Benzylether and benzylamino beta-secretase inhibitors for the treatment of alzheimer's disease

1. A compound of formula (I):

wherein:

X is O or NH;

Y is N;

R 1 is (1) aryl selected from the group consisting of phenyl and napthyl, or

(2) heterocyclyl selected from the group consisting of piperazinyl, piperidinyl, pyrrolidinyl, pyrazinyl, dihydropyrazinyl, pyrazolyl, dihydropyrazolyl, pyridazinyl, pyridyl, dihydropyridinyl, pyrimidinyl, dihydropyrimidinyl, pyrrolyl, dihydropyrrolyl, tetrazolyl, dihydrotetrazolyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, imidazolyl, dihydroimidazolyl, triazinyl, pyranyl, tetrahydropyranyl, thiazolyl, thienyl, dihydrothienyl, thiophenyl, triazolyl, dihydrotriazolyl, morpholinyl, thiomorpholinyl, dihydrothiadiazolyl, tetrahydrothienyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl and benzoxazolyl,

wherein said aryl or heterocyclyl is unsubstituted or substituted with one or more

(a) halo,

(b) —C 1-6 alkyl,

(c) —C 2-6 alkenyl,

(d) —C 2-6 alkynyl,

(e) —OH,

(f) —CN, or

(g) —O—C 1-6 alkyl;

R 2 is selected from the group consisting of:

(1) R 4 —S(O) 2 N(R 7 )—, wherein R 4 is C 1-6 alkyl, wherein said alkyl is unsubstituted or substituted with one or more

(a) halo,

(b) —C 2-6 alkynyl,

(c) —OH,

(d) —CN, or

(e) —O—C 1-6 alkyl; and

R 7 is selected from the group consisting of

(a) hydrogen, and

(b) —C 1-6 alkyl,

wherein said alkyl is unsubstituted or substituted with one or more

(i) halo,

(ii) —C 1-6 alkyl,

(iii) —OH,

(iv) —CN, or

(v) —O—C 1-6 alkyl;

R 3 is selected from the group consisting of:

wherein R 5 is C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl;

R 6a , R 6b , and R 6c are independently selected from the group consisting of:

(1) hydrogen,

(2) halo,

(3) —C 1-6 alkyl,

(4) —C 2-6 alkenyl,

(5) —C 2-6 alkynyl,

(6) —OH,

(7) —CN, and

(8) —O—C 1-6 alkyl;

R 9 and R 10 are independently selected from the group consisting of:

(1) hydrogen, and

(2) C 1-6 alkyl,

(3) —C 2-6 alkenyl, and

(4) —C 2-6 alkynyl,

or R 9 and R 10 are joined together with the nitrogen atom to which they are attached to form a pyrrolidine ring, which is optionally substituted with

(a) C 1-6 alkyl,

(b) —C 2-6 alkenyl,

(c) —C 2-6 alkynyl,

(d) (CH 2 ) n -phenyl, and

(e) (CH 2 ) n -furanyl;

wherein said alkyl, phenyl and furanyl are unsubstituted or substituted with one or more

i) halo,

ii) —C 1-6 alkyl,

iii) —OH,

iv) —CN, or

v) —O—C 1-6 alkyl; and

R 11 is selected from the group consisting of

(1) —CH—,

(2) —O—, and

(3) —NH—,

provided that when R 11 is —CH— the dotted line forms a bond and when R 11 is —O— or —NH— the dotted line is absent;

R 12 is hydrogen, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl;

m is 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 1, 2, 3 or 4;

and pharmaceutically acceptable salts thereof.

2. The compound of claim 1 , wherein m is 1 and R 1 is phenyl unsubstituted or substituted with one or more chloro or fluoro.

3. The compound of claim 1 , wherein m is 2 and R 1 is phenyl unsubstituted or substituted with one or more chloro or fluoro.

4. The compound of claim 1 , wherein m is 1 and R 1 is thiophenyl.

5. The compound of claim 1 , wherein R 2 is (R 4 )—S(O) 2 N(R 7 )— and R 7 is C 1-6 alkyl.

6. The compound of claim 5 wherein R 4 and R 7 are each methyl.

7. The compound of claim 1 , wherein R 2 is

8. The compound of claim 1 wherein R 3 is

9. The compound of claim 8 wherein R 5 is methyl.

10. The compound of claim 9 wherein R 6a and R 6c are hydrogen and R 6b is fluoro.

11. The compound of claim 10 , wherein R 3 is

12. The compound of claim 1 wherein R 3 is

and R 9 and R 10 are joined together with the nitrogen atom to which they are attached to form a pyrrolidine ring which is unsubstituted or substituted with

(a) C 1-6 alkyl,

(b) (CH 2 ) n -phenyl, or

(c) (CH 2 ) n -furanyl.

13. The compound of claim 12 wherein R 9 and R 10 are joined together with the nitrogen atom to which they are attached to form a pyrrolidine ring which is substituted with —(CH 2 ) n — furanyl wherein n is 0.

14. The compound of claim 13 , wherein R 3 is

15. The compound of claim 1 wherein R 3 is

16. The compound of claim 1 of formula II:

wherein X, Y, R 1 , R 2 , R 5 , R 6a , R 6b , R 6c and m are as defined in claim 1 .

17. The compound of claim 1 of formula (III):

wherein X, Y, R 1 , R 2 , R 9 , R 10 and m are as defined in claim 1 .

18. The compound of claim 1 of formula (IV):

wherein X, Y, R 1 , R 2 , R 11 , R 12 and m are as defined in claim 1 .

19. A compound of claim 1 which is:

or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising an effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.