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(12) United States Patent (10) Patent No.: US 9,346,762 B2 Nazare Et Al

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(12) United States Patent (10) Patent No.: US 9,346,762 B2 Nazare Et Al USOO9346762B2 (12) United States Patent (10) Patent No.: US 9,346,762 B2 Nazare et al. (45) Date of Patent: May 24, 2016 (54) PYRAZOLE DERIVATIVES AND THEIR USE W 38: 28 3. A. 5.38: AS LPARSANTAGONSTS WO 2013171316 A1 11 2013 (71) Applicant: SANOFI, Paris (FR) OTHER PUBLICATIONS (72) Inventors: Marc Nazare, Frankfurt am Main (DE); Database Registry Chemical Abstracts Service, Columbus, Ohio, Detlef Kozian, Frankfurt am Main (DE); Accession No. RN 1280538-92-2, RN 1279877-48-3, RN 1279845 Andreas Evers, Frankfurt am Main 01-0, RN 1279842-08-8, RN 1279831-82-1, RN 1279830-96-4, and (DE); Werngard Czechtizky, Frankfurt RN 1279828-94-2, Entered STN: Apr. 14, 2011.* am Main (DE) Ito, Nobuyuki. Cancer Science 94(1), (2003) 3-8.* International Search Report for International Patent Application No. (73) Assignee: Sanofi, Paris (FR) PCT/EP2013/060171 dated Jun. 11, 2013 (mailed Jun. 27, 2013) p. 1-11. (*) Notice: Subject to any disclaimer, the term of this A. F. Littke et al., “Palladium-Catalyzed Coupling Reactions of Aryl Chlorides' Angew. Chem. Int. Ed. 2002, 41, 4176-4211. patent is extended or adjusted under 35 A. Padwa et al., “Reaction of Hydrazonyl Chlorides and U.S.C. 154(b) by 0 days. Carboalkoxymethylene Triphenylphosphoranes to Give 5-Alkoxy Substituted Pyrazoles' J. Heterocycl. Chem., 1987, 24, 1225-1227. (21) Appl. No.: 14/401,050 A. R. Mucietal, “Practical Palladium Catalysts for C N and C–O Bond Formation' Topics in current Chemistry 2002, 219, 131-209. (22) PCT Filed: May 16, 2013 A. Tunoori et al., “Polymer-Bound Triphenylphosphine as Traceless Reagent for Mitsunobu Reactions in Combinatorial Chemistry: Syn (86). PCT No.: PCT/EP2013/06O171 thesis of Aryl Ethers from Phenols and Alcohols' Tetrahedron Lett. 39 (1998) 8751-8754. S371 (c)(1), Amisten et al., “Gene expression profiling for the identification of (2) Date: Nov. 13, 2014 G-protein coupled receptors inhuman platelets' Thromb Res (2008), 122,47-57 (Oct. 24, 2007). (87) PCT Pub. No.: WO2013/171317 B. Yang et al. “Palladium-catalyzed amination of aryl halides and sulfonates' J. Organomet. Chem. 1999, 576, 125-146. PCT Pub. Date: Nov. 21, 2013 (Continued) (65) Prior Publication Data Primary Examiner — Samantha Shterengarts US 2015/O141477 A1 May 21, 2015 (74) Attorney, Agent, or Firm — McDonnell Boehnen (30) Foreign Application Priority Data Hulbert & Berghoff LLP (57) ABSTRACT May 18, 2012 (EP) ..................................... 12305552 The present invention relates to compounds of the formula (I), (51) Int. Cl. wherein the residues R' to R. V. GandM have the meanings CO7D 23L/2 (2006.01) indicated in the claims. The compounds of the formula (I) are CO7D 409/04 (2006.01) valuable pharmacologically active compounds for use in the CO7D 23L/56 (2006.01) treatment of diverse disorders, for example cardiovascular disorders like thromboembolic diseases or restenoses. The A6 IK3 L/45 (2006.01) compounds of the invention are effective antagonists of the (52) U.S. Cl. platelet LPA receptor LPAR5 (GPR92) and can in general be CPC ............ C07D 231/12 (2013.01); A61K31/415 applied in conditions in which an undesired activation of the (2013.01); C07D 231/56 (2013.01); C07D platelet LPA receptor LPAR5, the mast cell LPA receptor 409/04 (2013.01) LPAR5 or the microglia cell LPA receptor LPAR5 is present (58) Field of Classification Search or for the cure or prevention of which an inhibition of the CPC. C07D 231/12: C07D 231/56; C07D 409/04; platelet, mast cell or microglia cell LPA receptor LPAR5 is A61K 31/415 intended. The invention furthermore relates to processes for See application file for complete search history. the preparation of compounds of the formula (I), their use, in particular as active ingredients in medicaments, and pharma (56) References Cited ceutical compositions comprising them. U.S. PATENT DOCUMENTS 2008. O1946.17 A1 8, 2008 Tawaraishi (I) FOREIGN PATENT DOCUMENTS EP O382.276 A2 8, 1990 WO 2004022526 A1 3, 2004 WO 2009080227 A2 T 2009 WO 2009109613 A2 9, 2009 WO 2009109616 A2 9, 2009 WO 2009109618 A2 9, 2009 19 Claims, No Drawings US 9,346,762 B2 Page 2 (56) References Cited J. Wolfe et al. “Simple, Efficient Catalyst System for the Palladium Catalyzed Amination of Aryl Chlorides, Bromides, and Triflates' J. OTHER PUBLICATIONS Org. Chem. 2000, 65, 1158-1174. K. I. Booker-Milburn "A Convenient Method for the Synthesis of C-5 C. Baldolietal. 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Trifluoromethylpyrazole Derivatives via 1.3 Rearrangements of Khandoga et al., “Lysophosphatidic acid-induced platelet shape Benzoyl Group Using tert-Butyllithium” Synth. Commun., 1998, change revealed through LPA 1-5 receptor-selective probes and albu min' Platelets (2008), 19, 415-427. vol. 28, No. 12, S. 2159-2166. Kinloch et al., “New targets for neuropathic pain therapeutics' D. L. Hughes et al. “A Mechanistic Study of the Mitsunobu Expert Opin TherTargets (2005), 9, 685-698. Esterification Reaction' J. Am. Chem. Soc. 110, 1988, 6487-6491. Kovanen et al., “Infiltrates of Activated Mast Cells at the Site of D. Nichols, “1-(2,5-Dimethoxy-4(-t rifluoromethyl)phenyl-)2- Coronary Atheromatous Erosion or Rupture in Myocardial Infarc aminopropane: A Potent Serotonin 5-HT2A/2C Agonist' J. Med. tion” Circulation (1995), 92, 1084-1088. Chem, 1994, 37,4346-4351. Leighton, “The Formation of Hydrazides by the Action of D. Sauer et al., “The Synthesis of 3(5)- Phenylhydrazine Upon Organic Acids in the Cold” American chemi (2-Hydroxyethoxy)methylpyrazole-5(3)-carboxamide, an Acyclic cal Journal (1898) 20, 676-679. Analogue of 4-Deoxypyrazofurin' J. Org. Chem., 1990, 40, 5535 Lundecquist, "Synergistic Induction of IL-23 Expression in Fibro 5538. blast-like Synoviocytes by IL-17 and TNF-Alpha: A Positive Feed F. Farina et al. “1,3-Dipolar Cycloadditions With Methyl 4-Oxo- and back Loop in Rheumatoid Arthritis' J Allergy Clin Immunol (2008), 4-Hydroxy-2-Butynoates. Synthesis of Functionalized Pyrazoles and 121, Suppl 1, Abstr 518, p. 1. Triazoles” Heterocycles, 1989, vol. 29. No. 5, S. 967–974. M. A. Martins et al., “One-Pot Synthesis of 3(5)- F. Fotietal. “First Synthesis of a Bromonitrilimine. Direct Formation Ethoxycarbonylpyrazoles' Synthesis 1995, 1491-1492. of 3-Bromopyrazole Derivatives.” Tetrahedron Lett., 1999, 40, 2605 M. Elnagdietal, “Recent Developments in the Synthesis of Pyrazole 2606. 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