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

1. A compound of formula (I):

or its tautomer (I′)

wherein

X is N;

X′ is NH;

Y is selected from the group consisting of

(1) O, and

(2) S;

R 1 is selected from the group consisting of

(1) —C 1-10 alkyl, and

(2) —C 3-12 cycloalkyl, wherein one or two of the ring carbon atoms is optionally replaced by a —Si(C 1-6 alkyl) 2 — group,

wherein said alkyl and said cycloalkyl R 1 moiety

is optionally substituted with one or more

(a) halo, and

(b) —C 1-10 alkyl;

R 2 is selected from the group consisting of phenyl or thienyl,

wherein said phenyl or thienyl R 2 moiety is optionally substituted with one or more

(a) halo, and

(b) —C 0-6 alkyl-aryl, wherein said aryl is optionally substituted with one or more —SO 2 Cl 1-3 alkyl;

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

(a) halo,

(b) —OH,

(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 phenyl or —C 3-12 cycloalkyl,

wherein said phenyl or cycloalkyl, R 3 moiety is optionally substituted with one or more

(a) halo,

(b) —C 2-10 alkenyl,

(c) —C 3-12 cycloalkyl,

(d) —O—C — 12 cycloalkyl,

(e) —O—C 1-10 alkyl,

(f) —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, and

(g) heteroaryl;

R 4 is —C 2-4 alkenyl;

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

2. A compound of claim 1 of formula (I) or (I′), wherein Y is O.

3. A compound of claim 1 , wherein R 1 is selected from the group consisting of optionally substituted C 1-6 alkyl or C 3-6 cycloalkyl.

4. A compound of claim 1 , wherein R 2 is phenyl, wherein the phenyl is optionally substituted with one or more

(i) halo, and

(ii) phenyl optionally substituted with —SO 2 C 1-3 alkyl.

5. 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, and

(B) —OC 1-10 alkyl.

6. A compound of claim 5 , wherein Q is —CH 2 —.

7. A compound of claim 1 , wherein R 4 is C 2-3 alkenyl.

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

or its tautomer (II′)

wherein X, X′, R 1 , R 2 , and R 4 are as defined in claim 1 , and R 10 is selected from the group consisting of

(1) halo,

(2) —C 2-10 alkenyl, and

(3) —OC 1-10 alkyl,

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

9. A compound of claim 8 , wherein R 2 is phenyl which is optionally substituted with one or more

(i) halo,

(ii) phenyl, optionally substituted with —SO 2 C 1-3 alkyl.

10. A compound of claim 8 , wherein R 4 is —C 2-3 alkenyl.

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

or its tautomer (III′)

wherein X, X′, Q, R 1 , R 3 , and R 4 are as defined in claim 1 , and R 11 is selected from the group consisting of

(1) halo, and

(2) optionally substituted phenyl;

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

12. A compound of claim 11 , wherein Q is C 1-3 alkylene, and R 3 is phenyl, wherein the phenyl is optionally substituted with one or more

(A) halo, and

(B) —OC 1-10 alkyl.

13. A compound of claim 11 , wherein R 4 is C 2-3 alkyl.

14. 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)

and its tautomer (IB′):

15. A compound which is selected from the group consisting of

Ex

Chemical

#

Structure

name

51

(5R,7R)-8- benzyl-4- (cyclohexyl- amino)-1-(3- fluorophenyl)- 7-vinyl- 1,3,8-triaza- spiro[4.5]dec- 3-en-2-one,

52

(5R,7R)-4- (cyclohexyl- amino)-1-(3- fluorophenyl)- 8-(3-{[(1R)- 1-methyl-pro- pyl]oxy}benzyl)- 7-vinyl-1,3,8- triaza- spiro[4.5]dec- 3-en-2-one,

53

(5R,7R)-4- (cyclohexyl- amino)-1-(3- fluorophenyl)- 8-(3-isopro- poxybenzyl)-7- [(1E)-prop-1- en-1-yl]- 1,3,8-triaza- spiro[4.5]dec- 3-en-2-one, and

54

(5R,7R)-4- (cyclohexyl- amino)-1-(3- fluorophenyl)- 8-(3-isopro- poxybenzyl)-7- [(1Z)-prop-1- en-1-yl]- 1,3,8-triaza- spiro[4.5]dec- 3-en-2-one,

or a pharmaceutically acceptable salt thereof.

16. A pharmaceutically acceptable salt of a compound of claim 15 , wherein the salt is selected from the group consisting of sulfate, phosphate, citrate, malate, mandelate, hippurate, trifluoroacetate and hydrochloric acid salts.

17. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.