US2018072758A1PendingUtilityA1
5ht3 receptor antagonists

Assignee: TAKEDA PHARMACEUTICALS COPriority: Jul 17, 2012Filed: May 31, 2017Published: Mar 15, 2018
Est. expiryJul 17, 2032(~6 yrs left)· nominal 20-yr term from priority
Inventors:Stephen Hitchcock Holger Monenschein Holly Reichard Huikai Sun Shota Kikuchi Todd Macklin Maria Hopkins
A61P 37/02A61P 43/00A61P 39/00A61P 9/10A61P 39/02A61P 25/14A61P 25/04A61P 25/24A61P 25/28A61P 25/06A61P 25/22A61P 29/00A61P 25/18A61P 25/16A61P 29/02A61P 3/04A61P 25/30A61P 21/00A61P 1/00A61P 19/04A61P 1/08A61P 25/00A61P 1/04A61P 1/14C07D 519/00C07D 451/12C07D 453/02C07D 221/22C07D 498/08A61K 31/19C07D 471/04C07C 53/40C07D 401/14A61K 31/5386C07C 53/18C07D 487/14C07D 471/08C07D 403/14C07D 498/04
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References
Claims
Abstract

The present invention provides compounds of the formula: that are 5-HT3 receptor antagonists and are therefore useful for the treatment of diseases treatable by inhibition of 5-HT3 receptor such as emesis, pain, drug addiction, neurodegenerative and psychiatric disorders, and GI disorders. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.
Claims

exact text as granted — not AI-modified
1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         Z is O or NR a ; 
         R a  is hydrogen or C 1-6  alkyl; 
         R 1  is a ring of the formula (a)-(h) below: 
       
       
         
           
           
               
               
           
         
         wherein:
 R 2  is hydrogen, C 1-6  alkyl, or C 1-6  haloalkyl; 
 each R 3  is independently hydrogen, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkoxy, or halo and can be present on any carbon atom in the rings; 
 R 4  is heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, pyrimidyl, azepinyl, diazepinyl, quinolyl, isoquinolyl, quinolizidine, benzofuranyl, benzothienyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzoxadiazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzopyrazinyl, benzopyrazidinyl, benzoazepinyl, benzodiazepinyl, imidazopyridyl, pyrazolopyridyl, pyrrolopyridyl, quinazolyl, purinyl, furopyridyl, and thienopyridyl, each R 4  heteroaryl is optionally substituted with one or two substituents independently selected from C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  haloalkoxy, C 1-6  alkoxy, hydroxy, cyano, or halo; 
 all of X 1 -X 4  are CR 5  or one of X 1 -X 4  is N and the others are CR 5 ; 
 each R 5  is independently hydrogen, C 1-6  alkyl, halo, hydroxy, or cyano provided that at least one of R 5  is hydrogen; 
 X 5  is N or CR 6  where R 6  is hydrogen, C 1-6  alkyl, or halo; 
 or a pharmaceutically acceptable salt thereof or N-oxide 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-Indazole-3-carboxamide. 
 
       
     
     
         2 . The compound or pharmaceutically acceptable salt of  claim 1 , wherein R 4  is selected from the group consisting of furanyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, each optionally substituted with one or two substituents independently selected from C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  haloalkoxy, C 1-6  alkoxy, hydroxy, cyano, or halo. 
     
     
         3 . The compound or pharmaceutically acceptable salt of  claim 1 , wherein Z is O. 
     
     
         4 . The compound or pharmaceutically acceptable salt of  claim 1 , wherein Z is NH. 
     
     
         5 . The compound or pharmaceutically acceptable salt of  claim 1 , wherein R 1  is a ring of formula (a), (d), (e), (f), or (g). 
     
     
         6 . The compound or pharmaceutically acceptable salt of  claim 5 , wherein R 1  is a ring of formula (a) or (d). 
     
     
         7 . The compound or pharmaceutically acceptable salt of  claim 5 , wherein R 1  is a ring of formula (e), (f), or (g). 
     
     
         8 . The compound or pharmaceutically acceptable salt of  claim 5 , wherein R 1  is a ring of formula (e). 
     
     
         9 . The compound or pharmaceutically acceptable salt of  claim 1 , wherein each R 3  is hydrogen. 
     
     
         10 . The compound or pharmaceutically acceptable salt of  claim 1 , wherein R 2  is methyl. 
     
     
         11 . The compound or pharmaceutically acceptable salt of  claim 1 , wherein is where all of X 1 -X 4  are CR 5  and each R 5  is hydrogen. 
     
     
         12 . The compound or pharmaceutically acceptable salt of  claim 11 , wherein X 5  is N. 
     
     
         13 . The compound or pharmaceutically acceptable salt of  claim 11 , wherein X 5  is CR 6  and R 6  is hydrogen. 
     
     
         14 . A compound of  claim 1  selected from:
 (1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 5-fluoro-1-(2,2,2-trifluoroethyl)-1H-indole-3-carboxylate; 
 (1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 5-fluoro-1-((R)-tetrahydrofuran-3-yl)-1H-indole-3-carboxylate; 
 (1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-methyl-1-(methylsulfonyl)-1H-indole-3-carboxylate; 
 (1R,3R,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl 1-(methylsulfonyl)-1H-indazole-3-carboxylate; 
 N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; 
 N-((1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-5-fluoro-1-(2,2,2-trifluoroethyl)-1H-indole-3-carboxamide; 
 1-(2,2-difluoroethyl)-N-((1R,3R,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-1H-indazole-3-carboxamide; 
 N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(2,2,2-trifluoroethyl)-1H-indole-3-carboxamide; 
 (1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(isopropylsulfonyl)-1H-indole-3-carboxylate; 
 1-(isopropylsulfonyl)-N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1H-indole-3-carboxamide; 
 1-(2-fluoroethyl)-N-((1R,3R,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-1H-indazole-3-carboxamide; 
 (1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-chloro-1-(methylsulfonyl)-1H-indole-3-carboxylate; 
 (1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl 1-(2,2,2-trifluoroethyl)-1H-indole-3-carboxylate (1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 1-(2-fluoroethyl)-2-methyl-1H-indole-3-carboxylate; 
 (1R,3R,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl 1-(2-fluoroethyl)-1H-indazole-3-carboxylate; 
 (1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 1-(2,2,2-trifluoroethyl)-1H-indazole-3-carboxylate; 
 5-fluoro-N-((1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1-(methylsulfonyl)-1H-indole-3-carboxamide; 
 (1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 5-fluoro-1-(methylsulfonyl)-1H-indole-3-carboxylate; 
 1-(2,2-difluoroethyl)-N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1H-indazole-3-carboxamide; 
 1-(2,2-difluoroethyl)-N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1H-indole-3-carboxamide; 
 N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-((S)-1,2,2,2-tetrafluoroethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; 
 5-fluoro-1-(2,2,2-trifluoroethyl)-N-((1R,5S,7S)-9-(1,1,1-trideuteriomethyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; 
 (1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(pyrimidin-2-yl)-1H-indole-3-carboxylate; 
 (1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 1-(methylsulfonyl)-1H-indole-3-carboxylate; 
 (1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 1-(2,2-difluoroethyl)-5-fluoro-1H-indole-3-carboxylate; 
 (1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2,3-dihydrooxazolo[3,2-a]indole-9-carboxylate; 
 (1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 5-fluoro-1-(tetrahydrofuran-3-yl)-1H-indole-3-carboxylate; 
 (1R,3R,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl 2-chloro-1-(2-fluoroethyl)-1H-indole-3-carboxylate; 
 (1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(2,2-difluoroethyl)-5-fluoro-1H-indole-3-carboxylate; 
 (1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 5-fluoro-1-(2,2,2-trifluoroethyl)-1H-indole-3-carboxylate; 
 (1R,5S,7S)-9-(2-fluoroethyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl difluoroethyl)-5-fluoro-1H-indole-3-carboxylate; 
 (1R,3R,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl 5-fluoro-1-(methylsulfonyl)-1H-indole-3-carboxylate; 
 5-fluoro-N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(2,2,2-trifluoroethyl)-1H-indole-3-carboxamide; 
 5-fluoro-N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(methylsulfonyl)-1H-indole-3-carboxamide; 
 quinuclidin-4-yl 5-fluoro-1-(methylsulfonyl)-1H-indole-3-carboxylate; 
 N-((1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; 
 N-((1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(2,2-difluoroethyl)-5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; 
 (1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 1-(2,2-difluoroethyl)-1H-indole-3-carboxylate; 
 (1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate; 
 (1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 1-(tetrahydrofuran-3-yl)-1H-indole-3-carboxylate; 
 (1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-chloro-1-(2,2-difluoroethyl)-1H-indole-3-carboxylate; 
 (1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-chloro-1-(2,2,2-trifluoroethyl)-1H-indole-3-carboxylate; 
 (1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl 1-(2,2-difluoroethyl)-1H-indole-3-carboxylate N-((1R,3R,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-1-(methylsulfonyl)-1H-indazole-3-carboxamide; 
 (1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(methylsulfonyl)-1H-indole-3-carboxylate; 
 (1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate; 
 (1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate; 
 (1R,5S,7S)-9-(2-fluoroethyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 5-fluoro-1-(2,2,2-trifluoroethyl)-1H-indole-3-carboxylate; 
 (1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(2-fluoroethyl)-1H-indole-3-carboxylate; 
 5-fluoro-N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; 
 5-fluoro-N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(1,1,2,2-tetrafluoroethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; 
 (1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 5-fluoro-1-(isopropylsulfonyl)-1H-indole-3-carboxylate; 
 (1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-chloro-1-(2-fluoroethyl)-1H-indole-3-carboxylate; 
 (1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 1-(2-fluoroethyl)-1H-indole-3-carboxylate; 
 (1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 1-(2-fluoroethyl)-1H-indazole-3-carboxylate; 
 (1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(2,2-difluoroethyl)-5-fluoro-1H-indole-3-carboxylate; 
 (1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 5-fluoro-1-(2,2,2-trifluoroethyl)-1H-indole-3-carboxylate; 
 (1R,3R,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl 1-(2,2-difluoroethyl)-5-fluoro-1H-indole-3-carboxylate; 
 (1R,3R,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl 1-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate; 
 N-((1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1-(methylsulfonyl)-1H-indazole-3-carboxamide; 
 1-(2,2-difluoroethyl)-5-fluoro-N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]-nonan-7-yl)-1H-indole-3-carboxamide; 
 1-(2,2-difluoroethyl)-N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; 
 N-((1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(2,2-difluoroethyl)-1H-indazole-3-carboxamide; 
 1-(2,2-difluoroethyl)-N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide; 
 (R)-1-(2,2-difluoroethyl)-N-(quinuclidin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; 1-(2,2-difluoroethyl)-5-fluoro-N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]-nonan-7-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; 
 N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; 
 N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-((R)-1,2,2,2-tetrafluoroethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; 
 (1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 1-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate; 
 (1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 1-(2,2-difluoroethyl)-2-methyl-1H-indole-3-carboxylate; 
 N-((1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1-(methylsulfonyl)-1H-indole-3-carboxamide; 
 1-(2,2-difluoroethyl)-5-fluoro-N-((1R,3R,5 S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-3-carboxamide; 
 1-(2,2-difluoroethyl)-N-((1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; 
 1-(2,2-difluoroethyl)-N-((1R,3R,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; 
 N-((1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-5-fluoro-1-(methylsulfonyl)-1H-indole-3-carboxamide; 
 1-(2-fluoroethyl)-N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1H-indole-3-carboxamide; 
 N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(1,1,2,2-tetrafluoroethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; 
 N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(1,2,2,2-tetrafluoroethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; 
 N-((1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; 
 (1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 1-((S)-tetrahydrofuran-3-yl)-1H-indole-3-carboxylate; 
 (1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2,3,4,5-tetrahydro-[1,3]oxazepino-[3,2-a]indole-11-carboxylate; 
 (1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxylate; 
 (1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 5-fluoro-1-(methylsulfonyl)-1H-indole-3-carboxylate; 
 (1R,3R,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl 1-(2-fluoroethyl)-1H-indole-3-carboxylate; 
 (1R,3R,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl 1-(2-fluoroethyl)-2-methyl-1H-indole-3-carboxylate; 
 (1R,3R,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl 5-fluoro-1-(2,2,2-trifluoroethyl)-1H-indole-3-carboxylate; 
 1-(2,2-difluoroethyl)-N-((1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indazole-3-carboxamide; 
 (1S,5R,6S)-4-oxa-1-azabicyclo[3.3.1]nonan-6-yl 1-(2,2-difluoroethyl)-5-fluoro-1H-indole-3-carboxylate; 
 5-fluoro-1-(isopropylsulfonyl)-N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]-nonan-7-yl)-1H-indole-3-carboxamide; 
 (1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 1-((S)-tetrahydrofuran-3-yl)-1H-indole-3-carboxylate; 
 (1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 5-fluoro-1-((S)-tetrahydrofuran-3-yl)-1H-indole-3-carboxylate; 
 1-(2,2-difluoroethyl)-5-fluoro-N-((1R,3R,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-1H-indole-3-carboxamide; 
 (1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 5-fluoro-1-(methylsulfonyl)-1H-indole-3-carboxylate; 
 5-fluoro-N-((1R,3R,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-1-(methylsulfonyl)-1H-indole-3-carboxamide; 
 (1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate; 
 N-((1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; 
 (1R,3R,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl 1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate; 
 1-(2,2-difluoroethyl)-N-((1R,5S,7S)-9-(trifluoromethyl)-3-oxa-9-azabicyclo[3.3.1]-nonan-7-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; 
 N-((1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-5-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; 
 N-((1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(pyrimidin-2-yl)-1H-indole-3-carboxamide; 
 1-(2,2-difluoropropyl)-N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; 
 1-(2,2-difluoroethyl)-5-fluoro-N-((1R,5S,7S)-9-methyl-d 3 -3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; 
 N-((1R,5S,7S)-9-methyl-d 3 -3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(methylsulfonyl)-1H-indole-3-carboxamide; 
 N-((1R,5S,7S)-9-methyl-d 3 -3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(isopropylsulfonyl)-1H-indole-3-carboxamide; 
 1-(2,2,2-trifluoroethyl)-5-fluoro-N-((1R,5S,7S)-9-methyl-d 3 -3-oxa-9-azabicyclo-[3.3.1]nonan-7-yl)-1H-indole-3-carboxamide; 
 1-(2,2-difluoroethyl)-5-fluoro-N-((1R,5S,7S)-9-methyl-d 3 -3-oxa-9-azabicyclo-[3.3.1]nonan-7-yl)-1H-indole-3-carboxamide; 
 (S)-1-(2,2-difluoroethyl)-N-(quinuclidin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; 
 N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(pyridazin-3-yl)-1H-indole-3-carboxamide; 
 N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(thiazol-2-yl)-1H-indole-3-carboxamide; 
 N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(thiazol-5-yl)-1H-indole-3-carboxamide; 
 N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(pyrimidin-5-yl)-1H-indole-3-carboxamide; 
 N-((1R,5S,7S)-9-methyl-d 3 -3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(pyrimidin-2-yl)-1H-indole-3-carboxamide; 
 N-((1R,5S,7S)-9-methyl-d 3 -3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(pyridazin-3-yl)-1H-indole-3-carboxamide; 
 (1R,5S,7S)-9-methyl-d 3 -3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(2,2,2-difluoroethyl)-1H-indole-3-carboxylate; 
 (1R,5S,7S)-9-methyl-d 3 -3-oxa-9-azabicyclo[3.3.1]nonan-7-yl difluoroethyl)-1H-indole-3-carboxylate; 
 N-((1R,5S,7S)-9-methyl-d 3 -3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-3-carboxamide; 
 1-(2-fluoroethyl)-N-((1R,5S,7S)-9-methyl-d 3 -3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1H-indole-3-carboxamide; 
 (1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(thiazol-2-yl)-1H-indole-3-carboxylate; 
 N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(pyrazin-2-yl)-1H-indole-3-carboxamide; 
 N-((1R,5S,7S)-9-methyl-d 3 -3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(pyrazin-2-yl)-1H-indole-3-carboxamide; 
 (1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(isopropylsulfonyl)-1H-indole-3-carboxylate; 
 (1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 5-fluoro-1-(methylsulfonyl)-1H-indole-3-carboxylate; 
 (1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(ethylsulfonyl)-1H-indole-3-carboxylate; (1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(cyclopropylsulfonyl)-1H-indole-3-carboxylate; 
 (1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(isobutylsulfonyl)-1H-indole-3-carboxylate; 
 (1R,5S,7s)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(pyridazin-3-yl)-1H-indole-3-carboxylate; (1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(6-fluoropyridazin-3-yl)-1H-indole-3-carboxylate; 
 (1R,5S,7s)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(pyrazin-2-yl)-1H-indole-3-carboxylate; (1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(cyanomethyl)-7-fluoro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate; 
 (1R,5S,7s)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(isothiazol-4-yl)-1H-indole-3-carboxylate; 1-(isothiazol-4-yl)-N-((1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1H-indole-3-carboxamide; 
 (1R,5S,7s)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(isothiazol-3-yl)-1H-indole-3-carboxylate; N-((1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; 
 N-((1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(thiazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; 
 N-((1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; 
 1-(isothiazol-3-yl)-N-((1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1H-indole-3-carboxamide; 
 1-(1-methyl-1H-imidazol-5-yl)-N-((1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1H-indole-3-carboxamide; 
 (1R,5S,7s)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(isothiazol-5-yl)-1H-indole-3-carboxylate; 1-(isothiazol-5-yl)-N-((1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1H-indole-3-carboxamide; 
 1-(cyanomethyl)-N-((1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1H-indole-3-carboxamide; 
 (1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 5-cyano-1-(2-fluoroethyl)-1H-indole-3-carboxylate; 
 (1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 5-cyano-1-(6-fluoropyridazin-3-yl)-1H-indole-3-carboxylate; 
 5-fluoro-N-((1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; 
 5-fluoro-N-((1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(thiazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; 
 5-fluoro-N-((1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; 
 N-((1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(thiazol-5-yl)-1H-indazole-3-carboxamide; 
 (1R,5S,7s)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-1H-indole-3-carboxylate; 
 (1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(6-hydroxypyridazin-3-yl)-1H-indole-3-carboxylate; 
 (1R,5S,7s)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(2-cyanophenyl)-1H-indole-3-carboxylate; 
 (1R,5S,7s)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(3-cyanophenyl)-1H-indole-3-carboxylate; 
 N-((1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-phenyl-1H-indole-3-carboxamide; 
 (1R,5S,7s)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(oxazol-2-yl)-1H-indole-3-carboxylate; N-((1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(oxazol-2-yl)-1H-indole-3-carboxamide; 
 (1R,5S,7s)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(4-cyanophenyl)-1H-indole-3-carboxylate; (1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(pyrazin-2-yl)-1H-indole-3-carboxylate; 
 (1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(isothiazol-3-yl)-1H-indole-3-carboxylate; 
 (1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(thiazol-5-yl)-1H-indole-3-carboxylate; 
 (1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(5-fluoropyrazin-2-yl)-1H-indole-3-carboxylate; 
 N-((1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(isothiazol-4-yl)-N-methyl-1H-indole-3-carboxamide; 
 1-(isothiazol-4-yl)-N-methyl-N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1H-indole-3-carboxamide; 
 (1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(cyanomethyl)-1H-indole-3-carboxylate; 
 (1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(pyrimidin-2-yl)-1H-indole-3-carboxylate; 
 (1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(pyrimidin-5-yl)-1H-indole-3-carboxylate; and 
 N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(pyridazin-4-yl)-1H-indole-3-carboxamide; 
 or a pharmaceutically acceptable salt of each above mentioned compound. 
 
     
     
         15 . A pharmaceutical composition comprising a compound of  claim 1 , or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         16 . The use of a compound of  claim 1 , or pharmaceutically acceptable salt thereof, as a medicament.
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