Piperidine isoxazole and isothiazole orexin receptor antagonists
View Patent ↗The present invention is directed to piperidine isoxazole and isothiazole orexin compounds which are antagonists of orexin receptors. Such compounds are of the general structural formula I: wherein the variables are defined herein. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the prevention or treatment of such diseases in which orexin receptors are involved.
1. A compound of the formula I:
wherein:
A ring is selected from the group consisting of phenyl, pyridyl, thiophenyl, thiazolyl, pyrazinyl and pyrazolyl;
B ring is
wherein Y is O or S; and wherein symbol
indicates a bond of attachment;
each of R 1a , R 1b and R 1c is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4) C 1-6 alkyl, which is unsubstituted or substituted with one to four substituents independently selected from the group consisting of halogen, hydroxyl, C 3-6 cycloalkyl and phenyl.
(5) —O—C 1-6 alkyl, which is unsubstituted or substituted with one to four substituents independently selected from the group consisting of halogen, hydroxyl, C 3-6 cycloalkyl and phenyl.
(6) C 3-6 cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one to four substituents independently selected from R 4 , and
(7) —CN;
R 2 is selected from the group consisting of:
(1)
wherein each of R 6 and R 7 is independently selected from the group consisting of hydrogen, —C 1-2 alkyl, —C 1-2 alkyl substituted with 1-3 halogens and —C 3-6 cycloalkyl; and R 8 is hydrogen or —C 1-6 alkyl, and
(2) C 3-6 cycloalkyl, which is unsubstituted or substituted with one to three substituents independently selected from the group consisting of C 1-6 alkyl, halogen, hydroxyl, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, —(C═O)O—C 1-6 alkyl, and phenyl, wherein the phenyl is unsubstituted or substituted with C 1-6 alkyl, halogen, or C 1-6 alkyl-OH;
R 3 is selected from C 1-6 alkyl and C 3-6 cycloalkyl, wherein each of the alkyl and cycloalkyl is unsubstituted or substituted with one to two substituents independently selected from R 4 ;
R 4 is selected from the group consisting of:
(1) hydroxyl,
(2) halogen,
(3) C 1-6 alkyl,
(4) —C 3-6 cycloalkyl,
(5) —O—C 1-6 alkyl,
(6) —O—(C═O)—C 1-6 alkyl,
(7) —NH 2 ,
(8) —NH—C 1-6 alkyl,
(9) —NO 2 ,
(10) phenyl,
(11) —CO 2 H,
(12) —CN, and
(13) —S(O) 2 —C 1-6 alkyl,
each of R 10 and R 11 is independently selected from the group consisting of:
(a) hydrogen,
(b) C 1-6 alkyl, which is unsubstituted or substituted with one to four substituents independently selected from R 4 ,
(c) C 3-6 alkenyl, which is unsubstituted or substituted with one to four substituents independently selected from R 4 ,
(d) C 3-6 alkynyl, which is unsubstituted or substituted with one to four substituents independently selected from R 4 ,
(e) C 3-6 cycloalkyl which is unsubstituted or substituted with one to four substituents independently selected from R 4 ,
(f) phenyl, which is unsubstituted or substituted with one to four substituents independently selected from R 4 , and
(g) heterocycle, which is unsubstituted or substituted with one to four substituents independently selected from R 4 ; and
m is 0 or 1, n is 0 or 1 (wherein if m is 0 or n is 0, a bond is present);
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 of the formula Ia:
wherein Y is O or S; or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 of the formula Id:
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 of the formula Ie:
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 of the formula If:
wherein each of V and W is independently CH or N; or a pharmaceutically acceptable salt thereof.
6. The compound of claim 1 of the formula Ig;
wherein each of V and W is independently CH or N; or a pharmaceutically acceptable salt thereof.
7. The compound of claim 1 of the formula IIa:
wherein Y is O or S; or a pharmaceutically acceptable salt thereof.
8. The compound of claim 7 of the formula IId:
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 7 of the formula IIe:
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1c , if present, is hydrogen, and R 1a and R 1b are independently selected from the group consisting of:
(1) hydrogen,
(2) fluoro;
(3) chloro,
(4) bromo,
(5) methyl,
(6) ethyl,
(7) trifluoromethyl,
(8) cyclopropyl, which is unsubstituted or substituted with —CN, and
(9) —O—C 1-4 alkyl which is unsubstituted or substituted with 1-3 halogens.
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of:
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is methyl or ethyl.
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of:
(1) hydroxyl,
(2) halogen,
(3) C 1-6 alkyl,
(4) —C 3-6 cyclalkyl,
(5) —NH 2 ,
(6) phenyl, and
(7) —CN.
14. A compound which is selected from the group consisting of:
(1 2-{3-[(3R,6R)-6-Methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]isoxazol-5-yl}propan-2-ol),
(1-(2-((2R,5R)-5-(5-(2-Hydroxypropan-2-yl)isoxazol-3-yl)-2-methylpiperidine-1-carbonyl)phenyl)cyclopropanecarbonitrile),
(5-Chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-5-(5-(2-hydroxypropan-2-yl)isoxazol-3-yl)-2-methylpiperidin-1-yl)methanone,
(5-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-5-(5-(2-hydroxypropan-2-yl)isoxazol-3-yl)-2-methylpiperidin-1-yl)methanone,
((2-Ethoxyphenyl)((2R,5R)-5-(5-(2-hydroxypropan-2-yl)isoxazol-3-yl)-2-methylpiperidin-1-yl)methanone),
(((2R,5R)-5-(5-(2-Hydroxypropan-2-yl)isoxazol-3-yl)-2-methylpiperidin-1-yl)(2-isopropoxypyridin-3-yl)methanone),
((2R,5R)-5-(5-(2-Hydroxypropan-2-yl)isoxazol-3-yl)-2-methylpiperidin-1-yl)(2-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanone,
(2-(2H-1,2,3-Triazol-2-yl)phenyl)((2R,5R)-5-(5-(3-hydroxypentan-3-yl)isoxazol-3-yl)-2-methylpiperidin-1-yl)methanone),
(1-Cyclopropyl-1-{3-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]isoxazol-5-yl}ethanol),
((2R)-2-{3-[(3R,6R)-6-Methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]isoxazol-5-yl}butan-2-ol),
((2S)-2-{3-[(3R,6R)-6-Methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}pipieridin-3-yl]isoxazol-5-yl}butan-2-ol),
(1-{3-[(3R,6R)-6-Methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl)isoxazol-5-yl}cyclobutanol),
(1,1,1-Trifluoro-2-{3-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]isoxazol-5-yl}propan-2-ol),
(3-Methyl-2-{3-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperiden-3-yl]isoxazol-5-yl}butan-2-ol),
((2S)-1,1-Diflouro-2-{3-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]isoxazol-5-yl}propan-2-ol),
((2R,5R)-5-[5-(1-Methoxy-1-methylethyl)isoxazol-3-yl]-2-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidine),
(2-{5-[(3R,6R)-6-Methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]isoxazol-3-yl}propan-2-ol),
(2-}5-[(3R,6R)-1-{[2-(Methoxymethyl)phenyl]carbonyl}-6-methylpiperidin-3-yl]isoxazol-3-yl}propan-2-ol),
2-(5-{(3R,6R)-6-Methyl-1-[(2-pyrimidin-2-ylphenyl)carbonyl]piperidin-3-yl}isoxazol-3-yl)propan-2-ol,
2-(5-{(3R,6R)-1-[(2-Ethoxypyridin-3-yl)carbonyl]-6-methylpiperidin-3-yl}isoxazol-3-yl)propan-2-ol,
2-{5-[(3R,6R)-1-{[5-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}methylpiperidin-3-yl]isoxazol-3-yl}propan-2-ol,
2-{5-[(3R,6R)-6-methyl-1-{[3-(1H-pyrazol-1-yl)pyrazin-2-yl]carbonyl}piperidin-3-yl]isoxazol-3-yl}propan-2-ol,
2-{5-[(3R,6R)-1-(Biphenyl-2-ylcarbonyl)-6-methpiperidin-3-yl]isoxazol-3-yl}propan-2-ol,
2-{5-[(3R,6R)-1-{[5-Chloro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]isoxazol-3-yl}propan-2-ol,
2-(5-{(3R,6R)-6-Methyl-1-[(3-pyridin-2-ylpyrazin-2-yl)carbonyl]piperidin-3-yl}isoxazol-3-yl)propan-2-ol,
1-[2-({(2R,5R)-5-[3-(1-Hydroxy-1-methylethyl)isoxazol-5-yl]-2-methylpiperidin-1-yl}carbonyl)phenyl]cyclopropanecarbonitrile,
Methyl 2-({(2R,5R)-5-[3-(1-hydroxy-1-methylethyl)isoxazol-5-yl]-2-methylpiperidin-1-yl}carbonyl)benzoate,
2-(5-{(3R,6R)-1-[(2-Ethoxyphenyl)carbonyl]-6-methylpiperidin-3-yl}isoxazol-3-yl)propan-2-ol
2-{5-[(3R,6R)-6-Methyl-1-{[2-(2H-tetrazol-2-yl)phenyl]carbonyl}piperidin-3-yl]isoxazol-3-yl}propan-2-ol,
2-(5-{(3R,6R)-6-Methyl-1-[(2phenylpyridin-3-yl)carbonyl]piperidin-3-yl}isoxazol-3-yl)propan-2-ol,
2-(5-{(3R,6R)-6-Methyl-1-[(3-phenylpyridin-2-yl)carbonyl]piperidin-3-yl}isoxazol-3-yl)propan-2-ol,
2-{5-[(3R,6R)-1-{[2-(2,2-Difluoroethoxy)phenyl]carbonyl}-6-methylpiperidin-3-yl]isoxazol-3-yl}propan-2-ol,
2-{5-[(3R,6R)-6-Methyl-1-{[2-(2,2,2-trifluoroethoxy)phenyl]carbonyl}piperidin-3-yl]isoxazol-3-yl}propan-2-ol,
2-(5-{(3R,6R)-6-Methyl-1-[(2-pyrazin-2-ylphenyl)carbonyl]piperidin-3-yl}isoxazol-3-yl)propan-2-ol,
2-{5-[(3R,6R)-1-{[2-(2,2-Difluorocyclopropyl)phenyl]carbonyl}-6-methylpiperidin-3-yl]isoxazol-3-yl}propan-2-ol,
(2-{5-[(3R,6R)-6-Ethyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]isoxazol-3-yl}propan-2-ol),
((1R)-2,2,2-Trifluoro-1-{5-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]isoxazol-3-yl}ethanol),
((1S)-2,2,2-Trifluoro-1-{5-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]isoxazol-3-yl}ethanol),
((1R)-2,2,2-Trifluoro-1-{5-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)thiophen-3-yl]carbonyl}piperidin-3-yl]isoxazol-3-yl}ethanol),
((1S)-2,2,2-Trifluoro-1-{5-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)thiophen-3-yl]carbonyl}piperidin-3-yl]isoxazol-3-yl}ethanol),
1-(2-{[(2R,5R)-2-Methyl-5-{3-[(1R)-2,2,2-Trifluoro-1-hydroxyethyl]isoxazol-5-yl}piperidin-1-yl]carbonyl}phenyl)cyclopropanecarbonitrile,
1-(2-{[(2R,5R)-2-Methyl-5-{3-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]isoxazol-5-yl}piperidin-1-yl]carbonyl}phenyl)cyclopropanecarbonitrile,
(1R)-2,2,2-Trifluoro-1-{5-[(3R,6R)-6-methyl-1-{[2-(2H-tetrazol-2-yl)phenyl]carbonyl}piperidin-3-yl]isoxazol-3-yl}ethanol,
(1S)-2,2,2-Trifluoro-1-{5-[(3R,6R)-6-methyl-1-{[2-(2H-tetrazol-2-yl)phenyl]carbonyl}piperidin-3-yl]isoxazol-3-yl}ethanol,
((1S)-2,2,2-Trifluoro-1-(5-{(3R,6R)-6-methyl-1-[(2-pyrimidin-2-ylthiophen-3-yl)carbonyl]piperidin-3-yl}isoxazol-3-yl)ethanol),
((1R)-2,2,2-Trifluoro-1-(5-{(3R,6R)-6-methyl-1-[(2-pyrimidin-2-ylthiophen-3-yl)carbonyl]piperidin-3-yl}isoxazol-3-yl)ethanol),
((1R)-2,2,2-Trifluoro-1-(5-{(3R,6R)-6-methyl-1-[(2-pyrimidin-2-ylphenyl)carbonyl]piperidin-3-yl}isoxazol-3-yl)ethanol),
((1S)-2,2,2-Trifluoro-1-(5-{(3R,6R)-6-methyl-1-[(2-pyrimidin-2-ylphenyl)carbonyl]piperidin-3-yl}isoxazol-3-yl)ethanol),
(1-Cyclopropyl-1-{5-[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]isoxazol-3-yl}ethanol),
2-{5-[(3R,6R)-6-Methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]isoxazol-3-yl}butan-2-ol,
((2R,5R)-2-Methyl-5-[3-(tetrahydrofuran-2-yl)isoxazol-5-yl]-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidine),
((2R,5R)-5[3-(1-Methoxy-1-methylethyl)isoxazol-5-yl]-2-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidine),
(2-{3-[(3R,6R)-6-Methyl-1-{[2-(2H-1,2,3-triazol-2-yl)thiophen-3-yl]carbonyl}piperidin-3-yl]isothiazol-5-yl}propan-2-ol),
2-{3-[(3R,6R)-6-Methyl-1-{[2-(2H-tetrazol-2-yl)phenyl]carbonyl}piperidin-3-yl]isothiazol-5-yl}propan-2-ol,
2-{3-[(3R,6R)-1-{[4-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]isothiazol-5-yl}propan-2-ol,
1-[2-({(2R,5R)-5-[5-(1-Hydroxy-1-methylethyl)isothiazol-3-yl]-2-methylpiperidin-1-yl}carbonyl)phenyl]cyclopropanecarbonitrile,
2-(3-{(3R,6R)-6-Methyl-1-[(2-pyrimidin-2-ylphenyl)carbonyl]piperidin-3-isothiazol-5-yl)propan-2-ol,
(2-(3-{(3R,6R)-6-Methyl-1-[(2-pyrimidin-2-ylthiophen-3-yl)carbonyl]piperidin-3-yl}isothiazol-5-yl)propan-2-ol),
2-(3-{(3R,6R)-6-Methyl-1-[(4-pyrimidin-2-ylthiophen-3-yl)carbonyl]piperidin-3-yl}isothiazol-5-yl)propan-2-ol,
2-{3-[(3R,6R)-6-Methyl-1-{[4-(2H-1,2,3-triazol-2-yl)thiophen-3-yl]carbonyl}piperidin-3-yl]isothiazol-5-yl}propan-2-ol,
Methyl 2-({(2R,5R)-5-[5-(1-hydroxy-1-methylethyl)isothiazol-3-yl]-2-methylpiperidin-1-yl}carbonyl)benzoate,
2-{3-[(3R,6R)-6-Methyl-1-{[2-(trifluoromethoxy)phenyl]carbonyl}piperidin-3-yl]isothiazol-5-yl}propan-2-ol,
2-{3-[(3R,6R)-1-{[2-(2,2-Difluoroethoxy)pyridin-3-yl]carbonyl}-6-methylpiperidin-3-yl]isothiazol-5-yl}propan-2-ol, and
2-{3-[(3R,6R)-1-{[2-(2-methoxyethyl)phenyl]carbonyl}-6-methylpiperidin-3-yl]isothiazol-5-yl}propan-2-ol;
or a pharmaceutically acceptable salt thereof.
15. A composition which comprises an inert carrier and a compound of claim 1 , or a pharmaceutically acceptable salt thereof.