Pyrrolidin-3-yl compounds useful as beta-secretase inhibitors for the treatment of Alzheimer's disease

1. A compound of formula (I):

wherein:

R 1 is

—(CH 2 ) x —Q 1 ;

R 2 is selected from the group consisting of:

(1) (R 5 —SO 2 )N(R 7 )—,

(2) R 5 —S(O) m —,

(3) R 5 NHC(═O)—,

(4) R 5 C(═O)NH—,

(5) R 5 R 5 ′N—,

(6) CN,

(7) —C 1-6 alkyl,

(8) halogen, and

(9)

R 3 is selected from the group consisting of:

R 4 is selected from the group consisting of:

(1) hydrogen, and

(2) —C 1-6 alkyl;

R 5 , R 5 ′ and R 6 are each independently selected from the group consisting of:

(1) —C 1-6 alkyl,

(2) —C 2-6 alkenyl,

(3) —C 2-6 alkynyl,

(4) —C 3-8 cycloalkyl, and

(5) —(CH 2 ) x — phenyl;

R 7 is selected from the group as consisting of;

(1) hydrogen,

(2) —C 1-6 alkyl,

(3) —C 2-6 alkenyl,

(4) —C 2-6 alkynyl, and

(5) —(CH 2 ) x —phenyl;

R 8a and R 8b are independently selected from the group consisting of:

(1) —CN,

(2) hydrogen,

(3) halogen,

(4) -Q 2 R 5 ,

(5) —C 1-6 alkyl,

(6) —CO 2 R 5 , and

(7) tetrazolyl;

R 9a , R 9b , R 9c , R 9d and R 9e are each independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) -Q 2 R 5 , and

(4) —C 1-6 alkyl;

R 10 is selected from the group consisting of

(1) —HC—

(2) —O—,

(3) —S—, and

(4) —NH—,

provided that when R 10 is —CH— the dashed line forms a bond and when R 10 is —O—, —S— or —NH— the dashed line is absent;

R 11 is selected from the same group as R 7 ;

R 12 and R 13 are independently selected from the group consisting of:

(1) —C 1-6 alkyl;

(2) —C 2-6 alkyl;

(3) —C 2-6 alkynyl;

(4) —(CH 2 ) x — phenyl, or

R 12 and R 13 are linked together with the nitrogen atom to which they are attached, to form the group

R 14 is selected from the group consisting of:

(1) —HC═CH—,

(2) —O—,

(3) —S—, and

(4) —NH—:

Q 1 is phenyl;

Q 2 is selected from the group consisting of —O— or —S—;

wherein each R 1 , R 2 , R 5 , R 5 ′, R 6 , R 7 , R 8a , R 8b , R 9a-9e , R 11 , R 12 and R 13 alkyl, alkenyl and alkynyl moiety herein is unsubstituted or substituted with one or more

(a) halo,

(b) —OH,

(c) —CN,

(d) —C 1-10 alkyl

(e) —C 3-8 cycloalkyl,

(f) —O—C 1-10 alkyl,

(g) aryl selected from the group consisting of phenyl or naphthyl,

(h) heteroaryl selected from the group consisting of pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl, furanyl, imidazolyl, triazinyl, pyranyl, thiazolyl, thienyl, thiophenyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl and benzoxazolyl, or

(i) —NR 7 R 11 ;

and each R 5 , R 5 ′, R 6 , R 7 , R 11 , R 12 , R 13 and Q 1 phenyl or naphthyl moiety herein is unsubstituted or substituted with one or more

(a) halo,

(b) —OH,

(c) —CN,

(d) —C 1-10 alkyl

(e) —C 3-8 cycloalkyl,

(f) —O—C 1-10 alkyl,

(g) aryl selected from the group consisting of phenyl or naphthyl,

(h) heteroaryl selected from the group consisting of pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl, furanyl, imidazolyl, triazinyl, pyranyl, thiazolyl, thienyl, thiophenyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl and benzoxazolyl, or

(i) —NR 7 R 11 ;

m is independently 0, 1, or 2;

x is independently 0 or 1;

or a pharmaceutically acceptable salt thereof, or an individual enantiomer or diastereomer thereof.

2. The compound of claim 1 wherein R 1 is —(CH 2 )-phenyl.

3. The compound of claim 1 wherein R 4 is hydrogen or C 1-6 alkyl.

4. The compound of claim 3 wherein R 4 is hydrogen.

5. The compound of claim 1 wherein R 2 is (R 5 —SO 2 )N(R 7 )—.

6. The compound of claim 5 wherein R 5 and R 7 are C 1-6 alkyl.

7. The compound of claim 1 wherein R 2 is

8. The compound of claim 7 wherein R 8a is hydrogen and R 8b is CN.

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

wherein R 11 is selected from the group consisting of

(1) halo,

(2) —OH,

(3) —CN, and

(4) —O—C 1-10 alkyl.

10. The compound of claim 9 wherein R 11 is halogen.

11. The compound of claim 9 wherein R 4 is hydrogen.

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

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

14. A compound of claim 1 which is a compound of formula (VI):

15. A compound of claim 1 which is a compound of formula (VII):

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

N-[(2S,3R)-2-benzylpyrrolidin-3-yl]—N′-[(1R)—1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]isophthalamide;

N-[(2S,3R)-2-(3-chlorobenzyl)pyrrolidin-3-yl]-3-{[(2-methylcyclopropyl)oxy]methyl}-5-[methyl(methylsulfonyl)amino]benzamide;

N-[(2S,3R)-2-benzylpyrrolidin-3-yl]-3-[methyl(methylsulfonyl)amino]-5-[(2-phenylcyclopropyl)methoxy]benzamide;

N-[(2S,3R)-2-benzylpyrrolidin-3-yl]-3-[(cyclopropyloxy)methyl]-5-[methyl(methylsulfonyl)amino]benzamide;

N-[(2S,3R)-2-(3-chlorobenzyl)pyrrolidin-3-yl]-3-{(Z)-2-[(1S,2S)-2-methylcyclopropyl]vinyl}-5-[methyl(methylsulfonyl)amino]benzamide; and

N-butyl-N′-[(2S,3R)-2-(3-chlorobenzyl)pyrrolidin-3-yl]-2′-cyano-N-methylbiphenyl-3,5-dicarboxamide;

or a pharmaceutically acceptable salt thereof.

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

18. A method for 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.