1-aryl-3-azabicyclo[3.1.0]hexanes: preparation and use to treat neuropsychiatric disorders

1. A compound of the following formula II:

and enantiomers and pharmaceutically acceptable salts thereof, wherein:

R 1 and R 2 are independently selected from hydrogen, unsubstituted C 1-10 alkyl, C 3-10 alkenyl and C 3-10 alkynyl, and substituted C 1-10 alkyl, C 3-10 alkenyl and C 3-10 alkynyl wherein the substituent is one or more of hydroxy, cyano, halogen, C 1-6 alkoxy, aryl substituted C 1-6 alkoxy, aryloxy, aryloxy substituted with one or more halogens, C 1-6 alkyl, C 1-6 alkyl independently substituted with one or more of cyano and halogen, C 1-4 alkoxy, and C 1-4 haloalkoxy;

R 3 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxycarbonyl, C 2-6 alkanoyl, C 3-8 cycloalkyl, C 4-9 cycloalkanoyl, aryl, heteroaryl, saturated heterocyclic, C 2-10 alkenyl, C 2-10 alkynyl, and substituted C 1-6 alkyl, C 2-10 alkenyl and C 2-10 alkynyl wherein the substituent is one or more of cyano, halogen, hydroxy, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, C 2-6 alkyloxycarbonyloxy, C 1-6 alkanoyl, C 1-6 alkanoyloxy, C 3-8 cycloalkyl, C 3-8 cycloalkyloxy, C 4-9 cycloalkanoyl, aryl, aryloxy, heteroaryl and saturated heterocyclic; and

R 4 and R 5 are independently hydrogen or 1-4 substituents independently selected from halogen, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo(C 1-3 )alkyl, cyano, hydroxy, C 3-5 cycloalkyl, C 1-3 alkoxy, C 1-3 alkoxy(C 1-3 )alkyl, carboxy(C 1-3 )alkyl, C 1-3 alkanoyl, halo(C 1-3 )alkoxy, nitro, amino, C 1-3 alkylamino, and di(C 1-3 )alkylamino.

2. A compound of the following formula IIa:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 and R 2 are independently selected from hydrogen, unsubstituted C 1-10 alkyl, C 3-10 alkenyl and C 3-10 alkynyl, and substituted C 1-10 alkyl, C 3-10 alkenyl and C 3-10 alkynyl wherein the substituent is one or more of hydroxy, cyano, halogen, C 1-6 alkoxy, aryl substituted C 1-6 alkoxy, aryloxy, aryloxy substituted with one or more halogens, C 1-6 alkyl, C 1-6 alkyl independently substituted with one or more of cyano and halogen, C 1-4 alkoxy, and C 1-4 haloalkoxy;

R 3 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxycarbonyl, C 2-6 alkanoyl, C 3-8 cycloalkyl, C 4-9 cycloalkanoyl, aryl, heteroaryl, saturated heterocyclic, C 2-10 alkenyl, C 2-10 alkynyl, and substituted C 1-6 alkyl, C 2-10 alkenyl and C 2-10 alkynyl wherein the substituent is one or more of cyano, halogen, hydroxy, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, C 2-6 alkyloxycarbonyloxy, C 1-6 alkanoyl, C 1-6 alkanoyloxy, C 3-8 cycloalkyl, C 3-8 cycloalkyloxy, C 4-9 cycloalkanoyl, aryl, aryloxy, heteroaryl and saturated heterocyclic; and

R 4 and R 5 are independently hydrogen or 1-4 substituents independently selected from methyl, ethyl, fluoro, chloro, trifluoromethyl, cyano, nitro, propyl, methoxy, ethoxy and trifluoromethoxy.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are hydrogen, R 3 is hydrogen, methyl, ethyl, or isopropyl, and R 4 and R 5 are independently selected from hydrogen, methyl, chloro, fluoro, propyl, methoxy, and ethoxy.

4. The compound according to claim 3 , wherein the compound is:

1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane;

3-methyl-1-(naphthalen-2-yl)-3-aza-bicyclo [3 .1.0]hexane;

3-ethyl-1-(naphthalen-2-yl)-3-aza-bicyclo [3 .1.0]hexane;

3-isopropyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane;

1-(2-methoxynaphthalen-6-yl)-3-aza-bicyclo[3.1.0]hexane;

1-(2-methoxynaphthalen-6-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane;

1-(2-ethoxynaphthalen-6-yl)-3-aza-bicyclo[3.1.0]hexane; or

1-(2-ethoxynaphthalen-6-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane;

or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 4 , wherein the compound is:

(1R,5S)-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane;

(1S,5R)-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane;

(1R,5S)-3-methyl-1-(naphthalen-2-yl)-3-aza-bicyclo [3 .1.0]hexane;

(1S,5R)-3-methyl-1-(naphthalen-2-yl)-3-aza-bicyclo [3 .1.0]hexane;

(1R,5S)-3-isopropyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane; or

(1S,5R)-3-isopropyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane;

or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 4 , wherein the compound is 1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 6 , wherein the compound is 1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane hydrochloride.

8. The compound according to claim 6 , wherein the compound is 1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane.

9. The compound according to claim 6 , wherein the compound is (1S,5R)-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 9 , wherein the compound is (1S,5R)-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane hydrochloride.

11. The compound according to claim 9 , wherein the compound is (1S,5R)-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane.

12. The compound according to claim 6 , wherein the compound is (1R,5S)-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 12 , wherein the compound is (1R,5S)-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane hydrochloride.

14. The compound according to claim 12 , wherein the compound is (1R,5S)-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane.

15. The compound according to claim 4 , wherein the compound is 3-methyl -1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 15 , wherein the compound is (1R,5S)-3-methyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 15 , wherein the compound is (1S,5R)-3-methyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.

18. The compound according to claim 4 , wherein the compound is 3-ethyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.

19. The compound according to claim 4 , wherein the compound is 3-isopropyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.

20. The compound according to claim 4 , wherein the compound is 1-(2-methoxynaphthalen-6-yl)-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.

21. The compound according to claim 4 , wherein the compound is 1-(2-methoxynaphthalen-6-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.

22. The compound according to claim 4 , wherein the compound is 1-(2-ethoxynaphthalen-6-yl)-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.

23. The compound according to claim 4 , wherein the compound is 1-(2-ethoxynaphthalen-6-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.

24. A pharmaceutical composition comprising a compound according to claim 4 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle therefor.

25. A pharmaceutical composition comprising 1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane hydrochloride and a pharmaceutically acceptable carrier or vehicle therefor.

26. The pharmaceutical composition according to claim 25 comprising (1R,5S)-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane hydrochloride.

27. The pharmaceutical composition according to claim 25 comprising (1S,5R)-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane hydrochloride.