Perfluorinated cyclopropyl fused 1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use

Patent metadata

Field	Value
Publication number	US-9611261-B2
Application number	US-201514932787-A
Country	US
Kind code	B2
Filing date	Nov 4, 2015
Priority date	Mar 8, 2013
Publication date	Apr 4, 2017
Grant date	Apr 4, 2017

Abstract

The present invention provides a new class of compounds useful for the modulation of beta-secretase enzyme (BACE) activity. The compounds have a general Formula I:

wherein variables A 4 , A 5 , A 6 , A 8 , each of R a , R b , R 1 , R 2 , R 3 and R 7 of Formula I, independently, are defined herein. The invention also provides pharmaceutical compositions comprising the compounds, and uses of the compounds and compositions for treatment of disorders and/or conditions related to A-beta plaque formation and deposition, resulting from the biological activity of BACE. Such BACE mediated disorders include, for example, Alzheimer's Disease, cognitive deficits, cognitive impairments, schizophrenia and other central nervous system conditions. The invention further provides compounds of Formulas II and III, and sub-formula embodiments thereof, intermediates and methods for preparing compounds of the invention.

First claim

What is claimed is:

1. A compound of formula

or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.

3. A method of reducing beta amyloid peptide levels in the cerebral spinal fluid of a subject, the method comprising administering to the subject an effective dosage amount of the compound of claim 1 .

4. A method of treating Alzheimer's disease, cognitive impairment or a combination thereof in a subject, the method comprising administering to the subject an effective dosage amount of the compound of claim 1 .

5. A compound of formula

or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition comprising the compound of claim 5 and a pharmaceutically acceptable excipient.

7. A method of reducing beta amyloid peptide levels in the cerebral spinal fluid of a subject, the method comprising administering to the subject an effective dosage amount of the compound of claim 5 .

8. A method of treating Alzheimer's disease, cognitive impairment or a combination thereof in a subject, the method comprising administering to the subject an effective dosage amount of the compound of claim 5 .

9. A compound of formula

or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising the compound of claim 9 and a pharmaceutically acceptable excipient.

11. A method of reducing beta amyloid peptide levels in the cerebral spinal fluid of a subject, the method comprising administering to the subject an effective dosage amount of the compound of claim 9 .

12. A method of treating Alzheimer's disease, cognitive impairment or a combination thereof in a subject, the method comprising administering to the subject an effective dosage amount of the compound of claim 9 .

13. A compound of formula

or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising the compound of claim 13 and a pharmaceutically acceptable excipient.

15. A method of reducing beta amyloid peptide levels in the cerebral spinal fluid of a subject, the method comprising administering to the subject an effective dosage amount of the compound of claim 13 .

16. A method of treating Alzheimer's disease, cognitive impairment or a combination thereof in a subject, the method comprising administering to the subject an effective dosage amount of the compound of claim 13 .

17. A compound of formula

or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising the compound of claim 17 and a pharmaceutically acceptable excipient.

19. A method of reducing beta amyloid peptide levels in the cerebral spinal fluid of a subject, the method comprising administering to the subject an effective dosage amount of the compound of claim 17 .

20. A method of treating Alzheimer's disease, cognitive impairment or a combination thereof in a subject, the method comprising administering to the subject an effective dosage amount of the compound of claim 17 .

21. A compound of formula

or a pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition comprising the compound of claim 21 and a pharmaceutically acceptable excipient.

23. A method of reducing beta amyloid peptide levels in the cerebral spinal fluid of a subject, the method comprising administering to the subject an effective dosage amount of the compound of claim 21 .

24. A method of treating Alzheimer's disease, cognitive impairment or a combination thereof in a subject, the method comprising administering to the subject an effective dosage amount of the compound of claim 21 .

25. A compound of formula

or a pharmaceutically acceptable salt thereof.

26. A pharmaceutical composition comprising the compound of claim 25 and a pharmaceutically acceptable excipient.

27. A method of reducing beta amyloid peptide levels in the cerebral spinal fluid of a subject, the method comprising administering to the subject an effective dosage amount of the compound of claim 25 .

28. A method of treating Alzheimer's disease, cognitive impairment or a combination thereof in a subject, the method comprising administering to the subject an effective dosage amount of the compound of claim 25 .

29. A compound of formula

or a pharmaceutically acceptable salt thereof.

30. A pharmaceutical composition comprising the compound of claim 29 and a pharmaceutically acceptable excipient.

31. A method of reducing beta amyloid peptide levels in the cerebral spinal fluid of a subject, the method comprising administering to the subject an effective dosage amount of the compound of claim 29 .

32. A method of treating Alzheimer's disease, cognitive impairment or a combination thereof in a subject, the method comprising administering to the subject an effective dosage amount of the compound of claim 29 .

33. A compound of formula

or a pharmaceutically acceptable salt thereof.

34. A pharmaceutical composition comprising the compound of claim 33 and a pharmaceutically acceptable excipient.

35. A method of reducing beta amyloid peptide levels in the cerebral spinal fluid of a subject, the method comprising administering to the subject an effective dosage amount of the compound of claim 33 .

36. A method of treating Alzheimer's disease, cognitive impairment or a combination thereof in a subject, the method comprising administering to the subject an effective dosage amount of the compound of claim 33 .

37. A compound of formula

or a pharmaceutically acceptable salt thereof.

38. A pharmaceutical composition comprising the compound of claim 37 and a pharmaceutically acceptable excipient.

39. A method of reducing beta amyloid peptide levels in the cerebral spinal fluid of a subject, the method comprising administering to the subject an effective dosage amount of the compound of claim 37 .

40. A method of treating Alzheimer's disease, cognitive impairment or a combination thereof in a subject, the method comprising administering to the subject an effective dosage amount of th

Assignees

• Amgen Inc

Inventors

• Minatti Ana Elena
• Low Jonathan D
• Allen Jennifer R
• Amegadzie Albert
• Brown James
• Frohn Michael J
• Guzman-Perez Angel
• Harrington Paul E
• Lopez Patricia
• Ma Vu Van
• Nishimura Nobuko
• Qian Wenyuan
• Rumfelt Shannon
• Rzasa Robert M
• Sham Kelvin
• Smith Adrian L
• White Ryan
• Xue Qiufen

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07D413/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title