BACE1 inhibitors

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-fluorophenyl)-5-chloropicolinamide,

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-difluoropicolinamide,

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-methylpicolinamide,

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)-2-methylpyrimidine-5-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-(2,2,3,3-tetrafluoropropoxy) pyrazine-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)-3,5-dimethylpicolinamide,

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-methoxypicolinamide,

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-ethoxypicolinamide,

N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-methoxy-3-methylpicolinamide, and

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-ethoxypyrazine-2-carboxamide,

or pharmaceutically acceptable salts thereof.

15. The compound according to claim 1 , selected from the group consisting of:

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-cyano-3-methylpicolinamide,

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)-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,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-(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-3,3a4,7-tetra hydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-3-chloro-5-(difluoromethoxy)picolinamide, and

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-methoxypyrazine-2-carboxamide,

or pharmaceutically acceptable salts thereof.

16. The compound according to claim 1 , selected from the group consisting of:

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 and 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,

or pharmaceutically acceptable salts thereof.

17. A method for treating diseases and disorders characterized by elevated β-amyloid levels and/or β-amyloid oligomers and/or β-amyloid plaques and further deposits, comprising the step of administering a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, to a human being or animal in need thereof.

18. A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

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