Gamma secretase modulators
Disclosed herein are compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein each of the substituents is given the definition as set forth in the specification and claims. Also disclosed are pharmaceutical compositions containing compounds of Formula (I) and use of the compounds in the treatment of neurodegenerative diseases or conditions such as Alzheimer's disease.
1. A compound of the Formula (I)
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is 1) hydrogen, 2) (C1-C6)alkyl optionally substituted with 1 to 5 halogens or phenyl, wherein the phenyl is optionally substituted with 1 to 3 halogens, 3) phenyl optionally substituted with 1 to 3 (C1-C6)alkyls or 1 to 5 halogens, or 4) (C4-C6)cycloalkyl optionally substituted with 1 to 3 (C1-C6)alkyls or 1 to 5 halogens;
R 2 is 1) hydrogen, 2) (C1-C6)alkyl optionally substituted with 1 to 5 halogens or phenyl, wherein the phenyl is optionally substituted with 1 to 3 halogens, or 3) phenyl optionally substituted with 1 to 3 halogens;
R 3 is (C1-C6)alkyl, —OH or halogen;
X is —NR 4 —, —O—, —S—, or —SO 2 —;
R 4 is hydrogen or (C1-C3)alkyl;
p is 1 to 3;
m is 0 or 1;
n is 0 to 3; and
Ar 2 —Ar 1 is selected from the group consisting of
2. The compound of claim 1 , wherein Ar 2 —Ar 1 is
3. The compound of claim 1 , wherein p is 2 and n is 0.
4. The compound of claim 1 , wherein the halogen is fluoro.
5. The compound of claim 1 , wherein X is —NR 4 —, m is 1, n is 0, and R 1 is (C1-C6)alkyl optionally substituted with 1 to 5 halogens or phenyl, wherein the phenyl is optionally substituted with 1 to 3 halogens.
6. The compound of claim 5 , wherein R 1 is (C1-C6)alkyl substituted with phenyl, and wherein the phenyl is substituted with 1 or 2 halogens.
7. The compound of claim 6 , wherein the halogen is fluoro.
8. The compound of claim 1 , wherein X is —NR 4 —, m is 1, n is 0, and R 1 is phenyl optionally substituted with 1 to 3 (C1-C6)alkyls or 1 to 5 halogens.
9. The compound of claim 8 , wherein R 1 is phenyl substituted with 1 or 2 halogens.
10. The compound of claim 9 , wherein the halogen is fluoro.
11. The compound of claim 1 , wherein X is —O—, m is 1, n is 0, and R 1 is 1) alkyl optionally substituted with 1 to 5 halogens or phenyl, wherein the phenyl is optionally substituted with 1 to 3 halogens or 2) phenyl optionally substituted with 1 to 3 (C1-C6)alkyls or 1 to 5 halogens.
12. The compound of claim 1 , wherein X is —O—, m is 1, n is 0, R 1 is H, and R 2 is phenyl optionally substituted with 1 to 3 halogens.
13. The compound of claim 1 , wherein X is —O—, m is 1, n is 0, R 1 is H, R 2 is (C1-C6)alkyl substituted with phenyl, wherein the phenyl is optionally substituted with 1 or 2 halogens.
14. The compound of claim 1 , wherein X is —NR 4 —, m is 1, n is 0, and R 1 is (C4-C6)cycloalkyl optionally substituted with 1 to 3 (C1-C6)alkyls or 1 to 5 halogens.
15. A compound which is selected from the group consisting
or a pharmaceutically acceptable salt thereof.
16. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
17. A pharmaceutical composition comprising the compound of claim 15 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
18. A method of treating Alzheimer's disease comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt thereof.