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

Abstract

Provided herein are compounds of formula (I) or pharmaceutically acceptable salts 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. TIFF2023531517000239.tif53165

Description

[Technical Field]

[0001] Cross-reference of related applications This international PCT application claims the benefits of U.S. Provisional Patent Application No. 63 / 043,641, filed on 24 June 2020. This document is incorporated herein by reference in its entirety. [Background technology]

[0002] Brain excitability is defined as the level of arousal in animals, on a continuum from coma to seizure, and is regulated by various neurotransmitters. Generally, neurotransmitters play a role in regulating the conductance of ions across the neuronal membrane. At rest, the neuronal membrane has a potential (or membrane voltage) of approximately -70mV, and the inside of the cell is negative relative to the outside. The potential (voltage) is regulated by the conductance of ions (K) across the neuronal semipermeable membrane. + kaNa + Cl - This is the result of the balance of (organic anions). Neurotransmitters are stored in presynaptic vesicles and released under the influence of neuronal action potentials. When released into the synaptic cleft, excitatory chemical neurotransmitters such as acetylcholine cause membrane depolarization (a change in potential of -70mV to -50mV). This effect is stimulated by acetylcholine and Na + This 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 GABA receptor complexes (GRCs), the effect on brain excitability is mediated by the neurotransmitter gamma-aminobutyric acid (GABA). Because up to 40% of brain neurons utilize GABA as a neurotransmitter, GABA has a significant impact on overall brain excitability. GABA regulates the excitability of individual neurons by modulating the conductance of chloride ions across the neuronal membrane. GABA interacts with its recognition site on GRCs to promote the influx of chloride ions into the cell downwards along the GRC's electrochemical gradient. An increase in the intracellular level of this anion causes hyperpolarization of the transmembrane potential, reducing the neuron's sensitivity to excitatory input, i.e., decreasing neuronal excitability. In other words, the higher the chloride ion concentration in a neuron, the lower the brain excitability and arousal level.

[0004] It is well documented that GRCs mediate anxiety, seizure activity, and sedation. Therefore, GABA, and drugs that act like GABA or enhance the effects of GABA (e.g., therapeutically beneficial barbiturates and benzodiazepines (BZs) (e.g., Valium®)), exert their therapeutically beneficial effects by interacting with specific regulatory sites on GRCs. Accumulated evidence now suggests that GRCs contain specific sites for neurostimulant steroids in addition to benzodiazepine and barbiturate binding sites. See, for example, 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 pregnane-20-one and 3α-21-dihydroxy-5-reduced pregnane-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, N Let al., J Pharmacol. Exp. Ther. 241:346-353 (1987)). Novel and improved compounds are needed that act as modulators of brain excitability, as well as agents for the prevention and treatment of CNS-related disorders. The compounds, compositions, and methods described herein are intended for this purpose. [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) [Overview of the Initiative]

[0007] In this specification, for example, GABA A Compounds designed to act as regulatory agents are provided. In some embodiments, such compounds are assumed to be useful as therapeutic agents for treating CNS-related disorders.

[0008] The present invention provides a compound of formula (I-1), [Chemical formula] 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 heterocyclic ring, or a substituted or unsubstituted 8- to 12-membered bicyclic heterocyclic ring, and the monocyclic or bicyclic heterocyclic ring independently has 1 to 3 heteroatoms selected from N, O, and S, and each R D1 independently represents 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- to 8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0 to 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 are joined to form a substituted or unsubstituted 3- to 6-membered monocyclic heterocyclic ring or an 8- to 12-membered bicyclic heterocyclic ring, and the monocyclic or bicyclic heterocyclic ring independently has 1 to 3 heteroatoms selected from N, O, and S, or R 2a and R 2b , R 4a and R 4b , or R11a and R 11b One of them joins together to form an oxo (=O) group, R 16 and R 17 Each of these can independently be hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, -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 independently, a substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected from N, O, and S, with each R A1 These are, independently, hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6Alkynnyl, independently, a substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected from N, O, and S, an oxygen protecting group if attached to an oxygen atom, a sulfur protecting group if attached to a sulfur atom, a nitrogen protecting group if attached to a nitrogen atom, -SO2R A2 , -C(O)R A2 is either or two R A1 The groups join together to independently form substituted or unsubstituted 3-6 member saturated, partially unsaturated, or fully unsaturated monocyclic heterocycles having 1-3 heteroatoms selected from N, O, and S, with each R A2 These are independently substituted or non-substituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, or independently, a substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected from N, O, and S, R 3a is unsubstituted C 1~6 Alkyl, -CH2OCH3, or -CH2OCH2CH3, R 5 is hydrogen, unsubstituted methyl, or absent. [ka] It is either a single bond or a double bond, however, [ka] If it is a single bond, R 5 is hydrogen or methyl, [ka] If R is a double bond, 5 It is conditional on non-existence, R 19 is hydrogen or unsubstituted C 1~6 Alkyl, R X is hydrogen, or substituted or unsubstituted C1~6 is alkyl, R Y is substituted or unsubstituted pyrazinyl, pyrimidine substituted with cyano, substituted or unsubstituted pyridine, or substituted phenyl, provided that R 3a is -CH2OCH2CH3 and R Y is substituted or unsubstituted pyrazinyl, then R 19 is unsubstituted methyl.

[0009] In some embodiments, each of R 2a and R 2b is independently 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 is independently hydrogen, substituted or unsubstituted C 1~6 alkyl, or independently a substituted or unsubstituted 3- to 8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0 to 3 heteroatoms selected from N, O, and S. In some embodiments, each of R 2a and R 2b is independently hydrogen, C 1~6 alkyl optionally substituted with 1 to 3 halogens, C 1~6 alkoxy optionally substituted with 1 to 3 halogens, or -OH. In some embodiments, each of R 2a and R 2b is independently hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2. In some embodiments, one of R 2a and R 2b is hydrogen. In some embodiments, each of R 2a and R 2b is hydrogen.

[0010] In some embodiments, each of R 4a and R 4bEach of these can independently be hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenil, -OR D1 -OC(=O)R D1 -NH2, -N(R D1 )2, R D1 Each case independently involves hydrogen, substituted or unsubstituted carbon. 1~6 Alkyl is a substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected from N, O, and S. In some embodiments, R 4a and R 4b Each of these can be independently replaced by hydrogen or 1 to 3 halogens. 1~6 C is optionally substituted with alkyl or 1 to 3 halogens. 1~6 It is an alkoxy or -OH group. In some embodiments, R 4a and R 4b Each of these is independently hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2. In some embodiments, R 4a and R 4b One of them is hydrogen. In some embodiments, R 4a and R 4b Each of them is hydrogen.

[0011] In some embodiments, R 11a and R 11b Each of these can independently be hydrogen, halogen, cyano, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenil, -OR D1 -OC(=O)R D1 -NH2, or -N(R D1 )2, R D1 Each case independently involves hydrogen, substituted or unsubstituted C 1~6 Alkyls are independently substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic rings having 0-3 heteroatoms selected from N, O, and S. In some embodiments, R11a and R 11b Each of these can be independently replaced by hydrogen or 1 to 3 halogens. 1~6 C is optionally substituted with alkyl or 1 to 3 halogens. 1~6 It is an alkoxy. In some embodiments, R 11a and R 11b Each of these is independently hydrogen, -CH3, -CH2CH3, -OCH3, or -CH(CH3)2. In some embodiments, R 11a and R 11b One of them is hydrogen. In some embodiments, R 11a and R 11b Each of them is hydrogen.

[0012] In some embodiments, R 7 C is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenil, -OR D1 -OC(=O)R D1 -NH2, or -N(R D1 )2, R D1 Each case independently involves hydrogen, substituted or unsubstituted carbon. 1~6 Alkyl is a substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected from N, O, and S. In some embodiments, R 7 C is optionally substituted with hydrogen or 1 to 3 halogens. 1~6 C is optionally substituted with alkyl or 1 to 3 halogens. 1~6 It is an alkoxy or -OH. In some embodiments, is hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2. In some embodiments, R 7 It is hydrogen.

[0013] In some embodiments, R 6 C is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C2~6 Alkenil, -OR D1 -OC(=O)R D1 -NH2, or -N(R D1 )2, R D1 Each case independently involves hydrogen, substituted or unsubstituted carbon. 1~6 Alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or independently, a substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected from N, O, and S. In some embodiments, R 6 C is optionally substituted with hydrogen or 1 to 3 halogens. 1~6 C is optionally substituted with alkyl or 1 to 3 halogens. 1~6 It is an alkoxy or -OH group. In some embodiments, R 6 R is hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2. In some embodiments, R 6 It is hydrogen.

[0014] In some embodiments, R 16 C is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenil, -OR D1 -OC(=O)R D1 -NH2, or -N(R D1 )2, R D1 Each case independently involves hydrogen, substituted or unsubstituted C 1~6 Alkyls are independently substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic rings having 0-3 heteroatoms selected from N, O, and S. In some embodiments, R 16 C is optionally substituted with hydrogen or 1 to 3 halogens. 1~6 C is optionally substituted with alkyl or 1 to 3 halogens. 1~6 It is an alkoxy or -OH group. In some embodiments, R 16R is hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2. In some embodiments, R 16 It is hydrogen.

[0015] In some embodiments, R 17 C is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenil, -OR D1 -OC(=O)R D1 -NH2, or -N(R D1 )2, R D1 Each case independently involves hydrogen, substituted or unsubstituted C 1~6 Alkyls are independently substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic rings having 0-3 heteroatoms selected from N, O, and S. In some embodiments, R 17 C is optionally substituted with hydrogen or 1 to 3 halogens. 1~6 C is optionally substituted with alkyl or 1 to 3 halogens. 1~6 It is an alkoxy or -OH group. In some embodiments, R 17 R is hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2. In some embodiments, R 17 It is hydrogen.

[0016] In some embodiments, R 19 is hydrogen or unsubstituted C 1~5 It is alkyl. In some embodiments, R 19 is hydrogen or unsubstituted C 1~4 It is alkyl. In some embodiments, R 19 is hydrogen, -CH3, or -CH2CH3. In some embodiments, R 19 is hydrogen. In some embodiments, R 19 This is -CH3 or -CH2CH3.

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

[0018] In some embodiments, the compound of formula (I-1) is the compound of formula (I-2), [ka] or a pharmaceutically acceptable salt thereof, where R 3a R is -CH2OCH3 or unsubstituted methyl, 5 is hydrogen, unsubstituted methyl, or absent. [ka] It is either a single bond or a double bond, however, [ka] If it is a single bond, R 5 is hydrogen or methyl, [ka] If R is a double bond, 5 It is conditional on non-existence, R 19 is hydrogen, or substituted or unsubstituted C 1~6 It is alkyl, R X is hydrogen, or substituted or unsubstituted C 1~6 It is alkyl, R Y This is a pyridine substituted with cyano. 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 these is defined as a compound of formula (I-1) or as defined in any embodiment thereof.

[0019] In some embodiments, the compound of formula (I-1) is the compound of formula (I-3), [ka] or a pharmaceutically acceptable salt thereof, where R 3a R is -CH2OCH3 or unsubstituted methyl, 5 is hydrogen, unsubstituted methyl, or absent. [ka] It is either a single bond or a double bond, however, [ka] If it is a single bond, R 5 is hydrogen or methyl, [ka] If R is a double bond, 5 It is conditional on non-existence, R 19 is hydrogen, or substituted or unsubstituted C 1~6 It is alkyl, R X is hydrogen, or substituted or unsubstituted C 1~6 It is alkyl, R Y This is a pyridine substituted with fluoropolymer.

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

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

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

[0023] In some embodiments, if the compound is a compound of formula (I-a1), (I-a2), or (I-a3), R 17 R is hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2. In some embodiments, R 17 It is hydrogen.

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

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

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

[0027] In some embodiments, the compound of formula (I-a1) is the 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 the 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 the 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 the 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 the 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 the 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 the 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 the 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 the 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 It is alkyl. In some embodiments, R X is hydrogen, -CH3, or -CH2CH3. In some embodiments, R X It is hydrogen.

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

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

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

[0040] In some embodiments, R Y teeth, [ka] Selected from, In the formula, each R D These are independently hydrogen, halogen, -NO2, -CN, and -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 , substitution or non-substitution C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynnyls are independently substituted or unsubstituted 3-10 member saturated, partially unsaturated, or fully unsaturated monocyclic rings having 0-3 heteroatoms selected from N, O, and S, or two R D The groups, together with the atoms to which they are attached, independently form substituted or unsubstituted 5-6 member saturated, partially unsaturated, or fully unsaturated rings having up to 3 heteroatoms selected from N, O, or S, with each R GA These are, independently, hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynnyl, independently, a substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected from N, O, and S, being an oxygen protecting group if attached to oxygen, a nitrogen protecting group if attached to nitrogen, or two R GA The groups, together with the atoms to which they are attached, independently form a substituted or unsubstituted 5-6 member saturated, partially unsaturated, or fully unsaturated ring having up to 3 heteroatoms selected from N, O, or S, where e is 0, 1, 2, 3, 4, or 5.

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

[0042] Another aspect of the present invention relates to compounds of formula (I-4): [ka] or provides a pharmaceutically acceptable salt thereof, in the formula R 2a , R 2b , R 4a , R 4b , R 6 , R 7 , R 11a , R 11b , R 15a , and R 15b Each of these independently consists of hydrogen, halogen, hydroxyl, substituted or unsubstituted C. 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, -OR D1 -OC(=O)R D1 -NH2, -N(R D1 )2, -NR D1 C(=O)R D1 , substituted or unsubstituted 3-6 member monocyclic heterocycles, or substituted or unsubstituted 8-12 member bicyclic heterocycles, where each monocyclic or bicyclic heterocycle independently has 1-3 heteroatoms selected from N, O, and S, and each R D1 These are, independently, hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynnyls are independently substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic rings having 0-3 heteroatoms selected from N, O, and S, being oxygen protecting groups when attached to an oxygen atom, nitrogen protecting groups when attached to a nitrogen atom, or two R atoms. D1 The groups join to form substituted or unsubstituted 3-6 member monocyclic heterocycles or 8-12 member bicyclic heterocycles, and the monocyclic or bicyclic heterocycles independently have 1-3 heteroatoms selected from N, O, and S, or R 2a and R 2b , R 4a and R 4b , or R 11a and R 11b One of them joins together to form an oxo (=O) group, R 16 and R17 Each of these can independently be hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, -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 independently, a substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected from N, O, and S, with each R A1 These are, independently, hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6Alkynnyl, independently, a substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected from N, O, and S, an oxygen protecting group if attached to an oxygen atom, a sulfur protecting group if attached to a sulfur atom, a nitrogen protecting group if attached to a nitrogen atom, -SO2R A2 , -C(O)R A2 is either or two R A1 The groups join together to independently form substituted or unsubstituted 3-6 member saturated, partially unsaturated, or fully unsaturated monocyclic heterocycles having 1-3 heteroatoms selected from N, O, and S, with each R A2 These are independently substituted or non-substituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, or independently, a substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected from N, O, and S, R 3a C is hydrogen, substituted or unsubstituted. 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynnyl is an independently substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected from N, O, and S, and R 5 is hydrogen, unsubstituted methyl, or absent. [ka] It is either a single bond or a double bond, however, [ka] If it is a single bond, R 5 is hydrogen or methyl, [ka] If R is a double bond,5 It is conditional on non-existence, R 19 is hydrogen, or substituted or unsubstituted C 1~6 It is alkyl, R X is hydrogen, or substituted or unsubstituted C 1~6 It is alkyl, R Y is a substituted or unsubstituted phenyl, or a substituted or unsubstituted 3-6 member monocyclic heteroaryl or an 8-12 member bicyclic heteroaryl, where the monocyclic or bicyclic heteroaryl independently has 1-5 heteroatoms selected from N, O, and S, and t is 2 or 3.

[0043] In some embodiments, R 2a and R 2b Each of these can independently be hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenil, -OR D1 -OC(=O)R D1 -NH2, or -N(R D1 )2, and each R D1 These are, independently, hydrogen, substituted or unsubstituted C 1~6 Alkyl, or independently, a substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected from N, O, and S. In some embodiments, R 2a and R 2b Each of these can be independently replaced by hydrogen or 1 to 3 halogens. 1~6 C is optionally substituted with alkyl or 1 to 3 halogens. 1~6 It is an alkoxy or -OH group. In some embodiments, R 2a and R 2b Each of these is independently hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2. In some embodiments, R 2a and R 2b One of them is hydrogen. In some embodiments, R 2a and R 2b Each of them is hydrogen.

[0044] In some embodiments, R 4a and R 4b Each of these can be independently replaced by hydrogen or 1 to 3 halogens. 1~6 C is optionally substituted with alkyl or 1 to 3 halogens. 1~6 It is an alkoxy or -OH group. In some embodiments, R 4a and R 4b Each of these is independently hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2. In some embodiments, R 4a and R 4b One of them is hydrogen. In some embodiments, R 4a and R 4b Each of them is hydrogen.

[0045] In some embodiments, R 11a and R 11b Each of these can independently be hydrogen, halogen, cyano, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenil, -OR D1 -OC(=O)R D1 -NH2, or -N(R D1 )2, R D1 Each case independently involves hydrogen, substituted or unsubstituted C 1~6 Alkyls are independently substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic rings having 0-3 heteroatoms selected from N, O, and S. In some embodiments, R 11a and R 11b Each of these can be independently replaced by hydrogen or 1 to 3 halogens. 1~6 C is optionally substituted with alkyl or 1 to 3 halogens. 1~6 It is an alkoxy. In some embodiments, R 11a and R 11b Each of these is independently hydrogen, -CH3, -CH2CH3, -OCH3, or -CH(CH3)2. In some embodiments, R 11a and R11b One of them is hydrogen. In some embodiments, R 11a and R 11b Each of them is hydrogen.

[0046] In some embodiments, R 7 C is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenil, -OR D1 -OC(=O)R D1 -NH2, or -N(R D1 )2, R D1 Each case independently involves hydrogen, substituted or unsubstituted C 1~6 Alkyls are independently substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic rings having 0-3 heteroatoms selected from N, O, and S. In some embodiments, R 7 C is optionally substituted with hydrogen or 1 to 3 halogens. 1~6 C is optionally substituted with alkyl or 1 to 3 halogens. 1~6 It is an alkoxy or -OH group. In some embodiments, R 7 R is hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2. In some embodiments, R 7 It is hydrogen.

[0047] In some embodiments, R 6 C is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenil, -OR D1 -OC(=O)R D1 -NH2, or -N(R D1 )2, R D1 Each case independently involves hydrogen, substituted or unsubstituted carbon. 1~6Alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or independently, a substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected from N, O, and S. In some embodiments, R 6 C is optionally substituted with hydrogen or 1 to 3 halogens. 1~6 C is optionally substituted with alkyl or 1 to 3 halogens. 1~6 It is an alkoxy or -OH group. In some embodiments, R 6 R is hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2. In some embodiments, R 6 It is hydrogen.

[0048] In some embodiments, R 16 C is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenil, -OR D1 -OC(=O)R D1 -NH2, or -N(R D1 )2, R D1 Each case independently involves hydrogen, substituted or unsubstituted C 1~6 Alkyls are independently substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic rings having 0-3 heteroatoms selected from N, O, and S. In some embodiments, R 16 C is optionally substituted with hydrogen or 1 to 3 halogens. 1~6 C is optionally substituted with alkyl or 1 to 3 halogens. 1~6 It is an alkoxy or -OH group. In some embodiments, R 16 R is hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2. In some embodiments, R 16 It is hydrogen.

[0049] In some embodiments, R 17C is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenil, -OR D1 -OC(=O)R D1 -NH2, or -N(R D1 )2, R D1 Each case independently involves hydrogen, substituted or unsubstituted C 1~6 Alkyls are independently substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic rings having 0-3 heteroatoms selected from N, O, and S. In some embodiments, R 17 C is optionally substituted with hydrogen or 1 to 3 halogens. 1~6 C is optionally substituted with alkyl or 1 to 3 halogens. 1~6 It is an alkoxy or -OH group. In some embodiments, R 17 R is hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2. In some embodiments, R 17 It is hydrogen.

[0050] In some embodiments, R 19 is hydrogen or unsubstituted C 1~5 It is alkyl. In some embodiments, R 19 is hydrogen or unsubstituted C 1~4 It is alkyl. In some embodiments, R 19 is hydrogen, -CH3, or -CH2CH3. In some embodiments, R 19 is hydrogen. In some embodiments, R 19 This is -CH3 or -CH2CH3.

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

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

[0053] In some embodiments, the compound of formula (I-4) is the 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 the compound of formula (I-b4b) or formula (I-b5b), [ka] or a pharmaceutically acceptable salt thereof.

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

[0056] In some embodiments, R Y teeth, [ka] Selected from, In the formula, each R D These are independently hydrogen, halogen, -NO2, -CN, and -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 , substitution or non-substitution C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynnyls are independently substituted or unsubstituted 3-10 member saturated, partially unsaturated, or fully unsaturated monocyclic rings having 0-3 heteroatoms selected from N, O, and S, or two R GA However, together with intervening atoms, they independently form substituted or unsubstituted 3-5 member saturated, partially unsaturated, or fully unsaturated monocyclic rings having 0-3 heteroatoms selected from N, O, and S, and each X independently has -N= or -C(R D )= and each R GA These are, independently, hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynnyl, independently, a substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected from N, O, and S, being an oxygen protecting group if attached to oxygen, a nitrogen protecting group if attached to nitrogen, or two R GA The group, together with the intervening atom, independently forms a substituted or unsubstituted 5-6 member heterocyclic ring having 2-3 heteroatoms selected from N, O, or S, R X1 is hydrogen, or substituted or unsubstituted C 1~6 Alkyl, or independently, a substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected from N, O, and S, where e is 0, 1, 2, or 3.

[0057] In some embodiments, R Y teeth, [ka] Selected from, In the formula, R D Each case independently involves hydrogen, halogen, substituted or unsubstituted C 1~6 The elements are alkyl, -CN, substituted or unsubstituted 5- to 6-membered heteroaryl, or substituted or unsubstituted 5-membered heterocyclyl, where e is 0, 1, 2, 3, or 4.

[0058] In some embodiments, R Y teeth, [ka] Selected from, In the formula, each R is independently -CH3, -CH2CH3, -i-Pr, cyclopropyl, or -CN.

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

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

[0061] Another aspect of the present invention relates to a compound of formula (X), [ka] or provides a pharmaceutically acceptable salt thereof, in the formula R 2a is hydrogen, or substituted or unsubstituted C 1~6 It is alkyl, R 3a is a substitution or non-substitution C 1~6 Alkyl, or substituted or unsubstituted C 1~6 Alkyl-OC 1~6 It is alkyl, R 19 is hydrogen, or substituted or unsubstituted C 1~6 It is alkyl, R Y R is a 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-2 nitrogen atoms, Y The 3-8 member rings are independently halogen, -CN, or C 1~6 It is optionally substituted with 1 to 3 groups selected from alkyl groups, and t is 1 or 2, however, if t is 1, R 3a It is -CH2OCH2CH3, and R Y is a substituted or unsubstituted pyrazinyl, followed by R 19 This is conditional on it being -CH3.

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

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

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

[0065] In some embodiments, R Y These are substituted or unsubstituted pyrazinyls, cyano-substituted pyrimidines, substituted or unsubstituted phenyls, cyano- or fluoro-substituted pyridines, or pyrazoles substituted with two unsubstituted methyl groups.

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

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

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

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

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

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

[0072] Another aspect of the present invention is GABA A The present invention provides a method for modulating receptors in subjects requiring such modulation, 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 The present invention provides a method for modulating receptor-mediated CNS-related disorders in subjects requiring such modulation, comprising administering to such subjects a therapeutically effective dose of any one of the compounds described herein or a pharmaceutically acceptable salt thereof, or any pharmaceutical composition described herein.

[0074] Another aspect of the present invention provides a method for treating a CNS-related disorder in a subject requiring treatment of such disorder, 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.

[0075] In some implementations of the method described above, CNS-related disorders are sleep disorders, mood disorders, schizophrenia spectrum disorders, convulsive disorders, memory and / or cognitive impairments, motor disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and / or withdrawal syndromes, tinnitus, or status epilepticus. In some implementations, CNS-related disorders are mood disorders. In some implementations, mood disorders are depression. In some implementations, depression is postpartum depression. In some implementations, depression is major depressive disorder. In some implementations, major depressive disorder is moderate major depressive disorder. In some implementations, major depressive disorder is severe major depressive disorder.

[0076] In preferred embodiments, the compounds described herein are GABA A Selectively modulates a specific subunit composition of the receptor, such as the α4β3δ subunit composition. [Modes for carrying out the invention]

[0077] Generally as described herein, the present invention relates to, for example, GABA A The present invention provides neuroactive steroids designed to function as receptor modulators. In one embodiment, the compounds described herein are GABA A A specific subunit composition of the receptor, for example, an α4β3δ subunit composition, is selectively modified. In certain embodiments, such compounds are assumed to be useful as therapeutic agents for treating CNS-related disorders (e.g., the disorders described herein, such as depression, including postpartum depression or major depressive disorder).

[0078] I. Definition A. Definition of chemical substances The definitions of specific functional groups and chemical terms are explained in detail below. Chemical elements are based on the periodic table of elements, the CAS edition, and Handbook of Chemistry and Physics, 75. thIdentified according to the ed. endpapers, specific functional groups are generally defined as described herein. In addition, general principles of organic chemistry, as well as specific functional groups and reactivity, are referenced in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999, and 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 This information is found in Edition, Cambridge University Press, Cambridge, 1987.

[0079] Isomers, such as stereoisomers, can be isolated from a mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers can be prepared by asymmetric synthesis. See, for example, 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 (ELEliel, 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 enantiomerized compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., enantiomer-rich). In other words, the "S" compound is substantially free of the "R" compound and is therefore enantiomer-rich in the "R" compound. The terms "enantiomerically pure" or "pure enantiomer" mean that the compound contains more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, 99.8% by weight, or more than 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, enantiomerically pure compounds may be present together with other active or inactive components. For example, a pharmaceutical composition containing an enantiomerically pure R-position / center / carbon compound may contain, for example, about 90% excipients and about 10% enantiomerically pure R-compounds. In certain embodiments, the enantiomerically pure R-compound in such a composition may consist, for example, at least about 95% by weight of the R-compound and as much as about 5% by weight of the S-compound by the total weight of the compound. For example, a pharmaceutical composition containing an enantiomerically pure S-compound may contain, for example, about 90% excipients and about 10% enantiomerically pure S-compound by the total weight of the compound. In certain embodiments, the enantiomerically pure S-compound in such a composition may consist, for example, at least about 95% by weight of the S-compound and as much as about 5% by weight of the R-compound by the total weight of the compound. In certain embodiments, the active ingredient may be formulated with little or no excipients or carriers.

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

[0083] "Stereoisomers": It should be understood that compounds having the same molecular formula but differing in the bonding properties or arrangement of their atoms or their spatial arrangement are called "isomers." Isomers with different spatial arrangements of atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are mirror images of each other but cannot be superimposed are called "enantiomers." For example, if a compound has a chiral center and is bonded to four different groups, a set of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their chiral center and are described by the Cahn and Prelog R- and S- sequencing rules, or by the way the molecule rotates the plane of polarization 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 enantiomers in equal proportions is called a "racemic mixture."

[0084] The articles “a” and “an” may be used herein to refer to one or more (i.e., at least one) of the grammatical objects of the article. For example, “an analogue” means one analogue or two or more analogues.

[0085] When a range of values ​​is enumerated, it is intended to include each value and subrange within that 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 It is intended to include alkyl groups.

[0086] The following terms are intended to have the meanings set forth below and are useful in understanding the scope intended in this specification and the present invention.

[0087] "Alkyl" refers to a radical of a linear or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1~20 (alkyl). In some embodiments, the alkyl group has 1 to 12 carbon atoms ("C"). 1~12 ("alkyl"). In some embodiments, the alkyl group has 1 to 10 carbon atoms ("C"). 1~10 (alkyl). In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C"). 1~9 (alkyl). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C"). 1~8 (alkyl). In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C"). 1~7 ("alkyl"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C"). 1~6 "Alkyl" (also referred to as "lower alkyl" in this specification). In some embodiments, the alkyl group consists of 1 to 5 carbon atoms ("C"). 1~5 The alkyl group has 1 to 4 carbon atoms ("C"). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C"). 1~4 (alkyl). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C"). 1~3 Alkyl). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C"). 1~2 In some embodiments, the alkyl group has one carbon atom ("C1 alkyl"). In some embodiments, the alkyl group has two to six carbon atoms ("C1 alkyl"). 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), iso-butyl (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) and n-octyl (C8). Unless otherwise specified, each alkyl group can be independently and 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, the alkyl group is unsubstituted C 1~10 It is an alkyl group (e.g., -CH3). In certain embodiments, the alkyl group is a substituted C 1~10 It is an alkyl group. Common abbreviations for alkyl groups include Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2).

[0088] "Alkylene" refers to an alkyl group in which two hydrogen atoms are removed to give a divalent radical, and this alkyl group may be substituted or unsubstituted. Examples of unsubstituted alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), and hexylene (-CH2CH2CH2CH2CH2CH2-). For example, exemplary substituted alkylene groups substituted with one or more alkyl(methyl) groups include, but are not limited to, substituted methylene (-CH(CH3)-, (-C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-). When a range or number of carbon atoms is indicated for a particular alkylene group, this range or number is understood to refer to the range or number of carbon atoms in the divalent linear carbon chain. The alkylene group may be substituted or unsubstituted with one or more substituents as described herein.

[0089] "Alkenyl" refers to a radical of a linear 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 ("Alkenyl"). In certain embodiments, the alkenyl does not contain any triple bond. In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C"). 2~10 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C"). 2~9 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C"). 2~8("Alkenyl"). In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C"). 2~7 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C"). 2~6 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C"). 2~5 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C"). 2~4 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C"). 2~3 "Alkenyl"). In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). One or more carbon-carbon double bonds may be internal (e.g., 2-butenyl) or terminal (e.g., 1-butenyl). C 2~4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), and butadienyl (C4). 2~6 An example of an alkenyl group is the aforementioned C 2~4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and others. Additional examples of alkenyls include heptenyl (C7), octenyl (C8), and octatrienyl (C8). Unless otherwise specified, each alkenyl group can be independently and 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, the alkenyl group is unsubstituted C 2~10 It is an alkenyl. In certain embodiments, the alkenyl group is a substituted C 2~10 It is Alkenil.

[0090] "Alkynyl" refers to a radical of a linear 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 ("Alkynyl"). In certain embodiments, the alkynyl group contains no double bonds at all. In some embodiments, the alkynyl group has 2 to 10 carbon atoms ("C"). 2~10 In some embodiments, the alkynyl group has 2 to 9 carbon atoms ("C"). 2~9 In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C"). 2~8 In some embodiments, the alkynyl group has 2 to 7 carbon atoms ("C"). 2~7 In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C"). 2~6 In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C"). 2~5 In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C"). 2~4 In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C"). 2~3 "Alkynyl"). In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). One or more carbon-carbon triple bonds may be internal (e.g., 2-butynyl) or terminal (e.g., 1-butynyl). C 2~4 Examples of alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), and 2-butynyl (C4). 2~6 An example of an alkenyl group is the aforementioned C 2~4Examples of alkynyl groups include pentynyl (C5) and hexynyl (C6). Additional examples of alkynyls include heptynyl (C7) and octinyl (C8). Unless otherwise specified, each alkynyl group can be independently and 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, the alkynyl group is unsubstituted C 2~10 It is an alkynyl group. In certain embodiments, the alkynyl group is a substituted C 2~10 It is alkinyl.

[0091] As used herein, the term “heteroalkyl” refers to an alkyl group as defined herein, further comprising one or more (e.g., one, two, three, or four) 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 one or more heteroatoms are inserted between carbon atoms and the parent molecule, i.e., between bonding sites. 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 ("Alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms ("hetero C"). 1~9 ("Alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms ("hetero C"). 1~8 ("Alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms ("hetero C"). 1~7 ("Alkyl"). In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms ("hetero C"). 1~6("Alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms ("hetero C"). 1~5 ("Alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms ("hetero C"). 1~4 ("Alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom ("hetero C"). 1~3 ("Alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1-2 carbon atoms and 1 heteroatom ("hetero C"). 1~2 In some embodiments, the heteroalkyl group is a saturated group having one carbon atom and one heteroatom ("heteroC1 alkyl"). In some embodiments, the heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms ("heteroC1 alkyl"). 2~6 (Alkyl). Unless otherwise specified, each heteroalkyl group is independently either unsubstituted ("unsubstituted heteroalkyl") or substituted with one or more substituents ("substituted heteroalkyl"). In certain embodiments, the heteroalkyl group is an unsubstituted heteroC 1~10 It is alkyl. 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 14π electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms provided to the aromatic ring system ("C"). 6~14 In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10"Aryl"; for example, naphthyl (such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C"). 14 "Aryl" (e.g., anthracyl). "Aryl" also includes ring systems in which the aryl ring as defined above is fused with one or more carbocyrillic or heterocyclyl groups, in which case the bonding radical or bond site is located on the aryl ring, and in such cases the number of carbon atoms still represents the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, those derived from acetantrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluorantene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indan, indene, naphthalene, octacene, octafen, octaene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiaden, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. In particular, examples of aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each aryl group can be independently substituted at will, i.e., either unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In a particular embodiment, the aryl group is an unsubstituted C 6~14 It is aryl. In certain embodiments, the aryl group is substituted C 6~14 It is Ariel.

[0093] In certain embodiments, the aryl group is a 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 groups.

[0094] Typical examples of substitution aryls include the following: [ka] In the formula, R 56 and R 57 One of them may be hydrogen, R 56 and R 57 At least one of them is, independently, C 1~8 Alkyl, C 1~8 Haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C 1~8 Alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, modulator 58 COR 59 , NR 58 SOR 59 NR 58 SO2R 59 COOalkyl, COOaryl, CONR 58 R 59 CONR 58 Ure 59 , NR 58 R 59 SO2NR 58 R 59 Selected from S-alkyl, SOalkyl, SO2alkyl, S-aryl, SOaryl, SO2aryl, or R 56 and R 57 These can join to form a 5-8 atom cyclic ring (saturated or unsaturated) containing, optionally, one or more heteroatoms selected from N, O, or S. 60 and R 61 These are, independently, hydrogen and C 1~8 Alkyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 4-10 membered heterocyclyl, C 6~10 Aryl substitution C 6~10 They are aryl, 5-10 member heteroaryl, or substituted 5-10 member heteroaryl.

[0095] A "condensed aryl" refers to an aryl ring in which two of its ring carbons are shared with a second aryl ring, heteroaryl ring, or carbocykryl ring, or heterocyclyl ring.

[0096] "Heteroaryl" refers to a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10π electrons shared in a cyclic arrangement) having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the bond site can be a carbon atom or a nitrogen atom, as long as the valency is acceptable. A heteroaryl bicyclic ring system may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which the heteroaryl ring defined above is fused with one or more carbocykyl or heterocyclyl groups, in which case the bond site is located on the heteroaryl ring, and in such cases the number of rings still represents the number of rings in the heteroaryl ring system. "Hyperaryl" also includes ring systems in which the heteroaryl ring defined above is fused with one or more aryl groups, in which case the bond site is located on the aryl ring or heteroaryl ring, and in such cases the number of rings represents the number of rings 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), the bond site can be on either ring, i.e., the ring containing a heteroatom (e.g., 2-indolyl) or the ring without a heteroatom (e.g., 5-indolyl).

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

[0098] Examples of five-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Examples of five-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Examples of five-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Examples of five-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Examples of six-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Examples of six-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Examples of six-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetradinyl, respectively. Examples of seven-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Examples of 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranil, benzoisofuranil, benzimimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzthiadiazolyl, indolidinyl, and prinyl. Examples of 6,6-bicyclic heteroaryl groups include, without limitation, naphthylidinyl, pteridinyl, quinolinyl, isoquinolinyl, sinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0099] Typical examples of heteroaryls include the following: [ka] In the formula, each Z is a carbonyl, N, or NR. 65 Selected from O and S, R 65 These are, independently, hydrogen and C 1~8Alkyl, C 3~10 Cycloalkyl, 4-10 membered heterocyclyl, C 6~10 They are aryl and 5- to 10-membered heteroaryl groups.

[0100] A "carbocyclyl" or "carbocyclic" is a non-aromatic ring system with 3 to 10 ring carbon atoms ("C"). 3~10 This refers to a radical of a non-aromatic cyclic hydrocarbon group having 0 heteroatoms ("carbocyryl"). In some embodiments, the carbocyryl group has 3 to 8 ring carbon atoms ("C"). 3~8 Carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C"). 3~6 Carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C"). 3~6 Carbocyclyl). In some embodiments, the carbocyclyl group has 5 to 10 ring carbon atoms ("C"). 5~10 Carbocyclyl). Exemplary C 3~6 Examples of carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). 3~8 The carbocyric group is not limited to the aforementioned C 3~6 Examples of carbocyclyl groups include cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), and bicyclo[2.2.2]octanyl (C8). 3~10 The carbocyric group is not limited to the aforementioned C 3~8 Carbocyclyl group, similarly cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C9) 10), spiro[4.5]decanil(C 10 Examples include the following. When the above examples are illustrated, in certain embodiments the carbocyclyl group may be monocyclic ("monocyclic carbocyclyl") or include fused, bridging, or spirocyclic systems (e.g., bicyclic systems ("bicyclic carbocyclyl")) and may be saturated or partially unsaturated. "Carbocyclyl" also includes cyclic systems in which the carbocyclyl ring as defined above is fused with one or more aryl or heteroaryl groups, in which case the bond site is located on the carbocyclyl ring, and in such cases the number of carbons still represents the number of carbons in the carbocyclyl cyclic system. Unless otherwise specified, each presence of a carbocyclyl group may be independently and optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments the carbocyclyl group may be unsubstituted C 3~10 It is a carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C 3~10 It is carbocyclyl.

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

[0102] A "heterocyclyl" or "heterocyclic" refers to a 3- to 10-membered non-aromatic cyclic radical having a ring carbon atom and 1 to 4 ring heteroatoms, each heteroatom 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 bond sites can be carbon or nitrogen atoms, as long as the valency is acceptable. Heterocyclyl groups can be monocyclic ("monocyclic heterocyclyl"), or fused, bridging, or spirocyclic (e.g., bicyclic ("bicyclic heterocyclyl")), and can be saturated or partially unsaturated. A heterocyclyl bicyclic system may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes a ring system in which a heterocyclyl ring as defined above is fused with one or more carbocyrill groups, and the bond site is located on the carbocyrill ring or the heterocyclyl ring, or a ring system in which a heterocyclyl ring as defined above is fused with one or more aryl or heteroaryl groups, and the bond site is located on the heterocyclyl ring, in which case the number of rings still represents the number of rings in the heterocyclyl ring system. Unless otherwise specified, each presence 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, the heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

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

[0104] Examples of three-membered heterocyclyl groups containing one heteroatom include, without limitation, azilidinyl, oxylanil, and thiorenyl. Examples of four-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanil, and thietanil. Examples of five-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranil, dihydrofuranil, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Examples of five-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanil, oxasulfuranil, disulfuranil, and oxazolidine-2-one. Examples of five-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Examples of six-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranil, dihydropyridinyl, and thianyl. Examples of six-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanil. Examples of six-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinyl. Examples of seven-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl, and thiepanyl. Examples of eight-membered heterocyclyl groups containing one heteroatom include, without limitation, azokanyl, oxecanyl, and thiokanyl. Examples of five-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, and benzoxazolinonyl. Examples of six-membered heterocyclyl groups condensed to an aryl ring (also referred to herein as 6,6-bicyclic heterocycles) include, but are not limited to, tetrahydroquinolinyl and tetrahydroisoquinolinyl.

[0105] The "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] When "hetero" is used to describe a compound or a group present on a compound, it means that one or more carbon atoms of the compound or group are substituted with nitrogen, oxygen, or sulfur heteroatoms. Hetero can be applied to any of the above hydrocarbyl groups, such as alkyl groups, e.g., heteroalkyl groups, cycloalkyl groups, e.g., heterocyclyl groups, aryl groups, e.g., heteroaryl groups, cycloalkenyl groups, e.g., cycloheteralkenyl groups, which have 1 to 5 heteroatoms, and especially 1 to 3 heteroatoms.

[0107] "Acyl" is a radical-C(O)R 20 It refers to R 20 As defined herein, "alkanoyl" is hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. 20 However, groups other than hydrogen are acyl groups. Representative acyl groups include formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph), -C(O)-C1~C8 alkyl, and -C(O)-(CH2). t (C6~C 10 aryl), -C(O)-(CH2) t (5-10 member heteroaryl), -C(O)-(CH2)t (C3~C 10 Cycloalkyl, and -C(O)-(CH2) t Examples include (4-10 member heterocyclyls), but are not limited to these, and t is an integer from 0 to 4. In a particular embodiment, R 21 This refers to C1-C8 alkyl groups substituted with halo or hydroxyl, or C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 These are aryl, arylalkyl, 5-10 membered heteroaryl, or heteroarylalkyl, each of which is substituted with an 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 It refers to the base, R 29 These are 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. Certain alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Certain alkoxy groups are lower alkoxy groups, i.e., alkoxy groups having 1 to 6 carbon atoms. Further specific alkoxy groups have 1 to 4 carbon atoms.

[0109] In a particular embodiment, R 29 is amino, substituted amino, C6~C 10 Aryl, aryloxy, carboxyl, cyano, C3~C 10The group is selected from groups consisting of cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2-, and aryl-S(O)2-, and has one or more substituents, for example, 1-5 substituents, and in particular 1-3 substituents, and especially 1 substituent. An example of a "substituted alkoxy" group is -O-(CH2) t (C6~C 10 aryl), -O-(CH2) t (5-10 member heteroaryl), -O-(CH2) t (C3~C 10 Cycloalkyl, and -O-(CH2) t Examples include, but are not limited to, 4- to 10-membered heterocyclyl groups, where t is an integer from 0 to 4, and any existing aryl, heteroaryl, cycloalkyl, or heterocyclyl group may itself be substituted with an unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. Specific exemplary "substituted alkoxy" groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2NMe2.

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

[0111] The term "oxo group" refers to the oxygen atom (=O).

[0112] "Substituting amino" is defined by the formula -N(R 38 ) refers to the amino group of 2, and in the formula, R 38 R is hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or an amino protecting group. 38At least one of them is not hydrogen. In a particular embodiment, each R 38 These are, independently, hydrogen and C 1~8 Alkyl, C 3~8 Alkenil, C 3~8 Alkinyl, C 6~10 Aryl, 5-10 member heteroaryl, 4-10 member heterocyclyl, or C 3~10 Cycloalkyl; or C with halo or hydroxy substitution 1~8 Alkyl; C substituted with halo or hydroxyl 3~8 Alkenyl; C substituted with halo or hydroxyl 3~8 Alkinyl, or -(CH2) t (C6~C 10 Aryl), -(CH2) t (5-10 member heteroaryl), -(CH2) t (C3~C 10 Cycloalkyl, or -(CH2) t Selected from (4-10 member heterocyclyls), where t is an integer from 0 to 8, and each of these is an unsubstituted C 1~4 Alkyl, halo, and unsubstituted C 1~4 alkoxy, unsubstituted C 1~4 Haloalkyl, unsubstituted C 1~4 Hydroxyalkyl or unsubstituted C 1~4 The R is substituted with either a haloalkoxy or a hydroxyl group, or both R groups. 38 The groups bond together to form an alkylene group.

[0113] Examples of "substituted amino" groups include -NR 39 -C1~C8 alkyl, -NR 39 -(CH2) t (C6~C 10 Ariel), -NR 39 -(CH2) t (5-10 member heteroaryl), -NR 39 -(CH2) t (C3~C 10 Cycloalkyl, and -NR 39 -(CH2) tExamples include (4-10 member heterocyclyls), but are not limited to these. t is an integer from 0 to 4, for example, 1 or 2, and each R 39 H or C 1~8 Any alkyl group representing or presenting alkyl may itself be substituted with a halo, substituted or unsubstituted amino, or hydroxyl, and any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present may itself be unsubstituted C 1~4 Alkyl, halo, and unsubstituted C 1~4 alkoxy, unsubstituted C 1~4 Haloalkyl, unsubstituted C 1~4 Hydroxyalkyl or unsubstituted C 1~4 They may be substituted with haloalkoxy or hydroxyl groups. To avoid misunderstanding, the term “substituted amino” includes alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino groups, as defined below. Substituted aminos include both monosubstituted and disubstituted amino groups.

[0114] "Carboxylate" 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 iodine(I). In certain embodiments, the halo group is either fluoro or chloro.

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

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

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

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

[0121] Alkyl groups, alkenyl groups, alkynyl groups, carbosicryl groups, heterocyclyl groups, aryl groups, and heteroaryl groups as 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" carbosicryl groups, "substituted" or "unsubstituted" heterocyclyl groups, "substituted" or "unsubstituted" aryl groups, or "substituted" or "unsubstituted" heteroaryl groups). Generally, the term "substituted" means that at least one hydrogen atom present on a group (e.g., a carbon or nitrogen atom) is substituted with an acceptable substituent, e.g., a substituent that, when substituted, produces a stable compound, e.g., a compound that does not spontaneously transform (e.g., by rearrangement, cyclization, elimination, or other reactions). Unless otherwise specified, a “substituted” group has substituents at one or more of its substituted positions, and when two or more positions in any given structure are substituted, the substituents are either the same or different at each position. The term “substituted” is intended to include substitution by all acceptable substituents of an organic compound, i.e., substitution by any of the substituents described herein that result in the formation of a stable compound. The present invention intends any combination that results in a stable compound. For the purposes of the present invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any preferred substituents described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety.

[0122] Examples of carbon atom substituents include halogens, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, and -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 Alkenil, C 2~10 Alkinyl, C 3~10 Carbocyclyl, 3-14 member heterocyclyl, C 6~14 Examples include, but are not limited to, aryls and 5- to 14-membered heteroaryls. Each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with a group, or two geminal hydrogens on a carbon atom, group =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 Replaced with R aa Each of these cases is independent of C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenil, C 2~10 Alkinyl, C 3~10 Carbocyclyl, 3-14 member heterocyclyl, C 6~14 Selected from aryls and 5-14 member heteroaryls, or two R aa The groups join to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with R bb Each of these cases is independent of hydrogen, -OH, and -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 Alkenil, C 2~10 Alkinyl, C 3~10 Carbocyclyl, 3-14 member heterocyclyl, C 6~14Selected from aryl and 5- to 14-membered heteroaryl, or two R bb groups are joined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, and each instance of R cc is independently selected from hydrogen, C 1~10 alkyl, C 1~10 haloalkyl, C 2~10 alkenyl, C 2~10 alkynyl, C 3~10 carbocyclic, 3- to 14-membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R cc groups are joined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, and each instance of R dd is independently 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 carbocyclic, 3 - 10 member heterocyclic, C 6~10 aryl, 5 - 10 member heteroaryl, and each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups or two geminal R dd substituents may join to form =O or =S, and R ee is independently C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C2~6 Alkinyl, C 3~10 Carbocyclyl, C 6~10 Selected from aryls, 3-10 membered heterocyclyls, and 3-10 membered heteroaryls, each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg Substituted with R ff Each of these cases is independent of hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 Selected from aryls and 5-10 member heteroaryls, or two R ff The groups join to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. gg Substituted with R gg Each of these cases is independent of halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, and -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)(C 1~6Alkyl), -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 1~6 Alkyl, -P(=O)2(C1~6 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 Alkenil, C 2~6 Alkinyl, C 3~10 Carbocyclyl, C 6~10 It is either an aryl, a 3-10 member heterocyclyl, a 5-10 member heteroaryl, or two geminal Rs. gg Substituents can join to form =O or =S, X - It is a counterion.

[0123] A "counterion" or "anionic counterion" is a negatively charged group that maintains electrical neutrality by associating with a cationic quaternary amino group. Examples of counterions include halides (e.g., F - Cl - , Br - , I - ), NO3 - ClO4 - OH - H2PO4 - HSO4 - Examples include 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 salt ions (e.g., acetate, ethaneate, propaneate, benzoate, glycerolate, lactate, tartrate, glycolate, etc.).

[0124] Such and other exemplary substituents are described in detail in the modes for carrying out the invention and in the claims. The present invention is not intended to be limited in any way by the substituents listed above as exemplary.

[0125] B. Other definitions As used herein, the term “modification” refers to GABA A This refers to the inhibition or enhancement of receptor function. A "modulator" (e.g., a modulatory compound) is, for example, GABA. A It may be a receptor agonist, partial agonist, antagonist, or partial antagonist.

[0126] As used herein, “selectively adjust” means GABA A This means a higher or better regulation of a particular subunit composition compared to other subunit compositions of the receptor.

[0127] "Pharmacologically acceptable" means that it is approved or eligible for approval by a federal or state regulatory authority or a corresponding agency in a country other than the United States, or that it is listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in animals, more specifically in humans.

[0128] "Pharmacologically acceptable salt" refers to a salt of the compound of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. In particular, such salts are nontoxic and may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts may be formed with (1) inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; or 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, Examples of acid addition salts formed with organic acids such as 4-methylbicyclo[2.2.2]-octa-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion; or when the compound coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, or N-methylglucamine. Further examples of salts include, but are merely illustrative, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc.; and, if the compound contains a basic functional group, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, and oxalate. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counterion of an acidic functional group. Examples of such cations include sodium cations, potassium cations, calcium cations, magnesium cations, ammonium cations, and tetraalkylammonium cations.For example, see 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 into therapeutic activators of the present invention under physiological conditions. One method for producing a prodrug involves designing a selective moiety that is hydrolyzed or cleaved at the target in vivo site of action under physiological conditions, thereby exposing the target molecule and subsequently producing a therapeutic effect. In certain embodiments, the prodrug is converted by the activity of the target enzyme.

[0130] In an alternative embodiment, the present invention provides a prodrug of a compound described herein, the prodrug comprising a cleavable portion on a C3 hydroxyl group as shown in the formula shown herein.

[0131] A "tautomer" is a compound that is an interchangeable form of a particular compound structure, characterized by altered hydrogen atom and electron transfer. Therefore, two structures can reach equilibrium through the transfer of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either an acid or a base. Another example of tautomerism is phenylnitromethane in its ac and nitro forms, similarly formed by treatment with an acid or a base. Tautomerism can be relevant to achieving optimal chemical reactivity and biological activity of the compound in question.

[0132] The “subjects” to which administration is intended 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., crab-eating macaques, rhesus macaques), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs). In certain embodiments, the subject is 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 called a hydroxyl protecting group). Examples of 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 is one example, but it is not limited to these, R aa , R bb , and R cc The oxygen protecting group is as defined herein. The oxygen protecting group is well known in the art and is incorporated herein by reference in Protecting Groups in Organic Synthesis, TWGreene and PGMWuts, 3 rd This includes details as described in edition, John Wiley & Sons, 1999.

[0134] Examples of oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), 2-methoxyethoxymethyl (MEM), benzyl (Bn), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBDMS), t-butylmethoxyphenylsilyl (TBMPS), methanesulfonates (mesylates), and tosylates (Ts).

[0135] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also called a thiol protecting group). The sulfur protecting base is -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 is one example, but it is not limited to these, R aa , R bb , and R cc The sulfur protecting groups are as defined herein. Sulfur protecting groups include those well known in the art and incorporated herein by reference, as described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGMWuts, 3rd edition, John Wiley & Sons, 1999.

[0136] In certain embodiments, the substituent present on the nitrogen atom is an amino protecting group (also called a nitrogen protecting group). Examples of amino protecting groups include -OH and -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 Alkenil, C 2~10 Alkinyl, C 3~10 Carbocyclyl, 3-14 member heterocyclyl, C 6~14 Examples include, but are not limited to, aryl and 5-14 membered heteroaryl groups. Each alkyl, alkenyl, alkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R dd Substituted with R aa , R bb , R cc , and R dd The amino protecting group is as defined herein. The amino protecting group is well known in the art and is incorporated herein by reference in Protecting Groups in Organic Synthesis, TWGreene and PGMWuts, 3 rd This includes details as described in edition, John Wiley & Sons, 1999.

[0137] Examples of amino protecting groups include, but are not limited to, formamide and acetamide, other amide groups (e.g., -C(=O)R). aa ); Carbamate groups including, but not limited to, 9-fluorenylmethylcarbamate (Fmoc), t-butylcarbamate (BOC), and benzylcarbamate (Cbz) (e.g., -C(=O)OR aa ); Includes, but is not limited to, p-toluenesulfonamide (Ts), methanesulfonamide (Ms), and N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), sulfonamide groups (e.g., -S(=O)2R aa ) are some examples, but are not limited to these.

[0138] The terms “disease,” “disorder,” and “pathological condition” are used synonymously in this specification.

[0139] As used herein, unless otherwise specified, the terms “to treat,” “to treat,” and “treatment” refer to actions performed while the subject is suffering from a particular disease, disorder, or condition, with the intention of reducing the severity of the disease, disorder, or condition, or delaying or slowing the progression of the disease, disorder, or condition ("therapeutic treatment"), and also refer to actions performed before the subject suffers from a particular disease, disorder, or condition.

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

[0141] As used herein, unless otherwise specified, “therapeutic dose” of a compound means an amount sufficient to provide therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with that disease, disorder, or condition. A therapeutic dose of a compound means either the amount of the therapeutic agent alone or the amount of the therapeutic agent in combination with other therapies that provide therapeutic benefit in the treatment of that disease, disorder, or condition. The term “therapeutic dose” may include an amount that improves the overall treatment, alleviates or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effect of another therapeutic agent.

[0142] In alternative embodiments, the present invention intends to administer the compound of the present invention or a pharmaceutically acceptable salt or pharmaceutically acceptable composition thereof as a prophylactic agent before a subject develops a particular disease, disorder, or condition. As used herein, unless otherwise specified, “prophylactic effective dose” of a compound means an amount sufficient to prevent or prevent the recurrence of a disease, disorder, or condition, or one or more symptoms associated with that disease, disorder, or condition. The prophylactic effective dose of a compound means an amount of the therapeutic agent alone or an amount of the therapeutic agent in combination with other agents that provide a prophylactic benefit in the prevention of that disease, disorder, or condition. The term “prophylactic effective dose” may include an amount that improves overall prevention or enhances the prophylactic efficacy of another prophylactic agent.

[0143] As used herein, “episodic dosing regimen” is a dosing regimen in which a compound disclosed herein or a composition comprising a compound disclosed herein is administered to a subject over a finite period in response to a disorder or its symptoms, e.g., a diagnosis or symptoms of depression, an episode of major depressive disorder, bipolar depression, anxiety, or postpartum depression. In some embodiments, major depressive disorder is severe major depressive disorder. In some embodiments, the compound is formulated as individual dosing units, each unit comprising the compound disclosed herein and one or more suitable pharmaceutically acceptable excipients. In some embodiments, the duration of an episodic dosing regimen is several weeks, e.g., about eight weeks. In contrast to chronic dosing as defined herein, episodic dosing of a compound is performed over a finite period, e.g., about two weeks to about eight weeks, depending on the diagnosis or symptoms of a disorder, e.g., depression. In some embodiments, episodic dosing is performed once daily over several weeks, e.g., about two weeks to about six weeks. In one embodiment, the duration of episodic dosing is two weeks. In some embodiments, two or more episodic regimens are administered to the subject, for example, two or more episodic regimens are administered throughout the subject's lifetime.

[0144] As used herein, the term “optionally substituted” means substituted or not substituted.

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

[0146] A. Compound The present invention relates to a compound of formula (I), [ka] or provides a pharmaceutically acceptable salt thereof, in the formula R 2a , R 2b , R 4a , R 4b , R 6 , R 7 , R 11a , R 11b , R 15a , and R 15b Each of these can independently be hydrogen, halogen, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, -OR D1 -OC(=O)R D1 -NH2, -N(R D1 )2, -NR D1 C(=O)R D1 , substituted or unsubstituted 3-6 member monocyclic heterocycles, or substituted or unsubstituted 8-12 member bicyclic heterocycles, where each monocyclic or bicyclic heterocycle independently has 1-3 heteroatoms selected from N, O, and S, and each R D1 These are, independently, hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynnyls are independently substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic rings having 0-3 heteroatoms selected from N, O, and S, being oxygen protecting groups when attached to an oxygen atom, nitrogen protecting groups when attached to a nitrogen atom, or two R atoms. D1 The groups join to form substituted or unsubstituted 3-6 member monocyclic heterocycles or 8-12 member bicyclic heterocycles, and the monocyclic or bicyclic heterocycles independently have 1-3 heteroatoms selected from N, O, and S, or R 2a and R 2b , R 4a and R 4b , or R 11a and R11b One of them joins together to form an oxo (=O) group, R 16 and R 17 Each of these can independently be hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, -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 independently, a substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected from N, O, and S, with each R A1 These are, independently, hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6Alkynnyl, independently, a substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected from N, O, and S, an oxygen protecting group if attached to an oxygen atom, a sulfur protecting group if attached to a sulfur atom, a nitrogen protecting group if attached to a nitrogen atom, -SO2R A2 , -C(O)R A2 is either or two R A1 The groups join together to independently form substituted or unsubstituted 3-6 member saturated, partially unsaturated, or fully unsaturated monocyclic heterocycles having 1-3 heteroatoms selected from N, O, and S, with each R A2 These are independently substituted or non-substituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, or independently, a substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected from N, O, and S, R 3a C is hydrogen, substituted or unsubstituted. 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, substituted or unsubstituted C 1~6 Alkyl-OC 1~6 Alkyl, or independently, a substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected from N, O, and S, R 5 is hydrogen, unsubstituted methyl, or absent. [ka] It is either a single bond or a double bond, however, [ka] If it is a single bond, R 5 is hydrogen or methyl, [ka] If R is a double bond, 5 It is non-existent, R 19 is hydrogen, or substituted or unsubstituted C 1~6 It is alkyl, R X is hydrogen, or substituted or unsubstituted C 1~6 It is alkyl, R Y is a substituted or unsubstituted phenyl, or a substituted or unsubstituted 3-6 member monocyclic heteroaryl or an 8-12 member bicyclic heteroaryl, where the monocyclic or bicyclic heteroaryl independently has 1-5 heteroatoms selected from N, O, and S, and t is 1, 2, or 3, except when t is 1, R 3a It is -CH2OCH2CH3, and R Y is a substituted or unsubstituted pyrazinyl, then R 19 This is conditional on it being -CH3.

[0147] B. Substituents 1.R 2a and R 2b base In some embodiments, R 2a and R 2b Each of these can independently be hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenil, -OR D1 -OC(=O)R D1 -NH2, or -N(R D1 )2, and each R D1 These are, independently, hydrogen, substituted or unsubstituted C 1~6 Alkyl, or independently, a substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected from N, O, and S.

[0148] In some embodiments, R 2a and R 2b Each of these can be independently replaced by hydrogen or 1 to 3 halogens. 1~6C is optionally substituted with alkyl or 1 to 3 halogens. 1~6 It is an alkoxy or -OH group. In some embodiments, R 2a and R 2b Each of these is independently hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2. In some embodiments, R 2a and R 2b One of them is hydrogen. In some embodiments, R 2a and R 2b Each of them is hydrogen.

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

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

[0152] 2.R 4a and R 4b basis In some embodiments, R 4a and R 4b Each of these can independently be hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenil, -OR D1 -OC(=O)R D1 -NH2, or -N(R D1 )2, R D1 Each case independently involves hydrogen, substituted or unsubstituted C 1~6 Alkyls are independently substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic rings having 0-3 heteroatoms selected from N, O, and S.

[0153] In some embodiments, R 4a and R 4b Each of these can be independently replaced by hydrogen or 1 to 3 halogens. 1~6 C is optionally substituted with alkyl or 1 to 3 halogens. 1~6 It is an alkoxy or -OH group. In some embodiments, R 4a and R 4b Each of these is independently hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2. In some embodiments, R 4a and R 4b One of them is hydrogen. In some embodiments, R 4a and R4b Both are hydrogen.

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

[0155] 3.R 11a and R 11b base In some embodiments, R 11a and R 11b Each of these can independently be hydrogen, halogen, cyano, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenil, -OR D1 -OC(=O)R D1 -NH2, or -N(R D1 )2, R D1 Each case independently involves hydrogen, substituted or unsubstituted C 1~6 Alkyls are independently substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic rings having 0-3 heteroatoms selected from N, O, and S.

[0156] In some embodiments, R 11a and R 11b Each of these can be independently replaced by hydrogen or 1 to 3 halogens. 1~6 C is optionally substituted with alkyl or 1 to 3 halogens. 1~6 It is an alkoxy. In some embodiments, R 11a and R 11b Each of these is independently hydrogen, -CH3, -CH2CH3, -OCH3, or -CH(CH3)2. In some embodiments, R 11a and R 11b One of them is hydrogen. In some embodiments, R 11a and R 11b Each of them is hydrogen.

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

[0158] 4.R 15a and R 15b base and t In some embodiments, R 15a and R 15b Each of these can independently be hydrogen, halogen, cyano, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenil, -OR D1 -OC(=O)R D1 -NH2, or -N(R D1 )2, R D1 Each case independently involves hydrogen, substituted or unsubstituted C 1~6 Alkyls are independently substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic rings having 0-3 heteroatoms selected from N, O, and S.

[0159] In some embodiments, R 15a and R 15b Each of these can be independently replaced by hydrogen or 1 to 3 halogens. 1~6 C is optionally substituted with alkyl or 1 to 3 halogens. 1~6 It is an alkoxy. In some embodiments, R 15a and R 15b Each of these is independently hydrogen, -CH3, -CH2CH3, -OCH3, or -CH(CH3)2. In some embodiments, R 11a and R 11b One of them is hydrogen. In some embodiments, R 15a and R 15b Each of them 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 C is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenil, -OR D1 -OC(=O)R D1 -NH2, or -N(R D1 )2, R D1 Each case independently involves hydrogen, substituted or unsubstituted C 1~6 Alkyls are independently substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic rings having 0-3 heteroatoms selected from N, O, and S.

[0162] In some embodiments, R 7 R 7 C is optionally substituted with hydrogen or 1 to 3 halogens. 1~6 C, which can be optionally replaced with 1 to 3 halogens. 1~6 It is an alkoxy or -OH group. In some embodiments, R 7 R is hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2. In some embodiments, R 7 It is hydrogen.

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

[0164] In some embodiments, R 6 C is optionally substituted with hydrogen or 1 to 3 halogens. 1~6 C, which can be optionally replaced with 1 to 3 halogens. 1~6 It is an alkoxy or -OH group. In some embodiments, R 6 R is independently hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2. In some embodiments, R 6 It is hydrogen.

[0165] 7.R 16 In some embodiments, R 16 C is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenil, -OR D1 -OC(=O)R D1 -NH2, or -N(R D1 )2, R D1 Each case independently involves hydrogen, substituted or unsubstituted C 1~6 Alkyls are independently substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic rings having 0-3 heteroatoms selected from N, O, and S.

[0166] In some embodiments, R 16 C is optionally substituted with hydrogen or 1 to 3 halogens. 1~6 C, which can be optionally replaced with 1 to 3 halogens. 1~6 It is an alkoxy or -OH group. In some embodiments, R 16 R is hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2. In some embodiments, R16 It is hydrogen.

[0167] 8.R 17 In some embodiments, R 17 C is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenil, -OR D1 -OC(=O)R D1 -NH2, or -N(R D1 )2, R D1 Each case independently involves hydrogen, substituted or unsubstituted C 1~6 Alkyls are independently substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic rings having 0-3 heteroatoms selected from N, O, and S.

[0168] In some embodiments, R 17 Each of these is optionally substituted with hydrogen and 1 to 3 halogens. 1~6 C, which can be optionally replaced with 1 to 3 halogens. 1~6 It is an alkoxy or -OH group. In some embodiments, R 17 R is hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2. In some embodiments, R 17 It is hydrogen.

[0169] 9.R 19 In some embodiments, R 19 is hydrogen, or substituted or unsubstituted C 1~5 It is alkyl. In some embodiments, R 19 is hydrogen, or a substituted or unsubstituted C1-C4 alkyl group. In some embodiments, R 19 is hydrogen or unsubstituted C 1~5 It is alkyl. In some embodiments, R 19 is hydrogen or an unsubstituted C1-C4 alkyl group. In some embodiments, R 19 is hydrogen or unsubstituted C 1~3It is alkyl. In some embodiments, R 19 R is hydrogen, -CH3, -CH2CH3, or -CH2OCH(CH3)2. In some embodiments, R 19 is hydrogen, -CH3, or -CH2CH3. In some embodiments, R 19 is hydrogen. In some embodiments, R 19 is -CH2OCH(CH3)2. In some embodiments, R 19 is -CH3. In some embodiments, R 19 It is -CH2CH3.

[0170] 10.R 3a In some embodiments, R 3a C is hydrogen, substituted or unsubstituted. 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 Alkyls are independently substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic rings having 0-3 heteroatoms selected from N, O, and S.

[0171] In some embodiments, R 3a is a substitution or non-substitution C 1~6 It is alkyl. In some embodiments, R 3a is unsubstituted C 1~6 It is alkyl. In some embodiments, R 3a is a substitution or non-substitution C 1~4 It is alkyl. In some embodiments, R 3a is unsubstituted C 1~4 It is alkyl. In some embodiments, R 3a is unsubstituted C 1~3 It is alkyl. In some embodiments, R 3a This is an unsubstituted methyl group (i.e., -CH3).

[0172] In some embodiments, R3a is hydrogen, unsubstituted C 1~4 It is 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 It is alkyl or -CH2OCH2CH3.

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

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

[0175] In some embodiments, R 3a These are -CH2CH3, -CH3, -CH2OCH2CH3, and -CH2OCH3. In some embodiments, R 3a These are -CH3, -CH2CH2CH3, -CH2OCH3, and -CH2OCH2CH3. 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 It is -CH2OCH2CH3.

[0176] In some embodiments, when t is 2, R 3a is -CH3 or -CH2OCH2CH3. In some embodiments, R 2a and R 2b When one of them is hydrogen and the other is -CH3, R 3a It is -CH3.

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

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

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

[0180] In some embodiments, R 5This is a hydrogen atom in the cis position. In another embodiment, R 5 This is hydrogen in the transformer position. In yet another embodiment, R 5 R is an unsubstituted methyl group at the cis position. In one embodiment, R 5 This is an unsubstituted methyl group in the trans position.

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

[0182] 14.R Y In some embodiments, R Y is a substituted or unsubstituted pyrazinyl, a cyano-substituted pyrimidine, a substituted or unsubstituted pyridine, or a substituted phenyl. In some embodiments, R Y is a substituted or unsubstituted pyrazinyl, a cyano-substituted pyrimidine, or a substituted phenyl. In some embodiments, R Y is a pyridine substituted with cyano. In some embodiments, R Y R is a pyridine substituted with fluoropolymer. In some embodiments, RY R is a 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-2 nitrogen atoms, Y The 3-8 member rings are independently halogen, -CN, or C 1~6 It is optionally substituted with 1 to 3 groups selected from alkyl groups. In some embodiments, R Y These are substituted or unsubstituted pyrazinyls, cyano-substituted pyrimidines, substituted or unsubstituted phenyls, cyano- or fluoro-substituted pyridines, or pyrazoles substituted with two unsubstituted methyl groups.

[0183] In some embodiments, R Y teeth, [ka] Selected from, In the formula, each R D These are independently hydrogen, halogen, -NO2, -CN, and -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 , substitution or non-substitution C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6Alkynnyls are independently substituted or unsubstituted 3-10 member saturated, partially unsaturated, or fully unsaturated monocyclic rings having 0-3 heteroatoms selected from N, O, and S, or two R GA However, together with intervening atoms, they independently form substituted or unsubstituted 3-5 member saturated, partially unsaturated, or fully unsaturated monocyclic rings having 0-3 heteroatoms selected from N, O, and S, and each X independently has -N= or -C(R D )= and each R GA These are, independently, hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynnyl, independently, a substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected from N, O, and S, being an oxygen protecting group if attached to oxygen, a nitrogen protecting group if attached to nitrogen, or two R GA The group, together with the intervening atom, independently forms a substituted or unsubstituted 5-6 member heterocyclic ring having 2-3 heteroatoms selected from N, O, or S, R X1 is hydrogen, or substituted or unsubstituted C 1~6 Alkyl, or independently, a substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected from N, O, and S, where e is 0, 1, 2, or 3.

[0184] In some embodiments, R Y teeth, [ka] Selected from, In the formula, R D Each case independently involves hydrogen, halogen, substituted or unsubstituted C 1~6 The elements are alkyl, -CN, substituted or unsubstituted 5- to 6-membered heteroaryl, or substituted or unsubstituted 5-membered heterocyclyl, where e is 0, 1, 2, 3, or 4.

[0185] In some embodiments, R Y teeth, [ka] Selected from, In the formula, each R is independently -CH3, -CH2CH3, -i-Pr, cyclopropyl, or -CN.

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

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

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

[0189] In some embodiments, R Y teeth, [ka] Selected from, In the formula, each R D These are independently hydrogen, halogen, -NO2, -CN, and -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 , substitution or non-substitution C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynnyls are independently substituted or unsubstituted 3-10 member saturated, partially unsaturated, or fully unsaturated monocyclic rings having 0-3 heteroatoms selected from N, O, and S, or two R D The groups, together with the atoms to which they are attached, independently form substituted or unsubstituted 5-6 member saturated, partially unsaturated, or fully unsaturated rings having up to 3 heteroatoms selected from N, O, or S, with each R GA These are, independently, hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynnyl, independently, a substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected from N, O, and S, being an oxygen protecting group if attached to oxygen, a nitrogen protecting group if attached to nitrogen, or two R GA The groups, together with the atoms to which they are attached, independently form a substituted or unsubstituted 5-6 member saturated, partially unsaturated, or fully unsaturated ring having up to 3 heteroatoms selected from N, O, or S, where e is 0, 1, 2, 3, 4, or 5.

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

[0191] In some embodiments, R Y teeth, [ka] In some embodiments, two of W1, W2, W3, W4, and W5 are -N=, and the rest are -C(R')=, where 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] That is the case.

[0194] In some embodiments, R Y teeth, [ka] Selected from, In the formula, R DEach case independently involves hydrogen, halogen, substituted or unsubstituted C 1~6 The elements are alkyl, -CN, substituted or unsubstituted 5- to 6-membered heteroaryl, or substituted or unsubstituted 5-membered heterocyclyl, where e is 0, 1, 2, 3, or 4.

[0195] In some embodiments, R Y teeth, [ka] Selected from, In the formula, R D Each case independently involves hydrogen, halogen, substituted or unsubstituted C 1~6 These are alkyl, -CN, substituted or unsubstituted 5- to 6-membered heteroaryls, and substituted or unsubstituted 5-membered heterocyclines.

[0196] In some embodiments, R D Each case independently involves halogen, substituted, or unsubstituted C 1~6 It is alkyl or -CN. In some embodiments, R D Each of these cases is independently -F, -CH3, or -CN. In some embodiments, R D Each of these cases is -F. In some embodiments, R D Each of these examples is -CH3. In some embodiments, R D Each of these cases is -CN.

[0197] In some embodiments, R Y teeth, [ka] 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 requiring treatment comprises administering an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof to the subject. In some embodiments, the CNS-related disorder is a sleep disorder, mood disorder, schizophrenia spectrum disorder, convulsive disorder, memory and / or cognitive impairment, motor disorder, personality disorder, autism spectrum disorder, pain, traumatic brain injury, vascular disease, 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 present invention Another aspect of the present invention relates to a compound of formula (I-1), [ka] or provide a pharmaceutically acceptable salt thereof, 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 This is as defined in one 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 of these can independently be hydrogen, halogen, hydroxyl, cyano, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, -OR D1 -OC(=O)R D1 -NH2, -N(R D1 )2, -NR D1 C(=O)R D1 , substituted or unsubstituted 3-6 member monocyclic heterocycles, or substituted or unsubstituted 8-12 member bicyclic heterocycles, where each monocyclic or bicyclic heterocycle independently has 1-3 heteroatoms selected from N, O, and S, and each R D1 These are, independently, hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynnyls are independently substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic rings having 0-3 heteroatoms selected from N, O, and S, being oxygen protecting groups when attached to an oxygen atom, nitrogen protecting groups when attached to a nitrogen atom, or two R atoms. D1 The groups join to form substituted or unsubstituted 3-6 member monocyclic heterocycles or 8-12 member bicyclic heterocycles, and the monocyclic or bicyclic heterocycles independently have 1-3 heteroatoms selected from N, O, and S, or R 2a and R 2b , R 4a and R 4b , or R 11a and R 11b One of them joins together to form an oxo (=O) group, R 16 and R 17 Each of these can independently be hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, -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 independently, a substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected from N, O, and S, with each R A1 These are, independently, hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynnyl, independently, a substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected from N, O, and S, an oxygen protecting group if attached to an oxygen atom, a sulfur protecting group if attached to a sulfur atom, a nitrogen protecting group if attached to a nitrogen atom, -SO2R A2 , -C(O)R A2 is either or two R A1The groups join together to independently form substituted or unsubstituted 3-6 member saturated, partially unsaturated, or fully unsaturated monocyclic heterocycles having 1-3 heteroatoms selected from N, O, and S, with each R A2 These are independently substituted or non-substituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, or independently, a substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected from N, O, and S, R 3a is unsubstituted C 1~6 Alkyl, -CH2OCH3, or -CH2OCH2CH3, R 5 is hydrogen, unsubstituted methyl, or absent. [ka] It is either a single bond or a double bond, however, [ka] If it is a single bond, R 5 is hydrogen or methyl, [ka] If R is a double bond, 5 It is conditional on non-existence, R 19 is hydrogen or unsubstituted C 1~6 Alkyl, R X is hydrogen, or substituted or unsubstituted C 1~6 It is alkyl, R Y is a substituted or unsubstituted pyrazinyl, a cyano-substituted pyrimidine, a substituted or unsubstituted pyridine, or a substituted phenyl, however R 3a is -CH2OCH2CH3, and R Y If R is a substituted or unsubstituted pyrazinyl, 19 This is conditional on it being an unsubstituted methyl group.

[0202] In some embodiments, R Y These are substituted or unsubstituted pyrazinyls, cyano-substituted pyrimidines, or substituted phenyls.

[0203] In some embodiments, the compound of formula (I-1) is the compound of formula (I-2), [ka] or a pharmaceutically acceptable salt thereof, 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 This is as defined in one of the embodiments of the compound of formula (I) or (I-1).

[0204] In some embodiments, R 3a R is -CH2OCH3 or unsubstituted methyl, 5 is hydrogen, unsubstituted methyl, or absent. [ka] It is either a single bond or a double bond, however, [ka] If it is a single bond, R 5 is hydrogen or methyl, [ka] If R is a double bond, 5 It is conditional on non-existence, R 19 is hydrogen, or substituted or unsubstituted C 1~6 It is alkyl, R X is hydrogen, or substituted or unsubstituted C 1~6 It is alkyl, R Y This is a pyridine substituted with cyano.

[0205] In some embodiments, the compound of formula (I-1) is the compound of formula (I-3), [ka] or a pharmaceutically acceptable salt thereof, 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 This is as defined in any embodiment of the compound of formula (I), (I-1), or (I-2).

[0206] In some embodiments, R 3a R is -CH2OCH3 or unsubstituted methyl, 5 is hydrogen, unsubstituted methyl, or absent. [ka] It is either a single bond or a double bond, however, [ka] If it is a single bond, R 5is hydrogen or methyl, [ka] If R is a double bond, 5 It is conditional on non-existence, R 19 is hydrogen, or substituted or unsubstituted C 1~6 It is alkyl, R X is hydrogen, or substituted or unsubstituted C 1~6 It is alkyl, R Y This is a pyridine substituted with cyano.

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

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

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

[0210] In some embodiments, if the compound is a compound of formula (I-a1), (I-a2), or (I-a3), R 17 R is hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2. In some embodiments, R 17 It is hydrogen.

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

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

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

[0214] In some embodiments, the compound of formula (I-a1) is the compound of formula (I-b1a) or formula (I-b2a): [ka] or a pharmaceutically acceptable salt thereof, where R 3a , R 17 , R 19 , R X , and R Y This is as defined in any one of the embodiments of the compound 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 the compound of formula (I-b1b) or formula (I-b2b): [ka] or a pharmaceutically acceptable salt thereof, where R 3a , R 17 , R 19 , R X , and R Y This is as defined in any one of the embodiments of the compound 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 the compound of formula (I-b1c) or formula (I-b2c): [ka] or a pharmaceutically acceptable salt thereof, where R 3a , R 17 , R 19 , R X , and R YThis is as defined in any one of the embodiments of the compound 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 the compound of formula (I-c1a) or formula (I-c2a): [ka] or a pharmaceutically acceptable salt thereof, where R 3a , R 17 , R 19 , R X , and R Y This is as defined in any one of the embodiments of the compound 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 the compound of formula (I-c1b) or formula (I-c2b): [ka] or a pharmaceutically acceptable salt thereof, where R 3a , R 17 , R 19 , R X , and R Y This is as defined in any one of the embodiments of the compound 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 the compound of formula (I-c1c) or formula (I-c2c): [ka] or a pharmaceutically acceptable salt thereof, where R 3a , R 17 , R 19, R X , and R Y This is as defined in any one of the embodiments of the compound 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 the compound of formula (I-d1a) or formula (I-d2a): [ka] or a pharmaceutically acceptable salt thereof, where R 3a , R 17 , R 19 , R X , and R Y This is as defined in any one of the embodiments of the compound 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 the compound of formula (I-d1b) or formula (I-d2b): [ka] or a pharmaceutically acceptable salt thereof, where R 3a , R 17 , R 19 , R X , and R Y This is as defined in any one of the embodiments of the compound 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 the compound of formula (I-d1c) or formula (I-d2c): [ka] or a pharmaceutically acceptable salt thereof, where R3a , R 17 , R 19 , R X , and R Y This is as defined in any one of the embodiments of the compound 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 the compound of formula (I-e1): [ka] or a pharmaceutically acceptable salt thereof, where R 3a , R 19 , and R Y This is as defined in any embodiment 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 the compound of formula (I-e2): [ka] or a pharmaceutically acceptable salt thereof, where R 3a , R 19 , and R YThis is as defined in any embodiment 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 the compound of formula (I-e3): [ka]

[0226] or a pharmaceutically acceptable salt thereof, where R 3a , R 19 , and R Y This is as defined in any embodiment 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 provides a pharmaceutically acceptable salt thereof, in the formula R 3a , R 5 , R 6 , R 16 , R 19 , R X , and R Yis 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 embodiment of the compounds (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 relates to a compound of formula (Ig), [ka] or provides a pharmaceutically acceptable salt thereof, in the formula 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 embodiments of the compounds (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 relates to a compound of formula (I-4), [ka] or provides a pharmaceutically acceptable salt thereof, in the formula R 2a , R 2b , R 3a , R 4a , R 4b , R 5 , R6 , R 7 , R 11a , R 11b , R 16 , R 17 , R 19 , R X , R Y , and t are as defined in any embodiment 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), (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 of these independently consists of hydrogen, halogen, hydroxyl, substituted or unsubstituted C. 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, -OR D1 -OC(=O)R D1 -NH2, -N(R D1 )2, -NR D1 C(=O)R D1 , substituted or unsubstituted 3-6 member monocyclic heterocycles, or substituted or unsubstituted 8-12 member bicyclic heterocycles, where each monocyclic or bicyclic heterocycle independently has 1-3 heteroatoms selected from N, O, and S, and each R D1 These are, independently, hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6Alkynnyls are independently substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic rings having 0-3 heteroatoms selected from N, O, and S, being oxygen protecting groups when attached to an oxygen atom, nitrogen protecting groups when attached to a nitrogen atom, or two R atoms. D1 The groups join to form substituted or unsubstituted 3-6 member monocyclic heterocycles or 8-12 member bicyclic heterocycles, and the monocyclic or bicyclic heterocycles independently have 1-3 heteroatoms selected from N, O, and S, or R 2a and R 2b , R 4a and R 4b , or R 11a and R 11b One of them joins together to form an oxo (=O) group, R 16 and R 17 Each of these can independently be hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, -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)2ORA1 -S(=O)R A2 , -SO2R A2 -S(=O)2OR A1 , or independently, a substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected from N, O, and S, with each R A1 These are, independently, hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynnyl, independently, a substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected from N, O, and S, an oxygen protecting group if attached to an oxygen atom, a sulfur protecting group if attached to a sulfur atom, a nitrogen protecting group if attached to a nitrogen atom, -SO2R A2 , -C(O)R A2 is either or two R A1 The groups join together to independently form substituted or unsubstituted 3-6 member saturated, partially unsaturated, or fully unsaturated monocyclic heterocycles having 1-3 heteroatoms selected from N, O, and S, with each R A2 These are independently substituted or non-substituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, or independently, a substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected from N, O, and S, R 3a C is hydrogen, substituted or unsubstituted. 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynnyl is an independently substituted or unsubstituted 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected from N, O, and S, and R 5 is hydrogen, unsubstituted methyl, or absent. [ka] It is either a single bond or a double bond, however, [ka] If it is a single bond, R 5 is hydrogen or methyl, [ka] If R is a double bond, 5 It is conditional on non-existence, R 19 is hydrogen, or substituted or unsubstituted C 1~6 It is alkyl, R X is hydrogen, or substituted or unsubstituted C 1~6 It is alkyl, R Y is a substituted or unsubstituted phenyl, or a substituted or unsubstituted 3-6 member monocyclic heteroaryl or an 8-12 member bicyclic heteroaryl, where the monocyclic or bicyclic heteroaryl independently has 1-5 heteroatoms selected from N, O, and S, and t is 2 or 3.

[0231] In some embodiments, the compound of formula (I-4) is the compound of formula (I-a4), [ka] or a pharmaceutically acceptable salt thereof, where R 2a , R 2b , R 3a , R 5 , R 19 , R X , and R YThis is defined in any of the embodiments of the 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 the compound of formula (I-b4a) or formula (I-b5a), [ka] or a pharmaceutically acceptable salt thereof, where R 2a , R 2b , R 3a , R 19 , R X , and R Y This is as defined in any embodiment 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), (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 the compound of formula (I-b4b) or formula (I-b5b), [ka] or a pharmaceutically acceptable salt thereof, where R2a , R 2b , R 3a , R 19 , R X , and R Y This is defined in any of the embodiments of the 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 relates to a compound of formula (X), [ka] or provides a pharmaceutically acceptable salt thereof, in the formula 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 embodiments of the compounds 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 It is alkyl, R 3ais a substitution or non-substitution C 1~6 Alkyl, or substituted or unsubstituted C 1~6 Alkyl-OC 1~6 It is alkyl, R 19 is hydrogen, or substituted or unsubstituted C 1~6 It is alkyl, R Y R is a 3-8 member saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-2 nitrogen atoms, Y The 3-8 member rings are independently halogen, -CN, or C 1~6 It is optionally substituted with 1 to 3 groups selected from alkyl groups, and t is 1 or 2, however, if t is 1, R 3a It is -CH2OCH2CH3, and R Y is a substituted or unsubstituted pyrazinyl, followed by R 19 This is conditional on it being -CH3.

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

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

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

[0239] In some embodiments, R YThese are substituted or unsubstituted pyrazinyls, cyano-substituted pyrimidines, substituted or unsubstituted phenyls, cyano- or fluoro-substituted pyridines, or pyrazoles substituted with two unsubstituted methyl groups.

[0240] Another aspect of the present invention relates to a compound of formula (XI), [ka] or provides a pharmaceutically acceptable salt thereof, in the formula 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 embodiment of the compound (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 unsubstituted C 1~3 It is alkyl, R 19 is hydrogen or unsubstituted C 1~3 It is alkyl, R Y teeth, [ka] Therefore, two of W1, W2, W3, W4, and W5 are -N=, and the rest are -C(R')=, where each R' is independently either hydrogen or -CN, and at least one R' is -CN.

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

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

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

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

[0246] Another aspect of the present invention relates to a compound of formula (II): [ka] or provide a pharmaceutically acceptable salt thereof, in the formula, [ka] R represents a single bond or a double bond, however, if a double bond is present, R 5 and R 6a or R 6b The condition is that one of them does not exist, R 3a is a substitution or non-substitution C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, 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] If R is a double bond, 5 It does not exist, R 6a and R 6b Each of these can independently be 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 It is either alkinyl or R 6a and R 6b They join together to form an oxo (=O) group, 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 of these can independently be 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 case independently involves hydrogen, substituted or unsubstituted carbon. 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 join 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 One of them joins to form an oxo (=O) group, R 15a and R 15b Each of these can independently be 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 Alkinyl, -OR D1 -OC(=O)R D1 -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 And R D1 Each case independently involves hydrogen, substituted or unsubstituted carbon. 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 join to form a substituted or unsubstituted heterocyclic ring, or R 15a and R 15b They join together to form an oxo (=O) group, R 15a and R 15b One of them is not hydrogen, but R 16a and R 16b Each of these independently consists of hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, 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 case independently involves hydrogen, substituted or unsubstituted carbon. 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, oxygen protecting group if attached to an oxygen atom, sulfur protecting group if attached to a sulfur atom, nitrogen protecting group if attached to a nitrogen atom, -SO2R A2 , -C(O)R A2 is either or two R A1 The groups are joined to form a substituted or unsubstituted heterocyclic ring or heteroaryl ring, R A2 is a substitution or non-substitution C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6Alkinyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R 19 C is hydrogen, substituted or unsubstituted. 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, or substituted or unsubstituted C 2~6 It is alkinyl, R X is hydrogen, or substituted or unsubstituted C 1~6 It is alkyl, R Y These are, independently, substituted or unsubstituted phenyl or heteroaryl compounds.

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

[0248] Another aspect of the present invention relates to a compound of formula (III), [ka] or provide a pharmaceutically acceptable salt thereof, in the formula, [ka] R represents a single bond or a double bond, however, if a double bond is present, R 5 and R 6a or R 6b The condition is that either one of them does not exist, R 3a is a substitution or non-substitution C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, 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] If R is a double bond, 5 It is non-existent, R 6a and R 6b Each of these can independently be 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 It is either alkinyl or R 6a and R 6b They are joined together, forming 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 of these can independently be 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 Alkinyl, -OR D1 -OC(=O)R D1 -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 And R D1 Each case independently involves hydrogen, substituted or unsubstituted carbon. 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 The 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 One of them joins to form an oxo (=O) group, R 16a and R 16b Each of these independently consists of hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, 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 case independently involves hydrogen, substituted or unsubstituted carbon. 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, oxygen protecting group if attached to an oxygen atom, sulfur protecting group if attached to a sulfur atom, nitrogen protecting group if attached to a nitrogen atom, -SO2R A2 , -C(O)R A2 is either or two R A1 The groups join together to form a substituted or unsubstituted heterocyclic or heteroaryl ring, R A2 is a substitution or non-substitution C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R 19 C is hydrogen, substituted or unsubstituted. 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, or substituted or unsubstituted C 2~6 It is alkinyl, R X is hydrogen, or substituted or unsubstituted C 1~6 It is alkyl, R Y is independently a substituted or unsubstituted phenyl or heteroaryl, and t is 2 or 3.

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

[0250] Another aspect of the present invention relates to a compound of formula (IVa) or formula (IVb): [ka] or provide a pharmaceutically acceptable salt thereof, in the formula, [ka] R represents a single bond or a double bond, however, if a double bond is present, R 5 and R 6a or R 6b The condition is that either one of them does not exist, R 3a is a substitution or non-substitution C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, 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] If R is a double bond, 5 It is non-existent, R 6a and R 6b Each of these can independently be 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 It is either alkinyl or R 6a and R 6b They are joined together, forming 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 of these can independently be 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 Alkinyl, -OR D1 -OC(=O)R D1 -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 And R D1 Each case independently involves hydrogen, substituted or unsubstituted carbon. 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 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 One of them joins to form an oxo (=O) group, R 16a and R 16b Each of these is independently hydrogen, halogen, substituted or unsubstituted C1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, 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 case independently involves hydrogen, substituted or unsubstituted carbon. 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, oxygen protecting group if attached to an oxygen atom, sulfur protecting group if attached to a sulfur atom, nitrogen protecting group if attached to a nitrogen atom, -SO2R A2 , -C(O)R A2 is either or two RA1 The groups join together to form a substituted or unsubstituted heterocyclic or heteroaryl ring, R A2 is a substitution or non-substitution C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R 19 C is hydrogen, substituted or unsubstituted. 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, or substituted or unsubstituted C 2~6 It is alkinyl, R X is hydrogen, or substituted or unsubstituted C 1~6 It is alkyl, R Y r is independently a substituted or unsubstituted phenyl or heteroaryl, and r is 2 or 3.

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

[0252] Another aspect of the present invention relates to a compound of formula (V): [ka] or provide a pharmaceutically acceptable salt thereof, in the formula, [ka] R represents a single bond or a double bond, however, if a double bond is present, R 5 and R 6a or R 6b The condition is that either one of them does not exist, R 3a is a substitution or non-substitution C1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, 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] If R is a double bond, 5 It is non-existent, R 6a and R 6b Each of these can independently be 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 It is either alkinyl or R 6a and R 6b They are joined together, forming 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 of these can independently be 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 Alkinyl, -OR D1 -OC(=O)R D1 -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 And R D1Each case independently involves hydrogen, substituted or unsubstituted carbon. 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 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 One of them joins to form an oxo (=O) group, R 16a and R 16b Each of these independently consists of hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, 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 case independently involves hydrogen, substituted or unsubstituted carbon. 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, oxygen protecting group if attached to an oxygen atom, sulfur protecting group if attached to a sulfur atom, nitrogen protecting group if attached to a nitrogen atom, -SO2R A2 , -C(O)R A2 is either or two R A1 The groups join together to form a substituted or unsubstituted heterocyclic or heteroaryl ring, R A2 is a substitution or non-substitution C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R 19 C is hydrogen, substituted or unsubstituted. 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, or substituted or unsubstituted C 2~6 It is alkinyl, R X is hydrogen, or substituted or unsubstituted C 1~6 It is alkyl, R Y These are, independently, substituted or unsubstituted phenyl or heteroaryl compounds.

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

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

[0255] Another aspect of the present invention relates to a compound of formula (VI): [ka] or provide a pharmaceutically acceptable salt thereof, in the formula, [ka] R represents a single bond or a double bond, however, if a double bond is present, R 5 and R 6a or R 6b The condition is that either one of them does not exist, R 3a is a substitution or non-substitution C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, 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] If R is a double bond, 5 It is non-existent, R6a and R 6b Each of these can independently be 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 It is either alkinyl or R 6a and R 6b They are joined together, forming 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 of these can independently be 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 Alkinyl, -OR D1 -OC(=O)R D1 -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 And R D1 Each case independently involves hydrogen, substituted or unsubstituted carbon. 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 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 One of them joins to form an oxo (=O) group, R 16a and R 16b Each of these independently consists of hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, 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 case independently involves hydrogen, substituted or unsubstituted carbon. 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, oxygen protecting group if attached to an oxygen atom, sulfur protecting group if attached to a sulfur atom, nitrogen protecting group if attached to a nitrogen atom, -SO2R A2 , -C(O)R A2 is either or two R A1 The groups join together to form a substituted or unsubstituted heterocyclic or heteroaryl ring, R A2 is a substitution or non-substitution C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R 18 is substitution C 1~6 Alkyl, or unsubstituted C2-C6 alkyl, substituted or unsubstituted C 2~6 Alkenyl, or substituted or unsubstituted C 2~6 It is alkinyl, R 19 C is hydrogen, substituted or unsubstituted. 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, or substituted or unsubstituted C 2~6 It is alkinyl, R X is hydrogen, or substituted or unsubstituted C 1~6 It is alkyl, R Y These are independently substituted or unsubstituted phenyl or heteroaryl compounds.

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

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

[0258] Another aspect of the present invention relates to a compound of formula (VII): [ka] or provide a pharmaceutically acceptable salt thereof, in the formula, [ka] R represents a single bond or a double bond, however, if a double bond is present, R 5 and R 6a or R 6b The condition is that either one of them does not exist, R 3a is a substitution or non-substitution C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, 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] If R is a double bond, 5 It is non-existent, R 6a and R 6b Each of these can independently be 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 It is either alkinyl or R 6a and R6b They are joined together, forming 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 of these can independently be 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 Alkinyl, -OR D1 -OC(=O)R D1 -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 And R D1 Each case independently involves hydrogen, substituted or unsubstituted carbon. 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 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 One of them joins to form an oxo (=O) group, R 16aand R 16b Each of these independently consists of hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, 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 case independently involves hydrogen, substituted or unsubstituted carbon. 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, oxygen protecting group if attached to an oxygen atom, sulfur protecting group if attached to a sulfur atom, nitrogen protecting group if attached to a nitrogen atom, -SO2RA2 , -C(O)R A2 is either or two R A1 The groups join together to form a substituted or unsubstituted heterocyclic or heteroaryl ring, R A2 is a substitution or non-substitution C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R 19 C is ethyl, substituted, or unsubstituted. 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, substituted or unsubstituted C3-C6 carbocyrill, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted aryl, R X is hydrogen, or substituted or unsubstituted C 1~6 It is alkyl, R Y These are, independently, substituted or unsubstituted phenyl or heteroaryl compounds.

[0259] Another aspect of the present invention relates to a compound of formula (VIII): [ka] or provide a pharmaceutically acceptable salt thereof, in the formula, [ka] R represents a single bond or a double bond, however, if a double bond is present, R 5 and R 6a or R 6b Condition that either one of them is nonexistent, R 2a and R 2b Each of these can independently be 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 Alkinyl, -OR D1 -OC(=O)R D1 -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 And R D1 Each case independently involves hydrogen, substituted or unsubstituted carbon. 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 join to form a substituted or unsubstituted heterocyclic ring, or R 2a and R 2b They join together to form an oxo (=O) group, R 2a and R 2b At least one of them is not hydrogen, but R 3a is a substitution or non-substitution C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, 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] If R is a double bond, 5 It is non-existent, R 6a and R 6b Each of these can independently be hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, or substituted or unsubstituted C2~6 It is either alkinyl or R 6a and R 6b They join together to form an oxo (=O) group, 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 of these can independently be 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 Alkinyl, -OR D1 -OC(=O)R D1 -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 And R D1 Each case independently involves hydrogen, substituted or unsubstituted carbon. 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 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 One of them joins to form an oxo (=O) group, R 16a and R 16bEach of these independently consists of hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, 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 case independently involves hydrogen, substituted or unsubstituted carbon. 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, oxygen protecting group if attached to an oxygen atom, sulfur protecting group if attached to a sulfur atom, nitrogen protecting group if attached to a nitrogen atom, -SO2R A2 , -C(O)RA2 is either or two R A1 The groups join together to form a substituted or unsubstituted heterocyclic or heteroaryl ring, R A2 is a substitution or non-substitution C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R 19 C is hydrogen, substituted or unsubstituted. 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, or substituted or unsubstituted C 2~6 It is alkinyl, R X is hydrogen, or substituted or unsubstituted C 1~6 It is alkyl, R Y These are, independently, substituted or unsubstituted phenyl or heteroaryl compounds.

[0260] Another aspect of the present invention relates to a compound of formula (IX): [ka] or provide a pharmaceutically acceptable salt thereof, in the formula, [ka] R represents a single bond or a double bond, however, if a double bond is present, R 5 and R 6a or R 6b One of them is nonexistent, R 11a and R 11b These 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 Alkinyl, -OR D1 -OC(=O)R D1-NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 And R D1 Each case independently involves hydrogen, substituted or unsubstituted carbon. 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 join to form a substituted or unsubstituted heterocyclic ring, or R 11a and R 11b They join together to form an oxo (=O) group, R 2a and R 2b At least one of them is not hydrogen, R 3a is a substitution or non-substitution C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, 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] If R is a double bond, 5 It does not exist, R 6a and R 6b Each of these can independently be 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 It is either alkinyl or R 6a and R 6b They join together to form an oxo (=O) group, 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 of these can independently be 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 Alkinyl, -OR D1 -OC(=O)R D1 -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 And R D1 Each case independently involves hydrogen, substituted or unsubstituted carbon. 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 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 One of them joins to form an oxo (=O) group, R 16a and R 16b Each of these independently consists of hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C2~6 Alkinyl, 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 case independently involves hydrogen, substituted or unsubstituted carbon. 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, oxygen protecting group if attached to an oxygen atom, sulfur protecting group if attached to a sulfur atom, nitrogen protecting group if attached to a nitrogen atom, -SO2R A2 , -C(O)R A2 is either or two R A1 The groups join together to form a substituted or unsubstituted heterocyclic or heteroaryl ring, R A2is a substitution or non-substitution C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R 19 C is hydrogen, substituted or unsubstituted. 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, or substituted or unsubstituted C 2~6 It is alkinyl, R X is hydrogen, or substituted or unsubstituted C 1~6 It is alkyl, R Y These are, independently, substituted or unsubstituted phenyl or heteroaryl compounds.

[0261] Another aspect of the present invention relates to a compound of formula (XII): [ka] or provide a pharmaceutically acceptable salt thereof, in the formula, [ka] R represents a single bond or a double bond, however, if a double bond is present, R 5 and R 6a or R 6b Condition that either one of them is nonexistent, R 7a and R 7b Each of these can independently be 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 Alkinyl, -OR D1 -OC(=O)R D1 -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 And R D1Each case independently involves hydrogen, substituted or unsubstituted carbon. 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 join to form a substituted or unsubstituted heterocyclic ring, or R 11a and R 11b They join together to form an oxo (=O) group, R 7a and R 7b At least one of them is not hydrogen, but R 3a is a substitution or non-substitution C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, 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] If R is a double bond, 5 It is non-existent, R 6a and R 6b Each of these can independently be 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 It is either alkinyl or R 6a and R 6b They join together to form an oxo (=O) group, 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 of these can independently be 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 Alkinyl, -OR D1 -OC(=O)R D1 -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 And R D1 Each case independently involves hydrogen, substituted or unsubstituted carbon. 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 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 One of them joins to form an oxo (=O) group, R 16a and R 16b Each of these independently consists of hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, 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 case independently involves hydrogen, substituted or unsubstituted carbon. 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, oxygen protecting group if attached to an oxygen atom, sulfur protecting group if attached to a sulfur atom, nitrogen protecting group if attached to a nitrogen atom, -SO2R A2 , -C(O)R A2 is either or two R A1 The groups join together to form a substituted or unsubstituted heterocyclic or heteroaryl ring, R A2 is a substitution or non-substitution C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6Alkinyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R 19 C is hydrogen, substituted or unsubstituted. 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, or substituted or unsubstituted C 2~6 It is alkinyl, R X is hydrogen, or substituted or unsubstituted C 1~6 It is alkyl, R Y These are independently substituted or unsubstituted phenyl or heteroaryl compounds.

[0262] D. General Synthesis Scheme The compounds of the present invention can be synthesized according to the following general synthesis scheme. In the following general scheme, it is understood that all variables used in the scheme have the definitions provided herein. Where used in the general scheme, LG means “leaving group” and PG means “protecting group”. The enantiomerically pure compounds of the general scheme are assumed by using stereospecific reaction conditions or chiral resolution using methods known to those skilled in the art, and / or are described in detail in the specific examples provided herein.

[0263] Following Scheme 1, the compound of formula C (wherein R 3a The compound of formula A (as defined herein) can be synthesized by first converting the acetyl group of the compound of formula A, for example, a Br2 / NaOH or Cl2 / NaOH mixture, under appropriate conditions to produce the compound of formula B. Then, the resulting compound of formula B is converted into a compound of formula R Y It can be coupled with amines of -NH2, where R YThe compound of formula C is produced by optionally substituting alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl with an alkyl, cycloalkyl, heteroalkyl, or heteroaryl group. Alternatively, the compound of formula B can be coupled with ammonia to produce the compound of formula D. The coupling of the compound of formula B to produce the compound of formula C or D can be achieved using any number of coupling agents and coupling conditions known to experts, such as HATU using DMF as the solvent. The compound of formula D is then coupled with the amide nitrogen of formula D, Br-R XX It can be converted to the compound of formula C by coupling with the compound of formula C, where R XX These are aryl or heteroaryl compounds using catalytic coupling conditions known to experts, such as a combination of XantPhos, Cs2CO3, and Pd2(dba)3 in dioxane. Compounds of formulas A, B, C, and D may also be substituted as described herein.

[0264] Scheme 1: [ka] The compound of formula O can be synthesized according to the general procedures of schemes 2 and 3. Referring to scheme 2, the compound of formula F (wherein R 3a (as defined herein) (a) Grignard reagent R 3a MgBr(R 3a (b)S(CH3)3 can be synthesized in one step from formula E by reacting with (as defined herein). This transformation is also (b)S(CH3)3 + I - (c) Form the oxirane compound of formula G using appropriate reagents such as sodium hydride, then open the oxirane with a nucleophile, so that the nucleophile is added together with substituent R when added to the methylene group of the oxirane. 3aThis can also be achieved in two steps by forming [a compound]. When the compound of formula F is reacted in a mixture of LDA and ethyl diazoacetate, an adduct of formula H is produced, and then, when formula H is treated with a reagent such as Rh2(OAc)4 in DME, it can undergo an intramolecular reaction to produce the compound of formula I.

[0265] Scheme 2: [ka] Referring to Scheme 3, the precipitation and decarboxylation of the compound of formula I to form the compound of formula J can be achieved with hydroxides. The compound of formula K can be synthesized by converting the ketone portion 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. Then, the terminal olefin of formula K is hydroxylated using conditions such as 9-BBN dimer, followed by NaOH / H2O2, to produce the compound of formula L. Formula L is treated with a mild oxidizing agent such as Dess-Martin reagent to produce the aldehyde of formula M, and then with a second oxidizing agent such as NaClO2 to produce the carboxylic acid of formula N. Then, the compound of formula N is converted to formula R using any number of coupling agents and coupling conditions known to experts, e.g., HATU using DMF as a solvent. W -NH2(wherein, R W The compound of formula O is produced by coupling it with an amine (as defined herein). Compounds of formulas E, F, G, H, I, J, K, L, M, N, and O may 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 tetrabutylammonium fluoride (TBAF), etc. Those skilled in the art will recognize that this is just one example of many different methods for protecting and deprotecting alcohol functional groups, i.e., for producing compounds of formula Q from formula P. Oxidation of the alcohol moiety with a mild oxidizing agent such as Dess-Martin reagent can produce the aldehyde of formula R. The aldehyde moiety of the compound of formula R can be converted to a terminal olefin, for example, by treatment with methyltriphenylphosphine bromide, to produce compounds of formula S. Reduction of the compound of formula S using any number of common reduction techniques known to those skilled in the art, e.g., H2, can produce compounds of formula T. Compounds of formulas 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 specified in Table 1 or pharmaceutically acceptable salts 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 embodiment, the compounds provided herein are those 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) These are pharmaceutically acceptable salts of compounds (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 embodiment, the compounds provided herein are those 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 pharmaceutical composition comprises a compound of (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, 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] In certain embodiments, the compounds of the present invention described herein act, for example, as GABA modulators that affect GABAA receptors in either a positive or negative manner. Such compounds are expected to have CNS activity as modulators of central nervous system (CNS) excitability mediated by their ability to modulate GABAA receptors.

[0272] Accordingly, in another embodiment, a method is provided for doing so in a subject requiring a CNS-related disorder, comprising administering an effective amount of the compound of the present invention to the subject. In certain embodiments, the CNS-related disorder is a sleep disorder, mood disorder, schizophrenia spectrum disorder, convulsive disorder, memory and / or cognitive impairment, motor disorder, personality disorder, autism spectrum disorder, pain, traumatic brain injury, vascular disease, 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 long-term. 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 skilled in the art or certain references. In one embodiment, provided herein are compounds of formulas (e.g., 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) These are pharmaceutically acceptable salts of compounds (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 include one or more isotopic substitutions. For example, hydrogen may be: 2 H (D or deuterium) or 3 H (or T or tritium) may also be used, and carbon can be, for example, 13 C or 14 It could also be C, and oxygen could be, for example, 18 It could be O, and nitrogen could be, for example, 15 N may also be used in other embodiments. 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 of the compound.

[0275] A. Pharmaceutical Compositions In one embodiment, the compounds provided herein are those 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 pharmaceutical composition comprises (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) (compounds thereof) or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients. In certain embodiments, the compounds of the present invention are provided in an effective amount as a pharmaceutical composition. In certain embodiments, the compounds of the present invention are provided in a therapeutically effective amount.

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

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

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

[0279] When used to prevent the development of CNS disorders, the compounds provided herein are typically administered to subjects 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 as particularly susceptible to its development through genetic testing or screening.

[0280] The pharmaceutical compositions provided herein may also be administered chronically ("chronic administration"). Chronic administration means administering the compound or the pharmaceutical composition over a long period of time, such as three months, six months, one year, two years, three years, five years, or continuing indefinitely, for example, throughout the lifetime of the subject. In certain embodiments, chronic administration is intended to deliver the compound to the blood at a constant level, for example, within the therapeutic range, over a long period of time.

[0281] The pharmaceutical compositions of the present invention can be delivered using a variety of administration methods. For example, in certain embodiments, the pharmaceutical composition may be administered as a bolus, for example, to raise the blood concentration of the compound to an effective level. The location of the bolus administration varies depending on the desired systemic level of the active ingredient throughout the body. For example, intramuscular or subcutaneous bolus administration allows for the slow release of the active ingredient, while a bolus delivered directly to a vein (e.g., by IV drip) allows for much faster delivery and a rapid increase in the blood concentration of the active ingredient to an effective level. In other embodiments, the pharmaceutical composition may be administered as a continuous infusion, for example by IV drip, to maintain a steady-state concentration of the active ingredient in the target body. Furthermore, in yet another embodiment, the pharmaceutical composition may be administered first as a bolus and then by continuous infusion.

[0282] Compositions for oral administration may take the form of a bulk liquid solution or suspension, or a bulk powder. However, more generally, compositions are provided in unit dosage forms to facilitate precise administration. The term "unit dosage form" refers to a physical individual unit suitable as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of the active substance calculated to obtain the desired therapeutic effect, along with suitable pharmaceutical excipients. Typical unit dosage forms include pre-filled ampoules or syringes for liquid compositions, or pills, tablets, capsules, etc., for solid compositions. In such compositions, the compound is usually present in small amounts (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various vehicles or excipients and processing aids that help form the desired dosage form.

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

[0284] The transdermal dose is generally selected to result in blood levels equivalent to or lower than those achieved using the injectable dose, and is generally in the range of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably about 0.5 to about 15% by weight.

[0285] The injection dose levels are all in the range of approximately 0.1 mg / kg / hour to at least 20 mg / kg / hour, over approximately 1 to 120 hours, and especially 24 to 96 hours. A preload bolus of approximately 0.1 mg / kg to 10 mg / kg or more may also be administered to achieve an appropriate steady-state level. The maximum total dose is not expected to exceed approximately 5 g / day for human patients weighing 40-80 kg.

[0286] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle containing buffers, suspending agents and dispersants, colorants, flavorings, etc. Solid forms may include, for example, any of the following components or compounds of similar properties: binders (such as microcrystalline cellulose, tragacanth gum, or gelatin); excipients (such as starch or lactose); disintegrants (such as alginic acid, Primogel, or corn starch); lubricants (such as magnesium stearate); lubricants (such as colloidal silicon dioxide); sweeteners (such as sucrose or saccharin); or flavorings (such as peppermint, methyl salicylate, or orange flavor).

[0287] Injectable compositions typically use sterile saline or phosphate-buffered saline for injection, or other injectable excipients known in the art, as a base. As mentioned above, the active compound in such compositions is typically a small component, often about 0.05 to 10% by weight, with the remainder being injectable excipients, etc.

[0288] Transdermal compositions are typically formulated as topical ointments or creams containing active ingredients(s). When formulated as ointments, the active ingredients are typically miscible with a paraffinic ointment base or a water-miscible ointment base. Alternatively, the active ingredients may be formulated as a cream containing, for example, 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 transdermal devices. Therefore, transdermal administration can also be achieved using container-type or porous membrane-type patches, or solid matrix type patches.

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

[0291] The compounds of the present invention can also be administered in sustained-release form or via sustained-release drug delivery systems. 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 pharmaceutically acceptable anions (e.g., hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, p-toluenesulfonate, etc.).

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

[0294] Pharmaceutically acceptable excipients include any diluent or other liquid vehicle suitable for the specific dosage form of the intended product, such as injection; dispersing or suspending agents; surfactants; isotonic agents; preservatives; and lubricants. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, EW 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 aqueous suspensions for injection can be formulated according to known techniques using suitable dispersants or wetting 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, each comprising 6, 7, and 8 α-1,4-linked glucose units, with one or more optionally substituted substituents (including, but not limited to, substituted or unsubstituted methylation, hydroxyalkylation, acylation, and sulfoalkyl ether substitution) on the bonded sugar moiety. In certain embodiments, the cyclodextrin is sulfoalkyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as CAPTISOL®. See, for example, 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] The injectable composition can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

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

[0299] The composition is provided in unit dosage forms to facilitate precise administration. The term "unit dosage form" refers to a physical individual unit suitable as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of the active substance calculated to obtain the desired therapeutic effect, along 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 present in small amounts (about 0.1% to about 50% by weight, or preferably about 1% to about 40% by weight), with the remainder being various vehicles or carriers and processing aids that help form the desired dosage form.

[0300] The compounds provided herein may be administered as single activators or in combination with other activators. In one embodiment, the present invention provides a combination of the compound of the present invention with another pharmacological activator. Combination administration can be carried out by any technique apparent to those skilled in the art (e.g., individual administration, sequential administration, simultaneous administration, and alternating administration).

[0301] The descriptions of pharmaceutical compositions provided herein primarily concern pharmaceutical compositions suitable for administration to humans, but those skilled in the art will understand that such compositions are generally suitable for administration to all types of animals. It is well understood that pharmaceutical compositions suitable for administration to humans can be modified to make them suitable for administration to various animals, and veterinary pharmacologists skilled in the art can design and / or carry out such modifications using conventional experiments. 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 embodiment, the provided formulas are (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 The kit comprises a composition (e.g., a solid composition) containing the compound (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 Compounds or compositions described herein (e.g., 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- Compounds of 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 pharmaceutically acceptable salts 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), A compound comprising (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, may be administered in combination with additional agents or therapies. Subjects administered with the compounds disclosed herein may have diseases, disorders, or conditions, or symptoms thereof, that would benefit from treatment with another agent or therapy.Combination therapy can be administered by administering two or more drugs, each individually formulated and administered, or by administering two or more drugs in single formulation form. In some embodiments, two or more drugs can be administered simultaneously in combination therapy. In other embodiments, two or more drugs are administered individually in combination therapy. For example, the first drug (or combination of drugs) can be administered minutes, hours, days, or weeks before the second drug (or combination of drugs) is administered. 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, longer intervals are possible. Often, it is desirable, but not necessary, that the two or more drugs used in combination therapy be present in the patient's body at the same time.

[0304] Combination therapy may also involve two or more administrations of one or more drugs used in combination, with the component drugs used in different sequences. For example, when drugs X and Y are used in combination, they can be administered one or more times consecutively in any combination, for example, in the order XYX, XXY, YXY, YYX, XXYY, etc. Exemplary additional drugs are listed below.

[0305] 1. Selective serotonin reuptake inhibitors (SSRIs) In some embodiments, the compounds or compositions described herein (e.g., 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), Compounds of (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 their pharmaceutically acceptable salts. , 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), ( 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), or compositions containing pharmaceutically acceptable salts thereof, are administered in combination with an SSRI (or more). SSRIs include antidepressants that increase serotonin levels in the brain.Examples of 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, the compounds or compositions described herein (e.g., 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), Compounds of (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 their pharmaceutically acceptable salts. , 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), ( 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), or compositions containing pharmaceutically acceptable salts thereof, are administered in combination with NERI(plural).Examples of NERI 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), talspram (Lu 5-005), tandamin (AY-23,946), and biloxazine (Vivaran).

[0307] 3. Antipsychotic drugs In some embodiments, the compounds or compositions described herein (e.g., 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), Compounds of (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 their pharmaceutically acceptable salts. , 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 Compounds of (-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 compositions containing pharmaceutically acceptable salts thereof, are administered in combination with antipsychotics. Antipsychotics include D2 antagonists, which reduce dopaminergic neurotransmission in the dopamine pathway.Examples of antipsychotic drugs include, but are not limited to, asenapine (Safris), aripiprazole (Abilify), caliprazine (Braelar), clozapine (Clozaril), droperidol, fluperlapine, mesolidazine, quetiapine hemifumarate, lacloprid, spiperone, sulpiride, trimethobenzuamide hydrochloride, trifluoperazine dihydrochloride, lurasidone (Latuda), olanzapine (Zyprexa), quetiapine (Seroquel), zotepine, risperidone (Risperidar), ziprasidone (Giodon), mesolidazine, chlorpromazine hydrochloride, and haloperidol (Haldol).

[0308] 4. Cannabinoids In some embodiments, the compounds or compositions described herein (e.g., 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), ( Compounds of 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 pharmaceutically acceptable salts 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 compound of (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 containing a pharmaceutically acceptable salt thereof, is administered in combination with a 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, the compounds or compositions described herein (e.g., 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- Compounds of (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 pharmaceutically acceptable salts 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 Compounds of (-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 compositions containing pharmaceutically acceptable salts thereof, are administered in combination with an NMDA receptor antagonist(s). NMDA receptor antagonists are a type of drug that inhibits the action of the N-methyl-d-aspartate receptor.Examples of NMDA antagonists include, but are not limited to, ketamine, esketamine, ketobemidone, ifendopril, 5,7-dichloroquinurenic acid, licostinel, memantine, gabestinel, phencyclidine, dextromethorphan, remasemide, serfotel, tiletamine, dextropropoxifen, aptiganel, dexanabinol, and amantadine. NMDA receptor antagonists also include opioids such as methadone, dextropropoxifen, pethidine, levorphanol, tramadol, neramexane, and ketobemidone.

[0310] 6. GABA receptor antagonists In some embodiments, the compounds or compositions described herein (e.g., 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 Compounds of (-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 pharmaceutically acceptable salts 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) A compound containing (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 GABA receptor antagonist(s). A GABA receptor antagonist is a type of drug that is an antagonist of one or more GABA receptors.Examples of GABA receptor antagonists include clobazam, topiramate, muscimol, progavid, riluzole, baclofen, gabapentin, vigabatrin, valproic acid, thiagabine, lamotrigine, pregabalin, pheniloin, carbamazepine, thiopental, thiamylal, pentobarbital, secobarbital, hexobarbital, butobarbital, amobarbital, barbital, mehobarbital, phenobarbital, primidone, midazolam, triazolam, lormetazepam, flutazolam, nitrazepam, fluritrazepam, nimetazepam, diazepam, medazepam, oxazolam, prazeam, tofisopam, rilmazafone, lorazepam, temazepam, oxazepam, and fludiazepam. Chlordiazepoxide, cloxazolam, flutoprazepam, alprazolam, estazolam, bromazepam, flurazepam, potassium clorazepate, haloxazolam, ethyl loflazepate, quazepam, clonazepam, mesazolam, etizolam, brotizolam, clotiazepam, propofol, fospropofol, zolpidem, zopiclone, eszopiclone, muscimol, TFQP / gaboxadol, isogbacin, kodiamine, GABA, homotaurine, homohypotaurine, trans-aminocyclopentane-3-carboxylic acid, trans-amino-4-crotonic acid, β-guanidinopropionic acid, homo-β-proline, isonipecotinic acid, 3-((aminoiminomethyl)thio)-2-propenic acid (ZAP A) Examples include, but are not limited to, imidazole acetate and piperidine-4-sulfonic acid (P4S).

[0311] 7. Cholinesterase inhibitors In some embodiments, the compounds or compositions described herein (e.g., 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 Compounds of (-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 pharmaceutically acceptable salts thereof, or 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), Compounds of (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 compositions containing pharmaceutically acceptable salts thereof, are administered in combination with cholinesterase inhibitors. Generally, cholinergics are compounds that mimic the action of acetylcholine and / or butyrylcholine.Cholinesterase inhibitors are a type of drug that prevents the breakdown of acetylcholine. Examples of cholinesterase inhibitors include, but are not limited to, donepezil (Aricept), tacrine (Cognex), rivastigmine (Exelon, Exelon Patch), galantamine (Razadine, Reminyl), memantine / donepezil (Namzalic), amvenonium (Myterase), neostigmine (Broxivertz), pyridostigmine (Mestinon Timespan, Regonol), and galantamine (Razadine).

[0312] This disclosure also relates, in particular, to the compounds or pharmaceutical compositions described herein (e.g., 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 Compounds of formula (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 pharmaceutically acceptable salts thereof, or 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), Administration of a composition containing compounds of (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, to a subject is permitted if the subject has previously received a drug selected from the group consisting of bronchostomy / airway relaxants, antivirals, oxygen agents, antibodies, and antibacterial agents.In some embodiments, the additional agent is a compound or composition described herein (e.g., 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 Compounds of (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 pharmaceutically acceptable salts 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 The subject is administered a composition containing a compound of (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, prior to administration of the additional agent, which is selected from the group consisting of bronchostomy / airway relaxants, antivirals, oxygen agents, antibodies, and antibacterial agents.In some embodiments, the compounds or pharmaceutical compositions described herein (e.g., 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), Compounds of (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 pharmaceutically acceptable salts thereof, or 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 A composition containing compounds of (-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 to the subject concurrently with an agent selected from bronchostomy / airway relaxants, antivirals, oxygen agents, antibodies, and antibacterial agents.

[0313] C. Method of Use and Treatment In one embodiment, the compounds described herein, for example, 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), (III Compounds a), (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 CNS-related disorders (e.g., sleep disorders, mood disorders such as depression, schizophrenia spectrum disorders, convulsive disorders, epileptic seizures, memory and / or cognitive impairments, motor disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders, and / or withdrawal symptoms, or tinnitus) in subjects who require them (e.g., subjects with Rett syndrome, fragile X syndrome, or Angelman syndrome).Exemplary CNS conditions associated with GABAergic modulation include sleep disorders [e.g., insomnia], mood disorders [e.g., depression (e.g., major depressive disorder (MDD)), dysthymia (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 (e.g., obsessive-compulsive disorder (OCD))], schizophrenia spectrum disorders [e.g., schizophrenia, schizoaffective disorder], convulsive disorders [e.g., epilepsy (e.g., status epilepticus (SE), seizures)], memory impairment and / or cognitive impairment [e.g., attention deficit (e.g., attention deficit hyperactivity disorder (ADHD), dementia (e.g.)] Examples include, but are not limited to, Alzheimer's disease, Lewy body dementia, vascular dementia, motor disorders [e.g., Huntington's disease, Parkinson's disease], personality disorders [e.g., antisocial personality disorder], autism spectrum disorder (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 diseases [e.g., stroke, ischemia, vascular malformations], substance abuse disorders and / or withdrawal syndromes [e.g., opium, cocaine, and / or alcohol addiction], and tinnitus.

[0314] In certain embodiments, CNS-related disorders include sleep disorders, mood disorders, schizophrenia spectrum disorders, convulsive disorders, memory and / or cognitive impairments, motor disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and / or withdrawal syndromes, tinnitus, or status epilepticus. In certain embodiments, CNS-related disorders include depression. In certain embodiments, CNS-related disorders include postpartum depression. In certain embodiments, CNS-related disorders include major depressive disorder. In certain embodiments, major depressive disorder includes moderate major depressive disorder. In certain embodiments, major depressive disorder includes severe major depressive disorder.

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

[0316] In yet another embodiment, the present invention provides combinations of the compound with another pharmacological activator. The compounds provided herein may be administered as a single activator or in combination with other agents. Combination administration can be carried out by any technique apparent to those skilled in the art (e.g., individual administration, sequential administration, simultaneous administration, and alternating administration).

[0317] In another embodiment, the present invention provides a method for treating or preventing brain excitability in subjects who are susceptible to or suffering from brain excitability-related conditions, the method comprising administering an effective amount of the compound of the present invention to the subjects.

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

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

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

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

[0322] In yet another embodiment, a method is provided for treating or preventing a mood disorder in a subject, comprising administering an effective amount of the compound of the present invention to a subject in need of such treatment. In a particular embodiment, the mood disorder is depression.

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

[0324] In yet another embodiment, the present invention provides a method for treating attention disorders by administering a therapeutically effective dose of the compound to a subject. In a particular embodiment, the attention disorder is ADHD.

[0325] In certain embodiments, the compound is administered to the subject over a long period of time. In certain embodiments, the compound is administered to the subject orally, subcutaneously, intramuscularly, or intravenously.

[0326] 1. Neuroendocrine disorders and dysfunctions This specification provides methods that can be used to treat neuroendocrine disorders and dysfunctions. As used herein, “neuroendocrine disorder” or “neuroendocrine dysfunction” refers to a range of conditions caused by imbalances in the production of hormones in the body that are directly related to the brain. Neuroendocrine disorders involve interactions between the nervous and endocrine systems. Because the hypothalamus and pituitary gland are two regions 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 related to women’s health disorders or conditions (e.g., women’s health disorders or conditions described herein). In some embodiments, the neuroendocrine disorder or dysfunction related to women’s health disorders or conditions is polycystic ovary syndrome.

[0327] Symptoms of neuroendocrine disorders include, but are not limited to, behavioral, emotional, and sleep-related symptoms, reproductive function-related symptoms, and physical symptoms, which include, but are not limited to, fatigue, memory impairment, anxiety, depression, weight gain or loss, emotional instability, difficulty concentrating, attention deficit, decreased libido, infertility, amenorrhea, decreased muscle mass, increased abdominal fat, hypotension, low heart rate, hair loss, anemia, constipation, cold intolerance, and dry skin.

[0328] 2. Neurodegenerative diseases and disorders The methods described herein may be used in the treatment of neurodegenerative diseases and disorders. The term “neurodegenerative disease” encompasses diseases and disorders associated with the progressive loss of structure or function of neurons, or the death of neurons. Neurodegenerative diseases and disorders include: Alzheimer’s disease (including symptoms associated with mild, moderate, or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic and ischemic injuries; ataxia and seizures (including for treatment and prevention, and for the prevention of seizures caused by schizoaffective disorder or drugs used to treat schizophrenia); benign amnesia; cerebral edema; cerebellar ataxia, including McLeod neuroacanocyte syndrome (MLS); closed head injury; coma; contusion injuries (e.g.) (e.g., spinal cord injury and head injury); dementia including multiple infarct dementia and senile dementia; impaired consciousness; Down syndrome; drug-induced or medication-induced Parkinson's disease (e.g., neuroleptic-induced acute akathisia, acute dystonia, parkinsonism, or tardive dyskinesia, neuroleptic-induced malignant syndrome, or medication-induced postural tremor); epilepsy; fragile X syndrome; Zildra-Tourette syndrome; head trauma; hearing loss and hearing impairment; Huntington's disease; Lennox syndrome; levodopa-induced Dyskinesia; intellectual disability; motor disorders including immobility and akinesia (rigidity) syndrome (including brainstem nerve calcification, corticobasal degeneration, multiple system atrophy, parkinsonism-ALS dementia complex, Parkinson's disease, post-encephalitis-Parkinsonian syndrome, and progressive supranuclear palsy); disorders associated with muscle spasms and muscle spasticity or weakness (chorea (e.g., benign hereditary chorea, drug-induced chorea, unilateral ballism, Huntington's disease, neuroacanthoptosis, Sydenham's chorea, and symptomatic chorea), dyskinesia (complex dyskinesia) tics (including simple tics and asymptomatic tics), myoclonus (including generalized myoclonus and focal syloclonus), tremors (such as resting tremor, postural tremor, and intention tremor), and dystonia (including truncal dystonia, dystorhinoloneous writer's cramp, hemiplegic dystonia, paroxysmal dystonia, and focal dystonia, e.g., blepharospasm, temporomandibular joint 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 neurotoxic disorders 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 neurotoxic disorders following cardiac arrest. Methods of treating or preventing neurodegenerative diseases also include treating or preventing the loss of neuronal function characteristic of neurodegenerative disorders.

[0329] 3. Mood disorders Furthermore, this specification also provides methods for treating mood disorders, such as clinical depression, postnatal depression or postpartum depression, perinatal depression, atypical depression, melancholic depression, psychotic major depression, catatonic depression, seasonal affective disorder, dysthymia, double depression, depressive personality disorder, relapsing short-term depression, mild depressive disorder, bipolar disorder 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 effect to subjects suffering from depression (e.g., moderate or severe depression). In some embodiments, the mood disorder is related to a disease or disorder described herein (e.g., neuroendocrine disorders and disorders, neurodegenerative diseases and disorders (e.g., epilepsy), movement disorders, tremors (e.g., Parkinson's disease), women's health disorders or conditions).

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

[0331] Perinatal depression refers to depression during pregnancy. Symptoms include irritability, tearfulness, restlessness, sleep disturbances, extreme fatigue (emotional and / or physical), changes in appetite, difficulty concentrating, increased anxiety and / or worry, feelings of isolation from the infant 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 affects women after childbirth. Symptoms may include grief, fatigue, changes in sleep and eating habits, decreased libido, episodes of tearfulness, anxiety, and irritability. In some embodiments, PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein). In some embodiments, PND is treatment-refractory depression (e.g., treatment-refractory depression as described herein).

[0333] In some embodiments, subjects with PND have also experienced depression or depressive symptoms during pregnancy. This depression is referred to herein as perinatal depression. In one embodiment, subjects who have experienced perinatal depression are at high risk of experiencing PND.

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

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

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

[0337] Catastrophic depression refers to major depressive disorder accompanied by motor behavioral disturbances and other symptoms. Individuals may be mutist and stupor, or exhibit akinesia or aimless or paranoid movements.

[0338] Seasonal affective disorder (SAD) is a type of seasonal depression in which individuals experience depressive episodes that follow a seasonal pattern, typically occurring in autumn or winter. Dysthymia refers to a condition associated with unipolar depression, characterized by the same physical and cognitive problems. It tends to be less severe and lasts for a long period (e.g., at least two years).

[0339] Double depression refers to a condition in which a significant depressed mood (dysthymia) lasts for at least two years, accompanied by a period of major depression.

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

[0341] Recurrent short-term depression (RBD) is a condition in which an individual experiences depressive episodes approximately once a month, each episode lasting for a short period of two weeks or less, typically less than two to three days.

[0342] Minor depressive disorder, or minor depression, is a type of depression characterized by the presence of at least two symptoms for two weeks.

[0343] Bipolar disorder, or manic-depressive disorder, is characterized by extreme mood swings, including periods of heightened emotion (mania or hypomania) and low mood (depression). During manic episodes, individuals may experience unusual euphoria, energy, or irritability in their emotions or behavior. Such individuals often make impulsive decisions with little regard for the consequences. They typically experience a decreased need for sleep. During depressive episodes, they may be tearful, avoid eye contact with others, and become pessimistic about life. The suicide risk for individuals with this disorder is high, over 6% over a 20-year period, with 30-40% engaging in self-harm. Bipolar disorder is often accompanied by other mental health problems, such as anxiety disorders and substance abuse disorders.

[0344] Depression caused by chronic illness refers to depression triggered by chronic conditions such as cancer, including chronic pain, chemotherapy, and chronic stress.

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

[0346] Postoperative depression refers to feelings of depression that persist after surgical procedures (for example, as a result of facing death). For example, this may include persistent feelings of sadness or emptiness, loss of pleasure or interest in hobbies and activities that were normally enjoyed, or persistent feelings of worthlessness or despair.

[0347] A mood disorder associated with a women's health condition or disorder means a mood disorder (e.g., depression) associated with (e.g., caused by) a women's health condition or disorder (e.g., as described herein).

[0348] Suicidal ideation and suicidal behavior refer to an individual's tendency to attempt suicide. Suicidal ideation relates to thoughts about suicide or an abnormal preoccupation with suicide. The range of suicidal ideation varies significantly, for example, from fleeting thoughts to widespread thoughts, detailed plans, role-playing, and incomplete attempts. Symptoms include talking about suicide, obtaining means to attempt suicide, withdrawing from social contact, being preoccupied with death, feeling trapped or desperate about a particular situation, increased alcohol or drug use, engaging in dangerous or self-destructive behavior, and saying goodbye to people as if never to see them again.

[0349] Symptoms of depression include persistent anxiety or sadness, helplessness, despair, pessimism, worthlessness, low energy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, difficulty moving, loss of interest in enjoyable activities or hobbies, difficulty concentrating, low self-esteem, lack of positive thinking or planning, hypersomnia, overeating, loss of appetite, insomnia, self-injury, suicidal thoughts, and suicide attempts. The presence, severity, frequency, and duration of symptoms may vary from case to case. The symptoms of depression and their alleviation can be confirmed by a physician or psychologist (e.g., by a mental health assessment).

[0350] In some embodiments, this method involves monitoring subjects using known depression rating scales, such as the Hamilton Depression-D Rating Scale (HAM-D), the Clinical Global Impression Improvement Scale (CGI), and the Montgomery-Asberg Depression Rating Scale (MADRS). In some embodiments, treatment effectiveness can be determined by the reduction in the subject's Hamilton Depression-D total score. The reduction in the HAM-D total score may occur within 4, 3, 2, or 1 day; or within 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, or 8 hours. Treatment effectiveness can be evaluated over a specific treatment period. For example, the therapeutic effect is measured from baseline with respect to the compounds described herein, e.g., 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), (X This can be determined by the decrease in the total HAM-D score after administration of compound I), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII) (for example, 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, for example, a mild major depressive disorder. In some embodiments, the subject has a moderate depressive disorder, for example, a moderate major depressive disorder. In some embodiments, the subject has a severe depressive disorder, for example, a severe major depressive disorder. In some embodiments, the subject has a very severe depressive disorder, for example, a very severe major depressive disorder. In some embodiments, the baseline HAM-D total score of the target compound (i.e., the compounds described herein, e.g., 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), The baseline HAM-D total score of the subject (before treatment with compounds (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)) is at least 24. In some embodiments, the baseline HAM-D total score of the subject is at least 18. In some embodiments, the baseline HAM-D total score of the subject is between 14 and 18, including both ends. In some embodiments, the baseline HAM-D total score for the subject is between 19 and 22 (including 19 and 22).In some embodiments, compounds described herein, for example, 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- The subject's total HAM-D score before treatment with the compounds 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 23 or higher. In some embodiments, the baseline score is at least 10, 15, or 20.In some embodiments, compounds described herein, for example, 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) The total HAM-D score of subjects after treatment with compounds (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 approximately 0-10 (e.g., less than 10; 0-10, 0-6, 0-4, 0-3, 0-2, or 1.8). In some embodiments, compounds described herein, for example, 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) The HAM-D total score after treatment with the following compounds is 10, 7, 5, or less than 3: (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 reduction in the HAM-D total score is approximately 20-30 (e.g., 22-28, 23-27, 24-27, 25-27, 26-27) from the baseline score to the compounds described herein, e.g., 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), This refers to a total HAM-D score of approximately 0-10 (e.g., less than 10; 0-10, 0-6, 0-4, 0-3, 0-2, or 1.8) after treatment with compounds (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 used to determine the compounds described herein, for example, 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), (I The reduction in the total HAM-D score after treatment with compounds 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 times.In some embodiments, the baseline HAM-D total score is used to determine the compounds described herein, for example, 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) The percentage reduction in the total HAM-D score after treatment with compounds (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 50% (e.g., 60%, 70%, 80%, or 90%).In some embodiments, the compounds described herein, for example, 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 The therapeutic effect, measured as a reduction in the HAM-D total score after treatment with compounds (e.g., 12, 24, 48 hours after administration; or 24, 48, 72, 96 hours or more; or 1 day, 2 days, 14 days or more) of (X), (XI), (II), (IIa), (IIb), (III), (IIIa), (IVa), (IVb), (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIaa), (VIab), (VII), (VIII), (IX), or (XII) (e.g., 12, 24, 48 hours after administration; or 24, 48, 72, 96 hours or more; or 1 day, 2 days, 14 days or more), is at least 10, 15, or 20 points.

[0352] In some embodiments, a method for treating depressive disorders, such as major depressive disorder, produces a therapeutic effect within 14, 10, 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours (e.g., by a decrease in the Hamilton Depression Rating Scale (HAM-D)). In some embodiments, a method for treating a depressive disorder, such as major depressive disorder, is a compound described herein, for example, 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 The treatment provides a therapeutic effect within 1 or 2 days of treatment with the compound (e.g., determined by a statistically significant reduction in the HAM-D total score), (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) (for example, determined by a statistically significant reduction in the HAM-D total score).In some embodiments, a method for treating a depressive disorder, such as major depressive disorder, is a compound described herein, for example, 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 3) Provide a therapeutic effect within 14 days of initiating treatment with the compounds (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) (determined, for example, by a statistically significant reduction in the HAM-D total score).In some embodiments, a method for treating a depressive disorder, such as major depressive disorder, is a compound described herein, for example, 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 3) Provide a therapeutic effect within 21 days of initiation of 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) (determined, for example, by a statistically significant reduction in the HAM-D total score).In some embodiments, a method for treating a depressive disorder, such as major depressive disorder, is a compound described herein, for example, 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 3) Provide a therapeutic effect within 28 days of initiation of 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) (determined, for example, by a statistically significant reduction in the HAM-D total score).In some embodiments, the therapeutic effect is achieved by compounds described herein, for example, 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), ( Treatment with compounds of (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) (for example, as described herein). 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 This is the reduction from baseline in the total HAM-D score after treatment with one of the following compounds once daily for 14 days: (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, compounds described herein, for example, 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 3) The subject's total HAM-D score prior to treatment with the following compounds is at least 24: (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, compounds described herein, for example, 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 3) The subject's total HAM-D score prior to treatment with the following compounds is at least 18: (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, compounds described herein, for example, 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), (I The HAM-D total score of subjects prior to treatment with compounds 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 14-18 (including 14 and 18). In some embodiments, the compounds described herein, for example, 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- The reduction in the total HAM-D score after treating the subject with one of the following compounds is at least 10: (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 compounds described herein, for example, 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- The reduction in the total HAM-D score after treating the subject with the compound 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 15 (e.g., at least 17). In some embodiments, compounds described herein, for example, 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), (I The HAM-D total score associated with treatment of a subject with compounds 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 less than or equal to a number in the range of 6 to 8.In some embodiments, compounds described herein, for example, 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 The HAM-D total score associated with treatment of the subject with compounds ), (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 7 or less.

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

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

[0355] The effectiveness of treatment for major depressive disorder can be determined by the reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) score, which varies by patient. For example, the MADRS score may decrease by 4, 3, 2, or within 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 (related to outwardly expressed sadness, verbally expressed sadness, internal tension, decreased sleep, decreased appetite, difficulty concentrating, retardation, lack of affect, pessimistic thoughts, and suicidal thoughts) that psychiatrists use to measure the severity of depressive episodes in patients with mood disorders.

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

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

[0358] 4. Anxiety Disorders This specification provides methods for treating anxiety disorders (e.g., generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, phobias, and post-traumatic stress disorder). Anxiety disorder is a comprehensive term encompassing several different forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic criteria identify a wide variety of anxiety disorders.

[0359] Generalized anxiety disorder (GPD) is a common chronic disorder characterized by persistent anxiety that is not focused on any single purpose or situation. Individuals with GPD experience nonspecific, persistent fears and worries, and tend to become overly concerned with trivial everyday matters. GPD is the most common anxiety disorder affecting older adults.

[0360] In panic disorder, patients suffer from short, intense episodes of fear and anxiety, often characterized by tremors, shaking, confusion, dizziness, nausea, and shortness of breath. Defined by APA as sudden onset of fear or discomfort that peaks in less than 10 minutes, such panic attacks can last for several 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 potential effects of the attack, persistent fear of future attacks, or marked behavioral changes associated with the attack). Therefore, individuals with panic disorder also experience symptoms beyond specific panic episodes. Often, when a panic sufferer notices normal changes in heart rate, they may believe there is something wrong with their heart or that another panic attack is imminent. In some cases, heightened awareness of bodily functions (hypervigilance) occurs during a panic attack, and the perceived physiological changes are interpreted as a potentially life-threatening illness (i.e., extreme hypochondria).

[0361] Obsessive-compulsive disorder (OCD) is a type of anxiety disorder characterized primarily by recurrent obsessions (urgency, persistent, intrusive thoughts or images) and compulsions (the urge to perform specific actions or habitual behaviors). OCD thought patterns are sometimes likened to superstitions because they involve beliefs about causal relationships that do not actually exist. The process is often entirely illogical; for example, a person might engage in a compulsive behavior, such as walking in a specific pattern, to alleviate an obsession with impending harm. Furthermore, in many cases, the compulsion is completely inexplicable, simply an urge to complete a habitual behavior triggered by nervousness. A small number of OCD patients experience only obsessions without overt compulsions, and even fewer experience only compulsions.

[0362] The largest single category of anxiety disorders is phobias, which include all cases in which fear and anxiety are triggered by a specific stimulus or situation. Patients typically anticipate the horrific consequences that will result from encountering their object of fear (which can be anything from animals to places or bodily fluids).

[0363] Post-traumatic stress disorder, or PTSD, is an anxiety disorder resulting from a traumatic experience. Post-traumatic stress can arise from extreme situations, such as combat, rape, hostage situations, or even serious accidents. It can also result from prolonged (chronic) exposure to a significant stressor (for example, a soldier who can tolerate individual combat but becomes unable to cope with continued fighting). Common symptoms include flashbacks, avoidance behaviors, and depression.

[0364] 5. Women's Health Disorders This specification provides methods for treating conditions or disorders related to women's health. These conditions or disorders include, but are not limited to, gynecological health conditions and disorders (e.g., premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD)), pregnancy problems (e.g., miscarriage, abortion), infertility and related disorders (e.g., polycystic ovary syndrome (PCOS)), other disorders and conditions, and problems related to women's overall health and wellness (e.g., amenorrhea).

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

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

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

[0368] Pregnancy-related issues include prenatal and prenatal care, abortion (miscarriage and stillbirth), premature birth and early delivery, sudden infant death syndrome (SIDS), breastfeeding, and congenital abnormalities.

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

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

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

[0372] Polycystic ovary syndrome (PCOS) refers to an endocrine disorder in women of reproductive age. PCOS is a set of symptoms resulting from elevated levels of male hormones in women. In most women with PCOS, numerous small cysts proliferate in the ovaries. Symptoms of PCOS include irregular menstruation, amenorrhea, heavy menstruation, excessive body and facial hair growth, acne, pelvic pain, difficulty conceiving, and thickened, dark, velvety skin patches. 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 related to women's overall health and wellness include violence against women, women with disabilities and their specific challenges, osteoporosis and bone health, and amenorrhea.

[0375] Atrial fibrillation refers to the 12 months following a woman's last menstrual period and is characterized by the cessation of the menstrual cycle. Atrial fibrillation typically occurs in women in their 40s or 50s. Physical (such as facial flushing) and emotional symptoms of atrial fibrillation may include sleep disturbance, decreased energy, and anxiety or feelings of sadness or loss. Atrial fibrillation includes spontaneous menopause and surgical menopause, with surgical menopause being a type of atrial fibrillation induced by events such as surgery (e.g., hysterectomy, oophorectomy, cancer). This can be induced when the ovaries are severely damaged by radiation, chemotherapy, or other drug therapies.

[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 Compounds of (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 pharmaceutically acceptable salts thereof, or pharmaceutically acceptable excipients thereof, can be used in the manner described herein, for example, in the treatment of the disorders described herein, such as epilepsy, status epilepticus, or seizures.

[0377] Epilepsy is a brain disorder characterized by recurrent seizures over time. Types of epilepsy may include, but are not limited to, generalized epilepsy, such as childhood absence epilepsy, juvenile myoclonic epilepsy, epilepsy with grand mal seizures during wakefulness, West syndrome, Lennox-Gastaut syndrome, and 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 for the treatment or prevention of 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 sudden neuronal damage caused by initial damage (e.g., status epilepticus).

[0379] 8. Status epilepticus (SE) Status epilepticus (SE) may include, for example, convulsive status epilepticus, such as early status epilepticus, confirmed status epilepticus, refractory status epilepticus, and extremely refractory status epilepticus; non-convulsive status epilepticus, such as generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptic-like discharges; and periodic unilateral epileptic discharges. Convulsive status epilepticus is characterized by the presence of convulsive status epilepticus seizures and may include early status epilepticus, confirmed status epilepticus, refractory status epilepticus, and extremely refractory status epilepticus. Early status epilepticus is treated with primary therapy. Confirmed status epilepticus is characterized by status epilepticus seizures that persist despite treatment with primary therapy and to which secondary therapy is administered. Refractory status epilepticus is characterized by epileptic seizures that persist despite primary and secondary therapy and require systemic administration of general anesthetics. Extremely refractory status epilepticus is characterized by epileptic seizures that persist despite primary therapy, secondary therapy, and treatment with general anesthetics for 24 hours or more.

[0380] Nonconvulsive status epilepticus may include, for example, focal nonconvulsive status epilepticus, such as complex partial nonconvulsive status epilepticus, simple partial nonconvulsive status epilepticus, or latent nonconvulsive status epilepticus; or generalized nonconvulsive status epilepticus, such as delayed absence nonconvulsive status epilepticus, atypical absence nonconvulsive status epilepticus, or typical absence nonconvulsive 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 Compounds of (IVa-I), (V), (Va), (Vb), (Vaa), (Vab), (VI), (VIa), (VIb), (VIaa), (VIab), (VII), (VIII), (IX), or (XII), or pharmaceutically acceptable salts thereof, may also be administered as prophylactic agents before the onset of seizures to subjects with CNS disorders, e.g., traumatic brain injury; status epilepticus, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, extremely refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptic-like discharges; and periodic unilateral epileptic-like discharges.

[0382] 9. Seizures A seizure is a physical finding or behavioral change that follows 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 ...

Claims

1. A compound selected from the following: Table 3-1 Table 3-2 Table 3-3 Table 3-4 Table 3-5 Table 3-6 Table 3-7 or a pharmaceutically acceptable salt thereof.

2. The compound or pharmaceutically acceptable salt is a compound selected from the following: Table 4-1 Table 4-2 Table 4-3 Table 4-4 Table 4-5 Table 4-6 Table 4-7 Table 4-8 The compound or pharmaceutically acceptable salt thereof according to claim 1.

3. The compound or pharmaceutically acceptable salt according to claim 1 or claim 2, wherein the compound or pharmaceutically acceptable salt is a compound.

4. The compound or pharmaceutically acceptable salt according to claim 1 or claim 2, wherein the compound or pharmaceutically acceptable salt is a pharmaceutically acceptable salt.

5. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt according to any one of claims 1 to 4, and a pharmaceutically acceptable excipient.

6. A composition for treating CNS-related disorders in subjects requiring treatment of CNS-related disorders, comprising a compound or pharmaceutically acceptable salt described in any one of claims 1 to 4, or the pharmaceutical composition described in claim 5.

7. The composition according to claim 6, wherein the CNS-related disorder is a sleep disorder, mood disorder, schizophrenia spectrum disorder, convulsive disorder, memory and / or cognitive impairment, motor disorder, personality disorder, autism spectrum disorder, pain, traumatic brain injury, vascular disease, substance abuse disorder and / or withdrawal syndrome, tinnitus, or status epilepticus.

8. The composition according to claim 6, wherein the CNS-related disorder is depression.

9. The composition according to claim 8, wherein the depression is postpartum depression.

10. The composition according to claim 8, wherein the depression is major depressive disorder.

11. The composition according to claim 10, wherein the major depressive disorder is a moderate major depressive disorder.

12. The composition according to claim 10, wherein the major depressive disorder is severe major depressive disorder.

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