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WO 2018/087126 Al 17 May 2018 (17.05.2018) W !P O PCT

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WO 2018/087126 Al 17 May 2018 (17.05.2018) W !P O PCT (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2018/087126 Al 17 May 2018 (17.05.2018) W !P O PCT (51) International Patent Cli MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, C07D 401/14 (2006.01) C07D 213/81 (2006 .01 OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, 67 57/552 (2006.01) C07D 311/18 (2006 .01 SC, SD, SE, SG, SK, SL, SM, ST, SV, SY,TH, TJ, TM, TN, A61K 31/357 {2006.01) C07D 215/48 (2006 .01 TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. A61K 31/416 (2006.01) C07D 215/54 (2006 .01 (84) Designated States (unless otherwise indicated, for every A61K 31/4188 (2006.01) C07D 319/18 (2006 .01 kind of regional protection available): ARIPO (BW, GH, 67 57/426 (2006.01) C07D 231/54 (2006 .01 GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, A61K 31/4375 (2006.01) C07D 401/12 (2006 .01 UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, A61K 31/44 (2006.01) C07D 241/44 (2006 .01 TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, 67 57/4459 (2006.01) C07D 471/04 (2006 .01 EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, 67 57/47 (2006.01) C07D 487/04 (2006 .01 MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, A61K 31/498 (2006.01) C07D 277/56 (2006 .01 TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, A61K 31/519 (2006.01) C07D 513/04 (2006 .01 KM, ML, MR, NE, SN, TD, TG). C07D 213/72 (2006.01) (21) International Application Number: Declarations under Rule 4.17: PCT/EP2017/078567 — as to applicant's entitlement to apply for and be granted a patent (Rule 4.1 7(H)) (22) International Filing Date: 08 November 201 7 (08. 11.201 7) Published: — with international search report (Art. 21(3)) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 16197975.2 09 November 2016 (09. 11.20 16) EP (71) Applicant: BAYER PHARMA AKTIENGESEL- LSCHAFT [DE/DE]; Mullerstr. 178, 13353 Berlin (DE). (72) Inventors: BUCHGRABER, Philipp; Kastanienallee 25, 10435 Berlin (DE). EIS, Knut; Fichtenweg 1, 13587 Berlin (DE). WAGNER, Sarah; Moritz-Sommer-Str. 12 A, 40225 Dusseldorf (DE). SULZLE, Detlev; Otternweg 15, 13465 Berlin (DE). BENDER, Eckhard; Erzgebirgsstr. 5, 65520 Bad Camberg (DE). LI, Volkhart, Min-Jian; Im Wiesen- grund 40, 42553 Velbert (DE). LIU, Ningshu; Ringstr. 89a, 12203 Berlin (DE). SIEGEL, Franziska; Pappelallee 58, 10437 Berlin (DE). LIENAU, Philip; Jahnstr. 13, 10967 Berlin (DE). (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, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, (54) Title: AMIDO-SUBSTITUTED CYCLOHEXANE DERIVATIVES AS INHIBITORS OF TANKYRASE (57) Abstract: The present invention relates to amido-substituted cyclohexane compounds of general formula (I), in which A, R4, R6, R7, R8, R9, R10 and R 11 are as defined herein, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for m an ufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of neoplasms, as a sole agent or in combination with other active ingredients. AMIDO-SUBSTITUTED CYCLOHEXANE DERIVATIVES AS INHIBITORS OF TANKYRASE The present invention relates to amido-substituted cyclohexane compounds of general formula (I) as described and defined herein, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of neoplasms, as a sole agent or in combination with other active ingredients. BACKGROUND OF THE INVENTION Cancer is the leading cause of death in developed countries and the second leading cause of death in developing countries. Deaths from cancer worldwide are projected to continue rising, with an estimated 12 million deaths in 2030. While substantial progress has been made in developing effective therapies, there is a need for additional therapeutic modalities that target cancer and related diseases. The complexity of cancer disease arises after a selection process for cells with acquired functional capabilities to enhance survival and/or resistance towards apoptosis and a limitless proliferative potential. In addition, bi-direction interaction of cancer cells and stromal cells provides further advantage of cancer cell survival and distant metastasis to the secondary organs and tissues [Liotta LA, Kohn EC. The microenvironment of the tumour-host interface. Nature 2001, 4 11:375]. Furthermore, cancer stem cells (CSCs) represent the apex in the hierarchical model of tumor genesis, heterogeneity and metastasis. CSCs possess the capacity for unlimited self-renewal, the ability to give rise to progeny cells, and also an innate resistance to cytotoxic therapeutics [Meacham CE and Morrison SJ. Tumour heterogeneity and cancer cell plasticity. Nature 2013, 501:328]. Thus, there is need to develop drugs for cancer therapy addressing distinct features of established tumors. The discovery that Drosophila segment polarity gene Wingless had a common origin with the murine oncogene lnt-1 led to intensive studies on Wnt signaling pathway and identification of 19 mammalian Wnts and 10 Wnt receptors [Rijsewijk F, Schuermann M, Wagenaar E, Parren P, Weigel D, Nusse R. The Drosophila homolog of the mouse mammary oncogene int-1 is identical to the segment polarity gene wingless. Cell. 1987, 50: 649]. Wnts are secreted glycoproteins which bind to cell surface receptors to initiate signaling cascades. Wnt signaling cascades have classified into two categories: canonical and non-canonical, differentiated by their dependence on β-catenin. Non-canonical Wnt pathways, such as the planar cell polarity (PCP) and Ca2+ pathway, function through β-catenin independent mechanisms. Canonical Wnt signalling is initiated when a Wnt ligand engages co-receptors of the Frizzled (Fzd) and low- density lipoprotein receptor related protein (LRP) families, ultimately leading to β-catenin stabilization, nuclear translocation and activation of target genes [Angers S, Moon RT. Proximal events in Wnt signal transduction. Nat Rev Mol Cell Biol. 2009, 10: 468. Cadigan KM, Liu Yl. Wnt signaling: complexity at the surface. J Cell Sci. 2006, 119: 395. Gordon MD, Nusse R. Wnt signaling: multiple pathways, multiple receptors, and multiple transcription factors. J Biol Chem. 2006, 281: 22429. Huang H, He X. Wnt/beta-catenin signaling: new (and old) players and new insights. Curr Opin Cell Biol. 2008, 20: 119. Polakis P. The many ways of Wnt in cancer. Curr Opin Genet Dev. 2007, 17: 45. Rao TP, Kuhl M. An updated overview on Wnt signaling pathways: a prelude for more. Circ Res. 2010, 106: 1798]. In the absence of Wnt stimulus, β-catenin is held in an inactive state by a multimeric "destruction" complex comprised of adenomatous polyposis coli (APC), Axin, glycogen synthase kinase 3β (GSK33) and casein kinase 1a (CK1 a). APC and Axin function as a scaffold, permitting GSK33- and CK1a-mediated phosphorylation of critical residues within β- catenin. These phosphorylation events mark β-catenin for ubiquitination recognition by the E3 ubiquitin ligase β-transducin-repeat-containing protein and lead to subsequent proteasomal degradation [He X, Semenov M, Tamai K, Zeng X. LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: arrows point the way. Development.2004, 131:1663. Kimelman D, Xu W. beta-catenin destruction complex: insights and questions from a structural perspective. Oncogene 2006, 25: 7482]. In the presence of Wnt stimulus, Axin, β and Dvl are recruited to the co-receptor complex Fzd and LRP5/6 and lead to disruption of the β-catenin destruction complex. Therefore, β- catenin is stabilized and translocated to the nucleus. Once in the nucleus, β-catenin forms a complex with members of the T-cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors, recruiting co-factors such as CBP, p300, TNIK, Bcl9 and Pygopus, and ultimately driving transcription of target genes including c-myc, Oct4, cyclin D, survivin. [Curtin JC and Lorenzi MV. Drug Discovery Approaches to Target Wnt Signaling in Cancer Stem Cells. Oncotarget2010, 1: 552]. Tankyrases play a key role in the destruction complex by regulating the stability of the rate- limiting AXIN proteins, RNF146 and tankyrase itself. The E3 ubiquitin ligase RNF146 recognizes tankyrase-mediated PARsylation and eartags AXIN, tankyrase and itself for proteasome-mediated degradation. Thus, tankyrases control the protein stability and turnover of key components of the destruction complex, and consequently the cellular levels of β- catenin [Huang SMA, Mishina YM, Liu S, Cheung A, Stegmeier F, et al. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 2009, 461:614, Zhang Y, Liu S, Mickanin C, Feng Y, Charlat O, et al. RNF146 is a poly(ADP-ribose)-directed E3 ligase that regulates axin degradation and Wnt signalling. Nature Cell Biology 201 1, 13:623, 201 1].
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