USOO9303045B2

(12) United States Patent (10) Patent No.: US 9,303,045 B2 Hitchcock et al. (45) Date of Patent: Apr. 5, 2016

(54) 5-HT3 RECEPTOR ANTAGONISTS 4,886,808 A 12/1989 King et al. 4,910, 193 A 3, 1990 Buchheit et al. 4,948,803 A 8/1990 Tyers (71) Applicant: Takeda Pharmaceutical Company 5,017,573 A 5/1991 Kon et al. Limited, San Diego, CA (US) 5,034,398 A 7/1991 King et al. 5,298,510 A 3/1994 Tyers (72) Inventors: Stephen Hitchcock, San Diego, CA 5,344,831 A 9, 1994 Satoh et al. 5,684,003 A 11/1997 Kikuchi et al. (US); Holger Monenschein, San Diego, 2004/0038958 A1 2/2004 Rundfeldt et al. CA (US); Holly Reichard, San Diego, 2005/0234095 A1 10/2005 Xie et al. CA (US); Huikai Sun, San Diego, CA 2007,0191313 A1 8, 2007 Beard et al. (US); Shota Kikuchi, San Diego, CA 2010.0113405 A1 5, 2010 Gant et al. 2011/0319407 A1 12/2011 Xie et al. (US); Todd Macklin, San Diego, CA 2012/0101094 A1 4/2012 Xie et al. (US); Maria Hopkins, San Diego, CA 2012/O190680 A1* 7/2012 Bakthavatchalam ... B64D 33/04 (US) 514,234.5 (73) Assignee: Takeda Pharmaceutical Company FOREIGN PATENT DOCUMENTS Limited, Osaka (JP) EP O20044 5, 1986 (*) Notice: Subject to any disclaimer, the term of this EP 0223385 5, 1987 EP O469449 2, 1992 patent is extended or adjusted under 35 EP O491664 6, 1992 U.S.C. 154(b) by 0 days. EP O708105 4f1996 EP 1156.045 11, 2001 (21) Appl. No.: 14/415,712 EP 1243268 9, 2002 (22) PCT Filed: Jul. 16, 2013 (Continued) (86). PCT No.: PCT/US2013/050762 OTHER PUBLICATIONS S371 (c)(1), Naghdietal. “The effect of intrahippocampal injections of ritanserin (2) Date: Jan. 19, 2015 (5HT2A 2C antagonist) and granisetron (5HT3 antagonist) on learn ing as assessed in the spatial version of the water maze' Behavioural (87) PCT Pub. No.: WO2014/014962 Brain Research 157 (2005) p. 205-210. PCT Pub. Date: Jan. 23, 2014 (Continued) (65) Prior Publication Data US 2015/O291624 A1 Oct. 15, 2015 Primary Examiner — Niloofar Rahmani (74) Attorney, Agent, or Firm — Matthew J. Russo; David (51) Int. Cl. M. Stemerick CO7D 47L/04 (2006.01) CO7D 49.8/04 (2006.01) A 6LX3/537 (2006.01) (57) ABSTRACT C07D 519/00 (2006.01) CO7D 49.8/08 (2006.01) The present invention provides compounds of the formula: CO7D 45L/2 (2006.01) A6 IK3I/9 (2006.01) A6 IK3I/5386 (2006.01) R O f CO7D 22L/22 (2006.01) Z (52) U.S. Cl. CPC ...... C07D 519/00 (2013.01); A61K3I/19 (2013.01); A61 K3I/5386 (2013.01); C07D x:1 s N 221/22 (2013.01); C07D 451/12 (2013.01); X22 NN Xs C07D 471/04 (2013.01); C07D498/08 X V (2013.01) R4 (58) Field of Classification Search CPC. C07D 471/04: CO7D 519/00; C07D 498/04; A61K 3.1 F537 that are 5HT3 receptor antagonists and are therefore useful USPC ...... 54.6/121; 54.4/105: 514/299 for the treatment of diseases treatable by inhibition of 5HT3 See application file for complete search history. receptor Such as emesis, pain, drug addiction, neurodegen erative and psychiatric disorders, and GI disorders. Also pro (56) References Cited vided are pharmaceutical compositions containing Such com U.S. PATENT DOCUMENTS pounds and processes for preparing such compounds. 4,789,673 A 12/1988 Donatsch et al. 4,803, 199 A 2f1989 Donatsch et al. 11 Claims, No Drawings US 9,303,045 B2 Page 2

(56) References Cited WO WO/2008/048.981 4/2008 WO WO, 2008/097930 8, 2008 FOREIGN PATENT DOCUMENTS WO WO, 2009/023623 2, 2009 WO WO, 2009/108551 9, 2009 WO WO95/27490 10, 1995 WO WOf O3,035.625 5, 2003 OTHER PUBLICATIONS W. W858; 8.3% 1858: Bermudez, Jose et al. “5-Hydroxytryptamine (5HT3) Receptor WO WO, 2005/092890 10/2005 Antagonist. 1. Indiazole and Indolzine-3-carboxylic Acid Deriva WO WO, 2006/077365 T 2006 tives' J. Med. Chem 1990, 33, p. 1924-29. WO WO, 2007/038367 4/2007 WO WO/2007/095561 8, 2007 * cited by examiner US 9,303,045 B2 1. 2 5-HT3 RECEPTOR ANTAGONSTS Depend 84, 256-263), autish spectrum disorders (see Ander son et al Neurogenetics 10, 209-216) and pain (see Kayser et CROSS-REFERENCE TO RELATED al, 2007 Pain 130, 235; Glaum et al., 1998 Neurosci Lett 95, APPLICATIONS 313-317; Schworer & Ramadori 1993 Clin Investig 71, 659; Thompson and Lummis 2007 Exp Opin Ther Targets, 11, This application is the U.S. National Stage entry under 35 527-540). In addition, 5HT3 receptors are expressed in the GI U.S.C. S371 (c) of International Application PCT/US2013/ tract and hence may play a role in GI disorders such as 050762, filed Jul. 16, 2013, which claims the benefit of U.S. dyspepsia, gastroesophagal reflux disease and irritable bowel Provisional Application No. 61/708,521, filed Oct. 1, 2012, syndrome (see Graeff 1997 Psychiatr Clin North Am 20,723; and U.S. Provisional Application No. 61/672,709, filed Jul. 10 Thompson and Lummis 2007 Exp Opin Ther Targets, 11, 17, 2012, which is herein incorporated by reference. 527-540; Barnes et al. 2009 Neuropharmacology 56, 273). Expression of the 5HT3A subsunit has also been discovered FIELD OF INVENTION extraneuronally in immune cells such as monocyes, chondro The present invention provides compounds that are 5HT3 15 cytes, T-cells, synovial tissue and platelets (Fiebich et al., receptor antagonists and are therefore useful for the treatment 2004 Scan J Rheumatol Suppl, 9-11, Stratz et al., 2008 of diseases treatable by inhibition of the 5HT3 receptor such Thromb Haemost 99, 784) and of 5HT3A, C-E within the as emesis, pain, drug addiction, neurodegenerative and psy lamina propia in the epithelium of the gut mucose (Kapelleret chiatric disorders, and GI disorders. Also provided are phar al., JCompNeuro., 2008: 509:356-371) thus suggesting they maceutical compositions containing Such compounds and may be involved in immunological and inflammatory dis processes for preparing Such compounds. eases like atherosclerosis, tendomyopathies and fibromyal BACKGROUND The 5HT3 antagonists currently on the market are approved only for the treatment of emesis or irritable bowel Serotonin type 3 (5HT3) receptors are part of the seroton 25 ergic system. Unlike other receptors of this system, which are syndrome. It is desirable to discover 5HT3 antagonists that all G-protein coupled receptors, the 5HT3 receptors are can be used to treat other diseases amenable to alleviation by ligand-gated ion channels and belongs to the Superfamily of 5HT3 receptors such as schizophrenia and cognitive disorder Cys-loop receptors that include nicotinic acetylcholine, associated with Schizophrenia. The present invention can full fill this and related needs. It is desirable to discover 5HT3 y-aminobutyric acid (GABA)A and glycine receptors and a 30 Zn-2 activated cation channel (see Davies et al., 2003, J. Biol. antagonists that have desirable pharmacokinetic and pharma Chem., 278, 712-717: Connolly et al., 2004, Biochem Soc codynamic properties, such as selectivity over nicotinic-O7 Trans 32, 529-534). The 5HT, receptors are made up of 5 receptors. Subunits arranged around a central ion conducting pore, Certain antagonists the 5HT3 receptor are described in which is permeable to sodium, potassium, and calcium ions 35 U.S. Pat. Nos. 4,789,763; 4,803, 199: 4,886,808: 4,910, 193; (see Boess et al., 1995, J. Neurochem. 64, 1401-1405; Con 5,334,831; EP 0469 449; and EPO 491 664. Certain inhibi nolly et al., 2004, Biochem Soc Trans 32, 529-534). Binding tors of TGF-3 are described in EP 1 156 045 and certain of serotonin to the 5HT receptors opens the channel, which, treatment of nephritis is described in EP1 243 268. Certain in turn, leads to an excitatory response in neurons. Functional antagonists of 5HT4 are described in EP 0708 105. Certain data reported for 5HT3 receptors refer to 5HT3A or 5HT3AB 40 ligands of nicotinic-C7 receptors are described in WO 2007/ receptors since the properties of these receptor Subtypes have 038367. Certain P2X7 antagonists are disclosed in WO 2009/ been most extensively studies to date. O23623. 5HT3 receptors are known to be expressed in the central nervous system in regions involving Vomiting reflex, process ing of pain, cognition and anxiety control and play a role in 45 SUMMARY the pathogenesis of diseases Such as emesis, migraine, drug addiction, and neurodegenerative and psychiatric disorders In a first aspect, this invention is directed to a compound of such as anxiety and depression (see Hewlett et al., 2003 J. Formula (IA): Clin. Psychiatry 64, 1025-1030; Kelley et al., 2003a, Eur J. Pharmacol., 461, 19-25; Haus et al., 2000 Scand.J Rheumatol 50 Suppl 113, 55-58; and Faris et al., 2006J affect Disorder 92, 79-90), eating disorders (Hammer et al., 1990 Am J Physiol 259, R627-R636, and Jiang & Gietzen 1994 Pharmacol Bio chem Behav 47, 59-63), schizophrenia (see Hermann et al. (IA) 1996 Biochem Biophy's Res Commun 225,957-960; Sirota et 55 al., 2000 Am J Psychiatry 157,287-289; Adleret al., 2005 Am J Psychiatry 162,386-388: Koike et al., Levkovitz et al., 2005 Schizophr Res 76, 67-72), cognitive dysfunction associated with schizophrenia (see Zhang et al., 2006 Schizophr Res 88. 102-110; Akhondzadeh et al., 2009 Schizophr Res 107, 206 60 212), cognitive dysfunction associated with Parkinson's dis ease, Huntington's Chorea, presenile dementias and Alzhe imer's disease (see Costall and Naylor 2004 CNS Neurol Disord 3, 27-37) substance abuse and addiction (see Johnson wherein: et al., 2002 Psycho-pharmacology (Berl) 160, 408-413; 65 Johnson, 2004 CNS Drugs 18, 1105-1118; Dawes et al., 2005 Z is O or NR; Addict Behav 30, 1630-1637, Johnson 2006 Drug Alcohol R is hydrogen or Ce alkyl; US 9,303,045 B2 3 4 R is a ring of the formula (a)-(h) below: -continued (h)

10

wherein: (b) R is hydrogen, Ce alkyl, or Chaloalkyl; 15 each R is independently hydrogen, Ce alkyl, Ce alkoxy, Chaloalkoxy, or halo and can be present on any carbon atom in the rings; Ra is Chaloalkyl, C. cyanoalkyl, Calkylsulfonyl: Cs cycloalkylsulfonyl; heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, (c) thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, pyrimidyl, azepinyl, diazepinyl, quinolyl, isoquinolyl, 25 quinolizidine, benzofuranyl, benzothienyl, indolyl, isoin dolyl, indazolyl, benzimidazolyl, benzisothiazolyl, ben Zisoxazolyl, benzoxadiazolyl, benzoxazolyl, benzothiaz olyl, benzothiadiazolyl, benzotriazolyl, benzopyrazinyl, benzopyrazidinyl, benzoazepinyl, benzodiazepinyl, imi (d) 30 dazopyridyl, pyrazolopyridyl, pyrrolopyridyl, quinazolyl, purinyl, furopyridyl, and thienopyridyl, each Rheteroaryl is optionally substituted with one or two substituents inde pendently selected from C alkyl, Ce haloalkyl, C. haloalkoxy, Calkoxy, hydroxy, cyano, or halo: Chet 35 erocycloalkyl optionally substituted with one or two sub stituents independently selected from C alkyl, C. alkoxy, Chaloalkoxy, Ce alkylsulfonyl, or halo: C oxoheterocycloalkyl optionally substituted with one or two 40 Substituents independently selected from C alkyl, C. (e) alkoxy, Ce haloalkoxy, Ce alkylsulfonyl, or halo; or phenyl optionally substituted with one, two, or three sub stituents independently selected from C alkyl, C. haloalkyl, Chaloalkoxy, Calkoxy, hydroxyl, cyano, 45 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, Ce alkyl, halo, hydroxy, 50 or cyano provided that at least one of Rs is hydrogen;

(f) X is Nor CR where R is hydrogen, Calkyl, or halo or R together with Randatoms to which they are attached form O—(CH) , —O—(CH) , or —O-(CH2) ; or a pharmaceutically acceptable salt thereof or N-oxide 55 thereof and provided that the compound of Formula (IA) is not: N-(3)-1-azabicyclo[2.2.2]oct-3-yl-6-bromo-1-(difluorom (g) ethyl)-1H-indazole-3-carboxamide, N-(3)-1-azabicyclo 60 2.2.2]oct-3-yl-1-(difluoromethyl)-6-methoxy-1H-inda Zole-3-carboxamide, N-(3)-1-azabicyclo[2.2.2]oct-3-yl 5-bromo-1-(2.2.2-trifluoroethyl)-1H-indazole-3- carboxamide, N-(3)-1-azabicyclo[2.2.2]oct-3-yl-5- 65 methoxy-1-(2.2.2-trifluoroethyl)-1H-indazole-3- carboxamide, or N-(3)-1-azabicyclo[2.2.2]oct-3-yl-1-(3- thienyl)-1H-indazole-3-carboxamide. US 9,303,045 B2 5 6 In one embodiment of the first aspect, the compounds have -continued Formula (I): (f)

(I) R O I Z

(g) x1 s N 10 X22 NN Xs R4 15 wherein: (h) Z is O or NR; R is hydrogen or C. alkyl; R is a ring of the formula (a)-(h) below:

25 wherein: R is hydrogen, C alkyl, or Chaloalkyl: each R is independently hydrogen, Ce alkyl, Ce alkoxy, Chaloalkoxy, or halo and can be present on any carbon 30 atom in the rings; Ra is heteroaryl selected from the group consisting of furanyl. thienyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, oxadia (b) Zolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetra 35 Zolyl pyrazinyl, pyridazinyl, pyrimidyl, azepinyl, diazepi nyl, quinolyl, isoquinolyl, quinolizidine, benzofuranyl. benzothienyl, indolyl, isoindolyl, indazolyl, benzimida Zolyl, benzisothiazolyl, benzisoxazolyl, benzoxadiazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzot (c) 40 riazolyl, benzopyrazinyl, benzopyrazidinyl, benzoaZepi nyl, benzodiazepinyl, imidazopyridyl, pyrazolopyridyl, pyrrolopyridyl, quinazolyl, purinyl, furopyridyl, and thienopyridyll; each Ra heteroaryl is optionally substituted with one or two substituents independently selected from 45 Co alkyl, Ce haloalkyl, C- haloalkoxy, C- alkoxy, hydroxy, cyano, or halo; all of X-X are CRs or one of X-X is N and the others are (d) CRs: each Rs is independently hydrogen, Calkyl, halo, hydroxy, 50 or cyano provided that at least one of Rs is hydrogen; X is Nor CR where R is hydrogen, Calkyl, or halo or R together with Randatoms to which they are attached form O—(CH) , —O—(CH) , or —O-(CH2) ; or a pharmaceutically acceptable salt thereof or N-oxide 55 thereof and provided that the compound of Formula (I) is not: N-(3)-1-azabicyclo[2.2.2]oct-3-yl-1-(3-thienyl)-1H-India (e) Zole-3-carboxamide. In a second aspect, this present invention is directed to a pharmaceutical composition comprising a compound of For 60 mula (IA) or (I) (or any embodiments thereof disclosed herein) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, provided the com pound of Formula (IA) is not N-(3)-1-azabicyclo[2.2.2]oct 3-yl-6-bromo-1-(difluoromethyl)-1H-Indazole-3-carboxam 65 ide, N-(3)-1-azabicyclo[2.2.2]oct-3-yl-1-(difluoromethyl)- 6-methoxy-1H-Indazole-3-carboxamide, N-(3)-1- azabicyclo[2.2.2]oct-3-yl-5-bromo-1-(2.2.2-trifluoroethyl)- US 9,303,045 B2 7 8 1H-Indazole-3-carboxamide, N-(3)-1-azabicyclo[2.2.2]oct Formula (I) is not N-(3)-1-azabicyclo[2.2.2]oct-3-yl-1-(3- 3-yl-5-methoxy-1-(2.2.2-trifluoroethyl)-1H-Indazole-3- thienyl)-1H-Indazole-3-carboxamide. In one embodiment of carboxamide, or N-(3)-1-azabicyclo[2.2.2]oct-3-yl-1-(3- the fourth aspect, the antipsychotic drug is AMG 747, bitop thienyl)-1H-Indazole-3-carboxamide or the compound of ertin (RG1678), RG1578, AMG579, GSK1018921, aripipra Formula (I) is not N-(3)-1-azabicyclo[2.2.2]oct-3-yl-1-(3- 5 Zole, risperidone, olanzapine, quetiapine, Ziprasidone, or thienyl)-1H-Indazole-3-carboxamide; individual stereoiso clozapine. mers, or a pharmaceutically acceptable salt thereof. In a fifth aspect, the invention is directed to use of com In a third aspect, this present invention is directed to a pound of Formula (IA) or (I) (or any embodiments thereof method of treating a disease treatable by administration of a disclosed herein) or a pharmaceutically acceptable salt 5HT3 receptor antagonist which method comprises adminis 10 trating to the patient a pharmaceutical composition compris thereofas a medicament; provided the compound of Formula ing a compound of Formula (IA) or (I) (or any embodiments (IA) is not N-(3)-1-azabicyclo[2.2.2]oct-3-yl-6-bromo-1-(di thereof disclosed herein) and/or a pharmaceutically accept fluoromethyl)-1H-Indazole-3-carboxamide, N-(3)-1-azabi able salt and a pharmaceutically acceptable excipient pro cyclo[2.2.2]oct-3-yl-1-(difluoromethyl)-6-methoxy-1H-In vided the compound of Formula (IA) is not N-(3)-1-azabicy 15 dazole-3-carboxamide, N-(3)-1-azabicyclo[2.2.2]oct-3-yl-5- clo2.2.2]oct-3-yl-6-bromo-1-(difluoromethyl)-1H bromo-1-(2.2.2-trifluoroethyl)-1H-Indazole-3-carboxamide, Indazole-3-carboxamide, N-(3)-1-azabicyclo[2.2.2]oct-3-yl N-(3)-1-azabicyclo[2.2.2]oct-3-yl-5-methoxy-1-(2.2.2-trif 1-(difluoromethyl)-6-methoxy-1H-Indazole-3- luoroethyl)-1H-Indazole-3-carboxamide, or N-(3)-1-azabi carboxamide, N-(3)-1-azabicyclo[2.2.2]oct-3-yl-5-bromo-1- cyclo[2.2.2]oct-3-yl-1-(3-thienyl)-1H-Indazole-3-carboxa (2.2.2-trifluoroethyl)-1H-Indazole-3-carboxamide, N-(3)-1- mide or the compound of Formula (I) is not N-(3)-1- azabicyclo[2.2.2]oct-3-yl-5-methoxy-1-(2.2.2- azabicyclo[2.2.2]oct-3-yl-1-(3-thienyl)-1H-Indazole-3- trifluoroethyl)-1H-Indazole-3-carboxamide, or N-(3)-1- carboxamide; individual stereoisomers, O a azabicyclo[2.2.2]oct-3-yl-1-(3-thienyl)-1H-Indazole-3- pharmaceutically acceptable salt thereof. carboxamide or the compound of Formula (I) is not N-(3)-1- In a sixth aspect, the invention is directed to a compound of azabicyclo[2.2.2]oct-3-yl-1-(3-thienyl)-1H-Indazole-3- 25 Formula (IA) or (I) (or any embodiments thereof disclosed carboxamide. That is, In a the present invention provides a herein) or a pharmaceutically acceptable salt thereof for use method of treating a disease treatable by administration of a as medicament; provided the compound of Formula (IA) is 5HT3 receptor antagonist comprising: administrating to the not N-(3)-1-azabicyclo[2.2.2]oct-3-yl-6-bromo-1-(difluo patient in need thereof an effective amount of a compound of romethyl)-1H-Indazole-3-carboxamide, N-(3)-1-azabicyclo Formula (IA) or (I) (or any embodiments thereof disclosed 30 2.2.2]oct-3-yl-1-(difluoromethyl)-6-methoxy-1H-Indazole herein) or a pharmaceutically acceptable salt thereof pro 3-carboxamide, N-(3)-1-azabicyclo[2.2.2]oct-3-yl-5-bromo vided the compound of Formula (IA) is not N-(3)-1-azabicy 1-(2.2.2-trifluoroethyl)-1H-Indazole-3-carboxamide, N-(3)- clo2.2.2]oct-3-yl-6-bromo-1-(difluoromethyl)-1H-India 1-azabicyclo[2.2.2]oct-3-yl-5-methoxy-1-(2.2.2- Zole-3-carboxamide, N-(3)-1-azabicyclo[2.2.2]oct-3-yl-1- trifluoroethyl)-1H-Indazole-3-carboxamide, or N-(3)-1- (difluoromethyl)-6-methoxy-1H-Indazole-3-carboxamide, 35 azabicyclo[2.2.2]oct-3-yl-1-(3-thienyl)-1H-Indazole-3- N-(3)-1-azabicyclo[2.2.2]oct-3-yl-5-bromo-1-(2.2.2-trifluo carboxamide or the compound of Formula (I) is not N-(3)-1- roethyl)-1H-Indazole-3-carboxamide, N-(3)-1-azabicyclo azabicyclo[2.2.2]oct-3-yl-1-(3-thienyl)-1H-Indazole-3- 2.2.2]oct-3-yl-5-methoxy-1-(2.2.2-trifluoroethyl)-1H-India carboxamide; individual stereoisomers, O a Zole-3-carboxamide, or N-(3)-1-azabicyclo[2.2.2]oct-3-yl pharmaceutically acceptable salt thereof. 1-(3-thienyl)-1H-Indazole-3-carboxamide or the compound 40 In one embodiment of the fifth and sixth aspects, the use is of Formula (I) is not N-(3)-1-azabicyclo[2.2.2]oct-3-yl-1-(3- for the treatment of emesis, migraine, Substance abuse and thienyl)-1H-Indazole-3-carboxamide. addiction, neurodegenerative and psychiatric disorders such In one embodiment of the third aspect, the disease is eme as anxiety and depression, eating disorders, Schizophrenia, sis, migraine, Substance abuse and addiction, neurodegenera cognitive dysfunction associated with Schizophrenia, Parkin tive and psychiatric disorders such as anxiety and depression, 45 son's disease, Huntington's Chorea, presenile dementias and eating disorders, Schizophrenia, cognitive dysfunction asso Alzheimer's disease, and pain; GI disorders such as dyspep ciated with Schizophrenia, Parkinson's disease, Huntington's sia, gastroesophagal reflux disease, and irritable bowel syn Chorea, presenile dementias and Alzheimer's disease, and drome; and immunological disorders and inflammation Such pain; GI disorders such as dyspepsia, gastroesophagal reflux as atherosclerosis, tendomyopathies and fibromyalgia. In disease, and irritable bowel syndrome; and immunological 50 another embodiment of the fifth and the sixth aspects the use disorders and inflammation Such as atherosclerosis, ten is for the treatment of schizophrenia or cognitive dysfunction domyopathies and fibromyalgia. In another embodiment of associated with Schizophrenia also known as cognitive the third aspect the disease is schizophrenia or cognitive impairment associated with Schizophrenia. In yet another dysfunction associated with Schizophrenia. embodiment of the fifth and the sixth aspects, and embodi In a fourth aspect, the compound of Formula (IA) or (I) (or 55 ments contained therein, the compound of Formula (IA) or (I) any embodiments thereof disclosed herein) or a pharmaceu is administered in combination with an antipsychotic drug. In tically acceptable salt thereof is administered in combination one embodiment, the antipsychotic drug is AMG 747, bitop with an antipsychotic drug provided the compound of For ertin (RG1678), RG1578, AMG579, GSK1018921, aripipra mula (IA) is not N-(3)-1-azabicyclo[2.2.2]oct-3-yl-6-bromo Zole, risperidone, olanzapine, quetiapine, or ziprasidone, 1-(difluoromethyl)-1H-Indazole-3-carboxamide, N-(3)-1- 60 clozapine. azabicyclo[2.2.2]oct-3-yl-1-(difluoromethyl)-6-methoxy 1H-Indazole-3-carboxamide, N-(3)-1-azabicyclo[2.2.2]oct DETAILED DESCRIPTION OF THE INVENTION 3-yl-5-bromo-1-(2.2.2-trifluoroethyl)-1H-Indazole-3- carboxamide, N-(3)-1-azabicyclo[2.2.2]oct-3-yl-5- Definitions: methoxy-1-(2.2.2-trifluoroethyl)-1H-Indazole-3- 65 Unless otherwise stated, the following terms used in the carboxamide, or N-(3)-1-azabicyclo[2.2.2]oct-3-yl-1-(3- specification and claims are defined for the purposes of this thienyl)-1H-Indazole-3-carboxamide or the compound of application and have the following meaning: US 9,303,045 B2 10 "Ce alkyl means a linear Saturated monovalent hydro tively, when the prodrug is administered to a mammalian carbon radical of one to six carbon atoms or a branched subject. Release of the active ingredient occurs in vivo. Pro saturated monovalent hydrocarbon radical of three to six car drugs can be prepared by techniques known to one skilled in bon atoms, e.g., methyl, ethyl, propyl. 2-propyl, butyl (in the art. These techniques generally modify appropriate func cluding all isomeric forms), pentyl (including all isomeric tional groups in a given compound. These modified func forms), and the like. tional groups however regenerate original functional groups “Calkoxy” means a —OR radical where R is C alkyl in vivo or by routine manipulation. Prodrugs of compounds of as defined above, e.g., methoxy, ethoxy, propoxy, or 2-pro Formula (IA) and (I) include compounds wherein a hydroxy, poxy, n-, iso-, or tert-butoxy, and the like. amino, carboxylic, or a similar group is modified. Examples “C. alkylsulfonyl' means a SOR radical where R is 10 of prodrugs include, but are not limited to esters (e.g., acetate, C. alkyl as defined above, e.g., methylsulfonyl, ethylsulfo formate, and benzoate derivatives), carbamates (e.g., N.N- nyl, 2-propylsulfonyl, and the like. dimethylaminocarbonyl) of hydroxy or amino functional “Cs cycloalkyl” means a 3 to 8 membered saturated groups in compounds of Formula (IA) and (I)), amides (e.g., cyclic hydrocarbon radical e.g., cyclopropyl, cyclobutyl, trifluoroacetylamino, acetylamino, and the like), and the like. cyclopentyl, cyclohexyl, and the like. 15 Prodrugs of compounds of Formula (IA) and (I) are also “Cs cycloalkylsulfonyl' means a —SOR radical where within the scope of this invention. R is Cls cycloalkyl as defined above, e.g., cyclopropylsulfo The present invention also includes protected derivatives nyl, and the like. of compounds of Formula (IA) and (I). For example, when "Ce cyanoalkyl means C alkyl radical as defined compounds of Formula (IA) and (I) contain groups such as above where one hydrogen atoms in the alkyl radical is hydroxy, carboxy, thiol or any group containing a nitrogen replaced by cyano, e.g., cyanoethyl, cyanopropyl, and the atom(s), these groups can be protected with a Suitable pro like. tecting groups. A comprehensive list of Suitable protective "Halo' means fluoro, chloro, bromo, or iodo, preferably groups can be found in T. W. Greene, Protective Groups in fluoro or chloro. Organic Synthesis, John Wiley & Sons, Inc. (1999), the dis “Chaloalkyl means Calkyl radical as defined above, closure of which is incorporated herein by reference in its which is Substituted with one or more halogenatoms, prefer 25 entirety. The protected derivatives of compounds of Formula ably one to five halogen atoms, preferably fluorine or chlo (IA) and (I) can be prepared by methods well known in the art. rine, including those Substituted with different halogens, e.g., A "pharmaceutically acceptable salt” of a compound —CHCl, —CF, —CHF, —CHCF, CFCF, CF means a salt that is pharmaceutically acceptable and that (CH), and the like. When the C-alkyl is substituted with possesses the desired pharmacological activity of the parent only fluoro, it can be referred to in this application as C. 30 compound. Such salts include: acid addition salts, formed fluoroalkyl. with inorganic acids such as hydrochloric acid, hydrobromic "Chaloalkoxy” means a —OR radical where R is C. acid, sulfuric acid, nitric acid, phosphoric acid, and the like: haloalkyl as defined above e.g., —OCF. —OCHF, and the or formed with organic acids such as formic acid, acetic acid, like. When R is haloalkyl where the C alkyl is substituted propionic acid, hexanoic acid, cyclopentanepropionic acid, with only fluoro, it can be referred to in this application as 35 glycolic acid, pyruvic acid, lactic acid, malonic acid, Succinic C fluoroalkoxy. acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric "Ce heterocycloalkyl means a saturated or unsaturated acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cin monovalent monocyclic group of 4 to 8 ring atoms in which 1 namic acid, mandelic acid, methanesulfonic acid, ethane or 2 ring atoms are heteroatom selected from N, O, or S(O), Sulfonic acid, 1.2-ethanedisulfonic acid, 2-hydroxyethane where n is an integer from 0 to 2, the remaining ring atoms sulfonic acid, benzenesulfonic acid, being C, unless stated otherwise. More specifically the term 40 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, heterocyclyl includes, but is not limited to, pyrrolyl, piperidi 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic nyl, homopiperidinyl, morpholinyl, piperazinyl, tetrahydro acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic furanyl, tetrahydropyranyl, thiomorpholinyl, and the like. acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary When the heterocyclyl ring is unsaturated it can contain one butylacetic acid, lauryl Sulfuric acid, gluconic acid, glutamic or two ring double bonds provided that the ring is not aro 45 acid, hydroxynaphthoic acid, salicylic acid, Stearic acid, matic. muconic acid, and the like; or salts formed when an acidic "Cs heteroaryl means a monovalent monocyclic aro proton present in the parent compound either is replaced by a matic radical of 5 or 6 ring atoms where one, two, or three, metalion, e.g., an alkali metalion, an alkaline earth ion, oran ring atoms are heteroatom selected from N, O, or S, the aluminum ion; or coordinates with an organic base Such as remaining ring atoms being carbon. Representative examples 50 ethanolamine, diethanolamine, triethanolamine, include, but are not limited to, pyrrolyl, thienyl, thiazolyl, tromethamine, N-methylglucamine, and the like. It is under imidazolyl pyrazoly, furanyl, oxazolyl, isoxazolyl pyridi stood that the pharmaceutically acceptable salts are non nyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, and the toxic. Additional information on Suitable pharmaceutically like. acceptable salts can be found in Remington's Pharmaceutical "C. oxoheterocycloalkyl means a saturated or unsatur Sciences, 17th ed., Mack Publishing Company, Easton, Pa., ated monovalent monocyclic group of 4 to 8 ring atoms in 55 1985, which is incorporated herein by reference. which 1 or 2 ring atoms are heteroatom selected from N, O, or The compounds of the present invention may have asym S(O), where n is an integer from 0 to 2, and 1 or 2 rings atoms metric centers. Compounds of the present invention contain are —C(O)—, the remaining ring atoms being C, unless ing an asymmetrically substituted atom may be isolated in stated otherwise. More specifically the term heterocyclyl optically active or racemic forms. It is well known in the art includes, but is not limited to, 2-oxo-1,2-dihydropyridinyl, 60 how to prepare optically active forms, such as by resolution of and the like. When the heterocyclyl ring is unsaturated it can materials. All chiral, diastereomeric, meso, racemic forms are contain 1 or 2 ring double bonds provided that the ring is not within the scope of this invention, unless the specific Stere aromatic. ochemistry or isomeric form is specifically indicated. The present invention also includes the prodrugs of com Additionally, as used herein the term C alkyl and terms pounds of Formula (IA) and (I). The term prodrug is intended 65 derived therefrom includes all the possible isomeric forms of to represent covalently bonded carriers, which are capable of said C. alkyl group. Furthermore, the cyclic groups such as releasing the active ingredient of Formula (IA) and (I) respec aryl, heteroaryl, C. heterocycloalkyl include all the posi US 9,303,045 B2 11 12 tional isomers. Furthermore, all polymorphic forms and (2) inhibiting the disease, i.e., arresting, controlling, slow hydrates of a compound of Formula (IA) and Formula (I) are ing, stopping, or reducing the development of the disease or its clinical symptoms; or within the scope of this invention. (3) relieving the disease, i.e., causing regression of the The terms “compound' and “a compound of the invention” disease or its clinical symptoms or improvement of the dis and “compound of the present invention' and the like, and ease or its clinical symptoms their plural expressions include the embodiment of Formula The terms “treat,” “treating, and “treatment.” do not nec (IA) and Formula (I) and the other more particular embodi essarily indicate a total elimination of any or all symptoms or ments encompassed by Formula (IA) and Formula (I) a cure of the disease. described herein and exemplified compounds described As used herein the terms “patient' and “subject' includes herein and a pharmaceutically acceptable salt of each of these 10 humans and non-human animals, for example, mammals, embodiments. All references to compounds, include all iso such as mice, rats, guinea pigs, dogs, cats, rabbits, cows, topes of the atoms contained therein, including isotopically horses, sheep, goats, and pigs. The term also includes birds, labeled compounds. fish, reptiles, amphibians, and the like. It is understood that a The compounds of the present invention exist as tautomers. more particular patient is a human. Also, more particular All tautomeric forms the compounds of the invention are 15 patients and subjects are non-human mammals, such as mice, contemplated to be within the scope of the present invention. rats, and dogs. “Optional” or “optionally” means that the subsequently A “therapeutically effective amount” means the amount of described event or circumstance may but need not occur, and a compound of Formula (I) or Formula (IA) or a pharmaceu that the description includes instances where the event or tically acceptable salt thereof that, when administered in circumstance occurs and instances in which it does not. For single or multiple doses, to a mammal for treating a disease, example, "Cheterocycloalkyl group optionally substituted is sufficient to effect such treatment for the disease. The with an C. alkyl group” means that the alkyl may but need “therapeutically effective amount” will vary depending on not be present, and the description includes situations where the compound, the disease and its severity and the age, the heterocycloalkyl group is substituted with an alkyl group weight, etc., of the mammal to be treated, the degree of or and situations where the heterocycloalkyl group is not sub involvement or the severity of the condition, disorder, or stituted with alkyl. 25 disease, the response of the individual patient; the particular A “pharmaceutically acceptable carrier or excipient compound administered; the mode of administration; the bio means a carrier or an excipient that is useful in preparing a availability characteristics of the preparation administered; pharmaceutical composition that is generally safe, non-toxic the dose regimen selected; the use of concomitant medica and neither biologically nor otherwise undesirable, and tion; and other relevant circumstances. includes a carrier or an excipient that is acceptable for Veteri 30 The term “disease treatable by administration of a 5HT3 nary use as well as human pharmaceutical use. A pharma receptor antagonist” includes emesis, migraine, Substance ceutically acceptable carrier/excipient” as used in the speci abuse and addiction, neurodegenerative and psychiatric dis fication and claims includes both one and more than one such orders such as anxiety and depression, eating disorders, excipient. Pharmaceutically acceptable excipients are well schizophrenia, cognitive dysfunction associated with schizo known in the art, such as those in Remington's Pharmaceu 35 phrenia, Parkinson's disease, Huntington's Chorea, presenile tical Sciences, 17th ed., Mack Publishing Company, Easton, dementias and Alzheimer's disease, and pain; GI disorders Pa., 1985. such as dyspepsia, gastroesophagal reflux disease, and irri The terms “condition.” “disorder and “disease' relate to table bowel syndrome; and immunological disorders and any unhealthy or abnormal state. inflammation such as atherosclerosis, tendomyopathies and “Treat,” “treating,” or “treatment” of a disease includes: fibromyalgia. In a particular embodiment the disease is cog (1) preventing the disease, i.e. causing the clinical symp 40 nitive dysfunction associated with schizophrenia also known toms of the disease not to develop in a mammal that may be as cognitive impairment associated with schizophrenia. exposed to or predisposed to the disease but does not yet Representative compounds of the Invention are shown in experience or display symptoms of the disease; Table I below:

O

x1's--\X4 | Xs X22X NN Cpd. \ MS Obs. No. R4 Salt Name MW Calcd. (M + 1)"

TFA (1R,3R,5S)-8-methyl-8- 384.3679 385.2 azabicyclo3.2.1]octan 3-yl 5-fluoro-1-(2,2,2- N trifluoroethyl)-1H indole-3-carboxylate; 2.2.2-trifluoroacetate

CF

US 9,303,045 B2 77 78 -continued

O

x1's--\X4 Xs X2 Yx2 N Cpd. \ MS Obs. No. R4 —Z R' Salt Name MW Calcd. (M + 1)" 188 O 378.42 379.30 azabicyclo3.3.1 nonan

1H-indole-3- (d * 4 / carboxylate

189 O TFA (1R,5S,7S)-9-methyl-3- 378.42 379.30 oxa-9- azabicyclo3.3.1 nonan 7-yl 1-(pyrimidin-5-yl)- 1H-indole-3- carboxylate

190 O / N methyl-3-Oxa-9- azabicyclo3.3.1 nonan 7-yl)-1-(pyridazin-4- yl)-1H-indole-3- carboxamide N w 4 e

NN-N 4

45 Embodiments Summary is where R is heteroaryl selected from the group Compounds of Formula (I) consisting of furanyl, pyrrolyl, imidazolyl, oxazolyl, isox Embodiment (A) azolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tria In one embodiment, the compound of Formula (I) or a Zolyl, tetrazolyl pyrazinyl, pyridazinyl, and pyrimidyll; each pharmaceutically acceptable salt thereof, as defined in the 50 optionally substituted with one or two substituents indepen Summary is where R is heteroaryl selected from the group consisting of furanyl, pyrrolyl, imidazolyl, oxazolyl, isox dently selected from C alkyl, Ce haloalkyl, C. azolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tria haloalkoxy, Calkoxy, hydroxy, cyano, or halo. Zolyl, tetrazolyl pyrazinyl, pyridazinyl, pyrimidyl, azepinyl, Embodiment (C) diazepinyl, quinolyl, isoquinolyl, quinolizidine, benzofura 55 In another embodiment, the compound of Formula (I) or a nyl, benzothienyl, indolyl, isoindolyl, indazolyl, benzimida pharmaceutically acceptable salt thereof as defined in the Zolyl, benzisothiazolyl, benzisoxazolyl, benzoxadiazolyl, Summary is where R is heteroaryl selected from the group benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotria consisting of quinolyl, isoquinolyl, quinolizidine, benzofura Zolyl, benzopyrazinyl, benzopyrazidinyl, benzoazepinyl, nyl, benzothienyl, indolyl, isoindolyl, indazolyl, benzimida benzodiazepinyl, imidazopyridyl, pyrazolopyridyl, pyrrol 60 Zolyl, benzisothiazolyl, benzisoxazolyl, benzoxadiazolyl, opyridyl, quinazolyl, purinyl, furopyridyl, and thienopyridyl; benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotria each optionally substituted with one or two substituents inde Zolyl, benzopyrazinyl, benzopyrazidinyl, benzoazepinyl, pendently selected from C alkyl, C. haloalkyl, C benzodiazepinyl, imidazopyridyl, pyrazolopyridyl, pyrrol haloalkoxy, Calkoxy, hydroxy, cyano, or halo. opyridyl, quinazolyl, purinyl, furopyridyl, and thienopyridyl; Embodiment (B) 65 each optionally substituted with one or two substituents inde In another embodiment, the compound of Formula (I) or a pendently selected from C alkyl, Ce haloalkyl, C. pharmaceutically acceptable salt thereof as defined in the haloalkoxy, Calkoxy, hydroxy, cyano, or halo. US 9,303,045 B2 79 80 Embodiment (D) -continued In another embodiment, the compound of Formula (I) or a (d) pharmaceutically acceptable salt thereof as defined in the R2 Summary is where R is pyrimidinyl, pyridazinyl, isothiaz olyl, thiazolyl, oxazolyl, isoxazolyl, or furanyl; each option ally substituted with one or two substituents independently selected from Calkyl, Chaloalkyl, Chaloalkoxy, C. alkoxy, or halo. Within this embodiment, in another group of compounds, 10 Ra is heteroaryl oxazolyl optionally substituted with one or two substituents independently selected from C alkyl, C. (e) haloalkyl, Ce haloalkoxy, Ce alkoxy, hydroxy, cyano, or halo. Within this embodiment, in another group of compounds 15 R is pyrimidinyl optionally substituted with one or two sub stituents independently selected from C alkyl, C. haloalkyl, Chaloalkoxy, cyano, Calkoxy, or halo. Within this embodiment, in another group of compounds Ra is pyridazinyl optionally substituted with one or two sub stituent(s), preferably one Substituent, independently (f) selected from methyl, ethyl, isopropyl, difluoromethyl, 2-fluoroethyl, trifluoromethyl, cyano, or fluoro. Within this embodiment, in another group of compounds 25 Rathiazolyl optionally substituted with one or two substitu ents independently selected from C alkyl, Chaloalkyl, Chaloalkoxy, cyano, Calkoxy, or halo. (g) Within this embodiment, in another group of compounds R is pyrimidin-2-yl, pyridazin-3-yl, 6-fluoropyridazin-3-yl, 30 pyrazin-2-yl, thiazol-2-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, 1-methyl-1H-imidazol-5-yl, oxazol-2-yl, or pyrimidin-5-yl.

Embodiment (E) 35 In one embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt thereof as defined in the (a) Within groups in embodiment (G), in one group of Summary and embodiments (A), (B), (C), and (D) above and compounds R is a ring of formula (a) or (d). Within (a), in one embodiments contained therein, is where Z is O. embodiment, R is a ring of formula Embodiment (F) 40 In one embodiment, the compound of Formula (I) or a I pharmaceutically acceptable salt thereof as defined in the Summary and embodiments (A), (B), (C), and (D) above and embodiments contained therein, is where Z is NR. Within Xi XA. this embodiment, in another group of compounds R is hydro 45 gen. Within this embodiment, in another group of compounds A 7 R is methyl. Embodiment (G) In one embodiment within embodiment G, the compound 50 of Formula (I) or a pharmaceutically acceptable salt thereofas (b) Within groups in embodiment (G), in another group of defined in the Summary and embodiments (A), (B), (C), (D), compounds R is a ring of formula (e), (f) or (g). Within (b). (E), and (F) above and embodiments contained therein, is in one group of compounds R is a ring of formula (e). Within where R is a ring of formula (b), in one group of compounds R is a ring of formula (f) or 55 (g). Within (b), in one group of compounds R is a ring of formula (a)

60

65 US 9,303,045 B2 81 82 (i) Within groups in embodiment (G) and embodiments embodiment, in one group of compounds the stereochemistry contained therein i.e., (a) and (b) and groups contained at the chiral carbon is (R) or (S). therein, in one group of compounds each R is independently (b1) Within groups in embodiment (H), in one group of hydrogen or methyl. Within these groups of compounds in compounds R' is a ring of formula (b). one group of compounds each R is hydrogen. (vi) Within groups in embodiment (H) and embodiments (ii)Within groups in embodiment (G) and embodiments contained therein i.e., (al) and (b1) and groups contained contained therein i.e., (a) and (b) and groups contained therein, in one group of compounds each R is independently therein, in one group of compounds each R is independently hydrogen or methyl. Within these groups of compounds in hydrogen or methyl and R is hydrogen. Within these groups one group of compounds each R is hydrogen. of compounds in one group of compounds R2 is hydrogen and 10 Embodiment I In another embodiment, the compound of Formula (I) or a each R is hydrogen. pharmaceutically acceptable salt thereof as defined in the (iii) Within groups in embodiment (G) and embodiments Summary and embodiments (A), (B), (C), (D), (E), (F), (G), contained therein i.e., (a) and (b) and groups contained and (H) above and groups contained therein, in one group of therein, in one group of compounds each R is independently 15 compounds, each of X, X2, X, and X is CRs and X is Nor hydrogen or methyl and R is C alkyl. Within these groups CR. Within this embodiment, in another group of com of compounds in one group of compounds R2 is methyl, ethyl, pounds each Rs is hydrogen. or propyl and each R is hydrogen. Within these groups of (c1) Within the groups in embodiment I, in one group of compounds in one group of compounds R is methyl and each compounds, Xs is N. R is hydrogen. (d1) Within the groups in embodiment I, in another group (iv) Within groups in embodiment (G) and embodiments of compounds X is CR. Within these groups of compounds, contained therein i.e., (a) and (b) and groups contained in one group of compounds X is CR and R is hydrogen. therein, in one group of compounds each R is independently Within the groups in embodiment I, in another group of hydrogen or methyl and R is Chaloalkyl. Within these compounds one of Rs is fluoro, or cyano. Within this group of groups of compounds in one group of compounds each R is 25 compounds, in another group the Rs cyano is located at C-5 trifluoromethyl 2-fluoroethyl, or 2.2.2-trifluoroethyl and position, the nitrogenatom Substituted with Rabeing position each R is hydrogen. Within these groups of compounds in 1. Within this group of compounds, in another group of com one group of compounds R2 is trifluoromethyl and each R is pounds in another group the Rs fluoro is located at C-5 posi hydrogen. tion, the nitrogen atom substituted with R' being position 1. 30 Embodiment J (v) Within groups in embodiment (G) and embodiments In another embodiment, the compound of Formula (I) or a contained therein i.e., (a) and (b) and groups contained pharmaceutically acceptable salt thereof as defined in the therein, in one group of compounds each R is independently Summary and embodiments (A), (B), (C), (D), (E), (F), and hydrogen or methyl. (G), and (H) above and groups is where one of X, X2, X, or Embodiment (H) 35 X is N and X is N or CR. Within these groups of com In another embodiment, the compound of Formula (I) or a pounds in one group of compounds X is N. pharmaceutically acceptable salt thereof as defined in the (el) Within the groups in embodiment J, in one group of Summary and embodiments (A), (B), (C), (D), (E), and (F) compounds X is N. above and embodiments contained therein, is where R is a (f1) Within the groups in embodiment J, in another group ring of formula 40 of compounds X is CR and R is hydrogen. Within the groups in embodiment J, in one group of com pounds each Rs is hydrogen. (b) Within the groups in embodiment J, (e1) and (f1), in another group of compounds one of Rs is fluoro, or cyano. 45 Within this group of compounds, in another group the Rs cyano is located at C-5 position, the nitrogenatom Substituted with Ra being position 1. Within this group of compounds, in another group of compounds in another group the Rs fluoro is located at C-5 position, the nitrogenatom substituted with R. (c) 50 being position 1. Embodiment K In another embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt thereof as defined in the Summary and embodiments (E), (F), (G), and (H) above and 55 groups contained therein, in one group of compounds each of X-X is CRs or one of X-X is N and X is CR where R. (h) together with R forms —O-(CH2) - or —O-(CH2). (g1) Within the groups in embodiment K, in one group of compounds each X-X is CRs. 60 (h1) Within the groups in embodiment I, in another group of compounds one of X-X is N. Within the groups in embodiment K, (g1) and (h1), in one group of compounds each Rs is hydrogen. Within these groups of compounds, in one group of com 65 pounds X is N. (a1) Within groups in embodiment (H), in one group of Within the groups in embodiment K, (g1) and (h1), in compounds R is a ring of formula (c) or (h). Within this another group of compounds one of Rs is fluoro, or cyano. US 9,303,045 B2 83 84 Within this group of compounds, in another group the Rs one, two, or three substituents independently selected from cyano is located at C-5 position, the nitrogenatom Substituted C. alkyl, C. haloalkyl, Ce haloalkoxy, C alkoxy, with Rabeing position 1. Within this group of compounds, in hydroxyl, cyano, or halo. Within this embodiment, in one another group of compounds in another group the Rs fluoro is group of compounds R is phenyl optionally substituted with located at C-5 position, the nitrogenatom substituted with R. one, two, or three substituents independently selected from being position 1. Compounds of Formula (IA): methyl, cyano, fluoro, chloro, hydroxyl, trifluoromethoxy or Embodiment (A1) cyano. In one embodiment, the compound of Formula (IA) or a Embodiment (H1) pharmaceutically acceptable salt thereof, as defined in the In one embodiment, the compound of Formula (IA) or a Summary is where R is Chaloalkyl. Within this embodi 10 pharmaceutically acceptable salt thereof as defined in the ment, in another group of compounds R is 2.2.2-trifluoroet Summary and embodiments (A1), (B1), (C1), (D1), (E1), hyl, 2,2-difluoroethyl 2-fluoroethyl, 1.2.2.2-tetrafluoroethyl, (F1), and (G1) above and embodiments contained therein, is 1.1.2.2.-tetrafluoroethyl, 1,1,1-trifluoro-2-methylpropan-2- where Z is O. yl, (R)-1.2.2.2-tetrafluoroethyl, (S)-1.2.2.2-tetrafluoroethyl, Embodiment (I1) or 2,2-difluoropropyl. Within this embodiment, in another 15 In one embodiment, the compound of Formula (IA) or a group of compounds R is 2,2-difluoroethyl. Within this pharmaceutically acceptable salt thereof as defined in the embodiment, in another group of compounds R is 2.2.2- Summary and embodiments (A1), (B1), (C1), (D1), (E1), trifluoroethyl. (F1), and (G1) above and embodiments contained therein, is Embodiment (B1) where Z is NR. Within this embodiment, in another group of In another embodiment, the compound of Formula (IA) or compounds R is hydrogen. Within this embodiment, in a pharmaceutically acceptable Salt thereofas defined in the another group of compounds R is methyl. Summary is where R is Calkylsulfonyl or Cs cycloalkyl Embodiment (J1) sulfonyl. Within this embodiment, in one group of com In one embodiment within embodiment J1, the compound pounds R is C alkylsulfonyl, preferably methylsulfonyl, of Formula (IA) or a pharmaceutically acceptable salt thereof ethylsulfonyl, or isopropylsulfonyl. Within this embodiment, 25 as defined in the Summary and embodiments (A1), (B1), in another group of compounds R is methylsulfonyl. Within (C1), (D1), (E1), (F1), (G1), and (H1) above and embodi this embodiment, in another group of compounds R is iso ments contained therein, is where R' is as disclosed in propylsulfonyl. Within this embodiment, in another group of Embodiment G and groups (a), (b), and (i)-(V) above. compounds R is Cls cycloalkylsulfonyl. Embodiment (K1) Embodiment (C1) 30 In one embodiment within embodiment K1, the compound In another embodiment, the compound of Formula (IA) or of Formula (IA) or a pharmaceutically acceptable salt thereof a pharmaceutically acceptable salt thereofas defined in the as defined in the Summary and embodiments (A1), (B1), Summary is where R is C. heterocycloalkyl optionally (C1), (D1), (E1), (F1), (G1), and (H1) above and embodi substituted with one or two substituents independently ments contained therein, is where R is as disclosed in Selected from C alkyl, Calkoxy, Chaloalkoxy, C. 35 Embodiment H and groups (al), (b1), and (vi) above, includ alkylsulfonyl, or halo. Within this embodiment, in one group ing groups contained therein. of compounds R is tetrahydrofuranyl, pyrrolidinyl, aZetidi Embodiment (L1) nyl, or piperidinyl. Within this embodiment, in one group of In one embodiment within embodiment J1, the compound compounds Ra is RS, R, or Stetrahydrofuran-3-yl. of Formula (IA) or a pharmaceutically acceptable salt thereof Embodiment (D1) 40 as defined in the Summary and embodiments (A1), (B1), In another embodiment, the compound of Formula (IA) or (C1), (D1), (E1), (F1), (G1) (H1), (I1), (J1), and (K1) above a pharmaceutically acceptable Salt thereofas defined in the and embodiments contained therein, X-X and Xs are as Summary is where R is C. oxoheterocycloalkyl optionally disclosed in Embodiment I and groups (e1), (d1) and groups substituted with one or two substituents independently contained therein above, including groups contained therein. Selected from C- alkyl, C. alkoxy, Chaloalkoxy, C. 45 Embodiment (M1) alkylsulfonyl, or halo. In one embodiment within embodiment M1, the compound Embodiment (E1) of Formula (IA) or a pharmaceutically acceptable salt thereof In another embodiment, the compound of Formula (IA) or as defined in the Summary and embodiments (A1), (B1), a pharmaceutically acceptable Salt thereofas defined in the (C1), (D1), (E1), (F1), (G1) (H1), (I1), (J1) and (K1) above Summary is where R is C. cyanoalkyl. Within this embodi 50 and embodiments contained therein, X-X and Xs are as in ment, in one group of compounds R is cyanomethyl or 2-cya Embodiment J and groups (el), (fl) including groups con noethyl. tained therein above. Embodiment (F1) Embodiment (N1) In another embodiment, the compound of Formula (IA) or In one embodiment within embodiment M1, the compound a pharmaceutically acceptable Salt thereofas defined in the 55 of Formula (IA) or a pharmaceutically acceptable salt thereof Summary is where R is Coxoheterocycloalkyl optionally as defined in the Summary and embodiments (A1), (B1), substituted with one or two substituents independently (C1), (D1), (E1), (F1), (G1) (H1), (I1), (J1) and (K1) above Selected from C- alkyl, C. alkoxy, Chaloalkoxy, C. and embodiments contained therein, X-X and Xs are as alkylsulfonyl, or halo. disclosed in Embodiment K and groups (f1), (h1) including Within this embodiment, in one group of compounds R is 60 groups contained therein above. 1-methyl-2-oxo-1,2-dihydropyridin-4-yl, 1-methyl-2-oxo-1, General Synthetic Scheme 2-dihydropyridin-5-yl, or 1-methyl-2-oxo-1,2-dihydropyri Compounds of this invention can be made by the methods din-6-yl. depicted in the reaction schemes shown below and other Embodiment (G1) methods known in the art. In another embodiment, the compound of Formula (IA) or 65 The starting materials and reagents used in preparing these a pharmaceutically acceptable Salt thereofas defined in the compounds are either available from commercial Suppliers Summary is where R is phenyl optionally substituted with such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem US 9,303,045 B2 85 86 (Torrance, Calif.), or Sigma (St. Louis, Mo.) or are prepared cycloalkysulfonyl halide in the presence of a suitable based by methods known to those skilled in the art following pro Such as triethylamine, pyridine, and the like, in a Suitable cedures set forth in references such as Fieser and Fieser's organic solvent such as THF, DMF, and the like. When R is Reagents for Organic Synthesis, Volumes 1-17 (John Wiley heteroaryl, the C N bond can either be formed by reacting and Sons, 1991); Rodd's Chemistry of Carbon Compounds, heteroaryl halide with a compound of formula 1 by displace Volumes 1-5 and Supplementals (Elsevier Science Publish ment of halide or by reacting heteroarylboronic acid with ers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and compound 1 under Chan-Lam coupling conditions. Com Sons, 1991), March's Advanced Organic Chemistry, (John pounds of formula 1, RLG, wherein LG is a leaving group Wiley and Sons, 4th Edition) and Larock's Comprehensive such as sulfonate or halo, and RB(OH), or ester thereof, are Organic Transformations (VCHPublishers Inc., 1989). These 10 either commercially available or they can be prepared by schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various methods well known in the art. For example 5-fluoro-2-me modifications to these schemes can be made and will be thylindole-3-carboxylic acid ethyl ester, 4.5-difluoro-2-me Suggested to one skilled in the art having referred to this thylindole-3-carboxylic acid ethyl ester, 1H-indole-3-car disclosure. The starting materials and the intermediates, and 15 boxylic acid, 5-methoxy-, methyl ester, 5-fluoro-1H-indole the final products of the reaction may be isolated and purified 3-carboxylic acid methyl ester, ethyl 5-methyl-1H-indole-3- if desired using conventional techniques, including but not carboxylate, 4,5-difluoro-2-methylindole-3-carboxylic acid limited to filtration, distillation, crystallization, chromatog ethyl ester, 5-cyano-2-methyl-1H-indole-3-carboxylic acid raphy and the like. Such materials may be characterized using methyl ester, 1H-indazole-3-carboxylic acid, 5-cyano-6- conventional means, including physical constants and spec fluoro-, methyl ester, 1H-indazole-3-carboxylic acid, 5-cy tral data. ano-, methyl ester, 1H-indazole-3-carboxylic acid, 5-meth Unless specified to the contrary, the reactions described oxy-, ethyl ester, 1H-indazole-3-carboxylic acid, 5-methyl-, herein take place at atmospheric pressure over a temperature ethyl ester, 1H-indazole-3-carboxylic acid, 5-fluoro-, ethyl range from about -78°C. to about 150° C., more preferably ester, 1H-pyrazolo 3,4-bipyridine-3-carboxylic acid, from about 0°C. to about 12°C. and most preferably at about 25 5-fluoro-, methyl ester, 1 H-pyrrolo2,3-bipyridine-3-car room (or ambient) temperature, e.g., about 20° C. boxylic acid, 5-methyl-, methyl ester, 1H-pyrrolo2,3-bpy Compounds of Formula (I) can be prepared as illustrated ridine-3-carboxylic acid, 5-fluoro-, methyl ester, CHI, meth and described in Scheme A below. ylsulfonyl chloride, ethylsulfonyl chloride, isopropylsulfonyl

Scheme A R O O OH OR "\ld x:1 s N ROH f X's \ 2. Saponification Xs X2 NaNN Xs X2 2 N^ 2n-2X N X V 1 R4 R4 (I)

R O I NRa

N Xs N V R4

55 Step 1 involves formation of the C N bond between R. chloride, cyclopropylsulfonyl chloride, 2-bromo-2,2,2-trif and N-1 nitrogen of the compound of formula 1 where R is an luoroethane, and 2-bromo-2,2-difluoroethane are commer acid protecting group Such as C. alkyl. The reaction condi cially available. tions utilized is based on the nature of the Ra group. When R. Hydrolysis of the ester group under basic aqueous condi is Chaloalkyl the reaction is carried out by heating com 60 tions provides the corresponding compound of formula 2. pound 1 with an C- alkyl halide respectively or C. alkyl Compound 2 is then converted to a compound of Formula (I) mesylate under standard alkylation reaction conditions e.g., where Z is NR, or O or nitrogen protected derivative thereof, in the presence of a base Such as potassium carbonate, cesium by forming an activated acid derivative of compound 2, fol carbonate, and the like, in a suitable organic solvent Such as lowed by reaction with RRNH or ROH where R is as DMF, and the like. When R is C alkylsulfonyl or Cs 65 defined in the Summary or nitrogen protected derivative cycloalkylsulfonyl, the reaction is carried out by reacting thereof. For example, the activated acid derivative can be compound 1 with Ce alkylsulfonyl halide or Cs mixed anhydride such as with a mixture of TFAA and TFA in US 9,303,045 B2 87 88 toluene or CDI or Boc-O; or acid halide such as with oxalyl immunological and inflammatory diseases like atherosclero chloride, thionyl chloride; or under standard using standard sis, tendomyopathies and fibromyalgia. peptide coupling reagents such as HATU in the presence of a base Such as N,N-diisopropylethylamine, and a solvent. Such Testing as DMF and the like. When nitrogen protected derivative of 5 R. RanH or ROH are used, removal of the protecting group The 5HT3 inhibitory activity of the compounds of the provides the compound of Formula (I). Amines and alcohols present invention can be tested using the in vitro assay and in of formula RRNH or ROH or nitrogen protected derivative vivo assay described in Biological Example 1 and 2 below. thereof are either commercially available or they can be pre Administration and Pharmaceutical Composition 10 In general, the compounds of this invention will be admin pared by methods known in the art e.g., (1S,5R,6S)-4-Oxa-1- istered in a therapeutically effective amount by any of the azabicyclo[3.3.1 nonan-6-ol can be prepared as described in accepted modes of administration for agents that serve simi Journal of Medicinal Chemistry, 1993, 36,683-689. lar utilities. Therapeutically effective amounts of compounds Alternatively, compound of Formula I can be synthesized of Formula (I) may range from about 0.01 to about 75 mg per by first coupling the acid derivative of compound 1 (R is H) 15 kg patient body weight per day, which can be administered in with RRNH or ROH as described above, followed by single or multiple doses. Preferably, the dosage level will be formation of N C bond as described in Step 1 of Scheme A about 0.01 to about 10 mg/kg per day; more preferably about above. 0.5 to about 5 mg/kg per day or 0.1-2 mg/kg/day. For oral Detailed descriptions of synthesis of compounds of For administration, the compositions are preferably provided in mula (I) via above procedures are provided in Working the form of tablets containing about 0.5 to about 200 milli Examples below. grams of the active ingredient, from about 0.5, 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, or 200 milligrams of the active Utility ingredient. The actual amount of the compound of this inven tion, i.e., the active ingredient, will depend upon numerous 5HT3 receptors are known to be expressed in the central 25 factors such as the severity of the disease to be treated, the age nervous system in regions involving Vomiting reflex, process and relative health of the subject, the potency of the com ing of pain, cognition and anxiety control and play a role in pound utilized, the route and form of administration, and the pathogenesis of diseases Such as emesis, migraine, drug other factors. Although these dosages are based on an average addiction, and neurodegenerative and psychiatric disorders human Subject having a mass of about 60 kg to about 70 kg, such as anxiety and depression (see Hewlett et al., 2003 J. 30 the physician will be able to determine the appropriate dose Clin. Psychiatry 64, 1025-1030; Kelley et al., 2003a, Eur J. for a patient (e.g., an infant) whose mass falls outside of this Pharmacol., 461, 19-25; Haus et al., 2000 Scand.J Rheumatol weight range. Suppl 113, 55-58; and Faris et al., 2006J affect Disorder 92, In general, compounds of this invention will be adminis 79-90), eating disorders (Hammer et al., 1990 Am J Physiol tered as pharmaceutical compositions by any one of the fol 35 lowing routes: oral, systemic (e.g., transdermal, intranasal or 259, R627-R636, and Jiang & Gietzen 1994 Pharmacol Bio by Suppository), or parenteral (e.g., intramuscular, intrave chem Behav 47, 59-63), schizophrenia (see Hermann et al. nous or Subcutaneous) administration. The preferred manner 1996 Biochem Biophy's Res Commun 225,957-960; Sirota et of administration is oral using a convenient daily dosage al., 2000 Am J Psychiatry 157,287-289; Adleret al., 2005 Am regimen, which can be adjusted according to the degree of J Psychiatry 162,386-388: Koike et al., Levkovitz et al., 2005 40 affliction. Compositions can take the form of tablets, pills, Schizophr Res 76, 67-72), cognitive dysfunction associated capsules, semisolids, powders, Sustained release formula with schizophrenia (see Zhang et al., 2006 Schizophr Res 88. tions, Solutions, Suspensions, elixirs, aerosols, or any other 102-110; Akhondzadeh et al., 2009 Schizophr Res 107, 206 appropriate compositions. 212), cognitive dysfunction associated with Parkinson's dis The choice of formulation depends on various factors such ease, Huntington's Chorea, presenile dementias and Alzhe 45 as the mode of drug administration (e.g., for oral administra imer's disease (see Costall and Naylor 2004 CNS Neurol tion, formulations in the form of tablets, pills or capsules are Disord 3, 27-37) substance abuse and addiction (see Johnson preferred) and the bioavailability of the drug substance. et al., 2002 Psycho-pharmacology (Berl) 160, 408-413; Recently, pharmaceutical formulations have been developed Johnson, 2004 CNS Drugs 18, 1105-1118; Dawes et al., 2005 especially for drugs that show poor bioavailability based Addict Behav 30, 1630-1637, Johnson 2006 Drug Alcohol 50 upon the principle that bioavailability can be increased by Depend 84, 256-263), and pain (see Kayser et al., 2007 Pain increasing the Surface area i.e., decreasing particle size. For 130, 235; Glaum et al., 1998 Neurosci Lett 95, 313-317; example, U.S. Pat. No. 4,107.288 describes a pharmaceutical Schworer & Ramadori 1993 Clin Investig 71,659; Thompson formulation having particles in the size range from 10 to and Lummis 2007 Exp Opin Ther Targets, 11, 527-540). In 1,000 nm in which the active material is supported on a addition, 5HT3 receptors are expressed in the GI tract and 55 crosslinked matrix of macromolecules. U.S. Pat. No. 5,145, hence may play a role in GI disorders such as dyspepsia, 684 describes the production of a pharmaceutical formulation gastroesophagal reflux disease and irritable bowel syndrome in which the drug Substance is pulverized to nanoparticles (see Graeff 1997 Psychiatr Clin North Am 20, 723: Thomp (average particle size of 400 nm) in the presence of a Surface son and Lummis 2007 Exp Opin Ther Targets, 11, 527-540: modifier and then dispersed in a liquid medium to give a Barnes et al. 2009 Neuropharmacology 56, 273). Expression 60 pharmaceutical formulation that exhibits remarkably high of the 5HT3A subsunit has also been discovered extraneu bioavailability. ronally in immune cells such as monocyes, chondrocytes, The compositions are comprised of in general, a compound T-cells, synovial tissue and platelets (Fiebichet al., 2004 Scan of formula (I) in combination with at least one pharmaceuti J Rheumatol Suppl. 9-11, Stratz et al., 2008 Thromb Haemost cally acceptable excipient. Acceptable excipients are non 99,784) and of 5HT3A, C-E within the lamina propia in the 65 toxic in the amount used, aid administration, and do not epithelium of the gut mucose (Kapeller et al., J. Comp Neuro., adversely affect the therapeutic benefit of the compound of 2008: 509: 356-371) thus suggesting they may be involved in formula (I). Such excipient may be any Solid, liquid, semi US 9,303,045 B2 89 90 Solidor, in the case of anaerosol composition, gaseous excipi agents, beta-secretase inhibitors, gamma-secretase inhibi ent that is generally available to one of skill in the art. tors, HMG-CoA reductase inhibitors, NSAID’s including Solid pharmaceutical excipients include starch, cellulose, ibuprofen, vitamin E, and anti-amyloid antibodies. In another talc, glucose, lactose, Sucrose, gelatin, malt, rice, flour, chalk, embodiment, the compound of the present invention may be silica gel, magnesium Stearate, Sodium Stearate, glycerol 5 administered in combination with sedatives, hypnotics, anxi monostearate, sodium chloride, dried skim milk and the like. olytics, antipsychotics, antianxiety agents, cyclopyrrolones, Liquid and semisolid excipients may be selected from glyc imidazopyridines, pyrazolopyrimidines, minor tranquilizers, erol, propylene glycol, water, ethanol and various oils, includ melatonin agonists and antagonists, melationergic agents, ing those of petroleum, animal, vegetable or synthetic origin, benzodiazepines, barbiturates, mGlu2/3 agonists, 5HT2 e.g., peanut oil, soybean oil, mineral oil, Sesame oil, etc. 10 antagonists, PDE10 antagonists, GlyT1 inhibitors, and the Preferred liquid carriers, particularly for injectable solutions, like. Such as: adinazolam, allobarbital, alonimid, alprazolam, include water, Saline, aqueous dextrose, and glycols. amisulpride, amitriptyline, amobarbital, amoxapine, arip Compressed gases may be used to disperse a compound of iprazole, bentazepam, benzoctamine, brotizolam, bupropion, this invention in aerosol form. Inert gases Suitable for this buspirione, butabarbital, butalbital, capuride, carbocloral, purpose are nitrogen, carbon dioxide, etc. 15 chloral betaine, chloral hydrate, clomipramine, clonazepam, Other suitable pharmaceutical excipients and their formu cloperidone, cloraZepate, chlordiazepoxide, clorethate, chlo lations are described in Remington’s Pharmaceutical Sci rpromazine, clozapine, cyprazepam, desipramine, dex ences, edited by E. W. Martin (Mack Publishing Company, clamol, diazepam, dichloralphenaZone, divalproex, diphen 18th ed., 1990). hydramine, doxepin, estazolam, ethchlorVynol, etomidate, The level of the compound in a formulation can vary within fenobam, flunitrazepam, flupentixol, fluphenazine, flu the full range employed by those skilled in the art. Typically, razepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, the formulation will contain, on a weight percent (wt %) halazepam, haloperidol, hydroxy Zine, imipramine, lithium, basis, from about 0.01-99.99 wt % of a compound of formula loraZopam, lormetazepam, maprotiline, mecloqualone, mela (I) based on the total formulation, with the balance being one tonin, mephobarbital, meprobamate, methaqualone, or more suitable pharmaceutical excipients. Preferably, the midaflur, midazolam, nefazodone, nisobamate, nitraZopam, compound is present at a level of about 1-80 wt %. 25 nortriptyline, olanzapine, oxazepam, paraldehyde, paroxet The compounds of the present invention may be used in ine, pentobarbital, perlapine, perphenazine, phenelzine, phe combination with one or more other drugs in the treatment of nobarbital, prazepam, promethazine, propofol, protriptyline, diseases or conditions for which compounds of the present quazepam, quetiapine, reclazepam, risperidone, roletamide, invention or the other drugs may have utility, where the com secobarbital, Sertraline, Suproclone, temaZopam, thior bination of the drugs together are safer or more effective than 30 idazine, thiothixene, tracazolate, kanylcypromaine, traZ either drug alone. Such other drug(s) may be administered, by odone, triazolam, trepipam, tricetamide, triclofos, trifluop a route and in an amount commonly used therefore, contem erazine, trimetozine, trimipramine, uldazepam, Venlafaxine, poraneously or sequentially with a compound of the present Zaleplon, Ziprasidone, Zolazepam, Zolpidem, 4-(3-fluoro-5- invention. When a compound of the present invention is used trifluoromethylpyridin-2-yl)piperazin-1-yl)5-methane contemporaneously with one or more other drugs, a pharma 35 sulfonyl-2-((S)-2.2.2-trifluoro-1-methylethoxy)phenyl ceutical composition in unit dosage form containing Such methanone (RG1678), glyt1 inhibitors disclosed in U.S. Pat. other drugs and the compound of the present invention can be No. 7,538,114, Table 1 in column 14, and salts thereof, and used. However, the combination therapy may also include combinations thereof. therapies in which the compound of the present invention and In another embodiment, the compound of the present one or more other drugs are administered on different over invention may be administered in combination with levodopa lapping schedules. It is also contemplated that when used in 40 (with or without a selective extracerebral decarboxylase combination with one or more other active ingredients, the inhibitor Such as carbidopa or benserazide), anticholinergics compounds of the present invention and the other active Such as biperiden (optionally as its hydrochloride or lactate ingredients may be used in lower doses than when each is salt) and trihexyphenidyl (benzhexol) hydrochloride, COMT used singly. inhibitors such as entacapone, MOA-B inhibitors, antioxi Accordingly, the pharmaceutical compositions of the 45 dants, A2a adenosine receptor antagonists, cholinergic ago present invention also include those that contain one or more nists, NMDA receptor antagonists, serotonin receptor other active ingredients, in addition to a compound of the antagonists and dopamine receptor agonists such as alente present invention. mol, bromocriptine, fenoldopam, lisuride, naxagolide, per The above combinations include combinations of a com golide and prarnipexole. It will be appreciated that the pound of the present invention not only with one other active 50 dopamine agonist may be in the form of a pharmaceutically compound, but also with two or more other active com acceptable salt, for example, alentemol hydrobromide, bro pounds. Likewise, compounds of the present invention may mocriptine mesylate, fenoldopam meSylate, naxagolide be used in combination with other drugs that are used in the hydrochloride and pergolide mesylate. Lisuride and prami prevention, treatment, control, amelioration, or reduction of pexol are commonly used in a non-salt form. risk of the diseases or conditions for which compounds of the In another embodiment, the compound of the present present invention are useful. Such other drugs may be admin 55 invention may be administered in combination with a com istered, by a route and in an amount commonly used there pound from the phenothiazine, thioxanthene, heterocyclic fore, contemporaneously or sequentially with a compound of dibenzazepine, butyrophenone, diphenylbutylpiperidine and the present invention. Accordingly, the pharmaceutical com indolone classes of neuroleptic agent. Suitable examples of positions of the present invention also include those that also phenothiazines include chlorpromazine, mesoridazine, thior contain one or more other active ingredients, in addition to a 60 idazine, acetophenazine, fluphenazine, perphenazine and tri compound of the present invention. The weight ratio of the fluoperazine. Suitable examples of thioxanthenes include compound of the present invention to the second active ingre chlorprothixene and thiothixene. An example of a dibenza dient may be varied and will depend upon the effective dose Zepine is clozapine. An example of abutyrophenone is halo of eachingredient. Generally, an effective dose of each will be peridol. An example of a diphenylbutylpiperidine is used. 65 pimozide. An example of an indolone is molindolone. Other In one embodiment, the compound of the present invention neuroleptic agents include loxapine, Sulpiride and risperi may be administered in combination with anti-Alzheimer's done. It will be appreciated that the neuroleptic agents when US 9,303,045 B2 91 92 used in combination with the Subject compound may be in the azabicyclo[3.3.1 nonane-9-carboxylate (550 mg, 2.279 form of a pharmaceutically acceptable salt, for example, mmol) in MeOH (4559 ul) at 0°C. After 5 min, the reaction chlorpromazine hydrochloride, mesoridazine besylate, thior mixture was allowed to warm to RT then stirred for 30 min. idazine hydrochloride, acetophenazine maleate, fluiphenazine The mixture was concentrated under reduced pressure, dis hydrochloride, flurphenazine enathate, fluphenazine solved in EtOAc and washed with brine. The combined decanoate, trifluoperazine hydrochloride, thiothixene hydro organic layers were dried over anhydrous NaSO, filtered chloride, haloperidol decanoate, loxapine Succinate and and concentrated under reduced pressure to afford the title molindone hydrochloride. Perphenazine, chlorprothixene, compound as a white solid, which was used without further clozapine, haloperidol, pimozide and risperidone are com purification. monly used in a non-salt form. Thus, the compound of the present invention may be administered in combination with 10 acetophenazine, alentemol, aripiprazole, amisulpride, ben Reference 2 Zhexol, bromocriptine, biperiden, chlorpromazine, chlorpro thixene, clozapine, diazepam, fenoldopam, fluphenazine, Synthesis of (1R,5S,7S)-9-methyl-d-Oxa-9-azabicy haloperidol, levodopa, levodopa with benserazide, levodopa clo3.3.1 nonan-7-amine with carbidopa, lisuride, loxapine, mesoridazine, molin 15 dolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine, risperidone, Sulpiride, tetrabenazine, trihexyphenidyl, thioridazine, thiothixene, tri fluoperazine or ziprasidone. In another embodiment, the compound of the present invention may be administered in combination with an anti depressant or anti-anxiety agent, including norepinephrine reuptake inhibitors (including tertiary amine tricyclics and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), 25 reversible inhibitors of monoamine oxidase (RIMAs), sero Step 1: (1R,5S)-9-Methyl-d-Oxa-9-azabicyclo[3.3.1 tonin and noradrenaline reuptake inhibitors (SNRls), corti nonan-7-one cotropin releasing factor (CRF) antagonists, adrenoreceptor antagonists, neurokinin-1 receptor antagonists, atypical anti To a solution of sodium dihydrogenphosphate hydrate depressants, benzodiazopines, 5HTA agonists or antagonists, (22.30 g, 162 mmol) and 2-hydroxypropane-1,2,3-tricar especially 5HTA partial agonists, and corticotropin releasing 30 boxylic acid (4.90g, 25.5 mmol) in water (Volume: 506 ml) factor (CRF) antagonists. Specific agents include: amitrip was added in turn methyl-d--amine hydrogen chloride (5 g, tyline, clomipramine, doxepin, imipramine and trimi pramine; amoxapine, desipramine, maprotiline, nortriptyline 70.9 mmol) and 3-oxopentanedioic acid (11.91 g, 82 mmol). and protriptyline; fluoxetine, fluvoxamine, paroxetine and The pH was adjusted to 4.6 with a 10% aqueous solution of Sertraline; isocarboxazid, phenelzine, tranylcypromine and 35 NaOH. A solution of 2,2'-oxydiacetaldehyde (3.62 g, 35.4 Selegiline; moclobemide, Venlafaxine; dulloxetine; aprepi mmol) in 8 mL Me?oH was added at RT and the resulting tant; bupropion, lithium, nefazodone, traZodone and vilox mixture was stirred at RT for 3 days. 10% aqueous NaOH was azine; alprazolam, chlordiazepoxide, clonaZopam, chloraZe used to basify the reaction solution, and extracted with DCM pate, diaZopam, halazepam, lorazepam, oxazopam and (100 mL). Purification with column chromatography (SiO, prazepam, buspirone, flesinoxan, gepirone and ipsapirone, 40 and pharmaceutically acceptable salts thereof. DCM/MeOH) gave the title compound as a white solid. EXAMPLES Step 2: (1R,5S)-9-methyl-d-3-oxa-9-azabicyclo 3.3.1 nonan-7-one oxime The following preparations of compounds of Formula (I) 45 are given to enable those skilled in the art to more clearly A solution of (1R,5S)-9-methy-d-oxa-9-azabicyclo understand and to practice the present invention. They should 3.3.1 nonan-7-one (1.65 g, 10.43 mmol), hydroxylamine not be considered as limiting the scope of the invention, but hydrochloride (0.761 g, 10.95 mmol) and pyridine (0.843 ml, merely as being illustrative and representative thereof. 10.43 mmol) in EtOH (Volume: 52.1 ml) was heated at 75° C. Synthetic Procedures 50 for 3 h. After 0.2 mL of triethylamine was added to the reaction solution, the solvent was removed. Purification by Reference 1 column chromatography (SiO; DCM/MeOH) gave the title compound as a white solid. Synthesis of (1R,5S,7S)-tert-butyl 7-hydroxy-3-oxa 9-azabicyclo[3.3.1 nonane-9-carboxylate 55 Step 3: (1R,5S,7S)-9-Methyl-d-Oxa-9-azabicyclo 3.3.1 nonan-7-amine Sulfuric acid (1.108 ml, 20.78 mmol) was added dropwise over 15 min to a well-stirred solution of aluminum(III) 60 lithium hydride (1.0 M in THF, 41.6 ml, 41.6 mmol) in THF (Volume: 41.6 ml) at 0°C. The mixture was stirred for another hour at 0° C. and then (1R,5S)-9-methyl-d3-3-oxa-9-azabi cyclo[3.3.1 nonan-7-one oxime (1.8 g. 10.39 mmol) was 65 added portionwise at 0°C. The reaction mixture was heated Sodium borohydride (259 mg, 6.84 mmol) was added por under reflux (80° C.) for 1.5 h. To the well-stirred reaction tion-wise to a solution of (1R,5S)-tert-butyl 7-oxo-3-oxa-9- mixture, 1.58 mL of water, 2.37 mL of 10 MNaOH and 3.95 US 9,303,045 B2 93 94 mL of water were subsequently added at 0°C. The resultant MgSO (1:1) followed by concentration gave the title com Suspension was filtered through a pad of Celite and washed pound as a colorless film, which was used without further with THF. The combined organic phase was concentrated purification. under reduced pressure to afford the title compound as a 5 pale-yellow oil, which was used without further purification. Reference 4

Reference 3 Synthesis of (1S,5R,6S)-4-oxa-1-azabicyclo[3.3.1 nonan-6-ol: (1R,5S,6R)-4-Oxa-1-azabicyclo[3.3.1 10 Synthesis of (1R,5S,7S)-9-(trifluoromethyl)-3-oxa-9- nonan-6-ol aZabicyclo3.3.1 nonan-7-amine 2.2.2-trifluoroac etate

15

CF O N1 Step 1: Ethyl -- f 4-(3-ethoxy-3-oxopropyl)morpholine-2-carboxylate HN O A mixture of ethyl morpholine-2-carboxylate (3 g, 18.85 25 mmol) and ethyl acrylate (5 ml, 18.85 mmol) was heated at 100° C. for 14 h. The reaction was cooled to RT then diluted Step 1: Benzyl (1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1 with EtO and extracted with aqueous 3M HCl. The com nonan-7-ylcarbamate bined aqueous layers were basified by solid KCO and 30 extracted with DCM. The combined organic layers were dried Benzyl chloroformate (330 ul, 2.319 mmol) was added to a over anhydrous NaSO filtered and concentrated under solution of (1R,5S,7S)-tert-butyl 7-amino-3-oxa-9-azabicy reduced pressure to afford the title compound as a pale clo3.3.1 nonane-9-carboxylate 2.2.2-trifluoroacetate (751.3 yellow oil, which was used without further purification. mg, 2.108 mmol) and triethylamine (619 ul, 4.43 mmol) in 35 DCM (10 ml) at RT. After 14 h, trifluoroacetic acid (2.4 mL, Step 2: (1S,5R)-4-Oxa-1-azabicyclo[3.3.1 nonan-6- 31.6 mmol) was added to the reaction mixture. After 15 min, one (1R,5S)-4-Oxa-1-azabicyclo[3.3.1 nonan-6-one the mixture was concentrated, dissolved with DMF, filtered, and purified by HPLC followed by neutralization (KCO) to A solution of ethyl 4-(3-ethoxy-3-oxopropyl)morpholine afford the title compound as a colorless oil. 40 2-carboxylate (3.07 g., 11.84 mmol) in toluene (8 ml) was added to a suspension of potassium 2-methylpropan-2-olate (3.65 g, 32.6 mmol) in toluene (39.5 ml) at 120° C. After Step 2: Benzyl (1R,5S,7S)-9-(trifluoromethyl)-3- being stirred at 120° C. for 3 h, the reaction mixture was oxa-9-azabicyclo[3.3.1 nonan-7-yl)carbamate cooled to RT and extracted with water (20 mL). The aqueous 45 layer was treated with conc. HCl (20 ml, 240 mmol) then A solution of benzyl (1R,5S,7S)-3-oxa-9-azabicyclo heated at 110°C. for 14 h. The reaction mixture was cooled to 3.3.1 nonan-7-ylcarbamate (27 mg, 0.098 mmol) and dibro RT then concentrated under reduced pressure. The resulting modifluoromethane (18.06 ul, 0.195 mmol) in DMSO (489 Solid was taken up in Saturated aq. KCOs and extracted with ul) was treated with tetrakis(dimethylamino)ethylene (50.1 DCM. The combined organic layers were dried over anhy ul, 0.215 mmol), dropwise at 0° C. The mixture slowly 50 drous NaSO, filtered and concentrated under reduced pres warmed to RT overnight then was poured into a 1:1 mixture of sure to afford the title compounds as a brown oil, which was NaHCO/Na2SO, and extracted twice with EtO. The com used without further purification. bined extracts were concentrated and purified by prep-TLC to give the title compound as a yellow oil. 55 Step 3: (1S,5R,6S)-4-Oxa-1-azabicyclo3.3.1 nonan 6-ol: (1R,5S,6R)-4-Oxa-1-azabicyclo[3.3.1 nonan-6- Step 3: (1R,5S,7S)-9-(Trifluoromethyl)-3-oxa-9- ol aZabicyclo3.3.1 nonan-7-amine 2.2.2-trifluoroac etate 60 Sodium borohydride (53.6 mg, 1.417 mmol) was added to a solution of (1S,5R)-4-oxa-1-azabicyclo[3.3.1 nonan-6-one In a vial containing benzyl (1R,5S,7S)-9-(trifluorom and (1R,5S)-4-oxa-1-azabicyclo3.3.1 nonan-6-one (100 ethyl)-3-oxa-9-azabicyclo[3.3.1 nonan-7-yl)carbamate (10 mg, 0.708 mmol) in MeOH (3542 ul) at 0°C. The reaction mg, 0.029 mmol), palladium on carbon (10 wt %, 1.020 mg. mixture was stirred at RT for 30 min, then concentrated under 9.58 umol), and TFA (4.47 ul, 0.058 mmol) in MeOH (Vol 65 reduced pressure. The residue was taken up in EtOAc and ume: 145 ul) was purged with hydrogen gas and left under 1 washed with brine. The organic layer was dried over anhy atm H atmosphere for 2 h. Filtration through a pad of Celite/ drous NaSO, filtered and concentrated under reduced pres US 9,303,045 B2 95 96 sure to afford the title compounds as a yellow oil, which was Step 1: methyl used without further purification 1-(pyrimidin-2-yl)-1H-indole-3-carboxylate Reference 5 To a suspension of sodium hydride (46 mg, 1.142 mmol. 60% dispersion in mineral oil) in DMF (1.1 mL) was added 5 methyl 1H-indole-3-carboxylate (200 mg, 1.142 mmol) and Synthesis of 2-chloropyrimidine (131 mg, 1.142 mmol). The resulting 1-(pyrimidin-5-yl)-1H-indole-3-carboxylic acid suspension was stirred at RT for 1 h. The reaction mixture was diluted with DMF, filtered, and purified by HPLC to afford the title compound as a white-pink Solid. 10 Step 2: 1-(pyrimidin-2-yl)-1H-indole-3-carboxylic acid The title compound was synthesized by utilizing similar 15 conditions as described in Reference 5, Step 2. Proceeding as described above, 1-(pyrazin-2-yl)-1H-in Crs dole-3-carboxylic acid was synthesized. / Reference 7 NS/ Synthesis of 1-(thiazol-2-yl)-1H-indole-3-carboxylic acid O Step 1: Methyl OH 1-(pyrimidin-5-yl)-1H-indole-3-carboxylate 25 To a vial containing methyl 1H-indole-3-carboxylate (471 mg, 2.69 mmol), pyrimidin-5-ylboronic acid (1.0 g, 8.07 mmol), copper(II)acetate (635 mg, 3.5 mmol), 4 A molecular sieves (4 g) and 1,10-phenanthroline (970 mg, 5.38 mmol) 30 were added DCM (10.7ml) and triethylamine (0.375 ml, 2.69 mmol). The mixture was stirred at RT for 7 days then filtered through a pad of Celite (washed with MeOH). Evaporation and purification by HPLC (after dilution with DMF and fil tration) afforded the title compound as a tan solid. 35 Step 1: Methyl 1-(thiazol-2-yl)-1H-indole-3-carboxylate Step 2: 1-(pyrimidin-5-yl)-1H-indole-3-carboxylic acid To a solution of methyl 1H-indole-3-carboxylate (200 mg. 1.142 mmol) in NMP (Volume: 1142 ul) were added 2-bro To a solution of methyl 1-(pyrimidin-5-yl)-1H-indole-3- 40 mothiazole (206 ul, 2.283 mmol) and cesium carbonate (1116 mg, 3.42 mmol) at RT. The mixture was heated at 110°C. for carboxylate (16 mg, 0.063 mmol) in water MeOH (316 ul) 2 h, then diluted with DMF, filtered and purified by HPLC to was added 2M KOH (158 ul, 0.316 mmol). The mixture was afford the title compound as a brown solid. heated at 80° C. for 4 h then neutralized with 1M HC1. The precipitate was collected by filtration to afford the title com 45 Step 2: 1-(Thiazol-2-yl)-1H-indole-3-carboxylic acid pound as a white solid, which was used without further puri fication. The title compound was synthesized by utilizing similar Proceeding as described above 1-(pyrimidin-5-yl)-1H-in conditions as described in Reference 5, Step 2. dole-3-carboxylic acid was prepared. Proceeding as described above, 1-(pyridazin-3-yl)-1H-in 50 dole-3-carboxylic acid; and 1-(thiazol-5-yl)-1H-indole-3- Reference 6 carboxylic acid was synthesized. Synthesis of Reference 8 1-(pyrimidin-2-yl)-1H-indole-3-carboxylic acid 55 Synthesis of 1-(1,1,1-trifluoro-2-methylpropan-2-yl)- O OH 1H-pyrrolo2,3-bipyridine-3-carboxylic acid

OH

60 21

N N

65 US 9,303,045 B2 97 98 Step 1: 2-(((1,1,1-Trifluoro-2-methylpropan-2-yl) Methanesulfonyl chloride (48.1 ul, 0.617 mmol) was amino)methylene)Succinonitrile added to a solution of 1H-indazole-3-carboxylic acid (100 mg, 0.617 mmol) and triethylamine (86 ul, 0.617 mmol) in A solution of ethyl formate (330 mg, 4.46 mmol) and THF (1542 ul) and the mixture was stirred for 1 h. The succinonitrile (300 mg, 3.75 mmol) in toluene (1561 ul) was s reaction was then poured into water and extracted twice with added dropwise to a Suspension of sodium methanolate (215 EtOAc. The combined organic layers were filtered through mg, 3.97 mmol) in toluene (1561 ul) at 0° C. After being MgSO and concentrated to give the title compound as a stirred at RT for 3 h, the reaction mixture was treated with 1,1,1-trifluoro-2-methylpropan-2-amine (486 mg, 3.82 white solid, which was used without further purification. mmol) and acetic acid (255ul, 4.46 mmol) then heated at 120° Reference 10 C. for 3 h. After being cooled to RT, the reaction mixture was 10 washed with brine, then dried over anhydrous NaSO fil Synthesis of tered and concentrated under reduced pressure to afford the 5-fluoro-1-(methylsulfonyl)-1H-indole-3-carboxylic title compound as a brown oil, which was used without further acid purification. Step 2: 5-Amino-1-(1,1,1-trifluoro-2-methylpropan- 15 2-yl)-1H-pyrrole-3-carbonitrile O OH

A solution of 2-(((1,1,1-trifluoro-2-methylpropan-2-yl) F amino)methylene)-succinonitrile (187.2 mg 0.862 mmol) in EtOH (539 ul) was added to a solution of KOH (87 mg, 1.551 mmol) in water (539 ul) at RT. After being stirred at RT for 4 N h, the reaction mixture was concentrated under reduced pres V sure. The residual brown solid was taken up in water and sonicated. The resulting precipitate was collected by filtra tion, dissolved in EtOAc, washed with brine, dried over anhy- 25 O drous NaSO filtered and concentrated under reduced pres sure to afford the title compound as a brown solid, which was Step 1: tert-Butyl 5-fluoro-1-(methylsulfonyl)-1H used without further purification. indole-3-carboxylate Step 3: 1-(1,1,1-Trifluoro-2-methylpropan-2-yl)-1H- 30 pyrrolo2,3-bipyridine-3-carbonitrile To a solution of tert-butyl 5-fluoro-1H-indole-3-carboxy late (500mg, 2.125 mmol) and triethylamine (1721 mg, 17.00 4-Methylbenzenesulfonic acid (10.57 mg, 0.061 mmol) mmol) in THF (5 ml) was added methanesulfonyl chloride was added in one portion to a solution of 5-amino-1-(1,1,1- (0.658 ml, 8.50 mmol). The mixture was stirred at RT for 2 h. trifluoro-2-methylpropan-2-yl)-1H-pyrrole-3-carbonitrile 35 The reaction mixture was then poured into water and (133.3 mg, 0.614 mmol) and 1,1,3,3-tetramethoxypropane extracted twice with EtO. The organic extracts were com (111 ul, 0.675 mmol) in toluene (1227 ul) at RT. The mixture bined, filtered through MgSO concentrated, and purified by was heated at 100° C. for 1 h and purified directly by HPLC column chromatography (SiO2; EtOAc/hex) to afford the title to afford the title compound as a brown solid. compound as a white solid. Step 2: Step 4: 1-(1,1,1-Trifluoro-2-methylpropan-2-yl)-1H- 40 5-Fluoro-1-(methylsulfonyl)-1H-indole-3-carboxylic pyrrolo2,3-bipyridine-3-carboxylic acid acid KOH (174 mg, 3.11 mmol) was added to a solution of A mixture of tert-butyl 5-fluoro-1-(methylsulfonyl)-1H 1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrrolo2,3-b indole-3-carboxylate (150 mg, 0.479 mmol) and conc. HCl pyridine-3-carbonitrile (78.7 mg, 0.311 mmol) in 1:1:1 THF/ 45 (0.2 ml, 2.394 mmol) in EtOAc (10 ml) was stirred at RT for MeOH/water (621 ul) at RT. After being stirred at 100° C. for 2 h. The mixture was then partially concentrated, and the 4h, the reaction mixture was acidified (pH-2-3) by conc. HCl resulting precipitate was collected by filtration, washed with and the resulting suspension was extracted with EtOAc. The EtOAc and dried in vacuo to afford the title compound as a combined organic layers were concentrated to afford the title white solid, which was used without further purification. compound as a brown foam, which was used without further so purification. Reference 11 Reference 9 Synthesis of 5-fluoro-1-(isopropylsulfonyl)-1H-in dole-3-carboxylic acid Synthesis of 1-(methylsulfonyl)-1H-indazole-3-carboxylic acid 55 O OH OH

N 60

O 65 US 9,303,045 B2 99 100 Step 1: Methyl Step 1: (1R,5S,7s)-9-benzyl-3-oxa-9-azabicyclo 1-(isopropylsulfonyl)-1H-indole-3-carboxylate 3.3.1 nonan-7-ol To a solution of methyl 1H-indole-3-carboxylate (0.234 g. Sodium borohydride (24.54 g. 649 mmol) was added por 1.336 mmol) in THF (6.68 ml) was added sodium bis(trim tionwise over 30 minto a suspension of (1R,5S)-9-benzyl-3- ethylsilyl)amide (2.67 ml, 2.67 mmol) at RT. After 30 min, oxa-9-azabicyclo[3.3.1 nonan-7-one (50 g. 216 mmol) in propane-2-sulfonyl chloride (0.3 ml, 2.67 mmol) was added and the mixture was stirred for 2 h. The reaction mixture was MeOH (540 ml) and THF (540 ml) at 0°C. The mixture was then poured into brine and extracted twice with EtOAc. The allowed to gradually warm to RT over 1 h. After an additional combined extracts were filtered through MgSO and concen 10 hour at RT, the mixture was concentrated and the white resi trated to give the title compound as a brown solid, which was due was partitioned between ethyl acetate and brine. The used without further purification. combined organic layers were dried over NaSO filtered and concentrated under reduced pressure to afford the title com pound as a white solid, which was used without further puri Step 2: 5-Fluoro-1-(isopropylsulfonyl)-1H-indole-3- fication. carboxylic acid 15 The title compound was synthesized by utilizing similar Step 2: (1R,5S,7s)-9-benzyl-3-oxa-9-azabicyclo conditions as described in Reference 5, Step 2. 3.3.1 nonan-7-ol Proceeding as described above, 1-(isopropylsulfonyl)-1H indole-3-carboxylic acid was synthesized. 2.2.2-Trifluoroacetic anhydride (34.5 ml, 244 mmol) and TFA (123 ml) were subsequently added to a solution of 1H-indole-3-carboxylic acid (39.4g, 244 mmol) in toluene Reference 12 (987 ml) at RT. After 30 min, (1R,5S,7s)-9-benzyl-3-oxa-9- 25 azabicyclo[3.3.1 nonan-7-ol (51.8 g. 222 mmol) was added Synthesis of (1R,5S,7s)-9-methyl-3-oxa-9-azabicy to the mixture in one portion at RT. After 2 h, the mixture was clo3.3.1 nonan-7-yl 1H-indole-3-carboxylate concentrated under reduced pressure to the half of the original NMe volume. Then, 800 mL of 10% NaCO (aq) was added. The mixture was concentrated under reduced pressure until most 30 of the organic solvent was removed. The product was 'N O/ extracted with ethyl acetate and the combined organic layers were washed with brine, dried over NaSO filtered and concentrated under reduced pressure. The residual dark N 35 purple solid was triturated with EtO/EtOAc (4:1) to yield the N title compound as a white-pink Solid. H Step 3: (1R,5S,7s)-3-oxa-9-azabicyclo[3.3.1 nonan To a solution of 1H-indole-3-carboxylic acid (250 mg. 7-yl 1H-indole-3-carboxylate, hydrogen chloride salt 1.551 mmol) in PhMe (5171 ul) was added TFAA (219 ul, 40 1.551 mmol) then TFA (1293 ul). The mixture was stirred for 30 min then commercially available (1R,5S,7s)-9-methyl-3- A suspension of (1R,5S,7s)-9-benzyl-3-oxa-9-azabicyclo oxa-9-azabicyclo[3.3.1 nonan-7-(203 mg, 1.293 mmol) was 3.3.1 nonan-7-yl 1H-indole-3-carboxylate (2g, 5.31 mmol) added. The reaction mixture stirred at RT for 1 h then was and palladium on carbon (200 mg, 1.879 mmol. 10 wt %) in poured into aq NaHCO, and stirred until pH-7 and bubbling 45 EtOH (4.43 ml), THF (4.43 ml) and 3N HC1 (4.43 ml) was stopped. The reaction mixture was extracted with EtOAc and stirred at RT under a hydrogen atmosphere (balloon) for 14h. dried over MgSO. Purification by ISCO (0-20% MeOH/ Then, the mixture was filtered through a pad of Celite and the DCM) yielded the title compound as a pink solid. filtrate was concentrated under reduced pressure to afford the title compound as a pink solid, which was used without fur 50 Reference 13 ther purification. Step 4: (1R,5S,7s)-tert-butyl 7-((1H-indole-3-carbo Synthesis of (1R,5S,7s)-tert-butyl 7-((1H-indole-3- nyl)oxy)-3-oxa-9-azabicyclo[3.3.1 nonane-9-car carbonyl)oxy)-3-oxa-9-azabicyclo[3.3.1 nonane-9- boxylate carboxylate 55 NBoc Di-tert-butyl dicarbonate (1.275 g, 5.84 mmol) was added in one portion to a suspension of (1R,5S,7s)-3-oxa-9-azabi cyclo[3.3.1 nonan-7-yl 1H-indole-3-carboxylate hydrochlo "N O/ 60 ride (1.714g, 5.31 mmol) and triethylamine (1.628 ml, 11.68 mmol) in THF (26.6 ml) at RT. After 1 h, the mixture was partitioned between sat. NHCl (aq) and ethyl acetate. The aqueous layer was extracted with ethyl acetate and combined organic layers were washed with brine, dried over anhydrous N 65 NaSO filtered and concentrated under reduced pressure to afford the title compound as a pale-brown oil, which was used without further purification. US 9,303,045 B2 101 102 Reference 14 Step 1: methyl 1-(1-methyl-1H-imidazol-5-yl)-1H indole-3-carboxylate Synthesis of 1-phenyl-1H-indole-3-carboxylic acid A solution of methyl 1H-indole-3-carboxylate (300 mg. O 5 OH 1.712 mmol) and 5-bromo-1-methyl-1H-imidazole (303 mg, 1.884 mmol) in toluene (3425ul) was treated with (1R,2R)- N1,N2-dimethylcyclohexane-1,2-diamine (82 ul, 0.514 mmol), potassium phosphate (763 mg, 3.60 mmol) and cop per(I) iodide (98 mg, 0.514 mmol) and the resulting reaction 10 mixture stirred at 110° C. overnight. HPLC purification afforded the title compound as a yellow solid. Step 2: 1-(1-methyl-1H-imidazol-5-yl)-1H-indole-3- carboxylic acid 15 A solution of methyl 1-(1-methyl-1H-imidazol-5-yl)-1H indole-3-carboxylate (40 mg, 0.157 mmol) in THF (1567 ul) Step 1: methyl 1-phenyl-1H-indole-3-carboxylate was treated with potassium trimethylsilanolate (223 mg, 1.567 mmol) in one portion at RT and the resulting reaction A 5 mL screwtop vial containing methyl 1H-indole-3- mixture stirred overnight. ISCO purification (10% MeOH/ carboxylate (100 mg, 0.571 mmol) and potassium phosphate DCM) afforded the title compound as a white solid. (254 mg, 1.199 mmol) was degassed and purged with nitro gen after the addition of each of the following in sequential Reference 17 order: PhMe (1142 ul), bromobenzene (59.7 ul, 0.571 mmol), (1R,2R)- N1,N2-dimethylcyclohexane-1,2-diamine (54.4 25 Synthesis of 1-(thiazol-2-yl)-1H-pyrrolo2,3-bipyri ul, 0.342 mmol), and copper(I) iodide (32.6 mg, 0.171 mmol). dine-3-carboxylic acid The vial was sealed, wrapped in aluminum foil, and heated to 110° C. for 24 h. Concentration on silica gel and ISCO puri fication (20% EtOAc/hexanes) gave the title compound as a 30 white solid. OH Step 2: 1-phenyl-1H-indole-3-carboxylic acid To a solution of methyl 1-phenyl-1H-indole-3-carboxylate (108 mg 0.430 mmol) in MeCH (1433 ul) was added aqKOH 35 (1074 ul, 2.149 mmol, 2M). The mixture was heated at 90° C. for 1 h then the MeOH was removed under reduced pressure. The residual aqueous layer was acidified with 1M HCl then extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO, filtered, and concentrated to 40 afford the title compound as a white solid, which was used Step 1: methyl 1-(thiazol-2-yl)-1H-pyrrolo2,3-b without further purification. pyridine-3-carboxylate The following carboxylic acids were prepared by a similar procedure: 45 A mixture of methyl 1H-pyrrolo2,3-bipyridine-3-car 1-(isothiazol-4-yl)-1H-indole-3-carboxylic acid; 1-(isothia boxylate (200 mg, 1.135 mmol), 2-bromothiazole (205 ul, Zol-3-yl)-1H-indole-3-carboxylic acid; 1-(isothiazol-5- 2.271 mmol) and cesium carbonate (1110 mg, 3.41 mmol) in yl)-1H-indole-3-carboxylic acid; and 1-(oxazol-2-yl)-1H NMP (1135ul) was heated at 130° C. for 2h. The mixture was indole-3-carboxylic acid. then purified by HPLC to afford the title compound as a 50 brownish-white solid. Reference 15 Step 2: 1-(thiazol-2-yl)-1H-pyrrolo2,3-bipyridine-3- Synthesis of 1-(1-methyl-1H-imidazol-5-yl)-1H carboxylic acid indole-3-carboxylic acid 55 Potassium hydroxide (38.5 mg, 0.687 mmol) was added to O a solution of methyl 1-(thiazol-2-yl)-1H-pyrrolo2,3-bipyri OH dine-3-carboxylate (35.6 mg, 0.137 mmol) in MeOH (343 ul) and water (343 ul) at RT. The mixture was heated at 100° C. for 2 h. After cooling to RT, the mixture was acidified with 2 60 N HCl and then concentrated under reduced pressure. The crude mixture was used without further purification. The following carboxylic acids were prepared by a similar procedure: 1-(thiazol-4-yl)-1H-pyrrolo2,3-bipyridine-3-carboxylic 65 acid; 1-(thiazol-5-yl)-1H-pyrrolo2,3-bipyridine-3-car boxylic acid; 5-fluoro-1-(thiazol-2-yl)-1H-pyrrolo2,3-b pyridine-3-carboxylic acid; 5-fluoro-1-(thiazol-4-yl)-1H US 9,303,045 B2 103 104 pyrrolo2,3-bipyridine-3-carboxylic acid; 5-fluoro-1- Step 2: Synthesis of (1R,3R,5S)-8-methyl-8-azabicy (thiazol-5-yl)-1H-pyrrolo2,3-bipyridine-3-carboxylic clo3.2.1]octan-3-yl 1-(2,2-difluoroethyl)-1H-pyr acid and 1-(thiazol-5-yl)-1H-indazole-3-carboxylic acid. rolo2,3-bipyridine-3-carboxylate 2.2.2-trifluoroac etate Reference 18 2-Bromo-1,1-difluoroethane (54.4 mg. 0.376 mmol) was added in one portion to a suspension of (1R,3R,5S)-8-methyl tert-Butyl (1R,5S,7S)-7-(methylamino)-3-oxa-9- 8-azabicyclo[3.2.1]octan-3-yl 1H-pyrrolo2,3-bipyridine-3- azabicyclo[3.3.1 nonane-9-carboxylate carboxylate 2.2.2-trifluoroacetate (50 mg 0.125 mmol) and 10 KCO, (87 mg, 0.626 mmol) in DMF (Volume: 626 ul) at RT. The mixture was heated at 70° C. for 14 h, cooled to RT, diluted with DMF, filtered, and purified by HPLC to afford the title compound as a colorless oil. MS (ESI, pos. ion) m/z: 350.2 (M+1). 15 Example 2

In a vial containing (1R,5S,7S)-tert-butyl 7-amino-3-oxa Synthesis of N-((1R,3R,5S)-9-methyl-9-azabicyclo 9-azabicyclo[3.3.1 nonane-9-carboxylate (108.mg, 0.446 3.3.1 nonan-3-yl)-1-(methylsulfonyl)-1H-indazole mmol) and formaldehyde (39.8 ul, 0.535 mmol) in DCE 3-carboxamide 2,2,2-trifluoroacetic acid (Volume: 1114 ul) was added sodium triacetoxyborohydride (132 mg, 0.624 mmol) and stirred for 2 h. The mixture was N1 poured into 10% NaOH, and extracted twice with DCM. The 25 extracts were combined, filtered through MgSO, and con O centrated to give the title compound. O Example 1 30 Y. -> N Synthesis of (1R,3R,5S)-8-methyl-8-azabicyclo es\ 3.2.1]octan-3-yl 1-(2,2-difluoroethyl)-1H-pyrrolo2, Of 3-bipyridine-3-carboxylate 2.2.2-trifluoroacetate O 35 A mixture of 1-(methylsulfonyl)-1H-indazole-3-carboxy N 1 lic acid (60 mg 0.250 mmol; see Reference 9 for the synthe sis), di-tert-butyl dicarbonate (75 ul, 0.325 mmol), (1R,3R, 5S)-9-methyl-9-azabicyclo[3.3.1 nonan-3-ol (38.8 mg, O 40 0.250 mmol), and DMAP (3.05 mg, 0.025 mmol) in THF O (1249 ul) was heated to 80° C. overnight. Concentration and O HPLC purification (after dilution with DMF and filtration) gave the title compound as a clear oil. MS (ESI, pos. ion) m/z: 21 N HO ls CF 45 378.2 (M+1). N - F Example 3 F Synthesis of quinuclidin-4-yl 5-fluoro-1-(methylsul 50 fonyl)-1H-indole-3-carboxylate 2.2.2-trifluoroacetic acid Step 1: (1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1 octan-3-yl 1H-pyrrolo2,3-bipyridine-3-carboxylate 2.2.2-trifluoroacetate 55 N Oxalyl dichloride (318 ul, 3.70 mmol) was added to a O solution of 1H-pyrrolo2,3-bipyridine-3-carboxylic acid O O (500 mg, 3.08 mmol) and a drop of DMF in DMC (Volume: 10.0 ml) at 0°C. After 1 h, the mixture was allowed to warm 60 to RT and concentrated under reduced pressure. The residue was redissolved in DCM (Volume: 10.0 ml). (1R,3R,5S)-8- methyl-8-azabicyclo[3.2.1]octan-3-ol (653 mg, 4.63 mmol) and N,N-diisopropylethylamine (1343 ul. 7.71 mmol) were added to the suspension. After being stirred at RT for 14h, the 65 mixture was diluted with DMF, filtered and purified by HPLC to afford the title compound as a colorless oil. US 9,303,045 B2 105 106 In a vial containing 5-fluoro-1-(methylsulfonyl)-1H-in Example 5 dole-3-carboxylic acid (20 mg, 0.078 mmol; see Reference 10 for the synthesis) and trifluoroacetic anhydride (10.98 ul, Synthesis of (1R,3R,5S)-8-azabicyclo[3.2.1]octan-3- 0.078 mmol) in toluene (259 ul) was added TFA (64.8 ul). y1 1-(2.2.2-trifluoroethyl)-1H-indole-3-carboxylate After 30 min, quinuclidin-4-ol (8.24 mg., 0.065 mmol) was 2.2.2-trifluoroacetate added and the mixture was stirred at RT overnight. Direct NH HPLC purification (after dilution with DMF and filtration) gave the title compound as a clear film. MS (ESI, pos. ion) 10 m/z. 367.2 (M+1). O Compound 181 in Table 1 was synthesized as described in ls Example 3 above. HO CF 15 Example 4 Sct, Synthesis of (1R,3R,5S)-8-methyl-8-azabicyclo 3.2.1]octan-3-yl 2-chloro-1-(2,2-difluoroethyl)-1H Steps 1 and 2: (1R,3R,5S)-8-((Benzyloxy)carbonyl)- indole-3-carboxylate 2.2.2-trifluoroacetate 8-azabicyclo[3.2.1]octan-3-yl 1-(2.2.2-trifluoroet hyl)-1H-indole-3-carboxylate (1R,3R,5S)-8-((Benzyloxy)carbonyl)-8-azabicyclo[3.2.1 25 octan-3-yl 1-(2.2.2-trifluoroethyl)-1H-indole-3-carboxylate (prepared as described in Example 1 above) was convered to the title compound by utilizing a similar procedure as described in Example 4 above. 30 Step 3: (1R,3R,5S)-8-AZabicyclo[3.2.1]octan-3-yl N C -S, 1-(2.2.2-trifluoroethyl)-1H-indole-3-carboxylate 2.2, N 2-trifluoroacetate 35 A suspension of (1R,3R,5S)-8-((benzyloxy)carbonyl)-8- \- azabicyclo[3.2.1]octan-3-yl 1-(2.2.2-trifluoroethyl)-1H-in F dole-3-carboxylate (47.7 mg, 0.098 mmol) and palladium on carbon (10 wt %, 5 mg, 4.70 Lumol) was stirred under 1 atm H. atmosphere in EtOH/EtOAc (1:1, Volume: 980 ul) at RT. Step 1: (1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1 40 After 2 h, the mixture was filtered through a pad of Celite and octan-3-yl 2-chloro-1H-indole-3-carboxylate 2.2.2- the filtrate was concentrated, diluted with DMF and purified by HPLC to afford the title compound as a colorless oil. MS trifluoroacetate (ESI, pos. ion) m/z. 353.2 (M+1) Utilizing a similar procedure as described above com The title compound was synthesized by utilizing similar 45 pound 45 in Table 1 above was prepared. conditions as described in Example 3 above. Example 6 Step 2: (1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1 octan-3-yl 2-chloro-1-(2,2-difluoroethyl)-1H-indole 50 Synthesis of (1R,3R,5S)-8-methyl-8-azabicyclo 3-carboxylate 2.2.2-trifluoroacetate 3.2.1]octan-3-yl 2-chloro-1-(methylsulfonyl)-1H indole-3-carboxylate 2.2.2-trifluoroacetate A solution of (1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1 octan-3-yl 2-chloro-1H-indole-3-carboxylate 2.2.2-trifluo 55 N1 roacetate (23 mg 0.053 mmol), 2-bromo-1,1-difluoroethane (23.11 mg 0.159 mmol) and KCO (36.7 mg, 0.266 mmol) in DMF (266 ul) was heated at 80°C. for 14 h. After cooling to RT, the mixture was diluted with DMF, filtered and purified 60 by HPLC to afford the title compound as a white solid. MS N C l (ESI, pos. ion) m/z: 383.2 (M+1) HO CF Compounds in Table 1 above 1, 2, 15,27, 40,56, 83, 88,95, 96, and 97 were synthesized as described in Example 4 above. 65 Step 1 of compound 41 was carried out as in Example 1, followed by Step 2 of Example 4. US 9,303,045 B2 107 108 Step 1: (1R,3R,5S)-8-Methyl-8-azabicyclo[3.2.1 7); 120 (Reference 5); 121 (Reference 2 for the amine syn octan-3-yl 2-chloro-1H-indole-3-carboxylate 2.2.2- thesis and Reference 6 for the carboxylic acid synthesis); 122 trifluoroacetate (Reference 2 for the amine synthesis and Reference 6 for the carboxylic acid synthesis); 123 (Reference 2 for the amine The title compound was synthesized by similar conditions 5 synthesis and Reference 7 for the carboxylic acid synthesis). as described in Example 3 above. Step 2: (1R,3R,5S)-8-Methyl-8-azabicyclo[3.2.1 Example 8 octan-3-yl 2-chloro-1-(methylsulfonyl)-1H-indole-3- carboxylate 2.2.2-trifluoroacetate 10 Synthesis of 1-(2,2-difluoroethyl)-N-((1R,3R,5S)-8- methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indazole Sodium bis(trimethylsilyl)amide (1.0 M THF, 150 ul, 3-carboxamide 2.2.2-trifluoroacetate 0.150 mmol) was added to a solution of (1R,3R,5S)-8-me thyl-8-azabicyclo3.2.1]octan-3-yl 2-chloro-1H-indole-3- N1 carboxylate 2.2.2-trifluoroacetate (28.3 mg, 0.065 mmol) in 15 THF (327 ul) at 0°C. After 5 min, methanesulfonyl chloride O (6.58 ul, 0.085 mmol) was added and the mixture was stirred NH at RT for 1 h. The mixture was diluted with DMF, filtered and O purified by HPLC to afford the title compound as a colorless film. MS (ESI, pos. ion) m/z. 397.2 (M+1). N N -- Utilizing a similar procedure as described above, com M pounds 3, 26, 34, 86, and 99 in Table 1 above were prepared. N Example 7 \- F N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1 25 nonan-7-yl)-1-(1,1,1-trifluoro-2-methylpropan-2-yl)- 1H-pyrrolo2,3-bipyridine-3-carboxamide 2.2.2- trifluoroacetate Step 1: N-((1R,3R,5S)-8-Methyl-8-azabicyclo[3.2.1 octan-3-yl)-1H-indazole-3-carboxamide 2.2.2-trif 30 luoroacetate The title compound was synthesized by utilizing similar conditions as described in Example 7. 35 O NH Step 2: 1-(2,2-Difluoroethyl)-N-((1R,3R,5S)-8-me O O thyl-8-azabicyclo3.2.1]octan-3-yl)-1H-indazole-3- carboxamide 2.2.2-trifluoroacetate 21 N HO ls CF 40 s N Similar conditions as described in Example 4, Step 2 were utilized to afford the title compound as a colorless film. MS (ESI, pos. ion) m/z: 349.25 (M+1) -)-. Following compounds in Table 1 above were synthesized 45 by utilizing a similar procedure as described in Example 8 HATU (34.1 mg 0.090 mmol) was added to a solution of above: Compounds 7, 12, 20, 66, 75, and 98. 1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrrolo2,3-b pyridine-3-carboxylic acid (24.4 mg., 0.090 mmol; see Ref Example 9 erence 8 for the synthesis), (1R,5S,7S)-9-methyl-3-oxa-9- azabicyclo[3.3.1 nonan-7-amine (14.00 mg, 0.090 mmol) 50 and N,N-diisopropylethylamine (46.8 ul, 0.269 mmol) in Synthesis of N-((1R,3R,5S)-8-methyl-8-azabicyclo DMF (Volume: 179 ul) at RT. After 20 min, the mixture was 3.2.1]octan-3-yl)-1-(methylsulfonyl)-1H-indazole diluted with DMF, filtered and purified by HPLC to afford the 3-carboxamide 2.2.2-trifluoroacetate title compound as a yellow film. MS (ESI, pos. ion) m/z: N1 411.3 (M+1). 55 Compounds 10, 36, 46, 69, 71, 92,93, 94, 107, 111, 114, 117-123 in Table 1 above were synthesized by utilizing a similar procedure as described in Example 7 above using the carboxylic acid intermediate prepared by procedures indi cated below: 60 Compound 69 (Reference 8): 71 (Reference 5); 92 (Refer ence 6): 94 (Reference 5); 107 (Reference 6); 10 (Reference 11); 36 (Reference 10): 46 (Reference 9); 93 (Reference 11): 111 (Reference 2 for the amine synthesis and Reference 11 for the carboxylic acid synthesis); 114 (Reference 2 for the 65 amine synthesis and Reference 5 for the carboxylic acid syn thesis): 117 (Reference 7); 118 (Reference 7); 119 (Reference US 9,303,045 B2 109 110 Step 1: N-((1R,3R,5S)-8-Methyl-8-azabicyclo[3.2.1 separate vial, Sodium hydride (4.24 mg., 0.106 mmol) was octan-3-yl)-1H-indazole-3-carboxamide 2.2.2-trif added to a solution of (1R,3R,5S)-9-methyl-9-azabicyclo luoroacetate 3.3.1 nonan-3-ol (16.47 mg, 0.106 mmol) in DMF (Volume: 442 ul) at RT and the resulting mixture was heated at 60° C. The title compound was synthesized by utilizing similar 5 for 1 h. The resulting alkoxide solution was added to the conditions as described in Example 7 above. imidazolide solution and the mixture was heated at 70° C. for 2 h. The mixture was diluted with DMF, filtered and purified Step 2: N-((1R,3R,5S)-8-Methyl-8-azabicyclo[3.2.1 by HPLC to afford the title compound as a colorless film. MS octan-3-yl)-1-(methylsulfonyl)-1H-indazole-3-car (ESI, pos. ion) m/z. 364.3 (M+1). boxamide 2.2.2-trifluoroacetate 10 Compounds 16, 57,91, 103, 17, 60, 116 and 89 in Table 1 above were synthesized by utilizing a similar procedure as Similar conditions as described in Example 6, Step 2 were described in Example 10 above unless indicated otherwise utilized to afford the title compound as a colorless film. MS below: (ESI, pos. ion) m/z. 363.2 (M+1) 15 Compound 16 (Similar conditions as described in Example 2 Following compounds in Table 1 above were synthesized above were utilized for Step 3): by utilizing a similar procedure as described in Example 9 Compound 57 (Similar conditions as described in Example 2 above: Compounds 18, 74, 101, and 110 (azabicyclic inter above were utilized for Step 3): mediate prepared by Reference 2). Compound 91 (Similar conditions as described in Example 3 above were utilized for Step 3): Example 10 Compound 103 (Similar conditions as described in Example Synthesis of (1R,3R,5S)-9-methyl-9-azabicyclo 3 above were utilized for Step 3): 3.3.1 nonan-3-yl 1-(2,2-difluoroethyl)-1H-pyrrolo Compound 17 (Similar conditions as described in Example 2 2,3-bipyridine-3-carboxylate 2.2.2-trifluoroacetate above were utilized for Step 3): 25 Compound 60 (Similar conditions as described in Example 3 above were utilized for Step 3); and Compound 89 (Similar conditions as described in Example 3 N1 above were utilized for Step 3). 30 Example 11 O O Synthesis of 1-(2,2-difluoroethyl)-N-((1R,5S,7S)-9- O methyl-3-oxa-9-azabicyclo[3.3.1 nonan-7-yl)-1H 21 ls pyrrolo2,3-bipyridine-3-carboxamide 2.2.2-trifluo N HO CF 35 rOacetate s - F 40 N1

O Step 1: Methyl 1-(2,2-difluoroethyl)-1H-pyrrolo2,3- NH bipyridine-3-carboxylate O 45 2-Bromo-1,1-difluoroethane (677 ul, 8.51 mmol) was 21 l N HO CF added to a suspension of methyl 1H-pyrrolo2,3-bipyridine N N 3-carboxylate (500 mg, 2.84 mmol) and KCO (1177 mg, 8.51 mmol) in DMF (2838 ul) at RT. The mixture was heated at 70° C. for 14 h and purified by column chromatography 50 \- (SiO; DCM/MeOH) to afford the title compound as a white F solid. Step 2: 1-(2,2-Difluoroethyl)-1H-pyrrolo2,3-bipyri Step 1 and 2: 1-(2,2-Difluoroethyl)-1H-pyrrolo2,3- dine-3-carboxylic acid 55 bipyridine-3-carboxylic acid The title compound was synthesized by utilizing similar The title compound was synthesized by utilizing similar conditions as described in Reference 5, Step 2. conditions as described in Example 10, Steps 1 and 2.

Step 3: (1R,3R,5S)-9-Methyl-9-azabicyclo[3.3.1 60 Step 3: 1-(2,2-Difluoroethyl)-N-((1R,5S,7S)-9-me nonan-3-yl 1-(2,2-difluoroethyl)-1H-pyrrolo2,3-b thyl-3-oxa-9-azabicyclo3.3.1 nonan-7-yl)-1H-pyr pyridine-3-carboxylate 2.2.2-trifluoroacetate rolo2,3-bipyridine-3-carboxamide 2.2.2-trifluoroac etate CDI (14.34 mg., 0.088 mmol) was added to a solution of 1-(2,2-difluoroethyl)-1H-pyrrolo2,3-bipyridine-3-carboxy 65 Similar conditions as described in Example 7 were utilized lic acid (20 mg, 0.088 mmol) in DMF (Volume: 442 ul) at RT to afford the title compound as a colorless oil. MS (ESI, pos. and the resulting mixture was heated at 60° C. for 1 h. In a ion) m/z. 365.3 (M+1) US 9,303,045 B2 111 112 Following compounds in Table 1 above were synthesized Steps 1 and 2: 1-(2,2-Difluoroethyl)-5-fluoro-1H by utilizing a similar procedure as described in Example 11: indole-3-carboxylic acid Compounds 5, 9, 21, 22, 52,53, 63, 67,68, 70, 76, 77, 79,80, 81, 102, 104 (Reference 3 for amine synthesis), 108, 109 The title compound was synthesized by utilizing similar (Reference 2 for amine synthesis), 112, 113, 126 and 127 5 conditions as described in Example 10, Step 1 and 2. (Reference 2 for amine synthesis). Step 3: (1R,5S,7S)-3-Oxa-9-azabicyclo3.3.1 nonan Example 12 7-yl 1-(2,2-difluoroethyl)-5-fluoro-1H-indole-3-car boxylate 2.2.2-trifluoroacetic acid Synthesis of (1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1 10 nonan-7-yl 1-(2,2-difluoroethyl)-1H-pyrrolo2,3-b In a vial containing 1-(2,2-difluoroethyl)-5-fluoro-1H-in pyridine-3-carboxylate 2.2.2-trifluoroacetate dole-3-carboxylic acid (100 mg, 0.411 mmol) and trifluoro acetic anhydride (58.1 ul, 0.411 mmol) in toluene (1371 ul) NH was added TFA (343 ul). The reaction mixture was stirred at 15 RT for 30 min then (1R,5S,7S)-tert-butyl 7-hydroxy-3-oxa 9-azabicyclo[3.3.1 nonane-9-carboxylate (83 mg 0.343 mmol; see Reference 1 for the synthesis) was added and stirring continued for 2 h. Direct HPLC purification (after dilution with DMF and filtration) gave the title compound as a white solid. MS (ESI, pos. ion) m/z. 369.2 (M-1). HO CF Following compounds in Table 1 above were synthesized by utilizing a similar procedure as described in Example 13 above Compounds 11, 23, 25, 54, 59, and 128 using acid 25 synthesized by the procedure indicated below: Example 54 (See Reference 11 for the carboxylic acid syn thesis) Example 11 (See Reference 5 for the carboxylic acid synthe Step 1: (1R,5S,7S)-tert-Butyl 7-(1-(2,2-difluoroet hyl)-1H-pyrrolo2,3-bipyridine-3-carbonyl)oxy)-3- sis) oxa-9-azabicyclo[3.3.1 nonane-9-carboxylate 30 Example 23 (See Reference 6 for the carboxylic acid synthe sis) Example 25 (See Reference 6 for the carboxylic acid synthe The title compound was synthesized by utilizing a similar sis) procedure as described in Example 10 above. Example 128 (See Reference 7 for the carboxylic acid syn 35 Step 2: (1R,5S,7S)-3-Oxa-9-azabicyclo[3.3.1 nonan thesis). 7-yl 1-(2,2-difluoroethyl)-1H-pyrrolo2,3-bipyri dine-3-carboxylate 2.2.2-trifluoroacetate Example 14 TFA (325 ul) was added to a solution of (1R,5S,7S)-tert 40 Synthesis of (1R,5S,7S)-9-methyl-3-oxa-9-azabicy butyl 7-((1-(2,2-difluoroethyl)-1H-pyrrolo2,3-bipyridine clo3.3.1 nonan-7-y1 1-(2,2-difluoroethyl)-1H-pyr 3-carbonyl)oxy)-3-oxa-9-azabicyclo[3.3.1 nonane-9-car rolo2,3-bipyridine-3-carboxylate 2.2.2-trifluoroac boxylate (58.6 mg, 0.130 mmol) in DCM (325ul) at RT. After etate 10 min, the reaction mixture was diluted with DMF, filtered and purified by HPLC to afford the title compound as a white 45 solid. MS (ESI, pos. ion) m/z. 352.2 (M+1) Example 13

50 Synthesis of (1R,5S,7S)-3-Oxa-9-azabicyclo[3.3.1 nonan-7-y1 1-(2,2-difluoroethyl)-5-fluoro-1H-indole 3-carboxylate 2.2.2-trifluoroacetic acid HO CF NH 55 O O O F O -- 60 N Steps 1 and 2: (1R,5S,7S)-3-Oxa-9-azabicyclo[3.3.1 nonan-7-y1 1-(2,2-difluoroethyl)-1H-pyrrolo2,3-b pyridine-3-carboxylate \- 65 The title compound was synthesized by utilizing similar conditions as described in Example 12 above. US 9,303,045 B2 113 114 Step 3: (1R,5S,7S)-9-Methyl-3-oxa-9-azabicyclo Compound 50 in Table 1 above was synthesized by utiliz 3.3.1 nonan-7-y1 1-(2,2-difluoroethyl)-1H-pyrrolo ing a similar procedure as described in Example 15 above. 2,3-bipyridine-3-carboxylate 2.2.2-trifluoroacetate Example 16 Sodium triacetoxyborohydride (11.44 mg., 0.054 mmol) was added to a solution of (1R,5S,7S)-3-oxa-9-azabicyclo Synthesis of N-((1R,5S,7S)-3-oxa-9-azabicyclo 3.3.1 nonan-7-y1 1-(2,2-difluoroethyl)-1H-pyrrolo2,3-b 3.3.1 nonan-7-yl)-5-fluoro-1-(2.2.2-trifluoroethyl)- pyridine-3-carboxylate (15.81 mg 0.045 mmol) and formal 1H-indole-3-carboxamide 2.2.2-trifluoroacetic acid dehyde (4.91 mg, 0.054 mmol) in DCM (225 ul) at RT. After 10 15 min, the reaction mixture was diluted with DMF, filtered and purified by HPLC to afford the title compound as a colorless film. MS (ESI, pos. ion) m/z. 366.2 (M+1). NH Compounds 32, 49, and 58 in Table 1 above were synthe sized by utilizing a similar procedure as described in Example 15 14 above.

Example 15 HO ls CF Synthesis of (1R,5S,7S)-9-(2-fluoroethyl)-3-oxa-9- azabicyclo[3.3.1 nonan-7-y1 1-(2,2-difluoroethyl)-5- Sct, fluoro-1H-indole-3-carboxylate, 2.2.2-trifluoroacetic acid 25 Step 1: (1R,5S,7S)-tert-Butyl 7-(5-fluoro-1-(2,2,2- trifluoroethyl)-1H-indole-3-carboxamido)-3-oxa-9- azabicyclo[3.3.1 nonane-9-carboxylate

30 The title compound was synthesized by a similar procedure as described in Example 11 above. Step 2: N-((1R,5S,7S)-3-Oxa-9-azabicyclo[3.3.1 nonan-7-yl)-5-fluoro-1-(2.2.2-trifluoroethyl)-1H 35 indole-3-carboxamide, 2.2.2-trifluoroacetic acid salt Similar conditions as described in Example 12, Step 2 were utilized to afford the title compound as a clear oil. MS (ESI, pos. ion) m/z. 386.2 (M-1). 40 Following compounds in Table 1 above were synthesized by utilizing a similar procedure as described in Example 16 above: Compounds 39, 38, 65 (Step 1 used from Example 8 above), 78 (see Reference 10 for carboxylic acid synthesis), 82, 105, and 185. Step 1: (1R,5S,7S)-3-Oxa-9-azabicyclo[3.3.1 nonan 45 7-yl 1-(2,2-difluoroethyl)-5-fluoro-1H-indole-3-car Example 17 boxylate 2.2.2-trifluoroacetic acid Synthesis of N-((1R,5S,7S)-3-oxa-9-azabicyclo The title compound was synthesized by utilizing similar 50 3.3.1 nonan-7-yl)-5-fluoro-1-(2.2.2-trifluoroethyl)- procedure as described in Example 13 above. 1H-indole-3-carboxamide 2.2.2-trifluoroacetate Step 2: (1R,5S,7S)-9-(2-Fluoroethyl)-3-oxa-9-azabi cyclo[3.3.1 nonan-7-yl 1-(2,2-difluoroethyl)-5- fluoro-1H-indole-3-carboxylate, 2.2.2-trifluoroacetic acid

A solution of (1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1 nonan-7-y1 1-(2,2-difluoroethyl)-5-fluoro-1H-indole-3-car 60 boxylate 2.2.2-trifluoroacetate (20 mg, 0.041 mmol), triethy lamine (28.9 ul, 0.207 mmol), and 1-bromo-2-fluoroethane HO CF (9.29 ul, 0.124 mmol) in MeCN (415 ul) was heated to 100° C. for 2 days. HPLC purification (after dilution with DMF and 65 filtration) gave the title compound as a white solid. MS (ESI, pos. ion) m/z.: 415.2 (M+1) US 9,303,045 B2 115 116 Step 1 and 2: N-((1R,5S,7S)-3-Oxa-9-azabicyclo MeCN (324 ul) was heated at 80° C. for 10 min and purified 3.3.1 nonan-7-yl)-5-fluoro-1-(2.2.2-trifluoroethyl)- by HPLC (after dilution with DMF and filtration). Neutral 1H-indole-3-carboxamide 2.2.2-trifluoroacetate ization with KCO, and prep-TLC (DCM/MeOH) afforded the title compound as a colorless film. MS (ESI, pos. ion) m/z: The title compound was synthesized by utilizing similar 404.2 (M+1). conditions as described in Example 16 above. Compound 130 in Table 1 above were synthesized by uti Step 3: N-((1R,5S,7S)-3-Oxa-9-azabicyclo[3.3.1 lizing a similar procedure as described in Example 18 above. nonan-7-yl)-5-fluoro-1-(2.2.2-trifluoroethyl)-1H 10 indole-3-carboxamide 2.2.2-trifluoroacetate Example 19

Similar conditions as described in Example 14, Step 3 were Synthesis of (1R,3R,5S)-8-methyl-8-azabicyclo utilized to afford the title compound as a clear film. MS (ESI, 3.2.1]octan-3-yl 3,4-dihydro-2H-1,3oxazino.3.2- pos. ion) m/z: 400.25 (M-1) 15 alindole-10-carboxylate 2.2.2-trifluoroacetate Compounds 129 and 186 in Table 1 above was synthesized by utilizing a similar procedure as described in Example 17 above. Carboxylic acid was synthesized using method in Reference 6 above). Example 18

Synthesis of 5-fluoro-N-((1R,5S,7S)-9-methyl-d-3- 25 oxa-9-azabicyclo[3.3.1 nonan-7-yl)-1-(2.2.2-trifluo roethyl)-1H-pyrrolo2,3-bipyridine-3-carboxamide 2.2.2-trifluoroacetate

30

CD3 N1 35 Step 1: (1R,3R,5S)-8-Methyl-8-azabicyclo[3.2.1 octan-3-yl 2-(3-bromopropoxy)-1H-indole-3-car O NH boxylate O 40 NCS (35.2 mg, 0.264 mmol) was added to a suspension of F 21 ul (1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 1H-in N HO CF dole-3-carboxylate (50 mg, 0.176 mmol) and 4A MS (100 N N mg) in chloroform (879 ul) at RT. After 30 min, 3-bromopro pan-1-ol (48.9 mg, 0.352 mmol) was added to the solution. 45 After being stirred at RT for 14 h, the reaction mixture was filtered through a pad of Celite. The filtrate was washed with Steps 1 and 2: N-((1R,5S,7S)-3-Oxa-9-azabicyclo brine, dried over anhydrous NaSO filtered and concen 3.3.1 nonan-7-yl)-5-fluoro-1-(2.2.2-trifluoroethyl)- trated under reduced pressure to afford the title compound, 1H-pyrrolo2,3-bipyridine-3-carboxamide 2.2.2- 50 which was used without further purification. trifluoroacetate Step 2: (1R,3R,5S)-8-Methyl-8-azabicyclo[3.2.1 The title compound was synthesized by utilizing similar octan-3-yl 3,4-dihydro-2H-1,3oxazino.3.2-ain conditions as described in Example 16 above. 55 dole-10-carboxylate 2.2.2-trifluoroacetate (1R,3R,5S)-8-Methyl-8-azabicyclo3.2.1]octan-3-yl 2-(3- 9-azabicyclo[3.3.1 nonan-7-yl)-1-(2.2.2-trifluoroet bromopropoxy)-1H-indole-3-carboxylate (74.2 mg, 0.176 hyl)-1H-pyrrolo2,3-bipyridine-3-carboxamide 2.2, mmol) and KCO (73.0 mg. 0.528 mmol) were suspended in 2-trifluoroacetate 60 acetone (1760 ul) at RT. After being stirred for 24 h, the reaction mixture was diluted with DMF, filtered and purified A mixture of N-((1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1 by HPLC to afford the title compound as colorless film. MS nonan-7-yl)-5-fluoro-1-(2.2.2-trifluoroethyl)-1H-pyrrolo2, (ESI, pos. ion) m/z: 341.3 (M+1) 3-bipyridine-3-carboxamide 2.2.2-trifluoroacetate (16.2 mg, 65 Compounds 28 and 84 in Table 1 above were synthesized 0.032 mmol), methyl-d-4-methylbenzenesulfonate (12.25 by utilizing a similar procedure as described in Example 19 mg, 0.065 mmol) and KCO (13.42 mg, 0.097 mmol) in above. US 9,303,045 B2 117 118 Example 20 Steps 1, 2 and 3: (1R,5S,7S)-9-Methyl-3-oxa-9- azabicyclo[3.3.1 nonan-7-yl 1H-indole-3-carboxy Synthesis of (1R,5S,7S)-9-methyl-3-oxa-9-azabicy late 2.2.2-trifluoroacetate clo3.3.1 nonan-7-yl 1-(2-fluoroethyl)-1H-indole-3- 5 The title compound was synthesized by utilizing a similar carboxylate 2.2.2-trifluoroacetic acid procedure as described in Example 14 above. Similar condi tions as described in Example 1 above were utilized for Step 1 1. 10 Step 4: (1R,5S,7S)-9-Methyl-3-oxa-9-azabicyclo O O 4 O 3.3.1 nonan-7-y1 1-(methylsulfonyl)-1H-indole-3- carboxylate 2.2.2-trifluoroacetic acid N -- Similar conditions as described in Example 6, Step 2 were 15 N utilized to afford the title compound as a colorless oil. MS (ESI, pos. ion) m/z. 379.15 (M+1). Example 22 F Synthesis of (1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1 nonan-7-y1 1-(isopropylsulfonyl)-1H-indole-3-car Steps 1, 2 and 3: (1R,5S,7S)-9-Methyl-3-oxa-9- boxylate 2.2.2-trifluoroacetate azabicyclo[3.3.1 nonan-7-yl 1H-indole-3-carboxy late 25 NH The title compound was synthesized by utilizing a similar procedure as described in Example 14 above. Similar condi tions as described in Example 1 above were utilized for Step 1. 30

Step 4: (1R,5S,7S)-9-Methyl-3-oxa-9-azabicyclo 3.3.1 nonan-7-y1 1-(2-fluoroethyl)-1H-indole-3- carboxylate 2.2.2-trifluoroacetic acid 35 Sodium hydride (11.98 mg, 0.300 mmol. 60% dispersion in mineral oil) was added to a solution of (1R,5S,7S)-9- methyl-3-oxa-9-azabicyclo[3.3.1 nonan-7-yl 1H-indole-3- carboxylate (60 mg, 0.200 mmol) in DMF (600 ul) at RT. 40 Step 1: (1R,5S,7S)-3-Oxa-9-azabicyclo3.3.1 nonan After 15 min, 1-bromo-2-fluoroethane (22.38 ul, 0.300 7-yl 1H-indole-3-carboxylate 2.2.2-trifluoroacetate mmol) was added and the reaction was stirred for a further 1 h. Direct HPLC purification (after dilution with DMF and The title compound was synthesized by utilizing similar filtration) gave the title compound as a clear oil. MS (ESI, pos. conditions as described in Example 13, Step 3. ion) m/z: 347.3 (M+1). 45 Step 2: (1R,5S,7S)-tert-Butyl 7-((1H-indole-3-carbo nyl)oxy)-3-oxa-9-azabicyclo[3.3.1-nonane-9-car Example 21 boxylate Synthesis of (1R,5S,7S)-9-methyl-3-oxa-9-azabicy 50 Di-tert-butyl dicarbonate (168 ul, 0.731 mmol) was added clo3.3.1 nonan-7-y1 1-(methylsulfonyl)-1H-indole to a solution of (1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1 nonan 3-carboxylate 2.2.2-trifluoroacetic acid 7-yl 1H-indole-3-carboxylate 2.2.2-trifluoroacetate (278.6 mg, 0.696 mmol) and N,N-diisopropylethylamine (182 ul, / N 1.044 mmol) in THF (Volume: 3479 ul) at RT. After 30 min, 55 the mixture was concentrated under reduced pressure, taken up in EtOAc, washed with saturated aqueous NHCl and brine. The combined organic layers were dried over anhy M-4 drous NaSO, filtered and concentrated under reduced pres sure to afford the title compound as a white foam. N O 60 Step 3: (1R,5S,7S)-3-Oxa-9-azabicyclo3.3.1 nonan 7-yl 1-(isopropylsulfonyl)-1H-indole-3-carboxylate N -- 2.2.2-trifluoroacetate of2S N O 65 In a round-bottom flask containing (1R,5S,7S)-tert-butyl 7-((1H -indole-3-carbonyl)oxy)-3-oxa-9-azabicyclo[3.3.1 nonane-9-carboxylate (304 mg. 0.787 mmol) in THF (Vol

US 9,303,045 B2 125 126 Example 32 Direct HPLC purification gave the title compound as a white solid. MS (ESI, pos. ion) m/z. 397.20 (M+1). Synthesis of (1R,5S,7s)-9-methyl-3-oxa-9-azabicy Example 34 clo3.3.1 nonan-7-y1 1-(6-hydroxypyridazin-3-yl)- 5 1H-indole-3-carboxylate, 2.2.2-trifluoroacetic acid Synthesis of (1R,5S,7S)-9-methyl-3-oxa-9-azabicy salt clo3.3.1 nonan-7-yl 1-(isothiazol-3-yl)-1H-indole 3-carboxylate, 2.2.2-trifluoroacetic acid salt

10 NMe 1 & O C./ 15 N O N-4 , N -- N - , Z NW N N S. OH ( ) 25 Potassium trimethylsilanolate (5.83 mg 0.045 mmol) was A solution of (1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo added to a solution of (1R,5S,7s)-9-methyl-3-oxa-9-azabicy 3.3.1 nonan-7-yl 1H-indole-3-carboxylate (200 mg, 0.666 clo3.3.1 nonan-7-yl 1-(6-fluoropyridazin-3-yl)-1H-indole mmol) and 3-bromoisothiazole (138 mg, 0.799 mmol) in 3-carboxylate (18 mg, 0.045 mmol) in THF (227 ul) at RT. 30 toluene (Volume: 1332 ul) was treated with (1R,2R)- N1, After 1 h, 2Maq KOH (100 uL) was added and the mixture N2-dimethylcyclohexane-1,2-diamine (32.6 ul, 0.200 was stirred at RT for 14 h. HPLC purification yielded the title mmol), potassium phosphate (306 mg, 1.398 mmol) and cop compound as a white solid. MS (ESI, pos. ion) m/z: 395.20 per(I) iodide (38.0 mg, 0.200 mmol). The resulting reaction (M+1). mixture was stirred at 120° C. overnight. HPLC purification 35 afforded the title compound as a tan solid. MS (ESI, pos. ion) m/z: 384.3 (M+1). Example 33 Compound 189 in Table 1 above was synthesized by uti lizing a similar procedure as described in Example 34 above. (1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1 nonan-7-y1 1-(5-fluoropyrazin-2-yl)-1H-indole-3- 40 BIOLOGICAL, EXAMPLES carboxylate, 2.2.2-trifluoroacetic acid salt Biological Example 1

45 Inhibition of Ca Flux Activity of 5HT3 In Vitro 1 Assay The 5HT3 antagonist activity of the compounds of the invention was determined by measuring the ability of the M-4 50 compounds to inhibit the calcium flux activity of 3HT3a receptor expressed in HEK-293T cells. HEK-293T cells were N O transfected with the 5HT3a expression construct using Xtreme Gene 9 (Roche) in 150 mm tissue culture treated N -> plates and incubated for 24 hours at 37° C. Cells were then 55 split and plated at a density of 60K cells/well in poly-lysine coated, black 96-well plates with clear bottoms (BD Bio Y Sciences) and incubated overnight at 37° C. Growth media NS was removed and cells loaded with 200 uL calcium indicator dye in HBSS containing 20 mM HEPES (Calcium 5 Assay F 60 kit, Molecular Devices) and incubated at 37° C. for 1 hour. While cells were incubating, the 10x antagonist and agonist/ antagonist addition plates were made. For 10x antagonist A solution of (1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo plate: half log serial dilutions (final concentrations range 3.3.1 nonan-7-y1 1-(5-chloropyrazin-2-yl)-1H-indole-3- from 107 through 10' with the bottom well a negative, no carboxylate (10 mg, 0.024 mmol), 1,4,7,10,13,16-hexaox 65 ligand control) were made from test compounds in DMSO at acyclooctadecane (3.20 mg, 0.012 mmol) and potassium a 1000x concentration and then diluted to 10x in HBSS/20 fluoride (4.22 mg, 0.073 mmol) was heated at 120° C. for 1 h. mM HEPES. For addition plate: 5HT was diluted to 100x in US 9,303,045 B2 127 HBSS/20 mM HEPES (final concentration in the assay 216 TABLE 2-continued nM) and 15ul was added to each well of the addition plate, Cpd. No. Cpd. No. Cpd. No. 15ul of 10x compound was also added to the addition plate, from from from and finally 120 uL of HBSS/20 mMHEPES (for a total of 150 Table I IC50 Table I IC50 Table I IC50 uL). Cells were then removed from the incubator and equili 5 above nM above nM above nM brated to room temperature for 10 minutes, then 22.5 uL of 171 1.1OSS 172 2.89 174 2.06S 10x test compounds were added in triplicate to the plates and 175 O861 177 3.219 178 1.027 incubated at room temperature for 10 minutes (Tropisetron 18O S.914 181 1.10 182 1.62 was used as a positive control in every assay). Test plate and 183 1.27 184 1.25 18S 3.06 addition plate were loaded into the FlexStation III (Molecular 10 186 1...SO 187 1.18 188 1.75 Devices), and using the fluidics, 22.5ull compound additions 189 O46 190 0.75 were made (at t=-17 seconds), and fluorescence was mea Sured for 90 seconds, reading every 2.2 seconds. Data sets were analyzed as max minus min using Software Max Pro Biological Example 2 (Molecular Devices). ICso curves were generated using non 15 linear regression in GraphPad Prism. Rodent Novel Object Recognition (NOR) Assay in Approximate ICso values of a representative number of Phencyclidine-Induced Cognitive Deficits Modeling compounds of the invention this assay are provided in the Schizophrenia Table 2 below. The aim of this study was to investigate the ability of the TABLE 2 compounds of the invention to improve subchronic PCP Cpd. No. Cpd. No. Cpd. No. induced impairment in cognition memory using the NOR task from from from in the rat, a paradigm of relevance to cognition in Schizophre Table I IC50 Table I IC50 Table I IC50 nia. Adult male Sprague-Dawley rats (250-350 g; Harlan, above nM above nM above nM USA) were used for the experiments Animal were acclimated 1 2.13 2 1.71 3 1.03 to the facility for 7 days prior to experimentation. Seven 4 1.4 5 1.35 6 2.33 groups of 14 animals per group were used for the experiment. 7 O.49 8 O.68 9 1.8 10 0.57 11 O.95 12 O.45 One group of animals received vehicle (0.9% saline twice 13 O.93 14 3.71 15 O.S3 30 daily) and the remaining six groups received PCP (2.5 mg/kg, 16 3.25 17 4.39 18 4.06 s.c. twice daily) for 7 days, followed by 5-days drug free. On 19 7.72 2O 0.4 21 O40 22 1.13 24 1.06 25 3.88 the test day, the animals were allowed to acclimate to the 26 O.S4 27 O.89 28 O8 testing room for 30 min prior to initiation of experiments. 29 O.9S 30 O.2O 31 29 Experiments were carried out in a white plexiglass chamber, 32 1.38 33 14.41 34 O.74 35 designated as experimental arena. The arena was placed in a 35 O.S4 36 OSO 37 >1000 38 1.82 39 24.1 40 O.78 dark experimental room that was illuminated by a halogen 41 5.56 42 O.94 43 O2 lamp, providing a dim light to the arena. 44 1.87 45 3.09 46 O.S9 Animals were placed in the arena for a 5 minute period to 47 O.33 48 O.84 49 82 freely explore the test chamber in the absence of objects 50 13.0 51 O.6O 52 OS 40 53 1.OS S4 S.61 55 O.90 (habituation). Animals were then returned to their home cage 56 O.S3 57 >1000 58 O.24 immediately upon completion of habituation for a 120 min 59 2.36 60 0.44 61 O period. (1R,3R,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 62 0.75 63 O49 64 43 1-(2.2.2-trifluoroethyl)-1H-indole-3-carboxylate (0.1. 1, 10 65 4.09 66 1.07 67 >1000 68 O.9S 69 1.06 70 13 mg/kg, s.c.), or vehicle (veh, Saline) was administered 120 min 71 O.S1 72 3.59 73 3.15 45 prior to T1 and galantamine (5 mg/kg, i.p.) was administered 74 O.42 75 3.15 76 22 30 min prior to T1. Animals were returned to the arena which 77 1O.S 78 4.81 79 O41 contained two identical objects (plastic balls) placed at one 8O O3 81 1.44 82 >1000 83 .04 84 1.64 85 .04 end of the arena (acquisition, T1), and allowed to explore for 86 2.48 87 O.18 88 O.22 a 5 min period. The time spent exploring the two objects was 89 O.66 90 0.75 91 >1000 50 recorded Animals were once again returned to the home cage 93 39 95 O.89 96 O.83 97 45 98 5.45 99 O.29 for a period of 120 min (ITI). OO 12.79 O1 >1000 O2 >1000 ITI was followed by the retention phase (T2) where one of O3 8.2 O4 >1000 05 34.13 the objects presented in the first trial was replaced by a novel O7 .1 O8 1.OS 09 1.11 object and animals were allowed to explore for an additional 10 11 O.77 12 O.S3 55 5 min period. Again, the time spent exploring the two objects 13 O.23 16 >1000 17 O.39 18 O.86 19 O4O 2O O.39 was recorded. 22 O1 23 O.28 26 O.86 For the retention phase, the differences between the time 27 O.22 28 2.16 29 O.64 spent exploring the familiar object and the novel object were 30 0.55 31 1.93 32 2.30 33 SO 34 1.99 35 11.7 examined. All sessions were recorded and scored blindly for 36 O.914 37 O681 41 1119 60 the time exploring objects. Exploration is defined as touching 42 O.9457 43 O41SS 44 O.61 the object or directing nose towards object at a distance less 45 2.71 46 O.702 47 O40 that 2 cm. A minimal exploration criterion was used such that 48 O.40 53 O.87 S4 O.328 only animals with exploration time of greater than 5 seconds 55 1.26 58 1.36 59 O.2985 60 0.746 61 >1000 62 1.81 per object were included. 63 1.81 64 1.1795 65 1.533 65 Comparisons of all treatment groups were conducted using 68 1.16S 69 0.5975 70 1.5 a one-way ANOVA followed by a Bonferroni’s post hoc test for multiple comparisons. US 9,303,045 B2 129 130 Results: Vehicle/vehicle-treated animals displayed a statis What is claimed is: tically significant discrimination between familiar (TF) and 1. A compound of Formula (I): novel objects (TN) (27.99+2.77 (TN) versus 15.74+2.118 (TF) at a 2h ITI, indicative of good performance and/or lack 5 (I) or cognitive deficit. In contrast, the vehicle/PCP-treated ani R mals displayed a statistically non-significant discrimination O | between familiar and novel objects 23.31+1.998 (TN) versus Z 17.13+1.112 (TF). Galantamine-treated animals, the posi X4 tive control group, displayed a statistically significant dis 10 x1's--\ crimination between familiar and novel objects 22.8-2.2 X22 NNAs (TN) versus 11.19+1.376 (TF) at a 2 h ITI, indicative of X V reversal of the PCP-induced cognitive deficits. (1R,3R,5S)- R4 8-methyl-8-azabicyclo3.2.1]octan-3-yl 1-(2.2.2-trifluoroet 15 hyl)-1H-indole-3-carboxylate did not demonstrate a statisti wherein: Z is O or NR; cally significant discrimination between familiar and novel R is hydrogen or Ce alkyl, objects at 0.1 mg/kg 0.01 mg/kg. 22.9+3.65 (TN) versus R is a ring of the formula (a), (d), (e), or (g) below: 12.5+2.152 (TF) but demonstrated a statistically significant discrimination between familiar and novel objects at 1 and 10 mg/kg, 0.1 mg/kg: 25.3+2.51 (TN) versus 12.7+1.027 (TF). (a) 10 mg/kg 22.8+2.48 (TN) versus 9.831+1.53 (TF)), indica tive of an attenuation of PCP-induced cognitive deficits. 25 Formulation Examples The following are representative pharmaceutical formula tions containing a compound of Formula (I). 30 (d) Tablet Formulation

The following ingredients are mixed intimately and 35 pressed into single scored tablets.

Ingredient Quantity per tablet 40 (e) compound of this invention 0.5-150 mg cornstarch 50 mg croscarmellose sodium 25 mg lactose 120 mg 45 magnesium Stearate 5 mg Capsule Formulation

50 The following ingredients are mixed intimately and loaded (f) into a hard-shell gelatin capsule.

Ingredient Quantity per capsule 55

compound of this invention 0.5-150 mg (g) lactose spray dried 148 mg magnesium Stearate 2 mg 60 Injectable Formulation

Compound of the invention (e.g., compound 1) in 2% 65 HPMC, 1% Tween 80 in DI water, pH 2.2 with MSA, q.s. to at least 20 mg/mL.