BACE1 inhibitors

Patent metadata

Field	Value
Publication number	US-11447478-B2
Application number	US-201414783478-A
Country	US
Kind code	B2
Filing date	Apr 8, 2014
Priority date	Apr 11, 2013
Publication date	Sep 20, 2022
Grant date	Sep 20, 2022

Abstract

The present invention provides a compound of formula I having BACE1 inhibitory activity, their manufacture, pharmaceutical compositions containing them and their use as therapeutically active substances. The active compounds of the present invention are useful in the therapeutic and/or prophylactic treatment of e.g. Alzheimer's disease.

First claim

The invention claimed is:

1. A compound of formula I,

wherein
R 1 is selected from the group consisting of
i) aryl,
ii) aryl substituted by 1-4 substituents individually selected from amino, cyano, cyano-C 1-6 -alkyl, halogen, halogen-C 1-6 -alkoxy, halogen-C 1-4 -alkyl, C 1-6 -alkoxy, C 1-6 -alkoxy-C 1-6 -alkyl, C 2-6 -alkynyl-C 1-6 -alkoxy, C 2-6 -alkynyl and C 1-6 -alkyl,
iii) heteroaryl, and
iv) heteroaryl substituted by 1-4 substituents individually selected from amino, cyano, cyano-C 1-4 -alkyl, halogen, halogen-C 1-6 -alkoxy, halogen-C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkoxy-C 1-6 -alkyl, C 2-6 -alkynyl-C 1-4 -alkoxy, C 2-6 -alkynyl and C 1-4 -alkyl;

R 2 is selected from the group consisting of
i) hydrogen,
ii) C 1-4 -alkyl, and
iii) halogen;

R 3 is selected from the group consisting of
i) C 1-6 -alkyl, and
ii) halogen-C 1-6 -alkyl,

R 4 is selected from the group consisting of
i) halogen, and
ii) hydrogen,

R 5 is halogen-C 1-4 -alkyl;
or a pharmaceutically acceptable salt thereof.

2. The compound of formula I, of formula Ia-1

wherein
R 1 is selected from the group consisting of
i) aryl,
ii) aryl substituted by 1-2 substituents individually selected from amino, cyano, cyano-C 1-6 -alkyl, halogen, halogen-C 1-6 -alkoxy, halogen-C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkoxy-C 1-6 -alkyl, C 2-6 -alkynyl-C 1-6 -alkoxy, C 2-6 -alkynyl and C 1-4 -alkyl,
iii) heteroaryl, and
iv) heteroaryl substituted by 1-2 substituents individually selected from amino, cyano, cyano-C 1-6 -alkyl, halogen, halogen-C 1-6 -alkoxy, halogen-C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkoxy-C 1-6 -alkyl, C 2-6 -alkynyl-C 1-6 -alkoxy, C 2-6 -alkynyl and C 1-6 -alkyl; and

R 3 is selected from the group consisting of
i) C 1-6 -alkyl, and
ii) halogen-C 1-6 -alkyl,

R 4 is selected from the group consisting of
i) halogen, and
ii) hydrogen,

or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 , wherein R 1 is heteroaryl substituted by 1-2 substituents individually selected from cyano, halogen, halogen-C 1-6 -alkoxy, halogen-C 1-6 -alkyl, C 1-6 -alkoxy and C 1-6 -alkyl.

4. The compound according to claim 1 , wherein R 1 is heteroaryl substituted by 1-2 substituents individually selected from amino and cyano.

5. The compound according to claim 1 , wherein R 1 is pyridinyl, 1H-pyrazolyl or pyrazinyl.

6. The compound according to claim 1 , wherein R 1 is pyridinyl or pyrazinyl.

7. The compound according to claim 1 , wherein R 1 is pyridinyl.

8. The compound according to claim 1 , wherein R 1 is 3,5-dichloro-pyridinyl, 3-chloro-5-cyano-pyridinyl, 3-chloro-5-trifluoromethyl-pyridinyl, 4-chloro-1-(difluoromethyl)-1H-pyrazolyl, 5-(difluoromethyl)-pyrazinyl, 5-(fluoromethoxy)pyridinyl, 5-cyano-3-methyl-pyridinyl, 5-cyano-pyridinyl, 5-methoxy-pyrazinyl or 5-methoxy-pyridinyl.

9. The compound according to claim 1 , wherein R 1 is 5-cyano-pyridine-2-yl.

10. The compound according to claim 1 , wherein R 2 is halogen.

11. The compound according to claim 1 , wherein R 2 is F.

12. The compound according to claim 1 , wherein R 3 is C 1-6 -alkyl.

13. The compound according to claim 1 , wherein R 3 is methyl.

14. The compound according to claim 1 , wherein R 4 is halogen.

15. The compound according to claim 1 , wherein R 4 is fluoro.

16. The compound according to claim 1 , wherein R 4 is hydrogen.

17. The compound according to claim 1 , wherein R 5 is fluoro-C 1-6 -alkyl.

18. The compound according to claim 1 , wherein R 5 is trifluoromethyl.

19. The compound according to claim 1 selected from the group consisting of:
N-(6-((4R,5R,6R)-2-amino-5-fluoro-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-5-cyanopicolinamide,
N-(6-((4R,5R,6S)-2-amino-5-fluoro-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-5-cyanopicolinamide,
N-(6-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-5-cyanopicolinamide,
N-(6-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-3-chloro-5-cyanopicolinamide,
N-(6-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-3-chloro-5-(trifluoromethyl)picolinamide 2,2,2-trifluoroacetate,
N-(6-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-5-methoxypyrazine-2-carboxamide 2,2,2-trifluoroacetate,
N-(6-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-5-cyano-3-methylpicolinamide 2,2,2-trifluoroacetate,
N-(6-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-5-methoxypicolinamide 2,2,2-trifluoroacetate,
N-(6-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carboxamide 2,2,2-trifluoroacetate,
N-(6-(4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-5-(difluoromethyl)pyrazine-2-carboxamide 2,2,2-trifluoroacetate,
N-(6-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-3,5-dichloropicolinamide 2,2,2-trifluoroacetate,
N-(6 ((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-5-(fluoromethoxy)picolinamide 2,2,2-trifluoroacetate, and
N-(6-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-chloropyridin-2-yl)-5-cyanopicolinamide,
or a pharmaceutically acceptable salt thereof.

20. The compound according to claim 1 , wherein said compound is N-(6-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-5-cyanopicolinamide or a pharmaceutically acceptable salt thereof.

21. A process for preparing a compound according to claim 1 , comprising the step of reacting a compound of formula XI′ with a compound of formula XII′

to form a compound of formula I, wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined in claim 1 and X is an amino protecting group.

22. A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier and/or a pharmaceutically acceptable auxiliary substance.

23. A method for treating a disease or disorder characterized by elevated β-amyloid levels and/or β-amyloid oligomers and/or β-amyloid plaques and further deposits or Alzheimer's disease, comprising the step of administering a therapeutically effective amount of a compound according to claim 1 to a human being or animal in need thereof.

24. A method for treating Alzheimer's disease, comprising the step of administering a therapeutically effective amount of a compound according to claim 1 to a human being or animal in need thereof.

Assignees

• Hoffmann La Roche
• Siena Biotech Spa

Inventors

• Hilpert Hans
• Humm Roland
• Muser Thorsten
• Schnider Christian
• Wermuth Roger
• Woltering Thomas

Classifications

• A61P1/00

  Drugs for disorders of the alimentary tract or the digestive system · CPC title

• A61P43/00

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

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title

• C07D413/14 Primary

  containing three or more hetero rings · 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