5-HT3 receptor antagonists

Patent metadata

Field	Value
Publication number	US-9303045-B2
Application number	US-201314415712-A
Country	US
Kind code	B2
Filing date	Jul 16, 2013
Priority date	Jul 17, 2012
Publication date	Apr 5, 2016
Grant date	Apr 5, 2016

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

What is claimed is:

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), (d), (e), or (g) 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, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, and pyridazinyl, 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 ;
each R 5 is hydrogen;
X 5 is CR 6 where R 6 is hydrogen, C 1-6 alkyl, or halo;
or a pharmaceutically acceptable salt thereof or N-oxide thereof.

2. The compound or pharmaceutically acceptable salt according to claim 1 , wherein Z is O.

3. The compound or pharmaceutically acceptable salt according to claim 1 , wherein Z is NH.

4. The compound or pharmaceutically acceptable salt according to claim 3 , wherein R 1 is a ring of formula (a) or (d).

5. The compound or pharmaceutically acceptable salt according to claim 3 , wherein R 1 is a ring of formula (e), (f), or (g).

6. The compound or pharmaceutically acceptable salt according to claim 3 , wherein R 1 is a ring of formula (e).

7. The compound or pharmaceutically acceptable salt according to claim 6 , wherein each R 3 is hydrogen.

8. The compound or pharmaceutically acceptable salt according to claim 7 , wherein R 2 is methyl.

9. The compound or pharmaceutically acceptable salt according to claim 1 , wherein X 5 is CR 6 and R 6 is hydrogen.

10. The compound according to claim 1 which is selected from:
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-d 3 -3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(pyridazin-3-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-(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;
(1 R,5S,7s)-3-oxa-9-azabicyclo [3.3.1 ]nonan-7-yl 1-(pyrazin-2-yl)-1H-indole-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;
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-yl1-(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;
(1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl1-(6-hydroxypyridazin-3-yl) -1H-indole-3-carboxylate;
(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)-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; 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.

11. A pharmaceutical composition comprising a compound as defined in claim 1 , or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

Assignees

• Takeda Pharmaceutical

Inventors

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

Classifications

• A61P39/02

  Antidotes · CPC title

• 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

• A61P39/00

  General protective or antinoxious agents · CPC title

• A61P43/00

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

• A61P37/02

  Immunomodulators · CPC title