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

1 . A compound of formula (I):

wherein

X is selected from the group consisting of

(1) N—R 5 ,

(2) O, and

(3) S,

and R 5 is selected from the group consisting of

(a) hydrogen,

(b) —C 1-10 alkyl,

(c) —C 2-10 alkenyl,

(d) —C 3-12 cycloalkyl,

(e) —C 0-6 alkyl-aryl, and

(f) —C 0-6 alkyl-heteroaryl,

wherein said alkyl, alkenyl, cycloalkyl, aryl and heteroaryl R 5 moiety is optionally substituted with one or more

(i) aryl,

(ii) heteroaryl,

(iii) halogen,

(iv) —C 1-10 alkyl,

(v) —C 1-10 alkyl,

(vi) —C 3-12 cycloalkyl,

(vii) —NC(═O)—R 6 ,

(viii) —C(═O)NR 6 R 6 ′,

(ix) —C(═O)—OR 6 ,

(x) —C(═O)—R 6 ,

(xi) —CN

(xii) —NR 6 R 6 ′,

wherein said aryl, alkly, cycloalkyl and heteroaryl moiety is optionally substituted with one or more

(I) halogen,

(II) —C 1-6 alkyl,

(III) —OC 1-6 alkyl,

R 1A and R 1B are each hydrogen, provided that when X is NR 5 , then R 1A and R 1B may together form ═O;

R 2 is selected from the group consisting of

(1) hydrogen,

(2) —C 1-10 alkyl,

(3) —C 2-10 alkenyl,

(4) —C 2-10 alkynyl,

(5) —C 3-12 cycloalkyl,

(6) a heterocyclic group having 4 to 8 ring atoms, wherein one ring atom is a heteroatom selected from the group consisting of nitrogen and oxygen,

(7) aryl, and

(8) heteroaryl,

wherein said alkyl, cycloalkyl, heterocyclic group, alkenyl, alkynyl, aryl or heteroaryl R 2 moiety is optionally substituted with one or more

(a) halo,

(b) —OH,

(c) —CN,

(d) —C 1-10 alkyl,

(e) —C 2-10 alkenyl,

(f) —C 2-10 alkynyl,

(g) —C 3-12 cycloalkyl,

(h) —O—C 1-10 alkyl,

(i) —C 0-6 alkyl-aryl, or

(j) —C 0-6 alkyl-heteroaryl,

wherein said alkyl, alkenyl, alkynyl, aryl and heteroaryl moiety is optionally substituted with one or more

(i) halo,

(ii) —OH,

(iii) —CN,

(iv) —C 1-6 alkyl,

(v) —C 2-6 alkenyl,

(vi) —OC 1-6 alkyl,

(vii) —C 1-6 haloalkyl,

(viii) —SO 2 C 1-3 alkyl,

(ix) —SO 2 NR 6 R 6 ′,

(x) —OC 2 R 6 ,

(xi) —NR 6 SO 2 R 6 ′,

(xii) —CONR 6 R 6 ′;

(xiii) —NC(═O)—C 0-3 alkyl-NR 6 R 6 ′;

(xiv) —NC(═O)R 6

(xv) —NR 6 R 6 ′, and

(xvi) a heterocyclic group having 4 to 8 ring atoms, wherein one ring atom

is a heteroatom selected from the group consisting of nitrogen and oxygen;

Q is —C 1-6 alkylene, wherein said alkylene is optionally substituted with one or more:

(a) halo,

(b)

(c) —CN,

(d) —C 1-10 alkyl

(e) —C 3-12 cycloalkyl,

(f) —O—C 1-10 alkyl,

(g) aryl, and

(h) heteroaryl;

R 3 is selected from the group consisting of

(1) hydrogen,

(2) —C 1-10 alkyl,

(3) —C 2-10 alkenyl,

(4) —C 2-10 alkynyl,

(5) —C 3-12 cycloalkyl,,

(6) —C 3-12 cycloalkenyl,

(7) aryl, and

(8) heteroaryl,

wherein said alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl or aryl or heteroaryl R 3 moiety is optionally substituted with one or more

(a) halo,

(b) —OH,

(c) —CN,

(d) —C 1-10 alkyl,

(e) —C 2-10 alkenyl,

(f) —C 3-12 cycloalkyl,

(g) —O—C 3-12 cycloalkyl

(h) —O—C 1-10 alkyl,

(i) —O—C 3-12 heterocyclic, wherein said heterocyclic group has from 4 to 8 ring atoms, wherein one ring atom is a heteroatom selected from the group consisting of nitrogen, sulfur and oxygen,

(j) aryl,

(k) heteroaryl,

(l) —NR 6 R 6 ′,

and said alkyl, cycloalkyl, aryl and heteroaryl moiety is optionally substituted with one or more

(i) halo,

(ii) —OH,

(iii) —CN,

(iv) —C 1-10 alkyl,

(v) —OC 1-10 alkyl, and

(vi) —NR 6 R 6 ′

(vii) —C 2-6 alkenyl,

(viii) —C 1-6 haloalkyl,

(ix) —SO 2 C 1-3 alkyl,

(x) —SO 2 NR 6 R 6 ′,

(xi) —CONR 6 R 6 ,

(xii) —NR 5 COR 5 ′, wherein R 5 ′ is selected from the same group as R 5 , or

(xiii) —NR 7 SO 2 R 6 , wherein R 7 is selected from the group consisting of

 (A) hydrogen

 (B) —C 1-10 alkyl, and

 (C) —C 3-4 alkenyl;

R 4 is selected from the group consisting of

(1) hydrogen,

(2) —C 1-10 alkyl, and

(3) —C 3-4 alkenyl,

wherein said alkyl or alkenyl R 4 group is optionally substituted with one or more

(a) halo,

(b) —OH

(c) —C 1-6 alkyl,

(d) —CN,

(e) —O—C 1-10 alkyl,

(f) —NR 8 R 9 , wherein R 8 and R 9 are selected from the group consisting of

(i) hydrogen, and

(ii) —C 1-6 alkyl,

(g) —S(O) n —C 1-6 alkyl, wherein n is 0, 1 or 2,

(h) —C(═O)—R 7 , wherein R 7 is selected from the group consisting of

(i) hydrogen,

(ii) —OH,

(iii) —C 1-6 alkyl, and

(iv) —OC 1-6 alkyl, and

(v) aryl;

R 6 and R 6 ′ are selected from the group consisting of

(1) hydrogen,

(2) —C 1-6 alkyl,

(3) —C 3-7 cycloalkyl,

(4) —C 1-6 haloalkyl,

(5) —C 0-6 alkyl-aryl,

(6) —C 0-6 alkyl-heteroaryl,

(7) halo, and

(8) a heterocyclic group having 4 to 8 ring atoms, wherein one ring atom is a heteroatom selected from the group consisting of nitrogen and oxygen, wherein said aryl or heteroaryl R 5 moiety is optionally substituted with one or more

(a) halo,

(b) —C 1-6 alkyl,

(c) O—C 1-6 alkyl, and

(d) —NO 2 ;

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

2 . A compound of claim 1 , wherein X is NR 5 .

3 . A compound of claim 1 , wherein R 2 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) —SO 2 C 1-3 alkyl,

(G) —SO 2 NR 5 R 5 ′,

(H) —NR 5 SO 2 C 1-3 alkyl,

(I) —CO 2 R 5 , and

(J) —CONR 5 R 5 ′.

4 . A compound of claim 1 , wherein Q is C 1-3 alkylene and R 3 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) NR 5 R 5 ′.

5 . A compound of claim 1 , wherein R 4 is —C 1-6 alkyl.

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

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

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

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

8 . A compound of claim 6 , wherein X is NR 5 .

9 . A compound of any of claim 6 , wherein R 2 is phenyl, wherein the phenyl 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 1-6 alkyl,

(E) —OC 1-6 alkyl,

(F) —SO 2 C 1-3 alkyl,

(G) —SO 2 NR 5 R 5 ′,

(H) —NR 5 SO 2 C 1-3 alkyl,

(I) —CO 2 R 5 , and

(J) —CONR 5 R 5 ′, and

(K) —NR 5 CO 2 R 5 ′.

10 . A compound of claim 6 , wherein

R 4 is C 1-6 alkyl.

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

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

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

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

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 T isopropoxybenzyl)-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.