N-(2-(2-amino-6-substituted-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]OXAZIN-8a(8H)-yl)-thiazol-4-yl) amides

1. A compound of Formula I

wherein

R 1 is a 5- to 6-membered heteroaryl, having one to four heteroatoms independently selected from N, O or S, wherein at least one of the heteroatoms is N and wherein said N is optionally substituted with R 6 ; and wherein said 5- to 6-membered heteroaryl is optionally substituted on carbon with one to three R 5 ;

R 2 and R 3 are each independently selected from the group consisting of hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl and 3- to 7-membered heterocycloalkyl; wherein the C 1-3 alkyl is optionally and independently with one to three fluoro or C 1-3 alkoxy, and the C 3-6 cycloalkyl and 3- to 7-membered heterocycloalkyl are each optionally and independently substituted with one to three fluoro, C 1-3 alkyl or C 1-3 alkoxy;

or R 2 and R 3 taken together with the carbon to which they are attached form a C 3-6 cycloalkyl ring or a 3- to 7-membered heterocycloalkyl, each of which is optionally and independently substituted with one to three fluoro, C 1-3 alkyl or C 1-3 alkoxy;

R 4 is hydrogen or C 1-3 alkyl optionally substituted with one to three fluoro;

X is CH 2 or a bond;

R 5 at each occurrence is independently selected from the group consisting of halo, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 alkenyl, C 3-6 alkenyloxy, C 3-6 alkynyl, C 3-6 alkynyloxy, C 1-6 alkoxy-C 1-6 alkyl, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 3-6 cycloalkyl-C 1-6 alkoxy, 4- to 6-membered heterocycloalkyl and 4- to 6-membered heterocycloalkyl-C 1-6 alkyl; wherein said C 1-6 alkyl, C 1-6 alkoxy, C 3-6 alkenyl, C 3-6 alkenyloxy, C 3-6 alkynyl, C 3-6 alkynyloxy, C 1-6 alkoxy-C 1-6 alkyl, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 3-6 cycloalkyl-C 1-6 alkoxy, 4- to 6-membered heterocycloalkyl and 4- to 6-membered heterocycloalkyl-C1-6alkyl are each optionally substituted with one to three substituents independently selected from fluoro, chloro, hydroxy, cyano, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy and trifluoromethoxy; and

R 6 is hydrogen or C 1-6 alkyl;

or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

2. The compound of claim 1 of formula Ia

or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

3. The compound of claim 1 of formula Ib

or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

4. The compound of claim 1 wherein

R 2 is hydrogen or methyl;

R 3 is methyl, fluoromethyl, difluoromethyl or trifluoromethyl; and

R 4 is hydrogen, fluoromethyl or trifluoromethyl;

or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

5. The compound of claim 2 wherein

R 2 and R 4 are each hydrogen;

R 3 is methyl; and

X is CH 2 ;

or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

6. The compound of claim 2 wherein

R 2 and R 3 are each methyl;

R 4 is hydrogen; and

X is a bond;

or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

7. The compound of claim 2 wherein

R 2 is hydrogen;

R 3 is methyl or trifluoromethyl;

R 4 is hydrogen, fluoromethyl or trifluoromethyl; and

X is a bond;

or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

8. The compound of claim 2 wherein

R 2 and R 3 taken together with the carbon to which they are attached form a C 3-6 cycloalkyl ring;

R 4 is hydrogen; and

X is a bond;

or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

9. The compound of claim 8 wherein

R 2 and R 3 taken together with the carbon to which they are attached form a cyclobutyl ring;

or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

10. The compound of claim 3 wherein

R 2 is hydrogen;

R 3 is trifluoromethyl;

R 4 is hydrogen; and

X is a bond;

or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

11. The compound of claim 4 wherein

R 1 is pyridinyl or pyrazinyl substituted with one or two R 5 ; and

each R 5 is independently selected from chloro, cyano, methyl and difluoromethoxy;

or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

12. The compound of claim 11 wherein

R 1 is 3-chloro-5-(difluoromethoxy)pyridin-2-yl, 5-chloropyridin-2-yl, 5-cyanopyridin-2-yl, 5-(difluoromethoxy)pyridin-2-yl, 5-(difluoromethoxy)-3-methylpyridin-2-yl or 5-(difluoromethoxy)pyrazin-2-yl;

or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

13. The compound of claim 5 selected from the group consisting of

N-(2-((5aR,7S,9aR)-2-amino-7-methyl-5,5a,6,7-tetrahydro-4H-pyrano[3,4-d][1,3]oxazepin-9a(9H)-yl)thiazol-4-yl)-5-(difluoromethoxy)picolinamide; and

N-(2-((5aR,7S,9aR)-2-amino-7-methyl-5,5a,6,7-tetrahydro-4H-pyrano[3,4-d][1,3]oxazepin-9a(9H)-yl)thiazol-4-yl)-5-(difluoromethoxy)-3-methylpicolinamide;

or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

14. The compound of claim 6 selected from the group consisting of

N-(2-((4aR,8aR)-2-amino-6,6-dimethyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]oxazin-8a(8H)-yl)thiazol-4-yl)-5-(difluoromethoxy)picolinamide; and

N-(2-((4aR,8aR)-2-amino-6,6-dimethyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]oxazin-8a(8H)-yl)thiazol-4-yl)-5-(difluoromethoxy)-3-methylpicolinamide;

or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

15. The compound of claim 7 selected from the group consisting of

N-(2-((4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]oxazin-8a(8H)-yl)thiazol-4-yl)-5-(difluoromethoxy)picolinamide;

N-(2-((4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]oxazin-8a(8H)-yl)thiazol-4-yl)-3-chloro-5-(difluoromethoxy)picolinamide;

N-(2-((4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]oxazin-8a(8H)-yl)thiazol-4-yl)-5-(difluoromethoxy)-3-methylpicolinamide;

N-(2-((4S,4aR,6S,8aR)-2-amino-4-(fluoromethyl)-6-methyl-4,4a,5,6-tetrahydropyrano [3,4-d][1,3]oxazin-8a(8H)-yl)thiazol-4-yl)-5-(difluoromethoxy)picolinamide;

N-(2-((4S,4aR,6S,8aR)-2-amino-6-methyl-4-(trifluoromethyl)-4,4a,5,6-tetrahydropyrano [3,4-d][1,3]oxazin-8a(8H)-yl)thiazol-4-yl)-5-(difluoromethoxy)picolinamide;

N-(2-((4aR,6R,8aR)-2-amino-6-(trifluoromethyl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]oxazin-8a(8H)-yl)thiazol-4-yl)-5-chloropicolinamide;

N-(2-((4aR,6R,8aR)-2-amino-6-(trifluoromethyl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]oxazin-8a(8H)-yl)thiazol-4-yl)-5-(difluoromethoxy)-3-methylpicolinamide;

N-(2-((4aR,6R,8aR)-2-amino-6-(trifluoromethyl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]oxazin-8a(8H)-yl)thiazol-4-yl)-5-(difluoromethoxy)picolinamide;

N-(2-((4aR,6R,8aR)-2-amino-6-(trifluoromethyl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]oxazin-8a(8H)-yl)thiazol-4-yl)-3-chloro-5-(difluoromethoxy)picolinamide;

N-{2-[(4aR,6R,8aR)-2-amino-6-(trifluoromethyl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]oxazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-(difluoromethoxy)pyrazine-2-carboxamide;

N-{2-[(4aR,6R,8aR)-2-amino-6-(trifluoromethyl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]oxazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-cyano-3-methylpyridine-2-carboxamide;

N-{2-[(4aR,6R,8aR)-2-amino-6-(trifluoromethyl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]oxazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-(difluoromethoxy)-3-methylpyrazine-2-carboxamide;

N-{2-[(4aR,6R,8aR)-2-amino-6-(trifluoromethyl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]oxazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-methoxy-3-methylpyrazine-2-carboxamide; and

N-{2-[(4aR,6R,8aR)-2-amino-6-(trifluoromethyl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]oxazin-8a(8H)-yl]-1,3-thiazol-4-yl}-5-cyano pyridine-2-carboxamide;

or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

16. The compound of claim 10 selected from the group consisting of

N-(2-((4aS, 6S,8aS)-2-amino-6-(trifluoromethyl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]oxazin-8a(8H)-yl)thiazol-4-yl)-5-chloropicolinamide;

N-(2-((4aS,6S,8aS)-2-amino-6-(trifluoromethyl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]oxazin-8a(8H)-yl)thiazol-4-yl)-5-(difluoromethoxy)-3-methylpicolinamide;

N-(2-((4aS,6S,8aS)-2-amino-6-(trifluoromethyl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]oxazin-8a(8H)-yl)thiazol-4-yl)-5-(difluoromethoxy)picolinamide; and

N-(2-((4aS,6S,8aS)-2-amino-6-(trifluoromethyl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]oxazin-8a(8H)-yl)thiazol-4-yl)-3-chloro-5-(difluoromethoxy)picolinamide;

or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

17. The compound of claim 9 selected from the group consisting of

N-(2-((4a′R,8a′R)-2′-amino-4a′,5′-dihydro-4′H-spiro[cyclobutane-1,6′-pyrano3,4-d][1,3]oxazin]-8a′(8′H)-yl)thiazol-4-yl)-5-(difluoromethoxy)picolinamide;

N-(2-((4a′R,8a′R)-2′-amino-4a′,5′-dihydro-4′H-spiro[cyclobutane-1,6′-pyrano[3,4-d][1,3]oxazin]-8a′(8′H)-yl)thiazol-4-yl)-5-(difluoromethoxy)-3-methyl picolinamide;

N-(2-((4a′R,8a′R)-2′-amino-4a′,5′-dihydro-4′H-spiro[cyclobutane-1,6′-pyrano[3,4-d][1,3]oxazin]-8a′(8′H)-yl)thiazol-4-yl)-5-cyano picolinamide N-(2-((4a′R, 8a′ R)-2′-amino-4a′,5′-dihydro-4′H-spiro[cyclobutane-1,6′-pyrano[3,4-d][1,3]oxazin]-8a′(8′H)-yl)thiazol-4-yl)-5-cyano picolinamide;

N-(2-((4a′R,8a′R)-2′-amino-4a′,5′-dihydro-4′H-spiro[cyclobutane-1,6′-pyrano[3,4-d][1,3]oxazin]-8a′(8′H)-yl)thiazol-4-yl)-5-(difluoromethoxy)pyrazine-2-carboxamide;

N-(2-((4a′R,8a′R)-2′-amino-4a′,5′-dihydro-4′H-spiro[cyclobutane-1,6′-pyrano[3,4-d][1,3]oxazin]-8a′(8′H)-yl)thiazol-4-yl)-3-chloro-5-(difluoromethoxy)picolinamide; and

N-(2-((4a′R,8a′R)-2′-amino-4a′,5′-dihydro-4′H-spiro[cyclobutane-1,6′-pyrano[3,4-d][1,3]oxazin]-8a′(8′H)-yl)thiazol-4-yl)-5-cyano-3-methylpicolinamide;

or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

18. The compound N-(2-((4aR,6S,8aR)-2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]oxazin-8a(8H)-yl)thiazol-4-yl)-5-(difluoromethoxy)-3-methylpicolinamide; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

19. The compound N-(2-((4S,4aR,6S,8aR)-2-amino-4-(fluoromethyl)-6-methyl-4,4a,5,6-tetrahydro pyrano[3,4-d][1,3]oxazin-8a(8H)-yl)thiazol-4-yl)-5-(difluoromethoxy)picolinamide; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

20. The compound N-(2-((4aR,8aR)-2-amino-6,6-dimethyl-4,4a,5,6-tetrahydro pyrano[3,4-d][1,3]oxazin-8a(8H)-yl)thiazol-4-yl)-5-(difluoromethoxy) picolinamide; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

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

22. A method of inhibiting production of amyloid-β protein, inhibiting beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), treating Alzheimer's disease or treating Type 2 diabetes in a patient, the method comprising administering a therapeutically effective amount of a compound according to claim 1 , or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer, to a patient in need of inhibition of production of amyloid-β protein, inhibition of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), treatment of Alzheimer's disease or treatment of Type 2 diabetes.

23. The method of claim 22 wherein Alzheimer's disease is treated.

24. The method of claim 22 wherein Type 2 diabetes is treated.

25. The method of claim 22 wherein the production of amyloid-β protein is inhibited.

26. The method of claim 22 wherein beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is inhibited.