Spiropiperidine beta-secretase inhibitors for the treatment of Alzheimer's disease

• US 20070021454A1
• Filed: 07/14/2006
• Published: 01/25/2007
• Est. Priority Date: 07/18/2005
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme LLC (Merck & Co., Inc.), Sunesis Pharmaceuticals, Inc. (Viracta Therapeutics, Inc.)
• Original Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Inventors: Yang, Wenjin, Stauffer, Shaun, Nantermet, Philippe, Fahr, Bruce, Lu, Wanli, Coburn, Craig, Rajapakse, Hemaka, Egbertson, Melissa, Stachel, Shawn, McGaughey, Georgia, Graham, Samuel
• Granted Patent: US 8,211,904 B2
• Time in Patent Office: Days
• US Class Current: 514/278
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 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 Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 471/10 Spiro-condensed systems

Abstract

The present invention is directed to spiropiperidine compounds of formula (I) and tautomers thereof, which are inhibitors of the beta-secretase enzyme and that are useful in the treatment of diseases in which the beta-secretase enzyme is involved, such as Alzheimer'"'"'s disease. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the treatment of such diseases in which the beta-secretase enzyme is involved.

Claims

1. A compound of formula (I):

2. A compound of claim 1 of formula (I) or (I′

), wherein Y is O.

3. A compound of claim 1 of formula (I) wherein X is N, or of formula (I′

), wherein X′

is NH.

4. A compound of claim 1, wherein R¹ is selected from the group consisting of optionally substituted C_1-6 alkyl or C_3-6 cycloalkyl.

5. A compound of claim 1, wherein R² is phenyl, wherein the phenyl is optionally substituted with one or more

(i) halo,

(ii) —

OH,

(iii) —

CN,

(iv) —

C_1-10 alkyl, and

(v) phenyl optionally substituted with

(A) halo,

(B) —

OH,

(C) —

CN,

(D) —

C_1-10 alkyl,

(E) —

OC_1-10 alkyl,

(F) —

SO₂C_1-3 alkyl,

(G) —

SO₂NR⁵R⁵′

,

(H) —

NR⁵SO₂C_1-3alkyl,

(I) —

CO₂R⁵, and

(J) —

CONR⁵R⁵′

.

6. A compound of claim 1, wherein Q is C_1-3 alkylene and R³ is phenyl, wherein the phenyl is optionally substituted with one or more

(A) halo,

(B) —

OH,

(C) —

CN,

(D) —

C_1-10 alkyl,

(E) —

OC₁₀ alkyl, and

(F) phenyl optionally substituted with

(i) —

C_1-6 alkyl,

(ii) —

OC_1-6 alkyl, and

(iii) —

NR⁵R<sup>5′

.</sup>

7. A compound of claim 6, wherein Q is —

CH₂—

.

8. A compound of claim 1, wherein R⁴ is —

C_1-6 alkyl.

9. A compound of claim 1, which is a compound of formula (II)

10. A compound of claim 9 of formula (11) wherein X is N, or of formula (II′

), wherein X′

is NH.

11. A compound of claim 9, wherein R² is phenyl which is optionally substituted with one or more

(i) halo,

(ii) —

OH,

(iii) —

CN,

(iv) —

C_1-10 alkyl, or

(v) phenyl, optionally substituted with

(A) halo,

(B) —

OH,

(C) —

CN,

(D) —

C_1-10 alkyl,

(E) —

OC_1-10alkyl,

(F) —

SO₂C_1-3 alkyl,

(G) —

SO₂NR⁵R⁵′

,

(H) —

NR₅SO₂C_1-3alkyl,

(I) —

CO₂R⁵, and

(J) —

CONR⁵R⁵′

.

12. A compound of claim 9, wherein R⁴ is —

C_1-6 alkyl.

13. A compound of claim 1 which is a compound of formula (III)

14. A compound of claim 13 of formula (III) wherein X is N, or of formula (III′

) wherein X′

is NH.

15. A compound of claim 13, wherein Q is C_1-3 alkylene, and R³ is phenyl, wherein the phenyl is optionally substituted with one or more

(A) halo,

(B) —

OH,

(C) —

CN,

(D) —

C_1-10 alkyl,

(E) —

OC₁₀ alkyl, and

(F) phenyl optionally substituted with

(i) —

C_1-6 alkyl,

(ii) —

OC_1-6 alkyl, and

(iii) —

NR⁵R⁵′

.

16. A compound of claim 13, wherein R⁴ is C_1-6 alkyl.

18. A compound of claim 1, or a pharmaceutically acceptable salt thereof, or an individual enantiomer thereof, wherein the compound of formula (I) and (I′

) is a compound of formula (IB)

19. A compound of claim 1 which is selected from the group consisting of

Racemic 5(R,S)7(R,S)-8-benzyl-4-(cyclohexylamino)-1-(3-fluorophenyl)-7-methyl 1,3,8-triazaspiro[4.5]dec-3-en-2-one diastereomer A;

Racemic 5(R,S)7(S,R)-8-benzyl-4-(cyclohexylamino)-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one Diastereomer B;

Racemic 5(R,S)7(R,S)-4-(cyclohexylamino)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one Diastereomer A;

Racemic 5(R,S)7(S,R)-4-(cyclohexylarmino)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one Diastereomer B;

Racemic 5(R,S)7(R,S)-8-benzyl-4-(cyclohexylamino)-7-methyl-1-phenyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one Diastereomer A;

Racemic 5(R,S)7(S,R)-8-benzyl-4-(cyclohexylamino)-7-methyl-1-phenyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one Diastereomer B;

Racemic 5(R,S)7(R,S)-8-(3-isopropoxybenzyl)-4-(isopropylamino)-7-methyl-1-(3-methylphenyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one Diastereomer A;

Racemic 5(R,S)7(S,R)-8-(3-isopropoxybenzyl)-4-(isopropylamino)-7-methyl-1-(3-methylphenyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one Diastereomer B;

5(R,S)7(R,S)-8-benzyl-4-(cyclohexylamino)-1,7-dimethyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one Diastereomer A; and

5(R,S)7(S,R)-8-benzyl-4-(cyclohexylamino)-1,7-dimethyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one Diastereomer B; and

enantiomers thereof, and pharmaceutically acceptable salts thereof.

20. A compound of claim 1, which is selected from the group consisting of

(5R,7S)-4-(cyclohexylamino)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-(cyclohexylamino)-1-(3-fluorophenyl)-7-methyl-8-(3-thienylmethyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-(cyclohexylamino)-8-(2-fluorobenzyl)-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-(cyclohexylamino)-1-(3-fluorophenyl)-7-methyl-8-[3-(1H-pyrrol-1-yl)benzyl]-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-(cyclohexylamino)-1-(3-fluorophenyl)-7-methyl-8-[3-(trifluoromethyl)benzyl]-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-8-(3-tert-butoxybenzyl)-4-(cyclohexylamino)-1-(3-fluorophenyl)-7-methyl 1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-(cyclohexylamino)-8-[(2E)-3,7-dimethylocta-2,6-dien-1-yl]-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-(cyclohexylamino)-1-(3-fluorophenyl)-7-methyl-8-(3-methylbut-2-en-1-yl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-(cyclohexylamino)-1-(3-fluorophenyl)-7-methyl-8-[(trimethylsilyl)methyl]-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-(cyclohexylamino)-1-(3-fluorophenyl)-7-methyl-8-[2-(trimethylsilyl)ethyl]-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-(cyclohexylamino)-8-[3-(1-cyclopropylethoxy)benzyl]-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-(cyclohexylamino)-1-(3-fluorophenyl)-7-methyl-8-(3-{[(1R)-1-methylpropyl]oxy}benzyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-(cyclohexylaniino)-8-(2-fluoro-5-{[(1R)-1-methylpropyl]oxy}benzyl)-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-(cyclohexylamino)-8-[3-(cyclopropylmethyl)benzyl]1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-(cyclohexylamino)-1-(3-fluorophenyl)-7-methyl-8-[(2E)-3-methylpent-2-en-1-yl]-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-(cyclohexylamino)-8-[3-(cyclopropyloxy)benzyl]-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-(cyclohexylamino)-8-{3-[(1 s)-1-cyclopropylethyl]benzyl}-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-(cyclohexylamino)-8-{3-[(1R)-1-cyclopropylethyl]benzyl}-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-8-(cyclohex-1-en-1-ylmethyl)-4-(cyclohexylamino)-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-(cyclohexylamino)-8-(cyclopent-1-en-1-ylmethyl)-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-(cyclohexylamino)-1-(3-fluorophenyl)-8-[(1-isopropyl-1H-indol-6-yl)methyl]-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-(cyclohexylamino)-1-(3-fluorophenyl)-7-methyl-8-[(2-methylcyclopent-1-en-1-yl)methyl]-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-[(1R,4R)-bicyclo[2.2.1]hept-2-ylamino]-1-(3-fluorophenyl)-7-methyl-8-(3-{[(1R)-1-methylpropyl]oxy}benzyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-[(1S,4S)-bicyclo[2.2.1]hept-2-ylamino]-1-(3-fluorophenyl)-7-methyl-8-(3-{[(1R)-1-methylpropyl]oxy}benzyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-(cyclobutylamino)-1-(3-fluorophenyl)-7-methyl-8-(3-{[(1S,2R)-2-methylcyclopropyl]oxy}benzyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-(cyclobutylamino)-1-(3-fluorophenyl)-7-methyl-8-(3-{[(1R,2S)-2-methylcyclopropyl]oxy}benzyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-8-(cyclopentylmethyl)-4-{[(1S,2S)-2-fluorocyclohexyl]amino}-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-8-(cyclopentylmethyl)-4-{[(1R,2R)-2-fluorocyclohexyl]amino}-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-(cyclopentylamino)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-8-benzyl-1-(3-fluorophenyl)-7-methyl-4-(spiro[2.5]oct-6-ylamino)-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-4-{[(5S,6R)-6-phenylspiro[2.4]hept-5-yl]amino}-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-4-{[(5R,6S)-6-phenylspiro[2.4]hept-5-yl]amino}-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-[(4,4-difluorocyclohexyl)amino]-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-8-benzyl-4-[(4,4-difluorocyclohexyl)amino]-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-8-(cyclobutylmethyl)-4-{[(3R)-1,1-dimethylsilolan-3-yl]amino}-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-8-(cyclobutylmethyl)-4-{[(3S)-1,1-dimethylsilolan-3-yl]amino}-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

this is example 41

(5R,7S)-8-(cyclobutylmethyl)-4-{[(1R,2R)-2-fluorocyclohexyl]amino}-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-8-(cyclobutylmethyl)-4-{[(1S,2S)-2-fluorocyclohexyl]amino}-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-{[(1R)-1,2-dimethylpropyl]amino}-1-(3-fluorophenyl)-7-methyl-8-(3-methylbut-2-en-1-yl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-{[(1S)-1,2-dimethylpropyl]amino}-1-(3-fluorophenyl)-7-methyl-8-(3-methylbut-2-en-1-yl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-1-(3-chlorophenyl)-8-(cyclobutylmethyl)-4-(cyclohexylamino)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-1-(3-bromophenyl)-8-(cyclobutylmethyl)-4-(cyclohexylamino)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-(cyclohexylaniino)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4,5]dec-3-ene-2-thione;

(5R,7S)-4-(cyclohexylamino)-8-[(2,2-dimethyl-1,2-dihydroquinolin-8-yl)methyl]-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-(cyclohexylamino)-8-[(2,2-dimethyl-1,2,3,4-tetrahydroquinolin-8-yl)methyl]-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7R)-4-(cyclohexylamino)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-vinyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7R)-8-benzyl-4-(cyclohexylamino)-1-(3-fluorophenyl)-7-vinyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7R)-4-(cyclohexylamino)-1-(3-fluorophenyl)-8-(3-{[(1R)-1-methylpropyl]oxy}benzyl)-7-vinyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7R)-4-(cyclohexylamino)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-[(1E)-prop-1-en-1-yl]-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7R)-4-(cyclohexylamino)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-[(1Z)-prop-1-en-1-yl]-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-1-(3-fluorophenyl)-7-methyl-4-(methylamino)-8-[(2′

-methylbiphenyl-3-yl)methyl]-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-8-(cyclobutylmethyl)-4-(cyclohexylamino)-1-[4′

-(isopropylsulfonyl)biphenyl-2-yl]-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-8-benzyl-4-(cyclohexylamino)-1-(cyclopropylmethyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-(5S,7R)-8-benzyl-4-(cyclohexylamino)-1-cyclopropyl-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-(5S,7R)-8-benzyl-1-cyclobutyl-4-(cyclohexylamino)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-(5S,7R)-8-benzyl-4-(cyclohexylamino)-1-cyclopentyl-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-(5S,7R)-8-benzyl-1-cyclohexyl-4-(cyclohexylamino)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-(5S,7R)-8-benzyl-4-(cyclohexylamino)-7-methyl-1-(2-methylprop-2-en-1-yl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-(5S,7R)-8-benzyl-4-(cyclohexylamino)-7-methyl-1-(tetrahydrofuran-3-yl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-4-{[(3S)-1-(methylsulfonyl)pyrrolidin-3-yl]amino}-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-[(3,3-difluorocyclohexyl)amino]-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-(5S,7R)-4-[(2-fluoro-1-methylethyl)amino]-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-(5S,7R)-4-{[(1S)-1,2-dimethylpropyl]amino}-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-{[(1R,2R)-2-fluorocyclohexyl]amino}-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-{[(1S,2S)-2-fluorocyclohexyl]amino}-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-4-[(2-isopropylcyclopropyl)amino]-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-{[(1R,2R)-2-fluorocyclopentyl]amino}-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-{[(1S,2S)-2-fluorocyclopentyl]amino}-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-4-[(2-propylcyclopropyl)amino]-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-{[(1R)-2,2-difluorocyclohexyl]amino}-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-{[(1S)-2,2-difluorocyclohexyl]amino}-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-{[(1R)-2,2-difluorocyclopentyl]amino}-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-{[(1S)-2,2-difluorocyclopentyl]amino}-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-{[(1R,2S)-2-fluorocyclohexyl]amino}-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-{[(1S,2R)-2-fluorocyclohexyl]amino}-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-8-benzyl-1-(3-fluorophenyl)-7-methyl-4-{[(1S)-1,2,2-trimethylpropyl]amino}-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-(cyclohexylimino)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-3,7-dimethyl-1,3,8-triazaspiro[4.5]decan-2-one; and

pharmaceutically acceptable salts thereof.

21. A compound of claim 20, which is selected from the group consisting of

5(R),7(S)-8-benzyl-4-(cyclohexylamino)-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-(cyclohexylamino)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-(cyclohexylamino)-8-[(2E)-3,7-dimethylocta-2,6-dien-1-yl]-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-(cyclohexylamino)-1-(3-fluorophenyl)-7-methyl-8-(3-{[(1R)-1-methylpropyl]oxy}benzyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-(cyclohexylamino)-8-[3-(cyclopropylmethyl)benzyl]-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-8-(cyclobutylmethyl)-4-{[(1R,2R)-2-fluorocyclohexyl]amino}-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-8-(cyclobutylmethyl)-4-{[(1S,2S)-2-fluorocyclohexyl]amino}-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-[(4,4-difluorocyclohexyl)amino]-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-1-(3-chlorophenyl)-8-(cyclobutylmethyl)-4-(cyclohexylamino)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-1-(3-bromophenyl)-8-(cyclobutylmethyl)-4-(cyclohexylamino)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-1-(3-fluorophenyl)-7-methyl-4-(methylamino)-8-[(2′

-methylbiphenyl-3-yl)methyl]-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-[(3,3-difluorocyclohexyl)amino]-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-{[(1R,2R)-2-fluorocyclohexyl]amino}-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-{[(1R)-2,2-difluorocyclopentyl]amino}-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-{[(1S)-2,2-difluorocyclopentyl]amino}-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;

and pharmaceutically acceptable salts thereof.

22. A pharmaceutically acceptable salt of a compound of claim 20, wherein the salt is selected from the group consisting of sulfate, phosphate, citrate, malate, mandelate, hippurate, trifluoroacetate and hydrochloric acid salts.

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

24. The pharmaceutical composition of claim 23, further comprising a P450 inhibitor.

25. The pharmaceutical composition of claim 24, wherein the P450 inhibitor is ritonavir.

26. A method of treating Alzheimer'"'"'s disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

27. A method of treating Alzheimer'"'"'s disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in combination with a P-450 inhibitor, and a pharmaceutically acceptable carrier.

28. The method of claim 27, wherein the P450 Inhibitor is ritonavir.

17. A compound of formula (I)