroaryl group, a (C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a C(=O)-NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7 group, a C(=O)-NA7-(CH2CH2O)i(C1-C6)alkyl group, a C(=O)-NA7-aryl group, a C(=O)-NA7-heteroaryl group, a C(=O)-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-NA7 group, a NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7 group, a C(=O)-NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, or a C(=O)-NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group; wherein i, A7 and A8 are as defined above.

Among the compounds of formula (IV) that are subject matter of the disclosure, a more preferred group of compounds is composed of the compounds for which (AA)w in L of formula (II) contains at least one substituted amino acid AAs and/or w non-substituted amino acid AAns and L2 represents:

a NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7 group, a NA7-(CH2CH2O)i(C1-C6)alkyl group, a (C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a C(=O)-NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7 group, a C(=O)-NA7-(CH2CH2O)i(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-NA7 group, a NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7 group, a C(=O)-NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, or a C(=O)-NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group; wherein i, A7 and A8 are as defined above.

Among the compounds of formula (IV) that are subject matter of the disclosure, a still more preferred group of compounds is composed of the compounds for which (AA)w in L of formula (II) contains at least one substituted amino acid AAs and/or w non-substituted amino acid AAns and L2 represents:

a NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7 group, a (C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7 group, a C(=O)-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7 group, a NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-

NA8-(C1-C6)alkyl-NA7 group, a C(=O)-NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, or a C(=O)-NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group; wherein A7 and A8 are as defined above.

Among the compounds of formula (IV) that are subject matter of the disclosure, a most preferred group of compounds is composed of the compounds for which (AA)w in L of formula (II) contains at least one substituted amino acid AAs and/or w non-substituted amino acid AAns and L2 represents:

a (C1-C6)alkyl-NA7-(C1-C6)alkyl group; wherein A7 is as defined above.

Among the compounds of formula (IV) that are subject matter of the disclosure, a group of compounds is composed of the compounds for which (AA)w in L of formula (II) contains at least one substituted amino acid AAs and/or w non-substituted amino acid AAns and L2 comprises a A7 representing :

a C(=O)-[(CH2)2-O]4-CH3 group; a C(=O)-[(CH2)2-O]7-CH3 group; a C(=O)-[(CH2)2-O]24-CH3 group; a C(=O)-(CH2)2-C(=O)-NH-(CH2)2-SO3H group; a C(=O)-(CH2)2-C(=O)-NH-[(CH2)2-O]4-(CH2)2-C(=O)-NH-(CH2)2-SO3H group;

being understood that each A7 comprising a SO3H function can be under salt forms such as alkali metal salts, for instance sodium salts (SO3- +Na).

Among the compounds of formula (IV) that are subject matter of the disclosure, a group of compounds is composed of the compounds for which (AA)w in L of formula (II) contains at least one substituted amino acid AAs and/or w non-substituted amino acid AAns and L2 represents :

Compound 25: tert-butyl 2,5,8,11,14,17,20-heptaoxatricosan-23-oate

To a solution of hexaethylene glycol monomethyl ether (926.0 µL, 3.24 mmol) in THF (3 mL), was added, under Ar, Na (0.7 mg, 32.4 µmol). The reaction medium was stirred for 1 h at RT until complete dissolution of Na then tert-butyl acrylate (570 µL, 3.89 mmol) was added and the stirring carried on at RT overnight. The reaction medium was then concentrated in vacuo, diluted with H2O and extracted with EtOAc (3 x). The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give 1.04 g of compound 25 as a colorless oil (76%).

RMN 1H (400 MHz,■ in ppm, DMSO-d6): 1.40 (s, 9 H); 2.40 (t, J = 6.4 Hz, 2 H); 3.23 (s, 3 H); 3.43 (m, 2 H); 3.47 to 3.54 (m, 22 H); 3;59 (t, J = 6.4 Hz, 2 H).

Compound 26: 2,5,8,11,14,17,20-heptaoxatricosan-23-oic acid

To a solution of compound 25 (1.04 g, 2.45 mmol) in DCM (15 mL) was added TFA (1.84 mL, 24.5 mmol). The reaction medium was stirred at RT overnight, concentrated in vacuo, diluted with DCM and co-evaporated with toluene (3 x) to give 1 g of compound 26 as a colorless oil (quant.).

Compound 27: 2,5,8,11,14,17,20-heptaoxatricosan-23-oyl chloride

To compound 26 (400 mg, 1.09 mmol) was added MsCl (1.27 mL, 16.3 mmol); the reaction medium was heated 3 h at 60°C, concentrated in vacuo, diluted with DCM and concentrated in vacuo (3 x) to give 420 mg of compound 27 as a colorless oil (quant.).

Compound 28: allyl 24-(3-(tert-butoxy)-3-oxopropyl)-23-oxo-2,5,8,11,14,17,20-heptaoxa-24-azaheptacosan-27-oate

To a solution of compound 3 (200 mg, 777.2 µmol) in DCM (5 mL) was added DIEA (262 µL, 1.55 mmol). The reaction medium was cooled down at 0°C and a solution of compound 27 (360.8 mg, 932.7 µmol) in DCM (2 mL) was added dropwise at 0°C. The reaction medium was stirred for 1 h at RT and concentrated in vacuo. The crude product was purified by two consecutive flash chromatographies on 12 g and 10 g of silica gel (gradient elution DCM/MeOH) to give 72 mg of compound 28 (15%).

RMN 1H (400 MHz,■ in ppm, DMSO-d6): 50:50 conformer mixture; 1.39 (s, 4.5 H); 1.40 (s, 4.5 H); 2.22 to 2.75 (partially masked m, 6 H); 3.23 (s, 3 H); 3.38 to 3.63 (m, 30 H); 4.55 (m, 2 H); 5.19 to 5.36 (m, 2 H); 5.90 (m, 1 H).

Compound 29: 24-(3-(allyloxy)-3-oxopropyl)-23-oxo-2,5,8,11,14,17,20-heptaoxa-24-azahepta-cosan-27-oic acid

To a solution of compound 28 (72 mg, 118.5 µmol) in DCM (3 mL) was added TFA (100 µL, 1.33 mmol); the reaction medium was stirred at RT overnight then additional TFA (100 µL, 1.33 mmol) was added and the stirring carried on for 1 d. The reaction medium was concentrated in vacuo, diluted with DCM and co-evaporated with toluene (3 x) to give 66 mg of compound 29 (quant.).

Compound 30: allyl 24-(3-((2,5-dioxopyrrolidin-1-yl)oxy)-3-oxopropyl)-23-oxo-2,5,8,11,14,17,20-heptaoxa-24-azaheptacosan-27-oate

To a solution of compound 29 (66 mg, 119.7 µmol) in THF (2 mL), were added, under Ar, DIEA (20.2 µL, 119.9 µmol) and DSC (34.4 mg, 131.6 µmol); the reaction medium was stirred for 4 d at RT, concentrated in vacuo and purified by flash chromatography on 900 mg of diol-modified silica gel (gradient elution DCM/iPrOH) to give 35 mg of compound 30 (45%).

Compound 31: allyl 24-(3-(((S)-1-(((S)-1-((4-((((4-((2R,3R)-3-((S)-1-((3S,10R,16S,E)-10-(3-chloro-4-methoxybenzyl)-3-isobutyl-6,6-dimethyl-2,5,9,12-tetraoxo-1,4-dioxa-8,11-diazacyclo-hexadec-13-en-16-yl)ethyl)oxiran-2-yl)benzyl)carbamoyl)oxy)-methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-oxopropyl)-23-oxo-2,5,8,11,14,17,20-heptaoxa-24-azaheptacosan-27-oate

To a solution of compound 23 (45 mg, 44.2 µmol) in THF (5 mL) were added compound 30 (28.7 mg, 44.2 µmol) and DIEA (11.2 µL, 66.3 µmol). The reaction medium was stirred at RT overnight, diluted with H2O (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with brine, dried over MgSO4, filtered, concentrated in vacuo and purified by flash chromatography on 5 g of silica gel (gradient elution DCM/MeOH) to give 35 mg of compound 31 as a white solid (51%).

RMN 1H (500 MHz,■ in ppm, DMSO-d6): 60:40 conformer mixture; 0.80 (split d, J = 6.8 Hz, 6 H); 0.82 (d, J = 7.0 Hz, 1.8 H); 0.84 (d, J = 7.0 Hz, 1.2 H); 0.86 (d, J = 7.0 Hz, 1.8 H); 0.88 (d, J = 7.0 Hz, 1;2 H); 1.00 (s, 3 H); 1.04 (d, J = 7.0 Hz, 3 H); 1.11 (s, 3 H); 1.28 (m, 1 H); 1.30 (m, 3 H); 1.56 (m, 2 H); 1.79 (m, 1 H); 1.95 (m, 1 H); 2.27 (m, 1 H); 2.35 to 2.60 (partially masked m, 6 H); 2.62 to 2.73 (m, 2 H); 2.93 to 3.05 (m, 3 H); 3.23 (s, 3 H); 3.33 (masked m, 1 H); 3.38 to 3.64 (m, 30 H); 3.80 (s, 3 H); 3.87 (d, J = 2.3 Hz, 1 H); 4.15 to 4.27 (m, 4 H); 4.38 (m, 1 H); 4.52 to 4.58 (m, 2 H); 4.90 (dd, J = 3.8 and 9.8 Hz, 1 H); 4.97 (s, 2 H); 5.10 (m, 1 H); 5.50 (m, 1 H); 5.30 (m, 1 H); 5.80 (d, J = 16.0 Hz, 1 H); 5.90 (m, 1 H); 6.47 (ddd, J = 4.7, 10.5 and 16.0 Hz, 1 H); 7.05 (d, J = 8.6 Hz, 1 H); 7.15 (dd, J = 2.5 and 8.6 Hz, 1 H); 7.20 to 7.32 (m, 8 H); 7.59 (m, 2 H); 7.78 (t, J = 6.5 Hz, 1 H); 7.95 (d, J = 9.0 Hz, 0.4 H); 8.07 (d, J = 9.0 Hz, 0.6 H); 8.18 (d, J = 7.0 Hz, 0.4 H); 8.27 (d, J = 7.0 Hz, 0.6 H); 8.36 (d, J = 8.0 Hz, 1 H); 9.90 (s, 0.4 H); 9.95 (s, 0.6 H). LCMS (A): ES m/z = 698; m/z = 1552 [M+H]+; m/z = 1595 [M-H+HCO2H]-; tR = 1.39 min.

Example 10: 24-(3-(((S)-1-(((S)-1-((4-((((4-((2R,3R)-3-((S)-1-((3S,10R,16S,E)-10-(3-chloro-4-methoxybenzyl)-3-isobutyl-6,6-dimethyl-2,5,9,12-tetraoxo-1,4-dioxa-8,11-diazacyclohexadec-13-en-16-yl)ethyl)oxiran-2-yl)benzyl)carbamoyl)oxy)methyl)-phenyl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-oxopropyl)-23-oxo-2,5,8,11,14,17,20-heptaoxa-24-azaheptacosan-27-oic acid

To a solution of compound 31 (30 mg, 19.3 µmol) in DCM (5 mL) were added, under Ar, dimethylbarbituric acid (9.24 mg, 58.0 µmol) and

tetrakis(triphenylphosphine)palladium (0) (1.13 mg, 0.97 µmol). The reaction medium was stirred for 3 h at RT then concentrated in vacuo and purified by two consecutive flash chromatographies on 5 g and 0.9 g of silica gel (gradient elution DCM/MeOH) to give 14 mg of example 10 as a white solid (50%).

RMN 1H (500 MHz,■ in ppm, DMSO-d6): 50:50 conformer mixture; 0.78 (split d, J = 6.8 Hz, 6 H); 0.81 to 0.89 (m, 6 H); 1.00 (s, 3 H); 1.04 (d, J = 7.0 Hz, 3 H); 1.12 (s, 3 H); 1.28 (m, 1 H); 1.30 (d, J = 7.0 Hz, 1.5 H); 1.32 (d, J = 7.0 Hz, 1.5 H); 1.51 to 1.62 (m, 2 H); 1.79 (m, 1 H); 1.96 (m, 1 H); 2.26 (m, 1 H); 2.33 to 2.60 (partially masked m, 6 H); 2.61 to 2.73 (m, 2 H); 2.93 to 3.03 (m, 3 H); 3.22 (s, 3 H); 3.30 (masked m, 1 H); 3.38 to 3.62 (m, 30 H); 3.80 (s, 3 H); 3.87 (d, J = 2.3 Hz, 1 H); 4.12 to 4.29 (m, 4 H); 4.39 (m, 1 H); 4.90 (dd, J = 3.8 and 9.8 Hz, 1 H); 4.96 (s, 2 H); 5.10 (m, 1 H); 5.78 (d, J = 16.0 Hz, 1 H); 6.46 (ddd, J = 4.7, 10.5 and 16.0 Hz, 1 H); 7.05 (d, J = 8.6 Hz, 1 H); 7,16 (dd, J = 2.5 and 8,6 Hz, 1 H); 7.20 to 7.32 (m, 8 H); 7.59 (m, 2 H); 7.79 (m, 1 H); 8.04 (m, 0.5 H); 8.10 (d, J = 9.0 Hz, 0.5 H); 8.25 to 8.41 (m, 2 H); 9.95 (s, 0.5 H); 9.98 (s, 0.5 H); 12.20 (m, 1 H). LCMS (D): ES m/z = 769; m/z = 1511 [M+H]+; tR = 3.16 min.

Synthesis of examples 11 & 12: PEG24-Val-Ala-PABA-C52 benzylic amine and NHS ester of PEG24-Val-Ala-PABA-C52 benzylic amine

Compound 32: allyl 75-(3-(tert-butoxy)-3-oxopropyl)-74-oxo- 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71- tetracosaoxa-75-azaoctaheptacontan-78-oate

To a solution of compound 3 (45 mg, 174.9 µmol) in THF (5 mL) were added, under Ar, MEO-DPEG(24)-NHS (212.4 mg, 174.9 µmol) and DIEA (44.2 µL, 262.3 µmol). The reaction medium was stirred at RT overnight then concentrated in vacuo and purified by flash chromatography on 20 g of silica gel (gradient elution DMC/MeOH) to give 125 mg of a mixture of compound 32 (60%) and MEO-DPEG(24)-NHS (40%). This mixture was diluted in THF (3 mL), 15 mg of compound 3 and 20 µL of DIEA were added; the reaction medium was stirred at RT overnight then concentrated in vacuo and purified by flash chromatography on 12 g of silica gel to give 105 mg of compound 32 (44%).

RMN 1H (400 MHz,■ in ppm, DMSO-d6): 1.40 (s, 9 H); 2.25 to 2.78 (m, 6 H); 3.22 (s, 3 H); 3.32 to 3.70 (m, 98 H); 4.52 (m, 2 H); 5.20 (m, 1 H); 5.30 (m, 1 H); 5.90 (m, 1 H). LCMS (A): ES m/z = 679 [M+2H]2+; m/z = 1356 [M+H]+; m/z = 1400 [M-H+HCO2H]-; tR = 1.15 min.

Compound 33: 75-(3-(allyloxy)-3-oxopropyl)-74-oxo-2,5,8,11,14,17,20,23,26,29,32, 35,38,41,44,47,50,53,56,59,62,65,68,71-tetracosaoxa-75-azaoctaheptacontan-78-oic acid

To a solution of compound 32 (105 mg, 77.4 µmol) in DCM (2 mL) was added TFA (116.2 µL, 1.55 mmol); the reaction medium was stirred at RT overnight, 150 µL of TFA were then added and the reaction carried on one more day. The reaction medium was then concentrated in vacuo, diluted with DCM and co-evaporated with toluene (3 x) to give 110 mg of crude product that were purified by RP-HPLC on a 5 µm C18 SunFire column (Waters, 30 x 100 mm, gradient elution MeCN + 0.07% TFA/H20 + 0.07% TFA) to provide 60 mg of compound 33 (60%).

RMN 1H (400 MHz,■ in ppm, DMSO-d6): 50:50 conformer mixture; 2.37 to 2.60 (partially masked m, 6 H); 3.23 (s, 3 H); 3.32 to 3.44 (partially masked m, 38 H); 3.47 to 3.52 (m, 58 H); 3.60 (m, 2 H); 4.54 (m, 2 H); 5.22 (dm, J = 10.5 Hz, 1 H); 5.30 (dm, J = 17.3 Hz, 1 H); 5,84 to 5,98 (m, 1 H); 12.32 (broad m, 1 H).

Compound 34: allyl 75-(3-(((S)-1-(((S)-1-((4-((((4-((2R,3R)-3-((S)-1-((3S,10R,16S,E)-10-(3-chloro-4-methoxybenzyl)-3-isobutyl-6,6-dimethyl-2,5,9,12-tetraoxo-1,4-dioxa-8,11-diazacyclo-hexadec-13-en-16-yl)ethyl)oxiran-2-yl)benzyl)carbamoyl)oxy)-methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-oxopropyl)-74-oxo-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71-

tetracosaoxa-75-azaoctaheptacontan-78-oate

To a solution of compound 33 (30 mg, 23.1 µmol) in THF (5 mL) were added, under Ar, DIEA (11.7 µL, 69.2 µmol) and DSC (6.03 mg, 23.1 µmol). The reaction medium was stirred for 3 h at RT then was added compound 23 (23.5 mg, 23.1 µmol) and the stirring carried on 1h. The reaction medium was concentrated in vacuo and purified by flash chromatography on 5 g of silica gel to give 23 mg of compound 34 (40%).

RMN 1H (500 MHz,■ in ppm, DMSO-d6): 60:40 conformer mixture: 0.80 (split d, J = 6.8 Hz, 6 H); 0.82 (d, J = 7.0 Hz, 1.8 H); 0.84 (d, J = 7.0 Hz, 1.2 H); 0.86 (d, J = 7.0 Hz, 1.8 H); 0.88 (d, J = 7.0 Hz, 1.2 H); 1.00 (s, 3 H); 1.04 (d, J = 7.0 Hz, 3 H); 1.11 (s, 3 H); 1.28 (m, 1 H); 1.30 (d, J = 7.0 Hz, 3 H); 1.51 to 1.62 (m, 2 H); 1.80 (m, 1 H); 1.96 (m, 1 H); 2.26 (m, 1 H); 2.38 (m, 1 H); 2.45 to 2.61 (partially masked m, 5 H); 2.61 to 2.72 (m, 2 H); 2.93 to 3.05 (m, 3 H); 3.23 (s, 3 H); 3.32 (masked m, 1 H); 3.40 to 3.77 (m, 98 H); 3.80 (s.3 H); 3.88 (d, J = 2.3 Hz, 1 H ; 4.14 to 4.27 (m, 4 H); 4.39 (m, 1 H); 4.51 to 4.60 (m, 2 H); 4.90 (dd, J = 3.8 and 9.8 Hz, 1 H); 4.97 (s, 2 H); 5.10 (m, 1 H); 5.18 to 5.33 (m, 2 H); 5.78 (d, J = 16.0 Hz, 1 H); 5.90 (m, 1 H); 6.45 (m, 1 H); 7.05 (d, J = 8.6 Hz, 1 H); 7.16 (dd, J = 2.5 and 8.6 Hz, 1 H); 7.20 to 7.32 (m, 8 H); 7.59 (m, 2 H); 7.77 (t, J = 6.5 Hz, 1 H); 7.95 (d, J = 9.0 Hz, 0.4 H); 8.07 (d, J = 9.0 Hz, 0.6 H); 8.19 (d, J = 7.0 Hz, 0.4 H); 8.25 (d, J = 7.0 Hz, 0.6 H); 8.36 (d, J = 8.0 Hz, 1 H); 9.90 (s, 0.4 H); 9.96 (s, 0.6 H).

Example 11: 75-(3-(((S)-1-(((S)-1-((4-((((4-((2R,3R)-3-((S)-1-((3S,10R,16S,E)-10-(3-chloro-4-methoxybenzyl)-3-isobutyl-6,6-dimethyl-2,5,9,12-tetraoxo-1,4-dioxa-8,11-diazacyclohexadec-13-en-16-yl)ethyl)oxiran-2-yl)benzyl)carbamoyl)oxy)methyl)-phenyl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-oxopropyl)-74-oxo-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65, 68,71-tetracosaoxa-75-azaoctaheptacontan-78-oic acid

To a solution of compound 34 (37 mg, 161 µmol) in DCM were added, under Ar, 1,3-dimethylbarbituric acid (5.13 mg, 32.2 µmol) and tetrakis(triphenylphosphine)palladium(0) (0.94 mg, 0.80 µmol); the reaction medium was stirred at RT for 2 h then concentrated in vacuo and purified by flash chromatography on 5 g of diol-modified silica gel (gradientn elution DCM/MeOH) to give 16 mg of example 11 (44%).

RMN 1H (500 MHz,■ in ppm, DMSO-d6): 0.77 (d, J = 7.0 Hz, 6 H); 0.80 to 0.90 (m,

6 H); 0,99 (s, 3 H); 1.04 (d, J = 7.0 Hz, 3 H); 1.11 (s, 3 H); 1.28 (m, 1 H); 1.30 (d, J = 7.0 Hz, 1.5 H); 1.32 (d, J = 7.0 Hz, 1.5 H); 1.52 to 1.61 (m, 2 H); 1.79 (m, 1 H); 1.98 (m, 1 H); 2.22 to 2.58 (partially masked m, 7 H); 2.68 (m, 2 H); 2.92 to 3.04 (m, 3 H); 3.21 (s, 3 H); 3.30 (partially masked m, 1 H); 3.37 to 3.67 (m, 98 H); 3.81 (s, 3 H); 3.88 (s, 1 H); 4.08 to 4.28 (m, 4 H); 4.39 (m, 1 H); 4.90 (m, 1 H); 4.98 (s, 2 H); 5.10 (m, 1 H); 5.80 (d, J = 16.0 Hz, 1 H); 6.48 (ddd, J = 4.7, 10.5 and 16.0 Hz, 1 H); 7.04 (d, J = 8.6 Hz, 1 H); 7.16 (broad d, J = 8.6 Hz, 1 H); 7.20 to 7.32 (m, 8 H); 7.57 to 7.67 (m, 2 H); 7.80 (m, 1 H); 8.20 (m, 1 H); 8.35 to 8.70 (m, 2 H); 10.08 (m, 1 H); 12.30 (broad m, 1 H). LCMS (D): ES m/z = 698; m/z = 2259 [M+H]+; tR = 3.14 min.

Example 12: 2,5-dioxopyrrolidin-1-yl 75-(3-(((S)-1-(((S)-1-((4-((((4-((2R,3R)-3-((S)-1-((3S,10R,16S,E)-10-(3-chloro-4-methoxybenzyl)-3-isobutyl-6,6-dimethyl-2,5,9,12-tetraoxo-1,4-dioxa-8,11-diazacyclohexadec-13-en-16-yl)ethyl)oxiran-2-yl)benzyl)-carbamoyl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-oxopropyl)-74-oxo-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50, 53,56,59,62,65,68,71-tetracosaoxa-75-azaoctaheptacontan-78-oate

To a solution of example 11 (16 mg, 7.1 µmol) in DCM were added DIEA (1.2 µL, 7.1 µmol) and DSC (1.8 mg, 7.1 µmol). The reaction medium was stirred for 3 h at RT then concentrated in vacuo and purified by flash chromatography on 1.3 g of diol-modified silica gel (gradient elution DCM/iPrOH) to give 5 mg of a mixture of example 12 (30%) and example 11 (70%).

LCMS (D): ES m/z = 698; m/z = 2356 [M+H]+; tR = 3.2 min.

Synthesis of example 13: sulfo-PEG4-Val-Ala-PABA-C52 benzylic amine

Compound 35: 4-((3-(allyloxy)-3-oxopropyl)(3-(tert-butoxy)-3-oxopropyl)amino)-4- oxobutanoic acid

To a solution of compound 3 (100 mg, 388.6 µmol) in DCM (5 mL) was added succinic anhydride (78.6 mg, 777.2 µmol). The reaction medium was stirred at RT overnight then concentrated in vacuo and purified by flash chromatography on 4 g of silica gel (gradient elution DCM/MeOH) to give 102 mg of compound 35 as a colorless oil (73%).

Compound 36: 1-ammonio-15-oxo-3,6,9,12-tetraoxa-16-azaoctadecane-18- sulfonate

To a solution of 15-(Boc-amino)-4,7,10,13-tetraoxapentadecanoic acid (500 mg, 1.3 mmol) in THF (5 mL) were added, under Ar, DIEA (438.4 µL, 2.6 mmol) and DSC (381.6 mg, 1.43 mmol). The reaction medium was stirred for 6 h at RT then 50 mg of DSC were added and the stirring was

CLAIMS

1. Compounds 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;

■ J1, J2, J3 and J4 are chosen, independently of each other, from CA1 and N;

■ ALK represents a (C1-C12)alkylene group, for instance (C1-C6)alkylene, such as of the form -(CH2)n-, n being an integer ranging from 1 to 12 and for example ranging from 1 to 6;

■ A1, A2, A3, A4, A5, and A6 represent, independently of each other, a hydrogen atom or a (C1-C6)alkyl group, such as a hydrogen atom or a methyl group.

■ (AA)w represents a sequence of w substituted AAs or non-substituted amino acids AAns connected together via peptide bonds; ■ w represents an integer ranging from 1 to 12, for instance from 1 to 6, such as 2 or 3;

• if (AA)w contains at least one substituted amino acid AAs, then L2 represents a single bond, a (C1-C6)alkyl group, a (C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-(OCH2CH2)i-O(C1-C6)alkyl group, a (CH2CH2O)i(C1-C6)alkyl group, a CH(SO3H)-(C1-C6)alkyl group, a (C1-C6)alkyl-CH(SO3H) group, a (C1-C6)alkyl-cyclohexyl group, a C(=O)-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-(OCH2CH2)i-O(C1-C6)alkyl group, a C(=O)-(CH2CH2O)i(C1-C6)alkyl group, a C(=O)-CH(SO3H)-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-CH(SO3H) group, a C(=O)-(C1-C6)alkyl-cyclohexyl group, a NA8-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-(OCH2CH2)i-O(C1-C6)alkyl group, a NA8-(CH2CH2O)i(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-CH(SO3H) group, a C(=O)-NA8-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-(OCH2CH2)i-O(C1-C6)alkyl group, a C(=O)-NA8-(CH2CH2O)i(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-CH(SO3H) group, a NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7 group, a NA7-(CH2CH2O)i(C1-C6)alkyl group, a NA7-aryl group, a NA7-heteroaryl group, a (C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a C(=O)-NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7 group, a C(=O)-NA7-(CH2CH2O)i(C1-C6)alkyl group, a C(=O)-NA7-aryl group, a C(=O)-NA7-heteroaryl group, a C(=O)-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7 group, a NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl- NA7-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7 group, a C(=O)-NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group or a C(=O)-NA8-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group;

• if (AA)w represents a sequence of w non-substituted amino acids AAns, then L2 represents a NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7 group, a NA7-(CH2CH2O)i(C1-C6)alkyl group, a NA7-aryl group, a NA7-heteroaryl group, a (C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a C(=O)-NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7 group, a C(=O)-NA7-(CH2CH2O)i(C1-C6)alkyl group, a C(=O)-NA7-aryl group, a C(=O)-NA7-heteroaryl group, a C(=O)-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7 group, a NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7 group, a C(=O)-NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group or a C(=O)-NA8-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group;

■ A7 representing a straight or branched, saturated or unsaturated, optionally substituted C1-C160 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(SO3H)- , -O-, - C(=O)-, -S(=O)-, -S(=O)2-, -NHS(=O)2-, -N(alkyl)S(=O)2-, -S(=O)2NH-, - S(=O)2N(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, -NH2, - NHalkyl, and -N(alkyl)2, being understood that each A7 comprising a SO3H function can be under salt forms such as alkali metal salts, for instance sodium salts (SO - 3 +Na);

■ A8 representing a hydrogen atom or a (C1-C6)alkyl group, for instance a hydrogen atom or a methyl group;

■ i representing an integer ranging from 1 to 50, for instance ranging from 1 to 35.

2. Compounds of formula (I) according to claim 1, wherein said sequence (AA)w of non-substituted amino acids AAns 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, such as Val-Ala and Val-Cit, for instance Val-Ala.

3. Compounds of formula (I) according to claim 1, wherein said substituted amino acids AAs have the formula (VI):

wherein:

■ T represents a saturated or unsaturated, linear or branched, (C1-C8) trivalent

alkyl group, preferably T
is , ;

■ 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)2NH-, -S(=O)2N(alkyl)-, - P(=O)(OH)-, -P(=O)(OH)O-, -O-P(=O)(OH)-, or -O-P(=O)(OH)-O, such as U group represents -NH-C(=O)-, or -C(=O)NH-;

■ A9 represents a straight or branched, saturated or unsaturated, optionally substituted C1-C160 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(SO3H)-, -CH(Oalkyl)-, -CHF-, -CF2-, - 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)2NH-, -S(=O)2N(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, -NH2, - NHalkyl, and -N(alkyl)2, for instance A9 is–[(CH2)2-O]4-CH3, -[(CH2)2-O]24-CH3,

or -[(CH2)2-O)]4-(CH2)2-C(=O)-NH-(CH2)2-SO3H;

being understood that each A9 comprising a SO3H function can be under salt forms such as alkali metal salts, for instance sodium salts (SO3- +Na).

4. Compounds of formula (I) according to claim 1, wherein the substituted amino acids AAs have the formula (VI) as defined in claim 3 in which;

■ U group represents -NH-C(=O)-, or -C(=O)NH-;

■ A9 represents–[(CH2)2-O]b-CH3 wherein b represents an integer ranging from 1 to 50, for instance ranging from 1 to 24, such as 4, 7 and 24, for instance 4 and 24.

5. Compounds of formula (I) according to claim 1, wherein the sequence (AAs)w containing at least one substituted amino acid AAs, is selected from the list:

6. Compounds of formula (I) according to claim 1, wherein (AA)w contains at least one substituted amino acid AAs and L2 represents:

- a (C1-C6)alkyl group, such as a–(CH2)3- group;

- a -C(=O)-(C1-C6)alkyl group, such as a -C(=O)-(CH2)3- group; or

- a (C1-C6)alkyl-NA7-(C1-C6)alkyl group, such as a -(CH2)2-NA7-(CH2)2- group in which A7 is a -C(=O)-(CH2)2-C(=O)-NH-(CH2)2-SO3H group;

being understood that each A7 comprising a SO3H function can be under salt forms such as alkali metal salts, for instance sodium salts (SO3- +Na).

7. Compounds of formula (I) according to claim 1, wherein (AA)w contains w non- substituted amino acid AAns and L2 represents :

a (C1-C6)alkyl-NA7-(C1-C6)alkyl group, such as a -(CH2)2-NA7-(CH2)2- group in which A7 represents:

- a–C(=O)-[(CH2)2-O]a-CH3 group wherein“a” represents an integer ranging from 1 to 50, such as ranging from 1 to 24, for instance 4, 7 and 24, such as A7 is a -C(=O)-[(CH2)2-O]4-CH3 group, a -C(=O)-[(CH2)2-O]7-CH3 group, or a -C(=O)-[(CH2)2-O]24-CH3 group;

-a -C(=O)-(CH2)2-C(=O)-NH-(CH2)2-SO3H group; or

-a -C(=O)-(CH2)2-C(=O)-NH-[(CH2)2-O]a-(CH2)2-C(=O)-NH-(CH2)2-SO3H group wherein“a” represents an integer ranging from 1 to 50, such as ranging from 1 to 24, for instance 4, such as A7 is -C(=O)-(CH2)2-C(=O)-NH-[(CH2)2-O]4-(CH2)2-C(=O)-NH-(CH2)2-SO3H group;

being understood that each A7 comprising a SO3H function can be under salt forms such as alkali metal salts, for instance sodium salts (SO3- +Na).

8. Compounds of formula (I) according to claim 1, wherein A7 represents a -C(=O)-[(CH2)2-O]4-CH3 group; a -C(=O)-[(CH2)2-O]7-CH3 group,

a -C(=O)-[(CH2)2-O]24-CH3 group; a -C(=O)-(CH2)2-C(=O)-NH-(CH2)2-SO3H group; a -C(=O)-(CH2)2-C(=O)-NH-[(CH2)2-O-]4-(CH2)2-C(=O)-NH-(CH2)2-SO3H group;

being understood that each A7 comprising a SO3H function can be under salt forms such as alkali metal salts, for instance sodium salts (SO3- +Na).

9. Compounds of formula (I) according to claim 1, wherein (AA)w contains at least one substituted amino acid AAs and/or w non-substituted amino acid AAns and L2 represents:

a NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7 group, a NA7-(CH2CH2O)i(C1-C6)alkyl group, a NA7-aryl group, a NA7-heteroaryl group, a (C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl group, a (C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a (C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a C(=O)-NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7 group, a C(=O)-NA7-(CH2CH2O)i(C1-C6)alkyl group, a C(=O)-NA7-aryl group, a C(=O)-NA7-heteroaryl group, a C(=O)-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7 group, a NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group, a NA8-(C1-C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7 group, a C(=O)-NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7C(=O)-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-C(=O)NA7-(C1-C6)alkyl-(OCH2CH2)i group, a C(=O)-NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl group, a C(=O)-NA8-(C1-C6)alkyl-NA7-(C1-C6)alkyl-(OCH2CH2)i group or a C(=O)-NA8-(C1-

C6)alkyl-(OCH2CH2)i-NA7-(C1-C6)alkyl group.

10. Compounds of formula (I) according to claim 1, wherein (AA)w contains at least one substituted amino acid AAs and/or w non-substituted amino acid AAns and L2 re resents :

or

11. Compounds of formula (I) according to claim 1, wherein (AA)w contains at least one substituted amino acid AAs and/or w non-substituted amino acid AAns and L2 comprises a A7 representing :

a C(=O)-[(CH2)2-O]4-CH3 group; a C(=O)-[(CH2)2-O]7-CH3 group; a C(=O)-[(CH2)2-O]24-CH3 group; a C(=O)-(CH2)2-C(=O)-NH-(CH2)2-SO3H group; a C(=O)-(CH2)2-C(=O)-NH-[(CH2)2-O]4-(CH2)2-C(=O)-NH-(CH2)2-SO3H group; being understood that each A7 comprising a SO3H function can be under salt forms such as alkali metal salts, for instance sodium salts (SO3- +Na).

12. Compounds of formula (I) according to anyone of claims 1 to 11, wherein said linker L is selected from the following list:

13. Compounds of formula (I) according to anyone of claims 1 to 12, wherein RCG1 is selected from the following list:

(i) a RaZa-C(=O) reactive group for which Za represents a single bond, -O- or -NH-, for instance -O-, and Ra represents a hydrogen atom, a (C1-C6)alkyl group, a (C3- C7)cycloalkyl group, an alkenyl group, an aryl group, a heteroaryl group or a (C3- C7)heterocycloalkyl group, the aryl group, the heteroaryl group and/or the (C3- C7)heterocycloalkyl group being optionally substituted by 1 to 5 atoms/groups chosen from a halogen atom, for instance a fluorine atom, an alkyl group, an alkoxy group, a hydroxyl group, an oxo group, a nitro group and a cyano group;

(ii) one of the following reactive groups: a maleimido
group; a haloacetamido

group with R21 representing a hydrogen atom or a (C1-C6)alkyl group, such as Me; Cl-; N3-; HO-; HS-; an activated disulfide such as

; H2N-; HC■C- group or an activated C■C rou such as a

c clooct ne moiet for instance a DBCO-amine or BCN

; an O-alkyl hydroxylamine or a Pictet-Spengler

reaction substrate such as
;

for instance RCG1 is selected from the following list:

14. Cryptophycin payloads of formula (IV):

wherein:

■ R1 represents a (C1-C6)alkyl group;

■ R2 and R3 represent, independently of each other, a hydrogen atom or a (C1- C6)alkyl group;

or alternatively R2 and R3 form together with the carbon atom to which they are attached a (C3-C6)cycloalkyl or a (C3-C6)heterocycloalkyl group;

■ R4 and R5 represent, independently of each other, a hydrogen atom or a (C1- C6)alkyl group or a (C1-C6)alkyl-NH(R12) group or a (C1-C6)alkyl-OH group or a (C1- C6)alkyl-SH group or a (C1-C6)alkyl-CO2H group;

or alternatively R4 and R5 form together with the carbon atom to which they are attached a (C3-C6)cycloalkyl or a (C3-C6)heterocycloalkyl group;

■ X represents O or N(R6);

■ R6 represents a hydrogen atom or a (C1-C6)alkyl group;

■ R7 and R8 represent, independently of each other, a hydrogen atom or a (C1- C6)alkyl group or a (C1-C6)alkyl-CO2H group or a (C1-C6)alkyl-N(C1-C6)alkyl2 group; or alternatively R7 and R8 form together with the carbon atom to which they are attached a (C3-C6)cycloalkyl group or a (C3-C6)heterocycloalkyl group;

■ R9 represents at least one substituent of the phenyl nucleus chosen, independently of each other, from: a hydrogen atom, -OH, (C1-C4)alkoxy, a halogen atom, -NH2, -NH(C1-C6)alkyl or -N(C1-C6)alkyl2 or -NH(C1-C6)cycloalkyl or (C3- C6)heterocycloalkyl group;

■ R10 represents at least one substituent of the phenyl nucleus chosen from a hydrogen atom and a (C1-C4)alkyl group;

■ Y represents

■ -NR11-(C1-C6)alkyl-, such as -NR11-(CH2)n- like

;

■ -O-(C1-C6)alkyl-, such as -O-(CH2)n- like

;

■ -S-(C1-C6)alkyl-, such as -S-(CH2)n- like

Y being positioned in an ortho (o), meta (m) or para (p) position of the phenyl nucleus;

■ R11 and R12 represent, independently of each other, a hydrogen atom or (C1- C6)alkyl, such as a hydrogen atom or a methyl group;

■ 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 any one of claims 1 to 12;

■ 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. Cryptophycin payloads of formula (IV) according to claim 14, having the following structure:

wherein:

■ R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, n, RCG1, X, Y and L are as defined in formula (IV) according to claim 14.

16. Cryptophycin payloads of formula (IV) according to claim 14 which are selected from the following list:

wherein:

■ R1, R2, R3, R4, R5, R6, R7, R8, R9 ,R10, R11, R12, n, X, Y and L are as defined in formula (IV) according to claims 14 or 15;

■ 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 any one of claims 1 to 12, and RCG2, an orthogonal reactive chemical group present on a polypeptide such as the antibody (Ab); and

■ Ab represents an antibody.

18. Conjugates of formula (V) according to claim 17, having the following structure:

wherein:

■ R1, R2, R3, R4, R5, R6, R7, R8, R9 ,R10, R11, R12, n, X, Y, L, G, RCG1, RCG2 and Ab are as in formula (V) according to claim 17.

19. Conjugates of formula (V) according to claim 17 or 18, wherein RCG2 is selected from:

(i)■-amino groups of lysines borne by the side chains of the lysine residues that are present at the surface of an antibody;

(ii) α-amino groups of N-terminal amino acids of antibody heavy and light chains; (iii) the saccharide groups of the hinge region;

(iv) the thiols of cysteines generated by reducing intra-chain disulfide bonds or the thiols of engineered cysteines;

(v) amide groups borne by the side chains of some glutamine residues that are present at the surface of an antibody; and

(vi) aldehyde groups introduced using formylglycine generating enzyme.

20. Conjugates of formula (V) according to claim 17 or 18, wherein:

- when RCG1 represents a N-hydroxysuccinimidyl ester, RCG2 represents a NH2 group;

- when RCG1 represents a maleimido function, a haloacetamido function, a chlorine atom or an activated disulfide, RCG2 represents a -SH group;

- when RCG1 represents a N3 group, RCG2 represents a C■CH group or an activated C■C group such as a cyclooctyne moiety;

- when RCG1 represents a OH or NH2 group, RCG2 represents a carboxylic acid or amide function;

- when RCG1 represents a SH group, RCG2 represents a maleimido function, a haloacetamido function or an activated disulfide function;

- when RCG1 represents a C■CH group or an activated C ^C group, RCG2 represents a N3 group;

- when RCG1 represents a O-alkyl hydroxylamine function or a Pictet-Spengler reaction substrate, RCG2 represents an aldehyde or ketone function.

21. Conjugates of formula (V) according to any one of claims 17 to 20, wherein G is selected from:

22. Conjugates of formula (V) according to claim 17, which is selected from the following list:

wherein Ab represents an antibody.

23. Process for preparing a conjugate of formula (V) as defined in any one of claims 17 to 22 comprising at least the steps of :

(i) placing in contact and leaving to react:

- an optionally buffered aqueous solution of an antibody, optionnally modified by means of a modifying agent,

and

- a solution of a cryptophycin payload of formula (IV) as defined in any one of claims 14 to 16,

the chemical group RCG1 of the cryptophycin payload of formula (IV) being reactive towards the chemical groups RCG2 present on the polypeptide such as the antibody especially towards the amino groups present on antibodies, the said chemical groups RCG2 having been introduced, where appropriate, by the modifying agent, so as to attach the cryptophycin payload of formula (IV) to the antibody by formation of a covalent bond;

(ii) and then optionally to separate the conjugate formed in step (i) from the cryptophycin payload of formula (IV) and/or from the unreacted antibody and/or from any aggregates that may have formed.

24. Medicament, wherein it comprises at least one conjugate of formula (V) according to any one of claims 17 to 22.

25. Pharmaceutical composition, wherein it comprises at least one conjugate of formula (V) according to any one of claims 17 to 22, and also at least one pharmaceutically acceptable excipient.

26. Use of the conjugates of formula (V) according to any one of claims 17 to 22 as anticancer agents.

27. Conjugates of formula (V) according to any one of claims 17 to 22 for use in the treatment of cancer.