BACE1 inhibitors

Patent metadata

Field	Value
Publication number	US-9920072-B2
Application number	US-201515522877-A
Country	US
Kind code	B2
Filing date	Oct 30, 2015
Priority date	Nov 3, 2014
Publication date	Mar 20, 2018
Grant date	Mar 20, 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 I:

wherein:
n is 2 or 3;
R 1 is selected from the group consisting of
i) H,
ii) halogen,
iii) C 1-6 -alkyl, and
iv) halogen-C 1-6 -alkyl;

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

R 3 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 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;
or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

7. The compound according to claim 1 , wherein R 3 is heteroaryl substituted by cyan and C 1-6 -alkyl.

8. The compound according to claim 1 , wherein R 3 pyridinyl substituted by cyano and methyl.

9. The compound according to claim 1 , which is of formula Ia, wherein n, R 1 and R 2 are as described in claim 1 and R 4 is 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 -alkoxyl, 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 a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1 , selected from the group consisting of:
N-[6-(5-amino-4a,7-dimethyl-9-oxido-2,3,4,4a,7,8-hexahydro-9λ 4 -[1,4]thiazino[2,1-f][1,2]thiazin-7-yl)-5-fluoropyridin-2-yl]-5-methoxypyrazine-2-carboxamide,
N-[6-(5-amino-4a,7-dimethyl-9-oxido-2,3,4,4a,7,8-hexahydro-9λ 4 -[1,4]thiazino[2,1-f][1,2]thiazin-7-yl)-5-fluoropyridin-2-yl]-3,5-dichloropyridine-2-carboxamide,
N-[6-(5-amino-4a,7-dimethyl-9-oxido-2,3,4,4a,7,8-hexahydro-9λ 4 -[1,4]thiazino[2,1-f][1,2]thiazin-7-yl)-5-fluoropyridin-2-yl]-5-fluoro-3-methylpyridine-2-carboxamide,
N-[6-(5-amino-4a,7-dimethyl-9-oxido-2,3,4,4a,7,8-hexahydro-9λ 4 -[1,4]thiazino[2,1-f][1,2]thiazin-7-yl)-5-fluoropyridin-2-yl]-5-(difluoromethoxy)pyridine-2-carboxamide,
N-[6-(5-amino-4a,7-dimethyl-9-oxido-2,3,4,4a,7,8-hexahydro-9λ 4 -[1,4]thiazino[2,1-f][1,2]thiazin-7-yl)-5-fluoropyridin-2-yl]-5-(2,2-difluoroethoxy)pyridine-2-carboxamide,
N-[6-(5amino-4a,7-dimethyl-9-oxido-2,3,4,4a,7,8-hexahydro-9λ 4 -[1,4]thiazino[2,1-f][1,2]thiazin-7-yl)-5-fluoropyridin-2-yl]-5-(2,2,3,3-tetrafluoropropoxy)pyridine-2-carboxamide,
N-[6-(6-amino-5a,8-dimethyl-10-oxido-3,4,5,5a,8,9-hexahydro-2H-10λ 4 -[1,4]thiazino[2,1-g][1,2]thiazepin-8-yl)-5-fluoropyridin-2-yl]-5-cyano-3-methylpyridine-2-carboxamide (stereoisomer A),
N-[6-(6-amino-5a,8-dimethyl-10-oxido-3,4,5,5a,8,9-hexahydro-2H-10λ 4 -[1,4]thiazino[2,1-g][1,2]thiazepin-8-yl)-5-fluoropyridin-2-yl]-5-cyano-3-methylpyridine-2-carboxamide (stereoisomer B),
N-[6-(6-amino-5a,8-dimethyl-10-oxido-3,4,5,5a,8,9-hexahydro-2H-10λ 4 -[1,4]thiazino[2,1-g][1,2]thiazepin-8-yl)-5-fluoropyridin-2-yl]-5-cyano-3-methylpyridine-2-carboxamide (stereoisomer D),
N-[6-(6-amino-5a,8-dimethyl-10-oxido-3,4,5,5a,8,9-hexahydro-2H-10λ 4 -[1,4]thiazino[2,1-g][1,2]thiazepin-8-yl)-5-fluoropyridin-2-yl]-5-methoxypyrazine-2-carboxamide,
N-[6-(6-amino-5a,8-dimethyl-10-oxido-3,4,5,5a,8,9-hexahydro-2H-10λ 4 -[1,4]thiazino[2,1-g][1,2]thiazepin-8-yl)-5-fluoropyridin-2-yl]-3,5-dichloropyridine-2-carboxamide,
N-[6-(6-amino-5a,8-dimethyl-10-oxido-3,4,5,5a,8,9-hexahydro-2H-10λ 4 -[1,4]thiazino[2,1-g][1,2]thiazepin-8-yl)-5-fluoropyridin-2-yl]-5-fluoro-3-methylpyridine-2-carboxamide,
N-[6-(6-amino-5a,8-dimethyl-10-oxido-3,4,5,5a,8,9-hexahydro-2H-10λ 4 -[1,4]thiazino[2,1-g][1,2]thiazepin-8-yl)-5-fluoropyridin-2-yl]-3-chloro-5-cyanopyridine-2-carboxamide
N-[6-(6-amino-5a,8-dimethyl-10-oxido-3,4,5,5a,8,9-hexahydro-2H-10λ 4 -[1,4]thiazino[2,1-g][1,2]thiazepin-8-yl)-5-fluoropyridin-2-yl]-5-(difluoromethoxy)pyridine-2-carboxamide,
N-[6-(6-amino-5a,8-dimethyl-10-oxido-3,4,5,5a,8,9-hexahydro-2H-10λ 4 -[1,4]thiazino[2,1-g][1,2]thiazepin-8-yl)-5-fluoropyridin-2-yl]-5-(2,2-difluoroethoxy)pyridine-2-carboxamide,
N-[6-(6-amino-5a,8-dimethyl-10-oxido-3,4,5,5a,8,9-hexahydro-2H-10λ 4 -[1,4]thiazino[2,1-g][1,2]thiazepin-8-yl)-5-fluoropyridin-2-yl]-5-(2,2,3,3-tetrafluoropropoxy)pyridine-2-carboxamide,
N-{6-[(4aR,7R)-5-amino-4a,7-dimethyl-9-oxido-2,3,4,4a,7,8-hexahydro-9λ 4 -[1,4]thiazino[2,1-f][1,2]thiazin-7-yl]-5-fluoropyridin-2-yl}-5-cyano-3-methylpyridine-2-carboxamide
N-{6-[(4aS,7R)-5-Amino-4a,7-dimethyl-9-oxido-2,3,4,4a,7,8-hexahydro-9λ 4 -[1,4]thiazino[2,1-f][1,2]thiazin-7-yl]-5-fluoropyridin-2-yl}-5-cyano-3-methylpyridine-2-carboxamide,
N-{6-[(4aR,7R)-5-amino-4a,7-dimethyl-9-oxido-2,3,4,4a,7,8-hexahydro-9λ 4 -[1,4]thiazino[2,1-f][1,2]thiazin-7-yl]-5-fluoropyridin-2-yl}-3-chloro-5-cyanopyridine-2-carboxmide,
N-{6-[(4aS,7R)-5-amino-4a,7-dimethyl-9-oxido-2,3,4,4a,7,8-hexahydro-9λ 4 -[1,4]thiazino[2,1-f][1,2]thiazin-7-yl]-5-fluoropyridin-2-yl}-3-chloro-5-cyanopyridine-2-carboxamide,
N-{6-[(4aR,7R)-5-amino-4a,7-dimethyl-9-oxido-2,3,4,4a,7,8-hexahydro-9λ 4 -[1,4]thiazino[2,1-f][1,2]thiazin-7-yl]-5-fluoropyridin-2-yl}-5-2,2,3

Assignees

• Hoffmann La Roche

Inventors

• Bartels Bjoern
• Dolente Cosimo
• Guba Wolfgang
• Haap Wolfgang
• Obst Sander Ulrike
• Peters Jens-Uwe
• Rogers-Evans Mark
• Rombach Didier
• Woltering Thomas

Classifications

• 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