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(2006.01) (84) Designated States (Unless Otherwise Indicated, For ) ( (51) International Patent Classification: ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, A61K 47/68 (2017.01) A61P 35/00 (2006.01) NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, ST, SV, SY, TH, TJ, TM, TN, (21) International Application Number: TR, TT, TZ, UA, UG, US, UZ, VC, VN, WS, ZA, ZM, ZW. PCT/EP2020/070149 (84) Designated States (unless otherwise indicated, for every (22) International Filing Date: kind of regional protection available) . ARIPO (BW, GH, 16 July 2020 (16.07.2020) GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, (25) Filing Language: English UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (26) Publication Language: English EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (30) Priority Data: MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, 19187692.9 23 July 2019 (23.07.2019) EP TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (71) Applicants: BAYER PHARMA AKTIENGESEL- LSCHAFT [DE/DE]; Mullerstr. 178, 13353 Berlin (DE). Declarations under Rule 4.17: BAYER AKTIENGESELLSCHAFT [DE/DE]; Kaiser- — as to applicant's entitlement to apply for and be granted a Wilhelm-Allee 1, 51373 Leverkusen (DE). patent (Rule 4.17(H)) (72) Inventors: BOHNKE, Niels; Sachsische Str. 41, 10713 Published: Berlin (DE). GRIEBENOW, Nils; Kurfurstenstr. 39, — with international search report (Art. 21(3)) 41541 Dormagen (DE). SOMMER, Anette; Chodowieck- — with sequence listing part of description (Rule 5.2(a)) istr. 28, 10405 Berlin (DE). HAMMER, Stefanie; Neue Welt 12, 10247 Berlin (DE). BERNDT, Sandra; Kathestr. 9, 16540 Hohen Neuendorf (DE). STELTE-LUDWIG, Beatrix; Gdrtzheide lOf, 42489 Wulfrath (DE). BEIER, Rudolf; Kiautschoustr. 1, 13353 Berlin (DE). MAHLERT, Christoph; Kranichweg 11, 421 11 Wuppertal (DE). GREVEN, Simone; Am Schneckenacker 45, 41541 Dor- magen (DE). GIESE, Anja; Horst-Kohl Stralk 15a, 12157 Berlin (DE). GLTNTHER, Judith; Parkstr. 60, 13 187 Berlin (DE). BARAK, Naomi; c/o Bayer Pharma Ak- tiengesellschaft, Mullerstralk 170, 13353 Berlin (DE). BOMER, Ulf; Leipziger Str. 49, 16548 Glienicke (DE). DIETZ, Lisa; An der Grenze 17, 421 11 Wuppertal (DE). JORISSEN, Hannah; Borkumstralk 31, 42579 Heiligen- haus (DE). ERKELENZ, Michael; Methfesselstrasse 3 1, 10965 Berlin (DE). ROTTMANN, Antje; Schneehornpfad 11A, 13089 Berlin (DE). WENGNER, Antje, Margret; Binzstr. 60, 13 189 Berlin (DE). FERNANDEZ-MON- TALVAN, Amaury, Ernesto; 9 bis Avenue du Centre, 78230 Le Pecq (FR). (74) Agent: BIP PATENTS; Alfred-Nobel-Str. 10, 40789 Mon- heim am Rhein NRW (DE). (81) Designated States (unless otherwise indicated, for every kind of national protection available) : AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, IT, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, (54) Title: ANTIBODY DRUG CONJUGATES (ADCS) WITH NAMPT INHIBITORS (57) Abstract: Conjugate of a binder having formula (AA) wherein AB stands for a binder, Z' stands for (AA) AB - Z'—D a linker, D stands for an active component which is a NAMPT inhibitor and its use as pharmaceuticals Antibody drug conjugates (ADCs) with NAMPT inhibitors Field of application of the invention The present invention relates to novel conjugates of a binder or a derivative thereof with one or more molecules of an active component, wherein the active component is a NAMPT inhibitor, which is conjugated to the binder via a linker Z’ as described and defined herein, and methods for their preparation, their use for the treatment and/or prophylaxis of disorders, in particular of hyper-proliferative disorders. Background of the invention Nicotinamide adenine dinucleotide (NAD) is a biologically important coenzyme that plays a critical role in many cell metabolism-related transformations and in cell signaling [Lin, S-J.; Guarente L. Current Opinion Cell Biol. 2003, 15, 241–146; Ziegler M. Eur. J. Biochem. 2000, 267, 1550–1564]. In mammalian cells, the two step salvaging of NAD+ from nicotinamide (NAM) – nicotinamide pathway - is the most efficient process compared to the de novo synthesis of NAD+ from the essential amino acid L-tryptophan which takes mainly place in the liver [Schramm V. L. et al. PNAS 2009, 106, 13748–13753]. NAMPT (nicotinamide phosphoribosyltransferase also known as pre-B-cell-colony-enhancing factor (PBEF) and visfatin, NMPRT, NMPETase or NAmPRTase, international nomenclature E.C.2.4.2.12) catalyzes the first step of this process, the phosphoribosylation of NAM to NMN (nicotinamide mononucleotide) which is further converted to NAD+ by NMNAT (nicotinamide mononucleotide adenylyltransferase). NAMPT is the rate-limiting enzyme in the production of NAD+ and its inhibition leads to a rapid depletion of NAD+ [Deng Y. et al. Bioanalysis 2014, 6, 1145–1457]. In general, an altered cell metabolism is one of the basic characteristics of cancer cells as hypothesized by Otto Heinrich Warburg [Warburg, O. Über den Stoffwechsel der Carcinomzelle. Klin. Wochenschr. 4, 534–536 (1925)]. As cancer cells proliferate continuously, these cells have to adapt to a stressful and dynamic microenvironment. This results in an increased need for energy, macromolecules and the maintenance of the cellular redox status by cancer cells [Cairns R. A. et al. Nature Rev. 2011, 11, 85–95]. With this regard, NAD+ is used as electron carrier in glycolysis, which is up-regulated in cancer cells due to the Warburg effect, as well as in mitochondrial oxidative phosphorylation. Further, NAD+ serves as a substrate for several enzymes, for example poly-ADP-ribose polymerases (PARPs) and sirtuins (SIRTs) which are involved in DNA repair and gene expression, processes often aberrantly regulated in cancer cells and leading to consumption of NAD+ [Berger F et al. 2004 Trends Biochem. Sci. 29, 111–118]. Phosphorylated forms of NAD+/NADH also exist and are often employed for biosynthetic and/or cell protection purposes in addition to energy generation. They are also involved in the cellular response to oxidative stress [Massudi H. Redox Rep. 2012, 17, 28–46]. For these reasons, many cancer cells have an increased need for NAD+ and its synthesis is constantly required, rendering cancer cells particularly sensitive to NAMPT inhibition. Moreover, it was demonstrated that NAMPT is implicated in the regulation of cell viability during genotoxic or oxidative stress and that NAMPT inhibitors are potentially useful for the treatment of e.g. inflammation, metabolic disorders and cancer [Tong L. et al. Expert Opin. Ther. Targets 2007, 11, 695–705; Galli, M. et al. Cancer Res. 2010, 70, 8–11, J. Med. Chem 2013, 56, 6279– 6296]. Daporinad also known as APO866, FK866, WK175 or WK22 ((E)-N-[4-(I-benzoylpiperidin-4- yl)butyl]-3-(pyrldine-3-yl)-acrylamide) is a highly potent and selective inhibitor of NAMPT which interferes with NAD biosynthesis, ATP generation and induces cell death. In vivo efficacy of daporinad was shown in murine renal cell carcinoma model RENCA [Drevs J. et al. Anticancer Res 2003, 23, 4853-4858]. Clinical trials with daporinad have been completed for the treatment of chronic lymphocytic leukemia (CLL), cutaneous T cell lymphoma (CTL), and advanced melanoma [ClinicalTrials.gov Identifier: NCT00435084, NCT00431912, NCT00432107]. CHS-828 also known as GMX1778 (N-[6-(4-chlorophenoxy)hexyl]-N'-cyano-N''-4-pyridinyl- guanidine), an inhibitor of NAMPT as well as an inhibitor of NF-^B pathway activity [Hassan S. B. et al. Anticancer Res 2006, 26, 4431-4436], showed highly cytotoxic effects in vitro and in vivo in human breast and lung cancer cell line-derived in vivo models [Hijarnaa PJ et al. Cancer Res. 1999, 59, 5751–5757]. A Phase I study for this compound in patients with solid tumors was published in the year 2002 [Hovstadius P et al. ClinCancerRes 2002, 9, 2843–2850]. Best observed responses in the clinical trials were stable disease. Therefore, it has been assumed that the lack of significant activity in clinical trials may result from the inability to dose NAMPT inhibitors to higher drug exposures due to dose-limiting toxicities [Sampath D. et al. Pharmacology and Therapeutics 2015, 151, 16–31]. Combining targeting of a cytotoxic drug to cancer cells eg by employing a binder or an antibody may improve the therapeutic window and may thus result in better tolerability and better clinical responses. The present invention relates to novel conjugates of a binder or a derivative thereof with one or more molecules of an active component, wherein the active component is a NAMPT inhibitor, which is conjugated to the binder via a linker. A number of chemical compounds have been shown to act as NAMPT inhibitors. For example, Bioorganic & Medicinal Chemistry Letters (2013), 23, 4875–4885; WO 2014111871 and WO 2013067710 discloses 1,3-dihydro-2H-isoindoles as NAMPT inhibitors. DE10010423, WO9206087 and WO2006064189 disclose 1-alkyl-6-oxo-1,4,5,6- tetrahydropyridazin-3-yl derivatives which may be useful for the treatment of anemia, cardiovascular and diglyceride acyltransferase (DGAT) mediated disorders (e.g. diabetes), respectively. WO2012067965 discloses 4-oxo-3,4-dihydrophthalazine phenyl cyclic urea derivatives which may be useful as NAMPT and ROCK inhibitors. Despite the progress made during the last decades in the treatment of uncontrolled proliferative cellular processes in humans and animals, like cancer diseases, there is still a huge unmet medical need to expand therapeutic options especially based on new drugs selectively addressing new targets. Summary of the Invention Therefore, inhibitors of NAMPT represent valuable compounds that should complement therapeutic options either as single agents or in combination with other drugs, particularly those NAMPT inhibitors with increased selectivity over other biological targets.
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