5-HT3 receptor antagonists
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.
1. 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 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, cyano, or halo;
each R 5 is independently hydrogen, C 1-6 alkyl, halo, hydroxy, or cyano provided that at least one of R 5 is hydrogen;
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 of claim 1 wherein R 1 is a ring of formula (a) or (d).
3. The compound or pharmaceutically acceptable salt of claim 1 wherein R 1 is a ring of formula (e), (f), or (g).
4. The compound or pharmaceutically acceptable salt of claim 1 wherein R 1 is a ring of formula (e).
5. The compound or pharmaceutically acceptable salt any one of claims 1 , 2 , 3 and 4 wherein each R 3 is hydrogen.
6. The compound or pharmaceutically acceptable salt any one of claims 1 , 2 , 3 and 4 wherein R 2 is hydrogen and each R 3 is hydrogen.
7. The compound or pharmaceutically acceptable salt any one of claims 1 , 2 , 3 and 4 wherein each R 3 is independently hydrogen or methyl and R 2 is C 1-6 alkyl.
8. The compound or pharmaceutically acceptable salt any one of claims 1 , 2 , 3 and 4 wherein R 2 is methyl and each R 3 is hydrogen.
9. The compound or pharmaceutically acceptable salt of claim 8 wherein each R 5 is hydrogen.
10. A compound claim 1 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,7)-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-d 3 -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-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,
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,
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; and
N-((1R,5S,7S)-9-ethyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(1-methyl-1H-pyrazol-4-yl)-1H-indole-3-carboxamide;
or a pharmaceutically acceptable salt of each above mentioned compound.
11. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
12. The compound of claim 1 which is N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(pyridin-3-yl)-1H-indole-3-carboxamide or a pharmaceutically acceptable salt thereof.
13. The compound of claim 1 which 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 or a pharmaceutically acceptable salt thereof.
14. A method of treating depression comprising: administrating to a patient in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
15. A method of treating cognitive impairment associated with schizophrenia comprising: administrating to a patient in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.