BACE1 inhibitors

Patent metadata

Field	Value
Publication number	US-10246468-B2
Application number	US-201615735890-A
Country	US
Kind code	B2
Filing date	Aug 8, 2016
Priority date	Aug 12, 2015
Publication date	Apr 2, 2019
Grant date	Apr 2, 2019

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 1-4 -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 3-4 -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 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;

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as described and when n=1, then the 5-ring has cis configuration.

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 and R 2 are methyl.

5. The compound according to claim 1 , wherein R 3 and R 4 are hydrogen.

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

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

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

9. 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 and C 1-6 -alkyl.

10. The compound according to claim 1 , wherein R 8 is heteroaryl which is selected from pyridinyl, pyrazinyl, pyrimidyl or 1H-pyrazolyl, each substituted by 1-2 substituents individually selected from cyano, halogen, halogen-C 1-6 -alkoxy, halogen-C 1-6 -alkyl and C 1-6 -alkyl.

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

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

13. The compound according to claim 1 , wherein n is 1.

14. The compound according to claim 1 , selected from the group consisting of:
N-(3-((3aR,4R,8S)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-3-chloro-5-cyanopicolinamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-3,5-dichloropicolinamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-2-chloro-4-cyanobenzamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-(difluoromethoxy) picolinamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carboxamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-(2,2-difluoroethoxy)pyrazine-2-carboxamide,
N-(3-((3aS,4R8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-3-chloro-5-(trifluoromethyl)picolinamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-4-cyano-2-methylbenzamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-(2,2-difluoroethoxy)picolinamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5 (difluoromethoxy)-3-methylpicolinamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-(2,2,3,3-tetrafluoropropoxy)picolinamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-3-chloro-5-(difluoromethoxy)picolinamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetra hydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-methoxypyrazine-2-carboxamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-(difluoromethoxy)pyrazine-2-carboxamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trim ethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-cyanopicolinamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-fluoropicolinamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-f

Assignees

• Hoffmann La Roche

Inventors

• Bartels Bjoern
• Dolente Cosimo
• Guba Wolfgang
• Haap Wolfgang
• Obst Sander Ulrike
• Vifian Walter
• 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

• C07D513/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/542

  ortho- or peri-condensed with heterocyclic ring systems · CPC title