Phosphinites as reductive disulfide rebridging agents

Abstract

The present invention generally relates to the field of bioconjugation. More specifically, it relates to phosphinites and their use as reductive disulfide rebridging agents. Thus, the present invention concerns a compound selected from compounds of formulae (la) and (lb), a conjugate which is obtainable by linking such compounds to another moiety, a method of modifying a disulfide-containing compound using a compound selected from compounds of formulae (la) and (lb), as well as a compound obtainable by the method.

Description

[0001] Phosphinites as reductive disulfide rebridging agents

[0002] Field of the invention

[0003] The present invention generally relates to the field of bioconjugation. More specifically, it relates to phosphinites and their use as reductive disulfide rebridging agents. Thus, the present invention concerns a compound selected from compounds of formulae (la) and (lb), a conjugate which is obtainable by linking such compounds to another moiety, a method of modifying a disulfide-containing compound using a compound selected from compounds of formulae (la) and (lb), as well as a compound obtainable by the method.

[0004] Background of the invention

[0005] Bioconjugation, i.e. the attachment of "cargo" molecules to large biomolecules in a predictable and uniform manner, has been successfully used in the past for producing antibody-drug conjugates and for developing probes to detect, visualize, and enrich certain compounds in cellular samples or extracts.

[0006] The conjugation of cargo substances to biomolecules ideally is done in a highly specific and reproducible manner, giving homogenous products. One method for bioconjugation that is particularly useful is the concept of disulfide rebridging, wherein disulfide bonds are reduced and then "re-bridged" with the cargo. As antibodies have multiple disulfide bonds, this offers a good opportunity for Antibody Drug Conjugate synthesis. Conjugation at cysteines via disulfide rebridging has been shown in the literature. For example patent literatures 1 and 2 as well as non-patent literatures 1 to 12 describe certain approaches.

[0007] The two steps of reduction and rebridging at best typically lead to mixtures of two products; one wherein all interchain disulfides are natively rebridged, and one wherein some interchain disulfides have been scrambled, resulting in a "half-stapled" antibody.

[0008] Accordingly, there is a need for agents for conjugation at cysteines via disulfide rebridging which can be used in a one-step reaction. Single reagent systems that accomplish disulfide rebridging have been previously reported (Lee et al. Chem. Sci. 2016, 7, 799 and Lu et al. Chem. Comm. 2022, 58, 12439. The molecule reported by Lee et al. is a heterobifunctional substance, with a prototypical disulfide reducing functional group (phosphine) chemically linked to a disulfide rebridging functional group (pyradazinedione). The pyradazinedione scaffold is susceptible to cross reaction with native cysteines, and is conceptually different from the herein described use of a single functional group for both reduction and rebridging. The phosphine reported by Lu et al. cross reacts with lysines and performs poorly at physiological pH. In view of these reports, it is unexpected that phosphinites, which would normally be expected to be less reactive than phosphines toward disulfides, perform so well as reductive disulfide rebridging agents.

[0009] Background Literature

[0010] Patent Literature 1: WO 2018 / 041985 Al

[0011] Patent Literature 2: WO 2022 / 223783 Al

[0012] Non-Patent Literature 1: ADC - Antibody-Drug-Conjugates, see Dumontet et. aL, Nature reviews Drug Discovery, 2023, 22, 641.

[0013] Non-Patent Literature 2: Fu et. al., Signal Transduction and Targeted Therapy 2022, 7, 93

[0014] Non-Patent Literature 3: Lu 2022, Chem. Commun., 2022, 58, 12439-12442,

[0015] 10.1039 / d2cc04967h Non-Patent Literature 4: Lee 2015, Chem. Sci., 2016,7, 799-802

[0016] Non-Patent Literature 5: C. E. Stieger et al, Angewandte Chemie International Edition

[0017] 2021, 60(28), 15359-15364; 10.1002 / anie.202100683

[0018] Non-Patent Literature 6: A. Beck et al., Nature Rev. Drug Discov. 2017, 16, 315-337.

[0019] Non-Patent Literature 7: S. C. Owen et aL, AAPS J. 2015, 17, 339-351.

[0020] Non-Patent Literature 8: C. P. R. Hackenberger et al., Curr. Opin. Chem. Biol. 2020, 58, 28-

[0021] 36.

[0022] Non-Patent Literature 9: J. R. Baker et al., Chem. Commun. 2021, 57, 10689-10702.

[0023] Non-Patent Literature 10: A. Madder et al. ChemBioChem 2016, 17, 529-553.

[0024] Non-Patent Literature 11: C. P. R. Hackenberger et aL, Chem. Sci. 2019, 10, 6322-6329.

[0025] Non-Patent Literature 12: C. P. R. Hackenberger et al., J. Am. Chem. Soc. 2020, 142, 9544-

[0026] 9552.

[0027] Summary of the invention

[0028] The present invention is defined in the appended claims and thus concerns a compound selected from compounds of formulae (la) and (lb), a conjugate which is obtainable by linking such compounds to another moiety, a method of modifying a disulfide-containing compound using a compound selected from compounds of formulae (la) and (lb), as well as a compound obtainable by the method.

[0029] The present inventors surprisingly found that both reduction of a disulfide and concomitant rebridging functions can be incorporated into one molecule by using a compound selected from compounds of formulae (la) and (lb). As result, it is possible to achieve more effective conjugation using such molecules without requiring two or more steps.

[0030] Furthermore, using the technology of the present invention, probes that can give a readout on the redox status (e.g. disulfide bonds) of proteins in cells or organisms can be obtained. This is valuable for redox biology and cannot be done with current technologies. More specifically, as the compounds of the present invention react with disulfide groups, but not free thiols, the degree to which the compounds of the present invention react with proteins etc. is an indication of the absolute amount of disulfides present in a sample. The redox status can then be determined by comparing this amount with the total amount of thiol groups (whether free thiols or oxidized this (e.g. in the form of disulfides)) known to be present in the sample.

[0031] The presently claimed compounds are phosphinites which are capable of reducing disulfides.

[0032] Reduction of the disulfide with the phosphinite forms a covalent linkage between the two reagents, generating an electrophilic vinyl (or alkynyl) phosphinothioate, and a nucleophilic thiolate, which recombine rapidly. Fast recombination means that cross-linked disulfides do not become separated by diffusion before the reaction has completed. Furthermore, the rapid reduction / rebridging sequence means that multiple disulfides that are in close proximity to each other do not become scrambled.

[0033] By using this technology, a one-step disulfide-specific bioconjugation method that retains the native disulfide linkage of an antibody can be achieved.

[0034] Description of the Figures

[0035] Fig. 1 shows a general structure of an antibody drug conjugate

[0036] Fig. 2 shows the mechanism of uptake and intracellular drug release from Antibody drug conjugates, (a) Antigen binding on the cell surface (b) receptor mediated endocytosis (c) endolysomal transportation (d) digestion of the antibody and linker (e) drug release to the cytosol. Detailed description of the invention

[0037] The compounds according to the present invention

[0038] In a first aspect, the present invention relates to a compound selected from compounds of formulae (la) and (lb) or a salt or solvate thereof.

[0039] The compounds of formulae (la) and (lb) are herein also referred to as phosphinite compounds of formulae (la) and (lb).

[0040] It is preferred that the compound is compound is a compound of formula (la).

[0041] R1is selected from optionally substituted -(CRm2)-aryl, optionally substituted -(CRm2)- heteroaryl, optionally substituted -(CRm2)-ethenyl, optionally substituted -(CRm2)-ethynyl, and -Si(Rs')3, wherein the one or more optional substituents of the optionally substituted aryl, optionally substituted heteroaryl, optionally substituted ethenyl and optionally substituted ethynyl are selected from Group C (wherein at least one of these substituents is preferably selected from Group A), each Rmis independently selected from Group D, and each RSiis independently selected from Group S.

[0042] Preferably, R1is selected from optionally substituted allyl, and optionally substituted benzyl, wherein the one or more optional substituents of the allyl and benzyl are selected from Group A, preferably wherein at least one of the one or more optional substituents of the benzyl in R1are present in ortho, ortho' or para position, relative to the position at which the methylene group of the benzyl is bound to the phenyl group of the benzyl. More preferably, R1is selected from benzyl having one two or three substituents selected from -O-alkyl, -O-heteroalkyl, N H (alkyl), and N (alkyl)2 and optionally one or two substituents selected from Group C; dityl (diphenylmethyl) optionally having one two orthree substituents selected from Group C (preferably selected from -O-alkyl, -O-heteroalkyl, NH(alkyl), and N(alkyl)2); and trityl optionally having one two or three substituents selected from Group C (preferably selected from -O-alkyl, -O-heteroalkyl, NH(alkyl), and N(alkyl)2); furyl, pyrrolyl, thienyl, oxazolyl, benzofuryl, benzothienyl, indolyl, any of which optionally having one two or three substituents selected from Group C; allyl optionally having a substituent selected from Group C (preferably selected from-O-alkyl, -O-heteroalkyl, NH(alkyl), and N (alkyl^); propargyl optionally having a substituent selected from Group C (preferably selected from-O-alkyl, -O- heteroalkyl, NH(alkyl), and N(alkyl)z); and -Si(Rs')3 wherein each RSiis independently selected from alkyl and aryl wherein the carbon being the attachment point in the alkyl is optionally replaced by Si. Still more preferably R1is selected from the following formulae: Preferred among these are the following formulae:

[0043] It is even more preferable that R1be selected from the following formulae:

[0044] R1preferably contains a solubilizing group which can help to improve water solubility of the compound of the first aspect. For this reason, it is to be understood that in any of the preceding formulae representing preferred examples of R1, one or more (preferably one) MeO- or (Me)N- group may be replaced by Me(O-CHRox-CHRox)noxO-, wherein each Roxis independently selected from H and alkyl (preferably C1-3 alkyl, such as methyl), and nox is an integer of from 1 to 50, preferably from 1 to 25, more preferably from 1 to 15, even more preferably from 1 to 10, still more preferably from 1 to 8, most preferably from 1 to 5. Preferably, one of the two Roxin each repeating unit is H and the other is H or methyl. Even more preferably all Roxare hydrogen.

[0045] An advantage of including the solubilizing group in R1is the fact that the substituent R1is cleaved when the compound of the first aspect reacts with a disulfide group, as intended in the present invention. Accordingly, in such a case a solubilizing group in R1will help with improve water solubility of the compound of the first aspect without being present in the product obtained after the reaction of the compound with the disulfide group.

[0046] Specific examples of group R1with water-solubilizing groups are shown in the following scheme:

[0047] G2= H or Me

[0048] R2is a group containing 1 to 300 carbon atoms and optionally 1 to 150 heteroatoms selected from S, N, O and P. It is to be understood that the number of hydrogens in R2does not have to be specifically limited because it is inherently limited by the number of carbon atoms and hetero atoms. R2 preferably does not contain any atoms other than C, S, N, O;P and H. However, it is to be understood that R2may contain cationic (e.g. ammonium or pyridinium) or anionic groups (e.g. sulfonate, phosphonate or carboxylate) which may be accompanied by counterions (e.g. alkali metal cations, alkaline earth metal cations, halide anions, phosphate anions, sulfate anions, etc.). Examples of preferable counterions are specified herein as "pharmaceutically acceptable salt forms". It is to be understood that such counterions may be different from C, S, N, 0, P and H and do not form part of the "1 to 300 carbon atoms and optionally 1 to 150 heteroatoms".

[0049] Preferably, R2is selected from optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, wherein the one or more optional substituents are of a nature that R2as a whole contains not more than 300 carbon atoms and not more than 150 heteroatoms, wherein the heteroatoms are selected from S, N, O and P.

[0050] Preferably, the one or more optional substituents of the optionally substituted alkyl and heteroalkyl are selected from Group B, and the one or more optional substituents of the optionally substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl are selected from Group C.

[0051] Even more preferably, R2is selected from optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, wherein the one or more optional substituents are of a nature that R2as a whole contains not more than 300 carbon atoms and not more than 150 heteroatoms, wherein the heteroatoms are selected from S, N, O and P. Still more preferably, R2is selected from optionally substituted aryl and optionally substituted heteroaryl, wherein the one or more optional substituents are of a nature that R2as a whole contains not more than 300 carbon atoms and not more than 150 heteroatoms, wherein the heteroatoms are selected from S, N, O and P. Even still more preferably, R2is selected from optionally substituted aryl (preferably optionally substituted phenyl), wherein the one or more optional substituents are of a nature that R2as a whole contains not more than 300 carbon atoms and not more than 150 heteroatoms, wherein the heteroatoms are selected from S, N, O and P.

[0052] R2is even more preferably selected from optionally substituted phenyl, wherein the one or more optional substituents of the phenyl are selected from group C.

[0053] It is particularly preferred that R2include a functional group for attachment of other groups.

[0054] This can be illustrated by the following formula:

[0055] wherein R2contains an alkyne group which can be reacted with a compound containing an azide, even after the compound of the first aspect has already reacted with the disulfide bond. This is particularly useful for the purpose of attaching fluorophores, enrichment handles, or drug cargos.

[0056] Thus, R2may preferably contain one or more groups selected from the following: a) a group which can be conjugated to biotin, desthiobiotin, fluorescent dyes, oligonucleotides, peptides, proteins, small molecules drugs such as N-Ac-y-calicheamicin (ozogamicin), mertansine, ravtansine, monomethyl auristatin, SN38, exatecan, deruxtecan, govitecan, or amanitin, b) a group selected from a terminal alkyne, cyclooctyne, 1,2,4,5-tetrazine, carboxylic acid, N- succidinimyl carboxylate, primary or secondary amine, and halogen, c) a group selected from the following bivalent groups: In particular, when a bio-orthogonal linking group is desired in R2, group R2preferably contains (or consists of) one or more selected from alkyne, cyclooctyne, or 1,2, 4, 5 tetrazine, preferably R2is selected from the following formulae:

[0057] R3is selected from hydrogen, optionally substituted alkyl and optionally substituted aryl, wherein the one or more substituents of the optionally substituted alkyl are selected from Group B, and the one or more substituents of the optionally substituted aryl are selected from Group C.

[0058] Preferably, R3is hydrogen or optionally substituted alkyl, wherein the one or more substituents of the alkyl are selected from Group X, preferably wherein R3is hydrogen or alkyl, more preferably R3is selected from hydrogen, methyl and ethyl, even more preferably R3is selected from hydrogen and methyl, still even more preferably R3is hydrogen.

[0059] R3ais selected from hydrogen and optionally substituted alkyl and optionally substituted aryl, wherein the one or more substituents of the optionally substituted alkyl are selected from Group B, and the one or more substituents of the optionally substituted aryl are selected from Group C.

[0060] R3bis selected from hydrogen and optionally substituted alkyl and optionally substituted aryl, wherein the one or more substituents of the optionally substituted alkyl are selected from Group B, and the one or more substituents of the optionally substituted aryl are selected from Group C. Preferably, R3aand R3bare independently selected from hydrogen and optionally substituted alkyl, wherein the one or more substituents of the alkyl are selected from Group X. More preferably R3aand R3bare independently selected from hydrogen and alkyl. Even more preferably R3aand R3bare independently selected from hydrogen, methyl and ethyl. Still more preferably R3aand R3bare independently selected from hydrogen and methyl. Still even more preferably R3aand R3bare each hydrogen.

[0061] R3cis selected from hydrogen, fluoro, cyano and optionally substituted alkyl, wherein the one or more substituents of the alkyl are selected from Group B.

[0062] More preferably, R3cis selected from hydrogen, fluoro, cyano and optionally substituted alkyl, wherein the one or more substituents of the alkyl are selected from Group X. Still more preferably R3cis selected from hydrogen, fluoro, cyano and alkyl. Even still more preferably R3cis selected from hydrogen, fluoro, cyano, methyl and ethyl; selected from hydrogen, fluoro, cyano and methyl. Most preferably R3cis hydrogen or fluoro. Among these R3cis preferably hydrogen.

[0063] A number of substituent groups are defined herein. These will be described in the following:

[0064] Group A: -OH, -OR, -NH2, -NHR, -NR2, -NHC(O)R, -NHC(O)OR, -OC(O)R, -OC(O)NH2, -OC(O)NHR, -OC(O)NR2, -PR2, -SH, -SR, optionally substituted alkyl, optionally substituted heteroalkyl and optionally substituted cycloalkyl, wherein the one or more optionally substituents of the alkyl and heteroalkyl are selected from group X, the one or more optionally substituents of the cycloalkyl are selected from group Y, and each R is independently selected from optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, wherein the one or more optional substituents of the alkyl and heteroalkyl are selected from group X and the one or more optional substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are selected from Group Y;

[0065] Preferred Group A: -OH, -OR, -NH2, -NHR, -NR2, -NHC(O)R, -NHC(O)OR, -OC(O)R, -OC(O)NH2, -

[0066] OC(O)NHR, and -OC(O)NR2, wherein each R is independently selected from optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, wherein the one or more optional substituents of the alkyl and heteroalkyl are selected from group X and the one or more optional substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are selected from Group Y;

[0067] Most preferred Group A: -OR, and -NR2, wherein each R is independently selected from optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, wherein the one or more optional substituents of the alkyl and heteroalkyl are selected from group X and the one or more optional substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are selected from Group Y.

[0068] Group B: -halogen, -OH, -O-R, -CN, -NO2, -COOH, -C(0)0-R, -C(O)NH2, -C(O)NHR, -C(O)NR2, - C(O)-R, -NH2, -NH(R), -N(R)2, -NHC(O)R, -NHC(O)OR, -NHS(O)2-R, -OC(O)R, -OC(O)NH2, - OC(O)NHR, -OC(O)NR2, -PR2, -SH, -S-R, -S(O)(R), -S(O)2(R), -S(O)2NH(R), -SO3H, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, wherein the one or more optional substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are selected from Group Y and each R is independently selected from optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, wherein the one or more optional substituents of the alkyl and heteroalkyl are selected from group X and the one or more optional substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are selected from Group Y;

[0069] Preferred Group B: -O-R, -C(O)NHR, -C(O)NR2, -N(R)2, -NHC(O)R, -NHS(O)2-R, -S-R, -S(O)(R), - S(O)2(R), -S(O)2NH(R), optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, wherein the one or more optional substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are selected from Group Y and each R is independently selected from optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, wherein the one or more optional substituents of the alkyl and heteroalkyl are selected from group X and the one or more optional substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are selected from Group Y;

[0070] Most preferred Group B: -O-R, -NHCO-R, -S(O)2NH(R), optionally substituted aryl and optionally substituted heteroaryl, wherein the one or more optional substituents of the aryl and heteroaryl are selected from Group Y and each R is independently selected from optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, wherein the one or more optional substituents of the alkyl and heteroalkyl are selected from group X and the one or more optional substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are selected from Group Y.

[0071] Group C: -halogen, -OH, -O-R, -CN, -NO2, -COOH, -C(O)O-R, -C(O)-R, -C(O)NH2, -C(O)NHR, - C(O)NR2, -NH2, -NH(R), -N(R)2, -NHC(O)-R, -NHC(O)OR, -NHS(O)2-R, -OC(O)R, -OC(O)NHR, -OC(O)NR2, -PR2, -SH, -S-R, -S(O)(R), -S(O)2(R), -S(O)2NH(R), -SO3H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, wherein the one or more optional substituents of the alkyl, alkenyl, alkynyl and heteroalkyl are selected from group X, the one or more optionally substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are selected from group Y, and each R is independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, wherein the one or more optional substituents of the alkyl, alkenyl, alkynyl and heteroalkyl are selected from group X and the one or more optional substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are selected. from Group Y;

[0072] More Preferred Group C: -halogen, -O-R, -C(O)O-R, -C(O)-R, -C(O)NHR, -C(O)NR2, -NH(R), - N(R)2, -NHC(O)-R, -NHC(O)OR, -NHS(O)2-R, -OC(O)R, -OC(O)NHR, -OC(O)NR2, -S(O)(R), - S(O)2(R), -S(O)2NH(R), optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, wherein the one or more optional substituents of the alkyl, alkenyl, alkynyl and heteroalkyl are selected from group X, the one or more optionally substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are selected from group Y, and each R is independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, wherein the one or more optional substituents of the alkyl, alkenyl, alkynyl and heteroalkyl are selected from group X and the one or more optional substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are selected from Group Y;

[0073] Most Preferred Group C: -halogen, -O-R, -C(O)NHR, -C(O)NR2, -NH(R), -N(R)2, -NHC(O)-R, - NHC(O)OR, -NHS(O)2-R, -OC(O)R, -OC(O)NHR, -OC(O)NR2, -S(O)(R), -S(O)2(R), - S(O)2NH(R), optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, wherein the one or more optional substituents of the alkyl, alkenyl, alkynyl and heteroalkyl are selected from group X, the one or more optionally substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are selected from group Y, and each R is independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, wherein the one or more optional substituents of the alkyl, alkenyl, alkynyl and heteroalkyl are selected from group X and the one or more optional substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are selected from Group Y.

[0074] Group D: hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, wherein the one or more optionally substituents of the alkyl and heteroalkyl are selected from group X, the one or more optionally substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are selected from group Y.

[0075] More preferred Group D: hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, wherein the one or more optionally substituents of the alkyl are selected from group X and the one or more optionally substituents of the cycloalkyl are selected from group Y, and each R is independently selected from optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, wherein the one or more optional substituents of the alkyl and heteroalkyl are selected from group X and the one or more optional substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are selected from Group Y;

[0076] Most preferred Group D: hydrogen.

[0077] Group S: optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, wherein the one or more optionally substituents of the alkyl and heteroalkyl are selected from group X, the one or more optional substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are selected from group Y; wherein the carbon being the attachment point of Group S in the optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl is optionally replaced by Si.

[0078] More preferred Group S: optionally substituted alkyl, optionally substituted cycloalkyl and optionally substituted aryl, wherein the one or more optionally substituents of the alkyl are selected from group X, the one or more optional substituents of cycloalkyl and aryl are selected from group Y; wherein the carbon being the attachment point of Group S in the optionally substituted alkyl or optionally substituted cycloalkyl is optionally replaced by Si.

[0079] Most preferred Group S: alkyl and aryl.

[0080] Group X: -halogen, -OH, -O-alkyl, -O-heteroalkyl, -CN, -NO2, -COOH, -C(O)O-alkyl, -C(O)-alkyl, - NH2, -NH(alkyl), -N(alkyl)2, -NHCO-alkyl, -NHC(O)O-alkyl, -NHS(O)2-alkyl, -OCO-alkyl, OC(O)NH-alkyl, -SH, -S-alkyl, -S(O)(alkyl), -S(O)2(alkyl), -S(O)2NH (alkyl) and -SO3H;

[0081] More preferable Group X: -OH, -O-alkyl, -O-heteroalkyl, -C(O)O-alkyl, -NH2, -NH(alkyl), - N(alkyl)2, -NHCO-alkyl, -NHC(O)O-alkyl, -NHS(O)2-alkyl, -OCO-alkyl, OC(O)NH-alkyl, - S(O)2NH(alkyl);

[0082] Most preferable Group X: -OH, -O-alkyl, -NH2, -N(alkyl)2, -NHCO-alkyl, -NHC(O)O-alkyl, - OC(O)NH-alkyl, -S(O)2NH(alkyl).

[0083] Group Y: -alkyl, -heteroalkyl, -cycloalkyl, -halogen, -OH, -O-alkyl, -O-heteroalkyl, -CN, -NO2, - COOH, -C(O)O-alkyl, -C(O)-alkyl, -NH2, -NH(alkyl), -N(alkyl)2, -NHCO-alkyl, -NHC(O)O- alkyl, -NHS(O)2-alkyl, -OCO-alkyl, -OC(O)NH-alkyl, -SH, -S-alkyl, -S(O)(alkyl), -S(O)2(alkyl), -S(O)2NH(alkyl) and -SO3H, wherein the -alkyl, -heteroalkyl and -cycloalkyl are optionally further substituted by one or more selected from -heteroalkyl, -cycloalkyl, -O-heteroalkyl, -CN, -NO2, -COOH, - C(O)O-alkyl, -C(O)-alkyl, -NH2, -NH(alkyl), -N(alkyl)2, -NHCO-alkyl, -NHS(O)2-alkyl, -OCO- alkyl, -SH, -S-alkyl, -S(O)(alkyl), -S(O)2(alkyl), -S(O)2NH(alkyl) and -SO3H;

[0084] More preferable Group Y: -alkyl, -OH, -O-alkyl, -C(O)O-alkyl, -NH2, -NH(alkyl), -N(alkyl)2, - NHCO-alkyl, -NHC(O)O-alkyl, -NHS(O)2-alkyl, -OCO-alkyl, -OC(O)NH-alkyl, and - S(O)2NH(alkyl), wherein the -alkyl are optionally further substituted by one or more selected from - heteroalkyl, -cycloalkyl, -O-heteroalkyl, -CN, -NO2, -COOH, -C(O)O-alkyl, -C(O)-alkyl, - NH2, -NH(alkyl), -N(alkyl)2, -NHCO-alkyl, -NHS(O)2-alkyl, -OCO-alkyl, -SH, -S-alkyl, - S(O)(alkyl), -S(O)2(alkyl), -S(O)2NH(alkyl) and -SO3H;

[0085] Most preferable Group Y: -alkyl, -OH, -O-alkyl, -NH2, -NH(alkyl), -N(alkyl)2, -NHCO-alkyl, - NHC(O)O-alkyl, -NHS(O)2-alkyl, -OC(O)NH-alkyl, and -S(O)2NH(alkyl), wherein the -alkyl are optionally further substituted by one or more selected from - heteroalkyl, -cycloalkyl, O-heteroalkyl, -CN, -NO2, -COOH, -C(O)O-alkyl, -C(O)-alkyl, -NH2, -NH(alkyl), -N(alkyl)2, -NHCO-alkyl, -NHS(O)2-alkyl, -OCO-alkyl, -SH, -S-alkyl, -S(O)(alkyl), -S(O)2(alkyl), -S(O)2NH(alkyl) and -SO3H.

[0086] It is to be understood that any -alkyl and -heteroalkyl are preferably not substituted with any -alkyl and -heteroalkyl. More preferably, they are also not substituted with any -cycloalkyl and -heterocycloalkyl.

[0087] It is to be understood that any - cycloalkyl and -heterocycloalkyl are preferably not substituted bywith any -alkyl and -heteroalkyl. More preferably, they are also not substituted bywith any cycloalkyl and -heterocycloalkyl.

[0088] The salts of formulae la and lb typically comprise salts with non-coordinating and / or non- nucleophilic anions such as tetrafluoroboric salts, perchlorate salts, borate salts, and hexafluoroantiminate salts.

[0089] More preferably, the salts of formulae la and lb are tetrafluoroboric salts and perchlorate salts. It has been found that such salts exhibit particularly preferred properties such as improved stability.

[0090] The solvates of formulae la and lb typically comprise solvates with borane (preferably monoborane), water (i.e., as a hydrate) or solvates with organic solvents such as, e.g., methanol, ethanol, isopropanol, ethyl acetate, ethanolamine, DMSO, or acetonitrile. More preferably, solvates of formulae la and lb are solvates with monoborane (also referred to as BH3adducts). It has been found that such solvates exhibit particularly preferred properties such as improved stability.

[0091] In a particularly preferred embodiment, the compound of the first aspect has preferably the following formula:

[0092] The conjugate of the present invention

[0093] In a second aspect, the present invention relates to a conjugate of the compound of formulae (la) and (lb). It is to be understood that also the conjugate may be a salt or solvate as defined for the compound of formulae (la) and (lb).

[0094] The conjugate is typically obtainable by linking a compound of formula (la) or (lb), or a salt or solvate thereof, with one or more selected from a peptide, a protein, an antibody, a nucleotide, an oligonucleotide, a saccharide, a polysaccharide, a detectable label, a radioactive or non-radioactive nuclide, biotin, desthiobiotin, a reporter enzyme, a protein tag, a fluorophore such as CY5, fluorescein or EDANS, biotin, a linker, a drug, a linker-drug conjugate, a linker-fluorophore conjugate, a polymer, a small molecule drug such as N-Ac-y- calicheamicin (ozogamicin), mertansine, ravtansine, monomethyl auristatin, SN38, exatecan, deruxtecan, govitecan, or amanatin.

[0095] Thus, the conjugate of the present invention preferably differs from the compound of the first aspect of the present invention in that the conjugate further contains a moiety which results from the reaction with the one or more selected from a peptide, a protein, an antibody, a nucleotide, an oligonucleotide, a saccharide, a polysaccharide, a detectable label, a radioactive or non-radioactive nuclide, biotin, desthiobiotin, a reporter enzyme, a protein tag, a fluorophore such as CY5, fluorescein or EDANS, biotin, a linker, a drug, a linker-drug conjugate, a linker-fluorophore conjugate, a polymer, a small molecule drug such as N-Ac-y- calicheamicin (ozogamicin), mertansine, ravtansine, monomethyl auristatin, SN38, exatecan, deruxtecan, govitecan, or amanatin.

[0096] Preferably, the conjugate of the present invention differs from the compound of the first aspect of the present invention in that the conjugate further contains a moiety which results from the reaction with the one or more selected from a peptide, a protein, an antibody, biotin, desthiobiotin, a protein tag, a fluorophore such as CY5, fluorescein or EDANS, a linker, a drug, a linker-drug conjugate, a linker-fluorophore conjugate, a polymer, a small molecule drug such as N-Ac-y-calicheamicin (ozogamicin), mertansine, ravtansine, monomethyl auristatin, SN38, exatecan, deruxtecan, govitecan, or amanatin.

[0097] Most preferably, the conjugate of the present invention preferably differs from the compound of the first aspect of the present invention in that the conjugate further contains a moiety which results from the reaction with the one or more selected from a peptide, a protein, an antibody, a linker, a drug, a linker-drug conjugate, a linker-fluorophore conjugate, a polymer, a small molecule drug such as N-Ac-y-calicheamicin (ozogamicin), mertansine, ravtansine, monomethyl auristatin, SN38, exatecan, deruxtecan, govitecan, or amanatin.

[0098] It is contemplated that the conjugate may also be formed by linking a compound of formula (la) or (lb), or a salt or solvate thereof, with other groups of interest not recited in the above list, depending on the actions intended to be performed with the conjugate.

[0099] The compound of formula (la) or (lb), or a salt or solvate thereof, may be linked directly with the one or more selected from a peptide, protein etc. mentioned above, or may be linked via a spacer. The use of an explicit spacer is not mandatory. Rather a direct link between the compound of formula (la) or (lb), or a salt or solvate thereof and the one or more selected from a peptide, protein etc. mentioned above is feasible.

[0100] Preferred spacers contain one or more groups (preferably 1 to 50, more preferably 1 to 20, even more preferably 1 to 10) selected from - N(RL)~ , -C1-10 alkylene-, -C(O)-, -O-, - heteroarylene-, -phenylene-, -S-, -S(O)- and -S(O)2~ wherein each RLis independently selected from hydrogen and C1-6 alkyl, each C1-10 alkylene is independently optionally substituted with one or more selected from halogen, C(O)OH and OH, each heteroarylene is independently 4 to 6 membered heteroarylene comprising 1 to 3 heteroatoms selected from N, O and S and the heteroarylene is optionally substituted with one or more selected from halogen and C1-6 alkyl, and each phenylene is optionally substituted with one or more selected from halogen and C1-6 alkyl.

[0101] Furthermore, the spacer group may comprise one or two or three side chains which can be attached to the main chain of the spacer group by replacing one or two or three hydrogen residues, preferably in a -C1-10 alkylene- moiety, in the main chain of the spacer group by the side chain(s). These side chains may comprise 1 to 10, preferably 1 to 8, groups selected from -N(RL)-, -C1-10 alkylene-, — C(O)— , -O-, -heteroarylene-, -phenylene-, -S-, -S(O)- and - S(O)2— and are terminated by -H, wherein the definitions of RLand the optional substituents of the other groups are as defined for the main chain of the spacer group.

[0102] The spacer group preferably consists of one or more groups selected from -N(RL)-, -Ci-io alkylene-, -C(O)-, -O-, -heteroarylene-, -phenylene-, -S-, -8(0)- and -S(O)2-.

[0103] In the present invention, it is preferred that the spacer group comprises or consists of 3 to 15, more preferably 3 to 12, even more preferably 3 to 10 and most preferably 4 to 8 of the above groups.

[0104] Furthermore, as will be apparent to a skilled person, two adjacent groups in the spacer group should be chosen so as to avoid a direct bond between two groups which would result in a partial structure which is not stable, in particular, in an aqueous medium at 25°C and a pressure of 1 atm. From this standpoint, combinations such as -N(RL)-N(RL)-, -C(O)-C(O)-, -O-O-, -S-S-, -S(O)-S(O)-, -S(O)2-S(O)2- -N(RL)-O-, -O-N(RL)-, -N(RL)-S-, - S-N(RL)-, -N(RL)-S(O)-, -S(O)-N(RL)-, -C(O)-S-, -S-C(O)-, -C(O)-S(O)-, -S(O)-C(O)-, -C(O)- S(O)2-, -S(O)2-C(O)-, -S-O-, -O-S-, -S(O)-O- -O-S(O)-,

[0105] —8(0)— 8—, -S-S(O)-, — S(O)2— S— , -S-S(O)2-, S(O)2— 8(0)- and -S(O)-S(O)2- are preferably excluded. Furthermore, it is preferred that the combinations -C1-10 alkylene-C1-10 alkylene-, - heteroarylene-heteroarylene- and -phenylene-phenylene- are excluded in the spacer.

[0106] Irrespective of whether a spacer is used, it is evident to a skilled person that the linking of two chemical entities (such as a compound of formula (la) or (lb), or a salt or solvate thereof with a peptide, protein etc. mentioned above) requires a chemical reaction between a chemical group in both chemical entities to be linked. Persons skilled in the art are aware of a plethora of suitable chemical reactions which can be used for achieving such a linking of two chemical entities. For example, a carboxylic acid in one chemical entity may be linked to a primary (or secondary) amine in the other chemical entity by activation of the carboxylic acid. There is a multitude of known activation methods, as can be seen, e.g. from "Large-Scale Amidations in Process Chemistry: Practical Considerations for Reagent Selection and Reaction Execution", Org. Process Res. Dev. 2022, 26(6), 1562-1689.

[0107] Particular versatile linking approaches are set out in the following:

[0108] The linking of a carboxylic acid and an amine via the coupling agent HATU and a non- nucleophilic amine. The linking of an amine with a succinic ester. The linking of an amine with a carboxylic acid chloride in the presence of a non-nucleophilic amine. The linking of an amine with a sulfonyl chloride and a non-nucleophilic amine.

[0109] The method of modifying a disulfide-containing compound

[0110] In a third aspect, the present invention relates to a method of modifying a disulfide-containing compound. The method comprises reactingthe compound of the first aspect, or the conjugate of the second aspect, with a disulfide-containing compound.

[0111] The disulfide-containing compound is preferably a protein. Thus, the disulfide-containing compound is preferably a protein containing at least one S-S bond.

[0112] The method preferably involves the reaction of: with a disulfide represented by sented by or the reaction of with a disulfide illustrated by esented by

[0113] In both options, each of R1, R2, R3, R3a, R3band R3care as defined above for the compound of the present invention in the first aspect.

[0114] It is to be understood that the disulfide which can be illustrated by can be any disulfide group capable of reacting with compound la and / or compound lb and / or the conjugate. Preferably, the disulfide is a disulfide in which both sulfurs of the disulfide are linked to carbon atoms.

[0115] Preferred disulfide groups are disulfide groups formed by the reaction of two cysteine amino acids that are preferably present in an amino acid containing polymer such as a protein, preferably an antibody.

[0116] As a skilled person readily understands from the above, the disulfide group participating in the reaction of the method of the present will be chemically modified and therefore cease to be a disulfide group in the common chemical sense because the two sulfur atoms of the disulfide group will no longer be bonded directly to each other but via a bridge containing at least two carbon atoms and a phosphorous atom between the two sulfurs.

[0117] In the method of modifying a disulfide-containing compound of the present invention, it is to be understood that the disulfide-containing compound may contain more than one disulfide group and that not all of the disulfide groups in such a disulfide-containing compound have to take part in the reaction of the method of modifying a disulfide-containing compound of the present invention. Rather, it is preferred that from 1 to 4, preferably 2 to 4, more preferably 3 or 4, most preferably 4 of the disulfide groups in such a disulfide-containing compound take part in the reaction of the method of modifying a disulfide-containing compound of the present invention.

[0118] The disulfide group reacting in the method of modifying a disulfide-containing compound of the present invention can be a cyclic disulfide group, i.e. a disulfide group, wherein the atoms to which the two sulfurs of the disulfide group are bound would be part of the same molecule if the two sulfurs were not bound to each other. In other words, the disulfide group reacting in the method of modifying a disulfide-containing compound of the present invention may be an intramolecular disulfide group.

[0119] However, it is preferred that the disulfide group reacting in the method of modifying a disulfide-containing compound of the present invention be a non-cylic disulfide group, i.e. a disulfide group, wherein the atoms to which the two sulfurs of the disulfide group are bound would not be part of the same molecule if the two sulfurs were not bound to each other. In other words, the disulfide group reacting in the method of modifying a disulfide-containing compound of the present invention is preferably an intermolecular disulfide group. More preferable, the disulfide group reacting in the method of modifying a disulfide-containing compound of the present invention is part of an interchain disulfide in an antibody.

[0120] The compound obtainable by the method

[0121] In a fourth aspect, the present invention relates to a compound obtainable by the method described above (third aspect). This compound may also be referred to herein as "modified disulfide-containing compound".

[0122] This compound preferably contains one or more of the following groups: wherein R2, R3, R3a, R3band R3care as defined in the first aspect and may have been modified as described in the second aspect to form the conjugate.

[0123] This group (or these groups) is / are typically present in parts of the compound where there was a disulfide group before the reaction with compound la and / or compound lb and / or the conjugate.

[0124] It is preferred that R2in the above formulae comprises one or more selected from a peptide, a protein, an antibody, a nucleotide, an oligonucleotide, a saccharide, a polysaccharide, a detectable label, a radioactive or non-radioactive nuclide, biotin, desthiobiotin, a reporter enzyme, a protein tag, a fluorophore such as CY5, fluorescein or EDANS, biotin, a linker, a drug, a linker-drug conjugate, a linker-fluorophore conjugate, a polymer, a small molecule drug such as N-Ac-y-calicheamicin (ozogamicin), mertansine, ravtansine, monomethyl auristatin, SN38, exatecan, deruxtecan, govitecan, or amanitin. More preferably, the R2in the above formulae comprises a small molecule drug such as N-Ac-y-calicheamicin (ozogamicin), mertansine, ravtansine, monomethyl auristatin, SN38, exatecan, deruxtecan, govitecan, or amanitin. As will be evident to the skilled person, the term "comprises one or more selected from" as used in the present paragraph means that a chemical link has been established between these and the rest of R2.

[0125] It is to be understood that the compound of the fourth aspect may furthermore contain one or more disulfide groups, i.e. one or more disulfide groups which have not been reacted with compound la and / or compound lb and / or the conjugate.

[0126] The compound that has been modified is preferably a protein, more preferably an antibody, even more preferably an IgGl or IgGlx antibody. Examples of other antibodies include IgA, IgD, IgE, IgG, IgM, a humanized antibody, a chimeric antibody, a monoclonal antibody, and an isolated antibody. Specific antibodies are the following antibodies: trastuzumab, cetuximab, brentuximab, inotuzumab, polatuzumab, belantamab, tisotumab, disitamab, mirvetuximab, loncastuximab and enfortumab.

[0127] Preferred compounds of the fourth aspect have a molecular weight of about 50 to about 300 kDa, preferably 100 to 200 kDa, more preferably 130 to 170 kDa. The molecular weight can be determined by intact mass spectrometry.

[0128] Medical uses

[0129] The compound of the first aspect, the conjugate of the second aspect and the compound of the fourth aspect can be used in many areas of medicine.

[0130] For ease of reference, the compound of the first aspect, the conjugate of the second aspect and the compound of the fourth aspect are also collectively referred to as the "compounds of the present formulae". Preferably, the term "compounds of the present formulae" refers to the compound of the fourth aspect. The compounds of the present formulae can preferably be used in targeted disease treatment. Targeted disease treatment is intended go directly to the aimed cell structures and leave healthy tissue unaffected. Therapeutic antibodies, as a new class of tools for disease treatment emerging in the last decades, are immunological proteins designed by nature to bind specific cell structures. To yield highly homogeneous and well-characterized products, antibodies can be artificially produced as monoclonal antibodies. Their target-binding and immune-cell-recruiting properties can be used in different ways to fight malignant cells, for example in tumors. A possible application of unmodified antibodies is cancer immunotherapy, where the patient's immune-cells are recruited or extracellular growth factors are blocked by monoclonal antibodies. But also monoclonal antibodies with no intrinsic antitumor activity can be useful tools in cancer therapy. Among other possibilities, they can act as effective guiding units to direct a drug into the tumor cells. This is the concept behind antibody drug conjugates, a class of modern cancer therapeutics in which a highly cytotoxic payload is connected to a cancer specific monoclonal antibody via a chemical linker (cf. Figure 1).

[0131] The mechanisms behind antibody drug conjugate cancer treatment can be understood as antibody drug conjugates circulating in the patient's blood without affecting the surrounding tissue and cells, because drug targets are selected to be intracellular and cannot be affected by the drug while it is bound to the antibody. The process of drug release and activation typically starts when an antibody drug conjugate reaches a cell that presents the antibody's specific antigen (cf. Figure 2). Binding of the antibody to the antigen takes place and the bound immunoconjugate is internalized by the cell, which usually happens via receptor mediated endocytosis. Most commonly, clathrin mediated endocytosis is stated as the uptake mechanism for antibody drug conjugates but distinction from caveolin mediated endocytosis is often not clear. The early endosome which is formed during endocytosis then matures and directs the internalized antibody drug conjugate along the endolysomal degradation pathway, where it finally ends up in the lysosome. Lysosomes are acidic (typically pH 4.5-5), and digestive cell compartments that contain several proteolytic enzymes. The antibody-part of the antibody drug conjugate and optionally (part of a) linker are digested there, which finally leads to release of the now active drug into the cytoplasm where it causes cell death. Antibody drug conjugates typically have two or three parts (see Figure 1): a monoclonal antibody, an optional linker and a cytotoxic payload.

[0132] Thus, in the context of the compound of the fourth aspect, the present invention preferably relates to antibody drug conjugates in which a cytotoxic compound has been attached to a monoclonal antibody by means of the compound of the first aspect or the conjugate of the second aspect. Accordingly, the compound of the first aspect or the conjugate of the second aspect can be part of (preferably act as) the linker between the monoclonal antibody and the cytotoxic payload.

[0133] Specifically, an antibody drug conjugate is preferably obtained by one of the following procedures A and B:

[0134] Procedure A:

[0135] (A-i) Linking a compound as defined in formulae (la) and (lb), or a salt or solvate thereof, to a cytotoxic compound, and

[0136] (A-ii) Reacting the product of (i) with a monoclonal antibody.

[0137] Procedure B:

[0138] (B-i) reacting a compound as defined in formulae (la) and (lb), or a salt or solvate thereof, with a monoclonal antibody, and

[0139] (B-ii) Linking a cytotoxic compound to the moiety originating from the compound as defined in formulae (la) and (lb).

[0140] The present invention may furthermore be used for the enrichment of disulfide-containing molecules from complex mixtures, visualization of disulfide-containing molecules in in-vitro analysis (e.g. non-reducing gels, fixed and permeabilized cells), as well as for labelling of surfaces. Preferably the compound of the first aspect, the conjugate of the second aspect and the compound of the fourth aspect are for use in the treatment of a cancer.

[0141] The cancer is preferably selected from anaplastic large-cell lymphoma (ALCL), acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML), breast cancers (BC) including triple-negative breast cancer (TNBC), B-cell lymphomas (BCL) including diffuse large-B-cell lymphoma (DLBCL), gastric cancers (GC), gastro-oesophageal junction cancer (GOJ), Hodgkin lymphoma (HL), multiple myeloma (MM), non small-cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), myeloproliferative neoplasm MPN), nasopharyngeal carcinoma (NPC), chronic lymphocytic leukemia (CLL), urethral cancers, epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, CD30-positive T cell lymphoma, TROP-2 positive tumors, HER2-positive tumors, and nectin-4 positive tumors.

[0142] The following definitions apply throughout the present specification and the claims, unless specifically indicated otherwise.

[0143] The term "hydrocarbon group" refers to a group consisting of carbon atoms and hydrogen atoms.

[0144] The term "alicyclic" is used in connection with cyclic groups and denotes that the corresponding cyclic group is non-aromatic.

[0145] As used herein, the term "alkyl" refers to a monovalent saturated acyclic (i.e., non-cyclic) hydrocarbon group which may be linear or branched. Accordingly, an "alkyl" group does not comprise any carbon-to-carbon double bond or any carbon-to-carbon triple bond. A "Ci- 5 alkyl" denotes an alkyl group having 1 to 5 carbon atoms. Preferred exemplary alkyl groups are methyl, ethyl, propyl (e.g., n-propyl or isopropyl), or butyl (e.g., n-butyl, isobutyl, sec-butyl, or tert-butyl). Unless defined otherwise, the term "alkyl" preferably refers to Ci-4 alkyl, more preferably to methyl or ethyl, and even more preferably to methyl. As used herein, the term "heteroalkyl" refers to alkyl in which one or more (preferably 1, 2, or 3) secondary carbon atoms have been replaced by NH, O or S, one or more (preferably 1, 2, or 3) tertiary carbon atoms have been replaced by N, and / or one or more (preferably 1, 2, or 3) quaternary carbon atoms have been replaced by N+ (with a counter anion).

[0146] The carbon atom replaced is preferably not the carbon atom of the attachment point of the heteroalkyl group (to the remainder of the molecule). This applies preferably to the first "optionally substituted heteroalkyl" mentioned in each of groups D and S. This preferably also applies to the "heteroalkyl" in "-O-heteroalkyl". In contrast, this preferably does not apply to any other "optionally substituted heteroalkyl" groups.

[0147] Polyethylene glycol groups are a preferred type of heteroalkyl groups. The other terminus of the polyethylene glycol groups is preferably capped with an alkyl group.

[0148] For example the term "heteroalkyl" may preferably refer to Me(O-CHRox-CHRox)noxO-, wherein each Roxis independently selected from H and alkyl (preferably C1-3 alkyl, such as methyl), and nox is an integer of from 1 to 50, preferably from 1 to 25, more preferably from 1 to 15, even more preferably from 1 to 10, still more preferably from 1 to 8, most preferably from 1 to 5. Preferably, one of the two Roxin each repeating unit is H and the other is H or methyl. Even more preferably all Roxare hydrogen.

[0149] It is generally preferred that the "heteroalkyl" group contains not more than 100 nonhydrogen atoms, more preferably not more than 50 non-hydrogen atoms, even more preferably not more than 20 non-hydrogen atoms.

[0150] If two heteroatoms are present adjacent to each other in the "heteroalkyl" group combinations such as -N(RL)-N(RL)-, -C(O)-C(O)-, -O-O-, -S-S-, -S(O)-S(O)-, -S(O)2-S(O)2- , -N(RL)-O-, -O-N(RL)-, -N(RL)-S-, -S-N(RL)-, -N(RL)-S(O)-, -S(O)-N(RL)-, -C(O)-S-, -S- C(O)-, -C(O)-S(O)-, -S(O)-C(O)-, -C(O)-S(O)2-, -S(O)2-C(O)-, -S-O-, -O-S-, -S(O)-O-, -o- S(O)-, — S(O)-S-, -S-S(O)-, -S(O)2-S-, -S-S(O)2-, S(O)2-S(O)- and -S(O)-S(O)2- are preferably excluded.

[0151] As used herein, the term "alkenyl" refers to a monovalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon- to-carbon double bonds while it does not comprise any carbon-to-carbon triple bond. The term "C2-s alkenyl" denotes an alkenyl group having 2 to 5 carbon atoms. Preferred exemplary alkenyl groups are ethenyl, propenyl (e.g., prop-l-en-l-yl, prop-l-en-2-yl, or prop-2-en-l-yl), butenyl, butadienyl (e.g., buta-l,3-dien-l-yl or buta-l,3-dien-2-yl), pentenyl, or pentadienyl (e.g., isoprenyl). Unless defined otherwise, the term "alkenyl" preferably refers to C2-4 alkenyl.

[0152] As used herein, the term "alkynyl" refers to a monovalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon- to-carbon triple bonds and optionally one or more (e.g., one or two) carbon-to-carbon double bonds. The term "C2-5 alkynyl" denotes an alkynyl group having 2 to 5 carbon atoms. Preferred exemplary alkynyl groups are ethynyl, propynyl (e.g., propargyl), or butynyl. Unless defined otherwise, the term "alkynyl" preferably refers to C2-4 alkynyl.

[0153] As used herein, the term "alkylene" refers to an alkanediyl group, i.e. a divalent saturated acyclic hydrocarbon group which may be linear or branched. A "C1-5 alkylene" denotes an alkylene group having 1 to 5 carbon atoms; the term "C0-5 alkylene" indicates that a covalent bond (corresponding to the option "Co alkylene") or a C1-5 alkylene is present. Preferred exemplary alkylene groups are methylene (-CH2-), ethylene (e.g., -CH2-CH2- or -CH(-CH3)-), propylene (e.g., -CH2-CH2-CH2-, -CH(-CH2-CH3)-, -CH2-CH(-CH3)-, or -CH(-CH3)-CH2-), or butylene (e.g., -CH2-CH2-CH2-CH2-). Unless defined otherwise, the term "alkylene" preferably refers to C1-4 alkylene (including, in particular, linear C1-4 alkylene), more preferably to methylene or ethylene, and even more preferably to methylene.

[0154] As used herein, the term "alkenylene" refers to an alkenediyl group, i.e. a divalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon double bonds while it does not comprise any carbon-to-carbon triple bond. A "C25 alkenylene" denotes an alkenylene group having 2 to 5 carbon atoms. Unless defined otherwise, the term "alkenylene" preferably refers to C2-4 alkenylene (including, in particular, linear C2-4 alkenylene).

[0155] As used herein, the term "alkynylene" refers to an alkynediyl group, i.e. a divalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon triple bonds and optionally one or more (e.g., one or two) carbon-to-carbon double bonds. A "C2-5 alkynylene" denotes an alkynylene group having 2 to 5 carbon atoms. Unless defined otherwise, the term "alkynylene" preferably refers to C2-4 alkynylene (including, in particular, linear C2-4 alkynylene).

[0156] As used herein, the term "carbocyclyl" refers to a hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings), wherein said ring group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic. Unless defined otherwise, "carbocyclyl" preferably refers to aryl, cycloalkyl or cycloalkenyl.

[0157] As used herein, the term "heterocyclyl" refers to a ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings), wherein said ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein said ring group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic. For example, each heteroatom-containing ring comprised in said ring group may contain one or two 0 atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. Unless defined otherwise, "heterocyclyl" preferably refers to heteroaryl, heterocycloalkyl or heterocycloalkenyl.

[0158] As used herein, the term "aryl" refers to an aromatic hydrocarbon ring group, including monocyclic aromatic rings as well as bridged ring and / or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic). If the aryl is a bridged and / or fused ring system which contains, besides one or more aromatic rings, at least one non-aromatic ring (e.g., a saturated ring or an unsaturated alicyclic ring), then one or more carbon ring atoms in each non-aromatic ring may optionally be oxidized (i.e., to form an oxo group). "Aryl" may, e.g., refer to phenyl, naphthyl, dialinyl (i.e., 1,2-dihydronaphthyl), tetralinyl (i.e., 1, 2,3,4- tetrahydronaphthyl), indanyl, indenyl (e.g., lH-indenyl), anthracenyl, phenanthrenyl, 9H-fluorenyl, or azulenyl. Unless defined otherwise, an "aryl" preferably has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms, even more preferably refers to phenyl or naphthyl, and most preferably refers to phenyl.

[0159] As used herein, the term "heteroaryl" refers to an aromatic ring group, including monocyclic aromatic rings as well as bridged ring and / or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic), wherein said aromatic ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring comprised in said aromatic ring group may contain one or two O atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. "Heteroaryl" may, e.g., refer to thienyl (i.e., thiophenyl), benzo[b]thienyl, naphtho[2,3- b]thienyl, thianthrenyl, furyl (i.e., furanyl), benzofuranyl, isobenzofuranyl, chromanyl, chromenyl (e.g., 2H-l-benzopyranyl or 4H-l-benzopyranyl), isochromenyl (e.g., 1H-2- benzopyranyl), chromonyl, xanthenyl, phenoxathiinyl, pyrrolyl (e.g., lH-pyrrolyl), imidazolyl, pyrazolyl, pyridyl (i.e., pyridinyl; e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolyl (e.g., 3H-indolyl), isoindolyl, indazolyl, indolizinyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, pteridinyl, carbazolyl, P-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl (e.g., [l,10]phenanthrolinyl, [l,7]phenanthrolinyl, or [4,7]phenanthrolinyl), phenazinyl, thiazolyl, isothiazolyl, phenothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,2,5- oxadiazolyl (i.e., furazanyl), or 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,2,5- thiadiazolyl, or 1,3,4-thiadiazolyl), phenoxazinyl, pyrazolo[l,5-a]pyrimidinyl (e.g., pyrazolo[l,5-a]pyrimidin-3-yl), l,2-benzoisoxazol-3-yl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzo[b]thiophenyl (i.e., benzothienyl), triazolyl (e.g., lH-l,2,3-triazolyl, 2H-l,2,3-triazolyl, lH-l,2,4-triazolyl, or 4H-l,2,4-triazolyl), benzotriazolyl, lH-tetrazolyl, 2H-tetrazolyl, triazinyl (e.g., 1,2,3-triazinyl, 1,2,4-triazinyl, or 1,3,5-triazinyl), furo[2,3-c]pyridinyl, dihydrofuropyridinyl (e.g., 2,3-dihydrofuro[2,3-c]pyridinyl or l,3-dihydrofuro[3,4-c]pyridinyl), imidazopyridinyl (e.g., imidazo[l,2-a]pyridinyl or imidazo[3,2-a]pyridinyl), quinazolinyl, thienopyridinyl, tetrahydrothienopyridinyl (e.g., 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl), dibenzofuranyl, 1,3-benzodioxolyl, benzodioxanyl (e.g., 1,3-benzodioxanyl or 1,4-benzodioxanyl), or coumarinyl. Unless defined otherwise, the term "heteroaryl" preferably refers to a 5 to 14 membered (more preferably 5 to 10 membered) monocyclic ring or fused ring system comprising one or more (e.g., one, two, three or four) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; even more preferably, a "heteroaryl" refers to a 5 or 6 membered monocyclic ring comprising one or more (e.g., one, two or three) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized. Moreover, unless defined otherwise, particularly preferred examples of a "heteroaryl" include pyridinyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), imidazolyl, thiazolyl, lH-tetrazolyl, 2H-tetrazolyl, thienyl (i.e., thiophenyl), or pyrimidinyl.

[0160] As used herein, the term "cycloalkyl" refers to a saturated hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings). "Cycloalkyl" may, e.g., refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl (i.e., decahydronaphthyl), or adamantyl. Unless defined otherwise, "cycloalkyl" preferably refers to a C3-11 cycloalkyl, and more preferably refers to a C3-7 cycloalkyl. A particularly preferred "cycloalkyl" is a monocyclic saturated hydrocarbon ring having 3 to 7 ring members. Moreover, unless defined otherwise, particularly preferred examples of a "cycloalkyl" include cyclohexyl or cyclopropyl, particularly cyclohexyl.

[0161] As used herein, the term "cycloalkylene" refers to a cycloalkyl group, as defined herein above, but having two points of attachment, i.e. a divalent saturated hydrocarbon ring group. "Cycloalkylene" may, e.g., refer to cyclopropylene (e.g., cyclopropan-l,l-diyl or cyclopropan- 1,2-diyl), cyclobutylene (e.g., cyclobutan-l,l-diyl, cyclobutan-l,2-diyl, or cyclobutan-l,3-diyl), cyclopentylene (e.g., cyclopentan-1, 1-diyl, cyclopentan-1, 2-diyl, or cyclopentan-1, 3-diyl), or cyclohexylene (e.g., cyclohexan-1, 1-diyl, cyclohexan-1, 2-diyl, cyclohexan-1, 3-diyl, or cyclohexan-l,4-diyl). Unless defined otherwise, "cycloalkylene" preferably refers to a C3-7 cycloalkylene, and more preferably refers to a C3-5 cycloalkylene. Moreover, unless defined otherwise, a particularly preferred example of a "cycloalkylene" is cyclopropylene.

[0162] As used herein, the term "heterocycloalkyl" refers to a saturated ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring comprised in said saturated ring group may contain one or two 0 atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. "Heterocycloalkyl" may, e.g., refer to aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl (e.g., 1,4-diazepanyl), oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, morpholinyl (e.g., morpholin-4-yl), thiomorpholinyl (e.g., thiomorpholin-4-yl), oxazepanyl, oxiranyl, oxetanyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, thiiranyl, thietanyl, tetrahydrothiophenyl (i.e., thiolanyl), 1,3-dithiolanyl, thianyl, thiepanyl, decahydroquinolinyl, decahydroisoquinolinyl, or 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl. Unless defined otherwise, "heterocycloalkyl" preferably refers to a 3 to 11 membered saturated ring group, which is a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings), wherein said ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; more preferably, "heterocycloalkyl" refers to a 5 to 7 membered saturated monocyclic ring group containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized. Moreover, unless defined otherwise, particularly preferred examples of a "heterocycloalkyl" include tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, or tetrahydrofuranyl.

[0163] As used herein, the term "heterocycloalkylene" refers to a heterocycloalkyl group, as defined herein above, but having two points of attachment. "Heterocycloalkylene" may, e.g., refer to aziridinylene, azetidinylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, piperidinylene, piperazinylene, azepanylene, diazepanylene (e.g., 1,4-diazepanylene), oxazolidinylene, isoxazolidinylene, thiazolidinylene, isothiazolidinylene, morpholinylene, thiomorpholinylene, oxazepanylene, oxiranylene, oxetanylene, tetrahydrofuranylene, 1,3-dioxolanylene, tetrahydropyranylene, 1,4-dioxanylene, oxepanylene, thiiranylene, thietanylene, tetrahydrothiophenylene (i.e., thiolanylene), 1,3-dithiolanylene, thianylene, or thiepanylene. Unless defined otherwise, "heterocycloalkylene" preferably refers to a divalent 3 to 7 membered saturated monocyclic ring group, wherein said ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, wherein the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; more preferably, "heterocycloalkylene" refers to a divalent 3 to 5 membered saturated monocyclic ring group containing one or two (preferably one) ring heteroatoms independently selected from O, S and N, wherein the remaining ring atoms are carbon atoms. Moreover, unless defined otherwise, particularly preferred examples of a "heterocycloalkylene" include aziridinylene, oxiranylene, thiiranylene, azetidinylene (e.g., azetid i n-3,3-d iyl), oxetanylene (e.g., oxetan-3,3- diyl), thietanylene (e.g., thietan-3,3-diyl), pyrrolidinylene, tetrahydrofuranylene, or tetrahydrothiophenylene.

[0164] As used herein, the term "cycloalkenyl" refers to an unsaturated alicyclic (non-aromatic) hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said hydrocarbon ring group comprises one or more (e.g., one or two) carbon-to-carbon double bonds and does not comprise any carbon-to-carbon triple bond. "Cycloalkenyl" may, e.g., refer to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, or cycloheptadienyl. Unless defined otherwise, "cycloalkenyl" preferably refers to a C3-11 cycloalkenyl, and more preferably refers to a C3-7 cycloalkenyl. A particularly preferred "cycloalkenyl" is a monocyclic unsaturated alicyclic hydrocarbon ring having 3 to 7 ring members and containing one or more (e.g., one or two; preferably one) carbon-to-carbon double bonds.

[0165] As used herein, the term "heterocycloalkenyl" refers to an unsaturated alicyclic (non-aromatic) ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein said ring group comprises at least one double bond between adjacent ring atoms and does not comprise any triple bond between adjacent ring atoms. For example, each heteroatom-containing ring comprised in said unsaturated alicyclic ring group may contain one or two 0 atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. "Heterocycloalkenyl" may, e.g., refer to imidazolinyl (e.g., 2-imidazolinyl (i.e., 4,5-dihydro-lH-imidazolyl), 3-imidazolinyl, or 4-imidazolinyl), tetrahydropyridinyl (e.g., 1,2,3,6-tetrahydropyridinyl), dihydropyridinyl (e.g., 1,2- dihydropyridinyl or 2,3-d ihyd ropy rid inyl ), pyranyl (e.g., 2H-pyranyl or 4H-pyranyl), thiopyranyl (e.g., 2H-thiopyranyl or 4H-th iopyranyl), dihydropyranyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrazinyl, dihydroisoindolyl, octahydroquinolinyl (e.g., 1, 2, 3, 4, 4a, 5,6,7- octahydroquinolinyl), or octahydroisoquinolinyl (e.g., 1,2,3,4,5,6,7,8-octahydroisoquinolinyl). Unless defined otherwise, "heterocycloalkenyl" preferably refers to a 3 to 11 membered unsaturated alicyclic ring group, which is a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings), wherein said ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbon ring atoms are optionally oxidized, and wherein said ring group comprises at least one double bond between adjacent ring atoms and does not comprise any triple bond between adjacent ring atoms; more preferably, "heterocycloalkenyl" refers to a 5 to 7 membered monocyclic unsaturated non-aromatic ring group containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbon ring atoms are optionally oxidized, and wherein said ring group comprises at least one double bond between adjacent ring atoms and does not comprise any triple bond between adjacent ring atoms.

[0166] As used herein, the term "halogen" refers to fluoro (-F), chloro (-CI), bromo (-Br), or iodo (-1).

[0167] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more (preferably 1 to 6, more preferably 1 to 3) halogen atoms which are selected independently from fluoro, chloro, bromo and iodo, and are preferably all fluoro atoms. It will be understood that the maximum number of halogen atoms is limited bythe number of available attachment sites and, thus, depends on the number of carbon atoms comprised in the alkyl moiety of the haloalkyl group. "Haloalkyl" may, e.g., refer to -CF3, -CHF2, -CH2F, -CF2-CH3, -CH2-CF3, -CH2-CHF2, -CH2-CF2-CH3, -CH2-CF2-CF3, or -CH(CF3)2.

[0168] A particularly preferred "haloalkyl" group is -CF3.

[0169] The terms "bond" and "covalent bond" are used herein synonymously, unless explicitly indicated otherwise or contradicted by context.

[0170] The terms "preferably” and "preferred” as used herein refer to features which are not essential for the present invention and may or may not be fulfilled, but may lead to further improvements.

[0171] As used herein, the terms "optional", "optionally" and "may" denote that the indicated feature may be present but can also be absent. Whenever the term "optional", "optionally" or "may" is used, the present invention specifically relates to both possibilities, i.e., that the corresponding feature is present or, alternatively, that the corresponding feature is absent. For example, the expression "X is optionally substituted with Y" (or "X may be substituted with Y") means that X is either substituted with Y or is unsubstituted. Likewise, if a component of a composition is indicated to be "optional", the invention specifically relates to both possibilities, i.e., that the corresponding component is present (contained in the composition) or that the corresponding component is absent from the composition.

[0172] Various groups are referred to as being "optionally substituted" in this specification. Generally, these groups may carry one or more substituents, such as, e.g., one, two, three or four substituents. It will be understood that the maximum number of substituents is limited by the number of attachment sites available on the substituted moiety. Unless defined otherwise, the "optionally substituted" groups referred to in this specification carry preferably not more than two substituents and may, in particular, carry only one substituent. Unless defined otherwise, the optional substituents of any "optionally substituted" groups are preferably one or more substituents selected from group X. Moreover, unless defined otherwise, it is preferred that the optional substituents are absent, i.e. that the corresponding groups are unsubstituted. A skilled person will appreciate that the substituent groups comprised in the compounds of the present invention may be attached to the remainder of the respective compound via a number of different positions of the corresponding specific substituent group. Unless defined otherwise, preferred attachment positions for the various specific substituent groups are as illustrated in the examples.

[0173] As used herein, unless explicitly indicated otherwise or contradicted by context, the terms "a", "an" and "the" are used interchangeably with "one or more" and "at least one". Thus, for example, a composition comprising "a" compound of formula (I) can be interpreted as referring to a composition comprising "one or more" compounds of formula (I).

[0174] It is to be understood that wherever numerical ranges are provided / disclosed herein, all values and subranges encompassed by the respective numerical range are meant to be encompassed within the scope of the invention. Accordingly, the present invention specifically and individually relates to each value that falls within a numerical range disclosed herein, as well as each subrange encompassed by a numerical range disclosed herein.

[0175] As used herein, the term "comprising" (or "comprise", "comprises", "contain", "contains", or "containing"), unless explicitly indicated otherwise or contradicted by context, has the meaning of "containing, inter alia", i.e., "containing, among further optional elements, In addition thereto, this term also includes the narrower meanings of "consisting essentially of" and "consisting of". For example, the term "A comprising B and C" has the meaning of "A containing, inter alia, B and C", wherein A may contain further optional elements (e.g., "A containing B, C and D" would also be encompassed), but this term also includes the meaning of "A consisting essentially of B and C" and the meaning of "A consisting of B and C" (i.e., no other components than B and C are comprised in A).

[0176] The scope of the present invention embraces all pharmaceutically acceptable salt forms of the compounds of the present formulae which may be formed, e.g., by protonation of an atom carrying an electron lone pair which is susceptible to protonation, such as an amino group, with an inorganic or organic acid, or as a salt of an acid group (such as a carboxylic acid group) with a physiologically acceptable cation. Exemplary base addition salts comprise, for example: alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, ethylenediamine salts, or choline salts; aralkyl amine salts such as N,N- dibenzylethylenediamine salts, benzathine salts, benethamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts or tetrabutylammonium salts; and basic amino acid salts such as arginine salts, lysine salts, or histidine salts. Exemplary acid addition salts comprise, for example: mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate salts (such as, e.g., sulfate or hydrogensulfate salts), nitrate salts, phosphate salts (such as, e.g., phosphate, hydrogenphosphate, or dihydrogenphosphate salts), carbonate salts, hydrogencarbonate salts, perchlorate salts, borate salts, or thiocyanate salts; organic acid salts such as acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, adipate, gluconate, glycolate, nicotinate, benzoate, salicylate, ascorbate, pamoate (embonate), camphorate, glucoheptanoate, or pivalate salts; sulfonate salts such as methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate (isethionate), benzenesulfonate (besylate), p-toluenesulfonate (tosylate), 2-naphthalenesulfonate (napsylate), 3-phenylsulfonate, or camphorsulfonate salts; glycerophosphate salts; and acidic amino acid salts such as aspartate or glutamate salts. A pharmaceutically acceptable salt of the compound of the present formulae is preferably not a hydroiodide salt. Preferred pharmaceutically acceptable salts of the compounds of the present formulae include a hydrochloride salt, a hydrobromide salt, a mesylate salt, a sulfate salt, a tartrate salt, a fumarate salt, an acetate salt, an oxalate salt, a citrate salt, and a phosphate salt. A particularly preferred pharmaceutically acceptable salt of the compound of the present formulae is a hydrochloride salt. Accordingly, if a compound of the present formulae, including any one of the specific compounds of the present formulae described herein, is provided in the form of a pharmaceutically acceptable salt, it is preferred that the respective compound is in the form of a hydrochloride salt, a hydrobromide salt, a mesylate salt, a sulfate salt, a tartrate salt, a fumarate salt, an acetate salt, an oxalate salt, a citrate salt, or a phosphate salt, and it is particularly preferred that it is in the form of a hydrochloride salt.

[0177] The present invention also specifically relates to the compound of the present formulae, including any one of the specific compounds of the present formulae described herein, in nonsalt form.

[0178] Moreover, the scope of the invention embraces the compounds of the present formulae in any solvated form, including, e.g., solvates with water (i.e., as a hydrate) or solvates with organic solvents such as, e.g., methanol, ethanol, isopropanol, acetic acid, ethyl acetate, ethanolamine, DMSO, or acetonitrile. All physical forms, including any amorphous or crystalline forms (i.e., polymorphs), of the compounds of the present formulae are also encompassed within the scope of the invention. It is to be understood that such solvates and physical forms of pharmaceutically acceptable salts of the compounds of the present formulae are likewise embraced by the invention.

[0179] Furthermore, the compounds of the present formulae may exist in the form of different isomers, in particular stereoisomers (including, e.g., geometric isomers (or cis / trans isomers), enantiomers and diastereomers) or tautomers (including, in particular, prototropic tautomers, such as keto / enol tautomers or thione / thiol tautomers). All such isomers of the compounds of the present formulae are contemplated as being part of the present invention, either in admixture or in pure or substantially pure form. As for stereoisomers, the invention embraces the isolated optical isomers of the compounds according to the invention as well as any mixtures thereof (including, in particular, racemic mixtures / racemates). The racemates can be resolved by physical methods, such as, e.g., fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. The individual optical isomers can also be obtained from the racemates via salt formation with an optically active acid followed by crystallization. The present invention further encompasses any tautomers of the compounds of the present formulae. It will be understood that some compounds may exhibit tautomerism. In such cases, the formulae provided herein expressly depict only one of the possible tautomeric forms. The formulae and chemical names as provided herein are intended to encompass any tautomeric form of the corresponding compound and not to be limited merely to the specific tautomeric form depicted by the drawing or identified by the name of the compound.

[0180] The scope of the invention also embraces compounds of the present formulae, in which one or more atoms are replaced by a specific isotope of the corresponding atom. For example, the invention encompasses compounds of the present formulae, in which one or more hydrogen atoms (or, e.g., all hydrogen atoms) are replaced by deuterium atoms (i.e.,2H; also referred to as "D"). Accordingly, the invention also embraces compounds of the present formulae which are enriched in deuterium. Naturally occurring hydrogen is an isotopic mixture comprising about 99.98 mol-% hydrogen-1 (1H) and about 0.0156 mol-% deuterium (2H or D). The content of deuterium in one or more hydrogen positions in the compounds of the present formulae can be increased using deuteration techniques known in the art. For example, a compound of the present formulae or a reactant or precursor to be used in the synthesis of the compound of the present formulae can be subjected to an H / D exchange reaction using, e.g., heavy water (D2O). Further suitable deuteration techniques are described in: Atzrodt J et al., Bioorg Med Chem, 20(18), 5658-5667, 2012; William JS et al., Journal of Labelled Compounds and Radiopharmaceuticals, 53(11-12), 635-644, 2010; Modvig A et al., J Org Chem, 79, 5861-5868, 2014. The content of deuterium can be determined, e.g., using mass spectrometry or NMR spectroscopy. Unless specifically indicated otherwise, it is preferred that the compound of the present formulae is not enriched in deuterium. Accordingly, the presence of naturally occurring hydrogen atoms or1H hydrogen atoms in the compounds of the present formulae is preferred.

[0181] The present invention also embraces compounds of the present formulae, in which one or more atoms are replaced by a positron-emitting isotope of the corresponding atom, such as, e.g.,18F,nC,13N,15O,76Br,77Br,120l and / or124l. Such compounds can be used as tracers, trackers or imaging probes in positron emission tomography (PET). The invention thus includes (i) compounds of the present formulae, in which one or more fluorine atoms (or, e.g., all fluorine atoms) are replaced by18F atoms, (ii) compounds of the present formulae, in which one or more carbon atoms (or, e.g., all carbon atoms) are replaced bynC atoms, (iii) compounds of the present formulae, in which one or more nitrogen atoms (or, e.g., all nitrogen atoms) are replaced by13N atoms, (iv) compounds of the present formulae, in which one or more oxygen atoms (or, e.g., all oxygen atoms) are replaced by15O atoms, (v) compounds of the present formulae, in which one or more bromine atoms (or, e.g., all bromine atoms) are replaced by76Br atoms, (vi) compounds of the present formulae, in which one or more bromine atoms (or, e.g., all bromine atoms) are replaced by77Br atoms, (vii) compounds of the present formulae, in which one or more iodine atoms (or, e.g., all iodine atoms) are replaced by120l atoms, and (viii) compounds of the present formulae, in which one or more iodine atoms (or, e.g., all iodine atoms) are replaced by124l atoms. In general, it is preferred that none of the atoms in the compounds of the present formulae are replaced by specific isotopes.

[0182] The compounds of the present formulae may be administered as compounds per se or may be formulated as medicaments. The medicaments / pharmaceutical compositions may optionally comprise one or more pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricating agents, binders, colorants, pigments, stabilizers, preservatives, antioxidants, and / or solubility enhancers.

[0183] The pharmaceutical compositions may comprise one or more solubility enhancers, such as, e.g., poly(ethylene glycol), including polyethylene glycol) having a molecular weight in the range of about 200 to about 5,000 Da (e.g., PEG 200, PEG 300, PEG 400, or PEG 600), ethylene glycol, propylene glycol, glycerol, a non-ionic surfactant, tyloxapol, polysorbate 80, macrogol- 15-hydroxystearate (e.g., Kolliphor HS 15, CAS 70142-34-6), a phospholipid, lecithin, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, a cyclodextrin, a-cyclodextrin, P-cyclodextrin, y-cyclodextrin, hydroxyethyl-P-cyclodextrin, hydroxypropyl-(3-cyclodextrin, hydroxyethyl-y-cyclodextrin, hydroxypropyl-y-cyclodextrin, dihydroxypropyl-P-cyclodextrin, sulfobutylether-P- cyclodextrin, sulfobutylether-y-cyclodextrin, glucosyl-a-cyclodextrin, glucosyl-P-cyclodextrin, diglucosyl-P-cyclodextrin, maltosyl-a-cyclodextrin, maltosyl-P-cyclodextrin, maltosyl-y- cyclodextrin, maltotriosyl-P-cyclodextrin, maltotriosyl-y-cyclodextrin, dimaltosyl-P- cyclodextrin, methyl-P-cyclodextrin, a carboxyalkyl thioether, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, a vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, or any combination thereof. The pharmaceutical compositions may also comprise one or more preservatives, particularly one or more antimicrobial preservatives, such as, e.g., benzyl alcohol, chlorobutanol, 2-ethoxyethanol, m-cresol, chlorocresol (e.g., 2-chloro-3-methyl-phenol or4-chloro-3-methyl- phenol), benzalkonium chloride, benzethonium chloride, benzoic acid (or a pharmaceutically acceptable salt thereof), sorbic acid (or a pharmaceutically acceptable salt thereof), chlorhexidine, thimerosal, or any combination thereof.

[0184] The pharmaceutical compositions can be formulated by techniques known to the person skilled in the art, such as the techniques published in "Remington: The Science and Practice of Pharmacy", Pharmaceutical Press, 22ndedition. The pharmaceutical compositions can be formulated as dosage forms for oral, parenteral, such as intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardial, rectal, nasal, topical, aerosol or vaginal administration. Dosage forms for oral administration include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, troches, solutions, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitution, dispersible powders and granules, medicated gums, chewing tablets and effervescent tablets. Dosage forms for parenteral administration include solutions, emulsions, suspensions, dispersions and powders and granules for reconstitution. Emulsions are a preferred dosage form for parenteral administration. Dosage forms for rectal and vaginal administration include suppositories and ovula. Dosage forms for nasal administration can be administered via inhalation and insufflation, for example by a metered inhaler. Dosage forms for topical administration include creams, gels, ointments, salves, patches and transdermal delivery systems.

[0185] The compounds of the present formulae or the above described pharmaceutical compositions comprising a compound of the present formulae may be administered to a subject by any convenient route of administration, whether systemically / peripherally or at the site of desired action, including but not limited to one or more of: oral (e.g., as a tablet, capsule, or as an ingestible solution), topical (e.g., transdermal, intranasal, ocular, buccal, and sublingual), parenteral (e.g., using injection techniques or infusion techniques, and including, for example, by injection, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, or intrasternal by, e.g., implant of a depot, for example, subcutaneously or intramuscularly), pulmonary (e.g., by inhalation or insufflation therapy using, e.g., an aerosol, e.g., through mouth or nose), gastrointestinal, intrauterine, intraocular, subcutaneous, ophthalmic (including intravitreal or intracameral), rectal, or vaginal administration.

[0186] If said compounds or pharmaceutical compositions are administered parenterally, then examples of such administration include one or more of: intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracardially, intracranially, intramuscularly or subcutaneously administering the compounds or pharmaceutical compositions, and / or by using infusion techniques. For parenteral administration, the compounds are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

[0187] The present invention thus relates to the compounds or the pharmaceutical compositions provided herein, wherein the corresponding compound or pharmaceutical composition is to be administered by any one of: an oral route; topical route, including by transdermal, intranasal, ocular, buccal, or sublingual route; parenteral route using injection techniques or infusion techniques, including by subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, intrasternal, intraventricular, intraurethral, or intracranial route; pulmonary route, including by inhalation or insufflation therapy; gastrointestinal route; intrauterine route; intraocular route; subcutaneous route; ophthalmic route, including by intravitreal, or intracameral route; rectal route; or vaginal route. A particularly preferred route of administration is parenteral administration, more specifically intravenous administration.

[0188] Typically, a physician will determine the actual dosage which will be most suitable for an individual subject. The specific dose level and frequency of dosage for any particular individual subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual subject undergoing therapy.

[0189] A proposed, yet non-limiting dose of the compounds according to the invention for administration to a human may be 0.1 mg / kg to 50 mg / kg, preferably 1 mg / kg to 5 mg / kg, of the active ingredient per unit dose. The unit dose may be administered, e.g., every 1 to 4 weeks. It will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient / subject as well as the severity of the condition to be treated. The precise dose and also the route of administration will ultimately be at the discretion of the attendant physician or veterinarian.

[0190] The compound of the present formulae or a pharmaceutical composition comprising the compound of the present formulae can be administered in monotherapy (e.g., without concomitantly administering any further therapeutic agents, or without concomitantly administering any further therapeutic agents against the same disease that is to be treated or prevented with the compound of the present formulae). However, the compound of the present formulae or a pharmaceutical composition comprising the compound of the present formulae can also be administered in combination with one or more further therapeutic agents, preferably in combination with one or more further therapeutic agents selected from chemotherapy (e.g. antimetabolites, platinum-based agents, topoisomerase inhibitors, microtubule inhibitors), a targeted therapy (e.g. tyrosine kinase inhibitors), an immunotherapy (e.g. anti-PD-l / PD-Ll and anti-CTLA-4 agents), or an anti-angiogenic therapy (e.g. bevacizumab).. If the compound of the present formulae is used in combination with a second therapeutic agent active against the same disease or condition, the dose of each compound may differ from that when the corresponding compound is used alone, in particular, a lower dose of each compound may be used. The combination of the compound of the present formulae with one or more further therapeutic agents may comprise the simultaneous / concomitant administration of the compound of the present formulae and the further therapeutic agent(s) (either in a single pharmaceutical formulation or in separate pharmaceutical formulations), or the sequential / separate administration of the compound of the present formulae and the further therapeutic agent(s). If administration is sequential, either the compound of the present formulae according to the invention or the one or more further therapeutic agents may be administered first. If administration is simultaneous, the one or more further therapeutic agents may be included in the same pharmaceutical formulation as the compound of the present formulae, or they may be administered in two or more different (separate) pharmaceutical formulations.

[0191] The subject or patient to be treated in accordance with the present invention may be an animal (e.g., a non-human animal). Preferably, the subject / patient is a mammal. More preferably, the subject / patient is a human (e.g., a male human or a female human) or a non- human mammal (such as, e.g., a guinea pig, a hamster, a rat, a mouse, a rabbit, a dog, a cat, a horse, a monkey, an ape, a marmoset, a baboon, a gorilla, a chimpanzee, an orangutan, a gibbon, a sheep, cattle, or a pig). Most preferably, the subject / patient to be treated in accordance with the invention is a human.

[0192] The term "treatment" of a disorder or disease, as used herein, is well-known in the art. "Treatment" of a disorder or disease implies that a disorder or disease is suspected or has been diagnosed in a patient / subject. A patient / subject suspected of suffering from a disorder or disease typically shows specific clinical and / or pathological symptoms which a skilled person can easily attribute to a specific pathological condition (i.e., diagnose a disorder or disease).

[0193] The "treatment" of a disorder or disease may, for example, lead to a halt in the progression of the disorder or disease (e.g., no deterioration of symptoms) or a delay in the progression of the disorder or disease (in case the halt in progression is of a transient nature only). The "treatment" of a disorder or disease may also lead to a partial response (e.g., amelioration of symptoms) or complete response (e.g., disappearance of symptoms) of the subject / patient suffering from the disorder or disease. Accordingly, the "treatment" of a disorder or disease may also refer to an amelioration of the disorder or disease, which may, e.g., lead to a halt in the progression of the disorder or disease or a delay in the progression of the disorder or disease. Such a partial or complete response may be followed by a relapse. It is to be understood that a subject / patient may experience a broad range of responses to a treatment (such as the exemplary responses as described herein above). The treatment of a disorder or disease may, inter alia, comprise curative treatment (preferably leading to a complete response and eventually to healing of the disorder or disease) and palliative treatment (including symptomatic relief).

[0194] The term "prevention" of a disorder or disease, as used herein, is also well-known in the art. For example, a patient / subject suspected of being prone to suffer from a disorder or disease may particularly benefit from a prevention of the disorder or disease. The subject / patient may have a susceptibility or predisposition for a disorder or disease, including but not limited to hereditary predisposition. Such a predisposition can be determined by standard methods or assays, using, e.g., genetic markers or phenotypic indicators. It is to be understood that a disorder or disease to be prevented in accordance with the present invention has not been diagnosed or cannot be diagnosed in the patient / subject (for example, the patient / subject does not show any clinical or pathological symptoms). Thus, the term "prevention" comprises the use of a compound of the present invention before any clinical and / or pathological symptoms are diagnosed or determined or can be diagnosed or determined by the attending physician.

[0195] It is to be understood that the present invention specifically relates to each and every combination of features described herein, including any combination of general and / or preferred features. In particular, the invention specifically relates to each combination of meanings (including general and / or preferred meanings) for the various groups and variables comprised in the present formulae.

[0196] In this specification, a number of documents including patent applications, scientific literature and manufacturers' manuals are cited. The disclosure of these documents, while not considered relevant for the patentability of this invention, is herewith incorporated by reference in its entirety. More specifically, all referenced documents are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference. The reference in this specification to any prior publication (or information derived therefrom) is not and should not be taken as an acknowledgment or admission or any form of suggestion that the corresponding prior publication (or the information derived therefrom) forms part of the common general knowledge in the technical field to which the present specification relates.

[0197] The invention will now be described by reference to the following examples which are merely illustrative and are not to be construed as a limitation of the scope of the present invention.

[0198] EXAMPLES

[0199] The compounds / examples described in this section are defined by their chemical formulae and their corresponding chemical names. In case of conflict between any chemical formula and the corresponding chemical name indicated herein, the present invention relates to both the compound / example defined by the chemical formula and the compound / example defined by the chemical name, and particularly relates to the compound / example defined by the chemical formula. All of the following materials used in the synthesis procedures were sourced from Merck / Sigma-Aldrich: P,P-dichlorophenylphosphine, vinylmagnesium bromide, 4- methoxybenzyl alcohol, ethynylmagnesium chloride, pyridine, ethanol, diethyl ether, tetrahydrofuran (THF), ethyl acetate, and n-hexane (hexane).

[0200] An exemplary synthesis of a desired compound of formula la is shown in the following:

[0201] 68%

[0202] P-Chloroethoxyphenylphosphine was prepared according to the following procedure Diethyl phenylphosphonite: Following a procedure by N. Kreutzkamp, J. Pluhatsch, Arch. Pharm. 1959, 292, 159-164, anhydrous ethanol (13.1 mL, 224 mmol, 2.0 eq.) and anhydrous pyridine (18.0 mL, 224 mmol, 2.0 eq.) were dissolved in anhydrous diethyl ether (125 mL) under an argon atmosphere. The mixture was cooled to 0 °C and P,P-dichlorophenylphosphine (15.2 mL, 112 mmol, 1.0 eq.) was added dropwise during 15 min while stirring. The cooling bath was removed and the reaction was stirred for 1 h while warming to room temperature. After rapid filtration through a plug of Celite to remove precipitates, the solvent was evaporated under reduced pressure. Distillation of the residue (58-60 °C, 0.018 mbar) gave the title compound as a colorless oil (13.5 g, 68.1 mmol, 61%).

[0203] 1H NMR (400 MHz, CDCI3): δ = 7.63-7.57 (m, 2H), 7.44-7.38 (m, 3H), 4.00-3.78 (m, 4H), 1.29 (td, J = 7.0 Hz,4JP-H = 0.4 Hz, 6H) ppm.

[0204] 31P NMR (162 MHz, CDCh): δ = 159.2 ppm.

[0205] Spectral data in accordance with those reported in the literature in M. Lutter, K. Jurkschat, Eur. J. Inorg. Chem. 2018, 3481-3490.

[0206] P-Chloroethoxyphenylphosphine: Similar to a procedure by E. Steininger, Chem. Ber. 1962, 95, 2993-2996, In a flame-dried flask, P,P-dichlorophenylphosphine (7.16 g, 40.0 mmol, 1.0 eq.) was added to diethyl phenylphosphonite (7.92 g, 40.0 mmol, 1.0 eq.) at 0 °C under an argon atmosphere. After 30 minutes, the cooling was removed and the reaction mixture was stirred for 1 h while warming to room temperature. Distillation of the crude material (69— 70 °C, 0.012 mbar) gave the product as a colorless liquid (9.85 g, 52.2 mmol, 65%).

[0207] 1H NMR (400 MHz, CDCI3): δ = 7.83-7.77 (m, 2H, H-2), 7.52-7.47 (m, 3H, H-3, H-4), 4.12-3.96 (m, 2H, H-5), 1.37 (td, J = 7.1 Hz,4JP H = 0.5 Hz, 3H, H-6) ppm.

[0208] 13C NMR (101 MHz, CDCI3): δ = 141.1 (d, VP-C = 37.2 Hz, C-l), 131.5 (C-4), 129.9 (d,2JP-c = 25.6 Hz, C-2), 128.6 (d, J = 6.3 Hz, C-3), 65.1 (d,2JP-c = 9.0 Hz, C-5), 16.6 (d,3JP-c = 6.1 Hz, C-6) ppm.

[0209] 31P NMR (162 MHz, CDCI3): δ = 178.2 ppm. Although the compound is literature known, no sufficient NMR data for comparison were available. The31P-NMR chemical shift is in accordance with the one reported in C. J. Schaverien, R. Ernst, W. Terlouw, P. Schut, O. Sudmeijer, P. H. M. Budzelaar, J. Mol. Catal. A Chem. 1998, 128, 245-256.

[0210] Ethyl phenylvinylphosphinite: To a solution of P-chloroethoxyphenylphosphine (4.50 g, 23.9 mmol, 1.0 eq.) and pyridine (3.77 g, 3.85 mL, 47.7 mmol, 2.0 eq.) in anhydrous THF (60 mL) was added vinylmagnesium bromide in THF (1 M, 23.9 mL, 23.9 mmol, 1.0 eq) at -78 °C dropwise during 45 min under an argon atmosphere with vigorous stirring. After the addition was complete, the cooling bath was removed and the mixture was stirred for 1 h while warming to room temperature. The solvents were removed under reduced pressure and the residue was taken up in degassed hexane / ethyl acetate (9:1, 200 mL). The mixture was filtered through a plug of celite and neutral aluminum oxide. The filtrate was collected and concentrated in vacuo to yield the title compound as a yellowish oil (2.92 g, 16.2 mmol, 68%).

[0211] 1H NMR (400 MHz, CDCI3): δ = 7.60-7.54 (m, 2H, H-2), 7.46-7.35 (m, 3H, H-3, H-4), 6.53 (ddd, J = 18.4, 15.1, 12.1 Hz, 1H, H-5), 5.95-5.83 (m, 2H, H-6), 3.87 (dq,3JP-H= 9.5 Hz, J = 7.0 Hz, 2H, H-7), 1.32 (td, J = 7.0 Hz,4JP-H= 0.5 Hz, 3H, H-8) ppm.

[0212] 13C NMR (101 MHz, CDCI3): δ = 141.4 (d,1JP.C= 21.1 Hz, C-5), 141.3 (d,1JP.C= 17.6 Hz, C-l), 130.0 (d,2JP-c = 21.0, C-2), 129.3 (C-4), 128.4 (d,3JP-c = 6.4 Hz, C-3), 127.1 (d,2JP.C= 27.1 Hz, C-6), 65.3 (d,2Jp-c = 17.1 Hz, C-7), 17.2 (d,3JP.C= 7.2 Hz, C-8) ppm.

[0213] 31P NMR (162 MHz, CDCI3): δ = 114.1 ppm.

[0214] HRMS (APCI) m / z: [M+H]+Calcd for CI0HI4OP+181.0777; Found 181.0771.

[0215] 4-Methoxybenzyl phenylvinylphosphinite: Ethyl phenylvinylphosphinite (1.80 g, 10.0 mmol, 1.0 eq.) was added to 4-methoxybenzyl alcohol (2.76 g, 2.50 mL, 20.0 mmol, 2.0 eq.) in a Schlenk flask under an argon atmosphere. The flask was connected to a cooling trap and the mixture was stirred at 35 °C for 16 h while constantly applying a vacuum of lxlO-2mbar. After completion of the reaction, the crude product was dissolved in degassed hexane / ethyl acetate (9:1, 200 mL) and filtered through a plug of celite and neutral aluminum oxide. The filtrate was concentrated to afford the title compound as a colorless oil (1.98 g, 7.27 mmol, 73%).

[0216] 1H NMR (400 MHz, CDCI3): δ = 7.59-7.54 (m, 2H, H-2), 7.44-7.37 (m, 3H, H-3, H-4), 7.31-7.28 (m, 2H, H-9), 6.91-6.87 (m, 2H, H-10), 6.60-6.48 (m, 1H, H-5), 5.95-5.82 (m, 2H, H-6), 4.77 (d,3JP-H = 9.6 Hz, H-7), 3.81 (s, 3H, H-12) ppm.

[0217] 13C NMR (101 MHz, CDCI3): δ = 159.4 (C-ll), 141.1 (d, VP-C = 21.4 Hz, C-5), 141.0 (d, ^P-C = 17.7 Hz, C-l), 131.1 (d,3JP-c = 6.7 Hz, C-8), 130.2 (d,2JP.C= 21.3 Hz, C-2), 129.4 (C-4), 129.3 (C-9), 128.5 (d,3JP-C = 6.7 Hz, C-3), 127.7 (d,2JP.C= 27.8 Hz, C-6), 113.9 (C-10), 71.0 (d,2JP-c = 16.8 Hz, C-7), 55.4 (C-12) ppm.

[0218] 31P NMR (162 MHz, CDCI3): δ = 116.1 ppm.

[0219] HRMS (El) m / z: [M]+Calcd for Ci6Hi7O2P+272.0966; Found 272.0982.

[0220] Synthesis of the alkyne analogues:

[0221] Ethyl ethynylphenylphosphinite: To a solution of P-chloroethoxyphenylphosphine (875 mg, 4.63 mmol, 1.0 eq.) in dry THF (15 mL) under an argon atmosphere was added ethynylmagnesium chloride in THF (0.5 M, 10.0 mL, 5.00 mmol, 1.1 eq.) at 0 °C during 30 min while stirring vigorously. The mixture was stirred for 1 h at 0 °C after which it was concentrated in vacuo while being kept at that temperature. The resulting residue was taken up in degassed hexane / ethyl acetate (9:1, 50 mL) and quickly filtered through a celite and neutral aluminum oxide. The solvents were evaporated under reduced pressure at 0 °C to obtain the product as a light brown oil (423 mg, 2.73 mmol, 51%).

[0222] 1H NMR (400 MHz, CDCI3): δ = 7.81-7.77 (m, 2H, H-2), 7.47-7.43 (m, 3H, H-3, H-4), 3.89-3.79 (m, 1H, H-7a), 3.62-3.53 (m, 1H, H-7p), 3.51 (d, J = 2.5 Hz, 1H, H-6), 1.20 (td, J = 7.0 Hz, JP. H = 0.6 Hz, 3H, H-8) ppm.

[0223] 13C NMR (101 MHz, CDCI3): δ = 137.0 (d, JP C = 16.1 Hz, C-l), 131.7 (d, JP-c = 21.4 Hz, C-2), 130.2 (C-4), 128.6 (d, JP-C = 6.0 Hz, C-3), 98.8 (d, JP.C= 1.9 Hz, C-6), 83.8 (d, JP.C= 42.1 Hz, C-5), 64.6 (d, Jp-c = 4.6 Hz, C-7), 16.7 (d, JP.C= 4.6 Hz, C-8) ppm.

[0224] 31P NMR (162 MHz, CDCI3): δ = 88.1 ppm.

[0225] The final 4-methoxybenzyl ethynylphenylphosphinite may be prepared by a reaction analogous to the preparation of the 4-methoxybenzyl phenyivinylphosphinite.

[0226] Functionalization of Somatostatin

[0227] Somatostatin (SST) was used as a small peptide containing a native disulfide bond as a model compound for disulfide rebridging:

[0228] SST, 16367167 m / z SST-bridged, 17887558 m / z

[0229] The experiments were conducted similar to a procedure by Hackenberger et al. for the cysteine-conjugation of proteins via diethynylphosphinates in C. E. Stieger, L. Franz, F. Korlin, C. P. R. Hackenberger, Angew. Chem. Int. Ed. 2021, 60, 15359-15364. A stock solution of SST in DPBS (143 pM, 700 pL, 1.0 eq., pH 7.4) was added a stock solution of 4-Methoxybenzyl phenyivinylphosphinite in DMSO (6.7 mM, 300 pL, 20 eq.) at room temperature. The reaction was conducted with degassed solvents under an argon atmosphere and the final concentration of SST was 100 pM. After a reaction time of 1.5 h at room temperature, the mixture was analyzed by LC-MS and then lyophilized and stored at -24 °C. The expected mass for the conjugation product SST-bridged was detected with a retention time of 4.14 min. A high-resolution MALDI-TOF mass spectrum of the material obtained after lyophilization confirmed the measured mass for [SST-bridged+H]+, which was calculated as 1789.7630 m / z and measured as 1789.7611 m / z for the monoisotopic mass. Addition of iodoacetamide to SST-bridged resulted in no cysteine labelling, indicating that re-bridging truly took place.

[0230] An antibody drug conjugate may be prepared using this invention in one of two ways.

[0231] 1. A phosphinite of formula la or lb is prepared with a bivalent linker and cytotoxic drug (as listed above) fully incorporated into R2. A certain excess of the phosphinite is then combined with an antibody and the two are allowed to react until all interchain disulfides are rebridged as determined by intact mass spectrometry. The antibody drug conjugate is then purified with conventional techniques, and can be used for in vivo experiments in animals or humans.

[0232] 2. A phosphinite of formula la or lb is prepared with a chemical handle on R2, which is suitable for subsequent linking to a bivalent linker and cytotoxic drug (as listed above). First, the phosphite is combined with an antibody and the two are allowed to react until all interchain disulfides are rebridged as determined by intact mass spectrometry. Then the rebridged antibody is further derivatized at the chemical handle on R2to add a bivalent linker and cytotoxic drug. The thus-obtained antibody drug conjugate is then purified with conventional techniques, and can be used for in vivo experimental in animals or humans.

Claims

CLAIMS1. A phosphinite compound selected from compounds of formulae (la) and (lb)or a salt or solvate thereof, whereinR1is selected from optionally substituted -(CRm2)-aryl, optionally substituted -(CRm2)- heteroaryl, optionally substituted -(CRm2)-ethenyl, optionally substituted -(CRm2)- ethynyl, and -Si(Rs')3, wherein the one or more optional substituents of the optionally substituted aryl, optionally substituted heteroaryl, optionally substituted ethenyl and optionally substituted ethynyl are selected from Group C (wherein at least one of these substituents is preferably selected from Group A), each Rmis independently selected from Group D, and each RSiis independently selected from Group S,R2is a group containing 1 to 300 carbon atoms and optionally 1 to 150 heteroatoms selected from S, N, 0 and P,R3is selected from hydrogen, optionally substituted alkyl and optionally substituted aryl, wherein the one or more substituents of the optionally substituted alkyl are selected from Group B, and the one or more substituents of the optionally substituted aryl are selected from Group C,R3ais selected from hydrogen and optionally substituted alkyl and optionally substituted aryl, wherein the one or more substituents of the optionally substituted alkyl are selected from Group B, and the one or more substituents of the optionally substituted aryl are selected from Group C,R3bis selected from hydrogen and optionally substituted alkyl and optionally substituted aryl, wherein the one or more substituents of the optionally substituted alkyl are selected from Group B, and the one or more substituents of the optionally substituted aryl are selected from Group C, andR3Cis selected from hydrogen, fluoro, cyano and optionally substituted alkyl, wherein the one or more substituents of the alkyl are selected from Group B,Group A: -OH, -OR, -NH2, -NHR, -NR2, -NHC(O)R, -NHC(O)OR, -OC(O)R, -OC(O)NH2, - OC(O)NHR, -OC(O)NR2, -PR2, -SH, -SR, optionally substituted alkyl, optionally substituted heteroalkyl and optionally substituted cycloalkyl, wherein the one or more optionally substituents of the alkyl and heteroalkyl are selected from group X, the one or more optionally substituents of the cycloalkyl are selected from group Y, and each R is independently selected from optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, wherein the one or more optional substituents of the alkyl and heteroalkyl are selected from group X and the one or more optional substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are selected from Group Y;Group B: -halogen, -OH, -O-R, -CN, -NO2, -COOH, -C(O)O-R, -C(O)NH2, -C(O)NHR, - C(O)NR2, -C(O)-R, -NH2, -NH(R), -N(R)2, -NHC(O)R, -NHC(O)OR, -NHS(O)2-R, - OC(O)R, -OC(O)NH2, -OC(O)NHR, and -OC(O)NR2, -PR2, -SH, -S-R, -S(O)(R), - S(O)2(R), -S(O)2NH(R), -SO3H, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, wherein the one or more optional substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are selected from Group Y and each R is independently selected from optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, wherein the one or more optional substituents of the alkyl and heteroalkyl areselected from group X and the one or more optional substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are selected from Group Y;Group C: -halogen, -OH, -O-R, -CN, -NO2, -COOH, -C(O)O-R, -C(O)-R, -C(O)NH2, -C(O)NHR, -C(O)NR2, -NH2, -NH(R), -N(R)2, -NHC(O)-R, -NHC(O)OR, -NHS(O)2-R, -OC(O)R, - OC(O)NHR, -OC(O)NR2, -PR2, -SH, -S-R, -S(O)(R), -S(O)2(R), -S(O)2NH(R), -SO3H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, wherein the one or more optional substituents of the alkyl, alkenyl, alkynyl and heteroalkyl are selected from group X, the one or more optionally substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are selected from group Y, and each R is independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, wherein the one or more optional substituents of the alkyl, alkenyl, alkynyl and heteroalkyl are selected from group X and the one or more optional substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are selected from Group Y;Group D: hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, wherein the one or more optionally substituents of the alkyl and heteroalkyl are selected from group X, the one or more optionally substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are selected from group Y;Group S: optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, wherein the one or more optionally substituents of the alkyl and heteroalkyl are selected from group X, theone or more optionally substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are selected from group Y; wherein the carbon being the attachment point of Group S in the optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl is optionally replaced by Si.Group X: -halogen, -OH, -O-alkyl, -O-heteroalkyl, -CN, -NO2, -COOH, -C(O)O-alkyl, -C(O)- alkyl, -NH2, -NH(alkyl), -N(alkyl)2, -NHCO-alkyl, -NHC(O)O-alkyl, -NHS(O)2-alkyl, - OCO-alkyl, OC(O)NH-alkyl, -SH, -S-alkyl, -S(O)(alkyl), -S(O)2(alkyl), -S(O)2NH(alkyl) and -SO3H ;Group Y: -alkyl, -heteroalkyl, -cycloalkyl, -halogen, -OH, -O-alkyl, -O-heteroalkyl, -CN, - NO2, -COOH, -C(O)O-alkyl, -C(O)-alkyl, -NH2, -NH(alkyl), -N(alkyl)2, -NHCO-alkyl, - NHC(O)O-alkyl, -NHS(O)2-alkyl, -OCO-alkyl, -OC(O)NH-alkyl, -SH, -S-alkyl, - S(O)(alkyl), -S(O)2(alkyl), -S(O)2NH(alkyl) and -SO3H, wherein the -alkyl, -heteroalkyl and -cycloalkyl are optionally further substituted by one or more selected from -heteroalkyl, -cycloalkyl, O-heteroalkyl, -CN, -NO2, - COOH, -C(O)O-alkyl, -C(O)-alkyl, -NH2, -NH(alkyl), -N(alkyl)2, -NHCO-alkyl, - NHS(O)2-alkyl, -OCO-alkyl, -SH, -S-alkyl, -S(O)(alkyl), -S(O)2(alkyl), -S(O)2NH(alkyl) and -SO3H.

2. The phosphinite compound according to claim 1, wherein R1is selected from optionally substituted allyl, and optionally substituted benzyl, wherein the one or more optional substituents of the allyl and benzyl are selected from Group A, preferably wherein at least one of the one or more optional substituents of the benzyl in R1are present in ortho, ortho' or para position, relative to the position at which the methylene group of the benzyl is bound to the phenyl group of the benzyl.

3. The phosphinite compound according to claim 1 or 2, wherein R1is selected from benzyl having one two or three substituents selected from -O-alkyl, -O-heteroalkyl, NH(alkyl), and N(alkyl)2and optionally one or two substituents selected from Group C; dityl(diphenylmethyl) optionally having one two or three substituents selected from Group C (preferably selected from-O-alkyl, -O-heteroalkyl, NH(alkyl), and N(alkyl)2); and trityl optionally having one two or three substituents selected from Group C (preferably selected from-O-alkyl, -O-heteroalkyl, NH(alkyl), and N(alkyl)z); furyl, pyrrolyl, thienyl, oxazolyl, benzofuryl, benzothienyl, indolyl, any of which optionally having one two or three substituents selected from Group C; allyl optionally having a substituent selected from Group C (preferably selected from-O-alkyl, -O-heteroalkyl, NH(alkyl), and N(alkyl)z); propargyl optionally having a substituent selected from Group C (preferably selected from-O-alkyl, -O-heteroalkyl, NH(alkyl), and N(alkyl)z); and -Si(RSi)3 wherein each RSiis independently selected from alkyl and aryl wherein the carbon being the attachment point in the alkyl is optionally replaced by Si; preferably wherein R1is selected from the following formulae:preferably the following formulae:more preferably the following formulae:

4. The phosphinite compound according to any one of claims 1 to 3, wherein R2is selected from optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, wherein the one or more optional substituents are of a nature that R2as a whole contains not more than 300 carbon atoms and not more than 150 heteroatoms, wherein the heteroatoms are selected from S, N, O and P; preferably wherein R2is selected from optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, wherein the one or more optional substituents of the optionally substituted alkyl and heteroalkyl are selected from Group B, and the one or more optional substituents of the optionally substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl are selected from Group C; more preferably wherein R2is selected from optionally substituted phenyl, wherein the one or more optional substituents of the phenyl are selected from group C.

5. The phosphinite compound according to any one of claims 1 to 4, wherein R2contains one or more groups selected from the following: a) a group which can be conjugated to biotin, desthiobiotin, fluorescent dyes, oligonucleotides, peptides, proteins, small molecules drugs such as N-Ac-y- calicheamicin (ozogamicin), mertansine, ravtansine, monomethyl auristatin, SN38, exatecan, deruxtecan, govitecan, or amanatin b) a group selected from a terminal alkyne, cyclooctyne, 1,2,4,5-tetrazine, carboxylic acid, N-succidinimyl carboxylate, primary or secondary amine, and halogen, c) a group selected from the following bivalent groups:

6. The phosphinite compound according to any one of claims 1 to 3, wherein R2is contains one or more selected from alkyne, cyclooctyne, or 1,2, 4, 5 tetrazine, preferably whereinR2is selected from the following formulae:

7. The phosphinite compound according to any one of claims 1 to 6, wherein R3is hydrogen or optionally substituted alkyl, wherein the one or more substituents of the alkyl are selected from Group X, preferably wherein R3is hydrogen or alkyl, more preferably wherein R3is selected from hydrogen, methyl and ethyl, even more preferably whereinR3is selected from hydrogen and methyl, still even more preferably wherein R3is hydrogen.

8. The phosphinite compound according to any one of claims 1 to 7, wherein R3aand R3bare independently selected from hydrogen and optionally substituted alkyl, wherein the one or more substituents of the alkyl are selected from Group X, preferably wherein R3aand R3bare independently selected from hydrogen and alkyl, more preferably wherein R3aand R3bare independently selected from hydrogen, methyl and ethyl, even more preferably wherein R3aand R3bare independently selected from hydrogen and methyl, still even more preferably wherein R3aand R3bare each hydrogen.

9. The phosphinite compound according to any one of claims 1 to 8, wherein R3cis selected from hydrogen, fluoro, cyano and optionally substituted alkyl, wherein the one or more substituents of the alkyl are selected from Group X, preferably wherein R3cis selected from hydrogen, fluoro, cyano and alkyl, more preferably wherein R3cis selected from hydrogen, fluoro, cyano, methyl and ethyl, even more preferably wherein R3cis selected from hydrogen, fluoro, cyano and methyl, still more preferably hydrogen or fluoro, even still more preferably hydrogen.

10. The phosphinite compound according to any one of claims 1 to 9, wherein the compound is a compound of formula (la) or wherein the compound has the following formula11. A conjugate which is obtainable by linking a phosphinite compound of according to any one of claims 1 to 10 to one or more selected from a peptide, a protein, an antibody, a nucleotide, an oligonucleotide, a saccharide, a polysaccharide, a detectable label, a radioactive or non-radioactive nuclide, biotin, desthiobiotin, a reporter enzyme, a protein tag, a fluorophore such as CY5, fluorescein or EDANS, biotin, a linker, a drug, a linker-drug conjugate, a linker-fluorophore conjugate, a polymer, a small molecule drugsuch as N-Ac-y-calicheamicin (ozogamicin), mertansine, ravtansine, monomethyl auristatin, SN38, exatecan, deruxtecan, govitecan, or amanatin.

12. A method of modifying a disulfide-containing compound (preferably a protein), the method comprising reacting the phosphinite compound according to any of claims 1 to10, or the conjugate according to claim 11, with a disulfide-containing compound(preferably a protein containing at least one S-S bond).

13. The method of claim 12, wherein the method involves the reaction of:or the reaction ofa disulfide illustrated byto form a group representedwherein Rl, R2, R3, R3a, R3band R3care as defined in claim 1.

14. A compound obtainable by the method according to claim 12 or 13, wherein the compound preferably contains one or more of the following groups:wherein R2, R3, R3a, R3band R3care as defined in claim 1, and / or wherein the compound that has been modified is preferably protein, more preferably an antibody, even more preferably an IgGl or IgGlK antibody.

15. The compound of claim 14, which is preferably a modified protein, for use in medicine, preferably for use in the treatment of a cancer, wherein the cancer is preferably selected from anaplastic large-cell lymphoma (ALCL), acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML), breast cancers (BC) including triple-negative breast cancer (TNBC), B-cell lymphomas (BCL) including diffuse large-B-cell lymphoma (DLBCL), gastric cancers (GC), gastro-oesophageal junction cancer (GOJ), Hodgkin lymphoma (HL), multiple myeloma (MM), non small-cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), myeloproliferative neoplasm MPN), nasopharyngeal carcinoma (NPC), chronic lymphocytic leukemia (CLL), urethral cancers, epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, CD30- positive T cell lymphoma, TROP-2 positive tumors, HER2-positive tumors, or nectin-4 positive tumors.

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