Deuterized 21-[4-cyanopyrazole-1-yl]-19-norpregan-3.α-ol-20-one derivatives for treating CNS disorders

Abstract

To provide a method for treating disease.SOLUTION: Provided herein is a deuterated compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R3a, R5, R6a, R6b, R17, R21a, R21b, Rm, Rn, R16a, R16b, R7a, R7b, R12a, R12b, R11a, R11b, R2a, R2b, R19, R4a, and R4b are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I) and methods of using the compounds, e.g., in the treatment of CNS-related disorders.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Cross-reference with related applications This application claims priority to U.S. Application No. 62 / 596,725 (filed December 8, 2017) and U.S. Application No. 62 / 731,539 (filed September 14, 2018) (the entire contents of each are incorporated herein by reference). [Background technology]

[0002] Background of the Invention Brain excitability is defined as the range of animal arousal from coma to convulsions and is controlled by various neurotransmitters. Generally, neurotransmitters are involved in regulating the conductance of ions across the neuronal membrane. At rest, the neuronal membrane has a potential (or membrane voltage) of approximately -70mV, and the inside of the cell is negative relative to the outside. The potential (voltage) is controlled by ions (K) across the neuronal semipermeable membrane. + kaNa + Cl - This is a result of the balance of organic anions. Neurotransmitters are stored in presynaptic vesicles and released under the influence of neuronal action potentials. When released into the synaptic cleft, excitatory chemical mediators such as acetylcholine cause membrane depolarization (a change in potential from -70mV to -50mV). This action is due to Na + This process is mediated by postsynaptic nicotinic receptors, which are stimulated by acetylcholine, an ion-permeability enhances membrane permeability. The reduced membrane potential stimulates neuronal excitability in the form of postsynaptic action potentials.

[0003] In the case of GABA receptor complexes (GRCs), their effect on brain excitability is mediated by the neurotransmitter gamma-aminobutyric acid (GABA). Since up to 40% of neurons in the brain utilize GABA as a neurotransmitter, GABA has a significant impact on overall brain excitability. GABA regulates the excitability of individual neurons by controlling the conductance of chloride ions across the neuronal membrane. By interacting with recognition sites on GRCs, GABA promotes the flow of chloride ions into the cell downwards along the GRC's electrochemical gradient. This increase in intracellular anion levels causes hyperpolarization of the membrane potential, reducing the neuron's sensitivity to excitatory input (i.e., decreasing neuronal excitability). In other words, the higher the chloride ion concentration within a neuron, the lower the brain's excitability and arousal levels.

[0004] GRCs are well-established to be involved in mediating anxiety, seizure activity, and sedation. Therefore, GABA, and drugs that act like GABA or enhance its effects (e.g., therapeutically beneficial barbiturates and benzodiazepines (BZs), e.g., Valium®), derive their therapeutically beneficial effects by interacting with specific regulatory sites on GRCs. Accumulated evidence now suggests that GRCs contain distinct sites for neurostimulant steroids, in addition to benzodiazepine and barbiturate binding sites. See, for example, Lan, NC et al., Neurochem. Res. (1991) 16:347-356.

[0005] 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 (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); Harris on, NL et al., J Pharmacol. Exp. Ther. 241:346-353 (1987). Novel and improved compounds that act as modulators of brain excitability, as well as agents for the prevention and treatment of CNS-related disorders, are needed. The compounds, compositions, and methods described herein are intended for this purpose. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Lan, NC et al., Neurochem. Res. (1991) 16:347-356 [Non-Patent Document 2] Majewska, MD et al., Science 232:1004-1007(1986) [Non-Patent Document 3] Harrison, NL et al., J Pharmacol. Exp. Ther. 241:346-353 (1987) [Overview of the project] [Means for solving the problem]

[0007] For example, neurostimulant steroids designed to act as GABA modulators are provided herein. The compound of formula (I) is a compound containing deutherium in levels exceeding those found in nature. In some embodiments, such compounds are envisioned to be useful as therapeutic agents for treating CNS-related disorders.

[0008] In one phase, equation (I) [ka] (In the formula, R 3a is 1 or more deuteria or X 2 -OX 3is C1-C6 alkyl optionally substituted so as to exist independently, where X 2 and X 3 each is independently C1-C6 alkylene optionally substituted so as to have another deuterium; R 5 、R 6a 、R 6b 、R 17 、R 21a 、R 21b 、R m 、R n 、R 16a 、R 16b 、R 7a 、R 7b 、R 12a 、R 12b 、R 11a 、R 11b 、R 2a 、R 2b 、R 19 、R 4a 、and R 4b each is independently selected from the group consisting of hydrogen and deuterium, provided that (a) R 3a is C1-C6 alkyl in which neither deuterium nor X 2 -OX 3 exists, where X 2 and X 3 each is independently C1-C6 alkylene in which no deuterium exists, then at least one of R 5 、R 6a 、R 6b 、R 17 、R 21a 、R 21b 、R m 、and R n 、R 16a 、R 16b 、R 7a 、R 7b 、R 12a 、R 12b 、R 11a 、R 11b 、R 2a 、R 2b 、R 19 、R 4a 、and R 4b is deuterium, or (b) R 5 、R6a , R 6b , R 17 , R 21a , R 21b , R m , R n , R 16a , R 16 b , R 7a , R 7b , R 12a , R 12b , R 11a , R 11b , R 2a , R 2b , R 19 , R 4a , and R 4b If all of them are hydrogen, then R 3a is 1 or more deuteria or X 2 -OX 3 A C1-C6 alkyl group is substituted such that X exists independently, where X 2 and X 3 Compounds of (which must be substituted so that at least one deutherium is present) or pharmaceutically acceptable salts thereof are provided herein.

[0009] In some embodiments, R3a is a C1-C3 alkyl group substituted such that 0-7 deutherium or X2a-OX3a are independently present, where X2a is a C1-C3 alkylene substituted such that 0-7 deutherium are independently present, and X3a is a C1-C3 alkylene substituted such that 0-7 deutherium are independently present. In some embodiments, when R3a is -CH3, at least one of R5, R6a, R6b, R17, R21a, R21b, Rm, and Rn is a deutherium, or when all of R5, R6a, R6b, R17, R21a, R21b, Rm, and Rn are hydrogen, R3a is a methyl group substituted such that 1-3 deutherium are independently present. In some embodiments, R3a is selected from the group consisting of -CH3 and CD3. In some embodiments, R3a is -CH3. In some embodiments, R3a is -CD3. In some embodiments, at least one of R5, R6a, R6b, R17, R21a, R21b, Rm, Rn, R16a, R16b, R7a, R7b, R12a, R12b, R11a, R11b, R2a, R2b, R19, R4a, and R4b is deuterium. In some embodiments, at least one of R5, R6a, R6b, R17, R21a, R21b, Rm, and Rn is deuterium. In some embodiments, R3a is -CH3, and at least one of R5, R6a, R6b, R17, R21a, R21b, Rm, Rn, R16a, R16b, R7a, R7b, R12a, R12b, R11a, R11b, R2a, R2b, R19, R4a, and R4b is deuterium. In some embodiments, R3a is -CH3, and at least one of R5, R6a, R6b, R17, R21a, R21b, Rm, and Rn is deuterium. In some embodiments, R5 and R6a are hydrogen. In some embodiments, R5 and R6a are deuterium. In some embodiments, R17 is hydrogen. In some embodiments, R17 is deuterium. In some embodiments, each of R21a and R21b is independently selected from the group consisting of hydrogen and deuterium. In some embodiments, R21a and R21b are hydrogen.In some embodiments, R21a and R21b are deuterium. In some embodiments, Rm and Rn are hydrogen. In some embodiments, Rm and Rn are deuterium. In some embodiments, R21a, R21b, Rm, and Rn are deuterium. In some embodiments, R17 and R16a are deuterium, and R16b is hydrogen. In some embodiments, R19 is hydrogen.

[0010] In some embodiments, the compound of formula (I) is of formula (IA) [ka] It is a compound of [the compound].

[0011] In some embodiments, the compound of formula (I) is of formula (IB) [ka] It is a compound of [the compound].

[0012] In some embodiments, the compound of formula (I) is of formula (IC) [ka] It is a compound of [the compound].

[0013] In some embodiments, the compound of formula (IC) is selected from the group of compounds specified in Table 1 below: [Table 1-1] (Here, any atom not specifically labeled as deutherium exists in its natural isotopic abundance.)

[0014] In one aspect, pharmaceutically acceptable salts of compounds described herein (e.g., compounds of formula (I)) are provided herein.

[0015] In one aspect, the Specified Pharmaceutical Composition is provided herein, comprising a compound described herein (e.g., a compound of formula (I)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the compound of the present invention is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the compound of the present invention is provided in a therapeutically effective amount.

[0016] The compounds of the present invention, as described herein, act in certain embodiments, for example, as GABA modulators that act on GABAA receptors in a positive or negative manner. Such compounds are expected to have CNS activity as modulators of central nervous system (CNS) excitability, mediated by their ability to modulate GABAA receptors.

[0017] Accordingly, in another context, a method for treating a CNS-related disorder in a subject requiring treatment for a CNS-related disorder is provided, the method comprising the step of administering an effective amount of the compound of the present invention to the subject. In certain embodiments, the CNS-related disorder is a sleep disorder, mood disorder, schizophrenia spectrum disorder, seizure disorder, memory and / or cognitive impairment, motor disorder, personality disorder, autism spectrum disorder, pain, traumatic brain injury, vascular disorder, substance abuse disorder and / or withdrawal syndrome, tinnitus, or status epilepticus. In certain embodiments, the CNS-related disorder is depression. In certain embodiments, the CNS-related disorder is postpartum depression. In certain embodiments, the CNS-related disorder is major depressive disorder. In certain embodiments, the major depressive disorder is moderate major depressive disorder. In certain embodiments, the major depressive disorder is severe major depressive disorder. In certain embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In certain embodiments, the compound is administered orally. In certain embodiments, the compound is administered over a long period. In certain embodiments, the compound is administered continuously, for example, by continuous intravenous infusion. [Modes for carrying out the invention]

[0018] Detailed description of specific embodiments of the invention As generally described herein, the present invention provides deuterium-enriched neurostimulant steroids designed to act, for example, as GABA modulators. In certain embodiments, such compounds are envisioned to be useful as therapeutic agents for treating CNS-related disorders (e.g., depression, such as the disorders described herein, e.g., postpartum depression or major depressive disorder).

[0019] definition chemical definition

[0020] The definitions of specific functional groups and chemical terms are explained in detail below. Chemical elements are identified according to the periodic table (CAS version, Handbook of Chemistry and Physics, 75th edition, inside cover), and specific functional groups are generally defined as described therein. Furthermore, general rules of organic chemistry, as well as specific functional parts and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th edition, John Wiley & Sons, Inc., New This is described in York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987.

[0021] The compounds described herein (for example, the compound of formula (I), for example, the compound of formula (I)) are deutherium-enriched.

[0022] Deuterium (D or 2H) is a stable, non-radioactive isotope of hydrogen with an atomic weight of 2.0144. Hydrogen exists naturally as a mixture of isotopes 1H (hydrogen or protium), D (2H or deuterium), and T (3H or tritium). The natural abundance of deuterium is 0.015%. Those skilled in the art recognize that in all compounds containing an H atom, the H atom actually exists as a mixture of H and D, with approximately 0.015% being D. Therefore, compounds containing deuterium enriched to levels exceeding its natural abundance of 0.015% should be considered unnatural and, consequently, novel to their unenriched counterparts.

[0023] The effect of deuterium modification on the metabolic properties of a compound is unpredictable, even when the deuterium atom is incorporated into a known metabolic site. Only by actually preparing and testing the deuterized compound can it be determined whether, and how, its metabolic rate differs from that of its non-deuterized counterpart. See, for example, Fukuto et al. (J.Med.Chem. 1991, 34, 2871-76). Many compounds have multiple metabolizable sites. Even if there are multiple sites, the site(s) where deuterium substitution is required to observe a metabolic effect, and the degree of deuterization needed, vary from compound to compound.

[0024] Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen," that position is understood to contain hydrogen (i.e., 1H) in its isotopic composition at its natural abundance. Also, unless otherwise stated, when a position is specifically designated as "D" or "deuterium," that position is understood to contain deuterium (i.e., 2H) at least 3000 times the natural abundance of deuterium, which is 0.015% (i.e. (The term "D" or "Deuterium" indicates the inclusion of at least 45% deuterium.)

[0025] As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance of D at a specific position in the compound of the present invention and the naturally occurring abundance of that isotope.

[0026] An increase in the abundance of deutherium in a compound (for example, the compound of formula (I)) is called "deutherium enrichment," and such a compound is called a "deutherium-enriched" compound. Unless otherwise specified, the percentage of enrichment refers to the percentage of deutherium present in the compound.

[0027] In other embodiments, the isotopic enrichment coefficients of each deuterium present at sites designated as potential deuterium sites on the compound of the present invention are at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), and at least 6633.3 (99.5% deuterium incorporation). The isotopic enrichment coefficients of each deuterium present at sites designated as deuterium sites are understood to be independent of other deuterium sites. For example, if two deuterization sites are present on a compound, one site may be deuterized by 52.5%, while the other may be deuterized by 75%. The resulting compound is considered to have an isotope enrichment factor of at least 3500 (52.5%).

[0028] Given that the natural abundance of deutherium is approximately 0.015%, it is expected that deutherium is present at approximately one position for every 6,667 naturally occurring hydrogen atoms in the compounds described herein (e.g., the compound of formula (I)).

[0029] A given percentage of the amount of deuteria present is expressed as a molar percentage.

[0030] Achieving 100% deuteriumization at any single site of a compound in laboratory-scale quantities (e.g., milligrams or more) can be challenging in the laboratory. If 100% deuteriumization is described, or if a deuterium atom is specifically indicated in the structure, it is assumed that small amounts of hydrogen may still be present. Deuterium can be enriched by exchanging protons for deuterium or by synthesizing molecules using enriched starting materials.

[0031] The isolation or purification of the deutherium-enriched compound of formula (I) is also described herein. The isolated or purified deutherium-enriched compound of formula (I) is shown.

[0032] Isomers (e.g., 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 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 Resolutions See "ing Agents and Optical Resolutions" p.268 (edited by ELEliel, Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention further includes the compounds described herein as individual isomers substantially free of other isomers, and / or as mixtures of various isomers.

[0033] As used herein, a pure enantiomerized compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., enantiomer-rich). In other words, an "S" type compound is substantially free of "R" type compounds and is therefore enantiomer-rich of "R" type. The terms "enantiomerically pure" or "pure enantiomer" mean that the compound contains more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight of an enantiomer. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0034] 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-compound may, for example, contain about 90% excipients 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 about 5% by weight of the S-compound, based on the total weight of the compound. For example, a pharmaceutical composition containing an enantiomerically pure S-compound may, for example, contain about 90% excipients 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 about 5% by weight of the R-compound, based on the total weight of the compound. In certain embodiments, the active ingredient may be formulated with small amounts of excipients or carriers, or without excipients or carriers.

[0035] The term “diastereomerically pure” means that a 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 a single diastereomer. Methods for determining diastereomer purity and enantiomer purity are well known in the art. Diastereomer purity can be determined by any analytical method that can quantitatively distinguish between the compound and its diastereomer (such as high-performance liquid chromatography (HPLC)).

[0036] The articles "a" and "an" may be used herein to indicate that the grammatical object of the article is one or more (i.e., at least one). For example, "an analogue" means one analog or more analogs.

[0037] When a range of values ​​is listed, it is intended to include each value and subrange within that range. For example, "C1-6 alkyl" includes C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl It is intended to include the 'ru'. C2~5

[0038] The following terms are intended to have the meanings presented below and are useful in understanding the scope intended in this specification and the invention.

[0039] "Alkyl" refers to a linear or branched saturated hydrocarbon radical having 1 to 4 carbon atoms ("C1-4 alkyl"). In some embodiments, alkyl groups have 1 to 3 carbon atoms ("C1-3 alkyl"). In some embodiments, alkyl groups have 1 to 2 carbon atoms ("C1-2 alkyl"). In some embodiments, alkyl groups have 1 carbon atom ("C1 alkyl"). Unless otherwise specified, each alkyl group is independently substituted as necessary, i.e., unsubstituted ("unsubstituted alkyl") or with one or more substituents; for example, substituted with 1 to 3 substituents or substituted with one substituent ("substituted alkyl"). In certain embodiments, alkyl groups are unsubstituted C1-4 alkyl (e.g., -CH3). In certain embodiments, alkyl groups are substituted C1-4 alkyl. Common abbreviations for alkyl groups include Me(-CH3), Et(-CH2CH3), or iPr(-CH(CH3)2).

[0040] A "counterion" or "anionic counterion" is a negatively charged group that associates with a cationic quaternary amino group to maintain electrical neutrality. Examples of counterions include halide ions (e.g., F-, Cl-, Br-, I-), NO3-, ClO4-, OH-, H2PO4-, HSO4-, sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.) and carboxylate ions (e.g., acetate, ethanolate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

[0041] These and other exemplary substituents are described in detail in the detailed description and claims. The present invention is not intended to be limited in any way by the exemplary enumeration of substituents described above.

[0042] Other definitions As used herein, the term “modulation” refers to the inhibition or synergistic effect of GABA receptor function. A “modulator” (e.g., a modulatory compound) may be, for example, a GABA receptor agonist, partial agonist, antagonist, or partial antagonist.

[0043] "Pharmacologically acceptable" means that it is approved or can be approved by a federal or state regulatory authority or a corresponding authority in a country other than the United States, or that it is listed in the United States Pharmacopeia or other generally accepted pharmacopoeias for use in animals (more specifically, humans).

[0044] "Pharmacologically acceptable salt" refers to a salt of the compound of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. In particular, such salts are nontoxic and may be inorganic acid addition salts or organic acid addition salts and inorganic base addition salts or organic base addition salts. Specifically, such salts may be formed with (1) inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or with organic acids, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydro) Acid addition salts formed with roxybenzoyl)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-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 formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion; or when it coordinates with an organic base, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Salts include, but are not limited to, sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium; and, if the compound contains a basic functional group, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, and oxalate. The term "pharmaceutically acceptable cation" refers to a cationic counterion that can accept an acidic functional group. Such cations are exemplified by sodium cations, potassium cations, calcium cations, magnesium cations, ammonium cations, and tetraalkylammonium cations. See, for example, Berge et al., J. Pharm. Sci. (1977) 66(1):1-79.

[0045] The term "prodrug" is intended to include compounds that are converted into the therapeutically active agent of the present invention under physiological conditions. A common method for preparing prodrugs is to include a selective moiety that is hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, prodrugs are converted by the enzymatic activity of the subject.

[0046] In some embodiments, the compound of formula (I) is a prodrug, where the prodrug contains a moiety cleavable on a C3 hydroxyl group as shown in formula (I). Exemplary hydroxyl-containing prodrugs include, for example, esters.

[0047] A “solvate” refers to a form of compound that is associated with a solvent or water (also called a “hydrate”), usually by solvolysis. This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, and acetic acid. The compounds of the present invention may be prepared, for example, in crystalline form and then solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric and non-stoichiometric solvates. In certain examples, solvates may be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. “Solvates” encompass both solution phases and isolateable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0048] "Stereoisomers": It should be understood that compounds having the same molecular formula but differing in atomic properties, bond order, or spatial arrangement of atoms are also called "isomers." Isomers that differ in spatial arrangement of atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and 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 set of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and expressed by the Kahn-Prelogue R and S ordering rules, or by the way the molecule rotates its plane of polarization, and are dextrorotatory or levorotatory (i.e., (+) or (-)-isomers, respectively). Chiral compounds can exist either as individual enantiomers or as mixtures thereof. A mixture containing mar is called a "racemic mixture."

[0049] A "tautomer" is a compound whose specific compound structure is interchangeable, and whose displacement of hydrogen atoms and electrons varies. Thus, the two structures can be in equilibrium through the movement of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either an acid or a base. Another example of tautomerism is the acidic and nitro forms of phenylnitromethane, which are similarly formed by treatment with either an acid or a base. Tautomerism can be relevant to achieving optimal chemical reactivity and biological activity of a compound of interest.

[0050] The “subjects” to which the administration is intended include, but are not limited to, human (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, e.g., mammals (e.g., primates (e.g., cynomolgus 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.

[0051] Diseases, disorders, and conditions are used interchangeably in this specification.

[0052] As used herein, unless otherwise specified, the terms “treat,” “treating,” and “treatment” refer to actions taken while a subject is suffering from a particular disease, disorder, or condition, which reduce the severity of that disease, disorder, or condition, or delay or slow the progression of that disease, disorder, or condition.

[0053] Generally, the “effective dose” of a compound refers to an amount sufficient to elicit a desired biological response, for example, to treat a CNS-related disorder, or to induce anesthesia or sedation. As will be understood by those skilled in the art, the effective dose of the compound of the present invention may vary depending on factors such as the desired biological target, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health status, and condition of the subject.

[0054] Where used herein, unless otherwise specified, “therapeutic dose” of a compound means an amount sufficient to provide therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with that disease, disorder, or condition. “Therapeutic dose” of a compound means the amount of the therapeutic agent, alone or in combination with other treatments, that provides therapeutic benefit in the treatment of that disease, disorder, or condition. The term “therapeutic dose” may include an amount that improves the overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effect of another therapeutic agent.

[0055] In alternative embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutically acceptable composition thereof may be administered in a “preventive effective dose.” As used herein, unless otherwise specified, “preventive effective dose” of a compound means an amount sufficient to prevent or prevent the recurrence of a disease, disorder or condition, or one or more symptoms associated with that disease, disorder or condition. The preventive effective dose of a compound means the amount of the therapeutic agent, alone or in combination with other agents, that provides a preventive benefit in the prevention of the disease, disorder or condition. The term “preventive effective dose” may include an amount that improves overall prevention or enhances the preventive efficacy of another preventive agent. compound

[0056] In one phase, equation (I) [ka] (wherein, R 3a is C1-C6 alkyl optionally substituted so that one or more deuteriums or X 2 -OX 3 are present independently, where X 2 and X 3 each are, independently, C1-C6 alkylene optionally substituted so that another deuterium is present; R 5 , R 6a , R 6b , R 17 , R 21a , R 21b , R m , R n , R 16a , R 16b , R 7a , R 7b , R 12a , R 12b , R 11a , R 11b , R 2a , R 2b , R 19 , R 4a , and R 4b each are, independently, selected from the group consisting of hydrogen and deuterium, provided that (a) when R 3a is C1-C6 alkyl in which neither deuterium nor X 2 -OX 3 is present, where X 2 and X 3 each are, independently, C1-C6 alkylene in which no deuterium is present, then R 5 , R 6a , R 6b , R 17 , R 21a , R 21b , R m , and R n , R 16a , R 16b , R 7a , R 7b , R 12a , R 12b , R 11a , R 11b , R 2a , R 2b , R 19 , R 4a, and R 4b At least one of them is a deuterium, or (b)R 5 , R 6a , R 6b , R 17 , R 21a , R 21b , R m , R n , R 16a , R 16b , R 7a , R 7b , R 12a , R 12b , R 11a , R 11b , R 2a , R 2b , R 19 , R 4a , and R 4b If all of them are hydrogen, then R 3a is 1 or more deuteria or X 2 -OX 3 A C1-C6 alkyl group is substituted such that X exists independently, where X 2 and X 3 Compounds of (which must be substituted so that at least one deutherium is present) or pharmaceutically acceptable salts thereof are provided herein.

[0057] In some embodiments, R3a is a C1-C3 alkyl group substituted such that 0-7 deutherium or X2a-OX3a are independently present, where X2a is a C1-C3 alkylene substituted such that 0-7 deutherium are independently present, and X3a is a C1-C3 alkylene substituted such that 0-7 deutherium are independently present. In some embodiments, when R3a is -CH3, at least one of R5, R6a, R6b, R17, R21a, R21b, Rm, and Rn is a deutherium, or when all of R5, R6a, R6b, R17, R21a, R21b, Rm, and Rn are hydrogen, R3a is a methyl group substituted such that 1-3 deutherium are independently present. In some embodiments, R3a is selected from the group consisting of -CH3 and CD3. In some embodiments, R3a is -CH3. In some embodiments, R3a is -CD3. In some embodiments, at least one of R5, R6a, R6b, R17, R21a, R21b, Rm, Rn, R16a, R16b, R7a, R7b, R12a, R12b, R11a, R11b, R2a, R2b, R19, R4a, and R4b is deuterium. In some embodiments, at least one of R5, R6a, R6b, R17, R21a, R21b, Rm, and Rn is deuterium. In some embodiments, R3a is -CH3, and at least one of R5, R6a, R6b, R17, R21a, R21b, Rm, Rn, R16a, R16b, R7a, R7b, R12a, R12b, R11a, R11b, R2a, R2b, R19, R4a, and R4b is deuterium. In some embodiments, R3a is -CH3, and at least one of R5, R6a, R6b, R17, R21a, R21b, Rm, and Rn is deuterium. In some embodiments, R5 and R6a are hydrogen. In some embodiments, R5 and R6a are deuterium. In some embodiments, R17 is hydrogen. In some embodiments, R17 is deuterium. In some embodiments, each of R21a and R21b is independently selected from the group consisting of hydrogen and deuterium. In some embodiments, R21a and R21b are hydrogen. In some embodiments, R21a and R21b are deuterium. In some embodiments, Rm and Rn are hydrogen. In some embodiments, Rm and Rn are deuterium. In some embodiments, R21a, R21b, Rm, and Rn are deuterium. In some embodiments, R17 and R16a are deuterium, and R16b is hydrogen. In some embodiments, R19 is hydrogen.

[0058] In some embodiments, the compound of formula (I) is of formula (IA) [ka] It is a compound of [the compound].

[0059] In some embodiments, the compound of formula (I) is of formula (IB) [ka] It is a compound of [the compound].

[0060] In some embodiments, the compound of formula (I) is of formula (IC) [ka] It is a compound of [the compound].

[0061] In some embodiments, the compound of formula (IC) is selected from the group of compounds specified in Table 1 below: [Table 1-2] (Here, any atom not specifically labeled as deutherium exists in its natural isotopic abundance.)

[0062] 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 references (e.g., U.S. Patent No. 9,512,165, as incorporated herein by reference): [ka]

[0063] In some embodiments, starting materials can be used to synthesize the compound of formula (I) (wherein R3a is -CD3, and each of R21a, R21b, Rm, and Rn is independently hydrogen or deutherium). In some embodiments, starting materials can be used to synthesize the compound of formula (I) (wherein R3a is -CH3, and each of R21a, R21b, Rm, and Rn is independently hydrogen or deutherium). In some embodiments, starting materials can be used to synthesize the compound of formula (I) (wherein R3a is -CD3, R21a and R21b are hydrogen, and Rm and Rn are deutherium). In some embodiments, starting materials can be used to synthesize the compound of formula (I) (wherein R3a is CH3, R21a and R21b are hydrogen, and Rm and Rn are deutherium). In some embodiments, starting materials can be used to synthesize compounds of formula (I) (wherein R3a is -CD3, and R21a, R21b, Rm, and Rn are deutherium).

[0064] In one aspect, pharmaceutically acceptable salts of compounds described herein (e.g., compounds of formula (I)) are provided herein.

[0065] Alternative Embodiments In alternative embodiments, the compounds described herein may also involve isotopic substitution of one or more non-hydrogen atoms. For example, carbon may be, for example, 13C or 14C; oxygen may be, for example, 18O; nitrogen may be, for example, 15N, and so on. In other embodiments, specific isotopes (e.g., 13C, 14C, 1) may be used. 8O or 15N) may correspond to at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of the element occupying a particular site in the compound. Pharmaceutical composition

[0066] In one aspect, the Specified Pharmaceutical Composition is provided herein, comprising a compound described herein (e.g., a compound of formula (I)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the compound of the present invention is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the compound of the present invention is provided in a therapeutically effective amount.

[0067] 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.

[0068] The pharmaceutical compositions provided herein may be administered by various routes, including, but not limited to, oral (enteral), parenteral (injection), rectal, transdermal, intradermal, intrathin, subcutaneous (SC), intravenous (IV), intramuscular (IM), and intranasal.

[0069] Generally, the compounds provided herein are administered in effective doses. The actual amount of compound administered is typically determined by a physician in light of the relevant circumstances, including the symptoms being treated, the chosen route of administration, the specific compound administered, the individual patient's age, weight and response, and the severity of the patient's symptoms.

[0070] When used to prevent the development of CNS disorders, the compounds provided herein may typically be administered to subjects at risk of developing the symptoms at the dosage levels described above, with the advice and supervision of a physician. Subjects at risk of developing specific symptoms generally include those with a family history of the symptoms or those identified by genetic testing or screening as particularly susceptible to developing the symptoms.

[0071] The pharmaceutical compositions provided herein are also intended for long-term administration ("long-term administration"). Long-term administration means the administration of a compound or its pharmaceutical composition over a long period of time, for example, three months, six months, one year, two years, three years, five years, or can be continued indefinitely, for example, over the remainder of the subject's life. In certain embodiments, long-term administration is intended to provide a certain level of the compound in the blood over a long period of time, for example, within the therapeutic window.

[0072] The pharmaceutical compositions of the present invention may be delivered using a variety of administration methods. For example, in certain embodiments, the pharmaceutical composition may be given as a bolus, for example, for the purpose of raising the concentration of the compound in the blood to an effective level. The placement of the bolus dose depends on the desired systemic level of the active ingredient throughout the body; for example, intramuscular or subcutaneous bolus doses allow for the slow release of the active ingredient, while boluses delivered directly to a vein (e.g., by IV drip) allow for faster delivery, which 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 IV drip, to provide maintenance of a steady-state concentration of the active ingredient in the subject's body. Furthermore, in yet another embodiment, This pharmaceutical composition may be administered initially as a bolus dose, followed by continuous infusions.

[0073] Compositions for oral administration may take the form of a bulk liquid solution or suspension or a bulk powder. However, more generally, compositions are provided in unit dosage forms to facilitate precise administration. The term “unit dosage form” refers to a physically discontinuous unit suitable as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect together with suitable pharmaceutically acceptable excipients. Typical unit dosage forms include pre-measured and pre-filled ampoules or syringes for liquid compositions, or pills, tablets, capsules, etc., for solid compositions. In such compositions, the compound is usually present in small amounts (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various vehicles or excipients and processing aids that help form the desired dosage form.

[0074] For oral administration, a typical regimen involves 1 to 5 oral doses per day, particularly 2 to 4 doses, and usually 3 oral doses. When using these dosing patterns, each dose yields approximately 0.01 to approximately 20 mg / kg of the compound provided herein, with preferred doses yielding approximately 0.1 to approximately 10 mg / kg, particularly approximately 1 to approximately 5 mg / kg.

[0075] Transdermal doses are generally selected to provide blood levels similar to or lower than those achieved using injectable doses, and are generally in the range of about 0.01% to about 20% by weight, preferably about 0.1% to about 20% by weight, preferably about 0.1% to about 10% by weight, and more preferably about 0.5% to about 15% by weight.

[0076] The dose levels of the injectable agent range from approximately 0.1 mg / kg / hour to at least 20 mg / kg / hour, all over a period of approximately 1 to 120 hours, particularly 24 to 96 hours. Preloading bolus of approximately 0.1 mg / kg to 10 mg / kg or more may also be administered to achieve an appropriate steady-state level. The maximum total dose is not expected to exceed approximately 5 g / day for human patients weighing 40-80 kg.

[0077] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle containing buffers, suspending agents and dispensing agents, colorants, flavorings, etc. Solid forms may include, for example, any of the following components or compounds of similar properties: binders (e.g., microcrystalline cellulose, tragacanth gum or gelatin); excipients (e.g., starch or lactose); disintegrants (e.g., alginic acid, Primogel or corn starch); lubricants (e.g., magnesium stearate); lubricants (e.g., colloidal silicon dioxide); sweeteners (e.g., sucrose or saccharin); or flavorings (e.g., peppermint, methyl salicylate or orange flavor).

[0078] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline or other injectable excipients known in the art. As is conventional, the active compound in such compositions is typically a trace component, often about 0.05–10% by weight, with the remainder being injectable excipients, etc.

[0079] Transdermal compositions are typically formulated as topical ointments or creams containing one or more active ingredients. When formulated as an ointment, the active ingredients are typically miscible with a paraffinic ointment base or a water-miscible ointment base. Alternatively, the active ingredients may be formulated as a cream, for example, containing an oil-in-water cream base. Such transdermal formulations are well known in the art and generally enhance the skin penetration or stability of the active ingredients or formulation. It contains further components. All such known transdermal formulations and components are included within the scope provided herein.

[0080] The compounds provided herein may also be administered by transdermal devices. Therefore, transdermal administration can be achieved using reservoir-type, porous membrane-type, or solid matrix-type patches.

[0081] The components described above for orally, injectably, or topically administered compositions are merely representative. Other materials and processing methods are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania (as incorporated herein by reference).

[0082] The compounds of the present invention may also be administered in sustained-release form or via sustained-release drug delivery systems. A description of typical sustained-release materials can be found in Remington's Pharmaceutical Sciences.

[0083] The present invention also relates to pharmaceutically acceptable acid addition salts of the compounds of the present invention. Acids that can be used to prepare pharmaceutically acceptable salts are those that form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions (e.g., hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, p-toluenesulfonate, etc.).

[0084] In another aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable excipient (for example, a composition suitable for injection, such as intravenous (IV) administration).

[0085] Pharmaceutically acceptable excipients include any diluent or other liquid vehicle suitable for injection, such as any desired specific dosage form, dispersing or suspending agent, surfactants, isotonic agents, preservatives, and lubricants. General considerations for the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington's Pharmaceutical Sciences, 16th edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980) and Remington: The Science and Practice of Pharmacy, 21st edition (Lippincott Williams & Wilkins, 2005).

[0086] For example, preparations for injection, such as sterile aqueous suspensions for injection, can be formulated by known techniques using appropriate dispersants or wetting and suspending agents. Exemplary excipients that may be used include, but are not limited to, water, sterile saline or phosphate-buffered saline, or Ringer's solution.

[0087] 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, respectively, with one or more substituents optionally on the linked sugar moiety (including, but not limited to, substituted or unsubstituted methylation, hydroxyalkylation, acylation, and sulfoalkyl ether substitution). In certain embodiments, the cyclodextrin is sulfoalkyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as CAPTISOL®. See, for example, U.S. Patent No. 5,376,645. In certain embodiments, the composition , containing hexapropyl-β-cyclodextrin. In a more specific embodiment, the composition contains hexapropyl-β-cyclodextrin (10-50% in water).

[0088] The injectable composition may be sterilized, for example, by filtration using a bacterial-retaining filter, or by incorporating a sterilizer in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0089] Generally, the compounds provided herein are administered in effective doses. The actual amount of compound administered is typically determined by a physician in light of the relevant circumstances, including the symptoms being treated, the chosen route of administration, the actual compound administered, the individual patient's age, weight, response, and the severity of the patient's symptoms.

[0090] The composition is provided in unit dosage forms to facilitate precise administration. The term “unit dosage form” refers to a physically discontinuous unit appropriate as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect, along with appropriate pharmaceutically acceptable excipients. Typical unit dosage forms include pre-measured and pre-filled ampoules or syringes of liquid compositions. In such compositions, the compound is usually present in small amounts (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various vehicles or carriers and processing aids that help form the desired dosage form.

[0091] The compounds provided herein may be administered as single activators or in combination with other activators. In one aspect, the present invention provides combinations of the compounds of the present invention with another pharmacologically active agent. Dosage in combination may be carried out by any technique apparent to those skilled in the art (e.g., separate administration, sequential administration, simultaneous administration, and alternating administration).

[0092] The descriptions of pharmaceutical compositions provided herein primarily concern those suitable for administration to humans; however, those skilled in the art will understand that such compositions are generally suitable for administration to all types of animals. Modifications of pharmaceutical compositions suitable for administration to humans to compositions suitable for administration to various animals are well understood, and a veterinary pharmacologist of ordinary knowledge can design and / or carry out such modifications in ordinary experiments. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy. It can be found in the 21st edition, Lippincott Williams & Wilkins, 2005.

[0093] In one aspect, a kit is provided that includes a composition (e.g., a solid composition) containing a compound of formula (I).

[0094] Instructions for use and handling In certain contexts, the compounds described herein (e.g., compounds of formula (I)) are expected to be useful as therapeutic agents for treating CNS-related disorders (e.g., sleep disorders, mood disorders (e.g., depression), schizophrenia spectrum disorder, seizure disorders, epilepsy, memory and / or cognitive impairment, motor disorders, personality disorders, autism spectrum disorder, pain, traumatic brain injury, vascular disorders, substance abuse disorders and / or withdrawal syndromes, or tinnitus) in subjects in need (e.g., subjects with Rett syndrome, fragile X syndrome, or Angelman syndrome). Exemplary CNS conditions related to GABA regulation include sleep disorders [e.g., insomnia], mood disorders [e.g., depression, dysthymic disorder (e.g., mild depression), bipolar disorder (e.g., type I and / or type II), anxiety disorders (e.g., generalized anxiety) Social anxiety disorder (GAD), stress, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), schizophrenia spectrum disorder (e.g., schizophrenia, schizoaffective disorder), seizure disorder (e.g., epilepsy, status epilepticus (SE), seizures), memory and / or cognitive impairment (e.g., attention deficit hyperactivity disorder (ADHD)), dementia (e.g., Alzheimer's disease, Lewis body type dementia) This includes, but is not limited to, dementia, vascular dementia, motor 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, one-host causes of autism such as synaptic degeneration (e.g., Rett syndrome, fragile X syndrome, Angelman syndrome)), pain (e.g., neuropathic pain, injury-related pain syndrome, acute pain, chronic pain), traumatic brain injury (TBI), vascular disorders (e.g., stroke, ischemia, vascular malformations), substance abuse disorders and / or withdrawal syndromes (e.g., addiction to opioid preparations, cocaine, and / or alcohol)), and tinnitus.

[0095] In certain embodiments, 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 disorders, substance abuse disorders and / or withdrawal syndromes, tinnitus, or status epilepticus. In certain embodiments, CNS-related disorders include depression. In certain embodiments, CNS-related disorders include postpartum depression. In certain embodiments, CNS-related disorders include major depressive disorder. In certain embodiments, major depressive disorder includes moderate major depressive disorder. In certain embodiments, major depressive disorder includes severe major depressive disorder.

[0096] In one aspect, a method is provided for reducing or preventing seizure activity in a subject, the method comprising the step of administering an effective amount of the compound of the present invention to a subject requiring such treatment. In some embodiments, the method reduces or prevents the occurrence of epilepsy.

[0097] In another context, combinations of the compounds of the present invention with other pharmacologically active agents are provided. The compounds provided herein may be administered as single activators or in combination with other agents. Combination administration may be carried out by any technique apparent to those skilled in the art (e.g., separate administration, sequential administration, simultaneous administration, and alternating administration).

[0098] In another context, a method is provided for treating or preventing brain excitation in a subject who is susceptible to or suffering from a condition related to brain excitation, the method comprising the step of administering to the subject an effective amount of the compound of the present invention.

[0099] In another context, a method is provided for treating or preventing stress or anxiety in a subject, the method comprising administering an effective amount of the compound or composition of the present invention to a subject in need of such treatment.

[0100] In another context, a method is provided for reducing or preventing insomnia in a subject, the method comprising administering an effective amount of the compound or composition of the present invention to a subject in need of such treatment.

[0101] In another context, a method is provided for inducing sleep and substantially maintaining the level of REM sleep observed in normal sleep, without inducing substantial rebound insomnia, the method comprising the step of administering an effective amount of the compound of the present invention.

[0102] In another context, a method is provided for reducing or preventing PMS or PND in a subject, the method comprising the step of administering an effective amount of the compound of the present invention to a subject requiring such treatment.

[0103] In another context, a method is provided for treating or preventing a mood disorder in a subject, comprising the step of 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.

[0104] In another context, a method is provided for treating cognitive enhancement or memory impairment by administering a therapeutically effective amount of the compound of the present invention to a subject. In certain embodiments, the disorder is Alzheimer's disease. In certain embodiments, the disorder is Rett syndrome.

[0105] In another context, a method is provided for treating attention disorders by administering a therapeutically effective amount of the compound of the present invention to a subject. In a particular embodiment, this attention disorder is ADHD.

[0106] 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.

[0107] Neuroendocrine disorders and dysfunctions Methods that may be used to treat neuroendocrine disorders and dysfunctions are provided herein. As used herein, “neuroendocrine disorder” or “neuroendocrine dysfunction” refers to a range of conditions caused by imbalances in the production of hormones in the body that are directly related to the brain. Neuroendocrine disorders involve interactions between the nervous and endocrine systems. 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.

[0108] Symptoms of neuroendocrine disorders include, but are not limited to, behavioral, emotional, and sleep-related symptoms, reproductive function-related symptoms, and physical symptoms, including, but are not limited to, fatigue, memory impairment, anxiety, depression, weight gain or loss, emotional instability, lack of concentration, difficulty concentrating, loss of lipids, infertility, amenorrhea, decreased muscle mass, increased abdominal fat, hypotension, low heart rate, hair loss, anemia, constipation, cold intolerance, and dry skin.

[0109] Neurodegenerative diseases and disorders Methods that may be used to treat neurodegenerative diseases and disorders are provided herein. The term “neurodegenerative disease” encompasses diseases and disorders associated with the progressive loss of structure or function of neurons, or the death of neurons. Neurodegenerative diseases and disorders include: Alzheimer’s disease (including symptoms associated with mild, moderate, or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic and ischemic injuries; ataxia and seizures (including for treatment and prevention, and for the prevention of seizures caused by schizoaffective disorder or 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 injuries and head injuries); Dementia (including dementia due to multiple strokes and senile dementia); impaired consciousness; Down syndrome; drug-induced or drug-induced tremor paralysis (e.g., acute sitting incapacitation, acute ataxia, tremor paralysis or tardive dyskinesia induced by psychotropic agents, 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 dysfunction and akinesia (rigidity) syndrome. Disorders (including brainstem nerve calcification, corticobasal degeneration, multiple system atrophy, tremor palsy-ALS dementia complex, Parkinson's disease, post-encephalitis tremor palsy and progressive supranuclear palsy); disorders related to muscle spasticity and muscle spasticity or weakness (chorea (e.g., benign hereditary chorea, drug-induced chorea, hemiplegia, Huntington's disease, neuroacanthocytosis, Sydenham's chorea and symptomatic chorea), dyskinesia (including tics such as complex tics, simple tics and symptomatic tics), myoclonus (generalized myoclonus and focal syloclonus (focal) Examples include 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 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 neurodegeneration induced by viral infections (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.

[0110] Mood disorder Methods for treating mood disorders, such as clinical depression, postpartum depression or postnatal depression, perinatal depression, atypical depression, melancholic depression, psychogenic major depression, catatonic depression, seasonal affective disorder, mood swings, double depression, depressive personality disorder, relapsing brief depression, minor depressive disorder, bipolar disorder or manic-depressive disorder, depression caused by chronic conditions, treatment-resistant depression, treatment-resistant depression, suicide, suicidal ideation or suicidal behavior are also provided herein. In some embodiments, the methods described herein provide a therapeutic effect on subjects suffering from depression (e.g., moderate or severe depression). In some embodiments, the mood disorder is related to the 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 health conditions).

[0111] Clinical depression, also known as major depressive disorder (MDD), 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 have difficulty sleeping, become thin, generally feel agitated, and become irritable. Clinical depression affects how an individual feels, thinks, and behaves and can lead to a range of emotional and physical problems. Individuals with clinical depression may struggle to perform daily activities and may feel that life is not worth living.

[0112] Perinatal depression refers to depression during pregnancy. Symptoms include irritability, crying, restlessness, and insomnia. These include difficulty, extreme fatigue (emotional and / or physical), changes in appetite, difficulty concentrating, increased anxiety and / or worry, a desire to separate from the infant and / or fetus, and loss of interest in previously enjoyable activities.

[0113] 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 sexual desire, crying episodes, anxiety, and irritability. In some embodiments, PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein). In some embodiments, PND is treatment-refractory depression (e.g., treatment-refractory depression as described herein).

[0114] In some embodiments, subjects with PND also experience depression or symptoms of depression during pregnancy. This depression is referred to herein as perinatal depression. In some embodiments, subjects who experience perinatal depression are at higher risk of experiencing PND.

[0115] Atypical depression (AD) is characterized by mood reactivity (e.g., paradoxical anhedonia) and positivity, marked weight gain or increased appetite. Patients with AD may also have significant social impairment as a result of excessive sleepiness or somnolence (hypersomnia), heaviness in the limbs, and hypersensitivity to perceived social rejection.

[0116] 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.

[0117] 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.

[0118] Catastrophic depression refers to major depressive disorder accompanied by motor and behavioral impairments and other symptoms. Individuals may become mute, enter a stuporous state, become immobile, or exhibit aimless or paranoid movements.

[0119] 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.

[0120] Mood disorders refer to conditions associated with unipolar depression, where the same physical and cognitive problems are evident. They tend to be less severe and last longer (e.g., at least two years).

[0121] Bipolar disorder refers to a period of severe depression (mood disorder) that lasts for at least two years, interspersed with periods of major depression.

[0122] Depressive personality disorder (DPD) refers to a personality disorder characterized by depressive traits.

[0123] Recurrent brief depression (RBD) is a condition in which an individual experiences depressive episodes approximately once a month, each lasting for two weeks or less, typically less than two to three days.

[0124] Minor depressive disorder, or minor depression, is a type of depression characterized by at least two symptoms present for two weeks. This refers to the matter.

[0125] 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.

[0126] Depression caused by a chronic condition refers to depression that is caused by a chronic medical condition such as cancer, chronic pain, chemotherapy, or chronic stress.

[0127] 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 improve their symptoms but then relapse. 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, as well as anxiolytics, and non-pharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagal stimulation, and / or transcranial magnetic stimulation).

[0128] Postoperative depression refers to a depressive state following a surgical procedure (for example, as a result of facing death). For example, an individual may experience persistent sadness or emptiness, loss of pleasure or interest in hobbies and activities they normally enjoyed, or persistent feelings of worthlessness or despair.

[0129] Mood disorders associated with a woman's health condition or health disorder refer to mood disorders (e.g., depression) associated with (e.g., caused by) a woman's health condition or health disorder (e.g., those described herein).

[0130] 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 momentary thoughts to broader 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.

[0131] 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 alleviation can be confirmed by a physician or psychologist (e.g., by a mental state assessment).

[0132] In some embodiments, the method uses a known depression scale, such as Hamiltonian depression scale. The procedure includes monitoring subjects using the Hamilton Depression-D (HAM-D) scale, the Clinical Global Impression Improvement Scale (CGI), and the Montgomery-Asberg Depression Rating Scale (MADRS). In some embodiments, the therapeutic effect may be measured by a decrease in the subject's total HAM-D score. This decrease in the total HAM-D 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 less. The therapeutic effect may be evaluated over a specific treatment period. For example, therapeutic effect may be measured by a decrease in the HAM-D total score from baseline after administration of a compound described herein (e.g., a compound of formula (I)) (e.g., 12, 24, or 48 hours after administration; or 24, 48, 72, or 96 hours after administration or beyond; or 1, 2, 14, 21, or 28 days after administration; or 1, 2, 3, or 4 weeks after administration; or 1, 2, 6, or 10 months after administration; or 1, 2, or 1 year, or 2 years or over a lifetime).

[0133] In some embodiments, the subject has a mild depressive disorder, e.g., mild major depressive disorder. In some embodiments, the subject has a moderate depressive disorder, e.g., moderate major depressive disorder. In some embodiments, the subject has a severe depressive disorder, e.g., severe major depressive disorder. In some embodiments, the subject has a very severe depressive disorder, e.g., very severe major depressive disorder. In some embodiments, the subject's baseline HAM-D total score (i.e., before treatment with the compounds described herein (e.g., the compound of formula (I))) is at least 24. In some embodiments, the subject's baseline HAM-D total score is at least 18. In some embodiments, the subject's baseline HAM-D total score is between 14 and 18, including 14 and 18. In some embodiments, the subject's baseline HAM-D total score is between 19 and 22, including 19 and 22. In some embodiments, the total HAM-D score of a subject before treatment with a compound described herein (e.g., a compound of formula (I)) is greater than or equal to 23. In some embodiments, the baseline score is at least 10, 15, or 20. In some embodiments, the total HAM-D score of a subject after treatment with a compound described herein (e.g., a compound of formula (I)) is about 0 to 10 (e.g., less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 1.8). In some embodiments, the total HAM-D score after treatment with a compound described herein (e.g., a compound of formula (I)) is 10, 7, 5, or less than 3. In some embodiments, the reduction in the HAM-D total score is a decrease from a baseline score of about 20–30 (e.g., 22–28, 23–27, 24–27, 25–27, 26–27) to a HAM-D total score of about 0–10 (e.g., less than 10; 0–10, 0–6, 0–4, 0–3, 0–2, or 1.8) after treatment with a compound described herein (e.g., a compound of formula (I)).In some embodiments, the reduction from the baseline HAM-D total score to the HAM-D total score after treatment with a compound described herein (e.g., a 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 from the baseline HAM-D total score to the HAM-D total score after treatment with a compound described herein (e.g., a 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 reduction in the HAM-D total score after treatment with a compound described herein (e.g., a compound of formula (I)) compared to the baseline HAM-D total score (e.g., 12, 24, 48 hours after administration; or 24, 48, 72, 96 hours or more after administration; or 1, 2, 14 days or more after administration), and is at least 10, 15, or 20 points.

[0134] In some embodiments, a method for treating a depressive disorder, such as major depressive disorder, involves achieving a therapeutic effect (e.g., on the Hamilton Depression Rating Scale (HAM)) within 14, 10, 4, 3, 2, or 1 day or within 24, 20, 16, 12, 10, or 8 hours or less. The method provides a therapeutic effect (as measured by a decrease in HAM-D) as described herein. In some embodiments, a method for treating a depressive disorder, such as major depressive disorder, provides a therapeutic effect (e.g., as determined by a statistically significant decrease in the HAM-D total score) within one or two days of treatment with the compounds described herein (e.g., compounds of formula (I)). In some embodiments, a method for treating a depressive disorder, such as major depressive disorder, provides a therapeutic effect (e.g., as determined by a statistically significant decrease in the HAM-D total score) within a period of less than 14 days or equal to 14 days from the start of treatment with the compounds described herein (e.g., compounds of formula (I)). In some embodiments, a method for treating a depressive disorder, such as major depressive disorder, provides a therapeutic effect (e.g., as determined by a statistically significant decrease in the HAM-D total score) within a period of less than 21 days or equal to 21 days from the start of treatment with the compounds described herein (e.g., compounds of formula (I)). In some embodiments, a method for treating a depressive disorder, such as major depressive disorder, provides a therapeutic effect (e.g., as determined by a statistically significant decrease in the HAM-D total score) within a period of less than 28 days or equal to 28 days from the start of treatment with a compound described herein (e.g., a compound of formula (I)). In some embodiments, the therapeutic effect is a decrease from baseline in the HAM-D total score after treatment with a compound described herein (e.g., a compound of formula (I)) (e.g., treatment with compound 1 once daily for 14 days). In some embodiments, the subject's HAM-D total score before treatment with a compound described herein (e.g., a compound of formula (I)) is at least 24. In some embodiments, the subject's HAM-D total score before treatment with a compound described herein (e.g., a compound of formula (I)) is at least 18. In some embodiments, the subject's HAM-D total score before treatment with a compound described herein (e.g., a compound of formula (I)) is between 14 and 18, including 14 and 18. In some embodiments, the reduction in the total HAM-D score after treating the subject with a compound described herein (e.g., a compound of formula (I)) compared to the baseline total HAM-D score is at least 10.In some embodiments, the decrease in the total HAM-D score after treating the subject with the compound described herein (e.g., the compound of formula (I)) compared to the baseline total HAM-D score is at least 15 (e.g., at least 17). In some embodiments, the total HAM-D score associated with treating the subject with the compound described herein (e.g., the compound of formula (I)) is less than or equal to a number in the range of 6 to 8. In some embodiments, the total HAM-D score associated with treating the subject with the compound described herein (e.g., the compound of formula (I)) is 7 or less.

[0135] In some embodiments, the method provides a therapeutic effect (e.g., 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 a depressive disorder, e.g., major depressive disorder, provides a therapeutic effect within 2 days of the treatment period. In some embodiments, the therapeutic effect is a decrease in the CGI score from baseline at the end of the treatment period (e.g., 14 days after administration).

[0136] In some embodiments, the method provides a therapeutic effect (e.g., measured by a decrease in the Montgomery-Asberg Depression Rating Scale (MADRS)) within 14, 10, 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours, or less. In some embodiments, the CNS disorder is a depressive disorder, e.g., major depressive disorder. In some embodiments, the method for treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic effect within 2 days of the treatment period. In some embodiments, the therapeutic effect is a decrease in the MADRS score from baseline at the end of the treatment period (e.g., 14 days after administration).

[0137] The effectiveness of treatment for major depressive disorder can be determined by a decrease in the subject's Montgomery-Asberg Depression Rating Scale (MADRS) score. For example, the MADRS score may decrease within 4, 3, 2, or 1 day; or within 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, or 8 hours or less. The Montgomery-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, relating to outwardly expressed sadness, verbal expressed sadness, internal tension, decreased sleep, decreased appetite, difficulty concentrating, fatigue, inability to feel, pessimistic thinking, and suicidal thoughts.

[0138] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a decline in the Edinburgh Postnatal Depression Scale (EPDS)) within 4 days, 3 days, 2 days, 1 day; 24 hours, 20 hours, 16 hours, 12 hours, 10 hours, 8 hours, or less. In some embodiments, the therapeutic effect is an improvement as measured by the EPDS.

[0139] In some embodiments, the method provides therapeutic effects (e.g., as measured by a decrease in the Generalized Anxiety Disorder 7-Item Scale (GAD-7)) within 4 days, 3 days, 2 days, 1 day; 24 hours, 20 hours, 16 hours, 12 hours, 10 hours, 8 hours, or less.

[0140] Anxiety disorder Methods for treating anxiety disorders (e.g., generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, phobias, post-traumatic stress disorder) are provided herein. 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 anxiety disorders.

[0141] Generalized anxiety disorder is a common chronic disorder characterized by chronic anxiety that cannot be focused on any one object or situation. People suffering from generalized anxiety experience non-specific, persistent fears and worries and tend to worry excessively about ordinary situations. Generalized anxiety disorder is the most common anxiety disorder affecting older adults.

[0142] In panic disorder, humans suffer from intense fear and short-lived attacks of unease, often characterized by tremors, shaking, disorientation, dizziness, nausea, and difficulty breathing. These panic attacks (defined by the APA as sudden, reaching a peak in less than 10 minutes, feelings of fear or discomfort) can last for hours and can be triggered by stress, fear, or even exercise, although the specific cause is not always clear. In addition to recurrent, unpredictable panic attacks, a diagnosis of panic disorder also requires that the attacks have chronic consequences (any of worry about the potential meaning of the attack, persistent fear of future attacks, or significant changes in behavior related to the attack). Thus, patients with panic disorder experience symptoms even outside the scope of a specific panic episode. Often, normal changes in heart rate are noticed by people suffering from panic, leading them to think that something is wrong with their heart or that they are having another panic attack. In some cases, heightened awareness of body functions (hypervigilance) occurs during a panic attack, in which case any perceived physiological changes are interpreted as a potentially life-threatening illness (i.e., excessive hypochondria).

[0143] Obsessive-compulsive disorder is a type of anxiety disorder, mainly characterized by repetitive obsessive thoughts (obsessive, persistent, intrusive thoughts or mental images) and compulsive behaviors (the urge to perform specific actions or rituals). The thought patterns of OCD can be associated with superstition insofar as the person believes in causal relationships that do not actually exist in reality. Often, the pro Cess is completely illogical. For example, the compulsion of walking in a specific pattern can be used to reduce the compulsive idea of an imminent danger. And in many cases, this compulsion is not completely inexplicable, but simply the impulse to complete the rituals induced by neuroticism. In a small number of cases, patients with OCD may only experience obsessive thoughts without obvious compulsions, and an even smaller number of patients may only experience compulsions.

[0144] One of the largest categories of anxiety disorders is phobias, which encompasses all cases where fear and anxiety are induced by specific stimuli or situations. Patients typically anticipate terrifying consequences from encountering the object of their fear, which can range from animals, places, to something related to body fluids.

[0145] Post-traumatic stress disorder or PTSD is an anxiety disorder resulting from a traumatic experience. Post-traumatic stress can arise from extreme situations (such as war, rape, hostage situations, or even major disasters). It can also result from long-term (chronic) exposure to severe stressors (such as soldiers who can endure individual battles but cannot cope well with continuous warfare). Common symptoms include flashbacks, avoidance behaviors, and depression.

[0146] Women's health disorders Methods for treating conditions or disorders related to women's health are provided herein. Conditions or disorders related to women's health include gynecological health and disorders (such as premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD)), pregnancy-related problems (such as miscarriage, abortion), infertility and related disorders (such as polycystic ovary syndrome (PCOS)), other disorders and conditions, as well as problems related to women's overall health and well-being (such as menopause), but are not limited thereto.

[0147] Gynecological health issues affecting women include menstruation and menstrual irregularities; urinary tract health (including urinary incontinence and pelvic floor disorders); and conditions such as bacterial vaginosis, vaginitis, uterine fibrosis, and vulvodysia.

[0148] Premenstrual syndrome (PMS) refers to physical and emotional symptoms that occur one to two weeks before menstruation. Symptoms vary but may include bleeding, mood swings, breast tenderness, bulimia, fatigue, irritability, acne, and depression.

[0149] Premenstrual dysphoric disorder (PMDD) is a severe form of PMS. The symptoms of PMDD are similar to those of PMS but are more severe and can interfere with work, social activities, and relationships. Symptoms of PMDD include mood swings, depressed mood or feelings of hopelessness, marked anger, increased interpersonal conflict, tension and anxiety, irritability, decreased interest in usual activities, difficulty concentrating, fatigue, changes in appetite, feelings of uncontrollability or confusion, sleep problems, and physical problems (e.g., bloating, breast tenderness or swelling, headache, joint pain or muscle pain).

[0150] Pregnancy-related 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.

[0151] A miscarriage refers to the spontaneous termination of a pregnancy within 20 weeks of gestation.

[0152] Abortion refers to the intentional termination of a pregnancy, which can be performed up to 28 weeks of gestation.

[0153] Infertility and related disorders include uterine fibrosis, polycystic ovary syndrome, endometriosis, and Primary ovarian insufficiency is one example.

[0154] 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. Many women with PCOS develop numerous small cysts on their ovaries. Symptoms of PCOS include irregular or absent menstruation, heavy periods, excessive body and facial hair, acne, pelvic pain, difficulty conceiving, and thickened, dark, smooth skin patches. PCOS may be associated with conditions such as type 2 diabetes, obesity, obstructive sleep apnea, heart disease, mood disorders, and endometrial cancer.

[0155] Other disorders and conditions that affect only women include Turner syndrome, Rett syndrome, and ovarian and cervical cancer.

[0156] Issues related to women's overall health and well-being include violence against women, women with physical disabilities and unique challenges, osteoporosis and bone health, and menopause.

[0157] 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 symptoms, such as hot flashes and emotional disturbances, can disrupt sleep, reduce energy levels, or cause anxiety, sadness, or feelings of loss. Menopause can be spontaneous or surgical (induced by events such as surgery, e.g., hysterectomy, oophorectomy; cancer). Menopause can be induced, for example, when the ovaries are severely damaged by radiation, chemotherapy, or other drug therapies.

[0158] epilepsy Compounds of formula (I) or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable compositions thereof, may be used in the methods described herein, for example, in the treatment of disorders described herein, such as epilepsy, status epilepticus, or seizures.

[0159] Epilepsy is a brain disorder characterized by recurrent seizures over a long period of time. Types of epilepsy include, but are not limited to, generalized epilepsy, such as childhood absence epilepsy, juvenile myoclonus (nyoclonic) epilepsy, epilepsy with grand mal seizures while awake, West syndrome, Lennox-Gastaut syndrome, and partial epilepsy, such as temporal lobe epilepsy, frontal lobe epilepsy, and benign focal epilepsy in childhood.

[0160] Epilepsy occurs The compounds and methods described herein can be used to treat or prevent epilepsy development. Epilepsy development is a stepwise process in which a normal brain develops epilepsy (a chronic condition characterized by seizures). Epilepsy development arises from nerve damage caused by an initial injury (e.g., persistent status epilepticus).

[0161] Status epilepticus (SE) Status epilepticus (SE) can 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, complex 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 can include early status epilepticus, established status epilepticus, refractory status epilepticus, and extremely refractory status epilepticus. It can include the state. Status epilepticus is treated with first-line therapy. Established status epilepticus is characterized by continuous epileptic seizures despite treatment with first-line therapy, and second-line therapy is performed. Refractory status epilepticus is characterized by continuous epileptic seizures despite treatment with first-line and second-line therapies, and general anesthetics are commonly administered. Super-refractory status epilepticus is characterized by continuous epileptic seizures despite treatment with first-line therapy, second-line therapy, and general anesthetics for 24 hours or more.

[0162] Non-convulsive status epilepticus can include, for example, focal non-convulsive status epilepticus, such as complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, subtle non-convulsive status epilepticus; generalized non-convulsive status epilepticus, such as late-onset absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus.

[0163] Seizure A seizure is a behavioral physical finding or change that occurs after an episode of abnormal electrical activity in the brain. The term "seizure" is often used interchangeably with "convulsion". A convulsion is when the human body shakes rapidly and uncontrollably. During a convulsion, the muscles of that human repeat contraction and relaxation.

[0164] Based on the type of behavior and brain activity, seizures are divided into two broad categories, namely, generalized and partial (also called local or focal). Classifying the type of seizure helps a doctor diagnose whether a patient has epilepsy.

[0165] 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 part of the brain. The part of the brain that causes a seizure is sometimes called a lesion.

[0166] 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 period of generalized rigidity (called the "tonic" phase of the seizure) for 30–60 seconds, followed by a period of intense spasms ("clonic" phase) for 30–60 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.

[0167] Absence seizures cause brief (only a few seconds) periods of loss of consciousness with little or no symptoms. Patients (most frequently children) typically stop their activities and stare blankly. These seizures begin and end suddenly and can occur several times a day. Patients are usually unaware they are having seizures unless they notice they are "losing time."

[0168] 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.

[0169] Clonic seizures are recurrent, rhythmic spasms that involve both sides of the body simultaneously.

[0170] Tonic seizures are characterized by muscle rigidity.

[0171] 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.

[0172] 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; Jackson's 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.

[0173] Compounds of formula (I) or pharmaceutically acceptable salts or pharmaceutically acceptable compositions thereof may also be administered as prophylactic agents to subjects with CNS disorders (e.g., traumatic brain injury, status epilepticus, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, extremely refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptic discharge; and periodic unilateral epileptic discharge) before the onset of a seizure.

[0174] Movement impairment Methods for treating motor disorders are also described herein. As used herein, “motor disorder” refers to a range of diseases and disorders associated with hyperkinetic disorders and abnormalities in the control of the muscles involved. Examples of motor disorders include, but are not limited to, Parkinson’s disease and tremor paralysis (defined especially by bradykinesia), dystonia, 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.

[0175] shaking The methods described herein may be used to treat tremors, for example, the compound of formula (I) may be used to treat, for example, cerebellar tremor or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, Parkinsonian tremor, physiological tremor, psychogenic tremor or rubral 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 diseases, 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, and toluene); disorders induced by drugs (hypnotics, tricyclic antidepressants, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, and vincristine); and psychogenic disorders. Clinical tremors can be classified into physiological tremors, fatigue-induced physiological tremors (enhanced physiologic tremors), essential tremor syndromes (including classical essential tremor, primary orthostatic tremor, and task-specific and positional tremors), dystonic tremors, Parkinsonian tremors, cerebellar tremors, Holmes tremor (i.e., red nucleus tremor), palatal tremors, neuropathic tremors, toxic or drug-induced tremors, and psychogenic tremors.

[0176] Tremors are involuntary, sometimes rhythmic, muscle contractions and relaxations that may involve vibration or spasms of one or more body parts (e.g., hands, arms, eyes, face, head, vocal cords, trunk, legs).

[0177] Cerebellar tremor, or intention tremor, is a slow, widespread tremor of the limbs that occurs after an intentional movement. Cerebellar tremors are caused by lesions or damage to the cerebellum, for example, resulting from tumors, strokes, or diseases (e.g., multiple sclerosis, hereditary degenerative disorders).

[0178] Dystonic tremors occur 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 tremors can affect any muscle in the body. They occur irregularly and can often be relieved by complete rest.

[0179] 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.

[0180] 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 patients may tremble uncontrollably when asked to stand in one place. Orthostatic tremor can occur in patients with essential tremor.

[0181] Parkinsonian tremors are caused by damage to the brain structures that control movement. Often a precursor to Parkinson's disease, tremors typically manifest as a "pill-rolling" movement of the hand, but can also affect the chin, lips, legs, and trunk. The onset of Parkinsonian tremors typically begins after age 60. The movement may begin in one limb or one side of the body and progress to the other side.

[0182] 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. These tremors typically have a frequency of approximately 10 Hz.

[0183] Psychogenic tremors or hysterical tremors can occur at rest, during postural movements, or during active movements. Patients with psychogenic tremors may also have conversion disorder or another psychiatric disorder.

[0184] Red nuclear tremor is characterized by slow, coarse tremors that can occur at rest, in posture, and when intentional. This tremor may be associated with conditions affecting the red nucleus in classic, rare strokes of the midbrain.

[0185] Parkinson's disease affects the nerve cells in the brain that produce dopamine. Symptoms include muscle rigidity, tremors, and changes in speech and gait. Tremor paralysis is characterized by tremors, bradykinesia, rigidity, and postural instability. Tremor paralysis shares symptoms with Parkinson's disease, but it is a group of symptoms rather than a progressive neurodegenerative disease.

[0186] 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 trembling. Dystonia is often triggered or aggravated by voluntary movement and is often associated with an overflow of muscle activation.

[0187] 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.

[0188] Ataxia refers to the loss of complete control over bodily movements and can affect fingers, hands, arms, legs, body, speech, and eye movements.

[0189] Myoclonus and startle are responses to sudden and unexpected stimuli that may be auditory, tactile, visual, or vestibular.

[0190] Tics are involuntary movements that typically begin suddenly, are short, repetitive but not rhythmic, and often mimic normal behavior, occurring outside the context 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.

[0191] Lower limb restlessness syndrome is a neurological sensorimotor disorder characterized by an irresistible urge to move the legs while at rest.

[0192] 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 typically observed in EMG recordings of continuous motor unit activity of the paravertebral axial muscles. A variant is "stiff-limb syndrome," which results in localized rigidity, typically affecting the distal legs and feet.

[0193] Gait disorders refer to abnormalities in the manner 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.

[0194] Anesthesia / Sedation Anesthesia is a pharmacologically induced, reversible state characterized by amnesia, analgesia, loss of responsiveness, loss of skeletal muscle reflexes, a reduced stress response, or a combination of all of these simultaneously. These effects can be obtained from a single drug that provides the correct combination of effects on its own, or sometimes from a combination of drugs (e.g., hypnotics, sedatives, paralyzing agents, analgesics) to achieve a very specific combination of results. Anesthesia allows patients to undergo surgical and other procedures without experiencing the difficulties and pain they would otherwise experience.

[0195] Sedation is generally the reduction of nervousness or agitation through the administration of pharmacological agents to facilitate medical or diagnostic procedures.

[0196] Sedation and analgesia encompass a continuum of states of consciousness ranging from minimal sedation (anxiety relief) to general anesthesia.

[0197] Minimal sedation is also known as anxiety relief. Minimal sedation is a drug-induced state in which the patient responds normally to verbal commands. Cognitive function and coordination may be impaired. Ventilation and cardiovascular function are typically unaffected.

[0198] Moderate sedation / analgesia (conscious sedation) is a drug-induced decrease in consciousness in which the patient intentionally responds to verbal commands, either alone or with light tactile stimulation. Typically, intervention to maintain the patient's airway is not required. Spontaneous ventilation is usually adequate. Cardiovascular function is usually maintained.

[0199] Deep sedation / analgesia is a drug-induced decrease in consciousness in which the patient cannot easily awaken but responds intentionally (rather than reflexively withdrawing from painful stimuli) after repeated or painful stimuli. Independent ventilatory function may be impaired, and the patient may require assistance to maintain their airway. Spontaneous ventilation may be insufficient. Cardiovascular function is usually maintained.

[0200] General anesthesia is drug-induced loss of consciousness in which the patient is unable to awaken even in response to painful stimuli. Because the ability to maintain independent ventilatory function is often impaired, assistance to maintain the patient's airway is frequently required. Positive pressure ventilation may be necessary due to reduced spontaneous ventilation or drug-induced neuromuscular dysfunction. Cardiovascular function may be impaired.

[0201] Sedation in the intensive care unit (ICU) allows for a reduced awareness of the patient's environment and decreased response to external stimuli. This can play a role in treating patients with critical illness and encompasses a wide range of symptom control, which varies from patient to patient and individual to individual throughout the course of the patient's illness. Heavy sedation in intensive care is used to facilitate endotracheal tube tolerance and ventilator synchronization (often accompanied by neuromuscular blocking agents).

[0202] In some embodiments, sedation (e.g., prolonged sedation, sustained sedation) is induced in the ICU and maintained over extended periods (e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months). Prolonged sedatives may have a long duration of action. Sedatives in the ICU may have a short elimination half-life.

[0203] Sedation and analgesia during a procedure (also known as conscious sedation) is a technique that involves administering sedatives or dissociative agents, with or without analgesics, to enable a subject to tolerate an uncomfortable procedure while maintaining cardiopulmonary function. [Examples]

[0204] For the purpose of enabling a better understanding of the invention as described herein, the following examples are provided. The synthetic and biological examples described herein are provided to illustrate the compounds, pharmaceutical compositions and methods provided herein and should not be construed as limiting their scope.

[0205] material and method 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 given, it is understood that other process conditions may 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 those skilled in the art through conventional optimization.

[0206] Furthermore, as may be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. The selection of suitable protecting groups for specific functional groups, as well as the conditions suitable for protection and deprotection, are well known in the art. For example, numerous protecting groups and their introduction and removal are described in TW Greene and PGMWuts, *Protecting Groups in Organic Synthesis*, 2nd edition, Wiley, New York, 1991, and the references cited therein.

[0207] The compounds provided herein may 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 schemes are presented in detail with respect to the preparation of representative oxysterols listed herein. The compounds provided herein may be prepared by those skilled in the art of organic synthesis from known or commercially available starting materials and reagents. Exemplary chiral columns available for use in the separation / purification of 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.

[0208] The 1H-NMR reported herein (e.g., for the region between approximately 0.5 and 4 ppm of δ(ppm)) is understood to be an exemplary interpretation (e.g., an exemplary peak integral) of the NMR spectrum of the compound.

[0209] 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 NH3H2O). Flow rate: 25 mL / min.

[0210] Exemplary general method for analytical HPLC: Mobile phase: A: Water (10 mM NH4HCO3), B: Acetonitrile, Gradient: 5% to 95% of B for 1.6 or 2 minutes, Flow rate: 1.8 or 2 mL / min; Column: XBridge C18, 4.6 × 50 mm, 3.5 μm, 45°C.

[0211] LC-ELSD / MS mobile phase: 1.5 mL / 4 L water containing TFA (solvent A) and 0.75 mL / 4 L acetonitrile containing TFA (solvent B), with a flow rate of 1.2 mL / min and an elution gradient of 30% to 90% (solvent B) for 0.9 minutes and retention at 90% for 0.6 minutes; Column: Xtimate C18 2.1 × 30 mm, 3 μm; Column temperature: 50 °C; PDA wavelength: UV 220 nm; MS ionization: ESI and ELSD.

[0212] Exemplary general method for SFC: Column: CHIRALPAK(registered trademark) AD C SP (250mm x 30mm, 10μm), gradient: 45% B, A=NH3H2O, B=MeOH, flow rate: 60mL / min. For example, AD_3_EtOH_DEA_5_40_25ML represents the following: "Column: Chiralpak AD-3 150×4.6mm ID, 3um Mobile phase: A:CO2 B:Ethanol (0.05% DEA) Gradient: 5% to 40% B over 5 minutes, held at 40% for 2.5 minutes, then 5% B for 2.5 minutes. Flow rate: 2.5mL / min. Column temperature: 35℃."

[0213] HRMS instrument: Agilent G230B LCMS-TOF. Mobile phase: Water containing 0.1% FA (solvent A) and ACN (solvent B); Elution gradient: 5% to 95% (solvent B) over 3 minutes at a flow rate of 1 mL / min, and hold at 95% for 1 minute; Column: Xbridge Shield RP 18 5 μm, 2.1 × 50 mm; Ion source: AJS ESI supply source; Ion mode: Positive; Nebulize gas: Nitrogen; Dry gas (N2) flow: 8 L / min; Nebulize pressure: 35 psig; Gas temperature: 325 °C; Sheath gas temperature: 350 °C; Sheath gas flow: 11 L / min; Capillary voltage: 3.5 KV; Fragmenter voltage: 175 V.

[0214] Abbreviations: PE: Petroleum ether; TLC: Thin-layer chromatography; Petroleum ether; Depositphotos: Ethyl acetate; THF: Tetrahydrofuran; 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 tetrachloride Sopropoxide; 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; DMAP: 4-dimethylaminopyridine; DMP: des-martin-periodinane; EtMgBr: ethylmagnesium bromide; 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); 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.

[0215] Example 1: Synthesis of 1-(2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-13-methyl-3-(methyl-d3)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (Compound 1). [ka]

[0216] A2 synthesis [ka] A suspension of ether (10 mL) containing Mg (660 mg, 27.3 mmol) was added dropwise to a solution of anhydrous ether (2.5 mL) containing CD3I (4 g, 27.3 mmol) under N2 at 25°C, and the internal temperature was raised to 35°C. The mixture was then stirred at 25°C for 3 hours to obtain CD3MgI. This can be used directly. To a toluene (20 mL) solution containing 2,6-di-tert-butyl-4-methylphenol (12 g, 54.6 mmol), AlMe3 (13.7 mL, 2 M toluene solution, 27.3 mmol) was added dropwise at 10°C. The mixture was then stirred at 25°C for 1 hour. A suspension of toluene (7.5 mL) containing A1 (2.5 g, 9.1 mmol) (listed in U.S. Patent No. 9,512,165) was added dropwise under N2 at -70°C. The mixture was stirred at -70°C for 1 hour, and then a CD3MgI ether solution was added dropwise over 15 minutes at -70°C. After the addition, the mixture was stirred for a further 3 hours at -70°C, and then quenched by adding a saturated NH4Cl (100 mL) aqueous solution at -70°C. The mixture was then warmed to 25°C and filtered. The filtration cake was washed with dimethyl acetate (200 mL), and the filtrates were combined. The organic layer was dried over Na₂SO₄, concentrated under reduced pressure, and purified by silica gel column chromatography (eluting PE:dimethyl acetate at a ratio of 10:1 to 2:1) to obtain A2 (1.1 g, 39%) as a solid. 11H NMR (400 MHz, CDCl3) δ H 2.49-2.35 (m, 1H), 2.14-1.98 (m, 1H), 1.95-1.70 (m, 7H), 1.70-1.00 (m, 15H), 0.86 (s, 3H).

[0217] A3 composite [ka] To a 10 mL THF solution containing EtPPh3Br (6.33 g, 17.05 mmol), a 15 mL THF solution containing t-BuOK (1.91 g, 17.05 mmol) was added. The reaction mixture was stirred at 60°C for 1 hour, then a 10 mL THF solution containing A2 (1 g, 3.41 mmol) was added to the mixture, and the mixture was stirred at 60°C for a further 15 hours. When TLC indicated that the starting material had been consumed, the reaction mixture was quenched with water (10 mL) and extracted with 150 mL of ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to obtain the crude product. The residue was purified by silica gel column chromatography (eluting at PE:ethyl = 200:1 to 10:1) to obtain A3 (1 g, 95.89%) as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 5.14-5.08 (m, 1H), 2.38-2.30 (m, 1H), 2.25-2.21 (m, 2H), 1.81-1.64 (m, 10H), 1.40-1.07 (m, 14H), 0.87 (s, 3H).

[0218] A4 composition [ka] To a solution of dry THF (10 mL) containing A3 (1 g, 3.72 mmol), BH3.Me2S (3.27 mL, 10 equivalents) was added at 0°C. After stirring at 20°C for 2 hours, the reaction mixture was cooled in an ice bath and slowly quenched by adding 3M NaOH (30 mL) aqueous solution followed by 30% H2O2 aqueous solution (20 mL). After stirring at 20°C for 1 hour, the mixture was filtered, and the filtrate was extracted with ELISA (50 mL x 2). The combined organic layers were washed with Na2S2O3 aqueous solution (30 mL), dried over Na2SO4, and concentrated to obtain A4 (1.2 g, crude). The crude product was used in the next step without further purification.

[0219] A5 synthesis [ka] To a 15 mL solution of CH2Cl2 containing A4 (1.2 g, crude), silica gel (1.1 g) and PCC (0.96 g, 4.46 mmol) were added at 20°C, and the reaction mixture was stirred at 20°C for 2 hours. After TLC showed consumption of the starting material, the mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (eluting at PE:ԅ = 20:1, 15:1, 10:1, 8:1, and 6:1) to obtain A5 (0.8 g, 83.6%) as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 2.56-2.51 (m, 1H), 2.14-2.11 (m, 4H), 2.05-1.95 (m, 1H), 1.81-1.64 (m, 7H), 1.44-1.05 (m, 15H), 0.61 (s, 3H).

[0220] A6 synthesis [ka] To a 50 mL solution of MeOH containing A5 (0.8 g, 2.49 mmol), HBr (3 drops) and Br2 (0.14 mL, 2.74 mmol) were added at 25°C. The reaction mixture was stirred at 25°C for 1.5 hours. When TLC showed consumption of the starting material, the reaction mixture was quenched by adding an aqueous solution of NaHCO3 (30 mL) and concentrated. The mixture was extracted with 500 mL of ethyl acetate, washed with brine (100 mL), dried over Na2SO4, and concentrated to obtain A6 (1 g, crude) as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 3.92-3.91 (m, 2H), 2.85-2.75 (m, 1H), 2.20-2.10 (m, 1H), 1.93-1.71 (m, 11H), 1.44-1.09 (m, 12H), 0.63 (s, 3H).

[0221] Synthesis of Compound 1 [ka] To a 10 mL solution of acetone containing A6 (0.15 g, 0.37 mmol), K2CO3 (0.15 g, 1.11 mmol, 3 equivalents) and 1H-pyrazole-4-carbonitrile (50 mg, 0.55 mmol, 1.5 equivalents) were added. The reaction mixture was stirred at 23°C for 2 hours. After TLC indicated that the starting materials had been completely consumed, the reaction product was filtered using CH2Cl2 (20 mL) and concentrated. The residue was purified by silica gel column chromatography (PE:Â=10:1~8:1~6:1~5:1~4:1~2:1) to obtain compound 1 (54 mg, yield 35.14%) as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 7.86-7.81 (m, 2H), 5.04-4.88 (m, 2H), 2.61-2.59 (m, 1H), 2.25-2.15 (m, 1H), 2.06-2.03 (m, 1H), 1.81-1.74 (m, 6H), 1.49-1.27 (m, 12H) , 1.11-1.09 (m, 3H), 0.67 (s, 3H).MS ESI calculated value for C25H32D3N3O2[M+H]+ 412.58, measured value 395.

[0222] Example 2: Synthesis of 1-(2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl-17-d)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (A10) [ka]

[0223] A8 synthesis [ka] To a solution of THF (20 mL) containing A7 (1 g, 3.1 mmol, reported in patent "WO2014 / 169833, 2014, A1"), D2O (10 mL), CD3OD (5 mL), and NaOD (96.2 mg, 40% D2O solution, 0.94 mmol) were added. The mixture was stirred at 60°C for 16 hours. After cooling, the reaction mixture was adjusted to pH 7 with AcOD (0.1 M D2O solution). NaCl (3 g) and PE (20 A (mL) was added. The mixture was stirred for 5 minutes, the organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain an oily substance. Analysis showed complete deuterization, so these reaction conditions were repeated. To a solution of THF (20 mL) containing the aforementioned oily substance, D2O (10 mL), CD3OD (5 mL), and NaOD (96.2 mg, 40% D2O solution, 0.94 mmol) were added. The mixture was stirred at 60°C for 16 hours. After cooling, the reaction mixture was adjusted to pH 7 with AcOD (0.1 M D2O solution). NaCl (3 g) and PE (20 mL) were added to the mixture. The mixture was stirred for 5 minutes, the organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain A8 (900 mg, 90%) as an oily substance. 1 1H NMR (400 MHz, CD3OD) δ H 2.25-1.95 (m, 3H), 1.85-1.55 (m, 10H), 1.50-0.80 (m, 14H), 0.60 (s, 3H).

[0224] A9 synthesis [ka] To a solution of MeOH (3 mL) containing A8 (0.3 g, 0.93 mmol), HBr (37.5 mg, 40%, 0.18 mmol) and Br2 (148 mg, 0.93 mmol) were added. The mixture was stirred at 15°C for 3 hours. The mixture was quenched with NaHCO3 (20 mL, saturated) and extracted with RINKAN (20 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain A9 (0.35 g, 94%) as an oily substance. 1 1H NMR (400 MHz, CD3OD) δ H 2.25-2.10 (m, 1H), 1.85-1.55 (m, 11H), 1.50-0.80 (m, 15H), 0.63 (s, 3H).

[0225] Synthesis of A10 [ka] To a solution of A9 (0.35 g, 0.87 mmol) in acetone (3 mL), 4-cyanopyrazole (323 mg, 3.5 mmol) and K2CO3 (487 mg, 3.5 mmol) were added. The mixture was stirred at 15°C for 1 hour. The mixture was quenched with NH4Cl (20 mL, saturated) and extracted with HCl (20 mL). The organic layer was separated, dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by flash column (PE containing 20-60% HCl) to obtain A10 (0.23 g, 64%, 12%). The remaining 1-D was obtained as a solid. To a solution of THF (5 mL) containing A10 (0.23 g, 12% 21-D remaining, 0.56 mmol), water (5 mL) containing MeOH (10 mL) and NaHCO3 (47 mg, 0.56 mmol) was added. The mixture was stirred at 20°C for 16 hours. The mixture was diluted with Depositphotos (50 mL), washed with water (2 × 50 mL), dried over Na2SO4, filtered, concentrated under reduced pressure, and ground in hexane (30 mL) at 60°C to obtain A10 (162 mg, 70%, D ratio: 97.89%) as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 7.86 (s, 1H), 7.81 (s, 1H), 5.10-4.80 (m, 2H), 2.25-2.15 (m, 1H), 2.10-2.00 (m, 1H), 1.90-1.65 (m, 7H), 1.45-1.30 (m, 9H), 1.30-1.20 (m, 6H), 1.30-1.00 (m, 3H), 0.67 (s, 3H); LC-ELSD / MS purity 100%, MS of C25H35DN3O2 [M+H]+ ESI calculated value 411, measured value 411; HRMS calculated value of C25H35DN3O2 [M+H]+ 411.2865, measured value 411.2815.

[0226] Example 3. Biological data

[0227] TBPS-binding steroid inhibition

[0228] A [35S]-t-butylbicyclophosphorothionate (TBPS) binding assay using rat cortical membrane in the presence of 5 mM GABA has been reported (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).

[0229] In short, after decapitation of carbon dioxide-anesthetized Sprague-Dawley rats (200-250g), the cortex is promptly removed. The cortex is homogenized in 10 volumes of ice-cold 0.32M sucrose using a glass / Teflon® homogenizer and centrifuged at 4°C and 1500×g for 10 minutes. The resulting supernatant is centrifuged at 4°C and 10,000×g for 20 minutes to obtain a P2 pellet. The P2 pellet is resuspended in 200mM NaCl / 50mM sodium potassium phosphate pH 7.4 buffer and centrifuged at 4°C and 10,000×g for 10 minutes. This washing procedure is repeated twice, and the pellet is resuspended in 10 volumes of buffer. Aliquots (100 mL) of the membrane suspension are incubated with 5 mL aliquots of the test drug (final 0.5%) dissolved in dimethyl sulfoxide (DMSO) in the presence of 3 nM [35S]-TBPS and 5 mM GABA. This incubation yields a final volume of 1.0 mL including buffer. Nonspecific binding is measured in the presence of 2 mM unlabeled TBPS, ranging 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. Radioactivity bound to the filter is measured by liquid scintillation spectrometry. Nonlinear curve fitting of the overall data for each drug, averaged for each concentration, is performed using Prism (GraphPad). If the sum of squares is significantly lower by 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 by the F-test, fit the data to a two-component inhibition model instead of a one-component inhibition model. Measure the concentration of the test compound that yields 50% inhibition of specific binding (IC50) and the maximum degree of inhibition (Imax) for each experiment using the same model used for the entire dataset, and then calculate the mean ± SEM for those individual experiments. Picrotoxin serves as a positive control for these studies because it has been demonstrated to strongly inhibit TBPS binding.

[0230] Various compounds may be screened or evaluated to measure their potential as regulators of [35S]-TBPS binding in vitro. These assays may be performed or evaluated according to the procedures discussed above.

[0231] In Table 2 below, A represents a TBPS IC50 (μM) of less than 0.01 μM, B represents a TBPS IC50 (μM) of 0.01 μM to less than 0.1 μM, C represents a TBPS IC50 (μM) of 0.1 μM to less than 1.0 μM, D represents a TBPS IC50 (μM) of 1.0 μM to less than 10 μM, and E represents 10 μM or more. [Table 2]

[0232] Example 4. Evaluation of the metabolic stability of the compound -- Human CYP3A4 SUPERSOMES (trademark).

[0233] SUPERSOMES® Assay - The following assay can be used to evaluate the metabolic stability of the compounds described herein (e.g., compounds of formula (I)). This assay is provided for illustrative purposes only and is a non-limiting method for evaluating the metabolic stability of the compounds described herein.

[0234] A 7.5 mM preservation solution of the compounds described herein can be prepared in DMSO. The 7.5 mM preservation solution can be diluted to 50 mM with acetonitrile (ACN). Human CYP3A4 SUPERSOMES® (1000 pmol / mL, purchased from BD Gentest.™ Products and Services) can be diluted to 62.5 pmol / mL with 0.1 M potassium phosphate buffer (pH 7.4) containing 3 mM MgCl2. The diluted supersomes can be added in triplicate to the wells of a 96-well polypropylene plate. A 10 mL aliquot of the 50 mM test compound can be added to the SUPERSOMES®, and the mixture can be preheated for 10 minutes. The reaction can be initiated by adding the preheated NADPH solution. The final volume of the reaction mixture may be 0.5 mL and may contain 0.1 M potassium phosphate buffer (pH 7.4) containing 50 pmol / mL CYP3A4 SUPERSOMES™, 1.0 mM test compound, and 2 mM NADPH, and 3 mM MgCl2. The reaction mixture can be incubated at 37°C, and 50 mL aliquots can be taken out after 0, 5, 10, 20, and 30 minutes and added to a 96-well plate which may contain 50 mL of ice-cold ACN containing an internal standard for stopping the reaction. The plate can be stored at 4°C for 20 minutes, after which 100 mL of water was added to the wells of the plate, and the precipitated protein was pelleted by centrifugation. The supernatant was transferred to another 96-well plate, and the amount of parent material remaining was analyzed by LC-MS / MS using an Applied Bio-systems API 4000 mass spectrometer.

[0235] Data analysis: In vitro half-life (t) of the test compound 1 / 2 The value can be calculated from the slope of the linear regression between LN (percentage remaining of parent material) and incubation time: in vitro t1 / 2 = 0.693 / k (where k = -[slope of the linear regression between percentage remaining of parent material (ln) and incubation time]).

[0236] Example 5. Evaluation of the pharmacokinetics of the compound in rats

[0237] The following assays can be used to evaluate the pharmacokinetics of the compounds described herein (e.g., compounds of formula (I)). These assays are provided for illustrative purposes only and are non-limiting methods for evaluating the pharmacokinetics of the compounds described herein.

[0238] The compounds described herein can be administered individually to rats via oral gastric tube feeding (PO). Each compound can be administered to three rats at a dose of 10 mg / kg (N=3 rats / compound; a total of 9 rats in the study). Each compound can be formulated in 100% PEG400 at a concentration of 2 mg / mL. Blood samples can be collected from each rat 15 and 30 minutes after administration, and at 1, 2, 4, 6, 8, 12, 24, 48, and 72 hours after administration. Plasma can be obtained by centrifugation of the blood samples. Plasma samples can be analyzed for the administered concentration of the compound at each time point using LC-MS / MS. The limit of quantification for each compound was 1 ng / mL.

[0239] The rat t1 / 2 value can be determined by non-compartmental analysis using WinNonlin software.

[0240] Equivalents and range In a claim, an article (e.g., "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 group members are present in, used in, or otherwise related to a given product or process. The present invention includes embodiments in which exactly one member of the group is present in, used in, or otherwise related to a given product or process. The present invention includes embodiments in which more than one or all group members are present in, used in, or otherwise related to a given product or process.

[0241] 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 in another claim. For example, any claim dependent on another claim is the same basic claim This section may be modified to include one or more limitations found in any other claim dependent on it. If 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 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 allow for the inclusion of further elements or processes. Where a range is given, 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 particular value or subrange within the ranges described in the various embodiments of the present invention up to one-tenth of the lower limit of that range.

[0242] This application refers to various issued patents, published patent applications, academic articles, 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. Furthermore, any particular embodiment of the Invention that falls within the scope of the Prior Art may be expressly excluded from any one or more of the claims. Such embodiments are considered to be known to those skilled in the art and may be excluded even if such exclusion is not expressly indicated herein. Any particular embodiment of the Invention may be excluded from any claim for any reason, whether or not it relates to the existence of the Prior Art.

[0243] Those skilled in the art will be able to recognize or verify, by mere conventional experimental methods, many equivalents to the specific embodiments described herein. The scope of the embodiments described herein is not intended to be limited to the above description, as is set forth 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.

[0244] According to a preferred embodiment of the present invention, for example, the following is provided: (Section 1) Equation (I) [ka] (In the formula, R 3a is 1 or more deuteria or X 2 -OX 3 They exist independently A C1-C6 alkyl group which is substituted as necessary, where X 2 and X 3 Each of them is independently a C1-C6 alkylene that has been substituted as necessary so that another deuterium exists; R 5 , R 6a , R 6b , R 17 , R 21a , R 21b , R m , R n , R 16a , R 16b , R 7a , R 7b , R 12a , R 12b , R 11a , R 11b , R 2a , R 2b , R 19 , R 4a , and R 4b Each of them is independently selected from the group consisting of hydrogen and deutherium, however, (a)R 3a However, Deuterium is also X 2 -OX 3 It is a C1-C6 alkyl group that does not exist, and here, X 2 and X 3 Each of these is independently a C1-C6 alkylene in which deuterium does not exist, R 5 , R 6a , R 6b , R 17 , R 21a , R 21b , R m , and R n , R 16a , R 16b , R 7a , R 7b , R 12a , R 12b , R 11a , R 11b , R 2a , R 2b , R 19 , R 4a , and R 4b At least one of them is a deuterium, or (b)R 5 , R 6a , R 6b , R 17 , R 21a , R 21b , R m , R n , R 16a , R 16b , R 7a , R 7b , R 12a , R 12b , R 11a , R 11b , R 2a , R 2b , R 19 , R 4a , and R 4b If all of them are hydrogen, then R 3a is 1 or more deuteria or X 2 -OX 3 A C1-C6 alkyl group is substituted such that X exists independently, where X 2 and X 3A compound of (which must be substituted so that at least one deuterium is present) or a pharmaceutically acceptable salt thereof. (Section 2) R 3a This is a deuterium or X from 0 to 7. 2a -OX 3a A C1-C3 alkyl group is substituted such that X exists independently, where X 2a This is a C1-C3 alkylene in which 0-7 deuteria exist independently, and X 3a The compound described in item 1 above, wherein the compound is a C1-C3 alkylene substituted such that 0-7 deutherium atoms exist independently. (Section 3) R 3a If R is -CH3, 5 , R 6a , R 6b , R 17 , R 21a , R 21b , R m , and R n At least one of them is a deuterium, or R 5 , R 6a , R 6b , R 17 , R 21a , R 21b , R m , and R n If all of them are hydrogen, then R 3a The compound according to item 1 or 2 above, wherein the methyl group is substituted such that 1 to 3 deutherium atoms are independently present. (Section 4) R 3a (Item 5) is a compound selected from the group consisting of -CH3 and CD3, as described in Item 1 above. R 3a The compound described in item 1 or 2 above, wherein is -CH3. (Section 6) R 3a The compound described in item 1 or 2 above, wherein is -CD3. (Section 7) R 5 , R 6a , R 6b , R17 , R 21a , R 21b , R m , R n , R 16a , R 16b , R 7a , R 7b , R 12a , R 12b , R 11a , R 11b , R 2a , R 2b , R 19 , R 4a , and R 4b A compound according to any one of items 1 to 6 above, wherein at least one of them is deutherium. (Section 8) R 5 , R 6a , R 6b , R 17 , R 21a , R 21b , R m , and R n A compound according to any one of items 1 to 7 above, wherein at least one of them is deutherium. (Section 9) R 3a is -CH3, R 5 , R 6a , R 6b , R 17 , R 21a , R 21b , R m , R n , R 16a , R 16b , R 7a , R 7b , R 12a , R 12b , R 11a , R 11b , R 2a , R 2b , R 19 , R 4a , and R 4b At least one of them is a Deuterium. A compound described in any one of items 1 to 6 above. (Section 10) R 3a is -CH3, R 5 , R6a , R 6b , R 17 , R 21a , R 21b , R m , and R n A compound according to any one of items 1 to 9 above, wherein at least one of the compounds is deutherium. (Section 11) R 5 and R 6a A compound described in any one of items 1 to 10 above, wherein is hydrogen. (Section 12) R 5 and R 6a The compound is deutherium, as described in any one of items 1 to 10 above. (Section 13) R 17 A compound described in any one of items 1 to 12 above, wherein is hydrogen. (Section 14) R 17 The compound is deutherium, as described in any one of items 1 to 12 above. (Section 15) R 21a and R 21b Each of these is independently selected from the group consisting of hydrogen and deutherium, and is a compound according to any one of the above items 1 to 14. (Section 16) R 21a and R 21b The compound is hydrogen, as described in any one of items 1 to 15 above. (Item 17) R 21a and R 21b The compound is deutherium, as described in any one of items 1 to 15 above. (Section 18) R m and R n A compound described in any one of items 1 to 17 above, wherein is hydrogen. (Section 19) R m and R n The compound is deutherium, as described in any one of items 1 to 17 above. (Section 20) R21a , R 21b , R m , and R n The compound is deutherium, as described in any one of items 1 to 13 above. (Section 21) R 17 and R 16a It is Deuterium, R 16b A compound described in any one of items 1 to 10 above, wherein is hydrogen. (Section 22) R 19 A compound described in any one of items 1 to 21 above, wherein is hydrogen. (Section 23) The compound of formula (I) is of formula (IA) [ka] A compound that is one of the compounds described in any one of items 1 to 23 above. (Section 24) The compound of formula (I) is of formula (IB) [ka] A compound that is one of the compounds described in any one of items 1 to 10 above. (Section 25) The compound of formula (I) is of formula (IC) [ka] The compound described in item 1 above, which is a compound of the above. (Section 26) The compounds of the above formula (IC) are shown in the following table: [Table 3-1] [Table 3-2] A compound as described in item 23 above, selected from the group consisting of compounds identified by (wherein any atom not specified as deuterium exists in its natural isotopic abundance). (Section 27) A pharmaceutically acceptable salt of any of the compounds described in any one of the above items. (Section 28) A pharmaceutical composition comprising a compound described in any one of items 1 to 24 above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. (Section 29) A method for treating a CNS-related disorder in a subject requiring treatment for a CNS-related disorder, comprising the step of administering an effective amount of a compound described in any one of the above items 1 to 24 or a pharmaceutically acceptable salt thereof to the subject. (Section 30) The method according to paragraph 29, wherein the CNS-related disorder is a sleep disorder, mood disorder, schizophrenia spectrum disorder, seizure disorder, memory and / or cognitive impairment, motor disorder, personality disorder, autism spectrum disorder, pain, traumatic brain injury, vascular disorder, substance abuse disorder and / or withdrawal syndrome, tinnitus, or status epilepticus. (Section 31) The CNS-related disorder is depression, as described in item 29 above. (Section 32) The CNS-related disorder is postpartum depression, as described in item 29 above. (Section 33) The method described in item 29 above, wherein the CNS-related disorder is major depressive disorder. (Section 34) The method according to item 31, wherein the major depressive disorder is a moderate major depressive disorder. (Section 35) The method according to item 31 above, wherein the major depressive disorder is a severe major depressive disorder.

Claims

1. Compound 1 【Chemistry 1】 A process for preparing, The process described above is represented by formula A6: [Chemistry 1-6] The compound, 【Chemistry 1-1】 A process comprising reacting a compound represented by with potassium carbonate and acetone to provide compound 1.

2. Formula A5: [Transformation 3-5] The compound of Br ２ By reacting the compound of formula A6 in the presence of an acid, the compound of formula A6 is obtained. 【Chemistry 3-6】 The process according to claim 1, further comprising preparing the compound.

3. The process according to claim 2, wherein the acid contains hydrogen bromide.

4. Formula A4: 【Chemistry 5-4】 By reacting the compound with an alcohol oxidizing agent and a solvent, a compound of formula A5 is obtained, thereby providing the compound of formula A5: 【Transformation 5-5】 The process according to claim 2, further comprising preparing the compound.

5. The process according to claim 4, wherein the alcohol oxidizing agent is pyridinium chlorochromate and the solvent is dichloromethane.

6. Formula A3: 【Transformation 7-3】 By reacting the compound with a) a borane reagent; and then b) a hydroxide base and an oxidizing agent in the presence of a solvent, the compound of formula A4 is obtained. 【Chemistry 7-4】 The process according to claim 4, further comprising preparing the compound.

7. The process according to claim 6, wherein the borane reagent is borane dimethyl sulfide, the hydroxide base is sodium hydroxide, the oxidizing agent is hydrogen peroxide, and the solvent is tetrahydrofuran or water.

8. Formula A2: 【Chemistry 9-2】 The compound, EtPPh ３ By reacting Br with a base and a solvent to provide the compound of formula A3, the compound of formula A3: 【Chemistry 9-3】 The process according to claim 6, further comprising preparing the compound.

9. The process according to claim 8, wherein the base is potassium tert-butoxide and the solvent is tetrahydrofuran.

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