Compositions and methods for treating cns disorders

Abstract

Described herein are neuroactive steroids of the Formula (II): or a pharmaceutically acceptable salt thereof; wherein A, R 1 , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5 , R 6 and are as defined herein. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. The present invention also provides pharmaceutical compositions comprising a compound of the present invention and methods of use and treatment, e. g., such for inducing sedation and/or anesthesia.

We claim: 
     
         1 - 64 . (canceled) 
     
     
         65 . A method for treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (II), 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein: 
         Ring A is substituted or unsubstituted aryl or heteroaryl, wherein A is linked through a carbon atom; 
         R 1  is hydrogen, or substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, or substituted or unsubstituted C 3-6  carbocyclyl; 
         each of R 2a  and R 2b  is independently selected from hydrogen, halogen, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, substituted or unsubstituted C 3-6  carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(R A )(R B ), or —OR A2 , wherein each of R A  and R B  is independently hydrogen, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, substituted or unsubstituted C 3-6  carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R A  and R B , together with the nitrogen atom to which they are attached form a ring, or R 2a  and R 2b , together with the carbon atom to which they are attached form a ring; R A2  is hydrogen or substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, substituted or unsubstituted C 3-6  carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         R 3a  is hydrogen, —N(R A )(R B ), or —OR A3 , wherein R A3  is hydrogen, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, or substituted or unsubstituted C 3-6  carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and 
         R 3b  is hydrogen or —N(R A )C(O)R A3 ; or 
         R 3a  and R 3b  are joined to form an oxo (═O) group; 
         each of R 4a  and R 4b  is independently selected from hydrogen or halogen; 
         R 5  is hydrogen, unsubstituted C 1-6  alkyl, or —CH 2 OR A5 , wherein R A5  is hydrogen, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, or substituted or unsubstituted C 3-6  carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; 
         R 6  is absent or hydrogen; and 
            represents a single or double bond, wherein 
         when one of   is a double bond, the other   is a single bond; and 
         when one of the   is a double bond, R 6  is absent. 
       
     
     
         66 . A method for treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein: 
         Ring A is substituted or unsubstituted aryl or heteroaryl, wherein A is linked through a carbon atom; 
         R 1  is hydrogen, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl, or substituted or unsubstituted C 3-6  carbocyclyl; 
         R 2  is hydrogen, halogen, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, substituted or unsubstituted C 3-6  carbocyclyl, —N(R A )(R B ), or —OR A2 , wherein each of R A  and R B  is independently hydrogen, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, substituted or unsubstituted C 3-6  carbocyclyl, or substituted or unsubstituted heterocyclyl, or R A  and R B , together with the nitrogen atom to which they are attached form a ring; R A2  is hydrogen or substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, or substituted or unsubstituted C 3-6  carbocyclyl; 
         R 3a  is hydrogen, —N(R A )(R B ), or —OR A3 , wherein R A3  is hydrogen, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, or substituted or unsubstituted C 3-6  carbocyclyl, and R 3b  is hydrogen or —N(R A )C(O)R A3 ; or 
         R 3a  and R 3b  are joined to form an oxo (═O) group; 
         R 4  is hydrogen or halogen; 
         R 5  is hydrogen, unsubstituted C 1-6  alkyl, or —CH 2 OR A5 , wherein R A5  is hydrogen, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, or substituted or unsubstituted C 3-6  carbocyclyl; 
         R 6  is absent or hydrogen; and 
            represents a single or double bond, wherein
 when one of   is a double bond, the other   is a single bond; and 
 when one of the   is a double bond, R 6  is absent. 
 
       
     
     
         67 . The method of  claim 66 , wherein the compound of Formula (I) is a compound of Formula (I-a): 
       
         
           
           
               
               
           
         
         wherein: 
         n is 0, 1, 2, 3, 4, 5, or 6; and 
         each R a  is independently halogen, cyano, C 1-6  alkyl, —N(R A )(R B ), —N(R A )C(O)R AA , —N(R A )C(O)OR AA , —SR AA  or —OR AA , wherein R AA  is hydrogen, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, substituted or unsubstituted C 3-6  carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or 
         two R a  groups, together with the atoms with which they are attached form a ring. 
       
     
     
         68 . The method of  claim 66 , wherein the compound of Formula (I) is a compound of Formula (I-b): 
       
         
           
           
               
               
           
         
         wherein: 
         n is 0, 1, 2, 3, 4, 5, or 6; and 
         each R a  is independently halogen, cyano, C 1-6  alkyl, —N(R A )(R B ), —N(R A )C(O)R AA , —N(R A )C(O)OR AA , —SR AA  or —OR AA , wherein R AA  is hydrogen, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, substituted or unsubstituted C 3-6  carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or 
         two R a  groups, together with the atoms with which they are attached form a ring. 
       
     
     
         69 . The method of  claim 68 , wherein the compound of Formula (I-b) is a compound of Formula (I-b-i) or (I-b-ii): 
       
         
           
           
               
               
           
         
       
     
     
         70 . The method of  claim 66 , wherein the compound of Formula (I) is a compound of Formula (I-c): 
       
         
           
           
               
               
           
         
         wherein: 
         n is 0, 1, 2, 3, 4, 5, or 6; and 
         each R a  is independently halogen, cyano, C 1-6  alkyl, —N(R A )(R B ), —N(R A )C(O)R AA , —N(R A )C(O)OR AA , —SR AA  or —OR AA , wherein R AA  is hydrogen, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, substituted or unsubstituted C 3-6  carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or 
         two R a  groups, together with the atoms with which they are attached form a ring. 
       
     
     
         71 . The method of  claim 70 , wherein the compound of Formula (I-c) is a compound of Formula (I-c-i) or (I-c-ii): 
       
         
           
           
               
               
           
         
       
     
     
         72 . The method of  claim 66 , wherein the compound of Formula (I) is a compound of Formula (I-d): 
       
         
           
           
               
               
           
         
         wherein: 
         n is 0, 1, 2, 3, 4, 5, or 6; and 
         each R a  is independently halogen, cyano, C 1-6  alkyl, —N(R A )(R B ), —N(R A )C(O)R AA , —N(R A )C(O)OR AA , —SR AA  or —OR AA , wherein R AA  is hydrogen, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, substituted or unsubstituted C 3-6  carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or 
         two R a  groups, together with the atoms with which they are attached form a ring. 
       
     
     
         73 . The method of  claim 72 , wherein the compound of Formula (I-d) is a compound of Formula (I-d-i) or (I-d-ii): 
       
         
           
           
               
               
           
         
       
     
     
         74 . The method of  claim 66 , wherein A is a 5-10-membered ring. 
     
     
         75 . The compound of  claim 74 , wherein A is phenyl, naphthyl, furan, thiophene, thiazole, pyrrole, imidazole, pyrazole, or triazole. 
     
     
         76 . The method of  claim 66 , wherein the compound is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         77 . The method of  claim 65 , wherein the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory, a disorder of cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder, a substance abuse withdrawal syndrome, a neurodegenerative disorder, or tinnitus. 
     
     
         78 . The method of  claim 77 , wherein the CNS-related disorder is tremor. 
     
     
         79 . The method of  claim 78 , wherein the tremor is essential tremor. 
     
     
         80 . The method of  claim 66 , wherein the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory, a disorder of cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder, a substance abuse withdrawal syndrome, a neurodegenerative disorder, or tinnitus. 
     
     
         81 . The method of  claim 80 , wherein the CNS-related disorder is tremor. 
     
     
         82 . The method of  claim 81 , wherein the tremor is essential tremor.