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

• US 20100298342A1
• Filed: 09/04/2007
• Published: 11/25/2010
• Est. Priority Date: 09/07/2006
• Status: Abandoned Application

• Current Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.), Sunesis Pharmaceuticals, Inc. (Viracta Therapeutics, Inc.)
• Original Assignee: Merck & Co., Inc., Sunesis Pharmaceuticals, Inc. (Viracta Therapeutics, Inc.)
• Inventors: Neilson, Lou Anne, Stauffer, Shaun R., Wai, Jenny M., Fahr, Bruce, Lu, Wanli, Egbertson, Melissa S., Barrow, James C., Yang, Wenjin, Coburn, Craig A.
• Application Number:
  US12/310,573
• Publication Number:
  US 20100298342A1
• Time in Patent Office: Days
• US Class Current: 514/255.05
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 471/10 Spiro-condensed systems
• CPC Class Codes: C07D 498/10 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, wherein X is NR⁵.

3. 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_1-6 alkyl,

(E) —

OC_1-6 alkyl,

(F) —

SO₂C_1-3 alkyl,

(G) —

SO₂NR⁵R⁵′

,

(H) —

NR⁵SO₂C_1-3alkyl,

(I) —

CO₂R⁵, and

(J) —

CONR⁵R⁵′

.

4. 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) —

OC_1-10 alkyl, and

(F) phenyl, optionally substituted with

(i) —

C_1-6 alkyl,

(ii) —

OC_1-6 alkyl,

(iii) NR⁵R⁵′

.

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

C_1-6 alkyl.

6. A compound of claim 1, wherein the compound of formula (I) is a compound of formula (II)

7. A compound of claim 6, wherein the compound of formula (II is a compound of formula (II″

);

8. A compound of claim 6, wherein X is NR⁵.

9. A compound of any of claim 6, wherein R² is phenyl, wherein the phenyl is optionally substituted with one or more

(i) halo,

(ii) —

OH,

(iii) —

CN,

(iv) —

C_1-10alkyl, or

(v) phenyl, optionally substituted with

(A) halo,

(B) —

OH,

(C) —

CN,

(D) —

C_1-6 alkyl,

(E) —

OC_1-6 alkyl,

(F) —

SO₂C_1-3 alkyl,

(G) —

SO₂NR⁵R⁵′

,

(H) —

NR⁵SO₂C_1-3alkyl,

(I) —

CO₂R⁵, and

(J) —

CONR⁵R⁵′

, and

(K) —

NR⁵CO₂R⁵′

.

10. A compound of claim 6, wherein

R⁴ is C_1-6 alkyl.

11. A compound of claim 1, wherein the compound of formula (I) is a compound of formula (III)

12. A compound of claim 1, wherein the compound of formula (I) is a compound of formula (IV)

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

1-(3-fluorophenyl)-8-[(2′

-methylbiphenyl-3-yl)methyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione;

4′

-fluoro-2′

-[8-(3-isopropoxybenzyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]dec-1-yl]-N,N,3-trimethylbiphenyl-4-sulfonamide;

4′

-fluoro-2′

-[8-(3-isopropoxybenzyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]dec-1-yl]-N,N-dimethylbiphenyl-4-sulfonamide;

4′

-fluoro-2′

-[8-(3-isopropoxybenzyl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]dec-1-yl]-N,N-dimethylbiphenyl-4-sulfonamide;

4′

-fluoro-2′

-[8-(3-isopropoxybenzyl)-2,4-dioxo-3-propyl-1,3,8-triazaspiro[4.5]dec-1-yl]-N,N-dimethylbiphenyl-4-sulfonamide;

4′

-fluoro-2′

-[8-(3-isopropoxybenzyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]dec-1-yl]-N,N-dimethylbiphenyl-4-sulfonamide;

2′

-(8-benzyl-2,4-dioxo-1,3,8-triazaspiro[4.5]dec-1-yl)-4′

-fluoro-N,N-dimethylbiphenyl-4-sulfonamide;

4′

-fluoro-2′

-[8-(3-isopropoxybenzyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]dec-1-yl]-N,N,3-trimethylbiphenyl-4-carboxamide;

5-{4-fluoro-2-[8-(3-isopropoxybenzyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]dec-1-yl]phenyl}-N,N-dimethylthiophene-2-sulfonamide;

(5R,7S)-8-benzyl-1-(2-bromo-5-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-1-(2-bromo-5-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-(5S,7R)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione;

1-(2-bromo-5-fluorophenyl)-8-(3-isopropoxybenzyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-(5S,7R)-8-benzyl-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione;

N-(3-{4-fluoro-2-[8-(3-isopropoxybenzyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]dec-1-yl]phenyl}prop-2-yn-1-yl)-N-methylmethanesulfonamide;

(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-(5S,7R)-8-benzyl-1-[4-fluoro-4′

-(methylsulfonyl)biphenyl-2-yl]-7-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione;

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

-methylbiphenyl-3-yl)methyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione;

1-(3-fluorophenyl)-8-[(2′

-methylbiphenyl-3-yl)methyl]-3-(pyridin-2-ylmethyl)-1,3,8-triazaspiro[4.5]decan-2-one;

4′

-fluoro-2′

-[8-(3-isopropoxybenzyl)-2-oxo-1,3,8-triazaspiro[4.5]dec-1-yl)-N,N-dimethylbiphenyl-4-sulfonamide;

4′

-fluoro-2′

-[8-(3-isopropoxybenzyl)-2-oxo-3-propyl-1,3,8-triazaspiro[4.5]dec-1-yl]-N,N-dimethylbiphenyl-4-sulfonamide;

4′

-fluoro-2′

-[8-(3-isopropoxybenzyl)-3-methyl-2-oxo-1,3,8-triazaspiro[4.5]dec-1-yl]-N,N-dimethylbiphenyl-4-sulfonamide;

1-[4-fluoro-4′

-(methylsulfonyl)biphenyl-2-yl]-8-(3-isopropoxybenzyl)-1,3,8-triazaspiro[4.5]decan-2-one;

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

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

(5R,7S)-1-(3-fluorophenyl)-8-3-[(1R)-2-methoxy-1-methylethoxy]benzyl}-7-methyl-1,3,8-triazaspiro[4.5]decan-2-one;

(5R,7S)-(5S,7R)-8-benzyl-1-[4-fluoro-4′

-(methylsulfonyl)-1,1′

-biphenyl-2-yl]-7-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-1-(3-fluorophenyl)-7-methyl-8′

-[(2′

-methylbiphenyl-3-yl)methyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione;

1-(3-fluorophenyl)-8-[(2′

-methylbiphenyl-3-yl)methyl]-3-(pyridin-2-ylmethyl)-1,3,8-triazaspiro[4.5]decan-2-one;

(5R,7S)-8-benzyl-1-(3-fluorophenyl)-7-methyl-3-oxa-1,8-diazaspiro[4.5]decan-2-one;

(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-3-[2-(4-methoxyphenyl)ethyl]-7-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-3-(cyclohexylmethyl)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-3-(3-methoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione;

N-{2-[(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]dec-3-ylethyl}benzamide;

(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-[2-(1H-pyrazol-1-yl)ethyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-3-(2-fluoroethyl)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-3-(1,2-benzisoxazol-3-ylmethyl)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-1-(3-fluorophenyl)-3-[2-(2-fluorophenyl)-2-oxoethyl]-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-3-[(1-benzyl-1H-1,2,4-triazol-5-yl)methyl]-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-1-(3-fluorophenyl)-3-(1H-imidazol-2-ylmethyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-3-{[5-(4-chlorophenyl)-1,3-oxazol-2-yl]methyl)}-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-[(3-phenyl-1,2,4-oxadiazol-5-yl)methyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-3-[(5-cyclopropyl-1,3,4-thiadiazol-2-yl)methyl]-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-[(5-methylisoxazol-3-yl)methyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-[(2-methyl-1,3-thiazol-4-yl)methyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-3-{[5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methyl) -7-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-3-[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-[(5-phenylisoxazol-3-yl)methyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-3-{[5-(3,4-dichlorophenyl)isoxazol-3-yl]methyl)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione;

3-[(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]dec-3-yl]propanoic acid;

[(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]dec-3-yl]acetic acid;

N-(4-chlorophenyl)-2-[(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]dec-3-yl]acetamide;

(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-(1,2,4-oxadiazol-3-ylmethyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-(pyridin-2-ylmethyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-1-(3-fluorophenyl)-3-(3-furylmethyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-3-(isoxazol-3-ylmethyl)-7-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-(1,3-oxazol-2-ylmethyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-3-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-3-(isoxazol-5-ylmethyl)-7-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-[(1-methyl-1H-1,2,4-triazol-5-yl)methyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-[(1-methyl-1H-imidazol-1-yl)methyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-[(1-phenyl-1H-1,2,3-triazol-4-yl)methyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-(pyrazin-2-ylmethyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-3-tert-butyl-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-(1-methyl-1-phenylethyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-(1,3-thiazol-2-ylmethyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-(1,3-thiazol-4-ylmethyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-3-(2-methoxy-1,1-dimethylethyl)-7-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-1-(3-fluorophenyl)-3-(2-furylmethyl)-8-(3_Tisopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-2,4-dioxo-3-phenyl-1,3-diaza-8-azoniaspiro[4.5]decane;

(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-3-phenyl-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-1,3-bis(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione;

3-[(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]dec-3-yl]benzonitrile;

(5R,7S)-3-[3-(dimethylamino)phenyl]-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-1-(3-fluorophenyl)-3-(1H-indol-5-yl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione;

3-[(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]dec-3-yl]benzoic acid;

(5R,7S)-1-(3-fluorophenyl)-8-(3-furylmethyl)-7-methyl-3-[(5-methylisoxazol-3-yl)methyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione;

N-[4-({(5R,7S)-1-(3-fluorophenyl)-7-methyl-3-[(5-methylisoxazol-3-yl)methyl]-2,4-dioxo-1,3,8-triazaspiro[4.5]dec-8-yl) methyl)phenyl]acetamide;

(5R,7S)-1-(3-fluorophenyl)-7-methyl-3-[(5-methylisoxazol-3-yl)methyl]-8-(pyridin-3-ylmethyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-8-benzyl-1-(3-fluorophenyl)-7-methyl-3-[(5-methylisoxazol-3-yl)methyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-8-(2-fluorobenzyl)-1-(3-fluorophenyl)-7-methyl-3-[(5-methylisoxazol-3-yl)methyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-8-(cyclobutylmethyl)-1-(3-fluorophenyl)-7-methyl-3-[(5-methylisoxazol-3-yl)methyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-8-benzyl-3-{[5-(3,4-dichlorophenyl)isoxazol-3-yl]methyl)-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione;

N-(4-{[(5R,7S)-1-(3-fluorophenyl)-7-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]dec-8-yl]methyl}phenyl)acetamide;

(5R,7S)-3-{[5-(3,4-dichlorophenyl)isoxazol-3-yl]methyl}-8-(2-fluorobenzyl)-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione;

(5R,7S)-8-(cyclobutylmethyl)-3-{[5-(3,4-dichlorophenyl)isoxazol-3-yl]methyl}-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione;

3-[(5R,7S)-8-(3-isopropoxybenzyl)-7-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]dec-1-yl]benzonitrile;

3-{(5R,7S)-8-(3-isopropoxybenzyl)-7-methyl-3-[(5-methylisoxazol-3-yl)methyl]-2,4-dioxo-1,3,8-triazaspiro[4.5]dec-1-yl)benzonitrile;

3-[(5R,7S)-3-[(5-cyclopropyl-1,3,4-thiadiazol-2-yl)methyl]-8-(3-isopropoxybenzyl)-7-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]dec-1-yl]benzonitrile;

3-[(5R,7S)-3-{[5-(3,4-dichlorophenyl)isoxazol-3-yl]methyl}-8-(3-isopropoxybenzyl)-7-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]dec-1-yl]benzonitrile;

3-{(5R,7S)-8-(3-isopropoxybenzyl)-7-methyl-2,4-dioxo-3-[(1-phenyl-1H-1,2,3-triazol-4-yl)methyl]-1,3,8-triazaspiro[4.5]dec-1-yl)benzonitrile;

3-{(5R,7S)-8-(3-isopropoxybenzyl)-3-[2-methoxyphenyl)ethyl]-7-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]dec-1-yl)benzonitrile;

N-{2-[(5R,7S)-1-(3-cyanophenyl)-8-(3-isopropoxybenzyl)-7-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]dec-3-yl]ethyl}benzamide;

3-((5R,7S)-8-(3-isopropoxybenzyl)-3-{[5-(4-methoxyphenyl)isoxazol-3-yl]methyl}-7-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]dec-1-yl)benzonitrile; and

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

-methylbiphenyl-3-yl)methyl]-3-[(5-methylisoxazol-3-yl)methyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione;

and pharmaceutically acceptable salts thereof, and individual enantiomers and diastereomers thereof.

14. 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.

15. 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.

16. A method for the manufacture of a medicament for inhibiting β

-secretase enzyme activity in mammals, comprising combining a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.