Oxysterols and methods of use thereof
Compounds are provided according to Formula (I) and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, wherein X, Y, R 1 , R 2a , R 2b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7 , and R 8 are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof;
wherein:
R 1 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, carbocyclyl, or heterocyclyl;
each of R 2a and R 2b is independently hydrogen, C 1 -C 6 alkyl, halo, cyano,—OR A , or —NR B R C , or
R 2a and R 2b together with the carbon atom to which they are attached form a 3-7 membered ring;
each of R 4a and R 4b is independently absent, hydrogen, C 1 -C 6 alkyl, or halo;
X is —C(R X ) 2 — or —O—, wherein R X is independently hydrogen, halo, or one R X group and R 5b are joined to form a double bond;
Y is —OR Y , wherein R Y is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —C(O)R A , —C(O)OR A , —C(O)NR B R C , or —S(O) 2 R D ;
each instance of R 5a and R 5b is independently hydrogen, halo, or C 1 -C 6 alkyl;
each of R 6a and R 6b is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, or
R 6a and R 6b , taken together with the carbon atom to which they are attached, form a 3-6 membered ring; or
R 5a and R 6a , together with the carbon atoms to which they are attached, form a 3-6-membered ring; and
R 7 is absent or hydrogen in the alpha configuration;
R 8 is hydrogen, halo, C 1 - 6 alkyl, carbocyclyl, or —OR A ;
represents a single or double bond, wherein when one is a double bond, the other is a single bond;
wherein when the between —CR 7 and —CR 4a R 4b is a double bond, then one of R 4a or R 4b is absent; and
when one of the is a double bond, R 7 is absent;
R A is hydrogen, C 1 -C 6 alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl;
each of R B and R C is independently hydrogen, C 1 -C 6 alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or taken together with the atom to which they are attached form a 3-7-membered ring; and
R D is hydrogen, C 1 -C 6 alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is unsubstituted C 1 - 3 alkyl.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is substituted C 1 - 3 alkyl.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2a or R 2a is hydrogen.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4a is hydrogen.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is —CH 2 —.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8 is substituted or unsubstituted C 1 - 3 alkyl.
8. The compound of claim 1 , wherein the compound of Formula (I) is a compound of Formula (II):
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 8 , wherein the compound of Formula (II) is a compound of Formula (II-A):
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 8 , wherein the compound of Formula (II) is a compound of Formula (II-B):
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5a or R 5b is hydrogen.
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6a is a substituted or unsubstituted C 1 - 3 alkyl.
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6a is a substituted or unsubstituted C 2 - 4 alkyl, substituted or unsubstituted C 2 - 3 alkenyl, substituted or unsubstituted C 2 - 3 alkynyl, or substituted or unsubstituted carbocyclyl.
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6b is substituted or unsubstituted C 1 - 3 alkyl.
15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6a and R 6b , taken together with the atom to which they are attached, form a 3-6 membered ring.
16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R Y is substituted or unsubstituted C 1 - 3 alkyl.
17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R Y is substituted or unsubstituted heterocyclyl.
18. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
19. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
20. The compound of claim 18 , wherein the compound is: