Oxysterols and methods of use thereof

Abstract

Compounds are provided according to Formula (I), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein A, R 1 , and R 5 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-A): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 A is carbocyclyl or heterocyclyl; 
 R 1  is C 1-6  alkyl; 
 R 5  is absent or hydrogen; 
    represents a single or double bond, wherein when one   is a double bond, then the other   is a single bond and R 5  is absent. 
 
       
     
     
         2 . A compound of Formula (I-B): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is hydrogen or C 1-6  alkyl; 
 R 5  is absent or hydrogen; 
 Z is —C(R A ) 2 —, —NR B —, —O—, or —S—; 
 X is halogen, C 1-6  alkyl, or —OR C ; 
 R A  is hydrogen, halogen, or C 1-6  alkyl; 
 R B  is hydrogen, C 1-6  alkyl, —C(O)R C , —C(O)OR C , —C(O)N(R D ) 2 , or —S(O) 2 R C ; 
 R C  is hydrogen or C 1-6  alkyl; 
 each R D  is independently hydrogen, C 1-6  alkyl, aryl, or heteroaryl; 
 m is an integer selected from 1, 2, and 3; 
 n is an integer selected from 1, 2, and 3; 
 p is an integer selected from 0, 1, 2, 3, 4, and 5; and 
   represents a single or double bond, wherein when one   is a double bond, then the other   is a single bond and R 5  is absent. 
 
       
     
     
         3 . The compound of  claim 2 , wherein the compound is a compound of Formula (II-A), Formula (II-B), or Formula (II-C): 
       
         
           
           
               
               
           
         
       
     
     
         4 - 7 . (canceled) 
     
     
         8 . The compound of  claim 3 , wherein the compound is of Formula (II-D), Formula (II-E), or Formula (II-F): 
       
         
           
           
               
               
           
         
       
     
     
         9 - 11 . (canceled) 
     
     
         12 . The compound of  claim 2 , wherein the compound is of Formula (II-G) or Formula (II-H): 
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound of  claim 2 , wherein the compound is of Formula (II-I) or Formula (II-J): 
       
         
           
           
               
               
           
         
       
     
     
         14 - 26 . (canceled) 
     
     
         27 . The compound of  claim 2 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         28 . A pharmaceutically acceptable salt of the compound of  claim 2 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         29 . A pharmaceutical composition comprising a compound according to  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         30 . A method of inducing sedation or anesthesia comprising administering to a subject an effective amount of a compound according to  claim 1  or pharmaceutical composition thereof. 
     
     
         31 . A method for treating or preventing a disorder described herein, comprising administering to a subject in need thereof an effective amount of a compound according to  claim 1  or pharmaceutical composition thereof. 
     
     
         32 . The method according to  claim 31 , wherein the disorder is a gastrointestinal (GI) disorder, structural disorders affecting the GI, anal disorders, colon polyps, cancer, colitis. 
     
     
         33 . The method according to  claim 31 , wherein the disorder is inflammatory bowel disease. 
     
     
         34 . The method according to  claim 31 , wherein the disorder is cancer, diabetes, or a sterol synthesis disorder. 
     
     
         35 . The method according to  claim 31 , wherein the disorder is a metabolic disorder. 
     
     
         36 . A method for treating or preventing a CNS-related condition comprising administering to a subject in need thereof an effective amount of a compound according to  claim 1  or pharmaceutical composition thereof. 
     
     
         37 - 38 . (canceled) 
     
     
         39 . A method for treating or preventing Smith-Lemli-Opitz Syndrome (SLOS), Desmosterolosis, Sitosterolemia, Cerebrotendinous xanthomatosis (CTX), Mevalonate Kinase Deficiency Syndromes (MKD), SC4MOL gene mutation (SMO Deficiency), Niemann-Pick disease, Autism Disorders Associated with Phenylketonuria, comprising administering to a subject in need thereof an effective amount of a compound according to  claim 1  or pharmaceutical composition thereof.