Isoxazole based neuronal nicotinic receptor ligands and methods of use
View Patent ↗The invention relates to isoxazole derivatives, compositions comprising such compounds, and methods of preventing or treating conditions and disorders using such compounds and compositions.
1. A compound of formula (Ia):
wherein
Ar 1 is heteroaryl, substituted with 0, 1, 2 or 3 substitutions selected from the group consisting of acetyl, alkoxy, alkyl, alkylamino, amino, cyano, halo, haloalkoxy, haloalkyl, hydroxy, and nitro, wherein the heteroaryl is pyrazinyl, or pyrimidinyl;
Ar 2 is aryl, substituted with 1, 2 or 3 substitutions selected from the group consisting of acetyl, alkoxy, alkyl, alkylamino, amino, halo, haloalkoxy, haloalkyl, and nitro;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein Ar 1 is pyrazinyl.
3. The compound of claim 1 , wherein Ar 1 is pyrimidinyl.
4. The compound of claim 1 , selected from the group consisting of:
5-(2,4-difluorophenyl)-3-(pyrimidin-5-yl)isoxazole,
3-(pyrimidin-5-yl)-5-(3,4,5-trifluorophenyl)isoxazole,
5-(3,5-difluorophenyl)-3-(pyrimidin-5-yl)isoxazole,
5-(3-fluorophenyl)-3-(pyrimidin-5-yl)isoxazole,
5-(4-bromophenyl)-3-(pyrimidin-5-yl)isoxazole,
5-(4-chlorophenyl)-3-(pyrimidin-5-yl)isoxazole,
5-(3,4-difluorophenyl)-3-(pyrimidin-5-yl)isoxazole,
3-(pyrimidin-5-yl)-5-p-tolylisoxazole,
5-(3,4-dichlorophenyl)-3-(pyrimidin-5-yl)isoxazole,
5-(3-(difluoromethoxy)phenyl)-3-(pyrimidin-5-yl)isoxazole,
5-(4-fluorophenyl)-3-(pyrimidin-5-yl)isoxazole, and
3-(pyrimidin-5-yl)-5-m-tolylisoxazole,
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 , selected from the group consisting of:
5-(3-chlorophenyl)-3-(pyrazin-2-yl)isoxazole,
5-(3-fluorophenyl)-3-(pyrazin-2-yl)isoxazole,
5-(4-fluorophenyl)-3-(pyrazin-2-yl)isoxazole,
5-(3,4-difluorophenyl)-3-(pyrazin-2-yl)isoxazole,
3-(pyrazin-2-yl)-5-(3,4,5-trifluorophenyl)isoxazole, and
1-(3-(3-(pyrazin-2-yl)isoxazol-5-yl)phenyl)ethanone,
or a pharmaceutically acceptable salt thereof.
6. A compound of formula (Ib)
wherein
Ar 1 is heteroaryl, substituted with 0, 1, 2 or 3 substitutions selected from the group consisting of acetyl, alkoxy, alkyl, alkylamino, amino, cyano, halo, haloalkoxy, haloalkyl, hydroxy, and nitro, wherein the heteroaryl is pyridin-3-yl, pyrazinyl, or pyrimidinyl;
Ar 2 is an aryl, substituted with 2 or 3 substitutions selected from the group consisting of acetyl, alkoxy, alkyl, alkylamino, amino, halo, haloalkoxy, haloalkyl, and nitro
or a pharmaceutically acceptable salt thereof.
7. The compound of claim 6 , selected from the group consisting of:
5-(3,4-dichlorophenyl)-3-(pyridin-3-yl)isoxazole,
5-(4-fluoro-3-methylphenyl)-3-(pyridin-3-yl)isoxazole,
5-(3-fluoro-4-(trifluoromethoxy)phenyl)-3-(pyridin-3-yl)isoxazole,
5-(3,5-difluorophenyl)-3-(pyridin-3-yl)isoxazole,
5-(3,5-dimethoxyphenyl)-3-(pyridin-3-yl)isoxazole,
5-(2,4-difluorophenyl)-3-(pyridin-3-yl)isoxazole,
5-(3,4-difluorophenyl)-3-(pyridin-3-yl)isoxazole,
5-(3,4,5-trifluorophenyl)-3-(pyridin-3-yl)isoxazole,
or a pharmaceutically acceptable salt thereof.
8. A compound selected from the group consisting of:
5-(3-fluorophenyl)-3-(5-fluoropyridin-3-yl)isoxazole,
5-(4-chlorophenyl)-3-(5-fluoropyridin-3-yl)isoxazole,
5-(4-bromophenyl)-3-(5-fluoropyridin-3-yl)isoxazole,
5-(3,4-dichlorophenyl)-3-(5-fluoropyridin-3-yl)isoxazole,
5-(3,5-difluorophenyl)-3-(5-fluoropyridin-3-yl)isoxazole,
3-(5-fluoropyridin-3-yl)-5-(3,4,5-trifluorophenyl)isoxazole,
3-(5-fluoropyridin-3-yl)-5-(4-fluorophenyl)isoxazole,
5-(4-fluoro-3-methylphenyl)-3-(5-fluoropyridin-3-yl)isoxazole,
3-(5-fluoropyridin-3-yl)-5-(3-(trifluoromethyl)phenyl)isoxazole,
3-(5-fluoropyridin-3-yl)-5-(3-methylphenyl)isoxazole,
5-(3-fluoro-4-(trifluoromethoxy)phenyl)-3-(5-fluoropyridin-3-yl)isoxazole,
3-(3-(5-fluoropyridin-3-yl)isoxazol-5-yl) aniline,
5-(2-chlorophenyl)-3-(5-fluoropyridin-3-yl)isoxazole,
1-(3-(3-(5-fluoropyridin-3-yl)isoxazol-5-yl)phenyl)ethanone,
5-(3-(difluoromethoxy)phenyl)-3-(5-fluoropyridin-3-yl)isoxazole, and
5-(3,5-dimethoxyphenyl)-3-(5-fluoropyridin-3-yl)isoxazole,
or a pharmaceutically acceptable salt thereof.
9. A compound of selected from the group consisting of:
3-(5-chloropyridin-3-yl)-5-(3,4-dichlorophenyl)isoxazole,
3-(5-chloropyridin-3-yl)-5-(2,4-difluorophenyl)isoxazole,
5-(4-chlorophenyl)-3-(5-chloropyridin-3-yl)isoxazole,
3-(5-chloropyridin-3-yl)-5-(3,5-difluorophenyl)isoxazole,
3-(5-chloropyridin-3-yl)-5-(3,4,5-trifluorophenyl)isoxazole,
3-(5-chloropyridin-3-yl)-5-p-tolylisoxazole,
3-(5-chloropyridin-3-yl)-5-(3,4-difluorophenyl)isoxazole,
3-(5-chloropyridin-3-yl)-5-(4-fluorophenyl)isoxazole,
5-(3-chlorophenyl)-3-(5-chloropyridin-3-yl)isoxazole,
3-(5-chloropyridin-3-yl)-5-m-tolylisoxazole,
3-(5-chloropyridin-3-yl)-5-(4-fluoro-3-methylphenyl)isoxazole,
3-(6-chloropyridin-3-yl)-5-(2,4-difluorophenyl)isoxazole, and
5-(3-chlorophenyl)-3-(6-chloropyridin-3-yl)isoxazole;
or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1 , 8 , 9 and 6 , or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.