OXYSTEROLS AND METHODS OF USE THEREOF
Compounds are provided according to Formula (I) and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5 , 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 . (canceled)
2 . A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen or substituted or unsubstituted C 1-6 alkyl;
each of R 2 and R 3 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, 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 or a moiety cleavable under biological conditions;
R 8 is absent or hydrogen; and
represents a single or double bond, wherein when one is a double bond, the other is a single bond and R 8 is absent.
3 . The compound or pharmaceutically acceptable salt thereof, of claim 2 , wherein R 4 and R 5 are not both hydrogen.
4 .- 5 . (canceled)
6 . The compound or pharmaceutically acceptable salt thereof, of claim 2 , wherein each of R 4 and R 5 is independently hydrogen, —P(O)(R a ) 2 , —S(O) x R b , —C(O)R c , —C(O)OR c , —C(O)N(R d ) 2 , —(CH 2 ) x C(O)N(R d ) 2 , —(CH 2 ) n OP(O)(R a ) 2 , —(CH 2 ) m OS(O) x R b , —(CH 2 ) p OC(O)R c , or —(CH 2 ) p C(O)OR c ;
each of R a and R b is independently selected from —OR d or substituted or unsubstituted alkyl;
each R c is independently substituted or unsubstituted alkyl;
each R d is independently hydrogen or substituted or unsubstituted alkyl;
each x is independently 1 or 2; and
each of n, m, p is independently 1, 2, 3, or 4.
7 . (canceled)
8 . The compound or pharmaceutically acceptable salt thereof, of claim 2 , wherein R 1 is substituted or unsubstituted C 1-6 alkyl.
9 . The compound or pharmaceutically acceptable salt thereof, of claim 2 , wherein R 1 is hydrogen.
10 .- 11 . (canceled)
12 . The compound or pharmaceutically acceptable salt thereof, of claim 2 , wherein each of R 2 and R 3 is independently hydrogen, methyl, —CF 3 , ethyl, isopropyl, cyclopropyl, or butyl.
13 . The compound or pharmaceutically acceptable salt thereof, of claim 2 , wherein R 4 is a moiety cleavable under biological conditions and R 5 is hydrogen.
14 . The compound or pharmaceutically acceptable salt thereof, of claim 2 , wherein R 4 is hydrogen and R 5 is a moiety cleavable under biological conditions.
15 . The compound or pharmaceutically acceptable salt thereof, of claim 2 , wherein each of R 4 and R 5 is a moiety cleavable under biological conditions.
16 . The compound or pharmaceutically acceptable salt thereof, of claim 2 , wherein:
each of R 4 and R 5 is independently hydrogen, —P(O)(R a ) 2 , —S(O) x R b , —C(O)R c , —C(O)OR c , —C(O)N(R d ) 2 , —(CH 2 ) x C(O)N(R d ) 2 , —(CH 2 ) n OP(O)(R a ) 2 , —(CH 2 ) m OS(O) x R b , —(CH 2 ) p OC(O)R c , or —(CH 2 ) p C(O)OR c ;
each of R a and R b is independently selected from —OR d or substituted or unsubstituted alkyl;
each R c is independently substituted or unsubstituted alkyl;
each R d is independently hydrogen or substituted or unsubstituted alkyl;
each x is independently 1 or 2; and
each of n, m, p is independently 1, 2, 3, or 4.
17 . The compound or pharmaceutically acceptable salt thereof, of claim 16 , wherein when R 4 is hydrogen and R 5 is —S(O) x R b and x is 2, R b is not —OH.
18 . The compound or pharmaceutically acceptable salt thereof, of claim 16 , wherein not both of R 4 or R 5 are hydrogen.
19 . The compound or pharmaceutically acceptable salt thereof, of claim 2 , wherein R 4 is —P(O)(R a ) 2 , —S(O) x R b , —C(O)R c , —C(O)OR c , —C(O)N(R d ) 2 , —(CH 2 ) x C(O)N(R d ) 2 , —(CH 2 ) n OP(O)(R a ) 2 , —(CH 2 ) m OS(O) x R b , —(CH 2 ) p OC(O)R c , or —(CH 2 ) p C(O)OR c ;
R 5 is hydrogen;
each of R a and R b is independently selected from —OR d or substituted or unsubstituted alkyl;
each R c is independently substituted or unsubstituted alkyl;
each R d is independently hydrogen or substituted or unsubstituted alkyl;
each x is independently 1 or 2; and
each of n, m, p is independently 1, 2, 3, or 4.
20 . The compound or pharmaceutically acceptable salt thereof, of claim 2 , wherein R 4 is hydrogen;
R 5 is —P(O)(R a ) 2 , —S(O) x R b , —C(O)R c , —C(O)OR c , —C(O)N(R d ) 2 , —(CH 2 ) x C(O)N(R d ) 2 , —(CH 2 ) n OP(O)(R a ) 2 , —(CH 2 ) m OS(O) x R b , —(CH 2 ) p OC(O)R c , or —(CH 2 ) p C(O)OR c ;
each of R a and R b is independently selected from —OR d or substituted or unsubstituted alkyl;
each R c is independently substituted or unsubstituted alkyl;
each R d is independently hydrogen or substituted or unsubstituted alkyl;
each x is independently 1 or 2;
each of n, m, p is independently 1, 2, 3, or 4; wherein when R 5 is —S(O) x R b and x is 2, R b is not —OH.
21 . The compound or pharmaceutically acceptable salt thereof, of claim 18 , wherein R 4 is —P(O)(R a ) 2 , —S(O) x R b , —C(O)R c , —C(O)N(R d ) 2 , —(CH 2 ) x C(O)N(R d ) 2 , —(CH 2 ) n OP(O)(R a ) 2 , —(CH 2 ) m OS(O) x R b , or —(CH 2 ) p OC(O)R c .
22 . The compound or pharmaceutically acceptable salt thereof, of claim 21 , wherein each of R a and R b is independently —OR d , R d is hydrogen or substituted or unsubstituted alkyl, and x is 2.
23 . The compound of claim 21 , wherein R c is substituted or unsubstituted alkyl; and R d is hydrogen or substituted or unsubstituted alkyl.
24 . The compound or pharmaceutically acceptable salt thereof, of claim 21 , wherein R c is —CH 2 NH 2 , —CH 2 CH 2 CO 2 H, —CH(CH(CH 3 ) 2 )NH 2 , —CH 2 CH 2 C(O)OH, or —CH(CH 3 )NH 2 .
25 . The compound or pharmaceutically acceptable salt thereof, of claim 21 , wherein each of n, m, and p is independently 1 or 2.
26 . The compound or pharmaceutically acceptable salt thereof, of claim 21 , wherein R 4 is hydrogen, —P(O) 2 OH, —S(O) 2 OH, —CH 2 OP(O)(OH) 2 , —C(O)CH 3 , —C(O)CH 2 NH 2 , —C(O)CH 2 CH 2 C(O)OH, —C(O)CH(CH(CH 3 ) 2 )NH 2 , —C(O)CH(CH 3 )NH 2 , or any amino acid residue.
27 . The compound or pharmaceutically acceptable salt thereof, of claim 16 , wherein R 5 is —P(O)(R a ) 2 , —S(O) x R b , —C(O)R c , —C(O)N(R d ) 2 , —(CH 2 ) x C(O)N(R d ) 2 , —(CH 2 ) n OP(O)(R a ) 2 , —(CH 2 ) m OS(O) x R b , or —(CH 2 ) p OC(O)R c .
28 . The compound or pharmaceutically acceptable salt thereof, of claim 27 , wherein each of R a and R b is independently —OR d , R d is hydrogen or substituted or unsubstituted alkyl, and x is 2.
29 . The compound or pharmaceutically acceptable salt thereof, of claim 27 , wherein R c is substituted or unsubstituted alkyl; and R d is hydrogen or substituted or unsubstituted alkyl.
30 . The compound or pharmaceutically acceptable salt thereof, of claim 27 , wherein each of n, m, and p is independently 1 or 2.
31 . The compound or pharmaceutically acceptable salt thereof, of claim 27 , wherein R 5 is hydrogen, —P(O) 2 OH, —S(O) 2 OH, —CH 2 OP(O)(OH) 2 , —C(O)CH 3 , —C(O)CH 2 NH 2 , —C(O)CH 2 CH 2 C(O)OH, —C(O)CH(CH(CH 3 ) 2 )NH 2 , —C(O)CH(CH 3 )NH 2 , or any amino acid residue.
32 . The compound or pharmaceutically acceptable salt thereof, of claim 2 , wherein when R 4 is hydrogen, R 5 is not —S(O) 2 OH.
33 . The compound or pharmaceutically acceptable salt thereof, of claim 2 , wherein each of is a singe bond.
34 . The compound or pharmaceutically acceptable salt thereof, of claim 2 , wherein the compound of Formula (I) is a compound of Formula (I-A) or Formula (I-B):
or a pharmaceutically acceptable salt thereof.
35 - 63 . (canceled)
64 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
65 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
66 . A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to claim 2 , and a pharmaceutically acceptable carrier.
67 . A method of inducing sedation or anesthesia comprising administering to a subject an effective amount of a compound or a pharmaceutically acceptable salt thereof according to claim 2 , or pharmaceutical composition thereof.
68 . A method for treating or preventing a disease or disorder, comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable salt thereof according to claim 2 , or pharmaceutical composition thereof, wherein the disease or disorder is selected from the group consisting of a gastrointestinal (GI) disorder, inflammatory bowel disease (IBD), a structural disorder affecting the GL an anal disorder, a colon polyp, cancer, diabetes, a sterol synthesis disorder, and colitis.
69 - 71 . (canceled)
72 . A method for treating or preventing a CNS-related condition comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt thereof according to claim 2 , or pharmaceutical composition 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, schizophrenia or other 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, a seizure disorder, stroke, traumatic brain injury, a movement disorder, vision impairment, hearing loss, and tinnitus.
73 - 74 . (canceled)