3. alpha-hydroxy, 17.beta-C(O)-N-aryl substituted neuroactive steroids and compositions thereof

Abstract

3. alpha.-hydroxy, 17. beta.-C(O)-N-aryl substituted neuroactive steroids and compositions thereof are provided. Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 2a , R 2b , R 3a , R 4a , R 4b , R 5 , R 6 , R 7 , R 11a , R 11b , R 15a , R 15b , R 16 , R 17 , R 19 , R X , R Y and t are defined herein. Pharmaceutical compositions comprising compounds of formula (I) and methods of using the compounds, for example, in the treatment of CNS-related disorders, are also provided herein. JPEG2026042854000238.jpg53164

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This international PCT application claims the benefit of U.S. Provisional Patent Application No. 63 / 043,641, filed June 24, 2020, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Brain excitability is defined as the level of alertness of an animal, a continuum from coma to seizures, and is regulated by various neurotransmitters. Generally, neurotransmitters serve to regulate the conductance of ions across the neuronal membrane. At rest, the neuronal membrane has a potential (or membrane voltage) of approximately -70 mV, with the interior of the cell being negative relative to the exterior of the cell. The potential (voltage) is determined by the flow of ions (K) across the neuronal semipermeable membrane. + , Na + , Cl - Neurotransmitters are stored in presynaptic vesicles and are released under the influence of a neuronal action potential. When released into the synaptic cleft, excitatory chemical transmitters such as acetylcholine cause membrane depolarization (a change in potential from -70 mV to -50 mV). This effect is stimulated by acetylcholine and Na + It is mediated by postsynaptic nicotinic receptors, which increase membrane permeability to ions. The reduction in membrane potential stimulates neuronal excitability in the form of postsynaptic action potentials.

[0003] In the case of the GABA receptor complex (GRC), its effects on brain excitability are mediated by the neurotransmitter gamma-aminobutyric acid (GABA). Because up to 40% of brain neurons utilize GABA as a neurotransmitter, GABA has a profound influence on global brain excitability. GABA regulates the excitability of individual neurons by modulating the conductance of chloride ions across neuronal membranes. GABA interacts with its recognition site on the GRC, promoting the influx of chloride ions into the cell down the GRC's electrochemical gradient. Increased intracellular levels of this anion cause hyperpolarization of the transmembrane potential, reducing neuronal sensitivity to excitatory inputs and thus neuronal excitability. In other words, the higher the chloride ion concentration in neurons, the lower the brain excitability and arousal levels.

[0004] It is well documented that the GRC is responsible for mediating anxiety, seizure activity, and sedation. Thus, GABA and drugs that act like or potentiate the actions of GABA, such as therapeutically useful barbiturates and benzodiazepines (BZs) (e.g., Valium®), exert their therapeutically useful effects by interacting with specific regulatory sites on the GRC. Accumulating evidence now suggests that the GRC contains unique sites for neuroactive steroids in addition to benzodiazepine and barbiturate binding sites. See, e.g., Lan, NC et al., Neurochem. Res. (1991) 16:347-356.

[0005] Neuroactive steroids can occur endogenously. The most potent endogenous neuroactive steroids are 3α-hydroxy-5-reduced pregnan-20-one and 3α-21-dihydroxy-5-reduced pregnan-20-one, which are metabolites of the hormonal steroids progesterone and deoxycorticosterone, respectively. The ability of these steroid metabolites to alter brain excitability was recognized in 1986 (Majewska, MD et al., Science 232:1004-1007 (1986); Harrison, NL et al., J Pharmacol. Exp. Ther. 241:346-353 (1987)). There is a need for new and improved compounds that act as modulators of brain excitability and as agents for the prevention and treatment of CNS-related disorders. The compounds, compositions, and methods described herein are directed to this end. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Lan, NC et al., Neurochem. Res. (1991) 16:347-356 [Non-patent document 2] Majewska, MD et al., Science 232:1004-1007(1986) [Non-patent document 3] Harrison,NLet al.,J Pharmacol.Exp.Ther.241:346-353(1987) Summary of the Invention

[0007] As used herein, for example, GABA A Compounds designed to act as modulators are provided, and in some embodiments, such compounds are contemplated to be useful as therapeutic agents for treating CNS-related disorders.

[0008] The present invention relates to a compound of formula (I-1): [ka] or a pharmaceutically acceptable salt thereof, wherein R 2a , R 2b , R 4a , R 4b , R 6 , R 7 , R 11a , R 11b , R 15a , and R 15b each independently represents hydrogen, halogen, hydroxyl, cyano, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, -NR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, -NR D1 C(=O)R D1 , a substituted or unsubstituted 3- to 6-membered monocyclic heterocycle, or a substituted or unsubstituted 8- to 12-membered bicyclic heterocycle, wherein the monocyclic or bicyclic heterocycle has 1 to 3 heteroatoms independently selected from N, O, and S, and each R D1 are independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 alkynyl, a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R D1 groups join to form a substituted or unsubstituted 3- to 6-membered monocyclic heterocycle or 8- to 12-membered bicyclic heterocycle, wherein the monocyclic or bicyclic heterocycle has 1 to 3 heteroatoms independently selected from N, O, and S, or R 2a and R 2b , R 4a and R 4b , or R11a and R 11b are joined together to form an oxo (=O) group, and R 16 and R 17 each independently represents hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, -OR A1 , -SR A1 , -N(R A1 )2, -N(R A1 ), -CN(R A1 )2, -C(O)R A1 , -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)SR A1 , -OC(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 , -SC(=O)SR A1 , -NHC(=O)R A1 , -SC(=O)N(R A1 )2, -NHC(=O)OR A1 , -NHC(=O)SR A1 , -NHC(=O)N(R A1 )2, -OS(=O)2R A2 , -OS(=O)2OR A1 , -SS(=O)2R A2 , -SS(=O)2OR A1 , -S(=O)R A2 , -SO2R A2 , -S(=O)2OR A1 or a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S; A1 are independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6Alkynyl, a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S; 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; -SO2R A2 , -C(O)R A2 or two R A1 groups joined together to form a substituted or unsubstituted 3- to 6-membered saturated, partially unsaturated, or fully unsaturated monocyclic heterocycle having 1 to 3 heteroatoms independently selected from N, O, and S; and each R A2 are independently substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 alkynyl, or a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S; R 3a is the unsubstituted C 1~6 alkyl, -CH2OCH3, or -CH2OCH2CH3, and R 5 is hydrogen, unsubstituted methyl, or absent; [ka] is a single or double bond, with the proviso that [ka] is a single bond, R 5 is hydrogen or methyl, [ka] is a double bond, R 5 is non-existent, and R 19 is hydrogen or unsubstituted C 1~6 Alkyl, R X is hydrogen or substituted or unsubstituted C1~6 alkyl, and R Y is a substituted or unsubstituted pyrazinyl, a cyano-substituted pyrimidine, a substituted or unsubstituted pyridine, or a substituted phenyl, with the proviso that R 3a is -CH2OCH2CH3, and R Y When R is substituted or unsubstituted pyrazinyl, 19 is unsubstituted methyl.

[0009] In some embodiments, R 2a and R 2b each independently represents hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2, and each R D1 are independently hydrogen, substituted or unsubstituted C 1~6 alkyl, or a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S. In some embodiments, R 2a and R 2b each independently represents hydrogen, C optionally substituted with 1 to 3 halogens 1~6 Alkyl, C optionally substituted with 1 to 3 halogens 1~6 In some embodiments, R 2a and R 2b Each of R is independently hydrogen, —CH, —CHCH, —OH, —OCH, or —CH(CH). 2a and R 2b In some embodiments, one of R 2a and R 2b Each of is hydrogen.

[0010] In some embodiments, R 4a and R 4beach independently represents hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2 and R D1 Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 alkyl, a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S. In some embodiments, R 4a and R 4b each independently represents hydrogen, C optionally substituted with 1 to 3 halogens 1~6 Alkyl, C optionally substituted with 1 to 3 halogens 1~6 In some embodiments, R 4a and R 4b Each of R is independently hydrogen, —CH, —CHCH, —OH, —OCH, or —CH(CH). 4a and R 4b In some embodiments, one of R 4a and R 4b Each of is hydrogen.

[0011] In some embodiments, R 11a and R 11b each independently represents hydrogen, halogen, cyano, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2 and R D1 Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 alkyl, a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S. In some embodiments, R11a and R 11b each independently represents hydrogen, C optionally substituted with 1 to 3 halogens 1~6 C optionally substituted with alkyl or 1 to 3 halogens 1~6 In some embodiments, R 11a and R 11b Each of R is independently hydrogen, —CH, —CHCH, —OCH, or —CH(CH). 11a and R 11b In some embodiments, one of R 11a and R 11b Each of is hydrogen.

[0012] In some embodiments, R 7 is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2 and R D1 Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 alkyl, a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S. In some embodiments, R 7 is hydrogen, C optionally substituted with 1 to 3 halogens 1~6 Alkyl, C optionally substituted with 1 to 3 halogens 1~6 In some embodiments, R is hydrogen, —CH, —CHCH, —OH, —OCH, or —CH(CH). In some embodiments, R 7 is hydrogen.

[0013] In some embodiments, R 6 is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C2~6 Alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2 and R D1 Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S. In some embodiments, R 6 is hydrogen, C optionally substituted with 1 to 3 halogens 1~6 Alkyl, C optionally substituted with 1 to 3 halogens 1~6 In some embodiments, R 6 is hydrogen, —CH, —CHCH, —OH, —OCH, or —CH(CH). In some embodiments, R 6 is hydrogen.

[0014] In some embodiments, R 16 is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2 and R D1 Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 alkyl, a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S. In some embodiments, R 16 is hydrogen, C optionally substituted with 1 to 3 halogens 1~6 Alkyl, C optionally substituted with 1 to 3 halogens 1~6 In some embodiments, R 16is hydrogen, —CH, —CHCH, —OH, —OCH, or —CH(CH). In some embodiments, R 16 is hydrogen.

[0015] In some embodiments, R 17 is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2 and R D1 Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 alkyl, a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S. In some embodiments, R 17 is hydrogen, C optionally substituted with 1 to 3 halogens 1~6 Alkyl, C optionally substituted with 1 to 3 halogens 1~6 In some embodiments, R 17 is hydrogen, —CH, —CHCH, —OH, —OCH, or —CH(CH). In some embodiments, R 17 is hydrogen.

[0016] In some embodiments, R 19 is hydrogen or unsubstituted C 1~5 In some embodiments, R 19 is hydrogen or unsubstituted C 1~4 In some embodiments, R 19 is hydrogen, —CH, or —CHCH. In some embodiments, R 19 is hydrogen. In some embodiments, R 19 is -CH3, or -CH2CH3.

[0017] In some embodiments, R 3a is the unsubstituted C1~6 In some embodiments, R 3a is the unsubstituted C 1~4 It is alkyl.

[0018] In some embodiments, the compound of formula (I-1) is a compound of formula (I-2): [ka] or a pharmaceutically acceptable salt thereof, wherein R 3a is -CH2OCH3 or unsubstituted methyl, and R 5 is hydrogen, unsubstituted methyl, or absent; [ka] is a single or double bond, with the proviso that [ka] is a single bond, R 5 is hydrogen or methyl, [ka] is a double bond, R 5 is non-existent, and R 19 is hydrogen or substituted or unsubstituted C 1~6 alkyl, and R X is hydrogen or substituted or unsubstituted C 1~6 alkyl, and R Y is a cyano-substituted pyridine. 2a , R 2b , R 3a , R 4a , R 4b , R 5 , R 6 , R 7 , R 11a , R 11b , R 15a , R 15b , R 16, and R 17 each of which is as defined in compounds of formula (I-1) or any embodiment thereof.

[0019] In some embodiments, the compound of formula (I-1) is a compound of formula (I-3): [ka] or a pharmaceutically acceptable salt thereof, wherein R 3a is -CH2OCH3 or unsubstituted methyl, and R 5 is hydrogen, unsubstituted methyl, or absent; [ka] is a single or double bond, with the proviso that [ka] is a single bond, R 5 is hydrogen or methyl, [ka] is a double bond, R 5 is non-existent, and R 19 is hydrogen or substituted or unsubstituted C 1~6 alkyl, and R X is hydrogen or substituted or unsubstituted C 1~6 alkyl, and R Y is a fluoro-substituted pyridine.

[0020] In some embodiments, the compound of formula (I-1) is a compound of formula (I-a1): [ka] or a pharmaceutically acceptable salt thereof.

[0021] In some embodiments, the compound of formula (I-2) is a compound of formula (I-a2): [ka] or a pharmaceutically acceptable salt thereof.

[0022] In some embodiments, the compound of formula (I-3) is a compound of formula (I-a3): [ka] or a pharmaceutically acceptable salt thereof.

[0023] In some embodiments, when the compound is of formula (I-a1), (I-a2), or (I-a3), R 17 is hydrogen, —CH, —CHCH, —OH, —OCH, or —CH(CH). In some embodiments, R 17 is hydrogen.

[0024] In some embodiments, when the compound is of formula (I-a1), (I-a2), or (I-a3), R 19 is hydrogen or unsubstituted C 1~4 In some embodiments, R 19 is hydrogen or unsubstituted C 1~4 In some embodiments, R 19 is hydrogen, -CH3, or -CH2CH3.

[0025] In some embodiments, when the compound is of formula (I-a1), (I-a2), or (I-a3), R 3a is hydrogen, unsubstituted C 1~4 alkyl, or -CH2OCH2CH3.

[0026] In some embodiments, when the compound is of formula (I-a1), (I-a2), or (I-a3), R 5is hydrogen. In some embodiments, R 5 is unsubstituted methyl.

[0027] In some embodiments, the compound of Formula (I-a1) is a compound of Formula (I-b1a) or Formula (I-b2a): [ka] or a pharmaceutically acceptable salt thereof.

[0028] In some embodiments, the compound of Formula (I-a2) is a compound of Formula (I-b1b) or Formula (I-b2b): [ka] or a pharmaceutically acceptable salt thereof.

[0029] In some embodiments, the compound of Formula (I-a3) is a compound of Formula (I-b1c) or Formula (I-b2c): [ka] or a pharmaceutically acceptable salt thereof.

[0030] In some embodiments, the compound of Formula (I-a1) is a compound of Formula (I-c1a) or Formula (I-c2a): [ka] or a pharmaceutically acceptable salt thereof.

[0031] In some embodiments, the compound of Formula (I-a2) is a compound of Formula (I-c1b) or Formula (I-c2b): [ka] or a pharmaceutically acceptable salt thereof.

[0032] In some embodiments, the compound of Formula (I-a3) is a compound of Formula (I-c1c) or Formula (I-c2c): [ka] or a pharmaceutically acceptable salt thereof.

[0033] In some embodiments, the compound of Formula (I-a1) is a compound of Formula (I-d1a) or Formula (I-d2a): [ka] or a pharmaceutically acceptable salt thereof.

[0034] In some embodiments, the compound of Formula (I-a2) is a compound of Formula (I-d1b) or Formula (I-d2b): [ka] or a pharmaceutically acceptable salt thereof.

[0035] In some embodiments, the compound of Formula (I-a3) is a compound of Formula (I-d1c) or Formula (I-d2c): [ka] or a pharmaceutically acceptable salt thereof.

[0036] In some embodiments, R X is hydrogen or substituted or unsubstituted C 1~4 In some embodiments, R X is hydrogen, —CH, or —CHCH. In some embodiments, R X is hydrogen.

[0037] In some embodiments, the compound of Formula (I-a1) is a compound of Formula (I-e1): [ka] or a pharmaceutically acceptable salt thereof.

[0038] In some embodiments, the compound of Formula (I-a2) is a compound of Formula (I-e2): [ka] or a pharmaceutically acceptable salt thereof.

[0039] In some embodiments, the compound of Formula (I-a3) is a compound of Formula (I-e3): [ka] or a pharmaceutically acceptable salt thereof.

[0040] In some embodiments, R Y teeth, [ka] is selected from In the formula, each R D are independently hydrogen, halogen, -NO2, -CN, -OR GA , -N(R GA )2, -C(=O)R GA , -C(=O)OR GA , -C(=O)N(R GA )2, -OC(=O)R GA , -OC(=O)OR GA , -N(R GA )C(=O)R GA , -OC(=O)N(R GA )2, -N(R GA )C(=O)OR GA , -S(=O)2R GA , -S(=O)2OR GA, -OS(=O)2R GA , -S(=O)2N(R GA )2, or -N(R GA )S(=O)2R GA , substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 alkynyl, a substituted or unsubstituted 3-10 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S, or two R D groups, together with the atoms to which they are attached, form a substituted or unsubstituted 5-6 membered saturated, partially unsaturated, or fully unsaturated ring having up to three heteroatoms independently selected from N, O, or S, and each R GA are independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 alkynyl, a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, or two R GA The groups, together with the atoms to which they are attached, form a substituted or unsubstituted 5-6 membered saturated, partially unsaturated, or fully unsaturated ring having up to three heteroatoms independently selected from N, O, or S, and e is 0, 1, 2, 3, 4, or 5.

[0041] In some embodiments, R Y teeth, [ka] is selected from.

[0042] Another aspect of the present invention is a compound of formula (I-4): [ka] or a pharmaceutically acceptable salt thereof, wherein R 2a , R 2b , R 4a , R 4b , R 6 , R 7 , R 11a , R 11b , R 15a , and R 15b each independently represents hydrogen, halogen, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, -NR D1 C(=O)R D1 , a substituted or unsubstituted 3- to 6-membered monocyclic heterocycle, or a substituted or unsubstituted 8- to 12-membered bicyclic heterocycle, wherein the monocyclic or bicyclic heterocycle has 1 to 3 heteroatoms independently selected from N, O, and S, and each R D1 are independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 alkynyl, a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R D1 groups join to form a substituted or unsubstituted 3- to 6-membered monocyclic heterocycle or 8- to 12-membered bicyclic heterocycle, wherein the monocyclic or bicyclic heterocycle has 1 to 3 heteroatoms independently selected from N, O, and S, or R 2a and R 2b , R 4a and R 4b , or R 11a and R 11b are joined together to form an oxo (=O) group, and R 16 and R17 each independently represents hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, -OR A1 , -SR A1 , -N(R A1 )2, -N(R A1 ), -CN(R A1 )2, -C(O)R A1 , -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)SR A1 , -OC(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 , -SC(=O)SR A1 , -NHC(=O)R A1 , -SC(=O)N(R A1 )2, -NHC(=O)OR A1 , -NHC(=O)SR A1 , -NHC(=O)N(R A1 )2, -OS(=O)2R A2 , -OS(=O)2OR A1 , -SS(=O)2R A2 , -SS(=O)2OR A1 , -S(=O)R A2 , -SO2R A2 , -S(=O)2OR A1 or a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S; A1 are independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6Alkynyl, a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S; 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; -SO2R A2 , -C(O)R A2 or two R A1 groups joined together to form a substituted or unsubstituted 3- to 6-membered saturated, partially unsaturated, or fully unsaturated monocyclic heterocycle having 1 to 3 heteroatoms independently selected from N, O, and S; and each R A2 are independently substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 alkynyl, or a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S; R 3a is hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 alkynyl, a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S; R 5 is hydrogen, unsubstituted methyl, or absent; [ka] is a single or double bond, with the proviso that [ka] is a single bond, R 5 is hydrogen or methyl, [ka] is a double bond, R5 is non-existent, and R 19 is hydrogen or substituted or unsubstituted C 1~6 alkyl, and R X is hydrogen or substituted or unsubstituted C 1~6 alkyl, and R Y is a substituted or unsubstituted phenyl, or a substituted or unsubstituted 3- to 6-membered monocyclic heteroaryl or 8- to 12-membered bicyclic heteroaryl, wherein the monocyclic or bicyclic heteroaryl has 1 to 5 heteroatoms independently selected from N, O, and S; and t is 2 or 3.

[0043] In some embodiments, R 2a and R 2b each independently represents hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2, and each R D1 are independently hydrogen, substituted or unsubstituted C 1~6 alkyl, or a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S. In some embodiments, R 2a and R 2b each independently represents hydrogen, C optionally substituted with 1 to 3 halogens 1~6 Alkyl, C optionally substituted with 1 to 3 halogens 1~6 In some embodiments, R 2a and R 2b Each of R is independently hydrogen, —CH, —CHCH, —OH, —OCH, or —CH(CH). 2a and R 2b In some embodiments, one of R 2a and R 2b Each of is hydrogen.

[0044] In some embodiments, R 4a and R 4b each independently represents hydrogen, C optionally substituted with 1 to 3 halogens 1~6 Alkyl, C optionally substituted with 1 to 3 halogens 1~6 In some embodiments, R 4a and R 4b Each of R is independently hydrogen, —CH, —CHCH, —OH, —OCH, or —CH(CH). 4a and R 4b In some embodiments, one of R 4a and R 4b Each of is hydrogen.

[0045] In some embodiments, R 11a and R 11b each independently represents hydrogen, halogen, cyano, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2 and R D1 Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 alkyl, a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S. In some embodiments, R 11a and R 11b each independently represents hydrogen, C optionally substituted with 1 to 3 halogens 1~6 C optionally substituted with alkyl or 1 to 3 halogens 1~6 In some embodiments, R 11a and R 11b Each of R is independently hydrogen, —CH, —CHCH, —OCH, or —CH(CH). 11a and R11b In some embodiments, one of R 11a and R 11b Each of is hydrogen.

[0046] In some embodiments, R 7 is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2 and R D1 Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 alkyl, a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S. In some embodiments, R 7 is hydrogen, C optionally substituted with 1 to 3 halogens 1~6 Alkyl, C optionally substituted with 1 to 3 halogens 1~6 In some embodiments, R 7 is hydrogen, —CH, —CHCH, —OH, —OCH, or —CH(CH). In some embodiments, R 7 is hydrogen.

[0047] In some embodiments, R 6 is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2 and R D1 Each instance of is independently hydrogen, substituted or unsubstituted C 1~6alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S. In some embodiments, R 6 is hydrogen, C optionally substituted with 1 to 3 halogens 1~6 Alkyl, C optionally substituted with 1 to 3 halogens 1~6 In some embodiments, R 6 is hydrogen, —CH, —CHCH, —OH, —OCH, or —CH(CH). In some embodiments, R 6 is hydrogen.

[0048] In some embodiments, R 16 is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2 and R D1 Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 alkyl, a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S. In some embodiments, R 16 is hydrogen, C optionally substituted with 1 to 3 halogens 1~6 Alkyl, C optionally substituted with 1 to 3 halogens 1~6 In some embodiments, R 16 is hydrogen, —CH, —CHCH, —OH, —OCH, or —CH(CH). In some embodiments, R 16 is hydrogen.

[0049] In some embodiments, R 17is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2 and R D1 Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 alkyl, a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S. In some embodiments, R 17 is hydrogen, C optionally substituted with 1 to 3 halogens 1~6 Alkyl, C optionally substituted with 1 to 3 halogens 1~6 In some embodiments, R 17 is hydrogen, —CH, —CHCH, —OH, —OCH, or —CH(CH). In some embodiments, R 17 is hydrogen.

[0050] In some embodiments, R 19 is hydrogen or unsubstituted C 1~5 In some embodiments, R 19 is hydrogen or unsubstituted C 1~4 In some embodiments, R 19 is hydrogen, —CH, or —CHCH. In some embodiments, R 19 is hydrogen. In some embodiments, R 19 is -CH3, or -CH2CH3.

[0051] In some embodiments, R 3a is the unsubstituted C 1~6 In some embodiments, R 3a is the unsubstituted C 1~4 It is alkyl.

[0052] In some embodiments, the compound of formula (I-4) is a compound of formula (I-a4): [ka] or a pharmaceutically acceptable salt thereof.

[0053] In some embodiments, the compound of Formula (I-4) is a compound of Formula (I-b4a) or Formula (I-b5a): [ka] or a pharmaceutically acceptable salt thereof.

[0054] In some embodiments, the compound of Formula (I-4) is a compound of Formula (I-b4b) or Formula (I-b5b): [ka] or a pharmaceutically acceptable salt thereof.

[0055] In some embodiments, R X is hydrogen or unsubstituted methyl. In some embodiments, R X is hydrogen.

[0056] In some embodiments, R Y teeth, [ka] is selected from In the formula, each R D are independently hydrogen, halogen, -NO2, -CN, -OR GA , -N(R GA )2, -C(=O)R GA , -C(=O)OR GA , -C(=O)N(R GA )2, -OC(=O)R GA , -OC(=O)OR GA , -N(RGA )C(=O)R GA , -OC(=O)N(R GA )2, -N(R GA )C(=O)OR GA , -S(=O)2R GA , -S(=O)2OR GA , -OS(=O)2R GA , -S(=O)2N(R GA )2, or -N(R GA )S(=O)2R GA , substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 alkynyl, a substituted or unsubstituted 3-10 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S, or two R GA together with intervening atoms form a substituted or unsubstituted 3-5 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S; and each X is independently -N= or -C(R D ) = and each R GA are independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 alkynyl, a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, or two R GA groups together with intervening atoms form a substituted or unsubstituted 5- to 6-membered heterocyclic ring having 2 to 3 heteroatoms independently selected from N, O, or S; R X1 is hydrogen or substituted or unsubstituted C 1~6 alkyl, or a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S; and e is 0, 1, 2, or 3.

[0057] In some embodiments, R Y teeth, [ka] is selected from In the formula, R D Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1~6 alkyl, —CN, substituted or unsubstituted 5- to 6-membered heteroaryl, substituted or unsubstituted 5-membered heterocyclyl, and e is 0, 1, 2, 3, or 4.

[0058] In some embodiments, R Y teeth, [ka] is selected from wherein each R is independently -CH, -CHCH, -i-Pr, cyclopropyl, or -CN.

[0059] In some embodiments, R Y teeth, [ka] is selected from.

[0060] In some embodiments, R Y teeth, [ka] In some embodiments, R Y teeth, [ka] is.

[0061] Another aspect of the present invention is a compound of formula (X): [ka] or a pharmaceutically acceptable salt thereof, wherein R 2a is hydrogen or substituted or unsubstituted C 1~6 alkyl, and R 3a is a substituted or unsubstituted C 1~6 Alkyl, or substituted or unsubstituted C 1~6 Alkyl-OC 1~6 alkyl, and R 19 is hydrogen or substituted or unsubstituted C 1~6 alkyl, and R Y is a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-2 nitrogen atoms, and R Y The 3- to 8-membered rings are independently halogen, -CN, or C 1~6 alkyl, and t is 1 or 2, provided that when t is 1, R 3a is -CH2OCH2CH3, and R Y is a substituted or unsubstituted pyrazinyl, and then R 19 is -CH3.

[0062] In some embodiments, R 2a is hydrogen or unsubstituted C 1~3 In some embodiments, R 2a is hydrogen or -CH3.

[0063] In some embodiments, R 3a is the unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 Alkyl-OC 1~3 In some embodiments, R 3a is -CH3, -CH2CH2CH3, -CH2OCH3, or -CH2OCH2CH3.

[0064] In some embodiments, R 19 is hydrogen or unsubstituted C 1~3In some embodiments, R 19 is hydrogen, -CH3, or -CH2CH3.

[0065] In some embodiments, R Y is a substituted or unsubstituted pyrazinyl, a cyano-substituted pyrimidine, a substituted or unsubstituted phenyl, a cyano- or fluoro-substituted pyridine, or a pyrazole substituted with two unsubstituted methyl groups.

[0066] Another aspect of the present invention is a compound of formula (XI): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is the unsubstituted C 1~3 alkyl, and R 19 is hydrogen or unsubstituted C 1~3 alkyl, and R Y teeth, [ka] wherein two of W1, W2, W3, W4, and W5 are -N= and the rest are -C(R')=, each R' is independently hydrogen or -CN, and at least one R' is -CN.

[0067] In some embodiments, R 1 is -CH3, or -CH2CH3.

[0068] In some embodiments, R 19 is hydrogen or -CH3.

[0069] In some embodiments, W1 and W2 are -N=, or W1 and W3 are -N=, or W1 and W4 are -N=, or W1 and W5 are -N=, or W2 and W4 are -N=.

[0070] In some embodiments, R Y teeth, [ka] is.

[0071] Another aspect of the present invention provides a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt of any one of the compounds described herein and a pharmaceutically acceptable carrier, vehicle, or excipient.

[0072] Another aspect of the present invention is GABA A A method for modulating a receptor in a subject in need thereof is provided, comprising administering to the subject a therapeutically effective amount of any one of the compounds described herein or a pharmaceutically acceptable salt thereof, or any pharmaceutical composition described herein.

[0073] Another aspect of the present invention is GABA A A method for modulating a receptor-mediated CNS-related disorder in a subject in need thereof is provided, comprising administering to the subject a therapeutically effective amount of any one of the compounds described herein or a pharmaceutically acceptable salt thereof, or any of the pharmaceutical compositions described herein.

[0074] Another aspect of the present invention provides a method of treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any one of the compounds or a pharmaceutically acceptable salt thereof described herein, or any pharmaceutical composition described herein.

[0075] In some implementations of the above-described methods, the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a seizure disorder, a memory and / or cognitive disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder and / or withdrawal syndrome, tinnitus, or status epilepticus. In some implementations, the CNS-related disorder is a mood disorder. In some implementations, the mood disorder is depression. In some implementations, the depression is postpartum depression. In some implementations, the depression is major depressive disorder. In some implementations, the major depressive disorder is moderate major depressive disorder. In some implementations, the major depressive disorder is severe major depressive disorder.

[0076] In a preferred embodiment, the compounds described herein are GABA A It selectively modulates certain subunit compositions of the receptor, for example, the α4β3δ subunit composition. DETAILED DESCRIPTION OF THE INVENTION

[0077] As generally described herein, the present invention provides a method for treating GABA- A In one embodiment, the compounds described herein are GABA receptor modulators. A The compounds selectively regulate certain receptor subunit compositions, such as the α4β3δ subunit composition. In certain embodiments, such compounds are expected to be useful as therapeutic agents for treating CNS-related disorders (e.g., disorders described herein, e.g., depression, such as postpartum depression or major depressive disorder).

[0078] I. Definition A. Definition of Chemical Substances Specific functional groups and definitions of chemical terms are explained in detail below. Chemical elements are defined as follows: thEd., and specific functional groups are generally defined as described herein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 th Edition, John Wiley&Sons, Inc., New York, 2001, Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989, and Carruthers, Some Modern Methods of Organic Synthesis, 3. rd Edition, Cambridge University Press, Cambridge, 1987.

[0079] Isomers, e.g., stereoisomers, can be isolated from mixtures by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC) and chiral salt formation and crystallization, or preferred isomers can be prepared by asymmetric synthesis. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention further encompasses the compounds described herein as individual isomers substantially free of other isomers or as mixtures of various isomers.

[0080] As used herein, a pure enantiomer compound is substantially free of other enantiomers or stereoisomers of a compound (i.e., in enantiomeric excess). In other words, the "S" form of a compound is substantially free of the "R" form of the compound and is thus in enantiomeric excess of the "R" form. The terms "enantiomerically pure" or "pure enantiomer" indicate that a compound contains more than 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98.5%, 99%, 99.2%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% by weight of an enantiomer. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0081] In the compositions provided herein, the enantiomerically pure compound can be present together with other active or inactive ingredients. For example, a pharmaceutical composition containing an enantiomerically pure R-position / center / carbon compound can contain, for example, about 90% excipients and about 10% enantiomerically pure R-compound. In certain embodiments, the enantiomerically pure R-compound in such a composition can contain, for example, at least about 95% by weight of the R-compound and at most about 5% by weight of the S-compound, based on the total weight of the compound. For example, a pharmaceutical composition containing an enantiomerically pure S-compound can contain, for example, about 90% excipients and about 10% by weight of the enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S-compound in such a composition can contain, for example, at least about 95% by weight of the S-compound and at most about 5% by weight of the R-compound, based on the total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipients or carriers.

[0082] The term "diastereomerically pure" means that a compound contains greater than 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98.5%, 99%, 99.2%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% by weight of a single diastereomer. Methods for determining diastereomeric and enantiomeric purity are well known in the art. Diastereomeric purity can be determined by any analytical method capable of quantitatively distinguishing a compound and its diastereomers, such as high performance liquid chromatography (HPLC).

[0083] "Stereoisomers": It is also understood that compounds that have identical molecular formulas but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are referred to as "isomers." Isomers that differ in the spatial arrangement of their atoms are termed "stereoisomers." Stereoisomers that are not mirror images of each other are termed "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are termed "enantiomers." For example, if a compound has an asymmetric center and is bonded to four different groups, a set of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R- and S-sequencing rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light and is designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is termed a "racemic mixture."

[0084] The articles "a" and "an" may be used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an analogue" means one analogue or more than one analogue.

[0085] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1~6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 , and C 5~6 Alkyl is intended to be included.

[0086] The following terms are intended to have the meanings provided below and are useful in understanding the specification and the intended scope of the invention.

[0087] "Alkyl" refers to the radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms ("C 1~20 In some embodiments, the alkyl group has 1 to 12 carbon atoms ("C 1~12 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1~10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1~9 In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1~8 In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1~7 In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1~6 In some embodiments, an alkyl group is a group having 1 to 5 carbon atoms ("C 1~5 In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C 1~4 In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1~3 In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1~2 In some embodiments, the alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2~6 alkyl). C 1~6Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each occurrence of an alkyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1~10 In certain embodiments, the alkyl group is a substituted C 1~10 It is alkyl. Common abbreviations for alkyl include Me(-CH), Et(-CHCH), iPr(-CH(CH)), nPr(-CHCHCH), n-Bu(-CHCHCHCHCH), or i-Bu(-CHCH(CH)).

[0088] "Alkylene" refers to an alkyl group in which two hydrogens are removed to provide a divalent radical, which can be substituted or unsubstituted. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), butylene (-CHCHCHCHCH-), pentylene (-CHCHCHCHCHCH-), hexylene (-CHCHCHCHCHCHCH-), and the like. For example, exemplary substituted alkylene groups substituted with one or more alkyl (methyl) groups include, but are not limited to, substituted methylene (-CH(CH)-, (-C(CH)-), substituted ethylene (-CH(CH)CH-, -CHCH(CH)-, -C(CH)CH-, -CHC(CH)-), substituted propylene (-CH(CH)CHCH-, -CHCH(CH)CH-, -CHCHCH(CH)CH-, -CHCHCH(CH)-, -C(CH)CHCH-, -CHC(CH)CH-, -CHCHC(CH)-), and the like. When a range or number of carbons is given for a particular alkylene group, it is understood that the range or number refers to the range or number of carbons in a divalent, linear carbon chain. An alkylene group can be substituted or unsubstituted with one or more substituents described herein.

[0089] "Alkenyl" refers to the radical of a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) ("C 2~20 In certain embodiments, the alkenyl does not contain any triple bonds. In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C 2~10 In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2~8In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as 2-butenyl) or terminal (such as 1-butenyl). C 2~4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each occurrence of an alkenyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2~10 In certain embodiments, the alkenyl group is a substituted C 2~10 It is alkenyl.

[0090] "Alkynyl" refers to the radical of a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) ("C 2~20 In certain embodiments, alkynyl does not contain any double bonds. In some embodiments, alkynyl groups have 2 to 10 carbon atoms ("C 2~10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). C 2~4 Examples of alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4Alkynyl groups include pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each occurrence of an alkynyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2~10 In certain embodiments, the alkynyl group is a substituted C 2~10 It is alkynyl.

[0091] The term "heteroalkyl," as used herein, refers to an alkyl group, as defined herein, further comprising one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) in the parent chain, wherein one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, a heteroalkyl group refers to a saturated group having 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC"). 1~10 In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~9 In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~8 In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~7 In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms ("heteroC 1~6In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms ("heteroC 1~5 In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms ("heteroC 1~4 In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom ("heteroC 1~3 In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom ("heteroC 1~2 In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroC1 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms ("heteroC 2~6 Unless otherwise specified, each occurrence of a heteroalkyl group is independently unsubstituted ("unsubstituted heteroalkyl") or substituted ("substituted heteroalkyl") with one or more substituents. In certain embodiments, a heteroalkyl group is an unsubstituted heteroC 1~10 In certain embodiments, the heteroalkyl group is a substituted heteroC 1~10 It is alkyl.

[0092] "Aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system ("C 6~14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 "Aryl"; e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, in which case the bonding radical or point of attachment is on the aryl ring, and in such cases the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each occurrence of the aryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl"), or substituted with one or more substituents ("substituted aryl"). In certain embodiments, the aryl group is an unsubstituted C 6~14 In certain embodiments, the aryl group is a substituted C 6~14 It is aryl.

[0093] In certain embodiments, the aryl group is selected from halo, C 1~8 Alkyl, C 1~8 Haloalkyl, cyano, hydroxy, C 1~8 It is substituted with one or more groups selected from alkoxy and amino.

[0094] Representative examples of substituted aryl include: [ka] In the formula, R 56 and R 57 may be hydrogen, and one of R 56 and R 57 At least one of 1~8 Alkyl, C 1~8 Haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C 1~8 Alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 , N.R. 58 SOR 59 NR 58 SO2R 59 , COO alkyl, COO aryl, CONR 58 R 59 ,CONR 58 OR 59 , N.R. 58 R 59 , SO2NR 58 R 59 , S-alkyl, SO alkyl, SO alkyl, S aryl, SO aryl, SO aryl, or R 56 and R 57 can join to form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms, optionally containing one or more heteroatoms selected from N, O, or S. R 60 and R 61 are independently hydrogen, C 1~8 Alkyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 4-10 membered heterocyclyl, C 6~10 Aryl, substituted C 6~10 It is aryl, 5- to 10-membered heteroaryl, or substituted 5- to 10-membered heteroaryl.

[0095] "Fused aryl" refers to an aryl having two of its ring carbons in common with a second aryl or heteroaryl ring, or a carbocyclyl or heterocyclyl ring.

[0096] "Heteroaryl" refers to the radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon atom or a nitrogen atom, as far as valence allows. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, in which case the point of attachment is on the heteroaryl ring; in such cases, the ring member number continues to refer to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused with one or more aryl groups, in which case the point of attachment can be on either the aryl ring or the heteroaryl ring, and in such cases the ring member count refers to the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be in either ring, i.e., either the ring containing a heteroatom (e.g., 2-indolyl) or the ring without a heteroatom (e.g., 5-indolyl).

[0097] In some embodiments, heteroaryl groups are 5- to 10-membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In some embodiments, heteroaryl groups are 5- to 8-membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heteroaryl"). In some embodiments, heteroaryl groups are 5- to 6-membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heteroaryl"). In some embodiments, 5- to 6-membered heteroaryls have 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, 5- to 6-membered heteroaryls have 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each occurrence of a heteroaryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, a heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, a heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0098] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0099] Representative examples of heteroaryls include: [ka] where each Z is a carbonyl, N, NR 65 , O, and S; R 65 are independently hydrogen, C 1~8Alkyl, C 3~10 Cycloalkyl, 4-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl.

[0100] "Carbocyclyl" or "carbocyclic" refers to a ring system containing 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5~10 carbocyclyl). Exemplary C 3~6 Carbocyclyl groups include, without limitation, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. 3~8 The carbocyclyl group is not limited to the above-mentioned C 3~6 Carbocyclyl groups include cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C 3~10 The carbocyclyl group is not limited to the above-mentioned C 3~8 Carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10), spiro[4.5]decanyl (C 10 ) and the like. Illustrating the foregoing, in certain embodiments, a carbocyclyl group is monocyclic ("monocyclic carbocyclyl") or contains a fused, bridged, or spiro ring system (e.g., a bicyclic system ("bicyclic carbocyclyl")), which may be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, in which case the point of attachment is on the carbocyclyl ring, and in such cases the number of carbons continues to refer to the number of carbons in the carbocyclyl ring system. Unless otherwise specified, each occurrence of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, a carbocyclyl group is an unsubstituted C 3~10 In certain embodiments, the carbocyclyl group is a substituted C 3~10 It is a carbocyclyl.

[0101] In some embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl group having 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5~6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5~10 Cycloalkyl). C 5~6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3~6 Examples of cycloalkyl groups include the aforementioned C 5~6Cycloalkyl groups include cyclopropyl (C3) and cyclobutyl (C4). 3~8 Examples of cycloalkyl groups include the aforementioned C 3~6 Cycloalkyl groups include cycloalkyl groups, as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each occurrence of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C 3~10 In certain embodiments, the cycloalkyl group is a substituted C 3~10 It is cycloalkyl.

[0102] "Heterocyclyl" or "heterocyclic" refers to the radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon atom or a nitrogen atom, where valence allows. Heterocyclyl groups can be monocyclic ("monocyclic heterocyclyl") or can be fused, bridged, or spiro ring systems (e.g., bicyclic systems ("bicyclic heterocyclyl")), and can be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring, as defined above, is fused to one or more carbocyclyl groups, with the point of attachment located on either the carbocyclyl or heterocyclyl ring, or in which a heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, with the point of attachment located on the heterocyclyl ring; in such cases, the number of ring members continues to refer to the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each occurrence of a heterocyclyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, a heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, a heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0103] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (a "5- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur (a "5- to 8-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur (a "5- to 6-membered heterocyclyl"). In some embodiments, a 5- to 6-membered heterocyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur, hi some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0104] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocycles) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0105] A "nitrogen-containing heterocyclyl" group refers to a 4- to 7-membered non-aromatic cyclic group containing at least one nitrogen atom, such as, but not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazine (e.g., N-methylpiperazine). Specific examples include azetidine, piperidone, and piperazone.

[0106] "Hetero," when used to describe a compound or a group present on a compound, means that one or more carbon atoms of the compound or group are replaced with a nitrogen, oxygen, or sulfur heteroatom. Hetero can apply to any of the above hydrocarbyl groups, such as alkyl, e.g., heteroalkyl; cycloalkyl, e.g., heterocyclyl; aryl, e.g., heteroaryl; cycloalkenyl, e.g., cycloheteroalkenyl, etc., having 1 to 5, especially 1 to 3, heteroatoms.

[0107] "Acyl" is the radical -C(O)R 20 refers to R 20 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, as defined herein. "Alkanoyl" refers to a group formed by the reaction of R 20 is a group other than hydrogen, an acyl group. Representative acyl groups include formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph), -C(O)-C1 to C8 alkyl, -C(O)-(CH2) t (C6~C 10 aryl), -C(O)-(CH2) t (5-10 membered heteroaryl), -C(O)-(CH2)t (C3~C 10 cycloalkyl), and -C(O)-(CH2) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4. In certain embodiments, R 21 is C1-C8 alkyl substituted with halo or hydroxy, or C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.

[0108] "Alkoxy" is -OR 29 R refers to the group 29 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, or substituted or unsubstituted heteroaryl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e., alkoxy having 1 to 6 carbon atoms. More particular alkoxy groups have 1 to 4 carbon atoms.

[0109] In certain embodiments, R 29 is amino, substituted amino, C6-C 10 Aryl, aryloxy, carboxyl, cyano, C3-C 10The "substituted alkoxy" group has one or more substituents, for example, 1 to 5 substituents, and particularly 1 to 3 substituents, and particularly 1 substituent, selected from the group consisting of cycloalkyl, 4- to 10-membered heterocyclyl, halogen, 5- to 10-membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2-, and aryl-S(O)2-. Exemplary "substituted alkoxy" groups include -O-(CH2) t (C6~C 10 aryl), -O-(CH2) t (5-10 membered heteroaryl), -O-(CH2) t (C3~C 10 cycloalkyl), and -O-(CH2) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present can itself be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. Certain exemplary "substituted alkoxy" groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2NMe2.

[0110] "Amino" refers to the radical -NH2.

[0111] An "oxo group" refers to =O.

[0112] "Substituted amino" refers to a group of the formula -N(R 38 )2, where R 38 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, or an amino protecting group; R 38At least one of R is not hydrogen. 38 are independently hydrogen, C 1~8 Alkyl, C 3~8 Alkenyl, C 3~8 Alkynyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl, or C 3~10 cycloalkyl; or halo- or hydroxy-substituted C 1~8 Alkyl; halo or hydroxy substituted C 3~8 Alkenyl; C substituted with halo or hydroxy 3~8 Alkynyl, or -(CH2) t (C6~C 10 aryl), -(CH2) t (5-10 membered heteroaryl), -(CH2) t (C3~C 10 cycloalkyl), or -(CH2) t (4- to 10-membered heterocyclyl), t is an integer from 0 to 8, each of which is selected from unsubstituted C 1~4 Alkyl, halo, unsubstituted C 1~4 Alkoxy, unsubstituted C 1~4 Haloalkyl, unsubstituted C 1~4 Hydroxyalkyl, or unsubstituted C 1~4 substituted by haloalkoxy or hydroxy, or both R 38 The groups are joined to form an alkylene group.

[0113] Exemplary "substituted amino" groups include -NR 39 -C1-C8 alkyl, -NR 39 -(CH2) t (C6~C 10 aryl), -NR 39 -(CH2) t (5-10 membered heteroaryl), -NR 39 -(CH2) t (C3~C 10 cycloalkyl), and -NR 39 -(CH2) t(4- to 10-membered heterocyclyl), where t is an integer from 0 to 4, e.g., 1 or 2, and each R 39 are independently H or C 1~8 represents alkyl, and any alkyl group present may itself be substituted by halo, substituted or unsubstituted amino, or hydroxy; and any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present may itself be an unsubstituted C 1~4 Alkyl, halo, unsubstituted C 1~4 Alkoxy, unsubstituted C 1~4 Haloalkyl, unsubstituted C 1~4 Hydroxyalkyl, or unsubstituted C 1~4 It may be substituted by haloalkoxy or hydroxy. For the avoidance of doubt, the term "substituted amino" includes alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino groups, as defined below. Substituted amino includes both mono- and di-substituted amino groups.

[0114] "Carboxy" refers to the -C(O)OH radical.

[0115] "Cyano" refers to the -CN radical.

[0116] "Halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, a halo group is either fluoro or chloro.

[0117] "Haloalkyl" refers to an alkyl radical in which the alkyl group is substituted with one or more halogens. Typical haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl, tetrafluoroethyl, and the like.

[0118] "Hydroxy" refers to the -OH radical.

[0119] "Nitro" refers to the radical -NO2.

[0120] "Thioketo" refers to the group =S.

[0121] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups defined herein are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl groups, "substituted" or "unsubstituted" alkenyl groups, "substituted" or "unsubstituted" alkynyl groups, "substituted" or "unsubstituted" carbocyclyl groups, "substituted" or "unsubstituted" heterocyclyl groups, "substituted" or "unsubstituted" aryl groups, or "substituted" or "unsubstituted" heteroaryl groups). In general, the term "substituted," whether preceded by the term "optionally," means that at least one hydrogen atom present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent that, when substituted, results in a stable compound, e.g., a compound that does not undergo spontaneous transformation (e.g., by rearrangement, cyclization, elimination, or other reaction). Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents may be the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, i.e., any of the substituents described herein that result in the formation of a stable compound. The present invention contemplates all combinations that result in stable compounds. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety.

[0122] Exemplary carbon atom substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb)2、-N(R bb )2、-N(R bb )3 + X - 、-N(OR cc )R bb 、-SH、-SR aa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa, -SC(=S)SR aa , -SC(=O)SR aa , -OC(=O)SR aa , -SC(=O)OR aa , -SC(=O)R aa , -P(=O)2R aa , -OP(=O)2R aa , -P(=O)(R aa )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)2N(R bb )2, -OP(=O)2N(R bb )2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(NR bb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(R cc )3, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 and 5- to 14-membered heteroaryl, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently having 0, 1, 2, 3, 4, or 5 R dd groups, or the two geminal hydrogens on the carbon atom are substituted with groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa, =NR bb , or =NOR cc is replaced by R aa Each instance of C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R aa groups joined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with R bb Each instance of is independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, P(=O)(NR cc )2, C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14aryl, and 5- to 14-membered heteroaryl, or two R bb groups joined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd substituted with R cc Each instance of is independently hydrogen, C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R cc groups joined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with R dd Each instance of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff)2, -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)2R ee , -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently having 0, 1, 2, 3, 4, or 5 R gg substituted with a group or two geminal R dd The substituents can be joined to form =O or =S, and R ee independently, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently having 0, 1, 2, 3, 4, or 5 R gg substituted with R ff Each instance of is independently hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, or two R ff The groups are joined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R gg substituted with R gg Each instance of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6 Alkyl, -ON(C 1~6 alkyl)2, -N(C 1~6 alkyl)2, -N(C 1~6 Alkyl)3 + X - , -NH(C 1~6 alkyl)2 + X - , -NH2(C 1~6 alkyl) + X - , -NH3 + X - , -N(OC 1~6 Alkyl)(C 1~6 alkyl), -N(OH)(C 1~6 alkyl), -NH(OH), -SH, -SC 1~6 Alkyl, -SS(C 1~6 alkyl), -C(=O)(C1~6 alkyl), -CO2H, -CO2(C 1~6 alkyl), OC(O)(C 1~6 alkyl), -OCO2(C 1~6 alkyl), -C(=O)NH2, -C(=O)N(C 1~6 alkyl), 2, -OC(=O)NH(C 1~6 alkyl), -NHC(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(C 1~6 alkyl), -NHCO2(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1~6 alkyl), -OC(=NH)(C 1~6 alkyl), -OC(=NH)OC 1~6 Alkyl, -C(=NH)N(C 1~6 alkyl)2, -C(=NH)NH(C 1~6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1~6 alkyl)2, -OC(NH)NH(C 1~6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1~6 alkyl)2, -NHC(NH)NH2, -NHSO2(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 alkyl), -SO2NH2, -SO2C 1~6 Alkyl, -SO2OC 1~6 Alkyl, -OSO2C 1~6 Alkyl, -SOC 1~6 Alkyl, -Si(C 1~6 alkyl)3, -OSi(C 1~6 alkyl)3-C(=S)N(C 1~6 alkyl)2, C(=S)NH(C 1~6 alkyl), C(=S)NH2, -C(=O)S(C 1~6 alkyl), -C(=S)SC 1~6 Alkyl, -SC(=S)SC 1~6Alkyl, -P(=O)2(C 1~6 alkyl), -P(=O)(C 1~6 alkyl)2, -OP(=O)(C 1~6 alkyl)2, -OP(=O)(OC 1~6 Alkyl)2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or two geminal R gg The substituents can be joined to form =O or =S, and X - is the counter ion.

[0123] A "counterion" or "anionic counterion" is a negatively charged group that associates with a cationic quaternary amino group to maintain electroneutrality. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - OH - , H2PO4 - , HSO4 - , sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

[0124] These and other exemplary substituents are described in detail in the detailed description and claims. The present invention is not intended to be limited in any way by the exemplary substituents listed above.

[0125] B. Other Definitions As used herein, the term "modulation" refers to the A "Modulators" (e.g., modulatory compounds) refer to the inhibition or enhancement of receptor function, e.g., GABA receptors. A It can be an agonist, partial agonist, antagonist, or partial antagonist of the receptor.

[0126] As used herein, "selectively modulate" means to selectively modulate GABA A It refers to a higher or better modulation of a particular subunit composition of the receptor compared to other subunit compositions.

[0127] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of a federal or state government or a corresponding agency in a country other than the United States, or listed in the United States Pharmacopoeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0128] "Pharmaceutically acceptable salts" refers to salts of the compounds of the present invention that are pharmaceutically acceptable and possess the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and can be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include (1) salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or salts formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or when coordinated with an organic base, e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc.; and, if the compound contains a basic functional group, salts of non-toxic organic or inorganic acids, e.g., hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counterion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.See, e.g., Berge, et al., J. Pharm. Sci. (1977) 66(1):1-79.

[0129] The term "prodrug" is intended to encompass therapeutically inactive compounds that are converted under physiological conditions to the therapeutically active agents of the present invention. One method for creating a prodrug is to design a selected moiety that is hydrolyzed or cleaved under physiological conditions at the target in vivo site of action to expose the molecule of interest, which then produces a therapeutic effect. In certain embodiments, the prodrug is converted by the enzymatic activity of the subject.

[0130] In an alternative embodiment, the present invention provides prodrugs of the compounds described herein, wherein the prodrugs comprise a cleavable moiety on the C3 hydroxy as shown in the formulas presented herein.

[0131] "Tautomers" refer to compounds that are interchangeable forms of a particular compound structure, with changes in the displacement of hydrogen atoms and electrons. Thus, two structures can be in equilibrium with the displacement of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro-forms of phenylnitromethane, which are also formed by treatment with acid or base. Tautomers can be relevant to achieving optimal chemical reactivity and biological activity of a compound of interest.

[0132] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., men and women of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, e.g., mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs). In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.

[0133] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen protecting groups include -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa ) 3、 -P(R cc )2, -P(R cc )3, -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)2N(R bb )2, and -P(=O)(NR bb ) 2, and R aa , R bb , and R cc is as defined herein. Oxygen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 3, incorporated herein by reference. rd edition, John Wiley & Sons, 1999.

[0134] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), 2-methoxyethoxymethyl (MEM), benzyl (Bn), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBDMS), t-butylmethoxyphenylsilyl (TBMPS), methanesulfonate (mesylate), and tosylate (Ts).

[0135] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to as a thiol protecting group). Sulfur protecting groups include -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3, -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)OR cc )2, -P(=O)2N(R bb )2, and -P(=O)(NR bb ) 2, and R aa , R bb , and R cc is as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Butts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0136] In certain embodiments, the substituent present on the nitrogen atom is an amino protecting group (also referred to as a nitrogen protecting group). Amino protecting groups include -OH, -OR aa , -N(R cc )2, -C(=O)R aa , -C(=O)OR aa , -C(=O)N(R cc )2, -S(=O)2R aa , -C(=NR cc )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , C 1~10 Alkyl, C 2-10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 and 5- to 14-membered heteroaryl groups, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently having 0, 1, 2, 3, 4, or 5 R dd substituted with R aa , R bb , R cc , and R dd is as defined herein. Amino protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 3, incorporated herein by reference. rd edition, John Wiley & Sons, 1999.

[0137] Exemplary amino-protecting groups include, but are not limited to, amide groups (e.g., —C(═O)R aa ; carbamate groups (e.g., —C(═O)OR ), including, but not limited to, 9-fluorenylmethyl carbamate (Fmoc), t-butyl carbamate (BOC), and benzyl carbamate (Cbz); aa sulfonamide groups (e.g., —S(═O)R ), including, but not limited to, p-toluenesulfonamide (Ts), methanesulfonamide (Ms), and N-[2-(trimethylsilyl)ethoxy]methylamine (SEM); aa ), but are not limited to these.

[0138] The terms "disease," "disorder," and "condition" are used interchangeably herein.

[0139] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate actions taken while a subject is afflicted with a particular disease, disorder, or condition that lessen the severity of the disease, disorder, or condition or delay or slow the progression of the disease, disorder, or condition ("therapeutic treatment"), as well as actions taken before a subject is afflicted with a particular disease, disorder, or condition.

[0140] Generally, the "effective amount" of a compound refers to an amount sufficient to induce a desired biological response, for example, to treat a CNS-related disorder, and is sufficient to induce anesthesia or sedation.As will be understood by those skilled in the art, the "effective amount" of the compound of the present invention may vary depending on factors such as the biological endpoint of interest, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the age, weight, health status and condition of the subject.

[0141] As used herein, unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound means the amount of therapeutic agent alone, or in combination with other therapies, that provides a therapeutic benefit in the treatment of the disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, an amount that alleviates or avoids the symptoms or causes of a disease or condition, or an amount that enhances the therapeutic efficacy of another therapeutic agent.

[0142] In an alternative embodiment, the present invention contemplates administering a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof, as a prophylactic agent before a subject is affected by a particular disease, disorder, or condition. As used herein, unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent or prevent the recurrence of a disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition. A prophylactically effective amount of a compound refers to the amount of therapeutic agent alone or in combination with other agents that provides a prophylactic benefit in the prevention of the disease, disorder, or condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or an amount that enhances the prophylactic efficacy of another prophylactic agent.

[0143] As used herein, an "episodic dosing regimen" refers to a dosing regimen in which a compound disclosed herein or a composition comprising a compound disclosed herein is administered to a subject for a finite period of time in response to a diagnosis or symptom of a disorder or a symptom thereof, e.g., a diagnosis or symptom of depression, an episode of major depressive disorder, a diagnosis or symptom of bipolar depression, anxiety, or postpartum depression. In some embodiments, the major depressive disorder is a severe major depressive disorder. In some embodiments, the major depressive disorder is a severe major depressive disorder. In some embodiments, the compound is formulated as individual dosage units, each unit comprising a compound disclosed herein and one or more suitable pharmaceutical excipients. In some embodiments, the duration of an episodic dosing regimen is multiple weeks, e.g., about 8 weeks. In contrast to chronic administration as defined herein, episodic administration of a compound is administered for a finite period of time, e.g., about 2 weeks to about 8 weeks, depending on the diagnosis of a disorder, e.g., depression, or a symptom thereof. In some embodiments, episodic administration is administered once daily for multiple weeks, e.g., about 2 weeks to about 6 weeks. In one embodiment, the duration of episodic administration is 2 weeks. In some embodiments, more than one episodic dosing regimen is administered to a subject, for example, more than one episodic regimen throughout the subject's lifetime.

[0144] As used herein, the term "optionally substituted" means substituted or unsubstituted.

[0145] II. Compounds The formulas described herein may refer to specific carbon atoms, such as C17, C3, C19, etc. These references are based on the carbon atom positions according to steroid nomenclature known and used in the industry, as shown below: [ka] For example, C17 refers to the 17th carbon, and C3 refers to the 3rd carbon.

[0146] A. Compound The present invention relates to a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein R 2a , R 2b , R 4a , R 4b , R 6 , R 7 , R 11a , R 11b , R 15a , and R 15b each independently represents hydrogen, halogen, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, -NR D1 C(=O)R D1 , a substituted or unsubstituted 3- to 6-membered monocyclic heterocycle, or a substituted or unsubstituted 8- to 12-membered bicyclic heterocycle, wherein the monocyclic or bicyclic heterocycle has 1 to 3 heteroatoms independently selected from N, O, and S, and each R D1 are independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 alkynyl, a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R D1 groups join to form a substituted or unsubstituted 3- to 6-membered monocyclic heterocycle or 8- to 12-membered bicyclic heterocycle, wherein the monocyclic or bicyclic heterocycle has 1 to 3 heteroatoms independently selected from N, O, and S, or R 2a and R 2b , R 4a and R 4b , or R 11a and R11b are joined together to form an oxo (=O) group, and R 16 and R 17 each independently represents hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, -OR A1 , -SR A1 , -N(R A1 )2, -N(R A1 ), -CN(R A1 )2, -C(O)R A1 , -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)SR A1 , -OC(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 , -SC(=O)SR A1 , -NHC(=O)R A1 , -SC(=O)N(R A1 )2, -NHC(=O)OR A1 , -NHC(=O)SR A1 , -NHC(=O)N(R A1 )2, -OS(=O)2R A2 , -OS(=O)2OR A1 , -SS(=O)2R A2 , -SS(=O)2OR A1 , -S(=O)R A2 , -SO2R A2 , -S(=O)2OR A1 or a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S; A1 are independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6Alkynyl, a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S; 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; -SO2R A2 , -C(O)R A2 or two R A1 groups joined together to form a substituted or unsubstituted 3- to 6-membered saturated, partially unsaturated, or fully unsaturated monocyclic heterocycle having 1 to 3 heteroatoms independently selected from N, O, and S; and each R A2 are independently substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 alkynyl, or a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S; R 3a 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 1~6 Alkyl-OC 1~6 alkyl, or a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S; R 5 is hydrogen, unsubstituted methyl, or absent; [ka] is a single or double bond, with the proviso that [ka] is a single bond, R 5 is hydrogen or methyl, [ka] is a double bond, R 5 is non-existent, and R 19 is hydrogen or substituted or unsubstituted C 1~6 alkyl, and R X is hydrogen or substituted or unsubstituted C 1~6 alkyl, and R Y is a substituted or unsubstituted phenyl, or a substituted or unsubstituted 3- to 6-membered monocyclic heteroaryl or 8- to 12-membered bicyclic heteroaryl, wherein the monocyclic or bicyclic heteroaryl has 1 to 5 heteroatoms independently selected from N, O, and S; and t is 1, 2, or 3, with the proviso that when t is 1, R 3a is -CH2OCH2CH3, and R Y is a substituted or unsubstituted pyrazinyl, and then R 19 is -CH3.

[0147] B. Substituents 1.R 2a and R 2b basis In some embodiments, R 2a and R 2b each independently represents hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2, and each R D1 are independently hydrogen, substituted or unsubstituted C 1~6 alkyl, or a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S.

[0148] In some embodiments, R 2a and R 2b each independently represents hydrogen, C optionally substituted with 1 to 3 halogens 1~6Alkyl, C optionally substituted with 1 to 3 halogens 1~6 In some embodiments, R 2a and R 2b Each of R is independently hydrogen, —CH, —CHCH, —OH, —OCH, or —CH(CH). 2a and R 2b In some embodiments, one of R 2a and R 2b Each of is hydrogen.

[0149] In some embodiments, R 2a and R 2b one of which is hydrogen and the other is hydrogen or substituted or unsubstituted C 1~6 In some embodiments, R 2a and R 2b one of which is hydrogen and the other is hydrogen or substituted or unsubstituted C 1~3 In some embodiments, R 2a and R 2b One of the groups is hydrogen and the other is hydrogen or unsubstituted C 1~3 In some embodiments, R 2a and R 2b is hydrogen and the other is hydrogen or —CH. In some embodiments, R 2a and R 2b One of them is hydrogen and the other is -CH3.

[0150] In some embodiments, R 2a is hydrogen or substituted or unsubstituted C 1~6 In some embodiments, R 2a is hydrogen or unsubstituted C 1~6 In some embodiments, R 2a is hydrogen or substituted or unsubstituted C 1~3 In some embodiments, R 2a is hydrogen or unsubstituted C 1~3In some embodiments, R 2a is hydrogen or —CH. In some embodiments, R 2a is hydrogen. In some embodiments, R 2a is -CH3.

[0151] In some embodiments, R 2a and R 2b are joined together to form an oxo (=O) group.

[0152] 2.R 4a and R 4b base In some embodiments, R 4a and R 4b each independently represents hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2 and R D1 Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 alkyl, a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S.

[0153] In some embodiments, R 4a and R 4b each independently represents hydrogen, C optionally substituted with 1 to 3 halogens 1~6 Alkyl, C optionally substituted with 1 to 3 halogens 1~6 In some embodiments, R 4a and R 4b Each of R is independently hydrogen, —CH, —CHCH, —OH, —OCH, or —CH(CH). 4a and R 4b In some embodiments, one of R 4a and R4b are both hydrogen.

[0154] In some embodiments, R 4a and R 4b are joined together to form an oxo (=O) group.

[0155] 3.R 11a and R 11b basis In some embodiments, R 11a and R 11b each independently represents hydrogen, halogen, cyano, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2 and R D1 Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 alkyl, a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S.

[0156] In some embodiments, R 11a and R 11b each independently represents hydrogen, C optionally substituted with 1 to 3 halogens 1~6 C optionally substituted with alkyl or 1 to 3 halogens 1~6 In some embodiments, R 11a and R 11b Each of R is independently hydrogen, —CH, —CHCH, —OCH, or —CH(CH). 11a and R 11b In some embodiments, one of R 11a and R 11b Each of is hydrogen.

[0157] In some embodiments, R 11a and R 11bare joined together to form an oxo (=O) group.

[0158] 4.R 15a and R 15b Group and t In some embodiments, R 15a and R 15b each independently represents hydrogen, halogen, cyano, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2 and R D1 Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 alkyl, a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S.

[0159] In some embodiments, R 15a and R 15b each independently represents hydrogen, C optionally substituted with 1 to 3 halogens 1~6 C optionally substituted with alkyl or 1 to 3 halogens 1~6 In some embodiments, R 15a and R 15b Each of R is independently hydrogen, —CH, —CHCH, —OCH, or —CH(CH). 11a and R 11b In some embodiments, one of R 15a and R 15b Each of is hydrogen.

[0160] In some embodiments, t is 1 or 2. In some embodiments, t is 2 or 3. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3.

[0161] 5.R7 In some embodiments, R 7 is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2 and R D1 Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 alkyl, a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S.

[0162] In some embodiments, R 7 is R 7 is hydrogen, C optionally substituted with 1 to 3 halogens 1~6 , C optionally substituted with 1 to 3 halogens 1~6 In some embodiments, R 7 is hydrogen, —CH, —CHCH, —OH, —OCH, or —CH(CH). In some embodiments, R 7 is hydrogen.

[0163] 6.R 6 In some embodiments, R 6 is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2 and R D1 Each instance of is independently hydrogen, substituted or unsubstituted C 1~6alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S.

[0164] In some embodiments, R 6 is hydrogen, C optionally substituted with 1 to 3 halogens 1~6 , C optionally substituted with 1 to 3 halogens 1~6 In some embodiments, R 6 is independently hydrogen, —CH, —CHCH, —OH, —OCH, or —CH(CH). In some embodiments, R 6 is hydrogen.

[0165] 7.R 16 In some embodiments, R 16 is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2 and R D1 Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 alkyl, a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S.

[0166] In some embodiments, R 16 is hydrogen, C optionally substituted with 1 to 3 halogens 1~6 , C optionally substituted with 1 to 3 halogens 1~6 In some embodiments, R 16 is hydrogen, —CH, —CHCH, —OH, —OCH, or —CH(CH). In some embodiments, R16 is hydrogen.

[0167] 8.R 17 In some embodiments, R 17 is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2 and R D1 Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 alkyl, a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S.

[0168] In some embodiments, R 17 each of which is optionally substituted with hydrogen, 1 to 3 halogens; 1~6 , C optionally substituted with 1 to 3 halogens 1~6 In some embodiments, R 17 is hydrogen, —CH, —CHCH, —OH, —OCH, or —CH(CH). In some embodiments, R 17 is hydrogen.

[0169] 9.R 19 In some embodiments, R 19 is hydrogen or substituted or unsubstituted C 1~5 In some embodiments, R 19 is hydrogen or substituted or unsubstituted C1-C4 alkyl. In some embodiments, R 19 is hydrogen or unsubstituted C 1~5 In some embodiments, R 19 is hydrogen or unsubstituted C1-C4 alkyl. In some embodiments, R 19 is hydrogen or unsubstituted C 1~3In some embodiments, R 19 is hydrogen, —CH, —CHCH, or —CHOCH(CH). In some embodiments, R 19 is hydrogen, —CH, or —CHCH. In some embodiments, R 19 is hydrogen. In some embodiments, R 19 is —CHOCH(CH). In some embodiments, R 19 is -CH3. In some embodiments, R 19 is -CH2CH3.

[0170] 10.R 3a In some embodiments, R 3a 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 1~6 Alkyl-OC 1~6 alkyl, a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S.

[0171] In some embodiments, R 3a is a substituted or unsubstituted C 1~6 In some embodiments, R 3a is the unsubstituted C 1~6 In some embodiments, R 3a is a substituted or unsubstituted C 1~4 In some embodiments, R 3a is the unsubstituted C 1~4 In some embodiments, R 3a is the unsubstituted C 1~3 In some embodiments, R 3a is unsubstituted methyl (i.e., —CH3).

[0172] In some embodiments, R3a is hydrogen, unsubstituted C 1~4 alkyl, or -CH2OCH2CH3. In some embodiments, R 3a is —CH2OCH3 or unsubstituted methyl (i.e., —CH3). In some embodiments, R 3a is hydrogen, unsubstituted C 1~4 alkyl, or -CH2OCH2CH3.

[0173] In some embodiments, R 3a is a substituted or unsubstituted C 1~6 Alkyl, or substituted or unsubstituted C 1~6 Alkyl-OC 1~6 In some embodiments, R 3a is a substituted or unsubstituted C 1~3 Alkyl or substituted or unsubstituted C 1~3 Alkyl-OC 1~3 In some embodiments, R 3a is the unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 Alkyl-OC 1~3 It is alkyl.

[0174] In some embodiments, R 3a is the unsubstituted C 1~6 alkyl, -CH2OCH3, or -CH2OCH2CH3.

[0175] In some embodiments, R 3a is -CH2CH3, -CH3, -CH2OCH2CH3, -CH2OCH3. In some embodiments, R 3a is -CH, -CHCHCH, -CHOCH, -CHOCHCH. In some embodiments, R 3a is -CH3. In some embodiments, R 3a is -CH2CH3. In some embodiments, R 3a is -CH2CH2CH3. In some embodiments, R 3ais —CH2OCH3. In some embodiments, R 3a is -CH2OCH2CH3.

[0176] In some embodiments, when t is 2, R 3a is —CH or —CHOCHCH. In some embodiments, R 2a and R 2b When one of the groups is hydrogen and the other is -CH3, R 3a is -CH3.

[0177] In some embodiments, R 3a is -CH2OR 1 is.

[0178] 11.R 1 In some embodiments, R 1 is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, R 1 is an unsubstituted C1-C6 alkyl. In some embodiments, R 1 is a substituted or unsubstituted C 1~3 In some embodiments, R 1 is the unsubstituted C 1~3 In some embodiments, R 1 is -CH2CH3 or -CH3. In some embodiments, R 1 is -CH2CH3. In some embodiments, R 1 is -CH3.

[0179] 12.R 5 In some embodiments, R 5 is hydrogen or unsubstituted methyl. In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is unsubstituted methyl.

[0180] In some embodiments, R 5is a hydrogen in the cis position. 5 is a hydrogen in the trans position. 5 is an unsubstituted methyl in the cis position. 5 is an unsubstituted methyl in the trans position.

[0181] 13.R X In some embodiments, R X is hydrogen or substituted or unsubstituted C 1~6 In some embodiments, R X is hydrogen or unsubstituted C 1~6 In some embodiments, R X is hydrogen or substituted or unsubstituted C 1~4 In some embodiments, R X is hydrogen or unsubstituted C 1~4 In some embodiments, R X is hydrogen or unsubstituted methyl (i.e., —CH). In some embodiments, R X is hydrogen, —CH, or —CHCH. In some embodiments, R X is hydrogen. In some embodiments, R X is -CH3. In some embodiments, R X is -CH2CH3.

[0182] 14.R Y In some embodiments, R Y is substituted or unsubstituted pyrazinyl, cyano-substituted pyrimidine, substituted or unsubstituted pyridine, or substituted phenyl. In some embodiments, R Y is substituted or unsubstituted pyrazinyl, cyano-substituted pyrimidine, or substituted phenyl. In some embodiments, R Y is a cyano-substituted pyridine. In some embodiments, R Y is a fluoro-substituted pyridine. In some embodiments, RY is a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-2 nitrogen atoms, and R Y The 3- to 8-membered rings are independently halogen, -CN, or C 1~6 In some embodiments, R Y is a substituted or unsubstituted pyrazinyl, a cyano-substituted pyrimidine, a substituted or unsubstituted phenyl, a cyano- or fluoro-substituted pyridine, or a pyrazole substituted with two unsubstituted methyl groups.

[0183] In some embodiments, R Y teeth, [ka] is selected from In the formula, each R D are independently hydrogen, halogen, -NO2, -CN, -OR GA , -N(R GA )2, -C(=O)R GA , -C(=O)OR GA , -C(=O)N(R GA )2, -OC(=O)R GA , -OC(=O)OR GA , -N(R GA )C(=O)R GA , -OC(=O)N(R GA )2, -N(R GA )C(=O)OR GA , -S(=O)2R GA , -S(=O)2OR GA , -OS(=O)2R GA , -S(=O)2N(R GA )2, or -N(R GA )S(=O)2R GA , substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6alkynyl, a substituted or unsubstituted 3-10 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S, or two R GA together with intervening atoms form a substituted or unsubstituted 3-5 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S; and each X is independently -N= or -C(R D ) = and each R GA are independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 alkynyl, a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, or two R GA groups together with intervening atoms form a substituted or unsubstituted 5- to 6-membered heterocyclic ring having 2 to 3 heteroatoms independently selected from N, O, or S; R X1 is hydrogen or substituted or unsubstituted C 1~6 alkyl, or a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S; and e is 0, 1, 2, or 3.

[0184] In some embodiments, R Y teeth, [ka] is selected from In the formula, R D Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1~6 alkyl, —CN, substituted or unsubstituted 5- to 6-membered heteroaryl, substituted or unsubstituted 5-membered heterocyclyl, and e is 0, 1, 2, 3, or 4.

[0185] In some embodiments, R Y teeth, [ka] is selected from wherein each R is independently -CH, -CHCH, -i-Pr, cyclopropyl, or -CN.

[0186] In some embodiments, R Y teeth, [ka] is selected from.

[0187] In some embodiments, R Y teeth, [ka] is.

[0188] In some embodiments, R Y teeth, [ka] is.

[0189] In some embodiments, R Y teeth, [ka] is selected from In the formula, each R D are independently hydrogen, halogen, -NO2, -CN, -OR GA , -N(R GA )2, -C(=O)R GA , -C(=O)OR GA , -C(=O)N(R GA )2, -OC(=O)R GA, -OC(=O)OR GA , -N(R GA )C(=O)R GA , -OC(=O)N(R GA )2, -N(R GA )C(=O)OR GA , -S(=O)2R GA , -S(=O)2OR GA , -OS(=O)2R GA , -S(=O)2N(R GA )2, or -N(R GA )S(=O)2R GA , substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 alkynyl, a substituted or unsubstituted 3-10 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S, or two R D groups, together with the atoms to which they are attached, form a substituted or unsubstituted 5-6 membered saturated, partially unsaturated, or fully unsaturated ring having up to three heteroatoms independently selected from N, O, or S, and each R GA are independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 alkynyl, a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, or two R GA The groups, together with the atoms to which they are attached, form a substituted or unsubstituted 5-6 membered saturated, partially unsaturated, or fully unsaturated ring having up to three heteroatoms independently selected from N, O, or S, and e is 0, 1, 2, 3, 4, or 5.

[0190] In some embodiments, R Y teeth, [ka] is selected from.

[0191] In some embodiments, R Y teeth, [ka] and two of W1, W2, W3, W4, and W5 are -N= and the rest are -C(R')=, each R' is independently hydrogen or -CN, and at least one R' is -CN. In some embodiments, W1 and W2 are -N=, or W1 and W3 are -N=, or W1 and W4 are -N=, or W1 and W5 are -N=, or W2 and W4 are -N=. In some embodiments, W1 and W2 are -N=. In some embodiments, W1 and W3 are -N=. In some embodiments, W1 and W4 are -N=. In some embodiments, W1 and W5 are -N=. In some embodiments, W2 and W4 are -N=.

[0192] In some embodiments, W3 is -C(R')=, where R' is -CN. In some embodiments, W4 is -C(R')=, where R' is -CN.

[0193] In some embodiments, R Y teeth, [ka] is.

[0194] In some embodiments, R Y teeth, [ka] is selected from In the formula, R DEach instance of is independently hydrogen, halogen, substituted or unsubstituted C 1~6 alkyl, —CN, substituted or unsubstituted 5- to 6-membered heteroaryl, substituted or unsubstituted 5-membered heterocyclyl, and e is 0, 1, 2, 3, or 4.

[0195] In some embodiments, R Y teeth, [ka] is selected from In the formula, R D Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1~6 alkyl, -CN, substituted or unsubstituted 5- to 6-membered heteroaryl, substituted or unsubstituted 5-membered heterocyclyl.

[0196] In some embodiments, R D Each instance of is independently a halogen, substituted or unsubstituted C 1~6 alkyl, or -CN. In some embodiments, R D Each instance of is independently -F, -CH, or -CN. In some embodiments, R D Each instance of is -F. In some embodiments, R D is —CH. In some embodiments, R D Each instance of is -CN.

[0197] In some embodiments, R Y teeth, [ka] is selected from.

[0198] In some embodiments, the pharmaceutical composition comprises a compound described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0199] In some embodiments, a method for treating a CNS-related disorder in a subject in need thereof comprises administering to the subject an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a seizure disorder, a memory and / or cognition disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder and / or withdrawal syndrome, tinnitus, or status epilepticus. In some embodiments, the CNS-related disorder is depression. In some embodiments, the CNS-related disorder is postpartum depression. In some embodiments, the CNS-related disorder is major depressive disorder. In some embodiments, the major depressive disorder is severe major depressive disorder. In some embodiments, the major depressive disorder is severe major depressive disorder.

[0200] C. Other Compounds of the Invention Another aspect of the present invention is a compound of formula (I-1): [ka] or a pharmaceutically acceptable salt thereof, 2a , R 2b , R 3a , R 4a , R 4b , R 5 , R 6 , R 7 , R 11a , R 11b , R 15a , R 15b , R 16 , R 17 , R 19 , R X , and R Y is as defined in any of the embodiments of the compound of formula (I).

[0201] In some embodiments, R 2a , R 2b , R 4a , R 4b , R 6 , R 7 , R11a , R 11b , R 15a , and R 15b each independently represents hydrogen, halogen, hydroxyl, cyano, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, -NR D1 C(=O)R D1 , a substituted or unsubstituted 3- to 6-membered monocyclic heterocycle, or a substituted or unsubstituted 8- to 12-membered bicyclic heterocycle, wherein the monocyclic or bicyclic heterocycle has 1 to 3 heteroatoms independently selected from N, O, and S, and each R D1 are independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 alkynyl, a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R D1 groups join to form a substituted or unsubstituted 3- to 6-membered monocyclic heterocycle or 8- to 12-membered bicyclic heterocycle, wherein the monocyclic or bicyclic heterocycle has 1 to 3 heteroatoms independently selected from N, O, and S, or R 2a and R 2b , R 4a and R 4b , or R 11a and R 11b are joined together to form an oxo (=O) group, and R 16 and R 17 each independently represents hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, -OR A1, -SR A1 , -N(R A1 )2, -N(R A1 ), -CN(R A1 )2, -C(O)R A1 , -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)SR A1 , -OC(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 , -SC(=O)SR A1 , -NHC(=O)R A1 , -SC(=O)N(R A1 )2, -NHC(=O)OR A1 , -NHC(=O)SR A1 , -NHC(=O)N(R A1 )2, -OS(=O)2R A2 , -OS(=O)2OR A1 , -SS(=O)2R A2 , -SS(=O)2OR A1 , -S(=O)R A2 , -SO2R A2 , -S(=O)2OR A1 or a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S; A1 are independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S; 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; -SO2R A2 , -C(O)R A2 or two R A1groups joined together to form a substituted or unsubstituted 3- to 6-membered saturated, partially unsaturated, or fully unsaturated monocyclic heterocycle having 1 to 3 heteroatoms independently selected from N, O, and S; and each R A2 are independently substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 alkynyl, or a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S; R 3a is the unsubstituted C 1~6 alkyl, -CH2OCH3, or -CH2OCH2CH3, and R 5 is hydrogen, unsubstituted methyl, or absent; [ka] is a single or double bond, with the proviso that [ka] is a single bond, R 5 is hydrogen or methyl, [ka] is a double bond, R 5 is non-existent, and R 19 is hydrogen or unsubstituted C 1~6 Alkyl, R X is hydrogen or substituted or unsubstituted C 1~6 alkyl, and R Y is a substituted or unsubstituted pyrazinyl, a cyano-substituted pyrimidine, a substituted or unsubstituted pyridine, or a substituted phenyl, with the proviso that R 3a is -CH2OCH2CH3, and R Y When R is substituted or unsubstituted pyrazinyl, 19 is unsubstituted methyl.

[0202] In some embodiments, R Y is a substituted or unsubstituted pyrazinyl, a cyano-substituted pyrimidine, or a substituted phenyl.

[0203] In some embodiments, the compound of formula (I-1) is a compound of formula (I-2): [ka] or a pharmaceutically acceptable salt thereof, wherein R 2a , R 2b , R 3a , R 4a , R 4b , R 5 , R 6 , R 7 , R 11a , R 11b , R 15a , R 15b , R 16 , R 17 , R 19 , R X , and R Y is as defined in any of the embodiments of compounds of formula (I) or (I-1).

[0204] In some embodiments, R 3a is -CH2OCH3 or unsubstituted methyl, and R 5 is hydrogen, unsubstituted methyl, or absent; [ka] is a single or double bond, with the proviso that [ka] is a single bond, R 5 is hydrogen or methyl, [ka] is a double bond, R 5 is non-existent, and R 19 is hydrogen or substituted or unsubstituted C 1~6 alkyl, and R X is hydrogen or substituted or unsubstituted C 1~6 alkyl, and R Y is a cyano-substituted pyridine.

[0205] In some embodiments, the compound of formula (I-1) is a compound of formula (I-3): [ka] or a pharmaceutically acceptable salt thereof, wherein R 2a , R 2b , R 3a , R 4a , R 4b , R 5 , R 6 , R 7 , R 11a , R 11b , R 15a , R 15b , R 16 , R 17 , R 19 , R X , and R Y is as defined in any of the embodiments of compounds of formula (I), (I-1), or (I-2).

[0206] In some embodiments, R 3a is -CH2OCH3 or unsubstituted methyl, and R 5 is hydrogen, unsubstituted methyl, or absent; [ka] is a single or double bond, with the proviso that [ka] is a single bond, R 5is hydrogen or methyl, [ka] is a double bond, R 5 is non-existent, and R 19 is hydrogen or substituted or unsubstituted C 1~6 alkyl, and R X is hydrogen or substituted or unsubstituted C 1~6 alkyl, and R Y is a cyano-substituted pyridine.

[0207] In some embodiments, the compound of formula (I-1) is a compound of formula (I-a1): [ka] or a pharmaceutically acceptable salt thereof, wherein R 3a , R 5 , R 17 , R 19 , R X , and R Y is as defined in any of the embodiments of compounds of formula (I), (I-1), (I-2), or (I-3).

[0208] In some embodiments, the compound of formula (I-2) is a compound of formula (I-a2): [ka] or a pharmaceutically acceptable salt thereof, wherein R 3a , R 5 , R 17 , R 19 , R X , and R Y is as defined in any of the embodiments of compounds of formula (I), (I-1), (I-2), or (I-3).

[0209] In some embodiments, the compound of formula (I-3) is a compound of formula (I-a3): [ka] or a pharmaceutically acceptable salt thereof, wherein R 3a , R 5 , R 17 , R 19 , R X , and R Y is as defined in any of the embodiments of compounds of formula (I), (I-1), (I-2), or (I-3).

[0210] In some embodiments, when the compound is of formula (I-a1), (I-a2), or (I-a3), R 17 is hydrogen, —CH, —CHCH, —OH, —OCH, or —CH(CH). In some embodiments, R 17 is hydrogen.

[0211] In some embodiments, when the compound is of formula (I-a1), (I-a2), or (I-a3), R 19 is hydrogen or unsubstituted C 1~4 In some embodiments, R 19 is hydrogen or unsubstituted C 1~4 In some embodiments, R 19 is hydrogen, -CH3, or -CH2CH3.

[0212] In some embodiments, when the compound is of formula (I-a1), (I-a2), or (I-a3), R 3a is hydrogen, unsubstituted C 1~4 alkyl, or -CH2OCH2CH3.

[0213] In some embodiments, when the compound is of formula (I-a1), (I-a2), or (I-a3), R 5 is hydrogen. In some embodiments, R 5 is unsubstituted methyl.

[0214] In some embodiments, the compound of Formula (I-a1) is a compound of Formula (I-b1a) or Formula (I-b2a): [ka] or a pharmaceutically acceptable salt thereof, wherein R 3a , R 17 , R 19 , R X , and R Y is as defined in any of the embodiments of compounds of formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), or (I-a3).

[0215] In some embodiments, the compound of Formula (I-a2) is a compound of Formula (I-b1b) or Formula (I-b2b): [ka] or a pharmaceutically acceptable salt thereof, wherein R 3a , R 17 , R 19 , R X , and R Y is as defined in any of the embodiments of compounds of formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), or (I-a3).

[0216] In some embodiments, the compound of Formula (I-a3) is a compound of Formula (I-b1c) or Formula (I-b2c): [ka] or a pharmaceutically acceptable salt thereof, wherein R 3a , R 17 , R 19 , R X , and R Y is as defined in any of the embodiments of compounds of formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), or (I-a3).

[0217] In some embodiments, the compound of Formula (I-a1) is a compound of Formula (I-c1a) or Formula (I-c2a): [ka] or a pharmaceutically acceptable salt thereof, wherein R 3a , R 17 , R 19 , R X , and R Y is as defined in any of the embodiments of compounds of formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), or (I-a3).

[0218] In some embodiments, the compound of Formula (I-a2) is a compound of Formula (I-c1b) or Formula (I-c2b): [ka] or a pharmaceutically acceptable salt thereof, wherein R 3a , R 17 , R 19 , R X , and R Y is as defined in any of the embodiments of compounds of formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), or (I-a3).

[0219] In some embodiments, the compound of Formula (I-a3) is a compound of Formula (I-c1c) or Formula (I-c2c): [ka] or a pharmaceutically acceptable salt thereof, wherein R 3a , R 17 , R 19 , R X , and R Yis as defined in any of the embodiments of compounds of formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), or (I-a3).

[0220] In some embodiments, the compound of Formula (I-a1) is a compound of Formula (I-d1a) or Formula (I-d2a): [ka] or a pharmaceutically acceptable salt thereof, wherein R 3a , R 17 , R 19 , R X , and R Y is as defined in any of the embodiments of compounds of formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), or (I-a3).

[0221] In some embodiments, the compound of Formula (I-a2) is a compound of Formula (I-d1b) or Formula (I-d2b): [ka] or a pharmaceutically acceptable salt thereof, wherein R 3a , R 17 , R 19 , R X , and R Y is as defined in any of the embodiments of compounds of formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), or (I-a3).

[0222] In some embodiments, the compound of Formula (I-a3) is a compound of Formula (I-d1c) or Formula (I-d2c): [ka] or a pharmaceutically acceptable salt thereof, wherein R 3a , R 17 , R 19 , RX , and R Y is as defined in any of the embodiments of compounds of formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), or (I-a3).

[0223] In some embodiments, the compound of Formula (I-a1) is a compound of Formula (I-e1): [ka] or a pharmaceutically acceptable salt thereof, wherein R 3a , R 19 , and R Y is as defined in any of the embodiments of the compound of formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), or (I-d2c).

[0224] In some embodiments, the compound of Formula (I-a2) is a compound of Formula (I-e2): [ka] or a pharmaceutically acceptable salt thereof, wherein R 3a , R 19 , and R Y is as defined in any of the embodiments of the compound of formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), or (I-d2c).

[0225] In some embodiments, the compound of Formula (I-a3) is a compound of Formula (I-e3): [ka]

[0226] or a pharmaceutically acceptable salt thereof, wherein R 3a , R 19 , and R Y is as defined in any of the embodiments of the compound of formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), or (I-d2c).

[0227] Another aspect of the present invention is a compound of formula (If): [ka] or a pharmaceutically acceptable salt thereof, wherein R 3a , R 5 , R 6 , R 16 , R 19 , R X , and R Y is the formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2 a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), As defined in any of the compound embodiments of (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), or (I-e3).

[0228] Another aspect of the present invention is a compound of formula (Ig): [ka] or a pharmaceutically acceptable salt thereof, wherein R 3a , R 19 , R X , and R Y is the formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), ( I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), As defined in any of the compound embodiments of (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), or (If).

[0229] Another aspect of the present invention is a compound of formula (I-4): [ka] or a pharmaceutically acceptable salt thereof, wherein R 2a , R 2b , R 3a , R 4a , R 4b , R 5 , R 6 , R 7 , R 11a , R 11b , R 16 , R 17 , R 19 , R X , R Y, and t are as defined in any of the embodiments of compounds of formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), (If), or (Ig).

[0230] In some embodiments, R 2a , R 2b , R 4a , R 4b , R 6 , R 7 , R 11a , R 11b , R 15a , and R 15b each independently represents hydrogen, halogen, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, -NR D1 C(=O)R D1 , a substituted or unsubstituted 3- to 6-membered monocyclic heterocycle, or a substituted or unsubstituted 8- to 12-membered bicyclic heterocycle, wherein the monocyclic or bicyclic heterocycle has 1 to 3 heteroatoms independently selected from N, O, and S, and each R D1 are independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 alkynyl, a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two RD1 groups join to form a substituted or unsubstituted 3- to 6-membered monocyclic heterocycle or 8- to 12-membered bicyclic heterocycle, wherein the monocyclic or bicyclic heterocycle has 1 to 3 heteroatoms independently selected from N, O, and S, or R 2a and R 2b , R 4a and R 4b , or R 11a and R 11b are joined together to form an oxo (=O) group, and R 16 and R 17 each independently represents hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, -OR A1 , -SR A1 , -N(R A1 )2, -N(R A1 ), -CN(R A1 )2, -C(O)R A1 , -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)SR A1 , -OC(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 , -SC(=O)SR A1 , -NHC(=O)R A1 , -SC(=O)N(R A1 )2, -NHC(=O)OR A1 , -NHC(=O)SR A1 , -NHC(=O)N(R A1 )2, -OS(=O)2R A2 , -OS(=O)2OR A1 , -SS(=O)2R A2 , -SS(=O)2OR A1 , -S(=O)R A2 , -SO2R A2 , -S(=O)2OR A1or a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S; A1 are independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S; 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; -SO2R A2 , -C(O)R A2 or two R A1 groups joined together to form a substituted or unsubstituted 3- to 6-membered saturated, partially unsaturated, or fully unsaturated monocyclic heterocycle having 1 to 3 heteroatoms independently selected from N, O, and S; and each R A2 are independently substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 alkynyl, or a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S; R 3a is hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 alkynyl, a substituted or unsubstituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from N, O, and S; R 5 is hydrogen, unsubstituted methyl, or absent; [ka] is a single or double bond, with the proviso that [ka] is a single bond, R 5 is hydrogen or methyl, [ka] is a double bond, R 5 is non-existent, and R 19 is hydrogen or substituted or unsubstituted C 1~6 alkyl, and R X is hydrogen or substituted or unsubstituted C 1~6 alkyl, and R Y is a substituted or unsubstituted phenyl, or a substituted or unsubstituted 3- to 6-membered monocyclic heteroaryl or 8- to 12-membered bicyclic heteroaryl, wherein the monocyclic or bicyclic heteroaryl has 1 to 5 heteroatoms independently selected from N, O, and S; and t is 2 or 3.

[0231] In some embodiments, the compound of formula (I-4) is a compound of formula (I-a4): [ka] or a pharmaceutically acceptable salt thereof, wherein R 2a , R 2b , R 3a , R 5 , R 19 , R X , and R Yis as defined in any of the embodiments of compounds of formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), (If), (Ig), or (I-4).

[0232] In some embodiments, the compound of Formula (I-4) is a compound of Formula (I-b4a) or Formula (I-b5a): [ka] or a pharmaceutically acceptable salt thereof, wherein R 2a , R 2b , R 3a , R 19 , R X , and R Y is as defined in any of the embodiments of compounds of formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), (If), (Ig), (I-4), or (I-a4).

[0233] In some embodiments, the compound of Formula (I-4) is a compound of Formula (I-b4b) or Formula (I-b5b): [ka] or a pharmaceutically acceptable salt thereof, wherein R2a , R 2b , R 3a , R 19 , R X , and R Y is as defined in any of the embodiments of compounds of formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), (If), (Ig), (I-4), (I-a4).

[0234] Another aspect of the present invention is a compound of formula (X): [ka] or a pharmaceutically acceptable salt thereof, wherein R 2a , R 3a , R 19 , R Y , and t are formulas (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), ( I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d as defined in any of the compound embodiments of I-1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), (If), (Ig), (I-4), (I-a4), (I-b4a), (I-b5a), (I-b4b), or (I-b5b).

[0235] In some embodiments, R 2a is hydrogen or substituted or unsubstituted C 1~6 alkyl, and R 3ais a substituted or unsubstituted C 1~6 Alkyl, or substituted or unsubstituted C 1~6 Alkyl-OC 1~6 alkyl, and R 19 is hydrogen or substituted or unsubstituted C 1~6 alkyl, and R Y is a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-2 nitrogen atoms, and R Y The 3- to 8-membered rings are independently halogen, -CN, or C 1~6 alkyl, and t is 1 or 2, provided that when t is 1, R 3a is -CH2OCH2CH3, and R Y is a substituted or unsubstituted pyrazinyl, and then R 19 is -CH3.

[0236] In some embodiments, R 2a is hydrogen or unsubstituted C 1~3 In some embodiments, R 2a is hydrogen or -CH3.

[0237] In some embodiments, R 3a is the unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 Alkyl-OC 1~3 In some embodiments, R 3a is -CH3, -CH2CH2CH3, -CH2OCH3, or -CH2OCH2CH3.

[0238] In some embodiments, R 19 is hydrogen or unsubstituted C 1~3 In some embodiments, R 19 is hydrogen, -CH3, or -CH2CH3.

[0239] In some embodiments, R Yis a substituted or unsubstituted pyrazinyl, a cyano-substituted pyrimidine, a substituted or unsubstituted phenyl, a cyano- or fluoro-substituted pyridine, or a pyrazole substituted with two unsubstituted methyl groups.

[0240] Another aspect of the present invention is a compound of formula (XI): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 19 , and R Y is the formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2 b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), As defined in any of the compound embodiments of (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), (If), (Ig), (I-4), (I-a4), (I-b4a), (I-b5a), (I-b4b), (I-b5b), or (X).

[0241] In some embodiments, R 1 is the unsubstituted C 1~3 alkyl, and R 19 is hydrogen or unsubstituted C 1~3 alkyl, and R Y teeth, [ka] wherein two of W1, W2, W3, W4, and W5 are -N= and the rest are -C(R')=, each R' is independently hydrogen or -CN, and at least one R' is -CN.

[0242] In some embodiments, R 1is -CH3, or -CH2CH3.

[0243] In some embodiments, R 19 is hydrogen or -CH3.

[0244] In some embodiments, W1 and W2 are -N=, or W1 and W3 are -N=, or W1 and W4 are -N=, or W1 and W5 are -N=, or W2 and W4 are -N=.

[0245] In some embodiments, R Y teeth, [ka] is.

[0246] Another aspect of the present invention is a compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein: [ka] represents a single or double bond, provided that if a double bond is present, R 5 and R 6a or R 6b If one of R is absent, 3a is a substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 5 is hydrogen or substituted or unsubstituted methyl, or [ka] is a double bond, R 5 is non-existent, and R 6a and R 6b each independently represents hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, or substituted or unsubstituted C 2~6 alkynyl or R 6a and R 6b join to form an oxo (=O) group, and R 1a , R 1b , R 2a , R 2b , R 4a , R 4b , R 7a , R 7b 、 R 11a , R 11b , R 12a , and R 12b each independently represents hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 and R D1 Each instance of 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 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; an oxygen protecting group if attached to an oxygen atom; a nitrogen protecting group if attached to a nitrogen atom; or two R D1 The groups may be joined to form a substituted or unsubstituted heterocyclic ring, or R 1a and R 1b , R2a and R 2b , R 4a and R 4b , R 11a and R 11b , R 12a and R 12b are bonded to form an oxo (=O) group, and R 15a and R 15b each independently represents hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted C 2~6 Alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 and R D1 Each instance of 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 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; an oxygen protecting group if attached to an oxygen atom; a nitrogen protecting group if attached to a nitrogen atom; or two R D1 groups join to form a substituted or unsubstituted heterocyclic ring, or R 15a and R 15b joins to form an oxo (=O) group, and R 15a and R 15b One of them is not hydrogen, but R 16a and R 16b each independently represents 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 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORA1 , -SR A1 , -N(R A1 )2, -N(R A1 ), -CN(R A1 )2, -C(O)R A1 , -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)SR A1 , -OC(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 , -NHC(=O)SR A1 , -NHC(=O)N(R A1 )2, -OS(=O)2R A2 , -OS(=O)2OR A1 , -SS(=O)2R A2 , -SS(=O)2OR A1 , -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 and R A1 Each instance of 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 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, 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, -SOR A2 , -C(O)R A2 or two R A1 groups are joined to a substituted or unsubstituted heterocyclic or heteroaryl ring, and R A2 is a substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 19 is hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, or substituted or unsubstituted C 2~6 alkynyl, and R X is hydrogen or substituted or unsubstituted C 1~6 alkyl, and R Y is independently substituted or unsubstituted phenyl or heteroaryl.

[0247] In some embodiments, the compound of Formula (II) is a compound of Formula (IIa) or Formula (IIb): [ka] or a pharmaceutically acceptable salt thereof.

[0248] Another aspect of the present invention is a compound of formula (III): [ka] or a pharmaceutically acceptable salt thereof, wherein: [ka] represents a single or double bond, provided that if a double bond is present, R 5 and R 6a or R 6b If either of R 3a is a substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R5 is hydrogen or substituted or unsubstituted methyl, or [ka] is a double bond, R 5 is non-existent, and R 6a and R 6b each independently represents hydrogen, halogen, cyano, hydroxy, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, or substituted or unsubstituted C 2~6 alkynyl or R 6a and R 6b is bonded to an oxo (=O) group, and R 2a , R 2b , R 4a , R 4b , R 7a , R 7b 、 R 11a , R 11b , R 12a , R 12b , R 15a , R 15b , and R 17b each independently represents hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted C 2~6 Alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 and R D1 Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; an oxygen protecting group if attached to an oxygen atom; a nitrogen protecting group if attached to a nitrogen atom; or two R D1 groups join to form a substituted or unsubstituted heterocyclic ring, or R 1a and R 1b , R 2a and R 2b , R 4a and R 4b , R 11a and R 11b , R 12a and R 12b , and R 15a and R 15b are bonded to form an oxo (=O) group, and R 16a and R 16b each independently represents 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 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2, -N(R A1 ), -CN(R A1 )2, -C(O)R A1 , -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)SR A1 , -OC(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 , -NHC(=O)SR A1 , -NHC(=O)N(R A1 )2, -OS(=O)2RA2 , -OS(=O)2OR A1 , -SS(=O)2R A2 , -SS(=O)2OR A1 , -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 and R A1 Each instance of 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 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, 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, -SOR A2 , -C(O)R A2 or two R A1 groups joined to form a substituted or unsubstituted heterocyclic or heteroaryl ring, R A2 is a substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 19 is hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, or substituted or unsubstituted C 2~6 alkynyl, and R X is hydrogen or substituted or unsubstituted C 1~6 alkyl, and R Y is independently substituted or unsubstituted phenyl or heteroaryl; and t is 2 or 3.

[0249] In some embodiments, the compound of Formula (III) is a compound of Formula (IIIa): [ka] or a pharmaceutically acceptable salt thereof.

[0250] Another aspect of the present invention is a compound of formula (IVa) or formula (IVb): [ka] or a pharmaceutically acceptable salt thereof, wherein: [ka] represents a single or double bond, provided that if a double bond is present, R 5 and R 6a or R 6b If either of R 3a is a substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 5 is hydrogen or substituted or unsubstituted methyl, or [ka] is a double bond, R 5 is non-existent, and R 6a and R 6b each independently represents hydrogen, halogen, cyano, hydroxy, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, or substituted or unsubstituted C 2~6 alkynyl or R 6a and R 6b is bonded to an oxo (=O) group, and R 1a , R 1b , R2a , R 2b , R 4a , R 4b 、 R 7a , R 7b , R 11a , R 11b , R 12a , R 12b , R 15a , R 15b , and R 17b each independently represents hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted C 2~6 Alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 and R D1 Each instance of 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 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; an oxygen protecting group if attached to an oxygen atom; a nitrogen protecting group if attached to a nitrogen atom; or two R D1 groups join to form a substituted or unsubstituted heterocyclic ring, or R 1a and R 1b , R 2a and R 2b , R 4a and R 4b , R 11a and R 11b , R 12a and R 12b , and R 15a and R 15b are bonded to form an oxo (=O) group, and R 16a and R 16b each independently represents hydrogen, halogen, substituted or unsubstituted C1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2, -N(R A1 ), -CN(R A1 )2, -C(O)R A1 , -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)SR A1 , -OC(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 , -NHC(=O)SR A1 , -NHC(=O)N(R A1 )2, -OS(=O)2R A2 , -OS(=O)2OR A1 , -SS(=O)2R A2 , -SS(=O)2OR A1 , -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 and R A1 Each instance of 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 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, 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, -SOR A2 , -C(O)R A2 or two RA1 groups joined to form a substituted or unsubstituted heterocyclic or heteroaryl ring, R A2 is a substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 19 is hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, or substituted or unsubstituted C 2~6 alkynyl, and R X is hydrogen or substituted or unsubstituted C 1~6 alkyl, and R Y is independently substituted or unsubstituted phenyl or heteroaryl; and r is 2 or 3.

[0251] In some embodiments, the compound of formula (IVa) is a compound of formula (IVa-I): [ka] or a pharmaceutically acceptable salt thereof.

[0252] Another aspect of the present invention is a compound of formula (V): [ka] or a pharmaceutically acceptable salt thereof, wherein: [ka] represents a single or double bond, provided that if a double bond is present, R 5 and R 6a or R 6b If either of R 3a is a substituted or unsubstituted C1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 5 is hydrogen or substituted or unsubstituted methyl, or [ka] is a double bond, R 5 is non-existent, and R 6a and R 6b each independently represents hydrogen, halogen, cyano, hydroxy, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, or substituted or unsubstituted C 2~6 alkynyl or R 6a and R 6b is bonded to an oxo (=O) group, and R 1a , R 1b , R 2a , R 2b , R 4a , R 4b 、 R 7a , R 7b , R 11a , R 11b , R 12a , R 12b , R 15a , and R 15b each independently represents hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted C 2~6 Alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 and R D1Each instance of 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 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; an oxygen protecting group if attached to an oxygen atom; a nitrogen protecting group if attached to a nitrogen atom; or two R D1 groups join to form a substituted or unsubstituted heterocyclic ring, or R 1a and R 1b , R 2a and R 2b , R 4a and R 4b , R 11a and R 11b , R 12a and R 12b , and R 15a and R 15b are bonded to form an oxo (=O) group, and R 16a and R 16b each independently represents 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 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2, -N(R A1 ), -CN(R A1 )2, -C(O)R A1 , -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)SR A1 , -OC(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -NHC(=O)R A1, -NHC(=O)OR A1 , -NHC(=O)SR A1 , -NHC(=O)N(R A1 )2, -OS(=O)2R A2 , -OS(=O)2OR A1 , -SS(=O)2R A2 , -SS(=O)2OR A1 , -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 and R A1 Each instance of 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 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, 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, -SOR A2 , -C(O)R A2 or two R A1 groups joined to form a substituted or unsubstituted heterocyclic or heteroaryl ring, R A2 is a substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 19 is hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, or substituted or unsubstituted C 2~6 alkynyl, and R X is hydrogen or substituted or unsubstituted C 1~6 alkyl, and R Y is independently substituted or unsubstituted phenyl or heteroaryl.

[0253] In some embodiments, the compound of Formula (V) is a compound of Formula (Va) or Formula (Vb): [ka] or a pharmaceutically acceptable salt thereof.

[0254] In some embodiments, the compound of Formula (V) is a compound of Formula (Vaa) or Formula (Vab): [ka] or a pharmaceutically acceptable salt thereof.

[0255] Another aspect of the present invention is a compound of formula (VI): [ka] or a pharmaceutically acceptable salt thereof, wherein: [ka] represents a single or double bond, provided that if a double bond is present, R 5 and R 6a or R 6b If either of R 3a is a substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 5 is hydrogen or substituted or unsubstituted methyl, or [ka] is a double bond, R 5 is non-existent, and R 6aand R 6b each independently represents hydrogen, halogen, cyano, hydroxy, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, or substituted or unsubstituted C 2~6 alkynyl or R 6a and R 6b is bonded to an oxo (=O) group, and R 1a , R 1b , R 2a , R 2b , R 4a , R 4b 、 R 7a , R 7b , R 11a , R 11b , R 12a , R 12b , R 15a , and R 15b each independently represents hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted C 2~6 Alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 and R D1 Each instance of 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 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; an oxygen protecting group if attached to an oxygen atom; a nitrogen protecting group if attached to a nitrogen atom; or two R D1 groups join to form a substituted or unsubstituted heterocyclic ring, or R 1a and R 1b , R 2a and R 2b , R4a and R 4b , R 11a and R 11b , R 12a and R 12b , and R 15a and R 15b are bonded to form an oxo (=O) group, and R 16a and R 16b each independently represents 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 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2, -N(R A1 ), -CN(R A1 )2, -C(O)R A1 , -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)SR A1 , -OC(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 , -NHC(=O)SR A1 , -NHC(=O)N(R A1 )2, -OS(=O)2R A2 , -OS(=O)2OR A1 , -SS(=O)2R A2 , -SS(=O)2OR A1 , -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 and R A1 Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6Alkenyl, substituted or unsubstituted C 2~6 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 sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, -SOR A2 , -C(O)R A2 or two R A1 groups joined to form a substituted or unsubstituted heterocyclic or heteroaryl ring, R A2 is a substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 18 is a substitution C 1~6 Alkyl, or unsubstituted C2-C6 alkyl, substituted or unsubstituted C 2~6 Alkenyl, or substituted or unsubstituted C 2~6 alkynyl, and R 19 is hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, or substituted or unsubstituted C 2~6 alkynyl, and R X is hydrogen or substituted or unsubstituted C 1~6 alkyl, and R Y is independently substituted or unsubstituted phenyl or heteroaryl.

[0256] In some embodiments, the compound of Formula (VI) is a compound of Formula (VIa) or Formula (VIb): [ka] or a pharmaceutically acceptable salt thereof.

[0257] In some embodiments, the compound of Formula (VI) is a compound of Formula (VIaa) or Formula (VIab): [ka] or a pharmaceutically acceptable salt thereof.

[0258] Another aspect of the present invention is a compound of formula (VII): [ka] or a pharmaceutically acceptable salt thereof, wherein: [ka] represents a single or double bond, provided that if a double bond is present, R 5 and R 6a or R 6b If either of R 3a is a substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 5 is hydrogen or substituted or unsubstituted methyl, or [ka] is a double bond, R 5 is non-existent, and R 6a and R 6b each independently represents hydrogen, halogen, cyano, hydroxy, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, or substituted or unsubstituted C 2~6 alkynyl or R 6a and R 6bis bonded to an oxo (=O) group, and R 1a , R 1b , R 2a , R 2b , R 4a , R 4b 、 R 7a , R 7b , R 11a , R 11b , R 12a , R 12b , R 15a , and R 15b each independently represents hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted C 2~6 Alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 and R D1 Each instance of 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 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; an oxygen protecting group if attached to an oxygen atom; a nitrogen protecting group if attached to a nitrogen atom; or two R D1 groups join to form a substituted or unsubstituted heterocyclic ring, or R 1a and R 1b , R 2a and R 2b , R 4a and R 4b , R 11a and R 11b , R 12a and R 12b , and R 15a and R 15b are bonded to form an oxo (=O) group, and R 16a and R16b each independently represents 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 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2, -N(R A1 ), -CN(R A1 )2, -C(O)R A1 , -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)SR A1 , -OC(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 , -NHC(=O)SR A1 , -NHC(=O)N(R A1 )2, -OS(=O)2R A2 , -OS(=O)2OR A1 , -SS(=O)2R A2 , -SS(=O)2OR A1 , -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 and R A1 Each instance of 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 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, 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, -SOR A2, -C(O)R A2 or two R A1 groups joined to form a substituted or unsubstituted heterocyclic or heteroaryl ring, R A2 is a substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 19 is ethyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 alkynyl, substituted or unsubstituted C3-C6 carbocyclyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted aryl, and R X is hydrogen or substituted or unsubstituted C 1~6 alkyl, and R Y is independently substituted or unsubstituted phenyl or heteroaryl.

[0259] Another aspect of the present invention is a compound of formula (VIII): [ka] or a pharmaceutically acceptable salt thereof, wherein: [ka] represents a single or double bond, provided that if a double bond is present, R 5 and R 6a or R 6b If either of the two is absent, then R 2a and R 2b each independently represents hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6Alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted C 2~6 Alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 and R D1 Each instance of 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 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; an oxygen protecting group if attached to an oxygen atom; a nitrogen protecting group if attached to a nitrogen atom; or two R D1 groups join to form a substituted or unsubstituted heterocyclic ring, or R 2a and R 2b join to form an oxo (=O) group, and R 2a and R 2b At least one of these is not hydrogen but R 3a is a substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 5 is hydrogen or substituted or unsubstituted methyl, or [ka] is a double bond, R 5 is non-existent, and R 6a and R 6b each independently represents hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, or substituted or unsubstituted C2~6 alkynyl or R 6a and R 6b join to form an oxo (=O) group, and R 1a , R 1b , R 4a , R 4b , R 7a , R 7b 、 R 11a , R 11b , R 12a , R 12b , R 15a , and R 15b each independently represents hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted C 2~6 Alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 and R D1 Each instance of 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 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; an oxygen protecting group if attached to an oxygen atom; a nitrogen protecting group if attached to a nitrogen atom; or two R D1 groups join to form a substituted or unsubstituted heterocyclic ring, or R 1a and R 1b , R 4a and R 4b , R 11a and R 11b , R 12a and R 12b , and R 15a and R 15b are bonded to form an oxo (=O) group, and R 16a and R 16beach independently represents 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 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2, -N(R A1 ), -CN(R A1 )2, -C(O)R A1 , -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)SR A1 , -OC(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 , -NHC(=O)SR A1 , -NHC(=O)N(R A1 )2, -OS(=O)2R A2 , -OS(=O)2OR A1 , -SS(=O)2R A2 , -SS(=O)2OR A1 , -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 and R A1 Each instance of 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 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, 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, -SOR A2 , -C(O)RA2 or two R A1 groups joined to form a substituted or unsubstituted heterocyclic or heteroaryl ring, R A2 is a substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 19 is hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, or substituted or unsubstituted C 2~6 alkynyl, and R X is hydrogen or substituted or unsubstituted C 1~6 alkyl, and R Y is independently substituted or unsubstituted phenyl or heteroaryl.

[0260] Another aspect of the present invention is a compound of formula (IX): [ka] or a pharmaceutically acceptable salt thereof, wherein: [ka] represents a single or double bond, provided that if a double bond is present, R 5 and R 6a or R 6b One of the is non-existent and R 11a and R 11b are independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted C 2~6 Alkynyl, -OR D1 , -OC(=O)R D1, -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 and R D1 Each instance of 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 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; an oxygen protecting group if attached to an oxygen atom; a nitrogen protecting group if attached to a nitrogen atom; or two R D1 groups join to form a substituted or unsubstituted heterocyclic ring, or R 11a and R 11b join to form an oxo (=O) group, and R 2a and R 2b At least one of these is not hydrogen, and R 3a is a substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 5 is hydrogen or substituted or unsubstituted methyl, or [ka] is a double bond, R 5 is non-existent and R 6a and R 6b each independently represents hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, or substituted or unsubstituted C 2~6 alkynyl or R 6a and R 6b join to form an oxo (=O) group, and R 1a , R1b , R 2a , R 2b , R 4a , R 4b , R 7a , R 7b 、R 12a , R 12b , R 15a , and R 15b each independently represents hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted C 2~6 Alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 and R D1 Each instance of 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 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; an oxygen protecting group if attached to an oxygen atom; a nitrogen protecting group if attached to a nitrogen atom; or two R D1 groups join to form a substituted or unsubstituted heterocyclic ring, or R 1a and R 1b , R 4a and R 4b , R 2a and R 2b , R 12a and R 12b , and R 15a and R 15b are bonded to form an oxo (=O) group, and R 16a and R 16b each independently represents hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C2~6 Alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2, -N(R A1 ), -CN(R A1 )2, -C(O)R A1 , -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)SR A1 , -OC(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 , -NHC(=O)SR A1 , -NHC(=O)N(R A1 )2, -OS(=O)2R A2 , -OS(=O)2OR A1 , -SS(=O)2R A2 , -SS(=O)2OR A1 , -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 and R A1 Each instance of 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 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, 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, -SOR A2 , -C(O)R A2 or two R A1 groups joined to form a substituted or unsubstituted heterocyclic or heteroaryl ring, R A2is a substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 19 is hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, or substituted or unsubstituted C 2~6 alkynyl, and R X is hydrogen or substituted or unsubstituted C 1~6 alkyl, and R Y is independently substituted or unsubstituted phenyl or heteroaryl.

[0261] Another aspect of the present invention is a compound of formula (XII): [ka] or a pharmaceutically acceptable salt thereof, wherein: [ka] represents a single or double bond, provided that if a double bond is present, R 5 and R 6a or R 6b If either of the two is absent, then R 7a and R 7b each independently represents hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted C 2~6 Alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 and R D1Each instance of 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 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; an oxygen protecting group if attached to an oxygen atom; a nitrogen protecting group if attached to a nitrogen atom; or two R D1 groups join to form a substituted or unsubstituted heterocyclic ring, or R 11a and R 11b join to form an oxo (=O) group, and R 7a and R 7b At least one of these is not hydrogen but R 3a is a substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 5 is hydrogen or substituted or unsubstituted methyl, or [ka] is a double bond, R 5 is non-existent, and R 6a and R 6b each independently represents hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, or substituted or unsubstituted C 2~6 alkynyl or R 6a and R 6b join to form an oxo (=O) group, and R 1a , R 1b , R 2a , R 2b , R 4a , R 4b , R 11a, R 11b 、 R 12a , R 12b , R 15a , and R 15b each independently represents hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted C 2~6 Alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 and R D1 Each instance of 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 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; an oxygen protecting group if attached to an oxygen atom; a nitrogen protecting group if attached to a nitrogen atom; or two R D1 groups join to form a substituted or unsubstituted heterocyclic ring, or R 1a and R 1b , R 4a and R 4b , R 11a and R 11b , R 12a and R 12b , and R 15a and R 15b are bonded to form an oxo (=O) group, and R 16a and R 16b each independently represents 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 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORA1 , -SR A1 , -N(R A1 )2, -N(R A1 ), -CN(R A1 )2, -C(O)R A1 , -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)SR A1 , -OC(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 , -NHC(=O)SR A1 , -NHC(=O)N(R A1 )2, -OS(=O)2R A2 , -OS(=O)2OR A1 , -SS(=O)2R A2 , -SS(=O)2OR A1 , -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 and R A1 Each instance of 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 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, 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, -SOR A2 , -C(O)R A2 or two R A1 groups joined to form a substituted or unsubstituted heterocyclic or heteroaryl ring, R A2 is a substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 19 is hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, or substituted or unsubstituted C 2~6 alkynyl, and R X is hydrogen or substituted or unsubstituted C 1~6 alkyl, and R Y is independently substituted or unsubstituted phenyl or heteroaryl.

[0262] D. General Synthetic Scheme The compounds of the present invention can be synthesized according to the following general synthetic schemes. In the following general schemes, it is understood that all variables used in the schemes have the definitions provided herein. As used in the general schemes, LG means "leaving group" and PG means "protecting group." Enantiomerically pure compounds of the general schemes are envisioned by the use of stereospecific reaction conditions or chiral resolution using methods known to those skilled in the art and / or as detailed in the specific examples provided herein.

[0263] Following Scheme 1, a compound of formula C, where R 3a (wherein R is defined herein) can be synthesized by first converting the acetyl group of a compound of formula A under appropriate conditions, e.g., a Br / NaOH or Cl / NaOH mixture, to produce a compound of formula B. The resulting compound of formula B can then be converted to a compound of formula R Y -NH2, wherein R Yis optionally substituted with alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl to produce a compound of formula C. Alternatively, a compound of formula B can be coupled with ammonia to produce a compound of formula D. Coupling of a compound of formula B to produce a compound of formula C or formula D can be accomplished using any number of coupling agents and coupling conditions known to the skilled artisan, for example, HATU using DMF as a solvent. A compound of formula D can then be prepared by coupling the amide nitrogen of formula D with a group of formula Br-R. XX can be converted to a compound of formula C by coupling with a compound of formula XX is aryl or heteroaryl using catalytic coupling conditions known to those skilled in the art, for example, a combination of XantPhos, CsCO, and Pd(dba) in dioxane. Compounds of formula A, B, C, and D can also be substituted as described herein.

[0264] Scheme 1: [ka] Compounds of formula O can be synthesized according to the general procedures in Schemes 2 and 3. Referring to Scheme 2, compounds of formula F (wherein R 3a is defined herein) is a Grignard reagent R 3a MgBr(R 3a (b) S(CH3)3 + I - and a suitable reagent such as sodium hydride to form an oxirane compound of formula G, and then (c) opening the oxirane with a nucleophile, whereby the nucleophile, when added to the methylene of the oxirane, together with the substituent R 3aThis reaction can also be accomplished in two steps by forming the following: Reaction of a compound of formula F in a mixture of LDA and ethyl diazoacetate produces an adduct of formula H, which can then undergo an intramolecular reaction to produce a compound of formula I when treated with a reagent such as Rh2(OAc)4 in DME.

[0265] Scheme 2: [ka] Referring to Scheme 3, precipitation and decarboxylation of a compound of formula I to form a compound of formula J can be achieved with hydroxide. Compounds of formula K can be synthesized by converting the ketone moiety of formula J to a terminal olefin using appropriate conditions, such as methyltriphenylphosphonium bromide in the presence of a base, such as potassium tert-butoxide. The terminal olefin of formula K is then hydroxylated using conditions, such as 9-BBN dimer followed by NaOH / H2O2, to produce a compound of formula L. Formula L is treated with a mild oxidizing agent, such as the Dess-Martin reagent, to produce an aldehyde of formula M, followed by treatment with a second oxidizing agent, such as NaClO2, to produce a carboxylic acid of formula N. Compounds of formula N can then be coupled to a carboxylic acid of formula R using any number of coupling agents and coupling conditions known to those skilled in the art, for example, HATU using DMF as the solvent. W -NH2(wherein, R W is defined herein) to produce a compound of formula O. Compounds of formula E, F, G, H, I, J, K, L, M, N, and O can also be substituted as described herein.

[0266] Scheme 3: [ka] Compounds of general formula T can be produced according to Scheme 4. The tert-butyldimethylsilyl (TBS)-protected alcohol of formula P can be deprotected using, for example, tetrabutylammonium fluoride (TBAF). Those skilled in the art will recognize that this is only one example of many different methods for protecting and deprotecting the alcohol functionality, i.e., producing compounds of formula Q from formula P. Oxidation of the alcohol moiety with a mild oxidizing agent, such as the Dess-Martin reagent, can produce aldehydes of formula R. The aldehyde moiety of compounds of formula R can be converted to terminal olefins, for example, by treatment with methyltriphenylphosphine bromide, to produce compounds of formula S. Reduction of compounds of formula S using any number of common reduction techniques known to those skilled in the art, such as H2, in the presence of a Pd / C catalyst, can produce compounds of formula T. Compounds of formula P, Q, R, S, and T can also be substituted as described herein.

[0267] Scheme 4: [ka] In some embodiments, the compound is selected from the group consisting of the compounds identified in Table 1, or a pharmaceutically acceptable salt thereof.

[0268] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8]

[0269] In one aspect, provided herein are compounds described herein (e.g., compounds of Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1) , (I-e2), (I-e3), (If), (Ig), (I-4), (I-a4), (I-b4a), (I-b5a), (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII).

[0270] In one aspect, provided herein are compounds described herein (e.g., compounds of Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), A pharmaceutical composition comprising a compound of formula (I), (Ig), (I-4), (I-a4), (I-b4a), (I-b5a), (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the compound of the present invention is provided in an effective amount as a pharmaceutical composition. In certain embodiments, the compound of the present invention is provided in a therapeutically effective amount.

[0271] The compounds of the invention described herein, in certain embodiments, act as GABA modulators, for example, by affecting GABA receptors in either a positive or negative manner. Such compounds are expected to have central nervous system (CNS) activity as modulators of CNS excitability, as mediated by their ability to modulate GABA receptors.

[0272] Therefore, in another aspect, a method for treating a CNS-related disorder in a subject in need thereof is provided, comprising administering an effective amount of a compound of the present invention to the subject. In certain embodiments, the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a seizure disorder, a memory and / or cognitive disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder and / or withdrawal syndrome, tinnitus, or status epilepticus. In certain embodiments, the CNS-related disorder is depression. In certain embodiments, the CNS-related disorder is postpartum depression. In certain embodiments, the CNS-related disorder is major depressive disorder. In certain embodiments, the major depressive disorder is moderate major depressive disorder. In certain embodiments, the major depressive disorder is severe major depressive disorder. In certain embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In certain embodiments, the compound is administered orally. In certain embodiments, the compound is administered chronically. In certain embodiments, the compound is administered continuously, for example, by continuous intravenous infusion.

[0273] Exemplary compounds of the present invention may be synthesized from the following known starting materials using methods known to those of skill in the art or certain references. In one aspect, provided herein are compounds described herein (e.g., compounds of Formulas (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1) , (I-e2), (I-e3), (If), (Ig), (I-4), (I-a4), (I-b4a), (I-b5a), (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII).

[0274] III. Alternative Embodiments In alternative embodiments, the compounds described herein may also contain one or more isotopic substitutions. For example, hydrogen may be: 2 H (D or deuterium) or 3 H (T or tritium), and carbon can be, for example, 13 C or 14 C, and oxygen may be, for example, 18 O, and the nitrogen may be, for example, 15 In other embodiments, specific isotopes (e.g., 3 H, 13 C. 14 C. 18 O, or 15N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of the element occupying a particular site in the compound.

[0275] A. Pharmaceutical Compositions In one aspect, provided herein are compounds described herein (e.g., compounds of Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), A pharmaceutical composition comprising a compound of formula (I), (Ig), (I-4), (I-a4), (I-b4a), (I-b5a), (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the compound of the present invention is provided in an effective amount as a pharmaceutical composition. In certain embodiments, the compound of the present invention is provided in a therapeutically effective amount.

[0276] In certain embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient.

[0277] The pharmaceutical compositions provided herein can be administered by a variety of routes, including, but not limited to, oral (enteral), parenteral (by injection), rectal, transdermal, intradermal, intrathecal, subcutaneous (SC), intravenous (IV), intramuscular (IM), and intranasal administration.

[0278] Generally, the compounds provided herein are administered in an effective amount. The amount of compound actually administered will typically be determined by a physician in light of the relevant circumstances, including the condition being treated, the selected route of administration, the actual compound being administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0279] When used to prevent the development of a CNS disorder, the compounds provided herein will typically be administered to a subject at risk of developing the condition at the dosage levels described above, under the advice and supervision of a physician. Subjects at risk of developing a particular condition generally include those with a family history of the condition or those identified by genetic testing or screening as being particularly susceptible to developing the condition.

[0280] The pharmaceutical compositions provided herein can also be administered chronically ("chronic administration"). Chronic administration refers to administering a compound or pharmaceutical composition thereof for an extended period of time, such as 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, or can continue indefinitely, for example, for the life of the subject. In certain embodiments, chronic administration is intended to provide a compound at a constant level in the blood, for example, within the therapeutic range, for an extended period of time.

[0281] The pharmaceutical composition of the present invention can also be delivered using various administration methods.For example, in certain embodiments, the pharmaceutical composition can be given as a bolus, for example, to raise the blood concentration of the compound to an effective level.The location of the bolus administration depends on the systemic level of the active ingredient desired throughout the body; for example, intramuscular or subcutaneous bolus administration allows for a slow release of the active ingredient, while a bolus delivered directly into a vein (for example, by IV drip) allows for much faster delivery, and the blood concentration of the active ingredient can quickly rise to an effective level.In other embodiments, the pharmaceutical composition can be administered as a continuous infusion, for example, by IV drip, to maintain the steady-state concentration of the active ingredient in the subject's body.In addition, in still other embodiments, the pharmaceutical composition can be administered as a bolus first, and then by continuous infusion.

[0282] Compositions for oral administration can take the form of bulk liquid solutions or suspensions or bulk powders. However, more commonly, compositions are provided in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage for human subjects and other mammals, each unit containing a predetermined amount of active ingredient calculated to achieve a desired therapeutic effect, along with suitable pharmaceutical excipients. Typical unit dosage forms include prefilled ampoules or syringes containing premeasured amounts of liquid compositions, or pills, tablets, capsules, etc., for solid compositions. In such compositions, the compound is typically a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder consisting of various vehicles or excipients and processing aids useful in forming the desired dosage form.

[0283] For oral administration, a typical regimen is 1 to 5 times, particularly 2 to 4 times, and typically 3 times per day. When using such a dosing pattern, each dose provides about 0.01 to about 20 mg / kg of the compound provided herein, with preferred doses being about 0.1 to about 10 mg / kg, particularly about 1 to about 5 mg / kg.

[0284] Transdermal doses are generally selected to produce blood levels that are comparable to or lower than those achieved using injection doses, and are generally amounts ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.

[0285] Injection dose levels range from about 0.1 mg / kg / hour to at least 20 mg / kg / hour, all for about 1 to about 120 hours, particularly 24 to 96 hours. A preloading bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve adequate steady-state levels. The maximum total dose is expected to not exceed about 5 g / day for a 40-80 kg human patient.

[0286] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispersing agents, colorants, flavors, etc. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: binders (such as microcrystalline cellulose, gum tragacanth, or gelatin); excipients (such as starch or lactose); disintegrating agents (such as alginic acid, Primogel, or corn starch); lubricants (such as magnesium stearate); glidants (such as colloidal silicon dioxide); sweetening agents (such as sucrose or saccharin); or flavoring agents (such as peppermint, methyl salicylate, or orange flavoring).

[0287] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline, or other injectable vehicles known in the art. As noted above, the active compound in such compositions is typically a minor component, often about 0.05 to 10% by weight, with the remainder being the injectable vehicle or the like.

[0288] Transdermal compositions are typically formulated as topical ointments or creams containing active ingredient(s). When formulated as an ointment, the active ingredient is typically mixed with a paraffinic ointment base or a water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream, for example, with an oil-in-water cream base. Such transdermal formulations are well known in the art and generally contain additional ingredients that enhance the skin penetration or stability of the active ingredient or formulation. All such known transdermal formulations and ingredients are encompassed within the scope provided herein.

[0289] The compounds provided herein can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type or of a solid matrix variety.

[0290] The ingredients listed above for oral, injectable, or topical compositions are merely representative. Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0291] The compounds of this invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0292] The present invention also relates to pharmaceutically acceptable acid addition salts of the compounds of the present invention. Acids that can be used to prepare pharmaceutically acceptable salts are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions (e.g., hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, etc.).

[0293] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable excipient, e.g., a composition suitable for injection, such as intravenous (IV) administration.

[0294] Pharmaceutically acceptable excipients include any diluents or other liquid vehicles suitable for the particular dosage form desired, e.g., injection, dispersing or suspending aids, surfactants, isotonicity agents, preservatives, lubricants, etc. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005).

[0295] For example, injectable preparations, such as sterile injectable aqueous suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Exemplary excipients that can be used include, but are not limited to, water, sterile saline or phosphate-buffered saline, or Ringer's solution.

[0296] In certain embodiments, the pharmaceutical composition further comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, which consist of six, seven, and eight α-1,4-linked glucose units, respectively, optionally containing one or more substituents on the attached sugar moiety (including, but not limited to, substituted or unsubstituted methylation, hydroxyalkylation, acylation, and sulfoalkyl ether substitution). In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, also known as CAPTISOL®. See, e.g., U.S. Patent No. 5,376,645. In certain embodiments, the composition comprises hexapropyl-β-cyclodextrin. In more specific embodiments, the composition comprises hexapropyl-β-cyclodextrin (10-50% in water).

[0297] Injectable compositions can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0298] Generally, the compounds provided herein are administered in an effective amount. The amount of compound actually administered will typically be determined by a physician in light of the relevant circumstances, including the condition being treated, the selected route of administration, the actual compound being administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0299] The compositions are provided in unit dosage forms to facilitate accurate administration. The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage for human subjects and other mammals, each unit containing a predetermined amount of active agent calculated to obtain a desired therapeutic effect, together with suitable pharmaceutical excipients. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions. In such compositions, the compound is usually a minor component (about 0.1% to about 50% by weight, or preferably about 1% to about 40% by weight), with the remainder consisting of various vehicles or carriers and processing aids useful in forming the desired dosage form.

[0300] The compounds provided herein can be administered as a single active agent or in combination with other active agents. In one aspect, the present invention provides a combination of a compound of the present invention with another pharmacologically active agent. The administration of the combination can be carried out by any technique apparent to those skilled in the art, including, for example, separate administration, sequential administration, simultaneous administration, and alternating administration.

[0301] Although the description of pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for administration to humans, those skilled in the art will understand that such compositions are generally suitable for administration to all types of animals. Modifications of pharmaceutical compositions suitable for administration to humans to make them suitable for administration to various animals are well understood, and veterinary pharmacologists of ordinary skill in the art can design and / or perform such modifications using routine experimentation. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy, 21st ed., Lippincott Williams & Wilkins, 2005.

[0302] In one aspect, provided is a compound represented by formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), (If ), (Ig), (I-4), (I-a4), (I-b4a), (I-b5a), (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII).

[0303] B. Combination Therapy A compound or composition described herein (e.g., a compound of Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I- e3), (If), (Ig), (I-4), (I-a4), (I-b4a), (I-b5a), (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII), or a pharmaceutically acceptable salt thereof, ), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), ( I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), (If), (Ig), (I-4), (I-a4), A compound of formula (I-b4a), (I-b5a), (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII), or a composition comprising such a compound, or a pharmaceutically acceptable salt thereof, may be administered in combination with an additional drug or therapy. A subject receiving a compound disclosed herein may have a disease, disorder, or condition, or a symptom thereof, that would benefit from treatment with another drug or therapy.Combination therapy can be achieved by administering two or more drugs that are each formulated and administered separately, or by administering two or more drugs in a single formulation. In some embodiments, two or more drugs in combination therapy can be administered simultaneously. In other embodiments, two or more drugs in combination therapy are administered separately. For example, the administration of a first drug (or combination of drugs) can occur minutes, hours, days, or weeks before the administration of a second drug (or combination of drugs). Thus, two or more drugs can be administered within minutes of each other, or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 14 days of each other, or within 2, 3, 4, 5, 6, 7, 8, 9, or weeks of each other. In some cases, even longer intervals are possible. While it is often desirable for two or more drugs used in combination therapy to be present in the patient's body at the same time, this does not have to be the case.

[0304] Combination therapy can also include two or more administrations of one or more combined agents, using the component agents in a different order. For example, when agent X and agent Y are used in combination, they can be administered one or more times sequentially in any combination, for example, in the order XYX, XXY, YXY, YYX, XXYY, etc. Exemplary additional agents are described below.

[0305] 1. Selective serotonin reuptake inhibitors (SSRIs) In some embodiments, a compound or composition described herein (e.g., a compound of Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), Compound (I-e2), (I-e3), (If), (Ig), (I-4), (I-a4), (I-b4a), (I-b5a), (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII), or a pharmaceutically acceptable salt thereof. , or formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I -c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), (If), (Ig), (I-4), ( A composition comprising a compound of Formula I-a4), I-b4a), I-b5a), I-b4b), I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII), or a pharmaceutically acceptable salt thereof, is administered in combination with SSRI(s). SSRIs include antidepressants that increase levels of serotonin in the brain.Exemplary SSRIs include, but are not limited to, citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft).

[0306] 2. Norepinephrine reuptake inhibitors (NERIs) In some embodiments, a compound or composition described herein (e.g., a compound of Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), Compound (I-e2), (I-e3), (If), (Ig), (I-4), (I-a4), (I-b4a), (I-b5a), (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII), or a pharmaceutically acceptable salt thereof. , or formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I -c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), (If), (Ig), (I-4), ( (I-a4), (I-b4a), (I-b5a), (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII), or a composition comprising a compound thereof, is administered in combination with a NERI(s).Exemplary NERIs include, but are not limited to, atomoxetine (Strattera), reboxetine (Edronax, Bestra), bupropion (Wellbutrin, Zyban), duloxetine, desipramine (Norpramine), amedalin (UK-3540-1), daredalin (UK-3557-15), edivoxetine (LY-2216684), esreboxetine, lortalamine (LM-1404), nisoxetine (LY-94,939), talopram (taslopram) (Lu 3-010), talsupram (Lu 5-005), tandamine (AY-23,946), and viloxazine (Vivaran).

[0307] 3. Antipsychotics In some embodiments, a compound or composition described herein (e.g., a compound of Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), Compound (I-e2), (I-e3), (If), (Ig), (I-4), (I-a4), (I-b4a), (I-b5a), (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII), or a pharmaceutically acceptable salt thereof. , or formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I- c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), (If), (Ig), (I-4), (I

[0023] The compound of formula (I-a4), (I-b4a), (I-b5a), (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII), or a composition comprising a pharmaceutically acceptable salt thereof, is administered in combination with an antipsychotic agent(s). Antipsychotic agents include D2 antagonists that reduce dopaminergic neurotransmission in the dopamine pathway.Exemplary antipsychotic drugs include, but are not limited to, asenapine (Safris), aripiprazole (Abilify), cariprazine (Bleilar), clozapine (Clozaril), droperidol, fluperlapine, mesoridazine, quetiapine hemifumarate, raclopride, spiperone, sulpiride, trimethobenzamide hydrochloride, trifluoperazine dihydrochloride, lurasidone (Latuda), olanzapine (Zyprexa), quetiapine (Seroquel), zotepine, risperidone (Risperidal), ziprasidone (Geodon), mesoridazine, chlorpromazine hydrochloride, and haloperidol (Haldol).

[0308] 4. Cannabinoids In some embodiments, a compound or composition described herein (e.g., a compound of Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), (I-e4), (I-e5), (I-e6), (I-e7), (I-e8), (I-e9), (I-f), (I-f10), (I-f11), (I-f12), (I-f13), (I-f14), (I-f15), (I-f16), (I-f17), (I-f18), (I-f19), (I-f20), (I-f21), (I-f22), (I-f23), (I-f24), (I-f25), (I-f26), (I-f27), (I-f28), (I-f29), (I-f30), ​​(I-f31), (I-f32), (I-f33), (I-f34), (I-f35), (I-f36), (I-f37), (I-f38), (I-f40), (I-f41), (I-f42), (I-f43), (I-f44), (I-f45), (I-f46), (I-f47), (I-f48), (I-f I-e2), (I-e3), (If), (Ig), (I-4), (I-a4), (I-b4a), (I-b5a), (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII), or a pharmaceutically acceptable salt thereof; Or formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c 1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), (If), (Ig), (I-4), (I- a composition comprising a compound of Formula (I-a4), (I-b4a), (I-b5a), (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII), or a pharmaceutically acceptable salt thereof, is administered in combination with cannabinoid(s).Exemplary cannabinoids include, but are not limited to, cannabidiol (Epidiolex), tetrahydrocannabinolic acid, tetrahydrocannabinol, cannabidolic acid, cannabinol, cannabigerol, cannabichromene, tetrahydrocannabivarin, and cannabidivarin.

[0309] 5. NMDA receptor antagonists In some embodiments, a compound or composition described herein (e.g., a compound of Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e1), (I-e2), (I-e3), (I-e4), (I-e5), (I-e6), (I-e7), (I-e8), (I-e9), (I-f), (I-f10), (I-f11), (I-f12), (I-f13), (I-f14), (I-f15), (I-f16), (I-f17), (I-f18), (I-f19), (I-f20), (I-f21), (I-f22), (I-f23), (I-f24), (I-f25), (I-f26), (I-f27), (I-f28), (I-f29), (I-f30), ​​(I-f31), (I-f32), (I-f33), (I-f34), (I-f35), (I-f36), (I-f37), (I-f38), (I-f40), (I-f41), (I-f42), (I-f43), (I-f44), (I-f45), (I-f46), (I-f47), (I-f4 e2), (I-e3), (If), (Ig), (I-4), (I-a4), (I-b4a), (I-b5a), (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII), or a pharmaceutically acceptable salt thereof; Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a ), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), ( I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), (If), (Ig), (I-4), (I-a4), (I

[0023] The compound of formula (I-b4a), (I-b5a), (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII), or a composition comprising a pharmaceutically acceptable salt thereof, is administered in combination with an NMDA receptor antagonist(s). An NMDA receptor antagonist is a type of drug that inhibits the action of N-methyl-d-aspartate receptors.Exemplary NMDA antagonists include, but are not limited to, ketamine, esketamine, ketobemidone, ifendopril, 5,7-dichlorokynurenic acid, licostinel, memantine, gavestenel, phencyclidine, dextromethorphan, remacemide, selfotel, tiletamine, dextropropoxyphene, aptiganel, dexanabinol, and amantadine. NMDA receptor antagonists also include opioids such as methadone, dextropropoxyphene, pethidine, levorphanol, tramadol, neramexane, and ketobemidone.

[0310] 6. GABA receptor antagonists In some embodiments, a compound or composition described herein (e.g., a compound of Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), (I-e4), (I-e5), (I-e6), (I-e7), (I-e8), (I-e9), (I-e10), (I-e11), (I-e12), (I-e13), (I-e14), (I-e15), (I-e16), (I-e17), (I-e18), (I-e19 ...20), (I-e21), (I-e22), (I-e23), (I-e24), (I-e25), (I-e26), (I-e27), (I-e28), (I-e29), (I-e29), (I-e21), (I-e22), (I-e23), (I-e24), (I-e25), (I-e26), (I-e27), (I -e2), (I-e3), (If), (Ig), (I-4), (I-a4), (I-b4a), (I-b5a), (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII), or a pharmaceutically acceptable salt thereof; or formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b 2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b ), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), (If), (Ig), (I-4), (I-a4) , (I-b4a), (I-b5a), (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII), or a composition comprising a compound thereof, is administered in combination with a GABA receptor antagonist(s). A GABA receptor antagonist is a type of drug that is an antagonist of one or more GABA receptors.Exemplary GABA receptor antagonists include clobazam, topiramate, muscimol, progabide, riluzole, baclofen, gabapentin, vigabatrin, valproic acid, tiagabine, lamotrigine, pregabalin, phenyloin, carbamazepine, thiopental, thiamylal, pentobarbital, secobarbital, hexobarbital, butobarbital, amobarbital, barbital, mephobarbital, phenobarbital, primidone, midazolam, triazolam, lormetazepam, flutazolam, nitrazepam, fluritrazepam, nimetazepam, diazepam, medazepam, oxazolam, prazeam, tofisopam, rilmazafone, lorazepam, temazepam, oxazepam, fludiazepam, Chlordiazepoxide, cloxazolam, flutoprazepam, alprazolam, estazolam, bromazepam, flurazepam, clorazepate potassium, haloxazolam, ethyl loflazepate, quazepam, clonazepam, mexazolam, etizolam, brotizolam, clotiazepam, propofol, fospropofol, zolpidem, zopiclone, eszopiclone, muscimol, TFQP / gaboxadol, isoguvacine, kodiamine, GABA, homotaurine, homohypotaurine, trans-aminocyclopentane-3-carboxylic acid, trans-amino-4-crotonic acid, b-guanidinopropionic acid, homo-b-proline, isonipecotic acid, 3-((aminoiminomethyl)thio)-2-propenoic acid (ZAP) A), imidazole acetic acid, and piperidine-4-sulfonic acid (P4S).

[0311] 7. Cholinesterase inhibitors In some embodiments, a compound or composition described herein (e.g., a compound of Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), (I-e4), (I-e5), (I-e6), (I-e7), (I-e8), (I-e9), (I-e10), (I-e11), (I-e12), (I-e13), (I-e14), (I-e15), (I-e16), (I-e17), (I-e18), (I-e19 ...20), (I-e21), (I-e22), (I-e23), (I-e24), (I-e25), (I-e26), (I-e27), (I-e28), (I-e29), (I-e29), (I-e21), (I-e22), (I-e23), (I-e24), (I-e25), (I-e26), (I-e27), (I or a pharmaceutically acceptable salt thereof. is the formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2 a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b) , (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), ( I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), (If), (Ig), (I-4), (I-a4), A composition comprising a compound of formula (I-b4a), (I-b5a), (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII), or a pharmaceutically acceptable salt thereof, is administered in combination with a cholinesterase inhibitor(s). Generally, cholinergic agents are compounds that mimic the actions of acetylcholine and / or butyrylcholine.Cholinesterase inhibitors are a type of drug that prevents the breakdown of acetylcholine. Exemplary cholinesterase inhibitors include, but are not limited to, donepezil (Aricept), tacrine (Cognex), rivastigmine (Exelon, Exelon Patch), galantamine (Razadyne, Reminyl), memantine / donepezil (Namzalic), ambenonium (Mytelase), neostigmine (Broxivertz), pyridostigmine (Mestinon Timespan, Regonol), and galantamine (Razadyne).

[0312] The present disclosure also relates to, inter alia, a compound or pharmaceutical composition described herein (e.g., a compound or a pharmaceutical composition of Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I a compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (I-9), (I-10), (I-11), (I-12), (I-13), (I-14), (I-15), (I-16), (I-17), (I-18), (I-19), (I-22), (I-23), (I-24), (I-25), (I-26), (I-27), (I-28), (I-29), (I-30), (I-31), (I-32), (I-33), (I-34), (I-35), (I-36), (I-37), (I-38), (I-39), (I-40), (I-41), (I-42), (I-43), (I-44), (I-45), (I-46), (I-47), (I-48), (I-49 ... 2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b ), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I- c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), (If), (Ig), (I-4), (I-a4), (I-b4a), (I-b5a), (I-b4b), The administration of a compound of formula (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII), or a composition comprising a pharmaceutically acceptable salt thereof, to a subject who has previously received an agent selected from the group consisting of a bronchial muscle / airway relaxant, an antiviral agent, an oxygen agent, an antibody, and an antibacterial agent.In some embodiments, the additional agent is a compound or composition described herein (e.g., Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2 ), (I-e3), (If), (Ig), (I-4), (I-a4), (I-b4a), (I-b5a), (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII), or a pharmaceutically acceptable salt thereof, or a compound of formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I- b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1 ), (I-e2), (I-e3), (If), (Ig), (I-4), (I-a4), (I-b4a), (I-b5a), (I-b4b (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII), or a composition comprising a compound of Formula (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII), or a pharmaceutically acceptable salt thereof, wherein the additional agent is selected from the group consisting of a bronchial muscle / airway relaxant, an antiviral agent, an oxygen agent, an antibody, and an antibacterial agent.In some embodiments, a compound or pharmaceutical composition described herein (e.g., a compound of Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), (If), (Ig), (I-4), (I-a4), (I-b4a), (I-b5a), (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII), or a pharmaceutically acceptable salt thereof, or a compound of formula (I), (I-1) , (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I -b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c ), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I -e1), (I-e2), (I-e3), (If), (Ig), (I-4), (I-a4), (I-b4a), (I-b5a), (I (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII), or a composition comprising the compound of formula (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII), or a pharmaceutically acceptable salt thereof, is co-administered to a subject with an agent selected from a bronchial muscle / airway relaxant, an antiviral agent, an oxygen agent, an antibody, and an antibacterial agent.

[0313] C. Methods of Use and Treatment In one aspect, the compounds described herein, e.g., compounds of Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c) ), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), (If), (Ig), (I-4), (I-a4), (I-b4a), (I-b5a), (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (III The compounds of Formula (I), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII) are expected to be useful as therapeutic agents for treating a CNS-related disorder (e.g., a sleep disorder, a mood disorder such as depression, a schizophrenia spectrum disorder, a seizure disorder, an epileptic seizure, a disorder of memory and / or cognition, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder, and / or withdrawal symptoms, or tinnitus) in a subject in need thereof (e.g., a subject with Rett syndrome, Fragile X syndrome, or Angelman syndrome).Exemplary CNS conditions associated with GABA modulation include sleep disorders [e.g., insomnia], mood disorders [e.g., depression (e.g., major depressive disorder (MDD)), dysthymic disorder (e.g., mild depression), bipolar disorder (e.g., I and / or II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD))], schizophrenia spectrum disorders [e.g., schizophrenia, schizoaffective disorder], seizure disorders [e.g., epilepsy (e.g., status epilepticus (SE), seizures)], memory and / or cognitive disorders [e.g., attention disorders (e.g., attention deficit hyperactivity disorder (ADHD)), dementia (e.g., These conditions include, but are not limited to, Alzheimer's disease, dementia with Lewy bodies, vascular dementia], movement disorders (e.g., Huntington's disease, Parkinson's disease), personality disorders (e.g., antisocial personality disorder), autism spectrum disorders (ASD) (e.g., autism, synaptopathy, monogenic causes of autism such as Rett syndrome, Fragile X syndrome, Angelman syndrome), pain (e.g., neuropathic pain, injury-related pain syndrome, acute pain, chronic pain), traumatic brain injury (TBI), vascular disease (e.g., stroke, ischemia, vascular malformation), substance abuse disorders and / or withdrawal syndromes (e.g., opiate, cocaine, and / or alcohol addiction), and tinnitus.

[0314] In certain embodiments, the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a seizure disorder, a memory and / or cognition disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder and / or withdrawal syndrome, tinnitus, or status epilepticus. In certain embodiments, the CNS-related disorder is depression. In certain embodiments, the CNS-related disorder is postpartum depression. In certain embodiments, the CNS-related disorder is major depressive disorder. In certain embodiments, the major depressive disorder is moderate major depressive disorder. In certain embodiments, the major depressive disorder is severe major depressive disorder.

[0315] In one aspect, there is provided a method of reducing or preventing seizure activity in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the invention, hi some embodiments, the method reduces or prevents epileptic seizures.

[0316] In yet another aspect, the present invention provides a combination of a compound of the present invention with another pharmacologically active agent. The compounds provided herein can be administered as a single active agent or in combination with other agents. The administration of the combination can be carried out by any technique that is apparent to those skilled in the art, including, for example, separate administration, sequential administration, simultaneous administration, and alternating administration.

[0317] In another aspect, there is provided a method for treating or preventing brain excitability in a subject susceptible to or suffering from a condition associated with brain excitability, comprising administering to the subject an effective amount of a compound of the invention.

[0318] In yet another aspect, there is provided a method for treating or preventing stress or anxiety in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the invention, or a composition thereof.

[0319] In yet another aspect, there is provided a method for reducing or preventing insomnia in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the invention, or a composition thereof.

[0320] In yet another aspect, there is provided a method for inducing sleep and substantially maintaining the level of REM sleep seen in normal sleep, without inducing substantial rebound insomnia, comprising administering an effective amount of a compound of the invention.

[0321] In yet another aspect, there is provided a method for alleviating or preventing premenstrual syndrome (PMS) or postpartum depression (PND) in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the invention.

[0322] In yet another aspect, there is provided a method of treating or preventing a mood disorder in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the invention, hi certain embodiments, the mood disorder is depression.

[0323] In yet another aspect, the present invention provides a method for cognitive enhancement or treating memory impairment by administering a therapeutically effective amount of the compound of the present invention to a subject.In certain embodiments, the disorder is Alzheimer's disease.In certain embodiments, the disorder is Rett syndrome.

[0324] In yet another aspect, there is provided a method for treating attention disorders by administering to a subject a therapeutically effective amount of a compound of the invention. In certain embodiments, the attention disorder is ADHD.

[0325] In certain embodiments, the compound is administered chronically to the subject. In certain embodiments, the compound is administered orally, subcutaneously, intramuscularly, or intravenously to the subject.

[0326] 1. Neuroendocrine disorders and dysfunction Methods are provided herein that can be used to treat neuroendocrine disorders and dysfunctions. As used herein, "neuroendocrine disorder" or "neuroendocrine dysfunction" refers to various conditions caused by an imbalance in the body's hormone production that is directly related to the brain. Neuroendocrine disorders involve interactions between the nervous system and the endocrine system. Because the hypothalamus and pituitary gland are two areas of the brain that control hormone production, damage to the hypothalamus or pituitary gland, for example, due to traumatic brain injury, can affect hormone production and other neuroendocrine functions of the brain. In some embodiments, the neuroendocrine disorder or dysfunction is associated with a women's health disorder or condition (e.g., a women's health disorder or condition described herein). In some embodiments, the neuroendocrine disorder or dysfunction associated with a women's health disorder or condition is polycystic ovary syndrome.

[0327] Symptoms of neuroendocrine disorders include, but are not limited to, behavioral, emotional, and sleep-related symptoms, symptoms related to reproductive function, and physical symptoms, including, but not limited to, fatigue, poor memory, anxiety, depression, weight gain or loss, emotional lability, lack of concentration, difficulty paying attention, decreased libido, infertility, amenorrhea, loss of muscle mass, increased abdominal body fat, low blood pressure, low heart rate, hair loss, anemia, constipation, cold intolerance, and dry skin.

[0328] 2. Neurodegenerative diseases and disorders The methods described herein can be used to treat neurodegenerative diseases and disorders. The term "neurodegenerative disease" encompasses diseases and disorders associated with the progressive loss of neuronal structure or function, or the death of neurons. Neurodegenerative diseases and disorders include Alzheimer's disease (including associated symptoms of mild, moderate, or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic and ischemic injury; ataxia and seizures (including for the treatment and prevention, and for the prevention of seizures caused by schizoaffective disorder or medications used to treat schizophrenia); benign amnesia; cerebral edema; cerebellar ataxia, including McLeod neuroacanthocytosis syndrome (MLS); closed head injury; coma; contusion injury (e.g., spinal cord injury and head injury); dementia, including multi-infarct dementia and senile dementia; impairment of consciousness; Down's syndrome; drug-induced or medication-induced Parkinson's disease (such as neuroleptic-induced acute akathisia, acute dystonia, parkinsonism, or tardive dyskinesia, neuroleptic malignant syndrome, or medication-induced postural tremor); epilepsy; Fragile X syndrome; Gilles de la Tourette syndrome; head trauma; deafness and hearing impairment; Huntington's disease; Lennox syndrome; levodopa-induced Dyskinesias; mental retardation; movement disorders, including akinesia and akinesia (rigidity) syndromes (including brainstem neurocalcification, corticobasal degeneration, multiple system atrophy, Parkinsonism-ALS dementia complex, Parkinson's disease, postencephalitic parkinsonism, and progressive supranuclear palsy); muscle spasms and disorders associated with muscle spasms or weakness (chorea (e.g., benign hereditary chorea, drug-induced chorea, hemiballismus, Huntington's disease, neuroacanthocytosis, Sydenham's chorea, and symptomatic chorea), dyskinesias (complex chorea), tics, including tics such as tics, simple tics, and asymptomatic tics), myoclonus, including generalized myoclonus and focal cycloclonic jerks, tremors, such as rest tremor, postural tremor, and intention tremor, and dystonia, such as truncal dystonia, dystonic writer's cramp, hemiplegic dystonia, paroxysmal dystonia, and focal dystonia, including blepharospasm, temporomandibular dystonia, and spasmodic dysphonia and spasmodic torticollis; neuronal damage, including eye damage, retinopathy, or macular degeneration of the eye;Neurodegenerative diseases include, but are not limited to, stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia, and neurotoxicity following cardiac arrest; Parkinson's disease; seizures; status epilepticus; stroke; tinnitus; tuberous sclerosis; and viral infection-induced neurodegeneration (e.g., those caused by acquired immunodeficiency syndrome (AIDS) and encephalopathy). Neurodegenerative diseases also include, but are not limited to, stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia, and neurotoxicity following cardiac arrest. Methods for treating or preventing neurodegenerative diseases also include treating or preventing the loss of neuronal function characteristic of neurodegenerative disorders.

[0329] 3. Mood disorders Also provided herein are methods for treating mood disorders, such as clinical depression, postnatal or postpartum depression, perinatal depression, atypical depression, melancholic depression, psychotic major depression, catatonic depression, seasonal affective disorder, dysthymia, bipolar depression, depressive personality disorder, recurrent brief depression, mild depressive disorder, bipolar or manic-depressive disorder, depression caused by a chronic medical condition, treatment-resistant depression, treatment-refractory depression, suicidal tendencies, suicidal ideation, or suicidal behavior. In some embodiments, the methods described herein provide a therapeutic benefit to a subject suffering from depression (e.g., moderate or severe depression). In some embodiments, the mood disorder is associated with a disease or disorder described herein (e.g., neuroendocrine diseases and disorders, neurodegenerative diseases and disorders (e.g., epilepsy), movement disorders, tremors (e.g., Parkinson's disease), or women's health disorders or conditions).

[0330] Clinical depression, also known as major depression, major depressive disorder (MDD), severe depression, unipolar depression, unipolar disorder, and recurrent depression, refers to a mental disorder characterized by a pervasive and persistent low mood accompanied by low self-esteem and a loss of interest or pleasure in normally enjoyable activities. Some people with clinical depression experience sleep disturbances, weight loss, and generally feel agitated and irritable. Clinical depression affects how individuals feel, think, and behave, and can lead to a variety of emotional and physical problems. Individuals with clinical depression may have difficulty performing daily activities and may feel as if life is not worth living.

[0331] Perinatal depression refers to depression during pregnancy. Symptoms include irritability, tearfulness, restlessness, sleep disturbances, exhaustion (emotional and / or physical), changes in appetite, difficulty concentrating, increased anxiety and / or worry, feelings of disconnection from the baby and / or fetus, and loss of interest in previously enjoyed activities.

[0332] Postpartum depression (PND), also known as postpartum depression (PPD), refers to a type of clinical depression that women experience after giving birth. Symptoms may include sadness, fatigue, changes in sleep and eating habits, decreased libido, tearful episodes, anxiety, and irritability. In some embodiments, the PND is a treatment-resistant depression (e.g., a treatment-resistant depression described herein). In some embodiments, the PND is a treatment-refractory depression (e.g., a treatment-refractory depression described herein).

[0333] In some embodiments, the subject with PND also experiences depression or depressive symptoms during pregnancy.This depression is herein referred to as perinatal depression.In one embodiment, the subject who experiences perinatal depression has a high risk of experiencing PND.

[0334] Atypical depression (AD) is characterized by mood reactivity (e.g., paradoxical anhedonia) and aggressiveness, significant weight gain, or increased appetite. Patients with AD may also have significant social impairments as a result of excessive sleepiness or somnolence (hypersomnia), a feeling of heaviness in the limbs, and hypersensitivity to perceived interpersonal rejection.

[0335] Melancholic depression is characterized by loss of pleasure in most or all activities (anhedonia), unresponsiveness to pleasurable stimuli, depressed mood more pronounced than grief or loss, excessive weight loss, or excessive guilt.

[0336] Psychotic major depression (PMD) or psychotic depression refers to a major depressive episode, particularly one of a melancholic nature, in which an individual experiences psychotic symptoms such as delusions and hallucinations.

[0337] Catatonic depression refers to major depression accompanied by disturbances in motor behavior and other symptoms. Individuals may become mute and stuporous, become immobile, or exhibit purposeless or bizarre movements.

[0338] Seasonal affective disorder (SAD) refers to a type of seasonal depression in which an individual has a seasonal pattern of depressive episodes that occur in the fall or winter. Dysthymia refers to a condition related to unipolar depression that causes the same physical and cognitive problems, but tends to be less severe and last longer (e.g., at least 2 years).

[0339] Double depression is defined as at least two years of significant depressed mood (dysthymia) interspersed with periods of major depression.

[0340] Depressive personality disorder (DPD) refers to a personality disorder with depressive traits.

[0341] Recurrent brief depression (RBD) refers to a condition in which an individual has depressive episodes approximately once per month, each lasting for a short period of time (less than two weeks), typically less than two to three days.

[0342] Minor depressive disorder or minor depression refers to depression in which at least two symptoms are present for two weeks.

[0343] Bipolar disorder or manic-depressive disorder causes extreme mood swings, including emotional highs (mania or hypomania) and lows (depression). During manic periods, individuals may experience unusual euphoria, energy, or irritability in their emotions or behavior. Such individuals often make ill-considered decisions with little regard for the consequences. They usually have a decreased need for sleep. During depressive periods, individuals may become tearful, make less eye contact with others, and become pessimistic about life. The risk of suicide for people with this disorder is high—more than 6% over a 20-year period—and 30–40% will self-harm. Other mental health problems, such as anxiety disorders and substance abuse disorders, often coexist with bipolar disorder.

[0344] Chronic condition-induced depression refers to depression caused by a chronic medical condition such as cancer, chronic pain, chemotherapy, or chronic stress.

[0345] Treatment-resistant depression refers to a condition in which an individual is treated for depression but the symptoms do not improve. For example, antidepressants or psychological counseling (psychotherapy) do not alleviate the depressive symptoms of individuals with treatment-resistant depression. In some cases, individuals with treatment-resistant depression improve but then relapse. Treatment-resistant depression occurs in patients with depression who are resistant to standard pharmacological treatments, including tricyclic antidepressants, MAOIs, SSRIs, and double and triple doses of inhibitors and / or anxiolytics, as well as non-pharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagus nerve stimulation, and / or transcranial magnetic stimulation).

[0346] Postoperative depression refers to depressed feelings that continue after a surgical procedure (e.g., as a result of facing death). For example, patients may experience persistent feelings of sadness or emptiness, loss of pleasure or interest in hobbies and activities that they normally enjoy, or persistent feelings of worthlessness or hopelessness.

[0347] A mood disorder associated with a women's health condition or disorder refers to a mood disorder (eg, depression) that is associated with (eg, caused by) a women's health condition or disorder (eg, as described herein).

[0348] Suicidal tendencies, ideation, and behavior refer to an individual's tendency to attempt suicide. Suicidal ideation involves thoughts about or an abnormal preoccupation with suicide. The spectrum of suicidal ideation varies significantly, for example, from passing thoughts to widespread ideation, detailed plans, role-playing, and aborted attempts. Symptoms may include talking about suicide, obtaining the means to attempt suicide, withdrawing from social contacts, preoccupation with death, feeling trapped or hopeless about a situation, increased alcohol or drug use, engaging in risky or self-destructive behavior, and saying goodbye to people as if they will never see each other again.

[0349] Symptoms of depression include persistent anxiety or sadness, helplessness, hopelessness, pessimism, worthlessness, low energy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, difficulty exercising, loss of interest in enjoyable activities or hobbies, poor concentration, low energy, low self-esteem, lack of positive thinking or planning, excessive sleep, overeating, loss of appetite, insomnia, self-harm, suicidal thoughts, and suicide attempts. The presence, severity, frequency, and duration of symptoms may vary from case to case. Depression symptoms and their relief can be confirmed by a doctor or psychologist (for example, by mental status examination).

[0350] In some embodiments, the method includes monitoring the subject using known depression rating scales, such as the Hamilton Depression Rating Scale (HAM-D), Clinical Global Impression-Improvement Scale (CGI), and Montgomery-Asberg Depression Rating Scale (MADRS). In some embodiments, the effectiveness of treatment can be determined by a reduction in the subject's Hamilton Depression Rating Scale (HAM-D) total score. A reduction in the HAM-D total score can occur within 4, 3, 2, or 1 day; or within 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, or 8 hours. The effectiveness of treatment can be assessed over a specific treatment period. For example, the therapeutic effect can be measured by the change from baseline in the level of a compound described herein, e.g., a compound of Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1 ), (I-e2), (I-e3), (If), (Ig), (I-4), (I-a4), (I-b4a), (I-b5a), (I-b4b), (I-b5b), (X), (X (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII) compound (e.g., 12, 24, or 48 hours after administration; or 24, 48, 72, or 96 hours or more; or 1 day, 2 days, 14 days, 21 days, or 28 days; or 1 week, 2 weeks, 3 weeks, or 4 weeks; or 1 month, 2 months, 6 months, or 10 months, or 1 year, 2 years, or lifetime).

[0351] In some embodiments, the subject has a mild depressive disorder, e.g., mild major depressive disorder. In some embodiments, the subject has a moderate depressive disorder, e.g., moderate major depressive disorder. In some embodiments, the subject has a severe depressive disorder, e.g., severe major depressive disorder. In some embodiments, the subject has a very severe depressive disorder, e.g., very severe major depressive disorder. In some embodiments, the subject's baseline HAM-D total score (i.e., a compound described herein, e.g., a compound of Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), (If), (Ig), (I-4), (I-a4), (I-b4a), (I-b5a), (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII)). In some embodiments, the subject's baseline HAM-D total score is at least 24. In some embodiments, the subject's baseline HAM-D total score is 14 to 18, inclusive. In some embodiments, the subject's baseline HAM-D total score is between 19 and 22, inclusive.In some embodiments, a compound described herein may be selected from the group consisting of compounds of formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I- e3), (If), (Ig), (I-4), (I-a4), (I-b4a), (I-b5a), (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII) the subject's HAM-D total score prior to treatment with the compound is greater than or equal to 23. In some embodiments, the baseline score is at least 10, 15, or 20.In some embodiments, a compound described herein may be selected from the group consisting of compounds of formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), (If), (Ig), (I-4), The subject's HAM-D total score after treatment with the compound of (I-a4), (I-b4a), (I-b5a), (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII) is about 0 to 10 (e.g., less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 1.8). In some embodiments, a compound described herein, e.g., a compound of Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), the HAM-D total score after treatment with compound (If), (Ig), (I-4), (I-a4), (I-b4a), (I-b5a), (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII) is less than 10, 7, 5, or 3.In some embodiments, the reduction in HAM-D total score is from a baseline score of about 20-30 (e.g., 22-28, 23-27, 24-27, 25-27, 26-27) to a baseline score of about 20-30 (e.g., 22-28, 23-27, 24-27, 25-27, 26-27) with administration of a compound described herein, e.g., a compound of Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), a HAM-D total score of about 0 to 10 (e.g., less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 1.8) after treatment with compound (I-e1), (I-e2), (I-e3), (If), (Ig), (I-4), (I-a4), (I-b4a), (I-b5a), (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII).In some embodiments, the baseline HAM-D total score is increased by a compound described herein, e.g., Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), (I The reduction in HAM-D total score following treatment with compound of formula (I-f), (Ig), (I-4), (I-a4), (I-b4a), (I-b5a), (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII) is at least 1, 2, 3, 4, 5, 7, 10, 25, 40, 50, or 100 fold.In some embodiments, the baseline HAM-D total score is increased by a compound described herein, e.g., Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), (If , (Ig), (I-4), (I-a4), (I-b4a), (I-b5a), (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII), the percentage reduction in HAM-D total score after treatment with the compound is at least 50% (e.g., 60%, 70%, 80%, or 90%).In some embodiments, the efficacy of a compound described herein, e.g., a compound of Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-b2d), (I-b1e), (I-b2f), (I-b1g), (I-b1h), (I-b1m ... I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), ( I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), (If), (Ig), (I-4), (I-a4), (I-b4a (IVa-I), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII) compound (e.g., 12, 24, 48 hours; or 24, 48, 72, 96 hours or more; or 1 day, 2 days, 14 days or more after administration), the treatment effect is measured as a reduction in the HAM-D total score of at least 10, 15, or 20 points.

[0352] In some embodiments, the method of treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic effect (e.g., as measured by a reduction in the Hamilton Rating Scale for Depression (HAM-D)) within 14, 10, 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours. In some embodiments, the method of treating a depressive disorder, e.g., major depressive disorder, includes administering to a subject a compound described herein, e.g., a compound of Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), or a compound of Formula (I-e4). (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII).In some embodiments, the method of treating a depressive disorder, e.g., major depressive disorder, includes administering to a subject a compound described herein, e.g., a compound of Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII).In some embodiments, the method of treating a depressive disorder, e.g., major depressive disorder, includes administering to a subject a compound described herein, e.g., a compound of Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII) provides a therapeutic effect (e.g., as determined by a statistically significant reduction in the HAM-D total score) within 21 days following initiation of treatment with the compound ofIn some embodiments, the method of treating a depressive disorder, e.g., major depressive disorder, includes administering to a subject a compound described herein, e.g., a compound of Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII).In some embodiments, the therapeutic effect is achieved by administering to a subject a compound described herein, e.g., a compound of Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), (I-e4), (I-e5), (I-e6), (I-e7), (I-e8), (I-e9), (I-e10), (I-e11), (I-e12), (I-e13), (I-e14), (I-e15), (I-e16), (I-e17), (I-e18), (I-e19 ... Treatment with a compound of formula I-e2), (I-e3), (If), (Ig), (I-4), (I-a4), (I-b4a), (I-b5a), (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII) (e.g., treatment ...3), (Ig), (I-4), (I-a4), (I-b4a), (I-b5a), (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII) (e.g., treatment with a compound of formula I-e3), (Ig), (I-4), (I-a4), (I-b4 Compounds of formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a ), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), (If), (Ig), (I-4 (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII).In some embodiments, a compound described herein may be selected from the group consisting of compounds of Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e The subject's HAM-D total score prior to treatment with the compound of Formula I, II, IIa, IIb, III, IIIa, IVa, IVb, IVa-I, V, V, Va, Vb, Vaa, Vab, VI, VII, VIII, IX, or XII is at least 24. In some embodiments, a compound described herein may be selected from the group consisting of compounds of Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e The subject's HAM-D total score prior to treatment with the compound of Formula I, II, IIa, IIb, III, IIIa, IVa, IVb, IVa-I, V, Va, Vb, Vaa, Vab, VI, VII, VIII, IX, or XII is at least 18.In some embodiments, a compound described herein may be used, e.g., a compound of Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), (I The subject's HAM-D total score prior to treatment with compound of formula (I-f), (Ig), (I-4), (I-a4), (I-b4a), (I-b5a), (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII) is 14 to 18, inclusive.

[0023] In some embodiments, the efficacy of a compound described herein, e.g., a compound of Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e1), (I-e2), (I-e3), (I-e4), (I-e5), (I-e6), (I-e7), (I-e8), (I-e9), (I-f), (I-f10), (I-f11), (I-f12), (I-f13), (I-f14), (I-f15), (I-f16), (I-f17), (I-f18), (I-f19), (I-f20), (I-f21), (I-f22), (I-f23), (I-f24), (I-f25), (I-f26), (I-f27), (I-f28), (I-f29), (I-f30), ​​(I-f31), (I-f32), (I-f33), (I-f34), (I-f35), (I-f36), (I-f37), (I-f38), (I-f40), (I-f41), (I-f42), (I-f43), (I-f44), (I-f45), (I-f46), (I-f4 The reduction in HAM-D total score after treating a subject with a compound of formula (I-e2), (I-e3), (If), (Ig), (I-4), (I-a4), (I-b4a), (I-b5a), (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII) is at least 10. In some embodiments, the effect of a compound described herein, e.g., a compound of Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I- e3), (If), (Ig), (I-4), (I-a4), (I-b4a), (I-b5a), (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII), the reduction in HAM-D total score after treating the subject with the compound is at least 15 (e.g., at least 17). In some embodiments, a compound described herein may be used, e.g., a compound of Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), (I Treatment of a subject with a compound of Formula I, II, IIa, IIb, III, IIIa, IVa, IVb, IVa-I, V, V, V, V, Vb, V ...In some embodiments, a compound described herein, e.g., a compound of Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), Treatment of a subject with a compound of Formula (I), (If), (Ig), (I-4), (I-a4), (I-b4a), (I-b5a), (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII) is associated with a HAM-D total score of 7 or less.

[0353] In some embodiments, the method provides a therapeutic benefit (e.g., as measured by a reduction in the Clinical Global Impression (CGI) score) within 14, 10, 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours. In some embodiments, the CNS disorder is a depressive disorder, e.g., major depressive disorder. In some embodiments, the method of treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic benefit by day 2 of the treatment period. In some embodiments, the therapeutic benefit is a reduction in CGI score from baseline at the end of the treatment period (e.g., day 14 after administration).

[0354] In some embodiments, the method provides a therapeutic benefit (e.g., as measured by a reduction in the Montgomery-Asberg Depression Rating Scale (MADRS)) within 14, 10, 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours. In some embodiments, the CNS disorder is a depressive disorder, e.g., major depressive disorder. In some embodiments, the method of treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic benefit by day 2 of the treatment period. In some embodiments, the therapeutic benefit is a reduction in the MADRS score from baseline at the end of the treatment period (e.g., day 14 after administration).

[0355] The effectiveness of treatment for major depressive disorder can be determined by a reduction in the subject's Montgomery-Asberg Depression Rating Scale (MADRS) score. For example, the MADRS score may decrease within 4, 3, 2, or 1 day; or within 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, or 8 hours. The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item diagnostic questionnaire (relating to outward sadness, verbal sadness, internal tension, decreased sleep, decreased appetite, difficulty concentrating, inhibitions, lack of emotion, pessimistic thoughts, and suicidal thoughts) used by psychiatrists to measure the severity of depressive episodes in patients with mood disorders.

[0356] In some embodiments, the method results in a therapeutic effect (e.g., as measured by a reduction in the Edinburgh Postnatal Depression Scale (EPDS)) within 4, 3, 2, 1 day; 24, 20, 16, 12, 10, 8 hours. In some embodiments, the therapeutic effect is an improvement as measured by the EPDS.

[0357] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a reduction in the Generalized Anxiety Disorder 7-item scale (GAD-7)) within 4, 3, 2, 1 day; 24, 20, 16, 12, 10, 8 hours.

[0358] 4. Anxiety disorders Provided herein are methods for treating anxiety disorders (e.g., generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, phobias, and post-traumatic stress disorder). Anxiety disorder is an umbrella term that encompasses several different forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic criteria distinguish between a wide variety of anxiety disorders.

[0359] Generalized anxiety disorder (GAD) is a common chronic disorder characterized by long-term anxiety that is not focused on any one goal or situation. Those suffering from GAD experience persistent, nonspecific fear and worry, and become excessively concerned about minor everyday occurrences. GAD is the most common anxiety disorder affecting older adults.

[0360] In panic disorder, patients experience brief, intense attacks of fear and anxiety, often characterized by tremors, shaking, confusion, dizziness, nausea, and difficulty breathing. Defined by the APA as sudden onset of fear or discomfort that peaks in less than 10 minutes, these attacks can last for hours and can be triggered by stress, fear, or even exercise, although a specific cause is not always apparent. In addition to recurrent, unexpected panic attacks, a diagnosis of panic disorder also requires that the attacks have chronic consequences (either worry about the attack's potential impact, persistent fear of future attacks, or significant behavioral changes related to the attack). Thus, those suffering from panic disorder also experience symptoms outside of a specific panic episode. Often, when panic sufferers notice normal heartbeat changes, they believe there is something wrong with their heart or that another panic attack is coming. In some cases, heightened awareness of bodily functions (hypervigilance) occurs during a panic attack, and the perceived physiological changes are interpreted as potentially life-threatening illness (i.e., extreme hypochondria).

[0361] Obsessive-compulsive disorder (OCD) is a type of anxiety disorder characterized primarily by recurrent obsessions (distressing, persistent, intrusive thoughts or images) and compulsions (urges to perform specific actions or habitual behaviors). OCD thought patterns are sometimes likened to superstition because they involve belief in nonexistent causal relationships. The process is often entirely illogical; for example, a patient may engage in a compulsive behavior, such as walking in a particular pattern, to alleviate obsessive thoughts of impending harm. In many cases, the compulsions are entirely inexplicable and are simply urges to complete habitual behaviors triggered by nervousness. In a minority of cases, OCD patients experience only obsessions without overt compulsions, and even fewer experience only compulsions.

[0362] The largest single category of anxiety disorders is that of phobias, which includes all cases in which fear and anxiety are provoked by a particular stimulus or situation. Patients typically anticipate frightening consequences from encountering their feared object (which can be anything from an animal to a place or bodily fluid).

[0363] Post-traumatic stress disorder, or PTSD, is an anxiety disorder that results from a traumatic experience. Post-traumatic stress can result from extreme situations, such as combat, rape, hostage situations, or even serious accidents. It can also result from prolonged (chronic) exposure to significant stressors (e.g., soldiers who can tolerate individual combat but are unable to cope with sustained combat). Common symptoms include flashbacks, avoidance behaviors, and depression.

[0364] 5. Women's Health Disorders Provided herein are methods for treating women's health-related conditions or disorders, including, but not limited to, gynecological health conditions and disorders (e.g., premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD)), fertility issues (e.g., miscarriage, abortion), infertility and related disorders (e.g., polycystic ovary syndrome (PCOS)), other disorders and conditions, and issues related to women's overall health and wellness (e.g., menopause).

[0365] Gynecological conditions and disorders affecting women include menstruation and menstrual irregularities; urinary tract conditions, including urinary incontinence and pelvic floor disorders; and disorders such as bacterial vaginosis, vaginitis, uterine fibroids, and vulvodynia.

[0366] Premenstrual syndrome (PMS) refers to the physical and emotional symptoms that occur one to two weeks before a woman's period. Symptoms vary but can include bleeding, mood swings, breast tenderness, overeating, fatigue, irritability, acne, and depression.

[0367] Premenstrual dysphoric disorder (PMDD) is a severe form of PMS. Symptoms of PMDD are similar to those of PMS but are more severe and can interfere with work, social activities, and relationships. Symptoms of PMDD include mood swings, depressed mood or feelings of hopelessness, marked anger, increased interpersonal conflict, tension and anxiety, irritability, decreased interest in usual activities, difficulty concentrating, fatigue, appetite changes, uncontrollable or irresistible feelings, sleep disturbances, and physical problems (e.g., swelling, breast tenderness, edema, headaches, joint or muscle pain).

[0368] Pregnancy issues include preconception and prenatal care, pregnancy termination (miscarriage and stillbirth), preterm labor and delivery, sudden infant death syndrome (SIDS), breastfeeding, and congenital anomalies.

[0369] A miscarriage is a pregnancy that ends naturally within the first 20 weeks of pregnancy.

[0370] Abortion refers to the intentional interruption of a pregnancy, which can be performed during the first 28 weeks of pregnancy.

[0371] Infertility and related disorders include uterine fibroids, polycystic ovary syndrome, endometriosis, and primary ovarian insufficiency.

[0372] Polycystic ovary syndrome (PCOS) refers to an endocrine system disorder in women of reproductive age. PCOS is a group of symptoms resulting from elevated levels of male hormones in women. Most women with PCOS develop numerous small cysts on their ovaries. Symptoms of PCOS include irregular menstrual periods, amenorrhea, menorrhagia, excessive body and facial hair growth, acne, pelvic pain, difficulty conceiving, and thickened, dark, velvety patches of skin. PCOS can be associated with conditions including type 2 diabetes, obesity, obstructive sleep apnea, heart disease, mood disorders, and endometrial cancer.

[0373] Other disorders and conditions that affect only women include Turner syndrome, Rett syndrome, and ovarian and cervical cancer.

[0374] Issues relating to women's overall health and wellness include violence against women, women with disabilities and their particular challenges, osteoporosis and bone health, and menopause.

[0375] Menopause refers to the 12 months following a woman's last menstrual period and is characterized by the end of the menstrual cycle. Menopause usually occurs in women in their 40s or 50s. The physical symptoms of menopause (e.g., hot flushes) and emotional symptoms can disrupt sleep, reduce energy, and induce anxiety or feelings of sadness or loss. Menopause includes natural menopause and surgical menopause, which is a type of menopause induced by events such as surgery (e.g., hysterectomy, oophorectomy, cancer). It is induced when the ovaries are severely damaged, such as by radiation, chemotherapy, or other medications.

[0376] 6. Epilepsy Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1 b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c ), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), (If), (Ig), (I-4), (I-a4), (I-b4a), (I-b5a), (I-b4b), (I-b 5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable excipient thereof, can be used in the methods described herein, for example, in the treatment of a disorder described herein, such as epilepsy, status epilepticus, or seizures.

[0377] Epilepsy is a brain disorder characterized by recurrent seizures over time. Types of epilepsy can include, but are not limited to, generalized epilepsy, such as childhood absence epilepsy, juvenile myoclonic epilepsy, epilepsy with grand mal seizures on awakening, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, such as temporal lobe epilepsy, frontal lobe epilepsy, and benign focal childhood epilepsy.

[0378] 7. Epileptic seizures The compounds and methods described herein can be used to treat or prevent epileptic seizures. Epileptic seizures are a sequential process in which a normal brain develops epilepsy (a chronic condition in which seizures occur). Epileptic seizures result from neuronal damage that is suddenly triggered by an initial injury (e.g., status epilepticus).

[0379] 8. Status epilepticus (SE) Status epilepticus (SE) can include, for example, convulsive status epilepticus, e.g., early status epilepticus, confirmed status epilepticus, refractory status epilepticus, and very refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus, generalized periodic epileptiform discharges, and periodic unilateral epileptic discharges. Convulsive status epilepticus is characterized by the presence of convulsive status epilepticus and can include early status epilepticus, confirmed status epilepticus, refractory status epilepticus, and very refractory status epilepticus. Early status epilepticus is treated with first-line therapy. Confirmed status epilepticus is characterized by status epilepticus that persists despite treatment with first-line therapy, leading to the implementation of second-line therapy. Refractory status epilepticus is characterized by status epilepticus that persists despite treatment with first-line and second-line therapies and for which general anesthetics are administered systemically. Super-refractory status epilepticus is characterized by status epilepticus that persists despite treatment with first-line, second-line therapies, and general anesthetics for more than 24 hours.

[0380] Non-convulsive status epilepticus can include, for example, focal non-convulsive status epilepticus, e.g., complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, latent non-convulsive status epilepticus; generalized non-convulsive status epilepticus, e.g., delayed absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus.

[0381] Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I -b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), (If), (Ig), (I-4), (I-a4), (I -b4a), (I-b5a), (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb The compounds of Formula (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII), or a pharmaceutically acceptable salt thereof, can also be administered as a prophylactic agent prior to the onset of a seizure to a subject with a CNS disorder, e.g., traumatic brain injury, status epilepticus, e.g., convulsive status epilepticus, e.g., early status epilepticus, confirmed status epilepticus, refractory status epilepticus, very refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic unilateral epileptiform discharges.

[0382] 9. Seizures A seizure is a physical finding or behavioral change that occurs after an episode of abnormal electrical activity in the brain. The term "seizure" is often used interchangeably with "convulsion." A convulsion is when a person's body shakes rapidly and uncontrollably. A convulsion is when a person's body trembles rapidly and uncontrollably.

[0383] Based on the type of behavior and brain activity, seizures are classified into two broad categories: generalized and partial (also called focal or focal). Classifying the type of seizure helps doctors diagnose whether a patient has epilepsy.

[0384] Generalized seizures are caused by electrical excitation throughout the brain, whereas partial seizures are caused (at least initially) by electrical excitation in a smaller part of the brain. The part of the brain that produces the seizure is sometimes called the focus.

[0385] There are six types of generalized seizures. The most common, most severe, and therefore best known is a generalized convulsion, also known as a grand mal seizure. During this type of seizure, the patient loses consciousness and usually passes out. Following this loss of consciousness, there is a 30-60 second period of generalized rigidity (called the "tonic" phase of the seizure), followed by another 30-60 second period of violent convulsions (the "clonic" phase), after which the patient enters a deep sleep state (the "postictal" or postictal period). During a grand mal seizure, injuries and accidents such as tongue biting and urinary incontinence can occur.

[0386] Absence seizures cause a brief loss of consciousness (only a few seconds) with little to no symptoms. Typically, the patient (mostly a child) stops moving and stares blankly. These seizures begin and end suddenly and may occur several times a day. Patients are usually unaware that a seizure is occurring, except for the ability to keep track of "time."

[0387] Myoclonic seizures consist of sporadic jerks, usually on both sides of the body. Patients may describe the jerks as brief electric shocks. These seizures, when severe, may cause dropping or involuntary throwing of objects.

[0388] Clonic seizures are recurrent rhythmic convulsions that involve both sides of the body simultaneously.

[0389] Tonic seizures are characterized by muscle stiffness.

[0390] Cataplexy consists of a sudden generalized loss of muscle tone, especially in the arms and legs, often causing falls.

[0391] The seizures described herein may include epileptic seizures; acute repetitive seizures; cluster seizures; continuous seizures; persistent seizures; prolonged seizures; recurrent seizures; status epilepticus seizures, e.g., refractory convulsive status epilepticus, non-convulsive status epilepticus seizures; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondarily generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign rolandic seizures; febrile convulsions; affective seizures; focal seizures; galactoceles; generalized onset seizures; infantile spasms; Jacksonian seizures; widespread bilateral myoclonic seizures; multifocal seizures; neonatal onset seizures; nocturnal seizures; occipital lobe seizures; post-traumatic seizures; latency seizures; Sylvan seizures; visual reflex seizures; or withdrawal seizures. In some embodiments, the seizures are generalized seizures associated with Dravet syndrome, Lennox-Gastaut syndrome, tuberous sclerosis complex, Rett syndrome, or PCDH19 female epilepsy.

[0392] 10. Movement disorders Also described herein are methods for treating movement disorders. As used herein, "movement disorder" refers to various diseases and disorders associated with hyperkinetic movement disorders and related to abnormalities in muscle control. Exemplary movement disorders include, but are not limited to, Parkinson's disease and parkinsonism (particularly defined by bradykinesia), dystonia, chorea and Huntington's disease, ataxia, tremor (e.g., essential tremor), myoclonus and startle reflex, tic disorders and Tourette's syndrome, restless legs syndrome, stiff person syndrome, and gait disorders.

[0393] Tremor The methods described herein can be used to treat tremors, for example, by administering to a patient a compound of Formula (I), (I-1), (I-2), (I-3), (I-a1), (I-a2), (I-a3), (I-b1a), (I-b2a), (I-b1b), (I-b2b), (I-b1c), (I-b2c), (I-c1a), (I-c2a), (I-c1b), (I-c2b), (I-c1c), (I-c2c), (I-d1a), (I-d2a), (I-d1b), (I-d2b), (I-d1c), (I-d2c), (I-e1), (I-e2), (I-e3), (If), (Ig), (I-4), The compounds of (I-a4), (I-b4a), (I-b5a), (I-b4b), (I-b5b), (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII) can be used to treat cerebellar or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, Parkinsonian tremor, physiologic tremor, or rubral tremor. Tremors include genetic, degenerative, and idiopathic disorders (such as Wilson's disease, Parkinson's disease, and essential tremor, respectively); metabolic disorders (e.g., thyroid disease, parathyroid disease, liver disease, and hypoglycemia); peripheral neuropathies (associated with Charcot-Marie-Tooth disease, Lucy-Lewy syndrome, diabetes mellitus, and complex regional pain syndrome); toxins (nicotine, mercury, lead, CO, manganese, arsenic, toluene); drug-induced (sleep-inducing drugs, tricyclic antidepressants, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychogenic disorders. Clinical tremor can be classified as physiologic tremor, enhanced physiologic tremor, essential tremor syndrome (including classic essential tremor, primary orthostatic tremor, and task- and position-specific tremor), dystonic tremor, Parkinson's tremor, cerebellar tremor, Holmes tremor (i.e., red nucleus tremor), palatal tremor, neuropathic tremor, toxic or drug-induced tremor, and psychogenic tremor.

[0394] Tremor is an involuntary, intermittent rhythmic movement, muscle contraction, and relaxation that may involve vibration or twitching of one or more body parts (e.g., hands, arms, eyes, face, head, vocal cords, trunk, legs).

[0395] Cerebellar tremor or intention tremor is a slow, widespread tremor of the limbs that occurs after intentional movement.Cerebellar tremor is caused by lesions or damage to the cerebellum, such as tumors, stroke, or diseases (e.g., multiple sclerosis, hereditary degenerative diseases).

[0396] Dystonic tremor occurs in individuals with dystonia and is a movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive movements and / or painful, abnormal postures or positions. Dystonic tremor can affect any muscle in the body. Dystonic tremor occurs irregularly and is often relieved by complete rest.

[0397] Essential tremor, or benign essential tremor, is the most common type of tremor. Essential tremor can be mild and non-progressive or gradually develop, starting on one side of the body but affecting both sides within three years. It most often affects the hands, but can also affect the head, vocal cords, tongue, legs, and trunk. Tremor frequency may decrease with age, but severity may increase. Emotional arousal, stress, fever, physical fatigue, or hypoglycemia may trigger tremor and / or increase its severity. Symptoms generally evolve over time and can be visible and persistent after onset.

[0398] Orthostatic tremor is characterized by rapid (e.g., greater than 12 Hz) rhythmic muscle contractions in the legs and trunk immediately after standing. Patients may experience painful muscle spasms in the thighs and legs, and may tremble uncontrollably when asked to stand in one place. Patients with essential tremor may experience orthostatic tremor.

[0399] Parkinsonian tremor is caused by damage to structures in the brain that control movement. Parkinsonian tremor is often a precursor to Parkinson's disease and is typically seen as a "pill-rolling" movement of the hands, and may also affect the jaw, lips, legs, and trunk. Onset of Parkinsonian tremor usually begins after age 60. Movements may begin in one limb or side of the body and progress to involve the other side.

[0400] Physiologic tremor can occur in normal individuals and is not clinically significant. Physiologic tremor can be found in all voluntary muscle groups. Physiologic tremor can be caused by certain medications, alcohol withdrawal, or medical conditions including hyperthyroidism and hypoglycemia. Classic tremor has a frequency of approximately 10 Hz.

[0401] Psychogenic or hysterical tremor can occur at rest or during postural ...

Claims

[Claim 1] The invention described in the present specification.

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