Neuroactive steroids, compositions, and uses thereof

A compound of Formula (I):

• or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, and/or isotopic variant thereof;
• wherein:
• X is hydrogen, halo, —CF3, —CHF2, —CH2F, —NO2, —CN, —SCN, —ORX, —OC(═O)N(RX)2, —SRX, —SC(═O)N(RX)2, —N(RX)2, —NRXC(═O)RX, —NRXC(═O)ORX, —NRXC(═O)N(RX)2, —NRXSO2RX, —C(═O)RX, —C(═O)N(RX)2, —S(═O)RX, —S(═O)2RX, —SO2N(RX)2, or —OC(═O)RE1;
• wherein RX 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 RX groups are joined to form a substituted or unsubstituted heterocyclic ring;
• Z1 is halo, —CN, —CH2CN, —CH2CF3, —NO2, —CH2NO2, —ORZ1b, —CH2ORZ1b, —OC(═O)N(RZ1b)2, —SRZ1b, —N(RZ1b)2, —N(ORZ1b)(RZ1b), —NRZ1bC(═O)RZ1b, —NRZ1bC(═O)ORZ1b, —NRZ1bC(═O)N(RZ1b)2, —NRZ1bSO2RZ1b, —C(═O)RZ1b, —CH2C(═O)RZ1b, —C(═O)ORZ1b, —CH2C(═O)ORZ1b, —C(═O)N(RZ1b)2, —CH2C(═O)N(RZ1b)2, —S(═O)RZ1b, —S(═O)2RZ1b, —SO2N(RZ1b)2, —P(═O)2RZ1b, —P(═O)2ORZ1b, —P(═O)(ORZ1b)2, —P(═O)(RZ1b)2, or —P(═O)(RZ1b)(ORZ1b), —C(═O)CH2ORZ1a, or —C(═O)CH2N(RZ1a)2;
• and Z2 is hydrogen or —ORZ2;
• or Z1 and Z2 are joined to form a 3- to 6-membered substituted or unsubstituted heterocyclic ring;
• an oxo (═O);
• an oxime ═N(ORZ1b);
• or an alkenyl group ═CH(Z3), wherein Z3 is —CF3, —NO2, —ORZ1b, —C(═O)RZ1b, —C(═O)ORZ1b, or —C(═O)N(RZ1b)2;
• or Z1 and Z2 are joined to form an alkenyl group ═CH(CN), wherein CN is in the Z configuration;
• wherein each instance of RZ1a 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 nitrogen protecting group when attached to a nitrogen atom, —C(═O)RZ1b, —C(═O)ORZ1b, —C(═O)N(RZ1b)2, —C(═O)N(ORZ1b)(RZ1b), —S(═O)2RZ1b, —S(═O)2ORZ1b, —P(═O)2RZ1b, —P(═O)2ORZ1b, —P(═O)(ORZ1b)2, —P(═O)(RZ1b)2, or —P(═O)(RZ1b)(ORZ1b), or two RZ1a groups are joined to form a substituted or unsubstituted heterocyclic ring or substituted or unsubstituted heteroaryl ring, and
• wherein each instance of RZ1b and RZ2 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 sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two RZ1b groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring, or RZ1b and RZ2 are joined to form a substituted or unsubstituted heterocyclic ring;
• R1, R2, and R3 are independently selected from the group consisting of hydrogen or —OC(═O)RE1;
• R4 is hydrogen, or R3 and R4 are joined to form an oxo (═O) group or an alkenyl group ═C(RA3)2, wherein each instance of RA3 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, or two Ra3 groups are joined to form a substituted or unsubstituted carbocyclic ring or substituted or unsubstituted heterocyclic ring;
• and
• represents a single or double bond, wherein if is a single bond, then the C5 hydrogen is in the alpha or beta configuration;
• provided at least one of R1, R2, R3, and X is a group of the formula —OC(═O)RE1;
• wherein RE1 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, substituted or unsubstituted heteroaryl, or —ORE2, and wherein RE2 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, substituted or unsubstituted heteroaryl, an oxygen protecting group.