3,3 disubstituted 19-nor pregnane compounds, compositions, and uses thereof

Abstract

where R1, R2, R3, R3′, R4, R6a, R6a, R11a, and R11b areas defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, insomnia, anxiety, depression, traumatic brain injury (TBI), stress, and epilepsy.

What is claimed is: 
     
         1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; 
       wherein:
 R 1  is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR A1 , —SR A1 , —N(R A1 ) 2 , —OC(═O)R A1 , —OC(═O)OR A1 , —OC(═O)SR A1 , —OC(═O)N(R A1 ) 2 , —SC(═O)R A2 , —SC(═O)OR A1 , —SC(═O)SR A , —SC(═O)N(R A1 ) 2 , —NHC(═O)R A1 , —NHC(═O)OR A1 , —NHC(═O)SR A1 , —NHC(═O)N(R A1 ) 2 , —OS(═O) 2 R A2 , —OS(═O) 2 OR A1 , —S—S(═O) 2 R A2 , —S—S(═O) 2 OR A1 , —S(═O)R A2 , —SO 2 R A2 , or —S(═O) 2 OR A1 , wherein each instance of R A1  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R A1  groups are joined to form an substituted or unsubstituted heterocyclic or heteroaryl ring; and R A2  is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 2  is hydrogen, halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OH, —OR B1 , —OC(═O)R B1 , —NH 2 , —N(R B1 ) 2 , or —NR B1 C(═O)R B1 , wherein each instance of R B1  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R B1  groups are joined to form an substituted or unsubstituted heterocyclic ring; 
 R 3  is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 3′  is hydrogen, —C(═O)R C1 , —C(═O)OR C1 , —C(═O)SR C1 , —C(═O)N(R C1 ) 2 , —S(═O) 2 R C2 , —S(═O) 2 OR C1 , —P(═O) 2 R C2 , —P(═O) 2 OR C1 , —P(═O)(OR C1 ), —P(═O)(R C2 ) 2 , or —P(═O)(R C2 )(OR C1 ), wherein R C1  is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R C1  groups are joined to form an substituted or unsubstituted heterocyclic ring; and R C2  is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 4  is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; 
 each of R 6a  and R 6b  is independently hydrogen, halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, or R 6a  and R 6b  are joined to form an oxo (═O) group; 
 each of R 11a  and R 11b  is independently hydrogen, halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, —OH, —OR D1 , —OC(═O)R D1 , —NH 2 , —N(R D1 ) 2 , or —NR D IC(═O)R D1 , wherein each instance of R D1  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R D1  groups are joined to form an substituted or unsubstituted heterocyclic ring; or R 11a  and R 11b  are joined to form an oxo (═O) group; 
 wherein   represents a single or double bond, provided if a double bond is present in Ring B, then one of R 6a  or R 6b  is absent, and provided if a single bond is present in Ring B, then the hydrogen at C5 is in the alpha or beta position; 
 provided that the following compounds, and salts thereof, are specifically excluded: 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         2 . A compound of Formula (III): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; 
       wherein:
 R 1  is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR A1 , —SR A1 , —N(R A1 ) 2 , —OC(═O)R A1 , —OC(═O)OR A1 , —OC(═O)SR A1 , —OC(═O)N(R A1 ) 2 , —SC(═O)R A2 , —SC(═O)OR A1 , —SC(═O)SR A1 , —SC(═O)N(R A1 ) 2 , —NHC(═O)R A1 , —NHC(═O)OR A1 , —NHC(═O)SR A1 , —NHC(═O)N(R A1 ) 2 , —OS(═O) 2 R A2 , —OS(═O) 2 OR A1 , —S—S(═O) 2 R A2 , —S—S(═O) 2 OR A1 , —S(═O)R A2 , —SO 2 R A2 , or —S(═O) 2 OR A1 , wherein each instance of R A1  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R A1  groups are joined to form an substituted or unsubstituted heterocyclic or heteroaryl ring; and R A2  is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 2  is hydrogen, halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OH, —OR B1 , —OC(═O)R B1 , —NH 2 , —N(R B1 ) 2 , or —NR B C(═O)R B1 , wherein each instance of R B1  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R B1  groups are joined to form an substituted or unsubstituted heterocyclic ring; 
 R 3  is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 3′  is hydrogen, —C(═O)R C1 , —C(═O)OR C1 , —C(═O)SR C1 , —C(═O)N(R C1 ) 2 , —S(═O) 2 R C2 , —S(═O) 2 OR C1 , —P(═O) 2 R C2 , —P(═O) 2 OR C1 , —P(═O)(OR C1 ), —P(═O)(R C2 ) 2 , or —P(═O)(R C2 )(OR C1 ), wherein R C1  is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R C1  groups are joined to form an substituted or unsubstituted heterocyclic ring; and R C2  is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 4  is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; 
 each of R 6a  and R 6b  is independently hydrogen, halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, or R 6a  and R 6b  are joined to form an oxo (═O) group; 
 each of R 11a  and R 11b  is independently hydrogen, halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, —OH, —OR D1 , —OC(═O)R D1 , —NH 2 , —N(R D1 ) 2 , or —NR D1 C(═O)R D1 , wherein each instance of R D1  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R D1  groups are joined to form an substituted or unsubstituted heterocyclic ring; or R 11a  and R 11b  are joined to form an oxo (═O) group; 
 wherein   represents a single or double bond, provided if a double bond is present in Ring B, then one of R 6a  or R 6b  is absent, and provided if a single bond is present in Ring B, then the hydrogen at C5 is in the alpha or beta position; 
 
     
     
         3 . The compound of  claim 1 , wherein R 1  is hydrogen, halogen, —OR A1 , —SR A1 , —N(R A1 ) 2 , —OC(═O)R A1 , —OC(═O)OR A1 , —OC(═O)SR A1 , —OC(═O)N(R A1 ) 2 , —SC(═O)R A2 , —SC(═O)OR A1 , —SC(═O)SR A1 , —SC(═O)N(R A1 ) 2 , —NHC(═O)R A1 , —NHC(═O)OR A1 , —NHC(═O)SR A1 , —NHC(═O)N(R A1 ) 2 , —OS(═O) 2 R A2 , —OS(═O) 2 OR A1 , —S—S(═O) 2 R A2 , —S(═O) 2 OR A1 , —S(═O)R A2 , —SO 2 R A2 , or —S(═O) 2 OR A1 . 
     
     
         4 . The compound of  claim 1 , wherein R 1  is hydrogen, halogen, —OR A1 , —N(R A1 ) 2 , —S—S(═O) 2 R A2 , substituted or unsubstituted hetercyclyl, or substituted or unsubstituted heteroaryl. 
     
     
         5 . The compound of  claim 1 , wherein R 2  is hydrogen, substituted or unsubstituted heterocyclyl, —OH, —OR B1 , —OC(═O)R BI , —NH 2 , —N(R B1 ) 2 , or —NR B1 C(═O)R B1 . 
     
     
         6 . The compound of  claim 1 , wherein R 3  is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. 
     
     
         7 . The compound of  claim 1 , wherein R 3  is a group of formula: 
       
         
           
           
               
               
           
         
       
       wherein each instance of R 3a  is hydrogen, halo, or —ORF, wherein R F1  is substituted or unsubstituted alkyl; and each instance of R 3b  and R 3c  is independently hydrogen, halo, or substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl. 
     
     
         8 . The compound of  claim 1 , wherein R 3′  is hydrogen. 
     
     
         9 . The compound of  claim 1 , wherein R 4  is hydrogen. 
     
     
         10 . The compound of  claim 1 , wherein each of R 6a  and R 6b  is independently hydrogen, halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, or R 6a  and R 6b  are joined to form an oxo (═O) group. 
     
     
         11 . The compound of  claim 1 , wherein both R 6a  and R 6b  are hydrogen. 
     
     
         12 . The compound of  claim 1 , wherein one of R 6a  and R 6b  is a non-hydrogen group. 
     
     
         13 . The compound of  claim 1 , wherein R 6a  is a non-hydrogen alpha group. 
     
     
         14 . The compound of  claim 1 , wherein R 6a  is a non-hydrogen beta group. 
     
     
         15 . The compound of  claim 1 , wherein R 6a  is halo or alkyl and R 6b  is hydrogen. 
     
     
         16 . The compound of  claim 1 , wherein R 6a  and R 6b  are both halo. 
     
     
         17 . The compound of  claim 1 , wherein R 6a  and R 6b  are both alkyl. 
     
     
         18 . The compound of  claim 1 , wherein R 6a  and R 6b  are joined to form an oxo group. 
     
     
         19 . The compound of  claim 1 , wherein each of R 11a  and R 11b  is independently hydrogen, —OH, —OR D1 , —OC(═O)R D1 , —NH 2 , —N(R D1 ) 2 , or —NR D1 C(═O)R D1 , or R 11a  and R 11b  are joined to form an oxo (═O) group. 
     
     
         20 . The compound of  claim 1 , wherein both R 11a  and R 11b  are hydrogen. 
     
     
         21 . The compound of  claim 1 , wherein one of R 11a  and R 11b  is a non-hydrogen group. 
     
     
         22 . The compound of  claim 1 , wherein R 11a  and R 11b  are joined to form an oxo group 
     
     
         23 . The compound of  claim 1 , wherein the compound of Formula (I) is of the Formula (I-a1), (I-a2), or (I-a3): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         24 . The compound of  claim 2 , wherein the compound of Formula (III) is of the Formula (III-a1), (III-a2), or (III-a3): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         25 . The compound of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof. 
     
     
         26 . The compound of  claim 2 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof. 
     
     
         27 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of  claim 1 , or a pharmaceutically acceptable salt thereof.