A neurostimulant steroid with a cyclic group substituted at position 10, for use in the treatment of CNS disorders.

Abstract

To provide methods of treating diseases.SOLUTION: Provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where n, R19, R5, R3a, R6a, R6b, R1, R2a, R2b, R4a, R4b, R7a, R7b, R11a, R11b, R12a, R12b, R17b, R15a, R15b, R16a and R16b are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I) and methods of using the compounds, e.g., in treatment of CNS-related disorders.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Patent Application No. 62 / 745,109, filed October 12, 2018, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Background of the Invention Brain excitability is defined as a continuum of animal arousal levels, ranging from coma to convulsions, and is controlled by various neurotransmitters. Generally, neurotransmitters are responsible for controlling the conductivity of ions across the nerve unit membrane. At rest, the nerve unit 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 controlled by the conductivity of ions (K) across the nerve semipermeable membrane. + na + Cl - This is the result of the equilibrium of (organic anions). Neurotransmitters are stored in presynaptic vesicles and are released in response to nerve action potentials. When released into the synaptic cleft, a potential change occurs from -70mV to -50mV. This action is mediated by postsynaptic nicotinic receptors stimulated by acetylcholine, and Na + It increases membrane permeability to ions. The decrease 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). Since up to 40% of nerve cells in the brain utilize GABA as a neurotransmitter, GABA has a significant impact on overall brain excitability. GABA controls the excitability of individual nerve cells by regulating the conductivity of chloride ions across the nerve unit membrane. GABA interacts with its recognition site on GRCs to promote the flow of chloride ions toward the electrochemical gradient of GRCs into the cell. This intracellular increase in anion levels causes hyperpolarization of the membrane potential difference, reducing the nerve cell's sensitivity to excitatory input, i.e., leading to decreased nerve cell excitability. In other words, the higher the concentration of chloride ions in nerve cells, the lower the brain excitability and arousal levels.

[0004] The mediation of anxiety, seizure activity, and sedation by GRCs is well documented. Therefore, GABA and drugs that act like GABA or enhance the action of GABA (e.g., therapeutically beneficial barbiturates and benzodiazepines (BZs), e.g., Valium®) produce their therapeutically beneficial effects by interacting with specific regulatory sites on GRCs. Recent accumulated evidence indicates that, in addition to benzodiazepine and barbiturate binding sites, GRCs contain separate sites for neurostimulant steroids. See, for example, Lan, NC et al., Neurochem. Res. (1991) 16:347-356.

[0005] Neurostimulant steroids can be endogenously produced. The most potent endogenous neurostimulant 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)). There is a need for novel and improved neurostimulant steroids that act as modulators for 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, MDet al., Science 232:1004-1007(1986) [Non-Patent Document 3] Harrison,NLet al.,J Pharmacol.Exp.Ther.241:346-353 (1987) [Overview of the project] [Means for solving the problem]

[0007] This specification provides compounds designed to act, for example, as GABA modulators. In some embodiments, such compounds are conceived to be useful as therapeutic agents for treating CNS-related disorders. [Modes for carrying out the invention]

[0008] In one embodiment, the compound of formula (I) is used herein: [ka] (I) or provide a pharmaceutically acceptable salt thereof.

[0009] In some embodiments, the compound of formula (I) is the compound of formula (Ia): [ka] (Ia) or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments, the compound of formula (I) is the compound of formula (Ib): [ka] (Ib) or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments, the compound of formula (I) is the compound of formula (Ic): [ka] (I C) or a pharmaceutically acceptable salt thereof.

[0012] In some embodiments, the compound of formula (I) is the compound of formula (Id): [ka] (Id) or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, the compound of formula (I) is the compound of formula (Ie): [ka] (Ie) or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, the compound of formula (I) is the compound of formula (If): [ka] (If) or a pharmaceutically acceptable salt thereof.

[0015] In some embodiments, the compound of formula (I) is the compound of formula (Ig): [ka] (Ig) or a pharmaceutically acceptable salt thereof.

[0016] In some embodiments, the compound of formula (I) is the compound of formula (Ih): [ka] (Ih) or a pharmaceutically acceptable salt thereof.

[0017] In one embodiment, this specification provides a pharmaceutical composition comprising a compound described herein (for example, a compound of formula (I)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive. In certain embodiments, the compound of the present invention is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the compound of the present invention is provided in a therapeutically effective amount. In certain embodiments, the compound of the present invention is provided in a preventively effective amount.

[0018] In one embodiment, this specification provides pharmaceutically acceptable salts of compounds described herein (for example, compounds of formula (I)).

[0019] 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 over a long period. In certain embodiments, the compound is administered continuously, for example, by continuous intravenous infusion.

[0020] The compounds of the present invention as described herein, in certain embodiments, are, for example, GABA A It acts as a GABA modulator, either positively or negatively affecting the receptor. A As regulators of central nervous system (CNS) excitability mediated by their ability to modulate receptors, such compounds are predicted to possess CNS activity.

[0021] In one embodiment, this specification describes a method for treating a CNS-related disorder in a subject requiring treatment for a CNS-related disorder, comprising administering to the subject an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof.

[0022] In some embodiments, the CNS-related disorders include sleep disorders, mood disorders, schizophrenia spectrum disorders, seizure 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.

[0023] 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 moderate major depressive disorder. In some embodiments, the major depressive disorder is severe major depressive disorder.

[0024] In some embodiments, the above-mentioned compounds are selected from the group consisting of compounds identified in Table 1 of this specification.

[0025] Detailed Description of Certain Embodiments of the Invention As described generally herein, the present invention provides compounds designed to act as, for example, GABA A receptor modulators. In certain embodiments, such compounds are contemplated to be useful as therapeutic agents for treating CNS-related disorders (e.g., disorders as described herein, e.g., depression, e.g., postpartum depression or major depressive disorder).

[0026] Definitions Chemical Definitions The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, the inside cover of the Handbook of Chemistry and Physics, 75 th Ed., and specific functional groups are generally defined as described therein. In addition, principles of organic chemistry, and more particularly of specific functional group moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987.

[0027] Isomers, for example, stereoisomers, can be isolated from a mixture by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. For example, Jacques et al., Enantiomers, Racemates and See 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 includes the compounds described herein as individual isomers substantially free from other isomers, and, by other means, as mixtures of various isomers.

[0028] "Stereoisomers": Compounds that have the same molecular formula but differ in the properties, bonding order, or spatial arrangement of their atoms are also called "isomers." Isomers that differ in the spatial arrangement of their atoms are called "stereoisomers." Stereoiomers that are not mirror images of each other are called "diastereoisomers," while those that are mirror images that cannot be superimposed on each other are called "enantiomers." For example, if a compound has a chiral center, it is bonded to four different groups, and a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their chiral center, described by Cahn and Prelog's R- and S-ordering rules, or by a method of rotating the plane of polarization of the molecule, and specified as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0029] As used herein, a pure enantiomer compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., enantiomeric excess). In other words, the "S" isomer of the compound is substantially free of the "R" isomer and is therefore enantiomeric excess of the "R" isomer. The terms “enantiomerically pure” or “pure enantiomer” indicate 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, more than 99.8% by weight, or more than 99.9% by weight of enantiomers. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0030] 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 / central / carbon compound may, for example, contain about 90% additives and about 10% enantiomerically pure R compound. In certain embodiments, the enantiomerically pure R compound in such a composition may, for example, consist of at least about 95% by weight of the R compound and at most 5% by weight of the S compound, relative to the total weight of the compound. For example, a pharmaceutical composition containing an enantiomerically pure S compound may, for example, contain about 90% additives and about 10% enantiomerically pure S compound. In certain embodiments, the enantiomerically pure S compound in such a composition may, for example, consist of at least about 95% by weight of the S compound and at most 5% by weight of the R compound, relative to the total weight of the compound. In certain embodiments, the active ingredient may be formulated with little to no additives or carriers.

[0031] As used herein, the term “diathreomer purity” refers to the amount of the compound having the stated absolute stereochemistry, expressed as a percentage of the total amount of the stated compound and its diastereomers. The term “diastereomerically pure” means 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, more than 99.8% by weight, or more than 99.9% by weight of diastereomers. Methods for determining diastereomer and enantiomer purity are well known in the art. The diastereomer purity can be determined by any analytical method capable of quantitatively distinguishing between the compound and its diastereomer, such as high-performance liquid chromatography (HPLC).

[0032] 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, "one analogue" means one analogue or more than one analogue.

[0033] When a range of values ​​is listed, it is intended to include each value and the sub-ranges 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.

[0034] The following terms are intended to have the meanings represented therein and are useful in understanding the intended scope of this specification and the invention.

[0035] "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 herein as "lower alkyl"). In some embodiments, the alkyl has 1 to 5 carbon atoms ("C"). 1~5 ("alkyl"). 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 1~6 Examples 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), n-octyl (C8), etc. Unless otherwise specified, each example of an alkyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or with one or more substituents; for example, substituted with 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 alkyl. Common abbreviations for alkyl include Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2).

[0036] "Alkylene" refers to an alkyl group that has two hydrogen atoms removed to provide a divalent radical and may be substituted or unsubstituted. 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, which are 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-). Where a range or number of carbon atoms is indicated for a particular alkylene group, that range or number is understood to refer to a range or number of carbon atoms in a straight-chain carbon divalent chain. Alkylene groups may be substituted with one or more substituents as described herein, or they may be unsubstituted.

[0037] "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 bonds. 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., in 2-butenyl) or terminal (e.g., in 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 Examples of alkenyl groups include the C group mentioned above. 2~4 Alkenyl groups, and furthermore, pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Additional examples of alkenyls include heptenyl (C7), octenyl (C8), octatrienyl (C8), etc. Unless otherwise specified, each example of an alkenyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkenyl"). In certain embodiments, the above 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.

[0038] "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 does not contain any double bonds. In some embodiments, the alkynyl group has 2 to 10 carbon atoms ("C"). 2~10 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 9 carbon atoms ("C"). 2~9 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C"). 2~8 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 7 carbon atoms ("C"). 2~7 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C"). 2~6 ("Alkynyl"). 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 located internally (e.g., in 2-butynyl) or terminally (e.g., in 1-butynyl). C 2~4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), and 2-butynyl (C4). 2~6 Examples of alkenyl groups include the C group mentioned above. 2~4 This includes alkynyl groups, as well as pentinyl (C5) and hexynyl (C6). Additional examples of alkynyl groups include heptynyl (C7) and octinyl (C8). Unless otherwise specified, each example of an alkynyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents, for example, 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.

[0039] As used herein, the term “heteroalkyl” means an alkyl group as defined herein, further comprising one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, wherein the one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain, and / or the one or more heteroatoms are inserted between carbon atoms and the parent molecule, i.e., between bonding points. 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 consists of 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms ("hetero C"). 1~9 A saturated group having an alkyl group. 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 ("Alkyl"). In some embodiments, a heteroalkyl group is a saturated group having one carbon atom and one heteroatom ("heteroC1 alkyl"). In some embodiments, a 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 example of a heteroalkyl group is 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.

[0040] "Aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms that contribute 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 The aryl group has, for example, naphthyl (e.g., 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 an aryl ring, as defined above, is fused with one or more carbocyrillic or heterocyclyl groups on the aryl ring, in which case the number of carbon atoms continues to specify the number of carbon atoms in the aryl ring system. Typical aryl group This includes, but is not limited to, groups derived from acetantrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluorantene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indan, indene, naphthalene, octacene, octafen, octalen, ovalen, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiaden, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. In particular, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each example of an aryl group is independently optionally substituted, i.e., either unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, the aryl group is an unsubstituted C 6~14 It is aryl. In certain embodiments, the above aryl group is substituted C 6~14 It is Ariel.

[0041] In certain embodiments, the aryl group is substituted with one or more groups selected from halo, C1-C8 alkyl, C1-C8 haloalkyl, cyano, hydroxy, C1-C8 alkoxy, and amino groups.

[0042] Typical examples of substitution aryls include the following: [ka] [In the formula, R 56 and R 57One of which may be hydrogen and R 56 and R 57 At least one of each is independently C1-C8 alkyl, C1-C8 haloalkyl, 4-10 member heterocyclyl, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 、NR 58 SOR 59 、NR 58 SO2R 59 、COO alkyl, COO aryl, CONR 58 R 59 、CONR 58 OR 59 、NR 58 R 59 、SO2NR 58 R 59 、S-alkyl, SO alkyl, SO2 alkyl, S aryl, SO aryl, SO2 aryl; or R 56 and R 57 may together form a cyclic ring (saturated or unsaturated) of 5-8 atoms containing one or more heteroatoms optionally selected from the group of N, O, or S. R 60 and R 61 are independently hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, C3-C 10 cycloalkyl, 4-10 member heterocyclyl, C6-C 10 aryl, substituted C6-C 10 aryl, 5-10 member heteroaryl, or substituted 5-10 member heteroaryl].

[0043] "Fused aryl" refers to aryl in which two of its ring carbons are common with a second aryl or heteroaryl ring, or a carbocyclic or heterocyclic ring.

[0044] A "heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in the cyclic arrangement) having a ring carbon atom and 1-4 ring heteroatoms, each heteroatom independently contributing to an aromatic ring system selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the bond sites are, to the extent permitted by the valence, connected to the carbon atom. or it may be a nitrogen atom. A heteroaryl bicyclic ring system may contain one or more heteroatoms in one or both rings. "Hyperaryl" includes ring systems in which a heteroaryl ring as defined above is fused with one or more carbocyclyl or heterocyclyl groups whose bonding site is on the heteroaryl ring, in which case the ring member number continues to specify the number of ring members in that heteroaryl ring system. "Hyperaryl" also includes ring systems in which a heteroaryl ring as defined above is fused with one or more aryl groups whose bonding site is on either an aryl or heteroaryl ring, in which case the ring member number specifies the number of ring members in that fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the bonding site may be on either ring, i.e., on the ring containing a heteroatom (e.g., 2-indolyl) or on the ring not containing a heteroatom (e.g., 5-indolyl).

[0045] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, each heteroatom independently provided in an aromatic ring system 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, each heteroatom independently provided in an aromatic ring system selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, each heteroatom independently provided in an aromatic ring system selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the above 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the above 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each example of the 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 C5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted C5-14 membered heteroaryl.

[0046] Exemplary five-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary five-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary five-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary five-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary six-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary six-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary six-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetradinyl, respectively. Exemplary seven-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolidinyl, and prinyl. Exemplary 6,6-bicyclic Heteroaryl groups include, but are not limited to, naphthilidinyl, pteridinyl, quinolinyl, isoquinolinyl, cinolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0047] Typical examples of heteroaryls include the following: [ka] This includes, where each Z is a carbonyl, N, or NR. 65Selected from O and S; and R 65 These are independently hydrogen, C1-C8 alkyl, and C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 They are aryl and 5- to 10-membered heteroaryl groups.

[0048] A "carbocyrill" or "carbocyclic" is a non-aromatic ring system containing 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 consists of 3 to 6 ring carbon atoms ("C"). 3~6 It has a carbocyclyl group. In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C"). 3~6 It has a carbocyclyl group. In some embodiments, the carbocyclyl group has 5 to 10 ring carbon atoms ("C"). 5~10 It contains "carbocykrill". Exemplary C 3~6 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). Exemplary C 3~8 The carbocyclyl group is not limited to the above C 3~6 Carbocyclyl groups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), etc. Exemplary C 3~10 The carbocyclyl group is not limited to the above C 3~8 Carbocyclyl group, and furthermore, cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C9) 10 ), spiro[4.5]decanil(C 10 ) and others are included. As illustrated by the above examples, in certain embodiments, the carbocyrill group is either monocyclic ("monocyclic carbocyrill") or contains condensed, cross-linked, or spirocyclic systems such as bicyclic carbocyrills ("bicyclic carbocyrill"), and may be saturated or partially unsaturated. "Carbocyclyl" also includes cyclic systems in which the carbocyrill ring as defined above is condensed with one or more aryl or heteroaryl groups on the carbocyrill ring, in which case, The carbon number continues to specify the number of carbon atoms in the carbocyclic ring structure. Unless otherwise specified, each example of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, the above carbocyclyl group is unsubstituted C 3~10 It is a carbocyclyl. In certain embodiments, the above carbocyclyl group is a substituted C 3~10 It is carbocyclyl.

[0049] In some embodiments, "carbocyrill" is a monocyclic saturated carbocyrill 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). 3~6Examples of cycloalkyl groups include the C mentioned above. 5~6 This includes cycloalkyl groups, as well as cyclopropyl (C3) and cyclobutyl (C4). 3~8 Examples of cycloalkyl groups include the C mentioned above. 3~6 This includes cycloalkyl groups, and furthermore, cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each example of a cycloalkyl group is independently either unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, the above cycloalkyl groups are 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.

[0050] A "heterocyclyl" or "heterocyclic" radical refers to a 3- to 10-membered non-aromatic ring system having a ring carbon atom and 1 to 4 ring heteroatoms 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 the valence allows. Heterocyclyl groups can be monocyclic ("monocyclic heterocyclyl") or condensed, bridged, or spirocyclic structures such as bicyclic systems ("bicyclic cyclocyclyl"), and may be saturated or partially unsaturated. A heterocyclyl bicyclic ring 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 carbocykyl groups at a bonding site either on a carbocykyl ring or on 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 on the heterocyclyl ring, in which case the number of ring members continues to specify the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each example 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.

[0051] 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 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 independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, the heterocyclyl group is a ring carbon atom and 1-4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur It is a 5-6 member non-aromatic ring system having a nitrogen atom ("5-6 member heterocyclil"). In some embodiments, the 5-6 member heterocyclil has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 member heterocyclil has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 member heterocyclil has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0052] Exemplary three-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azildinyl, oxyranyl, and thiorenyl. Exemplary four-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary five-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary five-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranil, disulfuranil, and oxazolidine-2-one. Exemplary five-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary six-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranil, dihydropyridinyl, and thianyl. Exemplary six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinil, dithianyl, and dioxanil. Exemplary six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinyl. Exemplary seven-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary eight-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azokanyl, oxecanyl, and thiokanyl. Examples of five-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic rings) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, and benzoxazolinonyl. Examples of six-membered heterocyclyl groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocyclic rings) include, but are not limited to, tetrahydroquinolinyl and tetrahydroisoquinolinyl.

[0053] 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, such as N-methylpiperazine. Specific examples include azetidine, piperidone, and piperazone.

[0054] When "hetero" is used to describe a compound or a group present on a compound, it means that one or more carbon atoms in the compound or group are replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero can be applied to any of the above hydrocarbyl groups having 1 to 5, in particular 1 to 3, heteroatoms, for example, alkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g., heteroaryl, cycloalkenyl, e.g., cycloheteralkenyl.

[0055] "Acyl" is a radical-C(O)R 20 This refers to R 20 This includes hydrogen, substituted or unsubstituted alkyls as defined herein, substituted or unsubstituted alkenyls, substituted or unsubstituted alkynyls, substituted or unsubstituted carbocyclyls, and substituted or unsubstituted It is a heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. "Alkanoyl" is an acyl group, where R 20 These are groups other than hydrogen. Representative acyl groups include, but are not limited to, 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 (4- to 10-membered heterocyclines) are included, where t is an integer from 0 to 4. In a particular embodiment, R 21 C1-C8 alkyl groups substituted with halo or hydroxyl; or unsubstituted C1-C4 alkyl groups, halo, unsubstituted C1-C4 alkoxy groups, unsubstituted C1-C4 haloalkyl groups, unsubstituted C1-C4 hydroxyalkyl groups, or C3-C8 alkyl groups substituted with unsubstituted C1-C4 haloalkoxy groups or hydroxyl groups, respectively. 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 These are aryl, arylalkyl, 5-10 membered heteroaryl, or heteroarylalkyl.

[0056] "alkoxy" is a base-OR 29 This refers to 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.

[0057] In a particular embodiment, R 29 is amino, substituted amino, C6~C 10 Aryl, aryloxy, carboxyl, cyano, C3~C 10The group consists of one or more substituents selected from the group 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-, for example, a group having 1-5 substituents, particularly 1-3 substituents, especially 1 substituent. Exemplary "substituted alkoxy" groups include, but are not limited to, -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 The group includes (4-10 membered heterocyclyl), where t is an integer from 0 to 4, and any existing aryl, heteroaryl, cycloalkyl, or heterocyclyl group itself may 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.

[0058] "Amino" refers to the radical -NH2.

[0059] The "oxo group" refers to -C(=O)-.

[0060] "Substituting amino" is defined by the formula -N(R 38 ) refers to the amino group of 2, where R 38 This 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, a substituted or unsubstituted heteroaryl, or an amino protecting group. Here, R 38At least one of them is not hydrogen. In a particular embodiment, each R 38 These are independently hydrogen, C1-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, and C6-C 10 Aryl, 5-10 member heteroaryl, 4-10 member heterocyclyl, or C3-C 10 Cycloalkyl; or C1-C8 alkyl substituted with halo or hydroxyl; C3-C8 alkenyl substituted with halo or hydroxyl; C3-C8 alkynyl substituted with halo or hydroxyl, or -(CH2) t (C6~C 10 Aryl), -(CH2) t (5-10 member heteroaryl), -(CH2) t (C3~C 10 Cycloalkyl, or -(CH2) t (4-10 membered heterocyclyl) (where t is an integer from 0 to 8) are selected, and these are each substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; or both R 38 The groups come together to form an alkylene group.

[0061] Examples of "substituted amino" groups include, but are not limited to, -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) t (4-10 member heterocyclines) are included, where t is an integer from 0 to 4, e.g., 1 or 2, and each R 39'' independently represents H or C1-C8 alkyl; and any alkyl group present may be substituted with a halo, substituted or unsubstituted amino, or hydroxyl; and any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present may 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 hydroxyl. To avoid ambiguity, the term "substituted amino" includes the groups defined below: alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino. Substituted aminos include both monosubstituted and disubstituted amino groups.

[0062] "Carboxylate" refers to the radical -C(O)OH.

[0063] "Cyano" refers to the radical-CN.

[0064] "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.

[0065] "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.

[0066] "Hydroxy" refers to the radical -OH.

[0067] "Nitro" refers to the radical NO2.

[0068] "Thioketo" refers to the group = S.

[0069] Alkyl, alkenyl, alkynyl, carbocykyl, and he as defined herein. Telocyclyl, aryl, and heteroaryl groups are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl groups). Generally, whether preceded by the term "optionally," the term "substituted" means that at least one hydrogen atom on the group (e.g., a carbon or nitrogen atom) is replaced by a substituent that results in a substituted and stable compound, such as a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, or other reactions. Unless otherwise indicated, a "substituted" group has substituents at one or more substituted positions on the group, and when more than one position in any given structure is substituted, the substituents are either the same or different at each position. The term "substituted" is intended to include substitution by any of the permissible substituents of an organic compound, any substituent described herein that results in the formation of a stable compound. The present invention intends all such combinations to arrive at a stable compound. For the purposes of the present invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety.

[0070] Exemplary carbon atom substituents include, but are not limited to, halogens, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb -SH, -SR aa -SSRcc 、-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)2Raa -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 The compound includes aryls and 5-14 member heteroaryls, where each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 Rs. 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 It is replaced by the base; R aa Each example is independent, C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10Alkenil, 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 combine to form a 3-14 member heterocycline or a 5-14 member heteroaryl. A ring is formed, in which each alkyl, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd It is substituted with the base; R bb Each example is independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa -C(=O)N(R cc )2, -CO2R aa , -SO2R aa -C(=NR cc )OR aa -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc -SOR aa -C(=S)N(R cc )2, -C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 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 bbThe groups combine to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R groups. dd It is substituted with the base; R cc Each example is independent of hydrogen, 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 cc The groups combine to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R groups. dd It is substituted with the base; R dd Each example 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(=NRff )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 Alkenil, C 2~6 Alkinyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 Selected from aryls and 5-10 membered heteroaryls, where each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. gg Substituted by or two geminal R dd Substituents often come together to form either =O or =S; R ee Each example is independent, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6Alkenil, C 2~6 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 It is substituted with the base; R ff Each example 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 membered heteroaryls, or two R ff The groups combine to form a 3-14 member heterocyclyl or 5-14 member heteroaryl ring. In this process, each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R groups. gg It is substituted with the base; and R gg Each of these examples is independent: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6 Alkyl, -ON(C 1~6 Alkyl)2,-N(C 1~6 Alkyl)2,-N(C 1~6 Alkyl)3 + X - , -NH(C 1~6 Alkyl)2 + X - -NH2(C 1~6 Alkyl) + X - , -NH3 + X - , -N(OC 1~6 Alkyl)(C 1~6 Alkyl), -N(OH)(C 1~6 Alkyl), -NH(OH), -SH, -SC 1~6 Alkyl, -SS(C1~6 Alkyl), -C(=O)(C 1~6 Alkyl), -CO2H, -CO2(C 1~6 Alkyl), -OC(=O)(C 1~6 Alkyl), -OCO2(C 1~6 Alkyl), -C(=O)NH2, -C(=O)N(C 1~6 Alkyl)2,-OC(=O)NH(C 1~6 Alkyl), -NHC(=O)(C 1~6 Alkyl), -N(C 1~6 Alkyl)C(=O)(C 1~6 Alkyl), -NHCO2(C 1~6 Alkyl), -NHC(=O)N(C 1~6 Alkyl)2,-NHC(=O)NH(C 1~6 Alkyl), -NHC(=O)NH2, -C(=NH)O(C 1~6 Alkyl), -OC(=NH)(C 1~6 Alkyl), -OC(=NH)OC 1~6 Alkyl, -C(=NH)N(C 1~6 Alkyl)2,-C(=NH)NH(C 1~6 Alkyl), -C(=NH)NH2, -OC(=NH)N(C 1~6 Alkyl)2,-OC(NH)NH(C 1~6 Alkyl), -OC(NH)NH2, -NHC(NH)N(C 1~6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1~6 Alkyl), -SO2N(C 1~6 Alkyl)2,-SO2NH(C 1~6 Alkyl), -SO2NH2, -SO2C 1~6 Alkyl, -SO2OC 1~6 Alkyl, -OSO2C 1~6 Alkyl, -SOC 1~6 Alkyl, -Si(C 1~6 Alkyl)3,-OSi(C 1~6 Alkyl)3,-C(=S)N(C 1~6 Alkyl)2, C(=S)NH(C 1~6 Alkyl), C(=S)NH2, -C(=O)S(C 1~6 Alkyl), -C(=S)SC 1~6Alkyl, -SC(=S)SC 1~6 Alkyl, -P(=O)2(C 1~6 Alkyl), -P(=O)(C 1~6 Alkyl)2, -OP(=O)(C 1~6 Alkyl)2, -OP(=O)(OC 1~6 Alkyl)2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 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 R gg The substituents may combine to form =O or =S; where X - It is a counterion.

[0071] A "counterion" or "anionic counterion" is a negatively charged electrochemical group that associates with a cationic quaternary amino group to maintain electronic neutrality. Exemplary counterions include halide ions (e.g., F - Cl - , Br - , I - ), NO3 - ClO4 - , OH - H2PO4 - HSO4 - This includes sulfonate ions (e.g., methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, 10-camphor sulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.) and carboxylate ions (e.g., acetic acid, ethaneic acid, propanoic acid, benzoic acid, glyceric acid, lactic acid, tartaric acid, glycolic acid, etc.).

[0072] These and other exemplary substituents are described in more 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 above-mentioned list of exemplary substituents.

[0073] 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 modulator compound) is, for example, GABA. A Receptor A It can be a gonist, a partial agonist, an antagonist, or a partial antagonist.

[0074] "Pharmacologically acceptable" means that it is approved or appropriable by a federal or state regulatory authority or an equivalent authority 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.

[0075] "Pharmacologically acceptable salts" refer to salts of the compounds of the present invention that are pharmaceutically acceptable and have 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 include (1) salts formed with inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or organic acids, e.g., 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, 4 - Acid addition salts formed with 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, muconic acid, etc.; or (2) salts produced when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or when it is coordinated to an organic base, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Salts further include, but are not limited to, 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, oxalate, etc. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counterion of an acidic functional group. Examples of such cations include sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium cations.For example, see Berge, et al., J. Pharm. Sci. (1977) 66(1):1-79.

[0076] The term “prodrug” is intended to encompass therapeutically inactive compounds that are converted into the therapeutically active agents of the present invention under physiological conditions. One method for constructing a prodrug is to design a selected moiety that, under physiological conditions, is hydrolyzed or cleaved at a targeted in vivo site of action to reveal a desired molecule, and then produces its therapeutic effect. In certain embodiments, the prodrug is converted by the activity of a target enzyme. In an alternative embodiment, the present invention provides a prodrug of a compound of formula (I) in which the cleavable moiety is located on a C3 hydroxyl group as illustrated in formula (I).

[0077] In some embodiments, the compound of formula (I) is a prodrug, in which the prodrug contains a cleavable portion on a C3 hydroxyl group as illustrated in formula (I). Exemplary hydroxyl-containing prodrugs include, for example, esters.

[0078] A "tautomer" refers to a compound whose structural equilibrium is interchangeable with a particular compound structure, and in which the displacement of hydrogen atoms and electrons changes. Therefore, two structures can be in equilibrium through the transfer of π electrons and one atom (usually H). For example, enols and ketones are tautomers. This is because they rapidly interconvert upon treatment with either an acid or a base. Another example of tautomerism is the aci and nitro forms of phenylnitromethane, which are also formed upon treatment with an acid or a base. Tautomeristic forms can be involved in achieving the optimal chemical reactivity and biological activity of the compound of interest.

[0079] The “subjects” to which the drug is intended to be administered include, but are not limited to, humans (i.e., males or females 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)) and / or non-human animals, such as mammals including primates (e.g., cynomolgus 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.

[0080] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also called a hydroxyl protecting group). Oxygen protecting groups include, but are not limited to, -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 included, where 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, TW Greene and PGMWuts, 3 rdThis includes details described in edition, John Wiley & Sons, 1999.

[0081] 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), methanesulfonate (mesylate), and tosylate (Ts).

[0082] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also called a thiol protecting group). Sulfur protecting groups include, but are not limited to, -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 included, where R aa , R bb , and R ccThe term is as defined herein. Sulfur protecting groups are well known in the art and are incorporated herein by reference in Protecting Groups in Organic Synthesis, TW Greene and PGMWuts, 3 rd This includes details described in edition, John Wiley & Sons, 1999.

[0083] In certain embodiments, the substituent present on the nitrogen atom is an amino protecting group (also called a nitrogen protecting group). Amino protecting groups include, but are not limited to, -OH and -OR groups. 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 It contains aryl and 5-14 membered heteroaryl groups, where each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd Substituted with R aa , R bb , R cc and R ddThe 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, TW Greene and PGMWuts, 3 rd This includes details described in edition, John Wiley & Sons, 1999.

[0084] Examples of amino protecting groups include, but are not limited to, amide groups (e.g., -C(=O)R aa )(but not limited to, formamide and acetamide); carbamate group (e.g., -C(=O)OR aa )(but not limited to, 9-fluorenylmethylcarbamate (Fmoc), t-butylcarbamate (BOC), and benzylcarbamate (Cbz); sulfonamide group (e.g., -S(=O)2R) aa (This includes, but is not limited to, p-toluenesulfonamide (Ts), methanesulfonamide (Ms), and N-[2-(trimethylsilyl)ethoxy]methylamine (SEM)).

[0085] Diseases, disorders, and conditions are used interchangeably in this specification.

[0086] As used herein, and unless otherwise specified, the terms “to treat,” “to treat,” and “treatment” refer to actions that occur while a subject is suffering from a particular disease, disorder, or condition, which reduce the severity of the disease, disorder, or condition, or delay or slow the progression of the disease, disorder, or condition. In an alternative embodiment, the present invention is intended to involve the administration of the compounds of the present invention as a preventative measure before the onset of a designated disease, disorder, or condition.

[0087] Generally, the “effective dose” of a compound refers to an amount sufficient to induce a desired biophysical response, for example, a CNS-related disease, or sufficient to induce anesthesia or sedation. As will be understood by those skilled in the art, the effective dose of the compound of the present invention may vary depending on the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and factors such as the age, weight, health, and condition of the subject. The effective dose encompasses therapeutic and prophylactic treatments.

[0088] As used herein, and unless otherwise specified, “therapeutic dose” of a compound means an amount sufficient to provide a therapeutic effect in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. The therapeutic dose of a compound means the amount of the agent alone or in combination with other agents that provide a therapeutic effect in the treatment of a disease, disorder, or condition. The term “therapeutic dose” may include an amount that improves overall treatment, reduces or avoids the cause of symptoms or disease or condition, or enhances the therapeutic effect of another agent.

[0089] As used herein, and unless otherwise specified, the “preventive dose” of a compound is an amount sufficient to prevent or prevent the recurrence of a disease, disorder, or condition, or one or more symptoms associated with that disease, disorder, or condition. The preventive dose of a compound means the amount of the drug alone or in combination with other agents that provide a preventive benefit in the prevention of the disease, disorder, or condition. The term “preventive dose” may include an amount that improves overall prevention or enhances the preventive efficacy of another preventive agent.

[0090] compound It should be acknowledged that the formulas described herein may refer to specific carbon atoms, such as C17, C3, C19, etc. These references are based on the position of the carbon atoms according to the steroid nomenclature known and used in the 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.

[0091] In one embodiment, the compound of formula (I) is used herein. [ka] (I) or to provide a pharmaceutically acceptable salt thereof. [In the formula, [ka] R represents a single bond or a double bond, except when a double bond is present. 6a or R 6b One of them is missing; R 1 This includes hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -N(R A1 )2, -SR A1 -C(=O)R A1 , -C(=O)OR A1 -C(=O)SR A1 -C(=O)N(R A1 )2, -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)N(R A1 )2, -OC(=O)SR A1 -OS(=O)2R A1 -OS(=O)2OR A1 -OS(=O)2N(R A1 )2, -N(R A1 )C(=O)R A1 , -N(R A1 )C(=NR A1 )R A1 , -N(R A1 )C(=O)OR A1 , -N(R A1)C(=O)N(R A1 )2, -N(R A1 )C(=NR A1 ), N(R A1 )2, -N(R A1 )S(=O)2R A1 , -N(R A1 )S(=O)2OR A1 , -N(R A1 )S(=O)2N(R A1 )2, -SC(=O)R A1 -SC(=O)OR A1 -SC(=O)SR A1 -SC(=O)N(R A1 )2, -S(=O)2R A1 -S(=O)2OR A1 , or -S(=O)2N(R A1 )2, and here, R A1 Each example independently includes hydrogen, substituted or unsubstituted alkyl, substituted or non A substituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbocyclyl, or a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, selected from an oxygen protecting group if bonded to oxygen, a nitrogen protecting group if bonded to nitrogen, or a sulfur protecting group if bonded to sulfur, or two R A1 The group, together with the intervening atom, forms a substituted or unsubstituted heterocyclic ring; R 2a , R 2b , R 4a , R 4b , R 7a , R 7b , R 11a , R 11b , R 12a , R 12b or R 17b Each of these can independently be hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -N(R A1)2、-SR A1 、-C(=O)R A1 、-C(=O)OR A1 、-C(=O)SR A1 、-C(=O)N(R A1 )2、-OC(=O)R A1 、-OC(=O)OR A1 、-OC(=O)N(R A1 )2、-OC(=O)SR A1 、-OS(=O)2R A1 、-OS(=O)2OR A1 、-OS(=O)2N(R A1 )2、-N(R A1 )C(=O)R A1 、-N(R A1 )C(=NR A1 )R A1 、-N(R A1 )C(=O)OR A1 、-N(R A1 )C(=O)N(R A1 )2、-N(R A1 )C(=NR A1 )N(R A1 )2、-N(R A1 )S(=O)2R A1 、-N(R A1 )S(=O)2OR A1 、-N(R A1 )S(=O)2N(R A1 )2、-SC(=O)R A1 、-SC(=O)OR A1 、-SC(=O)SR A1 、-SC(=O)N(R A1 )2、-S(=O)2R A1 、-S(=O)2OR A1 、または-S(=O)2N(R A1 )2であり、ここで、R A1Each example is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group if bonded to oxygen, a nitrogen protecting group if bonded to nitrogen, a sulfur protecting group if bonded to sulfur, or two R A1 The group, together with the intervening atom, forms a substituted or unsubstituted heterocyclic ring; R 3a 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; R 5 is hydrogen or methyl; [ka] If R is a double bond, 5 It does not exist; R 6a and R 6b Each of these is hydrogen, halogen, -CN, -NO2, -OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; or R 6a and R 6b Together, they form an oxo (=O) group; R 15a , R 15b , R 16a and R 16b Each of these is independently hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR C3 , -N(R C3 )2, -SR C3 -C(=O)R C3, -C(=O)OR C3 -C(=O)SR C3 -C(=O)N(R C3 )2, -OC(=O)R C3 , -OC(=O)OR C3 , -OC(=O)N(R C3 )2, -OC(=O)SR C3 -OS(=O)2R C3 -OS(=O)2OR C3 -OS(=O)2N(R C3 )2, -N(R C3 )C(=O)R C3 , -N(R C3 )C(=NR C3 )R C3 , -N(R C3 )C(=O)OR C3 , -N(R C3 )C(=O)N(R C3 )2, -N(R C3 )C(=NR C3 )N(R C3 )2, -N(R C3 )S(=O)2R C3 , -N(R C3 )S(=O)2OR C3 , -N(R C3 )S(=O)2N(R C3 )2, -SC(=O)R C 3 -SC(=O)OR C3 -SC(=O)SR C3 -SC(=O)N(R C3 )2, -S(=O)2R C3 -S(=O)2OR C3 , or -S(=O)2N(R C3 )2, and here, R C3 Each example is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group if bonded to oxygen, a nitrogen protecting group if bonded to nitrogen, or a sulfur protecting group if bonded to sulfur, or two RC3 The group, together with the intervening atom, forms a substituted or unsubstituted heterocyclic ring; R 19 is a substituted or unsubstituted C3-C6 carbocyric or substituted or unsubstituted aryl; and n is 0, 1, or 2.

[0092] base R 1 In some embodiments, R 1 These are hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0093] In some embodiments, R 1 These are hydrogen, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0094] In some embodiments, R 1 This is a substituted carbocyclyl, substituted heterocyclyl, substituted aryl, or substituted heteroaryl, which are further substituted with a substituted carbocyclyl, substituted heterocyclyl, substituted aryl, or substituted heteroaryl, respectively.

[0095] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is a substituted or unsubstituted alkyl group. In some embodiments, R 1 is methyl. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] That is the case.

[0096] In some embodiments, R 1 teeth, [ka] A group consisting of the following is selected, where, R a Each of these examples is independent: hydrogen, halogen, -NO2, -CN, -OR D4 , -N(R D4 )2, -C(=O)R D4 , -C(=O)OR D4 -C(=O)N(R D4 )2, -OC(=O)R D4 , -OC(=O)OR D4 , -N(R D4 )C(=O)R D4 , -OC(=O)N(R D4 )2, -N(R D4 )C(=O)OR D4 -S(=O)2R D4 -S(=O)2OR D4 -OS(=O)2R D4 -S(=O)2N(R D4 )2, or -N(R D4 )S(=O)2R D4 , substitution or non-substitution C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~6 Carbocyclyl, substituted or unsubstituted 3-6 member heterocyclyl, substituted or unsubstituted C 5~10 They are aryl, substituted, or unsubstituted 5- to 10-membered heteroaryls; R D4 Each example independently involves hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, substituted or unsubstituted C 3~6 Carbocyclyl, substituted or unsubstituted 3-6 member heterocyclyl, substituted or unsubstituted substitution C5~10 An aryl group, a substituted or unsubstituted 5-10 member heteroaryl group, an oxygen protecting group if bonded to oxygen, a nitrogen protecting group if bonded to nitrogen, or two R groups. D4 The group, together with the intervening atom, forms a substituted or unsubstituted heterocyclic ring; and p is an integer selected from 0 to 11.

[0097] In some embodiments, R 1 teeth, [ka] Selected from the group consisting of; Here, R a Each of these examples is independent: hydrogen, halogen, -NO2, -CN, -OR D4 , -N(R D4 )2, -C(=O)R D4 , -C(=O)OR D4 -C(=O)N(R D4 )2, -OC(=O)R D4 , -OC(=O)OR D4 , -N(R D4 )C(=O)R D4 , -OC(=O)N(R D4 )2, -N(R D4 )C(=O)OR D4 -S(=O)2R D4 -S(=O)2OR D4 -OS(=O)2R D4 -S(=O)2N(R D4 )2, or -N(R D4 )S(=O)2R D4 , 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 C 3~6 Carbocyclyl, substituted or unsubstituted 3-6 member heterocyclyl, substituted or unsubstituted C 5~10 They are aryl, substituted, or unsubstituted 5- to 10-membered heteroaryls; R D4Each example independently involves hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, substituted or unsubstituted C 3~6 Carbocyclyl, substituted or unsubstituted 3-6 member heterocyclyl, substituted or unsubstituted C 5~10 An aryl group, a substituted or unsubstituted 5-10 member heteroaryl group, an oxygen protecting group if bonded to oxygen, a nitrogen protecting group if bonded to nitrogen, or two R groups. D4 The group, together with the intervening atom, forms a substituted or unsubstituted heterocyclic ring; and p is an integer selected from 0 to 11.

[0098] base R 2a and R 2b In some embodiments, R 2a and R 2b Each of these independently represents hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR E5 -OC(=O)R E5 -OS(=O)2OR E5 , -N(R E5 )2, or -N(R E5 )C(=O)R E5 , -N(R E5 )S(=O)2 R E5 , -N(R E5 )S(=O)2OR E5 And here, R E5 Each example is independent, Hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R E5 The group, together with the intervening atom, forms a substituted or unsubstituted heterocyclic ring.

[0099] In some embodiments, R 2a and R 2b These are, independently, hydrogen, halogen, -CN, -NO2, and -OR. F6 -OC(=O)R F6 , -N(R F6 )2, or -N(R F6 )C(=O)R F6 And here, R F6 Each example independently consists of 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, or two R F6 The group, together with the intervening atom, forms a substituted or unsubstituted heterocyclic ring.

[0100] In some embodiments, R 2a and R 2b These are independently hydrogen, -OH, or substituted or unsubstituted C. 1~6 It is alkyl.

[0101] In some embodiments, R 2a and R 2b Each of these is independently hydrogen, -OH, and C. 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, or C 1~6 It is an alkoxyhalo.

[0102] In some embodiments, R 2a and R 2b These are independently -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0103] In some embodiments, R 2a and R 2b Both are hydrogen.

[0104] In some embodiments, R 2a and R 2b Together, they form an oxo (=O) group.

[0105] base R 3a In some embodiments, R 3a These are hydrogen, substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, or substituted or unsubstituted alkynyl groups.

[0106] In some embodiments, R 3a These are substituted or unsubstituted carbocyclyls, substituted or unsubstituted heterocyclyls, substituted or unsubstituted aryls, or substituted or unsubstituted heteroaryls.

[0107] In some embodiments, R 3a is a substitution or non-substitution C 1~6 It is alkyl.

[0108] In some embodiments, R 3 is a substituted alkyl group. In some embodiments, R 3a It is an unsubstituted alkyl group.

[0109] In some embodiments, R 3a is methyl. In some embodiments, R 3a It is hydrogen.

[0110] In some embodiments, R 3a teeth, [ka] That is the case.

[0111] In some embodiments, R 3a teeth, [ka] That is the case.

[0112] base R 4a and R 4b In some embodiments, R 4a and R 4bEach of these independently represents hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR E5 -OC(=O)R E5 -OS(=O)2OR E5 , -N(R E5 )2, or -N(R E5 )C(=O)R E5 , -N(R E5 )S(=O)2R E5 , -N(R E5 )S(=O)2OR E5 And here, R E5 Each example independently consists of 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, or two R E5 The group, together with the intervening atom, forms a substituted or unsubstituted heterocyclic ring.

[0113] In some embodiments, R 4a and R 4b These are, independently, hydrogen, halogen, -CN, -NO2, and -OR. F6 -OC(=O)R F6 , -N(R F6 )2, or -N(R F6 )C(=O)R F6 And here, R F6 Each example independently consists of 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, or two R F6 The group, together with the intervening atom, forms a substituted or unsubstituted heterocyclic ring.

[0114] In some embodiments, R 4a and R 4b These are independently hydrogen, -OH, or substituted or unsubstituted C. 1~6 It is alkyl.

[0115] In some embodiments, R 4a and R 4b each independently is hydrogen, -OH, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 alkoxy, or C 1~6 alkoxyhalo.

[0116] In some embodiments, R 4a and R 4b are independently -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0117] In some embodiments, R 4a and R 4b are both hydrogen.

[0118] In some embodiments, R 4a and R 4b together form an oxo (=O) group.

[0119] Group R 5 In some embodiments, R 5 is hydrogen in the cis position relative to R 19 . In some embodiments, R 5 is hydrogen in the trans position relative to R 19 . In some embodiments, R 5 is methyl in the cis position relative to R 19 . In some embodiments, R 5 is methyl in the trans position relative to R<000​​​​​​​​​​​​​​​​​​ In some embodiments, R 6a and R 6b are each independently hydrogen or a substituted alkyl.

[0122] In some embodiments, R 6a and R 6b are each independently hydrogen or an unsubstituted alkyl.

[0123] In some embodiments, R 6a and R 6b are both hydrogen.

[0124] In some embodiments, R 6a is halo or alkyl, and R 6b is hydrogen.

[0125] In some embodiments, R 6a and R 6b are both halo.

[0126] In some embodiments, R 6a and R 6b are both alkyl.

[0127] The groups R 7a and R 7b In some embodiments, R 7a and R 7b are each independently hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR E5 , -OC(=O)R E5 , -OS(=O)2OR E5 , -N(R E5 )2, or -N(R E5 )C(=O)R E5 , -N(R E5 )S(=O)2R E5 , -N(R E5 )S(=O)2OR E5 ; where R E5Each example independently consists of 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, or two R E5 The group, together with the intervening atom, forms a substituted or unsubstituted heterocyclic ring.

[0128] In some embodiments, R 7a and R 7b These are, independently, hydrogen, halogen, -CN, -NO2, and -OR. F6 -OC(=O)R F6 , -N(R F6 )2, or -N(R F6 )C(=O)R F6 And here, R F6 Each example independently involves hydrogen, substituted, or unsubstituted. Alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or two R F6 The group, together with the intervening atom, forms a substituted or unsubstituted heterocyclic ring.

[0129] In some embodiments, R 7a and R 7b These are independently hydrogen, -OH, or substituted or unsubstituted C. 1~6 It is alkyl.

[0130] In some embodiments, R 7a and R 7b Each of these is independently hydrogen, -OH, and C. 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, or C 1~6 It is an alkoxyhalo.

[0131] In some embodiments, R 7a and R 7bis independently -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0132] In some embodiments, R 7a and R 7b are both hydrogen.

[0133] In some embodiments, R 7a and R 7b together form an oxo (=O) group.

[0134] The group R 11a and R 11b In some embodiments, R 11a and R 11b are each independently hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR E5 , -OC(=O)R E5 , -OS(=O)2OR E5 , -N(R E5 )2, or -N(R E5 )C(=O)R E5 , -N(R E5 )S(=O)2R E5 , -N(R E5 )S(=O)2OR E5 ; wherein each instance of R E5 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R E5 groups together with intervening atoms form a substituted or unsubstituted heterocyclic ring.

[0135] In some embodiments, R 11a and R 11b are each independently hydrogen, halogen, -CN, -NO2, -OR F6 , -OC(=O)R F6 , -N(R F6)2, or -N(R F6 )C(=O)R F6 And here, R F6 Each example independently consists of 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, or two R F6 The group, together with the intervening atom, forms a substituted or unsubstituted heterocyclic ring.

[0136] In some embodiments, R 11a and R 11b These are independently hydrogen, -OH, or substituted or unsubstituted C. 1~6 It is alkyl.

[0137] In some embodiments, R 11a and R 11b Each of these is independently hydrogen, -OH, and C. 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, or C 1~6 It is an alkoxyhalo.

[0138] In some embodiments, R 11a and R 11b These are independently -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0139] In some embodiments, R 11a and R 11b Both are hydrogen.

[0140] In some embodiments, R 11a and R 11b Together, they form an oxo (=O) group.

[0141] base R 12a and R 12b In some embodiments, R 12a and R 12bEach of these independently represents hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR E5 -OC(=O)R E5 -OS(=O)2OR E5 , -N(R E5 )2, or -N(R E5 )C(=O)R E5 , -N(R E5 )S(=O)2R E5 , -N(R E5 )S(=O)2OR E5 And here, R E5 Each example independently consists of 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, or two R E5 The group, together with the intervening atom, forms a substituted or unsubstituted heterocyclic ring.

[0142] In some embodiments, R 12a and R 12b These are, independently, hydrogen, halogen, -CN, -NO2, and -OR. F6 -OC(=O)R F6 , -N(R F6 )2, or -N(R F6 )C(=O)R F6 And here, R F6 Each example independently includes hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted Alternatively, it may be an unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, or two R F6 The group, together with the intervening atom, forms a substituted or unsubstituted heterocyclic ring.

[0143] In some embodiments, R 12a and R 12b These are independently hydrogen, -OH, or substituted or unsubstituted C. 1~6 It is alkyl.

[0144] In some embodiments, R 12a and R 12b Each of these is independently hydrogen, -OH, and C. 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, or C 1~6 It is an alkoxyhalo.

[0145] In some embodiments, R 12a and R 12b These are independently -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0146] In some embodiments, R 12a and R 12b Both are hydrogen.

[0147] In some embodiments, R 12a and R 12b Together, they form an oxo (=O) group.

[0148] base R 17b In some embodiments, R 17b is fluorine, hydroxyl, methyl, or hydrogen; in this case, hydrogen may be optionally replaced with deutherium. In some embodiments, R 17b It is hydrogen.

[0149] base R 19 In some embodiments, R 19 is a substitution or non-substitution C 3~6 Carbocyclyl, or substituted or unsubstituted C 6~10 It is an arrow. In some embodiments, R 19 is a substitution or non-substitution C 3~6 It is carbocyclyl. In some embodiments, R 19 It is cyclopropyl.

[0150] In some embodiments, R 19is a substitution or non-substitution C 3~6 It is carbocyclyl.

[0151] In some embodiments, R 19 is a substitution or non-substitution C 6~10 It is Ariel.

[0152] In some embodiments, R 19 teeth, [ka] Selected from the group consisting of; Here, R b Each of these examples is independent: hydrogen, halogen, -NO2, -CN, -OR G7 , -N(R G7 )2, -C(=O)R G7 , -C(=O)OR G7 -C(=O)N(R G7 )2, -OC(=O)R G7 , -OC(=O)OR G7 , -N(R G7 )C(=O)R G7 , -OC(=O)N(R G7 )2, -N(R G7 )C(=O)OR G7 -S(=O)2R G7 -S(=O)2OR G7 -OS(=O)2R G7 -S(=O)2N(R G7 )2, or -N(R G7 )S(=O)2R G7 , substitution or non-substitution C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl substitution or is non-substituted C 3~6 Carbocyclyl, substituted or unsubstituted 3-6 member heterocyclyl, substituted or unsubstituted C 5~10 They are aryl, substituted, or unsubstituted 5- to 10-membered heteroaryls; R G7 Each example independently involves hydrogen, substituted or unsubstituted C 1~6Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, substituted or unsubstituted C 3~6 Carbocyclyl, substituted or unsubstituted 3-6 member heterocyclyl, substituted or unsubstituted C 5~10 An aryl group, a substituted or unsubstituted 5-10 member heteroaryl group, an oxygen protecting group if bonded to oxygen, a nitrogen protecting group if bonded to nitrogen, or two R groups. G7 The group, together with the intervening atom, forms a substituted or unsubstituted heterocyclic ring; and q is an integer selected from 0 to 11.

[0153] base R 15a and R 15b In some embodiments, R 15a and R 15b Each of these is independently hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR C3 , -N(R C3 )2, -SR C3 -C(=O)R C3 , -C(=O)OR C3 -C(=O)SR C3 -C(=O)N(R C3 )2, -OC(=O)R C3 , -OC(=O)OR C3 , -OC(=O)N(R C3 )2, -OC(=O)SR C3 -OS(=O)2R C3 -OS(=O)2OR C3 -OS(=O)2N(R C3 )2, -N(R C3 )C(=O)R C3 , -N(R C3 )C(=NR C3 )R C3 , -N(R C3 )C(=O)OR C3, -N(R C3 )C(=O)N(R C3 )2, -N(R C3 )C(=NR C3 )N(R C3 )2, -N(R C3 )S(=O)2R C3 , -N(R C3 )S(=O)2OR C3 , -N(R C3 )S(=O)2N(R C3 )2, -SC(=O)R C3 -SC(=O)OR C3 -SC(=O)SR C3 -SC(=O)N(R C3 )2, -S(=O)2R C3 -S(=O)2OR C3 , or -S(=O)2N(R C3 )2, and here, R C3 Each example is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group if bonded to oxygen, a nitrogen protecting group if bonded to nitrogen, or a sulfur protecting group if bonded to sulfur, or two R C3 The group, together with the intervening atom, forms a substituted or unsubstituted heterocyclic ring.

[0154] In some embodiments, R 15a and R 15b Both are hydrogen.

[0155] base R 16a and R 16b In some embodiments, R 16a and R 16bEach of these is independently hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR C3 , -N(R C3 )2, -SR C3 -C(=O)R C3 , -C(=O)OR C3 -C(=O)SR C3 -C(=O)N(R C3 )2, -OC(=O)R C3 , -OC(=O)OR C3 , -OC(=O)N(R C3 )2, -OC(=O)SR C3 -OS(=O)2R C3 -OS(=O)2OR C3 -OS(=O)2N(R C3 )2, -N(R C3 )C(=O)R C3 , -N(R C3 )C(=NR C3 )R C3 , -N(R C3 )C(=O)OR C3 , -N(R C3 )C(=O)N(R C3 )2, -N(R C3 )C(=NR C3 ), N(R C3 )2, -N(R C3 )S(=O)2R C3 , -N(R C3 )S(=O)2OR C3 , -N(R C3 )S(=O)2N(R C3 )2, -SC(=O)R C3 -SC(=O)OR C3 -SC(=O)SR C3 -SC(=O)N(R C3 )2, -S(=O)2R C3 -S(=O)2OR C3 , or -S(=O)2N(R C3 )2, and here, RC3 Each example is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group if bonded to oxygen, a nitrogen protecting group if bonded to nitrogen, or a sulfur protecting group if bonded to sulfur, or two R C3 The group, together with the intervening atom, forms a substituted or unsubstituted heterocyclic ring.

[0156] In some embodiments, R 16a and R 16b Both are hydrogen.

[0157] n In some embodiments, n is 0. In some embodiments, n is 1. In some other embodiments, n is 2.

[0158] In some embodiments, the compound of formula (I) is the compound of formula (Ia): [ka] (Ia) or a pharmaceutically acceptable salt thereof.

[0159] In some embodiments, the compound of formula (I) is the compound of formula (Ib): [ka] (Ib) or a pharmaceutically acceptable salt thereof.

[0160] In some embodiments, the compound of formula (I) is the compound of formula (Ic): [ka] (I C) or a pharmaceutically acceptable salt thereof.

[0161] In some embodiments, the compound of formula (I) is the compound of formula (Id): [ka] (Id) or a pharmaceutically acceptable salt thereof [wherein R a Each example is independently a halogen, cyano, hydroxyl, or substituted or unsubstituted alkyl; and p is 0, 1, 2, or 3.

[0162] In some embodiments, the compound of formula (I) is the compound of formula (Ie): [ka] (Ie) or a pharmaceutically acceptable salt thereof [in the formula, Each X is independent, -C(R N )-,-C(R N )2-, -O-, -S-, -N-, or N(R N )- and here, R N These are independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, C(=O)R GA , -C(=O)OR GA -C(=O)N(R GA )2, -S(=O)2R GA , or -S(=O)2N(R GA )2; R GA Each example independently involves hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, substituted or unsubstituted C 3~6 Carbocyclyl, substituted or unsubstituted 3-6 member heterocyclyl, substituted or unsubstituted aryl, substituted or An unsubstituted heteroaryl group, an oxygen protecting group if bonded to oxygen, a nitrogen protecting group if bonded to nitrogen, or two R groups. GAThe group, together with the intervening atom, forms a substituted or unsubstituted heterocyclyl or heteroaryl ring.

[0163] In some embodiments, the compound of formula (I) is the compound of formula (If): [ka] (If) or a pharmaceutically acceptable salt thereof [in the formula, Each X is independent, -C(R N )-,-C(R N )2-, -O-, -S-, -N-, or N(R N )- and here, R N These are independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, C(=O)R GA , -C(=O)OR GA -C(=O)N(R GA )2, -S(=O)2R GA , or -S(=O)2N(R GA )2; R GA Each example independently involves hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, substituted or unsubstituted C 3~6 Carbocyclyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group if bonded to oxygen, nitrogen protecting group if bonded to nitrogen, or two R GA The group, together with the intervening atom, forms a substituted or unsubstituted heterocyclyl or heteroaryl ring.

[0164] In some embodiments, the compound of formula (I) is the compound of formula (Ig): [ka] (Ig) or a pharmaceutically acceptable salt thereof [in the formula, Ra Each example is independently a halogen, alkyl, hydroxyl, or cyano; and p is an integer selected from 0 to 11.

[0165] In some embodiments, the compound of formula (I) is the compound of formula (Ih): [ka] (Ih) or a pharmaceutically acceptable salt thereof [in the formula, Each X is independent, -C(R N )-,-C(R N )2-, -O-, -S-, -N-, or N(R N )- and here, R N These are independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, C(=O)R GA , -C(=O)OR GA -C(=O)N(R GA )2, -S(=O)2R GA , or -S(=O)2N(R GA )2; R GA Each example independently involves hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, substituted or unsubstituted C 3~6 Carbocyclyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group if bonded to oxygen, nitrogen protecting group if bonded to nitrogen, or two R GA The group, together with the intervening atom, forms a substituted or unsubstituted heterocyclyl or heteroaryl ring.

[0166] In one embodiment, this specification provides a pharmaceutical composition comprising a compound described herein (for example, a compound of formula (I)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive. In certain embodiments, the compound of the present invention is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the compound of the present invention is provided in a therapeutically effective amount. In certain embodiments, the compound of the present invention is provided in a preventively effective amount.

[0167] In one embodiment, this specification provides pharmaceutically acceptable salts of compounds described herein (for example, compounds of formula (I)).

[0168] 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 over a long period. In certain embodiments, the compound is administered continuously, for example, by continuous intravenous infusion.

[0169] The compounds of the present invention as described herein, in certain embodiments, are, for example, GABA A It acts as a GABA modulator, either positively or negatively affecting the receptor. A As regulators of central nervous system (CNS) excitability mediated by their ability to modulate receptors, such compounds are predicted to possess CNS activity.

[0170] In one embodiment, this specification describes a method for treating a CNS-related disorder in a subject requiring treatment for a CNS-related disorder, comprising administering to the subject an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof.

[0171] In some embodiments, the CNS-related disorders include sleep disorders, mood disorders, schizophrenia spectrum disorders, seizure 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. The symptoms include tinnitus or status epilepticus.

[0172] 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 moderate major depressive disorder. In some embodiments, the major depressive disorder is severe major depressive disorder.

[0173] In some embodiments, the above-mentioned compounds are selected from the group consisting of the compounds identified in Table 1 below. [Table 1-1] [Table 1-2]

[0174] Exemplary compounds of the present invention can be synthesized from the following known starting materials using methods known to those skilled in the art or certain reference literature. In one embodiment, pharmaceutically acceptable salts of compounds described herein (e.g., compounds of formula (I)) are provided herein.

[0175] Alternative Embodiments In an alternative embodiment, the compounds described herein may include one or more isotopic substitutions. For example, hydrogen is 2 H (D or Deuterium) or 3 H (or tritium) may be H(T or tritium); carbon may be, for example, 13 C or 14 It may be C; oxygen is, for example, 18 It may be oxygen; nitrogen, for example, 15 In other embodiments, it may be N, for example, 3 H, 13 C, 14 C, 18 O, or 15N) may be 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 isotope abundance of the element occupying the specific site of the above compound.

[0176] Pharmaceutical composition In one embodiment, this specification provides a pharmaceutical composition comprising a compound described herein (for example, a compound of formula (I)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive. In certain embodiments, the compound of the present invention is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the compound of the present invention is provided in a therapeutically effective amount. In certain embodiments, the compound of the present invention is provided in a preventively effective amount.

[0177] 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. In certain embodiments, the pharmaceutical composition contains a preventatively effective amount of the active ingredient.

[0178] The pharmaceutical compositions provided herein can be administered by various routes, including, but not limited to, oral (intestinal) administration, parenteral (injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration.

[0179] Generally, the compounds provided herein are administered in an effective dose. The actual amount of compound administered is typically determined by a physician, taking into account the condition being treated, the chosen route of administration, the actual compound being administered, the individual patient's age, weight, and response, the severity of the patient's symptoms, and other relevant circumstances.

[0180] When used to prevent the development of CNS disorders, the compounds provided herein are to be administered to subjects at risk of developing the condition, typically under the advice and supervision of a physician, at the dosage levels described above. 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 the condition through genetic testing or screening.

[0181] The pharmaceutical compositions provided herein may also be administered over a long period of time ("long-term administration"). Long-term administration refers to the administration of the compound or its pharmaceutical composition over a long period of time, such as 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may continue indefinitely over the life of the subject, for example. In certain embodiments, the long-term administration is intended, for example, to provide a constant blood concentration of the compound within the therapeutic concentration range over a long period of time.

[0182] The pharmaceutical composition of the present invention can be further delivered using a variety of administration methods. For example, in certain embodiments, the pharmaceutical composition can be administered as a bolus to, for example, raise the concentration of the compound in the blood to an effective level. The setting of the bolus dose depends on the desired systemic level of the active ingredient throughout the body; for example, an intramuscular or subcutaneous bolus dose allows for sustained release of the active ingredient, while a bolus delivered directly into a vein (e.g., by intravenous infusion) allows for fairly rapid delivery that rapidly raises the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition may be administered as a continuous infusion, for example, by intravenous infusion, to maintain a steady-state concentration of the active ingredient in the subject's body. Furthermore, in yet another embodiment, the pharmaceutical composition can be administered first as a bolus dose, followed by a continuous infusion.

[0183] The above compositions for oral administration may take the form of bulk liquids, suspensions, or mixed powders. However, more generally, the compositions are provided in unit dosage forms to facilitate precise administration. The term "unit dosage form" refers to physically distinct units suitable for unit dosing for human subjects and other mammals, where each unit contains a predetermined amount of active substance calculated to produce the desired therapeutic effect in combination with appropriate pharmaceutical excipients. Typical unit dosage form The dosage forms include pre-filled, pre-measured ampoules or syringes of the liquid composition, or, in the case of a solid composition, pills, tablets, or capsules. In such compositions, the compound is usually present in small amounts (about 0.1 to about 50% by weight, or preferably 1 to 40% by weight), with the remainder being various vehicles or additives and processing aids that help form the desired dosage form.

[0184] For oral administration, typical regimens involve oral administration 1 to 5 times per day, particularly 2 to 4 times, and usually 3 times. Using these dosing patterns, each dose provides the compound provided herein in amounts of approximately 0.01 to 20 mg / kg, with preferred doses being approximately 0.1 to 10 mg / kg, particularly 1 to 5 mg / kg.

[0185] The transdermal dose is generally selected in an amount 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, so as to provide blood concentrations similar to or lower than those achieved by the use of the injectable dose.

[0186] The injection dose level ranges from approximately 0.1 mg / kg / hour to at least approximately 20 mg / kg / hour over a total period of approximately 1 to 120 hours, particularly over 24 to 96 hours. A preload bolus of approximately 0.1 mg / kg to approximately 10 mg / kg or more may be administered to achieve a sufficient steady-state concentration. The maximum total dose is not expected to exceed approximately 5 g / day in human patients weighing 40-80 kg.

[0187] Liquids suitable for oral administration may contain a suitable aqueous or non-aqueous vehicle including buffers, suspending agents and dispersants, colorants, flavoring agents, etc. Solids may contain, for example, any of the following components or compounds of similar properties: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; additives such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate; fluidity enhancers such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavor.

[0188] The injectable compositions typically consist of an injectable sterile saline or phosphate-buffered saline or other injectable additives known in the art as a base. As already mentioned, the active compound in such compositions is typically a small component, often about 0.05 to 10% by weight, with the remainder being the injectable additives, etc.

[0189] The transdermal composition is typically formulated as a topical ointment or cream containing the above-mentioned active ingredient(s). When formulated as an ointment, the active ingredient is typically mixed with either a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream, for example, with an oil-in-water cream base. Such transdermal formulations are well known in the art and generally contain additional components to enhance the stability of skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope provided herein.

[0190] The compounds provided herein can also be administered via transdermal devices. Therefore, transdermal administration can be performed using a transdermal patch that is either a laser bar, a porous membrane type, or a solid matrix manifold.

[0191] The above components for compositions that can be administered orally, by injection, or topically are representative only. Other substances and processing techniques are incorporated herein by reference in Part 8. This information is found in Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania.

[0192] The compounds of the present invention can also be administered in a sustained-release form or via a sustained-release drug delivery system. Representative examples of sustained-release substances can be found in Remington's Pharmaceutical Sciences.

[0193] 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 produce non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions such as hydrochloric acid, hydrogen iodide, hydrogen bromide, nitrates, sulfates, bisulfates, phosphates, acetates, lactates, citrates, tartrates, succinates, maleates, fumarates, benzoates, and p-toluenesulfonates.

[0194] In another aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable additive, for example, a composition suitable for injection, such as for intravenous (IV) administration.

[0195] Pharmaceutically acceptable excipients include all diluents or other liquid vehicles suitable for the desired specific dosage form, e.g., injection, dispersing or suspending agents, surfactants, isotonic agents, preservatives, lubricants, etc. For an overview of the formulation and / or manufacture of pharmaceutical compositions, see, for example, Remington's Pharmaceutical Sciences, Sixteenth Edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy,21 st This can be found in the Edition (Lippincott Williams & Wilkins, 2005).

[0196] For example, injectable formulations, such as sterile injectable aqueous suspensions, can be formulated according to known techniques using appropriate dispersants or wetting agents and suspension agents. Exemplary additives that can be used include, but are not limited to, water, sterile saline or phosphate-buffered saline, or Ringer's solution.

[0197] In certain embodiments, the pharmaceutical composition further comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, each consisting of 6, 7, and 8 α-1,4-linked glucose units, and optionally containing one or more substituents (but not limited to substituted or unsubstituted methylation, hydroxyalkylation, acylation, and sulfoalkyl ether substitution) on the linked sugar portion. In certain embodiments, the cyclodextrin is sulfoalkyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as CAPTISOL®. See, for example, US 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% aqueous solution).

[0198] The above-mentioned injectable composition can be sterilized, for example, by filtration using a bacterial-retaining filter, or by incorporating a sterilizing agent into the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media before use.

[0199] Generally, the compounds provided herein are administered in an effective amount. The actual amount of the above compound administered is typically determined by a physician, depending on the condition being treated, the selected route of administration, and the amount administered. The actual compound used will be determined by considering relevant circumstances, including the individual patient's age, weight, response, and the severity of the patient's symptoms.

[0200] The above composition is provided in unit dosage forms to facilitate precise administration. The term "unit dosage form" refers to a physically distinct unit suitable for unit dosing for human subjects and other mammals, where each unit contains a predetermined amount of active substance calculated to produce the desired therapeutic effect in combination with appropriate pharmaceutical excipients. Typical unit dosage forms include pre-filled, pre-measured ampoules, or syringes of the above liquid composition. In such compositions, the compound is usually present in small amounts (about 0.1 to about 50% by weight, or preferably 1 to 40% by weight), with the remainder being processing aids that help form various vehicles or carriers and the desired dosage form.

[0201] The compounds provided herein may be administered as sole active agents, or they may be administered in combination with other active agents. In one embodiment, the present invention provides combinations of the compounds of the present invention and other pharmacologically active agents. Combination administration can be carried out by any technique apparent to those skilled in the art, including, for example, separate, sequential, simultaneous, and alternating administration.

[0202] The descriptions of pharmaceutical compositions provided herein primarily concern pharmaceutical compositions suitable for administration to humans; however, it will be understood by those skilled in the art that such compositions are generally suitable for administration to all types of animals. Modifications of pharmaceutical compositions suitable for administration to humans to make them suitable for administration to various animals are well understood, and veterinary pharmacologists of the art can design and / or carry out such modifications using conventional experimental methods. An overview of the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21. st This can be found in Lippincott Williams & Wilkins, ed., 2005.

[0203] In one embodiment, a kit is provided that includes a composition (e.g., a solid composition) containing a compound of formula (I).

[0204] Instructions for use and handling In one embodiment, the compounds described herein, for example, the compound of formula (I), are intended to be useful as therapeutic agents for treating CNS-related disorders (e.g., sleep disorders, mood disorders such as depression, schizophrenia spectrum disorder, convulsive disorders, epileptic seizures, memory and / or cognitive impairments, motor disorders, personality disorders, autism spectrum disorder, pain, traumatic brain injury, vascular disease, substance abuse disorder and / or withdrawal syndrome, or tinnitus) in subjects requiring treatment (e.g., subjects having Rett syndrome, fragile X syndrome, or Angelman syndrome). Exemplary CNS conditions associated with GABA regulation include, but are not limited to, sleep disorders [e.g., insomnia], mood disorders [e.g., depression (e.g., major depressive disorder (MDD)), dysthymic disorder (e.g., mild depression), bipolar disorder (e.g., I and / or II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (e.g., obsessive-compulsive disorder (OCD))], schizophrenia spectrum disorders [e.g., schizophrenia, schizoaffective disorder], and convulsive disorders [e.g., [e.g., epilepsy (e.g., status epilepticus (SE)), seizures), memory and / or cognitive impairments [e.g., attention deficit (e.g., attention deficit hyperactivity disorder (ADHD)), dementia (e.g., Alzheimer's disease, Lewy body dementia, vascular dementia)], movement disorders [e.g., Huntington's disease, Parkinson's disease], personality disorders [e.g., antisocial personality disorder, obsessive-compulsive personality disorder], autism spectrum disorder (ASD) [e.g., autism, synaptic degeneration (synaptophathy), and other genetic causes of autism, e.g., Rett syndrome, fragility]. This includes X syndrome, Angelman syndrome, pain [e.g., neuropathic pain, trauma-related pain syndrome, acute gout, chronic pain], traumatic brain injury (TBI), vascular diseases [e.g., stroke, ischemic vascular malformations], substance abuse disorders and / or withdrawal syndromes [e.g., dependence on opium, cocaine, and / or alcohol], and tinnitus.

[0205] 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, 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.

[0206] In one embodiment, a method is provided for mitigating 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 mitigates or prevents epileptic seizures.

[0207] In another embodiment, combinations of the compounds of the present invention and other pharmacologically active agents are provided. The compounds provided herein may be administered as sole active agents, or they may be administered in combination with other agents. Combination administration can be carried out by any technique apparent to those skilled in the art, including, for example, separate, sequential, simultaneous, and alternating administration.

[0208] In another embodiment, the present invention provides a method for treating or preventing brain excitability in a subject who is susceptible to or suffering from a brain excitability-related condition, the method comprising administering an effective amount of the compound of the present invention to the subject.

[0209] In another embodiment, the present invention provides a method for treating or preventing stress or anxiety in a subject, comprising administering an effective amount of the compound or composition thereof to a subject in need of such treatment.

[0210] In another embodiment, the present invention provides a method for alleviating 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.

[0211] In another embodiment, the present invention provides a method for inducing sleep, substantially maintaining the level of REM sleep found in normal sleep, and without inducing substantial rebound insomnia, comprising administering an effective amount of the compound of the present invention.

[0212] In another embodiment, the present invention provides a method for alleviating 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.

[0213] In 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.

[0214] In another embodiment, by administering a therapeutically effective amount of the compound of the present invention to a subject, cognitive impairment may be impaired. The present invention provides a method for enhancing memory impairment or treating memory impairment. In certain embodiments, the impairment is Alzheimer's disease. In certain embodiments, the impairment is Rett syndrome.

[0215] In another embodiment, a method is provided for treating an attention disorder by administering a therapeutically effective amount of the compound of the present invention to a subject. In a particular embodiment, the attention disorder is ADHD.

[0216] 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.

[0217] Neuroendocrine disorders and functional disorders 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 variety of conditions resulting from an imbalance 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. Since 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 associated with a women’s health disorder or condition (e.g., the women’s health disorders or conditions described herein). In some embodiments, the neuroendocrine disorder or dysfunction associated with a women’s health disorder or condition is polycystic ovary syndrome.

[0218] Symptoms of neuroendocrine disorders include, but are not limited to, behavioral, emotional, and sleep-related symptoms, symptoms related to reproductive function, and physical symptoms; but are not limited to, fatigue, memory problems, anxiety, depression, weight gain or loss, emotional instability, difficulty concentrating, difficulty paying attention, loss of lipids, infertility, amenorrhea, decreased muscle mass, increased abdominal fat, hypotension, low heart rate, hair loss, anemia, constipation, cold intolerance, and dry skin.

[0219] Neurodegenerative diseases and disorders The methods described herein may be used to treat neurodegenerative diseases and disorders. The term “neurodegenerative disease” encompasses diseases and disorders that involve the progressive loss of structure or function of nerve cells, or the death of nerve cells. Neurodegenerative diseases and disorders include, but are not limited to, Alzheimer's disease (including symptoms associated with mild, moderate, or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic and ischemic injuries; ataxia and convulsions (including for treatment and prevention, and for the prevention of seizures caused by schizoaffective disorder or by drugs used to treat schizophrenia); benign amnesia; hydrocephalus; cerebellar ataxia (including McLeod neuroacanthocytosis syndrome (MLS)); closed head trauma; coma; contusion injuries (e.g., spinal cord injury and head injury); dementia (including multiple stroke dementia and senile dementia); impaired consciousness; Down syndrome; drug-induced or drug-induced Parkinsonian syndromes (e.g., depressant-induced acute zoostomy, acute ataxia, Parkinsonian syndrome or tardive dyskinesia). Gilles de la Tourette syndrome; neuroleptic malignant syndrome or drug-induced postural tremor; epilepsy; fragile X syndrome; Gilles de la Tourette syndrome; head trauma; hearing impairment and hearing loss; 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 atrophy, Parkinson's syndrome-ALS dementia complex, Parkinson's disease, post-encephalitis Parkinson's syndrome and progressive supranuclear palsy); muscle spasms and disorders associated with muscle spasticity or weakness (chorea (e.g., benign hereditary chorea, drug-induced chorea, hemiplegic ballism, Huntington's disease, neuroacanthocytosis, Sydenham's chorea and symptomatic chorea), dyskinesia (including tics such as complex tics, simple tics and symptomatic tics), myoclonus ( This includes generalized myoclonus and focal cyloclonus, tremors (e.g., resting tremor, postural tremor, and intention tremor), and ataxia (axial ataxia, dystonic writer's cramp, hemiplegic ataxia, paroxysmal ataxia, and focal ataxia (e.g., blepharospasm, oromandibular dystonia)). 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 after cardiac arrest; Parkinson's disease; seizures; status epilepticus; stroke; tinnitus; tubular sclerosis, and viral infection-induced neurodegeneration (e.g., those caused by acquired immunodeficiency syndrome (AIDS) and brain injury). 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 after cardiac arrest. Methods for treating or preventing neurodegenerative diseases also include treating or preventing the loss of neuronal function that is characteristic of neurodegenerative disorders.

[0220] Mood disorder Furthermore, this specification provides methods for treating mood disorders, such as clinical depression, postnatal or postpartum depression, perinatal depression, atypical depression, melancholic depression, psychotic major depression, catatonic depression, seasonal affective disorder, dysthymia, double depression, depressive personality disorder, recurrent short-term depression, minor depressive disorder, bipolar disorder or manic-depressive disorder, depression resulting from a chronic condition, treatment-resistant depression, treatment-resistant depression, suicidal tendencies, suicidal ideation, or suicidal behavior. In some embodiments, the methods described herein produce a therapeutic effect on subjects suffering from depression (e.g., moderate or severe depression). In some embodiments, the mood disorders are associated with diseases or disorders described herein (e.g., neuroendocrine diseases and disorders, neurodegenerative diseases and disorders (e.g., epilepsy), motor disorders, tremors (e.g., Parkinson's disease), women's health disorders or conditions).

[0221] 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 depressed mood accompanied by low self-esteem and a loss of interest or pleasure in activities that are normally enjoyable. Some people with clinical depression experience sleep disturbances, weight loss, generally feel agitated, and have irritability. 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 struggle to perform daily activities and may feel that life is not worth living.

[0222] Perinatal depression refers to depression during pregnancy. Symptoms include irritability, crying, restlessness, sleep disturbances, extreme fatigue (emotional and / or physical), changes in appetite, difficulty concentrating, increased anxiety and / or worry, feeling disconnected from the infant and / or fetus, and loss of interest in previously enjoyed activities.

[0223] Postpartum depression (PND), also known as postpartum depression (PPD), is a type of clinical depression that affects women after childbirth. Symptoms may include grief, fatigue, changes in sleep and eating habits, decreased libido, crying episodes, anxiety, and irritability. In some embodiments, the PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein). In some embodiments, the PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein).

[0224] In some embodiments, subjects with PND also exhibit symptoms of depression or depression during pregnancy. They have experienced this. 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.

[0225] Atypical depression (AD) is characterized by mood reactivity (e.g., paradoxical anhedonia) and positivity, marked weight gain or increased appetite. Patients with Alzheimer's disease may also experience significant social impairment as a result of excessive sleepiness or somnolence (hypersomnia), heaviness in the limbs, and hypersensitivity to perceived social rejection.

[0226] Melancholic depression is characterized by a loss of pleasure from almost or all activities (anhedonic syndrome), unresponsiveness to pleasant stimuli, depressed mood that is more pronounced than feelings of grief or loss, excessive weight loss, or excessive guilt.

[0227] 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.

[0228] Catastrophic depression refers to major depressive disorder accompanied by motor behavioral disturbances and other symptoms. Individuals may become mute, enter a stuporous state, become immobile, or exhibit aimless or paranoid movements.

[0229] Seasonal affective disorder (SAD) is a type of seasonal depression in which individuals experience depressive episodes that follow a seasonal pattern, typically occurring in the fall or winter.

[0230] Mood disorders refer to conditions associated with unipolar depression, characterized by the same physical and cognitive problems. They tend to be less severe and last for a longer period (e.g., at least two years).

[0231] Bipolar disorder refers to a period of moderately depressed mood (mood disorder) that lasts for at least two years, interspersed with periods of major depression.

[0232] Depressive personality disorder (DPD) refers to a personality disorder that has depressive characteristics.

[0233] Recurrent brief depression (RBD) is a condition in which an individual experiences depressive episodes approximately once a month, each lasting less than two weeks, typically less than two to three days.

[0234] Minor depressive disorder or minor depression is a type of depression in which at least two symptoms are present for a period of two weeks.

[0235] Bipolar disorder, or manic-depressive disorder, is characterized by extreme mood swings, including high (manic or hypomanic) and low (depressive) periods. During manic episodes, individuals may feel or act unusually happy, energetic, or irritable. They often make impulsive decisions with little regard for consequences. Sleep needs are typically reduced. During depressive episodes, individuals may cry uncontrollably, avoid eye contact with others, and have a pessimistic outlook on life. The suicide risk for individuals with this disorder is high, over 6% over a 20-year period, and 30-40% engage in self-harm. Other mental health problems, such as anxiety disorders and substance use disorders, commonly comorbid bipolar disorder.

[0236] Depression caused by a chronic condition refers to depression resulting from a chronic medical condition such as cancer, chronic pain, chemotherapy, or chronic stress.

[0237] Treatment-resistant depression refers to a condition in which an individual receives treatment for depression but their symptoms do not improve. For example, antidepressants or psychological counseling (psychotherapy) do not alleviate the depressive symptoms of individuals with treatment-resistant depression. In some cases, individuals with treatment-resistant depression relapse even after their symptoms improve. Treatment-resistant depression occurs in patients with depression that is resistant to standard pharmacological treatments, including tricyclic antidepressants, MAOIs, SSRIs, and double and triple reuptake inhibitors, and / or anxiolytics, as well as non-pharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagal stimulation, and / or transcranial magnetic stimulation).

[0238] Postoperative depression refers to feelings of depression following surgery (for example, as a result of facing the risk of death). For example, an individual may experience persistent sadness or emptiness, loss of enjoyment or interest in hobbies and activities they normally enjoyed, or persistent feelings of worthlessness or hopelessness.

[0239] Mood disorders associated with women's health conditions or disorders refer to mood disorders (e.g., depression) associated with (e.g., arising from) women's health conditions or disorders (e.g., as described herein).

[0240] Suicidal tendencies, suicidal ideation, and suicidal behavior refer to an individual's tendency to commit suicide. Suicidal ideation relates to thoughts about suicide or an abnormal preoccupation with suicide. The range of suicidal ideation varies greatly, for example, from fleeting thoughts to extensive thoughts, detailed plans, role-playing, and unsuccessful attempts. Symptoms include talking about suicide, obtaining means to commit suicide, withdrawing from social contact, constantly thinking about death, feeling trapped or hopeless about a 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.

[0241] Symptoms of depression include persistent feelings of anxiety or sadness, helplessness, hopelessness, pessimism, worthlessness, low energy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, motor challenges, loss of interest in enjoyable activities or hobbies, difficulty concentrating, low energy, low self-esteem, lack of positive thoughts or plans, excessive sleep, overeating, loss of appetite, insomnia, self-injury, suicidal thoughts, and suicide attempts. The presence, severity, frequency, and duration of symptoms may vary from person to person. The symptoms of depression and their relief can be confirmed by a physician or psychologist (e.g., by a mental state assessment).

[0242] In some embodiments, the method includes monitoring subjects using known depression scales, such as the Hamilton Depression-D scale, the Clinical Global Impression Improvement Scale (CGI), and the Mongolberg-Asberg Depression Rating Scale (MADRS). In some embodiments, the therapeutic effect can be determined by the reduction in the Hamilton Depression-D total score shown by the subject. 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 or shorter. The therapeutic effect can be evaluated throughout a specified treatment period. For example, the therapeutic effect described herein can be determined by the decrease in the HAM-D total score from the baseline after administration of a compound described herein, for example, a compound of formula (I) (e.g., 12, 24, or 48 hours after administration; or 24, 48, 72, or 96 hours or more; or 1, 2, 14, 21, 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 over a lifetime).

[0243] In some embodiments, the subject is mild depressive disorder, for example, mild major depressive disorder. In some embodiments, the subject has a moderate depressive disorder, e.g., a moderate major depressive disorder. In some embodiments, the subject has a severe depressive disorder, e.g., a severe major depressive disorder. In some embodiments, the subject has a very severe depressive disorder, e.g., a very severe major depressive disorder. In some embodiments, the baseline HAM-D total score of the subject (i.e., before treatment with the compounds described herein, e.g., the compound of formula (I)) 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, and includes those scores. In some embodiments, the baseline HAM-D total score of the subject is between 19 and 22, and includes those scores. In some embodiments, the HAM-D total score of the subject before treatment with the compounds described herein, e.g., the compound of formula (I)) is 23 or higher. In some embodiments, the baseline score is at least 10, 15, or 20. In some embodiments, the HAM-D total score of the subject after treatment with a compound described herein, for example, the compound of formula (I), is approximately 0 to 10 (e.g., less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 1.8). In some embodiments, the HAM-D total score after treatment with a compound described herein, for example, the compound of formula (I), is 10, 7, 5, or less than 3. In some embodiments, the reduction in the HAM-D total score is from a baseline score of approximately 20 to 30 (e.g., 22 to 28, 23 to 27, 24 to 27, 25 to 27, 26 to 27) to a HAM-D total score of approximately 0 to 10 (e.g., less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 1.8) after treatment with a compound described herein, for example, the compound of formula (I). In some embodiments, the reduction in baseline HAM-D total score to HAM-D total score after treatment with a compound described herein, e.g., the compound of formula (I), is at least 1, 2, 3, 4, 5, 7, 10, 25, 40, 50, or 100 times. In some embodiments, the percentage reduction in baseline HAM-D total score to HAM-D total score after treatment with a compound described herein, e.g., the compound of formula (I), is at least 50% (e.g., 60%, 70%, 80%, or 90%).In some embodiments, the therapeutic effect is measured as a decrease in the total HAM-D score after treatment with a compound described herein, for example, a compound of formula (I), which is at least 10, 15, or 20 points compared to the baseline total HAM-D score (e.g., 12, 24, or 48 hours after administration; or 24, 48, 72, or 96 hours or longer; or 1, 2, or 14 days or longer).

[0244] In some embodiments, a method for treating a depressive disorder, such as major depressive disorder, produces a therapeutic effect (e.g., measured by a decrease in the Hamilton Depression Score (HAM-D)) within 14, 10, 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours or less. In some embodiments, a method for treating a depressive disorder, such as major depressive disorder, produces a therapeutic effect (e.g., determined by a statistically significant decrease in the HAM-D total score) within 1 or 2 days of treatment with a compound described herein, such as the compound of formula (I). In some embodiments, a method for treating a depressive disorder, such as major depressive disorder, produces a therapeutic effect (e.g., determined by a statistically significant decrease in the HAM-D total score) within 14 days or less of the initiation of treatment with a compound described herein, such as the compound of formula (I). In some embodiments, a method for treating a depressive disorder, such as major depressive disorder, produces a therapeutic effect (e.g., as determined by a statistically significant decrease in the HAM-D total score) in less than 21 days or within 21 days of initiating treatment with a compound described herein, such as the compound of formula (I). In some embodiments, a method for treating a depressive disorder, such as major depressive disorder, produces a therapeutic effect (e.g., as determined by a statistically significant decrease in the HAM-D total score) in less than 28 days or within 28 days of initiating treatment with a compound described herein, such as the compound of formula (I). In some embodiments, the above therapeutic effect is achieved by treatment with a compound described herein, such as the compound of formula (I) (e.g., once daily for 14 days). This is a decrease from the baseline in the total HAM-D score after treatment with the compound of formula (I). In some embodiments, the total HAM-D score of the subject before treatment with the compound of formula (I) described herein is at least 24. In some embodiments, the total HAM-D score of the subject before treatment with the compound of formula (I) described herein is at least 18. In some embodiments, the total HAM-D score of the subject before treatment with the compound of formula (I) described herein is between 14 and 18, including those compounds. In some embodiments, the decrease in the total HAM-D score after treatment with the compound of formula (I) described herein is at least 10 compared to the baseline total HAM-D score. In some embodiments, the decrease in the total HAM-D score after treatment with the compound of formula (I) described herein is at least 15 (e.g., at least 17) compared to the baseline total HAM-D score. In some embodiments, the HAM-D total score associated with the treatment in question using the compounds described herein, for example, the compound of formula (I), is less than or equal to a number in the range of 6 to 8. In some embodiments, the HAM-D total score associated with the treatment in question using the compounds described herein, for example, the compound of formula (I), is 7 or less.

[0245] In some embodiments, the method produces a therapeutic effect (e.g., as measured by a decrease in the Clinical Global Impression Improvement Scale (CGI)) within 14, 10, 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours or less. In some embodiments, the CNS disorder is a depressive disorder, e.g., major depressive disorder. In some embodiments, the method for treating the depressive disorder, e.g., major depressive disorder, produces a therapeutic effect within 2 days of the treatment period. In some embodiments, the therapeutic effect is a decrease from the baseline in the CGI score at the end of the treatment period (e.g., 14 days after administration).

[0246] In some embodiments, the method produces a therapeutic effect (e.g., as measured by a decrease in the Mongolberg-Asberg Depression Rating Scale (MADRS)) within 14, 10, 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours or shorter. In some embodiments, the CNS disorder is a depressive disorder, such as major depressive disorder. In some embodiments, the method for treating the depressive disorder, such as major depressive disorder, produces a therapeutic effect within 2 days of the treatment period. In some embodiments, the therapeutic effect is a decrease from the baseline in the MADRS score at the end of the treatment period (e.g., 14 days after administration).

[0247] The effectiveness of treatment for major depressive disorder can be determined by a decrease in the Mongolberg-Asberg Depression Rating Scale (MADRS) score shown by the subjects described above. For example, the MADRS score may decrease within 4, 3, 2, or 1 day; or within 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, 8 hours, or shorter periods. The Mongolberg-Asberg Depression Rating Scale (MADRS) is a 10-item diagnostic questionnaire used by psychiatrists to measure the severity of depressive episodes in patients with mood disorders (related to outwardly expressed sadness, verbal expressed sadness, internal tension, decreased sleep, decreased appetite, difficulty concentrating, fatigue, loss of affect, pessimistic thinking, and suicidal ideation).

[0248] In some embodiments, the above method produces a therapeutic effect (e.g., as measured by a decrease in the Edinburgh Postnatal Depression Scale (EPDS)) within 4, 3, 2, 1 day, 24, 20, 16, 12, 10, 8 hours, or shorter periods. In some embodiments, the therapeutic effect is an improvement as measured by the EPDS.

[0249] In some embodiments, the above method produces a therapeutic effect (e.g., as measured by a decrease in the Generalized Anxiety Disorder 7-Item Scale (GAD-7)) within 4, 3, 2, 1 day, 24, 20, 16, 12, 10, 8 hours, or shorter periods.

[0250] Anxiety disorder This specification provides methods for treating anxiety disorders (e.g., generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, phobias, post-traumatic stress disorder). Anxiety disorder is a broad term encompassing several different forms of abnormal and pathological fears and anxieties. Current psychiatric diagnostic criteria recognize a wide range of diverse anxiety disorders.

[0251] Generalized anxiety disorder (GPD) is a common chronic disorder characterized by persistent anxiety that cannot be focused on any single object or situation. People suffering from GPD experience nonspecific, persistent fears and worries, and tend to worry excessively about ordinary things. GPD is the most common anxiety disorder affecting older adults.

[0252] In panic disorder, individuals suffer from short bursts of intense fear and anxiety, often characterized by tremors, shaking, confusion, dizziness, nausea, and shortness of breath. These panic attacks, defined by APA as sudden outbursts of fear or discomfort that peak in less than 10 minutes, can last for hours and can be triggered by stress, fear, or even exercise; however, a specific cause is not always apparent. In addition to recurrent, unpredictable panic attacks, a diagnosis of panic disorder also requires that the attacks have chronic consequences, which may be either worry about the potential implications of the attack, persistent fear of future attacks, or a significant change in behavior related to the attack. Thus, individuals with panic disorder may experience symptoms even outside the scope of a particular panic episode. Often, an unusual change in heart rate is noticed by someone suffering from panic, leading them to believe their heart is malfunctioning or about to experience another panic attack. In some cases, heightened perception of bodily functions (hyperarousal) occurs during panic attacks, and any perceived physiological changes are interpreted as life-threatening illnesses (i.e., excessive hypochondria).

[0253] Obsessive-compulsive disorder (OCD) is a type of anxiety disorder primarily characterized by recurrent obsessions (urgent, persistent, and disturbing thoughts or images) and compulsive behaviors (the urge to perform a specific action or ritual). OCD thought patterns can be linked to superstition insofar as they involve a person believing in causal relationships that do not actually exist. In many cases, the process is entirely illogical. For example, the compulsion to walk in a specific pattern may be used to alleviate an obsession with imminent danger. And in many cases, this compulsion is not entirely inexplicable, but simply an urge to complete a neurotic-induced ritual. In a small number of cases, individuals with OCD may experience only obsessions without overt compulsions, and in even fewer, only compulsions.

[0254] One of the largest categories of anxiety disorders is phobias, which encompass all cases in which fear and anxiety are triggered by a specific stimulus or situation. Patients typically anticipate horrific consequences from encountering their object of fear (which can range from an animal, a place, or a bodily fluid).

[0255] Post-traumatic stress disorder, or PTSD, is an anxiety disorder resulting from a traumatic experience. Post-traumatic stress can arise from extreme situations (e.g., war, rape, hostage situations, or even major disasters). It can also result from prolonged (chronic) exposure to severe stressors (e.g., soldiers who can tolerate individual battles but cannot cope with continuous warfare). Common symptoms include flashbacks, avoidance behaviors, and depression.

[0256] Women's health problems This specification provides methods for treating conditions or disorders of women's health. Conditions or disorders of women's health include, but are not limited to, gynecological health and This includes 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 issues relating to women's overall health and wellness (e.g., menopause).

[0257] Gynecological health issues affecting women include menstruation and menstrual irregularities; urinary tract health, including urinary incontinence and pelvic floor disorders; and disorders such as bacterial vaginosis, vaginitis, uterine fibroids, and vulvar pain.

[0258] Premenstrual syndrome (PMS) refers to physical and emotional symptoms that occur one to two weeks before menstruation. Symptoms vary and may include bleeding, mood swings, breast tenderness, overeating, fatigue, irritability, acne, and depression.

[0259] 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 can interfere with work, social activities, and relationships. Symptoms of PMDD include mood swings, depressed or hopeless moods, marked anger, increased interpersonal conflict, tension and anxiety, nervousness, decreased interest in normal activities, difficulty concentrating, fatigue, changes in appetite, uncontrollable or overwhelming feelings, sleep problems, and physical problems (e.g., bloating, breast tenderness, edema, headache, joint or muscle pain).

[0260] Pregnancy issues include prenatal and prenatal care, pregnancy loss (miscarriage and stillbirth), premature birth and early delivery, sudden infant death syndrome (SIDS), breastfeeding, and birth defects.

[0261] A miscarriage refers to a pregnancy that ends spontaneously within the first 20 weeks of gestation.

[0262] Abortion refers to the planned termination of a pregnancy and can be performed during the first 28 weeks of pregnancy.

[0263] Infertility and related disorders include uterine fibroids, polycystic ovary syndrome, endometriosis, and primary ovarian dysfunction.

[0264] 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. Most women with PCOS develop many small cysts on their ovaries. Symptoms of PCOS include irregular or absent menstruation, heavy periods, thick body and facial hair, acne, pelvic pain, difficulty conceiving, and thickened, dark, velvety skin patches. PCOS may be associated with conditions including type 2 diabetes, obesity, obstructive sleep apnea, heart disease, mood disorders, and endometrial cancer.

[0265] Other disorders and conditions that affect only women include Turner syndrome, Rett syndrome, and ovarian and cervical cancer.

[0266] Issues relating to women's overall health and wellness include violence against women, women with physical disabilities and the unique challenges they face, osteoporosis and bone health, and menopause.

[0267] Menopause refers to the 12-month period following a woman's last menstrual period, marking the end of the menstrual cycle. Menopause typically occurs in women in their 40s or 50s. Menopausal physical and emotional symptoms, such as hot flashes, can disrupt sleep, reduce energy, or induce feelings of anxiety, sadness, or loss. Menopause includes spontaneous menopause and surgical menopause, the latter being a type of menopause induced by events such as surgical procedures (e.g., hysterectomy, oophorectomy; cancer). Surgical menopause is caused by the ovaries being affected by, for example, radiation, chemotherapy, It can also be induced if the drug causes significant damage.

[0268] epilepsy A compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof may be used in the methods described herein, for example, in the treatment of a disorder described herein, such as epilepsy, status epilepticus, or seizure.

[0269] Epilepsy is a brain disorder characterized by recurrent seizures over time. Types of epilepsy include, but are not limited to, generalized epilepsy, e.g., childhood absence epilepsy, juvenile myoclonic epilepsy, epilepsy with grand mal seizures while awake, West syndrome, Lennox-Gastaut syndrome, and partial epilepsy, e.g., temporal lobe epilepsy, frontal lobe epilepsy, and benign focal epilepsy in children.

[0270] Epileptic seizure The compounds and methods described herein can be used to treat or prevent epileptic seizures. Epileptic seizures are a progressive course in which a normal brain develops epilepsy (a chronic condition characterized by seizures). Epileptic seizures arise from neurological damage initially caused by a seizure (e.g., status epilepticus).

[0271] Status epilepticus (SE) Status epilepticus (SE) may include, for example, convulsive status epilepticus, such as early status epilepticus, established status epilepticus, refractory status epilepticus, and extremely refractory status epilepticus; non-convulsive status epilepticus, such as generalized status epilepticus, complicated partial status epilepticus; generalized periodic epileptic 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, established status epilepticus, refractory status epilepticus, and extremely refractory status epilepticus. Early status epilepticus is treated with first-line therapy. Established status epilepticus is characterized by persistent status epilepticus despite first-line treatment, and second-line treatment is initiated. Refractory status epilepticus is characterized by persistent status epilepticus despite first-line and second-line treatment, and general anesthetics are generally administered. Extremely refractory status epilepticus is characterized by persistent status epilepticus despite first-line treatment, second-line treatment, and 24 hours or more of general anesthetic treatment.

[0272] Nonconvulsive status epilepticus may include, for example, focal nonconvulsive status epilepticus, such as complex partial nonconvulsive status epilepticus, simple partial nonconvulsive status epilepticus, or micrononconvulsive status epilepticus; or generalized nonconvulsive status epilepticus, such as late-onset absence nonconvulsive status epilepticus, atypical absence nonconvulsive status epilepticus, or typical absence nonconvulsive status epilepticus.

[0273] A compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof, may also be administered prophylactically to subjects having 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 discharge; and periodic unilateral epileptic discharge.

[0274] seizure A seizure is a physical manifestation or change in behavior 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. During a convulsion, the person’s muscles contract and relax repeatedly.

[0275] Based on the type of behavior and brain activity, seizures are divided into two broad categories: generalized and partial (also called focal or localized). Classifying seizure types helps doctors diagnose whether or not a patient has epilepsy.

[0276] Generalized seizures are caused by electrical impulses from the entire brain, while partial seizures are caused (at least initially) by electrical impulses from a relatively small area of ​​the brain. The part of the brain that causes a seizure is sometimes called a lesion.

[0277] There are six types of generalized seizures. The most common, dramatic, and therefore most well-known is the generalized convulsion (also called a grand mal seizure). In this type of seizure, the patient loses consciousness and usually collapses. Following this loss of consciousness, there is a generalized rigidity of the body (called the "tonic" phase of the seizure) lasting 30 to 60 seconds, followed by a violent spasm ("clonic" phase) lasting 30 to 60 seconds, after which the patient falls into a deep sleep ("postictal" or after-seizure phase). During a grand mal seizure, injuries and accidents (e.g., biting the tongue and urinary incontinence) can occur.

[0278] Absence seizures cause brief (only a few seconds) periods of loss of consciousness with little or no symptoms. Patients (most often children) typically stop what they are doing and stare blankly. These seizures begin and end suddenly and can occur several times a day. Patients are usually unaware that they are having seizures unless they notice they are "losing time."

[0279] Myoclonic seizures consist of sporadic spasms, usually on both sides of the body. Patients sometimes describe these spasms as short electric shocks. In severe cases, these seizures can result in dropping or involuntarily throwing objects.

[0280] Clonic seizures are recurrent, rhythmic spasms that involve both sides of the body simultaneously.

[0281] Tonic seizures are characterized by muscle rigidity.

[0282] A toneacic attack consists of a sudden decrease in muscle tone throughout the body (especially in the arms and legs) and often leads to falls.

[0283] The seizures described herein may include epileptic seizures; acute recurrent seizures; cluster seizures; serial seizures; uninterrupted seizures; persistent seizures; recurrent seizures; status epilepticus, e.g., refractory convulsive status epilepticus, nonconvulsive status epilepticus; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondary generalized seizures; atypical absence seizures; absence seizures; astonic seizures; benign Rolandic seizures; febrile seizures; affective seizures; focal seizures; laughter seizures; generalized onset seizures; infantile spasms; Jacksonian seizures; generalized bilateral myoclonic seizures; multifocal seizures; neonatal onset seizures; nocturnal seizures; occipital lobe seizures; post-traumatic seizures; microseizures; Sylvan seizures; visual reflex seizures; or withdrawal seizures. In some embodiments, the seizures are generalized seizures associated with Dravet syndrome, Lennox-Gastaut syndrome, compound tuberous sclerosis, Rett syndrome, or PCDH19 girl epilepsy.

[0284] Movement impairment Methods for treating motor disorders are also described herein. As used herein, “motor disorder” refers to a variety of diseases and disorders associated with hyperkinetic disorders and abnormalities in the control of the muscles involved. Exemplary motor disorders include, but are not limited to, Parkinson’s disease and Parkinsonian syndromes (defined in particular by bradykinesia), dystony, chorea and Huntington’s disease, ataxia, tremor (e.g., essential tremor), myoclonus and startle, tics and Tourette syndrome, restless legs syndrome, stiff person syndrome and gait disorders.

[0285] tremor The methods described herein can be used to treat tremors, for example, formula (I The compounds of ) can be used to treat cerebellar tremor or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, Parkinsonian tremor, physiological tremor, psychogenic tremor, or red tremor. Tremors include hereditary, degenerative, and idiopathic disorders, such as Wilson's disease, Parkinson's disease, and essential tremor, respectively; metabolic disorders (e.g., thyroid-parathyroid disorders, liver disease, and hypoglycemia); peripheral neuropathy (associated with Charcot-Marie-Tooth disease, Lucie-Lévy disease, diabetes mellitus, and complex focal pain syndrome); disorders induced by toxins (nicotine, mercury, lead, CO, manganese, arsenic, toluene); disorders induced by drugs (hypnotics, tricyclic antidepressants, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychogenic disorders. Clinical tremors include physiological tremors, fatigue-induced physiological tremors (enhanced physiological tremor), and essential tremor syndromes (classical essential tremor, primary orthostatic tremor, and...) Tremors can be classified into dystonic tremors, Parkinsonian tremors, cerebellar tremors, Holmesian tremors (i.e., red tremors), palatal tremors, neuropathic tremors, toxin or drug-induced tremors, and psychogenic tremors.

[0286] Tremor is an involuntary, sometimes rhythmic, contraction and relaxation of muscles, which may involve vibration or spasm of one or more body parts (e.g., hands, arms, eyes, face, head, vocal cords, trunk, legs).

[0287] Cerebellar tremor, or intention tremor, is a slow, widespread tremor of the limbs that occurs after an intentional movement. Cerebellar tremor is caused by lesions or damage to the cerebellum, such as those resulting from tumors, strokes, or diseases (e.g., multiple sclerosis, hereditary degenerative disorders).

[0288] Dystonic tremor occurs in individuals with dystonia, a movement disorder characterized by persistent, involuntary muscle contractions that cause twisting and repetitive movements and / or painful, abnormal postures or positions. Dystonic tremor can affect any muscle in the body. It occurs irregularly and can often be relieved by complete rest.

[0289] Essential tremor, or benign essential tremor, is the most common type of tremor. Essential tremor can be mild and non-progressive in some cases, or it can be slowly progressive, starting on one side of the body but affecting both sides within three years. The hands are most frequently affected, but the head, voice, tongue, legs, and trunk can also be involved. The frequency of tremors may decrease with age, but their severity may increase. Emotional agitation, stress, fever, physical fatigue, or hypoglycemia can trigger and / or increase the severity of tremors. Symptoms generally develop over a long period, becoming visible after onset and potentially persisting.

[0290] Orthostatic tremor is characterized by rapid (e.g., above 12 Hz) rhythmic muscle contractions in the legs and trunk immediately after standing. The spasms are felt in the thighs and legs, and the patient stands at a single point. When asked to do so, the person may tremble uncontrollably. Orthostatic tremor can occur in patients with essential tremor.

[0291] Parkinson's tremor is caused by damage to the brain structures that control movement. Often a precursor to Parkinson's disease, it typically manifests as a "pill-rolling" movement of the hand, but can also affect the chin, lips, legs, and trunk. The onset of Parkinson's tremor typically begins after age 60. The movement may begin in one limb or one side of the body and progress to the other side.

[0292] Physiological tremors can occur in normal individuals and are not clinically significant. They can be seen in all voluntary muscle groups. Physiological tremors can be caused by certain drugs, alcohol withdrawal, or medical conditions including hyperthyroidism and hypoglycemia. Classically, this tremor has a frequency of approximately 10 Hz.

[0293] Psychogenic tremor or hysterical tremor can occur at rest, during postural movements, or during active movements. Patients with psychogenic tremor may also have conversion disorder or another psychiatric disorder.

[0294] Red tremor is characterized by a slow, coarse tremor that can occur at rest, in posture, and intentionally. This tremor may be associated with a condition affecting the red nucleus in classic, rare strokes of the midbrain.

[0295] Parkinson's disease affects the nerve cells in the brain that produce dopamine. Symptoms include muscle rigidity, tremors, and changes in speech and gait. Parkinsonian syndromes are characterized by tremors, bradykinesia, rigidity, and postural instability. Parkinsonian syndromes share symptoms with Parkinson's disease, but are a group of symptoms rather than a progressive neurodegenerative disease.

[0296] Dystonia is a movement disorder characterized by persistent or intermittent muscle contractions that are abnormal and often cause repetitive movements or postures. Dystonic movements can be patterned, twisting, and tremor-like. Dystonia is often initiated or aggravated by voluntary movement and is frequently associated with muscle activation overflow.

[0297] Chorea is a neurological disorder typically characterized by rhythmic, involuntary movements affecting the shoulders, hips, and face. Huntington's disease is a genetic disorder that weakens nerve cells in the brain. Symptoms include uncontrolled movements, clumsiness, and balance problems. Huntington's disease can interfere with walking, speaking, and swallowing.

[0298] Ataxia refers to the loss of complete control over bodily movements and can affect fingers, hands, arms, legs, body, speech, and eye movements.

[0299] Myoclonus and startle are responses to sudden and unexpected stimuli that may be auditory, tactile, visual, or vestibular.

[0300] Tics are involuntary movements that typically begin suddenly, are short, repetitive but not rhythmic, and often mimic normal behavior, occurring outside the background of normal activity. Tics can be classified as motor tics or vocal tics; motor tics are associated with movement, and vocal tics are associated with sound. Tics can be characterized as simple or complex. For example, simple motor tics involve only a few muscles limited to a specific part of the body. Tourette syndrome is a hereditary neuropsychiatric disorder that begins in childhood and is characterized by multiple motor tics and at least one vocal tic.

[0301] Restless legs syndrome is a neurological sensorimotor disorder characterized by an irresistible urge to move the legs while at rest.

[0302] Stiff person syndrome is a progressive motor disorder typically characterized by involuntary, painful spasms and muscle rigidity involving the lumbar spine and legs. Typically, it presents with an ankylosing gait accompanied by excessive lumbar lordosis. Characteristic abnormalities are usually observed in EMG recordings of continuous motor unit activity of the paravertebral axial muscles. A variant includes "limb rigidity syndrome," which results in localized rigidity, typically affecting the distal legs and feet.

[0303] Gait disorders refer to abnormalities in the mode or style of walking, resulting from neuromuscular, arthritis, or other physical changes. Gaits are classified according to a system of abnormal walking movements and include hemiplegic gait, diplegic gait, neuropathic gait, myopathy gait, Parkinson's disease-like gait, chorea-like gait, ataxic gait, and sensory gait.

[0304] Anesthesia / Sedation Anesthesia is a pharmacologically induced, reversible state of amnesia, analgesia, loss of responsiveness, loss of skeletal muscle reflexes, reduced stress response, or all of these simultaneously. These effects can be obtained from a single drug that provides a suitable combination of effects on its own, or sometimes from a combination of drugs (e.g., hypnotics, sedatives, anesthetics, analgesics) to obtain a highly specific combination of results. Anesthesia allows a patient to undergo surgery and other procedures without the pain and discomfort they would otherwise experience.

[0305] Sedation is generally the reduction of hypersensitivity or agitation by administering medication to facilitate medical or diagnostic procedures.

[0306] Sedation and analgesia include a continuum of consciousness ranging from mild sedation (anxiety relief) to general anesthesia.

[0307] Mild sedation is also known to relieve anxiety. Minimal sedation is an induced state in which the patient responds normally to verbal instructions during that time. Cognitive function and coordination may be impaired. Respiratory and cardiovascular function are typically unaffected.

[0308] Moderate sedation / analgesia (conscious sedation) is drug-induced decreased consciousness in which the patient intentionally responds to verbal commands, either alone or in response to tactile or optical stimuli. Usually, no measures are needed to maintain an open airway. Spontaneous breathing is usually sufficient. Cardiovascular function is usually preserved.

[0309] Deep sedation / analgesia is a drug-induced decrease in consciousness during which the patient cannot easily awaken but responds intentionally (not a reflex elicited from painful stimuli), followed by repeated or painful stimuli. Independent respiratory function may be impaired, and the patient may require assistance to maintain an open airway. Spontaneous breathing may be insufficient. Cardiovascular function is usually maintained.

[0310] General anesthesia is drug-induced loss of consciousness in which the patient is unable to awaken even in response to painful stimuli. The ability to maintain independent respiratory function is often impaired, and assistance is frequently required to maintain an open airway. Positive pressure ventilation may be required due to decreased spontaneous respiration or drug-induced neuromuscular dysfunction. Cardiovascular function may be impaired.

[0311] Sedation in the intensive care unit (ICU) suppresses the patient's awareness of the environment and external stimuli. This allows for a reduction in the response to certain conditions. This can play a role in treating critically ill patients and encompasses a wide range of symptom management that will vary between patients and between individuals throughout the course of a patient's illness. Deep sedation has often been used in life-saving medicine, along with neuromuscular blocking agents, to facilitate endotracheal tube tolerance and respiratory synchronization.

[0312] In some embodiments, sedation (e.g., prolonged sedation, continuous sedation) is induced and maintained in the ICU over a long period (e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months). Long-acting drugs may have a long duration of action. Sedatives in the ICU may have a short elimination half-life.

[0313] Procedural sedation and analgesia, also known as conscious sedation, is a technique that involves administering sedatives or dissociative agents, with or without analgesics, to induce a state in which the subject can tolerate unpleasant procedures while maintaining cardiopulmonary function. [Examples]

[0314] The following examples are provided to allow for a better understanding of the present invention as described herein. The synthetic and biological examples provided herein are for illustrative purposes only and should not be construed as limiting their scope.

[0315] Substances and methods The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are indicated, it will be understood that other process conditions can also be used unless otherwise stated. Optimal reaction conditions may vary depending on the specific reactants or solvent used, but such conditions can be determined by routine optimization for those skilled in the art.

[0316] In addition, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. Selecting appropriate protecting groups for specific functional groups, and furthermore, appropriate conditions for protection and deprotection, is well known in the art. For example, numerous protecting groups, as well as their introduction and removal, are described in TW Greene and PGMWuts, *Protecting Groups in Organic Synthesis*, Second Edition, Wiley, New York, 1991, and the references cited therein.

[0317] The compounds provided herein can be isolated and purified by known standard procedures. Such procedures include, but are not limited to, recrystallization, column chromatography, HPLC, or supercritical fluid chromatography (SFC). The following scheme is shown with details of the preparation of representative oxysterols listed herein. The compounds provided herein can be prepared from starting materials and reagents known or commercially available to those skilled in the art of organic synthesis. Exemplary chiral columns available for use in the separation / purification of the enantiomers / diastereomers provided herein include, but are not limited to, CHIRALPAK® AD-10, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ, and CHIRALCEL® OK.

[0318] This specification reports 1 ¹H-NMR (e.g., for a δ(ppm) range between approximately 0.5 and 4 ppm) will be understood as an exemplary description of the NMR spectrum of a compound (e.g., exemplary peak integral). Exemplary general method for preparative HPLC: Column: Waters RBridge prep 10 μm C18, 19 × 250 mm. Mobile phase: Acetonitrile, water (NH4HCO3) (30 L water, 24 g NH4HCO3, 30 mL NH3.H2O). Flow rate: 25 mL / min.

[0319] Exemplary general method for analytical HPLC: Mobile phase: A: Water (10 mM NH4HCO3), B: Acetonitrile, Gradient: B 5% to 95% in 1.6 or 2 mins, Flow rate: 1.8 or 2 mL / min; Column: XBridge C18, 4.6 × 50 mm, 3.5 μm, 45C.

[0320] Exemplary general method for preparative HPLC: Column Waters Xbridge 150×25 5u, conditions: water (10mM NH4HCO3)-ACN, start B85, end B100, gradient time (min) 6.5, retention time (min) at B100% 1, flow rate (ml / min) 25, injection 4).

[0321] Exemplary general method for SFC: Column: DAISEL CHIRALPAK AD (250mm x 50mm, 10μm; Condition: 0.1% NH3H2O ​​ETOH; Start B: 25%, End B: 25%; Flow rate (ml / min): 200)

[0322] Exemplary general method for LC-MS / LC-ELSD: 30-90°A 2 mins. (Mobile phase: 1.5 mL / 4 L TFA in water (solvent A) and 0.75 mL / 4 L TFA in acetonitrile (solvent B), using a flow rate of 1.2 mL / min with an elution gradient of 30%-90% (solvent B) over 0.9 mins and retention at 90% over 0.6 mins; Column: Xtimate C18 2.1 × 30 mm, 3 μm; Wavelength: UV 220 nm; Column temperature: 50°C; MS ionization: ESI; Detector: PDA & ELSD)

[0323] Abbreviations: PE: Petroleum ether; Depositphotos: Ethyl acetate; THF: Tetrahydrofuran; PCC: Pyridinium chlorochromate; TLC: Thin-layer chromatography; PCC: Pyridinium chlorochromate; t-BuOK: Potassium tert-butoxide; 9-BBN: 9-borabicyclo[3.3.1]nonane; Pd(t-Bu3P)2: Bis(tri-tert-butylphosphine)palladium(0); AcCl: Acetyl chloride; i-PrMgCl: Isopropyl magnesium chloride; TBSCl: Tert-butyl(chloro)dimethylsilane; (i-PrO)4Ti: Titanium tetraisopropoxide; BHT: 2,6-di- t-butyl-4-methylphenoxide; Me: methyl; i-Pr: isopropyl; t-Bu: tert-butyl; Ph: phenyl; Et: ethyl; Bz: benzoyl; BzCl: benzoyl chloride; CsF: cesium fluoride; DCC: dicyclohexylcarbodiimide; DCM: dichloromethane; DMF: N,N-dimethylformamide; DMAP: 4-dimethylaminopyridine; DMSO: dimethyl sulfoxide; DMP: des-martinperiodinane; EtMgBr: ethylmagnesium bromide; Â: ethyl acetate; TEA: triethylamine; AlaOH: alanine; Boc: t-butoxycarbonyl. Py: Pyridine; TBAF: Tetra-n-butylammonium fluoride; THF: Tetrahydrofuran; TBS: t-butyldimethylsilyl; TMS: Trimethylsilyl; TMSCF3: (Trifluoromethyl)trimethylsilane; Ts: p-toluenesulfonyl; Bu: Butyl; Ti(OiPr)4: Tetraisopropoxytitanium; LAH: Lithium aluminum hydride; LDA: Lithium diisopropylamide; LiOH.H2O: Lithium hydroxide hydrate; MAD: Methylaluminum bis(2,6-di-t-butyl-4-methylphenoxide); MeCN: Acetonitrile; NBS: N-bromosuccinimide ;Na2SO4: Sodium sulfate;Na2S2O3: Sodium thiosulfate;MeCN: Acetonitrile;MeOH: Methanol;Boc: t-Butoxycarbonyl;MTBE: Methyl tert-butyl ether;K-Selectride: Potassium tri(s-butyl)borohydride;9-BBN dimer: 9-Borabicyclo(3.3.1)nonane (dimer).

[0324] Example 1: 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-one( compound Synthesis of A9) [ka] compound A2 synthesis [ka] To a suspension of MePPh3Br (145 g, 408 mmol) in THF (300 mL), t-BuOK (45.7 g, 408 mmol) was added at 15°C. After stirring at 45°C for 0.5 hours, the mixture was then added to THF (200 mL). compound A solution of A1 (CAS# 5696-44-6) (80 g, 204 mmol) was added at 45°C, and the reaction mixture was stirred at 45°C for 1 hour. The mixture was diluted with PE (300 mL) and then filtered. The filtrate was concentrated to obtain an oily substance (200 g). The product was stirred with PE (1 L) for 16 hours, after which the solid was filtered, and the filtrate was concentrated to obtain the product. compound A2 was obtained as an oily substance and used as is in the next step. 1 HNMR (400 MHz, CDCl3) δ H6.30 (dd, J = 11.2, 17.6 Hz, 1H),5.15-4.96(m, 2H), 3.94-3.81 (m, 8H), 2.02-1.73 (m, 7H), 1.58-1.35 (m, 13H), 1.22-1.14(m,2H), 0.81 (s, 3H).

[0325] compound A3 composite [ka] To a solution of Et2Zn (30.5 mL, 1 M in hexane) in 50 mL of DCM at 0°C, CF3COOH (3.47 g, 30.4 mmol) (in 5 mL of DCM) was added dropwise over 1 hour under an N2 atmosphere. Then, CH2I2 (8.16 g, 30.5 mmol) (in 5 mL of DCM) was added dropwise to the mixture over 15 minutes. After the addition, compound A2 (4g, 10.2 mmol) (in 5 mL of DCM) was added to the reaction mixture and stirred at 0°C for 3 hours, then stirred at 25°C for 16 hours. The reaction mixture was quenched by adding saturated NH4Cl aqueous solution (80 mL), and the aqueous phase was extracted with DCM (3 × 60 mL). The combined organic phase was washed with brine (50 mL), dried on anhydrous Na2SO4, filtered, and concentrated. compound A3 (4.5g) was obtained as an oily substance (based on H-NMR, approximately 40% of the starting material remained).

[0326] compound A4 and compound A5 synthesis [ka] THF (25 mL) compoundTo a solution of A3 (4.5g), hydrogen chloride (12mL, 2M aqueous solution) was added, and the reaction mixture was stirred at 25°C for 16 hours. Saturated NaHCO3 (50mL) was added to the reaction mixture to a pH of approximately 8, and the mixture was extracted with RINKAN (2×80mL). The combined organic phase was washed with brine (50mL), dried on anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column (0-10% RINKAN in PE), compound A5 (1.1g) was obtained. Purification by SFC (column: DAISEL CHIRALPAK AD (250mm x 50mm, 10μm; conditions: 0.1% NH3H2O ​​ETOH; start B: 25%, end B: 25%; flow rate (ml / min): 200) compound A4 (550 mg, 29.1%) and compound Both A5 (420 mg) were obtained as oily substances. compound A4: 1 1H NMR (400 MHz, CDCl3)δ H 2.73-2.61 (m, 1H), 2.47 (dd, J=8.8, 19.2 Hz, 1H), 2.35-2.22 (m, 1H),2.17-1.85 (m,8H), 1.77-1.61 (m,4H), 1.56-1.50 (m, 1H), 1.47-1.39 (m, 1H), 1.36-1.22(m, 5H),0.92 (s, 3H), 0.90-0.84 (m, 1H), 0.54- 0.40 (m, 2H), 0.34- 0.25 (m, 1H),0.12- 0.04(m, 1H).

[0327] compound A6 synthesis [ka] To a solution of BHT (2.22 g, 10.08 mmol) in toluene (6 mL) under nitrogen at 0°C, AlMe3 (2.6 mL, 2 M in toluene) was added dropwise. The mixture was stirred at 25°C for 1 hour. Without monitoring or further purification, the reaction mixture was used as is as a solution of MAD for the next step. In the MAD (5.04 mmol) solution, in DCM (5 mL) compound A solution of A4 (530 mg, 1.68 mmol) was added dropwise at -70°C. After stirring under N2 at -70°C for 1 hour, MeMgBr (1.7 mL, 5.1 mmol, 3 M in ethyl ether) was added dropwise at -70°C. The resulting solution was stirred at -70°C for a further 3 hours. The reaction mixture was poured into saturated citric acid aqueous solution (100 mL) at less than 10°C and extracted with pharmaceutically acceptable phosphate (2 × 80 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column (0-20% pharmaceutically acceptable phosphate in PE). compound A6 (480 mg, 86.4%) was obtained as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 2.44(dd, J=8.2, 19.2Hz, 1H), 2.14-1.88 (m, 4H), 1.87-1.76 (m, 2H), 1.64-1.60 (m, 1H),1.58-1.49 (m, 5H),1.48-1.33 (m, 4H), 1.31-1.21 (m, 6H), 1.19 (s, 3H), 0.88 (s,3H), 0.56-0.33 (m, 3H),0.30-0.20 (m, 1H), 0.10-0.00 (m, 1H). LC-MS Rt=2 min chromatography for 0.980 min, 30-90 AB_2 min. (Mobile phase: 1.5 mL / 4 L TFA in water (solvent A) and 0.75 mL / 4 L TFA in acetonitrile (solvent B), elution gradient 30-90% (solvent B) over 0.9 min at a flow rate of 1.2 mL / min and retention at 90% for 0.6 min; Column: Xtimate C18 2.1 × 30 mm, 3 μm; Wavelength: UV 220 nm; Column temperature: 50 °C; MS ionization: ESI; Detector: PDA & ELSD), LC-ELSD purity 99%; C 22 H 33 MS ESI calculation value for O [M-H2O+H] + 313.2, measured value 313.2.

[0328] compound A7 synthesis [ka] To a mixture of EtPPh3Br (1.52 g, 4.11 mmol) in THF (10 mL), t-BuOK (461 mg, 4.11 mmol) was added at 25°C under N2 conditions. The resulting mixture was stirred at 50°C for 30 minutes. compound A6 (455 mg, 1.37 mmol) was added at a temperature below 40°C. The reaction mixture was stirred at 40°C for 3 hours to obtain a suspension. The reaction mixture was quenched at 25°C with saturated NH4Cl aqueous solution (150 mL). The aqueous solution was extracted with toluene (2 × 80 mL). The combined organic phase was concentrated. The residue was purified by flash column (0-10% toluene in PE). compound A7 (320 mg, 68.2%) was obtained as an oily substance. 1 HNMR (400MHz, CDCl3) δ H5.16-5.07 (m, 1H), 2.42-2.31 (m, 1H),2.29-2.13(m, 2H), 2.07-1.89 (m, 2H), 1.68-1.61 (m, 5H), 1.54-1.40 (m, 6H), 1.38-1.14(m, 12H), 0.93-0.79 (m, 4H), 0.53-0.33 (m, 3H), 0.29-0.16 (m, 1H), 0.09-0.04 (m,1H).

[0329] compound A8 synthesis [ka] THF (10 mL) compound To a solution of A7 (300 mg, 0.88 mmol), 9-BBN dimer (427 mg, 1.75 mmol) was added and the mixture was stirred at 45°C for 14 hours. To the resulting mixture, ethanol (2 mL) was added at 15°C, followed by NaOH aqueous solution (1.75 mL, 5.0 M, 8.75 mmol) at 0°C. Hydrogen peroxide (1 mL, 10 M, 10 mmol) was added dropwise at 0°C. The reaction mixture was stirred at 78°C for 1 hour. The mixture was cooled to 15°C. The mixture was added to water (10 mL). Saturated Na2S2O3 aqueous solution (20 mL) was added, and the mixture was checked with potassium iodide starch test paper to confirm that the excess H2O2 had decomposed (did not turn blue). The aqueous phase was extracted with ELISA (3 × 40 mL). The combined organic phases were washed with brine (20 mL), dried on anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column (10-35% Â in PE) to obtain both isomer 1 (150 mg) and isomer 2 (80 mg) as solids. Isomer 1: 1 1H NMR (400 MHz, CDCl3) δ H3.76-3.63 (m, 1H),2.02-1.82 (m, 4H), 1.71-1.60 (m, 3H), 1.53-1.32 (m, 9H), 1.31-1.09(m, 15H), 0.67(s, 3H), 0.52-0.33 (m, 3H), 0.28 0.19 (m, 1H), 0.08-0.03 (m, 1H). Isomer 2: 1 1H NMR (400 MHz, CDCl3) δ H 3.79-3.66 (m, 1H),2.07-1.81 (m, 5H), 1.71-1.59(m, 4H),1.50-1.33 (m, 6H), 1.32-1.10 (m, 16H), 0.77(s, 3H), 0.51-0.33 (m, 3H), 0.27-0.19 (m, 1H), 0.07-0.02 (m, 1H).

[0330] compound A9 synthesis [ka] DCM (2 mL) compound To a solution of A8 (80 mg, 0.22 mmol), DMP (188 mg, 0.44 mmol) was added, and the reaction mixture was stirred at 25°C for 6 hours. The reaction mixture was quenched with saturated NaHCO3 (80 mL) and saturated Na2S2O3 (30 mL), and extracted with DCM (2 × 50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column (10-30% toluene in PE). compound A9 was obtained as a solid. 1 HNMR (400 MHz, CDCl3)δ H2.54 (t, J=8.8 Hz, 1H), 2.28-2.14(m, 1H), 2.11 (s, 3H), 2.06- 1.90(m, 3H), 1.72-1.57 (m,5H), 1.53-1.35 (m, 6H),1.33-1.11 (m, 11H),0.62 (s, 3H), 0.53-0.35(m, 3H), 0.28-0.20 (m, 1H), 0.07-0.01(m, 1H);LC-ELSD purity 99%;C 24 H 37 MS ESI calculation value for O [M-H2O+H] + 341.3, measured value 341.3.

[0331] Example 2: 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitriel compound Synthesis of A11) [ka] compound Synthesis of A10 [ka] MeOH (2ml) compound To a solution of A9 (60 mg, 0.17 mmol), HBr (6.75 mg, 0.03 mmol, 40% in water) and Br2 (32 mg, 0.2 mmol) were added at 25°C. The mixture was stirred at 25°C for 2 hours. The mixture was quenched with saturated NaHCO3 aqueous solution (10 mL), treated with water (30 mL), and extracted with siRNA (2 × 50 mL). The combined organic phase was washed with brine (30 mL), dried on anhydrous Na2SO4, filtered, and concentrated. compound A10 (65 mg) was obtained as an oily substance and used as is for the next step.

[0332] compound Synthesis of A11 [ka] In acetone (2 mL) compound To a solution of A10 (65 mg, 0.15 mmol), K2CO3 (61.5 mg, 0.45 mmol) and 1H-pyrazole-4-carbonitrile (20.7 mg, 0.22 mmol) were added, and the reaction mixture was stirred at 25°C for 14 hours. Water (20 mL) was added to the mixture, and it was extracted with RINKAN (2 × 30 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column (20-50% RINKAN in PE), compound A11 (15 mg, 22.4%) was obtained as a solid. 1 HNMR (400MHz, CDCl3) δ H 7.85 (s, 1H), 7.81 (s, 1H), 5.06-4.85(m, 2H),2.61 (t, J=8.8 Hz, 1H), 2.27-2.15 (m, 1H), 2.09-1.89 (m, 3H), 1.81-1.63(m, 4H),1.54-1.37 (m, 5H), 1.32-1.18 (m, 12H), 0.92-0.78 (m, 1H), 0.68 (s, 3H),0.54-0.35(m, 3H), 0.29-0.21 (m, 1H), 0.07-0.01 (m, 1H);LC-ELSD purity 99%; C 28 H 39 MS ESI calculation value for N3O2Na [M+Na] + 472.3, measured value 472.3.

[0333] Example 4: 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-cyclopropyl-3-(ethoxymethyl)-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane-1-one, compound 4.12 Synthesis [ka] compound 4.2 Synthesis In THF (500mL) compound To a solution of 4.1 (50 g, 165 mmol), Pd-C (wet, 10%, 5 g) was added under N2. The suspension was degassed under vacuum and purged three times with H2. The mixture was stirred under H2 (15 psi) at 25°C for 16 hours to obtain a suspension. The reaction mixture was filtered through a Celite pad and washed with THF (3 × 200 mL). The filtrate was concentrated, compound 4.2 (40g) was obtained as a solid. The solid was then divided into five other batches (5 × 50g) in acetone (150mL). compound Blend with (from 4.1) and stir at 25°C for 1 hour. Filter the mixture. compound 4.2 (180g) was obtained as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 3.94(dd, J = 4.8, 10.8Hz, 1H), 3.67 (dd, J = 5.6, 10.8 Hz, 1H), 2.64 (t, J = 14.4 Hz,1H), 2.45 (dd, J= 8.8, 19.6 Hz, 1H), 2.39-2.23 (m, 3H), 2.12-1.80 (m, 8H), 1.69-1.19(m, 10H), 0.86(s, 3H)

[0334] compound 4.3 Synthesis In toluene (1500 mL) compound To a solution of 4.2 (180 g, 591 mmol), pyridine hydrochloride (13.5 g, 118 mmol) and ethane-1,2-diol (183 g, 2955 mmol) were added. The mixture was stirred at 140°C for 48 hours. The mixture was cooled to 25°C. Then, water (1000 mL) was added to the mixture, and then extracted with dimethyl phosphate (3 × 1000 mL). The combined organic phase was washed with brine (2 × 1000 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated. compound 4.3 (180g, 460mmol) was obtained as an oily substance. 1 1H NMR (400 MHz, CDCl3) δ H3.95-3.79(m, 10H), 2.05-1.92(m, 3H), 1.78-1.64 (m, 5H), 1.56-1.36 (m, 10H), 1.30-1.03 (m,5H), 0.82 (s, 3H)

[0335] compound 4.4 Synthesis In DCM (1000mL) compound To a solution of 4.3 (100 g, 254 mmol), silica gel (82 g) and PCC (81.9 g, 381 mmol) were gradually added at 25°C. The mixture was stirred at 25°C for 1 hour. The mixture was filtered, and the filter cake was washed with DCM (3 × 200 mL). The combined filtrate was concentrated to obtain the product. compound 4.4 (100g, 254 mmol) was obtained as an oily substance. 1 1H NMR (400 MHz, CDCl3) δ H 9.57(s, 1H), 3.96-3.84(m, 8H), 2.26-2.07 (m, 2H), 1.84-1.46(m, 20H), 0.91 (s, 3H)

[0336] compound 4.5 synthesis To a solution of t-BuOK (86.1 g, 768 mmol) in THF (500 mL), PPh3MeBr (274 g, 768 mmol) was added at 25°C. After stirring at 50°C for 0.5 hours, the mixture was then added to THF (300 mL). compound 4.4 (100g, 256 mmol) solution was added to the reaction mixture at 50°C. After stirring at 50°C for 12 hours, the mixture was poured into water (1000mL) and extracted with ELISA (2×500mL). The combined organic phase was washed with saturated brine (2×500mL), dried on anhydrous Na2SO4, filtered, and concentrated under vacuum (100g). The solid was ground in MTBE (500mL) at 25°C, compound 4.5 (90g) was obtained as an oily substance. The oily substance was again ground in MTBE (500mL) at 25°C. compound4.5 (80 g) was obtained as an oily substance, which was purified by flash column (0-10% siRNA in PE), compound 4.5 (30g, 38%) was obtained as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 6.30(dd, J = 11.2, 17.6Hz, 1H), 5.13-5.01 (m, 2H), 3.94-3.83 (m, 8H), 2.01-1.76 (m,6H), 1.54-1.36 (m, 12H),1.27-1.15 (m, 4H), 0.81 (s, 3H)

[0337] Synthesis of compound 4.6 To a solution of Et2Zn (46.2 mL, 1 M in hexane) in 250 mL of DCM at 0°C, CF3COOH (4.38 g, 38.5 mmol) was added dropwise over 1 hour under an N2 atmosphere, followed by the dropwise addition of CH2I2 (12.3 g, 46.2 mmol) over 15 minutes, and finally, compound 4.5 (6 g, 15.4 mmol) from 50 mL of DCM was added dropwise. The reaction mixture was stirred at 0°C for 1 hour, and then stirred at 25°C for 12 hours. The reaction mixture was quenched by the addition of saturated NH4Cl aqueous solution (150 mL). The aqueous phase was extracted with DCM (3 × 100 mL). The combined organic phase was washed with brine (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain compound 4. 6 (6.0 g, 14.9 mmol) was obtained as an oily substance and used as is.

[0338] compound 4.7 Synthesis THF (50 mL) compoundTo a solution of 4.6 (6.0 g, 14.9 mmol), hydrogen chloride (14.9 mL, 29.8 mmol, 2 M) was added. After stirring at 25°C for 16 hours, the reaction mixture was adjusted to pH=8 with saturated NaHCO3 (150 mL) and extracted with toluene (3 × 50 mL). The combined organic phase was washed with brine (2 × 100 mL), dried on anhydrous Na2SO4, filtered, concentrated, and then purified by flash column (0-30% toluene in PE). compound 4.7 (1.8g, 52%) was obtained as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 2.72-2.62(m, 1H), 2.52-2.22(m, 3H), 2.16-2.06 (m, 4H), 2.01 -1.67 (m, 7H), 1.60-1.29 (m,8H), 0.92 (s, 3H),0.55-0.36 (m, 2H), 0.34-0.25 (m, 1H), 0.12 -0.02 (m, 1H)

[0339] compound 4.8 Synthesis To a stirred solution of trimethylsulfonium iodide (2.42 g, 11.9 mmol) in DMSO (10 mL) and THF (5 mL), NaH (475 mg, 11.9 mmol, 60% in oil) was added under N2 conditions at 0°C for 1.0 hour. To the mixture, in DMSO (5 mL) compound A solution of 4.7 (2.5 g, 7.9 mmol) was added at 0°C. After stirring at 25°C for 6 hours, the reaction product was diluted with water (50 mL) and extracted with SiO (3 × 20 mL). The combined organic phase was washed with water (2 × 50 mL) and brine (2 × 50 mL), dried on anhydrous Na₂SO₄, filtered, and concentrated under vacuum. compound 4.8 (2.5 g, 7.6 mmol) was obtained as an oily substance and used as is.

[0340] compound 4.9a and compound 4.9b Synthesis To 10 mL of anhydrous ethoxysodium, Na (874 mg, 38.0 mmol) was added in three portions at 25°C. After stirring at 75°C for 1 hour, the ethoxysodium solution was mixed with anhydrous ethoxysodium (20 mL) compound 4.8 (2.5 g, 7.6 mmol) was added at 75°C. After stirring at 75°C for 4 hours, the reaction mixture was diluted with water (50 mL), then concentrated to remove most of the solvent. The mixture was extracted with pharmaceutically acceptable toluene (2 × 30 mL). The combined organic phase was washed with saturated brine (2 × 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by flash column (0-30% toluene in PE). compound 4.9a (950mg, %de>99( 1 R by 1H NMR f =0.3, PE / A=3 / 1) and compound 4.9b(750mg, %de>99( 1 (by H NMR), R f Both (=0.55, PE / dimethyl=3 / 1) were obtained as oily substances.

[0341] compound 4.9a (50 mg) was further purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150×30 5μ, gradient: 50~80%B (water (10mM NH4HCO3)-ACN, flow rate: 25 mL / min), compound 4.9a (10 mg, 20%) was obtained as a solid.

[0342] compound 4.9b (50 mg) was further purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150×30 5μ, gradient: 60~90%B (water (10mM NH4HCO3)-ACN, flow rate: 25 mL / min), compound 4.9b (12 mg, 24%) was obtained as a solid.

[0343] compound 4.9a: 1 1H NMR (400 MHz, CDCl3) δ H3.52 (q, J = 7.2 Hz, 2H), 3.34 (dd, J= 8.8, 24.0Hz, 2H), 2.68 (s, 1H), 2.44 (dd, J = 8.4, 19.2 Hz, 1H), 2.14-1.59 (m,9H), 1.55-1.24(m, 12H), 1.20 (t, J = 6.8 Hz, 3H), 0.88 (s, 3H), 0.47-0.36 (m, 3H),0.29-0.21 (m,1H), 0.06--0.03 (m,1H) LC-ELSD / MS purity 99%, C 24 H 37 MS ESI calculation value for O2 [M-H2O+H] + 357.2, measured value 357.2. compound 4.9b: 1 1H NMR (400 MHz, CDCl3) δ H 3.52 (q, J = 7.2 Hz, 2H), 3.22 (dd, J= 8.8, 12.8Hz, 2H), 2.45 (dd, J = 8.4, 19.2 Hz, 1H), 2.13-1.61 (m, 9H), 1.56-1.08(m, 16H),0.95-0.85 (m, 4H), 0.47- 0.34 (m, 2H), 0.29-0.17 (m, 2H) LC-ELSD / MS purity 99%, C 24 H 37 MS ESI calculation value for O2 [M-H2O+H] + 357.3, measured value 357.3.

[0344] compound 4.10 Synthesis Ethyl triphenylphosphonium bromide (4.41 g, 11.9 mmol) was added at 25°C to a solution of t-BuOK (1.33 g, 11.9 mmol) in THF (20 mL). After stirring at 40°C for 0.5 hours, the mixture was added to THF (10 mL). compoundA solution of 4.9a (900 mg, 2.4 mmol) was added to the reaction mixture at 40°C. After stirring at 40°C for 16 hours, the mixture was poured into water (50 mL) and extracted with siRNA (2 × 20 mL). The combined organic phase was washed with saturated brine (2 × 50 mL), dried on anhydrous Na₂SO₄, filtered, and concentrated under vacuum to obtain the residue, which was purified by flash column (0-30% siRNA in PE). compound 4.10 (300 mg, 32%) was obtained as an oily substance. 1 1H NMR (400 MHz, CDCl3) δ H 5.14-5.09(m, 1H), 3.51(q, J = 7.2 Hz, 2H), 3.34 (dd, J = 9.6,15.2 Hz, 2H), 2.40-2.16 (m,4H), 2.01-1.82(m, 3H), 1.68-1.45 (m, 16H), 1.30-1.10 (m, 6H), 0.88 (s, 3H), 0.45-0.30(m, 3H),0.28-0.17 (m, 1H), 0.02--0.08 (m, 1H)

[0345] compound 4.11 synthesis THF (10 mL) compound9-BBN dimer (2.01 g, 8.24 mmol) was added to a solution of 4.10 (800 mg, 2.1 mmol) at 25°C. The mixture was then stirred at 40°C for 16 hours to obtain a solution. After cooling to 0°C, the mixture was very slowly diluted with ethanol (1.89 g, 41.2 mmol), and then with NaOH (8.24 mL, 41.2 mmol, 5 M). After the addition was complete, H2O2 (4 mL, 39.7 mmol, 30%) was slowly added, maintaining the internal temperature below 25°C. After stirring at 75°C for 1 hour, saturated Na2S2O3 aqueous solution (50 mL) was added, and the mixture was stirred at 0°C for another 1 hour. The reaction product was checked with potassium iodide-starch test paper to confirm that the excess H2O2 had decomposed. The mixture was cooled and added to water (50 mL). The mixture was extracted with toluene (3 × 20 mL), washed with saturated brine (2 × 50 mL), dried on anhydrous sodium 2SO4, filtered, and concentrated below. The residue (800 mg) was purified by flash column (0-30% toluene in PE), compound 4.11 (400 mg, 50%) was obtained as an oily substance. 1 1H NMR (400 MHz, CDCl3) δ H 3.72-3.65(m, 1H), 3.51(q, J = 6.8 Hz, 2H), 3.34 (dd, J = 9.6,24.0 Hz, 2H), 2.00-1.83 (m,7H), 1.69-1.32(m, 15H), 1.28-1.11 (m, 9H), 0.66 (s, 3H), 0.44-0.30 (m, 3H), 0.27-0.17(m, 1H),0.02-0.09 (m, 1H)

[0346] compound 4.12 Synthesis DCM (10 mL) compoundTo a solution of 4.11 (200 mg, 0.5 mmol), DMP (419 mg, 0.9884 mmol) was gradually added. After stirring at 25°C for 0.5 hours, the mixture was quenched with NaHCO3 (50 mL) and extracted with siRNA (3 × 10 mL). The combined organic layer was washed with Na2S2O3 (2 × 50 mL) and brine (2 × 50 mL), dried on anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue (190 mg) was purified by flash column (0-50% siRNA in PE), compound 4.12 (180 mg, 95%) was obtained as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 3.52 (q, J = 6.8 Hz, 2H), 3.34 (dd, J = 8.8, 23.2 Hz, 2H), 2.70 (s, 1H), 2.55 (t, J =8.8Hz, 1H), 2.11 (m, 4H), 2.03-1.86 (m, 3H), 1.74-1.59 (m, 5H), 1.54-1.36 (m, 7H),1.29-1.13(m, 9H), 0.62 (s,3H), 0.47-0.31 (m, 3H), 0.28-0.18 (m, 1H), 0.04--0.07(m, 1H);LC-ELSD / MS purity 98%, C 26 H 41 MS ESI calculation value for O2 [M-H2O+H] + 385.3, measured value 385.3.

[0347] Example 5: 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-cyclopropyl-3-(ethoxymethyl)-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile, compound 5.2 Synthesis [ka] MeOH (10ml) compoundTo a solution of 4.12 (60 mg, 0.15 mmol), HBr (6.5 mg, 0.03 mmol, 40% in water) and Br2 (26.1 mg, 0.16 mmol) were added at 25°C. After stirring at 25°C for 2 hours, the mixture was quenched with saturated NaHCO3 aqueous solution (30 mL) and water (30 mL), and then extracted with siRNA (3 × 20 mL). The combined organic phase was washed with brine (2 × 50 mL), dried on anhydrous Na2SO4, filtered, and concentrated under vacuum. compound 5.1 (70 mg, 0.15 mmol) was obtained as an oily substance and used directly for the next step without further purification.

[0348] compound 5.2 Synthesis In acetone (5 mL) compound To a solution of 5.1 (70 mg, 0.15 mmol), 1H-pyrazole-4-carbonitrile (20.2 mg, 0.22 mmol), followed by K2CO3 (40.1 mg, 0.29 mmol), was added. After stirring at 50°C for 2 hours, the mixture was diluted with water (30 mL) and then extracted with siRNA (3 × 10 mL). The combined organic phase was washed with brine (2 × 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 5 μm, gradient: 60~90% B (water (10 mM NH4HCO3)-ACN, flow rate: 25 mL / min)). compound 5.2 (17 mg, 24%) was obtained as a solid. 1 1H NMR (400 MHz, CDCl3) δ H7.85(s, 1H), 7.80(s,1H), 4.95 (dd, J = 18.0, 51.2 Hz, 2H), 3.52 (q, J = 6.8 Hz, 2H),3.34 (dd, J = 9.2,22.4 Hz, 2H), 2.72 (s, 1H), 2.61 (t, J = 8.4 Hz, 1H), 2.26-1.74(m, 6H), 1.65-1.42(m, 9H),1.37-1.17 (m, 10H), 0.67 (s, 3H), 0.47-0.32 (m, 3H),0.29-0.19 (m, 1H), 0.05--0.04(m,1H);LC-ELSD / MS purity 97%, C 30 H 42 MS ESI calculation value for N3O2 [M-H2O+H] + 476.3, measured value 476.3.

[0349] Example 6: 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-cyclopropyl-3-(ethoxymethyl)-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile, compound 6 synthesis [ka] In acetone (10 mL) compound To a solution of 5.1 (110 mg, 0.23 mmol), 1H-pyrazole-5-carbonitrile (31.8 mg, 0.34 mmol) and K2CO3 (63.1 mg, 0.46 mmol) were added. After stirring at 50°C for 2 hours, the mixture was added to saturated water (50 mL) and then extracted with RINKAN (3 × 10 mL). The combined organic phase was washed with brine (2 × 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by preparative HPLC (column: Xtimate C18 150 × 25 mm × 5 μm, gradient: 65~95% B (water (10 mM NH4HCO3)-ACN, flow rate: 30 mL / min)). compound 6 (28 mg, 25%) was obtained as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 7.48(d, J = 2.4 Hz,1H), 6.73 (d, J = 2.4 Hz, 1H), 4.97 (dd, J =18.0, 53.2 Hz, 2H),3.52 (q, J = 7.2Hz, 2H),3.35 (dd, J = 9.2, 22.4 Hz, 2H), 2.72 (s, 1H), 2.61 (t,J = 8.8 Hz, 1H),2.25-1.88 (m, 4H), 1.79-1.59 (m, 6H), 1.52-1.18 (m, 15H), 0.68(s, 3H), 0.48-0.34(m, 3H), 0.31-0.20 (m, 1H), 0.06-0.07 (m, 1H); Structure confirmed by HMBC (H1 showed a clear signal together with C4); LC-ELSD / MS purity 99%, C 30 H 42 MS ESI calculation value for N3O2 [M-H2O+H] + 476.3, measured value 476.3.

[0350] Example 7: 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-cyclopropyl-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-one, compound 7.4 Synthesis [ka] compound 7.1a and compound 7.1b Synthesis Three portions of Na (979 mg, 42.6 mmol) were added to 10 mL of anhydrous MeOH at 25°C. The reaction mixture was stirred at 65°C for 1 hour. In the sodium methylate solution, anhydrous MeOH (20 mL) compound4.8 (2.8 g, 8.5 mmol) was added at 65°C. After stirring at 65°C for 4 hours, the reaction mixture was diluted with water (50 mL), then concentrated to remove most of the solvent. The mixture was extracted with toluene (2 × 20 mL). The combined organic phase was washed with saturated brine (2 × 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by flash column (0-10% toluene in PE). compound 7.1a(900mg, Rf=0.2, PE / EtOAc=3 / 1,%de>99( 1 (by 1H NMR) and compound 7.1b(900mg, Rf=0.35, PE / EtOAc=3 / 1),%de>99( 1 The result was obtained by 1H NMR.

[0351] compound 7.1a (100 mg) was separated and purified by HPLC (column: Waters Xbridge Prep OBD C18 150×30 5 μm, gradient: 58~88%B (water (10 mM NH4HCO3)-ACN, flow rate: 25 mL / min), compound 7.1a (24 mg, 24%) was obtained as a solid.

[0352] compound 7.1b (100 mg) was separated and purified by HPLC (column: Waters Xbridge Prep OBD C18 150×30 5 μm, gradient: 58~88%B (water (10 mM NH4HCO3)-ACN, flow rate: 25 mL / min), compound 7.1b (25 mg, 25%) was obtained as a solid. compound 7.1a: 1 1H NMR (400 MHz, CDCl3) δ H3.38 (s, 3H), 3.32 (dd, J = 8.8, 23.2Hz, 2H), 2.57(s, 1H), 2.44 (dd, J = 8.8, 19.2 Hz, 1H), 2.15-1.57 (m, 9H), 1.54-1.16(m, 12H),0.88 (s, 3H), 0.49- 0.34 (m, 3H), 0.31-0.21 (m, 1H), 0.07-0.03 (m, 1H);LC-ELSD / MS purity 98%, C 23 H 35 MS ESI calculation value for O2 [M-H2O+H] + 343.3, measured value 343.3. compound 7.1b: 1 1H NMR (400 MHz, CDCl3) δ H 3.38 (s, 3H), 3.19 (d, J = 2.4 Hz, 2H),2.45 (dd,J = 8.4, 19.2 Hz, 1H), 2.13-1.60 (m, 9H), 1.55-1.10 (m, 13H), 0.89 (m,4H), 0.48-0.32(m, 2H), 0.29-0.16 (m, 2H); LC-ELSD / MS purity 98%, C 23 H 35 MS ESI calculation value for O2 [M-H2O+H] + 343.3, measured value 343.3.

[0353] compound 7.2 Synthesis Ethyl triphenylphosphonium bromide (4.08 g, 11.0 mmol) was added at 25°C to a solution of t-BuOK (1.23 g, 11.0 mmol) in THF (20 mL). After stirring at 40°C for 0.5 hours, the mixture was then added to THF (10 mL). compound7.1a (800 mg, 2.2 mmol) solution was added to the reactants at 40°C. After stirring at 40°C for 16 hours, the mixture was poured into water (50 mL) and extracted with siRNA (2 × 20 mL). The combined organic phase was washed with saturated brine (2 × 50 mL), dried on anhydrous Na₂SO₄, filtered, and concentrated under vacuum to obtain the residue, which was purified by flash column (0-20% siRNA in PE). compound 7.2 (500 mg, 1.3 mmol) was obtained as an oily substance.

[0354] compound 7.3 Synthesis THF (10 mL) compound 7.2 (500 mg, 1.3 mmol) solution was mixed with 9-BBN dimer (1.30 g, 5.4 mmol) at 25°C. The mixture was stirred at 40°C for 16 hours to obtain the solution. After cooling to 0°C, the mixture was very slowly diluted with ethanol (1.23 g, 26.8 mmol) and NaOH (5.36 mL, 26.8 mmol, 5 M). After the addition was complete, H2O2 (2.7 mL, 26.8 mmol, 30%) was slowly added, maintaining the internal temperature below 25°C. The resulting solution was stirred at 75°C for 1 hour. Saturated Na2S2O3 aqueous solution (50 mL) was added, and the mixture was stirred for another 1 hour at 0°C. The reaction product was checked with potassium iodide-starch test paper to confirm that the excess H2O2 had decomposed. The mixture was cooled and added to water (50 mL). The mixture was extracted with toluene (3 × 20 mL), washed with saturated brine (2 × 50 mL), dried on anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue (500 mg) was purified by flash column (0-30% toluene in PE), compound 7.3 (250 mg, 50%) was obtained as an oily substance. 80 mg compound 7.3 was purified by preparative HPLC (column HT Highload C18 250×25mm×5μm, conditions: water (10mM NH4HCO3)-ACN, start B75, end B95), compound 7.3 (23 mg) was obtained as a solid. 11H NMR (400 MHz, CDCl3) δ H 4.25-4.15(m, 1H), 3.40-3.27(m, 5H), 2.07-1.77 (m, 5H), 1.70-1.00 (m, 23H), 0.67 (m, 3H),0.45-0.30 (m,3H), 0.30-0.20(m, 1H), 0.05-(-0.05) (m, 1H). LC-ELSD / MS purity 98%, C 25 H 41 MS ESI calculation value for O [M-H2O+H] + 373.3, measured value 373.3.

[0355] compound 7.4 Synthesis DCM (10 mL) compound 7.3 (150 mg, 0.4 mmol) was mixed with DMP (325 mg, 0.8 mmol) dropwise. After stirring at 25°C for 0.5 hours, the mixture was quenched with saturated NaHCO3 solution (50 mL) and extracted with pharmaceutically acceptable ethyl acetate (3 × 10 mL). The combined organic layer was washed with Na2S2O3 (2 × 50 mL) and brine (2 × 50 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue (140 mg) was purified by flash column (0-50% ethyl acetate in PE). compound 7.4 (120 mg, 86%) was obtained as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 3.38(s, 3H), 3.32(dd,J = 9.2, 22.4 Hz, 2H), 2.60 (s, 1H), 2.54 (t, J = 9.2 Hz, 1H),2.32-2.11 (m, 5H),2.04-1.87 (m, 3H), 1.70-1.63 (m, 4H), 1.51-1.37 (m, 7H), 1.28-1.16(m, 6H), 0.62(s, 3H), 0.46-0.32 (m, 3H), 0.28-0.19 (m, 1H), 0.04--0.06 (m, 1H) LC-ELSD / MS purity 98%, C 25 H39 MS ESI calculation value for O2 [M-H2O+H] + 371.3, measured value 371.3.

[0356] Example 8: 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-cyclopropyl-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitriel compound 8.2b) Synthesis [ka] compound 8.1 Synthesis MeOH (10 mL) compound To a solution of 7.4 (100 mg, 0.3 mmol), HBr (10.4 mg, 0.05 mmol, 40% in water) and Br2 (45.2 mg, 0.3 mmol) were added at 25°C. After stirring at 25°C for 2 hours, the mixture was quenched with saturated NaHCO3 solution (30 mL) and water (30 mL), and then extracted with siRNA (3 × 20 mL). The combined organic phase was washed with brine (2 × 50 mL), dried on anhydrous Na2SO4, filtered, and concentrated under vacuum. compound 8.1 (120 mg, 0.3 mmol) was obtained as an oily substance and used as is, without further purification, for the next step.

[0357] compound 8.2b Synthesis In acetone (10 mL) compoundTo a solution of 8.1 (120 mg, 0.3 mmol), 1H-pyrazole-4-carbonitrile (35.8 mg, 0.4 mmol) was added, followed by K2CO3 (70.9 mg, 0.5 mmol). After stirring at 50°C for 12 hours, the mixture was diluted with water (30 mL) and then extracted with RINKAN (3 × 10 mL). The combined organic phase was washed with brine (2 × 30 mL), dried on anhydrous Na2SO4, filtered, and concentrated into a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 5 μm, gradient: 60-90% B (water (10 mM NH4HCO3)-ACN, flow rate: 25 mL / min)). compound 8.2b (35 mg, 28%) was obtained as a solid. compound 8.2b: 1 1H NMR (400 MHz, CDCl3) δ H 7.85 (s, 1H), 7.81 (s, 1H), 4.96 (dd, J = 18.0, 51.6Hz, 2H), 3.39 (s, 3H), 3.32(dd, J = 8.8, 22.0 Hz, 2H), 2.68-2.56 (m, 2H), 2.26-2.16(m, 1H), 2.08-1.65 (m,8H), 1.53-1.16 (m, 13H), 0.68 (s, 3H), 0.47-0.34 (m, 3H),0.28-0.19 (m, 1H), 0.05--0.03(m, 1H). The structure was confirmed by 2D NMR (H18 showed a clear signal with H20, and H18 showed a weak signal with H17); LC-ELSD / MS purity 99%, 100% de based on H-NMR; C 29 H 42 MS ESI calculation value for N3O3 [M+H] + 480.3, measured value 480.3.

[0358] Example 9: TBPS-binding steroid inhibition Using rat cortical membranes in the presence of 5 mM GABA [ 35The S]-t-butylbicyclophosphorothionate (TBPS) binding assay has been described (Gee et al, J. Pharmacol. Exp. Ther. 1987, 241, 346-353; Hawkinson et al, Mol. Pharmacol. 1994, 46, 977-985; Lewin, AH et al., Mol. Pharmacol. 1989, 35, 189-194).

[0359] In short, after femoral head resection of carbon dioxide-anesthetized Sprague-Dawley rats (200-250g), the cortex is rapidly removed. Using a glass / Teflon® homogenizer, the cortex is homogenized in 10 volumes of ice-cold 0.32M sucrose and centrifuged at 1500×g for 10 minutes at 4°C. The resulting supernatant is centrifuged at 10,000×g for 20 minutes at 4°C to obtain a P2 pellet. The P2 pellet is resuspended in 200mM NaCl / 50mM sodium potassium phosphate pH 7.4 buffer and centrifuged at 10,000×g for 10 minutes at 4°C. This washing procedure is repeated twice, and the pellet is resuspended in 10 volumes of buffer. A 100mL membrane suspension is dissolved in dimethyl sulfoxide (DMSO) (final 0.5%) in the presence of 5mM GABA to obtain 3nM [ 35Incubate with 5 mL alicot of [S]-TBPS and the test drug. Reduce the incubation volume to 1.0 mL with buffer. Nonspecific binding is determined in the presence of 2 mM unlabeled TBPS and ranges from 15 to 25%. After incubation at room temperature for 90 minutes, the assay is terminated by filtration through a glass fiber filter (Schleicher and Schuell No. 32) using a cell harvester (Brandel) and rinsed three times with ice-cold buffer. The radioactivity bound to the filter is measured by liquid scintillation spectroscopy. Nonlinear curve fitting of the overall data for each drug, averaged at each concentration, is performed using Prism (GraphPad). If the sum of squares is significantly lower according to the F-test, the data is fitted to a partial inhibition model instead of a complete inhibition model. Similarly, if the sum of squares is significantly lower according to the F-test, the data is fitted to a two-component inhibition model instead of a one-component inhibition model. 50% inhibition (IC) of specific binding. 50 ) and the maximum degree of inhibition (I max The concentration of the test compound that produces the reaction is determined for each experiment using the same model used for the overall data, and then the mean ± SEM of the individual experiments is calculated. Picrotoxin serves as a positive control for these studies because it has been demonstrated to strongly inhibit TBPS binding.

[0360] We screen various compounds and perform in vitro [ 35 Their potential as modulators of [S]-TBPS binding can be determined or can be determined. These assays can be performed or can be performed according to the above.

[0361] In Table 2 below, A is TBPS IC 50 (μM) indicates <0.1μM, and B is TBPS IC with a concentration of 0.1μM to <1.0μM. 50 (μM) is shown, and C is TBPS IC in the range of 1 μM to <10.0 μM. 50 (μM) is indicated, and D means ≥10μM. [Table 2-1] [Table 2-2] [Table 2-3]

[0362] Equivalents and range In a claim, articles such as “a,” “an,” and “the” may mean one or more unless otherwise indicated or evident from the context. Unless otherwise indicated or evident from the context, a claim or description containing “or” between one or more members of a group is considered to satisfy that one, more than one, or all of the group members are present, used, or otherwise related to a given product or process. The present invention includes embodiments in which exactly one member of the group is present, used, or otherwise related to a given product or process. The present invention includes embodiments in which more than one or all of the group members are present, used, or otherwise related to a given product or process.

[0363] Furthermore, the present invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the enumerated claims are introduced into another claim. For example, any claim dependent on another claim may be modified to include one or more limitations found in any other claim dependent on the same basic claim. Where elements are presented as a list, for example in the form of a Markush group, each subgroup of that element is also disclosed, and any element(s) may be removed from that group. In general, where the present invention or an aspect of the present invention is referred to as including certain elements and / or features, it should be understood that certain embodiments of the present invention or an aspect of the present invention consist of, or essentially consist of, such elements and / or features. For the sake of simplicity, those embodiments are not explicitly shown herein in these terms. Note that the terms “comprising” and “containing” are intended to be open and may also include additional elements or steps. Where a scope is indicated, the endpoint is included. Furthermore, unless otherwise indicated or evident from the context and the understanding of those skilled in the art, values ​​expressed as ranges may, unless the context clearly indicates otherwise, assume any specific value or subrange within the ranges described in the various embodiments of the present invention up to one-tenth of the lower limit unit of that range.

[0364] This application refers to various issued patents, published patent applications, academic papers, and other publications (all of which are incorporated herein by reference). In the event of any conflict between any reference incorporated herein and this specification, this specification shall prevail. In addition, any particular embodiment of the present invention that falls within the scope of the prior art may be expressly excluded from any one or more of the claims. Since such embodiments are considered to be known to those skilled in the art, they may be excluded even if their exclusion is not expressly indicated herein. Any particular embodiment of the present invention, whether or not it relates to the existence of the prior art, may be expressly excluded. A claim may be excluded for any reason.

[0365] Those skilled in the art will be able to identify or verify many equivalents to the particular embodiments described herein using only routine experimental methods. The scope of the embodiments described herein is not intended to be limited to the above description, as is set out in the appended claims. Those skilled in the art will recognize that various changes and modifications to this description can be made without departing from the spirit or scope of the invention as defined in the following claims.

[0366] According to a preferred embodiment of the present invention, for example, the following is provided: (Section 1) Compounds of formula I: [ka] (I) or a pharmaceutically acceptable salt thereof [In the formula, [ka] R represents a single bond or a double bond, except when a double bond is present. 6a or R 6b One of them is missing; R 1 This includes hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -N(R A1 ) 2 , -SR A1 -C(=O)R A1 , -C(=O)OR A1 -C(=O)SR A1 -C(=O)N(R A1 ) 2 -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)N(R A1) 2 -OC(=O)SR A1 -OS (=O) 2 R A1 -OS (=O) 2 Ure A1 -OS (=O) 2 N(R A1 ) 2 , -N(R A1 )C(=O)R A1 , -N(R A1 )C(=NR A1 )R A1 , -N(R A1 )C(=O)OR A1 , -N(R A1 )C(=O)N(R A1 ) 2 , -N(R A1 )C(=NR A1 ), N(R A1 ) 2 , -N(R A1 )S(=O) 2 R A1 , -N(R A1 )S(=O) 2 Ure A1 , -N(R A1 )S(=O) 2 N(R A1 ) 2 -SC(=O)R A1 , -SC(=O)OR A1 -SC(=O)SR A1 -SC(=O)N(R A1 ) 2 -S(=O) 2 R A1 -S(=O) 2 Ure A1 , or -S(=O) 2 N(R A1 ) 2 And here, RA1 Each example is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group if bonded to oxygen, a nitrogen protecting group if bonded to nitrogen, a sulfur protecting group if bonded to sulfur, or two R A1 The group, together with the intervening atom, forms a substituted or unsubstituted heterocyclic ring; R 2a 、R 2b 、R 4a 、R 4b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b or R 17b Each of these independently consists of hydrogen, halogen, -CN, and -NO. 2 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -N(R A1 ) 2 , -SR A1 -C(=O)R A1 , -C(=O)OR A1 -C(=O)SR A1 -C(=O)N(R A1 ) 2 -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)N(R A1 ) 2 -OC(=O)SR A1 -OS (=O) 2 R A1 -OS (=O) 2 Ure A1 -OS (=O) 2 N(R A1 ) 2 , -N(R A1 )C(=O)R A1 , -N(R A1 )C(=NR A1 )R A1 , -N(R A1 )C(=O)ORA1 , -N(R A1 )C(=O)N(R A1 ) 2 , -N(R A1 )C(=NR A1 ), N(R A1 ) 2 , -N(R A1 )S(=O) 2 R A1 , -N(R A1 )S(=O) 2 Ure A1 , -N(R A1 )S(=O) 2 N(R A1 ) 2 -SC(=O)R A1 , -SC(=O)OR A1 -SC(=O)SR A1 -SC(=O)N(R A1 ) 2 -S(=O) 2 R A1 -S(=O) 2 Ure A1 , or -S(=O) 2 N(R A1 ) 2 And here, R A1 Each example is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group if bonded to oxygen, a nitrogen protecting group if bonded to nitrogen, a sulfur protecting group if bonded to sulfur, or two R A1 The group, together with the intervening atom, forms a substituted or unsubstituted heterocyclic ring; R 3a 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; R 5 is hydrogen or methyl;

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Claims

1. Compound (A9) 【Chemistry 1-1】 A process for preparing, Compound (A8) [Chemistry 1-2] This involves reacting with des-martinperiodinane to produce compound (A9), process.

2. The process according to claim 1, wherein the reaction of the compound (A8) is carried out in the presence of dichloromethane (DCM).

3. Compound (A3) 【Chemistry 10-1】 A process for preparing, Et ２ Zn, CH ２ I ２ And CF ３ The reaction is carried out in the presence of COOH and dichloromethane (DCM) to form a reaction mixture, and compound (A2) 【Chemistry 10-2】 This includes contacting the above reaction mixture to form compound A3. process.

4. A process for preparing compound A11, comprising reacting compound A10 with 1H-pyrazole-4-carbonitride in the presence of potassium carbonate: 【Chemistry 11】 A process that includes this.

5. A process for preparing compound A10, comprising the process described in Claim 1, wherein the obtained compound (A9) is reacted with bromine to provide compound (A10): 【Chemistry 12】 ,process.

6. Compound (A8) is obtained by reacting compound (A7) with 9-borabicyclo(3.3.1)nonane dimer (9-BBN dimer), and then reacting it with an aqueous sodium hydroxide solution and hydrogen peroxide: 【Chemistry 14】 The process according to claim 1, further comprising:

7. The following structure: 【Chemistry 15】 A compound of formula (A8) having the same compound or a pharmaceutically acceptable salt thereof.

8. The following structure: 【Chemistry 16】 A compound of formula (A7) having the same compound or a pharmaceutically acceptable salt thereof.

9. The following structure: 【Chemistry 17】 A compound of formula (A6) having the same compound or a pharmaceutically acceptable salt thereof.

10. The following structure: [Chemistry 18] A compound of formula (A4) having the same compound or a pharmaceutically acceptable salt thereof.

11. The following structure: 【Chemistry 19】 A compound of formula (A3) having the same compound or a pharmaceutically acceptable salt thereof.

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