BACE1 inhibitors

Patent metadata

Field	Value
Publication number	US-9540397-B2
Application number	US-201514877250-A
Country	US
Kind code	B2
Filing date	Oct 7, 2015
Priority date	Oct 10, 2014
Publication date	Jan 10, 2017
Grant date	Jan 10, 2017

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:
n is 1, 2 or 3;
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 each independently selected from the group consisting of
i) hydrogen,
ii) C 1-6 -alkyl, and
iii) halogen;

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

or wherein R 3 and R 4 together are (CH 2 ) m —, wherein m is 2, 3, 4 or 5,
R 5 is hydrogen,
R 6 is selected from the group consisting of
i) C 1-6 -alkyl, and
ii) halogen-C 1-6 -alkyl;

R 7 is selected from the group consisting of
i) hydrogen, and
ii) halogen;

R 8 is selected from the group consisting of
i) aryl,
ii) aryl substituted by 1-4 substituents individually selected from amino, cyano, halogen, halogen-C 1-6 -alkyl, halogen-C 1-6 -alkoxy, C 1-6 -alkoxy, C 1-6 -alkoxy-C 1-6 -alkyl, C 2-6 -alkynyl-C 1-6 -alkoxy, C 2-6 -alkynyl, C 1-6 -alkyl, COOR 9 , wherein R 9 is H or C 1-6 -alkyl, CONR 10 R 11 , wherein R 10 is H or C 1-6 -alkyl C 3-6 -cycloalkyl and R 11 is H or C 1-6 -alkyl, C 3-6 -cycloalkyl that is optionally substituted by 1 to 4 substituents individually selected from the group consisting of halogen, cyano, C 1-6 -alkyl and C 1-6 -alkoxy, C 3-6 -cycloalkyl-C 1-6 -alkoxy and C 3-6 -cycloalkyl-C 1-6 -alkoxy, wherein the cycloalkyl unit is substituted by 1 to 4 substituents individually selected from the group consisting of halogen, cyano, C 1-6 -alkyl and C 1-6 -alkoxy;
iii) heteroaryl, and
iv) heteroaryl substituted by 1-4 substituents individually selected from amino, cyano, halogen, halogen-C 1-6 -alkyl, halogen-C 1-6 -alkoxy, C 1-6 -alkoxy, C 1-6 -alkoxy-C 1-6 -alkyl, C 2-6 -alkynyl-C 1-6 -alkoxy, C 2-6 -alkynyl, C 1-6 -alkyl, COOR 9 , wherein R 9 is H or C 1-6 -alkyl, CONR 10 R 11 , wherein R 10 is H or C 1-6 -alkyl C 3-6 -cycloalkyl and R 11 is H or C 3-6 -cycloalkyl that is optionally substituted by 1 to 4 substituents individually selected from the group consisting of halogen, cyano, C 1-6 -alkyl and C 1-6 -alkoxy, C 3-6 -cycloalkyl-C 1-6 -alkoxy and C 3-6 -cycloalkyl-C 1-6 -alkoxy, wherein the cycloalkyl unit is substituted by 1 to 4 substituents individually selected from the group consisting of halogen, cyano, C 1-6 -alkyl and C 1-6 -alkoxy;

or pharmaceutically acceptable salts thereof.

2. The compound according to claim 1 , wherein
n is 1, 2 or 3;
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 each independently selected from the group consisting of
i) hydrogen,
ii) C 1-6 -alkyl, and
iii) halogen;

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

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

R 7 is selected from the group consisting of
i) hydrogen, and
ii) halogen;

R 8 is selected from the group consisting of
i) aryl,
ii) aryl substituted by 1-4 substituents individually selected from amino, cyano, halogen, halogen-C 1-6 -alkyl, halogen-C 1-6 -alkoxy, C 1-6 -alkoxy, C 1-6 -alkoxy-C 1-6 -alkyl, C 2-6 -alkynyl-C 1-6 -alkoxy, C 2-6 -alkynyl, C 1-6 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl that is optionally substituted by 1 to 4 substituents individually selected from the group consisting of halogen, cyano, C 1-6 -alkyl and C 1-6 -alkoxy, C 3-6 -cycloalkyl-C 1-6 -alkoxy and C 3-6 -cycloalkyl-C 1-6 -alkoxy, wherein the cycloalkyl unit is substituted by 1 to 4 substituents individually selected from the group consisting of halogen, cyano, C 1-6 -alkyl and C 1-6 -alkoxy;
iii) heteroaryl, and
iv) heteroaryl substituted by 1-4 substituents individually selected from amino, cyano, halogen, halogen-C 1-6 -alkyl, halogen-C 1-6 -alkoxy, C 1-6 -alkoxy, C 1-6 -alkoxy-C 1-6 -alkyl, C 2-6 -alkynyl-C 1-6 -alkoxy, C 2-6 -alkynyl, C 3-6 -cycloalkyl that is optionally substituted by 1 to 4 substituents individually selected from the group consisting of halogen, cyano, C 1-6 -alkyl and C 1-6 -alkoxy, C 3-6 -cycloalkyl-C 1-6 -alkoxy and C 3-6 -cycloalkyl-C 1-6 -alkoxy, wherein the cycloalkyl unit is substituted by 1 to 4 substituents individually selected from the group consisting of halogen, cyano, C 1-6 -alkyl and C 1-6 -alkoxy;

or pharmaceutically acceptable salts thereof.

3. The compound according to claim 1 , which is of formula Ia:

wherein n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as described in claim 1 .

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

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

6. The compound according to claim 1 , wherein R 3 is hydrogen.

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

8. The compound according to claim 1 , wherein R 3 and R 4 together are —(CH 2 ) 2 —.

9. The compound according to claim 1 , wherein R 5 is hydrogen.

10. The compound according to claim 1 , wherein R 6 is methyl.

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

12. The compound according to claim 1 , wherein R 8 is aryl substituted by 1-2 substituents individually selected from cyano and halogen.

13. The compound according to claim 1 , wherein R 8 is phenyl substituted by 1-2 substituents individually selected from cyano and Cl.

14. The compound according to claim 1 , wherein R 8 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, C 2-6 -alkylnyl and C 1-6 -alkyl.

15. The compound according to claim 1 , wherein R 8 is heteroaryl, substituted by 1-2 substituents individually selected from cyano, halogen, halogen-C 1-6 -alkoxy, C 1-6 -alkoxy and C 1-6 -alkyl.

16. The compound according to claim 1 , wherein R 8 is 1H-pyrazolyl, pyridinyl, pyrazinyl or imidazo[1,2-a]pyridinyl, substituted by 1-2 substituents individually selected from cyano, halogen, halogen-C 1-6 -alkoxy, halogen-C 1-6 -alkyl, C 1-6 -alkoxy, C 2-6 -alkylnyl and C 1-6 -alkyl.

17. The compound according to claim 1 , wherein R 8 is pyridinyl, pyrazinyl or imidazo[1,2-a]pyridinyl, each substituted by 1-2 substituents individually selected from cyano, halogen, halogen-C 1-6 -alkoxy, C 1-6 -alkoxy and C 1-6 -alkyl.

18. The compound according to claim 1 , wherein n is 1 or 2.

19. The compound according to claim 1 , selected from the group consisting of:
N-(6-((4aR,5R,9R)-7-amino-5,8,8-trimethyl-9-oxido-2,3,4,4a,5,8-hexahydro-[1,4]thiaz

Assignees

• Hoffmann La Roche

Inventors

• Bartels Bjoern
• Cueni Philipp
• Dolente Cosimo
• Guba Wolfgang
• Haap Wolfgang
• Kuglstatter Andreas
• Sander Ulrike Obst
• Peters Jens-Uwe
• Rogers-Evans Mark
• Vifian Walter
• Woltering Thomas

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D513/04 Primary

  Ortho-condensed systems · 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