Oxysterols and methods of use thereof
Compounds are provided according to Formula (A): and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R G 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-63):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is alkyl;
R 2 is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl and R 3 is hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, or
R 2 and R 3 , together with the carbon atom to which they are attached form a 3-8 membered ring;
each of R 4 and R 5 is independently hydrogen, halo, or —OR C , wherein R C is hydrogen or C 1 -C 6 alkyl, or
R 4 and R 5 , together with the carbon atom to which they are attached form an oxo group;
R 6 is absent or hydrogen; and
represents a single or double bond, wherein when one of is a double bond, the other is a single bond and R 6 is absent; and wherein when both of are single bonds, R 6 is hydrogen.
2. The compound of claim 1 , or the pharmaceutically acceptable salt thereof, wherein R 1 is C 1 -C 6 alkyl.
3. The compound of claim 1 , or the pharmaceutically acceptable salt thereof, wherein R 2 is alkyl.
4. The compound of claim 1 , or the pharmaceutically acceptable salt thereof, wherein R 2 is unsubstituted C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
5. The compound of claim 1 , or the pharmaceutically acceptable salt thereof, wherein R 2 is unsubstituted C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, carbocyclyl, carbocyclylalkyl, aralkyl, or heterocyclylalkyl.
6. The compound of claim 1 , or the pharmaceutically acceptable salt thereof, wherein R 2 is aryl or heteroaryl and R 3 is hydrogen.
7. The compound of claim 1 , or the pharmaceutically acceptable salt thereof, wherein R 2 is carbocyclyl or heterocyclyl and R 3 is hydrogen.
8. The compound of claim 1 , or the pharmaceutically acceptable salt thereof, wherein R 2 and R 3 , together with the carbon atom to which they are attached form a 3-8 membered carbocyclic or heterocyclic ring.
9. The compound of claim 1 , or the pharmaceutically acceptable salt thereof, wherein the compound of Formula (I-63) is selected from the group consisting of a compound of Formula (I-A63), Formula (I-B63), and Formula (I-C63):
10. A compound of Formula (I-67):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is alkyl;
each of R 2 and R 3 is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, or
R 2 and R 3 , together with the carbon atom to which they are attached form a 3-8 membered ring;
each of R 4 and R 5 is independently hydrogen, halo, or —OR C , wherein R C is hydrogen or C 1 -C 6 alkyl, or
R 4 and R 5 , together with the carbon atom to which they are attached form an oxo group;
R 6 is absent or hydrogen; and
represents a single or double bond, wherein when one of is a double bond, the other is a single bond and R 6 is absent; and wherein when both of are single bonds, R 6 is hydrogen.
11. The compound of claim 10 , or the pharmaceutically acceptable salt thereof, wherein each of R 2 and R 3 is independently hydrogen or alkyl.
12. The compound of claim 10 , or the pharmaceutically acceptable salt thereof, wherein each of R 2 and R 3 is independently hydrogen or C 1 -C 6 haloalkyl.
13. The compound of claim 10 , or the pharmaceutically acceptable salt thereof, wherein the compound of Formula (I-67) is selected from the group consisting of a compound of Formula (I-A67), Formula (I-B67), and Formula (I-C67):
14. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
15. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
16. A method for treating a disorder, the method comprising administering to a subject in need thereof an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the disorder is a gastrointestinal (GI) disorder, a structural disorder affecting the GI system, an anal disorder, a colon polyp, cancer, diabetes, a sterol synthesis disorder, or colitis.
17. The method according to claim 16 , wherein the disorder is a gastrointestinal (GI) disorder, wherein the gastrointestinal (GI) disorder is inflammatory bowel disease.
18. A method for treating a central nervous system (CNS)-related condition, the method comprising administering to a subject in need thereof an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the CNS-related condition is an adjustment disorder, an anxiety disorder, a cognitive disorder, a dissociative disorder, an eating disorder, a mood disorder, a psychotic disorder, a sleep disorder, a substance-related disorder, a personality disorder, an autism spectrum disorder, a neurodevelopmental disorder, multiple sclerosis, a sterol synthesis disorder, pain, encephalopathy secondary to a medical condition, attention deficit disorder, attention deficit hyperactivity disorder, a seizure disorder, stroke, traumatic brain injury, a movement disorder, vision impairment, hearing loss, or tinnitus.
19. The method according to claim 18 , wherein the CNS-related condition is an anxiety disorder, wherein the anxiety disorder is obsessive-compulsive disorder, posttraumatic stress disorder, or social phobia.
20. The method according to claim 18 , wherein the CNS-related condition is a psychotic disorder, wherein the psychotic disorder is schizophrenia.
21. The method according to claim 18 , wherein the CNS-related condition is an autism spectrum disorder.
22. The method according to claim 18 , wherein the CNS-related condition is attention deficit disorder or attention deficit hyperactivity disorder.
23. The method according to claim 18 , wherein the CNS-related condition is a movement disorder, wherein the movement disorder is Huntington's disease or Parkinson's disease.
24. The method according to claim 18 , wherein the CNS-related condition is a cognitive disorder, wherein the cognitive disorder is Alzheimer's disease.
25. A method for modulating an NMDA receptor, the method comprising contacting the NMDA receptor with an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof.