5-ht3 receptor antagonists

Patent metadata

Field	Value
Publication number	US-2016185801-A1
Application number	US-201615064407-A
Country	US
Kind code	A1
Filing date	Mar 8, 2016
Priority date	Jul 17, 2012
Publication date	Jun 30, 2016
Grant date	—

Abstract

The present invention provides compounds of the formula:

that are 5HT3 receptor antagonists and are therefore useful for the treatment of diseases treatable by inhibition of 5HT3 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.

First claim

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,5 S)-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-(methyl-sulfonyl)-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 1-(2,2-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-di

Assignees

• Takeda Pharmaceutical

Inventors

• Hitchcock Stephen
• Monenschein Holger
• Reichard Holly
• Sun Huikai
• Kikuchi Shota
• Macklin Todd
• Hopkins Maria

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P39/02

  Antidotes · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P39/00

  General protective or antinoxious agents · CPC title

• A61P37/02

  Immunomodulators · CPC title