19-NOR C3, 3-DISUBSTITUTED C21-C-BOUND HETEROARYL STEROIDS AND METHODS OF USE THEREOF

摘要

Provided herein are 19-nor C3,3-disubstituted steroids of Formula (I): and pharmaceutically acceptable salts thereof; wherein, , R1, R2, R3a, R3b, R4a, and R4b are as defined herein, and A is a carbon bound substituted or unsubstituted 5- to 6-membered heteroaryl ring as defined herein. Such compounds are contemplated useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, schizophrenia spectrum disorders, convulsive disorders, disorders of memory and/or cognition, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and/or withdrawal syndromes, and tinnitus.;

主权项

1. A steroid of Formula (I): or a pharmaceutically acceptable salt thereof;
represents a single or double bond;R1 is substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3-6carbocyclyl;R2 is hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3-6 carbocyclyl, or —ORA2, wherein RA2 is hydrogen or substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3-6carbocyclyl;R3a is hydrogen or —ORA3, wherein RA3 is hydrogen or substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3-6carbocyclyl, and R3b is hydrogen; or R3a and R3b are joined to form an oxo (═O) group;each instance of R4a and R4b is independently hydrogen, substituted or unsubstituted C1-6 alkyl, or halogen, provided if the between C5 and C6 is a single bond, then the hydrogen at C5 and R4a are each independently provided in the alpha or beta configuration, and R4b is absent;A is a carbon bound substituted or unsubstituted 5 or 6-membered heteroaryl, or 6-membered aryl of formula: X is —O—, —S—, or —N(RN)—, wherein RN is independently hydrogen, substituted or unsubstituted C1-6 alkyl, —C(═O)RGA, —C(═O)ORGA, —C(═O)N(RGA)2, —S(═O)2RGA, —S(═O)2ORGA, —S(═O)2N(RGA)2, or a nitrogen protecting group;each instance of R5, R6, R7, R8, and R9 is, independently, hydrogen, halogen, —NO2, —CN, —ORGA, —N(RGA)2, —C(═O)RGA, —C(═O)ORGA, —OC(═O)RGA, —OC(═O)ORGA, —C(═O)N(RGA)2, —N(RGA)C(═O)RGA, —OC(═O)N(RGA)2, —N(RGA)C(═O)ORGA, —N(RGA)C(═O)N(RGA)2, —S(═O)2RGA, —S(═O)2ORGA, —OS(═O)2RGA, —S(═O)2N(RGA)2, —N(RGA)S(═O)2RGA, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6carbocylyl, or substituted or unsubstituted 3- to 6-membered heterocylyl; andeach instance of RGA is independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6carbocylyl, substituted or unsubstituted 3- to 6-membered heterocylyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, nitrogen protecting group when attached to nitrogen, or two RGA groups are taken with the intervening atoms to form a substituted or unsubstituted heterocylyl or heteroaryl ring.