19-NOR NEUROACTIVE STEROIDS AND METHODS OF USE THEREOF

摘要

Provided herein are 3,3-disubstituted 19-nor-steroidal compounds according to Formula (I): and pharmaceutical compositions thereof. 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, 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, tinnitus, status epilepticus.;

主权项

1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof; wherein: represents a single or double bond; R1 is substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3-6 carbocyclyl; R2 is hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3-6 carbocyclyl, or —ORA2, wherein RA2 is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3-6 carbocyclyl; R3a is hydrogen or —ORA3, wherein RA3 is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3-6 carbocyclyl, 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, alkoxy, halogen, or —ORA4, wherein RA4 is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3-6 carbocyclyl, provided if the between C5 and C6 is a single bond, then the hydrogen at C5 is in the alpha or beta configuration; and provided if the between C5 and C6 is a double bond, R4b is absent; A is one of the following formulae: each instance of R5 is, independently, 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, —S(═O)2RGA, —S(═O)2ORGA, —OS(═O)2RGA, —S(═O)2N(RGA)2, or —N(RGA)S(═O)2RGA; substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-4 carbocylyl, substituted or unsubstituted 3- to 4-membered heterocylyl, or optionally two RGA are taken with the intervening atoms to form a substituted or unsubstituted 3- to 4-membered carbocyclic or heterocyclic ring; each instance of RAN 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, —S(O)RGA, e.g., —S(═O)RGA, —S(═O)ORGA, —S(═O)N(RGA)2, or a nitrogen protecting group; each instance of RGA is independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocylyl, substituted or unsubstituted 3- to 6-membered heterocylyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, or two RGA groups are taken with the intervening atoms to form a substituted or unsubstituted carbocyclic or heterocyclic ring; p is 1 or 2; and e is 0, 1, 2, 3, 4, or 5; provided that when A is (A-2), (A-3), or (A-5), e is 1, 2, 3, 4, or 5.