Inhibitors of BACE1 and methods for treating Alzheimer's disease
Inhibitors of BACE1 and compositions containing them are described. Use of the inhibitors and compositions containing them to treat Alzheimer's disease are described.
1. A compound of formula
or a pharmaceutically acceptable salt, isomer, mixture of isomers, crystalline form, non crystalline form, hydrate, or solvate thereof, wherein
R is optionally substituted aryl, X 1 is optionally substituted alkylene, and A is NR 1 , where R 1 is hydrogen or alkyl; or
R is optionally substituted heteroaryl, X 1 is CH 2 , A is NR 1 , and R 1 is hydrogen or alkyl; or
A is NR 1 , R is heteroaryl, and R 1 , X 1 and the attached nitrogen form a heterocycle;
X 2 is C(O);
Q 1 is 1,3-phenylene, which is optionally substituted at the 5-position with N-methylmethylsulfonylamido, alkyl, or heteroalkyl;
X 3 is C(O);
R 2 , R 3 , and R 4 are each hydrogen;
R 5 is arylalkyl, which is optionally substituted;
R 6a is C(O)NHR 10a , where R 10a is alkyl; and R 6b is alkyl.
2. The compound of claim 1 which is the most potent isomer of diastereoisomers formed by R 6a and R 6b in the inhibition of BACE1.
3. The compound of claim 1 wherein R is optionally substituted aryl, X 1 is optionally substituted alkylene, and A is NR 1 , where R 1 is hydrogen or alkyl.
4. The compound of claim 3 wherein R 1 is hydrogen.
5. The compound of claim 3 wherein R is aryl, X 1 is alkylene, and R 1 is hydrogen.
6. The compound of claim 1 wherein R is optionally substituted heteroaryl, X 1 is CH 2 , A is NR 1 , and R 1 is hydrogen or alkyl.
7. The compound of claim 6 wherein the heteroaryl is optionally substituted oxazolyl or thiazolyl.
8. The compound of claim 1 wherein A is NR 1 , R is heteroaryl, and R 1 , X 1 and the attached nitrogen form a heterocycle.
9. The compound of claim 8 wherein the heterocycle is pyrrolidinyl.
10. The compound of claim 1 which is a compound of formula
wherein X is O, S, or NMe; R is hydrogen, alkyl, or heteroalkyl; and y is hydrogen, alkyl, or heteroalkyl.
11. The compound of claim 1 wherein A is NR 1 , where R 1 is hydrogen; and R—X 1 — form (R)-1-phenyl-1-ethyl.
12. The compound of claim 1 which is a compound of formula
13. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.