Heteroaryl derivatives as orexin receptor antagonists
The present invention relates to compounds of formula wherein Ar, Het, R 1 and n are as defined herein and to pharmaceutically suitable acid addition salts, optically pure enantiomers, racemates or diastereomeric mixtures thereof. Compounds of formula I are orexin receptor antagonists and are useful in the treatment of sleep apnea, narcolepsy, insomnia, parasomnia, jet lag syndrome, circadian rhythms disorder and sleep disorders associated with neurological diseases.
1. A compound of formula I
wherein
Ar is an unsubstituted or substituted aryl or heteroaryl group, wherein the substituted aryl and heteroaryl groups are substituted by one or more substituents R 2 ;
R 2 is hydroxy, halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, C(O)-lower alkyl, nitro, NR′R″, cyano, S-lower alkyl, SO 2 -lower alkyl, cycloalkyl, heterocycloalkyl, phenyloxy, benzyloxy, phenyl, NH-phenyl or heteroaryl, wherein the phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from lower alkyl and halogen;
R′/R″ are each independently hydrogen or lower alkyl;
R 1 is hydrogen or lower alkyl;
Het is a heteroaryl group selected from the group consisting of pyrimidinyl, pyridazinyl, quinolinyl, quinoxalinyl, quinazolinyl, benzooxazolyl, and benzothiazolyl, unsubstituted or substituted by one or more substituents selected from R 3 ;
R 3 is hydroxy, halogen, ═O, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, phenyl, lower alkoxy substituted by halogen, nitro, cyano, SO 2 -lower alkyl, cycloalkyl or heterocycloalkyl;
n is 1;
or a pharmaceutically suitable acid addition salt thereof.
2. The compound of claim 1 , wherein Het is benzooxazolyl, unsubstituted or substituted by one or more substituents selected from R 3 .
3. The compound of claim 2 , wherein Ar is aryl that is unsubstituted or substituted by R 2 .
4. The compound of claim 2 , wherein Ar is heteroaryl that is unsubstituted or substituted by R 2 .
5. The compound of claim 2 , selected from the group consisting of
[3-(6-chloro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-(2,6-dimethoxy-phenyl)-methanone;
[(R)-3-(6-chloro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-(2,6-dimethoxy-phenyl)-methanone;
[(R)-3-(6-chloro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-(2-pyrrol-1-yl-phenyl)-methanone;
[(R)-3-(6-chloro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-(2,6-dichloro-phenyl)-methanone;
[(R)-3-(6-chloro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-(2-chloro-6-methyl-phenyl)-methanone;
[(R)-3-(6-chloro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-(2-ethyl-phenyl)-methanone;
[(R)-3-(6-chloro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-(2-ethoxy-phenyl)-methanone;
[(R)-3-(6-chloro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-(2-methylsulfanyl-phenyl)-methanone;
[(R)-3-(6-chloro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-(2-difluoromethoxy-phenyl)-methanone;
[(R)-3-(6-chloro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-(2-furan-2-yl-phenyl)-methanone; and
[(R)-3-(6-chloro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-(5-phenyl-isoxazol-4-yl)-methanone.
6. The compound of claim 2 , selected from the group consisting of
[(R)-3-(6-chloro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-[2-(2H-[1,2,4]triazol-3-yl)-phenyl]-methanone;
[(R)-3-(6-chloro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-(2-trifluoromethyl-phenyl)-methanone;
[(R)-3-(6-chloro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-(2-pyridin-3-yl-phenyl)-methanone;
[(R)-3-(6-chloro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-(5-methyl-3-phenyl-isoxazol-4-yl)-methanone;
[(R)-3-(6-chloro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-(5-methyl-2-trifluoromethyl-phenyl)-methanone;
[(R)-3-(6-chloro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone;
[(R)-3-(6-chloro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-(2-thiophen-2-yl-phenyl)-methanone;
[(R)-3-(6-chloro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-(2-trifluoromethoxy-phenyl)-methanone;
[(R)-3-(6-chloro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-(2-fluoro-6-trifluoromethyl-phenyl)-methanone;
[(R)-3-(6-chloro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-(2,6-diethoxy-phenyl)-methanone; and
[(R)-3-(6-chloro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-(3′-methyl-biphenyl-2-yl)-methanone.
7. The compound of claim 2 , selected from the group consisting of
[(R)-3-(6-chloro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-(2-methyl-4-phenyl-thiazol-5-yl)-methanone;
[(R)-3-(6-chloro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-(2-chloro-6-trifluoromethyl-phenyl)-methanone;
[(R)-3-(6-chloro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-[2-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-methanone;
[(R)-3-(6-chloro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-(2-thiophen-3-yl-phenyl)-methanone;
[(R)-3-(6-chloro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-(5-methyl-2-trifluoromethyl-furan-3-yl)-methanone;
[(R)-3-(6-chloro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-(2-fluoro-6-pyrrolidin-1-yl-phenyl)-methanone;
[(R)-3-(6,7-difluoro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-(2,6-dimethoxy-phenyl)-methanone;
(2,6-dimethoxy-phenyl)-[(R)-3-(6-fluoro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-methanone;
[(R)-3-(7-chloro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-(2,6-dimethoxy-phenyl)-methanone; and
(2,6-dimethoxy-phenyl)-[(R)-3-(4-methyl-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-methanone.
8. The compound of claim 2 , selected from the group consisting of
[(R)-3-(7-fluoro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-[2-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-methanone;
[(R)-3-(6,7-difluoro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-(2-trifluoromethoxy-phenyl)-methanone;
[(R)-3-(6,7-difluoro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-[2-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-methanone;
[(R)-3-(6,7-difluoro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-(5-methyl-2-trifluoromethyl-phenyl)-methanone;
[(R)-3-(6,7-difluoro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-(5-methyl-3-phenyl-isoxazol-4-yl)-methanone;
[(R)-3-(6,7-difluoro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-(2-methyl-5-phenyl-thiazol-4-yl)-methanone;
[(R)-3-(6-fluoro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-(2-trifluoromethoxy-phenyl)-methanone;
[(R)-3-(6-fluoro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-[2-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-methanone;
[(R)-3-(6-fluoro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-(5-methyl-2-trifluoromethyl-phenyl)-methanone; and
[(R)-3-(6-fluoro-benzooxazol-2-ylamino)-pyrrolidin-1-yl]-(2-methyl-5-phenyl-thiazol-4-yl)-methanone.
9. The compound of claim 1 , wherein Het is quinoxalinyl unsubstituted or substituted by one or more substituents selected from R 3 .
10. The compound of claim 9 , wherein Ar is aryl that is unsubstituted or substituted by R 2 .
11. The compound of claim 9 , wherein Ar is heteroaryl that is unsubstituted or substituted by R 2 .
12. The compound of claim 9 , selected from the group consisting of
(2,6-dimethoxy-phenyl)-[3-(quinoxalin-2-ylamino)-pyrrolidin-1-yl]-methanone;
(2,6-dimethoxy-phenyl)-[(R)-3-(quinoxalin-2-ylamino)-pyrrolidin-1-yl]-methanone;
[(R)-3-(6-chloro-quinoxalin-2-ylamino)-pyrrolidin-1-yl]-(2,6-dimethoxy-phenyl)-methanone;
(2,6-dimethoxy-phenyl)-[(R)-3-(6-fluoro-quinoxalin-2-ylamino)-pyrrolidin-1-yl]-methanone;
[(R)-3-(6,7-difluoro-quinoxalin-2-ylamino)-pyrrolidin-1-yl]-(2-trifluoromethyl-phenyl)-methanone;
[(R)-3-(6,7-difluoro-quinoxalin-2-ylamino)-pyrrolidin-1-yl]-(2-trifluoromethoxy-phenyl)-methanone;
[(R)-3-(6,7-difluoro-quinoxalin-2-ylamino)-pyrrolidin-1-yl]-[2-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-methanone;
[(R)-3-(6,7-difluoro-quinoxalin-2-ylamino)-pyrrolidin-1-yl]-(5-methyl-3-phenyl-isoxazol-4-yl)-methanone;
[(R)-3-(6,7-difluoro-quinoxalin-2-ylamino)-pyrrolidin-1-yl]-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone; and
(2-chloro-5-methyl-phenyl)-[(R)-3-(6,7-difluoro-quinoxalin-2-ylamino)-pyrrolidin-1-yl]-methanone.
13. The compound of claim 9 , selected from the group consisting of
[(R)-3-(6,7-difluoro-quinoxalin-2-ylamino)-pyrrolidin-1-yl]-(2-methoxy-5-methyl-phenyl)-methanone;
[(R)-3-(6,7-difluoro-quinoxalin-2-ylamino)-pyrrolidin-1-yl]-(2-methyl-5-phenyl-thiazol-4-yl)-methanone;
[(R)-3-(6-chloro-quinoxalin-2-ylamino)-pyrrolidin-1-yl]-[2-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-methanone;
[(R)-3-(6-chloro-quinoxalin-2-ylamino)-pyrrolidin-1-yl]-(5-methyl-2-trifluoromethyl-phenyl)-methanone;
[(R)-3-(6-chloro-quinoxalin-2-ylamino)-pyrrolidin-1-yl]-(5-methyl-3-phenyl-isoxazol-4-yl)-methanone;
[(R)-3-(6-chloro-quinoxalin-2-ylamino)-pyrrolidin-1-yl]-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone;
(2-chloro-5-methyl-phenyl)-[(R)-3-(6-chloro-quinoxalin-2-ylamino)-pyrrolidin-1-yl]-methanone;
[(R)-3-(6-chloro-quinoxalin-2-ylamino)-pyrrolidin-1-yl]-(2-methyl-5-phenyl-thiazol-4-yl)-methanone; and
[(R)-3-(quinoxalin-2-ylamino)-pyrrolidin-1-yl]-(2-trifluoromethyl-phenyl)-methanone.
14. The compound of claim 9 , selected from the group consisting of
[(R)-3-(quinoxalin-2-ylamino)-pyrrolidin-1-yl]-(2-trifluoromethoxy-phenyl)-methanone;
[(R)-3-(quinoxalin-2-ylamino)-pyrrolidin-1-yl]-[2-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-methanone;
(5-methyl-2-trifluoromethyl-phenyl)-[(R)-3-(quinoxalin-2-ylamino)-pyrrolidin-1-yl]-methanone;
(2-methyl-5-phenyl-thiazol-4-yl)-[(R)-3-(quinoxalin-2-ylamino)-pyrrolidin-1-yl]-methanone;
[(R)-3-(7-chloro-quinoxalin-2-ylamino)-pyrrolidin-1-yl]-[2-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-methanone;
(R)-[3-(6-tert-butyl-quinoxalin-2-ylamino)-pyrrolidin-1-yl]-(5-methyl-2-trifluoromethyl-phenyl)-methanone;
(R)-[3-(6-fluoro-quinoxalin-2-ylamino)-pyrrolidin-1-yl]-(5-methyl-2-trifluoromethyl-phenyl)-methanone;
(R)-[3-(7-chloro-6-methyl-quinoxalin-2-ylamino)-pyrrolidin-1-yl]-(5-methyl-2-trifluoromethyl-phenyl)-methanone; and
(R)-[3-(6-Chloro-7-methyl-quinoxalin-2-ylamino)-pyrrolidin-1-yl]-(5-methyl-2-trifluoromethyl-phenyl)-methanone.
15. The compound of claim 1 , wherein Het is benzothiazolyl, unsubstituted or substituted by one or more substituents selected from R 3 .
16. The compound of claim 15 , wherein Ar is aryl that is unsubstituted or substituted by R 2 .
17. The compound of claim 15 , wherein Ar is heteroaryl that is unsubstituted or substituted by R 2 .
18. The compound of claim 15 , selected from the group consisting of
[3-(6-chloro-benzothiazol-2-ylamino)-pyrrolidin-1-yl]-(2,6-dimethoxy-phenyl)-methanone;
[(R)-3-(6-chloro-benzothiazol-2-ylamino)-pyrrolidin-1-yl]-(2,6-dimethoxy-phenyl)-methanone;
[(R)-3-(4-chloro-benzothiazol-2-ylamino)-pyrrolidin-1-yl]-(2,6-dimethoxy-phenyl)-methanone;
(2,6-dimethoxy-phenyl)-[(R)-3-(6-fluoro-benzothiazol-2-ylamino)-pyrrolidin-1-yl]-methanone;
(2,6-dimethoxy-phenyl)-[(R)-3-(4-fluoro-benzothiazol-2-ylamino)-pyrrolidin-1-yl]-methanone;
(2,6-dimethoxy-phenyl)-[(R)-3-(7-fluoro-benzothiazol-2-ylamino)-pyrrolidin-1-yl]-methanone;
[(R)-3-(5,7-difluoro-benzothiazol-2-ylamino)-pyrrolidin-1-yl]-(2,6-dimethoxy-phenyl)-methanone;
[(R)-3-(6-fluoro-benzothiazol-2-ylamino)-pyrrolidin-1-yl]-(2-trifluoromethyl-phenyl)-methanone; and
[(R)-3-(6-fluoro-benzothiazol-2-ylamino)-pyrrolidin-1-yl]-(2-trifluoromethoxy-phenyl)-methanone.
19. The compound of claim 15 , selected from the group consisting of
[(R)-3-(6-fluoro-benzothiazol-2-ylamino)-pyrrolidin-1-yl]-[2-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-methanone;
[(R)-3-(6-fluoro-benzothiazol-2-ylamino)-pyrrolidin-1-yl]-(5-methyl-2-trifluoromethyl-phenyl)-methanone;
[(R)-3-(6-fluoro-benzothiazol-2-ylamino)-pyrrolidin-1-yl]-(5-methyl-3-phenyl-isoxazol-4-yl)-methanone;
[(R)-3-(6-fluoro-benzothiazol-2-ylamino)-pyrrolidin-1-yl]-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone;
(2-chloro-5-methyl-phenyl)-[(R)-3-(6-fluoro-benzothiazol-2-ylamino)-pyrrolidin-1-yl]-methanone;
[(R)-3-(6-fluoro-benzothiazol-2-ylamino)-pyrrolidin-1-yl]-(2-methyl-5-phenyl-thiazol-4-yl)-methanone;
[(R)-3-(4-fluoro-benzothiazol-2-ylamino)-pyrrolidin-1-yl]-(2-trifluoromethoxy-phenyl)-methanone;
[(R)-3-(4-fluoro-benzothiazol-2-ylamino)-pyrrolidin-1-yl]-[2-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-methanone; and
[(R)-3-(4-fluoro-benzothiazol-2-ylamino)-pyrrolidin-1-yl]-(5-methyl-2-trifluoromethyl-phenyl)-methanone.
20. The compound of claim 15 , selected from the group consisting of
[(R)-3-(4-fluoro-benzothiazol-2-ylamino)-pyrrolidin-1-yl]-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone;
[(R)-3-(5,7-difluoro-benzothiazol-2-ylamino)-pyrrolidin-1-yl]-[2-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-methanone;
[(R)-3-(5,7-difluoro-benzothiazol-2-ylamino)-pyrrolidin-1-yl]-(5-methyl-3-phenyl-isoxazol-4-yl)-methanone;
[(R)-3-(5,7-difluoro-benzothiazol-2-ylamino)-pyrrolidin-1-yl]-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone;
[(R)-3-(5,6-difluoro-benzothiazol-2-ylamino)-pyrrolidin-1-yl]-(5-methyl-2-trifluoromethyl-phenyl)-methanone; and
(R)-[3-(4-chloro-benzothiazol-2-ylamino)-pyrrolidin-1-yl]-(5-methyl-2-trifluoromethyl-phenyl)-methanone.
21. The compound of claim 1 , wherein Het is pyrimidinyl, unsubstituted or substituted by one or more substituents selected from R 3 .
22. The compound of claim 21 , wherein Ar is aryl that is unsubstituted or substituted by R 2 .
23. The compound of claim 21 , wherein Ar is heteroaryl that is unsubstituted or substituted by R 2 .
24. The compound of claim 21 , wherein the compound is (5-methyl-2-trifluoromethyl-phenyl)-[(R)-3-(2-phenyl-pyrimidin-4-ylamino)-pyrrolidin-1-yl]-methanone.
25. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I
wherein
Ar is an unsubstituted or substituted aryl or heteroaryl group, wherein the substituted aryl and heteroaryl groups are substituted by one or more substituents R 2 ;
R 2 is hydroxy, halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, C(O)-lower alkyl, nitro, NR′R″, cyano, S-lower alkyl, SO 2 -lower alkyl, cycloalkyl, heterocycloalkyl, phenyloxy, benzyloxy, phenyl, NH-phenyl or heteroaryl, wherein the phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from lower alkyl and halogen;
R′/R″ are each independently hydrogen or lower alkyl;
R 1 is hydrogen or lower alkyl;
Het is a heteroaryl group selected from the group consisting of pyrimidinyl, pyridazinyl, quinolinyl, quinoxalinyl, quinazolinyl, benzooxazolyl, and benzothiazolyl, unsubstituted or substituted by one or more substituents selected from R 3 ;
R 3 is hydroxy, halogen, ═O, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, phenyl, lower alkoxy substituted by halogen, nitro, cyano, SO 2 -lower alkyl, cycloalkyl or heterocycloalkyl;
n is 1;
or a pharmaceutically suitable acid addition salt thereof and a pharmaceutically acceptable carrier.