EP2790731A2 - Fgfr-binder-wirkstoff konjugate und ihre verwendung - Google Patents

Fgfr-binder-wirkstoff konjugate und ihre verwendung

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Publication number
EP2790731A2
EP2790731A2 EP12808324.3A EP12808324A EP2790731A2 EP 2790731 A2 EP2790731 A2 EP 2790731A2 EP 12808324 A EP12808324 A EP 12808324A EP 2790731 A2 EP2790731 A2 EP 2790731A2
Authority
EP
European Patent Office
Prior art keywords
group
hydrogen
point
attachment
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP12808324.3A
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German (de)
English (en)
French (fr)
Inventor
Hans-Georg Lerchen
Stefanie Hammer
Axel Harrenga
Charlotte Christine Kopitz
Carl Friedrich Nising
Anette Sommer
Beatrix Stelte-Ludwig
Christoph Mahlert
Joachim Schuhmacher
Sven Golfier
Simone Greven
Sandra Bruder
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Seagen Inc
Original Assignee
Seattle Genetics Inc
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Publication date
Application filed by Seattle Genetics Inc filed Critical Seattle Genetics Inc
Priority to EP12808324.3A priority Critical patent/EP2790731A2/de
Publication of EP2790731A2 publication Critical patent/EP2790731A2/de
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K11/00—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof

Definitions

  • ADCs New binder drug conjugates
  • the present application relates to novel target fibroblast growth factor receptor 2 (FGFR2) targeting drug-conjugates (ADCs) of ⁇ , ⁇ -dialkylauristatins, active metabolites of these ADCs, methods for making these ADCs, use of these ADCs for treatment and / or Prevention of diseases and the use of these ADCs for the preparation of medicaments for the treatment and / or prevention of diseases, in particular hyperproliferative and / or angiogenic diseases such as cancer.
  • FGFR2 novel target fibroblast growth factor receptor 2
  • ADCs drug-conjugates
  • ⁇ , ⁇ -dialkylauristatins active metabolites of these ADCs
  • methods for making these ADCs methods for making these ADCs
  • Cancers are the result of uncontrolled cell growth of various tissues. In many cases, the new cells invade existing tissues (invasive growth) or they metastasize to distant organs. Cancers occur in various organs and often have tissue-specific disease courses. Therefore, the term cancer as a generic term describes a large group of defined diseases of various organs, tissues and cell types.
  • early stage tumors may be removed by surgical and radiotherapeutic measures.
  • metastatic tumors can only be treated palliatively by chemotherapeutic agents.
  • the goal here is to achieve the optimal combination of improving the quality of life and extending the lifetime.
  • chemotherapeutic agents administered parenterally today are often not targeted to tumor tissue or tumor cells, but are nonspecifically distributed in the body by systemic administration, i. even in places where drug exposure is undesirable, such as in healthy cells, tissues, and organs. This can lead to unwanted side effects and even serious general toxic effects, which then often severely limit the therapeutically useful dose range of the drug or require a complete discontinuation of the medication.
  • trastuzumab Herceptin ®
  • rituximab Renitux ®
  • cetuximab Erbitux ®
  • bevacizumab Avastin ®
  • small molecule drug binders can also be used as binders that selectively bind to a particular target, such as a receptor [see, e.g. E. Ruoslahti et al., Science 279, 377-380 (1998); D. Karkan et al., PLoS ONE 3 (6), e2469 (June 25, 2008)].
  • a target breakpoint may be, for example, in a peptide chain which can be selectively cleaved at a particular site by a specific enzyme at the site of action [see, e.g. R.A. Firestone and L.A. Telan, US Patent Application US 2002/0147138].
  • Herceptin ® and Erbitux ® are successfully used in the treatment of HER2 -positive breast cancer and EGFR-positive colorectal cancer.
  • cytotoxic compounds provides an advanced means of further inhibiting cancer therapy since these conjugates allow for tumor-specific toxophore accumulation while reducing systemic toxicity.
  • Efficacy and tolerability have been demonstrated in clinical trials with brentuximab vedotin in Hodgkin's lymphoma and trastuzumab-DMl in breast cancer have received encouraging results supporting the development of new antibodies and new ADCs against other tumor antigens.
  • Antibody-based therapy has proven to be very powerful in the treatment of various carcinomas, including solid tumors.
  • Herceptin ® has been successfully used for the treatment of breast cancer and Rituxan ® is in cancer types that are related to the B-cell related, powerful.
  • the fibroblast growth factor receptors are tyrosine receptor kinases (RTK), four of which are known in mammals (FGFR1, FGFR2, FGFR3, FGFR4).
  • FGF human fibroblast growth factors
  • FGFR alpha SEQ ID NO: l
  • FGFR beta SEQ ID NO: 2
  • Figure 1 An alternative splice in domain 3 results to two different variants, namely FGFR2 Illb, which is encoded by exons 7 and 8, and FGFR2 IIIc, which is encoded by exons 7 and 9 ( Figure 1). The latter splice affects ligand binding, leading to the specificity pattern.
  • FGFR2 IIIc is expressed primarily by mesenchymal cells and FGFR2 IIIb essentially by epithelial cells.
  • FGF7 is also known as Keratinocyte Growth Factor (KGF) and only binds to FGFR2 Illb, which therefore also KGFR is called. Subsequently, when FGF binds to their receptors, dimerization and phosphorylation of the FGFR and downstream signaling via the FRS-GRB2 docking protein complex to the RAS-MAPK signaling cascade and the PI3K-AKT signaling cascade take place. The former signaling cascade is involved in cell growth and differentiation, the latter being involved in cell survival and cell fate determination (Katoh and Katoh, Int., J. Oncol., 2006, 29: 163-168).
  • KGF Keratinocyte Growth Factor
  • FGFR1 to FGFR4 Correct organogenesis during embryogenesis requires orchestrated signaling from all four receptors (FGFR1 to FGFR4) and their splice variants via the different FGFs (Ornitz et al., Genome Biol 2001, 2: 3005).
  • FGFR2 the lack of all FGFR2 variants leads to defects in placental and limb bud formation and therefore leads to lethality at stage El 0.5.
  • Mouse specific knock-out of FGFR2 Illb also leads to lethality (in PO) associated with pulmonary, anterior lobe, thyroid, tooth and limb genesis, while a FGFR2-IIIc variant disorder is viable.
  • FGFR2 and / or KGF are associated with expansive growth of gastric carcinoma and shorter patient survival (Matsunobu et al., Int J. Cancer 2006, 28: 307-314; Toyokawa et al., Oncol. Reports 2009, 21 : 875-880).
  • Overexpression of FGFR2 was detected in 31-36.5% of all tested gastric carcinoma samples (Matsunobu et al., Int J. Cancer 2006, 28: 307-314; Toyokawa et al., Oncol. Reports 2009, 21: 875-880 ).
  • Adenocarcinoma (70% of all gastric cancers) is further divided into two distinct pathological types, intestinal-type and diffuse-type stomach cancers.
  • FGFR2 may be the result of gene amplification, as approximately 7% to 10% of all primary gastric carcinomas have amplifications of FGFR2 (Kunii et al., Cancer Res., 2008, 68: 23-40-2348). Furthermore, FGFR2 expression was not only found in metastases, but was even greater in metastases than in primary tumors (Yamashita et al., Surg. Today 2011, 41: 24-38).
  • TNBC triple-negative breast carcinomas
  • SNP single nucleotide polymorphism
  • the FGFR2 protein was found in all invasive cervical carcinomas tested with high expression at the invasive front of the tumors (Kawase et al., Int. J. Oncol. 2010, 36: 331-340).
  • FGFR2 expression was upregulated 4.7 times more in poorly differentiated tumors. This expression is associated with the occurrence of portal vein invasion and lower disease-free survival times (Harimoto et al., Oncology 2010, 78: 361-368).
  • FGFR2 signaling promotes migration and invasion of gastric cancer cell lines (Shin et al., J. Cancer Res. Clin. Oncol., 2002, 128: 596-602), breast cancer cell lines (Zhang et al., Anticancer Res. 1998, 18: 2541 -2546) and pancreatic cancer cell lines in vitro (Nomura et al., Br. J. Cancer 2008, 99: 305-313; Niu et al., J. Biol. Chem. 2007, 282: 6601-6011).
  • FGFR2 is the most upregulated gene in tumor-associated fibroblasts. Isolated tumor-associated fibroblasts released a soluble factor that promotes the proliferation of esophageal cancer cells (Zhang et al., Hum. Cancer Biol. 2009, 15: 4017-4022), demonstrating that FGFR2 also expressed by stromal cells can promote tumor progression.
  • FGFR2 Illb Illb
  • R & D Systems distributes anti-FGFR2 antibodies, which have the first activity-neutralizing effects in the as s ay s of the first.
  • WO2005 / 06621 1 describes antibodies which are directed against various cell surface FGFRs, inter alia FGFR2.
  • WO2009 / 100105 are isoform-specific anti-FGFR2 antibodies covalently with Effector molecules can be linked, described.
  • WO2007 / 134210 describes methods of treating colorectal cancer using anti-FGFR2 antibodies or immunoconjugates.
  • WO2007 / 144893 describes FGFR2 antibodies having binding affinity for other FGFRs that block ligand-dependent and constitutive ligand-independent FGFR2 receptor activation.
  • Auristatin E (AE) and monomethylauristatin E (MMAE) are synthetic analogs of the dolastatins, a special group of linear pseudopeptides originally isolated from marine sources, some of which have very potent cytotoxic activity against tumor cells [for review, see e.g. G.R. Pettit, Prog. Chem. Org. Nat. Prod. 70, 1-79 (1997); G.R. Pettit et al, Anti-Cancer Drug Design 1_0, 529-544 (1995); G.R. Pettit et al, Anti-Cancer Drug Design 1_3, 243-277 (1998)].
  • MMAE Monomethylauristatin E
  • MMAE has the disadvantage of a comparatively high systemic toxicity.
  • MMAE is used in particular in conjunction with enzymatically cleavable valine citrulline linkers in the ADC setting for more targeted tumor therapy [WO 2005/081711-A2; S.O. Doronina et al., Bioconjugate Chem. 17, 114-124 (2006)].
  • MMAE is preferably released intracellularly from corresponding ADCs.
  • Monomethylauristatin F is an auristatin derivative having a C-terminal phenylalanine moiety which has only moderate anti-proliferative activity compared to MMAE. This is most likely due to the free carboxyl group which, due to its polarity and charge, adversely affects the cellularity of this compound.
  • MMAF-OMe methyl ester of MMAF
  • MMAF-OMe methyl ester of MMAF
  • MMAF-OMe has been described as a neutrally charged, prodrug cell-permeable derivative that exhibits several orders of magnitude increased in vitro cytotoxicity to various carcinoma cell lines compared to MMAF [SO Doronina et al., Bioconjugate Chem. 1_7, 11 4-124 (2006)]. It is believed that this effect by MMAF itself caused by intracellular ester hydrolysis is rapidly released after uptake of the prodrug into the cells.
  • active compound compounds based on simple ester derivatives are generally subject to the risk of chemical instability due to an unspecific ester hydrolysis independent of the intended site of action, for example by esterases present in the blood plasma; this can significantly limit the applicability of such compounds in therapy.
  • MMAF Monomethylauristatin F
  • auristatin analogues with a C-terminal, amidically substituted phenylalanine unit are described in WO 01/18032-A2.
  • WO 02/088172-A2 and WO 2007/008603-A1 claim MMAF analogs which relate to side-chain modifications of phenylalanine, and in WO 2007/008848-A2 those in which the carboxyl group of the phenylalanine is modified.
  • Auristatin conjugates linked via the C-terminus have recently been described in WO 2009/117531 -AI [see also S.O. Doronina et al., Bioconjugate Chem. 19, 1960-1963 (2008)].
  • ADCs novel binder-drug conjugates
  • novel N, N-dialkylauristatin derivatives with novel, suitable linkers and binders, have a very attractive profile of action, for example as regards their specific tumor action and / or the lower potential of the intracellular metabolites formed as a substrate against transporter proteins, and are therefore suitable for the treatment and / or prophylaxis of hyperproliferative and / or angiogenic diseases such as cancers.
  • the present invention relates to binder-active compound conjugates of the general formula (Ia)
  • n is a number from 1 to 50
  • AK is a binder which binds FGFR2
  • the group ⁇ -GL 1 -B- ⁇ ⁇ is a linker
  • L 2 is linear (C 2 -C 10) -alkanediyl or a group of the formula where p is a number from 2 to 6,
  • ## 3 denotes the point of attachment to the group B
  • ## 4 denotes the point of attachment to the nitrogen atom
  • (C 2 -C 10) -alkanediyl having 1 to 4 substituents independently selected from the group of methyl, hydroxy and benzyl may be substituted, and wherein two carbon atoms of the alkanediyl chain in 1,2-, 1,3- or 1,4-relative to each other with the inclusion of any carbon atoms between them be bridged to a (C3-C6) -cycloalkyl ring or a phenyl ring can, for a group of formula
  • R is hydrogen or methyl
  • R is isopropyl, isobutyl, sec-butyl, tert. Butyl, phenyl, benzyl, 1-hydroxyethyl, 4-hydroxybenzyl, 4-hydroxy-3-nitrobenzyl, 4-hydroxy-3-aminobenzyl, 1-phenylethyl, diphenylmethyl, lH-imidazol-4-ylmethyl or lH-indole 3-ylmethyl stands,
  • # denotes the point of attachment to the adjacent nitrogen atom which denotes the point of attachment to the carbonyl group, the ring A with the NO group contained therein for a mono- or bicyclic, optionally substituted heterocycle of the formula
  • R j is hydrogen or methyl, isopropyl, isobutyl, sec-butyl, tert. Butyl, phenyl, benzyl, 1-hydroxyethyl, 4-hydroxybenzyl, 4-hydroxy-3-nitrobenzyl, 4-hydroxy-3-aminobenzyl, 1-phenylethyl, diphenylmethyl, lH-imidazol-4-ylmethyl or lH-indole 3-ylmethyl, or
  • R 7 is hydrogen, methyl, ethyl, n-propyl, tert. Butyl, benzyl or adamantylmethyl,
  • R 8 is hydrogen or methyl
  • R 9 is hydrogen, methyl, ethyl, n-propyl or benzyl, or
  • R 8 and R 9 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle
  • R 10 is benzoyl
  • R 11 is benzyl, which may be substituted in the phenyl group with methoxycarbonyl or carboxyl, is hydrogen, methyl or a group of the formula
  • -CHC (R) -T is phenyl which may be substituted by methoxycarbonyl, carboxyl or a group of the formula -S (0) 20H, is phenyl which may be substituted by methoxycarbonyl or carboxyl, R 26 is hydrogen or hydroxy,
  • T ⁇ 2 is phenyl, benzyl, 1H-indol-3-yl or 1H-indol-3-ylmethyl,
  • R 35 is methyl or hydroxy, and their salts, solvates and solvates of the salts.
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of the salts.
  • the compounds of the invention may exist in different stereoisomeric forms depending on their structure, i. in the form of configurational isomers or optionally also as conformational isomers (enantiomers and / or diastereomers, including those in atropisomers).
  • the present invention therefore includes the enantiomers and diastereoisomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or chiral phase.
  • the present invention encompasses all of the ADC character tautomeric forms.
  • the present invention also includes all suitable isotopic variants of the compounds of the invention.
  • An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature.
  • isotopes which can be incorporated into a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 13 C, 14 C, 15 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 129 I and 131 I.
  • Certain isotopic variants of a compound of the invention such as, in particular, those in which one or more radioactive isotopes are incorporated, may be useful, for example, for the study of the active compound.
  • isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing the required effective dose; Such modifications of the compounds of the invention may therefore optionally also constitute a preferred embodiment of the present invention.
  • Isotopic variants of the compounds according to the invention can be prepared by the methods known to the person skilled in the art, for example by the methods described below and the rules given in the exemplary embodiments, by using appropriate isotopic modifications of the respective reagents and / or starting compounds.
  • Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are themselves unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds of the invention.
  • Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, benzenesulfonic, toluenesulfonic, naphthalenedisulfonic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.
  • Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, benzenesulfonic, toluenesulfonic, naphthalenedisulfonic acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.
  • Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms.
  • alkali metal salts for example sodium and potassium salts
  • alkaline earth salts for example calcium and magnesium salts
  • ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms.
  • Atoms such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylpiperidine, N-methylmorpholine, arginine, lysine and 1,2-ethylenediamine.
  • Solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates in which the Coordination with water takes place. As solvates, hydrates are preferred in the context of the present invention.
  • the present invention also includes prodrugs of the compounds of the invention.
  • prodrugs refers to compounds which themselves may be biologically active or inactive, but are converted during their residence time in the body to compounds of the invention (for example metabolically or hydrolytically).
  • (C 1 -C 4) -alkyl in the context of the invention is a linear or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned by way of example include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl and tert. Butyl.
  • Alkanediyl is in the context of the invention a linear, ⁇ , ⁇ -divalent alkyl radical having the particular number of carbon atoms.
  • alkanediyl examples which may be mentioned by way of example and with preference are: methylene, ethane-1,2-diyl (1,2-ethylene), propane-1,3-diyl (1,3-propylene), butane-1,4-diyl (1,4-diyl).
  • Butylene pentane-1,5-diyl (1,5-pentylene), hexane-1,6-diyl (1,6-hexylene), heptane-1,1,7-diyl (1,7-hexylene), octane 1,8-diyl (1,8-octylene), nonane-l, 9-diyl (1,9-nonylene), decane-l, 10-diyl (1,10-decylene).
  • (C3-C7) -cycloalkyl or 3- to 7-membered carbocycle in the context of the invention is a monocyclic, saturated cycloalkyl group having 3 to 7 carbon atoms. Examples which may be mentioned by way of example include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • the side group of an amino acid q in the meaning of R 19 encompasses both the side groups of naturally occurring ⁇ -amino acids and the side groups of homologues and isomers of these ⁇ -amino acids.
  • the ⁇ -amino acid can be present in both the L and the D configuration or else as a mixture of the L and D form.
  • side groups are: methyl (alanine), propan-2-yl (valine), propan-1-yl (norvaline), 2-methylpropan-1-yl (leucine), 1-methylpropan-1-yl (isoleucine) , Butan-1-yl (norleucine), tert.
  • Preferred a-amino acid side groups in the meaning of R 19 are methyl (alanine), propan-2-yl (valine), 2-methylpropan-1-yl (leucine), benzyl (phenylalanine), imidazol-4-ylmethyl (histidine ), Hydroxymethyl (serine), 1-hydroxyethyl (threonine), 4-aminobutan-1-yl (lysine), 3-aminopropan-1-yl (ornithine), 2-aminoethyl (2,4-diaminobutyric acid), aminomethyl (2 , 3-diaminopropionic acid),
  • a 4- to 7-membered heterocycle is in the context of the invention for a monocyclic, saturated heterocycle having a total of 4 to 7 ring atoms containing one or two ring heteroatoms from the series N, O, S, SO and / or SO 2 and is linked via a ring carbon atom or optionally a ring nitrogen atom.
  • the end point of the line is at the character # 6 , * **, # 3 , # # 2 , ## 2 , ## 3 , ## 4 , ***, ****, # 4 , # 5 , # 6 , # 7 , # 8 or # 9 , does not represent a carbon atom or a CH 2 group, but is part of the bond to the respectively designated atom to which A, B, D, G, L 1 , L 2 , L 4 , R 1 , R 2 , R 3 , R 4 and R 5 is bonded.
  • radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. Substitution with one or two identical or different substituents is preferred. Particularly preferred is the substitution with a substituent.
  • linker is broadly understood to mean a chemical entity comprising a covalent bond or an array of atoms that covalently attaches a binder to an agent, Preferably, the term “linker” is used as an array of atoms in the sense of Understand the present invention, which covalently attaches a binder to a drug.
  • linkers may be, for example, divalent chemical moieties such as alkyldiyls, aryldiyls, heteroaryldyls, heterocyclyldyls, dicarbonylic acid esters, dicarbonylic acid amides.
  • binding is broadly understood to mean a molecule which binds to a target molecule present on a particular target cell population to be targeted with the binder-drug conjugate includes, for example, lectins, proteins that bind certain sugar chains, or phospholipid-binding proteins, such as high molecular weight proteins (binding proteins), polypeptides or peptides (binding peptides), non-peptidic (eg, aptamers (US5,270,163) review articles by Keefe AD Rev. Drag Discov 2010; 9: 537-550), or vitamins) and all other cell-binding molecules or substances, such as antibodies and antibody fragments or antibody mimetics such as Affibodies, Adnectins, Anticalins.
  • lectins proteins that bind certain sugar chains
  • phospholipid-binding proteins such as high molecular weight proteins (binding proteins), polypeptides or peptides (binding peptides), non-peptidic (eg, aptamers (US5,270,163)
  • Binding peptides are e.g. Ligands of a ligand-receptor pair, e.g. VEGF of the ligand receptor pair VEGF / KDR, such as transferrin of the ligand receptor pair transferrin / transferrin receptor or cytokine / cytokine receptor, such as TNF alpha of the ligand receptor pair TNFalpha / TNFalpha receptor.
  • Ligands of a ligand-receptor pair e.g. VEGF of the ligand receptor pair VEGF / KDR, such as transferrin of the ligand receptor pair transferrin / transferrin receptor or cytokine / cytokine receptor, such as TNF alpha of the ligand receptor pair TNFalpha / TNFalpha receptor.
  • epitope includes any determinant of a protein that can specifically bind to an immunoglobulin or T-cell receptor.
  • determinants usually consist of chemically active surface arrangements of molecules, e.g. Amino acids, carbohydrates or a combination thereof, which usually have a specific three-dimensional structure and also certain charge properties.
  • Two antibodies bind to the same epitope when it is shown in a competitive binding assay format that the first antibody competes with the second antibody. Such binding assays are known to the person skilled in the art.
  • a "target molecule” is broadly understood to be a molecule present in the target cell population, and may be a protein (eg, a growth factor receptor) or a non-peptidic molecule (eg, a sugar or phospholipid) Receptor or an antigen.
  • extracellular target molecule describes a cell-bound target molecule located on the outside of a cell or the part of a target molecule that is located on the outside of a cell, ie a binder can bind to an intact cell to its extracellular target molecule.
  • An extracellular targeting molecule may be anchored in the cell membrane or be part of the cell membrane.
  • the person skilled in the art knows methods to identify extracellular target molecules. For proteins, this can be done by determining the transmembrane domain (s) and the orientation of the protein in the membrane. This information is usually stored in protein databases (eg SwissProt).
  • cancer target molecule describes a target molecule that is more abundant on one or more types of cancer cells compared to non-cancerous cells of the same tissue type, Preferably, the cancer target molecule is on one or more cancer cell types compared to non-cancerous cells of the same tissue type selectively present, selectively expressing at least two-fold accumulation on cancer cells compared to non-cancer cells of the same tissue type (a "selective cancer target molecule”).
  • selective cancer target molecule allows the selective therapy of cancer cells with the conjugates of the invention.
  • the binder can be linked via a linkage with the linker.
  • the linkage of the binder can be effected by means of a heteroatom of the binder.
  • Inventive heteroatoms of the binder which can be used for linking are sulfur (in one embodiment via a sulfhydryl group of the binder), oxygen (according to the invention by means of a carboxyl or hydroxyl group of the binder) and nitrogen (in one embodiment via a primary or secondary amine group or Amide group of the binder).
  • These heteroatoms may be present in the natural binder or introduced by chemical or molecular biological methods.
  • the linkage of the binder with the toxophore has only a small influence on the binding activity of the binder to the target molecule. In a preferred embodiment, the linkage has no influence on the binding activity of the binder to the target molecule.
  • an immunoglobulin molecule preferably comprises a molecule having four polypeptide chains, two heavy chains (H chains) and two light chains (L chains), which are typically linked by disulfide bridges.
  • Each heavy chain comprises a heavy chain variable domain (abbreviated VH) and heavy chain constant domain.
  • the heavy chain constant domain may include three domains CHI, CH2 and CH3.
  • Each light chain comprises a variable domain (abbreviated VL) and a constant domain.
  • the constant domain of the light chain comprises a domain (abbreviated to CL).
  • VH and VL domains can be further subdivided into regions with hypervariability, including complementarity determining regions called "complementarity determining region”, abbreviated CDR) and regions with lower sequence variability ("framework region", abbreviated FR).
  • CDR complementarity determining region
  • FR frame region
  • Each VH and VL region typically consists of three CDRs and up to four FRs.
  • An antibody can be obtained from any suitable species, eg, rabbit, llama, camel, mouse, or rat.
  • the antibody is of human or murine origin.
  • an antibody can be human, humanized or chimeric.
  • monoclonal antibody refers to antibodies obtained from a population of substantially homogeneous antibodies, ie, individual antibodies of the population are identical except for naturally occurring mutations which can occur in small numbers.Monoclonal antibodies recognize with high specificity a single antigenic binding site The term monoclonal antibody does not refer to a particular manufacturing process.
  • the term "intact" antibody refers to antibodies comprising both an antigen-binding domain and the light and heavy chain constant domain
  • the constant domain may be a naturally occurring domain, or a variant thereof in which multiple amino acid positions are altered were.
  • modified intact antibody refers to intact antibodies that have been fused to another non-antibody polypeptide or protein via their amino terminus or carboxy-terminus via a covalent bond (eg, a peptide linkage) modified to introduce reactive cysteines at defined sites to facilitate coupling to a toxophore (see Junutula et al., Nat Biotechnol., 2008 Aug; 26 (8): 925-32).
  • a covalent bond eg, a peptide linkage
  • human antibody refers to antibodies that can be obtained from a human or that are synthetic human antibodies
  • a "synthetic” human antibody is an antibody that is available, in part or in whole, from synthetic sequences in silico that have been analyzed based on human antibody sequences.
  • a human antibody may be encoded by a nucleic acid isolated from a library of antibody sequences of human origin.
  • An example of such antibodies is in Söderlind et al., Nature Biotech. 2000, 18: 853-856.
  • the term “humanized” or “chimeric” antibody describes antibodies consisting of a non-human and a human sequence portion.
  • the human immunoglobulin In these antibodies, part of the sequences of the human immunoglobulin (recipient) is replaced by sequence portions of a non-human immunoglobulin (donor).
  • the donor is a murine immunoglobulin in many cases.
  • at humanized antibodies are replaced amino acids of the CDR of the recipient by amino acids of the donor.
  • amino acids of the framework are replaced by corresponding amino acids of the donor.
  • the humanized antibody contains amino acids that were not contained in either the recipient or the donor and that were inserted during optimization of the antibody.
  • the variable domains of the donor immunoglobulin are fused to the constant regions of a human antibody.
  • CDR complementarity determining region
  • Each variable region typically has three CDR regions, referred to as CDR1, CDR2 and CDR3.
  • Each CDR region may comprise amino acids as defined by Kabat and / or amino acids of a hypervariable loop defined by Chotia.
  • the Kabat definition includes, for example, the region of approximately amino acid position 24-34 (CDR1), 50-56 (CDR2) and 89-97 (CDR3) of the variable light chain and 31-35 (CDR1), 50-65 (CDR2). and 95-102 (CDR3) variable heavy chain (Kabat et al., Sequences of Proteins of Immulological Interest, 5th ed.
  • a CDR may comprise amino acids from a CDR region as defined by Kabat and Chotia.
  • antibodies can be divided into different classes. There are five major classes of intact antibodies: IgA, IgD, IgE, IgG and IgM, several of which can be broken down into other subclasses. (Isotypes), e.g. IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2.
  • the heavy chain constant domain corresponding to the different classes are referred to as [alpha / a], [delta / ⁇ ], [epsilon / ⁇ ], [gamma / ⁇ ] and [my / ⁇ ]. Both the three-dimensional structure and the subunit structure of antibodies are known.
  • the term "functional fragment” or "antigen-binding antibody fragment” of an antibody / immunoglobulin is defined as a fragment of an antibody / immunoglobulin (eg, the variable domains of an IgG) that still encompasses the antigen-binding domains of the antibody / immunoglobulin.
  • the "antigen-binding domain” of an antibody typically comprises one or more hypervariable regions of an antibody, eg, the CDR, CDR2, and / or CDR3 region, however, the "framework” or “scaffold” region of an antibody may also be used Antibody to bind the antibody to the antigen play a role.
  • the framework region provides the framework for the CDRs.
  • the antigen-binding domain comprises at least amino acids 4 to 103 of the variable light chain and amino acids 5 to 109 of the variable heavy chain, more preferably amino acids 3 to 107 of the variable light chain and 4 to 111 of the variable heavy chain, most preferably the complete ones variable light and heavy chains, so amino acid 1 - 109 of the VL and 1 to 1 13 of the VH (numbering according to WO97 / 08320).
  • “Functional fragments” or “antigen-binding antibody fragments” of the invention do not exhaustively include Fab, Fab ', F (ab') 2 and Fv fragments, diabodies, single domain antibodies (DAbs), linearae antibodies, single chain antibodies (single-chain Fv , abbreviated scFv); and multi-specific, e.g. bi- and tri-specific antibodies formed from antibody fragments C. A. K Borrebaeck, editor (1995) Antibody Engineering (Breakthroughs in Molecular Biology), Oxford University Press; R. Kontermann & S. Duebel, editors (2001) Antibody Engineering (Springer Laboratory Manual), Springer Verlag).
  • Multispecific antibodies are those with identical binding sites.
  • Multispecific antibodies may be specific for different epitopes of an antigen or may be specific for epitopes of more than one antigen (see eg WO93 / 17715, WO 92/08802, WO91 / 00360, WO92 / 05793, Tutt, et al., 1991, J. Immunol., 147: 60 69; U.S. Patent Nos. 4,474,893; 4,7 14,68 1; 4,925,648; 5,573,920; 5,601,819; or Kostelny et al., 1992, J. Immunol. 148: 1547 1553).
  • An F (ab ') 2 or Fab molecule can be designed to reduce or completely prevent the number of intermolecular disulfide interactions that occur between the Chi and CL domains.
  • “Functional fragments” or “antigen-binding antibody fragments” may be fused to another non-antibody polypeptide or protein via their amino-terminus or carboxy-terminus via a covalent bond (e.g., a peptide linkage). Furthermore, antibodies and antigen-binding fragments can be modified to introduce reactive cysteines at defined sites to facilitate coupling to a toxophore (see Junutula et al., Nat Biotechnol., 2008 Aug; 26 (8): 925-32) ).
  • Polyclonal antibodies can be prepared by methods known to those of ordinary skill in the art.
  • Monoclonal antibodies can be prepared by methods known to those of ordinary skill in the art (Köhler and Milstein, Nature, 256, 495-497, 1975).
  • Humanized human monoclonal antibodies can be prepared by methods known to those of ordinary skill in the art (Olsson et al., Meth Enzymol., 92, 3-16 and Cabilly et al., US 4,816,567 or Boss et al., US 4,816,397).
  • Antibodies of the invention can be obtained from recombinant antibody libraries consisting, for example, of the amino acid sequences of a variety of antibodies generated from a large number of healthy volunteers. Antibodies can also be made by known recombinant DNA technology. The nucleic acid sequence of an antibody can be obtained by routine sequencing, or is available from publicly available databases.
  • an “isolated” antibody or binder has been purified from other components of the cell Contaminating components of a cell that may interfere with a diagnostic or therapeutic use are, for example, enzymes, hormones, or other peptidic or non-peptidic components of a cell an antibody or binder that has been purified to more than 95% by weight of the antibody or binder (determined, for example, by Lowry method, UV-Vis spectroscopy, or by SDS capillary gel electrophoresis) and an antibody which has been purified to such an extent at least fifteen amino acids of the amino terminus or an internal amino acid sequence can be determined or purified to homogeneity, the homogeneity being determined by SDS-PAGE under reducing or non-reducing conditions (the detection can be determined by Coomassie blue staining or preferably by silver staining)
  • Antibodies usually produced by one or more purification steps.
  • specific binding refers to an antibody or binder that binds to a predetermined antigen / target molecule.
  • Specific binding of an antibody or binder typically describes an antibody with an affinity of at least 10 -7 M, the antibody or binding having at least two-fold higher affinity for the predetermined antigen / target than for a non-specific antigen / target (eg, bovine serum albumin, or casein) which is not the predetermined antigen / target molecule or a closely related antigen / target molecule.
  • a non-specific antigen / target eg, bovine serum albumin, or casein
  • Antibodies that are specific to a cancer cell antigen can be prepared by those of ordinary skill in the art by methods known to those in the art (such as recombinant expression) or purchased commercially (such as from Merck KGaA, Germany). Examples of known commercially available antibodies in cancer therapy are Erbitux® (Cetuximab, Merck KGaA), Avastin® (Bevacizumab, Roche) and Herceptin® (Trastuzumab, Genentech).
  • the antibody is produced recombinantly in CHO cells.
  • Preferred subject matter of the invention are binder-active compound conjugates of the general formula (Ia) in which n is a number from 1 to 50,
  • AKi is a binder which binds FGFR2 linked to the group G via a sulfur atom of the binder
  • AK 2 is a binder which binds FGFR 2 linked to the group G via a nitrogen atom of the binder
  • # 1 denotes the point of attachment to the sulfur atom of the binder
  • n is a number from 2 to 6
  • ## 5 denotes the point of linkage with group L 1A
  • 6 denotes the point of linkage with group L 1B
  • L 5 is a bond or (C 2 -C 4) -alkanediyl
  • L 6 represents a bond or a group of the formula
  • R 33 is hydrogen, (C 1 -C 4) -alkylcarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl, R 34 is hydrogen or methyl,
  • R 29 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 30 is hydrogen or (Ci-C 4 ) -alkyl, or
  • R 29 and R 30 together with the atoms to which they are attached, a 5- or
  • R 31 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 32 is hydrogen or (C 1 -C 4 ) -alkyl, or
  • R 31 and R 32 together with the atoms to which they are attached, a 5- or
  • L 1B is linear (C 2 -C 10) -alkanediyl, and wherein (C 1 -C 10) -alkanediyl may be substituted with 1 to 4 substituents independently selected from the group of methyl, hydroxy and benzyl, and wherein two carbon atoms of the alkanediyl chain in 1, 2, 1, 3 or 1, 4 relation to each other, including the carbon atoms optionally between them can be bridged to a (C3-C6) -cycloalkyl ring or a phenyl ring, for a bond or a Group of formula
  • P is O or NH
  • L 3 is a bond or (C 2 -C 12) -alkanediyl
  • L 4 represents a bond or a group of the formula
  • R 25 is hydrogen or methyl
  • R 28 is hydrogen, (C 1 -C 12) -alkylcarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl,
  • Q 1 is a 4- to 7-membered heterocycle
  • Q 2 is a 3- to 7-membered carbocycle or a 4- to 7-membered heterocycle
  • R 14 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 15 is hydrogen or (Ci-C 4 ) -alkyl, or
  • R 14 and R 15 together with the atoms to which they are attached form a 5- or 6-membered heterocycle
  • R 16 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 17 is hydrogen or (Ci-C 4 ) -alkyl, or
  • R 16 and R 17 together with the atoms to which they are attached form a 5- or 6-membered heterocycle
  • R 18 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 19 is hydrogen or the side group of a natural ⁇ -amino acid or its homologs or isomers
  • R 20 is hydrogen or (C 1 -C 4 ) -alkyl, or
  • R 19 and R 20 together with the atoms to which they are attached form a pyrrolidinyl ring
  • R 21 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 22 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 21 and R 22 together with the atoms to which they are attached form a 3- to 7-membered carbocycle
  • R 23 is (C 1 -C 4 ) -alkyl
  • R 24 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 27 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 36 represents hydrogen, (C 1 -C 4 ) -alkylcarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl,
  • R 37 is hydrogen or methyl
  • L 2 is linear (C 2 -Cio) alkanediyl or a group of the formula stands, where
  • P is a number from 2 to 6
  • ## 3 denotes the point of attachment to the group B
  • D for a group of the formula wherein the point of attachment to the nitrogen atom, is hydrogen or methyl, isopropyl, isobutyl, sec-butyl, tert. Butyl, phenyl, benzyl, 1-hydroxyethyl, 4-hydroxybenzyl, 4-hydroxy-3-nitrobenzyl, 4-hydroxy-3-aminobenzyl, 1-phenylethyl, diphenylmethyl, lH-imidazol-4-ylmethyl or lH-indole 3-ylmethyl, or together with the carbon atom to which they are attached, (1S, 2R) -2-phenylcyclopropane-1,1-diyl group of the formula
  • # 5 denotes the point of attachment with the carbonyl group, the ring A with the NO group contained therein for a mono- or bicyclic, optionally substituted heterocycle of the formula stands in which
  • # 6 denotes the point of attachment to the carbonyl group
  • R 6 is hydrogen, hydroxy or benzyloxy
  • R 3 is hydrogen or methyl
  • R 4 isopropyl, isobutyl, sec-butyl, tert. Butyl, phenyl, benzyl, 1-hydroxyethyl, 4-hydroxybenzyl, 4-hydroxy-3-nitrobenzyl, 4-hydroxy-3-aminobenzyl, 1-phenylethyl, diphenylmethyl, lH-imidazol-4-ylmethyl or lH-indole 3-ylmethyl, or
  • R 8 is hydrogen or methyl
  • R 9 is hydrogen, methyl, ethyl, n-propyl or benzyl, or
  • R 8 and R 9 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle
  • R 10 is benzoyl
  • R 11 is benzyl which may be substituted in the phenyl group by methoxycarbonyl or carboxyl,
  • R 5 is hydrogen, methyl or a group of the formula
  • # 9 identifies the point of attachment with -CHC (R 26 ) -T 2 ,
  • R 12 is phenyl which may be substituted by methoxycarbonyl, carboxyl or a group of the formula -S (O) 20H,
  • R 13 is phenyl which may be substituted by methoxycarbonyl or carboxyl,
  • R 26 is hydrogen or hydroxy
  • T 2 is phenyl, benzyl, 1H-indol-3-yl or 1H-indol-3-ylmethyl, is methyl or hydroxy, and their salts, solvates and solvates of the salts.
  • Preferred subject matter of the invention are binder active compound conjugates of the general formula (Ia) in which n is a number from 1 to 20, AK is AKi or AK 2 being
  • AKi is a binder which binds FGFR2 and is bonded to the group G via the sulfur atom of a cysteine residue of the binder,
  • AK 2 represents a binder which binds FGFR 2 and is linked to the group G via the NH side group of a lysine residue of the binder
  • ## 1 denotes the point of attachment to the group G
  • L 1A is linear (C 2 -C 6) -alkanediyl
  • L 6 represents a bond or a group of the formula
  • ## 7 denotes the point of attachment with the carbonyl group
  • R 33 is hydrogen, methylcarbonyl or tert-butyloxycarbonyl, R 34 is hydrogen or methyl,
  • R 29 is hydrogen
  • R 30 is hydrogen
  • R 31 is hydrogen or methyl
  • R 32 is hydrogen or methyl
  • L 1B is linear (C 2 -C 6) -alkanediyl
  • L 3 is a bond or ethane 1, 2-diyl, a bond or a group of the formula
  • R 25 is hydrogen or methyl
  • R 28 is hydrogen, methylcarbonyl or tert-butyloxycarbonyl, Q 1 is a 4- to 7-membered heterocycle, R 14 is hydrogen, R 15 is hydrogen,
  • R 16 is hydrogen or methyl
  • R 17 is hydrogen or methyl
  • R 18 is hydrogen
  • R 19 is hydrogen, methyl, propan-2-yl, 2-methylpropan-1-yl or 1-methylpropan-1-yl,
  • R 20 is hydrogen or methyl, or R 19 and R 20 together with the atoms to which they are attached form a pyrrolidinyl ring,
  • R 21 is hydrogen or methyl
  • R 22 is hydrogen or methyl
  • R 21 and R 22 together with the atoms to which they are attached form a cyclopropyl ring
  • R 23 is methyl
  • R 24 is hydrogen or methyl
  • R 27 is hydrogen
  • R 36 is hydrogen, methylcarbonyl or tert-butyloxycarbonyl
  • R 37 is hydrogen or methyl
  • L 2 is linear (C 2 -C 6) alkanediyl or a group of the formula where p is a number from 2 to 6, ## 3 denotes the point of attachment to the group B,
  • R 1 is hydrogen
  • R is 1-hydroxyethyl, benzyl, 4-hydroxybenzyl, 1-phenylethyl or 1H-indol-3-yl-methyl, or together with the carbon atom to which they are attached, (1S, 2R) -2-phenylcyclopropane-1 , l-diyl group of the formula
  • # 5 denotes the point of attachment with the carbonyl group, the ring A with the NO group contained therein for a mono- or bicyclic, optionally substituted heterocycle of the formula stands in which
  • # 6 denotes the point of attachment to the carbonyl group
  • R 6 is hydrogen, hydroxy or benzyloxy
  • R 3 is hydrogen
  • R 4 is 1-hydroxyethyl, benzyl, 4-hydroxybenzyl, 1-phenylethyl or 1H-indol-3-ylmethyl, or
  • R 8 is hydrogen or methyl
  • R 9 is hydrogen, methyl, ethyl, n-propyl or benzyl, or
  • R 8 and R 9 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle
  • R 10 is benzoyl
  • R 11 is benzyl which may be substituted in the phenyl group by methoxycarbonyl or carboxyl,
  • R 5 is hydrogen, methyl or a group of the formula
  • # 9 identifies the point of attachment with -CHC (R 26 ) -T 2 ,
  • R 12 is phenyl which may be substituted by methoxycarbonyl, carboxyl or a group of the formula -S (O) 20H,
  • R 13 is phenyl which may be substituted by methoxycarbonyl or carboxyl,
  • R 26 is hydrogen or hydroxy
  • T 2 is phenyl, benzyl, 1H-indol-3-yl or 1H-indol-3-ylmethyl, is methyl or hydroxy, and their salts, solvates and solvates of the salts.
  • Preferred subject of the invention are binder active ingredient conjugates of the general formula (Ia), in which n is a number from 1 to 10, AK for AKi or AK 2 is
  • AKi is a binder which binds FGFR2 and which is linked to the group G via the sulfur atom of a cysteine residue of the binder,
  • AK 2 represents a binder which binds FGFR 2 and which is bound to the group G via the NH side group of a lysine residue of the binder
  • ## 1 denotes the linkage point with the group G
  • (C 2 -C 6) -alkanediyl may be substituted by 1 or 2 substituents methyl, a bond or a group of the formula
  • R 28 is hydrogen, methylcarbonyl or tert-butyloxycarbonyl
  • Q 1 is piperidin-l, 4-diyl
  • R 16 is hydrogen or methyl
  • R 17 is hydrogen or methyl
  • R 21 is hydrogen or methyl
  • R 22 is hydrogen or methyl
  • R 21 and R 22 together with the atoms to which they are attached form a cyclopropyl ring
  • R 23 is methyl
  • R 24 is hydrogen
  • L 2 is linear (C 2 -C 6) -alkanediyl or a group of the formula where p is a number from 2 to 6,
  • ## 3 denotes the connection point with the group B
  • R 1 is hydrogen
  • R 2 is 1-hydroxyethyl, benzyl, 4-hydroxybenzyl, 1-phenylethyl or 1H-indol-3-yl-methyl, or
  • # 5 denotes the point of attachment with the carbonyl group, the ring A with the NO group contained therein for a mono- or bicyclic, optionally substituted heterocycle of the formula stands in which
  • # 6 denotes the point of attachment to the carbonyl group
  • R 6 is hydrogen, hydroxy or benzyloxy
  • R 3 is hydrogen
  • R 4 is benzyl, 4-hydroxybenzyl, 1-phenylethyl or 1H-indol-3-ylmethyl, or
  • R 7 is hydrogen, methyl, ethyl, n-propyl, tert. Butyl, benzyl or adamantylmethyl, R 8 is hydrogen or methyl,
  • R 9 is hydrogen, methyl, ethyl, n-propyl or benzyl
  • R u is benzyl which may be substituted in the phenyl group by methoxycarbonyl or carboxyl,
  • R ⁇ is hydrogen, methyl or a group of the formula stands in which
  • # 9 identifies the point of attachment with -CHCFhPhenyl
  • R 12 is phenyl which may be substituted by methoxycarbonyl, carboxyl or a group of the formula -S (O) 20H,
  • R 13 is phenyl which may be substituted by methoxycarbonyl or carboxyl,
  • R 35 is methyl or hydroxy, and their salts, solvates and solvates of the salts.
  • Preferred subject of the invention are binder active ingredient conjugates of the general formula (Ia), in which n is a number from 1 to 10, AK is AK 2 where AK? stands for a binder that binds FGFR2 and that links through the NH side group of a
  • Lysine residue of the binder is bound to the group G,
  • G is carbonyl
  • L 1 stands for a bond, there is a bond
  • L 2 is linear (C 3 -C 6) -alkanediyl or a group of the formula where p is a number of 2 or 3 which denotes the point of attachment to the group B,
  • R 1 is hydrogen
  • R 2 is benzyl, 4-hydroxybenzyl, or 1H-indol-3-ylmethyl, or
  • # 5 denotes the point of attachment with the carbonyl group, the ring A with the NO group contained therein for a mono- or bicyclic, optionally substituted heterocycle of the formula
  • R 3 is hydrogen
  • R 4 is benzyl, 4-hydroxybenzyl or 1H-indol-3-ylmethyl, or
  • R 7 is hydrogen, methyl, ethyl, n-propyl, tert-butyl, benzyl or adamantylmethyl
  • R 8 is hydrogen
  • R 9 is hydrogen or benzyl
  • R 35 is methyl, and their salts, solvates and solvates of the salts.
  • Preferred subject of the invention are binder active ingredient conjugates of the general formula (Ia), in which n is a number from 1 to 10, AK is AKi
  • AKi is a binder which binds FGFR2 and which is linked to the group G via the sulfur atom of a cysteine residue of the binder,
  • G is a group of the formula
  • # 1 denotes the point of attachment with the cysteine residue of the binder
  • # 2 denotes the point of attachment to the group L 1 , a bond, linear (C3-C5) alkanediyl or a group of Fonnel
  • n is a number of 2 or 3
  • ## 1 denotes the link with the group G
  • (C3-C5) -alkanediyl may be substituted with 1 or 2 substituents methyl, for a bond or a group of the formula denotes the linkage point with L 1 ,
  • R 28 is hydrogen, methylcarbonyl or tert-butyloxycarbonyl
  • R 16 is hydrogen or methyl
  • R 17 is hydrogen or methyl
  • R 16 and R 17 together with the atoms to which they are attached form a piperazinyl ring, for linear (C 3 -C 5) -alkanediyl or for a group of the formula
  • ## 3 denotes the point of attachment to the group B
  • R 1 is hydrogen
  • R 2 is benzyl, 4-hydroxybenzyl or 1H-indol-3-ylmethyl, together with the carbon atom to which they are attached, (1S, 2R) -2-phenylcyclopropane-1,1-diyl group of the formula
  • # 5 denotes the point of attachment with the carbonyl group, the ring A with the NO group contained therein for a mono- or bicyclic, optionally substituted heterocycle of the formula
  • R is benzyl, 4-hydroxybenzyl or 1H-indol-3-ylmethyl, or
  • # 7 denotes the point of attachment to the adjacent nitrogen atom
  • # 8 denotes the point of attachment to the group T 1 .
  • R 7 is hydrogen, methyl, ethyl, n-propyl, tert. Is butyl, benzyl or adamantylmethyl, R 8 is hydrogen,
  • R 9 is hydrogen or benzyl
  • R 35 is methyl, and their salts, solvates and solvates of the salts.
  • binder-drug conjugate as described above wherein the binder has the amino acid sequence of the M048-D01-hIgGl-b antibody light and heavy chain antibody shown in SEQ ID NO: 14 (VI) and SEQ ID NO: 13 (Vh) comprising the light and heavy chain amino acid sequence of the antibody M048-D01-hIgG1-b represented in SEQ ID NO: 9 (light chain) and SEQ ID NO: 10 (heavy chain).
  • Another object of the present invention are compounds of the formula (XXXa)
  • Cys is a cysteine radical which is bonded to the e carbon atom of the succinimide via the sulfur atom of the side chain,
  • L 1 is a bond, linear (Ci-Cio) alkanediyl, a group of the formula wherein m is a number from 2 to 6, the point of attachment to the group G denotes, the point of attachment to the group B, stands for linear (C2-Cio) -alkanediyl, a group of the formula
  • ## 6 denotes the point of linkage with group L 1B represents a bond or (C2-C4) -alkanediyl, L 6 stands for a bond,
  • R 29 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 30 is hydrogen or (Ci-C 4 ) -alkyl, or R 29 and R 30 together with the atoms to which they are attached, a 5- or
  • R 31 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 32 is hydrogen or (Ci-C 4 ) -alkyl, or R 31 and R 32 together with the atoms to which they are attached, a 5- or
  • L 1B is linear (C 2 -C 10) -alkanediyl, and wherein (C 1 -C 10) -alkanediyl may be substituted with 1 to 4 substituents independently selected from the group of methyl, hydroxy and benzyl, and wherein two carbon atoms of the alkanediyl chain in 1, 2, 1, 3 or 1, 4 relation to each other, including the carbon atoms optionally between them can be bridged to a (C3-C6) -cycloalkyl ring or a phenyl ring, for a bond or a Group of formula
  • L 3 is a bond or (C 2 -C 4 ) -alkanediyl, L 4 is a bond,
  • Q 1 is a 4- to 7-membered heterocycle
  • Q 2 is a 3- to 7-membered carbocycle or a 4- to 7-membered heterocycle
  • R 14 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 15 is hydrogen or (Ci-C 4 ) -alkyl, or
  • R 14 and R 15 together with the atoms to which they are attached form a 5- or 6-membered heterocycle
  • R 16 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 17 is hydrogen or (Ci-C 4 ) -alkyl, or R 16 and R 17 together with the atoms to which they are attached form a 5- or 6-membered heterocycle,
  • R 18 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 19 is hydrogen or the side group of a natural ⁇ -amino acid or its homologs or isomers
  • R 20 is hydrogen or (C 1 -C 4 ) -alkyl, or
  • R 19 and R 20 together with the atoms to which they are attached form a pyrrolidinyl ring, R 21 is hydrogen or (C 1 -C 4 ) -alkyl,
  • R 22 is hydrogen or (Ci-C 4 ) -alkyl, or
  • R 21 and R 22 together with the atoms to which they are attached form a 3- to 7-membered carbocycle, R 23 is (C 1 -C 4 ) -alkyl,
  • R 24 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 27 is hydrogen or (Ci-C 4 ) -alkyl, linear (C 2 -C 10) -alkanediyl or a group of the formula where p is a number from 2 to 6,
  • ## 3 denotes the point of attachment to the group B
  • ## 4 denotes the point of attachment to the nitrogen atom, wherein (C 2 -C 10) -alkanediyl may be substituted with 1 to 4 substituents independently selected from the group of methyl, hydroxy and benzyl, and wherein two carbon atoms of the alkanediyl chain in 1, 2, 1, 3 or 1, 4 Relation to each other can be bridged with the inclusion of any carbon atoms between them to a (C3-C6) -cycloalkyl ring or a phenyl ring, a group of the formula
  • # 3 denotes the point of attachment to the nitrogen atom
  • R 1 is hydrogen or methyl
  • R 2 isopropyl, isobutyl, ec. Butyl, tert. Butyl, phenyl, benzyl, 1-hydroxyethyl, 4-hydroxybenzyl, 4-hydroxy-3-nitrobenzyl, 4-hydroxy-3-aminobenzyl, 1-phenylethyl, diphenylmethyl, lH-imidazol-4-ylmethyl or lH-indole 3-ylmethyl, or
  • # 5 denotes the point of attachment with the carbonyl group, the ring A with the NO group contained therein for a mono- or bicyclic, optionally substituted heterocycle of the formula
  • # 6 denotes the point of attachment to the carbonyl group
  • R 6 is hydrogen, hydroxy or benzyloxy
  • R 3 is hydrogen or methyl
  • R 4 isopropyl, isobutyl, sec-butyl, tert. Butyl, phenyl, benzyl, 1-hydroxyethyl, 4-hydroxybenzyl, 4-hydroxy-3-nitrobenzyl, 4-hydroxy-3-aminobenzyl, 1-phenylethyl, diphenylmethyl, lH-imidazol-4-ylmethyl or lH-indole 3-ylmethyl, or together with the carbon atom to which they are attached, (1S, 2R) -2-phenylcyclopropane-1,1-diyl group of the formula
  • R 7 is hydrogen, methyl, ethyl, n-propyl, tert. Butyl, benzyl or adamantylmethyl,
  • R 8 is hydrogen or methyl
  • R 9 is hydrogen, methyl, ethyl, n-propyl or benzyl, or
  • R 8 and R 9 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle
  • R 10 is benzoyl
  • R 11 is benzyl which may be substituted in the phenyl group by methoxycarbonyl or carboxyl
  • R 5 is hydrogen, methyl or a group of the formula
  • R 12 is phenyl which may be substituted by methoxycarbonyl, carboxyl or a group of the formula -S (O) 20H,
  • R 13 is phenyl which may be substituted by methoxycarbonyl or carboxyl
  • R 26 is hydrogen or hydroxy
  • T 2 is phenyl, benzyl, lH-indol-3-yl or lH-indol-3-ylmethyl, R: represents ° methyl or hydroxy, and their salts, solvates and solvates of salts.
  • Cys represents a cysteine residue which is linked via the sulfur atom of the side chain via a carbon atom of the succinimide
  • L 1 is a bond, linear (C 2 -C 6) alkanediyl, a group of the formula
  • L 5 represents a bond
  • R 29 is hydrogen
  • R 30 is hydrogen
  • R 31 is hydrogen or methyl
  • R 32 is hydrogen or methyl
  • L 1B is linear (C 2 -C 6 ) -alkanediyl
  • R 14 is hydrogen
  • R 1? stands for hydrogen
  • R 16 is hydrogen or methyl
  • R 17 is hydrogen or methyl
  • R 23 is methyl
  • R 24 is hydrogen or methyl
  • L 2 is linear (C 2 -C 6) -alkanediyl or a group of the formula stands, where
  • P is a number of 2 or 3
  • R 1 is hydrogen
  • R is 1-hydroxyethyl, benzyl, 4-hydroxybenzyl, 1-phenylethyl or 1H-indol-3-yl-methyl, or
  • # 5 denotes the point of attachment with the carbonyl group, the ring A with the NO group contained therein for a mono- or bicyclic, optionally substituted heterocycle of the formula
  • R 6 is hydrogen, hydroxy or benzyloxy, R is hydrogen,
  • R 4 is 1-hydroxyethyl, benzyl, 4-hydroxybenzyl, 1-phenylethyl or 1H-indol-3-ylmethyl, or R 3 and R 4 together with the carbon atom to which they are attached are
  • R 7 is hydrogen, methyl, ethyl, n-propyl, tert. Butyl, benzyl or adamantylmethyl,
  • R 8 is hydrogen or methyl
  • R 9 is hydrogen, methyl, ethyl, n-propyl or benzyl, or
  • R 8 and R 9 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle
  • R 10 is benzoyl
  • R 11 is benzyl which may be substituted in the phenyl group by methoxycarbonyl or carboxyl
  • R 5 is hydrogen, methyl or a group of the formula stands in which
  • # 9 identifies the point of attachment with -CHCFhPhenyl
  • R 12 is phenyl which may be substituted by methoxycarbonyl, carboxyl or a group of the formula -S (O) 20H,
  • R 13 is phenyl which may be substituted by methoxycarbonyl or carboxyl,
  • R 35 is methyl or hydroxy, and their salts, solvates and solvates of the salts.
  • Cys represents a cysteine residue which is linked via the sulfur atom of the side chain via a carbon atom of the succinimide
  • L 1 is a bond or linear (C 2 -C 6) -alkanediyl
  • ## 3 denotes the point of attachment to the group B
  • # 5 denotes the point of attachment to the carbonyl group, with the NO group contained therein for a mono- or bicyclic, optionally substituted heterocycle of the formula
  • R is hydrogen
  • R is benzyl, 4-hydroxybenzyl or 1H-indol-3-ylmethyl, or together with the carbon atom to which they are attached, (1S, 2R) -2-phenylcyclopropane-1,1-diyl group of the formula
  • R 7 is hydrogen
  • R 8 is hydrogen
  • R 9 is hydrogen, R 35 is methyl, and their salts, solvates and solvates of the salts.
  • Another object of the present invention are compounds of formula (XXXI)
  • L is a bond, linear (Ci-Cio) alkanediyl, a group of the formula where m is a number from 2 to 6, ## 1 indicates the point of linkage with the group G, ## 2 indicates the point of attachment of group B, L 1A represents a linear (C2-Cio) -alkyl, B 1 is a group of the formula
  • ## 5 denotes the point of linkage with group L 1A
  • 6 denotes the point of linkage with group L 1B
  • L 5 is a bond or alkanediyl (C2-C i)
  • L 6 is a bond
  • R 29 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 30 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 29 and R 30 together with the atoms to which they are attached, a 5- or
  • R 31 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 32 is hydrogen or (C 1 -C 4 ) -alkyl, or
  • R 31 and R 32 together with the atoms to which they are attached, a 5- or
  • L 1B is linear (C 2 -C 10) -alkanediyl, and where (C 1 -C 10) -alkanediyl having 1 to 4 substituents independently of one another can be substituted from the group consisting of methyl, hydroxy and benzyl, and where two carbon atoms of the alkanediyl chain are in 1, 2, 1, 3 or 1, 4 Relation to each other can be bridged with the inclusion of any carbon atoms between them to a (C3-C6) -cycloalkyl ring or a phenyl ring, a bond or a group of the formula
  • Q 1 is a 4- to 7-membered heterocycle
  • Q 2 is a 3- to 7-membered carbocycle or a 4- to 7-membered heterocycle
  • R 18 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 19 is hydrogen or the side group of a natural ⁇ -amino acid or its homologs or isomers
  • R 20 is hydrogen or (C 1 -C 4 ) -alkyl, or
  • R 19 and R 20 together with the atoms to which they are attached form a pyrrolidinyl ring
  • R 21 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 22 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 21 and R 22 together with the atoms to which they are attached form a 3- to 7-membered carbocycle
  • R 27 is hydrogen or (C 1 -C 4 ) -alkyl
  • L 2 is linear (C 2 -C 10) -alkanediyl or a group of the formula where p is a number from 2 to 6,
  • ## 3 denotes the point of attachment to the group B
  • ## 4 denotes the point of attachment to the nitrogen atom
  • (C 2 -C 10) -alkanediyl having 1 to 4 substituents independently of one another can be substituted from the group consisting of methyl, hydroxy and benzyl, and where two carbon atoms of the alkanediyl chain are present in 1, 2, 1, 3 or 1, 4 relation to each other, taking into account the carbon atoms that may exist between them to form a (C3-
  • D is a group of the formula wherein the point of attachment to the nitrogen atom, is hydrogen or methyl, isopropyl, isobutyl, sec-butyl, tert. Butyl, phenyl, benzyl, 1-hydroxyethyl, 4-hydroxybenzyl, 4-hydroxy-3-nitrobenzyl, 4-hydroxy-3-aminobenzyl, 1-phenylethyl, diphenylmethyl, lH-imidazol-4-ylmethyl or lH-indole 3-ylmethyl, or together with the carbon atom to which they are attached, (1S, 2R) -2-phenylcyclopropane-1,1-diyl group of the formula
  • # 5 denotes the point of attachment with the carbonyl group, the ring A with the NO group contained therein for a mono- or bicyclic, optionally substituted heterocycle of the formula stands in which
  • # 6 denotes the point of attachment to the carbonyl group
  • R 6 is hydrogen, hydroxy or benzyloxy
  • R 3 is hydrogen or methyl
  • R 4 isopropyl, isobutyl, sec-butyl, tert. Butyl, phenyl, benzyl, 1-hydroxyethyl, 4-hydroxybenzyl, 4-hydroxy-3-nitrobenzyl, 4-hydroxy-3-aminobenzyl, 1-phenylethyl, diphenylmethyl, lH-imidazol-4-ylmethyl or lH-indole 3-ylmethyl, or
  • R 8 is hydrogen or methyl
  • R 9 is hydrogen, methyl, ethyl, n-propyl or benzyl, or
  • R 8 and R 9 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle
  • R 10 is benzoyl
  • R 11 is benzyl which may be substituted in the phenyl group by methoxycarbonyl or carboxyl,
  • R 5 is hydrogen, methyl or a group of the formula
  • # 9 identifies the point of attachment with -CHC (R 26 ) -T 2 ,
  • R 12 is phenyl which may be substituted by methoxycarbonyl, carboxyl or a group of the formula -S (O) 20H,
  • R 13 is phenyl which may be substituted by methoxycarbonyl or carboxyl,
  • R 26 is hydrogen or hydroxy
  • T 2 is phenyl, benzyl, 1H-indol-3-yl or 1H-indol-3-ylmethyl, is methyl or hydroxy, and their salts, solvates and solvates of the salts.
  • L 1 represents a bond, linear (C 2 -C 6) alkanediyl or a group of the formula , where m is an integer of 2 or 3, ## 1 denotes the point of linkage with the group G, ## 2 indicates the point of linkage with the group B, (C 2 -C 6) alkanediyl having 1 or 2 substituents methyl may be substituted, B for a bond or a group of the formula
  • R 19 is methyl, propan-2-yl, 2-methylpropan-1-yl or 1-methylpropan-1-yl,
  • R 20 is hydrogen or (C 1 -C 4 ) -alkyl, or
  • R 19 and R 20 together with the atoms to which they are attached form a pyrrolidinyl ring
  • R 21 is hydrogen or methyl
  • R 22 is hydrogen or methyl
  • R 21 and R 22 together with the atoms to which they are attached form a cyclopropyl ring
  • R 27 is hydrogen or methyl
  • L 2 is linear (C 2 -C 6) -alkanediyl or a group of the formula where p is a number of 2 or 3,
  • ## 3 denotes the point of attachment to the group B
  • (C 2 -Cio) -alkanediyl may be substituted by 1 or 2 substituents methyl, and wherein two carbon atoms of the alkanediyl chain in 1, 4 relative to each other
  • R 1 is hydrogen
  • R 2 is 1-hydroxyethyl, benzyl, 4-hydroxybenzyl, 1-phenylethyl or 1H-indol-3-yl-methyl, or
  • # 5 denotes the point of attachment with the carbonyl group, the ring A with the NO group contained therein for a mono- or bicyclic, optionally substituted heterocycle of the formula stands in which
  • # 6 denotes the point of attachment to the carbonyl group
  • R 6 is hydrogen, hydroxy or benzyloxy
  • R 3 is hydrogen
  • R 4 is 1-hydroxyethyl, benzyl, 4-hydroxybenzyl, 1-phenylethyl or 1H-indol-3-ylmethyl, or
  • R 8 is hydrogen or methyl
  • R 9 is hydrogen, methyl, ethyl, 77-propyl or benzyl, or
  • R 8 and R 9 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle
  • R 10 is benzoyl
  • R 11 is benzyl which may be substituted in the phenyl group by methoxycarbonyl or carboxyl,
  • R is hydrogen, methyl or a group of the formula stands in which
  • # 9 denotes the point of attachment with -CHCF phenyl
  • R 12 is phenyl which is linked to methoxycarbonyl, carboxyl or a group of
  • Formula -S (0) 20H may be substituted
  • R 13 is phenyl which may be substituted by methoxycarbonyl or carboxyl,
  • R 35 is methyl or hydroxy, and their salts, solvates and solvates of the salts.
  • L 1 is a bond
  • L 2 is linear (C 2 -C 6) -alkanediyl or a group of the formula where p is a number of 2 or 3 which denotes the point of attachment to the group B,
  • R 1 is hydrogen
  • R 2 is benzyl, 4-hydroxybenzyl or 1H-indol-3-ylmethyl, or
  • # 5 denotes the point of attachment to the carbonyl group, with the NO group contained therein for a mono- or bicyclic, optionally substituted heterocycle of the formula
  • # 6 denotes the point of attachment to the carbonyl group, represents hydrogen, hydroxyl or benzyloxy
  • R is hydrogen
  • R is benzyl, 4-hydroxybenzyl or 1H-indol-3-ylmethyl, or together with the carbon atom to which they are attached, (1S, 2R) -2-phenylcyclopropane-1,1-diyl group of the formula
  • R 7 is hydrogen
  • R 8 is hydrogen, is hydrogen
  • R is methyl, and ilire salts, solvates and solvates of the salts.
  • AKi is an antibody or an antigen-binding antibody fragment which binds to FGFR2 and is linked to the group G via the sulfur atom of a cysteine residue of the binder,
  • G is a group of the formula
  • # 1 denotes the point of attachment to the cysteine residue of the binder
  • # 2 denotes the point of attachment to the group L 1
  • n, L 1 , B, L 2 , D and R 35 have the meanings given above, and their salts, solvates and solvates of the salts.
  • AK 2 is an antibody or an antigen-binding antibody fragment which binds to FGFR2 and is linked to the group G via the NH side group of a lysine residue of the binder,
  • G is carbonyl, and n, L 1 , B, L 2 , D and R 35 have the meanings given above, and their salts, solvates and solvates of the salts.
  • AKi is a binder which binds FGFR2 and which is linked to the group G via the sulfur atom of a cysteine residue of the binder,
  • G is a group of the formula
  • AK 2 represents a binder which binds FGFR 2 and which is bound to the group G via the NH side group of a lysine residue of the binder
  • G is carbonyl, and n, L 1 , B, L 2 , D and R 35 have the meanings given above, and their salts, solvates and solvates of the salts.
  • preference is also given to compounds of the general formula (Ia) in which
  • AK 2 represents a binder which binds FGFR 2 and which is bound to the group G via the NH side group of a lysine residue of the binder
  • G is carbonyl
  • L 2 is linear (C 3 -C 6) -alkanediyl or a group of the formula where p is a number of 2 or 3,
  • ## 3 denotes the point of linkage with the group B
  • ## 4 denotes the point of linkage with the nitrogen atom
  • n, D and R: ° have the meanings given above, and their salts, solvates and solvates of the salts.
  • AKi is a binder which binds FGFR2 and which is linked to the group G via the sulfur atom of a cysteine residue of the binder,
  • G is a group of the formula
  • L # denotes the point of linkage with the cysteine residue of the binder
  • # 2 indicates the point of attachment to the group L 1
  • L 1 represents a bond
  • a linear (C3-C5) -alkanediyl or a group of Fomiel 2 stands, where
  • n is a number of 2 or 3
  • ## 1 denotes the point of attachment to the group G
  • (C3-C5) -alkanediyl may be substituted with 1 or 2 substituents methyl, for a bond or a group of the formula indicates the point of connection with L 1 ,
  • R 25 is methyl
  • R 28 is hydrogen, methylcarbonyl or tert-butyloxycarbonyl
  • R 16 is hydrogen or methyl
  • R and R together with the atoms to which they are attached form a piperazinyl ring, for linear (C3-Cs) -alkanediyl or for a group of the formula
  • L 2 is linear (C3-Ce) alkanediyl or a group of the formula
  • L 1 represents linear (C 1 -C 10) -alkanediyl or a group of the formula where m is a number from 2 to 6,
  • L 4 is a group of the formula
  • R 28 is hydrogen, (C 1 -C 4) -alkylcarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl,
  • Q 1 is a 4- to 7-membered heterocycle
  • R 16 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 17 is hydrogen or (C 1 -C 4 ) -alkyl, or R 16 and R 17 together with the atoms to which they are attached form a 5- or 6-membered heterocycle,
  • R 23 is (C 1 -C 4 ) -alkyl
  • R 24 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 36 represents hydrogen, (C 1 -C 4 ) -alkylcarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl,
  • R 37 is hydrogen or methyl
  • L 2 is linear (C 2 -C 10) -alkanediyl or a group of the formula where p is a number from 2 to 6,
  • ## 3 denotes the point of attachment to the group B
  • L 1 is linear (C 2 -C 6) -alkanediyl or a group of the formula where m is a number of 2 or 3,
  • ## 1 denotes the point of attachment to the group G
  • ## 2 denotes the point of attachment to the group B, for a bond or a group of the formula
  • the point of attachment denotes L 1
  • the point of attachment denotes L 2
  • R 28 is hydrogen, methylcarbonyl or tert-butyloxycarbonyl
  • R 16 is hydrogen or methyl
  • R 17 is hydrogen or methyl
  • R 36 is hydrogen, methylcarbonyl or tert-butyloxycarbonyl
  • R 37 is hydrogen or methyl
  • ## 3 denotes the point of linkage with the group B
  • ## 4 denotes the point of linkage with the nitrogen atom
  • n, AK, G, D, and R 35 have the meanings given above, and their salts, solvates and solvates of the salts.
  • G is a group of the formula
  • # ' identifies the point of attachment to the cysteine residue of the binder
  • # 2 identifies the point of attachment to the group L 1
  • L 1 is linear (C 3 -C 5) -alkanediyl or a group of the formula stands, where
  • n is a number of 2 or 3
  • ## 1 denotes the point of attachment to the group G
  • L 3 is a bond or ethane-l, 2-diyl
  • L 2 is linear (C 3 -C 5) -alkanediyl or a group of the formula stands, where
  • p is a number of 2 or 3
  • ## 3 denotes the point of attachment to the group B, ## denotes the point of attachment to the nitrogen atom, and n, AKi, Cys, D, R 16 and R 17 have the meanings given above, and their salts, solvates and solvates of the salts.
  • R is hydrogen or methyl
  • R 2 isopropyl, isobutyl, sec-butyl, tert. Butyl, phenyl, benzyl, 1-hydroxyethyl, 4-hydroxybenzyl, 4-hydroxy-3-nitrobenzyl, 4-hydroxy-3-aminobenzyl, 1-phenylethyl, diphenylmethyl, lH-imidazol-4-ylmethyl or lH-indole 3-ylmethyl, or
  • # 5 denotes the point of attachment to the carbonyl group, with the NO group contained therein for a mono- or bicyclic, optionally substituted heterocycle of the formula
  • # 6 denotes the point of attachment to the carbonyl group
  • R 6 is hydrogen, hydroxy or benzyloxy
  • R 3 is hydrogen or methyl
  • R 4 isopropyl, isobutyl, sec-butyl, tert. Butyl, phenyl, benzyl, 1-hydroxyethyl, 4-hydroxybenzyl, 4-hydroxy-3-nitrobenzyl, 4-hydroxy-3-aminobenzyl, 1-phenylethyl, diphenylmethyl, lH-imidazol-4-ylmethyl or lH-indole 3-ylmethyl, or
  • R 7 is hydrogen, methyl, ethyl, n-propyl, tert. Butyl, benzyl or adamantylmethyl,
  • R 8 is hydrogen or methyl
  • R 9 is hydrogen, methyl, ethyl, n-propyl or benzyl, or
  • R 8 and R 9 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle
  • R 10 is benzoyl
  • R 11 is benzyl which may be substituted in the phenyl group by methoxycarbonyl or carboxyl
  • R 5 is hydrogen, methyl or a group of the formula
  • R 12 is phenyl which may be substituted by methoxycarbonyl, carboxyl or a group of the formula -S (O) 20H,
  • R 13 is phenyl which may be substituted by methoxycarbonyl or carboxyl
  • R 26 is hydrogen
  • T 2 is phenyl, benzyl, 1H-indol-3-yl or 1H-indol-3-ylmethyl, and n, AK, Cys, G, L 1 , B, L 2 , D and R 35 have the meanings given above , and their salts, solvates and solvates of salts.
  • # 3 denotes the point of attachment to the nitrogen atom
  • R 1 is hydrogen or methyl
  • R 2 isopropyl, isobutyl, sec-butyl, tert. Butyl, phenyl, benzyl, 1-hydroxyethyl, 4-hydroxybenzyl, 4-hydroxy-3-nitrobenzyl, 4-hydroxy-3-aminobenzyl, 1-phenylethyl, diphenylmethyl, lH-imidazol-4-ylmethyl or lH-indole 3-ylmethyl, or
  • # 5 denotes the point of attachment to the carbonyl group, with the NO group contained therein for a mono- or bicyclic, optionally substituted heterocycle of the formula
  • R 1 is hydrogen
  • R 2 is benzyl, 4-hydroxybenzyl, 1-phenylethyl or 1H-indol-3-ylmethyl, or
  • R 1 and R 2 together with the carbon atom to which they are attached
  • # 5 denotes the point of attachment with the carbonyl group, the ring A with the NO group contained therein for a mono- or bicyclic, optionally substituted heterocycle of the formula
  • # 6 denotes the point of attachment with the carbonyl group
  • n, AK, Cys, G, L 1 , B, L 2 and R 35 have the meanings given above, and their salts, solvates and solvates of the salts.
  • R 35 is hydroxy, and n, AK, Cys, G, L 1 , B, L 2 , D and R 35 have the meanings given above, and their salts, solvates and solvates of the salts.
  • R 35 is methyl, and n, AK, Cys, G, L 1 , B, L 2 , D and R 35 have the meanings given above, and their salts, solvates and solvates of the salts.
  • a preferred object of the present invention are binder-drug conjugates of the general formula (Ia) in which D may have the following structures and * represents the linkage site with the nitrogen atom:
  • a preferred subject of the present invention are binder-drug conjugates of the general formula (Ia) in which D has a structure disclosed by any of the intermediates of the present invention; and the linker unit ⁇ -GL 1 -BL 2 - ⁇ ⁇ and all other variables are defined according to the present invention; and their salts, solvates and solvates of the salts.
  • AK is preferably an anti-FGFR2 antibody or antigen-binding fragment thereof.
  • a preferred object of the present invention are binder-drug conjugates of the general formula (Ia) in which the linker agent unit has a structure disclosed by one of the intermediates or examples of the present invention; and their salts, solvates and solvates of the salts.
  • AK is preferably an anti-FGFR2 antibody or antigen-binding fragment thereof.
  • a preferred subject matter of the present invention is binder-drug conjugates of the general formula (Ia) in which the linker agent unit has a structure disclosed by an example of the present invention; and their salts, solvates and solvates of the salts.
  • AK is preferably an anti-FGFR2 antibody or antigen-binding fragment thereof.
  • binder active ingredient is binder active ingredient
  • n is a number from 1 to 50
  • AK is a binder which binds to FGFR2
  • the group ⁇ -GL 1 -B- ⁇ ⁇ is a linker
  • L 2 is linear (C 2 -C 10) -alkanediyl or a group of the formula stands, where
  • P is a number from 2 to 6
  • (C2-Cio) -alkyl having 1 to 4 substituents independently selected from the group methyl, hydroxy, and benzyl may be substituted, and wherein two carbon atoms of the alkanediyl chain in 1, 2 , 1, 3 or 1, 4 relative to one another, including the carbon atoms which may be present between them, can be bridged to form a (C 3 -C 6) -cycloalkyl ring or a phenyl ring,
  • D is a group of the following formula, where * is the point of attachment to the nitrogen atom
  • AK is a binder which binds FGFR2 and n is a number from 1 to 10, and their salts, solvates and solvates of the salts. It is preferred if the binder is attached via an NH side group of a lysine residue to the linker-toxophore moiety.
  • AK is an antibody or an antibody fragment which binds FGFR2 and n is from 1 to 10, and their salts, solvates and solvates of the salts. It is preferred if the antibody or antibody fragment is linked to the linker-toxophore moiety via an NH side group of a lysine residue of the antibody or antibody fragment.
  • a particularly preferred object of the present invention is the compound of the following formula
  • AK2A is M048-D01-hIgGl and n is a number from 1 to 10, and their salts, solvates and solvates of the salts.
  • Another particularly preferred object of the present invention is the compound of the following formula
  • AK2B is M048-D01-hIgGl-b and n is a number from 1 to 10, and their salts, solvates and solvates of the salts.
  • Another object of the invention is a process for the preparation of compounds of the formula (Ia) according to the invention, characterized in that a solution of the binder in PBS buffer with a suitable reducing agent, such as dithiothreitol or tris (2-carboxyethyl) phosphine hydrochloride, and then with a compound of formula (IIa)
  • a suitable reducing agent such as dithiothreitol or tris (2-carboxyethyl) phosphine hydrochloride
  • the partial reduction of the antibody and the subsequent conjugation of the (partially) reduced antibody with a compound of the formula (IIa) is carried out by the methods known to the person skilled in the art, see e.g. Ducry et. al., Bioconj. Chem. 2010, 21, 5 and references herein, Klussman et al., Bioconj. Chem. 2004, 15 (4), 765-773.
  • the mild reduction of the antibody preferably takes place by addition of 2-6 equivalents of TCEP to the antibody present in a suitable buffer solution, preferably phosphate buffer, and stirring for 30-180 minutes at temperatures between 15 and 40 ° C., preferably at RT.
  • the conjugation is carried out by adding a solution of a compound of formula (IIa) in DMSO, acetonitrile or DMF to the solution of (partially) reduced antibody in PBS buffer, and subsequent reaction at a temperature of 0 ° C to + 40 ° C, in particular from + 10 ° C to + 30 ° C, for a period of 30 minutes to 6 hours, in particular 1 to 2 hours.
  • Lysine coupling First, the compounds of the formula (IIIa) or comparable activated carboxyl components are prepared by classical methods of peptide chemistry. These are then taken up in inert solvents such as DMSO or DMF and added to the antibody preferably present in phosphate buffer at neutral pH. The solution is stirred for 1-16 h at a temperature between 15 and 40 ° C, preferably RT.
  • inert solvents such as DMSO or DMF
  • PG 1 is an amino-protecting group such as (9H-fluoren-9-ylmethoxy) carbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, to give a compound of formula (VI)
  • L has the meaning of L as defined above, but is shortened by one carbon atom in the alkyl chain length, to give a compound of the formula (IX)
  • linkage site with the carbonyl group denotes the linkage site with L 2 ,
  • R 25 is hydrogen or methyl, can be prepared by reacting a compound of formula (IX) in an inert solvent in the presence of a suitable base and a suitable coupling reagent with a compound of formula (XI-A) or (XI-A).
  • Q 1A is an N-linked 4- to 7-membered heterocycle, can be prepared by reacting a compound of the formula (IX) in an inert solvent in the presence of a suitable base and a suitable coupling reagent with a compound of the formula (XXI)
  • the protecting group PG 2 is split off from this method known to the person skilled in the art, and the deprotected compound is subsequently dissolved in an inert solvent in the presence of a suitable base with N-hydroxysuccinimide to a compound of the formula (III-B)
  • the compounds of the formula (III) in which L 1 is a bond and B is a group of the formula (B 6 ) in which *, **, R, R and R are each as defined above, can be prepared by reacting a compound of formula (IX) in an inert solvent in the presence of a suitable coupling reagent and a suitable base with a compound of the formula (XV)
  • reaction (IV) + (V) - > (VI) and (IV) + (VIII) - > (IX) are carried out in the customary for a reductive amination, under the reaction conditions inert solvents, optionally in the presence of an acid and / or a dehydrating agent as a catalyst.
  • solvents include, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert.
  • the solvent used is preferably a 1,4-dioxane / water mixture with addition of acetic acid or dilute hydrochloric acid as catalyst.
  • Suitable reducing agents for this reaction are, in particular, complex borohydrides, such as, for example, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, tetra-n-butylammonium borohydride or borane-pyridine complex. Preference is given to using sodium cyanoborohydride or borane-pyridine complex.
  • the reactions (IV) + (V) -> (VI) and (IV) + (VIII) -> (IX) are generally carried out in a temperature range from 0 ° C to + 120 ° C, preferably at + 50 ° C to + 100 ° C.
  • the reactions may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar); usually one works at normal pressure.
  • Inert solvents for these coupling reactions are, for example, ethers, such as diethyl ether, diisopropyl ether, tert. Butyl methyl ether, tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane or bis (2-methoxyethyl) ether, hydrocarbons such as benzene, toluene, xylene, pentane, hexane, heptane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane , Tetrachloromethane, 1,2-dichloroethane, trichlorethylene or chlorobenzene, or dipolar aprotic solvents such as acetone, methyl ethyl ketone, acetonitrile, ethyl acetate, pyridine, dimethyl sulfoxide (DMSO), N,
  • N, N-dimethylformamide Suitable activating / condensing agents for these couplings are, for example, carbodiimides such as NN'-diethyl, NN'-dipropyl, NN'-diisopropyl, NN'-dicyclohexylcarbodiimide (DCC) or N- (3-dimethylaminoisopropyl) -N '-ethylcarbodiimide hydrochloride (EDC), phosgene derivatives such as NN'-carbonyldiimidazole (CDI) or isobutyl chloroformate, 1, 2-oxazolium compounds such as 2-ethyl-5-phenyl-l, 2-oxazolium-3-sulfate or 2 tert-butyl-5-methylisoxazolium perchlorate, acylamino compounds such as 2-ethoxy-1
  • the activating / condensing agent for such coupling reactions is preferably N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC) in combination with 1-hydroxybenzotriazole (HOBt) and NN-diisopropylethylamine, or O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU) also in conjunction with N, N-diisopropylethylamine used.
  • EDC 1-hydroxybenzotriazole
  • HATU 7-azabenzotriazol-1-yl
  • the coupling reactions (IX) + (X) -> (II-C), (XII-A) and (XII-B) + (X) -> (II-DA) and (II-D-B), (IX) + (XIII) -> (XIV), (IX) + (XV) -> (XVI) and (XXII) + (XXIII) -> (II-D) are usually in a temperature range of -20 ° C to + 60 ° C, preferably carried out at 0 ° C to + 40 ° C.
  • the reactions may be at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar); generally one works at normal pressure.
  • these reactions are carried out in dichloromethane using N- (3-dimethylarninoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC) and 4-dimethylaminopyridine at a temperature of + 50 ° C to 100 ° C at atmospheric pressure.
  • EDC N- (3-dimethylarninoisopropyl) -N'-ethylcarbodiimide hydrochloride
  • 4-dimethylaminopyridine at a temperature of + 50 ° C to 100 ° C at atmospheric pressure.
  • the introduction and removal of such protective groups is carried out by conventional methods known from peptide chemistry [see, e.g. T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, Wiley, New York, 1999; M. Bodanszky and A. Bodanszky, The Practice of Peptide Synthesis, Springer-Verlag, Berlin, 1984]. If several protected groups are present, their release may optionally be carried out simultaneously in a one-pot reaction or else in separate reaction steps.
  • amino-protecting group PG 1 is preferably tert. Butoxycarbonyl (Boc), benzyloxycarbonyl (Z) or (9H-fluoren-9-ylmethoxy) carbonyl (Fmoc); for a hydroxy or carboxyl function tert. Butyl or benzyl used as protecting group PG 2 . The splitting off of a tert. Butyl or tert.
  • Butoxycarbonyl group is usually carried out by treatment with a strong acid such as hydrogen chloride, hydrogen bromide or trifluoroacetic acid, in an inert solvent such as diethyl ether, 1, 4-dioxane, dichloromethane or acetic acid; if appropriate, this reaction can also be carried out without addition of an inert solvent.
  • a strong acid such as hydrogen chloride, hydrogen bromide or trifluoroacetic acid
  • an inert solvent such as diethyl ether, 1, 4-dioxane, dichloromethane or acetic acid
  • this reaction can also be carried out without addition of an inert solvent.
  • benzyl or benzyloxycarbonyl as a protective group these are preferably removed by hydrogenolysis in the presence of a suitable palladium catalyst, such as palladium on activated carbon.
  • the (9H-fluoren-9-ylmethoxy) carbonyl group is generally cleaved off with the aid of a secondary amine base such as diethylamine or piperidine.
  • the reaction (VI) -> (II-A) is carried out in a reaction-inert solvent such as ethers such as tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane or bis (2-methoxyethyl) ether, alcohols such as Methanol, ethanol, isopropanol, n-butanol or tert-butanol, or dipolar aprotic solvents such as acetone, methyl ethyl ketone, acetonitrile, ethyl acetate, pyridine, dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA ), N, N'-dimethylpropylene
  • Suitable bases for the reaction (VI) -> (II-A) are, for example, alkali metal carbonates such as potassium carbonate, sodium carbonate or lithium carbonate, alkali metal bicarbonates such as sodium or potassium bicarbonate or alkali metal such as sodium, sodium or potassium tert-butoxide.
  • alkali metal carbonates such as potassium carbonate, sodium carbonate or lithium carbonate
  • alkali metal bicarbonates such as sodium or potassium bicarbonate or alkali metal such as sodium, sodium or potassium tert-butoxide.
  • sodium bicarbonate is used.
  • the reaction (VI) -> (II-A) takes place in a temperature range from 0 ° C to + 50 ° C, preferably at + 10 ° C to + 30 ° C.
  • the reaction can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar); generally one works at normal pressure.
  • reaction (VI) + (VII) -> (II-B) is carried out in a reaction inert solvent such as ethers such as tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane or bis (2-methoxyethyl) - ethers, alcohols such as methanol, ethanol, isopropanol, n-butanol or tert-butanol, or dipolar aprotic solvents such as acetone, methyl ethyl ketone, acetonitrile, ethyl acetate, pyridine, dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), NN Dimethylacetamide (DMA), NN'-dimethylpropyleneurea (DMPU) or N-methylpyrrolidinone ( ⁇ ) or water.
  • a reaction inert solvent such as ethers such as tetrahydrofuran, 1, 4-
  • Suitable bases for the reaction (VI) + (VII) -> (II-B) are, for example, tertiary amine bases such as triethylamine, N-methylmorpholine, N-methylpiperidine, N, N-diisopropylethylamine, pyridine or 4-N, N-dimethylaminopyridine.
  • tertiary amine bases such as triethylamine, N-methylmorpholine, N-methylpiperidine, N, N-diisopropylethylamine, pyridine or 4-N, N-dimethylaminopyridine.
  • N, N-diisopropylethylamine is used.
  • the reaction (VI) + (VII) -> (II-B) is carried out in a temperature range from 0 ° C to + 50 ° C, preferably at + 10 ° C to + 30 ° C.
  • the reaction can be carried out at normal, at elevated or at reduced pressure (for example from 0.5 to 5 bar); generally one works at normal pressure.
  • the reactions (IX) -> (III-A), (XIV) -> (III-B) and (XVI) -> (III-C) and (VI) + (XVII) -> (III-D), (XIX) + (XX) -> (III-E) and (XXV) + (XX) -> (III-F) are carried out in a solvent which is inert under the reaction conditions.
  • Suitable solvents are, for example, ethers such as diethyl ether, diisopropyl ether, tert. Butyl methyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or bis (2-methoxyethyl) ether, hydrocarbons such as benzene, toluene, xylene, pentane, hexane, heptane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane , Trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichlorethylene or chlorobenzene, or dipolar aprotic solvents such as acetone, methyl ethyl ketone, acetonitrile, ethyl acetate, pyridine, dimethyl sulfoxide (DMSO), N, N-dimethyl
  • N, N-dimethylformamide Preference is given to using N, N-dimethylformamide.
  • Suitable bases for these reactions are, for example, tertiary amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, NN-diisopropylethylamine, pyridine or 4-N, N-dimethylaminopyridine.
  • the reactions (IX) -> (III-A), (XIV) -> (III-B) and (XVI) -> (III-C) and (VI) + (XVII) -> (III-D) and (XIX) + (XX) -> ( ⁇ - ⁇ ) are carried out in a temperature range from 0 ° C to + 50 ° C, preferably at + 10 ° C to + 30 ° C.
  • the reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar); generally one works at normal pressure.
  • the compounds of the formulas (II) and (III) are subsets of the compounds of the formulas (IIa) and (IIIa), respectively, where R 35 is methyl.
  • the preparation of the compounds (IIa) and (IIIa) is carried out analogously to the preparation of the compound of the formulas (II) and (III) as described above.
  • FGFR2 alpha SEQ ID NO: 1
  • FGFR2 beta SEQ ID NO: 2
  • An alternative splice in domain 3 leads to two different variants, namely FGFR2 Elb, which is encoded by exons 7 and 8, and FGFR2 IIIc, which is encoded by exons 7 and 9 (see Figure 1).
  • the binder binds, preferably specifically, to FGFR2. In a further aspect of the invention, the binder binds, preferably specifically, to the extracellular domain of the target molecule FGFR2 (see Figure 1).
  • the binder binds, preferably specifically, to one or more forms of the human FGFR2 polypeptide. In a further aspect of the invention, the binder binds, preferably specifically, to all isoforms and splice variants of FGFR2.
  • the term includes, but is not limited to, various "forms" of FGFR2, various isoforms, different splice variants, different glyco forms or FGFR2 polypeptides that undergo various translational and posttranslational modifications.
  • the binder binds, preferably specifically to the N-terminal domain of the cancer target molecule FGFR2. In a further aspect of the invention, the binder binds, preferably specifically, to the extracellular N-terminal epitope ORPSFSLVEDTTLEPE 15 ) of FGFR2 (SEQ ID NO: 23).
  • the binder binds, preferably specifically, also to the FGFR2 of other species.
  • Preferred species are rodents, especially mice or rats, but also dogs, pigs and non-human primates.
  • the binder after binding to FGFR2 on the target cell, the binder is internalized by binding from the target cell. This causes the binder-drug conjugate, which may be an immunoconjugate or an ADC, to be taken up by the target cell.
  • the binder-drug conjugate which may be an immunoconjugate or an ADC
  • the binder is a binding protein.
  • the binder is an antibody, an antigen-binding antibody fragment, a multispecific antibody or an antibody mimetic.
  • Preferred antibody mimetics are Affibodies, Adnectins, Anticalins, DARPins, Avimers, or Nanobodies.
  • Preferred multispecific antibodies are bispecific and trispecific antibodies.
  • the binder is an antibody or an antigen-binding antibody fragment, more preferably an isolated antibody or an isolated antigen-binding antibody fragment.
  • Preferred antigen-binding antibody fragments are Fab, Fab ', F (ab') 2 and Fv fragments, diabodies, DAbs, linear antibodies and scFv. Particularly preferred are Fab, diabodies and scFv.
  • the binder is an antibody.
  • Particularly preferred are monoclonal antibodies or antigen-binding antibody fragments thereof.
  • Further particularly preferred are human, humanized or chimeric antibodies or antigen-binding antibody fragments thereof.
  • the antibody or antigen-binding fragment comprises the amino acid sequence of the CDR variable light and heavy chain sequences of the antibody M048-D01-hIgG1.
  • the antibody or antigen-binding fragment comprises the amino acid sequence of the CDR antibody light-heavy chain and heavy chain antibody M048-D01-hIgGl represented in SEQ ID NO: 15 (H-CDR1), SEQ ID NO: 16 (H-CDR2), SEQ ID NO: 17 (H-CDR3), SEQ ID NO: 18 (L-CDR1), SEQ ID NO: 19 (L-CDR2) and SEQ ID NO: 20 (L-CDR3) ,
  • the antibody or antigen-binding fragment comprises the amino acid sequence of the M048-D01-hIgG1 or M048-D01-hIgGl-b antibody light and heavy chain antibodies.

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AU2012351685A1 (en) 2014-07-03
AR089252A1 (es) 2014-08-06
RU2014128467A (ru) 2016-02-10
IL233050A0 (en) 2014-07-31
CA2859255A1 (en) 2013-06-20
NZ625745A (en) 2016-07-29
JP2015505850A (ja) 2015-02-26
US20150023989A1 (en) 2015-01-22
BR112014014763A8 (pt) 2017-07-04
WO2013087716A2 (de) 2013-06-20
BR112014014763A2 (pt) 2017-06-13
ZA201405003B (en) 2016-01-27
HK1200714A1 (en) 2015-08-14
CN104254342A (zh) 2014-12-31
SG11201403085PA (en) 2014-10-30
MX2014007121A (es) 2014-09-04
WO2013087716A3 (de) 2013-08-22
KR20140114826A (ko) 2014-09-29

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