USOO9670229B2 (12) United States Patent (10) Patent No.: US 9,670.229 B2 Hitchcock et al. (45) Date of Patent: Jun. 6, 2017 (54) 5-HT3 RECEPTOR ANTAGONISTS USPC ................ 514/230.5, 299; 544/105:546/121 See application file for complete search history. (71) Applicant: Takeda Pharmaceutical Company Limited, San Diego, CA (US) (56) References Cited (72) Inventors: Stephen Hitchcock, San Diego, CA U.S. PATENT DOCUMENTS (US); Holger Monenschein, San Diego, CA (US); Holly Reichard, San Diego, 266 A 133 Ronal CA (US): Huikai Sun, San Diego, CA wW - onalscnet al. tSEN's,s s 5. s A 4,910,4,886,808. 193 A 12/19893, 1990 KingBuchheit et al. et al. (US); Todd Macklin, San Diego, CA 5,034,398 A 7/1991 King et al. (US); Maria Hopkins, San Diego, CA 5,298,510 A 3/1994 Tyers (US) 5,344,831 A 9/1994 Satoh et al. 9.012,447 B2 * 4/2015 Hitchcock ............ CO7D 498.08 (73) Assignee: Takeda Pharmaceutical Company 9,346,829 B2 * 5/2016 Hitchcock ............ coisi's Limited, Osaka (JP) 2004/0038958 A1 2/2004 Rundfeldt et al. 2005/0234095 A1 10, 2005 Xie et al. (*) Notice: Subject to any disclaimer, the term of this 2007,0191313 A1 8, 2007 Beard et al. patent is extended or adjusted under 35 (Continued) U.S.C. 154(b) by 0 days. FOREIGN PATENT DOCUMENTS (21) Appl. No.: 15/150,013 EP O200444 5, 1986 (22) Filed: May 9, 2016 EP O469449 2, 1992 EP O491664 6, 1992 (65) Prior Publication Data (Continued) US 2016/O251373 A1 Sep. 1, 2016 OTHER PUBLICATIONS O O Naghdi et al. “The effect of intrahippocampal injections of ritanserin Related U.S. Application Data (5HT2A/2C antagonist) and granisetron (5HT3 antagonist) on (62) Division of application No. 14/645,639, filed on Mar. learning as assessed in the spatial version of the water maze' 12, 2015, now Pat. No. 9,346,829, which is a division Behavioural Brain Research 157 (2005) p. 205-210. of application No. 13/943,634, filed on Jul. 16, 2013, (Continued) now Pat. No. 9,012,447. Primary Examiner — Kahsay Habte (60) Provisional application No. 61/708,521, filed on Oct. (74) Attorney, Agent, or Firm — Matthew J. Russo; David 1, 2012, provisional application No. 61/672,709, filed M. Stemerick on Jul. 17, 2012. (51) Int. Cl. (57) ABSTRACT C07D 519/00 (2006.01) The present invention provides 5-HT3 receptor antagonists CO7D 49.8/08 (2006.01) of Formula (I): CO7D 47L/04 (2006.01) CO7D 451/12 (2006.01) CO7D 22L/22 (2006.01) (I) A6 IK3I/I9 (2006.01) . A6 IK3I/5386 (2006.01) O Z CD7C 53/40 (2006.01) CO7D 453/02 (2006.01) -X4 CO7D 47/08 (2006.01) n \ C07C 53/18 (2006.01) X2, 2 /* (52) U.S. Cl. nx, N CPC ............ C07D 498/08 (2013.01); A61K 31/19 R4 (2013.01); A61 K3I/5386 (2013.01); C07C 53/18 (2013.01); C07C 53/40 (2013.01); C07D 221/22 (2013.01); C07D 451/12 (2013.01); which are useful for the treatment of diseases treatable by C07D 453/02 (2013.01); C07D 471/04 inhibition of 5-HT3 receptor such as emesis, pain, drug (2013.01); C07D 471/08 (2013.01); C07D addiction, neurodegenerative and psychiatric disorders, and 519/00 (2013.01) GI disorders. Also provided are pharmaceutical composi (58) Field of Classification Search tions containing Such compounds and processes for prepar CPC. C07D 51.9/00; C07D 498/08; C07D 471/04; ing Such compounds. C07D 451/12: C07D 221/22: A61 K 31/19; A61K 31/5386 11 Claims, No Drawings US 9,670.229 B2 Page 2 (56) References Cited U.S. PATENT DOCUMENTS 2011/0319407 A1 12/2011 Xie et al. FOREIGN PATENT DOCUMENTS EP O558923 9, 1993 EP O708105 4f1996 EP 1156.045 11 2001 EP 1243268 9, 2002 WO WO95/27.490 10, 1995 WO WOf O3,035.625 5, 2003 WO WO, 2004/OO6920 1, 2004 WO WO, 2004/O290SO 4/2004 WO WO, 2005/092890 10/2005 WO WO, 2006/077365 T 2006 WO WO, 2007/038367 4/2007 WO WO, 2007/095561 8, 2007 WO WO, 2008/048.981 4/2008 WO WO, 2008/097930 8, 2008 WO WO, 2008/100867 8, 2008 WO WO, 2009/023623 2, 2009 WO WO, 2011/126821 10, 2011 WO WO, 2011, 153553 12, 2011 OTHER PUBLICATIONS Javadi-Paydar et al. “Involvement of nitric oxide in granisetron improving effect on Scopolamine-induced memory impairment in mice” Brain Research 1429 (2 0 1 2) p. 6 1-7 1. * cited by examiner US 9,670,229 B2 1. 2 5-HT3 RECEPTOR ANTAGONSTS son and Lummis 2007 Exp Opin Ther Targets, 11, 527-540). In addition, 5-HT3 receptors are expressed in the GI tract and hence may play a role in GI disorders such as dyspepsia, RELATED APPLICATIONS gastroesophagal reflux disease and irritable bowel syndrome (see Graeff 1997 Psychiatr Clin North Am 20, 723: Thomp This application claims the benefit of U.S. Provisional son and Lummis 2007 Exp Opin Ther Targets, 11, 527-540: Application No. 61/672,709, filed Jul. 17, 2012, and U.S. Barnes et al. 2009 Neuropharmacology 56, 273). Expression Provisional Application No. 61/708,521, filed Oct. 1, 2012, of the 5-HT3A subsunit has also been discovered extraneu ronally in immune cells Such as monocyes, chondrocytes, which are herein incorporated by reference. T-cells, synovial tissue and platelets (Fiebich et al., 2004 10 Scan J Rheumatol Suppl, 9-11, Stratz et al., 2008 Thromb FIELD OF INVENTION Haemost 99, 784) and of 5-HT3A, C-E within the lamina propia in the epithelium of the gut mucose (Kapeller et al., The present invention provides compounds that are J Comp Neuro., 2008: 509: 356-371) thus suggesting they 5-HT3 receptor antagonists and are therefore useful for the may be involved in immunological and inflammatory dis treatment of diseases treatable by inhibition of the 5-HT3 eases like atherosclerosis, tendomyopathies and fibromyal 15 1a. receptor Such as emesis, pain, drug addiction, neurodegen 9. The 5-HT3 antagonists currently on the market are erative and psychiatric disorders, and GI disorders. Also approved only for the treatment of emesis or irritable bowel provided are pharmaceutical compositions containing Such syndrome. It is desirable to discover 5-HT3 antagonists that compounds and processes for preparing Such compounds. can be used to treat other diseases amenable to alleviation by 5-HT3 receptors such as Schizophrenia and cognitive disor BACKGROUND der associated with Schizophrenia. The present invention can fulfill this and related needs. It is desirable to discover Serotonin type 3 (5-HT3) receptors are part of the sero 5-HT3 antagonists that have desirable pharmacokinetic and tonergic system. Unlike other receptors of this system, pharmacodynamic properties, such as selectivity over nico which are all G-protein coupled receptors, the 5-HT3 recep tinic-C7 receptors. tors are ligand-gated ion channels and belongs to the Super 25 Certain antagonists the 5-HT3 receptor are described in family of Cys-loop receptors that include nicotinic acetyl U.S. Pat. Nos. 4,789,763; 4,803, 199: 4,886,808: 4,910, 193; choline, Y-aminobutyric acid (GABA)A and glycine 5,334,831; EP O 469 449; and EP O 491 664. Certain receptors and a Zn-2 activated cation channel (see Davies et inhibitors of TGF-B are described in EP 1 156 045 and al., 2003, J. Biol. Chem., 278, 712-717: Connolly et al., certain treatment of nephritis is described in EP1 243 268. 2004, Biochem Soc Trans 32, 529-534). The 5-HT, receptors 30 are made up of 5 subunits arranged around a central ion Certain antagonists of 5-HT4 are described in EP 0708 105. conducting pore, which is permeable to sodium, potassium, Certain ligands of nicotinic-C7 receptors are described in and calcium ions (see Boess et al., 1995, J. Neurochem. 64. WO 2007/038367. Certain P2X7 antagonists are disclosed 1401-1405; Connolly et al., 2004, Biochem Soc Trans 32, in WO 2009/O23623. 529-534). Binding of serotonin to the 5-HT receptors opens the channel, which, in turn, leads to an excitatory response 35 SUMMARY in neurons. Functional data reported for 5-HT3 receptors refer to 5-HT3A or 5-HT3AB receptors since the properties In a first aspect, this invention is directed to a compound of these receptor subtypes have been most extensively of Formula (I): studies to date. 5-HT3 receptors are known to be expressed in the central 40 nervous system in regions involving vomiting reflex, pro (I) cessing of pain, cognition and anxiety control and play a role R in the pathogenesis of diseases such as emesis, migraine, drug addiction, and neurodegenerative and psychiatric dis “N 4 orders such as anxiety and depression (see Hewlett et al., 2003.J. Clin. Psychiatry 64, 1025-1030; Kelley et al., 2003a, 45 X4 Eur J Pharmacol., 461, 19-25; Haus et al., 2000 Scand J Rheumatol Suppl 113, 55-58; and Faris et al., 2006 J affect X2 2 N^ Disorder 92, 79-90), eating disorders (Hammer et al., 1990 Am J Physiol 259, R627-R636, and Jiang & Gietzen 1994 R4 Pharmacol Biochem Behav 47, 59-63), schizophrenia (see 50 Hermann et al. 1996 Biochem Biophy's Res Commun 225, 957-960; Sirota et al., 2000 Am J Psychiatry 157, 287-289; wherein: Adler et al., 2005 Am J Psychiatry 162, 386-388: Koike et Z is O or NR where R is hydrogen or C. alkyl: al., Levkovitz et al., 2005 Schizophr Res 76, 67-72), cogni R is a ring of the formula (a)-(h) below: tive dysfunction associated with schizophrenia (see Zhanget 55 al., 2006 Schizophr Res 88, 102-110; Akhondzadeh et al., 2009 Schizophr Res 107, 206-212), congnitive dysfuntion (a) associated with Parkinson's disease, Huntington’s Chorea, presenile dementias and Alzheimer's disease (see Costall and Naylor 2004 CNS Neurol Disord 3, 27-37) substance abuse and addiction (see Johnson et al., 2002 Psycho 60 pharmacology (Berl) 160, 408-413: Johnson, 2004 CNS Drugs 18, 1105-1118; Dawes et al., 2005 Addict Behav 30, 1630-1637, Johnson 2006 Drug Alcohol Depend 84, 256 263), autish spectrum disorders (see Anderson et al Neuro genetics 10, 209-216) and pain (see Kayser et al., 2007 Pain 65 130, 235; Glaum et al., 1998 Neurosci Lett 95, 313-317; Schworer & Ramadori 1993 Clin Investig 71, 659; Thomp US 9,670,229 B2 3 4 -continued all of X-X are CRs or one of X-X is N and the others are (b) CRs: each Rs is independently hydrogen, C.