3α-Hydroxy-17β-amido neurostimulatory steroids and compositions thereof

Abstract

Formula (I) TIFF2022514385000162.tif3647 or a pharmaceutically acceptable salt thereof is provided herein, 2a , R 2b , R 4a , R 4b , R 6 , R 7 , R 11a , R 11b , R 16 , R 17 , R 3 , R 5 , R 19 , R X and R Y is as defined herein. Also provided herein are pharmaceutical compositions comprising compounds of formula (I) and methods of using the compounds, for example, in the treatment of CNS-related disorders. For example, provided herein are compounds designed to act as GABA modulators. In some embodiments, it is envisioned that such compounds are useful as therapeutic agents for treating CNS-related disorders.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims priority to U.S. Application No. 62 / 784,222, filed December 21, 2018, and U.S. Application No. 62 / 784,229, filed December 21, 2018 (the entire contents of each are incorporated herein by reference).

Background Art

[0002] Background of the Invention Brain excitability is defined as the continuous arousal level of an animal ranging from coma to seizure and is controlled by various neurotransmitters. Generally, neurotransmitters are involved in controlling the conductance of ions across the neuron membrane. At rest, the neuron membrane has a potential (or membrane voltage) of approximately - 70 mV, and the cell interior is negative relative to the cell exterior. The potential (voltage) is the result of the balance of ions (K + , Na + , Cl - , organic anions) across the neuron semi - permeable membrane. Neurotransmitters are stored in presynaptic vesicles and are released under the influence of the neuronal action potential. When released into the synaptic cleft, excitatory chemical transmitters such as acetylcholine cause membrane depolarization (a change in potential from - 70 mV to - 50 mV). This action is mediated by postsynaptic nicotinic receptors stimulated by acetylcholine, which increases the membrane permeability to Na + ions. The decreased membrane potential stimulates the excitability of the neuron in the form of a postsynaptic action potential.

[0003] In the case of the GABA receptor complex (GRC), the effect on brain excitability is mediated by the neurotransmitter γ-aminobutyric acid (GABA). Since up to 40% of the neurons in the brain utilize GABA as a neurotransmitter, GABA has a significant impact on the excitability of the entire brain. GABA controls the excitability of individual neurons by regulating the conductance of chloride ions across the neuronal membrane. GABA interacts with recognition sites on the GRC, promoting the flow of chloride ions intracellularly down the electrochemical gradient of the GRC. This intracellular increase in the level of anions causes hyperpolarization of the membrane potential across the membrane and decreases the sensitivity of the neuron to excitatory inputs (i.e., the excitability of the neuron decreases). In other words, the higher the chloride ion concentration within the neuron, the lower the excitability and arousal levels of the brain.

[0004] The GRC has been well demonstrated to be involved in the mediation of anxiety, seizure activity, and sedation. Thus, drugs such as GABA, or drugs that act like GABA or enhance the action of GABA (e.g., therapeutically useful barbiturates and benzodiazepines (BZ), e.g., Valium®) produce their therapeutically useful effects by interacting with specific control sites on the GRC. From the accumulated evidence, it is now suggested that the GRC contains a distinct site for neurosteroids in addition to the benzodiazepine and barbiturate binding sites. See, for example, Lan, N.C. et al., Neurochem. Res. (1991) 16:347 - 356.

[0005] Neuroexcitatory steroids can occur endogenously. The most potent endogenous neuroexcitatory steroids are 3α-hydroxy-5-reduced pregnan-20-one and 3α-21-dihydroxy-5-reduced pregnan-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, M.D. et al., Science 232:1004-1007 (1986); Harrison, N.L. et al., J Pharmacol. Exp. Ther. 241:346-353 (1987)). There is a need for modulators of brain excitability and for novel and improved compounds that act as agents for the prevention and treatment of CNS-related diseases. The compounds, compositions and methods described herein are directed to this end.

Prior Art Documents

Non-Patent Documents

[0006]

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Non-Patent Document 3

Summary of the Invention

Means for Solving the Problems

[0007] For example, compounds designed to act as GABA regulators are provided herein. In some embodiments, such compounds are envisioned to be useful as therapeutic agents for treating CNS-related disorders.

[0008] In some embodiments, provided herein is a compound of formula (I): [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0009] In some embodiments, provided herein is a compound of formula (I-X): [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments, provided herein is a compound of formula (I): [Chemical formula] or a pharmaceutically acceptable salt thereof.

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

[0012] In some embodiments, the compound of formula (I) is a compound of formula (I-b1) or formula (I-b2): [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, the compound of formula (I) is a compound of formula (I-c1) or formula (I-c2): [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, the compound of formula (I) is a compound of formula (I-d1) or formula (I-d2):

Chemical formula

[0015] In some embodiments, the compound of formula (I) is a compound of formula (I-d1):

Chemical formula

[0016] In some embodiments, the compound of formula (I) is a compound of formula (I-d2):

Chemical formula

[0017] In some embodiments, the compound of formula (I) is a compound of formula (I-e):

Chemical formula

[0018] In some embodiments, the compound of formula (I) is a compound of formula (I-f):

Chemical formula

[0019] In some embodiments, the compound of formula (I) is a compound of formula (I-g)

Chemical formula

[0020] In some embodiments, the pharmaceutical composition comprises a compound described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0021] In some embodiments, in a subject in need of treatment for a CNS-related disorder, a method of treating the CNS-related disorder comprises administering to the subject an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the CNS-related disorder is a sleep disorder, mood disorder, schizophrenia spectrum disorder, spasm disorder, memory and / or cognitive disorder, movement disorder, personality disorder, autism spectrum disorder, pain, traumatic brain injury, vascular disease, substance use disorder and / or withdrawal syndrome, tinnitus, or status epilepticus. In some 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 some embodiments, the major depressive disorder is moderate major depressive disorder. In some embodiments, the major depressive disorder is severe major depressive disorder.

[0022] In some embodiments, the compound is selected from the group consisting of the compounds identified in Table 1 herein.

[0023] In one aspect, provided herein are pharmaceutically acceptable salts of the compounds described herein (e.g., compounds of formula (I)).

[0024] In one aspect, provided herein is a pharmaceutical composition 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 invention is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the compound of the invention is provided in a therapeutically effective amount. In certain embodiments, the compound of the invention is provided in a prophylactically effective amount.

[0025] The compounds of the invention as described herein, in certain embodiments, for example, act as GABA modulators that act in a positive or negative manner on the GABA A receptor. Such compounds are expected to have CNS activity as modulators of the excitability of the central nervous system (CNS) as mediated by their ability to modulate the GABA A receptor.

[0026] Accordingly, in another aspect, there is provided a method of treating a CNS-related disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the invention. In certain embodiments, the CNS-related disorder is a sleep disorder, mood disorder, schizophrenia spectrum disorder, seizure disorder, memory and / or cognitive disorder, movement disorder, personality disorder, autism spectrum disorder, pain, traumatic brain injury, vascular disease, substance use 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 a major depressive disorder. In certain embodiments, the major depressive disorder is a moderate major depressive disorder. In certain embodiments, the major depressive disorder is a 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 for a long term. In certain embodiments, the compound is administered continuously, for example, by continuous intravenous infusion.

[0027] In a preferred embodiment, the compounds described herein selectively modulate a particular subunit composition of the GABA A receptor (e.g., the α4β3δ subunit composition). In an embodiment of the present invention, for example, the following items are provided. (Item 1) Formula (I):

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Best Mode for Carrying Out the Invention

[0028] Detailed Description of Specific Embodiments of the Invention As generally described herein, the present invention provides, for example, neuroactive steroids designed to act as GABA A modulators. In a preferred embodiment, the compounds described herein selectively modulate a particular subunit composition of the GABA A receptor (e.g., the α4β3δ subunit composition). As used herein, "selectively modulate" means to modulate a particular subunit composition to a greater extent or more significantly compared to other subunit compositions of the GABA A receptor. In certain embodiments, such compounds are contemplated to be useful as therapeutic agents for treating CNS-related disorders (e.g., disorders described herein, such as depression, e.g., postpartum depression or major depressive disorder).

[0029] Definitions Chemical Definitions The definitions of specific functional groups and chemical terms are described in detail below. Chemical elements are specified according to the Periodic Table of the Elements (CAS version, Handbook of Chemistry and Physics, 75th Edition, inside front cover), and specific functional groups are generally defined as described therein. Further, the general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0030] Isomers (e.g., stereoisomers) can be isolated from the mixture by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or the preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel editor, 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.

[0031] As used herein, a pure enantiomeric compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., enantiomeric excess). In other words, a compound of the "S" form is substantially free of the compound of the "R" form and thus has an "R" enantiomeric excess. The terms "enantiomerically pure" or "pure enantiomer" mean that the compound contains more than 75%, more than 80%, more than 85%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 98.5%, more than 99%, more than 99.2%, more than 99.5%, more than 99.6%, more than 99.7%, more than 99.8% or more than 99.9% enantiomer. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0032] In the compositions provided herein, an enantiomerically pure compound may be present with other active or inactive ingredients. For example, a pharmaceutical composition containing an enantiomerically pure R-position / center / carbon compound may contain, for example, about 90% excipient and about 10% enantiomerically pure R-compound. In certain embodiments, the enantiomerically pure R-compound in such a composition may contain, for example, at least about 95% by weight of the R-compound and at most about 5% by weight of the S-compound, based on the total weight of the compound. For example, a pharmaceutical composition containing an enantiomerically pure S-compound may contain, for example, about 90% excipient and about 10% enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S-compound in such a composition may contain, for example, at least about 95% by weight of the S-compound and at most about 5% by weight of the R-compound, based on the total weight of the compound. In certain embodiments, the active ingredient may be formulated with a minor amount of excipient or carrier or may be formulated without an excipient or carrier.

[0033] The term "diastereomerically pure" means that a compound contains more than 75%, more than 80%, more than 85%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 98.5%, more than 99%, more than 99.2%, more than 99.5%, more than 99.6%, more than 99.7%, more than 99.8%, or more than 99.9% of a single diastereomer. Methods for determining diastereomeric purity and enantiomeric purity are well known in the art. Diastereomeric purity can be determined by any analytical method (such as high performance liquid chromatography (HPLC)) that can quantitatively distinguish the compound from its diastereomers.

[0034] "Stereoisomers": It should also be understood that compounds having the same molecular formula but differing in the nature of the atoms or the order of bonding or the arrangement of atoms in space are called "isomers". Isomers that differ in the arrangement of atoms in space 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 an asymmetric center, it is bonded to four different groups and a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and are represented by the R and S ordering rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarization and are designated as dextrorotatory or levorotatory (i.e., (+) or (-)-isomers), respectively. Chiral compounds can exist either as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0035] The articles "a" and "an" may be used herein to refer to the grammatical object of the article being one or more (i.e., at least one). By way of example, "an analogue" means one analogue or more than one analogue.

[0036] When a range of values is recited, it is intended to encompass each value and sub-range within that range. For example, "C 1~6 alkyl" is intended to encompass C1, C2, C3, C4, C5, C6, C 1~6 、C 1~5 、C 1~4 、C 1~3 、C 1~2 、C 2~6 、C 2~5 、C 2~4 、C 2~3 、C 3~6 、C 3~5 、C 3~4 、C 4~6 、C 4~5 、and C 5~6 alkyl.

[0037] The following terms are intended to have the meanings presented below with respect thereto and are useful in understanding the specification and the intended scope of the invention.

[0038] "Alkyl" refers to a radical of a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1~20 alkyl"). In some embodiments, the alkyl group has 1 to 12 carbon atoms ("C 1~12 alkyl"). In some embodiments, the alkyl group has 1 to 10 carbon atoms ("C 1~10 alkyl"). In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C 1~9 alkyl"). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1~8 alkyl"). In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1~7 alkyl"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C 1~6 alkyl", also referred to herein as "lower alkyl"). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C 1~5 alkyl"). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C 1~4 alkyl"). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1~3 alkyl"). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1~2 alkyl"). In some embodiments, the alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2~6 alkyl"). C 1~6Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanil (C5), tertiary amyl (C5) and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), etc. Unless otherwise specified, each occurrence of an alkyl group is independently optionally substituted, i.e., unsubstituted (“unsubstituted alkyl”) or substituted with one or more substituents; for example, substituted with 1 to 5 substituents, 1 to 3 substituents or 1 substituent (“substituted alkyl”). In certain embodiments, the alkyl group is unsubstituted C 1~10 alkyl (e.g., -CH3). In certain embodiments, the alkyl group is substituted C 1~10 alkyl. Common abbreviations for alkyl include Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2).

[0039] "Alkylene" refers to an alkyl group from which two hydrogens have been removed to form a divalent radical, which may be substituted or unsubstituted. Examples of unsubstituted alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), and hexylene (-CH2CH2CH2CH2CH2CH2-). Exemplary substituted alkylene groups substituted with one or more alkyl (methyl) groups include, but are not limited to, substituted methylene (-CH(CH3)-, (-C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, and -CH2CH2C(CH3)2-). When a range or number of carbons is given for a particular alkylene group, it is understood that the foregoing range or number refers to the range or number of carbons in the divalent carbon straight chain. The alkylene group may be substituted or unsubstituted with one or more substituents described herein.

[0040] "Alkenyl" refers to a radical of a straight-chain or branched-chain hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) ("C 2~20 alkenyl"). In certain embodiments, alkenyl does not include any triple bonds. In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C 2~10 alkenyl"). In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C 2~9"(alkenyl). In some embodiments, the alkenyl group has from 2 to 8 carbon atoms ("C 2~8 alkenyl). In some embodiments, the alkenyl group has from 2 to 7 carbon atoms ("C 2~7 alkenyl). In some embodiments, the alkenyl group has from 2 to 6 carbon atoms ("C 2~6 alkenyl). In some embodiments, the alkenyl group has from 2 to 5 carbon atoms ("C 2~5 alkenyl). In some embodiments, the alkenyl group has from 2 to 4 carbon atoms ("C 2~4 alkenyl). In some embodiments, the alkenyl group has from 2 to 3 carbon atoms ("C 2~3 alkenyl). In some embodiments, the alkenyl group has 2 carbon atoms ("C2 alkenyl"). One or more carbon-carbon double bonds may be present internally (e.g., 2-butenyl) or terminally (e.g., 1-butenyl). C 2~4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. C 2~6 Examples of alkenyl groups include the above-described C 2~4 alkenyl groups, as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrieneyl (C8), and the like. Unless otherwise specified, each occurrence of an alkenyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkenyl"). In certain embodiments, the alkenyl group is unsubstituted C 2~10 alkenyl. In certain embodiments, the alkenyl group is substituted C 2~10 alkenyl.

[0041] "Alkynyl" refers to a radical of a linear or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) ( "C 2~20 alkynyl"). In certain embodiments, alkynyl does not contain any double bonds. In some embodiments, the alkynyl group has 2 to 10 carbon atoms ( "C 2~10 alkynyl"). In some embodiments, the alkynyl group has 2 to 9 carbon atoms ( "C 2~9 alkynyl"). In some embodiments, the alkynyl group has 2 to 8 carbon atoms ( "C 2~8 alkynyl"). In some embodiments, the alkynyl group has 2 to 7 carbon atoms ( "C 2~7 alkynyl"). In certain embodiments, the alkynyl group has 2 to 6 carbon atoms ( "C 2~6 alkynyl"). In certain embodiments, the alkynyl group has 2 to 5 carbon atoms ( "C 2~5 alkynyl"). In certain embodiments, the alkynyl group has 2 to 4 carbon atoms ( "C 2~4 alkynyl"). In certain embodiments, the alkynyl group has 2 to 3 carbon atoms ( "C 2~3 alkynyl"). In certain embodiments, the alkynyl group has 2 carbon atoms ( "C2 alkynyl"). One or more carbon-carbon triple bonds can be internal (e.g., 2-butynyl) or terminal (e.g., 1-butynyl). C 2~4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. C 2~6 Examples of alkenyl groups include the above-mentioned C 2~4Examples include alkynyl groups, such as pentynyl (C5), hexynyl (C6), etc. Further examples of alkynyl include heptynyl (C7), octynyl (C8), etc. Unless otherwise specified, each occurrence of an alkynyl group is independently optionally substituted, i.e., unsubstituted ( "unsubstituted alkynyl") or substituted with one or more substituents; for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ( "substituted alkynyl"). In certain embodiments, the alkynyl group is unsubstituted C 2~10 is alkynyl. In certain embodiments, the alkynyl group is substituted C 2~10 is alkynyl.

[0042] As used herein, the term "heteroalkyl" further includes one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, where the aforementioned one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or one or more heteroatoms are inserted between a carbon atom and the parent molecule (i.e., between the bonding points). It refers to an alkyl group as defined herein. In certain embodiments, a heteroalkyl group refers to a saturated group having 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms ( "heteroC 1~10 alkyl"). In some embodiments, the heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms ( "heteroC 1~9 alkyl"). In some embodiments, the heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms ( "heteroC 1~8 alkyl"). In some embodiments, the heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms ( "heteroC 1~7 alkyl"). In some embodiments, the heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms ( "heteroC 1~6"(alkyl)". In some embodiments, the heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms ("heteroC 1~5 alkyl)". In some embodiments, the heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms ("heteroC 1~4 alkyl)". In some embodiments, the heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom ("heteroC 1~3 alkyl)". In some embodiments, the heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom ("heteroC 1~2 alkyl)". In some embodiments, the heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroC1 alkyl"). In some embodiments, the heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms ("heteroC 2~6 alkyl)". Unless otherwise specified, in each case the heteroalkyl group is independently unsubstituted ("unsubstituted heteroalkyl") or substituted with one or more substituents ("substituted heteroalkyl"). In certain embodiments, the heteroalkyl group is unsubstituted heteroC 1~10 alkyl. In certain embodiments, the heteroalkyl group is substituted heteroC 1~10 alkyl.

[0043] "Aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) in which 6 to 14 ring carbon atoms and 0 heteroatoms are provided in the aromatic ring system ("C 6~14 aryl)". In some embodiments, the aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has 10 ring carbon atoms ("C 10"Aryl"; for example, naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C 14 "Aryl"; for example, anthracyl). "Aryl" also includes a ring system in which one or more aryl rings as defined above are condensed with one or more carbocyclic groups or heterocyclic groups, where the bonding radical or bonding point is present on the aryl ring, and in such cases, the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, preiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. In particular, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each occurrence of an aryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, the aryl group is unsubstituted C 6~14 aryl. In certain embodiments, the aryl group is substituted C 6~14 aryl.

[0044] In certain embodiments, the aryl group is substituted with one or more groups selected from halo, C1-C8 alkyl, C1-C8 haloalkyl, cyano, hydroxy, C1-C8 alkoxy, and amino.

[0045] Examples of representative substituted aryls include the following:

Chemical Structure

[0046] "Fused aryl" refers to aryl in which two of its ring carbons are shared with a second aryl ring, heteroaryl ring, carbocyclic ring or heterocyclic ring.

[0047] "Heteroaryl" refers to a radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) in which ring carbon atoms and 1 to 4 ring heteroatoms are provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In a heteroaryl group containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom when the valence allows. The heteroaryl bicyclic ring system can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused to one or more carbocyclic or heterocyclic groups, where the point of attachment is on the heteroaryl ring, and in such cases, the number of ring members continues to refer to the number of ring members within the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused to one or more aryl groups, where the point of attachment is on the aryl ring or on the heteroaryl ring, and in such cases, the number of ring members refers to the number of ring members within the fused (aryl / heteroaryl) ring system. For a bicyclic heteroaryl group in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., on the ring having a heteroatom (e.g., 2-indolyl) or on the ring not containing a heteroatom (e.g., 5-indolyl).

[0048] In some embodiments, the heteroaryl group is a 5- to 10-membered aromatic ring system in which ring carbon atoms and 1 to 4 ring heteroatoms are provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 10-membered heteroaryl”). In some embodiments, the heteroaryl group is a 5- to 8-membered aromatic ring system in which ring carbon atoms and 1 to 4 ring heteroatoms are provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heteroaryl”). In some embodiments, the heteroaryl group is a 5- to 6-membered aromatic ring system in which ring carbon atoms and 1 to 4 ring heteroatoms are provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heteroaryl”). In some embodiments, the 5- to 6-membered heteroaryl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each occurrence of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (“unsubstituted heteroaryl”) or substituted with one or more substituents (“substituted heteroaryl”). In certain embodiments, the heteroaryl group is unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5- to 14-membered heteroaryl.

[0049] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-fused bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-fused bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0050] Examples of representative heteroaryls include the following: [Chemical formula] are included, where each Z is carbonyl, N, NR65 selected from O and S; R 65 is independently hydrogen, C1-C8 alkyl, C3-C 10 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl.

[0051] "Carbocyclyl" or "carbocyclic" refers to a radical of a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms ("C 3~10 carbocyclyl") and 0 heteroatoms in the non-aromatic ring system. In some embodiments, the carbocyclyl group has 3 to 8 ring carbon atoms ("C 3~8 carbocyclyl"). In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 carbocyclyl"). In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 carbocyclyl"). In some embodiments, the carbocyclyl group has 5 to 10 ring carbon atoms ("C 5~10 carbocyclyl"). Exemplary C 3~6 carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), etc. Exemplary C 3~8 carbocyclyl groups include the above-mentioned C 3~6 carbocyclyl groups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), etc., but are not limited to these. Exemplary C 3~10 carbocyclyl groups include the above-mentioned C 3~8 carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10) Cyclodecenyl (C 10 ) Octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ) Spiro[4.5]decanyl (C 10 ) and the like, but not limited thereto. When the foregoing examples are illustrated, in certain embodiments, the carbocyclic group is monocyclic ("monocyclic carbocyclic") or includes a fused ring system, a bridged ring system or a spiro ring system (e.g., a bicyclic system ("bicyclic carbocyclic")), and may be saturated or partially unsaturated. "Carbocyclic" also includes a ring system in which one or more aryl groups or heteroaryl groups are fused to a carbocyclic ring as defined above, where the point of attachment is on the carbocyclic ring, and in such cases, the number of carbons continues to refer to the number of carbons in the carbocyclic ring system. Unless otherwise specified, each occurrence of a carbocyclic group is independently optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclic") or substituted with one or more substituents ("substituted carbocyclic"). In certain embodiments, the carbocyclic group is unsubstituted C 3~10 carbocyclic. In certain embodiments, the carbocyclic group is substituted C 3~10 carbocyclic.

[0052] In some embodiments, "carbocyclic" is a monocyclic saturated carbocyclic group having 3 to 10 ring carbon atoms ("C 3~10 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms ("C 3~8 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C 3~6 cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 6 ring carbon atoms ("C 5~6 cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 10 ring carbon atoms ("C 5~10 cycloalkyl"). C 5~6Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). C 3~6 Examples of cycloalkyl groups include the above-mentioned C 5~6 cycloalkyl groups, as well as cyclopropyl (C3) and cyclobutyl (C4). C 3~8 Examples of cycloalkyl groups include the above-mentioned C 3~6 cycloalkyl groups, as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each occurrence of a cycloalkyl group is independently unsubstituted (“unsubstituted cycloalkyl”) or substituted with one or more substituents (“substituted cycloalkyl”). In certain embodiments, the cycloalkyl group is unsubstituted C 3~10 cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C 3~10 cycloalkyl.

[0053] "Heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ("3- to 10-membered heterocyclyl"). In a heterocyclyl group containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom when the valence allows. The heterocyclyl group can be a monocyclic ring system ("monocyclic heterocyclyl") or a fused ring system, a bridged ring system or a spiro ring system (e.g., a bicyclic system ("bicyclic heterocyclyl")), and can be saturated or partially unsaturated. The heterocyclyl bicyclic ring system can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes a ring system in which a heterocyclyl ring as defined above is fused with one or more carbocyclic groups, where the point of attachment is on the carbocyclic or heterocyclyl ring, or on a ring system in which a heterocyclyl ring as defined above is fused with one or more aryl groups or heteroaryl groups, where the point of attachment is on the heterocyclyl ring, and in such cases, the number of ring members continues to refer to the number of ring members within the heterocyclyl ring system. Unless otherwise specified, each occurrence of heterocyclyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0054] In some embodiments, the heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5- to 10-membered heterocyclyl”). In some embodiments, the heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heterocyclyl”). In some embodiments, the heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heterocyclyl”). In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0055] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiirenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrol-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic rings) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocyclic rings) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0056] The term "nitrogen-containing heterocyclyl" group means a 4- to 7-membered non-aromatic cyclic group containing at least one nitrogen atom (e.g., but not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazine (such as N-methylpiperazine)). Specific examples include azetidine, piperidone, and piperazone.

[0057] When used to describe a compound or a group present on a compound, "hetero" means that one or more carbon atoms in the compound or group are replaced by a heteroatom of nitrogen, oxygen, or sulfur. Hetero can be applied to any of the above hydrocarbyl groups (alkyl having 1 to 5, particularly 1 to 3 heteroatoms, such as heteroalkyl, cycloalkyl, such as heterocyclyl, aryl, such as heteroaryl, and cycloalkenyl, such as cycloheteroalkenyl, etc.).

[0058] "Acyl" refers to -C(O)R 20 radical, where R 20 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl as defined herein. "Alkanoyl" is R 20is an acyl group which is a group other than hydrogen. Representative acyl groups include formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph), --C(O)-C1-C8 alkyl, -C(O)-(CH2) t (C6-C 10 aryl), -C(O)-(CH2) t (5- to 10-membered heteroaryl), -C(O)-(CH2) t (C3-C 10 cycloalkyl) and -C(O)-(CH2) t (4- to 10-membered heterocyclyl) (t is an integer from 0 to 4), but are not limited thereto. In certain embodiments, R 21 is C1-C8 alkyl substituted with halo or hydroxy; or C3-C 10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 aryl, arylalkyl, 5- to 10-membered heteroaryl or heteroarylalkyl (each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy).

[0059] "Alkoxy" refers to an -OR 29 group, where R 29 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. Specific alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1,2-dimethylbutoxy. Specific alkoxy groups are lower alkoxy, i.e., having 1 to 6 carbon atoms. Further specific alkoxy groups have 1 to 4 carbon atoms.

[0060] In certain embodiments, R 29 is one or more substituents selected from the group consisting of amino, substituted amino, C6-C 10 aryl, aryloxy, carboxyl, cyano, C3-C 10 cycloalkyl, 4- to 10-membered heterocyclyl, halogen, 5- to 10-membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2- and aryl-S(O)2-, for example, 1 to 5 substituents, particularly 1 to 3 substituents, particularly a group having 1 substituent. Exemplary "substituted alkoxy" groups include -O-(CH2) t (C6-C 10 aryl), -O-(CH2) t (5- to 10-membered heteroaryl), -O-(CH2) t (C3-C 10 cycloalkyl) and -O-(CH2) t (4- to 10-membered heterocyclyl), but are not limited thereto, where t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl or heterocyclyl group present may itself be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy. Particularly exemplary "substituted alkoxy" groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH and -OCH2CH2NMe2.

[0061] "Amino" refers to the -NH2 radical.

[0062] The "oxo" group refers to -C(=O)-.

[0063] "Substituted amino" refers to an amino group of the formula -N(R 38 )2, where R 38is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or an amino protecting group, where R 38 at least one of which is not hydrogen. In certain embodiments, each R 38 is independently hydrogen, C1-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C6-C 10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic or C3-C 10 cycloalkyl; or C1-C8 alkyl substituted with halo or hydroxy; C3-C8 alkenyl substituted with halo or hydroxy; C3-C8 alkynyl substituted with halo or hydroxy, or -(CH2) t (C6-C 10 aryl), -(CH2) t (5-10 membered heteroaryl), -(CH2) t (C3-C 10 cycloalkyl) or -(CH2) t (4-10 membered heterocyclic), where t is an integer from 0 to 8, each of which is unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy; or both R 38 groups are joined to form an alkylene group.

[0064] Exemplary "substituted amino" groups include -NR 39 -C1-C8 alkyl, -NR 39 -(CH2) t (C6-C 10 aryl), -NR 39 -(CH2) t (5-10 membered heteroaryl), -NR 39 -(CH2) t (C3-C 10 cycloalkyl) and -NR 39-(CH2) t (4 to 10-membered heterocyclyl) is exemplified, but not limited thereto, where t is an integer from 0 to 4, for example, 1 or 2, and each R 39 independently represents hydrogen or C1-C8 alkyl; any alkyl group present may itself be substituted by halo, substituted or unsubstituted amino or hydroxy; any aryl, heteroaryl, cycloalkyl or heterocyclyl group present may itself be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy. To avoid misunderstanding, the term "substituted amino" includes alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino and substituted dialkylamino groups as defined below. Substituted amino includes both mono-substituted amino groups and di-substituted amino groups.

[0065] "Carboxy" refers to the -C(O)OH radical.

[0066] "Cyano" refers to the -CN radical.

[0067] "Halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, the halo group is either fluoro or chloro.

[0068] "Haloalkyl" refers to an alkyl radical in which the alkyl group is substituted with one or more halogens. Typical haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl, and tetrafluoroethyl.

[0069] "Hydroxy" refers to the -OH radical.

[0070] "Nitro" refers to the -NO2 radical.

[0071] "Thioketone" refers to the =S group.

[0072] Alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl groups as defined herein are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyclic, "substituted" or "unsubstituted" heterocyclic, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl groups). Generally, the term "substituted" means that at least one hydrogen present on a given group (e.g., a carbon or nitrogen atom), whether or not the term "optionally" precedes it, is replaced by an acceptable substituent, e.g., a substituent that, when substituted, results in a stable compound, e.g., a compound that does not undergo spontaneous transformation (e.g., by rearrangement, cyclization, elimination, or other reactions). Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when two or more positions in any given structure are substituted, the substituents may be the same or different at each position. The term "substituted" is intended to include substitution by all acceptable substituents of organic compounds, substitution by any of the substituents described herein that form stable compounds. The present invention contemplates any and all such combinations to arrive at stable compounds. For the purposes of the present invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents as described herein that satisfy the valence of the heteroatom and, as a result, form a stable moiety.

[0073] Exemplary carbon atom substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(Rbb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO2H, -CHO, -C(OR cc )2, -CO2R aa , -OC(=O)R aa , -OCO2R aa , -C(=O)N(R bb )2, -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb )OR aa , -OC(=NR bb )R aa , -OC(=NR bb )OR aa , -C(=NR bb )N(R bb )2, -OC(=NR bb )N(R bb )2, -NR bb C(=NR bb )N(R bb )2, -C(=O)NR bb SO2R aa , -NR bb SO2R aa , -SO2N(R bb )2, -SO2R aa , -SO2OR aa , -OSO2R aa , -S(=O)R aa , -OS(=O)R aa , -Si(R aa )3, -OSi(R aa )3 - C(=S)N(R bb )2, -C(=O)SR aa , -C(=S)SRaa 、 -SC(=S)SR aa 、 -SC(=O)SR aa 、 -OC(=O)SR aa 、 -SC(=O)OR aa 、 -SC(=O)R aa 、 -P(=O)2R aa 、 -OP(=O)2R aa 、 -P(=O)(R aa )2、 -OP(=O)(R aa )2、 -OP(=O)(OR cc )2、 -P(=O)2N(R bb )2、 -OP(=O)2N(R bb )2、 -P(=O)(NR bb )2、 -OP(=O)(NR bb )2、 -NR bb P(=O)(OR cc )2、 -NR bb P(=O)(NR bb )2、 -P(R cc )2、 -P(R cc )3、 -OP(R cc )2、 -OP(R cc )3、 -B(R aa )2、 -B(OR cc )2、 -BR aa (OR cc )、 C 1~10 alkyl, C 1~10 haloalkyl, C 2~10 alkenyl, C 2~10 alkynyl, C 3~10 carbocyclic, 3 - 14 membered heterocyclic, C 6~14 aryl and 5 - 14 membered heteroaryl are included, but not limited to these. Here, each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups; or two geminal hydrogens on a carbon atom are a group =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa 、 =NNR bb C(=O)OR aa 、 =NNR bb S(=O)2Raa 、 =NR bb 、 or =NOR cc is replaced by;

[0074] R aa Each occurrence of is independently selected from C 1~10 alkyl, C 1~10 haloalkyl, C 2~10 alkenyl, C 2~10 alkynyl, C 3~10 carbocyclic, 3- to 14-membered heterocyclic, C 6~14 aryl and 5- to 14-membered heteroaryl, or two R aa groups are linked to form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups;

[0075] R bb Each occurrence of is independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1~10 alkyl, C 1~10 haloalkyl, C2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclic, 3- to 14-membered heterocyclic, C 6~14 Selected from aryl and 5- to 14-membered heteroaryl, or two R bb groups are linked to form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups;

[0076] R cc each occurrence of which is independently hydrogen, C 1~10 alkyl, C 1~10 haloalkyl, C 2~10 alkenyl, C 2~10 alkynyl, C 3~10 carbocyclic, 3- to 14-membered heterocyclic, C 6~14 selected from aryl and 5- to 14-membered heteroaryl, or two R cc groups are linked to form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups;

[0077] R dd each occurrence of which is independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2Ree , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff )OR ee , -OC(=NR ff )R ee , -OC(=NR ff )OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)2R ee , -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 carbocyclic, 3 - 10 membered heterocyclic, C 6~10Selected from aryl and 5- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R gg groups; or two geminal R dd substituents can together form =O or =S;

[0078] R ee each occurrence is independently selected from C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 carbocyclic, C 6~10 aryl, 3- to 10-membered heterocyclic and 3- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R gg groups;

[0079] R ff each occurrence is independently hydrogen, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 carbocyclic, 3- to 10-membered heterocyclic, C 6~10 aryl and 5- to 10-membered heteroaryl, or two R ff groups are linked to form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R gg groups;

[0080] R gg each occurrence is independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6 alkyl, -ON(C1~6 (alkyl)2, -N(C 1~6 (alkyl)2, -N(C 1~6 (alkyl)3 + X - , -NH(C 1~6 (alkyl)2 + X - , -NH2(C 1~6 (alkyl) + X - , -NH3 + X - , -N(OC 1~6 (alkyl)(C 1~6 (alkyl), -N(OH)(C 1~6 (alkyl), -NH(OH), -SH, -SC 1~6 (alkyl), -SS(C 1~6 (alkyl), -C(=O)(C 1~6 (alkyl), -CO2H, -CO2(C 1~6 (alkyl), -OC(=O)(C 1~6 (alkyl), -OCO2(C 1~6 (alkyl), -C(=O)NH2, -C(=O)N(C 1~6 (alkyl)2, -OC(=O)NH(C 1~6 (alkyl), -NHC(=O)(C 1~6 (alkyl), -N(C 1~6 (alkyl)C(=O)(C 1~6 (alkyl), -NHCO2(C 1~6 (alkyl), -NHC(=O)N(C 1~6 (alkyl)2, -NHC(=O)NH(C 1~6 (alkyl), -NHC(=O)NH2, -C(=NH)O(C 1~6 (alkyl), -OC(=NH)(C 1~6 (alkyl), -OC(=NH)OC 1~6 (alkyl), -C(=NH)N(C 1~6 (alkyl)2, -C(=NH)NH(C 1~6 (alkyl), -C(=NH)NH2, -OC(=NH)N(C 1~6 (alkyl)2, -OC(NH)NH(C 1~6 (alkyl), -OC(NH)NH2, -NHC(NH)N(C 1~6 (alkyl)2, -NHC(=NH)NH2, -NHSO2(C1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 alkyl), -SO2NH2, -SO2C 1~6 alkyl, -SO2OC 1~6 alkyl, -OSO2C 1~6 alkyl, -SOC 1~6 alkyl, -Si(C 1~6 alkyl)3, -OSi(C 1~6 alkyl)3-C(=S)N(C 1~6 alkyl)2, C(=S)NH(C 1~6 alkyl), C(=S)NH2, -C(=O)S(C 1~6 alkyl), -C(=S)SC 1~6 alkyl, -SC(=S)SC 1~6 alkyl, -P(=O)2(C 1~6 alkyl), -P(=O)(C 1~6 alkyl)2, -OP(=O)(C 1~6 alkyl)2, -OP(=O)(OC 1~6 alkyl)2, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 carbocyclic, C 6~10 aryl, 3- to 10-membered heterocyclic, 5- to 10-membered heteroaryl; or two geminal R gg substituents can together form =O or =S; where X - is a counterion.

[0081] A "counterion" or "anionic counterion" is a negatively charged group that associates with a cationic quaternary amino group to maintain electrical neutrality. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , OH - , H2PO4 - , HSO4 -, sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.) and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, etc.) can be mentioned.

[0082] These and other exemplary substituents are described in detail in the detailed description and the claims. The present invention is not intended to be limited by the exemplary listing of the above substituents in any way.

[0083] Other definitions As used herein, the term "modulate" refers to the inhibition or synergistic action of GABA A receptor function. A "modulator" (e.g., a modulator compound) can be, for example, an agonist, partial agonist, antagonist, or partial antagonist of the GABA A receptor.

[0084] "Pharmaceutically acceptable" means approved or approvable by the federal or state government regulatory authorities, or the corresponding authorities of a country outside the United States, or described in the United States Pharmacopeia or other generally recognized pharmacopeias for use in animals (more specifically, humans).

[0085] "Pharmaceutically acceptable salts" refers to salts of the compounds of the present invention that are pharmaceutically acceptable and have the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and can be inorganic acid addition salts or organic acid addition salts and inorganic base addition salts or organic base addition salts. Specifically, such salts include: (1) formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.; or (2) salts formed when the acidic proton present in the parent compound is replaced by a metal ion such as an alkali metal ion, alkaline earth ion, or aluminum ion; or coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Examples of salts further include, but are not limited to, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc.; and when the compound contains a basic functional group, salts of non-toxic organic acids or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counterion for acidic functional groups. Such cations are exemplified by sodium cation, potassium cation, calcium cation, magnesium cation, ammonium cation, tetraalkylammonium cation, etc.See, for example, Berge et al., J. Pharm. Sci. (1977) 66(1):1-79.

[0086] The term "prodrug" is intended to include a therapeutically inactive compound that is converted to the therapeutically active agent of the present invention under physiological conditions. One method of making a prodrug is to design a hydrolyzable or cleavable moiety at the targeted in vivo site of action such that the desired molecule appears, and then to generate the selected moiety that produces its therapeutic effect. In certain embodiments, the prodrug is converted by the enzymatic activity of the subject.

[0087] In an alternative embodiment, the present invention provides a prodrug of a compound of formula (I), the prodrug comprising a cleavable moiety on the C3 hydroxy as shown in formula (I).

[0088] "Tautomers" are compounds of a particular compound structure in exchangeable forms, and refer to compounds in which the displacement of hydrogen atoms and electrons fluctuates. Thus, the two structures can be in equilibrium by the movement of π electrons and atoms (usually H). For example, enol and ketone are tautomers because they are rapidly interconverted by treatment with either an acid or a base. Another example of tautomerism is the acid and nitro forms of phenylnitromethane, which are similarly formed by treatment with an acid or a base. Tautomers may be relevant to obtaining the optimal chemical reactivity and biological activity of the desired compound.

[0089] The "subject" for which administration is contemplated includes, but is not limited to, humans (i.e., male or female of any age group, such as 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, such as mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats and / or dogs). In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.

[0090] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Examples of oxygen protecting groups include -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb )OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3, -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)2N(R bb )2, and -P(=O)(NR bb )2 (where R aa , R bb , and R cc are as defined herein), but are not limited thereto. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3 rd edition, John Wiley & Sons, 1999 (incorporated herein by reference).

[0091] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), 2-methoxyethoxymethyl (MEM), benzyl (Bn), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBDMS), t-butylmethoxyphenylsilyl (TBMPS), methanesulfonate (mesylate), and tosylate (Ts).

[0092] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to as a thiol protecting group). Sulfur protecting groups include -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb )OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3, -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)2N(R bb )2, and -P(=O)(NR bb )2, but are not limited thereto, where R aa , R bb , and R cc are as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3 rd rd edition, John Wiley & Sons, 1999 (incorporated herein by reference).

[0093] In certain embodiments, the substituent present on the nitrogen atom is an amino protecting group (also referred to herein as a nitrogen protecting group). Examples of amino protecting groups include -OH, -OR aa , -N(R cc )2, -C(=O)R aa , -C(=O)OR aa , -C(=O)N(R cc )2, -S(=O)2R aa , -C(=NR cc )R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , C 1~10 alkyl, C 2~10 alkenyl, C 2~10 alkynyl, C 3~10 carbocyclic, 3- to 14-membered heterocyclic, C 6~14 aryl, and 5- to 14-membered heteroaryl groups, including but not limited to, where each of alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, where R aa , R bb , R cc , and R dd are as defined herein. Amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3 rd rd edition, John Wiley & Sons, 1999 (incorporated herein by reference).

[0094] Exemplary amino protecting groups include amide groups (e.g., -C(=O)R aa )(including, but not limited to, formamide and acetamide); carbamate groups (e.g., -C(=O)OR aa )(including, but not limited to, 9-fluorenylmethyl carbamate (Fmoc), t-butyl carbamate (BOC), and benzyl carbamate (Cbz)); sulfonamide groups (e.g., -S(=O)2R aa )(including, but not limited to, p-toluenesulfonamide (Ts), methanesulfonamide (Ms), and N-[2-(trimethylsilyl)ethoxy]methylamine (SEM)), but are not limited thereto. Disease, disorder, and condition are used interchangeably herein.

[0095] As used herein, unless otherwise specified, the terms "treat", "treating", and "treatment" are performed while a subject is suffering from a particular disease, disorder or condition, and are intended to reduce the severity of the disease, disorder or condition, or to delay or slow the progression of the disease, disorder or condition (therapeutic treatment), and also include actions that occur before a subject begins to suffer from a particular disease, disorder, or condition.

[0096] Generally, the "effective amount" of a compound refers to an amount sufficient to elicit a desired biological response, e.g., to treat a CNS-related disorder, and is sufficient to induce anesthesia or sedation. As will be understood by those skilled in the art, the effective amount of the compounds of the present invention can vary depending on factors such as the desired biological goal, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health status, and condition of the subject.

[0097] As used herein, unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with that disease, disorder or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other treatments, that provides a therapeutic benefit in the treatment of that disease, disorder or condition. The term "therapeutically effective amount" can include an amount that improves the overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0098] In an alternative embodiment, the invention contemplates administration of a compound of the invention or a pharmaceutically acceptable salt or pharmaceutically acceptable composition thereof as a prophylactic agent before a subject begins to suffer from a particular disease, disorder, or condition. As used herein, unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with that disease, disorder or condition, or to prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in the prevention of that disease, disorder or condition. The term "prophylactically effective amount" can include an amount that improves the overall prophylaxis, or enhances the prophylactic efficacy of another prophylactic agent.

[0099] As used herein, "episodic dosing regimen" is a dosing regimen in which a compound of formula (I) or a composition comprising a compound of formula (I) is administered to a subject over a limited period corresponding to the diagnosis of a disorder or its symptoms (e.g., diagnosis or symptoms of an episode of depression, major depressive disorder, bipolar depression, anxiety, or postpartum depression). In some embodiments, the major depressive disorder is a moderate major depressive disorder. In some embodiments, the major depressive disorder is a severe major depressive disorder. In some embodiments, the compound is formulated as individual dosage units (each unit comprising a compound of formula (I) and one or more suitable pharmaceutical excipients). In some embodiments, the period of the episodic dosing regimen is several weeks (e.g., about 8 weeks). In contrast to chronic administration as defined herein, the episodic dosing of the compound is carried out over a limited period (e.g., about 2 weeks to about 8 weeks) corresponding to the diagnosis of a disorder (e.g., depression or its symptoms). In some embodiments, the episodic dosing is carried out once a day over a plurality of weeks (e.g., about 2 weeks to about 6 weeks). In one embodiment, the episodic dosing period is 2 weeks. In some embodiments, more than one episodic dosing regimen (e.g., 2 or more episodic regimens) is administered to the subject over the subject's lifetime.

[0100] Compound It should be recognized that the formulas described herein can refer to specific carbon atoms (such as C17, C3, C19, etc.). These references are based on the positions of the carbon atoms according to the steroid nomenclature known and used in the art as shown below:

Chem.

[0101] In some embodiments, formula (I):

Chem.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0102] In some embodiments, the formula (I-X):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0103] In some embodiments, the formula (I-1):

Chemical formula

Chemical formula

[0104] In some embodiments, R and R are each independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR, 2a and R 2b wherein each R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. D1 -OC(=O)R, D1 -NH2, or -N(R D1 )2, and in each case D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0105] In some embodiments, each of R and R is independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkoxyhalo, or -OH. 2a and R 2b In some embodiments, each of R and R is independently hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0106] In some embodiments, each of R and R is independently hydrogen. 2a and R 2b In some embodiments, both R and R are hydrogen.

[0107] In some embodiments, both R and R are hydrogen. 2a and R 2b In some embodiments, each of R and R is independently hydrogen.

[0108] In some embodiments, both R and R are hydrogen. 2a and R 2b In some embodiments, both R and R are hydrogen. R 4a and R 4b groups In some embodiments, R 4a and R 4b are each independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2, where in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0109] In some embodiments, R 4a and R 4b are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkoxy halo, or -OH.

[0110] In some embodiments, R 4a and R 4b are independently hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0111] In some embodiments, R 4a and R 4b are each independently hydrogen.

[0112] In some embodiments, both R 4a and R 4b are hydrogen. R 11a and R 11b groups

[0113] In some embodiments, R 11a and R 11b are each independently hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 , -OC(=O)RD1 、 -NH2, or -N(R D1 )2, where in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0114] In some embodiments, R 11a and R 11b are independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 alkoxy, or substituted or unsubstituted C1-C6 alkoxyhalo.

[0115] In some embodiments, R 11a and R 11b are independently hydrogen, -CH3, -CH2CH3, -OCH3, or -CH(CH3)2.

[0116] In some embodiments, R 11a and R 11b are each independently hydrogen.

[0117] In some embodiments, both R 11a and R 11b are hydrogen. The R 7 group

[0118] In some embodiments, R 7 is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2, where in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0119] In some embodiments, R 7 is independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkoxy halo, or -OH.

[0120] In some embodiments, R 7 is independently hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0121] In some embodiments, R 7 is hydrogen. R 6 group

[0122] In some embodiments, R 6 is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2, where in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0123] In some embodiments, R 6 is independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkoxy halo, or -OH.

[0124] In some embodiments, R 6 is independently hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0125] In some embodiments, R 6 is hydrogen. R 16 group

[0126] In some embodiments, R 16 is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2, where in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0127] In some embodiments, R 16 is independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkoxy halo, or -OH.

[0128] In some embodiments, R 16 is independently hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0129] In some embodiments, R 16 is hydrogen. R 17 group

[0130] In some embodiments, R 17 is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2, where in each case R D1is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0131] In some embodiments, each of R 17 is independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkoxyhalo, or -OH.

[0132] In some embodiments, R 17 is independently hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0133] In some embodiments, R 17 is hydrogen. The R 19 group

[0134] In some embodiments, R 19 is independently hydrogen, or substituted or unsubstituted C1-C6 alkyl.

[0135] In some embodiments, R 19 is independently hydrogen, or substituted or unsubstituted C1-C4 alkyl.

[0136] In some embodiments, R 19 is independently hydrogen, -CH3, -CH2CH3, or -CH2OCH(CH3)2.

[0137] In some embodiments, R 19 is hydrogen.

[0138] In some embodiments, R 19 is -CH2OCH(CH3)2.

[0139] In some embodiments, R 19 is -CH3.

[0140] In some embodiments, R 19 is -CH2CH3. R 3 group

[0141] In some embodiments, R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, or substituted or unsubstituted heterocyclic.

[0142] In some embodiments, R 3 is substituted or unsubstituted alkyl.

[0143] In some embodiments, R 3 is substituted or unsubstituted C1-C6 alkyl.

[0144] In some embodiments, R 3 is -CH2CH3 or -CH3, -CH2OCH2CH3, -CH2OCH3.

[0145] In some embodiments, the compound of formula (I) is a compound of formula (I-a): [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein R 1 is substituted or unsubstituted alkyl. R 1 group

[0146] In some embodiments, R 1 is C1-C6 alkyl.

[0147] In some embodiments, R 1 is -CH2CH3 or -CH3.

[0148] In some embodiments, R 1 is -CH2CH3.

[0149] In some embodiments, R 1 is -CH3. R 5 group

[0150] In some embodiments, the compound of formula (I) is a compound of formula (I-b1) or formula (I-b2):

Chemical formula

[0151] In some embodiments, the compound of formula (I) is a compound of formula (I-c1) or formula (I-c2):

Chemical formula

[0152] In some embodiments, the compound of formula (I) is a compound of formula (I-d1) or formula (I-d2):

Chemical formula

[0153] In some embodiments, the compound of formula (I) is a compound of formula (I-d1):

Chemical formula

[0154] In some embodiments, the compound of formula (I) is a compound of formula (I-d2):

Chemical formula

[0155] In some embodiments, R X is independently hydrogen, or substituted or unsubstituted C 1~6 alkyl.

[0156] In some embodiments, R X is independently hydrogen, or substituted or unsubstituted C1-4 alkyl.

[0157] In some embodiments, R X is independently hydrogen, -CH3, or -CH2CH3.

[0158] In some embodiments, R X is hydrogen. R Y group

[0159] In some embodiments, the compound of formula (I) is a compound of formula (I-e):

Chemical formula

[0160] In some embodiments, R Y is

Chemical formula

[0161] In some embodiments, R Y is, [Chem.] selected from

[0162] In some embodiments, R D is independently hydrogen, halogen, substituted or unsubstituted C 1~6 alkyl, -CN, substituted or unsubstituted 5- to 6-membered heteroaryl, or substituted or unsubstituted 5-membered heterocyclyl,

[0163] and e is 0, 1, 2, 3, or 4.

[0164] In some embodiments, R Y is [Chem.] selected from, where R is -CH3, -CH2CH3, -i-Pr, cyclopropyl, or -CN.

[0165] In some embodiments, R Y is [Chem.] selected from.

[0166] In some embodiments, R Y is [Chem.] as follows.

[0167] In some embodiments, R Y is [Chem.] as follows.

[0168] In some embodiments, the compound of formula (I) is of formula (I-f): [Chem.] is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0169] In some embodiments, the compound of formula (I) is a compound of formula (I-g) [Chemical formula] is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0170] In some embodiments, the compound of formula (I) is a compound of formula (Ia), formula (I-b1), formula (I-b2), formula (I-c1), formula (I-c2), formula (I-d1), formula (I-d2), formula (I-e), formula (I-f), or formula (I-g).

[0171] In some embodiments, the pharmaceutical composition comprises a compound described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0172] In some embodiments, in a subject in need of treatment for a CNS-related disorder, a method of treating the CNS-related disorder comprises administering to the subject an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the CNS-related disorder is a sleep disorder, mood disorder, schizophrenia spectrum disorder, spastic disorder, memory and / or cognitive disorder, movement disorder, personality disorder, autism spectrum disorder, pain, traumatic brain injury, vascular disease, substance use disorder and / or withdrawal syndrome, tinnitus, or status epilepticus. In some 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 some embodiments, the major depressive disorder is moderate major depressive disorder. In some embodiments, the major depressive disorder is severe major depressive disorder.

[0173] In some embodiments, the compound is selected from the group consisting of the compounds identified in Table 1 below:

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

[0174] In one aspect, provided herein are pharmaceutically acceptable salts of the compounds described herein (e.g., the compounds of formula (I)).

[0175] In one aspect, provided herein is a pharmaceutical composition 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 compounds of the invention are provided in a pharmaceutical composition in an effective amount. In certain embodiments, the compounds of the invention are provided in a therapeutically effective amount.

[0176] The compounds of the invention described herein act, in certain embodiments, as GABA modulators that act in a positive or negative manner on the GABAA receptor. Such compounds are expected to have CNS activity as modulators of the excitability of the central nervous system (CNS) as mediated by their ability to modulate the GABAA receptor.

[0177] Accordingly, in another aspect, provided is a method of treating a CNS-related disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the invention. In certain embodiments, the CNS-related disorder is a sleep disorder, mood disorder, schizophrenia spectrum disorder, seizure disorder, memory and / or cognitive disorder, movement disorder, personality disorder, autism spectrum disorder, pain, traumatic brain injury, vascular disease, substance use 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 a major depressive disorder. In certain embodiments, the major depressive disorder is a moderate major depressive disorder. In certain embodiments, the major depressive disorder is a severe major depressive disorder. In certain embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In certain embodiments, the compound is administered orally. In certain embodiments, the compound is administered chronically. In certain embodiments, the compound is administered continuously, for example, by continuous intravenous infusion.

[0178] 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. In one aspect, provided herein are pharmaceutically acceptable salts of the compounds described herein (e.g., compounds of formula (I)).

[0179] Alternative embodiments In alternative embodiments, the compounds described herein may also contain one or more isotope substitutions. For example, hydrogen can be, for example, 2 H (D or deuterium) or 3 H (T or tritium); carbon can be, for example, 13 C or 14 C; oxygen can be, for example, 18 O; nitrogen can be, for example, 15 N, and so on. In other embodiments, a particular isotope (e.g., 3 H, 13 C, 14 C, 18 O or 15 N) can 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 of the compound. Pharmaceutical compositions

[0180] In one aspect, provided herein is a pharmaceutical composition 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 compounds of the present invention are provided in an effective amount in the pharmaceutical composition. In certain embodiments, the compounds of the present invention are provided in a therapeutically effective amount.

[0181] In certain embodiments, the pharmaceutical composition comprises an effective amount of an active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of an active ingredient.

[0182] The pharmaceutical compositions provided herein can be administered by a variety of routes, including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration.

[0183] Generally, the compounds provided herein are administered in an effective amount. The amount of the compound actually administered will typically be determined by a physician in light of the relevant circumstances, including the condition being treated, the route of administration selected, the actual compound being administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.

[0184] When used to prevent the occurrence of CNS disorders, the compounds provided herein can typically be administered at the dosage levels described above, to subjects at risk of developing the condition, by and under the advice of a physician. Subjects at risk of developing a particular condition generally include subjects having a family history of that condition, or subjects identified by genetic testing or screening as being particularly susceptible to the development of that condition.

[0185] The pharmaceutical compositions provided herein are also administered chronically ( "chronic administration"). Chronic administration refers to the administration of a compound or its pharmaceutical composition over an extended period of time, for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or indefinitely over the remaining period of the subject's life. In certain embodiments, chronic administration is intended to provide a constant level of the compound, for example, within the therapeutic window, in the blood over an extended period of time.

[0186] The pharmaceutical composition of the present invention can further be delivered using various dosing methods. For example, in certain embodiments, the pharmaceutical composition can be administered as a bolus, e.g., 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, an intramuscular or subcutaneous bolus dose allows for a slow release of the active ingredient, while a bolus delivered directly into a vein (e.g., by IV infusion) allows for a more rapid delivery, which rapidly raises the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition can be administered as a continuous infusion, e.g., by IV infusion, to provide for maintenance of a steady-state concentration of the active ingredient within the subject's body. Further, in still other embodiments, the pharmaceutical composition can be administered first as a bolus dose, followed by a continuous infusion.

[0187] Compositions for oral administration can take the form of bulk liquid solutions or suspensions or bulk powders. However, more commonly, the compositions are provided in unit dosage forms that facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of the active material calculated to produce the desired therapeutic effect, together with suitable pharmaceutical excipients. Typical unit dosage forms include pre-measured and pre-filled ampoules or syringes of liquid compositions, or in the case of solid compositions, pills, tablets, capsules, etc. In such compositions, the compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight), the remainder being various vehicles or excipients and processing aids useful for forming the desired dosage form.

[0188] In the case of oral administration, oral administration 1 to 5 times a day, particularly 2 to 4 times, typically 3 times, is a typical regimen. When using these dosing patterns, each dose results in the compounds provided herein at about 0.01 to about 20 mg / kg, and preferred doses each result in about 0.1 to about 10 mg / kg, particularly about 1 to about 5 mg / kg.

[0189] Transdermal dosages are generally selected to be similar to or provide lower blood levels than those achieved using injection dosages, and generally range from about 0.01 wt% to about 20 wt%, preferably from about 0.1 wt% to about 20 wt%, preferably from about 0.1 wt% to about 10 wt%, and more preferably from about 0.5 wt% to about 15 wt%.

[0190] Dosage levels for injections range from about 0.1 mg / kg / hour to at least 20 mg / kg / hour, all over about 1 to about 120 hours, particularly 24 to 96 hours. A preloading bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve appropriate steady-state levels. The maximum total dose is not expected to exceed about 5 g / day for a 40 - 80 kg human patient.

[0191] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle containing buffering agents, suspending agents and dispensing agents, coloring agents, flavorings, etc. Solid forms may include, for example, any of the following components or compounds of similar nature: 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); glidants (e.g., colloidal silicon dioxide); sweeteners (e.g., sucrose or saccharin); or flavorants (e.g., peppermint, methyl salicylate or orange flavor).

[0192] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline or other injectable excipients known in the art. Conventionally, the active compounds in such compositions are typically trace components, often in an amount of about 0.05 to 10% by weight, and the remainder is, for example, an injectable excipient.

[0193] Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient(s). When formulated as an ointment, the active ingredient is typically admixed with a paraffin ointment base or a water-miscible ointment base. Alternatively, the active ingredient can 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 contain additional components that enhance the skin penetration or stability of the active ingredient or the formulation. All such known transdermal formulations and components are included within the scope provided herein.

[0194] The compounds provided herein can also be administered by transdermal devices. Thus, transdermal administration can be achieved using patches of the reservoir type or porous membrane type or solid matrix type.

[0195] The components described above for orally administrable, injectable, or topically administrable compositions are merely representative. Other materials and processing techniques, etc., are shown in Part 8 of Remington’s Pharmaceutical Sciences, 17th Edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0196] The compounds of the present invention can also be administered in sustained release form or from a sustained release drug delivery system. Descriptions of representative sustained release materials can be found in Remington’s Pharmaceutical Sciences.

[0197] 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 non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions (e.g., hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, etc.).

[0198] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient (e.g., a composition suitable for injection such as intravenous (IV) administration).

[0199] Pharmaceutically acceptable excipients include any and all diluents or other liquid vehicles, dispersing or suspending aids, surfactants, isotonic agents, preservatives, lubricants, etc. appropriate for the particular dosage form desired, e.g., for injection. General considerations in 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).

[0200] For example, injectable preparations, such as sterile aqueous suspensions for injection, can be formulated by known techniques using suitable dispersing or wetting agents and suspending agents. Exemplary excipients that can be used include, but are not limited to, water, sterile physiological saline or phosphate buffered saline, or Ringer's solution.

[0201] 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 (including, but not limited to, substituted or unsubstituted methylation, hydroxyalkylation, acylation and sulfoalkyl ether substitution) on the sugar moieties to be linked as required. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, also known as CAPTISOL®. See, for example, U.S. Patent No. 5,376,645. In certain embodiments, the composition comprises heptapropyl-β-cyclodextrin. In a more specific embodiment, the composition comprises heptapropyl-β-cyclodextrin (10-50% in water).

[0202] Injectable compositions can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or another sterile injectable medium prior to use.

[0203] Generally, the compounds provided herein are administered in an effective amount. The amount of the compound actually administered is typically determined by a physician in light of the relevant circumstances, including the condition being treated, the route of administration selected, the actual compound being administered, the age, weight, response of the individual patient, the severity of the patient's symptoms, and the like.

[0204] The composition is provided in unit dosage forms that facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of the active material calculated to produce the desired therapeutic effect, together with the appropriate pharmaceutical excipients. Typical unit dosage forms include pre-measured and pre-filled ampoules or syringes of liquid compositions. In such compositions, the compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight), and the remainder is various vehicles or carriers and processing aids useful in forming the desired dosage form.

[0205] The compounds provided herein can be administered as a single active agent or in combination with other active agents. In one aspect, the invention provides combinations of a compound of the invention with another pharmacologically active agent. Administration in combination can proceed by any technique apparent to those skilled in the art, including, for example, separate, sequential, simultaneous, and alternating administrations.

[0206] The description of the pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for administration to humans, but it will be understood by those skilled in the art that such compositions are generally suitable for administration to all kinds of animals. Modifications for rendering pharmaceutical compositions suitable for administration to humans suitable for administration to various animals are well understood, and a veterinary pharmacologist of ordinary skill can design and / or effect such modifications by routine experimentation. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins, 2005.

[0207] In one aspect, a kit is provided that includes a composition (e.g., a solid composition) that contains a compound of formula (I).

[0208] Methods of Use and Treatment In certain aspects, the compounds described herein (e.g., compounds of formula (I)) are contemplated to be useful as therapeutic agents for treating CNS-related disorders (e.g., sleep disorders, mood disorders (e.g., depression), schizophrenia spectrum disorders, spastic disorders, seizure occurrence, memory and / or cognitive impairments, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular disorders, substance use disorders and / or withdrawal syndromes, or tinnitus) in a subject in need thereof (e.g., a subject having Rett syndrome, fragile X syndrome, or Angelman syndrome). Exemplary CNS conditions related to GABA modulation include sleep disorders [e.g., insomnia], mood disorders [e.g., depression (e.g., major depressive disorder (MDD)), mood dysregulation disorders (e.g., mild depression), bipolar disorder (e.g., type I and / or type II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (e.g., obsessive-compulsive disorder (OCD))], schizophrenia spectrum disorders [e.g., schizophrenia, schizoaffective disorder], spastic disorders [e.g., epilepsy (e.g., status epilepticus (SE)), seizures], memory and / or cognitive impairments [e.g., attention disorders (e.g., attention deficit hyperactivity disorder (ADHD)), dementia (e.g., Alzheimer's type dementia, Lewy body type dementia, vascular dementia], movement disorders [e.g., Huntington's disease, Parkinson's disease], personality disorders [e.g., antisocial personality disorder, obsessive-compulsive personality disorder], autism spectrum disorder (ASD) [e.g., autism, single-host causes of autism such as synaptophathy (e.g., Rett syndrome, fragile X syndrome, Angelman syndrome], pain [e.g., neuropathic pain, injury-related pain syndromes, acute pain, chronic pain], traumatic brain injury (TBI), vascular disorders [e.g., stroke, ischemia, vascular malformations], substance use disorders and / or withdrawal syndromes [e.g., addiction to opiates, cocaine, and / or alcohol], and tinnitus, but are not limited thereto.

[0209] In certain embodiments, the CNS-related disorder is a sleep disorder, mood disorder, schizophrenia spectrum disorder, seizure disorder, memory and / or cognitive disorder, movement disorder, personality disorder, autism spectrum disorder, pain, traumatic brain injury, vascular disease, substance use 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 a major depressive disorder. In certain embodiments, the major depressive disorder is a moderate major depressive disorder. In certain embodiments, the major depressive disorder is a severe major depressive disorder.

[0210] In one aspect, a method of reducing or preventing seizure activity in a subject is provided, the method comprising administering to a subject in need of such treatment an effective amount of a compound of the invention. In some embodiments, the method reduces or prevents the occurrence of seizures.

[0211] In yet another aspect, a combination of a compound of the invention and another pharmacologically active agent is provided. The compounds provided herein can be administered as a single active agent or in combination with other agents. Administration in combination can proceed by any technique apparent to one of ordinary skill in the art (e.g., separate administration, sequential administration, simultaneous administration, and alternating administration).

[0212] In another aspect, a method of treating or preventing brain excitation in a subject who is susceptible to or suffering from a condition associated with brain excitation is provided, the method comprising administering to the subject an effective amount of a compound of the invention.

[0213] In yet another aspect, a method of treating or preventing stress or anxiety in a subject is provided, the method comprising administering to a subject in need of such treatment an effective amount of a compound or composition thereof of the invention.

[0214] In yet another aspect, a method for reducing or preventing insomnia in a subject is provided, the method comprising administering to a subject in need of such treatment an effective amount of a compound or composition of the present invention.

[0215] In yet another aspect, a method for inducing sleep and substantially maintaining the level of REM sleep seen in normal sleep, without inducing substantial rebound insomnia, is provided, the method comprising administering an effective amount of a compound of the present invention.

[0216] In yet another aspect, a method for reducing or preventing premenstrual syndrome (PMS) or postnatal depression (PND) in a subject is provided, the method comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention.

[0217] In yet another aspect, a method for treating or preventing mood disorders in a subject is provided, the method comprising administering an effective amount of a compound of the present invention to a subject in need of such treatment. In certain embodiments, the mood disorder is depression.

[0218] In yet another aspect, a method for cognitive enhancement or treatment of memory impairment by administering a therapeutically effective amount of a compound of the present invention to a subject is provided. In certain embodiments, the disorder is Alzheimer's disease. In certain embodiments, the disorder is Rett syndrome.

[0219] In yet another aspect, a method for treating attention disorders by administering a therapeutically effective amount of a compound of the present invention to a subject is provided. In certain embodiments, the attention disorder is ADHD.

[0220] In certain embodiments, the compound is administered to the subject chronically. In certain embodiments, the compound is administered to the subject orally, subcutaneously, intramuscularly, or intravenously.

[0221] Neuroendocrine disorders and dysfunctions Methods that can be used to treat neuroendocrine disorders and dysfunctions are provided herein. As used herein, "neuroendocrine disorder" or "neuroendocrine dysfunction" refers to various conditions caused by an imbalance in the body's hormone production that is directly related to the brain. Neuroendocrine disorders involve the interaction between the nervous system and the endocrine system. Since the hypothalamus and the 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 female health disorder or condition (e.g., a female health disorder or condition described herein). In some embodiments, the neuroendocrine disorder or dysfunction associated with a female health disorder or condition is polycystic ovary syndrome.

[0222] Symptoms of neuroendocrine disorders include, but are not limited to, behavioral, emotional and sleep-related symptoms, symptoms related to reproductive function, and physical symptoms, such as fatigue, poor memory, anxiety, depression, weight gain or loss, emotional instability, lack of concentration, difficulty paying attention, loss of libido, infertility, amenorrhea, loss of muscle mass, increased abdominal body fat, low blood pressure, low heart rate, hair loss, anemia, constipation, cold intolerance and dry skin.

[0223] Neurodegenerative diseases and disorders Methods that can 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 the 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 injury; ataxia and spasticity (including for treatment and prevention, and for prevention of seizures caused by schizoid affective disorder or drugs used to treat schizophrenia); benign forgetfulness; cerebral edema; cerebellar ataxia (such as McLeod neuroacanthocytosis syndrome (MLS)); closed head injury; coma; injury due to contusion (e.g., spinal cord injury and head injury); dementia (including multi-infarct dementia and senile dementia); disturbance of consciousness; Down syndrome; drug-induced or agent-induced parkinsonism (e.g., acute akathisia, acute dystonia, parkinsonism or tardive dyskinesia induced by neuroleptics, neuroleptic malignant syndrome, or agent-induced postural tremor); epilepsy; fragile X syndrome; Gilles de la Tourette syndrome; head injury; hearing impairment and hearing loss; Huntington's disease; Lennox syndrome; dyskinesia induced by levodopa; mental retardation; movement disorders including akinesia and akinetic (rigid) syndromes (such as brainstem neurocalcification, corticobasal degeneration, multiple system atrophy, parkinsonism-ALS dementia complex, Parkinson's disease, postencephalitic parkinsonism and progressive supranuclear palsy);Disorders associated with muscle contraction and muscle spasticity or weakness (chorea (e.g., benign hereditary chorea, drug-induced chorea, hemiballismus, Huntington's disease, neuroacanthocytosis, Sydenham chorea, and symptomatic chorea), dystonia (including tics such as complex tics, simple tics, and symptomatic tics), myoclonus (including generalized myoclonus and focal cyloclonus), tremors (e.g., resting tremors, postural tremors, and intention tremors), and ataxia (axial ataxia, dystonic writer's cramp, hemiplegic ataxia, episodic ataxia, and focal ataxia (e.g., blepharospasm, oromandibular dystonia, as well as spastic dysphonia and torticollis)); neuronal damage (including eye damage, retinopathy of the eye, or macular degeneration); stroke, thrombotic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, neurotoxic disorders after perinatal asphyxia and cardiac arrest; Parkinson's disease; seizures; status epilepticus; stroke; tinnitus; tubulosclerosis, and neurodegeneration induced by viral infection (e.g., acquired immunodeficiency syndrome (AIDS) and those caused by brain disorders), but not limited to these. Neurodegenerative diseases also include, but are not limited to, stroke, thrombotic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, and neurotoxic disorders after perinatal asphyxia and cardiac arrest. Methods of treating or preventing neurodegenerative diseases also include treating or preventing the loss of neuronal function characteristic of neurodegenerative disorders.);

[0224] Mood disorder Methods for treating mood disorders such as clinical depression, postpartum depression or postpartum blues, perinatal depression, atypical depression, melancholic depression, psychotic major depression, catatonic depression, seasonal affective disorder, mood swings, double depression, depressive personality disorder, recurrent brief depression, minor depressive disorder, bipolar disorder or manic-depressive disorder, depression caused by chronic conditions, treatment-resistant depression, refractory depression, suicide, suicidal thoughts or suicidal behavior are also provided herein. In some embodiments, the methods described herein provide a therapeutic effect on a subject suffering from depression (e.g., moderate or severe depression). In some embodiments, the mood disorder is related to a disease or disorder described herein (e.g., neuroendocrine diseases and disorders, neurodegenerative diseases and disorders (e.g., epilepsy), movement disorders, tremors (e.g., Parkinson's disease), female health disorders or conditions).

[0225] Clinical depression, also known as major depression, major depressive disorder (MDD), unipolar depression, unipolar disorder and recurrent depression, refers to a mental disorder characterized by a pervasive and persistent low mood accompanied by low self-esteem and usually a loss of interest or pleasure in activities that are normally enjoyable. Some people with clinical depression have trouble sleeping, lose weight, generally feel agitated and become irritable. Clinical depression affects how an individual feels, thinks and behaves and can lead to a variety of emotional and physical problems. Individuals with clinical depression may have difficulty performing daily activities and may feel as if life is not worth living.

[0226] Perinatal depression refers to depression during pregnancy. Symptoms include irritability, crying spells, feelings of anxiety, difficulty sleeping, extreme fatigue (emotional and / or physical), changes in appetite, difficulty concentrating, increased anxiety and / or worry, feelings of wanting to be away from the baby and / or fetus, and loss of interest in activities that were previously enjoyable.

[0227] Postpartum depression (PND), also referred to as postpartum depression (PPD), refers to a type of clinical depression that affects women after childbirth. Symptoms may include sadness, 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-resistant depression (e.g., treatment-resistant depression as described herein).

[0228] In some embodiments, a subject having PND has also experienced depression or symptoms of depression during pregnancy. This depression is referred to herein as perinatal depression. In certain embodiments, subjects experiencing perinatal depression are at high risk of experiencing PND.

[0229] Atypical depression (AD) is characterized by mood reactivity (e.g., paradoxical anhedonia) and positivity, significant weight gain or increased appetite. Patients suffering from AD may also have excessive sleep or drowsiness (hypersomnia), heaviness in the limbs, and significant social impairment as a result of perceived hypersensitivity to interpersonal rejection.

[0230] Melancholic depression is characterized by the loss of pleasure in most or all activities (anhedonia), non-responsiveness to pleasurable stimuli, a depressive mood that is more pronounced than sadness or a mood of loss, significant weight loss, or excessive guilt.

[0231] Psychotic major depression (PMD) or psychotic depression refers to a major depressive episode, particularly a major depressive episode of melancholic nature, in which an individual experiences psychotic symptoms such as delusions and hallucinations.

[0232] Catatonic depression refers to major depression accompanied by disturbances in motor behavior and other symptoms. An individual may become mute and stuporose, unable to move, or exhibit purposeless or strange movements.

[0233] Seasonal affective disorder (SAD) refers to a type of seasonal depression in which an individual has a seasonal pattern of depressive episodes that begin in the fall or winter.

[0234] Mood swings refer to conditions associated with unipolar depression, and the same physical and cognitive problems are evident. They tend to be less severe and last longer (e.g., at least 2 years).

[0235] Double depression refers to a fairly depressed mood (mood swings) that lasts at least 2 years and is sometimes interrupted by periods of major depression.

[0236] Dysthymic personality disorder (DPD) refers to a personality disorder with depressive characteristics.

[0237] Recurrent Brief Depression (RBD) refers to a condition in which an individual has depressive episodes approximately once a month, and each episode lasts for 2 weeks or less, typically less than 2 - 3 days.

[0238] Minor depressive disorder or minor depression refers to depression in which at least two symptoms are present for 2 weeks.

[0239] Bipolar disorder or manic-depressive disorder causes extreme mood swings that include high (manic or hypomanic) and low (depressive) moods. During a manic episode, an individual may feel or act abnormally happy, energetic, or irritable. Such individuals often make impulsive decisions with little regard for the consequences. Usually, the need for sleep decreases. During a depressive episode, there may be crying, less eye contact with others, and a backward view of life. The risk of suicide in those with this disorder is high, exceeding 6% over 20 years, and 30 - 40% engage in self-harm. Other mental health problems such as anxiety disorders and substance use disorders commonly co-occur with bipolar disorder.

[0240] Depression caused by chronic medical conditions refers to depression caused by chronic medical conditions such as cancer or chronic pain, chemotherapy, chronic stress, etc.

[0241] Treatment-resistant depression refers to a state where an individual is undergoing treatment for depression but the symptoms do not improve. For example, antidepressants or psychological counseling (psychotherapy) do not relieve the depressive symptoms in individuals with treatment-resistant depression. In some cases, individuals with treatment-resistant depression improve but then relapse. Treatment-resistant depression occurs in patients suffering from depression that is resistant to standard pharmacological treatments including tricyclic antidepressants, MAOIs, SSRIs, and dual and triple uptake inhibitors, and / or anxiolytics, as well as non-pharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagus nerve stimulation, and / or transcranial magnetic stimulation).

[0242] Postoperative depression refers to a depressive state following a surgical procedure (e.g., as a result of facing death). For example, an individual may feel persistent sadness or emptiness, loss of pleasure or interest in hobbies and activities that were once enjoyed, or persistent feelings of worthlessness or despair.

[0243] Mood disorders related to a female's health condition or health disorder refer to mood disorders (such as depression) related to (e.g., caused by) a female's health condition or health disorder (such as those described herein).

[0244] Suicidal tendency, suicidal ideation, and suicidal behavior refer to the tendency of an individual to commit suicide. Suicidal ideation is related to thoughts about suicide or abnormal fixation on suicide. The scope of suicidal ideation can vary widely, for example, from momentary thoughts to extensive thoughts, detailed plans, role-playing, and incomplete attempts. Symptoms include talking about suicide, obtaining means to commit suicide, cutting off social contact, thinking only about death, feeling immobilized or hopeless about a situation, increased use of alcohol or drugs, engaging in dangerous or self-destructive behavior, and saying goodbye to people as if they will never see them again.

[0245] Symptoms of depression include persistent feelings of anxiety or sadness, feelings of weakness, hopelessness, pessimism, worthlessness, low energy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, motor challenges, loss of interest in pleasurable activities or hobbies, difficulty concentrating, decreased energy, low self-esteem, lack of positive thoughts or plans, excessive sleep, overeating, loss of appetite, insomnia, self-harm, thoughts of suicide, and attempts at suicide. The presence, severity, frequency, and duration of symptoms can vary depending on the case. The symptoms of depression and their alleviation can be confirmed by a physician or psychologist (e.g., through a mental status examination).

[0246] In some embodiments, the method includes monitoring a subject using known depression scales, such as the Hamilton Depression (HAM-D) scale, the Clinical Global Impression of Improvement scale (CGI), and the Montgomery-Asberg Depression Rating Scale (MADRS). In some embodiments, the treatment effect can be measured by a decrease in the total Hamilton Depression (HAM-D) score exhibited by the subject. The decrease in the total HAM-D score can occur within 4, 3, 2, or 1 day; or within or less than 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, 8 hours. The treatment effect can be evaluated over a specific treatment period. For example, the treatment effect can be measured by a decrease in the total HAM-D 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 after 24, 48, 72, or 96 hours or more after administration; or 1 day, 2 days, 14 days, 21 days, or 28 days; or 1 week, 2 weeks, 3 weeks, or 4 weeks; or 1 month, 2 months, 6 months, or 10 months; or 1 year, 2 years, or over a lifetime).

[0247] 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 baseline HAM-D total score of the subject (i.e., before treatment with a compound described herein (e.g., a compound of formula (I))) is at least 24. In some embodiments, the baseline HAM-D total score of the subject is at least 18. In some embodiments, the baseline HAM-D total score of the subject is between 14 and 18, including 14 and 18. In some embodiments, the baseline HAM-D total score of the subject is between 19 and 22, including 19 and 22. In some embodiments, the HAM-D total score of the 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 HAM-D total score of the subject after treatment with a compound described herein (e.g., a compound of formula (I)) is about 0 - 10 (e.g., less than 10; 0 - 10, 0 - 6, 0 - 4, 0 - 3, 0 - 2 or 1.8). In some embodiments, the HAM-D total score after treatment with a compound described herein (e.g., a compound of formula (I)) is less than 10, 7, 5 or 3. In some embodiments, the decrease in the HAM-D total score is from a baseline score of about 20 - 30 (e.g., 22 - 28, 23 - 27, 24 - 27, 25 - 27, 26 - 27) to a 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 decrease in the total HAM-D score from the baseline HAM-D total score to the total HAM-D 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-fold. In some embodiments, the percentage decrease in the total HAM-D score from the baseline HAM-D total score to the total HAM-D 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 decrease in the total HAM-D score after treatment with a compound described herein (e.g., a compound of formula (I)) (e.g., 12, 24, 48 hours after administration; or 24, 48, 72, 96 hours or more after; or 1 day, 2 days, 14 days or more after) compared to the baseline HAM-D total score, and is at least 10, 15 or 20 points.

[0248] In some embodiments, a method of treating a depressive disorder, such as major depressive disorder, provides a treatment effect (e.g., as measured by a decrease in the Hamilton Depression Rating Scale (HAM-D)) within 14, 10, 4, 3, 2, or 1 day or within 24, 20, 16, 12, 10, or 8 hours or less. In some embodiments, a method of treating a depressive disorder, such as major depressive disorder, provides a treatment effect (e.g., as determined by a statistically significant decrease in the HAM-D total score) within 1 or 2 days of treatment with a compound described herein (e.g., a compound of formula (I)). In some embodiments, a method of treating a depressive disorder, such as major depressive disorder, provides a treatment 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 a compound described herein (e.g., a compound of formula (I)). In some embodiments, a method of treating a depressive disorder, such as major depressive disorder, provides a treatment 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 a compound described herein (e.g., a compound of formula (I)). In some embodiments, a method of treating a depressive disorder, such as major depressive disorder, provides a treatment 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 treatment effect is a decrease in the HAM-D total score from baseline after treatment with a compound described herein (e.g., a compound of formula (I)) (e.g., once-daily treatment with Compound 1 for 14 days). In some embodiments, the HAM-D total score of the subject before treatment with a compound described herein (e.g., a compound of formula (I)) is at least 24. In some embodiments, the HAM-D total score of the subject before treatment with a compound described herein (e.g., a compound of formula (I)) is at least 18.In some embodiments, the HAM-D total score of the subject before treatment with the compounds described herein (e.g., the compounds of formula (I)) is between 14 and 18, including 14 and 18. In some embodiments, the decrease in the HAM-D total score after treating the subject with the compounds described herein (e.g., the compounds of formula (I)) as compared to the baseline HAM-D total score is at least 10. In some embodiments, the decrease in the HAM-D total score after treating the subject with the compounds described herein (e.g., the compounds of formula (I)) as compared to the baseline HAM-D total score is at least 15 (e.g., at least 17). In some embodiments, the HAM-D total score associated with the treatment of the subject with the compounds described herein (e.g., the compounds of formula (I)) is a numerical value less than or equal to in the range of 6 - 8. In some embodiments, the HAM-D total score associated with the treatment of the subject with the compounds described herein (e.g., the compounds of formula (I)) is 7 or less.

[0249] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a decrease in the Clinical Global Impression - Improvement Scale (CGI)) within 14, 10, 4, 3, 2, or 1 day or within or less than 24, 20, 16, 12, 10, or 8 hours. In some embodiments, the CNS disorder is a depressive disorder, e.g., major depressive disorder. In some embodiments, the method of treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic 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).

[0250] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a decrease in the Montgomery-Åsberg 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, such as major depressive disorder. In some embodiments, a method of treating a depressive disorder, such as 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).

[0251] The therapeutic effect on major depressive disorder can be determined by a decrease in the Montgomery-Åsberg Depression Rating Scale (MADRS) score exhibited by the subject. For example, the MADRS score can decrease within 4, 3, 2, or 1 day; or within 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, 8 hours or less. The Montgomery-Åsberg Depression Rating Scale (MADRS) is a 10-item diagnostic questionnaire (regarding sadness expressed externally, sadness expressed verbally, inner tension, decreased sleep, decreased appetite, difficulty concentrating, lassitude, inability to feel emotions, pessimistic thoughts, and suicidal thoughts) used by psychiatrists to measure the severity of depressive episodes in patients with mood disorders.

[0252] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a decrease in the Edinburgh Postnatal Depression Scale (EPDS)) within 4, 3, 2, or 1 day; 24, 20, 16, 12, 10, 8 hours or less. In some embodiments, the therapeutic effect is an improvement measured by the EPDS.

[0253] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a reduction in the Generalized Anxiety Disorder 7-item Scale (GAD-7)) within 4 days, within 3 days, within 2 days, within 1 day; within 24 hours, within 20 hours, within 16 hours, within 12 hours, within 10 hours, within 8 hours or less.

[0254] 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 general term encompassing several different forms of abnormal and pathological fears and anxieties. Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders.

[0255] Generalized anxiety disorder is a common chronic disorder characterized by persistent anxiety that cannot be focused on any one object or situation. People suffering from generalized anxiety experience nonspecific, persistent fears and worries and tend to worry excessively about ordinary situations. Generalized anxiety disorder is the most common anxiety disorder affecting older adults.

[0256] In panic disorder, humans suffer from intense fear and short-lived bouts of unease, often characterized by trembling, shaking, disorientation, dizziness, nausea, and difficulty breathing. These panic attacks (defined by the APA as sudden, reaching a peak in less than 10 minutes, fear or discomfort) can last for several 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 concern about the underlying 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 particular panic episode. Often, normal variations in heart rate are noticed by those 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 perception 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., hypochondria).

[0257] Obsessive-compulsive disorder is a type of anxiety disorder, mainly characterized by repetitive obsessive thoughts (intrusive, persistent, and unwanted 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 process is completely illogical. For example, the compulsive behavior of walking in a particular pattern can be used to relieve the obsessive thought of an impending danger. And in many cases, this compulsive behavior is not completely inexplicable but simply the urge to complete a ritual induced by nervousness. In a minority of cases, OCD patients may only experience obsessive thoughts without overt compulsive behaviors, and in an even smaller number of patients, only compulsive behaviors.

[0258] One of the largest categories of anxiety disorders is phobias, which encompasses all cases where fear and anxiety are triggered by specific stimuli or situations. Patients typically anticipate the terrifying consequences of encountering the object of their fear, which can range from animals, places, to something related to body fluids.

[0259] 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.

[0260] Female Health Disorders Methods for treating conditions or disorders related to female health are provided herein. Conditions or disorders related to female 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 the overall health and well-being of women (such as menopause), but are not limited thereto.

[0261] Gynecological health and disorders affecting women include menstruation and menstrual irregularities; urinary tract health (including urinary incontinence and pelvic floor disorders); and disorders such as bacterial vaginosis, vaginitis, uterine fibroids, and vulvodynia.

[0262] Premenstrual syndrome (PMS) refers to physical and emotional symptoms that occur 1 - 2 weeks before menstruation. The symptoms are diverse and can include bleeding, mood swings, breast tenderness, binge eating, fatigue, irritability, acne, and depression.

[0263] 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, extreme anger, increased interpersonal conflict, tension and anxiety, irritability, decreased interest in usual activities, difficulty concentrating, fatigue, changes in appetite, feelings of loss of control or confusion, sleep problems, and physical problems (e.g., bloating, breast tenderness, swelling, headache, joint pain, or muscle pain).

[0264] Problems related to pregnancy include preconception care and prenatal care, pregnancy loss (miscarriage and stillbirth), preterm labor and premature birth, sudden infant death syndrome (SIDS), breastfeeding, and birth defects.

[0265] A miscarriage refers to the spontaneous end of a pregnancy before 20 weeks of gestation.

[0266] An abortion refers to the intentional end of a pregnancy that can be performed up to 28 weeks of gestation.

[0267] Infertility and related disorders include uterine fibroids, polycystic ovary syndrome, endometriosis, and primary ovarian insufficiency.

[0268] Polycystic ovary syndrome (PCOS) refers to an endocrine disorder in women of reproductive age. PCOS is a set of symptoms caused by elevated 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 getting pregnant, and dark, smooth, thickened skin patches. PCOS can be associated with conditions such as type 2 diabetes, obesity, obstructive sleep apnea, heart disease, mood disorders, and endometrial cancer.

[0269] Other disorders and conditions that affect only women include Turner syndrome, Rett syndrome, and ovarian and cervical cancer.

[0270] Overall health and wellness issues for women include violence against women, women with disabilities and specific challenges, osteoporosis and bone health, and menopause.

[0271] Menopause refers to 12 months after a woman's last menstrual period and indicates the end of the menstrual cycle. Menopause typically occurs in women in their 40s or 50s. Physical symptoms such as hot flashes and mood symptoms can interfere with sleep, reduce energy, or cause anxiety or sadness or a sense of loss. Types of menopause include natural menopause and surgical menopause (induced menopause resulting from 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.

[0272] Epilepsy The compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof, can be used in the methods described herein, for example, for the treatment of the disorders described herein, such as epilepsy, status epilepticus, or seizures.

[0273] 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 myoclonic epilepsy, epilepsy with grand mal seizures on awakening, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, such as temporal lobe epilepsy, frontal lobe epilepsy, childhood benign focal epilepsy.

[0274] Epileptogenesis The compounds and methods described herein can be used to treat or prevent epileptogenesis. Epileptogenesis is a stepwise process in which a normal brain develops epilepsy (chronic symptoms in which seizures occur). Epileptogenesis results from nerve damage caused by an initial insult (e.g., status epilepticus).

[0275] Status epilepticus (SE) Status epilepticus (SE) can include, for example, convulsive status epilepticus, such as early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, such as generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform 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, super-refractory status epilepticus. Early status epilepticus is treated with first-choice therapy. Established status epilepticus is characterized by status epilepticus seizures that persist despite treatment with first-choice therapy, and second-choice therapy is performed. Refractory status epilepticus is characterized by status epilepticus seizures that persist despite treatment with first-choice and second-choice therapies, and general anesthetics are commonly administered. Super-refractory status epilepticus is characterized by status epilepticus seizures that persist despite treatment with first-choice, second-choice, and general anesthetics for 24 hours or more.

[0276] 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.

[0277] The compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof can also be administered prophylactically to a subject having a CNS disorder, such as traumatic brain injury, status epilepticus, such as convulsive status epilepticus, such as early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, such as generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges, prior to the onset of seizures.

[0278] Seizure A seizure is a physical finding or change in behavior 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 the human repeat contraction and relaxation.

[0279] 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.

[0280] 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 the seizure is sometimes called a lesion.

[0281] There are six types of generalized seizures. The most common and dramatic, and thus the most well-known, is the generalized convulsion (also called the grand mal). In this type of seizure, the patient loses consciousness and usually collapses. After this loss of consciousness, a general body stiffening (called the "tonic" phase of the seizure) occurs for 30 to 60 seconds, followed by intense contractions (the "clonic" phase) for 30 to 60 seconds, after which the patient falls into a deep sleep (the "postictal" or after-seizure phase). During a grand mal seizure, injuries and accidents (such as biting the tongue and urinary incontinence) can occur.

[0282] Absence seizures cause a brief (only a few seconds) loss of consciousness with little or no symptoms. The patient (most frequently children) typically interrupts activity and stares blankly. These seizures start and end abruptly and can occur several times a day. The patient usually is not aware that they are having a seizure, except perhaps when they notice "losing time."

[0283] Myoclonic seizures usually consist of sporadic contractions on both sides of the body. Patients sometimes describe these contractions as short electrical shocks. When severe, these seizures can result in dropping objects or involuntary throwing.

[0284] Clonic seizures are repetitive rhythmic contractions involving both sides of the body simultaneously.

[0285] Tonic seizures are characterized by muscle stiffening.

[0286] Atonic seizures consist of a sudden decrease in muscle tone throughout the body (especially in the arms and legs), often resulting in a fall.

[0287] The seizures described herein can include epileptic seizures; acute recurrent seizures; cluster seizures; continuous seizures; non - intermittent seizures; persistent seizures; recurrent seizures; status epilepticus, for example, refractory convulsive status epilepticus, non - convulsive 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; atonic seizures; benign Rolandic seizures; febrile seizures; emotional seizures; focal seizures; gelastic seizures; generalized onset seizures; infantile spasms; Jacksonian seizures; generalized bilateral myoclonic seizures; multifocal seizures; neonatal onset seizures; nocturnal seizures; occipital lobe seizures; post - traumatic seizures; subtle seizures; Sylvan seizures; visual reflex seizures; or dissociative seizures. In some embodiments, the seizures are generalized seizures associated with Dravet syndrome, Lennox - Gastaut syndrome, tuberous sclerosis complex, Rett syndrome or PCDH19 - related epilepsy in females.

[0288] Movement disorders Methods for treating movement disorders are also described herein. As used herein, "movement disorders" refers to various diseases and disorders associated with hyperkinetic disorders and related abnormalities of muscle control. Exemplary movement disorders include Parkinson's disease and paralysis agitans (particularly as defined by bradykinesia), dystonia, chorea and Huntington's disease, ataxia, tremors (e.g., essential tremor), myoclonus and startle, tics and Tourette syndrome, restless legs syndrome, stiff - person syndrome as well as gait disorders, but are not limited thereto.

[0289] Tremors The methods described herein can be used to treat tremors. For example, a compound of formula (I) can be used to treat, for example, cerebellar tremor or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, parkinsonian tremor, physiologic tremor, psychogenic tremor or rubral tremor. Tremors include genetic, degenerative and idiopathic disorders, such as Wilson's disease, Parkinson's disease and essential tremor, respectively; metabolic disorders (e.g., thyroid - parathyroid disorders, liver disease and hypoglycemia); peripheral neuropathies (associated with Charcot - Marie - Tooth disease, Lucie Levy disease, true diabetes, complex regional pain syndrome); disorders induced by toxins (nicotine, mercury, lead, CO, manganese, arsenic, toluene); disorders induced by drugs (sleep medications, tricyclics, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychogenic disorders. Clinical tremors can be classified as physiologic tremor, enhanced physiologic tremor, essential tremor syndrome (including classical essential tremor, primary orthostatic tremor and task - specific and posture - specific tremors), dystonic tremor, parkinsonian tremor, cerebellar tremor, Holmes tremor (i.e., rubral tremor), palatal tremor, neuropathic tremor, toxic or drug - induced tremor and psychogenic tremor.

[0290] Tremor is an involuntary, sometimes rhythmic, muscle contraction and relaxation that can be accompanied by vibration or contraction of one or more body parts (e.g., hands, arms, eyes, face, head, vocal cords, trunk, legs).

[0291] Cerebellar tremor or intention tremor is a slow, broad tremor of the extremities that occurs after an intentional movement. Cerebellar tremor is caused by, for example, a lesion in the cerebellum or damage to the cerebellum due to a tumor, stroke, disease (e.g., multiple sclerosis, hereditary degenerative disorders).

[0292] Dystonic tremors occur in individuals with dystonia, a movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive movements and / or painful abnormal postures or positions. Dystonic tremors can affect any muscle in the body. Dystonic tremors occur irregularly and can often be alleviated by absolute rest.

[0293] Essential tremor or benign essential tremor is the most common type of tremor. Essential tremor may be in part mild and non - progressive, or it may be slowly progressive starting on one side of the body and affecting both sides within 3 years. The hands are most frequently affected, but the head, voice, tongue, legs, and trunk can also be involved. The frequency of the tremor may decrease with age, while the severity may increase. Emotional arousal, stress, fever, physical fatigue, or hypoglycemia can trigger the tremor and / or increase its severity. The symptoms generally develop over a long period, become visible after onset, and can persist.

[0294] Orthostatic tremor is characterized by rapid (e.g., greater than 12 Hz) rhythmic muscle contractions that occur in the legs and trunk immediately after standing. The tremors are felt in the thighs and legs, and patients may be unable to suppress the shaking when asked to stand still. Orthostatic tremor can occur in patients with essential tremor.

[0295] Parkinsonian tremors are caused by damage to structures within the brain that control movement. Parkinsonian tremors are often a precursor to Parkinson's disease and are typically seen as a "pill - rolling" movement of the hand and can also affect the jaw, lips, legs, and trunk. The onset of Parkinsonian tremors typically begins after the age of 60. The movement starts in one limb or one side of the body and can progress to affect the other side.

[0296] Physiological tremors can occur in normal individuals and have no clinical significance. Physiological tremors 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. This tremor classically has a frequency of about 10 Hz.

[0297] Psychogenic or hysterical tremors can occur at rest, during postural movements, or during active movements. Patients with psychogenic tremors may have conversion disorders or other psychiatric illnesses.

[0298] Red nucleus tremors are characterized by slow, coarse tremors that can appear at rest, during posture, and when intended. This tremor can be associated with conditions that affect the red nucleus in classical, rare strokes of the midbrain.

[0299] Parkinson's disease affects the brain's nerve cells that produce dopamine. Symptoms include muscle rigidity, tremors, and changes in speech and walking. Parkinsonism is characterized by tremors, bradykinesia, rigidity, and postural instability. Parkinsonism shares the symptoms seen in Parkinson's disease but is a syndrome rather than a progressive neurodegenerative disease.

[0300] Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions that are abnormal and often repetitive, causing abnormal and often repetitive movements or postures. Dystonic movements can be patterned, torsional, or tremulous. Dystonia is often caused or worsened by voluntary movements and is often related to overflow of muscle activation.

[0301] Chorea is a neurological disorder typically characterized by rhythmic involuntary movements that affect the shoulders, hips, and face. Huntington's disease is a genetic disorder that weakens the brain's nerve cells. Symptoms include uncontrollable movements, clumsiness, and balance problems. Huntington's disease can interfere with walking, talking, and swallowing.

[0302] Ataxia refers to the loss of complete control of body movements and can affect the fingers, hands, arms, legs, body, speech, and eye movements.

[0303] Myoclonus and startle are responses to sudden and unexpected stimuli that can be auditory, tactile, visual, or vestibular.

[0304] Tics are involuntary movements that typically start suddenly, are short and repetitive but not rhythmic, often mimic normal behaviors, and typically occur outside the range of normal activity background. Tics can be classified as motor tics or vocal tics, where motor tics are related to movement and vocal tics are related to sound. Tics can be characterized as simple or complex. For example, simple motor tics involve only a few muscles limited to a specific body part. Tourette syndrome is a hereditary neuropsychiatric disorder that begins in childhood and is characterized by multiple motor tics and at least one vocal tic.

[0305] Restless legs syndrome is a neurological sensorimotor disorder characterized by an irresistible urge to move the legs at rest.

[0306] Stiff-person syndrome is a progressive movement disorder typically characterized by involuntary painful muscle contractions and muscle rigidity, usually involving the trunk and legs. Typically, a rigid gait with excessive lordosis of the lumbar spine occurs. Typically, characteristic abnormalities are observed in the EMG recording of the continuous motor unit activity of the paraspinal axial muscles. An atypical form is the "stiff-limb syndrome" that results in focal rigidity, typically affecting the distal parts of the legs and feet.

[0307] Gait disorder refers to an abnormality in the pattern or style of walking due to neuromuscular, arthritic, or other physical changes. Walking is classified according to a system of abnormal walking movements, which includes hemiplegic gait, diplegic gait, neuropathic gait, myopathic gait, parkinsonian gait, choreiform gait, ataxic gait, and sensory gait.

[0308] Anesthesia / Sedation Anesthesia is a pharmacologically induced reversible state of amnesia, analgesia, loss of responsiveness, loss of skeletal muscle reflexes, reduced stress response, or all of these simultaneously. These effects can be obtained from a single drug that provides the correct combination of effects alone, or sometimes from a combination of drugs (e.g., hypnotics, sedatives, paralytic agents, analgesics) to achieve a very specific combination of results. Anesthesia makes it possible for patients to undergo surgical and other procedures without experiencing the difficulties and pain they would experience without anesthesia.

[0309] Sedation generally refers to a decrease in nervousness or agitation by the administration of a pharmacological agent to facilitate a medical or diagnostic procedure.

[0310] Sedation and analgesia encompass a continuum of states of consciousness ranging from minimal sedation (anxiety relief) to general anesthesia.

[0311] Minimal sedation, also known as anxiety relief, is a drug-induced state in which patients respond normally to verbal commands. Cognitive function and coordination may be impaired. Ventilation and cardiovascular function are typically unaffected.

[0312] Moderate sedation / analgesia (conscious sedation) is a drug-induced decrease in consciousness in which patients respond purposefully to verbal commands, either alone or accompanied by light tactile stimulation. Usually, intervention to maintain the patient's airway is not required. Spontaneous ventilation is typically adequate. Cardiovascular function is usually maintained.

[0313] Deep sedation / analgesia is a drug-induced depression of consciousness in which patients cannot be easily aroused but will respond purposefully (not a reflex withdrawal from a painful stimulus) after repeated or painful stimuli. Since independent ventilatory function may be impaired, this patient may require assistance to maintain the patient's airway. Spontaneous ventilation may be inadequate. Cardiovascular function is usually maintained.

[0314] General anesthesia is a drug-induced loss of consciousness in which patients are not even arousable to painful stimuli. Since the ability to maintain independent ventilatory function is often impaired, assistance to maintain the patient's airway is often required. Positive pressure ventilation may be needed due to decreased spontaneous ventilation or drug-induced depression of neuromuscular function. Cardiovascular function may be impaired.

[0315] Sedation in the intensive care unit (ICU) enables a decrease in consciousness towards the patient's environment and a decrease in response to external stimuli. This can play a role in the treatment of patients with critical illnesses and encompasses a wide range of symptom control that varies from patient to patient and from individual to individual over the entire course of the patient's illness. Heavy sedation in intensive care is used to facilitate the tolerance of the endotracheal tube and synchronization with the ventilator (often with neuromuscular blocking agents).

[0316] In some embodiments, sedation (e.g., long-term sedation, continuous sedation) is induced in the ICU and maintained over an extended period (e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months). Long-acting sedatives may have a long duration of action. Sedatives in the ICU may have a short elimination half-life.

[0317] Sedation and analgesia during procedures (also referred to as conscious sedation) is a technique of administering sedatives or dissociative agents, with or without analgesics, to enable a subject to tolerate an uncomfortable procedure while maintaining cardiopulmonary function.

Examples

[0318] For the purpose of enabling a more complete understanding of the invention described herein, the following examples are provided. The synthetic and biological examples described in this application are provided to illustrate the compounds, pharmaceutical compositions and methods provided herein and should in no way be construed as limiting the scope thereof.

[0319] Materials and Methods The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It is understood that other process conditions can also be used when typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, unless otherwise stated. The optimal reaction conditions can vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art by conventional optimization.

[0320] Furthermore, as may be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing unwanted 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 T.W. Greene and P.G.M. Wuts, Protecting Groups in Organic Synthesis, 2nd Edition, Wiley, New York, 1991 and the references cited therein.

[0321] The compounds provided herein can be isolated and purified by known standard procedures. Such procedures include, but are not limited to, recrystallization, column chromatography, HPLC, or supercritical fluid chromatography (SFC). The following scheme is presented in detail regarding the preparation of representative oxysterols listed herein. The compounds provided herein can be prepared by those skilled in the art of organic synthesis from starting materials and reagents that are known or commercially available. 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.

[0322] The 1H-NMR reported herein (for example, for the region between about 0.5 to about 4 ppm δ (ppm)) is understood to be an exemplary interpretation (e.g., exemplary peak integration) of the NMR spectrum of the compound.

[0323] LC-ELSD / MS: (Mobile phase: water containing 1.5 mL / 4 L TFA (solvent A) and acetonitrile containing 0.75 mL / 4 L TFA (solvent B), elution gradient of 30% - 90% (solvent B) at a flow rate of 1.2 ml / min for 0.9 minutes and held at 90% for 0.6 minutes; Column: Xtimate C18 2.1×30 mm, 3 um; Wavelength: UV 220 nm; Column temperature: 50 °C; MS ionization: ESI; Detector: PDA&ELSD.

[0324] Abbreviations: CAN: acetonitrile; PE: petroleum ether; DCM: dichloromethane; EtOAc: ethyl acetate; EDCI: N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride. Intermediate Synthesis procedure of INT3 [Chemical formula] Synthesis of INT2 To a solution of 3,6-dibromo-2-methylpyridine (1.0 g, 3.98 mmol) in toluene (50 mL) at -70 °C, n-BuLi (2.5 M in hexane, 1.90 mL, 4.77 mmol) was slowly added. After stirring at -70 °C for 2 hours, tributyl(chloro)stannane (1.68 g, 5.17 mmol) was added. After stirring at -70 °C for 1 hour, the reaction mixture was warmed to -10 °C and saturated aqueous NH4Cl solution (10 mL) was added. The mixture was extracted with ethyl acetate (2 × 50 mL), the combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by flash column chromatography (PE) to give INT2 (1.61 g, 88%) as an oil. 1 H NMR (400 MHz, CDCl3) δ 7.63 - 7.56 (m, 1H), 7.11 - 7.03 (m, 1H), 2.66 (s, 3H), 1.63 - 1.43 (m, 5H), 1.36 - 1.29 (m, 6H), 1.12 - 1.05 (m, 4H), 0.93 - 0.85 (m, 12H). Synthesis of INT3 To a suspension of INT2 (1.3 g, 2.81 mmol) in xylene (15 mL), 2-bromo-5-fluoropyrimidine (470 mg, 2.66 mmol), Pd(PPh3)2Cl2 (100 mg, 0.1424 mmol), and PPh3 (75 mg, 0.2859 mmol) were added under N2. After stirring at 135 °C for 16 hours, the reaction mixture was quenched with water (50 mL) and extracted with DCM (2 × 50 mL). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by flash column chromatography (ethyl acetate in PE, 15%) to give INT3 (400 mg, 53%) as a solid. 11H NMR (400 MHz, CDCl3) δ 8.76 (s, 2H), 8.17 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 2.83 (s, 3H); 19 19F NMR (376 MHz, CDCl3) δ -137.524. Synthesis of INT4 and INT5 [Chemical formula] To a suspension of 3,6-dibromo-2-methylpyridine (1.5 g, 5.97 mmol), 3-methyl-1H-pyrazole (977 mg, 11.9 mmol), and TMEDA (1.38 g, 11.9 mmol) in DMSO (30 mL) was added K2CO3 (2.47 g, 17.9 mmol) under N2. The suspension was degassed under reduced pressure and purged with N2 three times. Then, CuI (1.13 g, 5.97 mmol) was added to the suspension, which was degassed under reduced pressure and purged with N2 three times. The mixture was first stirred at 20 °C for 30 minutes and then heated to 90 °C for 12 hours. The reaction mixture was then diluted with water (50 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL), and the combined organic solutions were washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column (PE) to obtain a solid (1.5 g), which was further purified by SFC (column: Chiralpak AD-3 150×4.6 mm I.D., 3 um; mobile phase: A: CO2 B: ethanol (0.05% DEA); gradient: 5% to 40% of B for 5 minutes, and 40% for 2.5 minutes, then held at 5% of B for 2.5 minutes; flow rate: 2.5 mL / min) to obtain both INT5 (384 mg, 26%, peak 1) and INT4 (106 mg, 7%, peak 2) as solids. The structure was confirmed by 2D NMR. INT5: 11H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 1.2 Hz, 1H), 6.18 (s, 1H), 2.68 (s, 3H), 2.65 (s, 3H). Example 1: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17S)-3-(ethoxymethyl)-3-hydroxy-N-(pyridin-4-yl)hexadecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide (A2) [Chemical formula] General method 1: To a mixture of A1 (100 mg, 0.274 mmol, reported in WO2018013613) in pyridine (5 mL) was added EDCI (57.4 mg, 0.301 mmol). After stirring at room temperature for 15 minutes, pyridin-4-amine (28.3 mg, 0.301 mmol) was added to the mixture. After stirring at 60 °C for 16 hours, the reaction mixture was quenched with HCl (1 M, 10 mL) and extracted with EtOAc (2 × 10 mL). The combined organic solutions were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: Xbridge 150 × 30 mm × 10 um, conditions: water (0.05% aqueous ammonia v / v)-ACN, starting B: 60%, ending B: 90%, gradient time: 7 minutes, flow rate: 25 ml / min) to obtain A2 (29 mg, 24%) as a solid. 1 1H NMR (400 MHz, CDCl3) δ 8.55-8.45 (m, 2H), 7.55-7.45 (m, 2H), 7.20-7.15 (s, 1H), 3.60-3.40 (m, 4H), 2.80-2.75 (m, 1H), 2.40-2.25 (m, 2H), 2.00-1.95 (m, 1H), 1.85-1.55 (m, 9H), 1.50-1.00 (s, 15H), 0.74 (s, 3H); LC-ELSD / MS purity 99%, C 27 H 41N2O3[M+H] + The calculated MS ESI value of + is 441, and the measured value is 441. Example 2: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17S)-3-(ethoxymethyl)-3-hydroxy-N-(3-methylpyridin-2-yl)hexadecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide (A4)

Chemical Structure

Chemical Structure

Chemical Structure

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical Structure

Chemical Structure

Chemical Structure

Chemical formula

Chemical Structure

Chemical Structure

Chemical formula

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

Table 3 - 1

Table 3 - 2

Table 3-3

Table 3-4

Table 3-5

Table 3-6

Table 3-7

Table 3-8

Table 3-9

Table 3-10

Table 3-11

Table 3-12

Table 3-13

Table 3-14

Table 3-15

Table 3-16

Table 3-17

Table 3-18

Table 3-19

Table 3-20

Table 3-21

Table 3-22

Table 3-23

Chemical formula

Chemical Structure

[0325] Briefly, after decapitation of Sprague-Dawley rats (200-250 g) anesthetized with carbon dioxide, the cortex is quickly removed. The cortex is homogenized in 10 volumes of ice-cold 0.32 M sucrose using a glass / Teflon (registered trademark) 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 200 mM NaCl / 50 mM Na-K phosphate buffer pH 7.4 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. An aliquot (100 μL) of the membrane suspension is incubated with a 5 μL aliquot of test compound (final 0.5%) dissolved in dimethyl sulfoxide (DMSO) in the presence of 3 nM 35 S]-TBPS and 5 mM GABA. This incubation results in a final volume of 1.0 mL containing buffer. Nonspecific binding is measured in the presence of 2 mM unlabeled TBPS, which is in the range of 15-25%. After a 90-minute incubation at room temperature, the assay is terminated by filtration through a glass fiber filter (Schleicher and Schuell No. 32) using a cell harvester (Brandel) and rinsed three times with ice-cold buffer. The radioactivity bound to the filter is measured by liquid scintillation spectrometry. Nonlinear curve fitting of the entire data for each drug averaged for each concentration is performed using Prism (GraphPad). When the sum of squares is significantly lower by the F-test, the data are fitted to a partial inhibition model instead of a complete inhibition model. Similarly, when the sum of squares is significantly lower by the F-test, the data are fitted to a two-component inhibition model instead of a one-component inhibition model. The concentration of the test compound that results in 50% inhibition of specific binding (IC 50 ) and the maximum extent of inhibition (I maxMeasure for each individual experiment using the same model applied to the entire data, and then calculate the mean value ± SEM of that individual experiment. Picrotoxin serves as a positive control for these studies because it has been demonstrated to strongly inhibit TBPS binding.

[0326] Various compounds can be screened or screened to measure their potential ability as regulators of 35 S]-TBPS binding in vitro. These assays are performed or can be performed according to the above.

[0327] In Table 2 below, A represents the TBPS IC less than 0.1 μM 50 (μM), B represents the TBPS IC from 0.1 μM to less than 1 μM 50 (μM), and C represents the TBPS IC of 1.0 μM or more 50 (μM).

Table 2-1

Table 2-2

Table 2-3

Table 2-4

Table 2-5

Table 2-6

Table 2-7

Table 2-8

Table 2-9

Table 2-10

Table 2-11

Table 2-12

Table 2-13

Table 2-14

[0328] Equivalents and Ranges In the claims, the articles (e.g., “a,” “an,” and “the”) can mean one or more than one unless the contrary is indicated or is otherwise apparent from the context. Unless the contrary is indicated or is otherwise apparent from the context, a claim or description that includes “or” between one or more members of a group is considered to be satisfied if one, more than one, or all of the 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 of the group members are present in, used in, or otherwise related to a given product or process.

[0329] 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 recited claims are introduced into another claim. For example, any claim that depends on another claim can be modified to include one or more limitations found in any other claim that depends on the same base claim. If an element is presented as a list, for example, in the form of a Markush group, each subgroup of that element is also disclosed, and any element can be removed from that group. Generally, when the present invention or an aspect of the present invention is referred to as including a particular element and / or feature, it should be understood that a particular embodiment of the present invention or aspect thereof consists of or consists essentially of such element and / or feature. For simplicity purposes, those embodiments are not explicitly shown herein in such words. It should also be noted that the terms "comprising" and "containing" are intended to be open and allow for the inclusion of further elements or steps. When a range is given, the endpoints are included. Further, unless otherwise indicated or otherwise apparent from the context and the understanding of one of ordinary skill in the art, values expressed as ranges can assume any specific value or subrange within the recited range, down to one tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise, for various embodiments of the present invention.

[0330] This application refers to various issued patents, published patent applications, academic papers, and other publications (all of which are incorporated herein by reference). In the event of a conflict between any of the incorporated references and this specification, this specification shall govern. Further, any particular embodiment of the present invention that falls within the prior art can be clearly excluded from any one or more of the claims. Such embodiments are considered to be known to one of ordinary skill in the art and thus can be excluded even if such exclusion is not explicitly shown herein. Any particular embodiment of the present invention can be excluded from any claim for any reason, regardless of whether it is related to the existence of the prior art.

[0331] One of ordinary skill in the art will recognize, or be able to ascertain using no more than routine experimentation, 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, but rather as set forth in the appended claims. One of ordinary skill in the art will recognize that various changes and modifications can be made to this description without departing from the spirit or scope of the invention as defined in the following claims.

Claims

1. Formula (I): 【Chemical 69】 A compound of, In formula (I), 【Chemical 70】 represents a single bond or a double bond when the valence allows; R ２ａ , R ２ｂ , R ４ａ , R ４ｂ , R ６ , R ７ , R １１ａ , and R １１ｂ each independently is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl, -OR Ｄ１ , -OC(=O)R Ｄ１ , -NH ２ , -N(R Ｄ１ ), ２ , or -NR Ｄ１ C(=O)R Ｄ１ where, in each case, R Ｄ１ is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when bonded to an oxygen atom, a nitrogen protecting group when bonded to a nitrogen atom, or two R Ｄ１ groups are bonded to form a substituted or unsubstituted heterocyclic ring; or one of R ２ａ and R ２ｂ , R ４ａ and R ４ｂ , R ７ａ and R ７ｂ , R １１ａ and R １１ｂ is bonded to form an oxo (=O) group; R １６ and R １７Each of them is, independently of each other, hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR Ａ１ , -SR Ａ１ , -N(R Ａ１ ), ２ , -N(R Ａ１ ), -CN(R Ａ１ ), ２ , -C(O)R Ａ１ , -OC(=O)R Ａ１ , -OC(=O)OR Ａ１ , -OC(=O)SR Ａ１ , -OC(=O)N(R Ａ１ ), ２ , -SC(=O)R Ａ２ , -SC(=O)OR Ａ１ , -SC(=O)SR Ａ１ , -SC(=O)N(R Ａ１ ), ２ , -NHC(=O)R Ａ１ , -NHC(=O)OR Ａ１ , -NHC(=O)SR Ａ１ , -NHC(=O)N(R Ａ１ ), ２ , -OS(=O) ２ R Ａ２ , -OS(=O) ２ OR Ａ１ , -S-S(=O) ２ R Ａ２ , -S-S(=O) ２ OR Ａ１ , -S(=O)R Ａ２ , -SO ２ R Ａ２ , or -S(=O) ２ OR Ａ１ ; where R in each case Ａ１is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when bonded to an oxygen atom, a sulfur protecting group when bonded to a sulfur atom, a nitrogen protecting group when bonded to a nitrogen atom, -SO ２ R Ａ２ , -C(O)R Ａ２ or two Rs Ａ１ are bonded to form a substituted or unsubstituted heterocyclic ring or heteroaryl ring; R Ａ２ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ３ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 【Chemical Formula 71】 When is a single bond, R ５ is hydrogen or methyl; 【Chemical Formula 72】 When is a double bond, R ５ does not exist; R １９ is hydrogen or substituted or unsubstituted alkyl; R Ｘ is independently hydrogen, or substituted or unsubstituted alkyl, and R Ｙ is (a) 【Chemical Formula 96】 selected from, wherein in each case R Ｄ is independently halogen, -NO ２, -CN, -OR ＧＡ , -N(R ＧＡ ), ２ , -C(=O)R ＧＡ , -C(=O)OR ＧＡ , -C(=O)N(R ＧＡ ), ２ , -OC(=O)R ＧＡ , -OC(=O)OR ＧＡ , -N(R ＧＡ ),C(=O)R ＧＡ , -OC(=O)N(R ＧＡ ), ２ , -N(R ＧＡ ),C(=O)OR ＧＡ , -S(=O) ２ R ＧＡ , -S(=O) ２ OR ＧＡ , -OS(=O) ２ R ＧＡ , -S(=O) ２ N(R ＧＡ ), ２ , or -N(R ＧＡ ),S(=O) ２ R ＧＡ , substituted or unsubstituted C １～６ alkyl, substituted or unsubstituted C ２～６ alkenyl, substituted or unsubstituted C ２～６ alkynyl, substituted or unsubstituted C ３～４ carbocyclic, substituted or unsubstituted 3- to 6-membered heterocyclic, C ５～１０ substituted or unsubstituted aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, or, optionally, two R ＧＡ together with the intervening atoms form a substituted or unsubstituted 3- to 4-membered carbocyclic or heterocyclic ring; Here, in each case R ＧＡ is independently hydrogen, substituted or unsubstituted C １～６ alkyl, substituted or unsubstituted C ２～６ alkenyl, substituted or unsubstituted C ２～６ alkynyl, substituted or unsubstituted C ３～６A carbocyclic ring, a substituted or unsubstituted 3- to 6-membered heterocyclic ring, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, an oxygen protecting group when bonded to oxygen, a nitrogen protecting group when bonded to nitrogen, or two R ＧＡ groups together with an intervening atom form a substituted or unsubstituted carbocyclic ring or heterocyclic ring; wherein, in each case, R Ｘ１ is hydrogen, or a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted carbocyclic ring, R Ｙ is 【Chemical formula 97】 in which case, e is 0, 1, 2, 3, 4, or 5, and R Ｙ is 【Chemical formula 98】 in which case, e is 1, 2, 3, 4, or 5; or (b) 【Chemical formula 99】 selected from wherein, in each case, R Ｄ is independently halogen, a substituted or unsubstituted C １～６ alkyl, -CN, a substituted or unsubstituted 5- to 6-membered heteroaryl, a substituted or unsubstituted 5-membered heterocyclic ring, R Ｙ is 【Chemical formula 100】 in which case, e is 0, 1, 2, 3, or 4; and R Ｙ is 【Chemical formula 101】 in which case, e is 1, 2, 3, or 4; or (c) 【Chemical formula 102】 【Chemical formula 103】 selected from wherein R is -CH ３ , -CH ２ CH ３ , -i-Pr, cyclopropyl or -CN; (d) 【Chemical 104】 selected from; (e) 【Chemical 105】 is; or (f) 【Chemical 106】 is, compound.

2. R １９ is hydrogen or methyl, the compound according to claim 1.

3. R ２ａ and R ２ｂ are (a) each independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR Ｄ１ , -OC(=O)R Ｄ１ , -NH ２ , or -N(R Ｄ１ ) ２ , where in each case R Ｄ１ is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or (b) each independently hydrogen, substituted or unsubstituted C １ ~C ６ alkyl, substituted or unsubstituted C １ ~C ６ haloalkyl, substituted or unsubstituted C １ ~C ６ alkoxy, substituted or unsubstituted C １ ~C ６ alkoxyhalo, or -OH, or (c) each independently hydrogen, -CH ３ , -CH ２ CH ３ , -OH, -OCH ３ , or -CH(CH ３ ), ２ or (d) each independently is hydrogen, The compound according to claim 1 or 2.

4. R ４ａ and R ４ｂ are (a) each independently is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR Ｄ１ , -OC(=O)R Ｄ１ , -NH ２ , or -N(R Ｄ１ ), ２ wherein in each case R Ｄ１ is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or (b) independently is hydrogen, substituted or unsubstituted C １ ~C ６ alkyl, substituted or unsubstituted C １ ~C ６ haloalkyl, substituted or unsubstituted C １ ~C ６ alkoxy, substituted or unsubstituted C １ ~C ６ alkoxyhalo, or -OH, or (c) independently is hydrogen, -CH ３ , -CH ２ CH ３ , -OH, -OCH ３ , or -CH(CH ３ ), ２ or (d) each independently is hydrogen, The compound according to any one of claims 1 to 3.

5. R １１ａ and R １１ｂ is (a) each independently is hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR Ｄ１ , -OC(=O)R Ｄ１ , -NH ２ , or -N(R Ｄ１ ) ２ , where in each case R Ｄ１ is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or (b) independently is hydrogen, substituted or unsubstituted C １ -C ６ alkyl, substituted or unsubstituted C １ -C ６ haloalkyl, substituted or unsubstituted C １ -C ６ alkoxy, or substituted or unsubstituted C １ -C ６ alkoxyhalo, or (c) independently is hydrogen, -CH ３ , -CH ２ CH ３ , -OH, -OCH ３ , or -CH(CH ３ ) ２ , or alternatively (d) each independently is hydrogen, The compound according to any one of claims 1 to 4.

6. R ７ is (a) independently is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR Ｄ１ , -OC(=O)R Ｄ１ , -NH ２ , or -N(R Ｄ１ ) ２ , where in each case R Ｄ１is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or (b) is independently hydrogen, substituted or unsubstituted C １ ~C ６ alkyl, substituted or unsubstituted C １ ~C ６ haloalkyl, substituted or unsubstituted C １ ~C ６ alkoxy, substituted or unsubstituted C １ ~C ６ alkoxy halo, or -OH, or (c) is independently hydrogen, -CH ３ , -CH ２ CH ３ , -OH, -OCH ３ , or -CH(CH ３ ) ２ or (d) is hydrogen, The compound according to any one of claims 1 to 5.

7. R ６ is (a) is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR Ｄ１ , -OC(=O)R Ｄ１ , -NH ２ , or -N(R Ｄ１ ) ２ and wherein each R Ｄ１ is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or (b) is independently hydrogen, substituted or unsubstituted C １ ~C ６ alkyl, substituted or unsubstituted C １ ~C ６ haloalkyl, substituted or unsubstituted C １ ~C ６An alkoxy group, substituted or unsubstituted C １ ~C ６ is an alkoxy halo, or -OH, or (c) independently, hydrogen, -CH ３ , -CH ２ CH ３ , -OH, -OCH ３ , or -CH(CH ３ ) ２ or (d) is hydrogen, The compound according to any one of claims 1 to 6.

8. R １６ is (a) independently, hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR Ｄ１ , -OC(=O)R Ｄ１ , -NH ２ , or -N(R Ｄ１ ) ２ wherein, in each case, R Ｄ１ is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or (b) independently, hydrogen, substituted or unsubstituted C １ ~C ６ alkyl, substituted or unsubstituted C １ ~C ６ haloalkyl, substituted or unsubstituted C １ ~C ６ alkoxy, substituted or unsubstituted C １ ~C ６ alkoxy halo, or -OH, or (c) independently, hydrogen, -CH ３ , -CH ２ CH ３ , -OH, -OCH ３ , or -CH(CH ３ ) ２ or (d) is hydrogen, The compound according to any one of claims 1 to 7.

9. R １７ is (a) independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR Ｄ１ , -OC(=O)R Ｄ１ , -NH ２ , or -N(R Ｄ１ ), ２ wherein in each case R Ｄ１ is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or (b) independently hydrogen, substituted or unsubstituted C １ ~C ６ alkyl, substituted or unsubstituted C １ ~C ６ haloalkyl, substituted or unsubstituted C １ ~C ６ alkoxy, substituted or unsubstituted C １ ~C ６ alkoxyhalo, or -OH, or (c) independently hydrogen, -CH ３ , -CH ２ CH ３ , -OH, -OCH ３ , or -CH(CH ３ ), ２ or (d) hydrogen, The compound according to any one of claims 1 to 8.

10. R １９ is (a) independently hydrogen, or substituted or unsubstituted C １ ~C ６ alkyl, (b) independently hydrogen, or substituted or unsubstituted C １ ~C ４ alkyl, (c) independently hydrogen, -CH ３, -CH ２ CH ３ 、or -CH ２ OCH(CH ３ ) ２ 、 (d) hydrogen, or (e) -CH ２ OCH(CH ３ ) ２ The compound according to any one of claims 1 to 9, wherein it is

11. R ３ is (a) substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, or substituted or unsubstituted heterocyclic, (b) substituted or unsubstituted alkyl, or (c) substituted or unsubstituted C １ ~C ６ alkyl The compound according to any one of claims 1 to 10, wherein it is

12. The compound of formula (I) is a compound of formula (I-a): 【Chemical Formula 81】 wherein Here, R １ is substituted or unsubstituted alkyl, or The compound of formula (I) is a compound of formula (I-b1) or formula (I-b2): 【Chemical Formula 82】 wherein The compound of formula (I) is a compound of formula (I-c1) or formula (I-c2): 【Chemical Formula 83】 wherein The compound of formula (I) is a compound of formula (I-d1) or formula (I-d2) 【Chemical Formula 84】 wherein or The compound of formula (I) is a compound of formula (I-e): 【Chemical Formula 87】 where R １ is -CH ２ CH ３ or -CH ３ or The compound of formula (I) is a compound of formula (I-f): 【Chemical Formula 94】 or The compound of formula (I) is of formula (I-g) 【Chemical Formula 95】 is The compound according to any one of claims 1 to 11.

13. R1 is (a) -CH2CH3 or -CH3, or (b) -CH2CH3, or (c) -CH3, is the compound according to claim 12.

14. R Ｘ is (a) independently hydrogen, or substituted or unsubstituted C １～６ alkyl, (b) independently hydrogen, or substituted or unsubstituted C １～４ alkyl, (c) independently hydrogen, -CH ３ or -CH ２ CH ３ or (d) hydrogen is the compound according to any one of claims 1 to 13.

15. R Ｙ is (a) 【Chemical Formula 90】 selected from; where R is -CH ３ -CH ２ CH ３ 、 -i-Pr, cyclopropyl, or -CN, or (b) [Chemical Formula 91] selected from, or (c) [Chemical Formula 92] or, or (d) [Chemical Formula 93] is, The compound according to any one of claims 1 to 14.

16. 【Table 4-1】 【Table 4-2】 【Table 4-3】 【Table 4-4】 【Table 4-5】 【Table 4-6】 【Table 4-7】 【Table 4-8】 【Table 4-9】 【Table 4-10】 【Table 4-11】 【Table 4-12】 【Table 4-13】 【Table 4-14】 【Table 4-15】 【Table 4-16】 【Table 4-17】 A compound selected from.

17. A pharmaceutical composition comprising the compound according to any one of claims 1 to 16 and a pharmaceutically acceptable excipient.

18. A composition for treating a CNS-related disorder in a subject in need thereof, the composition comprising an effective amount of the compound according to any one of claims 1 to 16, or a pharmaceutical composition according to claim 17 for use in a method of treating a CNS-related disorder in a subject in need thereof.

19. (a) The CNS-related disorder is a sleep disorder, mood disorder, schizophrenia spectrum disorder, seizure disorder, memory and / or cognitive disorder, movement disorder, personality disorder, autism spectrum disorder, pain, traumatic brain injury, vascular disease, substance use disorder and / or withdrawal syndrome, tinnitus, or status epilepticus, (b) The CNS-related disorder is depression, (c) The CNS-related disorder is postpartum depression, (d) The CNS-related disorder is major depressive disorder, (e) The CNS-related disorder is major depressive disorder, and the major depressive disorder is moderate major depressive disorder, or (f) The CNS-related disorder is major depressive disorder, and the major depressive disorder is severe major depressive disorder, The composition according to claim 18.

20. Formula (I): 【Chemical Formula 69】 A pharmaceutically acceptable salt of the compound of, In formula (I), 【Chemical Formula 70】 represents a single bond or a double bond when the valence allows; Each of R2a, R2b, R4a, R4b, R6, R7, R11a, and R11b is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl, -ORD1, -OC(=O)RD1, -NH2, -N(RD1)2, or -NRD1C(=O)RD1, where in each case RD1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when bonded to an oxygen atom, a nitrogen protecting group when bonded to a nitrogen atom, or two RD1 groups are bonded to form a substituted or unsubstituted heterocyclic ring; or any one of R2a and R2b, R4a and R4b, R7a and R7b, R11a and R11b is bonded to form an oxo (=O) group; Each of R16 and R17 is, independently of one another, hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1, -SR A1, -N(R A1)2, -N(R A1), -CN(R A1)2, -C(O)R A1, -OC(=O)R A1, -OC(=O)OR A1, -OC(=O)SR A1, -OC(=O)N(R A1)2, -SC(=O)R A2, -SC(=O)OR A1, -SC(=O)SR A1, -SC(=O)N(R A1)2, -NHC(=O)R A1, -NHC(=O)OR A1, -NHC(=O)SR A1, -NHC(=O)N(R A1)2, -OS(=O)2R A2, -OS(=O)2OR A1, -S-S(=O)2R A2, -S-S(=O)2OR A1, -S(=O)R A2, -SO2R A2, or -S(=O)2OR A1, where in each case R A1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when bonded to an oxygen atom, a sulfur protecting group when bonded to a sulfur atom, a nitrogen protecting group when bonded to a nitrogen atom, -SO2R A2, -C(O)R A2, or two R A1 groups are joined to form a substituted or unsubstituted heterocyclic ring or heteroaryl ring; and R A2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 【Chemical formula 71】 When is a single bond, R5 is hydrogen or methyl; 【Chemical formula 72】 When is a double bond, R5 does not exist; R19 is hydrogen or substituted or unsubstituted alkyl; RX is independently hydrogen, or substituted or unsubstituted alkyl, and RY is (a) 【Chemical formula 96】 selected from, where in each case RD is independently halogen, -NO2, -CN, -ORGA, -N(RGA)2, -C(=O)RGA, -C(=O)ORGA, -C(=O)N(RGA)2, -OC(=O)RGA, -OC(=O)ORGA, -N(RGA)C(=O)RGA, -OC(=O)N(RGA)2, -N(RGA)C(=O)ORGA, -S(=O)2RGA, -S(=O)2ORGA, -OS(=O)2RGA, -S(=O)2N(RGA)2, or -N(RGA)S(=O)2RGA, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-4 carbocyclic, substituted or unsubstituted 3-6 membered heterocyclic, C5-10 substituted or unsubstituted aryl, substituted or unsubstituted 5-10 membered heteroaryl, or optionally two RGAs together with intervening atoms form a substituted or unsubstituted 3-4 membered carbocyclic or heterocyclic ring; Here, in each case, RGA is independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocyclic, substituted or unsubstituted 3-6 membered heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when bonded to oxygen, a nitrogen protecting group when bonded to nitrogen, or two RGA groups together with an intervening atom form a substituted or unsubstituted carbocyclic ring or heterocyclic ring; Here, in each case, RX1 is hydrogen, or substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted carbocyclic, RY is [Chemical Formula 97] when it is, e is 0, 1, 2, 3, 4, or 5, and RY is [Chemical Formula 98] when it is, e is 1, 2, 3, 4, or 5; (b) [Chemical Formula 99] is selected from, Here, in each case, RD is independently halogen, substituted or unsubstituted C1-6 alkyl, -CN, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted 5 membered heterocyclic, RY is [Chemical Formula 100] when it is, e is 0, 1, 2, 3, or 4; And wherein RY is 【Chemical 101】 is e 1, 2, 3, or 4; (c) 【Chemical 102】 【Chemical 103】 selected from wherein R is -CH3, -CH2CH3, -i-Pr, cyclopropyl or -CN; (d) 【Chemical 104】 selected from; (e) 【Chemical 105】 is; or (f) 【Chemical 106】 is, a pharmaceutically acceptable salt of the compound.

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