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(12) (19) STANDARD PATENT AUSTRALIAN PATENT OFFICE (11) Application No. AU 2015296210 B2

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(12) (19) STANDARD PATENT AUSTRALIAN PATENT OFFICE (11) Application No. AU 2015296210 B2 (12) STANDARD PATENT (11) Application No. AU 2015296210 B2 (19) AUSTRALIAN PATENT OFFICE (54) Title Indolizine derivatives which are applicable to neurodegenerative diseases (51) International Patent Classification(s) C07D 471/04 (2006.01) A61P 25/28 (2006.01) A61K 31/437 (2006.01) (21) Application No: 2015296210 (22) Date of Filing: 2015.07.31 (87) WIPO No: WO16/019228 (30) Priority Data (31) Number (32) Date (33) Country 62/031,237 2014.07.31 US (43) Publication Date: 2016.02.04 (44) Accepted Journal Date: 2019.08.15 (71) Applicant(s) Merck Patent GmbH (72) Inventor(s) Karra, Srinivasa R.;Goutopoulos, Andreas (74) Agent / Attorney Griffith Hack, GPO Box 1285, MELBOURNE, VIC, 3001, AU (56) Related Art CAS RN 345292-71-9, STN Entry Date 11 Jul 2001 WO 2012080727 A2 US 7056941 B1 Ito N, Tamano S, Shirai T. A medium-term rat liver bioassay for rapid in vivo detection of carcinogenic potential of chemicals. Cancer Sci. 2003 Jan;94(1 ):3-8. WO 2007095223 A2 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII International Bureau (10) International Publication Number (43) International Publication Date WO 2016/019228 Al 4 February 2016 (04.02.2016) WIPO I PCT (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07D 471/04 (2006.01) A61P 25/28 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/437 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (21) International Application Number: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/US2015/043090 HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (22) International Filing Date: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, 31 July 2015 (31.07.2015) MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (25) Filing Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (26) Publication Language: English TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 62/031,237 31 July 2014 (31.07.2014) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (71) Applicant: MERCK PATENT GMBH [DE/DE]; Frank­ TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, furter Strasse 250, 64293 Darmstadt (DE). TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (72) Inventors; and LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, (71) Appficants for US only): KARRA, Srinivasa R. SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, [US/US]; 58 Four Winds Drive, Pembroke, Massachusetts GW, KM, ML, MR, NE, SN, TD, TG). 02359 (US). GOUTOPOUUOS, Andreas [GR/US]; 73 Worcester Street, Apt 5, Boston, Massachusetts 02118 Published: — with international search report (Art. 21(3)) (74) Agent: KIM, Dwight D.; EMD Serono Research and De­ velopment Instiute, One Technology Place, Rockland, Massachusetts 02370 (US). Al 2016/019228 (54) Title: INDOLIZINE DERIVATIVES WHICH ARE APPLICABLE TO NEURODEGENERATIVE DISEASES (57) Abstract: The present invention relates to indolizine compounds, and pharmaceutically acceptable compositions thereof, useful as antagonists of P2X7, and for the treatment of P2X7-related disorders. WO WO 2016/019228 PCT/US2015/043090 INDOLIZINE DERIVATIVES WHICH ARE APPLICABLE TO NEURODEGENERATIVE DISEASES RELATED APPLICATION [0001] This application claims the benefit of U.S. Provisional application 62/031,237, filed on July 31, 2014, the content of which is incorporated by reference in its entirety. Technical Field of the Invention [0002] The present invention relates to indolizine compounds useful as antagonists of P2X7. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders. Background of the Invention [0003] The P2X7 receptor is a ligand-gated ion channel that belongs to the Purinergic Receptor Family. The receptor is expressed on many cell types related to the immune and nervous systems. In the nervous system P2X7 is expressed on microglia, oligodendrocytes and astrocytes. Brief activation of the P2X7 receptor channel with its endogenous ligand ATP leads to several downstream events including the processing and release of the proinflammatory cytokine ILl-β from monocytes and macrophages. P2X7 activation also plays an important role in regulating the glutamate release/uptake in astrocytes. [0004] P2X7 receptors are ionotropic receptors activated by ATP, which may regulate neuro transmission in the CNS by activating presynaptic and/or postsynaptic P2X7 receptors on central and peripheral neurons and glia (Deuchars S. A. et al., J. Neurosci. 21:7143-7152, (2001), Kanjhan R. et al., J. Comp. Neurol. 407:11-32 (1997), Le K. T. et al., Neuroscience 83:177-190 (1998)). Activation of the P2X7 receptor on cells of the immune system (macrophages, mast cells and lymphocytes) leads to release of interleukin-1β (IL-Ιβ), giant cell formation, degranulation, and L-selectin shedding. ATP is able to increase local release and process of IL-1 in rats through a P2X7receptor mediated mechanism following lipopolysaccharide (LPS) intraperitoneal injections (Griffiths et al., J. Immunology Vol. 154, pages 2821-2828 (1995); Solle et al., J. Biol. Chemistry, Vol. 276, pages 125-132, (2001)). Docket no.: P 14/143 WO [0005] Antagonism of the P2X7 receptor is considered to be an attractive therapeutic approach for the treatment of multiple sclerosis and Alzheimer’s disease, due to its significant 2019 role in dampening the CNS inflammation and supporting neuroprotection. Jul Summary of the Invention 15 [0006] Compounds of this invention, and pharmaceutically acceptable compositions thereof, may be effective as antagonists of P2X7. Such compounds have general formula I: 2015296210 1 or a pharmaceutically acceptable salt thereof, wherein each of Ring A, X, Y, Z, R1, Ra, m, n, and p, is as defined and described in embodiments herein. [0007] Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders or conditions, associated with P2X7 activity. Such diseases, disorders, or conditions include those described herein. Detailed Description of Certain Embodiments 1. General Description of Compounds of the Invention [0008] In certain embodiments, the present invention provides antagonists of P2X7. In some embodiments, such compounds include those of the formulae described herein, or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein. 2. Compounds and Definitions [0009] Compounds of this invention include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, 2 11525626_1 (GHMatters) P105007.AU WO 2016/019228 PCT/US2015/043090 Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference. [0010] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C7 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Exemplary aliphatic groups are linear or branched, substituted or unsubstituted Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. [0011] The term “lower alkyl” refers to a C1-4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. [0012] The term “lower haloalkyl” refers to a C1-4 straight or branched alkyl group that is substituted with one or more halogen atoms. [0013] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, or phosphorus (including, any oxidized form of nitrogen, sulfur, or phosphorus; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2//- pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl)). [0014] The term “unsaturated”, as used herein, means that a moiety has one or more units of unsaturation. 3 WO 2016/019228 PCT/US2015/043090 [0015] As used herein, the term “bivalent Ci-s (or Ci-ό) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.
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