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WO 2017/055313 Al 6 April 2017 (06.04.2017) W P O PCT

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WO 2017/055313 Al 6 April 2017 (06.04.2017) 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 2017/055313 Al 6 April 2017 (06.04.2017) W P O PCT (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07D 233/54 (2006.01) A61K 31/4178 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/4164 (2006.01) A61P 35/00 (2006.01) 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, (21) Number: International Application DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/EP20 16/073040 HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (22) International Filing Date: KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, 28 September 2016 (28.09.201 6) MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (25) Filing Language: English SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, (26) Publication Language: English TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 15 188027.5 1 October 201 5 (01. 10.2015) EP (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant: BAYER PHARMA AKTIENGESELL- GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, SCHAFT [DE/DE]; Mullerstr. 178, 13353 Berlin (DE). TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (72) Inventors: EIS, Knut; Fichtenweg 1, 13587 Berlin (DE). DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, ACKERSTAFF, Jens; Christophstrasse 27, 40225 Dus- LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, seldorf (DE). WAGNER, Sarah; Moritz-Sommerstr. 12A, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, 40225 Dusseldorf (DE). BUCHGRABER, Philipp GW, KM, ML, MR, NE, SN, TD, TG). Kastaninenallee 25, 10435 Berlin (DE). SULZLE, Detlev Otternweg 15, 13465 Berlin (DE). BENDER, Eckhard Declarations under Rule 4.17 : Gudrunstr. 6, 40764 Langenfeld (DE). LI, Volkhart Min- — as to applicant's entitlement to apply for and be granted a Jian; Im Wiesengrund 40, 42553 Velbert (DE). LIU, patent (Rule 4.1 7(H)) Ningshu; Ringstr. 89a, 12203 Berlin (DE). SIEGEL, Franziska; Pappelallee 58, 10437 Berlin (DE). LIENAU, Published: Philip; Jahnstr. 13, 10967 Berlin (DE). — with international search report (Art. 21(3)) (74) Agent: BIP PATENTS; c/o Bayer Intellectual Property — with sequence listing part of description (Rule 5.2(a)) GmbH, Alfred-Nobel-Str. 10, 40789 Monheim am Rhein (DE). (54) Title: AMIDO-SUBSTFTUTED AZOLE COMPOUNDS (57) Abstract: The present invention relates to compounds of general formula (I), in which X 1, X2, R1, R2, R4, R5, R7, and R8 are as defined herein, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to phar maceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a phar - maceutical 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 AZOLE COMPOUNDS The present invention relates to amido-substituted azole compounds of general formula ( I) as described and defined herein , t o methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and t o 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 i n combination with other active ingredients. BACKGROUND OF THE INVENTION Cancer is the leading cause of death i n developed countries and the second leading cause of death i n developing countries. Deaths from cancer worldwide are projected t o continue rising, with an estimated 12 million deaths in 2030. While substantial progress has been made i n 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 t o 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 t o the secondary organs and tissues [Liotta LA, ohn EC. The microenvironmen t of the tumour- host interface. Nature 2001 , 4 11:375]. Furthermore, cancer stem cells (CSCs) represent the apex i n 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 t o 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 t o 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 t o cell surface receptors t o 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 Ca + 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. WntI 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 i n an inactive state by a multimeric "destruction" complex comprised of adenomatous polyposis coli (APC), Axin , glycogen synthase kinase 3 (GSK36) and casein kinase 1a (CK1 a). APC and Axin function as a scaffold, permitting GSK36- and CK1 a-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 t o 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, 13 1: 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 , GSK3B and Dv are recruited t o the co-receptor complex Fzd and LRP5/6 and lead t o disruption of the β -catenin destruction complex. Therefore, β -catenin is stabilized and translocated t o the nucleus. Once in the nucleus, - 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, 0ct4, cyclin D, survivin. [ Curtin JC and Lorenzi MV. Drug Discovery Approaches to Target Wnt Signaling in Cancer Stem Cells. Oncotarget 2010, 1: 552]. Tankyrases play a key role in the destruction complex by regulating the stability of the rate-limiting AXIN proteins, RNF1 6 and tankyrase itself. The E3 ubiquitin ligase RNF1 6 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, 46 1:614, Zhang Y, Liu S, Mickanin C, Feng Y, Charlat 0 , 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]. Aberrant regulation of the Wnt/ B-catenin signaling pathway is a common feature across a broad spectrum of human cancers and evolves as a central mechanism in cancer biology. First of all, Wnt overexpression could lead t o malignant transformation of mouse mammary tissue [Klaus A, BirchmeierW. Wnt signalling and its impact on development and cancer. Nat Rev Cancer 2008, 8: 387] . Second , tumor genome sequencing discovered the mutations in Wnt/ B-catenin pathway components as well as epigenetic mechanisms that altered the expression of genes relevant t o Wnt/ B-catenin pathway [Ying Y.
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