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(12) Patent Application Publication (10) Pub. No.: US 2014/0024644 A1 Hitchcock Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2014/0024644 A1 Hitchcock Et Al US 2014.0024644A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0024644 A1 Hitchcock et al. (43) Pub. Date: Jan. 23, 2014 (54) 5-HT3 RECEPTOR ANTAGONISTS (52) U.S. Cl. CPC .................................... C07D 498/08 (2013.01) (71) Applicant: ENVOY THERAPEUTICS, INC., San USPC ........................................ 514/230.5:544/105 Diego, CA (US) (72) Inventors: Stephen Hitchcock, San Diego, CA (57) ABSTRACT (US); Holger Monenschein, San Diego, CA (US); Holly Reichard, San Diego, The present invention provides 5-HT3 receptor antagonists of CA (US); Huikai Sun, San Diego, CA Formula (I): (US); Shota Kikuchi, San Diego, CA (US); Todd Macklin, San Diego, CA (US); Maria Hopkins, San Diego, CA O R (I) (US) / Z (21) Appl. No.: 13/943,634 x1's--\X4 (22) Filed: Jul. 16, 2013 Xs X2 2 N Related U.S. Application Data X Y, (60) Provisional application No. 61/672,709, filed on Jul. 17, 2012, provisional application No. 61/708,521, filed on Oct. 1, 2012. which are useful for the treatment of diseases treatable by inhibition of 5-HT3 receptor such as emesis, pain, drug addic Publication Classification tion, neurodegenerative and psychiatric disorders, and GI disorders. Also provided are pharmaceutical compositions (51) Int. Cl. containing Such compounds and processes for preparing Such CO7D 49.8/08 (2006.01) compounds. US 2014/0024644 A1 Jan. 23, 2014 5-HT3 RECEPTOR ANTAGONSTS Addict Behav 30, 1630-1637, Johnson 2006 Drug Alcohol Depend 84, 256-263), autism spectrum disorders (see Ander RELATED APPLICATIONS son et al Neurogenetics 10, 209-216) and pain (see Kayser et al, 2007 Pain 130, 235; Glaum et al., 1998 Neurosci Lett 95, 0001. This application claims the benefit of U.S. Provi 313-317; Schworer & Ramadori 1993 Clin Investig 71, 659; sional Application No. 61/672,709, filed Jul. 17, 2012, and Thompson and Lummis 2007 Exp Opin Ther Targets, 11, U.S. Provisional Application No. 61/708,521, filed Oct. 1, 527-540). In addition, 5-HT3 receptors are expressed in the 2012, which are herein incorporated by reference. GI tract and hence may play a role in GI disorders such as dyspepsia, gastroesophagal reflux disease and irritable bowel FIELD OF INVENTION syndrome (see Graeff 1997 Psychiatr Clin North Am 20,723; Thompson and Lummis 2007 Exp Opin Ther Targets, 11, 0002 The present invention provides compounds that are 527-540; Barnes et al. 2009 Neuropharmacology 56, 273). 5-HT3 receptor antagonists and are therefore useful for the Expression of the 5-HT3A subunit has also been discovered treatment of diseases treatable by inhibition of the 5-HT3 extraneuronally in immune cells such as monocyes, chondro receptor Such as emesis, pain, drug addiction, neurodegen cytes, T-cells, synovial tissue and platelets (Fiebich et al., erative and psychiatric disorders, and GI disorders. Also pro 2004 Scan J Rheumatol Suppl, 9-11, Stratz et al., 2008 vided are pharmaceutical compositions containing Such com Thromb Haemost 99, 784) and of 5-HT3A, C-E within the pounds and processes for preparing such compounds. lamina propia in the epithelium of the gut mucose (Kapelleret al., JCompNeuro., 2008: 509:356-371) thus suggesting they BACKGROUND may be involved in immunological and inflammatory dis eases like atherosclerosis, tendomyopathies and fibromyal 0003. Serotonin type 3 (5-HT3) receptors are part of the serotonergic system. Unlike other receptors of this system, which are all G-protein coupled receptors, the 5-HT3 recep 0005. The 5-HT3 antagonists currently on the market are tors are ligand-gated ion channels and belongs to the Super approved only for the treatment of emesis or irritable bowel family of Cys-loop receptors that include nicotinic acetylcho syndrome. It is desirable to discover 5-HT3 antagonists that line, y-aminobutyric acid (GABA)A and glycine receptors can be used to treat other diseases amenable to alleviation by and a Zn+2 activated cation channel (see Davies et al., 2003, 5-HT3 receptors such as schizophrenia and cognitive disorder J. Biol. Chem., 278,712-717: Connolly et al., 2004, Biochem associated with Schizophrenia. The present invention can full Soc Trans 32, 529-534). The 5-HT receptors are made up of fill this and related needs. It is desirable to discover 5-HT3 5 subunits arranged around a central ion conducting pore, antagonists that have desirable pharmacokinetic and pharma which is permeable to sodium, potassium, and calcium ions codynamic properties, such as selectivity over nicotinic-C7 (see Boess et al., 1995, J. Neurochem. 64, 1401-1405; Con receptors. nolly et al., 2004, Biochem Soc Trans 32, 529-534). Binding of serotonin to the 5-HT, receptors opens the channel, which, 0006 Certain antagonists the 5-HT3 receptor are in turn, leads to an excitatory response in neurons. Functional described in U.S. Pat. No. 4,789,763: U.S. Pat. No. 4,803, data reported for 5-HT3 receptors refer to 5-HT3A or 199: U.S. Pat. No. 4,886,808; U.S. Pat. No. 4,910, 193; U.S. 5-HT3AB receptors since the properties of these receptor Pat. No. 5,334,831; EPO 469 449; and EPO 491 664. Certain Subtypes have been most extensively studies to date. inhibitors of TGF-B are described in EP 1156.045 and certain treatment of nephritis is described in EP1 243 268. Certain 0004 5-HT3 receptors are known to be expressed in the antagonists of 5-HT4 are described in EP 0708 105. Certain central nervous system in regions involving Vomiting reflex, processing of pain, cognition and anxiety control and play a ligands of nicotinic-C7 receptors are described in WO 2007/ role in the pathogenesis of diseases such as emesis, migraine, 038367. Certain P2X7 antagonists are disclosed in WO 2009/ drug addiction, and neurodegenerative and psychiatric disor O23623. ders such as anxiety and depression (see Hewlett et al., 2003 J. Clin. Psychiatry 64, 1025-1030; Kelley et al., 2003a, EurJ. SUMMARY Pharmacol., 461, 19-25; Haus et al., 2000 Scand.J Rheumatol Suppl 113, 55-58; and Faris et al., 2006J affect Disorder 92, 0007. In a first aspect, this invention is directed to a com 79-90), eating disorders (Hammer et al., 1990 Am J Physiol pound of Formula (I): 259, R627-R636, and Jiang & Gietzen 1994 Pharmacol Bio chem Behav 47, 59-63), schizophrenia (see Hermann et al. 1996 Biochem Biophy's Res Commun 225,957-960; Sirota et (I) al., 2000 Am J Psychiatry 157,287-289; Adleret al., 2005 Am O J. J Psychiatry 162,386-388: Koike et al., Levkovitz et al., 2005 Schizophr Res 76, 67-72), cognitive dysfunction associated Z with schizophrenia (see Zhang et al., 2006 Schizophr Res 88. X4 102-110; Akhondzadeh et al., 2009 Schizophr Res 107, 206 x1's--\ 212), congnitive dysfunction associated with Parkinson's dis X2 2 N Xs ease, Huntington's Chorea, presenile dementias and Alzhe X V imer's disease (see Costall and Naylor 2004 CNS Neurol R4 Disord 3, 27-37) substance abuse and addiction (see Johnson et al., 2002 Psycho-pharmacology (Berl) 160, 408-413; Johnson, 2004 CNS Drugs 18, 1105-1118; Dawes et al., 2005 US 2014/0024644 A1 Jan. 23, 2014 wherein: -continued Z is O or NR where R is hydrogen or C. alkyl: (h) R is a ring of the formula (a)-(h) below: (a) R is hydrogen, Ce alkyl, or Chaloalkyl; each R is independently hydrogen, Ce alkyl, Ce alkoxy, Chaloalkoxy, or halo and can be present on any carbon R3 atom in the rings; Ra is pyridinyl or pyrazolyl each optionally substituted with one or two Substituents independently selected from C. (b) alkyl, Chaloalkyl, Chaloalkoxy, Calkoxy, cyano, or halo; all of X-X are CRs or one of X-X is N and the others are CRs: each Rs is independently hydrogen, Calkyl, halo, hydroxy, or cyano provided that at least one of Rs is hydrogen; X is N or CR where R is hydrogen, Calkyl, or halo; or a pharmaceutically acceptable salt thereof or N-oxide (c) thereof. 0008. In a second aspect, this present invention is directed to a pharmaceutical composition comprising a compound of Formula (I) (or any embodiments thereofdisclosed herein) or a pharmaceutically acceptable salt thereof and a pharmaceu aza S. tically acceptable excipient. 0009 Ina third aspect, this present invention is directed to a method of treating a disease treatable by administration of a R2 (d) 5-HT3 receptor antagonist which method comprises admin istrating to the patient a pharmaceutical composition com prising a compound of Formula (I) (or any embodiments thereof disclosed herein) and/or a pharmaceutically accept able salt and a pharmaceutically acceptable excipient. That is, the present invention provides a method of treating a disease treatable by administration of a 5-HT3 receptor antagonist comprising: administrating to a patient in need thereof a therapeutically effective amount of a compound of Formula (I) (or any embodiments thereof disclosed herein) or a phar (e) maceutically acceptable salt thereof. 0010. In one embodiment of the third aspect, the disease treatable by administration of a 5-HT3 receptor antagonist is emesis, migraine, Substance abuse and addiction, neurode generative and psychiatric disorders such as anxiety and depression, eating disorders, Schizophrenia, cognitive dys function associated with Schizophrenia, Parkinson's disease, Huntington's Chorea, presenile dementias and Alzheimer's disease, and pain; GI disorders such as dyspepsia, gastroe sophagal reflux disease, and irritable bowel syndrome; and (f) immunological disorders and inflammation Such as athero Sclerosis, tendomyopathies and fibromyalgia. In another embodiment of the third aspect the disease treatable by administration of a 5-HT3 receptor antagonist is schizophre nia or cognitive dysfunction associated with Schizophrenia.
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