BACE1 inhibitors

Patent metadata

Field	Value
Publication number	US-10047081-B2
Application number	US-201615558273-A
Country	US
Kind code	B2
Filing date	Mar 16, 2016
Priority date	Mar 20, 2015
Publication date	Aug 14, 2018
Grant date	Aug 14, 2018

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 1,

A is a heteroaryl group,
B is a heteroaryl group,
R 1 is selected from the group consisting of
i) C 1-6 -alkyl and
ii) halogen-C 1-6 -alkyl;

R 2 is selected from the group consisting of
i) C 1-6 -alkyl, and
ii) halogen-C 1-6 -alkyl;

or R 1 and R 2 form together with the C-atom they are attached to, a C 3-6 -cycloalkyl-, wherein the C 3-6 -cycloalkyl- is optionally substituted by one or more substituents selected from the group consisting of halogen and hydroxyl;
R 3 is selected from the group consisting of
i) hydrogen,
ii) C 3-6 -cycloalkyl,
iii) halogen-C 1-6 -alkyl, and
iv) C 1-6 -alkyl;

R 4 is selected from the group consisting of
i) hydrogen, and
ii) C 1-6 -alkyl;

R 5 is selected from the group consisting of
i) C 1-6 -alkyl, and
ii) halogen-C 1-6 -alkyl;

R 6 is halogen;
R 7 is selected from the group consisting of
i) amino,
ii) cyano,
iii) hydrogen,
iv) OH,
v) halogen,
vi) C 1-6 -alkyl,
vii) C 1-6 -alkyl-C 3-6 -cycloalkyl,
viii) halogen-C 1-6 -alkyl,
ix) C 1-6 -alkoxy-C 2-6 -alkyl,
x) C 2-6 -alkynyl,
xi) C 2-6 -alkynyl-C 1-6 -alkyl,
xii) C 2-6 -alkynyl-C 1-6 -alkoxy
xiii) C 1-6 -alkoxy, and
xiv) halogen-C 1-6 -alkoxy;

or pharmaceutically acceptable salts thereof.

2. The compound according to claim 1 , wherein
A is a heteroaryl group,
B is a heteroaryl group,
R 1 is selected from the group consisting of
i) C 1-6 -alkyl and
ii) halogen-C 1-6 -alkyl;

R 2 is selected from the group consisting of
i) C 1-6 -alkyl, and
ii) halogen-C 1-6 -alkyl;

or R 1 and R 2 form together with the C-atom they are attached to a C 3-6 -cycloalkyl-, wherein the C 3-6 -cycloalkyl- is optionally substituted by one or more substituents selected from the group consisting of halogen and hydroxyl;
R 3 is selected from the group consisting of
i) hydrogen,
ii) halogen-C 1-6 -alkyl, and
iii) C 1-6 -alkyl;

R 4 is selected from the group consisting of
i) hydrogen, and
ii) C 1-6 -alkyl;

R 5 is selected from the group consisting of
i) C 1-6 -alkyl, and
ii) halogen-C 1-6 -alkyl;

R 6 is halogen;
R 7 is selected from the group consisting of
i) amino,
ii) cyano,
iii) hydrogen,
iv) halogen,
v) C 1-6 -alkyl,
vi) halogen-C 1-6 -alkyl,
vii) C 1-6 -alkoxy-C 1-6 -alkyl,
viii) C 2-6 -alkynyl,
ix) C 2-6 -alkynyl-C 1-6 -alkyl,
x) C 2-6 -alkynyl-C 1-6 -alkoxy
xi) C 1-6 -alkoxy, and
xii) halogen-C 1-6 -alkoxy;

or pharmaceutically acceptable salts thereof.

3. The compound according to claim 1 , which is of formula Ia, wherein A, B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 is as defined in any one of claim 1 or 2

4. The compound according to claim 1 , wherein A is a 5-membered heteroaryl group.

5. The compound according to claim 1 , wherein A is isoxazolyl or triazolyl.

6. The compound according to claim 1 , wherein B is a 6-membered heteroaryl group.

7. The compound according to claim 1 , wherein B is pyrazinyl, pyrimidinyl or pyridinyl.

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

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

10. The compound according to claim 1 , wherein R 2 is C 1-6 -alkyl.

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

12. The compound according to claim 1 , wherein R 1 and R 2 form together with the C-atom they are attached to a C 3-6 -cycloalkyl-.

13. The compound according to claim 1 , wherein R 1 and R 2 form together with the C-atom they are attached to a cyclopentyl.

14. The compound according to claim 1 , wherein R 3 is H, CH 3 , CD 3 , CH 2 CF 3 or cyclopropyl.

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

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

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

18. The compound according to claim 1 , wherein R 5 is C 1-6 -alkyl or halogen-C 1-6 -alkyl.

19. The compound according to claim 1 , wherein R 5 is methyl or —CH 2 F.

20. The compound according to claim 1 , wherein R 6 is F.

21. The compound according to claim 1 , wherein R 7 is Br, CH 2 -cyclopropyl, Cl, CN, Et, Me, OCH 2 CF 2 CHF 2 , OCH 2 CF 3 , OCH 2 CHF 2 , OH or OMe.

22. The compound according to claim 1 , selected from the group consisting of:
(1R,3R)-3-[2-fluoro-5-[3-(5-methoxypyrazin-2-yl)isoxazol-5-yl]phenyl]-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine; 2,2,2-trifluoroacetic acid,
(1R,3R)-3-[2-fluoro-5-[3-(5-methoxypyrazin-2-yl)isoxazol-5-yl]phenyl]-3,6,6-trimethyl-1-oxo-1-(trideuteriomethylimino)-2H-1,4-thiazin-5-amine 2,2,2-trifluoroacetate,
(1R,3R)-3-[2-fluoro-5-[3-[5-(2,2,3,3-tetrafluoropropoxy)pyrimidin-2-yl]isoxazol-5-yl]phenyl]-3,6,6-trimethyl-1-oxo-1-(trideuteriomethylimino)-2H-1,4-thiazin-5-amine 2,2,2-trifluoroacetate,
(1R,3R)-3-[5-[1-(5-chloro-2-pyridyl)triazol-4-yl]-2-fluoro-phenyl]-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine; 2,2,2-trifluoroacetic acid,
(1R,3R)-3-[5-[3-(5-chloropyrimidin-2-yl)isoxazol-5-yl]-2-fluoro-phenyl]-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine; 2,2,2-trifluoroacetic acid,
(1R,3R)-3-[5-[3-(5-chloropyrimidin-2-yl)isoxazol-5-yl]-2-fluoro-phenyl]-1-cyclopropylimino-3,6,6-trimethyl-1-oxo-2H-1,4-thiazin-5-amine 2,2,2-trifluoroacetate,
(1R,3R)-3-[5-[3-(5-chloropyrimidin-2-yl)isoxazol-5-yl]-2-fluoro-phenyl]-1-imino-3,6,6-trimethyl-1-oxo-2H-1,4-thiazin-5-amine; 2,2,2-trifluoroacetic acid 2,2,2-trifluoroacetate,
(1R,3R)-3-[5-[3-(5-ethylpyrimidin-2-yl)isoxazol-5-yl]-2-fluoro-phenyl]-3,6,6-trimethyl-1-oxo-1-(trideuteriomethylimino)-2H-1,4-thiazin-5-amine 2,2,2-trifluoroacetate,
(1R,3R)-3-[5-[3-[5-(2,2-difluoroethoxy)pyrazin-2-yl]isoxazol-5-yl]-2-fluoro-phenyl]-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine; 2,2,2-trifluoroacetic acid,
(1R,3R)-3-[5-[3-[5-(2,2-difluoroethoxy)pyrimidin-2-yl]isoxazol-5-yl]-2-fluoro-phenyl]-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine,
(1R,3R)-5-amino-1-(cyclopropylimino)-3-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine 1-oxide,
(1R,3R)-5-amino-3-(2-fluoro-5-(3-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)isoxazol-5-yl)phenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine 1-oxide 2,2,2-trifluoroacetate,
(1R,3R)-5-amino-3-(2-fluoro-5-(3-(5-hydroxypyrazin-2-yl)isoxazol-5-yl)phenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine 1-oxide,
(1R,3R)-5-amino-3-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-3,6,6-trimethyl-1-((2,2,2-trifluoroethyl)imino)-3,6-dihydro-2H-1,4-thiazine 1-oxide 2,2,2-trifluoroacetate,
(1R,3R)-5-amino-3-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-1-imino-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine 1-oxide,
(1R,3R)-5-amino-3-(2-fluoro-5-(3-(5-methoxypyrimidin-2-yl)isoxazol-5-yl)phenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazin 1-oxide,
(1R,3R)-5-amino-3-(5-(3-(5-(cyclopropylmethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine 1-oxide,
(1R,3R)-5-amino-3-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3,6,6

Assignees

• Hoffmann La Roche
• Hoffmann La Roche

Inventors

• Bartels Bjoern
• Dolente Cosimo
• Guba Wolfgang
• Haap Wolfgang
• Obst Sander Ulrike
• Peters Jens-Uwe
• Woltering Thomas

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

• C07D417/14 Primary

  containing three or more hetero rings · CPC title

• A61K31/541

  Non-condensed thiazines containing further heterocyclic rings · CPC title