Neurostimulant steroids substituted at the 10 position with cyclic groups for use in the treatment of CNS disorders - Patent Application 20070123333

Abstract

Provided herein are compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein n, R 19 , R 5 , R 3a , R 6a , R 6b , R 1 , R 2a , R 2b , R 4a , R 4b , R 7a , R 7b , R 11a , R 11b , R 12a , R 12b , R 17b , R 15a , R 15b , R 16a and R 16b is defined herein. Also provided herein are pharmaceutical compositions comprising compounds of formula (I) and methods of using such compounds, for example, in the treatment of CNS-related disorders. JPEG2022504607000068.jpg4662(I)

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Patent Application No. 62 / 745,109, filed October 12, 2018, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] 2. Background of the Invention Brain excitability is defined as a continuum of states that ranges from the animal's level of arousal, from coma to convulsions, and is controlled by various neurotransmitters. In general, neurotransmitters are responsible for controlling the conductance of ions across the neuronal membrane. At rest, the neuronal membrane has an electrical potential (or membrane voltage) of approximately -70 mV, meaning that the inside of the cell is negative with respect to the outside of the cell. The electrical potential (voltage) is determined by the flow of ions (K + , Na + , Cl - Neurotransmitters are stored in presynaptic vesicles and are released under the influence of a nerve action potential. When released into the synaptic cleft, a potential shift occurs from -70 mV to -50 mV. This action is mediated by postsynaptic nicotinic receptors stimulated by acetylcholine, and is mediated by Na + Increases membrane permeability to ions. The decrease in membrane potential stimulates neuronal excitability in the form of postsynaptic action potentials.

[0003] In the case of the GABA receptor complex (GRC), the effect on brain excitability is mediated by the neurotransmitter gamma-aminobutyric acid (GABA). Since up to 40% of neurons in the brain utilize GABA as a neurotransmitter, GABA has a profound effect on global brain excitability. GABA controls the excitability of individual neurons by controlling the conductivity of chloride ions across the neuronal membrane. GABA interacts with its recognition site on the GRC to promote the flow of chloride ions up the electrochemical gradient of the GRC into the cell. An intracellular increase in the level of this anion causes hyperpolarization of the membrane potential, making neurons less sensitive to excitatory inputs, i.e., resulting in reduced neuronal excitability. In other words, the higher the concentration of chloride ions in neurons, the lower the level of brain excitability and arousal.

[0004] It is well documented that GRC mediates anxiety, seizure activity, and sedation. Thus, GABA and 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 regulatory sites on GRC. Nowadays, accumulating evidence shows that in addition to benzodiazepine and barbiturate binding sites, GRC contains separate sites for neuroactive steroids. See, for example, Lan, NC et al., Neurochem.Res.(1991)16:347-356.

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

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

[0007] For example, compounds are provided herein that are designed to act as GABA modulators.In some embodiments, such compounds are envisioned to be useful as therapeutic agents for treating CNS-related disorders. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] In one aspect, provided herein is a compound of formula (I): [ka] (I) or a pharma- ceutically acceptable salt thereof.

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

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

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

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

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

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

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

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

[0017] In one aspect, provided herein is a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula (I)) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically 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.

[0018] In one aspect, provided herein are pharma- ceutically acceptable salts of the compounds described herein (eg, compounds of Formula (I)).

[0019] In certain embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In certain embodiments, the compound is administered orally. In certain embodiments, the compound is administered chronically. In certain embodiments, the compound is administered continuously, for example, by continuous intravenous infusion.

[0020] The compounds of the invention as described herein may, in certain embodiments, be, for example, GABA A They act as GABA modulators, acting positively or negatively on GABA receptors. A As modulators of central nervous system (CNS) excitability mediated by their ability to modulate receptors, such compounds are predicted to have CNS activity.

[0021] In one aspect, described herein is a method of treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof.

[0022] In some embodiments, the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a seizure disorder, a disorder of memory and / or cognition, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder and / or withdrawal syndrome, tinnitus, or status epilepticus.

[0023] In some embodiments, the CNS-related disorder is depression. In some embodiments, the CNS-related disorder is postpartum depression. In some embodiments, the CNS-related disorder is major depressive disorder. In some embodiments, the major depressive disorder is moderate major depressive disorder. In some embodiments, the major depressive disorder is severe major depressive disorder.

[0024] In some embodiments, the compound is selected from the group consisting of the compounds identified in Table 1 herein.

[0025] Detailed Description of Certain Embodiments of the Invention As generally described herein, the present invention relates to a method for treating GABA A Provided is a compound designed to act as a receptor modulator.In certain embodiments, such compound is designed to be useful as a therapeutic agent for treating CNS-related disorders (e.g., disorders as described herein, such as depression, e.g., postpartum depression or major depressive disorder).

[0026] definition chemical definition Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are defined in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th In addition, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in detail in the following publications: Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Ed., 1999; and specific functional groups are generally defined as set forth therein. th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987.

[0027] Isomers, e.g., stereoisomers, can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention additionally encompasses the compounds described herein as individual isomers substantially free of other isomers, and alternatively as mixtures of various isomers.

[0028] "Stereoisomers": It should also be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are called "isomers". Isomers that differ in the arrangement of their atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of one another are called "diastereoisomers" and those that are non-superimposable mirror images of one another 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 described by the R- and S-ordering rules of Cahn and Prelog or by the way the molecule rotates the plane of polarized light and are designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers, respectively). Chiral compounds can exist as either individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0029] As used herein, a pure enantiomer compound is substantially free of other enantiomers or stereoisomers of said compound (i.e., in enantiomeric excess). In other words, the "S" forms of said compounds are substantially free of the "R" forms of said compounds and are thus in enantiomeric excess of the "R" forms. The term "enantiomerically pure" or "pure enantiomer" refers to the compound comprising 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% by weight of an enantiomer. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0030] In the compositions provided herein, the enantiomerically pure compounds may be present together with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure R site / center / carbon compound may, for example, comprise about 90% additive and about 10% enantiomerically pure R compound. In certain embodiments, the enantiomerically pure R compound in such a composition may, for example, comprise at least about 95% by weight of the R compound and at most 5% by weight of the S compound, based on the total weight of the compound. For example, a pharmaceutical composition comprising an enantiomerically pure S compound may, for example, comprise at least about 90% by weight of the additive and about 10% by weight of the enantiomerically pure S compound. In certain embodiments, the enantiomerically pure S compound in such a composition may, for example, comprise at least about 95% by weight of the S compound and at most 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 little or no additives or carriers.

[0031] As used herein, the term "diastereomeric purity" refers to the amount of a compound with the indicated absolute stereochemistry expressed as a percentage of the total amount of the indicated compound and its diastereomers. The term "diastereomerically pure" refers to the compound containing more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight, or more than 99.9% by weight of a diastereomer. Methods for determining diastereomeric and enantiomeric purity are well known in the art. Diastereomeric purity can be determined by any analytical method capable of quantitatively distinguishing between a compound and its diastereomer, for example, high performance liquid chromatography (HPLC).

[0032] The articles "a" and "an" may be used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an analog" means one analog or more than one analog.

[0033] When a range of values ​​is listed, it is intended to encompass each value and subrange within that range. For example, "C 1~6 Alkyl" is C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 , and C 5~6 Alkyl is intended to be included.

[0034] The following terms are intended to have the meanings ascribed thereto below and are useful in understanding the specification and the intended scope of the invention.

[0035] "Alkyl" refers to the radical of a straight or branched chain saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1~20 In some embodiments, the alkyl group has 1 to 12 carbon atoms ("C 1~12 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1~10 In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C 1~9 In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1~8 In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1~7In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C 1~6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1~5 In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C 1~4 In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1~3 In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1~2 In some embodiments, the alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2~6 "Alkyl"). C 1~6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents; for example, 1-5 substituents, 1-3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, the alkyl groups are unsubstituted C 1~10 In certain embodiments, the alkyl group is a substituted C 1~10 It is alkyl. Common abbreviations for alkyl include Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2).

[0036] "Alkylene" refers to an alkyl group in which two hydrogens have been removed to provide a divalent radical, and which may be substituted or unsubstituted. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), butylene (-CHCHCHCH-), pentylene (-CHCHCHCHCHCH-), hexylene (-CHCHCHCHCHCHCH-), and the like. For example, exemplary substituted alkylene groups substituted with one or more alkyl (methyl) groups include, but are not limited to, substituted methylene (-CH(CH)-, (-C(CH)-), substituted ethylene (-CH(CH)CH-, -CHCH(CH)-, -C(CH)CH-, -CHC(CH)-), substituted propylene (-CH(CH)CHCH-, -CHCH(CH)CH-, -CHCHCH(CH)-, -C(CH)CHCH-, -CHC(CH)CH-, -CHCHC(CH)-), and the like. When a range or number of carbons is given for a particular alkylene group, it is understood that the range or number refers to the range or number of carbons in a linear divalent carbon chain. An alkylene group can be unsubstituted or substituted with one or more substituents as described herein.

[0037] "Alkenyl" refers to the 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 In certain embodiments, the alkenyl does not contain any triple bonds. In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C 2~10 In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C2~8 In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, an alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). 2~4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2~6 Examples of alkenyl groups include those mentioned above. 2~4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, for example, 1-5 substituents, 1-3 substituents, or 1 substituent ("substituted alkenyl"). In certain embodiments, the alkenyl group is an unsubstituted C 2~10 In certain embodiments, the alkenyl group is a substituted C 2~10 It is alkenyl.

[0038] "Alkynyl" refers to the radical of a straight-chain or branched-chain hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) ("C 2~20 In certain embodiments, alkynyl does not contain any double bonds. In some embodiments, alkynyl groups have 2 to 10 carbon atoms ("C 2~10 In some embodiments, the alkynyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, the alkynyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, an alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). 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. 2~6 Examples of alkenyl groups include those mentioned above. 2~4 Alkynyl groups further include pentynyl (C5), hexynyl (C6) and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents, such as, for example, 1-5 substituents, 1-3 substituents, or 1 substituent ("substituted alkynyl"). In certain embodiments, the alkynyl group is an unsubstituted C 2~10 In certain embodiments, the alkynyl group is a substituted C 2~10 It is alkynyl.

[0039] The term "heteroalkyl" as used herein refers to an alkyl group, as defined herein, further comprising one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, said one or more heteroatoms being inserted between adjacent carbon atoms in the parent carbon chain and / or one or more heteroatoms being inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, a heteroalkyl group refers to a saturated group having 1-10 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~10 In some embodiments, a heteroalkyl group has 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~9 In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~8 In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~7 In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms ("heteroC 1~6In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms ("heteroC 1~5 In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms ("heteroC 1~4 In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and one heteroatom ("heteroC 1~3 In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom ("heteroC 1~2 In some embodiments, the heteroalkyl group is a saturated group having one carbon atom and one heteroatom ("heteroC1 alkyl"). In some embodiments, the heteroalkyl group is a saturated group having 2-6 carbon atoms and one or two heteroatoms ("heteroC 2~6 Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted ("unsubstituted heteroalkyl") or substituted ("substituted heteroalkyl") with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC 1~10 In certain embodiments, the heteroalkyl group is a substituted heteroalkyl group. 1~10 It is an alkyl.

[0040] "Aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in the cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system (see "C 6~14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl"; for example, naphthyl, e.g., 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C14 "Aryl"; e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups at the radical or point of attachment on the aryl ring, in which case the number of carbon atoms continues to designate the number of carbon atoms in the aryl ring system. Typical Aryl Groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene. In particular, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance 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 an unsubstituted C 6~14 In certain embodiments, the aryl group is a substituted C 6~14 It is aryl.

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

[0042] Representative examples of substituted aryl include: [ka] [In the formula, R 56 and R 57may be hydrogen, and R 56 and R 57 At least one of the above is independently selected from C1-C8 alkyl, C1-C8 haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 , N.R. 58 SOR 59 , N.R. 58 SO2R 59 , COO alkyl, COO aryl, CONR 58 R 59 ,CONR 58 OR 59 , N.R. 58 R 59 , SO2NR 58 R 59 , S-alkyl, SOalkyl, SO2alkyl, Saryl, SOaryl, SO2aryl; or R 56 and R 57 R may be joined together to form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O, or S. 60 and R 61 are independently hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, substituted C6-C 10 aryl, 5-10 membered heteroaryl, or substituted 5-10 membered heteroaryl.

[0043] "Fused aryl" refers to an aryl having two of its ring carbons in common with a second aryl or heteroaryl ring, or with a carbocyclyl or heterocyclyl ring.

[0044] "Heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in the cyclic arrangement) having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur, provided in the aromatic ring system ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be at any one of the carbons or rings, as valence permits. or nitrogen atom. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups whose point of attachment is on the heteroaryl ring, in which case the number of ring members continues to designate the number of ring members in that heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused to one or more aryl groups whose point of attachment is on either the aryl or heteroaryl ring, in which case the number of ring members continues to designate the number of ring members in that fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment may be on either ring, i.e., on the ring containing the heteroatom (e.g., 2-indolyl) or on the ring that does not contain a heteroatom (e.g., 5-indolyl).

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

[0046] 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-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0047] Representative examples of heteroaryls include: [ka] where each Z is a carbonyl, N, NR 65, O, and S; and R 65 are independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl.

[0048] "Carbocyclyl" or "carbocyclic" means a ring system having 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5~10 Carbocyclyl). 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), and the like. Exemplary C 3~8 Carbocyclyl groups include, but are not limited to, those described above for C 3~6 Carbocyclyl groups include cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C 3~10 Carbocyclyl groups include, but are not limited to, those described above for 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 As the above examples illustrate, in certain embodiments, the carbocyclyl groups are either monocyclic ("monocyclic carbocyclyl") or contain fused, bridged or spiro ring systems, such as bicyclic systems ("bicyclic carbocyclyl"), and may be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, in which case the point of attachment is on the carbocyclyl ring, The carbon number continues to designate the number of carbons in the carbocyclic ring structure. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, the carbocyclyl group is an unsubstituted C 3~10 In certain embodiments, the carbocyclyl group is a substituted C 3~10 It is a carbocyclyl.

[0049] In some embodiments, "carbocyclyl" is a monocyclic saturated carbocyclyl group having 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5~6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5~10 "Cycloalkyl"). C 5~6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3~6Examples of cycloalkyl groups include the above-mentioned C 5~6 Cycloalkyl groups further include cyclopropyl (C3) and cyclobutyl (C4). 3~8 Examples of cycloalkyl groups include the above-mentioned C 3~6 Cycloalkyl groups further include cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl") with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C 3~10 In certain embodiments, the cycloalkyl group is a substituted C 3~10 It is cycloalkyl.

[0050] "Heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and from 1 to 4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, as valence permits. Heterocyclyl groups may be either monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring structures, such as bicyclic systems ("bicyclic cyclocyclyl"), which may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring as defined above is fused to one or more carbocyclyl groups, either at the point of attachment on the carbocyclyl or heterocyclyl ring, or in which a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, at the point of attachment on the heterocyclyl ring, in which case the number of ring members continues to specify the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of a heterocyclyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-10 membered heterocyclyl.

[0051] In some embodiments, heterocyclyl groups are 5-10 membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10 membered heterocyclyl"). In some embodiments, heterocyclyl groups are 5-8 membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, heterocyclyl groups are 5-8 membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, heterocyclyl groups are 5-8 membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur. and a 5- to 6-membered non-aromatic ring system having an atom ("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 one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0052] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiorenyl. 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 pyrrolyl-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 (also referred to herein as 5,6-bicyclic heterocyclic rings) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc. Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclic rings) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0053] A "nitrogen-containing heterocyclyl" group refers to a 4-7 membered non-aromatic cyclic group containing at least one nitrogen atom, such as, but not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N-methylpiperazine. Particular examples include azetidine, piperidone, and piperazone.

[0054] "Hetero," when used to describe a compound or a group present on a compound, means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero can apply to any of the above hydrocarbyl groups having 1 to 5, especially 1 to 3, heteroatoms, such as alkyl, for example, heteroalkyl, cycloalkyl, for example, heterocyclyl, aryl, for example, heteroaryl, cycloalkenyl, for example, cycloheteroalkenyl, etc.

[0055] "Acyl" is the radical -C(O)R 20 where R 20 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl ... heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. "Alkanoyl" is an acyl group, where R 20 is a group other than hydrogen. Representative acyl groups include, but are not limited to, formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph), --C(O)-C1-C8 alkyl, -C(O)-(CH2) t (C6~C 10 Aryl), -C(O)-(CH2)t (5-10 membered heteroaryl), -C(O)-(CH2) t (C3~C 10 cycloalkyl), and -C(O)-(CH2) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4. In certain embodiments, R 21 is C1-C8 alkyl substituted with halo or hydroxy; or C3-C4 alkyl 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. 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 It is an aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl.

[0056] "Alkoxy" refers to the group -OR 29 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. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are lower, i.e., having 1 to 6 carbon atoms. Further particular alkoxy groups have 1 to 4 carbon atoms.

[0057] In certain embodiments, R 29 is amino, substituted amino, C6-C 10 Aryl, aryloxy, carboxyl, cyano, C3~C 10A group having one or more substituents selected from the group consisting of cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2-, and aryl-S(O)2-, for example, 1 to 5 substituents, particularly 1 to 3 substituents, and especially 1 substituent. Exemplary "substituted alkoxy" groups include, but are not limited to, -O-(CH2) t (C6~C 10 Aryl), -O-(CH2) t (5-10 membered heteroaryl), -O-(CH2) t (C3~C 10 cycloalkyl), and -O-(CH2) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl or heterocyclyl group present may itself be 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. Particular exemplary "substituted alkoxy" groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2NMe2.

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

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

[0060] "Substituted amino" refers to a group of the formula -N(R 38 )2, where R 38 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an amino protecting group, where R 38At least one of R is not hydrogen. 38 are independently hydrogen, C1-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C6-C 10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, 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 heterocyclyl), where t is an integer from 0 to 8, each of which is 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; or both R 38 The groups taken together form an alkylene group.

[0061] Exemplary "substituted amino" groups include, but are not limited to, -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 (4-10 membered heterocyclyl), where t is an integer from 0 to 4, e.g., 1 or 2, and each R 39independently represent H or C1-C8 alkyl; and any alkyl groups present may themselves be substituted by halo, substituted or unsubstituted amino, or hydroxy; any aryl, heteroaryl, cycloalkyl, or heterocyclyl groups present may themselves 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. For the avoidance of doubt, the term "substituted amino" includes the groups alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino, as defined below. Substituted amino includes both mono- and di-substituted amino groups.

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

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

[0064] "Halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, a halo group is either fluoro or chloro.

[0065] "Haloalkyl" refers to an alkyl radical in which the alkyl group is substituted with one or more halogens. Typical haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl, tetrafluoroethyl, and the like.

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

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

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

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

[0070] Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSRcc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2Raa , -OP(=O)2R aa , -P(=O)(R aa )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)2N(R bb )2, -OP(=O)2N(R bb )2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(NR bb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(R cc )3, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd or the two geminal hydrogens on the carbon atom are substituted with a group =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb , or =NOR cc is replaced by a group; R aa Each example of 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R aa The groups taken together represent a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl. ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with a group; R bb Each example is independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R bband the groups taken together form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with a group; R cc Each example is independently hydrogen, C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R cc and the groups taken together form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with a group; R dd Each example is independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NRff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)2R ee , -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg group or two geminal R dd The substituents together may form =O or =S; R ee Each example of 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently selected from 0, 1, 2, 3, 4, or 5 R gg is substituted with a group; R ff Each example is independently hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl and 5-10 membered heteroaryl, or two R ff The groups taken together form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring. wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg is substituted with a group; and R gg Each example is independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6 Alkyl, -ON(C 1~6 alkyl)2, -N(C 1~6 alkyl)2, -N(C 1~6 Alkyl)3 + X - , -NH(C 1~6 Alkyl)2 + X - , -NH2(C 1~6 Alkyl) + X - , -NH3 + X - , -N(OC 1~6 Alkyl)(C 1~6 alkyl), -N(OH)(C 1~6 alkyl), -NH(OH), -SH, -SC 1~6 Alkyl, -SS(C1~6 alkyl), -C(=O)(C 1~6 alkyl), -CO2H, -CO2(C 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -OCO2(C 1~6 alkyl), -C(=O)NH2, -C(=O)N(C 1~6 alkyl)2, -OC(=O)NH(C 1~6 alkyl), -NHC(=O)(C 1~6 alkyl), -N(C 1~6 Alkyl)C(=O)(C 1~6 alkyl), -NHCO2(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1~6 alkyl), -OC(=NH)(C 1~6 alkyl), -OC(=NH)OC 1~6 Alkyl, -C(=NH)N(C 1~6 alkyl)2, -C(=NH)NH(C 1~6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1~6 alkyl)2, -OC(NH)NH(C 1~6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1~6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1~6 Alkyl), -SO2N(C 1~6 Alkyl)2, -SO2NH(C 1~6 Alkyl), -SO2NH2, -SO2C 1~6 Alkyl, -SO2OC 1~6 Alkyl, -OSO2C 1~6 Alkyl, -SOC 1~6 Alkyl, -Si(C 1~6 alkyl)3, -OSi(C 1~6 Alkyl)3, -C(=S)N(C 1~6 alkyl)2, C(=S)NH(C 1~6 alkyl), C(=S)NH2, -C(=O)S(C 1~6 Alkyl), -C(=S)SC 1~6Alkyl, -SC(=S)SC 1~6 Alkyl, -P(=O)2(C 1~6 alkyl), -P(=O)(C 1~6 alkyl)2, -OP(=O)(C 1~6 Alkyl)2, -OP(=O)(OC 1~6 Alkyl)2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl; or two geminal R gg The substituents together may form =O or =S; where X - is the counter ion.

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

[0072] These and other exemplary substituents are described in more detail in the detailed description and claims, and the invention is not intended to be limited in any way by the recitation of exemplary substituents above.

[0073] Other definitions As used herein, the term "modulation" refers to the A The term "modulator" (e.g., a modulator compound) refers to the inhibition or enhancement of receptor function, e.g., GABA A Receptor A The therapeutic agent may be an agonist, partial agonist, antagonist, or partial antagonist.

[0074] "Pharmaceutically acceptable" means approved or approvable by a regulatory authority of the Federal or State government or the equivalent authority of a country other than the United States, or which is listed in the United States Pharmacopoeia or other generally recognized pharmacopoeias for use in animals, or more specifically, in humans.

[0075] "Pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or salts formed with organic acids, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-hydroxybenzoyl ... or (2) salts formed when an acidic proton present in the parent compound is either replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or coordinated to an organic base, e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc.; and, where the compound contains a basic functional group, salts of non-toxic organic or inorganic acids, e.g., hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc. The term "pharmacologically acceptable cation" refers to an acceptable cationic counterion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.See, e.g., Berge, et al., J. Pharm. Sci. (1977) 66(1):1-79.

[0076] The term "prodrug" is intended to encompass therapeutically inactive compounds that are converted to the therapeutically active agents of the present invention under physiological conditions. One method for making a prodrug is to design a selected moiety that is hydrolyzed or cleaved under physiological conditions at the targeted in vivo site of action to reveal the desired molecule, which then produces its therapeutic effect. In certain embodiments, the prodrug is converted by the enzymatic activity of the subject. In an alternative embodiment, the present invention provides a prodrug of the compound of formula (I), in which the prodrug contains a cleavable moiety on the C3 hydroxy as depicted in formula (I).

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

[0078] "Tautomers" refer to compounds that are interchangeable forms of a particular compound structure and that have changes in the displacement of hydrogen atoms and electrons. Thus, two structures can be in equilibrium through the shifting of pi electrons and one atom, usually H. For example, enols and ketones are tautomers; This is because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci and nitro forms of phenylnitromethane, which are also formed by treatment with acid or base. Tautomeric forms may be involved in achieving optimal chemical reactivity and biological activity of a compound of interest.

[0079] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly)) and / or non-human animals, e.g., mammals such as 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.

[0080] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen protecting groups include, but are not limited to, -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa ) 3、 -P(R cc )2, -P(R cc )3, -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)2N(R bb )2, and -P(=O)(NR bb )2, where R aa , R bb , and R cc is as defined herein. Oxygen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, TW Greene and PG M Huts, 3, incorporated herein by reference. rdThese include those described in detail in the 1999 edition of John Wiley & Sons.

[0081] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), 2-methoxyethoxymethyl (MEM), benzyl (Bn), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBDMS), t-butylmethoxyphenylsilyl (TBMPS), methanesulfonate (mesylate), and tosylate (Ts).

[0082] 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, but are not limited to, -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa ) 3、 -P(R cc )2, -P(R cc )3, -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)2N(R bb )2, and -P(=O)(NR bb )2, where R aa , R bb , and R ccis as defined herein. Sulfur protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Huts, 3rd Edition, incorporated herein by reference. rd These include those described in detail in the 1999 edition of John Wiley & Sons.

[0083] In certain embodiments, the substituent present on the nitrogen atom is an amino protecting group (also referred to as a nitrogen protecting group). Amino protecting groups include, but are not limited to, -OH, -OR aa , -N(R cc )2, -C(=O)R aa , -C(=O)OR aa , -C(=O)N(R cc )2, -S(=O)2R aa , -C(=NR cc )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl groups, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with an R aa , R bb , R cc and R ddis as defined herein. Amino protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Huts, 3rd Edition, incorporated herein by reference. rd These include those described in detail in the 1999 edition of John Wiley & Sons.

[0084] Exemplary amino protecting groups include, but are not limited to, 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-fluorenylmethylcarbamate (Fmoc), t-butylcarbamate (BOC), and benzylcarbamate (Cbz); sulfonamide groups (e.g., -S(=O)R aa ) (including but not limited to p-toluenesulfonamide (Ts), methanesulfonamide (Ms), and N-[2-(trimethylsilyl)ethoxy]methylamine (SEM)).

[0085] Disease, disorder, and condition are used interchangeably herein.

[0086] As used herein, and unless otherwise specified, the terms "treat", "treating" and "treatment" contemplate an action that occurs while a subject is suffering from a particular disease, disorder or condition that reduces the severity of the disease, disorder or condition, or slows or retards the progression of the disease, disorder or condition. In an alternative embodiment, the present invention contemplates administration of a compound of the present invention as a prophylaxis, prior to the onset of the specified disease, disorder or condition.

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

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

[0089] As used herein, and 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 the 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 a disease, disorder, or condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic effectiveness of another prophylactic agent.

[0090] compound It should be appreciated that the formulas set forth herein may refer to specific carbon atoms, e.g., C17, C3, C19, etc. These references are based on the position of the carbon atoms according to steroid nomenclature known and used in the art as shown below: [ka] For example, C17 refers to the 17th carbon and C3 refers to the 3rd carbon.

[0091] In one aspect, the present invention provides a compound of formula (I) [ka] (I) or a pharma- ceutically acceptable salt thereof. [In the formula, [ka] represents a single bond or a double bond, provided that when a double bond is present, R 6a or R 6b One of them is not present; R 1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -N(R A1 )2, -SR A1 , -C(=O)R A1 , -C(=O)OR A1 , -C(=O)SR A1 , -C(=O)N(R A1 )2, -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)N(R A1 )2, -OC(=O)SR A1 , -OS(=O)2R A1 , -OS(=O)2OR A1 , -OS(=O)2N(R A1 )2, -N(R A1 )C(=O)R A1 , -N(R A1 )C(=NR A1 )R A1 , -N(R A1 )C(=O)OR A1 , -N(R A1)C(=O)N(R A1 )2, -N(R A1 )C(=NR A1 ), N(R A1 )2, -N(R A1 )S(=O)2R A1 , -N(R A1 )S(=O)2OR A1 , -N(R A1 )S(=O)2N(R A1 )2, -SC(=O)R A1 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -S(=O)2R A1 , -S(=O)2OR A1 , or -S(=O)2N(R A1 )2, where R A1 Each instance of is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted or two R A1 the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring; R 2a , R 2b , R 4a , R 4b , R 7a , R 7b , R 11a , R 11b , R 12a , R 12b or R 17b each independently represents hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -N(R A1)2、-SR A1 、-C(=O)R A1 、-C(=O)OR A1 、-C(=O)SR A1 、-C(=O)N(R A1 )2、-OC(=O)R A1 、-OC(=O)OR A1 、-OC(=O)N(R A1 )2、-OC(=O)SR A1 、-OS(=O)2R A1 、-OS(=O)2OR A1 、-OS(=O)2N(R A1 )2、-N(R A1 )C(=O)R A1 、-N(R A1 )C(=NR A1 )R A1 、-N(R A1 )C(=O)OR A1 、-N(R A1 )C(=O)N(R A1 )2、-N(R A1 )C(=NR A1 )N(R A1 )2、-N(R A1 )S(=O)2R A1 、-N(R A1 )S(=O)2OR A1 、-N(R A1 )S(=O)2N(R A1 )2、-SC(=O)R A1 、-SC(=O)OR A1 、-SC(=O)SR A1 、-SC(=O)N(R A1 )2、-S(=O)2R A1 、-S(=O)2OR A1 、または-S(=O)2N(R A1 )2であり、ここで、R A1each instance of is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group if attached to oxygen, a nitrogen protecting group if attached to nitrogen, or a sulfur protecting group if attached to sulfur, or two R A1 the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring; R 3a 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; R 5 is hydrogen or methyl; [ka] If is a double bond, R 5 does not exist; R 6a and R 6b each of R is hydrogen, halogen, -CN, -NO2, -OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; or R 6a and R 6b together form an oxo (=O) group; R 15a , R 15b , R 16a and R 16b each independently represents hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR C3 , -N(R C3 )2, -SR C3 , -C(=O)R C3, -C(=O)OR C3 , -C(=O)SR C3 , -C(=O)N(R C3 )2, -OC(=O)R C3 , -OC(=O)OR C3 , -OC(=O)N(R C3 )2, -OC(=O)SR C3 , -OS(=O)2R C3 , -OS(=O)2OR C3 , -OS(=O)2N(R C3 )2, -N(R C3 )C(=O)R C3 , -N(R C3 )C(=NR C3 )R C3 , -N(R C3 )C(=O)OR C3 , -N(R C3 )C(=O)N(R C3 )2, -N(R C3 )C(=NR C3 )N(R C3 )2, -N(R C3 )S(=O)2R C3 , -N(R C3 )S(=O)2OR C3 , -N(R C3 )S(=O)2N(R C3 )2, -SC(=O)R C 3 , -SC(=O)OR C3 , -SC(=O)SR C3 , -SC(=O)N(R C3 )2, -S(=O)2R C3 , -S(=O)2OR C3 , or -S(=O)2N(R C3 )2, where R C3 each instance of is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group if attached to oxygen, a nitrogen protecting group if attached to nitrogen, or a sulfur protecting group if attached to sulfur, or two RC3 the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring; R 19 is a substituted or unsubstituted C3-C6 carbocyclyl or a substituted or unsubstituted aryl; and n is 0, 1 or 2].

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

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

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

[0095] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is substituted or unsubstituted alkyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] It is.

[0096] In some embodiments, R 1 teeth, [ka] wherein: R a Each example is independently hydrogen, halogen, -NO2, -CN, -OR D4 , -N(R D4 )2, -C(=O)R D4 , -C(=O)OR D4 , -C(=O)N(R D4 )2, -OC(=O)R D4 , -OC(=O)OR D4 , -N(R D4 )C(=O)R D4 , -OC(=O)N(R D4 )2, -N(R D4 )C(=O)OR D4 , -S(=O)2R D4 , -S(=O)2OR D4 , -OS(=O)2R D4 , -S(=O)2N(R D4 )2, or -N(R D4 )S(=O)2R D4 , 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 3~6 Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted C 5~10 aryl, substituted or unsubstituted 5-10 membered heteroaryl; R D4 Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~6 Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted substitution C5~10 an aryl, a substituted or unsubstituted 5- to 10-membered heteroaryl, an oxygen protecting group if attached to oxygen, a nitrogen protecting group if attached to nitrogen, or two R D4 the group, together with the intervening atoms, forms a substituted or unsubstituted heterocyclic ring; and and p is an integer selected from 0 to 11.

[0097] In some embodiments, R 1 teeth, [ka] selected from the group consisting of; Where: R a Each example is independently hydrogen, halogen, -NO2, -CN, -OR D4 , -N(R D4 )2, -C(=O)R D4 , -C(=O)OR D4 , -C(=O)N(R D4 )2, -OC(=O)R D4 , -OC(=O)OR D4 , -N(R D4 )C(=O)R D4 , -OC(=O)N(R D4 )2, -N(R D4 )C(=O)OR D4 , -S(=O)2R D4 , -S(=O)2OR D4 , -OS(=O)2R D4 , -S(=O)2N(R D4 )2, or -N(R D4 )S(=O)2R D4 , 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 3~6 Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted C 5~10 aryl, substituted or unsubstituted 5-10 membered heteroaryl; R D4Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~6 Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted C 5~10 an aryl, a substituted or unsubstituted 5- to 10-membered heteroaryl, an oxygen protecting group if attached to oxygen, a nitrogen protecting group if attached to nitrogen, or two R D4 the group, together with the intervening atoms, forms a substituted or unsubstituted heterocyclic ring; and and p is an integer selected from 0 to 11.

[0098] base R 2a and R 2b In some embodiments, R 2a and R 2b each independently represents hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR E5 , -OC(=O)R E5 , -OS(=O)2OR E5 , -N(R E5 )2, or -N(R E5 )C(=O)R E5 , -N(R E5 )S(=O)2 R E5 , -N(R E5 )S(=O)2OR E5 where R E5 Each example of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R E5 The groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring.

[0099] In some embodiments, R 2a and R 2b are each independently hydrogen, halogen, -CN, -NO2, -OR F6 , -OC(=O)R F6 , -N(R F6 )2, or -N(R F6 )C(=O)R F6 where R F6 Each instance of is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or two R F6 The groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring.

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

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

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

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

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

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

[0106] In some embodiments, R 3a is a substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0107] In some embodiments, R 3a is a substituted or unsubstituted C 1~6 It is an alkyl.

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

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

[0110] In some embodiments, R 3a teeth, [ka] It is.

[0111] In some embodiments, R 3a teeth, [ka] It is.

[0112] base R 4a and R 4b In some embodiments, R 4a and R 4beach independently represents hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR E5 , -OC(=O)R E5 , -OS(=O)2OR E5 , -N(R E5 )2, or -N(R E5 )C(=O)R E5 , -N(R E5 )S(=O)2R E5 , -N(R E5 )S(=O)2OR E5 where R E5 Each instance of is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R E5 The groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring.

[0113] In some embodiments, R 4a and R 4b are each independently hydrogen, halogen, -CN, -NO2, -OR F6 , -OC(=O)R F6 , -N(R F6 )2, or -N(R F6 )C(=O)R F6 where R F6 Each instance of is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or two R F6 The groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring.

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

[0115] In some embodiments, R 4a and R 4b each independently represents hydrogen, -OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, or C 1~6 It is an alkoxyhalo.

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

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

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

[0119] base R 5 In some embodiments, R 5 is R 19 In some embodiments, R 5 is R 19 In some embodiments, R 5 is R 19 In some embodiments, R 5 is R 19 It is a methyl in the trans position.

[0120] base R 6a and R 6b In some embodiments, R 6a and R 6b are independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. do.

[0121] In some embodiments, R 6a and R 6b is independently hydrogen or substituted alkyl.

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

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

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

[0125] In some embodiments, R 6a and R 6b Both are halos.

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

[0127] base R 7a and R 7b In some embodiments, R 7a and R 7b each independently represents hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR E5 , -OC(=O)R E5 , -OS(=O)2OR E5 , -N(R E5 )2, or -N(R E5 )C(=O)R E5 , -N(R E5 )S(=O)2R E5 , -N(R E5 )S(=O)2OR E5 where R E5Each instance of is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R E5 The groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring.

[0128] In some embodiments, R 7a and R 7b are each independently hydrogen, halogen, -CN, -NO2, -OR F6 , -OC(=O)R F6 , -N(R F6 )2, or -N(R F6 )C(=O)R F6 where R F6 Each instance of is independently hydrogen, substituted or unsubstituted. alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or two R F6 The groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring.

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

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

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

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

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

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

[0135] In some embodiments, R 11a and R 11b are each independently hydrogen, halogen, -CN, -NO2, -OR F6 , -OC(=O)R F6 , -N(R F6)2, or -N(R F6 )C(=O)R F6 where R F6 Each instance of is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or two R F6 The groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring.

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

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

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

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

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

[0141] base R 12a and R 12b In some embodiments, R 12a and R 12beach independently represents hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR E5 , -OC(=O)R E5 , -OS(=O)2OR E5 , -N(R E5 )2, or -N(R E5 )C(=O)R E5 , -N(R E5 )S(=O)2R E5 , -N(R E5 )S(=O)2OR E5 where R E5 Each instance of is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R E5 The groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring.

[0142] In some embodiments, R 12a and R 12b are each independently hydrogen, halogen, -CN, -NO2, -OR F6 , -OC(=O)R F6 , -N(R F6 )2, or -N(R F6 )C(=O)R F6 where R F6 Each instance of is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl ... or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or two R F6 The groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring.

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

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

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

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

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

[0148] base R 17b In some embodiments, R 17b is fluorine, hydroxyl, methyl, or hydrogen; where hydrogen may be optionally replaced by deuterium. In some embodiments, R 17b is hydrogen.

[0149] base R 19 In some embodiments, R 19 is a substituted or unsubstituted C 3~6 Carbocyclyl, or substituted or unsubstituted C 6~10 In some embodiments, R 19 is a substituted or unsubstituted C 3~6 In some embodiments, R 19 is cyclopropyl.

[0150] In some embodiments, R 19is a substituted or unsubstituted C 3~6 It is a carbocyclyl.

[0151] In some embodiments, R 19 is a substituted or unsubstituted C 6~10 It is aryl.

[0152] In some embodiments, R 19 teeth, [ka] selected from the group consisting of; Where: R b Each example is independently hydrogen, halogen, -NO2, -CN, -OR G7 , -N(R G7 )2, -C(=O)R G7 , -C(=O)OR G7 , -C(=O)N(R G7 )2, -OC(=O)R G7 , -OC(=O)OR G7 , -N(R G7 )C(=O)R G7 , -OC(=O)N(R G7 )2, -N(R G7 )C(=O)OR G7 , -S(=O)2R G7 , -S(=O)2OR G7 , -OS(=O)2R G7 , -S(=O)2N(R G7 )2, or -N(R G7 )S(=O)2R G7 , substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or is unsubstituted C 3~6 Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted C 5~10 aryl, substituted or unsubstituted 5-10 membered heteroaryl; R G7 Each instance of is independently hydrogen, substituted or unsubstituted C 1~6Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~6 Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted C 5~10 an aryl, a substituted or unsubstituted 5- to 10-membered heteroaryl, an oxygen protecting group if attached to oxygen, a nitrogen protecting group if attached to nitrogen, or two R G7 the group, together with the intervening atoms, forms a substituted or unsubstituted heterocyclic ring; and q is an integer selected from 0 to 11.

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

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

[0155] base R 16a and R 16b In some embodiments, R 16a and R 16beach independently represents hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR C3 , -N(R C3 )2, -SR C3 , -C(=O)R C3 , -C(=O)OR C3 , -C(=O)SR C3 , -C(=O)N(R C3 )2, -OC(=O)R C3 , -OC(=O)OR C3 , -OC(=O)N(R C3 )2, -OC(=O)SR C3 , -OS(=O)2R C3 , -OS(=O)2OR C3 , -OS(=O)2N(R C3 )2, -N(R C3 )C(=O)R C3 , -N(R C3 )C(=NR C3 )R C3 , -N(R C3 )C(=O)OR C3 , -N(R C3 )C(=O)N(R C3 )2, -N(R C3 )C(=NR C3 ), N(R C3 )2, -N(R C3 )S(=O)2R C3 , -N(R C3 )S(=O)2OR C3 , -N(R C3 )S(=O)2N(R C3 )2, -SC(=O)R C3 , -SC(=O)OR C3 , -SC(=O)SR C3 , -SC(=O)N(R C3 )2, -S(=O)2R C3 , -S(=O)2OR C3 , or -S(=O)2N(R C3 )2, where RC3 each instance of is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group if attached to oxygen, a nitrogen protecting group if attached to nitrogen, or a sulfur protecting group if attached to sulfur, or two R C3 The groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring.

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

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

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

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

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

[0161] In some embodiments, the compound of formula (I) is a compound of formula (Id): [ka] (Id) or a pharma- ceutically acceptable salt thereof, a each instance of is independently halogen, cyano, hydroxyl, or substituted or unsubstituted alkyl; and p is 0, 1, 2, or 3.

[0162] In some embodiments, the compound of formula (I) is a compound of formula (Ie): [ka] (Ie) or a pharma- ceutically acceptable salt thereof, Each X is independently -C(R N )-, -C(R N )2-, -O-, -S-, -N-, or N(R N )-, where R N are independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, C(=O)R GA , -C(=O)OR GA , -C(=O)N(R GA )2, -S(=O)2R GA , or -S(=O)2N(R GA )2;R GA Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~6 Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group if attached to oxygen, a nitrogen protecting group if attached to nitrogen, or two R GAThe groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclyl or heteroaryl ring.

[0163] In some embodiments, the compound of formula (I) is a compound of formula (If): [ka] (If) or a pharma- ceutically acceptable salt thereof, Each X is independently -C(R N )-, -C(R N )2-, -O-, -S-, -N-, or N(R N )-, where R N are independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, C(=O)R GA , -C(=O)OR GA , -C(=O)N(R GA )2, -S(=O)2R GA , or -S(=O)2N(R GA )2;R GA Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~6 carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group if attached to oxygen, a nitrogen protecting group if attached to nitrogen, or two R GA The groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclyl or heteroaryl ring.

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

[0165] In some embodiments, the compound of formula (I) is a compound of formula (Ih): [ka] (Ih) or a pharma- ceutically acceptable salt thereof, Each X is independently -C(R N )-, -C(R N )2-, -O-, -S-, -N-, or N(R N )-, where R N are independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, C(=O)R GA , -C(=O)OR GA , -C(=O)N(R GA )2, -S(=O)2R GA , or -S(=O)2N(R GA )2;R GA Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~6 carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group if attached to oxygen, a nitrogen protecting group if attached to nitrogen, or two R GA The groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclyl or heteroaryl ring.

[0166] In one aspect, provided herein is a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula (I)) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically 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.

[0167] In one aspect, provided herein are pharma- ceutically acceptable salts of the compounds described herein (eg, compounds of Formula (I)).

[0168] In certain embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In certain embodiments, the compound is administered orally. In certain embodiments, the compound is administered chronically. In certain embodiments, the compound is administered continuously, for example, by continuous intravenous infusion.

[0169] The compounds of the invention as described herein may, in certain embodiments, be, for example, GABA A They act as GABA modulators, acting positively or negatively on GABA receptors. A As modulators of central nervous system (CNS) excitability mediated by their ability to modulate receptors, such compounds are predicted to have CNS activity.

[0170] In one aspect, described herein is a method of treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof.

[0171] In some embodiments, the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a seizure disorder, a memory and / or cognition disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder, and / or a withdrawal syndrome. , tinnitus, or status epilepticus.

[0172] In some embodiments, the CNS-related disorder is depression. In some embodiments, the CNS-related disorder is postpartum depression. In some embodiments, the CNS-related disorder is major depressive disorder. In some embodiments, the major depressive disorder is moderate major depressive disorder. In some embodiments, the major depressive disorder is severe major depressive disorder.

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

[0174] Exemplary compounds of the invention can be synthesized from known starting materials using methods known to those skilled in the art or certain references. In one aspect, provided herein are pharma- ceutically acceptable salts of the compounds described herein (e.g., compounds of Formula (I)).

[0175] Alternative Embodiments In an alternative embodiment, the compounds described herein may contain one or more isotopic substitutions. For example, hydrogen can be: 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 may be, for example, 15 In other embodiments, a particular isotope (e.g., 3 H, 13 C. 14 C. 18 O, or 15N) may be at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of the elements occupying a specific site in said compound.

[0176] Pharmaceutical Compositions In one aspect, provided herein is a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula (I)) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically 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.

[0177] In certain embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a prophylactically effective amount of the active ingredient.

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

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

[0180] When used to prevent the onset of CNS disorders, the compounds provided herein will be administered at the dosage levels described above, typically under the advice and supervision of a physician, to subjects at risk of developing the condition.Subjects at risk of developing a particular condition generally include those who have a family history of the condition, or those who have been identified by genetic testing or screening as being particularly susceptible to developing the condition.

[0181] The pharmaceutical composition provided herein can also be administered chronically ("chronic administration").Chronic administration refers to administration of the compound or its pharmaceutical composition for a long period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or can continue indefinitely, for example, for the rest of a subject's life.In certain embodiments, the chronic administration is intended to provide a constant blood concentration of the compound, for example, within the therapeutic range, for a long period of time.

[0182] The pharmaceutical composition of the present invention can also be delivered using various administration methods. For example, in certain embodiments, the pharmaceutical composition can be given as a bolus, for example, to raise the concentration of the compound in the blood to an effective level. The placement of the bolus dose depends on the systemic level of the active ingredient desired in the whole body, for example, an intramuscular or subcutaneous bolus dose allows for a sustained release of the active ingredient, while a bolus delivered directly to a vein (for example, by intravenous drip) allows for a fairly fast delivery that quickly 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, for example, by intravenous drip, to maintain a steady-state concentration of the active ingredient in the subject's body. Furthermore, in still other embodiments, the pharmaceutical composition can be administered as a bolus dose first, followed by a continuous infusion.

[0183] The composition for oral administration may take the form of a bulk liquid solution or suspension, or a mixed powder. More commonly, however, the composition is provided in a unit dosage form to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable for unitary dosing for human subjects and other mammals, where each unit contains a predetermined amount of active material calculated to produce a desired therapeutic effect, together with suitable pharmaceutical excipients. A typical unit dosage form is The dosage forms include prefilled or premeasured ampoules or syringes of the liquid compositions or pills, tablets, capsules in the case of solid compositions. In such compositions, the compound is usually a minor component (about 0.1 to about 50% by weight or preferably 1 to 40% by weight), with the remainder being various vehicles or additives and processing aids that help to form the desired dosage form.

[0184] For oral dosing, a typical regimen is 1-5 times, particularly 2-4 times, typically 3 times per day. Using these dosing patterns, each dose provides about 0.01 to about 20 mg / kg of the compound provided herein, with preferred doses providing about 0.1 to about 10 mg / kg, particularly about 1 to about 5 mg / kg, respectively.

[0185] A transdermal dose is generally selected in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, more preferably from about 0.5 to about 15% by weight, to provide a blood concentration similar to or lower than that achieved using an injectable dose.

[0186] Injection dose levels range from about 0.1 mg / kg / hour to at least about 20 mg / kg / hour, total for about 1 to about 120 hours, particularly 24 to 96 hours. A preload bolus of about 0.1 mg / kg to about 10 mg / kg or more may be administered to achieve sufficient steady state concentrations. Maximum total doses are not expected to exceed about 5 g / day in a 40-80 kg human patient.

[0187] Liquids suitable for oral administration may include a suitable aqueous or nonaqueous vehicle, including buffers, suspending and dispensing agents, colorants, flavorings, etc. Solids may include, for example, any of the following ingredients, or compounds of a similar nature: binders such as microcrystalline cellulose, tragacanth, or gelatin; additives such as starch or lactose; disintegrating agents such as alginic acid, primogel, or corn starch; lubricants such as magnesium stearate; flow enhancers such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavoring.

[0188] Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline or other injectable additives known in the art. As previously mentioned, the active compound in such compositions is typically a minor component, often about 0.05-10% by weight, with the remainder being the injectable additives and the like.

[0189] 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 mixed with either a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream, for example with an oil-in-water cream base. Such transdermal formulations are well known in the art and generally contain additional ingredients to enhance the stability of the skin penetration of the active ingredient or formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.

[0190] The compounds provided herein can also be administered by a transdermal device.Thus, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.

[0191] The above components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials and processing techniques may be found in Part 8, which is incorporated herein by reference. of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania.

[0192] The compounds of the invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0193] The present invention also relates to pharma- ceutically acceptable acid addition salts of the compounds of the present invention. Acids that can be used to prepare pharma- ceutically acceptable salts are those which produce non-toxic acid addition salts, i.e., salts containing pharma- ceutically acceptable anions, such as hydrochloric acid, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, and the like.

[0194] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharma- ceutically acceptable excipient, e.g., a composition suitable for injection, such as for intravenous (IV) administration.

[0195] Pharmaceutically acceptable excipients include any and all diluents or other liquid vehicles suitable for the particular dosage form desired, e.g., injections, dispersion or suspension aids, surface active agents, isotonicity agents, preservatives, lubricants, etc. General information on the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy,21 st Edition (Lippincott Williams & Wilkins, 2005).

[0196] For example, injectable preparations, such as sterile injectable aqueous suspensions, can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. Exemplary excipients that can be used include, but are not limited to, water, sterile saline or phosphate-buffered saline, or Ringer's solution.

[0197] In certain embodiments, the pharmaceutical composition further comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, which consist of 6, 7, and 8 α-1,4-linked glucose units, respectively, and optionally contain one or more substituents (including but not limited to substituted or unsubstituted methylation, hydroxyalkylation, acylation, and sulfoalkyl ether substitution) on the linked sugar moiety. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, also known as CAPTISOL®. See, for example, US Pat. No. 5,376,645. In certain embodiments, the composition comprises hexapropyl-β-cyclodextrin. In more particular embodiments, the composition comprises hexapropyl-β-cyclodextrin (10-50% aqueous solution).

[0198] The injectable compositions can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0199] In general, the compounds provided herein are administered in an effective amount. The amount of the compound actually administered will typically be determined by a physician depending on the condition being treated, the selected route of administration, the dosage form being administered, and the dosage form used. The dosage will be determined taking into account the actual compound being administered and the relevant circumstances including the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0200] The composition is provided in a unit dosage form to facilitate accurate dosing. The term "unit dosage form" refers to a physically separate unit suitable for unitary dosing for human subjects and other mammals, where each unit contains a predetermined amount of active material calculated to produce a desired therapeutic effect, together with suitable pharmaceutical excipients. Typical unit dosage forms include prefilled or premeasured ampoules or syringes of the liquid composition. In such compositions, the compound is usually a minor component (about 0.1 to about 50% by weight or preferably 1 to 40% by weight), where the remainder are various vehicles or carriers and processing aids that serve to form the desired dosage form.

[0201] The compounds provided herein can be administered as the only active agent, or they can be administered in combination with other active agents. In one aspect, the present invention provides a combination of a compound of the present invention and another pharmacologically active agent. The administration of the combination can be by any technique apparent to those skilled in the art, including, for example, separate, sequential, simultaneous, and alternating administration.

[0202] Although the description of pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for administration to humans, it will be understood by those skilled in the art that such compositions are generally suitable for administration to any type of animal. Modifications of pharmaceutical compositions suitable for administration to humans to make such compositions suitable for administration to a variety of animals are well understood, and veterinary pharmacologists of ordinary skill in the art can design and / or perform such modifications with routine experimentation. A general discussion of the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21 st ed., Lippincott Williams & Wilkins, 2005.

[0203] In one aspect, a kit is provided that includes a composition (eg, a solid composition) that includes a compound of formula (I).

[0204] Methods of Use and Treatment In one aspect, the compounds described herein, e.g., compounds of Formula (I), are contemplated to be useful as therapeutic agents for treating a CNS-related disorder (e.g., a sleep disorder, a mood disorder such as depression, a schizophrenia spectrum disorder, a seizure disorder, an epileptic seizure, a disorder of memory and / or cognition, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder and / or withdrawal syndrome, or tinnitus) in a subject in need thereof (e.g., a subject having Rett Syndrome, Fragile X Syndrome, or Angelman Syndrome). Exemplary CNS conditions associated with GABA modulation include, but are not limited to, sleep disorders [e.g., insomnia], mood disorders [e.g., depression, (e.g., major depressive disorder (MDD)), dysthymic disorder (e.g., minor depression), bipolar disorder (e.g., I and / or II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (e.g., obsessive-compulsive disorder (OCD))], schizophrenia spectrum disorders [e.g., schizophrenia, schizoaffective disorder], seizure disorders [e.g., , epilepsy (e.g., status epilepticus (SE)), seizures)], memory and / or cognitive disorders [e.g., attention disorders (e.g., attention deficit hyperactivity disorder (ADHD)), dementia (e.g., Alzheimer's disease, dementia with Lewy bodies, vascular dementia], movement disorders [e.g., Huntington's disease, Parkinson's disease], personality disorders [e.g., antisocial personality disorder, obsessive-compulsive personality disorder], autism spectrum disorder (ASD) [e.g., autism, monogenic causes of autism such as synaptophathy, e.g., Rett syndrome, fragile syndrome, Angelman syndrome], pain (e.g., neuropathic pain, trauma-related pain syndrome, acute gout, chronic pain), traumatic brain injury (TBI), vascular disease (e.g., stroke, ischemic vascular malformation), substance abuse disorders and / or withdrawal syndromes (e.g., opiate, cocaine, and / or alcohol dependence), and tinnitus.

[0205] In certain embodiments, the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a memory and / or cognitive disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain disorder, a vascular disease, a substance abuse disorder and / or withdrawal syndrome, tinnitus, or status epilepticus. In certain embodiments, the CNS-related disorder is depression. In certain embodiments, the CNS-related disorder is postpartum depression. In certain embodiments, the CNS-related disorder is major depressive disorder. In certain embodiments, the major depressive disorder is moderate major depressive disorder. In certain embodiments, the major depressive disorder is severe major depressive disorder.

[0206] In one aspect, there is provided a method of alleviating or preventing seizure activity in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the invention, hi some embodiments, the method alleviates or prevents epileptic seizures.

[0207] In another aspect, a combination of a compound of the present invention and another pharmacologically active agent is provided. The compounds provided herein can be administered as the only active agent, or they can be administered in combination with other agents. The administration of the combination can be performed by any technique obvious to those skilled in the art, including, for example, separate, sequential, simultaneous, and alternating administration.

[0208] In another aspect, there is provided a method of treating or preventing brain excitability in a subject susceptible to or suffering from a condition associated with brain excitability, comprising administering to said subject an effective amount of a compound of the invention.

[0209] In yet another aspect, there is provided a method of treating or preventing stress or anxiety in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the invention, or a composition thereof.

[0210] In yet another aspect, there is provided a method of alleviating or preventing insomnia in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the invention, or a composition thereof.

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

[0212] In yet another aspect, there is provided a method of alleviating or preventing premenstrual syndrome (PMS) or postpartum depression (PND) in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the invention.

[0213] In another aspect, a method of treating or preventing a mood disorder in a subject is provided, comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention. In certain embodiments, the mood disorder is depression.

[0214] In another aspect, cognitive impairment is improved by administering to a subject a therapeutically effective amount of a compound of the invention. The present invention provides a method for enhancing memory loss or treating memory disorders. In certain embodiments, the disorder is Alzheimer's disease. In certain embodiments, the disorder is Rett Syndrome.

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

[0216] In certain embodiments, the compound is administered chronically to the subject. In certain embodiments, the compound is administered orally, subcutaneously, intramuscularly, or intravenously to the subject.

[0217] Neuroendocrine Disorders and Dysfunction Provided herein are methods that can be used to treat neuroendocrine disorders and dysfunctions. As used herein, "neuroendocrine disorder" or "neuroendocrine dysfunction" refers to various conditions resulting from an imbalance in the body's hormone production that is directly related to the brain. Neuroendocrine disorders involve interactions between the nervous system and the endocrine system. The hypothalamus and pituitary gland are two areas of the brain that control the production of hormones, so damage to the hypothalamus or pituitary gland, for example, from traumatic brain injury, can affect the production of hormones 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 ovarian syndrome.

[0218] Symptoms of neuroendocrine disorders include, but are not limited to, behavioral, emotional and sleep-related symptoms, symptoms related to reproductive function, and physical symptoms; including, but not limited to, fatigue, poor memory, anxiety, depression, weight gain or loss, emotional lability, lack of concentration, difficulty paying attention, loss of lipido, 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.

[0219] Neurodegenerative Diseases and Disorders The methods described herein can be used to treat neurodegenerative diseases and disorders. The term "neurodegenerative disease" includes diseases and disorders associated with the progressive loss of neuronal structure or function, or death of neuronal cells. Neurodegenerative diseases and disorders include, but are not limited to, Alzheimer's disease (including associated symptoms of mild, moderate or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic and ischemic injuries; ataxia and seizures (including for treatment and prevention, and for the prevention of seizures caused by schizoaffective disorder or by drugs used to treat schizophrenia); benign amnesia; cerebral edema; cerebellar ataxia (including McLeod neuroacanthocytosis syndrome (MLS)); closed head injury; coma; contusion injuries (e.g., spinal cord injury and head injury); dementia (including multi-infarct dementia and senile dementia); impairment of consciousness; Down's syndrome; drug-induced or pharmacologically induced parkinsonism (e.g., psycholeptic-induced acute akathisia, acute ataxia, parkinsonism or tardive dyskinesia). dyskinesia, neuroleptic malignant syndrome, or drug-induced postural tremor; epilepsy; fragile X syndrome; Gilles de la Tourette syndrome; head trauma; hearing impairment and hearing loss; Huntington's disease; Lennox syndrome; levodopa-induced dyskinesia; mental retardation; movement disorders including akinesia and akinetic (rigid) syndromes (including brain stem neurocalcification, corticobasal degeneration, multiple atrophy, Parkinsonism-ALS dementia complex, Parkinson's disease, postencephalitic parkinsonism, and progressive supranuclear palsy); muscle spasms and disorders associated with muscle spasticity or weakness (chorea (e.g. benign hereditary chorea, drug-induced chorea, hemiballismus, Huntington's disease, neuroacanthocytosis, Sydenham chorea, and symptomatic chorea), dyskinesias (including tics such as complex tics, simple tics, and symptomatic tics), myoclonus ( tremors (e.g., resting, postural and intention tremors) and ataxias (axial ataxia, dystonic writer's cramp, hemiplegic ataxia, paroxysmal ataxia and focal ataxias (e.g., blepharospasm, oromandibular dystonia) Neurodegenerative diseases include, but are not limited to, stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia, and neurotoxicity following cardiac arrest; Parkinson's disease; seizures; status epilepticus; stroke; tinnitus; renal tubular sclerosis; and viral infection-induced neurodegeneration (e.g., caused by acquired immune deficiency syndrome (AIDS) and brain damage). Neurodegenerative diseases also include, but are not limited to, stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia, and neurotoxicity following cardiac arrest. Methods of treating or preventing a neurodegenerative disease also include treating or preventing the loss of neuronal function that is characteristic of a neurodegenerative disorder.

[0220] Mood disorders Also provided herein are methods for treating mood disorders, such as clinical depression, postnatal or postpartum depression, perinatal depression, atypical depression, melancholic depression, psychotic major depression, catatonic depression, seasonal affective disorder, dysthymia, bipolar depression, depressive personality disorder, recurrent brief depression, minor depressive disorder, bipolar or manic depression disorder, depression due to chronic medical conditions, treatment-resistant depression, refractory depression, suicidal tendencies, suicidal ideation, or suicidal behavior. In some embodiments, the methods described herein provide a therapeutic benefit to a subject suffering from depression (e.g., moderate or severe depression). In some embodiments, the mood disorder is associated with a disease or disorder described herein (e.g., neuroendocrine diseases and disorders, neurodegenerative diseases and disorders (e.g., epilepsy), movement disorders, tremors (e.g., Parkinson's disease), women's health disorders or conditions).

[0221] Clinical depression, also known as major depression, major depressive disorder (MDD), severe depression, unipolar depression, unipolar disorder and recurrent depression, refers to a mental disorder characterized by a pervasive and persistent low mood, accompanied by low self-esteem and loss of interest or pleasure in activities that are usually enjoyed. Some people with clinical depression have trouble sleeping, lose weight, generally feel agitated and feel 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 struggle to carry out daily activities and may feel as if life is not worth living.

[0222] Perinatal depression refers to depression during pregnancy. Symptoms include irritability, crying, restlessness, sleep problems, exhaustion (emotional and / or physical), appetite changes, difficulty concentrating, increased anxiety and / or worry, feeling unconnected with the baby and / or fetus, and loss of interest in previously enjoyed activities.

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

[0224] In some embodiments, the subject with PND also has symptoms of depression or depression during pregnancy. This depression is referred to herein as perinatal depression. In one embodiment, subjects experiencing perinatal depression are at high risk of experiencing PND.

[0225] Atypical depression (AD) is characterized by mood reactivity (e.g., paradoxical anhedonia) and aggressiveness, as well as marked weight gain or increased appetite. Patients with AD may also have significant social impairments as a result of excessive sleepiness or somnolence (hypersomnia), a feeling of heaviness in the limbs, and hypersensitivity to perceived interpersonal rejection.

[0226] Melancholic depression is characterized by loss of pleasure from most or all activities (anhedonia), unresponsiveness to pleasurable stimuli, a depressed mood that is more pronounced than feelings of sadness or loss, excessive weight loss, or excessive feelings of guilt.

[0227] Psychotic major depression (PMD) or psychotic depression refers to a major depressive episode, particularly one of a melancholic nature, in which an individual experiences psychotic symptoms such as delusions and hallucinations.

[0228] Catatonic depression refers to major depression accompanied by disturbances in motor behavior and other symptoms. Individuals may become mute and stuporous, become immobile, or exhibit purposeless or bizarre movements.

[0229] Seasonal Affective Disorder (SAD) refers to a type of seasonal depression in which an individual has a seasonal pattern of depressive episodes that begin occurring in the fall or winter.

[0230] Dysthymia refers to a condition related to unipolar depression in which the same physical and cognitive problems are evident. They tend to be less severe and last longer (e.g., at least 2 years).

[0231] Dual depression refers to a very depressed mood (dysthymia) lasting at least 2 years and occasionally interrupted by periods of major depression.

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

[0233] Recurrent Brief Depression (RBD) refers to a condition in which an individual has depressive episodes approximately once per month, with each episode lasting no more than two weeks, typically less than two to three days.

[0234] Minor depressive disorder or minor depression refers to depression in which at least two symptoms are present for two weeks.

[0235] Bipolar or manic-depressive disorder causes extreme mood swings that include high emotions (mania or hypomania) and low emotions (depression). During manic periods, individuals may feel or act unusually happy, energetic, or irritable. They often make ill-considered decisions with little regard for the consequences. There is usually a decreased need for sleep. During periods of depression, individuals may cry a lot, make less eye contact with others, and have a negative outlook on life. The risk of suicide for those with the disorder is high at over 6% over a 20-year period, and 30-40% will self-harm. Other mental health problems, such as anxiety disorders and substance use disorders, commonly coexist with bipolar disorder.

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

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

[0238] Postoperative depression refers to feelings of depression following surgery (e.g., as a result of facing one's own mortality). For example, an individual may experience persistent feelings of sadness or emptiness, loss of enjoyment or interest in hobbies and activities that they normally enjoy, or persistent feelings of worthlessness or hopelessness.

[0239] A mood disorder associated with a women's health condition or disorder refers to a mood disorder (eg, depression) associated with (eg, resulting from) a women's health condition or disorder (eg, as described herein).

[0240] Suicidal tendencies, suicidal ideation, and suicidal behavior refer to an individual's tendency to commit suicide. Suicidal ideation involves thoughts about suicide or an abnormal obsession with suicide. The spectrum of suicidal ideation varies widely, for example, from passing thoughts to widespread thoughts, detailed plans, role-playing, and aborted attempts. Symptoms may include talking about suicide, obtaining the means to commit suicide, withdrawing from social contacts, preoccupying with death, feeling trapped or hopeless about a situation, increased alcohol or drug use, doing dangerous or self-destructive things, and saying goodbye to people as if they will never see each other again.

[0241] Symptoms of depression include persistent anxious or sad feelings, helpless feelings, hopelessness, pessimism, worthlessness, low energy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, motor challenges, loss of interest in pleasurable activities or hobbies, poor concentration, low energy, low self-esteem, lack of positive thoughts or plans, excessive sleeping, overeating, loss of appetite, insomnia, self-harm, thoughts of suicide and suicide attempts. The presence, severity, frequency and duration of symptoms may vary from case to case. Depression symptoms and their relief may be confirmed by a doctor or psychologist (e.g., mental status examination).

[0242] In some embodiments, the method includes monitoring the subject with known depression scales, such as the Hamilton Depression (HAM-D) scale, Clinical Global Impression-Improvement (CGI), and Montgobery-Asberg Depression Rating Scale (MADRS). In some embodiments, the therapeutic effect can be determined by the reduction in the Hamilton Depression (HAM-D) total score exhibited by the subject. The reduction in the HAM-D total score can occur within 4, 3, 2, or 1 day; or within 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, 8 hours or less. The therapeutic effect can be evaluated throughout the designated treatment period. For example, the therapeutic effect can be determined by the reduction in HAM-D total score from baseline following administration of a compound described herein, e.g., a compound of Formula (I) (e.g., 12, 24, or 48 hours after administration; or 24, 48, 72, or 96 hours or more; or 1 day, 2 days, 14 days, 21 days, or 28 days; or 1 week, 2 weeks, 3 weeks, or 4 weeks; or 1 month, 2 months, 6 months, or 10 months; or 1 year, 2 years, or over a lifetime).

[0243] In some embodiments, the subject has a mild depressive disorder, e.g., a mild major depressive disorder. In some embodiments, the subject has a moderate depressive disorder, e.g., a moderate major depressive disorder. In some embodiments, the subject has a severe depressive disorder, e.g., a severe major depressive disorder. In some embodiments, the subject has a very severe depressive disorder, e.g., a very severe major depressive disorder. In some embodiments, the subject has a baseline HAM-D total score (i.e., before treatment with a compound described herein, e.g., a compound of Formula (I)) of at least 24. In some embodiments, the subject has a baseline HAM-D total score of at least 18. In some embodiments, the subject has a baseline HAM-D total score of between, inclusive, 14-18. In some embodiments, the subject has a baseline HAM-D total score of between, inclusive, 19-22. In some embodiments, the subject has a HAM-D total score of 23 or greater, inclusive, before treatment with a compound described herein, e.g., a compound of Formula (I). In some embodiments, the baseline score is at least 10, 15, or 20. In some embodiments, the subject has 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 subject has a HAM-D total score of less than 10, 7, 5, or 3 after treatment with a compound described herein, e.g., a compound of Formula (I). In some embodiments, the reduction in HAM-D total score is from a baseline score of about 20-30 (e.g., 22-28, 23-27, 24-27, 25-27, 26-27) to a HAM-D total score of about 0-10 (e.g., less than 10; 0-10, 0-6, 0-4, 0-3, 0-2, or 1.8) after treatment with a compound described herein, e.g., a compound of Formula (I). In some embodiments, the reduction in baseline HAM-D total score after treatment with a compound described herein, e.g., a compound of Formula (I), is at least 1, 2, 3, 4, 5, 7, 10, 25, 40, 50, or 100-fold. In some embodiments, the reduction in baseline HAM-D total score after treatment with a compound described herein, e.g., a compound of Formula (I), is at least 50% (e.g., 60%, 70%, 80%, or 90%).In some embodiments, the therapeutic effect is measured as a reduction in HAM-D total score following treatment with a compound described herein, e.g., a compound of Formula (I) (e.g., 12, 24, 48 hours; or 24, 48, 72, 96 hours or longer; or 1 day, 2 days, 14 days or longer) of at least 10, 15, or 20 points compared to baseline HAM-D total score.

[0244] In some embodiments, the method for treating a depressive disorder, e.g., a major depressive disorder, provides a therapeutic effect (e.g., as measured by a decrease in Hamilton Depression Score (HAM-D)) within 14, 10, 4, 3, 2, or 1 day, or 24, 20, 16, 12, 10, or 8 hours or less. In some embodiments, the method for treating a depressive disorder, e.g., a major depressive disorder, provides a therapeutic effect (e.g., as determined by a statistically significant decrease in HAM-D total score) within the first or second day of treatment with a compound described herein, e.g., a compound of formula (I). In some embodiments, the method for treating a depressive disorder, e.g., a major depressive disorder, provides a therapeutic effect (e.g., as determined by a statistically significant decrease in HAM-D total score) within less than 14 days or within 14 days of starting treatment with a compound described herein, e.g., a compound of formula (I). In some embodiments, the method of treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic effect (e.g., as determined by a statistically significant decrease in HAM-D total score) in less than 21 days or within 21 days of initiating treatment with a compound described herein, e.g., a compound of Formula (I). In some embodiments, the method of treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic effect (e.g., as determined by a statistically significant decrease in HAM-D total score) in less than 28 days or within 28 days of initiating treatment with a compound described herein, e.g., a compound of Formula (I). In some embodiments, the therapeutic effect is determined by treatment with a compound described herein, e.g., a compound of Formula (I) (e.g., once daily for 14 days of treatment with a compound described herein, e.g., a compound of Formula (I)). In some embodiments, the subject's HAM-D total score before treatment with a compound described herein, e.g., a compound of Formula (I), is at least 24. In some embodiments, the subject's HAM-D total score before treatment with a compound described herein, e.g., a compound of Formula (I), is at least 18. In some embodiments, the subject's HAM-D total score before treatment with a compound described herein, e.g., a compound of Formula (I), is between, inclusive, 14-18. In some embodiments, the subject's HAM-D total score after treatment with a compound described herein, e.g., a compound of Formula (I), is at least 10 compared to the baseline HAM-D total score. In some embodiments, the subject's HAM-D total score after treatment with a compound described herein, e.g., a compound of Formula (I), is at least 15 (e.g., at least 17) compared to the baseline HAM-D total score. In some embodiments, treatment of a subject with a compound described herein, e.g., a compound of Formula (I), is associated with a HAM-D total score that is equal to or less than a number in the range of 6 to 8. In some embodiments, treatment of a subject with a compound described herein, e.g., a compound of Formula (I), is associated with a HAM-D total score that is equal to or less than 7.

[0245] 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 24, 20, 16, 12, 10, or 8 hours or less. In some embodiments, the CNS disorder is a depressive disorder, e.g., major depressive disorder. In some embodiments, the method of treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic effect within the second day of the treatment period. In some embodiments, the therapeutic effect is a decrease in CGI score from baseline at the end of the treatment period (e.g., 14 days after administration).

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

[0247] The therapeutic effect of major depressive disorder can be determined by the reduction of the Montgoberg-Asberg Depression Rating Scale (MADRS) score exhibited by the subject.For example, the MADRS score can be reduced within 4, 3, 2 or 1 day; or within 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, 8 hours or less.The Montgoberg-Asberg Depression Rating Scale (MADRS) is a 10-item diagnostic questionnaire (related to outward sadness, verbal sadness, inner tension, decreased sleep, decreased appetite, difficulty in concentrating, fatigue, loss of emotion, pessimistic thinking and suicidal ideation) that psychiatrists use to measure the severity of depressive episodes in patients with mood disorders.

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

[0249] In some embodiments, the methods provide a therapeutic benefit (e.g., as measured by a reduction in Generalized Anxiety Disorder 7-item scale (GAD-7)) within 4, 3, 2, 1 day, 24, 20, 16, 12, 10, 8 hours, or less.

[0250] Anxiety disorders Provided herein is a method for treating anxiety disorders (e.g., generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, phobias, post-traumatic stress disorder). Anxiety disorder is an umbrella term that encompasses several different forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic criteria recognize a wide range of different anxiety disorders.

[0251] Generalized anxiety disorder is a common chronic disorder characterized by long-term anxiety that cannot be focused on any one object or situation.People suffering from generalized anxiety experience non-specific persistent fear and worry, and become excessively worried about mundane events.Generalized anxiety disorder is the most common anxiety disorder affecting older adults.

[0252] In panic disorder, a person suffers from brief attacks of intense fear and anxiety, often characterized by trembling, shaking, confusion, dizziness, nausea, and difficulty breathing. These panic attacks, defined by the APA as fear or discomfort that occurs unexpectedly and peaks in less than 10 minutes, can last for hours and can even be triggered by stress, fear, or exercise; however, the specific cause is not always clear. In addition to recurrent and unpredictable panic attacks, a diagnosis of panic disorder also requires that the attacks have a chronic consequence, either worry about the potential meaning of the attack, persistent fear of future attacks, or significant changes in behavior related to the attack. Thus, a person suffering from panic disorder also experiences symptoms outside of a particular panic episode. In many cases, normal changes in heartbeat are noticed by the person suffering from panic, making them think that something is wrong with their heart or that they are about to have another panic attack. In some cases, a heightened perception of bodily functions (hyperarousal) occurs during a panic attack, where any perceived physiological change is interpreted as a potentially life-threatening illness (i.e., excessive hypochondriasis).

[0253] Obsessive-compulsive disorder is a type of anxiety disorder that is primarily characterized by recurrent obsessions (distressing, persistent, intrusive thoughts or images) and compulsions (urges to perform certain actions or rituals). OCD thought patterns can be linked to superstitions insofar as they involve the person believing in causal relationships that do not actually exist. In many cases, the process is completely illogical. For example, a compulsion to walk in a certain pattern can be used to alleviate an obsession of imminent danger. And in many cases, the compulsion is not completely inexplicable, but is simply a nervously induced urge to complete a ritual. In a minority of cases, OCD patients may only experience obsessions without overt compulsions, and even fewer experience only compulsions.

[0254] The single largest category of anxiety disorder is that of phobia, which encompasses all cases in which fear and anxiety are triggered by a particular stimulus or situation. Patients typically anticipate frightening consequences from encountering the object of their fear (which could be anything from an animal, a place, to bodily fluids).

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

[0256] Women's health problems Provided herein are methods for treating conditions or disorders related to female health, including, but not limited to, gynecological health and These include menstrual and postmenstrual disorders (e.g., premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD)), pregnancy problems (e.g., miscarriage, abortion), infertility and related disorders (e.g., polycystic ovary syndrome (PCOS)), other disorders and conditions, and issues related to women's overall health and wellness (e.g., menopause).

[0257] 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.

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

[0259] Premenstrual dysphoric disorder (PMDD) is a severe form of PMS. PMDD symptoms are similar to PMS but are more severe and can interfere with work, social activities and relationships. PMDD symptoms include mood swings, feelings of low mood or hopelessness, significant anger, increased interpersonal conflict, tension and anxiety, irritability, decreased interest in usual activities, difficulty concentrating, fatigue, appetite changes, feelings of being uncontrollable or overwhelming, sleep problems, and physical problems (e.g., abdominal bloating, breast tenderness, swelling, headaches, joint or muscle pain).

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

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

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

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

[0264] Polycystic ovary syndrome (PCOS) refers to an endocrine system disorder in women of reproductive age. PCOS is a set of symptoms resulting from an increase in male hormones in women. Most women with PCOS develop many small cysts on their ovaries. Symptoms of PCOS include irregular or absent menstrual periods, heavy periods, thickening of body and facial hair, acne, pelvic pain, difficulty in conceiving, and thickened, dark, velvety patches of skin. PCOS may be associated with conditions including type 2 diabetes, obesity, obstructive sleep apnea, heart disease, mood disorders, and endometrial cancer.

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

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

[0267] Menopause refers to the 12 months that have passed since a woman's last menstrual period, marking the end of the menstrual cycle. Menopause typically occurs in women in their 40s or 50s. Physical and emotional symptoms of menopause, such as hot flashes, can disrupt sleep, reduce energy, or induce feelings of anxiety or sadness or loss. Menopause includes natural menopause and surgical menopause, the latter being a type of menopause induced due to events such as surgery (e.g., hysterectomy, oophorectomy; cancer). Surgical menopause occurs when the ovaries are depleted by, for example, radiation, chemotherapy, or other factors. Or it can be induced when the body is severely damaged by other drugs.

[0268] Epilepsy The compounds of formula (I), or pharma- ceutically acceptable salts, or pharma- ceutically acceptable compositions thereof, can be used in the methods described herein, e.g., in the treatment of a disorder described herein, such as epilepsy, status epilepticus, or seizures.

[0269] Epilepsy is a brain disorder characterized by repeated seizures over time.Types of epilepsy can include, but are not limited to, generalized epilepsy, such as childhood absence epilepsy, juvenile myoclonic epilepsy, epilepsy with awakening grand mal seizures, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, such as temporal lobe epilepsy, frontal lobe epilepsy, and benign focal epilepsy of childhood.

[0270] Epileptic seizures The compounds and methods described herein can be used to treat or prevent epileptic seizures.Epileptic seizures are a gradual process in which a normal brain develops epilepsy (a chronic condition in which seizures occur).Epileptic seizures result from neurological damage (e.g., status epilepticus) that is initially caused by seizures.

[0271] Status epilepticus (SE) Status epilepticus (SE) may include, for example, convulsive status epilepticus, such as early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, such as generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic unilateral epileptic discharges. Convulsive status epilepticus is characterized by the presence of convulsive status epilepticus and may include early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus. Early status epilepticus is treated with first-line therapy. Established status epilepticus is characterized by persistent status epilepticus despite treatment with first-line therapy and second-line therapy is administered. Refractory status epilepticus is characterized by persistent status epilepticus despite treatment with first-line and second-line therapy and general anesthetic is typically administered. Super-refractory status epilepticus is characterized by persistent status epilepticus despite treatment with first-line, second-line and general anesthetic for 24 hours or more.

[0272] Non-convulsive status epilepticus can include, for example, focal non-convulsive status epilepticus, e.g., complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, fine non-convulsive status epilepticus; generalized non-convulsive status epilepticus, e.g., late onset absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus.

[0273] A compound of formula (I) or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable composition thereof may also be administered prophylactically to a subject having a CNS disorder, e.g., traumatic brain injury, status epilepticus, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, very refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic unilateral epileptic discharges, prior to the onset of a seizure.

[0274] Seizures A seizure is a physical manifestation 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 a person's body shakes rapidly and uncontrollably. During a convulsion, the person's muscles repeatedly contract and relax.

[0275] Based on the type of behavior and brain activity, seizures are divided into two broad categories: generalized and partial (also called focal or localized). Classifying the type of seizure helps doctors diagnose whether a patient has epilepsy.

[0276] Generalized seizures are caused by electrical impulses from the entire brain, while partial seizures are caused (at least initially) by electrical impulses in a smaller part of the brain. The part of the brain that generates the seizure is sometimes called the focus.

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

[0278] Absence seizures cause a brief (just a few seconds) loss of consciousness with few or no symptoms. Affected people (most often children) typically stop activity and stare blankly. These seizures start and end abruptly and can occur several times a day. Affected people usually do not realize they are having a seizure, except that they may be aware of "losing time."

[0279] Myoclonic seizures consist of sporadic jerks, usually on both sides of the body. Patients sometimes describe these jerks as brief electric shocks. When severe, these seizures can result in dropping or involuntary throwing of objects.

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

[0281] Tonic seizures are characterized by muscle stiffness.

[0282] Atonic seizures consist of a sudden loss of muscle tone throughout the body, especially the arms and legs, often resulting in a fall.

[0283] Seizures as described herein may include epileptic seizures; acute repetitive seizures; cluster seizures; continuous seizures; continuous seizures; continuous seizures; recurrent seizures; status epilepticus, e.g., refractory convulsive status epilepticus, nonconvulsive status epilepticus; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondary generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign rolandic seizures; febrile seizures; affective seizures; focal seizures; galvanic 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; petit mal seizures; Sylvan seizures; visual reflex seizures; or withdrawal seizures. In some embodiments, the seizures are generalized seizures associated with Dravet syndrome, Lennox-Gastaut syndrome, tuberous sclerosis complex, Rett syndrome, or PCDH19 female epilepsy.

[0284] Movement disorders Also described herein is a method for treating movement disorder.As used herein, "movement disorder" refers to various diseases and disorders related to hyperkinesia and related abnormalities in muscle control.Exemplary movement disorders include, but are not limited to, Parkinson's disease and Parkinsonism (particularly defined by bradykinesia), dystonia, chorea and Huntington's disease, ataxia, tremor (e.g., essential tremor), myoclonus and startle, tic and Tourette's syndrome, restless leg syndrome, stiff person syndrome and gait disorder.

[0285] Tremor The methods described herein can be used to treat tremors, for example, by administering to a patient a compound of formula (I) ) can be used to treat cerebellar or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, Parkinson's tremor, physiological tremor, psychogenic tremor or rubral tremor. Tremor includes genetic, degenerative and idiopathic disorders such as Wilson's disease, Parkinson's disease and essential tremor, respectively; metabolic diseases (e.g. thyroid-parathyroid disease, liver disease and hypoglycemia); peripheral neuropathy (associated with Charcot-Marie-Tooth disease, Lucy-Lewy disease, diabetes mellitus, complex regional pain syndrome); disorders induced by toxins (nicotine, mercury, lead, CO, manganese, arsenic, toluene); disorders induced by drugs (hypnotics, tricyclics, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychogenic disorders. Clinical tremor includes physiological tremor, fatigue-induced physiological tremor (enhanced physiologic tremor), essential tremor syndromes (classical essential tremor, primary orthostatic tremor and Tremors can be classified into: dystonic tremor, Parkinsonian tremor, cerebellar tremor, Holmes tremor (i.e. rubral tremor), palatal tremor, neuropathic tremor, toxin- or drug-induced tremor, and psychogenic tremor.

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

[0287] Cerebellar tremor or intention tremor is a slow, widespread tremor of the limbs that occurs after intentional movement. Cerebellar tremor is caused by lesions in or damage to the cerebellum, for example, from tumors, strokes, and diseases (e.g., multiple sclerosis, inherited degenerative disorders).

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

[0289] Essential tremor or benign essential tremor is the most common type of tremor. Essential tremor can be mild and non-progressive in some cases, and can be slow and progressive, starting on one side of the body but affecting both sides within 3 years. The hands are most frequently affected, but the head, voice, tongue, legs and trunk can also be involved. Tremor frequency can decrease with age, but severity can increase. Emotional excitement, stress, fever, physical fatigue or hypoglycemia can cause tremor and / or increase its severity. Symptoms generally develop over a long period of time, and can be visible and persistent after onset.

[0290] Orthostatic tremor is characterized by rapid (e.g., greater than 12 Hz) rhythmic muscle contractions of the legs and trunk immediately after standing. The spasms are felt in the thighs and legs, and the patient is unable to stand in one position. They may shake uncontrollably when asked to do so. Orthostatic tremor can occur in patients with essential tremor.

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

[0292] Physiological tremor can occur in normal individuals and has no clinical significance. Physiological tremor can be found in all voluntary muscle groups. Physiological tremor 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.

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

[0294] Rubral tremor is characterized by a slow, coarse tremor that can be present at rest, in posture, and with intention. This tremor may be associated with conditions affecting the red nucleus in the classical rare stroke of the midbrain.

[0295] Parkinson's disease affects the nerve cells in the brain that produce dopamine. Symptoms include muscle stiffness, tremors, and changes in speech and gait. Parkinsonism is characterized by tremors, bradykinesia, rigidity, and postural instability. Parkinsonism shares symptoms with Parkinson's disease, but is a constellation of conditions rather than a progressive neurodegenerative disease.

[0296] Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions that cause abnormal and often repetitive movements or postures. Dystonic movements can be patterned, twisting, or tremulous. Dystonia is often initiated or exacerbated by voluntary movements and is frequently associated with an overflow of muscle activation.

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

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

[0299] Myoclonus and startle are reactions to sudden and unexpected stimuli, which can be auditory, tactile, visual or vestibular.

[0300] Tics are involuntary movements that usually have a sudden onset, are brief, repetitive but not rhythmic, and typically mimic normal behaviors and often occur outside of a background of normal activity. Tics can be classified as motor or vocal tics, with motor tics being associated with movement and vocal tics being associated with sounds. Tics can be characterized as simple or complex. For example, simple motor tics involve only a few muscles that are confined to a particular body part. Tourette's syndrome is a childhood-onset inherited neuropsychiatric disorder characterized by multiple motor tics and at least one vocal tic.

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

[0302] Stiff person syndrome is a progressive movement disorder characterized by involuntary painful spasms and muscle stiffness, usually involving the lower back and legs. Typically, a stiff gait occurs with excessive lumbar hyperlordosis. Typically, characteristic abnormalities are seen in EMG recordings of sequential motor unit activity of paraspinal axial muscles. Variants include "stiff limb syndrome," which typically affects the distal legs and feet, resulting in focal stiffness.

[0303] Gait disorders refer to abnormalities in the manner or style of walking due to neuromuscular, arthritic, or other physical changes. Gaits are classified according to a system of abnormal gait movements, including hemiplegic gait, diplegic gait, neuropathic gait, myopathic gait, parkinsonian gait, choreic gait, ataxic gait, and sensory gait.

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

[0305] Sedation is the reduction of irritability or agitation due to the administration of a drug, generally to facilitate a medical or diagnostic procedure.

[0306] Sedation and analgesia encompass a continuum of states of consciousness ranging from mild sedation (anxiolysis) to general anesthesia.

[0307] Mild sedation is also known as anxiolysis. Minimal sedation is an induced state during which the patient responds normally to verbal commands. Cognitive function and coordination may be impaired. Respiratory and cardiovascular function are typically unaffected.

[0308] Moderate sedation / analgesia (conscious sedation) is a drug-induced reduction in consciousness during which the patient responds purposefully to verbal commands, either alone or in conjunction with phototactile stimulation. No measures are usually required to maintain a patent airway. Spontaneous breathing is usually sufficient. Cardiovascular function is usually preserved.

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

[0310] General anesthesia is a drug-induced unconsciousness during which the patient cannot be awakened even to painful stimuli. The ability to maintain independent respiratory function is often impaired, and assistance is often required to maintain a patent airway. Positive pressure ventilation may be required due to reduced spontaneous breathing or drug-induced neuromuscular depression. Cardiovascular function may be impaired.

[0311] Sedation in the intensive care unit (ICU) reduces the patient's awareness of the environment and external stimuli. This can play a role in the treatment of critically ill patients and encompasses a wide range of symptom management that may vary between patients and between individuals over the course of their disease. Deep sedation has been used in critical care medicine, often in conjunction with neuromuscular blockade, to facilitate endotracheal tube tolerance and respiratory synchrony.

[0312] In some embodiments, sedation (e.g., long-term sedation, continuous sedation) is induced and maintained in the ICU for an extended period of time (e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months). Long-term drugs can have a long duration of action. Sedative drugs in the ICU can have a short elimination half-life.

[0313] Procedural sedation and analgesia, also called conscious sedation, is the technique of administering sedatives or dissociative drugs, with or without analgesics, to induce a state that allows a subject to tolerate an unpleasant procedure while maintaining cardiopulmonary function. EXAMPLES

[0314] In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting the scope thereof.

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

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

[0317] The compounds provided herein can be isolated and purified by known standard procedures. Such procedures include (but are not limited to) recrystallization, column chromatography, HPLC, or supercritical fluid chromatography (SFC). The following schemes are shown with details regarding the preparation of representative oxysterols listed herein. The compounds provided herein can be prepared from known or commercially available starting materials and reagents by those skilled in the art of organic synthesis. 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.

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

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

[0320] Exemplary general method for preparative HPLC: Column Waters Xbridge 150x25 5u, Conditions: Water (10mM NH4HCO3)-ACN Start B85, End B100, Gradient time (min) 6.5, Hold time (min) 1 at 100% B, Flow rate (ml / min) 25, Injection 4).

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

[0322] Exemplary general method for LCMS / LC ELSD: 30-90AB_2 min. Lcm. (Mobile phase: 1.5 mL / 4 L TFA in water (solvent A) and 0.75 mL / 4 L TFA in acetonitrile (solvent B) using an elution gradient of 30%-90% (solvent B) over 0.9 min at a flow rate of 1.2 mL / min and a hold at 90% for 0.6 min; Column: Xtimate C18 2.1×30 mm, 3 μm; Wavelength: UV 220 nm; Column temperature: 50° C.; MS ionization: ESI; Detector: PDA & ELSD)

[0323] Abbreviations: PE: petroleum ether; EtOAc: ethyl acetate; THF: tetrahydrofuran; PCC: pyridinium chlorochromate; TLC: thin layer chromatography; PCC: pyridinium chlorochromate; t-BuOK: potassium tert-butoxide; 9-BBN: 9-borabicyclo[3.3.1]nonane; Pd(t-Bu3P)2: bis(tri-tert-butylphosphine)palladium(0); AcCl: acetyl chloride; i-PrMgCl: isopropylmagnesium chloride; TBSCl: tert-butyl(chloro)dimethylsilane; (i-PrO)4Ti: titanium tetraisopropoxide; BHT: 2,6-di- t-Butyl-4-methylphenoxide; Me: methyl; i-Pr: iso-propyl; t-Bu: tert-butyl; Ph: phenyl; Et: ethyl; Bz: benzoyl; BzCl: benzoyl chloride; CsF: cesium fluoride; DCC: dicyclohexylcarbodiimide; DCM: dichloromethane; DMF: N,N-dimethylformamide; DMAP: 4-dimethylaminopyridine; DMSO: dimethylsulfoxide; DMP: Dess-Martin periodinane; EtMgBr: ethyl magnesium bromide; EtOAc: ethyl acetate; TEA: triethylamine; AlaOH: alanine; Boc: t-butoxycarbonyl. Py: Pyridine; TBAF: Tetra-n-butylammonium fluoride; THF: Tetrahydrofuran; TBS: t-butyldimethylsilyl; TMS: Trimethylsilyl; TMSCF3: (Trifluoromethyl)trimethylsilane; Ts: p-Toluenesulfonyl; Bu: Butyl; Ti(OiPr)4: Tetraisopropoxytitanium; LAH: Lithium aluminum hydride; LDA: Lithium diisopropylamide; LiOH.H2O: Lithium hydroxide hydrate; MAD: Methylaluminum bis(2,6-di-t-butyl-4-methylphenoxide); MeCN: Acetonitrile; NBS: N-Bromosuccinimide ;Na2SO4: sodium sulfate; Na2S2O3: sodium thiosulfate; MeCN: acetonitrile; MeOH: methanol; Boc: t-butoxycarbonyl; MTBE: methyl tert-butyl ether; K-selectride: potassium tri(s-butyl)borohydride; 9-BBN dimer: 9-borabicyclo(3.3.1)nonane (dimer).

[0324] Example 1: 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one ( compound Synthesis of A9) [ka] compound Synthesis of A2 [ka] To a suspension of MePPh3Br (145 g, 408 mmol) in THF (300 mL) was added t-BuOK (45.7 g, 408 mmol) at 15° C. After stirring at 45° C. for 0.5 h, compound A solution of A1 (CAS# 5696-44-6) (80 g, 204 mmol) was added at 45° C. and the reaction mixture was stirred at 45° C. for 1 h. The mixture was diluted with PE (300 mL) and then filtered. The filtrate was concentrated to give an oil (200 g). After stirring the product with PE (1 L) for 16 h, the solid was filtered and the filtrate was concentrated to give the product. compound A2 was obtained as an oil which was used as is in the next step. 1 HNMR(400MHz, CDCl3) δ H 6.30 (dd, J = 11.2, 17.6 Hz, 1H),5.15-4.96(m, 2H), 3.94-3.81 (m, 8H), 2.02-1.73 (m, 7H), 1.58-1.35 (m, 13H), 1.22-1.14(m,2H), 0.81 (s, 3H).

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

[0326] compound A4 and compound Synthesis of A5 [ka] in THF (25 mL) compound To a solution of A3 (4.5 g), hydrogen chloride (12 mL, 2 M aqueous solution) was added and the reaction mixture was stirred at 25° C. for 16 h. Saturated NaHCO3 (50 mL) was added to the reaction mixture until pH ∼8 and extracted with EtOAc (2×80 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash column (0-10% EtOAc in PE) to give compound A5 (1.1 g) was obtained. Purification by SFC (column: DAICEL CHIRALPAK AD (250 mm × 50 mm, 10 μm; condition: 0.1% NH3H2O ​​ETOH; start B: 25%, end B: 25%; flow rate (ml / min): 200) was performed. compoundA4 (550 mg, 29.1%) and compound A5 (420 mg) was obtained both as oils. compound A4: 1 H NMR (400 MHz, CDCl3)δ H 2.73-2.61 (m, 1H), 2.47 (dd, J=8.8, 19.2 Hz, 1H), 2.35-2.22 (m, 1H),2.17-1.85 (m,8H), 1.77-1.61 (m,4H), 1.56-1.50 (m, 1H), 1.47-1.39 (m, 1H), 1.36-1.22(m, 5H),0.92 (s, 3H), 0.90-0.84 (m, 1H), 0.54- 0.40 (m, 2H), 0.34- 0.25 (m, 1H),0.12- 0.04(m, 1H).

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

[0328] compound Synthesis of A7 [ka] To a mixture of EtPPhBr (1.52 g, 4.11 mmol) in THF (10 mL) was added t-BuOK (461 mg, 4.11 mmol) under N at 25° C. The resulting mixture was stirred at 50° C. for 30 min. compound A6 (455 mg, 1.37 mmol) was added below 40° C. The reaction mixture was stirred at 40° C. for 3 h to give a suspension. The reaction mixture was quenched with saturated aqueous NH4Cl solution (150 mL) at 25° C. The aqueous solution was extracted with EtOAc (2×80 mL). The combined organic phase was concentrated. The residue was purified by flash column (0-10% EtOAc in PE) to give compound A7 (320 mg, 68.2%) was obtained as an oil. 1 HNMR (400MHz, CDCl3) δ H 5.16-5.07 (m, 1H), 2.42-2.31 (m, 1H),2.29-2.13(m, 2H), 2.07-1.89 (m, 2H), 1.68-1.61 (m, 5H), 1.54-1.40 (m, 6H), 1.38-1.14(m, 12H), 0.93-0.79 (m, 4H), 0.53-0.33 (m, 3H), 0.29-0.16 (m, 1H), 0.09-0.04 (m,1H).

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

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

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

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

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

[0334] compound 4.3 Synthesis in toluene (1500 mL) compound To a solution of 4.2 (180 g, 591 mmol) was added pyridine hydrochloride (13.5 g, 118 mmol) and ethane-1,2-diol (183 g, 2955 mmol). The mixture was stirred at 140° C. for 48 h. The mixture was cooled to 25° C. Then water (1000 mL) was added to the mixture, which was then extracted with EtOAc (3×1000 mL). The combined organic phase was washed with brine (2×1000 mL), dried over anhydrous Na2SO4, filtered and concentrated to give compound 4.3 (180 g, 460 mmol) was obtained as an oil. 1 H NMR (400 MHz, CDCl3) δ H3.95-3.79(m, 10H), 2.05-1.92(m, 3H), 1.78-1.64 (m, 5H), 1.56-1.36 (m, 10H), 1.30-1.03 (m,5H), 0.82 (s, 3H)

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

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

[0337] compound Synthesis of 4.6 To a solution of EtZn (46.2 mL, 1 M in hexanes) in DCM (250 mL) at 0 °C, CFCOOH (4.38 g, 38.5 mmol) was added dropwise over 1 h under N2 atmosphere, followed by CHI (12.3 g, 46.2 mmol) dropwise over 15 min, and finally EtZn (46.2 mL, 1 M in hexanes) in DCM (50 mL). compound 4.5 (6 g, 15.4 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1 h and then at 25° C. for 12 h. The reaction was quenched by the addition of saturated aqueous NH4Cl (150 mL). The aqueous phase was extracted with DCM (3×100 mL). The combined organic phase was washed with brine (150 mL), dried over anhydrous Na2SO4, filtered and concentrated to give compound 4.7 (6.0 g, 14.9 mmol) was obtained as an oil which was used as is.

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

[0339] compound 4.8 Synthesis To a stirred solution of trimethylsulfonium iodide (2.42 g, 11.9 mmol) in DMSO (10 mL) and THF (5 mL) was added NaH (475 mg, 11.9 mmol, 60% in oil) at 0° C. over 1.0 h under N2. The mixture was diluted with 100% DMSO (5 mL) compound A solution of 4.7 (2.5 g, 7.9 mmol) was added at 0° C. After stirring at 25° C. for 6 h, the reaction was diluted with water (50 mL) and extracted with EtOAc (3×20 mL). The combined organic phase was washed with water (2×50 mL), brine (2×50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give compound 4.8 (2.5 g, 7.6 mmol) was obtained as an oil which was used as is.

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

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

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

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

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

[0345] compound 4.11 Synthesis in THF (10 mL) compoundTo a solution of 4.10 (800 mg, 2.1 mmol), 9-BBN dimer (2.01 g, 8.24 mmol) was added at 25° C. The mixture was then stirred at 40° C. for 16 h to obtain a solution. After cooling to 0° C., the mixture was diluted very slowly with ethanol (1.89 g, 41.2 mmol) and then with NaOH (8.24 mL, 41.2 mmol, 5 M). After the addition was complete, H2O2 (4 mL, 39.7 mmol, 30%) was added slowly to maintain the internal temperature below 25° C. After stirring at 75° C. for 1 h, saturated aqueous Na2S2O3 (50 mL) was added and the mixture was stirred at 0° C. for another 1 h. The reaction was checked by potassium iodide-starch test paper to ensure that the excess H2O2 was decomposed. The mixture was cooled and added to water (50 mL). The mixture was extracted with EtOAc (3×20 mL), washed with saturated brine (2×50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue (800 mg) was purified by flash column (0-30% EtOAc in PE) to give compound Obtained 4.11 (400 mg, 50%) as an oil. 1 H NMR (400 MHz, CDCl3) δ H 3.72-3.65(m, 1H), 3.51(q, J = 6.8 Hz, 2H), 3.34 (dd, J = 9.6,24.0 Hz, 2H), 2.00-1.83 (m,7H), 1.69-1.32(m, 15H), 1.28-1.11 (m, 9H), 0.66 (s, 3H), 0.44-0.30 (m, 3H), 0.27-0.17(m, 1H),0.02-0.09 (m, 1H)

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

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

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

[0349] Example 6: 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-cyclopropyl-3-(ethoxymethyl)-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile, compound Synthesis of 6 [ka] in acetone (10 mL) compound To a solution of 5.1 (110 mg, 0.23 mmol) was added 1H-pyrazole-5-carbonitrile (31.8 mg, 0.34 mmol) and K2CO3 (63.1 mg, 0.46 mmol). After stirring at 50 °C for 2 h, the mixture was added to saturated water (50 mL) and then extracted with EtOAc (3 x 10 mL). The combined organic phase was washed with brine (2 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The residue was purified by preparative HPLC (column: Xtimate C18 150 x 25 mm x 5 μm, gradient: 65-95% B (water (10 mM NH4HCO3)-ACN, flow rate: 30 mL / min), affording ...), K2CO3-5-carbonitrile (31.8 mg, 0.34 mmol), K2CO3-5-carbonitrile (31.8 mg, 0.34 mmol), K2CO3-5-carbonitrile (31.8 mg, 0.3 compound Obtained 6 (28 mg, 25%) as a solid. 1 H NMR (400 MHz, CDCl3) δ H 7.48(d, J = 2.4 Hz,1H), 6.73 (d, J = 2.4 Hz, 1H), 4.97 (dd, J =18.0, 53.2 Hz, 2H),3.52 (q, J = 7.2Hz, 2H),3.35 (dd, J = 9.2, 22.4 Hz, 2H), 2.72 (s, 1H), 2.61 (t,J = 8.8 Hz, 1H),2.25-1.88 (m, 4H), 1.79-1.59 (m, 6H), 1.52-1.18 (m, 15H), 0.68(s, 3H), 0.48-0.34(m, 3H), 0.31-0.20 (m, 1H), 0.06--0.07 (m, 1H); Structure confirmed by HMBC (H1 showed clear signal along with C4); LC-ELSD / MS purity 99%, C 30 H 42 MS ESI calculations for N3O2 [M-H2O+H] + 476.3, actual value 476.3.

[0350] Example 7: 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-cyclopropyl-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one, compound 7.4 Synthesis [ka] compound 7.1a and compound Synthesis of 7.1b To anhydrous MeOH (10 mL) was added Na (979 mg, 42.6 mmol) in 3 portions at 25° C. The reaction mixture was stirred at 65° C. for 1 h. To the sodium methylate solution was added 100 g of anhydrous MeOH (20 mL) compound4.8 (2.8 g, 8.5 mmol) was added at 65° C. After stirring at 65° C. for 4 h, the reaction mixture was diluted with water (50 mL) and then concentrated to remove most of the solvent. The mixture was extracted with EtOAc (2×20 mL). The combined organic phase was washed with saturated brine (2×50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash column (0-10% EtOAc in PE) to give compound 7.1a(900mg, Rf=0.2, PE / EtOAc=3 / 1,%de>99( 1 1 H NMR) and compound 7.1b(900mg, Rf=0.35, PE / EtOAc=3 / 1),%de>99( 1 1 H NMR) was obtained.

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

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

[0353] compound 7.2 Synthesis To a solution of t-BuOK (1.23 g, 11.0 mmol) in THF (20 mL) was added ethyltriphenylphosphonium bromide (4.08 g, 11.0 mmol) at 25° C. After stirring at 40° C. for 0.5 h, the mixture was dissolved in THF (10 mL). compoundA solution of 7.1a (800 mg, 2.2 mmol) was added to the reaction at 40° C. After stirring at 40° C. for 16 h, the mixture was poured into water (50 mL) and extracted with EtOAc (2×20 mL). The combined organic phase was washed with saturated brine (2×50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue which was purified by flash column (0-20% EtOAc in PE) to give: compound 7.2 (500 mg, 1.3 mmol) was obtained as an oil.

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

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

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

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

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

[0359] Briefly, after decapitation of carbon dioxide-anesthetized Sprague-Dawley rats (200-250 g), the cortices are rapidly removed. Using a glass / Teflon homogenizer, the cortices are homogenized in 10 volumes of ice-cold 0.32 M sucrose and centrifuged at 1500×g for 10 min at 4° C. The resulting supernatant is centrifuged at 10,000×g for 20 min at 4° C. to obtain a P2 pellet. The P2 pellet is resuspended in 200 mM NaCl / 50 mM Na-K phosphate pH 7.4 buffer and centrifuged at 10,000×g for 10 min at 4° C. This washing procedure is repeated twice and the pellet is resuspended in 10 volumes of buffer. An aliquot (100 mL) of the membrane suspension is diluted with 5 mM In the presence of GABA, 3 nM [ 35S]-TBPS and 5 mL aliquots of the test drug are incubated. Incubations are brought to a final volume of 1.0 mL with buffer. Nonspecific binding is determined in the presence of 2 mM unlabeled TBPS and ranges from 15 to 25%. After 90 min of incubation at room temperature, the assay is terminated by filtration through glass fiber filters (Schleicher and Schuell No. 32) using a cell harvester (Brandel) and rinsed three times with ice-cold buffer. Filter-bound radioactivity is measured by liquid scintillation spectrometry. Nonlinear curve fitting of the entire data for each drug averaged at each concentration is performed using Prism (GraphPad). If the sum of squares is significantly lower according to the F test, the data are fitted to a partial inhibition model instead of a complete inhibition model. Similarly, if the sum of squares is significantly lower according to the F test, the data are fitted to a two-component inhibition model instead of a one-component inhibition model. The 50% inhibition of specific binding (IC 50 ) and the maximum degree of inhibition (I max The concentration of test compound that produces a β-blocking effect is determined for each experiment with the same model used for the overall data, and the mean ± SEM of each experiment is then calculated. Picrotoxin serves as a positive control for these studies, as it has been demonstrated to robustly inhibit TBPS binding.

[0360] Screening various compounds to confirm in vitro 35 S]-TBPS binding, their potential as modulators is or can be determined. These assays are or can be performed as described above.

[0361] In Table 2 below, A is the TBPS IC 50 (μM) <0.1 μM, B indicates TBPS IC of 0.1 μM to <1.0 μM 50 (μM), and C is the TBPS IC from 1 μM to <10.0 μM. 50 (μM) is indicated, and D means ≧10 μM. [Table 2-1] [Table 2-2] [Table 2-3]

[0362] Equivalents and Scope In the claims, articles such as "a," "an," and "the" can mean one or more than one, unless indicated to the contrary or otherwise clear from the context. Unless indicated to the contrary or otherwise clear from the context, a claim or description containing "or" between one or more members of a group is deemed to satisfy that one, more than one, or all group members are present in, used in, or otherwise relevant to a given product or process. The invention includes embodiments in which exactly one member of the group is present in, used in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one or all group members are present in, used in, or otherwise relevant to a given product or process.

[0363] Furthermore, the present invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the enumerated claims are introduced into another claim. For example, any claim that is dependent on another claim may be modified to include one or more limitations found in any other claim that is dependent on the same base claim. When elements are presented as a list, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) may be removed from the group. In general, when the invention or aspects of the invention are referred to as comprising certain elements and / or features, it is to be understood that certain embodiments of the invention or aspects of the invention consist of or consist essentially of such elements and / or features. For purposes of simplicity, those embodiments have not been expressly set forth herein in these exact terms. It should also be noted that the terms "comprising" and "containing" are intended to be open and allow for the inclusion of additional elements or steps. When ranges are presented, the endpoints are included. Additionally, 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 range set forth in various embodiments of the invention to the tenth of the unit of the lower limit of that range, unless the context clearly dictates otherwise.

[0364] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any incorporated reference and this specification, this specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be expressly excluded from any one or more of the claims. Because such embodiments are deemed known to those of skill in the art, they may be excluded even if the exclusion is not expressly set forth herein. Any particular embodiment of the present invention may be expressly excluded from any embodiment, whether or not related to the existence of prior art. Any object may be excluded from the claims for any reason.

[0365] Those skilled 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 is as set forth in the appended claims. Those skilled in the art will recognize that various changes and modifications to this description may be made without departing from the spirit or scope of the invention as defined in the following claims.

[0366] According to a preferred embodiment of the present invention, for example, the following is provided: (Section 1) Compounds of Formula I: [ka] (I) or a pharma- ceutically acceptable salt thereof [In the formula, [ka] represents a single bond or a double bond, provided that when a double bond is present, R 6a or R 6b One of them is not present; R 1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -N(R A1 ) 2 , -SR A1 , -C(=O)R A1 , -C(=O)OR A1 , -C(=O)SR A1 , -C(=O)N(R A1 ) 2 , -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)N(R A1) 2 , -OC(=O)SR A1 , -OS(=O) 2 R A1 , -OS(=O) 2 OR A1 , -OS(=O) 2 N(R A1 ) 2 , -N(R A1 )C(=O)R A1 , -N(R A1 )C(=NR A1 )R A1 , -N(R A1 )C(=O)OR A1 , -N(R A1 )C(=O)N(R A1 ) 2 , -N(R A1 )C(=NR A1 ), N(R A1 ) 2 , -N(R A1 )S(=O) 2 R A1 , -N(R A1 )S(=O) 2 OR A1 , -N(R A1 )S(=O) 2 N(R A1 ) 2 , -SC(=O)R A1 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 ) 2 , -S(=O) 2 R A1 , -S(=O) 2 OR A1 , or -S(=O) 2 N(R A1 ) 2 where RA1 each instance of is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group if attached to oxygen, a nitrogen protecting group if attached to nitrogen, or a sulfur protecting group if attached to sulfur, or two R A1 the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring; R 2a 、R 2b 、R 4a 、R 4b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b or R 17b each independently represents hydrogen, halogen, -CN, -NO 2 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -N(R A1 ) 2 , -SR A1 , -C(=O)R A1 , -C(=O)OR A1 , -C(=O)SR A1 , -C(=O)N(R A1 ) 2 , -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)N(R A1 ) 2 , -OC(=O)SR A1 , -OS(=O) 2 R A1 , -OS(=O) 2 OR A1 , -OS(=O) 2 N(R A1 ) 2 , -N(R A1 )C(=O)R A1 , -N(R A1 )C(=NR A1 )R A1 , -N(R A1 )C(=O)ORA1 , -N(R A1 )C(=O)N(R A1 ) 2 , -N(R A1 )C(=NR A1 ), N(R A1 ) 2 , -N(R A1 )S(=O) 2 R A1 , -N(R A1 )S(=O) 2 OR A1 , -N(R A1 )S(=O) 2 N(R A1 ) 2 , -SC(=O)R A1 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 ) 2 , -S(=O) 2 R A1 , -S(=O) 2 OR A1 , or -S(=O) 2 N(R A1 ) 2 where R A1 each instance of is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group if attached to oxygen, a nitrogen protecting group if attached to nitrogen, or a sulfur protecting group if attached to sulfur, or two R A1 the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring; R 3a 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; R 5 is hydrogen or methyl;

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Claims

1. Compounds of formula (I): 【Chemistry 47】 (I) or a pharma- ceutically acceptable salt thereof [In the formula, The partial structure of the formula 【Chemistry 48】 represents a single bond or a double bond, provided that when a double bond is present, R ６ａ Or R ６ｂ One of them is not present; R １ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR Ａ１ , -N(R Ａ１ ) ２ , -SR Ａ１ , -C(=O)R Ａ１ , -C(=O)OR Ａ１ , -C(=O)SR Ａ１ , -C(=O)N(R Ａ１ ) ２ , -OC(=O)R Ａ１ , -OC(=O)OR Ａ１ , -OC(=O)N(R Ａ１ ) ２ , -OC(=O)SR Ａ１ , -OS(=O) ２ R Ａ１ , -OS(=O) ２ OR Ａ１ , -OS(=O) ２ N (R Ａ１ ) ２ , -N(R Ａ１ ) C(=O)R Ａ１ , -N(R Ａ１ ) C(=NR Ａ１ ) R Ａ１ , -N(R Ａ１ ) C(=O)OR Ａ１ , -N(R Ａ１ )C(=O)N(R Ａ１ ) ２ , -N(R Ａ１ ) C(=NR Ａ１ ) N (R Ａ１ ) ２ , -N(R Ａ１ ) S(=O) ２ R Ａ１ , -N(R Ａ１ ) S(=O) ２ OR Ａ１ , -N(R Ａ１ ) S(=O) ２ N (R Ａ１ ) ２ , -SC(=O)R Ａ１ , -SC(=O)OR Ａ１ , -SC(=O)SR Ａ１ , -SC(=O)N(R Ａ１ ) ２ , -S(=O) ２ R Ａ１ , -S(=O) ２ OR Ａ１ Or -S(=O) ２ N (R Ａ１ ) ２ where each R Ａ１ are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or two R Ａ１ the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring; R ２ａ , R ２ｂ , R ４ａ , R ４ｂ , R ７ａ , R ７ｂ , R １１ａ , R １１ｂ , R １２ａ , R １２ｂ and R １７ｂ each independently represents hydrogen, halogen, -CN, -NO ２ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR Ａ１ , -N(R Ａ１ ) ２ , -SR Ａ１ , -C(=O)R Ａ１ , -C(=O)OR Ａ１ , -C(=O)SR Ａ１ , -C(=O)N(R Ａ１ ) ２ , -OC(=O)R Ａ１ , -OC(=O)OR Ａ１ , -OC(=O)N(R Ａ１ ) ２ , -OC(=O)SR Ａ１ , -OS(=O) ２ R Ａ１ , -OS(=O) ２ OR Ａ１ , -OS(=O) ２ N (R Ａ１ ) ２ , -N(R Ａ１ ) C(=O)R Ａ１ , -N(R Ａ１ ) C(=NR Ａ１ ) R Ａ１ , -N(R Ａ１ ) C(=O)OR Ａ１ , -N(R Ａ１ )C(=O)N(R Ａ１ ) ２ , -N(R Ａ１ ) C(=NR Ａ１ ) N (R Ａ１ ) ２ , -N(R Ａ１ ) S(=O) ２ R Ａ１ , -N(R Ａ１ ) S(=O) ２ OR Ａ１ , -N(R Ａ１ ) S(=O) ２ N (R Ａ１ ) ２ , -SC(=O)R Ａ１ , -SC(=O)OR Ａ１ , -SC(=O)SR Ａ１ , -SC(=O)N(R Ａ１ ) ２ , -S(=O) ２ R Ａ１ , -S(=O) ２ OR Ａ１ Or -S(=O) ２ N (R Ａ１ ) ２ where each R Ａ１ are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or two R Ａ１ groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring; or one or more of R 2a and R 2b , R 4a and R 4b , R 7a and R 7b , R 11a and R 11b , and R 12a and R 12b , taken together, form an oxo (═O) group; R ３ａ 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; R ５ is hydrogen or methyl; The partial structure of the formula 【Chemistry 49】 is a double bond, R ５ does not exist; R ６ａ and R ６ｂ are hydrogen, halogen, -CN, -NO ２ , —OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; or R ６ａ and R ６ｂ taken together form an oxo (=O) group; R １５ａ , R １５ｂ , R １６ａ and R １６ｂ Each of is independently hydrogen, halogen, —CN, —NO ２ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR Ｃ３ , -N(R Ｃ３ ) ２ , -SR Ｃ３ , -C(=O)R Ｃ３ , -C(=O)OR Ｃ３ , -C(=O)SR Ｃ３ , -C(=O)N(R Ｃ３ ) ２ , -OC(=O)R Ｃ３ , -OC(=O)OR Ｃ３ , -OC(=O)N(R Ｃ３ ) ２ , -OC(=O)SR Ｃ３ , -OS(=O) ２ R Ｃ３ , -OS(=O) ２ OR Ｃ３ , -OS(=O) ２ N (R Ｃ３ ) ２ , -N(R Ｃ３ ) C(=O)R Ｃ３ , -N(R Ｃ３ ) C(=NR Ｃ３ ) R Ｃ３ , -N(R Ｃ３ ) C(=O)OR Ｃ３ , -N(R Ｃ３ )C(=O)N(R Ｃ３ ) ２ , -N(R Ｃ３ ) C(=NR Ｃ３ ) N (R Ｃ３ ) ２ , -N(R Ｃ３ ) S(=O) ２ R Ｃ３ , -N(R Ｃ３ ) S(=O) ２ OR Ｃ３ , -N(R Ｃ３ ) S(=O) ２ N (R Ｃ３ ) ２ , -SC(=O)R Ｃ３ , -SC(=O)OR Ｃ３ , -SC(=O)SR Ｃ３ , -SC(=O)N(R Ｃ３ ) ２ , -S(=O) ２ R Ｃ３ , -S(=O) ２ OR Ｃ３ Or -S(=O) ２ N (R Ｃ３ ) ２ where each R Ｃ３ are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, or two R Ｃ３ the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring; R １９ is a substituted or unsubstituted C ３ ~C ６ carbocyclyl or substituted or unsubstituted aryl; and n is 0, 1 or 2.

2. R １ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

3. R １ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

4. R １ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein: R is a substituted carbocyclyl, a substituted heterocyclyl, a substituted aryl, or a substituted heteroaryl, each of which is further substituted with a substituted carbocyclyl, a substituted heterocyclyl, a substituted aryl, or a substituted heteroaryl.

5. R １ is a group represented by the formula: 【Chemistry 50】 【Chemistry 51】 selected from the group consisting of: Where: Each R ａ are independently hydrogen, halogen, -NO ２ , -CN, -OR Ｄ４ , -N(R Ｄ４ ) ２ , -C(=O)R Ｄ４ , -C(=O)OR Ｄ４ , -C(=O)N(R Ｄ４ ) ２ , -OC(=O)R Ｄ４ , -OC(=O)OR Ｄ４ , -N(R Ｄ４ ) C(=O)R Ｄ４ , -OC(=O)N(R Ｄ４ ) ２ , -N(R Ｄ４ ) C(=O)OR Ｄ４ , -S(=O) ２ R Ｄ４ , -S(=O) ２ OR Ｄ４ , -OS(=O) ２ R Ｄ４ , -S(=O) ２ N (R Ｄ４ ) ２ , or -N(R Ｄ４ ) S(=O) ２ R Ｄ４ , 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 ３～６ Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted C ６～１０ aryl, substituted or unsubstituted 5-10 membered heteroaryl; Each R Ｄ４ are 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 ３～６ Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted C ６～１０ aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, or two R Ｄ４ the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring; and 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein p is an integer selected from 0 to 11.

6. R １ is a group represented by the formula: 【Chemistry 52】 6. The compound of claim 5, selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

7. R ２ａ and R ２ｂ each independently represents hydrogen, halogen, -CN, -NO ２ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR Ｅ５ , -OC(=O)R Ｅ５ , -OS(=O) ２ OR Ｅ５ , -N(R Ｅ５ ) ２ , -N(R Ｅ５ ) C(=O)R Ｅ５ , -N(R Ｅ５ ) S(=O) ２ R Ｅ５ , or -N(R Ｅ５ ) S(=O) ２ OR Ｅ５ where each R Ｅ５ are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R Ｅ５ 7. The compound of any one of claims 1 to 6, wherein the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring, or a pharma- ceutically acceptable salt thereof.

8. R ２ａ and R ２ｂ each independently represents hydrogen, halogen, -CN, -NO ２ , -OR Ｆ６ , -OC(=O)R Ｆ６ , -N(R Ｆ６ ) ２ , or -N(R Ｆ６ ) C(=O)R Ｆ６ where each R Ｆ６ are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or two R Ｆ６ 7. The compound of any one of claims 1 to 6, wherein the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring, or a pharma- ceutically acceptable salt thereof.

9. R ２ａ and R ２ｂ each independently represents hydrogen, —OH, or a substituted or unsubstituted C １～６ Alkyl, or substituted or unsubstituted C １～６ 7. The compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof, which is alkoxy.

10. R ２ａ and R ２ｂ each independently represents hydrogen, —OH, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, or C １～６ The compound according to any one of claims 1 to 6, which is alkoxyhalo, or a pharma- ceutically acceptable salt thereof.

11. R ２ａ and R ２ｂ each independently represents hydrogen, —CH ３ , -CH ２ CH ３ , -OH, -OCH ３ , or -CH(CH ３ ) ２ 7. The compound according to any one of claims 1 to 6, wherein:

12. R ２ａ and R ２ｂ The compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof, wherein both are hydrogen.

13. R ２ａ and R ２ｂ The compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof, wherein:

14. R ３ａ The compound of any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.

15. R ３ａ The compound according to any one of claims 1 to 13, wherein is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or a pharma- ceutically acceptable salt thereof.

16. R ３ａ is a substituted or unsubstituted C １～６ 14. The compound according to any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof, wherein R is an alkyl group.

17. R ３ａ The compound according to any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof, wherein is substituted alkyl.

18. R ３ａ The compound according to any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof, wherein is unsubstituted alkyl.

19. R ３ａ The compound according to any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen, methyl, methoxymethyl, or ethoxymethyl.

20. R ３ａ The compound according to any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

21. R ４ａ and R ４ｂ each independently represents hydrogen, halogen, -CN, -NO ２ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR Ｅ５ , -OC(=O)R Ｅ５ , -OS(=O) ２ OR Ｅ５ , -N(R Ｅ５ ) ２ , -N(R Ｅ５ ) C(=O)R Ｅ５ , -N(R Ｅ５ ) S(=O) ２ R Ｅ５ , or -N(R Ｅ５ ) S(=O) ２ OR Ｅ５ where each R Ｅ５ are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R Ｅ５ 21. The compound of any one of claims 1 to 20, or a pharma- ceutically acceptable salt thereof, wherein the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring.

22. R ４ａ and R ４ｂ each independently represents hydrogen, halogen, -CN, -NO ２ , -OR Ｆ６ , -OC(=O)R Ｆ６ , -N(R Ｆ６ ) ２ , or -N(R Ｆ６ ) C(=O)R Ｆ６ where each R Ｆ６ are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or two R Ｆ６ 21. The compound of any one of claims 1 to 20, or a pharma- ceutically acceptable salt thereof, wherein the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring.

23. R ４ａ and R ４ｂ each independently represents hydrogen, —OH, or a substituted or unsubstituted C １～６ Alkyl, or substituted or unsubstituted C １～６ 21. The compound according to any one of claims 1 to 20, or a pharma- ceutically acceptable salt thereof, which is alkoxy.

24. R ４ａ and R ４ｂ each independently represents hydrogen, —OH, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, or C １～６ 21. The compound according to any one of claims 1 to 20, or a pharma- ceutically acceptable salt thereof, which is alkoxyhalo.

25. R ４ａ and R ４ｂ each independently represents hydrogen, —CH ３ , -CH ２ CH ３ , -OH, -OCH ３ , or -CH(CH ３ ) ２ 21. The compound according to any one of claims 1 to 20, wherein:

26. R ４ａ and R ４ｂ The compound according to any one of claims 1 to 20, or a pharma- ceutically acceptable salt thereof, wherein both are hydrogen.

27. R ４ａ and R ４ｂ The compound according to any one of claims 1 to 20, or a pharma- ceutically acceptable salt thereof, wherein:

28. R ５ But, R １９ The compound according to any one of claims 1 to 27, wherein R is hydrogen or methyl at the cis position relative to R, or a pharma- ceutically acceptable salt thereof.

29. R ５ But, R １９ The compound according to any one of claims 1 to 27, or a pharma- ceutically acceptable salt thereof, wherein R is hydrogen or methyl at the trans position relative to R.

30. R ６ａ and R ６ｂ 30. The compound of any one of claims 1 to 29, or a pharma- ceutically acceptable salt thereof, wherein each of is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.

31. R ６ａ and R ６ｂ 30. The compound of any one of claims 1 to 29, or a pharma- ceutically acceptable salt thereof, wherein each of is independently hydrogen or substituted alkyl.

32. R ６ａ and R ６ｂ 30. The compound of any one of claims 1 to 29, or a pharma- ceutically acceptable salt thereof, wherein each of is independently hydrogen or unsubstituted alkyl.

33. R ６ａ and R ６ｂ 30. The compound according to any one of claims 1 to 29, or a pharma- ceutically acceptable salt thereof, wherein both are hydrogen.

34. R ６ａ is halo or substituted or unsubstituted alkyl, and R ６ｂ 30. The compound according to any one of claims 1 to 29, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

35. R ６ａ and R ６ｂ 30. The compound of any one of claims 1 to 29, or a pharma- ceutically acceptable salt thereof, wherein both are halo.

36. R ６ａ and R ６ｂ 30. The compound of any one of claims 1 to 29, or a pharma- ceutically acceptable salt thereof, wherein both are substituted or unsubstituted alkyl.

37. R ７ａ and R ７ｂ each independently represents hydrogen, halogen, -CN, -NO ２ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR Ｅ５ , -OC(=O)R Ｅ５ , -OS(=O) ２ OR Ｅ５ , -N(R Ｅ５ ) ２ , -N(R Ｅ５ ) C(=O)R Ｅ５ , -N(R Ｅ５ ) S(=O) ２ R Ｅ５ , or -N(R Ｅ５ ) S(=O) ２ OR Ｅ５ where each R Ｅ５ are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R Ｅ５ 37. The compound of any one of claims 1 to 36, or a pharma- ceutically acceptable salt thereof, wherein the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring.

38. R ７ａ and R ７ｂ each independently represents hydrogen, halogen, -CN, -NO ２ , -OR Ｆ６ , -OC(=O)R Ｆ６ , -N(R Ｆ６ ) ２ , or -N(R Ｆ６ ) C(=O)R Ｆ６ where each R Ｆ６ are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or two R Ｆ６ 37. The compound of any one of claims 1 to 36, or a pharma- ceutically acceptable salt thereof, wherein the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring.

39. R ７ａ and R ７ｂ each independently represents hydrogen, —OH, or a substituted or unsubstituted C １～６ Alkyl, or substituted or unsubstituted C １～６ 39. The compound of any one of claims 1 to 38, or a pharma- ceutically acceptable salt thereof, which is alkoxy.

40. R ７ａ and R ７ｂ each independently represents hydrogen, —OH, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, or C １～６ 39. The compound of any one of claims 1 to 38, or a pharma- ceutically acceptable salt thereof, which is alkoxyhalo.

41. R ７ａ and R ７ｂ each independently represents hydrogen, —CH ３ , -CH ２ CH ３ , -OH, -OCH ３ , or -CH(CH ３ ) ２ 39. The compound according to any one of claims 1 to 38, wherein:

42. R ７ａ and R ７ｂ The compound according to any one of claims 1 to 38, or a pharma- ceutically acceptable salt thereof, wherein both are hydrogen.

43. R ７ａ and R ７ｂ The compound according to any one of claims 1 to 38, or a pharma- ceutically acceptable salt thereof, wherein:

44. R １１ａ and R １１ｂ each independently represents hydrogen, halogen, -CN, -NO ２ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR Ｅ５ , -OC(=O)R Ｅ５ , -OS(=O) ２ OR Ｅ５ , -N(R Ｅ５ ) ２ , -N(R Ｅ５ ) C(=O)R Ｅ５ , -N(R Ｅ５ ) S(=O) ２ R Ｅ５ , or -N(R Ｅ５ ) S(=O) ２ OR Ｅ５ where each R Ｅ５ are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R Ｅ５ 44. The compound of any one of claims 1 to 43, or a pharma- ceutically acceptable salt thereof, wherein the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring.

45. R １１ａ and R １１ｂ each independently represents hydrogen, halogen, -CN, -NO ２ , -OR Ｆ６ , -OC(=O)R Ｆ６ , -N(R Ｆ６ ) ２ , or -N(R Ｆ６ ) C(=O)R Ｆ６ and each R Ｆ６ are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or two R Ｆ６ 44. The compound of any one of claims 1 to 43, or a pharma- ceutically acceptable salt thereof, wherein the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring.

46. R １１ａ and R １１ｂ each independently represents hydrogen, —OH, or a substituted or unsubstituted C １～６ Alkyl, or substituted or unsubstituted C １～６ 44. The compound of any one of claims 1 to 43, or a pharma- ceutically acceptable salt thereof, which is alkoxy.

47. R １１ａ and R １１ｂ each independently represents hydrogen, —OH, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, or C １～６ 44. The compound of any one of claims 1 to 43, or a pharma- ceutically acceptable salt thereof, which is alkoxyhalo.

48. R １１ａ and R １１ｂ each independently represents hydrogen, —CH ３ , -CH ２ CH ３ , -OH, -OCH ３ , or -CH(CH ３ ) ２ 44. The compound according to any one of claims 1 to 43, wherein:

49. R １１ａ and R １１ｂ The compound according to any one of claims 1 to 43, or a pharma- ceutically acceptable salt thereof, wherein both are hydrogen.

50. R １１ａ and R １１ｂ The compound according to any one of claims 1 to 43, or a pharma- ceutically acceptable salt thereof, wherein: taken together, form an oxo (=O) group.

51. R １２ａ and R １２ｂ each independently represents hydrogen, halogen, -CN, -NO ２ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR Ｅ５ , -OC(=O)R Ｅ５ , -OS(=O) ２ OR Ｅ５ , -N(R Ｅ５ ) ２ , -N(R Ｅ５ ) C(=O)R Ｅ５ , -N(R Ｅ５ ) S(=O) ２ R Ｅ５ , or -N(R Ｅ５ ) S(=O) ２ OR Ｅ５ where each R Ｅ５ are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R Ｅ５ 51. The compound of any one of claims 1 to 50, or a pharma- ceutically acceptable salt thereof, wherein the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring.

52. R １２ａ and R １２ｂ each independently represents hydrogen, halogen, -CN, -NO ２ , -OR Ｆ６ , -OC(=O)R Ｆ６ , -N(R Ｆ６ ) ２ , or -N(R Ｆ６ ) C(=O)R Ｆ６ where each R Ｆ６ are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or two R Ｆ６ 51. The compound of any one of claims 1 to 50, or a pharma- ceutically acceptable salt thereof, wherein the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring.

53. R １２ａ and R １２ｂ each independently represents hydrogen, —OH, or a substituted or unsubstituted C １～６ Alkyl, or substituted or unsubstituted C １～６ 51. The compound of any one of claims 1 to 50, or a pharma- ceutically acceptable salt thereof, which is alkoxy.

54. R １２ａ and R １２ｂ each independently represents hydrogen, —OH, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, or C １～６ 51. The compound of any one of claims 1 to 50, or a pharma- ceutically acceptable salt thereof, which is alkoxyhalo.

55. R １２ａ and R １２ｂ each independently represents -CH ３ , -CH ２ CH ３ , -OH, -OCH ３ , or -CH(CH ３ ) ２ 51. The compound according to any one of claims 1 to 50, wherein:

56. R １２ａ and R １２ｂ 51. The compound of any one of claims 1 to 50, or a pharma- ceutically acceptable salt thereof, wherein both are hydrogen.

57. R １２ａ and R １２ｂ or a pharma- ceutically acceptable salt thereof. The compound of any one of claims 1 to 50, wherein:

58. R １７ｂ 58. The compound according to any one of claims 1 to 57, or a pharma- ceutically acceptable salt thereof, wherein is fluorine, hydroxyl, methyl, hydrogen, or deuterium.

59. R １９ is a substituted or unsubstituted C ３～６ Carbocyclyl, or substituted or unsubstituted C ６～１０ 59. The compound of any one of claims 1 to 58, or a pharma- ceutically acceptable salt thereof, which is aryl.

60. R １９ is a substituted or unsubstituted C ３～６ 59. The compound of any one of claims 1 to 58, or a pharma- ceutically acceptable salt thereof, which is carbocyclyl.

61. R １９ is a substituted or unsubstituted C ６～１０ 59. The compound of any one of claims 1 to 58, or a pharma- ceutically acceptable salt thereof, which is aryl.

62. R １９ is a group represented by the formula: 【Chemistry 53】 selected from the group consisting of: Where: Each R ｂ are independently hydrogen, halogen, -NO ２ , -CN, -OR Ｇ７ , -N(R Ｇ７ ) ２ , -C(=O)R Ｇ７ , -C(=O)OR Ｇ７ , -C(=O)N(R Ｇ７ ) ２ , -OC(=O)R Ｇ７ , -OC(=O)OR Ｇ７ , -N(R Ｇ７ ) C(=O)R Ｇ７ , -OC(=O)N(R Ｇ７ ) ２ , -N(R Ｇ７ ) C(=O)OR Ｇ７ , -S(=O) ２ R Ｇ７ , -S(=O) ２ OR Ｇ７ , -OS(=O) ２ R Ｇ７ , -S(=O) ２ N (R Ｇ７ ) ２ , or -N(R Ｇ７ ) S(=O) ２ R Ｇ７ , 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 ３～６ Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted C ６～１０ aryl, substituted or unsubstituted 5-10 membered heteroaryl; Each R Ｇ７ are 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 ３～６ Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted C ６～１０ aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, or two R Ｇ７ the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring; and 59. The compound according to any one of claims 1 to 58, or a pharma- ceutically acceptable salt thereof, wherein q is an integer selected from 0 to 11.

63. 63. The compound according to any one of claims 1 to 62, or a pharma- ceutically acceptable salt thereof, wherein n is 0.

64. 63. The compound according to any one of claims 1 to 62, or a pharma- ceutically acceptable salt thereof, wherein n is 1.

65. 63. The compound according to any one of claims 1 to 62, or a pharma- ceutically acceptable salt thereof, wherein n is 2.

66. The compound of formula (I) is a compound of formula (I-a): 【Chemical 54】 (I-a) or a pharma- ceutically acceptable salt thereof; Where: The partial structure of the formula 【Chemical 66A】 is as defined in claim 1; and R １ , R ３ａ , R ５ , R ６ａ , R ６ｂ , R １２ａ , R １２ｂ , R １６ａ , R １６ｂ , R １９ and n are each as defined in claim 1; 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

67. The compound of formula (I) may be a compound of formula (I-b): 【Chemistry 55】 (I-b) or a pharma- ceutically acceptable salt thereof; Where: R １ , R １９ and n are each as defined in claim 1; 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

68. The compound of formula (I) may be a compound of formula (I-c): 【Chemistry 56】 (I-c) or a pharma- ceutically acceptable salt thereof; Where: R １ , R １９ and n are each as defined in claim 1; 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

69. The compound of formula (I) may be a compound of formula (I-d): 【Chemistry 57】 (I-d) or a pharma- ceutically acceptable salt thereof. [In the formula, R １９ and n is as defined in claim 1; Each R ａ is independently halogen, cyano, hydroxyl, or substituted or unsubstituted alkyl; and p is 0, 1, 2 or 3.

70. The compound of formula (I) may be a compound of formula (I-e): 【Chemistry 58】 (I-e) or a pharma- ceutically acceptable salt thereof. [In the formula, R ３ａ , R ５ , R １９ and n are each as defined in claim 1; and Each X is independently -C(R Ｎ ) -, -C(R Ｎ ) ２ -, -O-, -S-, -N-, or -N(R Ｎ )-, where each R Ｎ are independently hydrogen, substituted or unsubstituted C １～６ Alkyl, -C(=O)R ＧＡ , -C(=O)OR ＧＡ , -C(=O)N(R ＧＡ ) ２ , -S(=O) ２ R ＧＡ Or -S(=O) ２ N (R ＧＡ ) ２ and each R ＧＡ are independently hydrogen, substituted or unsubstituted C １～６ Alkyl, substituted or unsubstituted C ２～６ Alkenyl, substituted or unsubstituted C ２～６ Alkynyl, substituted or unsubstituted C ３～６ carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or two R ＧＡ The groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclyl or heteroaryl ring.

71. The compound of formula (I) may be a compound of formula (If): 【Chemistry 59】 (If) or a pharma- ceutically acceptable salt thereof. [In the formula, R ３ａ , R ５ , R １９ and n are each as defined in claim 1; and Each X is independently -C(R Ｎ ) -, -C(R Ｎ ) ２ -, -O-, -S-, -N-, or -N(R Ｎ )-, where each R Ｎ are independently hydrogen, substituted or unsubstituted C １～６ Alkyl, -C(=O)R ＧＡ , -C(=O)OR ＧＡ , -C(=O)N(R ＧＡ ) ２ , -S(=O) ２ R ＧＡ Or -S(=O) ２ N (R ＧＡ ) ２ and each R ＧＡ are independently hydrogen, substituted or unsubstituted C １～６ Alkyl, substituted or unsubstituted C ２～６ Alkenyl, substituted or unsubstituted C ２～６ Alkynyl, substituted or unsubstituted C ３～６ carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or two R ＧＡ The groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclyl or heteroaryl ring.

72. The compound of formula (I) may be a compound of formula (I-g): 【Chemistry 60】 (I-g) or a pharma- ceutically acceptable salt thereof. [In the formula, The partial structure of the formula 【Chemical Formula 72】 is as defined in claim 1; R ３ａ , R ５ , R ６ａ , R ６ｂ , and R １９ each of which is as defined in claim 1; Each R ａ is independently halogen, alkyl, hydroxyl, or cyano; and and p is an integer selected from 0 to 11.

73. The compound of formula (I) may be a compound of formula (I-h): 【Chemistry 61】 (I-h) or a pharma- ceutically acceptable salt thereof. [In the formula, The partial structure of the formula 【Chemical 73】 is as defined in claim 1, R ３ａ , R ５ , R ６ａ , R ６ｂ , R １９ and n are each as defined in claim 1, and Each X is independently -C(R Ｎ ) -, -C(R Ｎ ) ２ -, -O-, -S-, -N-, or -N(R Ｎ )-, where each R Ｎ are independently hydrogen, substituted or unsubstituted C １～６ Alkyl, -C(=O)R ＧＡ , -C(=O)OR ＧＡ , -C(=O)N(R ＧＡ ) ２ , -S(=O) ２ R ＧＡ Or -S(=O) ２ N (R ＧＡ ) ２ and each R ＧＡ are independently hydrogen, substituted or unsubstituted C １～６ Alkyl, substituted or unsubstituted C ２～６ Alkenyl, substituted or unsubstituted C ２～６ Alkynyl, substituted or unsubstituted C ３～６ carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or two R ＧＡ The groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclyl or heteroaryl ring.

74. The following compounds A9, A11, 4.12, 5.2, 6, 7.4 and 8.2b: 【Chemistry 101】 【Chemistry 102】 or a pharma- ceutically acceptable salt thereof. Claim 75: Compounds A9, A11, 4.12, 5.2, 6, 7.4 and 8.2b: 【Chemistry 75-1】 【Chemistry 75-2】 A compound selected from:

76. 76. A pharmaceutical composition comprising a compound according to any one of claims 1 to 75 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

77. 77. A composition comprising a compound according to any one of claims 1 to 75 or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition according to claim 76 for treating a CNS-related disorder in a subject in need thereof, wherein the CNS-related disorder is depression, seizures, tremors, sleep disorders, mood disorders, schizophrenia spectrum disorders, convulsive disorders, epileptic seizures, memory and / or cognition disorders, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and / or withdrawal syndromes, tinnitus, or status epilepticus.

78. 78. The composition or pharmaceutical composition of claim 77, wherein the CNS-related disorder is depression.

79. 79. The composition or pharmaceutical composition of claim 78, wherein the depression is postpartum depression.

80. 79. The composition or pharmaceutical composition of claim 78, wherein the depression is major depressive disorder.

81. 78. The composition or pharmaceutical composition of claim 77, wherein the CNS-related disorder is seizures.

82. 78. The composition or pharmaceutical composition of claim 77, wherein the CNS-related disorder is tremor.

83. A composition comprising a compound according to any one of claims 1 to 75 or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition according to claim 76, for inducing sedation and / or anesthesia in a subject in need thereof.

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