Cyclic amine BACE-1 inhibitors having a benzamide substituent

1. A compound having the structural formula

or a pharmaceutically acceptable salt thereof, wherein

R 1 is

R is —C(O)—N(R 27 )(R 28 );

R 2 is H, alkyl, phenyl, or benzyl, wherein said phenyl and said benzyl are optionally unsusbtituted or substituted by from 1 to 5 independently selected R 32 groups;

R 3 is H or alkyl;

R 4 is H or alkyl;

R 5 is H or alkyl;

R 14 is 1 to 4 substituents independently selected from the group consisting of H, alkyl, halo, —CN, and haloalkyl;

R 27 and R 28 are independently selected from alkyl;

or R 27 and R 28 together with the nitrogen to which they are attached, form an unsubstituted 3-7 membered heterocycloalkyl ring, or a 3-7 membered heterocycloalkyl ring substituted by 1-3 substituents independently selected from the group consisting of alkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl and cycloalkyl-alkoxyalkyl;

R 6 and R 7 are each independently selected from the group consisting of H and alkyl,

or R 6 and R 7 , together with the ring carbon to which they are attached, form —C(O)—;

R 8 R 9 are each independently selected from the group consisting of H and alkyl,

or R 8 and R 9 , together with the ring carbon to which they are attached, form —C(O)—;

R 12 and R 13 are each independently selected from the group consisting of H and alkyl, wherein said alkyl is unsubstituted or substituted by from 1 to 5 independently selected R 32 groups,

or R 12 and R 13 , together with the ring carbon to which they are attached, form —C(O)—;

R 18 is H, alkyl, phenyl, phenylalkyl, pyridyl, oxazolyl, pyrazinyl, thienyl, imidazolyl, pyridylalkyl, oxazolylalkyl, pyrazinylalkyl, thienylalkyl, or imidazolylalkyl, wherein said alkyl, said phenyl, said phenylalkyl, said pyridyl, said oxazolyl, said pyrazinyl, said thienyl, said imidazolyl, said pyridylalkyl, said oxazolylalkyl, said pyrazinylalkyl, said thienylalkyl, and said imidazolylalkyl, are each unsubstituted or substituted by from 1 to 4 independently selected R 32 groups;

R 19 is H, alkyl, phenyl, phenylalkyl, pyridyl, oxazolyl, pyrazinyl, thienyl, imidazolyl, pyridylalkyl, oxazolylalkyl, pyrazinylalkyl, thienylalkyl, or imidazolylalkyl, —SOR 18 , —SO 2 R 18 or —CN, wherein said alkyl, said phenyl, said phenylalkyl, said pyridyl, said oxazolyl, said pyrazinyl, said thienyl, said imidazolyl, said pyridylalkyl, said oxazolylalkyl, said pyrazinylalkyl, said thienylalkyl, and said imidazolylalkyl, are each unsubstituted or substituted by from 1 to 4 independently selected R 32 groups; and

each R 32 is independently selected from the group consisting of halo, alkyl, alkoxy, —OH, phenyl, —NO 2 , —CN, and haloalkyl,

or two R 32 groups on the same ring carbon atom are taken together to form ═O.

2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 , R 4 and R 5 are hydrogen and R 2 is benzyl.

3. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is di-fluorobenzyl.

4. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is

5. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R is —C(O)—N(R 27 )(R 28 ).

6. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the cycloamino ring portion is selected from the group consisting of

wherein:

R 12 is H, alkyl, or di-hydroxyalkyl; and

R 19 is H, alkyl, optionally substituted benzyl, or phenyl.

7. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the stereochemical structure:

8. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

9. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is:

10. A pharmaceutical composition comprising an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically effective carrier.

11. A method of treating Alzheimer's Disease comprising administering to a patient in need of such treatment an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and an effective amount of at least one additional therapeutically active ingredient selected from a β-secretase inhibitor other than those of formula I, an HMG-CoA reductase inhibitor, a gamma-secretase inhibitor, a non-steroidal anti-inflammatory agent, an N-methyl-D-aspartate receptor antagonist, a cholinesterase inhibitor and an anti-amyloid antibody in a pharmaceutically effective carrier.

13. A kit comprising in separate containers in a single package pharmaceutical compositions for use in combination, in which one container comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier and a second container comprises a β-secretase inhibitor other than those of formula I, an HMG-CoA reductase inhibitor, a gamma-secretase inhibitor, a non-steroidal anti-inflammatory agent, an N-methyl-D-aspartate receptor antagonist, a cholinesterase inhibitor or an anti-amyloid antibody in a pharmaceutically acceptable carrier, the combined quantities being an effective amount to treat Alzheimer's Disease.

14. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 19 is alkyl, benzyl, or —SO 2 R 18 ; and R 6 , R 7 , R 8 ,R 9 , R 12 and R 13 are each hydrogen.

15. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 19 is alkyl, benzyll or —SO 2 R 18 ; and R 8 ,R 9 , R 12 and R 13 are each hydrogen and R 6 and R 7 together are ═O.

16. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

R 19 is alkyl, phenylalkyl, or —SO 2 R 18 ;

R 6 , R 7 , R 9 , and R 13 are each hydrogen;

R 8 is selected from the group consisting of H and alkyl; and

R 12 is selected from the group consisting of H and alkyl.

17. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

R 19 is alkyl, benzyl, or —SO 2 R 18 ;

and R 8 , R 9 , R 12 , and R 13 are H; and R 6 and R 7 together are ═O.

18. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 19 is selected from benzyl and fluorobenzyl.

19. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 19 is —SO 2 R 18 , wherein R 18 is selected from phenyl, pyridyl, thienyl, and imidazolyl.

20. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from:

21. A composition of claim 12 wherein the at least one additional therapeutically active ingredient is an HMG-CoA reductase inhibitor selected from the group consisting of atorvastatin, lovastatin, simvistatin, pravastatin, fluvastatin and rosuvastatin.

22. A composition of claim 12 wherein the at least one additional therapeutically active ingredient is a cholinesterase inhibitor selected from the group consisting of atorvastatin, lovastatin, simvistatin, pravastatin, fluvastatin and rosuvastatin.

23. A composition of claim 12 wherein the at least one additional therapeutically active ingredient is a non-steroidal anti-inflammatory agent selected from the group consisting of ibuprofen, naproxen, diclofenac, diflunisal, etodolac, flurbiprofen, indomethacin, ketoprofen, ketorolac, nabumetone, oxaprozin, piroxicam, sulindac, tolmetin, celecoxib and rofecoxib.

24. A composition of claim 12 wherein the at least one additional therapeutically active ingredient is an N-methyl-D-aspartate receptor antagonist.

25. A composition of claim 24 , wherein said N-methyl-D-aspartate receptor antagonist is memantine.