IP Library › Granted Patent US 9,133,159

Granted Patent B2

US 9,133,159 · App. 13/856,431 · Granted Sep 15, 2015

1-heteroaryl-3-azabicyclo[3.1.0]hexanes, methods for their preparation and their use as medicaments

Inventors: Phil Skolnick (Edgewater, NJ); Zhengming Chen (Belle Meade, NJ)

Assignee: NEUROVANCE, INC.

C07D401/04 C07D403/04 C07D405/04 C07D409/04 C07D417/04

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Quick Facts

Patent No.: US 9,133,159
App. No.: 13/856,431
Granted: Sep 15, 2015
Kind: B2

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USPTO Patent Center↗ Full Patent PDF↗

Abstract

The invention provides novel 1-heteroaryl-3-azabicyclo[3.1.0]hexanes, and related processes and intermediates for preparing these compounds, as well as compositions and methods employing these compounds for the treatment and/or prevention of central nervous system (CNS) disorders, including but not limited to depression and anxiety.

Claims (116)

1. A compound of the following Formula I:

and pharmaceutically acceptable salts, enantiomers, polymorphs, solvates, hydrates or prodrugs thereof, wherein:

Ar is a heterocyclic aryl group selected from furan, methylfuran, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, isothiazole, methoxypyridine, pyridazine, pyrazine, triazine, indole, methylindole, benzofuran, benzothiophene, benzothiazole, isoquinoline, cinnoline, phthalazine, quinazoline, chromane and isochromane, and Ar is either unsubstituted or substituted with one or more substituents independently selected from fluoro, chloro, bromo, iodo, —NO 2 , —CN, —NH 2 , carboxy, C 2-8 alkenyl, C 2-8 alkynyl, halo(C 1-8 )alkyl, hydroxy, trifluoromethyl, C 3-8 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 )alkoxyl, C 1-8 alkylamino, and di(C 1-8 )alkylamino; and

R 1 is selected from hydrogen, unsubstituted C 1-10 alkyl, C 3-8 cycloalkyl, C 2-10 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.

2. A compound of the following Formula Ia:

or a pharmaceutically acceptable salt thereof, wherein:

Ar is furan, methylfuran, fluorobenzothiophene, methoxypyridine, benzofuran, benzothiophene, chlorobenzothiophene, benzothiazole, indole, or methylindole; and

R 1 is hydrogen, methyl, ethyl, propyl, or isopropyl.

3. The compound according to claim 1 , wherein the compound is selected from the group consisting of:

1-(5-methylfuran-2-yl)-3-azabicyclo[3.1.0]hexane;

1-(6-methoxypyridin-3-yl)-3-azabicyclo[3.1.0]hexane;

1-(6-methoxypyridin-3-yl)-3-methyl-3-azabicyclo[3.1.0]hexane;

1-(benzofuran-2-yl)-3-methyl-3-azabicyclo[3.1.0]hexane;

1-(benzofuran-3-yl)-3-azabicyclo[3.1.0]hexane;

1-(benzofuran-3-yl)-3-methyl-3-azabicyclo[3.1.0]hexane;

1-methyl-2-(3-methyl-3-azabicyclo[3.1.0]hexan-1-yl)-1H-indole;

2-(3-ethyl-3-azabicyclo[3.1.0]hexan-1-yl)-1-methyl-1H-indole;

2-(3-isopropyl-3-azabicyclo[3.1.0]hexan-1-yl)-1-methyl-1H-indole;

1-methyl-5-(3-methyl-3-azabicyclo[3.1.0]hexan-1-yl)-1H-indole;

5-(3-ethyl-3-azabicyclo[3.1.0]hexan-1-yl)-1-methyl-1H-indole;

5-(3-isopropyl-3-azabicyclo[3.1.0]hexan-1-yl)-1-methyl-1H-indole;

1-(5-chlorobenzo[b]thiophen-3-yl)-3-azabicyclo[3.1.0]hexane;

1-(5-chlorobenzo[b]thiophen-2-yl)-3-methyl-3-azabicyclo[3.1.0]hexane;

1-(5-chlorobenzo[b]thiophen-3-yl)-3-methyl-3-azabicyclo[3.1.0]hexane;

1-(benzo[b]thiophen-2-yl)-3-aza-bicyclo[3.1.0]hexane;

1-(benzo[b]thiophen-2-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane;

1-(6-fluorobenzo[b]thiophen-2-yl)-3-aza-bicyclo[3.1.0]hexane;

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

1-(5-fluorobenzo[b]thiophen-2-yl)-3-aza-bicyclo[3.1.0]hexane;

1-(5-fluorobenzo[b]thiophen-2-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; and

2-(3-azabicyclo[3.1.0]hexan-1-yl)-benzo[d]thiazole;

or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein Ar is benzothiophene, fluorobenzothiophene, or chlorobenzothiophene.

5. The compound according to claim 3 , wherein the compound is selected from the group consisting of:

1-(5-chlorobenzo[b]thiophen-3-yl)-3-azabicyclo[3.1.0]hexane;

1-(5-chlorobenzo[b]thiophen-2-yl)-3-methyl-3-azabicyclo[3.1.0]hexane;

1-(5-chlorobenzo[b]thiophen-3-yl)-3-methyl-3-azabicyclo[3.1.0]hexane;

1-(benzo[b]thiophen-2-yl)-3-aza-bicyclo[3.1.0]hexane;

1-(benzo[b]thiophen-2-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane;

1-(6-fluorobenzo[b]thiophen-2-yl)-3-aza-bicyclo[3.1.0]hexane;

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

1-(5-fluorobenzo[b]thiophen-2-yl)-3-aza-bicyclo[3.1.0]hexane; and

1-(5-fluorobenzo[b]thiophen-2-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane;

or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 5 , wherein the compound is 1-(benzo[b]thiophen-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-(benzo[b]thiophen-2-yl)-3-aza-bicyclo[3.1.0]hexane hydrochloride.

8. The compound according to claim 6 , wherein the compound is (1S,5S)-1-(benzo[b]thiophen-2-yl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 8 , wherein the compound is (1S,5S)-1-(benzo[b]thiophen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride.

10. The compound according to claim 6 , wherein the compound is (1R,5R)-1-(benzo[b]thiophen-2-yl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 10 , wherein the compound is (1R,5R)-1-(benzo[b]thiophen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride.

12. The compound according to claim 5 , wherein the compound is 1-(benzo[b]thiophen-2-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 12 , wherein the compound is 1-(benzo[b]thiophen-2-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane hydrochloride.

14. The compound according to claim 12 , wherein the compound is (1S,5S)-1-(benzo[b]thiophen-2-yl)-3-methyl-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 14 , wherein the compound is (1S,5S)-1-(benzo[b]thiophen-2-yl)-3-methyl-3-azabicyclo[3.1.0]hexane hydrochloride.

16. The compound according to claim 12 , wherein the compound is (1R,5R)-1-(benzo[b]thiophen-2-yl)-3-methyl-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 16 , wherein the compound is (1R,5R)-1-(benzo[b]thiophen-2-yl)-3-methyl-azabicyclo[3.1.0]hexane hydrochloride.

18. The compound according to claim 5 , wherein the compound is 1-(6-fluorobenzo[b]thiophen-2-yl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.

19. The compound according to claim 18 , wherein the compound is 1-(6-fluorobenzo[b]thiophen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride.

20. The compound according to claim 18 , wherein the compound is (1S,5S)-1-(6-fluorobenzo[b]thiophen-2-yl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.

21. The compound according to claim 20 , wherein the compound is (1S,5S)-1-(6-fluorobenzo[b]thiophen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride.

22. The compound according to claim 18 , wherein the compound is (1R,5R)-1-(6-fluorobenzo[b]thiophen-2-yl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.

23. The compound according to claim 22 , wherein the compound is (1R,5R)-1-(6-fluorobenzo[b]thiophen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride.

24. The compound according to claim 5 , wherein the compound is 1-(6-fluorobenzo[b]thiophen-2-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.

25. The compound according to claim 5 , wherein the compound is 1-(5-fluorobenzo[b]thiophen-2-yl)-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.

26. The compound according to claim 5 , wherein the compound is 1-(5-fluorobenzo[b]thiophen-2-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.

27. A compound selected from the group consisting of:

N,N-dimethyl-2-(3-methyl-3-azabicyclo[3.1.0]hexane-1-yl)benzo[b]thiophen-5-amine;

1-(5-bromobenzo[b]thiophen-2-yl)-3-azabicyclo[3.1.0]hexane;

1-(5-bromobenzo[b]thiophen-2-yl)-3-methyl-3-azabicyclo[3.1.0]hexane;

2-(3-azabicyclo[3.1.0]hexan-1-yl)-N,N-dimethylbenzo[b]thiophen-5-amine;

2-(3-ethyl-3-azabicyclo[3.1.0]hexan-1-yl)-N,N-dimethylbenzo[b]thiophen-5-amine;

2-(3-isopropyl-3-azabicyclo[3.1.0]hexan-1-yl)-N,N-dimethylbenzo[b]thiophen-5-amine;

1-(6-bromobenzo[b]thiophen-2-yl)-3-azabicyclo[3.1.0]hexane;

1-(6-bromobenzo[b]thiophen-2-yl)-3-methyl-3-azabicyclo[3.1.0]hexane;

2-(3-azabicyclo[3.1.0]hexan-1-yl)-N,N-dimethylbenzo[b]thiophen-6-amine;

N,N-dimethyl-2-(3-methyl-3-azabicyclo[3.1.0]hexan-1-yl)benzo[b]thiophen-6-amine;

2-(3-ethyl-3-azabicyclo[3.1.0]hexan-1-yl)-N,N-dimethylbenzo[b]thiophen-6-amine; and

2-(3-isopropyl-3-azabicyclo[3.1.0]hexan-1-yl)-N,N-dimethylbenzo[b]thiophen-6-amine;

or a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt, enantiomer, polymorph, solvate, hydrate or prodrug thereof and a pharmaceutically acceptable carrier or vehicle therefore.

29. A pharmaceutical composition comprising a compound according to claim 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle therefore.

30. The pharmaceutical composition according to claim 29 comprising a compound selected from the group consisting of: