Oxysterols and methods of use thereof

Abstract

Compounds are provided according to Formula (I): Formula (I) and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, wherein R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , and n 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 C 1-6  alkyl; 
 each of R 2  and R 3  is independently hydrogen, halogen, C 1-6  alkyl, or carbocyclyl; or 
 R 2  and R 3 , together with the carbon atom to which they are attached, form a 3-8 membered ring; 
 R 6  is absent or hydrogen; 
 each of R 7  and R 8  is independently hydrogen, halogen, C 1-6  alkyl, or carbocyclyl; 
 
       or
 each of R 7  and R 8 , together with the carbon atom to which they are attached, form a 3-8 membered ring; or 
 R 2  and R 7 , together with the carbon atoms to which they are attached, form a 3-8 membered ring; 
 n is 1, 2, or 3; and 
    represents a single or double bond, wherein when one   is a double bond, the other   is a single bond; and when one of the   is a double bond, R 6  is absent. 
 
     
     
         2 . (canceled) 
     
     
         3 . The compound of  claim 1 , wherein R 1  is methyl, substituted alkyl, ethyl, or isopropyl. 
     
     
         4 . The compound of  claim 3 , wherein R 1  is methyl or ethyl. 
     
     
         5 . The compound of  claim 1 , wherein each of R 2  and R 3  is independently hydrogen, C 1-6  alkyl, or carbocyclyl, or wherein R 2  and R 3  are taken together with the carbon atom to which they are attached form a 3-8 membered ring. 
     
     
         6 . The compound of  claim 5 , wherein the 3-8 membered ring is a carbocyclyl ring. 
     
     
         7 . The compound of  claim 5 , wherein each of R 2  and R 3  is independently hydrogen, C 1-6  alkyl, or carbocyclyl. 
     
     
         8 . The compound of  claim 7 , wherein each of R 2  and R 3  is independently hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, propyl, isopropyl, cyclopropyl, or butyl. 
     
     
         9 . The compound of  claim 7 , wherein R 2  is hydrogen, substituted or unsubstituted methyl, or ethyl. 
     
     
         10 . The compound of  claim 7 , wherein R 3  is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, propyl, isopropyl, cyclopropyl, or butyl. 
     
     
         11 . The compound of  claim 7 , wherein R 2  is hydrogen and R 3  is C 1-6  alkyl. 
     
     
         12 . The compound of  claim 7 , wherein R 2  is C 1-6  alkyl and R 3  is C 1-6  alkyl. 
     
     
         13 . (canceled) 
     
     
         14 . The compound of  claim 1 , wherein R 7  and R 8  are hydrogen. 
     
     
         15 . The compound of  claim 1 , wherein n is 1. 
     
     
         16 . The compound of  claim 1 , wherein n is 1 and R 7  and R 8  are hydrogen. 
     
     
         17 . The compound of  claim 1 , wherein the compound Formula (I) is a compound of Formula (II): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         18 . The compound of  claim 17 , wherein the compound of Formula (I) is a compound of Formula (II-A) or Formula (II-B): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         19 . The compound of  claim 17 , wherein the compound of Formula (I) is a compound of Formula (II-B-i) or Formula (II-B-ii): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         20 . The compound of  claim 17 , wherein the compound of Formula (I) is a compound of Formula (II-B-iii): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         21 . The compound of  claim 1 , wherein the compound of Formula (I) is a compound of Formula (III): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         22 . The compound of  claim 21 , wherein the compound of Formula (III) is a compound of Formula (III-A) or Formula (III-B): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         23 . The compound of  claim 21 , wherein the compound of Formula (III-B) is a compound of Formula (III-C) or Formula (III-D): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         24 . The compound of  claim 21 , wherein the compound of Formula (III-A) is a compound of Formula (III-E) or Formula (III-F): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         25 . The compound of  claim 21 , wherein the compound of Formula (III) is a compound of Formula (III-A-i-a) or Formula (III-B-i-a): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         26 . The compound of  claim 25 , wherein R 1  is substituted or unsubstituted methyl, ethyl, or isopropyl. 
     
     
         27 . The compound of  claim 21 , wherein each of R 2  and R 3  is independently hydrogen, C 1-6  alkyl, or carbocyclyl, or wherein R 2  and R 3  are taken together with the carbon atom to which they are attached form a 3-8 membered ring. 
     
     
         28 . The compound of  claim 27 , wherein each of R 2  and R 3  is independently hydrogen, C 1-6  alkyl, or carbocyclyl. 
     
     
         29 . The compound of  claim 28 , wherein each of R 2  and R 3  is independently hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, propyl, isopropyl, cyclopropyl, or butyl. 
     
     
         30 . The compound of  claim 29 , wherein R 2  is hydrogen, substituted or unsubstituted methyl, or ethyl. 
     
     
         31 . The compound of  claim 27 , wherein R 3  is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, propyl, isopropyl, cyclopropyl, or butyl. 
     
     
         32 . The compound of  claim 21 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         33 . The compound of  claim 1 , wherein the compound of Formula (I) is a compound of Formula (IV): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         34 . The compound of  claim 33 , wherein R 1  is substituted or unsubstituted methyl, ethyl, or isopropyl. 
     
     
         35 . The compound of  claim 33 , wherein each of R 2  and R 3  is independently hydrogen, C 1-6  alkyl, or carbocyclyl, or wherein R 2  and R 3  are taken together with the carbon atom to which they are attached form a 3-8 membered ring. 
     
     
         36 . The compound of  claim 35 , wherein each of R 2  and R 3  is independently hydrogen, C 1-6  alkyl, or carbocyclyl. 
     
     
         37 . The compound of  claim 36 , wherein each of R 2  and R 3  is independently hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, propyl, isopropyl, cyclopropyl, or butyl. 
     
     
         38 . The compound of  claim 37 , wherein R 2  is hydrogen, substituted or unsubstituted methyl, or ethyl. 
     
     
         39 . The compound of  claim 36 , wherein R 3  is substituted or unsubstituted methyl, substituted or unsubstituted ethyl, propyl, isopropyl, cyclopropyl, butyl. 
     
     
         40 . The compound of  claim 33 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         41 . The compound of  claim 1 , wherein the compound Formula (I) is a compound of Formula (V): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         42 . The compound of  claim 17 , wherein the compound of Formula (I) is a compound of Formula (V-A): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         43 . The compound of  claim 1 , wherein the compound of Formula (I) is a compound of Formula (V-B): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         44 . The compound of  claim 21 , wherein the compound of Formula (III) is a compound of Formula (V-C) or Formula (V-D): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         45 . The compound of  claim 1 , wherein the compound of Formula (I) is a compound of Formula (V-E-i): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         46 . The compound of  claim 1 , wherein the compound of Formula (I) is a compound of Formula (V-E-ii) or (V-E-iii): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         47 . The compound of  claim 1 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         48 . A pharmaceutical composition comprising a compound of  claim 1 , or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         49 . A method of inducing sedation or anesthesia comprising administering to a subject an effective amount of a compound of  claim 1 , or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof. 
     
     
         50 . (canceled) 
     
     
         51 . A method of treating or preventing a disorder, comprising administering to a subject in need thereof an effective amount of a compound of  claim 1 , or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the disorder is a gastrointestinal (GI) disorder, constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), structural disorders affecting the GI, anal disorders, colon polyps, cancer, colitis. 
     
     
         52 .- 54 . (canceled) 
     
     
         55 . A method for treating or preventing a CNS-related condition comprising administering to a subject in need thereof an effective amount of a compound of  claim 1 , or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof. 
     
     
         56 . The method according to  claim 55 , wherein the CNS-related condition is an adjustment disorder, anxiety disorder, obsessive-compulsive disorder, posttraumatic stress disorder, and social phobia, cognitive disorder, Alzheimer's disease and other forms of dementia, dissociative disorder, eating disorder, mood disorder, depression, postpartum depression, bipolar disorder, dysthymic disorder, suicidality, schizophrenia or other psychotic disorder, schizoaffective disorder, sleep disorder, insomnia, substance-related disorder, personality disorder, obsessive-compulsive personality disorder, autism spectrum disorders, autism spectrum disorders involving mutations to the Shank group of proteins, neurodevelopmental disorder, Rett syndrome, Tuberous Sclerosis complex, multiple sclerosis, sterol synthesis disorders, pain, acute pain, chronic pain, encephalopathy secondary to a medical condition, hepatic encephalopathy, anti-NMDA receptor encephalitis, seizure disorder, status epilepticus, monogenic forms of epilepsy such as Dravet's disease, stroke, traumatic brain injury, movement disorder, Huntington's disease, Parkinson's disease, vision impairment, hearing loss, and tinnitus. 
     
     
         57 . (canceled)