Oxysterols and methods of use thereof

Abstract

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 2  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 ring (e.g., a 3-7-membered ring, e.g., a 5-7-membered ring; a ring containing at least one heteroatom, e.g., a nitrogen, oxygen, or sulfur atom); 
 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 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 ring (e.g., a 3-6-membered ring, e.g. a 4-6-membered ring containing one heteroatom); or 
 R 5a  and R 6a , together with the carbon atoms to which they are attached, form a ring (e.g., a 3-6-membered ring, e.g. a 4-6-membered ring containing one heteroatom); 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 ring (e.g., a 3-7-membered ring, e.g., a 5-7-membered ring; a ring containing at least one heteroatom, e.g., a nitrogen, oxygen, or sulfur atom); and 
 R D  is hydrogen, C 1 -C 6  alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl. 
 
     
     
         2 . The compound of  claim 1 , or the pharmaceutically
 acceptable salt thereof, wherein:   a. R 1  is unsubstituted C 1-3  alkyl;   b. R 1  is —CH 3 , —CH 2 CH 3 , or —CH 2 CH 2 CH 3 ;   c. R 1  is substituted C 1-3  alkyl; or   d. R 1  is haloalkyl (e.g., —CF 3 ) or —CH 2 OCH 3 .   
     
     
         3 - 5 . (canceled) 
     
     
         6 . The compound of  claim 1 , or the pharmaceutically acceptable salt thereof, wherein:
 a. R 2a  or R 2b  is hydrogen; or   b. R 2a  and R 2b  are both hydrogen.   
     
     
         7 . (canceled) 
     
     
         8 . The compound of  claim 1 , or the pharmaceutically acceptable salt thereof, wherein R 4a  is hydrogen. 
     
     
         9 . The compound of  claim 1 , or the pharmaceutically acceptable salt thereof, wherein X is —CH 2 —. 
     
     
         10 . The compound of  claim 1 , or the pharmaceutically acceptable salt thereof, wherein:
 a. R is substituted or unsubstituted C 1-3  alkyl; or   b. R 8  is —CH 3 .   
     
     
         11 . (canceled) 
     
     
         12 . The compound of  claim 1 , or the pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is a compound of Formula (II): 
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound of  claim 12 , or the pharmaceutically acceptable salt thereof, wherein the compound of Formula (II) is a compound of Formula (II-A): 
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound of  claim 12 , or the pharmaceutically acceptable salt thereof, wherein the compound of Formula (II) is a compound of Formula (II-B): 
       
         
           
           
               
               
           
         
       
     
     
         15 . The compound of  claim 1 , or the pharmaceutically acceptable salt thereof, wherein:
 a R 5a  or R 5b  is hydrogen; or   b. R 5a  and R 5b  are both hydrogen.   
     
     
         16 . (canceled) 
     
     
         17 . The compound of  claim 1 , or the pharmaceutically acceptable salt thereof, wherein:
 a. R 6a  is a substituted or unsubstituted C 1-3  alkyl;   b. R 6a  is —CH 3  or —CH 2 CH 3 ; or   c. 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.   
     
     
         18 .- 19 . (canceled) 
     
     
         20 . The compound of  claim 1 , or the pharmaceutically acceptable salt thereof, wherein:
 a. R 6b  is substituted or unsubstituted C 1-3  alkyl;   b. R 6b  is —CH 3  or —CH 2 CH 3 ;   c. R 6b  is hydrogen; or   d. R 6b  is —CH 3  or —CF 3 .   
     
     
         21 .- 23 . (canceled) 
     
     
         24 . The compound of  claim 1 , or the pharmaceutically acceptable salt thereof, wherein:
 a. R 6a  and R 6b  are both —CH 3 ;   b. R 6a  and R 6b , taken together with the atom to which they are attached, form a ring; or   c. R 6a  and R 6b , taken together with the atom to which they are attached, form a 3-membered ring.   
     
     
         25 .- 26 . (canceled) 
     
     
         27 . The compound of  claim 1 , or the pharmaceutically acceptable salt thereof, wherein R 1  is hydrogen or C 1-3  alkyl, R 6a  is substituted or unsubstituted C 1-3  alkyl, substituted or unsubstituted C 2-3  alkenyl, substituted or unsubstituted C 2-3  alkynyl, or substituted or unsubstituted carbocyclyl, and R 6b  is —CH 3 . 
     
     
         28 . The compound of  claim 27 , or the pharmaceutically acceptable salt thereof, wherein:
 a. R 6a  is selected from the group consisting of substituted or unsubstituted C 1-3  alkyl, unsubstituted C 2-3  alkenyl, unsubstituted C 2-3  alkynyl, or unsubstituted carbocyclyl; or   b. R 6a  is selected from a substituted or unsubstituted C 1-3  alkyl.   
     
     
         29 . (canceled) 
     
     
         30 . The compound of  claim 1 , or the pharmaceutically acceptable salt thereof, wherein R 1  is —CH 3  or —CH 2 CH 3  and R 6b  is —CH 3  or —CF 3 . 
     
     
         31 . The compound of  claim 1 , or the pharmaceutically acceptable salt thereof, wherein:
 a. R Y  is substituted or unsubstituted C 1-3  alkyl;   b. R Y  is substituted or unsubstituted heterocyclyl;   c. R is —CH 3 ; or   d. R Y  is —CF 3 .   
     
     
         32 .- 34 . (canceled) 
     
     
         35 . The compound of  claim 1 , or the pharmaceutically acceptable salt thereof, wherein the compound is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         36 . A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof according to  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         37 . A method of inducing sedation or anesthesia comprising administering to a subject an effective amount of a compound or pharmaceutically acceptable salt thereof according to  claim 1 , or pharmaceutical composition thereof. 
     
     
         38 . A method for treating or preventing a disorder, comprising administering to a subject in need thereof an effective amount of a compound of or pharmaceutically acceptable salt thereof according to  claim 1 , or pharmaceutical composition thereof;
 wherein the disorder is selected from the group consisting of a gastrointestinal (GI) disorder, inflammatory bowel disease (IBD), a structural disorder affecting the GI, an anal disorder, a colon polyp, cancer, diabetes, a sterol synthesis disorder, and colitis.   
     
     
         39 .- 41 . (canceled) 
     
     
         42 . 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 1 , or pharmaceutical composition thereof. 
     
     
         43 . The method according to  claim 42 , wherein the CNS-related condition is an adjustment disorder, anxiety disorder, cognitive disorder, dissociative disorder, eating disorder, mood disorder, schizophrenia or other psychotic disorder, disorder, substance-related disorder, personality disorder, autism spectrum disorders, neurodevelopmental disorder, multiple sclerosis, sterol synthesis disorders, pain, encephalopathy secondary to a medical condition, seizure disorder, stroke, traumatic brain injury, movement disorder, vision impairment, hearing loss, and tinnitus. 
     
     
         44 . (canceled)