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, and status epilepticus.

主权项

1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof; wherein: represents a single or double bond as valency permits; A is of Formula (A-1) or Formula (A-2):wherein the point of attachment is at G1 or G2 in Formula (A-1) and the point of attachment is at G2 or G3 in Formula (A-2);
G1 is N, NRN1, O, S, C, or C—RG1 as valency permits; G2 is N, NRN2, O, S, C, —C═N—, or C—RG2 as valency permits; G3 is N, NRN3, O, S, C, or C—RG3 as valency permits; G4 is N, NRN4, C—RG4, or C—(RG4)2 as valency permits; G5 is N, NRN5, C—RG5, or C—(RG5)2 as valency permits; G6 is N, NRN6, C—RG6, or C—(RG6)2 as valency permits; and G7 is N, NRN7, C—RG7, or C—(RG7)2 as valency permits; each instance of RG1, RG2, RG3, RG4, RG5, RG6, and RG7 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, —S(═O)2RGA, —S(═O)2ORGA, —OS(═O)2RGA, —S(═O)2N(RGA)2, —N(RGA)S(═O)2RGA, —S(═O)RGA, —S(═O)ORGA, —OS(═O)RGA, —S(═O)N(RGA)2, —N(RGA)S(═O)RGA, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each instance of RN1, RN2, RN3, RN4, RN5, RN6, and RN7 is independently hydrogen, substituted or unsubstituted C1-6 alkyl, 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 carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, 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; 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, substituted or unsubstituted C3-6 carbocyclyl, or —ORA2, wherein RA2 is hydrogen or 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 of R4a or R4b is independently hydrogen, substituted or unsubstituted C1-6 alkyl, or halogen; provided if bond p is a double bond, then bond q is a single bond, provided if bond q is a double bond, then bond p is a single bond and R4b is absent; and provided if both bonds p and q are single bonds, then the hydrogen at C5 is in the alpha or beta configuration.