Compounds and uses thereof in modulating amyloid β
View Patent ↗Novel compounds, compositions, and kits are provided. Methods of modulating Aβ levels, and methods of treating a disease associated with aberrant Aβ levels are also provided.
1. A compound having a structure corresponding to Formula (I):
(A)-L A -(B)-L B -(C)-L C -(D) (I)
and pharmaceutically acceptable salts thereof, wherein:
A is an optionally substituted 1,3-imidazole or an optionally substituted 1,2,3-triazole having the structure:
wherein each is independently N, NR, C, or CR 1 ;
R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylamino, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl; and
each R 1 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylamino, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl;
B is an optionally substituted pyridyl or an optionally substituted pyrimidinyl having the structure:
wherein each G is independently CR 2 or N; and
each R 2 is independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylamino, substituted or unsubstituted amino;
C is an optionally substituted thiazole having the structure:
wherein R 3 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted alkoxy;
D is a substituted aryl having the structure:
wherein each M is independently selected from CR 5 ; and
each R 5 is independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted amino, or substituted or unsubstituted alkylamino;
L A is a covalent bond;
L B is a covalent bond; and
L C is —NR—.
2. The compound of claim 1 , wherein D is
and d is 0-5.
3. The compound of claim 2 , wherein each R 5 is independently selected from the group consisting of halogen, substituted or unsubstituted C 1 -C 5 alkyl, substituted or unsubstituted C 1 -C 5 alkoxy, substituted or unsubstituted amino, and —N(R″) 2 wherein each R″ is independently a substituted or unsubstituted C 1 -C 5 alkyl or C 3 -C 10 cycloalkyl.
4. The compound of claim 2 , wherein D is
5. The compound of claim 2 , wherein D is
6. The compound of claim 5 , wherein each R 5 is independently selected from the group consisting of halogen, substituted or unsubstituted C 1 -C 5 alkyl, substituted or unsubstituted C 1 -C 5 alkoxy, and —N(R″) 2 wherein each R″ is independently a substituted or unsubstituted C 1 -C 5 alkyl or C 3 -C 10 cycloalkyl.
7. The compound of claim 1 , wherein L C is —NH—.
8. The compound of claim 1 , wherein C is
9. The compound of claim 1 , wherein B is
and b is 0-2.
10. The compound of claim 9 , wherein B is selected from
11. The compound of claim 10 , wherein B is selected from
12. The compound of claim 11 , wherein each R 2 is independently selected from halogen or substituted or unsubstituted C 1 -C 5 alkyl.
13. The compound of claim 1 , wherein A is
wherein F is CH or N.
14. The compound of claim 13 , wherein R 1 is halogen or substituted or unsubstituted C 1 -C 5 alkyl.
15. The compound of claim 1 , having a structure corresponding to Formula (III):
wherein b is 0-2 and d is 0-5.
16. The compound of claim 15 , having a structure corresponding to Formula (IV):
17. The compound of claim 16 , having a structure corresponding to Formula (V):
18. The compound of claim 17 , having a structure corresponding to Formula (VI):
19. The compound of claim 18 wherein E is CR 1 .
20. The compound of claim 18 , wherein R 1 at the 4-position of ring A is substituted or unsubstituted alkyl, and R 1 at the 5-position of ring A is hydrogen.
21. The compound of claim 18 , wherein R 2 is halogen or substituted or unsubstituted alkoxy, and b is 1.
22. The compound of claim 18 , wherein R 3 is hydrogen.
23. The compound of claim 1 , wherein said compound is selected from the group consisting of:
24. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
25. A composition comprising a compound of claim 15 and a pharmaceutically acceptable carrier.
26. A composition comprising a compound of claim 16 and a pharmaceutically acceptable carrier.
27. A composition comprising a compound of claim 17 and a pharmaceutically acceptable carrier.
28. A composition comprising a compound of claim 18 and a pharmaceutically acceptable carrier.
29. A kit comprising a compound of claim 1 and instructions for use.