5-HT3 receptor antagonists

Patent metadata

Field	Value
Publication number	US-10407443-B2
Application number	US-201816041875-A
Country	US
Kind code	B2
Filing date	Jul 23, 2018
Priority date	Jul 17, 2012
Publication date	Sep 10, 2019
Grant date	Sep 10, 2019

Abstract

The present invention provides 5-HT3 receptor antagonists of Formula (I):

which are 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.

First claim

What is claimed is:

1. A method of treating in a subject at least one disease, disorder, or condition treatable by inhibition of the 5-HT3 receptor, wherein the at least one disease, disorder, or condition treatable by inhibition of the 5-HT3 receptor is select from the group consisting of: emesis, migraine, substance abuse and addiction, anxiety, depression, eating disorders, schizophrenia, Parkinson's disease, cognitive dysfunction associated with Parkinson's disease, Huntington's Chorea, pre-senile dementia, Alzheimer's disease, pain, dyspepsia, gastroesophageal reflux disease, irritable bowel syndrome, atherosclerosis, tendomyopathies, and fibromyalgia, the method comprising
(a) administering to the subject a compound of Formula (I):

wherein:
Z is O or NR a where R a is hydrogen or C 1-6 alkyl;
R 1 is a ring of the formula (a)-(h) below:

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 pyridinyl or pyrazolyl 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, cyano, or halo;
all of X 1 , X 2 , X 3 , and X 4 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; and
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 method of claim 1 , wherein R 1 is a ring of formula (a) or (d).

3. The method of claim 1 , wherein R 1 is a ring of formula (e), (f), or (g).

4. The method of claim 1 , wherein R 1 is a ring of formula (e).

5. The method of claim 1 , wherein each R 3 is hydrogen.

6. The method of claim 1 , wherein R 2 is hydrogen and each R 3 is hydrogen.

7. The method of claim 1 , wherein each R 3 is independently hydrogen or methyl and R 2 is C 1-6 alkyl.

8. The method of claim 1 , wherein R 2 is methyl and each R 3 is hydrogen.

9. The method of claim 1 , wherein all of X 1 , X 2 , X 3 , and X 4 are CR 5 and each R 5 is hydrogen.

10. The method of claim 1 , wherein the compound is selected from:
(1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(pyridin-3-yl)-1H-indole-3-carboxylate;
(1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-1H-indole-3-carboxylate;
N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(pyridin-2-yl)-1H-indole-3-carboxamide;
N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(pyridin-4-yl)-1H-indole-3-carboxamide;
N-((1R,5S,7S)-9-methyl-d 3 -3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(pyridin-3-yl)-1H-indole-3-carboxamide;
N-((1R,5S,7S)-9-methyl-d3-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(pyridin-2-yl)-1H-indole-3-carboxamide;
N-((1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(2-methylpyridin-3-yl)-1H-indole-3-carboxamide;
N-((1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(4-methylpyridin-3-yl)-1H-indole-3-carboxamide;
1-(1-methyl-1H-pyrazol-4-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-pyrazol-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-pyrazol-5-yl)-N-((1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1H-indole-3-carboxamide;
1-(1-difluoromethyl)-1H-pyrazol-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)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(1-methyl-1H-pyrazol-4-yl)-1H-indole-3-carboxylate;
N-((1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(pyridin-3-yl)-1H-indole-3-carboxamide;
N-((1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(1-methyl-1H-pyrazol-4-yl)-1H-indole-3-carboxamide;
(1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(1H-pyrazol-4-yl)-1H-indole-3-carboxylate;
N-((1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(1H-pyrazol-4-yl)-1H-indole-3-carboxamide; or
N-((1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(1H-pyrazol-4-yl)-1H-indole-3-carboxamide,
or a pharmaceutically acceptable salt of each-above mentioned compound.

11. The method of claim 1 , wherein the compound is 1-(1-methyl-1H-pyrazol-4-yl)-N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1H-indole-3-carboxamide.

12. A method of inhibiting the 5-HT3 receptor in a subject, the method comprising
(a) administering to the subject a compound of Formula (I):

wherein:
Z is O or NR a where R a is hydrogen or C 1-6 alkyl;
R 1 is a ring of the formula (a)-(h) below:

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 pyridinyl or pyrazolyl 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, cyano, or halo;
all of X 1 , X 2 , X 3 , and X 4 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; and
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.

13. The method of claim 12 , wherein the compound is 1-(1-methyl-1H-pyrazol-4-yl)-N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1H-indole-3-carboxamide.

14. The method of claim 12 , wherein the compound is selected from:
(1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(pyridin-3-yl)-1H-indole-3-carboxylate;
(1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-1H-indole-3-carboxylate;
N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(pyridin-2-yl)-1H-indole-3-carboxamide;
N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(pyridin-4-yl)-1H-indole-3-carboxamide;
N-((1R,5S,7S)-9-methyl-d 3 -3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(pyridin-3-yl)-1H-indole-3-carboxamide;
N-((1R,5S,7S)-9-methyl-d3-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(pyridin-2-yl)-1H-indole-3-carboxamide;
N-((1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(2-methylpyridin-3-yl)-1H-indole-3-carboxamide;
N-((1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(4-methylpyridin-3-yl)-1H-indole-3-carboxamide;
1-(1-methyl-1H-pyrazol-4-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-pyrazol-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-pyrazol-5-yl)-N-((1R,5S,7s)-9-methyl-3-oxa-9-azabicycl

Assignees

• Takeda Pharmaceuticals Co

Inventors

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

Classifications

• A61P43/00

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

• A61P39/02

  Antidotes · CPC title

• A61P39/00

  General protective or antinoxious agents · CPC title

• A61P37/02

  Immunomodulators · 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