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

1. A compound of formula (I):

wherein

Y is N or CH;

Q is —C 0-3 alkylene, wherein said alkylene is unsubstituted or substituted with one or more

(1) halo,

(2) —C 3-12 cycloalkyl,

(3) —OH,

(4) —CN,

(5) —O—C 1-10 alkyl, and

(6) —C 1-10 alkyl;

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

(2) heteroaryl,

(3) —C 1-10 alkyl, and

(4) —C 3-8 cycloalkyl, said cycloalkyl optionally fused to a C 6-10 aryl group,

wherein said alkyl, cycloalkyl, aryl or heteroaryl is unsubstituted or substituted with one or more

(a) halo,

(b) —C 1-10 alkyl, wherein said alkyl is unsubstituted or substituted with halogen,

(c) —OH,

(d) —CN,

(e) —O—C 1-10 alkyl,

(f) —C 3-12 cycloalkyl, and

(g) —NR 12 R 13 , wherein R 12 and R 13 are selected from the group consisting of

(i) hydrogen,

(ii) —C 1-10 alkyl, and

(iii) —C 0-6 alkyl-C 6-10 aryl;

R 2 is selected from the group consisting of:

(1) (R 4 —SO 2 )N(R 7 )—, wherein R 4 is

(a) —C 1-10 alkyl,

(b) —C 2-10 alkenyl,

(c) —C 2-10 alkynyl, or

(d) —C 3-8 cycloalkyl,

wherein said alkyl, alkenyl, alkynyl and cycloalkyl is unsubstituted or substituted with one or more

(i) halo,

(ii) —OH,

(iii) —CN,

(iv) —O—C 1-10 alkyl,

(v) —C 1-10 alkyl,

(vi) —C 2-10 alkenyl,

(vii) —C 2-10 alkynyl,

(viii) —C 3-8 cycloalkyl,

(ix) aryl selected from the group consisting of phenyl and napthyl, or

(x) heteroaryl,

and said aryl and heteroaryl is unsubstituted or substituted with one or more

(i) halo,

(ii) —OH,

(iii) —CN,

(iv) —O—C 1-10 alkyl,

(v) —C 3-8 cycloalkyl,

(vi) —C 1-10 alkyl,

(vii) —C 2-10 alkenyl, or

(viii) —C 2-10 alkynyl;

R 7 is selected from the group consisting of

(a) hydrogen,

(b) —C 1-10 alkyl,

(c) —C 2-10 alkenyl, or

(d) —C 2-10 alkynyl,

wherein said alkyl, alkenyl or alkynyl is unsubstituted or substituted with one or more

(i) halo,

(ii) —OH,

(iii) —CN,

(iv) —O—C 1-10 alkyl,

(v) —C 3-8 cycloalkyl,

(vi) aryl selected from the group consisting of phenyl and napthyl, or

(vii) heteroaryl,

and said cycloalkyl, aryl or heteroaryl is unsubstituted or substituted with one or more

(i) halo,

(ii) —OH,

(iii) —CN,

(iv) —O—C 1-10 alkyl,

(v) —C 3-8 cycloalkyl, or

(vi) aryl selected from the group consisting of phenyl and napthyl;

R 3 is selected from the group consisting of

wherein R 5 is selected from the group consisting of

(1) —C 1-10 alkyl,

(2) —C 2-10 alkenyl, or

(3) —C 2-10 alkynyl,

wherein said alkyl, alkenyl or alkynyl is unsubstituted or is substituted with one or more halo;

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

(1) hydrogen,

(2) halo,

(3) —C 1-10 alkyl,

(4) —C 2-10 alkenyl,

(5) —C 2-10 alkynyl,

(6) —OH,

(7) —CN,

(8) —C 3-8 cycloalkyl, and

(9) —O—C 1-10 alkyl;

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

(1) hydrogen,

(2) —C 1-10 alkyl,

(3) —C 2-10 alkenyl,

(4) —C 2-10 alkynyl, or

(5) —C 3-8 cycloalkyl;

wherein said alkyl, alkenyl, alkynyl or cycloalkyl is unsubstituted or substituted with one or more

(a) halo,

(b) —OH,

(c) —CN,

(d) —C 3-8 cycloalkyl, or

(e) —O—C 1-10 alkyl,

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 unsubstituted or substituted with one or more

(a) C 1-10 alkyl,

(b) —C 2-10 alkenyl,

(c) —C 2-10 alkynyl,

(d) —C 3-8 cycloalkyl,

(e) —(CH 2 ) n -phenyl,

(f) —CN,

wherein said alkyl, alkenyl or alkynyl is unsubstituted or substituted with one or more

(i) halo,

(ii) —OH,

(iii) —CN,

(iv) —O—C 1-10 alkyl, or

(v) —C 3-8 cycloalkyl,

and said cycloalkyl and phenyl is unsubstituted or substituted with one or more

(i) halo,

(ii) —C 1-10 alkyl,

(iii) —C 2-10 alkenyl,

(iv) —C 2-10 alkynyl,

(v) —OH,

(vi) —CN,

(vii) —C 3-8 cycloalkyl, or

(viii) —O—C 1-10 alkyl;

R 8 is selected from the group consisting of

(1) hydrogen,

(2) —C 1-10 alkyl,

(3) —C 2-10 alkenyl,

(4) —C 2-10 alkynyl, or

(5) —CH 2-10 phenyl,

wherein said alkyl, alkenyl, alkynyl or phenyl is unsubstituted or substituted with one or more

(a) halo,

(b) —OH,

(c) —CN,

(d) —C 3-8 cycloalkyl, and

(e) —O—C 1-10 alkyl;

R 12 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) halo,

(6) —C 3-8 cycloalkyl,

(7) aryl selected from the group consisting of phenyl and napthyl, and

(8) heteroaryl,

wherein said aryl and heteroaryl is unsubstituted or substituted with one or more

(a) halo,

(b) —OH,

(c) —CN,

(d) —O—C 1-10 alkyl,

(e) —C 3-8 cycloalkyl,

(f) —C 1-10 alkyl,

(g) —C 2-10 alkenyl, or

(h) —C 2-10 alkynyl

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

p is 1, 2, 3 or 4;

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

2. A compound of claim 1 , wherein R 1 is phenyl and Q is CH 2 .

3. A compound of claim 1 , wherein R 1 is 4-fluorophenyl and Q is CH 2 .

4. A compound of claim 1 , wherein R 1 is heteroaryl selected from the group consisting of pyridyl, thienyl, thiazole and indynyl.

5. A compound of claim 1 , wherein R 1 is C 1-12 alkyl or C 3-8 cycloalkyl.

6. A compound of claim 1 , wherein R 2 is selected from the group consisting of

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

(i) halo,

(ii) —OH,

(iii) —CN,

(iv) —O—C 1-6 alkyl, or

(v) —C 1-6 alkyl,

R 7 is selected from the group consisting of

(a) hydrogen,

(b) —C 1-6 alkyl,

wherein said alkyl is unsubstituted or substituted with one or more

(i) halo,

(ii) —OH,

(iii) —CN,

(iv) —O—C 1-6 alkyl,

(v) —C 1-6 alkyl,

7. A compound of claim 1 , wherein R 3 is selected from the group consisting of

wherein R 5 is C 1-6 alkyl, optionally substituted with one or more halogen (preferably fluoro);

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) —OH,

(5) —CN, and

(6) —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,

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 unsubstituted or substituted with one or more

(a) C 1-6 alkyl,

(b) —(CH 2 ) n -phenyl;

wherein said alkyl and phenyl 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; and

R 12 is selected from the group consisting of

(1) hydrogen,

(2) —C 1-6 alkyl.

8. A compound of claim 7 , wherein R 3 is

wherein R 5 , R 6a , R 6b , R 6c are as defined above. In preferred embodiments, R 5 is C 1-6 alkyl, optionally substituted with one or more halogen (preferably fluoro); and 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) —OH,

(5) —CN, and

(6) —C 1-6 alkyl.

9. A compound of claim 8 , wherein R 5 is methyl, R 6a and R 6b are hydrogen and R 6c is fluoro.

10. A compound of claim 1 , wherein Y is CH.

11. A compound of claim 1 , wherein Y is N.

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

wherein R 2 , R 3 and Y are as defined in claim 1 , 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

and pharmaceutically acceptable salts thereof.

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

15. A method for inhibiting BACE1 enzyme activity in a mammal in need thereof which comprises administering to the mammal a therapeutically effective amount of a compound of claim 1 .

16. A method for inhibiting BACE2 enzyme activity in a mammal in need thereof which comprises administering to the mammal a therapeutically effective amount of a compound of claim 1 .

17. 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 .