Compositions and methods for treating CNS disorders

Abstract

To provide compositions and methods for treating CNS disorders.SOLUTION: Provided is an imidazole-substituted steroid derivative represented by, for example, the following formula (I): [R1a to R16b independently represent H, an alkyl group, an alkoxyalkyl group, or the like; one of RX and RY is a hydroxyl group and the other is a methyl group; R22 represents a cyano group or the like; t represents an integer of 1 to 3; n represents an integer of 0 to 3] or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 867,618, filed June 27, 2019, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Brain excitability is defined as the level of excitement of an animal, a continuum ranging from coma to seizures, and is regulated by various neurotransmitters. In general, neurotransmitters are responsible for regulating the conduction of ions across the neuronal cell membrane. At rest, the neuronal membrane has an electrical potential (or membrane voltage) of approximately -70 mV, with the cell interior being negative with respect to the cell exterior. The electrical potential (voltage) is determined by the current of ions (K + , Na + , Cl - Neurotransmitters are stored in presynaptic vesicles and are released under the influence of an action potential of the neuron. When released into the synaptic cleft, excitatory chemical transmitters such as acetylcholine cause membrane depolarization (a change in potential occurs between -70mV and -50mV). This effect is stimulated by acetylcholine and Na + It is mediated by postsynaptic nicotinic receptors that increase 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), its influence on brain excitability is mediated by the neurotransmitter gamma-aminobutyric acid (GABA). GABA has a profound effect on overall brain excitability, as up to 40% of neurons in the brain utilize GABA as a neurotransmitter. GABA regulates the excitability of individual neurons by modulating the conductance of chloride ions across the neuronal membrane. GABA interacts with its recognition sites on the GRC to facilitate chloride ions flowing down the GRC's electrochemical gradient into the cell. An intracellular increase in the level of this anion causes a hyperpolarization of the transmembrane potential, making the neuron less susceptible to excitatory inputs, i.e., a decrease in neuronal excitability. In other words, the higher the concentration of chloride ions in the neuron, the lower the brain's excitability and arousal levels.

[0004] It is well documented that GRC is responsible for mediating anxiety, seizure activity, and sedation. Thus, GABA and drugs that act like GABA or enhance the effects of GABA (e.g., therapeutically useful barbiturates and benzodiazepines (BZ), e.g., Valium®) exert their therapeutically useful effects by interacting with specific regulatory sites on GRC. Accumulating evidence now indicates that, in addition to the binding sites for benzodiazepines and barbiturates, 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, NLet al., J Pharmacol. Exp. Ther. 241:346-353 (1987)). There is a need for new and improved compounds that function as regulators of brain excitability and as agents for the prevention and treatment of CNS-related disorders. and methods 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, MD et 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 designed to act as GABA modulators are provided herein. In some embodiments, it is envisioned that such compounds are useful as therapeutic agents for treating CNS-related disorders.

[0008] In certain embodiments, provided herein is a compound of formula I: [ka] or a pharma- ceutically acceptable salt thereof is provided, wherein the variables are as defined herein.

[0009] In some embodiments, provided herein is a compound of formula II: [ka] or a pharma- ceutically acceptable salt thereof is provided, wherein the variables are as defined herein.

[0010] In some embodiments, the compound of formula II is a compound of formula IIIa or IIIb: [ka] or a pharma- ceutically acceptable salt thereof, in which the variables are as defined herein.

[0011] In some embodiments, provided herein is a compound of formula V: [ka] or a pharma- ceutically acceptable salt thereof is provided, wherein the variables are as defined herein.

[0012] In certain embodiments, provided herein are compounds of formula VIa or VIb: [ka] or a pharma- ceutically acceptable salt thereof is provided, wherein the variables are as defined herein.

[0013] In some embodiments, provided herein is a compound of formula VII: [ka] or a pharma- ceutically acceptable salt thereof is provided, wherein the variables are as defined herein.

[0014] In some embodiments, provided herein is a compound of formula VIII: [ka] or a pharma- ceutically acceptable salt thereof is provided, wherein the variables are as defined herein.

[0015] In some embodiments, provided herein is a compound of formula IX: [ka] or a pharma- ceutically acceptable salt thereof is provided, wherein the variables are as defined herein.

[0016] In some embodiments, provided herein is a compound of formula X: [ka] or a pharma- ceutically acceptable salt thereof is provided, wherein the variables are as defined herein.

[0017] In one aspect, provided herein are pharma- ceutically acceptable salts of the compounds described herein (e.g., compounds of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X).

[0018] In one aspect, provided herein is a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient. In certain embodiments, the compound of the present invention is provided in the pharmaceutical composition in an effective amount. In certain embodiments, the compound of the present invention is provided in a therapeutically effective amount.

[0019] In one aspect, a method for treating a CNS-related disorder in a subject in need thereof comprises administering to the subject an effective amount of a compound described herein or a pharma- ceutically acceptable salt thereof. In some embodiments, the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive 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 withdrawal syndrome, tinnitus, or status epilepticus. In some embodiments, the CNS-related disorder is depression. In some embodiments, the CNS-related disorder is postpartum depression. In some embodiments, the CNS-related disorder is major depressive disorder. In some embodiments, the major depressive disorder is moderate major depressive disorder. In some embodiments, the major depressive disorder is severe major depressive disorder.

[0020] In some embodiments, the compound is selected from the group consisting of the compounds identified in Table 1 herein.

[0021] The compounds of the invention described herein, in certain embodiments, function as GABA modulators, e.g., GABA A GABA acts on receptors in either a positive or negative manner as a regulator of central nervous system (CNS) excitability. A Such compounds are expected to have CNS activity, as mediated by their ability to modulate receptors.

[0022] Therefore, in another aspect, a method for performing a CNS-related disorder in a subject in need thereof is provided, comprising administering to the subject an effective amount of a compound of the present invention. 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 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 withdrawal syndrome, tinnitus, or status epilepticus. In certain embodiments, the CNS-related disorder is depression. In certain embodiments, the CNS-related disorder is postpartum depression. In certain embodiments, the CNS-related disorder is major depressive disorder. In certain embodiments, the major depressive disorder is moderate major depressive disorder. In certain embodiments, the major depressive disorder is severe major depressive disorder. In certain embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In certain embodiments, the compound is administered orally. In certain embodiments, the compound is administered chronically. In certain embodiments, the compounds are administered continuously, for example, by continuous intravenous infusion. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] As generally described herein, the present invention relates to a method for treating, and / or preventing, inflammatory bowel disease, including, for example, GABA. A Compounds designed to function as receptor modulators are provided. In certain embodiments, such compounds Such compounds are contemplated to be useful as therapeutic agents for treating CNS-related disorders (e.g., disorders described herein, e.g., depression such as postpartum depression or major depressive disorder).

[0024] definition chemical definition Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS edition, Handbook of Chemistry and Physics, 75th Ed. inside pages, and specific functional groups are generally defined as described herein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley&Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0025] Isomers, e.g., stereoisomers, can be isolated from mixtures by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers can be prepared by asymmetric synthesis (see, 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.

[0026] "Stereoisomers": It should also be understood that compounds that have identical molecular formulas but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are referred to as "isomers". Isomers that differ in the arrangement of their atoms in space are referred to as "stereoisomers". Stereoisomers that are not mirror images of each other are referred to as "diastereomers" and stereoisomers that are non-superimposable mirror images of each other are referred to as "enantiomers". When a compound has an asymmetric center, for example, when a compound is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and described by the R- and S-sequencing rules of Cahn and Prelog or by the way in which a molecule rotates the plane of polarized light and is designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers, respectively). A mixture containing equal proportions of enantiomers is referred to as a "racemic mixture".

[0027] As used herein, a pure enantiomer compound is substantially free of the other enantiomer or stereoisomer of the compound (i.e., in enantiomeric excess). In other words, the "S" forms of the compound are substantially free of the "R" forms of the compound, and thus , enantiomeric excess of the "R" form. The term "enantiomerically pure" or "pure enantiomer" means that a compound contains more than 75%, more than 80%, more than 85%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 98.5%, more than 99%, more than 99.2%, more than 99.5%, more than 99.6%, more than 99.7%, more than 99.8%, or more than 99.9% by weight of an enantiomer. In certain embodiments, the weights are based on the total weight of all enantiomers or stereoisomers of the compound.

[0028] 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 position / center / carbon compound may comprise, for example, about 90% excipient and about 10% enantiomerically pure R compound. In certain embodiments, the enantiomerically pure R compound in such a composition may comprise, for example, at least about 95% by weight of the R compound and at most about 5% by weight of the S compound, based on the total weight of the compound. For example, a pharmaceutical composition comprising an enantiomerically pure S compound may comprise, for example, about 90% excipient and about 10% enantiomerically pure S compound. In certain embodiments, the enantiomerically pure S compound in such a composition may comprise, for example, at least about 95% by weight of the S compound and at most about 5% by weight of the R compound, based on the total weight of the compound. In certain embodiments, the active ingredient may be formulated with little or no excipient or carrier.

[0029] The term "diastereomerically pure" means that a compound contains more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight, or more than 99.9% by weight of a single diastereomer. Methods for determining diastereomeric and enantiomeric purity are well known in the art. Diastereomeric purity can be determined by any analytical method capable of quantitatively distinguishing a compound from its diastereomer, for example, high performance liquid chromatography (HPLC).

[0030] 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.

[0031] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1~6 Alkyl" is C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , 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.

[0032] The following terms are intended to have the meanings presented below and are useful in understanding the description and intended scope of the present invention.

[0033] "Alkyl" refers to the radical of a linear or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1~20 In some embodiments, an 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, an alkyl group has 1 to 9 carbon atoms ("C 1~9 Alki In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1~8 In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1~7 In some embodiments, an 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, an alkyl group has 1 to 4 carbon atoms ("C 1~4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1~3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1~2 In some embodiments, the alkyl group has one carbon atom ("C 1 In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C 2~6 "Alkyl"). C 1~6 Examples of alkyl groups include methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-Butyl (C4 ), tertiary butyl (C 4 ), sec-Butyl (C 4 ), iso-butyl (C 4 ), n-pentyl (C 5 ), 3-pentanyl (C 5 ), Amyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ), and n-hexyl (C 6 Additional examples of alkyl groups include n-heptyl (C 7 ), n-octyl (C 8 Unless otherwise specified, each example of an alkyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents, e.g., 1-5 substituents, 1-3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1~10 Alkyl (e.g., -CH 3 In certain embodiments, the alkyl group is a substituted C 1~10 It is an alkyl group. A common abbreviation for alkyl is Me(-CH 3 ), Et(-CH 2 CH 3 ), iPr(-CH(CH 3 ) 2 ), nPr(-CH 2 CH 2 CH 3 ), n-Bu(-CH 2 CH 2 CH 2 CH 3 ), or i-Bu(-CH 2 CH(CH 3 ) 2 ) are mentioned.

[0034] "Alkylene" refers to an alkyl group in which two hydrogens are removed to provide a divalent radical, which may be substituted or unsubstituted. Unsubstituted alkylene groups include methylene (-CH 2 -), ethylene (-CH2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), butylene (-CH 2 CH 2 CH 2 CH 2 -), pentylene (-CH 2 CH 2 CH 2 CH 2 CH 2 -), hexylene (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 For example, an exemplary substituted alkylene group substituted with one or more alkyl (methyl) groups includes, but is not limited to, a substituted methylene (-CH(CH 3 )-, (-C(CH 3 ) 2 -), substituted ethylene (-CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, -C(CH 3 ) 2 CH 2 -, -CH 2 C(CH 3 ) 2 -), substituted propylene (-CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH 2 CH(CH 3 )-, -C(CH 3 ) 2 CH 2 CH 2 -, -CH 2 C(CH 3 ) 2 CH 2 -, -CH 2 CH 2 C(CH 3 ) 2-), and the like. When a range or number of carbons is provided for a particular alkylene group, it is understood that the range or number refers to the range or number of carbons in a linear carbon divalent chain. The alkylene group can be substituted or unsubstituted with one or more substituents described herein.

[0035] "Alkenyl" refers to the radical of a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) ("C 2~20 In certain embodiments, an alkenyl does not contain a triple bond. In some embodiments, an 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 (" C 2~8 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, the alkenyl group has two carbon atoms ("C 2 alkenyl). The one or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). 2~4 An example of an alkenyl is ethenyl (C2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ) etc. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4 Alkenyl groups, as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 Additional examples of alkenyl include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 Unless otherwise specified, each example of an alkenyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1-5 substituents, 1-3 substituents, or 1 substituent ("substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2~10 In certain embodiments, the alkenyl group is a substituted C 2~10 It is alkenyl.

[0036] "Alkynyl" refers to the radical of a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) ("C 2~20 In certain embodiments, an alkenyl does not contain a double bond. In some embodiments, an alkynyl group has 2 to 10 carbon atoms ("C 2~10 In some embodiments, the alkynyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C 2~8In 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, the alkynyl group has two carbon atoms ("C 2 The one or more carbon-carbon triple bonds can be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). 2~4 Examples of alkynyl include, without limitation, ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ) etc. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4 Alkynyl groups, as well as pentynyl (C 5 ), Hexynyl (C 6 Additional examples of alkynyl include heptynyl (C 7 ), Octynyl (C 8 Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1-5 substituents, 1-3 substituents, or 1 substituent ("substituted alkenyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2~10 In certain embodiments, the alkynyl group is a substituted C 2~10 It is alkynyl.

[0037] As used herein, the term "heteroalkyl" refers to one or more ( Heteroalkyl groups refer to alkyl groups, as defined herein, that further comprise (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), where one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or where one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, heteroalkyl groups refer to saturated groups having 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~10 In some embodiments, a heteroalkyl group is a saturated group having 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 1~6 In 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 1 heteroatom ("heteroC 1~3 In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom ("heteroC 1~2In some embodiments, a heteroalkyl group is a saturated group having one carbon atom and one heteroatom ("heteroC 1 In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 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, a 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.

[0038] "Aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) 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 six ring carbon atoms ("C 6 aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14"Aryl"; e.g., anthracyl). "Aryl" also includes ring systems in which the aryl ring is fused with one or more carbocyclyl or heterocyclyl groups, as defined above, and the radical or point of attachment is on the aryl ring, and in such instances the number of carbon atoms continues to designate the number of carbon atoms in the aryl ring system. Exemplary 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, and trinaphthalene. In particular, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each example of an aryl group is independently optionally Substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C 6~14 In certain embodiments, the aryl group is a substituted C 6~14 It is aryl.

[0039] In certain embodiments, the aryl group is halo, C 1~8 Alkyl, C 1~8 Haloalkyl, cyano, hydroxy, C 1~8 It is substituted with one or more groups selected from alkoxy and amino.

[0040] 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 1~8 Alkyl, C 1~8 Haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C 1~8 Alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 , N.R. 58 SOR 59 , N.R. 58 SO 2 R 59 , COO alkyl, COO aryl, CONR 58 R 59 ,CONR 58 OR 59 , N.R. 58 R 59 , S.O. 2 NR 58 R 59 , S-alkyl, SO alkyl, SO 2 Alkyl, S aryl, SO aryl, SO 2 aryl, or R 56 and R 57 can be joined to form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms, optionally containing one or more heteroatoms selected from N, O, or S. 60 and R 61 are independently hydrogen, C 1~8 Alkyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 4-10 membered heterocyclyl, C 6~10 Aryl, Substituted C 6~10 It is aryl, 5- to 10-membered heteroaryl, or substituted 5- to 10-membered heteroaryl.

[0041] "Fused aryl" refers to an aryl having two of its ring carbons in common with a second aryl or heteroaryl ring, or a carbocyclic or heterocyclic ring.

[0042] "Heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) 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 heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, as valence permits. 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 with one or more carbocyclyl or heterocyclyl groups, the point of attachment being on the heteroaryl ring, and in such instances the number of ring members continues to designate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused with one or more aryl groups, and the point of attachment can be on either the aryl or heteroaryl ring, and in such instances the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. For bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., either the ring with a heteroatom (e.g., 2-indolyl) or the ring without a heteroatom (e.g., 5-indolyl).

[0043] 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- to 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 aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, the heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0044] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0045] Representative examples of heteroaryls include: [ka] In the formula, each Z is carbonyl, N, NR 65 , O, and S; R 65 are independently hydrogen, C 1~8 Alkyl, C3~10 Cycloalkyl, 4-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl.

[0046] "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). Exemplary C 3~6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ) and others. 3~8 The carbocyclyl group is not limited to the above-mentioned C 3~6 Carbocyclyl groups, as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C8 ) and others. 3~10 The carbocyclyl group is not limited to the above-mentioned C 3~8 Carbocyclyl groups, as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or includes 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 the carbocyclyl ring defined above is fused with one or more aryl or heteroaryl groups, the point of attachment being on the carbocyclyl ring, and in such instances the number of carbons continues to designate the number of carbons in the carbocyclic ring system. 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.

[0047] 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 3~6In 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 (C 5 ) and cyclohexyl (C 5 ) are listed. C 3~6 Examples of cycloalkyl groups include the above-mentioned C 5~6 Cycloalkyl groups, as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ) are listed. C 3~8 Examples of cycloalkyl groups include the above-mentioned C 3~6 Cycloalkyl groups, such as cycloheptyl (C 7 ) and cyclooctyl (C 8 Unless otherwise specified, each example of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl") with one or more substituents. In certain embodiments, a cycloalkyl group is an unsubstituted C 3~10 In certain embodiments, the cycloalkyl group is a substituted C 3~10 It is cycloalkyl.

[0048] "Heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 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, where valence permits. Heterocyclyl groups may be either monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic heterocyclyl"), and 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 (the point of attachment is on either the carbocyclyl or heterocyclyl ring) or to one or more aryl or heteroaryl groups (the point of attachment is on the heterocyclyl ring), and in such instances the number of ring members continues to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-10 membered heterocyclyl.

[0049] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each of which is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each of which is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having carbon atoms and 1-4 ring heteroatoms, each of which is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, a 5-6 membered heterocyclyl group has 1-3 rings 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. Heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0050] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl, and thiocanyl. C 6 Exemplary 5-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0051] 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-alkylpiperazine, such as N-methylpiperazine. Particular examples include azetidine, piperidone, and piperazone.

[0052] "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, such as alkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g., heteroaryl, cycloalkenyl, e.g., cycloheteroalkenyl, having 1 to 5, especially 1 to 3, heteroatoms.

[0053] "Acyl" is the radical -C(O)R 20 R 20 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, as defined herein. "Alkanoyl" is an acyl group, R 20 is a group other than hydrogen. Representative acyl groups are formyl (-CHO), acetyl (-C(=O)CH 3 ), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH 2 Ph), --C(O)-C 1~8 Alkyl, -C( O)-(CH 2 ) t (C6~10 aryl), -C(O)-(CH 2 ) t (5-10 membered heteroaryl), -C(O)-(CH 2 ) t (C 3~10 cycloalkyl), and -C(O)-(CH 2 ) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4. 21 is a halo or hydroxy substituted C 1~8 Alkyl, or C 3~10 Cycloalkyl, 4-10 membered heterocyclyl, C 6~10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is an unsubstituted C 1~4 Alkyl, halo, unsubstituted C 1~4 Alkoxy, unsubstituted C 1~4 Haloalkyl, unsubstituted C 1~4 Hydroxyalkyl, or unsubstituted C 1~4 Substituted with haloalkoxy or hydroxy.

[0054] "Alkoxy" is -OR 29 R refers to the group 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, tertiary butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e., alkoxy having 1 to 6 carbon atoms. Further particular alkoxy groups have 1 to 4 carbon atoms.

[0055] In certain embodiments, R 29 is amino, substituted amino, C 6~10Aryl, aryloxy, carboxyl, cyano, C 3~10 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, and particularly 1 to 3 substituents, especially 1 substituent, selected from the group consisting of: -. Exemplary "substituted alkoxy" groups include -O-(CH 2 ) t (C 6~10 Aryl), -O-(CH 2 ) t (5-10 membered heteroaryl), -O-(CH 2 ) t (C 3~10 cycloalkyl), and -O-(CH 2 ) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present is itself an unsubstituted C 1~4 Alkyl, halo, unsubstituted C 1~4 Alkoxy, unsubstituted C 1~4 Haloalkyl, unsubstituted C 1~4 Hydroxyalkyl, or unsubstituted C 1~4 It may be substituted by haloalkoxy or hydroxy. A specific exemplary "substituted alkoxy" group is -OCF 3 , -OCH 2 CF 3 , -OCH 2 Ph, -OCH 2 -Cyclopropyl, -OCH 2 CH 2 OH and -OCH 2 CH 2 NMe 2 It is.

[0056] "Amino" is the radical -NH 2 Refers to...

[0057] An "oxo group" refers to -C(=O)-.

[0058] "Substituted amino" refers to a group of the formula -N(R 38 ) 2 In the formula, 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; R 38 At least one of R is not hydrogen. 38 are independently hydrogen, C 1~8 Alkyl, C 3~8 Alkenyl, C 3~8 Alkynyl, C 6~10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, or C 3~10 Cycloalkyl; or halo or hydroxy substituted C 1~8 Alkyl; halo or hydroxy substituted C 3~8 Alkenyl, halo or Hydroxy-substituted C 3~8 Alkynyl, or -(CH 2 ) t (C 6~10 Aryl), -(CH 2 ) t (5-10 membered heteroaryl), -(CH 2 ) t (C 3~10 cycloalkyl), or -(CH 2 ) t (4-10 membered heterocyclyl), t is an integer from 0 to 8, each of which is selected from unsubstituted C 1~4 Alkyl, halo, unsubstituted C 1~4 Alkoxy, unsubstituted C 1~4 Haloalkyl, unsubstituted C 1~4 Hydroxyalkyl, or unsubstituted C 1~4 or both R are substituted by haloalkoxy or hydroxy. 38are joined to form an alkylene group.

[0059] Exemplary "substituted amino" groups include -NR 39 -C 1~8 Alkyl, -NR 39 -(CH 2 ) t (C 6~10 Aryl), -NR 39 -(CH 2 ) t (5-10 membered heteroaryl), -NR 39 -(CH 2 ) t (C 3~10 cycloalkyl), and -NR 39 -(CH 2 ) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4, e.g., 1 or 2, and each R 39 are independently H or C 1~8 represents an alkyl group, where any alkyl group present may itself be substituted by halo, substituted or unsubstituted amino, or hydroxy, and any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present may itself be unsubstituted C 1~4 Alkyl, halo, unsubstituted C 1~4 Alkoxy, unsubstituted C 1~4 Haloalkyl, unsubstituted C 1~4 Hydroxyalkyl, or unsubstituted C 1~4 It may be substituted by haloalkyl or hydroxy. For the avoidance of doubt, the term "substituted amino" includes alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino groups as defined below. Substituted amino includes both mono- and di-substituted amino groups.

[0060] "Carboxy" refers to the radical -C(O)OH.

[0061] "Cyano" refers to the radical -CN.

[0062] "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.

[0063] "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.

[0064] "Hydroxy" refers to the radical -OH.

[0065] "Nitro" is the radical -NO 2 Refers to...

[0066] "Thioketo" refers to the =S group.

[0067] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups as defined herein are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, "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 allowed to substituted. Substituents, for example, are meant to be replaced with a substituent that upon substitution results in a stable compound, for example, 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 of any given structure is substituted, the substituents are either the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, any of the substituents described herein, that result in the formation of a stable compound. The present invention contemplates any and all such combinations to arrive at a stable compound. For purposes of this invention, heteroatoms, such as nitrogen, may have hydrogen substituents and / or any suitable substituents described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety.

[0068] Exemplary carbon atom substituents include halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -OH, -OR aa , -ON(R bb ) 2 , -N(R bb ) 2 , -N(R bb ) 3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO 2 H, -CHO, -C(OR cc ) 2 , -CO 2 R aa , -OC(=O)R aa , -OCO 2 R aa , -C(=O)N(R bb ) 2 , -OC(=O)N(R bb ) 2 , -NRbb C(=O)R aa 、-NR bb CO 2 R 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 SO 2 R aa 、-NR bb SO 2 R aa 、-SO 2 N(R bb ) 2 、-SO 2 R aa 、-SO 2 OR aa 、-OSO 2 R 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)2 R aa , -OP(=O) 2 R aa , -P(=O)(R aa ) 2 , -OP(=O)(R aa ) 2 ,-OP(=O)(OR cc ) 2 , -P(=O) 2 N(R bb ) 2 , -OP(=O) 2 N(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 Each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd group or the two geminal hydrogens on the carbon atom are replaced by the groups =O, =S, =NN(R bb )2 , =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O) 2 R aa , =NR bb , or =NOR cc is replaced by R aa Each instance of is independently 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 aa groups are joined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, R bb Each instance of is independently hydrogen, -OH, -OR aa , -N(R cc ) 2 , -CN, -C(=O)R aa , -C(=O)N(R cc ) 2 , -CO 2 R aa , -SO 2 R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N (R cc ) 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C(=S)N(Rcc ) 2 , -C(=O)SR cc , -C(=S)SR cc , -P(=O) 2 R aa , -P(=O)(R aa ) 2 , -P(=O) 2 N(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 bb groups are joined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and 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 instance of 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 groups are joined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and 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 a halogen, -CN, -NO 2 , -N 3 , -SO 2H、-SO 3 H、-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 、-CO 2 H、-CO 2 R ee 、-OC(=O)R ee 、-OCO 2 R ee 、-C(=O)N(R ff ) 2 、-OC(=O)N(R ff ) 2 、-NR ff C(=O)R ee 、-NR ff CO 2 R ee 、-NR ff C(=O)N(R ff ) 2 、-C(=NR ff )OR ee 、-OC(=NR ff )R ee 、-OC(=NR ff )OR ee 、-C(=NR ff )N(R ff ) 2 、-OC(=NR ff )N(R ff ) 2 、-NR ff C(=NR ff )N(R ff ) 2 、-NR ff SO 2 R ee 、-SO 2 N(R ff ) 2 、-SO 2 R ee 、-SO 2 ORee , -OSO 2 R 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) 2 R 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, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently having 0, 1, 2, 3, 4, or 5 R gg substituted with a group or two geminal R dd the substituents can be joined to form =O or =S; R ee Each instance of is independently 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, and 3- to 10-membered heteroaryl, each of which is independently selected from 0, 1, 2, 3, 4, or 5 R gg is substituted with a group, Rff Each instance of 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- to 10-membered heteroaryl, or two R ff groups are joined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and 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, R gg Each example is independently a halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -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 Alki L) 2 + X - , -NH 2 (C 1~6 Alkyl) + X - , -NH 3 + X - , -N(OC 1~6 Alkyl)(C 1~6 alkyl), -N(OH)(C 1~6 alkyl), -NH(OH), -SH, -SC 1~6 Alkyl, -SS(C 1~6 alkyl), -C(=O)(C 1~6 Alkyl), -CO 2 H, -CO 2 (C1~6 alkyl), -OC(=O)(C 1~6 Alkyl), -OCO 2 (C 1~6 alkyl), -C(=O)NH 2 , -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), -NHCO 2 (C 1~6 alkyl), -NHC(=O)N(C 1~6 Alkyl) 2 , -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)NH 2 , -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)NH 2 , -OC(=NH)N(C 1~6 Alkyl) 2 , -OC(NH)NH(C 1~6 alkyl), -OC(NH)NH 2 , -NHC(NH)N(C 1~6 Alkyl) 2 , -NHC(=NH)NH 2 , -NHSO 2 (C 1~6 Alkyl), -SO 2 N(C 1~6 Alkyl) 2 , -SO 2 NH(C 1~6 Alkyl), -SO 2 NH 2 , -SO 2 C 1~6 Alkyl, -SO 2 O.C. 1~6 Alkyl, -OSO 2 C 1~6Alkyl, -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)NH 2 , -C(=O)S(C 1~6 Alkyl), -C(=S)SC 1~6 Alkyl, -SC(=S)SC 1~6 Alkyl, -P(=O) 2 (C 1~6 alkyl), -P(=O)(C 1~6 Alkyl) 2 , -OP(=O)(C 1~6 Alkyl) 2 , -OP(=O)(OC 1~6 Alkyl) 2 , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or two geminal R gg The substituents can be joined to form =O or =S, and X - is the counter ion.

[0069] A "counterion" or "anionic counterion" is a negatively charged group associated with a cationic quaternary amino group to maintain electronic neutrality. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO 3 - , ClO 4 - , O.H. - , H 2 PO 4 - , HSO 4 -, sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

[0070] These and other exemplary substituents are described in further detail in the detailed description and claims. The invention is not intended to be limited in any manner by the recitation of exemplary substituents above.

[0071] Other definitions As used herein, the term "modulation" refers to the A The term "modulator" (e.g., a modulatory compound) refers to the inhibition or enhancement of receptor function, e.g., GABA receptor function. A The compound may be an agonist, partial agonist, antagonist, or partial antagonist of the receptor.

[0072] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of a federal or state government or a corresponding agency in a country other than the United States, or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in animals, or more specifically, in humans.

[0073] "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) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with 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-hydroxybenzoic acid)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- or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or an equivalent with an organic base, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Salts include, by way of example only, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc., if the compound contains a basic functional group. 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, etc. See, e.g., Berge, et al., J. Pharm. Sci. (1977) 66(1):1-79.

[0074] The term "prodrug" is intended to include therapeutically inactive compounds that are converted into the therapeutically active agent of the present invention under physiological conditions.One method for making prodrugs is to design selected moieties that are hydrolyzed or cleaved at the targeted in vivo action site under physiological conditions, and then reveal the desired molecule that produces its therapeutic effect.In certain embodiments, prodrugs are converted by the enzyme activity of the subject.

[0075] In an alternative embodiment, the present invention provides prodrugs of the compounds described herein, which contain a cleavable moiety on the C3 hydroxy as shown in the formulas presented herein.

[0076] "Tautomers" refer to compounds that are interchangeable forms of a particular compound structure and change with the displacement of hydrogen atoms and electrons. Thus, two structures can be in equilibrium through the movement of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is phenylnitromethane in its aci and nitro forms, which are also formed by treatment with acid or base. Tautomeric forms can be relevant to achieving optimal chemical reactivity and biological activity of a compound of interest.

[0077] "Subjects" to which administration is contemplated include humans (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or non-human animals. In certain embodiments, the subject is a human (a "human subject"). In certain embodiments, the subject is a non-human animal.

[0078] 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 -R aa , -N(R bb ) 2 , -C(=O)SR aa , -C(=O)R aa , -CO 2 R 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 , -SO 2 R aa , -Si(R aa ) 3 , -P(R cc ) 2 , -P(R cc ) 3 , -P(=O) 2 R aa , -P(=O)(R aa ) 2 , -P(=O)(OR cc ) 2 , -P(=O) 2 N(R bb ) 2 , and -P(=O)(NR bb ) 2 These include, but are not limited to, R aa , R bb , and R cc is as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Huts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0079] 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).

[0080] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to as a thiol protecting group). Sulfur protecting groups include -R aa , -N(R bb ) 2 , -C(=O)SR aa , -C(=O)R aa , -CO 2 R 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 , -SO 2 R aa , -Si(R aa ) 3 , -P(R cc ) 2 , -P(R cc ) 3 , -P(=O) 2 R aa , -P(=O)(R aa ) 2 , -P(=O)(OR cc ) 2 , -P(=O) 2 N(R bb ) 2 , and -P(=O)(NR bb ) 2 These include, but are not limited to, R aa , R bb , and R ccis as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Huts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0081] In certain embodiments, the substituent present on the nitrogen atom is an amino protecting group (also referred to herein as a nitrogen protecting group). Amino protecting groups include -OH, -OR aa , -N(R cc ) 2 , -C(=O)R aa , -C(=O)OR aa , -C(=O)N(R cc ) 2 , -S(=O) 2 R aa , -C(=NR cc )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 OR 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 Each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 Rdd is substituted with a R aa , R bb , R cc and R dd is as defined herein. Amino protecting groups are well known in the art and are described in the Protecting Groups, which are incorporated herein by reference. Groups in Organic Synthesis,TWGreene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999.

[0082] Exemplary amino protecting groups include, but are not limited to, amide groups (e.g., -C(=O)R aa ); carbamate groups (e.g., -C(=O)OR, including, but not limited to, 9-fluorenylmethyl carbamate (Fmoc), t-butyl carbamate (BOC), and benzyl carbamate (Cbz); aa ; sulfonamide groups (e.g., -S(=O)), including, but not limited to, p-toluenesulfonamide (Ts), methanesulfonamide (Ms), and N-[2-(trimethylsilyl)ethoxy]methylamine (SEM); 2 R aa ), but are not limited to these.

[0083] Disease, disorder, and condition are used interchangeably herein.

[0084] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate actions that occur while a subject is afflicted with a specified disease, disorder, or condition and that reduce the severity of the disease, disorder, or condition or slow or decelerate the progression of the disease, disorder, or condition ("therapeutic treatment"), as well as actions that occur before a subject begins to suffer from a specified disease, disorder, or condition.

[0085] In general, the "effective amount" of a compound refers to the amount sufficient to induce the desired biological response, for example, to treat CNS-related disorder, and is sufficient to induce anesthesia or sedation.As will be understood by those skilled in the art, the effective amount of the compound of the present invention can vary depending on factors such as the desired biological end point, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health and condition of the subject.

[0086] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent that, alone or in combination with other therapies, provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves overall therapy, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0087] In an alternative embodiment, the present invention contemplates administering the compound of the present invention, or its pharma- ceutically acceptable salt or pharma- ceutically acceptable composition, as a prophylactic agent before a subject begins to suffer from a particular disease, disorder or condition.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 a disease, disorder or condition, or to prevent its recurrence.A prophylactically effective amount of a compound refers to an amount of a therapeutic agent that provides a prophylactic benefit in the prevention of a disease, disorder or condition, alone or in combination with other agents.The term "prophylactically effective amount" can include an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0088] compound It is understood that the formulas set forth herein may refer to specific carbon atoms, such as C17, C3, C19, etc. These references are based on the position of the carbon atoms according to steroid nomenclature known and used in the industry, as set forth below. [ka] For example, C17 refers to the 17th carbon and C3 refers to the 3rd carbon.

[0089] In one aspect, provided herein is a compound of formula I: [ka] or a pharma- ceutically acceptable salt thereof is provided, During the ceremony, [ka] represents a single bond or a double bond, provided that when a double bond is present, R 6a or R 6b does not exist and R 5 Provided that there is no R X Halo, -OH, -OR Q1 and substituted or unsubstituted alkyl; R Q1 is substituted or unsubstituted alkyl; R Y is halo, or substituted or unsubstituted alkyl, or R Y and R X can be joined together with intervening atoms to form a substituted or unsubstituted carbocyclyl, or a substituted or unsubstituted heterocyclyl; R 3 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R 5is hydrogen or methyl; R 22 Each example of 2 , -CN, -OR GA , -N(R GA ) 2 , -C(=O)R GA , -C(=O)OR GA , -OC(=O)R GA , -OC(=O)OR GA , -C(=O)N(R GA ) 2 , -N(R GA )C(=O)R GA , -OC(=O)N(R GA ) 2 , -N(R GA )C(=O)OR GA , -N(R GA )C(=O)N(R GA ) 2 , -SR GA , -S(=O)R GA , -S(=O) 2 R GA , -S(=O) 2 OR GA , -OS(=O) 2 R GA , -S(=O) 2 N(R GA ) 2 , -N(R GA )S(=O) 2 R GA , substituted or unsubstituted alkyl, substituted or unsubstituted arsenic R is selected from the group consisting of aryl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbosilyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; 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 3~6carbosilyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, and a nitrogen protecting group when attached to nitrogen, or two R GA the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclyl or heteroaryl ring; R 1a , R 1b , R 2a , R 2b , R 4a , R 4b , R 7a , R 7b , R 11a , R 11b , R 12a , and R 12b each independently represents hydrogen, halogen, cyano, -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 )RA1 , -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 R A1 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, or a substituted or unsubstituted 3- to 6-membered heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur, or two R A1 the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring; R 6a and R 6b each independently represents hydrogen, halogen, cyano, -NO 2, —OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl, or R 6a and R 6b is joined to form an oxo (=O) group, R 15a , R 15b , R 16a , and R 16b 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 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(RC3 )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 R C3 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 or two R are selected from the group consisting of alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur; C3 the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring; R 19 is hydrogen, or substituted or unsubstituted alkyl; n is 0, 1, 2, or 3; t is 2 or 3.

[0090] In some embodiments, provided herein is a compound of formula II: [ka] or a pharma- ceutically acceptable salt thereof is provided, During the ceremony, [ka] represents a single bond or a double bond, provided that when a double bond is present, R 6a or R 6b does not exist and R 5 Provided that there is no R X Halo, -OH, -OR Q1 and substituted or unsubstituted alkyl; R Q1 is substituted or unsubstituted alkyl; R Y is halo, or substituted or unsubstituted alkyl, or R Y and R X can be joined together with intervening atoms to form a substituted or unsubstituted carbocyclyl, or a substituted or unsubstituted heterocyclyl; R 3 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R 5 is hydrogen or methyl; R 22 Each example of 2 , -CN, -OR GA , -N(R GA ) 2 , -C(=O)R GA , -C(=O)OR GA , -OC(=O)R GA , -OC(=O)OR GA , -C(=O)N(R GA ) 2 , -N(R GA )C(=O)R GA , -OC(=O)N(R GA ) 2 , -N(R GA )C(=O)OR GA , -N(RGA )C(=O)N(R GA ) 2 , -SR GA , -S(=O)R GA , -S(=O) 2 R GA , -S(=O) 2 OR GA , -OS(=O) 2 R GA , -S(=O) 2 N(R GA ) 2 , -N(R GA )S(=O) 2 R GA , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbosilyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted hete R is selected from the group consisting of aryl and 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 carbosilyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, and a nitrogen protecting group when attached to nitrogen, or two R GA the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclyl or heteroaryl ring; R 1a , R 1b , R 2a , R 2b , R 4a , R 4b , R 7a , R 7b , R 11a , R 11b , R 12a , and R 12b each independently represents hydrogen, halogen, cyano, -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 R A1 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, or a substituted or unsubstituted 3- to 6-membered heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur, or two R A1 the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring; R 6a and R 6b each independently represents hydrogen, halogen, cyano, -NO 2 , —OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl, or R 6a and R 6b is joined to form an oxo (=O) group, R 15a , R 15b , R 16a , and R 16b 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 C3 , -N(R C3 ) 2 , -SR C3 , -C(=O)RC3 、 -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 selected from the group consisting of, R C3Each 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 aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur, or two R C3 the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring; R 19 is hydrogen, or substituted or unsubstituted alkyl; R 18 is substituted or unsubstituted alkyl; n is 0, 1, 2, or 3, but However, R 5 If is hydrogen, R 18 Ha-CH 3 isn't it.

[0091] In some embodiments, the compound of formula II is a compound of formula IIIa or IIIb: [ka] or a pharma- ceutically acceptable salt thereof.

[0092] In some embodiments, provided herein is a compound of formula V: [ka] or a pharma- ceutically acceptable salt thereof is provided, During the ceremony, [ka] represents a single bond or a double bond, provided that if a double bond is present, R 6a or R 6b does not exist and R 5Provided that there is no R X Halo, -OH, -OR Q1 and substituted or unsubstituted alkyl; R Q1 is substituted or unsubstituted alkyl; R Y is halo, or substituted or unsubstituted alkyl, or R Y and R X can be joined together with intervening atoms to form a substituted or unsubstituted carbocyclyl, or a substituted or unsubstituted heterocyclyl; R 3 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R 5 is hydrogen or methyl; R 22 Each example of 2 , -CN, -OR GA , -N(R GA ) 2 , -C(=O)R GA , -C(=O)OR GA , -OC(=O)R GA , -OC(=O)OR GA , -C(=O)N(R GA ) 2 , -N(R GA )C(=O)R GA , -OC(=O)N(R GA ) 2 , -N(R GA )C(=O)OR GA , -N(R GA )C(=O)N(R GA ) 2 , -SR GA , -S(=O)R GA , -S(=O) 2 R GA , -S(=O) 2 OR GA, -OS(=O) 2 R GA , -S(=O) 2 N(R GA ) 2 , -N(R GA )S(=O) 2 R GA , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbosilyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; 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 carbosilyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, and a nitrogen protecting group when attached to nitrogen, or two R GA the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclyl or heteroaryl ring; R 1a , R 1b , R 2a , R 2b , R 4a , R 4b , R 7a , R 7b , R 11a , R 11b , R 12a , and R 12b each independently represents hydrogen, halogen, cyano, -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)RA1 、 -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 selected from the group consisting of, R A1Each 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, or substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, attached to oxygen an oxygen protecting group if attached to a nitrogen, a nitrogen protecting group if attached to a sulfur, and a sulfur protecting group if attached to a sulfur; or A1 the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring; R 6a and R 6b each independently represents hydrogen, halogen, cyano, -NO 2 , —OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl, or R 6a and R 6b is joined to form an oxo (=O) group, R 15a or R 15b 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 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 R C3 Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6or two R are selected from the group consisting of alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur; C3 the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring; R 19 is hydrogen, or substituted or unsubstituted alkyl; n is 0, 1, 2, or 3.

[0093] In certain embodiments, provided herein are compounds of formula VIa or VIb: [ka] or a pharma- ceutically acceptable salt thereof is provided, During the ceremony, [ka] represents a single bond or a double bond, provided that when a double bond is present, R 6a or R 6b does not exist and R 5 Provided that there is no R X Halo, -OH, -OR Q1 and substituted or unsubstituted alkyl; R Q1 is substituted or unsubstituted alkyl; R Y is halo, or substituted or unsubstituted alkyl, or R Y and R X can be joined together with intervening atoms to form a substituted or unsubstituted carbocyclyl, or a substituted or unsubstituted heterocyclyl; R 3is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R 5 is hydrogen or methyl; R 22 Each example of 2 , -CN, -OR GA , -N(R GA ) 2 , -C(=O)R GA , -C(=O)OR GA , -OC(=O)R GA , -OC(=O)OR GA , -C(=O)N(R GA ) 2 , -N(R GA )C(=O)R GA , -OC(=O)N(R GA ) 2 , -N(R GA )C(=O)OR GA , -N(R GA )C(=O)N(R GA ) 2 , -SR GA , -S(=O)R GA , -S(=O) 2 R GA , -S(=O) 2 OR GA , -OS(=O) 2 R GA , -S(=O) 2 N(R GA ) 2 , -N(R GA )S(=O) 2 R GA , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbosilyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted hetero aryl; R GA Each instance of is independently hydrogen, substituted or unsubstituted C1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~6 carbosilyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, and a nitrogen protecting group when attached to nitrogen, or two R GA the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclyl or heteroaryl ring; R 1a , R 1b , R 2a , R 2b , R 4a , R 4b , R 7a , R 7b , R 11a , R 11b , R 12a , and R 12b each independently represents hydrogen, halogen, cyano, -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 R A1 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, or a substituted or unsubstituted 3- to 6-membered heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur, or two R A1 the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring; R 6a and R 6b each independently represents hydrogen, halogen, cyano, -NO 2 , —OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl, or R 6a and R 6b is joined to form an oxo (=O) group, R 15a , R 15b , R 16a , and R 16b 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 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 R C3 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 aryl, substituted or unsubstituted heteroaryl, substituted or an unsubstituted carbocyclyl, or a substituted or unsubstituted heterocyclyl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur, or two R C3 the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring; R 19 is hydrogen, or substituted or unsubstituted alkyl; r is 2 or 3; p is 2 or 3; n is 0, 1, 2, or 3.

[0094] In some embodiments, provided herein is a compound of formula VII: [ka] or a pharma- ceutically acceptable salt thereof, During the ceremony, [ka] represents a single bond or a double bond, provided that when a double bond is present, R 6a or R 6b does not exist and R 5 Provided that there is no R X Halo, -OH, -OR Q1 and substituted or unsubstituted alkyl; R Q1 is substituted or unsubstituted alkyl; R Y is halo, or substituted or unsubstituted alkyl, or R Y and R X can be joined together with intervening atoms to form a substituted or unsubstituted carbocyclyl, or a substituted or unsubstituted heterocyclyl; R 3 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R 5 is hydrogen or methyl; R 22 Each example of 2 , -CN, -OR GA , -N(R GA ) 2 , -C(=O)R GA , -C(=O)OR GA , -OC(=O)R GA , -OC(=O)OR GA , -C(=O)N(R GA ) 2 , -N(R GA)C(=O)R GA , -OC(=O)N(R GA ) 2 , -N(R GA )C(=O)OR GA , -N(R GA )C(=O)N(R GA ) 2 , -SR GA , -S(=O)R GA , -S(=O) 2 R GA , -S(=O) 2 OR GA , -OS(=O) 2 R GA , -S(=O) 2 N(R GA ) 2 , -N(R GA )S(=O) 2 R GA , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbosilyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; 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 Carbosilyl, substituted or unsubstituted substituted 3-6 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group if attached to oxygen, and 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; R 2a , R 2b , R 4a , R 4b , R 7a , R 7b , R 11a , R 11b , R 12a , and R12b each independently represents hydrogen, halogen, cyano, -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 R A1 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, or a substituted or unsubstituted 3- to 6-membered heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur, or two R A1 the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring; R 6a and R 6b each independently represents hydrogen, halogen, cyano, -NO 2 , —OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl, or R 6a and R 6b is joined to form an oxo (=O) group, R 15a , R 15b , R 16a , and R 16b 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 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 、または-S(=O) 2 N(R C3 )2 R C3 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 or two R are selected from the group consisting of alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur; C3 The group is an intervening atom together with R 19 is hydrogen, or substituted or unsubstituted alkyl; n is 0, 1, 2, or 3.

[0095] In some embodiments, provided herein is a compound of formula VIII: [ka] or a pharma- ceutically acceptable salt thereof is provided, During the ceremony, [ka] represents a single bond or a double bond, provided that when a double bond is present, R 6a or R 6b does not exist and R 5 Provided that there is no R X Halo, -OH, -OR Q1 and substituted or unsubstituted alkyl; R Q1 is substituted or unsubstituted alkyl; R Y is halo, or substituted or unsubstituted alkyl, or R Y and R Xcan be joined together with intervening atoms to form a substituted or unsubstituted carbocyclyl, or a substituted or unsubstituted heterocyclyl; R 3 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R 5 is hydrogen or methyl; R 22 Each example of 2 , -CN, -OR GA , -N(R GA ) 2 , -C(=O)R GA , -C(=O)OR GA , -OC(=O)R GA , -OC(=O)OR GA , -C(=O)N(R GA ) 2 , -N(R GA )C(=O)R GA , -OC(=O)N(R GA ) 2 , -N(R GA )C(=O)OR GA , -N(R GA )C(=O)N(R GA ) 2 , -SR GA , -S(=O)R GA , -S(=O) 2 R GA , -S(=O) 2 OR GA , -OS(=O) 2 R GA , -S(=O) 2 N(R GA ) 2 , -N(R GA )S(=O) 2 R GA, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbosilyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; 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 carbosilyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, and a nitrogen protecting group when attached to nitrogen, or two R GA The group together with the intervening atoms forming a substituted or unsubstituted heterocyclyl or heteroaryl ring, R 1a , R 1b , R 2a , R 2b , R 4a , R 4b , R 7a , R 7b , R 11a , R 11b , R 12a , and R 12b each independently represents hydrogen, halogen, cyano, -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)ORA1 , -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 R A1 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 3~6carbocyclyl, or a substituted or unsubstituted 3- to 6-membered heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur, or two R A1 the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring; R 6a and R 6b each independently represents hydrogen, halogen, cyano, -NO 2 , —OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl, or R 6a and R 6b is joined to form an oxo (=O) group, R 15a , R 15b , R 16a , and R 16b 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 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 R C3 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 or two R are selected from the group consisting of alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur; C3 the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring; R19 is hydrogen, or substituted or unsubstituted alkyl; s is 2, n is 0, 1, 2, or 3.

[0096] In some embodiments, provided herein is a compound of formula IX: [ka] or a pharma- ceutically acceptable salt thereof is provided, During the ceremony, R X Halo, -OH, -OR Q1 and substituted or unsubstituted alkyl; R Q1 is substituted or unsubstituted alkyl; R Y is halo, or substituted or unsubstituted alkyl, or R Y and R X can be joined together with intervening atoms to form a substituted or unsubstituted carbocyclyl, or a substituted or unsubstituted heterocyclyl; R 3 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R 5 is hydrogen or methyl; R 22 Each example of 2 , -CN, -OR GA , -N(R GA ) 2 , -C(=O)R GA , -C(=O)OR GA , -OC(=O)R GA , -OC(=O)OR GA , -C(=O)N(R GA ) 2 , -N(R GA )C(=O)R GA, -OC(=O)N(R GA ) 2 , -N(R GA )C(=O)OR GA , -N(R GA )C(=O)N(R GA ) 2 , -SR GA , -S(=O)R GA , -S(=O) 2 R GA , -S(=O) 2 OR GA , -OS(=O) 2 R GA , -S(=O) 2 N(R GA ) 2 , -N(R GA )S(=O) 2 R GA , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbosilyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; 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 carbosilyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, and a nitrogen protecting group when attached to nitrogen, or two R GA the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclyl or heteroaryl ring; R 1a , R 1b , R 2a , R 2b , R 4a , R 4b , R 7a , R 7b , R 11a , R 11b , R 12a , and R12b each independently represents hydrogen, halogen, cyano, -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)RA1 , -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 R A1 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, or a substituted or unsubstituted 3- to 6-membered heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur, or two R A1 the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring; R 15a , R 15b , R 16a , and R 16b 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 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 R C3 Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6or two R are selected from the group consisting of alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur; C3 the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring; R 19 is hydrogen, or substituted or unsubstituted alkyl; n is 0, 1, 2, or 3.

[0097] In some embodiments, provided herein is a compound of formula X: [ka] or a pharma- ceutically acceptable salt thereof is provided, During the ceremony, [ka] represents a single bond or a double bond, provided that when a double bond is present, R 6a or R 6b does not exist and R 5 Provided that there is no R X Halo, -OH, -OR Q1 and substituted or unsubstituted alkyl; R Q1 is substituted or unsubstituted alkyl; R Y is halo, or substituted or unsubstituted alkyl, or R Y and R X can be joined together with intervening atoms to form a substituted or unsubstituted carbocyclyl, or a substituted or unsubstituted heterocyclyl; R 3is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R 5 is hydrogen or methyl; R 22 Each example of 2 , -CN, -OR GA , -N(R GA ) 2 , -C(=O)R GA , -C(=O)OR GA , -OC(=O)R GA , -OC(=O)OR GA , -C(=O)N(R GA ) 2 , -N(R GA )C(=O)R GA , -OC(=O)N(R GA ) 2 , -N(R GA )C(=O)OR GA , -N(R GA )C(=O)N(R GA ) 2 , -SR GA , -S(=O)R GA , -S(=O) 2 R GA , -S(=O) 2 OR GA , -OS(=O) 2 R GA , -S(=O) 2 N(R GA ) 2 , -N(R GA )S(=O) 2 R GA , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbosilyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R GA 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 carbosilyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, and a nitrogen protecting group when attached to nitrogen, or two R GA the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclyl or heteroaryl ring; R 1a , R 1b , R 2a , R 2b , R 4a , R 4b , R 7a , R 7b , R 11a , R 11b , R 12a , and R 12b each independently represents hydrogen, halogen, cyano, -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 R A1 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, or a substituted or unsubstituted 3- to 6-membered heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur, or two R A1the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring; R 6a and R 6b each independently represents hydrogen, halogen, cyano, -NO 2 , —OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl, or R 6a and R 6b is joined to form an oxo (=O) group, R 15a , R 15b , R 16a , and R 16b 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 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 R C3 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 or two R are selected from the group consisting of alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur; C3 the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring; R 19 is hydrogen, or substituted or unsubstituted alkyl; q is 2, n is 0, 1, 2, or 3.

[0098] R 1a and R 1b base In some embodiments, R 1a and R 1b each independently represents hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted carbo cyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -N(R A1 ) 2 , -C(=O)R A1 , -C(=O)OR A1 , or -C(=O)N(R A1 ) 2 and 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, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0099] In some embodiments, R 1a and R 1b each independently represents hydrogen, halogen, cyano, substituted or unsubstituted alkyl, or -OR A1 and R A1 Each instance of is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0100] In some embodiments, R 1a and R 1b Each of 1~6 Alkyl, C 1~3 Haloalkyl, or -OR A1 and R A1 is hydrogen or unsubstituted alkyl.

[0101] In some embodiments, R 1a and R1b Each of is independently hydrogen or a substituted or unsubstituted C 1~6 It is an alkyl.

[0102] In some embodiments, R 1a and R 1b are each independently hydrogen.

[0103] In some embodiments, R 1a and R 1b are both hydrogen. R 2a and R 2b base

[0104] In some embodiments, R 2a and R 2b each independently represents hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -N(R A1 ) 2 , -C(=O)R A1 , -C(=O)OR A1 , or -C(=O)N(R A1 ) 2 and 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, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0105] In some embodiments, R 2a and R 2b each independently represents hydrogen, halogen, cyano, substituted or unsubstituted alkyl, or -OR A1 and R A1Each instance of is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0106] In some embodiments, R 2a and R 2b Each of 1~6 Alkyl, C 1~3 Haloalkyl, or -OR A1 and R A1 is hydrogen or unsubstituted alkyl.

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

[0108] In some embodiments, R 2a and R 2b are both hydrogen.

[0109] R 4a and R 4b base In some embodiments, R 4a and R 4b each independently represents hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -N(R A1 ) 2 , -C(=O)R A1 , -C(=O)OR A1 , or -C(=O)N(R A1 ) 2 and 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, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0110] In some embodiments, R 4a and R 4b each independently represents hydrogen, halogen, cyano, substituted or unsubstituted alkyl, or -OR A1 and R A1 Each instance of is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0111] In some embodiments, R 4a and R 4b Each of 1~6 Alkyl, C 1~3 Haloalkyl, or -OR A1 and R A1 is hydrogen or unsubstituted alkyl.

[0112] In some embodiments, R 4a and R 4b are each independently hydrogen.

[0113] In some embodiments, R 4a and R 4b are both hydrogen.

[0114] R 7a and R 7b base In some embodiments, R 7a and R 7beach independently represents hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -N(R A1 ) 2 , -C(=O)R A1 , -C(=O)OR A1 , or -C(=O)N(R A1 ) 2 and 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, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0115] In some embodiments, R 7a and R 7b each independently represents hydrogen, halogen, cyano, substituted or unsubstituted alkyl, or -OR A1 and R A1 Each instance of is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0116] In some embodiments, R 7a and R 7b Each of 1~6 Alkyl, C 1~3 Haloalkyl, or -OR A1 and R A1 is hydrogen or unsubstituted alkyl.

[0117] In some embodiments, R 7a and R 7b are each independently hydrogen.

[0118] In some embodiments, R 7a and R 7b are both hydrogen.

[0119] R 11a and R 11b base In some embodiments, R 11a and R 11b each independently represents hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -N(R A1 ) 2 , -C(=O)R A1 , -C(=O)OR A1 , or -C(=O)N(R A1 ) 2 and 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, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0120] In some embodiments, R 11a and R 11b each independently represents hydrogen, halogen, cyano, substituted or unsubstituted alkyl, or -OR A1 and R A1 Each instance of is independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0121] In some embodiments, R 11a and R 11b Each of 1~6 Alkyl, C 1~3 Haloalkyl, or -OR A1and R A1 is hydrogen or unsubstituted alkyl.

[0122] In some embodiments, R 11a and R 11b are each independently hydrogen.

[0123] In some embodiments, R 11a and R 11b are both hydrogen.

[0124] R 12a and R 12b base In some embodiments, R 12a and R 12b each independently represents hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -N(R A1 ) 2 , -C(=O)R A1 , -C(=O)OR A1 , or -C(=O)N(R A1 ) 2 and 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, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0125] In some embodiments, R 12a and R 12b each independently represents hydrogen, halogen, cyano, substituted or unsubstituted alkyl, or -OR A1 and R A1Each instance of is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0126] In some embodiments, R 12a and R 12b Each of 1~6 Alkyl, C 1~3 Haloalkyl, or -OR A1 and R A1 is hydrogen or unsubstituted alkyl.

[0127] In some embodiments, R 12a and R 12b Each of is independently hydrogen.

[0128] In some embodiments, R 12a and R 12b are both hydrogen.

[0129] R 6a and R 6b base In some embodiments, R 6a and R 6b Each of is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.

[0130] In some embodiments, R 6a and R 6b Each of is independently hydrogen, or substituted or unsubstituted alkyl.

[0131] In some embodiments, R 6a and R 6b are each independently hydrogen.

[0132] In some embodiments, R 6a and R 6bare both hydrogen.

[0133] R 15a and R 15b base In some embodiments, R 15a and R 15b Each of is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heteroaryl.

[0134] In some embodiments, R 15a and R 15b Each of is independently hydrogen, or substituted or unsubstituted alkyl.

[0135] In some embodiments, R 15a and R 15b is each independently hydrogen or unsubstituted alkyl.

[0136] In some embodiments, R 15a and R 15b are each independently hydrogen or unsubstituted C 1~6 It is an alkyl.

[0137] In some embodiments, R 15a and R 15b are each independently hydrogen.

[0138] In some embodiments, R 15a and R 15b are each independently hydrogen.

[0139] In some embodiments, R 15a and R 15b are both hydrogen.

[0140] R 16a and R 16b base In some embodiments, R 16a and R 16bEach of is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heteroaryl.

[0141] In some embodiments, R 16a and R 16b Each of is independently hydrogen, or substituted or unsubstituted alkyl.

[0142] In some embodiments, R 16a and R 16b Each of is independently hydrogen or unsubstituted alkyl.

[0143] In some embodiments, R 16a and R 16b Each of is independently hydrogen.

[0144] In some embodiments, R 16a and R 16b are both hydrogen.

[0145] R 3 base In some embodiments, R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.

[0146] In some embodiments, R 3 is substituted or unsubstituted alkyl.

[0147] In some embodiments, R 3 is a substituted or unsubstituted C 1~6 It is an alkyl.

[0148] In some embodiments, R 3 is C 1~3 C optionally substituted with alkoxy 1~3 It is an alkyl.

[0149] In some embodiments, R 3 is methyl, ethyl, propyl, butyl, -CH 2 OCH 3 , or -CH 2 OCH 2 CH 3 It is.

[0150] In some embodiments, R 3 is methyl, ethyl, or n-propyl.

[0151] In some embodiments, R 3 is methyl.

[0152] In some embodiments, R 3 is ethyl.

[0153] In some embodiments, R 3 is propyl.

[0154] R 18 base In some embodiments, R 18 is substituted or unsubstituted alkyl.

[0155] In some embodiments, R 18 is a substituted or unsubstituted C 1~6 It is an alkyl.

[0156] In some embodiments, R 18 is a substitution C 1~6 It is an alkyl.

[0157] In some embodiments, R 18 is unsubstituted C 1~6 It is an alkyl.

[0158] In some embodiments, R 18 is methyl.

[0159] R 19 base In some embodiments, R 19 is hydrogen or substituted or unsubstituted C 1~6 It is an alkyl.

[0160] In some embodiments, R 19 is unsubstituted C 1~3 It is an alkyl.

[0161] In some embodiments, R 19 is hydrogen.

[0162] In some embodiments, R 19 is -CH 3 It is.

[0163] In some embodiments, R 19 is hydrogen or methyl.

[0164] R X Group and / or R Y base In some embodiments, R X is halo, -OH, -OR Q1 , or substituted or unsubstituted C 1~3 It is an alkyl.

[0165] In some embodiments, R X is -OH.

[0166] In some embodiments, R Y is halo or unsubstituted alkyl.

[0167] In some embodiments, R Y is halo or unsubstituted C 1~3 It is an alkyl.

[0168] In some embodiments, R Y is methyl, ethyl, or propyl.

[0169] In some embodiments, R Yis methyl.

[0170] In some embodiments, R X is -OH, and R Y is unsubstituted C 1~3 It is an alkyl.

[0171] In some embodiments, R X is -OH, and R Y is methyl.

[0172] In some embodiments, R Y and R X can be taken together with the intervening atoms to form a substituted or unsubstituted carbocyclic ring, or a substituted or unsubstituted heterocyclic ring.

[0173] In some embodiments, R Y and R X together with the intervening atoms, substituted or unsubstituted C 3~7 Carbocyclic ring, or substituted or unsubstituted C 3~7 Heterocyclic rings can be formed.

[0174] In some embodiments, R Y and R X together with the intervening atoms form a substituted or unsubstituted four-membered carbocyclic ring.

[0175] In some embodiments, R Y and R X together with the intervening atoms form a substituted or unsubstituted 4-membered heterocyclic ring.

[0176] In some embodiments, the 4-membered heterocyclic ring contains a heteroatom selected from N, O, and S.

[0177] R Q1 base In some embodiments, R Q1 is unsubstituted C 1~6 It is an alkyl.

[0178] In some embodiments, R Q1 is methyl.

[0179] R 22 base In some embodiments, R 22 is independently for each occurrence hydrogen, halogen, -NO 2 , -CN, -OR GA , -N(R GA ) 2 , -C(=O)R GA , -C(=O)OR GA , -N(R GA )C(=O)R GA , -SR GA , -S(=O)R GA , -S(=O) 2 R GA , -S(=O) 2 OR GA , -OS(=O) 2 R GA , -S(=O) 2 N(R GA ) 2 , substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 3~6 Carbosilyl, or substituted or unsubstituted C 3~6 Heterosilyl, R GA Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 3~6 Carbosilyl, substituted or unsubstituted C 3~6 It is heterosilyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0180] In some embodiments, R 22 is, for each occurrence, independently, -CN, -OR GA , -N(R GA ) 2 , substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 3~6 Carbosilyl, RGA Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, or substituted or unsubstituted C 3~6 It is a carbosilyl.

[0181] In some embodiments, R 22 is independently for each occurrence hydrogen, halogen, -CN, unsubstituted C 1~3 Alkyl, substituted or unsubstituted C 3~6 Heterosilyl, C 1~3 Haloalkyl, or -OR GA and R GA Each instance of is independently hydrogen, substituted or unsubstituted C 1~3 It is an alkyl.

[0182] In some embodiments, R 22 is located at the 4th position of the pyrazolyl.

[0183] In another embodiment, R 22 is located at the 3-position of the pyrazolyl.

[0184] In another embodiment, R 22 is located at the 5-position of the pyrazolyl.

[0185] In some embodiments, R 22 is -CN.

[0186] In another embodiment, R 22 is -CN located at the 4-position of the pyrazolyl.

[0187] integer n In some embodiments, n is 1 or 2.

[0188] In some embodiments, n is 1, 2, or 3.

[0189] In some embodiments, n is 0 or 1.

[0190] In some embodiments, n is 0.

[0191] In some embodiments, n is 1.

[0192] In some embodiments, n is 2.

[0193] In some embodiments, n is 3.

[0194] integer t In some embodiments, t is 2. In some embodiments, t is 3.

[0195] integer r In some embodiments, r is 2. In some embodiments, r is 3.

[0196] integer p In some embodiments, p is 2. In some embodiments, p is 3.

[0197] integer s In some embodiments, s is 2.

[0198] Integer q In some embodiments, q is 2.

[0199] R 5 base In some embodiments, R 5 is methyl in the alpha or beta configuration.

[0200] In some embodiments, R 5 is methyl in the alpha configuration.

[0201] In some embodiments, R 5 is a methyl in the beta configuration.

[0202] In some embodiments, R 5 is hydrogen in the alpha or beta configuration.

[0203] In some embodiments, R 5 is hydrogen in the alpha configuration.

[0204] In some embodiments, R 5 is hydrogen in the beta configuration.

[0205] In some embodiments, the compound of formula I is a compound of formula Ia: [ka] or a pharma- ceutically acceptable salt thereof, in which the variables are as defined herein.

[0206] In some embodiments, the compound of formula I is a compound of formula Ib: [ka] or a pharma- ceutically acceptable salt thereof, in which the variables are as defined herein.

[0207] In some embodiments, the compound of formula I is a compound of formula Ic or Id: [ka] or a pharma- ceutically acceptable salt thereof, in which the variables are as defined herein.

[0208] In some embodiments, the compound of formula VIa or VIb is a compound of formula VIa-a or VIb-a: [ka] or a pharma- ceutically acceptable salt thereof, in which the variables are as defined herein.

[0209] In some embodiments, the compound of formula VIa or VIb is a compound of formula VIa-b or VIb-b: [ka] or a pharma- ceutically acceptable salt thereof, in which the variables are as defined herein.

[0210] In some embodiments, the compound of formula VIa or VIb is a compound of formula VIa-c, VIa-d, VIb-c or VIb-d: [ka] or a pharma- ceutically acceptable salt thereof, in which the variables are as defined herein.

[0211] In some embodiments, the compound of formula VIa or VIb is a compound of formula VIa-e or VIb-e: [ka] or a pharma- ceutically acceptable salt thereof, in which the variables are as defined herein.

[0212] In some embodiments, the compound of formula VII is a compound of formula VII-a: [ka] or a pharma- ceutically acceptable salt thereof, in which the variables are as defined herein.

[0213] In some embodiments, the compound of formula VII is a compound of formula VII-b: [ka] or a pharma- ceutically acceptable salt thereof, in which the variables are as defined herein.

[0214] In some embodiments, the compound of formula VII is a compound of formula VII-c: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined herein.

[0215] In some embodiments, the compound is selected from the group consisting of the compounds identified in Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

[0216] In one aspect, provided herein are pharma- ceutically acceptable salts of the compounds described herein (e.g., compounds of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X).

[0217] In one aspect, provided herein is a pharmaceutical composition comprising a compound described herein (e.g., a compound of formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient. In certain embodiments, the compound of the present invention is provided in the pharmaceutical composition in an effective amount. In certain embodiments, the compound of the present invention is provided in a therapeutically effective amount.

[0218] The compounds of the invention described herein may, in certain embodiments, be A Regulators and For example, GABA A GABA acts on receptors in either a positive or negative manner as a regulator of central nervous system (CNS) excitability. A Such compounds are expected to have CNS activity, as mediated by their ability to modulate receptors.

[0219] Thus, in one aspect, provided herein is a method of modulating a GABAA receptor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described in any one of the claims herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0220] In another aspect, a method for administering a CNS-related disorder to a subject in need thereof is provided, comprising administering to the subject an effective amount of a compound of the present invention. 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 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 withdrawal syndrome, tinnitus, or status epilepticus. In certain embodiments, the CNS-related disorder is depression. In certain embodiments, the CNS-related disorder is postpartum depression. In certain embodiments, the CNS-related disorder is major depressive disorder. In certain embodiments, the major depressive disorder is moderate major depressive disorder. In certain embodiments, the major depressive disorder is severe major depressive disorder. In certain embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In certain embodiments, the compound is administered orally. In certain embodiments, the compound is administered chronically. In certain embodiments, the compounds are administered continuously, for example, by continuous intravenous infusion.

[0221] 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, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X).

[0222] Alternative Embodiments In alternative embodiments, the compounds described herein may also contain one or more isotopic substitutions. For example, hydrogen can be replaced by 2 H (D or deuterium) or 3 H (T or tritium), and carbon can be, for example, 13 C or 14 C, and oxygen may be, for example, 18 O, the nitrogen may be, for example, 15 In other embodiments, a particular isotope (e.g., 3 H, 13 C. 14 C. 18 O, or 15 N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of an element occupying a particular site on a compound.

[0223] Pharmaceutical Compositions In one aspect, provided herein is a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient. In certain embodiments, the compound of the present invention is provided in the pharmaceutical composition in an effective amount. In certain embodiments, the compound of the present invention is provided in a therapeutically effective amount.

[0224] 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.

[0225] The pharmaceutical compositions provided herein may 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.

[0226] In general, the compounds provided herein are administered in an effective amount. The amount of compound actually administered is typically determined by a physician taking into account the relevant circumstances, including the condition being treated, the selected route of administration, the compound actually administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0227] When used to prevent the development of CNS disorders, the compounds provided herein are typically administered at the dosage levels described above 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 subjects with a family history of the condition, or subjects identified by genetic testing or screening as being particularly susceptible to developing the condition.

[0228] The pharmaceutical compositions provided herein can also be administered chronically ("chronic administration"). Chronic administration refers to administering the compound or its pharmaceutical composition for an extended period of time, such as, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, or can continue indefinitely, for example, for the life of the subject. In certain embodiments, chronic administration is intended to provide a constant level of the compound in the blood, for example, within the therapeutic window, for an extended period of time.

[0229] The pharmaceutical composition of the present invention can further be delivered using various administration methods. For example, in certain embodiments, the pharmaceutical composition may 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 throughout the body, for example, an intramuscular or subcutaneous bolus dose allows for a slow release of the active ingredient, while a bolus delivered directly into a vein (e.g., through an infusion) allows for a much faster delivery, which quickly raises the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition may be administered as a continuous infusion, for example, by infusion, to provide maintenance of a steady-state concentration of the active ingredient in the subject's body. Furthermore, in still further embodiments, the pharmaceutical composition may be initially administered as a bolus dose, followed by a continuous infusion.

[0230] Compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, compositions are presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect in association with suitable pharmaceutical excipients. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions or pills, tablets, capsules, etc., in the case of solid compositions. In such compositions, the compound is usually a minor component (about 0.1 to about 50% by weight, preferably about 1 to about 40% by weight), with the remainder being various vehicles or excipients and processing aids that serve to form the desired dosage form.

[0231] For oral administration, the dosage is typically 1 to 5 times, especially 2 to 4 times, typically 3 times per day. Using these dosing patterns, each dose provides from about 0.01 to about 20 mg / kg of a compound provided herein, with preferred doses providing from about 0.1 to about 10 mg / kg, particularly from about 1 to about 5 mg / kg, respectively.

[0232] A transdermal dose will generally be selected to provide similar or lower blood levels than those achieved using an injection dose, and will generally be 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, and more preferably from about 0.5 to about 15% by weight.

[0233] Injection dose levels range from about 0.1 mg / kg / hour to at least 20 mg / kg / hour, all for about 1 to about 120 hours, particularly 24 to 96 hours. A preloading bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve adequate steady state levels. Maximum total doses are not expected to exceed about 5 g / day for a 40-80 kg human patient.

[0234] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavorings, etc. Solid forms may include, for example, any of the following ingredients or compounds of similar nature: binders such as microcrystalline cellulose, gum tragacanth, or gelatin; excipients such as starch or lactose; disintegrating agents such as alginic acid, primogel, or corn starch; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavoring.

[0235] Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art. As mentioned above, the active compound in such compositions is typically about 0.05-10% by weight, with the remainder being injectable excipients and the like.

[0236] Transdermal compositions are typically formulated as topical ointments or creams containing active ingredient(s). When formulated as ointments, active ingredients are typically combined with either paraffinic or water-miscible ointment bases. Alternatively, active ingredients may be formulated in creams, such as with an oil-in-water cream base. Such transdermal formulations are well known in the art and generally include additional ingredients to enhance skin penetration of active ingredients or the stability of the formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.

[0237] 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.

[0238] The above-mentioned components of the orally administrable, injectable or topically administrable compositions are merely representative. Other materials, as well as processing techniques, etc., are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0239] 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 Pharmaceutica can be found in the International Journal of Clinical Chemistry, Vol. 13, No. 1, 2014, 113–204.

[0240] 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 that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, paratoluenesulfonate, etc.

[0241] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention and a pharma- ceutically acceptable excipient, e.g., a composition suitable for injection, such as intravenous (IV) administration.

[0242] Pharmaceutically acceptable excipients include any diluent or other liquid vehicle suitable for the particular dosage form desired, e.g., injection, dispersing or suspending aids, surfactants, isotonicity agents, preservatives, lubricants, etc. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005).

[0243] For example, injectable preparations, such as sterile injectable aqueous suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Exemplary excipients that can be used include, but are not limited to, water, sterile saline or phosphate-buffered saline, or Ringer's solution.

[0244] In certain embodiments, the pharmaceutical composition further comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, consisting of 6, 7, and 8 α-1,4 linked glucose units, respectively, optionally containing one or more substituents on the linked sugar moieties, including, but not limited to, substituted or unsubstituted methylation, hydroxyalkylation, acylation, and sulfoalkyl ether substitution. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, also known as CAPTISOL®. See, for example, U.S. Patent No. 5,376,645. In certain embodiments, the composition comprises hexapropyl-β-cyclodextrin. In more specific embodiments, the composition comprises hexapropyl-β-cyclodextrin (10-50% in water).

[0245] 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.

[0246] Generally, the compounds provided herein are administered in an effective amount. The amount of the compound actually administered is typically determined by a physician taking into account the relevant circumstances, including the condition to be treated, the selected route of administration, the compound actually administered, the age, weight, response, and severity of the patient's symptoms of the individual patient.

[0247] The compositions are presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete, single, individual ... A unit dosage form refers to a unit amount of active material calculated to produce a desired therapeutic effect in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampoules or syringes of liquid compositions. In such compositions, the compound is usually a minor component (about 0.1 to about 50% by weight, preferably about 1 to about 40% by weight), with the remainder being various vehicles or excipients and processing aids that help form the desired dosage form.

[0248] The compounds provided herein can be administered as the sole active agent or in combination with other active agents. In one aspect, the present invention provides a combination of the compounds of the present invention with another pharmacologically active agent. Co-administration can proceed by any technique apparent to those skilled in the art, including, for example, separate, sequential, simultaneous, and alternating administration.

[0249] 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 create compositions suitable for administration to various animals are well understood, and those skilled in the art can design and / or perform such modifications with routine experimentation. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy, 21st ed., Lippincott Williams&Wilkins, 2005.

[0250] In one embodiment, a kit is provided that includes a composition (e.g., a solid composition) that includes a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X.

[0251] Combination therapy The compounds or compositions described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharma- ceutically acceptable salt thereof, may be administered in combination with an additional agent or therapy. The subject to whom the compounds disclosed herein are administered may have a disease, disorder, or condition, or a symptom thereof, that would benefit from treatment with another agent or therapy. Combination therapy may be achieved by administering two or more agents, each of which may be formulated and administered separately, or by administering two or more agents in a single formulation. In some embodiments, the combination Two or more drugs in a therapy can be administered simultaneously. In other embodiments, two or more drugs in a combination therapy are administered separately. For example, administration of a first drug (or combination of drugs) can be performed minutes, hours, days, or weeks before administration of a second drug (or combination of drugs). Thus, two or more drugs can be administered within minutes of each other, or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other, or within 2, 3, 4, 5, 6, 7, 8, 9, or weeks of each other. In some cases, even longer intervals are possible. In many cases, it is desirable for two or more drugs used in a combination therapy to be present in the patient's body at the same time, but this does not have to be the case.

[0252] Combination therapy can also include two or more administrations of one or more of the drugs used in the combination, using different sequences of the constituent drugs. For example, when drug X and drug Y are used in combination, the combination can be, for example, XYX, XXY, YXY, YYX, XX -YY, etc., in any combination, may be administered one or more times consecutively. Exemplary additional agents are described below.

[0253] Selective serotonin reuptake inhibitors (SSRIs) In some embodiments, a compound or composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharma- ceutically acceptable salt thereof) may be administered in combination with SSRI(s). SSRIs include antidepressants that increase serotonin levels in the brain. Exemplary SSRIs include, but are not limited to, citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft).

[0254] Norepinephrine reuptake inhibitors (NERIs) In some embodiments, a compound or composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharma- ceutically acceptable salt thereof) is administered in combination with a NERI(s). Exemplary NERIs include, but are not limited to, atomoxetine (Strattera), reboxetine (Edronax, Vestra), bupropion (Wellbutrin, Zyban), duloxetine, desipramine (Norpramin), amidaline (UK-3540-1), daredalin (UK-3557-15), edivoxetine (LY-2216684), esreboxetine, lortalamine (LM-1404), nisoxetine (LY-94,939), talopram (taslopram) (Lu 3-010), talsupram (Lu 5-005), tandamine (AY-23,946), and viloxazine (Vivalan).

[0255] Antipsychotics In some embodiments, a compound or composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharma- ceutically acceptable salt thereof) is administered in combination with an antipsychotic agent(s). Antipsychotic agents include D2 antagonists, which reduce dopaminergic neurotransmission in the dopamine pathway. Exemplary antipsychotics include, but are not limited to, asenapine (Saphris), aripiprazole (Abilify), cariprazine (Vrayar), clozapine (Clozaril), droperidol, fluperapine, mesoridazine, quetiapine hemi-fumarate, raclopride, spiperone, sulpiride, trimethobenzamide hydrochloride, trifluoroperazine dihydrochloride, lurasidone (Latuda), olanzapine (Zyprexa), quetiapine (Seroquel), zotepine, risperidone (Risperdal), ziprasidone (Geodon), mesothidazine, chlorpromazine hydrochloride, and haloperidol (Haldol).

[0256] Cannabinoids In some embodiments, a compound or composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharma- ceutical acceptable salt thereof) is used. The composition (including a salt thereof) may be administered in combination with a cannabinoid(s). Exemplary cannabinoids include, but are not limited to, cannabinoids (Epidiolex), tetrahydrocannabinolic acid, tetrahydrocannabinol, cannabinolic acid, cannabinol, cannabigerol, cannabichromene, tetrahydrocannabivarin, and cannabidivarin.

[0257] NMDA receptor antagonists In some embodiments, a compound or composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharma- ceutically acceptable salt thereof) is administered in combination with an NMDA receptor antagonist(s). NMDA receptor antagonists are a class of drugs that inhibit the action of N-methyl-d-aspartate receptors. Exemplary NMDA antagonists include, but are not limited to, ketamine, esketamine, ketobemidone, ifendopril, 5,7-dichlorokynuric acid, lycostinel, memantine, gabester, phencyclidine, dextromethorphan, remacemide, selfotel, tiletamine, dextropropoxyphene, aptiganel, dexanabinol, and amantadine. NMDA receptor antagonists also include opioids such as methadone, dextropropoxyphene, pethidine, levorphanol, tramadol, neramexane, and ketobemidone.

[0258] GABA receptor agonists In some embodiments, a compound or composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharma- ceutically acceptable salt thereof) is administered in combination with a GABA receptor agonist(s). GABA receptor agonists are a class of drugs that are agonists for one or more of the GABA receptors. Exemplary GABA receptor agonists include clobazam, topiramate, muscimol, progabide, riluzole, baclofen, gabapentin, vigabatrin, valproic acid, tiagabine, lamotrigine, pregabalin, phenyloin, carbamazepine, thiopental, thiamylal, pentobarbital, secobarbital, hexobarbital, butobarbital, amobarbital, barbital, mephobarbital, phenobarbital, primidone, midazolam, triazolam, lometazepam, flutazolam, nitrazepam, fluritrazepam, nimetazepam, diazepam, medazepam, oxazolam, prazeam, tofissoam, rilmazafone, lorazepam, temazepam, oxazepam, fludiazepam, chlordiazepine, chloramazepam ... oxid, cloxazolam, flutoprazepam, alprazolam, estazolam, bromazepam, flurazepam, potassium clorazepate, haloxazolam, ethyl loflazepate, quazepam, clonazepam, mexazolam, etizolam, brotizolam, clotiazepam, brotizolam, clotiazepam, propofol, fospropofol, zolpidem, zopiclone, eszopiclone, muscimol, TFQP / gaboxadol, isoguvacine, kodiamine, GABA, homotaurine, homohypotaurine, trans-aminocyclopentane-3-carboxylic acid, trans-amino-4-crotonic acid, b-guanidinopropionic acid, homo-b-proline, isonipecotic acid, 3-((aminoiminomethyl)thio)-2-propenoic acid (ZAP A), imidazole acetic acid, and piperidine-4-sulfonic acid (P4S).

[0259] Cholinesterase inhibitors In some embodiments, a compound or composition described herein (e.g., a compound represented by Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X) is or a pharmaceutical salt thereof, or a composition comprising a compound of formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharma- ceutically acceptable salt thereof, is administered in combination with a cholinesterase inhibitor(s). In general, cholinergics are compounds that mimic the action of acetylcholine and / or butyrylcholine. Cholinesterase inhibitors are a class of drugs that prevent the breakdown of acetylcholine. Exemplary cholinesterase inhibitors include, but are not limited to, donepidil (Aricept), tacrine (Cognex), rivastigmine (Exelon, Exelon Patch), galantamine (Razadyne, Reminyl), memantine / donepezil (Namzaric), ambenonium (Mytelase), neostigmine (Bloxiverz), pyridostigmine (Mestinon Timespan, Regonol), and galantamine (Razadyne).

[0260] The present disclosure also contemplates, inter alia, administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharma- ceutical acceptable salt thereof) to a subject who has previously been administered an agent selected from the group consisting of a bronchial muscle / airway relaxant, an antiviral agent, oxygen, an antibody, and an antibacterial agent. In some embodiments, an additional agent is administered to the subject prior to administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharma- ceutically acceptable salt thereof), and the additional agent is selected from the group consisting of a bronchial muscle / airway relaxant, an antiviral agent, oxygen, an antibody, and an antibacterial agent. In some embodiments, a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharma- ceutically acceptable salt thereof) is co-administered to a subject with an agent selected from a bronchial muscle / airway relaxant, an antiviral agent, oxygen, and an antibacterial agent.

[0261] Methods of Use and Treatment In certain embodiments, the compounds described herein, e.g., compounds of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, are contemplated to be useful as therapeutic agents for treating a CNS-related disorder, e.g., a sleep disorder, a mood disorder (e.g., depression, schizophrenia spectrum disorder, convulsive disorder, epileptogenesis, memory and / or cognitive disorder, movement disorder, personality disorder, autism spectrum disorder, pain, traumatic brain injury, vascular disease, substance abuse disorder and / or withdrawal syndrome, or tinnitus) in a subject in need of such treatment (e.g., a subject with Rett Syndrome, Fragile X Syndrome, or Angelman Syndrome). Exemplary CNS conditions associated with GABA modulation include sleep disorders [e.g., insomnia], mood disorders [e.g., depression (e.g., major depressive disorder (MDD)), dysthymic disorder (e.g., mild depression), bipolar disorder (e.g., I and / or II), anxiety disorder (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 disorder (e.g., schizophrenia, schizoaffective disorder), convulsive disorder (e.g., epilepsy (e.g., status epilepticus (SE), seizures)], memory and / or cognitive impairment (e.g., attention disorder (e.g., attention deficit hyperactivity disorder (ADHD), dementia (e.g., Alzheimer's disease, dementia with Lewy bodies, vascular dementia), movement disorder (e.g., Huntington's disease, Parkinson's disease), personality disorder (e.g., antisocial personality disorder, neurological disorders], autism spectrum disorders (ASD) [e.g., autism, synaptopathy, monogenic causes of autism such as Rett Syndrome, Fragile X Syndrome, Angelman Syndrome, etc.], pain [e.g., neuropathic pain, injury-related pain syndromes, acute pain, chronic pain], traumatic brain injury (TBI), vascular disease [e.g., stroke, ischemia, vascular malformations], substance abuse disorders and / or withdrawal syndromes [e.g., opiate, cocaine, and / or alcohol addiction], and tinnitus.

[0262] 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 injury, 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.

[0263] In certain aspects, methods are provided for 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. In some embodiments, the method alleviates or prevents epileptogenesis.

[0264] In yet another aspect, a combination of the compound of the present invention with another pharmacologically active agent is provided. The compound provided herein can be administered as the sole active agent or in combination with other agents. The combined administration can proceed by any technique apparent to those skilled in the art, including, for example, separate, sequential, simultaneous and alternating administration.

[0265] In another aspect, there is provided a method for treating or preventing brain excitability in a subject susceptible to or suffering from a condition associated with brain excitability, comprising administering to the subject an effective amount of a compound of the invention.

[0266] In yet another aspect, there is provided a method for 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.

[0267] In yet another aspect, there is provided a method for 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.

[0268] In yet another aspect, a method is provided for inducing sleep and substantially maintaining the level of REM sleep found in normal sleep without the induction of substantial rebound insomnia, comprising administering an effective amount of a compound of the invention.

[0269] 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.

[0270] In yet another aspect, a method for 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 invention. In certain embodiments, the mood disorder is depression.

[0271] In yet another embodiment, by administering to a subject a therapeutically effective amount of a compound of the invention, Methods for treating cognitive enhancement or memory disorders are provided. In certain embodiments, the disorder is Alzheimer's disease. In certain embodiments, the disorder is Rett syndrome.

[0272] In yet another aspect, a method for treating attention disorders is provided by administering to a subject a therapeutically effective amount of a compound of the invention. In certain embodiments, the attention disorder is ADHD.

[0273] Inflammation of the central nervous system (CNS) (neuroinflammation) is recognized as a hallmark of all neurological disorders. Major inflammatory neurological disorders include multiple sclerosis (characterized by an immune-mediated response to myelin proteins) and meningoencephalitis (infectious agents triggered an inflammatory response). Additional scientific evidence suggests a potential role for inflammatory mechanisms in other neurological conditions, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, stroke, and traumatic brain injury. In one embodiment, the compounds of the present invention are useful for treating neuroinflammation. In another embodiment, the compounds of the present invention are useful for treating inflammation in neurological conditions, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, stroke, and traumatic brain injury.

[0274] 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.

[0275] 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 caused by imbalances in the body's hormone production that are directly related to the brain. Neuroendocrine disorders involve interactions between the nervous system and the endocrine system. The hypothalamus and pituitary are two areas of the brain that regulate the production of hormones, so damage to the hypothalamus or pituitary, 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.

[0276] Symptoms of neuroendocrine disorders include, but are not limited to, behavioral, emotional, and sleep-related symptoms, symptoms related to reproductive function, and somatic symptoms, including, but not limited to, fatigue, poor memory, anxiety, depression, weight gain or loss, emotional sustainability, lack of concentration, decreased attention span, decreased lipids, infertility, amenorrhea, decreased muscle mass, increased abdominal body fat, low blood pressure, slow heart rate, hair loss, anemia, constipation, cold intolerance, and dry skin.

[0277] 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 progressive loss of neuronal structure or function, or death of neurons. Neurodegenerative diseases and disorders include Alzheimer's disease (including associated symptoms of mild, moderate, or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic and ischemic injury; ataxia and seizures (including treatment and prevention of seizures caused by schizoaffective disorder or drugs used to treat schizophrenia); benign amnesia; cerebral edema; cerebellar ataxia, including McLeod neurospinous syndrome (MLS); closed head injury; coma; contusion (e.g., spinal cord injury and head injury); dementia, including multi-infarct dementia and senile dementia; impaired consciousness; Down's syndrome; drug-induced or drug-induced parkinsonism (neuroleptic-induced acute akathisia, acute dystonia, parkinsonism, or tardive dyskinesia, neuroleptic malignant syndrome, or drug-induced postural tremor); epilepsy; fragile X syndrome; Tourette's syndrome; head trauma; hearing impairment and hearing loss; Huntington's disease; Lennox syndrome; levodopa-induced dyskinesia; mental retardation; akinesia and akinesia (rigid) syndrome, including Movement disorders (including basal ganglia calcification, corticobasal degeneration, multiple system atrophy, Parkinsonism-ALS dementia complex, Parkinson's disease, postencephalitic parkinsonism, and progressive supranuclear palsy); muscle spasms and disorders associated with muscle spasms or weakness (including chorea such as benign hereditary chorea, drug-induced chorea, hemiballismus, Huntington's disease, neuroacanthocytosis, Sydenham chorea, and symptomatic chorea), dyskinesias (complex tics, including tics such as tics, simple tics, and symptomatic tics), myoclonus (including generalized myoclonus and focal siroclonus), tremors (such as rest tremor, postural tremor, and intention tremor) and dystonia (such as axial dystonia, dystonic writer's cramp, hemiplegic dystonia, paroxysmal dystonia, and focal dystonia, e.g., blepharospasm, oromandibular dystonia, and spasmodic dystonia and torticollis); Neurological damage, including eye damage, retinopathy or ocular macular degeneration; stroke, thrombotic stroke, stroke, cerebral ischemia, cerebral thrombosis, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest; Parkinson's disease, seizures; status epilepticus; stroke; tinnitus; tuberous sclerosis, and viral infection-induced neurodegeneration (e.g., caused by acquired immune deficiency syndrome (AIDS) and encephalopathy). Neurodegenerative diseases also include, but are not limited to, neurotoxic damage following stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest. The method of treating or preventing neurodegenerative diseases also includes treating or preventing the loss of neuronal function that is characteristic of neurodegenerative diseases.

[0278] 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, mild depressive disorder, bipolar or manic depressive disorder, depression caused by a chronic medical condition, 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).

[0279] 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 normally enjoyable activities. Some people with clinical depression may have trouble sleeping, lose weight, and be generally agitated and irritable. Clinical depression can affect an individual's feelings, thoughts, and behaviors, leading to a variety of emotional and physical problems. People with clinical depression may have problems performing daily activities and feel like life is not worth living.

[0280] Perinatal depression refers to depression during pregnancy. Symptoms may include irritability, crying, restlessness, sleep problems, exhaustion (emotional and / or physical), changes in appetite, difficulty concentrating, increased anxiety and / or worry, feelings of disconnection from the baby and / or fetus, and loss of interest in previously enjoyed activities.

[0281] Postnatal depression (PND), also known as postpartum depression (PPD), refers to a type of clinical depression that affects women after giving birth. Symptoms can include sadness, fatigue, changes in sleep and eating habits, decreased sexual desire, crying episodes, anxiety, and irritability. In some embodiments, the PND is a treatment-resistant depression (e.g., a treatment-resistant depression as described herein). In some embodiments, the PND is a treatment-refractory depression (e.g., a treatment-refractory depression as described herein).

[0282] In some embodiments, subjects with PND also experienced depression, or symptoms of depression, during pregnancy. This depression is referred to herein as perinatal depression. In some embodiments, subjects who experience perinatal depression are at increased risk of experiencing PND.

[0283] Atypical depression (AD) is characterized by mood reactivity (e.g., paradoxical anhedonia) and aggressiveness, marked weight gain or increased appetite. Patients with AD may also have significant social impairment as a result of excessive sleep or sleepiness (hypersomnia), a feeling of heaviness in the limbs, and hypersensitivity to perceived interpersonal rejection.

[0284] Melancholic depression is characterized by loss of pleasure in most or all activities (anhedonia), failure to respond to pleasurable stimuli, a depressed mood that is more prominent than feelings of sadness or loss, excessive weight loss, or excessive feelings of guilt.

[0285] Psychotic major depression (PMD) or psychotic depression refers to a major depressive episode, particularly of a melancholic nature, in which an individual experiences psychotic symptoms such as delusions and hallucinations.

[0286] Catatonic depression refers to major depression accompanied by disturbances in motor behavior and other symptoms. The individual may become silent and stuporous, immobilize, or exhibit purposeless or bizarre movements.

[0287] Seasonal affective disorder (SAD) refers to a type of seasonal depression in which an individual has a seasonal pattern of depressive episodes occurring in the fall or winter.

[0288] Dysthymia refers to conditions related to unipolar depression that manifest with the same physical and cognitive problems. These tend to be less severe and last longer (e.g., at least 2 years).

[0289] Dual depression refers to a significant amount of depressed mood (dysthymia) lasting for at least two years and interrupted by periods of major depression.

[0290] Depressive personality disorder (DPD) refers to a personality disorder that has depressive features.

[0291] Recurrent brief depression (RBD) refers to a condition in which an individual has depressive episodes about once a month, with each episode lasting less than two weeks, or typically less than two to three days.

[0292] Mild depressive disorder or mild depression refers to depression in which at least two symptoms are present for two weeks.

[0293] Bipolar disorder or manic-depressive disorder causes extreme mood swings that include emotional highs (mania or hypomania) and lows (depression). During manic periods, the individual feels unusually happy, energetic, and They may feel or act angry, irritable, or agitated. They often make poorly considered decisions with little consideration for the consequences. The need for sleep is usually reduced. During periods of depression, they may cry, make less eye contact with others, and have a negative outlook on life. The risk of suicide for people with the disorder is high, at over 6% over a 20-year period, and self-harm occurs in 30-40%. Other mental health problems, such as anxiety disorders and substance use disorders, are commonly associated with bipolar disorder.

[0294] Depression caused by a chronic medical condition refers to depression caused by a chronic medical condition such as cancer or chronic pain, chemotherapy, or chronic stress.

[0295] Treatment-resistant depression refers to a state in which an individual is treated for depression, but symptoms do not improve. For example, antidepressants or physiological counseling (psychotherapy) do not alleviate the depressive symptoms of individuals with treatment-resistant depression. In some cases, individuals with treatment-resistant depression improve symptoms, but then return. Treatment-refractory 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).

[0296] Postoperative depression refers to feelings of depression following a surgical procedure (e.g., as a result of having to face one's own mortality). For example, an individual may experience persistent feelings of sadness or emptiness, loss of pleasure or interest in hobbies and activities that they normally enjoy, or persistent feelings of worthlessness or hopelessness.

[0297] A mood disorder associated with a women's health condition or disorder refers to a mood disorder (e.g., depression) associated with (e.g., caused by) a women's health condition or disorder (e.g., those described herein).

[0298] Suicidal tendencies, suicidal ideation, and suicidal behavior refer to an individual's tendency to attempt suicide. Suicidal ideation involves thoughts or abnormal preoccupation with suicide. Suicidal ideation can range from, for example, momentary thoughts to extensive thinking, detailed plans, role-playing, and unfinished attempts. Symptoms can include talking about suicide, obtaining the means to attempt suicide, withdrawing from social contacts, preoccupation with death, feeling trapped or hopeless in a situation, increasing alcohol or drug use, doing something risky or self-destructive, and saying goodbye to people as if they will never see each other again.

[0299] Symptoms of depression include persistent feelings of anxiety or sadness, helplessness, hopelessness, pessimism, worthlessness, low energy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, impaired mobility, loss of interest in enjoyable activities or hobbies, loss of concentration, loss of energy, low self-esteem, absence of positive thoughts or plans, excessive sleep, 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 can be confirmed by a doctor or psychologist (e.g., by mental status examination).

[0300] In some embodiments, the method includes monitoring the subject using a known depression scale, such as the Hamilton Depression (HAM-D) scale, the Clinical Global Impression Improvement Scale (CGI), and the Montgomery-Asberg Depression Rating Scale (MADRS). In some embodiments, the therapeutic effect can be determined by a reduction in the Hamilton Depression (HAM-D) total score exhibited by the subject. A reduction in the HAM-D total score can be observed within 4, 3, 2, or 1 day, or within 96, 84, 72, 60, 48, 24, 20, 30, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 120, 140, 160, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 700, 710, 720, 750, 760, 770, 78 , 16, 12, 10, 8 hours or less. The therapeutic effect can be evaluated over a certain treatment period. For example, the therapeutic effect can be determined by the reduction in HAM-D total score from baseline after administration of a compound described herein, for example, a compound of formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X (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 lifetime).

[0301] 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's baseline HAM-D total score (i.e., prior to treatment with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X) is at least 24. In some embodiments, the subject's baseline HAM-D total score is at least 18. In some embodiments, the subject's baseline HAM-D total score is between 14 and 18, inclusive. In some embodiments, the subject's baseline HAM-D total score is between 19 and 22, inclusive. In some embodiments, the subject's HAM-D total score prior to treatment with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, is 23 or greater. In some embodiments, the baseline score is at least 10, 15, or 20. In some embodiments, the subject's HAM-D total score after treatment with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, is about 0-10 (e.g., less than 10; 0-10, 0-6, 0-4, 0-3, 0-2, or 1.8). In some embodiments, the HAM-D total score after treatment with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, is less than 10, 7, 5, or 3.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, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X. In some embodiments, the reduction in HAM-D total score from the baseline HAM-D total score after treatment with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, is at least 1, 2, 3, 4, 5, 7, 10, 25, 40, 50, or 100 fold. In some embodiments, the reduction in HAM-D total score from baseline HAM-D total score after treatment with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, 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 after treatment with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X (e.g., 12, 24, 48 hours, or 24, 48, 72, 96 hours or more, or 1 day, 2 days, 14 days or more after administration), compared to the baseline HAM-D total score, of at least 10, 15, or 20 points.

[0302] 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 reduction in the Hamilton Depression Score (HAM-D)) within 14, 10, 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours. 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 reduction in the HAM-D total score) within the first or second day of treatment with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X. 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 reduction in the HAM-D total score) within 14 days of initiating treatment with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X. In some embodiments, the method of treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic benefit (e.g., as determined by a statistically significant reduction in HAM-D total score) within 21 days of initiating treatment with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X. In some embodiments, the method of treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic benefit (e.g., as determined by a statistically significant reduction in HAM-D total score) within 28 days of initiating treatment with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X. In some embodiments, the therapeutic effect is a decrease from baseline in HAM-D total score following treatment with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X (e.g., treatment with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, once daily for 14 days).In some embodiments, the subject's HAM-D total score prior to treatment with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, is at least 24. In some embodiments, the subject's HAM-D total score prior to treatment with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, is at least 18. In some embodiments, the subject's HAM-D total score prior to treatment with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, is between 14 and 18, inclusive. In some embodiments, the reduction in HAM-D total score after treating a subject with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, as compared to a baseline HAM-D total score, is at least 10. In some embodiments, the reduction in HAM-D total score after treating a subject with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, as compared to a baseline HAM-D total score, is at least 15 (e.g., at least 17). In some embodiments, the HAM-D total score associated with treating a subject with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, is no greater than a number in the range of 6-8. In some embodiments, treating a subject with a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, is associated with a HAM-D total score of 7 or less.

[0303] In some embodiments, the methods provide a therapeutic effect (e.g., clinical benefit) within 14, 10, 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours. In some embodiments, the CNS disorder is a depressive disorder, e.g., major depressive disorder. In some embodiments, the method of treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic benefit within the second day of the treatment period. In some embodiments, the therapeutic benefit is a reduction in CGI score from baseline at the end of the treatment period (e.g., 14 days after administration).

[0304] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a reduction in the Montgomery-Asberg Depression Rating Scale (MADRS)) within 14, 10, 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours. 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 reduction in MADRS score from baseline at the end of the treatment period (e.g., 14 days after administration).

[0305] The therapeutic effect on major depressive disorder can be determined by a reduction in the Montgomery-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. The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item diagnostic questionnaire (on apparent sadness, reported sadness, inner tension, decreased sleep, decreased appetite, difficulty concentrating, fatigue, loss of sensation, pessimistic thoughts, and suicidal thoughts) used by psychiatrists to measure the severity of depressive episodes in patients with mood disorders.

[0306] In some embodiments, the method provides a therapeutic effect (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. In some embodiments, the therapeutic effect is an improvement as measured by the EPDS.

[0307] In some embodiments, the methods provide a therapeutic effect (eg, as measured by a reduction in the Generalized Anxiety Disorder 7-item scale (GAD-7)) within 4, 3, 2, 1 day, within 24, 20, 16, 12, 10, 8 hours.

[0308] Anxiety disorders Provided herein is a method for treating anxiety disorders (e.g., generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, phobia, post-traumatic stress disorder). Anxiety disorder is an umbrella term that covers several different forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders.

[0309] Generalized anxiety disorder is a common chronic illness characterized by long-term anxiety that is not focused on any one object or situation.People who suffer from generalized anxiety experience non-specific persistent fear and worry, and become excessively concerned with everyday events.Generalized anxiety disorder is the most common anxiety disorder that affects older adults.

[0310] In panic disorder, a person suffers from brief attacks of intense fear and anxiety, often characterized by shaking, shaking, confusion, dizziness, nausea, and difficulty breathing. These panic attacks are defined by the APA as a sudden feeling of fear or discomfort that peaks in less than 10 minutes, but may last for hours and may also be triggered by stress, fear, or exercise. However, the specific cause is not always clear. Unexpected panic In addition to recurrent attacks, a diagnosis of panic disorder also requires that there be a chronic consequence, either worry about the potential impact of the attack, a continuing fear of future attacks, or a significant change in behavior related to the attacks. Thus, people with panic disorder experience symptoms outside of specific panic episodes. Often, normal changes in heart rate are noticed by the panic sufferer, leading them to believe that something is wrong with their heart or that another panic attack is about to occur. In some cases, heightened awareness of bodily functions (hypervigilance) occurs during a panic attack, where the perceived physiological changes are interpreted as a potentially life-threatening illness (i.e., extreme hypochondriasis).

[0311] Obsessive-compulsive disorder is a type of anxiety disorder characterized primarily by recurrent obsessions (distressing, persistent, intrusive thoughts or images) and compulsions (urges to perform certain actions or rituals). OCD thought patterns can be likened to superstition insofar as they involve belief in causal relationships that do not actually exist. Often, this process is not entirely logical; for example, a compulsion to walk in a certain pattern can be used to alleviate obsessions of impending harm. And often, compulsions are simply completely inexplicable urges to complete a ritual caused by tension. In a few cases, patients with OCD can experience only obsessions without obvious compulsions, and a much smaller number experience only compulsions.

[0312] The single largest category of anxiety disorder is that of phobias, which includes all cases in which fear and anxiety are triggered by a particular stimulus or situation. Patients typically anticipate frightening consequences from encountering the phobic object (anything from an animal to a place to a bodily fluid).

[0313] Post-traumatic stress disorder (PTSD) is an anxiety disorder resulting from a traumatic experience. Post-traumatic stress can result from extreme situations such as combat, rape, hostage situations, or even serious accidents. It can also result from long-term (chronic) exposure to intense stressors, such as soldiers who endure individual battles but are unable to cope with sustained combat. Common symptoms include flashbacks, avoidance behaviors, and depression.

[0314] Women's health problems Provided herein is a method for treating conditions or disorders related to female health.Conditions or disorders related to female health include, but are not limited to, gynecological health and disorders (e.g., premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD)), pregnancy problems (e.g., miscarriage, abortion), infertility and related disorders (e.g., polycystic ovarian syndrome (PCOS)), other disorders and conditions, and problems related to female overall health and wellness (e.g., menopause).

[0315] Gynecological health and disorders affecting women include urinary tract health, including menstruation and menstrual irregularities, urinary incontinence and pelvic floor disorders, as well as disorders such as bacterial vaginosis, vaginitis, uterine fibroids, and vulvar disorders.

[0316] Premenstrual syndrome (PMS) refers to the physical and emotional symptoms that occur one to two weeks before a woman's menstrual period. Symptoms vary but can include bleeding, mood swings, breast tenderness, food cravings, fatigue, irritability, acne, and depression.

[0317] Premenstrual dysphoric disorder (PMDD) is a severe form of PMS. Symptoms of PMDD are similar to PMS but are more severe and can interfere with work, social activities, and relationships. PMDD symptoms include mood swings, feelings of depression or hopelessness, and marked anger. , increased interpersonal conflict, tension and anxiety, irritability, decreased interest in usual activities, difficulty concentrating, fatigue, changes in appetite, feeling out of control or overwhelming, sleep disorders, physical problems (e.g., bloating, breast tenderness, swelling, headaches, joint or muscle pain).

[0318] 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.

[0319] A miscarriage is a pregnancy that ends naturally within the first 20 weeks of pregnancy.

[0320] Abortion refers to the intentional termination of a pregnancy, which can take place during the first 28 weeks of pregnancy.

[0321] Infertility and related disorders include uterine fibroids, polycystic ovarian syndrome, endometriosis, and primary ovarian failure.

[0322] Polycystic ovary syndrome (PCOS) refers to an endocrine system disorder in women of reproductive age. PCOS is a set of symptoms resulting from elevated 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 menstrual periods, excess body and facial hair, acne, pelvic pain, difficulty getting pregnant, and patches of thick, dark, velvety skin. PCOS may be associated with conditions including type 2 diabetes, obesity, obstructive sleep apnea, heart disease, mood disorders, and endometrial cancer.

[0323] Other diseases and conditions that only affect women include Turner syndrome, Rett syndrome, and ovarian and cervical cancer.

[0324] Issues related to women's overall health and wellness include violence against women, women with disabilities and their unique challenges, osteoporosis and bone health, and menopause.

[0325] Menopause refers to 12 months after a woman's last menstrual period and marks the end of the menstrual cycle. Menopause typically occurs in women's 40s or 50s. Physical symptoms such as hot flashes and emotional symptoms of menopause can disrupt sleep, reduce energy, or cause anxiety or feelings of sadness or loss. Menopause includes natural menopause and surgical menopause, which is a type of induced menopause resulting from events such as surgery (e.g., hysterectomy, oophorectomy, cancer). It is induced, for example, when the ovaries are severely damaged by radiation, chemotherapy, or other drugs.

[0326] Epilepsy A compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable composition 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.

[0327] Epilepsy is a brain disorder characterized by repeated seizures over time. Types of epilepsy include, but are not limited to, generalized epilepsy, such as childhood absence epilepsy, juvenile myoclonic epilepsy, epilepsy with grand mal awakening seizures, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, such as temporal lobe epilepsy, frontal lobe epilepsy, and benign focal epilepsy of childhood.

[0328] Epilepsy The compounds and methods described herein may be used to treat or prevent epileptogenesis. Epileptogenesis is the stepwise process by which a normal brain develops epilepsy, a chronic condition in which seizures occur. Epileptogenesis results from neuronal damage caused by an earlier seizure (e.g., status epilepticus).

[0329] Status epilepticus (SE) Status epilepticus (SE) includes, for example, convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptic discharges. Convulsive status epilepticus is characterized by the presence of bouts of convulsive status epilepticus and can include early status epilepticus, established status epilepticus, refractory status epilepticus, and super-refractory status epilepticus. Early status epilepticus is treated with first-line therapy. Established status epilepticus is characterized by bouts of status epilepticus that persist despite treatment with first-line therapy, and second-line therapy is administered. Refractory status epilepticus is characterized by persistent bouts of status epilepticus despite treatment with first-line and second-line therapies, typically with general anesthesia. Super-refractory status epilepticus is characterized by persistent bouts of status epilepticus despite treatment with first-line, second-line, and general anesthesia for 24 hours or more.

[0330] 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, subtle non-convulsive status epilepticus, generalized non-convulsive status epilepticus, e.g., delayed absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus.

[0331] A compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable composition thereof, can also be administered as a prophylactic agent prior to the onset of a seizure to a subject with 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, super refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges.

[0332] Seizures A seizure is a physical finding or behavioral change that occurs after an episode of abnormal electrical activity in the brain. The term "seizure" is often used interchangeably with "convulsion." A seizure is a rapid and uncontrollable shaking of a person's body. During a seizure, a person's muscles repeatedly contract and relax.

[0333] Based on the type of behavior and brain activity, seizures are classified 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.

[0334] Generalized seizures are caused by electrical impulses from throughout the brain, whereas 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.

[0335] There are six types of generalized seizures. The most common, dramatic, and therefore best known is the generalized convulsion, also called grand mal. In this type of seizure, the patient is not conscious. The individual loses consciousness and usually collapses. Loss of consciousness is followed by 30-60 seconds of total body rigidity (called the "tonic" phase of the seizure), followed by 30-60 seconds of violent jerking (the "clonic" phase), after which the patient enters a deep sleep (the "post-ictal" or postictal phase). Injuries and accidents such as tongue biting and urinary incontinence can occur during grand mal seizures.

[0336] Absence seizures cause a brief loss of consciousness (only a few seconds) with few or no symptoms. Affected people, most often children, typically stop their activities and have a blank stare. These seizures begin and end suddenly and may occur several times a day. Patients are usually unaware that they are having a seizure, but may be aware that they are "losing time."

[0337] Myoclonic seizures consist of sporadic jerks, usually on both sides of the body. Patients may describe the jerks as brief electric shocks. If severe, these seizures may cause objects to be dropped or thrown involuntarily.

[0338] Clonal seizures are repetitive, rhythmic jerks that involve both sides of the body simultaneously.

[0339] Tonic seizures are characterized by muscle stiffness.

[0340] Atonic seizures consist of a sudden generalized loss of muscle rigidity, especially in the arms and legs, often causing a fall.

[0341] The seizures described herein may include epileptic seizures; acute repetitive seizures; cluster seizures; continuous seizures; discontinuous seizures; prolonged seizures; recurrent seizures; status epilepticus seizures, e.g., refractory convulsive status epilepticus, nonconvulsive status epilepticus seizures; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondarily generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign rolandic seizures; febrile seizures; affective seizures; focal seizures; galvanic seizures; generalized seizures; infantile spasms; Jacksonian seizures; large bilateral myoclonic seizures; multiple 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, tuberculous sclerosis complex, Rett syndrome, or PCDH19 female epilepsy.

[0342] Movement disorders Also described herein is a method for treating movement disorders.As used herein, "movement disorder" refers to various diseases and disorders associated with hyperactivity movement disorders 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 legs syndrome, stiff person syndrome, and gait disorder.

[0343] Tremor The methods described herein can be used to treat tremors, for example, cerebellar or intention tremors, dystonic tremors, essential tremors, orthostatic tremors, Parkinsonian tremors, physiological tremors, psychogenic tremors, or rubral tremors using compounds of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X. Tremors include those caused by genetic, degenerative, and idiopathic disorders, such as Wilson's disease, Parkinson's disease, and essential tremor, respectively; metabolic disorders (e.g., thyroid and parathyroid disease, liver disease, and liver disease); and hypoglycemia); peripheral neuropathy (associated with Charcot-Marie-Tooth, Lucy-Lewy, diabetes, and complex regional pain syndrome); toxins (nicotine, mercury, lead, CO, manganese, arsenic, toluene); drug-induced disorders (narcolepsy, tricyclics, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychiatric disorders. Clinical tremor can be classified as physiologic tremor, enhanced physiologic tremor, essential tremor syndrome (including classic essential tremor, primary orthostatic tremor, and task- and position-specific tremor), dystonic tremor, Parkinsonian tremor, cerebellar tremor, Holmes tremor (i.e., rubral tremor), palatal tremor, neuropathic tremor, toxic or drug-induced tremor, and psychogenic tremor.

[0344] Tremor is an involuntary, sometimes rhythmic, contraction and relaxation of muscles that can involve vibration or twitching of one or more body parts (e.g., hands, arms, eyes, face, head, vocal cords, trunk, legs).

[0345] Cerebellar tremor or intention tremor is a slow, widespread tremor of the limbs that occurs after intentional movement. Cerebellar tremor is caused by lesions or damage to the cerebellum, for example, tumors, strokes, and diseases (e.g., multiple sclerosis, hereditary degenerative disorders).

[0346] Dystonic tremors occur in individuals affected by dystonia, a movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive movements and / or painful and abnormal postures or positions. Dystonic tremors can affect any muscle in the body. Dystonic tremors occur irregularly and can often be relieved by complete rest.

[0347] Essential tremor or benign essential tremor is the most common tremor. Essential tremor may be mild and non-progressive or may progress slowly, starting on one side of the body but affecting both sides within three years. The hands are most often affected, but the head, voice, tongue, legs, and trunk may also be involved. Tremor frequency may decrease with age, but severity may increase. Heightened emotions, stress, fever, physical fatigue, or hypoglycemia may trigger tremor and / or increase severity. Symptoms generally progress over time and may be both visible and persistent after onset.

[0348] Orthostatic tremor is characterized by rapid (e.g., greater than 12 Hz) rhythmic muscle contractions in the legs and trunk immediately after standing. Cramps can be felt in the thighs and legs, and patients may sway uncontrollably when asked to stand in one place. Patients with essential tremor may have orthostatic tremor.

[0349] Parkinsonian tremors are caused by damage to structures in the brain that control movement. Parkinsonian tremors are often a precursor to Parkinson's disease and are typically seen as "pill-making" movements of the hands, and may also affect the jaw, lips, legs, and trunk. Onset of Parkinsonian tremors typically begins after age 60. Movements may begin in one limb or on one side of the body and progress to include the other side.

[0350] Physiological tremor can occur in normal individuals and has no clinical significance. It can be seen in all voluntary muscle groups. Physiological tremor can be caused by certain drugs, alcohol withdrawal, or medical conditions including thyroid overactivity and hypoglycemia. Tremor classically has a frequency of about 10 Hz.

[0351] Psychogenic or hysterical tremor can occur at rest or during bodily movement or motor activity. Patients with psychogenic tremor may have conversion disorder or another psychiatric illness.

[0352] Rubral tremor is characterized by a coarse, slow tremor that can be present at rest, in position, and at will. Tremor is associated with conditions affecting the red nucleus of the midbrain, the classic abnormal stroke.

[0353] Parkinson's disease affects the nerve cells in the brain that produce dopamine. Symptoms include muscle rigidity, tremors, and changes in speech and gait. Parkinsonism is characterized by tremors, bradycardia, rigidity, and postural instability. Parkinsonism shares symptoms with Parkinson's disease, but is a group of conditions rather than a progressive neurodegenerative disease.

[0354] Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions that cause abnormal, often repetitive movements or postures. Dystonic movements can be patterned, twisting, or tremor-like. Dystonia is often initiated or exacerbated by voluntary actions and is associated with overflow muscle activation.

[0355] Chorea is a neurological disorder characterized by spasmodic, 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, talking, and swallowing.

[0356] Ataxia refers to the complete loss of control over bodily movements and can affect fingers, hands, arms, legs, torso, speech, and eye movements.

[0357] Myoclonus and startle are responses to sudden, unexpected stimuli, which can be acoustic, tactile, visual, or vestibular.

[0358] Tics are involuntary movements that are usually sudden in onset, brief, repetitive but not rhythmic, typically mimicking normal behavior, and often occurring against a background of normal activity. Tics can be classified as motor or vocal, with motor tics being associated with movement and vocal tics being associated with sound. Tics are characterized as simple or complex. For example, simple motor tics involve only a few muscles restricted to a specific body part. Tourette's syndrome is a childhood-onset genetic neuropsychiatric disorder characterized by multiple motor tics and at least one vocal tic.

[0359] Restless legs syndrome is a neurosensory-motor disorder characterized by an overwhelming urge to move the legs while at rest.

[0360] Stiff person syndrome is a progressive movement disorder characterized by involuntary painful spasms and muscle rigidity, usually involving the hips and legs. A stiff-legged gait with exaggerated lumbar hyperlordosis is the typical outcome. Characteristic abnormalities in EMG recordings with serial motor unit activity of the paraspinal axial muscles are typically observed. Variants include "stiff limb syndrome," which produces focal stiffness that typically affects the distal legs and feet.

[0361] Gait disorders refer to abnormalities in the manner or style of walking resulting from neuromuscular, arthritic, or other bodily changes. Gaits are classified according to the system responsible for the abnormal movement and include hemiplegic, diplegic, neuropathic, myopathic, parkinsonian, choreoataxic, ataxic, and sensory.

[0362] Anesthesia / Sedation Anesthesia is pharmacologically induced and produces amnesia, analgesia, loss of responsiveness, loss of skeletal muscle reflexes, and stress. Anesthesia is a reversible state that has either a decreased ability to respond to pain, a decreased ability to control pain, or all of these simultaneously. These effects can be obtained from a single drug that alone provides the right combination of effects, or sometimes with a combination of drugs (e.g., hypnotics, sedatives, paralyzing, analgesics) to achieve a very specific combination of results. Anesthesia allows patients to undergo surgery and other procedures without the pain they would otherwise experience.

[0363] Sedation is generally the reduction of irritability or excitability through the administration of pharmacological agents to facilitate a medical or diagnostic procedure.

[0364] Sedation and analgesia includes a continuum of states of consciousness ranging from minimal sedation (anxiolysis) to general anaesthesia.

[0365] Minimal sedation is also known as anxiolysis. Minimal sedation is a drug-induced state in which the patient responds normally to verbal commands. Cognitive function and coordination may be impaired. Ventilatory and cardiovascular function are usually unaffected.

[0366] Moderate sedation / analgesia (conscious sedation) is a drug-induced decrease in consciousness in which the patient responds purposefully to verbal commands, either alone or with light tactile stimulation. No intervention is usually required to maintain a patent airway. Spontaneous ventilation is typically sufficient. Cardiovascular function is usually preserved.

[0367] Deep sedation / analgesia is a drug-induced reduction in consciousness during which the patient is not easily aroused but responds purposefully after repetitive or painful stimuli (not a reflex withdrawal from painful stimuli). Independent ventilatory function may be impaired and the patient may require assistance to maintain a patent airway. Spontaneous ventilation may be inadequate. Cardiovascular function is usually preserved.

[0368] General anesthesia is a drug-induced loss of consciousness during which the patient is not aroused by even painful stimuli. The ability to maintain independent ventilatory function is often impaired, and assistance is often required to maintain a patent airway. Positive pressure ventilation may be required due to reduced spontaneous ventilation or drug-induced depression of neuromuscular function. Cardiovascular function may be impaired.

[0369] Sedation in the intensive care unit (ICU) allows the patient to be less aware of their environment and less responsive to external stimuli. This encompasses a wide range of symptom control that can play a role in the care of critically ill patients and will vary between patients and individuals throughout their illness course. Heavy sedation in critical care is often used with neuromuscular blocking agents to facilitate endotracheal tube tolerance and ventilator synchrony.

[0370] 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 sedation may have a long-term effect. Sedation in the ICU may have a short elimination half-life.

[0371] Procedural sedation and analgesia, also called conscious sedation, is a technique in which sedatives or dissociative agents are administered with or without analgesics to induce a state that allows the subject to tolerate an unpleasant procedure while maintaining cardiopulmonary function.

[0372] Provided herein is a method for ameliorating one or more symptoms of a respiratory disease in a subject, comprising administering to the subject an effective amount of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, II, IIIa, Also described are methods of treating rheumatoid arthritis, comprising administering a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharma- ceutical salt thereof.

[0373] In one aspect, provided herein is a method of treating a subject, wherein the subject exhibits one or more symptoms of a respiratory disorder and / or has been diagnosed with a respiratory disorder, comprising administering to the subject an effective amount of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharma- ceutical acceptable salt thereof).

[0374] In some embodiments, the disclosure contemplates a method of treating a subject having a respiratory disease, comprising administering to the subject a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharma- ceutical acceptable salt thereof).

[0375] In some embodiments, administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharma- ceutically acceptable salt thereof) to a subject exhibiting symptoms of a respiratory disease may result in a reduction in the severity of one or more symptoms of the respiratory disease, or a delay or slowing of the progression of one or more symptoms of the respiratory disease.

[0376] In some embodiments, the subject with a respiratory disorder has been or is being treated with mechanical ventilation or oxygen. In some embodiments, the subject with a respiratory disorder has been or is being treated with mechanical ventilation.

[0377] In some embodiments, a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharma- ceutically acceptable salt thereof) is administered to a subject who is being or has been treated with mechanical ventilation. In some embodiments, administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharma- ceutically acceptable salt thereof) is continued throughout the treatment of the subject with mechanical ventilation. In some embodiments, administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharma- ceutically acceptable salt thereof) continues after a subject has ceased treatment with mechanical ventilation.

[0378] In some embodiments, a compound or pharmaceutical composition described herein (e.g., A compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharma- ceutically acceptable salt thereof, is administered to a subject undergoing or who has undergone treatment with a sedative agent. In some embodiments, the sedative agent is propofol or a benzodiazepine.

[0379] In some embodiments, the disclosure includes administering a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharma- ceutically acceptable salt thereof) to a subject in need thereof in an amount sufficient to increase blood oxygen saturation. In some embodiments, blood oxygen saturation is measured using pulse oximetry.

[0380] In some embodiments, the present disclosure contemplates a method for treating a cytokine storm in a patient. In some embodiments, the method comprises administering to a patient a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharma- ceutical acceptable salt thereof). In some embodiments, a symptom of a cytokine storm is pulmonary inflammation. In some embodiments, the patient suffering from a cytokine storm has acute respiratory distress syndrome (ARDS).

[0381] respiratory disease In some embodiments, the subject with a respiratory disease suffers from respiratory distress, hi some embodiments, the respiratory distress comprises acute respiratory distress.

[0382] In some embodiments, a subject with a respiratory disorder may exhibit one or more symptoms selected from the group consisting of airway hyperresponsiveness, inflammation of lung tissue, pulmonary hyperresponsiveness, and inflammation-associated lung pain.

[0383] In some embodiments, a subject with a respiratory disease may exhibit inflammation of lung tissue. In some embodiments, the inflammation of lung tissue is bronchitis or bronchiectasis. In some embodiments, the inflammation of lung tissue is pneumonia. In some embodiments, the pneumonia is ventilator-associated pneumonia or hospital-acquired pneumonia. In some embodiments, the pneumonia is ventilator-associated pneumonia.

[0384] In some embodiments, administration of a compound or pharmaceutical composition described herein to a subject exhibiting symptoms of a respiratory disease results in a reduction in the severity of respiratory distress in the subject with the respiratory disease, or delays or slows the progression of respiratory distress in the subject with the respiratory disease.

[0385] In some embodiments, administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharma- ceutically acceptable salt thereof) to a subject exhibiting symptoms of a respiratory disease results in a reduction in the severity of airway hyperresponsiveness in a subject with a coronavirus-associated disease or delays or slows the progression of airway hyperresponsiveness in a subject with a respiratory disease.

[0386] In some embodiments, administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharma- ceutically acceptable salt thereof) to a subject exhibiting symptoms of a respiratory disease results in a reduction in the severity of inflammation of lung tissue in the subject with the respiratory disease, or delays or slows the progression of inflammation of lung tissue in the subject with the respiratory disease. In some embodiments, administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharma- ceutically acceptable salt thereof) to a subject exhibiting symptoms of a respiratory disease results in a reduction in the severity of pneumonia in the subject with the respiratory disease, or delays or slows the progression of pneumonia in the subject with the respiratory disease.

[0387] In some embodiments, administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharma- ceutically acceptable salt thereof) to a subject exhibiting symptoms of a respiratory disease results in a reduction in the severity of pulmonary hypersensitivity in the subject with the respiratory disease, or delays or slows the progression of pulmonary hypersensitivity in the subject with the respiratory disease.

[0388] In some embodiments, administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharma- ceutically acceptable salt thereof) to a subject exhibiting symptoms of a respiratory disease results in a reduction in the severity of inflammation-associated pulmonary pain in the subject with the respiratory disease, or delays or slows the progression of inflammation-associated pulmonary pain in the subject with the respiratory disease.

[0389] In some embodiments, the subject with a respiratory disease is receiving or has received treatment for an infection, fibrosis, a fibrotic episode, chronic obstructive pulmonary disease, sarcoidosis (or pulmonary sarcoidosis), or asthma / asthma-related inflammation.

[0390] In some embodiments, the subject exhibits symptoms of and / or has been diagnosed with asthma, hi some embodiments, the subject is experiencing or has experienced an asthma attack.

[0391] In some embodiments, the subject is undergoing or has undergone treatment for a fibrosis or fibrotic episode, hi some embodiments, the fibrosis is cystic fibrosis.

[0392] In some embodiments, the respiratory disease is selected from the group consisting of cystic fibrosis, asthma, smoke-induced COPD, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, congenital bilateral absence of vas deferens (CBAVD), mild lung disease, pulmonary sarcoidosis, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), liver disease, hereditary emphysema, hereditary hemochromatosis, coagulation fibrosis deficiencies (e.g., protein C deficiency), hereditary angioedema type 1, lipid processing deficiencies (e.g., familial hypercholesterolemia), type 1 chylomicronemia, abetalipoproteinemia, Hemolytic storage diseases (e.g., I-cell disease / pseudo-Hurler), mucopolysaccharidoses, Sandhoff / Taysachs, Crigler-Najjar type II, polyendocrinopathy / hyperinsulinemia, diabetes mellitus, Laron dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI), neurophysin DI, nephrogenic DI, Charcot-Marie-Tooth syndrome, Pelizaeus-Merzbacher disease, neurodegenerative diseases (e.g., Alzheimer's disease, and / or associated with a disease or condition selected from the group consisting of: myeloproliferative disorders (e.g., Parkinson's disease), amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, some polyglutamine neurological disorders (e.g., Huntington's), spinal angioedema type I, spinal and bulbar muscular atrophy, dentatorubral-pallidoluysian, and myotonic dystrophy, as well as spongiform encephalopathies (e.g., hereditary Creutzfeldt-Jakob disease) (caused by defects in prion protein processing), Fabry disease, Straussler-Scheinker syndrome, COPD, dry eye disease, or Sjogren's disease.

[0393] infectious disease The present disclosure contemplates, inter alia, the treatment of a subject having an infection. The present disclosure contemplates, inter alia, the treatment of a subject having a disease associated with an infection. In some embodiments, the infection is a viral infection or a bacterial infection. In some embodiments, the infection is a viral infection. In some embodiments, the infection is a bacterial infection.

[0394] In some embodiments, the viral infection is an infection with a virus selected from the group consisting of a coronavirus, influenza virus, human rhinovirus, human parainfluenza virus, human metapneumovirus, and hantavirus. In some embodiments, the virus is a coronavirus. In some embodiments, the coronavirus is selected from the group consisting of SARS-CoV, SARS-CoV-2, and MERS-CoV.

[0395] The present disclosure contemplates, inter alia, the treatment of a subject having a disease associated with a coronavirus. In some embodiments, the disease associated with a coronavirus is selected from the group consisting of coronavirus disease 2019 (COVID-19), severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS). In some embodiments, the disease associated with a coronavirus is selected from the group consisting of COVID-19. In some embodiments, the coronavirus is selected from the group consisting of SARS-CoV-1, SARS-CoV-2, and 2012-nCoV. In some embodiments, the coronavirus is SARS-CoV-2.

[0396] In some embodiments, the bacterial infection is an infection with a bacterium selected from the group consisting of Streptococcus pneumoniae, Chlamydia pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, and Haemophilus influenzae. In some embodiments, the Staphylococcus aureus is methicillin-resistant Staphylococcus aureus. EXAMPLES

[0397] In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and should not be construed in any way as limiting the scope thereof.

[0398] Materials and Methods The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. When typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, other process conditions may also be used. It will be understood that unless otherwise indicated, 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.

[0399] Additionally, as will be apparent to one skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The selection of a suitable protecting group for a particular functional group, as well as suitable conditions for protection and deprotection, are well known in the art. For example, many protecting groups and their introduction and removal can be found in TW Greene and PGM Wets, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1999. York, 1991, and the references cited therein.

[0400] The compounds provided herein may be isolated and purified by known standard procedures. Such procedures include (but are not limited to) trituration, column chromatography, HPLC, or supercritical fluid chromatography (SFC). The following schemes are presented with details regarding the preparation of representative oxysterols listed herein. The compounds provided herein may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis. Exemplary chiral columns available for use in the separation / purification of the enantiomers / diastereomers provided herein include, but are not limited to, ChiralPak® AD-10, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ, and CHIRALCEL® OK.

[0401] As reported herein 1 It will be understood that the H-NMR (eg, for the region between δ (ppm) of about 0.5 to about 4 ppm) is an exemplary interpretation of the NMR spectrum (eg, exemplary peak integrals) of a compound.

[0402] LC-ELSD / MS: (Mobile phase: 1.5ML / 4L TFA in water (solvent A) and 0.75ML / 4L TFA in acetonitrile (solvent B), elution gradient 30%-90% (solvent B) over 0.9 min, held at 90% for 0.6 min at a flow rate of 1.2ml / min; Column: Xtimate C18 2.1*30mm, 3um; Wavelength: UV220nm; Column temperature: 50℃; MS ionization: ESI; Detector: PDA&ELSD.

[0403] 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-Bu 3 P) 2 : bis(tri-tertiarybutylphosphine)palladium(0), AcCl: acetyl chloride, i-PrMgCl: isopropylmagnesium chloride; TBSCl: tert-butyl(chloro)dimethylsilane, (i-PrO) 4 Ti: titanium tetraisopropoxide, BHT: 2,6-di-t-butyl-4-methylphenoxide, Me: methyl, i-Pr: isopropyl, t-Bu: tertiary butyl, Ph: phenyl, Et: ethyl, Bz: benzoyl, BzCl: benzoyl chloride, CsF: cesium fluoride, DCC: dicyclohexylcarbodiimide, DCM: dichloromethane, DMAP: 4-dimethylaminopyridine, 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, T BS: t-butyldimethylsilyl, TMS: trimethylsilyl, TMSCF 3 : (Trifluoromethyl)trimethylsilane, Ts: p-toluenesulfonyl, Bu: butyl, Ti(OiPr) 4: tetraisopropoxytitanium, LAH: lithium aluminum hydride, LDA: lithium diisopropylamide, LiOH.H 2 O: Lithium hydroxide hydrate, MAD: Methylaluminum bis(2,6-di-t-butyl-4-methylphenoxide), MeCN: Acetonitrile, NBS: N-bromosuccinimide, Na 2 SO 4 : Sodium sulfate, Na 2 S 2 O 3 : sodium thiosulfate, MeCN: acetonitrile, MeOH: methanol, Boc: t-butoxycarbonyl, MTBE: methyl tertiary butyl ether, K-Selectride: potassium tri(s-butyl)borohydride, 9-BBN dimer: 9-borabicyclo(3.3.1)nonane (dimer), DIPEA: diisopropylethylamine, DMF: dimethylformamide, FA: formic acid, SM: starting material.

[0404] Examples 1 and 2: Synthesis of 1-((S)-2-hydroxy-2-((1S,4aS,4bR,6aS,8R,10aS,10bR,12aS)-8-hydroxy-12a-methyl-8-propyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile and 1-((R)-2-hydroxy-2-((1S,4aS,4bR,6aS,8R,10aS,10bR,12aS)-8-hydroxy-12a-methyl-8-propyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile [ka] Synthesis of 1.2 To a solution of (5α)-estrane-3,17-dione, 1.1 (20 g, 72.8 mmol) in THF (200 mL) was added n-PrMgCl (109 mL, 218 mmol, 2 M in THF) dropwise at −60° C. After stirring at −60° C. for 2 h, the reaction mixture was diluted with saturated NH 4 Poured into aqueous Cl (400 mL) and extracted with EtOAc (2×200 mL). 2 SO 4It was dried over, filtered, concentrated and purified by silica gel column (PE / EtOAc=0-20%) to give 1.2 (18.4 g) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H 2.43 (dd, J = 8.8, 19.3 Hz, 1H), 2.16-2.00 (m, 1H), 1.97-1.85 (m, 2H), 1.83-1.72 (m, 3H), 1.68-1.43 (m, 5H), 1.40-0.89 (m, 17H), 0.87 (s, 3H), 0.79-0.61 (m, 2H).

[0405] Synthesis of 1.3 To a solution of diisopropylamine (19.4 mL, 0.718 g / mL, 139 mmol) in THF (64 mL) was added n-butyl-lithium (55.6 mL, 2.5 M in hexanes, 139 mmol) at -78 °C. After stirring for 10 min at -78 °C, the LDA solution was added to a solution of 1.2 (11.7 g, 36.7 mmol) and ethyl diazoacetate (20.8 g, 183 mmol) in THF (400 mL) at -78°C. After stirring at -78°C for 2 h, the reaction was quenched with acetic acid (10.9 g, 183 mmol) in THF (50 mL), stirred at 15°C for 16 h, poured into water (1000 mL) and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (1500 mL) and diluted with anhydrous Na 2 SO 4 Drying over, filtration and evaporation under reduced pressure gave 1.3 (20 g) as an oil which was used as is.

[0406] Synthesis of 1.4 A solution of 1.3 (20 g) and DME (200 mL) was added to Rh 2 (OAc) 4 (204 mg, 0.462 mmol) was added in one portion at 15° C. After stirring at 15° C. for 2 h, the reaction mixture was concentrated to give 1.4 (20 g) as an oil, which was used as is.

[0407] Synthesis of 1.5 To a solution of 1.4 (20 g) in MeOH (200 mL) was added KOH (27.7 g, 494 mmol) at 15° C. After heating at 70° C. for 1 h, the reaction mixture was diluted with H 2 O (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with HCl (1 M, 100 mL), saturated NaHCO 3 (100 mL), brine (100 mL), and anhydrous Na 2 SO 4 The residue was purified by flash-combi (0-15% EtOAc in PE) to give 1.5 (4.0 g) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H 2.62(dt,J=6.8,14.1 Hz,1H),2.19(br d,J=10.3 Hz,1H),2.05(dt,J=2.6,6.6 Hz,1H),1.93-1.57(m,8H),1.54-1.12(m,12H),1.12-1.05(m,4H),1.05-0.84(m,7H),0.65(br dd,J=2.8,10.8 Hz,2H). LC-ELSD / MS purity 99%,C 22 H 35 O[MH 2 O+H] + MS ESI calculated value 315.2 found value 315.2.

[0408] Synthesis of 1.6 in anhydrous THF (50 mL) 3 To a suspension of PEtBr (10.6 g, 28.8 mmol), t-BuOK (4.84 g, 43.2 mmol) was added by N 2The mixture was added at 15° C. under reduced pressure. After stirring at 45° C. for 30 min, a solution of 1.5 (4.8 g, 14.4 mmol) in anhydrous THF (50 mL) was added dropwise. After stirring at 45° C. for 16 h, the reaction mixture was cooled, poured into ice water (100 mL), stirred for 10 min, and extracted with EtOAc (2×100 mL). The combined organic phase was washed with saturated brine (2×200 mL), filtered, and concentrated. The residue was purified by flash column (0-10% EtOAc in PE) to give 1.6 (1.8 g, 36.2%) as a solid and starting material 1.5 (1.2 g) was recovered as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H 5.15 (br t, J = 6.5 Hz, 1H), 2.50 (br d, J = 13.8 Hz, 1H), 2.25-2.06 (m, 1H), 2.02-1.59 (m, 9H), 1.41-1.02 (m, 14H), 0.95-0.61 (m, 4H).

[0409] Synthesis of 1.7 To a solution of 1.6 (1.8 g, 5.22 mmol) in THF (50 ml) was added 9-BBN dimer (3.80 g, 15.6 mmol) at 15° C. After stirring at 50° C. for 16 h, the reaction mixture was cooled and diluted with EtOH (6.05 ml, 104 mmol, 0.789 g / ml), dropwise NaOH (20.8 mL, 5 M, 104 mmol) and dropwise H 2 O 2 (11.7 g, 104 mmol, 30% in water) to maintain the internal temperature below 30° C. After stirring at 50° C. for 1 h, the reaction mixture was diluted with saturated Na 2 S 2 O 3 Aqueous solution ( After stirring at 0° C. for an additional hour, the reaction was checked by potassium iodide-starch test paper to determine the presence of excess H 2 O 2 The aqueous phase was extracted with DCM (3×50 mL). The combined organic phase was washed with saturated Na 2 S2 O 3 (2×100 mL), brine (2×100 mL), and anhydrous Na 2 SO 4 It was dried over ice, filtered and concentrated under reduced pressure to give 1.7 (800 mg) as a solid.

[0410] Synthesis of 1.8 To a solution of 1.7 (800 mg, 2.20 mmol) in DCM (30 mL) was added DMP (1.86 g, 4.40 mmol) at 25° C. After stirring at 25° C. for 1 h, the mixture was diluted with NaHCO 3 (50 mL) and Na 2 S 2 O 3 (50 mL, saturated) and extracted with DCM (2×50 mL). The combined organic phase was diluted with NaHCO 3 (100mL), Na 2 S 2 O 3 (100 mL, saturated) and brine (100 mL), and then washed with anhydrous Na 2 SO 4 Dry, filter, concentrate, and add Na 2 SO 4 It was dried over, filtered and concentrated. The residue was purified by flash column (0-15% EtOAc in PE) to give 1.8 (740 mg) as an oil. 1 H NMR (400 MHz, CDCl 3 ) δ H 2.32 (dd, J = 3.3, 12.5 Hz, 1H), 2.18-2.13 (m, 4H), 1.92-1.66 (m, 9H), 1.46-1.20 (m, 12H), 1.11-0.67 (m, 14H).

[0411] Synthesis of 1.8a and 1.8b To a solution of 1.8 (5.8 g, 16.0 mmol) in MeOH (100 mL) was added MeONa (12.9 g, 240 mmol) at 0° C. After stirring at 70° C. for 16 h, the reaction mixture was diluted with saturated NH 4Cl (100 mL) and extracted with EtOAc (2×100 mL). The combined organic phase was washed with saturated brine (100 mL) and anhydrous Na 2 SO 4 It was dried over 100 ml, filtered and concentrated. The residue (200 mg) was purified by column (0-3% acetone in DCM) to give both 1.8a (69.3 mg, 34.8%) and 1.8b (16.0 mg, 8.04%) as solids. 1.8a: 1 H NMR (400 MHz, CDCl 3 )δ H 2.30(dd,J=3.3,12.8 Hz,1H),2.14(s,3H),1.86-1.59(m,8H),1.51-1.21(m,9H),1.15-0.89(m,14H),0.87-0.50(m,5H). LC-ELSD / MS purity 99%,C 24 H 39 O[MH 2 O+H] + MS ESI calculated value 343.3 found value 343.3. 1.8b: 1 H NMR (400 MHz, CDCl 3 )δ H 2.47(d,J=5.9 Hz,1H),2.12(s,3H),1.74(br d,J=12.5 Hz,7H),1.51-1.19(m,12H),1.16-0.74(m,16H),0.68-0.51(m,1H). LC-ELSD / MS purity 99%,C 24 H 39 O[MH 2 O+H] + MS ESI calculated value 343.3 found value 343.3.

[0412] Synthesis of 1.9 MePh in anhydrous THF (20 mL) 3 A suspension of PBr (4.31 g, 12.2 mmol) was dissolved in t-BuOK (1.36 g, 12.2 mmol) and N 2After stirring at 40° C. for 30 min, a solution of 1.8a (2.2 g, 6.10 mmol) in anhydrous THF (20 mL) was added dropwise. After stirring at 40° C. for 16 h, the mixture was cooled, poured into ice water (150 mL), stirred for 10 min, and extracted with EtOAc (2×100 mL). The combined organic phase was washed with saturated brine (2×100 mL), filtered, and concentrated. The residue was purified by flash column (0-10% EtOAc in PE) to give 1.9 (1.9 g, 87.1%) as a solid. 1 H NMR (400 MHz, CDCl3) δH 4.80 (s, 1H), 4.61 (d, J = 2.0 Hz, 1H), 1.76 (br s, 4H), 1.73-1.47 (m, 11H), 1.37-1.18 (m, 7H), 1.13-0.84 (m, 12H), 0.83 (s, 3H), 0.81-0.53 (m, 3H).

[0413] Synthesis of 1.10 To a solution of 1.9 (700 mg, 1.95 mmol) in DCM (10 mL) was added m-CPBA (790 Mg, 85%, 3.90 mmol) at 0 °C. After stirring at 25 °C for 1 h, the mixture was diluted with NaHCO 3 (50mL, saturated aqueous solution) and Na 2 S 2 O 3 (20 mL, saturated aqueous solution). The organic layer was separated and 2 SO 4 The residue was purified by flash column (0-10% EtOAc in PE) to give 1.10 (340 mg, 46.5%) as a solid. 1 H NMR (400 MHz, CDCl3) δH 2.77-2.55 (m, 2H), 1.82-1.65 (m, 8H), 1.54-1.47 (m, 2H), 1.47-1.25 (m, 8H), 1.06-0.88 (m, 16H), 0.84-0.56 (m, 5H), 0.55-0.54 (m, 1H).

[0414] Synthesis of 1 and 2 A solution of 1.10 (340 mg, 0.908 mmol) in DMF (10 mL) was diluted with 1H-pyrazole-4-carbonitrile (168 mg, 1.81 mmol) and Cs 2 CO 3 (593 mg, 1.81 mmol) was added at 20° C. After stirring at 120° C. for 2 h, the mixture was diluted with water (100 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were concentrated and purified by flash column (30-50% EtOAc in PE) to give a mixture of diastereomers of 1 and 2 (350 mg) as a solid. The diastereomers were purified by SFC (column DAICEL CHIRALCEL OD-H (250 mm*30 mm, 5 um) conditions 0.1% NH 3 H 2 Separation by O EtOH Start B 30% End B 30% Gradient time (min) 100% B Hold time (min) Flow rate (ml / min) 50) gave both 2 (208.9 mg) and 1 (50.2 mg) as solids.

[0415] 1: 1 H NMR (400 MHz, CDCl 3 )δ H 7.88(s,1H),7.83(s,1H),4.27(d,J=14.0 Hz,1H),4.00(d,J=13.9 Hz,1H),3.00(s,1H),2.36(br d,J=12.8 Hz,1H),1.95-1.56(m,5H),1.42-1.35(m,6H),1.28-1.22(m,3H),1.18(s, 3H), 1.15-1.05(m, 5H), 1.01(s, 3H), 0.95-0.88(m, 8H), 0.88-0.56(m, 6H). LC-ELSD / MS purity 99%,C 29 H 42 N 3 [M-2H 2 O+H] + MS ESI calculated value 432.4 found 432.4.

[0416] 2: 1 H NMR (400 MHz, CDCl 3 )δH 7.92(s,1H),7.79(s,1H),4.52-4.13(m,2H),2.47(br s,1H),2.30(br d,J=13.0 Hz,1H),1.91-1.68(m,7H),1.45-1.20(m,12H),1.15-1.03(m,2H),1.00-0.70(m,17H),0.66-0.53(m,1H). LC-ELSD / MS purity 99%,C 29 H 42 N 3 [M-2H 2 O+H] + MS ESI calculated value 432.3 found value 432.3.

[0417] Examples 6 and 7: Synthesis of 1-((R)-2-((1S,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-ethyl-8-hydroxy-12a-methyloctadecahydrochrysen-1-yl)-2-hydroxypropyl-1H-pyrazole-4-carbonitrile and 1-((S)-2-((1S,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-ethyl-8-hydroxy-12a-methyloctadecahydrochrysen-1-yl)-2-hydroxypropyl-1H-pyrazole-4-carbonitrile [ka] Synthesis of 6.2 A solution of BHT (144 g, 654 mmol) in toluene (165 mL) was treated with AlMe at 0 °C under nitrogen. 3 (2M in toluene, 163 mL, 327 mmol) was added dropwise. After stirring at 25° C. for 1 h, the MAD solution was used without further purification. To the MAD (327 mmol) solution was added dropwise a solution of (5β)-estrane-3.17-dione, 6.1 (30 g, 109 mmol) in DCM (100 mL) at −70° C. 2After stirring at −70° C. for 1 h, EtMgBr (130 mL, 327 mmol, 2.5 M in ethyl ether) was added dropwise at −70° C. After stirring at −70° C. for an additional 2 h, the reaction mixture was poured into saturated aqueous citric acid (100 mL) at 10° C. and extracted with DCM (2×40 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried over 100 ml, filtered and concentrated. The residue was purified by silica gel chromatography (PE / EtOAc=0-20%) to give 6.2 (25 g, 76%) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H 2.50-2.36 (m, 1H), 2.14-2.01 (m, 1H), 1.97-1.88 (m, 1H), 1.84-1.74 (m, 4H), 1.68-1.45 (m, 7H), 1.43-0.97 (m, 12H), 0.92-0.82 (m, 6H).

[0418] 6.3 Synthesis To a solution of DIPA (34.7 g, 343 mmol) in THF (190 mL) was added BuLi (124 mL, 2.5 M in hexanes, 312 mmol) at -70°C. After warming to 0°C and stirring for 1 h, cold (-70°C) LDA solution (312 mL, 1.0 M, 312 mmol) was added to a stirred solution of 6.2 (19 g, 62.4 mmol) and ethyl diazoacetate (35.5 g, 312 mmol) in THF (100 mL) at -78°C. After stirring for 1 h at -70°C, the reaction mixture was quenched with acetic acid (18.7 g, 312 mmol) in THF (50 mL), warmed to 20°C, diluted with water (300 mL), and extracted with EtOAc (3 x 400 mL). The combined organic layers were washed with brine and diluted with Na 2 SO 4 The residue was purified by flash column (0-5% EtOAc in PE) to give 6.3 (6 g) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H 4.80 (m, 1H), 4.33-4.19 (m, 2H), 2.20-2.08 (m, 1H), 1.93-1.54 (m, 9H), 1.50-1.28 (m, 12H), 1.19-0.98 (m, 5H), 0.95-0.81 (m, 6H).

[0419] Synthesis of 6.4 A solution of 6.3 (6.0 g, 14.3 mmol) in DME (30 mL) was added to Rh 2 (O Ac) 4 (94.7 mg, 0.2 mmol) was added at 25° C. After stirring at 25° C. for 12 h, the reaction mixture was concentrated to give 6.4 (6 g) as a solid, which was used as is.

[0420] Synthesis of 6.5 To a mixture of 6.4 (6.00 g, 15.3 mmol) in MeOH / THF (30 mL / 30 mL) was added KOH (8.58 g, 153 mmol). After stirring at 70° C. for 12 h, the reaction mixture was extracted with ethyl acetate (4×80 mL). The combined organic phase was washed with water (80 mL), brine (50 mL) and diluted with Na 2 SO 4 The mixture was dried over 100 ml, filtered and concentrated under reduced pressure. The residue was purified by flash column (15-30% EtOAc in PE) to give 6.5 (3.9 g, 80%) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H 2.69-2.53 (m, 1H), 2.23-2.14 (m, 1H), 2.08-1.99 (m, 1H), 1.87-1.58 (m, 10H), 1.54-1.21 (m, 12H), 1.19-0.93 (s, 6H), 0.90-0.79 (m, 3H).

[0421] 6.6 Synthesis in anhydrous THF (100 mL) 3 To a suspension of PEtBr (13.5 g, 36.5 mmol), t-BuOK (5.47 g, 48.8 mmol) was added with N 2The mixture was added at 15° C. under reduced pressure. After stirring at 40° C. for 30 min, a solution of 6.5 (3.9 g, 12.2 mmol) in anhydrous THF (50 mL) was added dropwise. After stirring for 16 h, the mixture was cooled, poured into ice water (150 mL), stirred for 10 min, and extracted with EtOAc (2×100 mL). The combined organic phase was washed with saturated brine (2×200 mL), filtered, and concentrated. The residue was purified by flash column (10% to 30% ethyl ether in PE) to give 6.6 (3.1 g, 77%) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H 5.52-5.09 (m, 1H), 2.30-2.09 (m, 1H), 1.89-1.57 (m, 14H), 1.51-1.19 (m, 10H), 1.12-1.02 (m, 3H), 1.00-0.83 (m, 8H).

[0422] Synthesis of 6.7 To a solution of 6.6 (3.1 g, 9.4 mmol) in THF (10 mL) was added BH 3 Me 2 S (2.81 mL, 28.1 mmol) was added at 0° C. After stirring at 15° C. for 12 h, the reaction mixture was cooled and quenched with EtOH (5.46 ml, 93.7 mmol, 0.789 g / ml) at 0° C. and NaOH (18.7 mL, 5 M, 93.7 mmol) successively. Then, H 2 O 2 (9.38 mL, 93.7 mmol, 1.13 g / mL, 30% in water) was added slowly until the internal temperature no longer rose, maintaining the internal temperature below 30° C. After stirring at 50° C. for an additional hour, the reaction mixture was diluted with saturated Na 2 S 2 O 3 The mixture was quenched with aqueous solution (50 mL), stirred at 0° C. for 1 h, and extracted with DCM (3×50 mL). The combined organic phase was washed with saturated Na 2 S 2 O 3 (2 x 50 mL), and washed with brine (2 x 50 mL). 2 SO 4Drying over, filtration and concentration gave 6.7 (3.26 g) as a solid which was used as is.

[0423] 6.8 Synthesis To a mixture of 6.7 (3.26 g, 9.35 mmol) and silica gel (5 g) in DCM (15 mL) was added PCC (3.01 g, 14.0 mmol) in portions. After stirring at 15° C. for 1 h, the reaction mixture was filtered and the filtrate was concentrated to give 6.8 (3.24 g) as an oil.

[0424] Synthesis of 6.8a To a solution of 6.8 (2 g, 5.8 mmol) in MeOH (20 mL) at 0 °C, a (4.67 g, 86.5 mmol) was added. After stirring at 70 °C for 16 h, the reaction mixture was diluted with saturated NH 4 Cl (20 mL) and extracted with EtOAc (2×20 mL). The combined organic phase was washed with saturated brine (20 mL) and anhydrous Na 2 SO 4 The residue was purified by flash column (0-20% EtOAc in PE) to give 6.8a (1.5 g) as a solid.

[0425] 6.9 Synthesis MePPh in THF (12 mL) 3 To a mixture of Br (3.07 g, 8.63 mmol), t-BuOK (966 mg, 8.63 mmol) was added 2 After stirring at 50° C. for 30 min, 6.8a (1 g, 2.88 mmol) in THF (8 mL) was added in portions below 50° C. After stirring at 50° C. for 1 h, the reaction mixture was diluted with 10% NH 4 It was quenched with aqueous Cl (30 mL) at 15° C. and extracted with EtOAc (2×30 mL). The combined organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc / PE=0-15%) to give 6.9 (720 mg, 72.5%) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H4.80 (s, 1H), 4.62-4.58 (m, 1H), 1.86-1.58 (m, 5H), 1.57-1.50 (m, 6H), 1.49-1.39(m, 3H), 1.38-1.23 (m, 6H), 1.22-1.15(m, 2H), 1.14-0.85(m, 10H), 0.84-0.83(m, 3H), 0.82 (s, 3H).

[0426] 6.10 Synthesis To a solution of 6.9 (720 mg, 2.08 mmol) in DCM (5 mL) was added m-CPBA (893 mg, 4.16 mmol, 80%) at 15 °C. After stirring at 15 °C for 1 h, the mixture was diluted with saturated NaHCO 3 and Na 2 S 2 O 3 (10 mL, v:v=1:1) and extracted with DCM (2×10 mL). The combined organic phase was washed with saturated NaHCO 3 and Na 2 S 2 O 3 (10 mL, v:v=1:1), and washed with Na 2 SO 4 It was dried over, filtered and concentrated to give 6.10 (900 mg) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H 8.07-8.04 (m, 1H), 8.03-7.95 (m, 1H), 7.66-7.52 (m, 1H), 7.50-7.35 (m, 1H), 7.98 (s, 1H), 7.93 (s, 1H), 7.79 (s, 1H), 2.70-2.60 (m, 2H), 1.85-1.65 (m, 6H), 1.64-1.50 (m, 6H), 1.49-1.26 (m, 4H), 1.25-2.60 (m, 5H), 1.20-0.85(m, 10H).

[0427] Synthesis of 6 and 7 To a solution of 6.10 (900 mg, 2.49 mmol) in DMF (5 mL), 2 CO 3 (2.43 g, 7.47 mmol) and 1H-pyrazole-4-carbonitrile (579 mg, 6.22 mmol) were added. After stirring at 130° C. for 12 h, the mixture was diluted with saturated NH 4 The mixture was added to 10 mL of 100 mL of LiCl and extracted with EtOAc (3×10 mL). The combined organic layers were washed with LiCl (10 mL, 5% in water), saturated brine (2×10 mL) and anhydrous Na 2 SO 4 It was dried over, filtered and concentrated to give a mixture of diastereomers 6 and 7 (670 mg) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H 7.98 (s, 1H), 7.93 (s, 1H), 7.79 (s, 1H), 4.25-4.211 (m, 2H), 2.50 (m, 2H), 2.38-2.30 (m, 1H), 2.05 (s, 3H), 1.73-1.60 (m, 6H), 1.59-1.52 (m, 5H), 1.51-1.47 (m, 5H), 1.46-1.24 (m, 3H), 1.23 (s, 1H), 1.00-0.88(m, 6H), 0.87-0.85(m, 6H).

[0428] The diastereomers (670 mg) were subjected to SFC (DAICEL CHIRALCEL OJ-H (250 mm x 30 mm, 5 μm), conditions: 0.1% NH 3 H 2 6 (212.6 mg, 31.8%) and 7 (55 mg) were obtained as solids by separation with 0EtOH, starting B: 25%, ending B: 25%, flow rate (ml / min): 60). 7 was purified by SFC (column: DAICEL CHIRALCEL OJ-H (250 mm*30 mm, 5 um), condition: 0.1% NH 3 H 2 Further purification with O EtOH, start B: 25%, end B: 25%, flow rate (ml / min): 60) gave 7 (33.5 mg) as a solid.

[0429] 6: 1 H NMR (400 MHz, CDCl 3 ) δ H 7.92 (s, 1H), 7.80 (s, 1H), 4.39 - 4.20 (m, 2H), 2.45 - 2.25 (m, 2H), 1.74 - 1.62 (m, 7H), 1.61 - 1.55 (m, 6H), 1.54 - 1.48 (m, 7H), 1.47 - 1.35 (m, 6H), 1.35 - 1.25 (m, 4H), 1.05 - 0.95 (m, 4H), 0.90 - 0.85 (m, 3H). LC - ELSD / MS purity 99%, C 28 H 40 N 3 [M - 2H 2 O + H] + The calculated MS ESI value for [M - 2H + O + H] is 418, and the measured value is 418. SFC 99% de.

[0430] 7: 1 H NMR (400 MHz, CDCl 3 ) δ H 7.88 (s, 1H), 7.86 (s, 1H), 4.30 - 4.24 (m, 1H), 4.01 - 3.95 (m, 1H), 3.05 (s, 1H), 2.42 - 2.38 (m, 1H), 1.84 - 1.74 (m, 2H), 1.73 - 1.45 (m, 9H), 1.44 - 1.19 (m, 11H), 1.18 - 1.00 (m, 6H), 0.99 - 0.86 (m, 9H). LC - ELSD / MS purity 99%, C 28 H 40 N 3 [M - 2H 2 O + H] + The calculated MS ESI value for [M - 2H + O + H] is 418, and the measured value is 418. SFC 100% de.

[0431] Examples 8 and 9: Synthesis of 1-((R)-2-hydroxy-2-((1S,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-12a-methyl-8-propyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile and 1-((S)-2-hydroxy-2-((1S,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-12a-methyl-8-propyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile [ka] 8.2 Synthesis A solution of BHT (96 g, 436 mmol) in toluene (300 mL) was added to the reaction mixture under nitrogen at 0 °C with AlMe 3 (2M in toluene, 109 mL, 218 mmol) was added dropwise. After stirring for 1 h, the MAD solution was used directly without further purification. To a freshly prepared solution of MAD (218 mmol) was added a solution of 6.1 (20 g, 72.8 mmol) in DCM (80 mL) dropwise at -70 °C. 2 After stirring at −70° C. for 1 h, n-PrMgCl (72.5 mL, 145 mmol, 2 M in ethyl ether) was added dropwise at −70° C. After stirring at −70° C. for 2 h, the reaction mixture was poured into saturated aqueous citric acid (100 mL) at 10° C. and extracted with EtOAc (2×400 mL). The combined organic layers were washed with Na 2 SO 4 The residue was purified by flash column (0-20% EtOAc in PE) to give 8.2 (12 g, 52%) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H 2.44 (dd, J = 8.5, 19.3 Hz, 1H), 2.15-2.07 (m, 1H), 2.13-2.00 (m, 1H), 1.98-1.88 (m, 1H), 1.86-1.59 (m, 6H), 1.54-1.00 (m, 18H), 0.93 (t, J = 7.2 Hz, 3H), 0.87 (s, 3H).

[0432] 8.3 Synthesis To a solution of 8.2 (12.0 g, 37.6 mmol) and ethyl diazoacetate (19.7 mL, 188 mmol, 1.085 g / mL) in THF (800 mL) was added freshly prepared LDA (180 mL, 1.0 M, 180 mmol) at −78° C. After stirring at −78° C. for 2 h, the reaction mixture was quenched with acetic acid (10.6 mL, 188 mmol) in THF (50 mL), stirred at 15° C. for 16 h, poured into water (1000 mL) and extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (1500 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate, filtered and evaporated under reduced pressure. The residue was purified by flash column (0-10% EtOAc in PE) to give 8.3 (13 g, 80%) as an oil. 1 H NMR (400 MHz, CDCl 3 ) δ H 4.29-4.19 (m, 2H), 2.23-2.08 (m, 1H), 1.96-1.59 (m, 8H), 1.53-1.28 (m, 17H), 1.17-1.02 (m, 5H), 0.96-0.90 (m, 5H), 0.86 (br d, J = 6.8 Hz, 2H).

[0433] 8.4 Synthesis A solution of 8.3 (13 g, 30.0 mmol) and DME (150 mL) was added to the 2 (OAc) 4 (132 mg, 0.3 mmol) was added in one portion at 15° C. After stirring at 15° C. for 2 h, the reaction mixture was concentrated to give 8.4 (13 g) as an oil which was used as is.

[0434] 8.5 Synthesis To a solution of 8.4 (13 g, 32.1) in MeOH (200 mL) was added KOH (18.0 g, 321 mmol) at 15° C. After stirring at 70° C. for 1 h, the reaction mixture was cooled to 10° C. and cooled to 37° C. 2 The combined organic layers were poured into 200 mL of HCl (1 M, 100 mL), saturated NaHCO 3 (100 mL), brine (100 mL), and anhydrous Na 2 SO 4 The residue was purified by flash column (0-15% EtOAc in PE) to give 8.5 (8.3 g, 78.3%) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H 2.61 (dt, J = 6.8, 13.9 Hz, 1H), 2.27-2.15 (m, 1H), 2.08-2.02 (m, 1H), 1.87-1.49 (m, 13H), 1.48-1.20 (m, 12H), 1.18-1.10 (m, 1H), 1.08 (s, 3H), 1.03-0.96 (m, 1H), 0.93 (t, J = 7.3 Hz, 3H).

[0435] 8.6 Synthesis in anhydrous THF (100 mL) 3 To a suspension of PEtBr (27.6 g, 74.6 mmol), t-BuOK (11.1 g, 99.6 mmol) was added by N 2 After stirring at 40° C. for 30 min, a solution of 8.5 (8.3 g, 24.9 mmol) in anhydrous THF (50 mL) was added dropwise. After stirring at 40° C. for 16 h, the mixture was cooled, poured into ice water (150 mL), stirred for 10 min, and extracted with EtOAc (2×100 mL). The combined organic phase was washed with brine (2×200 mL) and diluted with anhydrous Na 2 SO 4 The residue was dissolved in MeOH / H 2 Purification by trituration with 0 (1:1, 320 mL) afforded 8.6 (5.3 g, 62%) as a solid.1 H NMR (400 MHz, CDCl 3 ) δ H 5.24-5.00 (m, 1H), 2.50 (br d, J = 13.8 Hz, 1H), 2.25-2.10 (m, 1H), 2.01-1.56 (m, 10H), 1.48-1.16 (m, 14H), 1.05 (s, 3H), 0.92-0.80 (m, 10H).

[0436] Synthesis of 8.7 A solution of 8.6 (5.3 g, 15.3 mmol) in THF (100 mL) was added to BH 3 Me 2 S (4.58 mL, 45.9 mmol) was added at 0° C. After stirring at 15° C. for 16 h, the reaction mixture was cooled (0° C.) and added EtOH (8.91 ml, 203 mmol, 0.789 g / ml), NaOH (30.5 mL, 5 M, 153 mmol) and H 2 O 2 (15.3 mL, 153 mmol, 1.13 g / mL, 30% in water) was added dropwise slowly in succession until the internal temperature no longer rose, maintaining the internal temperature below 30° C. After stirring at 50° C. for 1 h, the reaction was diluted with saturated Na 2 S 2 O 3 The reaction was quenched with aqueous solution (130 mL) and stirred for an additional hour at 0° C. The reaction was checked by potassium iodide-starch test paper to determine the presence of excess H 2 O 2 The combined organic phase was washed with saturated NaCl. 2 S 2 O 3 (2×100 mL), brine (2×100 mL), and anhydrous Na 2 SO 4 It was dried over, filtered and concentrated to give 8.7 (4.3 g) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H= 2.47 (br d, J = 5.2 Hz, 0.4H), 2.29 (dd, J = 3.2, 12.8 Hz, 0.6 H), 2.13 (d, J = 3.2 Hz, 3H), 1.88-1.66 (m, 3H), 1.54-1.44 (m, 6H), 1.41-1.14 (m, 13H), 1.11-0.80 (m, 13H).

[0437] 8.8 Synthesis To a mixture of PCC (3.70 g, 17.2 mmol) and silica gel (4 g) in DCM (20 mL) was added 8.7 (2.5 g, 6.89 mmol) in DCM (30 mL) at 25° C. After stirring at 25° C. for 1 h, the reaction mixture was filtered and washed with DCM (100 mL). The filtrate was collected and concentrated to give 8.8 (1.93 g) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H = 2.47 (br d, J = 5.2 Hz, 0.4H), 2.29 (dd, J = 3.2, 12.8 Hz, 0.6 H), 2.13 (d, J = 3.2 Hz, 3H), 1.88-1.66 (m, 3H), 1.54-1.44 (m, 6H), 1.41-1.14 (m, 13H), 1.11-0.80 (m, 13H).

[0438] 8.9 Synthesis To a solution of 8.8 (1.93 g, 5.35 mmol) in MeOH (20 mL) at 0° C. was added MeONa (4.33 g, 80.2 mmol). After stirring at 70° C. for 16 h, the reaction mixture was diluted with saturated NH 4 Cl (10 mL) and extracted with EtOAc (2×10 mL). The combined organic phase was washed with brine (10 mL) and anhydrous Na 2 SO 4 It was dried over, filtered and concentrated to give 8.9 (1.2 g) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H= 2.30 (dd, J = 3.2, 12.7 Hz, 1H), 2.14 (s, 3H), 1.82 (br d, J = 12.4 Hz, 2H), 1.76-1.63 (m, 5H), 1.57-1.43 (m, 7H), 1.40-1.23 (m, 10H), 1.07-0.84 (m, 12H).

[0439] 8.10 Synthesis MePPh in THF (20 mL) 3 To a mixture of Br (9.46 g, 26.5 mmol), t-BuOK (2.96 g, 26.5 mmol) was added 2 After stirring at 50° C. for 30 min, 8.9 (1.2 g, 3.32 mmol) in THF (10 mL) was added at 25° C. After stirring at 60° C. for 3 h, the reaction mixture was cooled, poured into ice water (50 mL), and extracted with EtOAc (2×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column (0-30% EtOAc in PE) to give 8.10 (1.1 g) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H = 4.80 (s, 1H), 4.61 (s, 1H), 1.83 (br d, J = 14.4 Hz, 2H), 1.70-1.57 (m, 6H), 1.53-1.43 (m, 4H), 1.40-1.22 (m, 12H), 1.19-1.04 (m, 2H), 0.99-0.87 (m, 9H), 0.82 (s, 3H).

[0440] 8.11 Synthesis To a solution of 8.10 (500 mg, 1.39 mmol) in DCM (10 mL) was added m-CPBA (446 mg, 2.08 mmol, 80%) at 25 °C. After stirring for 2 h at 25 °C, the mixture was diluted with saturated NaHCO 3 and Na 2 S 2 O 3(40 mL, v:v=1:1) and extracted with DCM (2×20 mL). The combined organic phase was washed with saturated NaHCO 3 and Na 2 S 2 O 3 (50mL, v:v=1:1), and washed with Na 2 SO 4 It was dried over, filtered and concentrated to give 8.11 (520 mg) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H 2.70 (br d, J = 5.2 Hz, 1H), 2.65-2.49 (m, 1H), 1.91-1.78 (m, 7H), 1.70-1.61 (m, 10H), 1.31 (br d, J = 7.6 Hz, 10H), 0.96-0.88 (m, 14H).

[0441] Synthesis of 8 and 9 To a solution of 8.11 (300 mg, 0.8008 mmol) in DMF (5 mL), add Cs 2 CO 3 (782 mg, 2.40 mmol) and 1H-pyrazole-4-carbonitrile (186 mg, 2.00 mmol) were added. After stirring at 130° C. for 12 h, the mixture was diluted with saturated NH 4 The mixture was poured into 50 mL of LiCl and extracted with EtOAc (3×50 mL). The combined organic layers were washed with LiCl (100 mL, 5% in water), brine (2×100 mL) and anhydrous Na 2 SO 4 The residue was purified by flash column (0-50% EtOAc in PE) to give a mixture of diastereomers 8 and 9 (165 mg) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H = 7.92 (s, 1H), 7.79 (s, 1H), 4.38-4.33 (m, 1H), 4.26-4.18 (m, 1H), 2.32 (br d, J = 13.2 Hz, 5H), 1.77-1.61 (m, 11H), 1.37-1.28 (m, 10H), 1.00-0.91 (m, 15H).

[0442] The C20 diastereomer was purified by SFC (column DAICEL CHIRALCEL OD (250mm*30mm, 10um); condition 0.1% NH 3 H 2 8 (67.3 mg, 32.2%) and 9 (11 mg) were separated as solids by SFC (column DAICEL CHIRALCE OD(250mm×30mm, 10um); Condition 0.1%NH 3 H 2 Further purification by elution with O EtOH; flow rate (ml / min) 70) gave 9 (6.5 mg) as a solid.

[0443] 8: 1 H NMR (400 MHz, CDCl 3 )δ H =7.92(s,1H),7.79(s,1H),4.39-4.32(m,1H),4.26-4.20(m,1H),2.43(s,1H),2.32(br d,J=12.8 Hz, 1H), 1.91-1.64 (m, 6H), 1.55-1.18 (m, 18H), 1.03-0.82 (m, 15H). LC-ELSD / MS purity 99%,C 29 H 42 N 3 [M-2H 2 O+H] + MS ESI calculated for 432.3, found 432.3. SFC 98.54% de.

[0444] 9: 1 H NMR (400 MHz, CDCl 3 )δ H=7.88(s,1H),7.85(s,1H),4.31-4.24(m,1H),4.02-3.96(m,1H),3.06(s,1H),2.43-2.34(m,1H),1.85-1.73(m,2H),1.70-1.59(m,4H),1. 54-1.42(m,12H),1.36-1.30(m,3H),1.30-1.23(m,5H),1.18(s,1H), 1.16-1.04(m,2H),1.00(s,1H),0.95-0.87(m,6H),0.86-0.71(m,3H). LC-ELSD / MS purity 99%,C 29 H 42 N 3 [M-2H 2 O+H] + MS ESI calculated for 432.3, found 432.3. SFC 99.02% de.

[0445] Examples 10 and 11: Synthesis of 1-((S)-2-((1S,4aS,4bR,6aS,8R,10aS,10bR,12aS)-8-ethyl-8-hydroxy-12a-methyloctadecahydrochrysen-1-yl)-2-hydroxypropyl-1H-pyrazole-4-carbonitrile and 1-((R)-2-((1S,4aS,4bR,6aS,8R,10aS,10bR,12aS)-8-ethyl-8-hydroxy-12a-methyloctadecahydrochrysen-1-yl)-2-hydroxypropyl-1H-pyrazole-4-carbonitrile [ka] 10.2 Synthesis To a solution of 1.1 (50 g, 182 mmol) in MeOH (600 mL) was added 4-methylbenzenesulfonic acid (6.26 g, 36.4 mmol) at 25 °C. After stirring for 6 h, the mixture was 3 Diluted with N (20 mL). The solid was filtered and the filtrate was concentrated to give 10.2 (52 g, 89.1%) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H0.73-0.83 (m, 1 H), 0.91 (s, 3 H), 0.98-1.13 (m, 2 H), 1.20-1.56 (m, 16 H), 1.72-1.78 (m, 1 H), 1.80-1.86 (m, 2 H), 1.88-1.99 (m, 2 H), 2.05-2.16 (m, 2 H), 2.25-2.35 (m, 3 H), 2.38-2.51 (m, 2 H), 3.15 (s, 1 H), 3.21 (s, 1 H), 3.50 (s, 6 H).

[0446] 10.3 Synthesis To a solution of 10.2 (4.5 g, 14.0 mmol) and ethyl diazoacetate (7.35 g, 1.085 g / mL, 70.0 mmol) in THF (300 mL) was added freshly prepared LDA (67.1 mL, 1.0 M, 67.1 mmol) at −78 °C. After stirring at −78 °C for 2 h, the reaction was quenched with acetic acid (4.00 mL, 1.0492 g / mL, 70.0 mmol) in THF (100 mL). After stirring at 15 °C for 16 h, the mixture was diluted with NH 4 Cl (200 mL) and extracted with EtOAc (2×125 mL). The combined organic layers were washed with brine (150 mL) and anhydrous Na 2 SO 4 The residue was purified by flash column (0-10% EtOAc in PE) to give 10.3 (3.7 g, 60.8%) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H4.77-4.64 (m, 1H), 4.25 (dq, J = 1.6, 7.2 Hz, 2H), 3.20 (s, 3H), 3.14 (s, 3H), 2.22-2.01 (m, 2H), 1.96-1.76 (m, 4H), 1.69-1.61 (m, 2H), 1.55-1.42 (m, 1H), 1.41-1.27 (m, 5H), 1.27-0.96 (m, 9H), 0.93 (s, 3H), 0.91-0.83 (m, 1H), 0.80-0.62 (m, 2H).

[0447] 10.4 Synthesis A solution of 10.3 (57 g, 147 mmol) and DME (500 mL) was added to the 2 (OAc) 4 (800 mg, 1.81 mmol) was added in one portion at 15° C. After stirring at 15° C. for 2 h, the reaction mixture was concentrated to give 10.4 (59.7 g) as an oil which was used as is.

[0448] 10.5 Synthesis To a solution of 10.4 (59.7 g) in MeOH (500 mL) was added KOH (81.9 g, 1460 mmol) at 15° C. After stirring at 70° C. for 1 h, the reaction mixture was 2 O (500 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with HCl (1 M, 100 mL), saturated NaHCO 3 (100 mL) and brine (200 mL), and 2 SO 4 The residue was purified by flash column (0-15% EtOAc in PE) to give 10.5 (30 g, 61.4%) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H3.21 (d, J = 1.2 Hz, 3H), 3.15 (d, J = 1.6 Hz, 3H), 2.24-2.01 (m, 3H), 1.98-1.78 (m, 5H), 1.76-1.61 (m, 2H), 1.59-1.13 (m, 8H), 1.10 (d, J = 6.4 Hz, 3H), 1.08-0.82 (m, 5H), 0.78-0.62 (m, 2H).

[0449] 10.6 Synthesis EtPPh in THF (400 mL) 3 Mixture of Br (99.4 g, 268 mmol) t-BuOK (30.0 g, 268 mmol) was added to N 2 After stirring at 15° C. for 30 min, 10.5 (30 g, 89.6 mmol) in THF (100 mL) was added. After stirring at 40° C. for 1 h, the mixture was diluted with saturated NH 4 Poured into aqueous Cl (400 mL) and extracted with EtOAc (2×200 mL). The combined organic layers were washed with brine (200 mL) and anhydrous Na 2 SO 4 Drying over, filtration and concentration gave 10.6 as a residue which was used directly in the next step.

[0450] 10.7 Synthesis To a solution of 10.6 (31 g, 89.4 mmol) in THF (300 mL) was added HCl (89.4 mL, 1 M, 89.4 mmol). After stirring at 15 °C for 2 h, the mixture was diluted with NaHCO 3 The combined organic phase was washed with brine (100 mL) and anhydrous Na 2 SO 4 The residue was purified by flash column (0-3% EtOAc in PE) to give 10.7 (14 g, 52.2%) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H5.25-5.07 (m, 1H), 2.45-2.36 (m, 1H), 2.35-2.12 (m, 4H), 2.07 (t, J = 13.2 Hz, 1H), 1.95-1.81 (m, 3H), 1.80-1.64 (m, 5H), 1.27-1.08 (m, 9H), 0.99-0.93 (m, 2H), 0.93-0.74 (m, 6H).

[0451] 10.8 Synthesis A stirred solution of trimethylsulfoxonium iodide (10.2 g, 46.5 mmol) and t-BuOK (6.81 g, 55.8 mmol) in DMSO (60 mL) and THF (20 mL) was diluted with N 2 The mixture was heated at 40° C. for 1 h under reduced pressure. The reaction mixture was added to 10.7 (14 g, 46.5 mmol) in DMSO (20 mL). After stirring at 40° C. for 30 min, the reaction was diluted with water (250 mL) to give a solid. The precipitate was filtered and dried under reduced pressure to give 10.8 (12.5 g, 85.6%) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H 5.32-5.01 (m, 1H), 2.64 (s, 2H), 2.55-2.48 (m, 1H), 2.28-2.10 (m, 1H), 2.03-1.96 (m, 1H), 1.90-1.80 (m, 3H), 1.80-1.58 (m, 7H), 1.47-1.21 (m, 4H), 1.12 (br s, 4H), 1.10-1.01 (m, 3H), 0.95 (s, 2H), 0.92-0.64 (m, 5H).

[0452] 10.9 Synthesis To a suspension of CuCN (4.21 g, 47.4 mmol) in THF (120 mL) at −40° C. was added MeLi (59.2 mL, 94.8 mmol, 1.6 M). After stirring at −40° C. for 1 h, 10.8 (5 g, 15.8 mmol) in THF (30 mL) was added at −40° C. After stirring at 25° C. for 2 h, the reaction was diluted with 10% NH 4Cl (20 mL) and extracted with EtOAc (2×50 mL). The combined organic phase was washed with brine (20 mL) and anhydrous Na 2 SO 4 The mixture was dried over ice, filtered and concentrated to give 10.9 (4.5 g, 86.2%) as a solid. 1 H NMR (400 MHz, CDCl3) δ H 5.23-5.05 (m, 1H), 2.30-2.09 (m, 1H), 2.04-1.70 (m, 7H), 1.56-1.39 (m, 4H), 1.39-1.23 (m, 4H), 1.22-0.95 (m, 10H), 0.95-0.83 (m, 8H), 0.83-0.55 (m, 3H).

[0453] 10.10 Synthesis To a solution of 10.9 (5.5 g, 16.6 mmol) in THF (100 mL) was added BH 3 Me 2 S (4.97 mL, 49.8 mmol, 10 M) was added at 0° C. After stirring at 20° C. for 12 h, the resulting mixture was treated with ethanol (20 mL) and aqueous NaOH (33.2 mL, 5.0 M) at 0° C. Hydrogen peroxide (19.9 mL, 10 M) was then added dropwise at 0° C. After stirring for 2 h, the reaction was diluted with saturated Na 2 S 2 O 3 The mixture was quenched with aqueous solution (30 mL) and extracted with EtOAc (2×30 mL). The combined organic phase was washed with brine (2×20 mL) and diluted with anhydrous Na 2 SO 4 It was dried over ice, filtered and concentrated to give 10.10 (5.5 g, 95.1%) as an oil. 1 H NMR (400 MHz, CDCl 3 ) δ H 1.95-1.73 (m, 5H), 1.72-1.55 (m, 7H), 1.54-1.39 (m, 5H), 1.21-1.04 (m, 7H), 1.04-0.96 (m, 5H), 0.94-0.84 (m, 6H), 0.83-0.55 (m, 5H).

[0454] 10.11 Synthesis To a solution of 10.10 (5.5 g, 15.7 mmol) in DCM (100 mL) was added PCC (10.1 g, 47.0 mmol) and silica gel (12 g) at 25 °C. After stirring at 25 °C for 1 h, the reaction mixture was filtered and the filter cake was washed with DCM (2 x 20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by column (15-20% EtOAc in PE) to give 10.11 (4.4 g, 81.4%) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H 2.50-2.25 (m, 1H), 2.17-2.09 (m, 3H), 1.87-1.67 (m, 6H), 1.50-1.38 (m, 4H), 1.36-1.17 (m, 5H), 1.17-0.94 (m, 7H), 0.93-0.92 (m, 3H), 0.91-0.87 (m, 4H), 0.87-0.54 (m, 5H).

[0455] 10.12 Synthesis To a solution of 10.11 (1.4 g, 4.03 mmol) in MeOH (50 mL) was added MeONa (3.26 g, 60.4 mmol) at 0° C. After stirring at 70° C. for 16 h, the reaction mixture was diluted with saturated NH 4 Cl (100 mL) and extracted with EtOAc (2×100 mL). The combined organic phase was washed with saturated brine (100 mL) and anhydrous Na 2 SO 4 It was dried over ice, filtered and concentrated to give 10.12 (1.2 g, 86.3%) as an oil. 1 H NMR (400 MHz, CDCl 3 ) δ H 2.31 (dd, J = 3.2, 12.8 Hz, 1H), 2.15 (s, 3H), 1.88-1.60 (m, 8H), 1.56-1.29 (m, 7H), 1.24-0.95 (m, 8H), 0.95-0.88 (m, 7H), 0.87-0.55 (m, 4H).

[0456] 10.13 Synthesis MePPh in THF (40 mL) 3 A mixture of Br (6.57 g, 18.4 mmol) and t-BuOK (2.06 g, 18.4 mmol) was added to N 2 After stirring at 15° C. for 30 min, 10.12 (800 mg, 2.30 mmol) in THF (10 mL) was added. After stirring at 40° C. for 2 h, the reaction mixture was diluted with NH 4 Poured into aqueous Cl (150 mL) and extracted with EtOAc (2×200 mL). The combined organic phase was washed with brine (20 mL) and anhydrous Na 2 SO 4 The residue was purified by flash column (12-20% EtOAc in PE) to give 10.13 (650 mg, 82.0%) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H 4.81 (s, 1H), 4.62 (d, J = 1.6 Hz, 1H), 1.90-1.75 (m, 4H), 1.73 (s, 3H), 1.73-1.58 (m, 5H), 1.56-1.20 (m, 8H), 1.12-0.94 (m, 7H), 0.91 (t, J = 7.6 Hz, 4H), 0.87-0.83 (m, 4H), 0.82-0.56 (m, 3H) ).

[0457] Synthesis of 10.14 To a solution of 10.13 (450 mg, 1.30 mmol) in DCM (15 mL) was added m-CPBA (527 mg, 85%, 2.60 mmol). After stirring at 0 °C for 1 h, the mixture was diluted with NaHCO 3 (50mL, saturated aqueous solution) and Na2 S 2 O 3 (20 mL, saturated aqueous solution). The organic layer was separated and 2 SO 4 The mixture was dried over ice, filtered and concentrated under reduced pressure to give 10.14 (360 mg, 76.9%) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H 2.77-2.70 (m, 1H), 2.68-2.61 (m, 1H), 1.87-1.72 (m, 6H), 1.52-1.41 (m, 5H), 1.30-1.23 (m, 9H), 0.94-0.90 (m, 7H), 0.89-0.87 (m, 3H), 0.86-0.59 (m, 8H).

[0458] Synthesis of 10 and 11 A solution of 10.14 (360 mg, 0.998 mmol) in DMF (10 mL) was diluted with 1H-pyrazole-4-carbonitrile (185 mg, 1.99 mmol) and Cs 2 CO 3 (648 mg, 1.99 mmol) was added at 20° C. After stirring at 130° C. for 2 h, the mixture was diluted with water (100 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were separated and washed with Na 2 SO 4 The residue was purified by flash column (30-65% EtOAc in PE) to give a mixture of diastereomers 10 and 11 (200 mg, 44.2% yield) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H 7.93 (s, 1H), 7.80 (s, 1H), 4.41-4.35 (m, 1H), 4.27-4.21 (m, 1H), 2.50 (s, 1H), 2.41-2.26 (m, 1H), 1.91-1.72 (m, 8H), 1.53-1.39 (m, 7H), 1.17-1.06 (m, 3H), 1.01 (s, 3H), 0.97 (s, 3H), 0.94-0.89 (m, 5H), 0.87-0.83 (m, 5H), 0.78-0.55 (m, 3H).

[0459] Diastereomers were separated by SFC: Column: DAICEL CHIRALCEL OJ-H 250mm*30mm, 5um; Condition: 0.1% NH 3 H 2 11 (30 mg) and 10 (130.5 mg) were obtained as solids by separation with 0EtOH; gradient: 25% to 25% B; flow rate: 60 mL / min; column temperature: 40°C). 11 was repurified by SFC. Column: DAICEL CHIRALCEL OJ-H 250 mm*30 mm, 5 um; Conditions: 0.1% NH 3 H 2 Repurification by elution with O (EtOH; gradient: 20% to 20% B; flow rate: 60 mL / min; column temperature: 40° C.) afforded 11 (16.9 mg) as a solid.

[0460] 10: 1 H NMR (400 MHz, CDCl3) δ H 7.93(s,1H),7.80(s,1H),4.40-4.35(m,1H),4.26-4.21(m,1H),2.47(s,1H),2.35-2.29(m,1H),1.91-1.59(m ,9H),1.53-1.35(m,6H),1.33-1.23(m,3H),1.18-1.03(m,3H),1.01(s,3H),0.99-0.95(m,5H),0.91(t,J=7.6 Hz,4H),0.87-0.68(m,3H),0.66-0.55(m,1H). LC-ELSD / MS purity 99%;C 28 H 40 N 3 [M-2H 2 O+H] + MS ESI calculated value 418.3 found 418.3. SFC: 95% de.

[0461] 11: 1 H NMR (400 MHz, CDCl 3 ) δ H7.89(s,1H),7 .84(s,1H),4.28(d,J=13.6 Hz,1H),4.01(d,J=13.6 Hz,1H),3.00(s,1H),2.41-2.34(m,1H),1.84-1.57(m,9H),1.52-1.40(m,6H),1.19(s,3H),1.10-1.06(m,3H) ,1.11-1.05(m,1H),1.02(s,3H),1.01-0.93(m,5H),0.93-0.89(m,4H),0.78-0.66(m,3H),0.62-0.54(m,1H). LC-ELSD / MS purity 99%;C 28 H 40 N 3 [M-2H 2 O+H] + MS ESI calcd for 418.3 found 418.3. SFC: 99% de.

[0462] Examples 12 and 13: Synthesis of 1-((S)-2-hydroxy-2-((1S,4aS,4bR,6aR,8R,10aS,10bS,12aS)-8-hydroxy-12a-dimethyl-8-propyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile and 1-((R)-2-hydroxy-2-((1S,4aS,4bR,6aR,8R,10aS,10bS,12aS)-8-hydroxy-10a,12a-dimethyl-8-propyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile [ka] 12.1 Synthesis To a freshly prepared solution of MAD (310 mmol) in toluene (300 mL) was added dropwise (5β)-androstane-3,17-dione, 12.0 (30 g, 104 mmol) in DCM (100 mL) at −70° C. 2After stirring at −70° C. for 1 h, n-PrMgCl (130 mL, 260 mmol, 2 M) was added dropwise at −70° C. After stirring at −70° C. for 4 h, the reaction mixture was poured into saturated aqueous citric acid (1000 mL) at 10° C. and extracted with EtOAc (2×1000 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried over 100 ml, filtered and concentrated under reduced pressure. The residue was purified by flash column (0-30% EtOAc in PE) to give 12.1 (16 g, 47.7%) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H 2.49-2.38 (m, 1H), 2.17-2.00 (m, 1H), 1.98-1.76 (m, 4H), 1.74-1.66 (m, 1H), 1.62-1.40 (m, 10H), 1.38-1.15 (m, 9H), 1.12-0.99 (m, 1H), 0.98-0.90 (m, 6H), 0.84 (s, 3H).

[0463] 12.2 Synthesis To a solution of freshly prepared LDA (150 mmol) in THF (100 mL) was added a solution of 12.1 (10 g, 30.0 mmol) and ethyl diazoacetate (19.0 g, 150 mmol, 90%) in THF (200 mL) at -70 °C. After stirring at -70 °C for 2 h, the reaction was quenched with acetic acid (8.57 mL, 150 mmol) in THF (20 mL). After warming to room temperature overnight, the reaction was diluted with water (300 mL) and EtOAc (3 × 2 The combined organic layers were washed with brine (300 mL) and extracted with anhydrous Na 2 SO 4 The residue was purified by flash column (0-20% EtOAc in PE) to give 12.2 (13 g, 97.7%) as an oil. 1 H NMR (400 MHz, CDCl 3 ) δ H4.75-4.65(m, 1H), 4.25 (q, J=7.2 Hz, 2H), 2.20-2.09 (m, 1H), 1.93-1.76 (m, 3H), 1.72-1.35 (m, 14H), 1.34-1.24 (m, 7H), 1.23-0.99 (m, 5H), 0.96-0.91 (m, 6H), 0.89 (s, 3H).

[0464] 12.3 Synthesis A solution of 12.2 (13 g, 29.1 mmol) in DME (130 mL) was diluted with Rh 2 (OAc) 4 (300 mg, 0.6787 mmol) was added in one portion at 15° C. After stirring at 15° C. for 16 h, the reaction was diluted with water (300 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (300 mL) and anhydrous Na 2 SO 4 The mixture was dried over ice, filtered and concentrated to give 12.3 (11 g, 90.9%) as an oil.

[0465] 12.4 Synthesis To a solution of 12.3 (11 g, 26.2 mmol) in MeOH (110 mL) was added KOH (14.6 g, 262 mmol) at 20° C. After stirring at 70° C. for 3 h, the reaction mixture was added to saturated brine (100 mL) and extracted with DCM (2×200 mL). The combined organic layers were washed with HCl (200 mL, 1N), saturated NaHCO 3 (200 mL), saturated brine (100 mL), and Na 2 SO 4 It was dried over, filtered and concentrated to give 12.4 (11 g) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H 2.61 (dt, J=6.8, 14.0 Hz, 1H), 2.24-2.15 (m, 1H), 2.09-2.01 (m, 1H), 1.91-1.68 (m, 6H), 1.67-1.43 (m, 10H), 1.42-1.19 (m, 10H), 1.06 (s, 3H), 0.96-0.90 (m, 6H).

[0466] 12.5 Synthesis EtPPh in THF (160 mL) 3 A mixture of Br (38.2 g, 103 mmol) and t-BuOK (11.5 g, 103 mmol) was added to N 2 After stirring at 40° C. for 30 min, 12.4 (9.0 g, 25.9 mmol) was added at 40° C. After stirring at 40° C. for 16 h, the reaction mixture was diluted with saturated NH 4 It was quenched with aqueous Cl (150 mL) at 20° C. and extracted with EtOAc (2×100 mL). The combined organic phase was concentrated. The residue was purified by flash column (0-20% EtOAc in PE) to give 12.5 (4.2 g, 45.2%) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δH 5.25-5.05 (m, 1H), 2.54-2.10 (m, 1H), 1.99-1.69 (m, 7H), 1.67-1.57 (m, 4H), 1.54-1.20 (m, 16H), 1.05-0.98 (m, 4H), 0.96-0.86 (m, 9H).

[0467] 12.6 Synthesis To a solution of 12.5 (4.2 g, 11.7 mmol) in THF (40 mL) was added BH 3 Me 2 S (3.51 mL, 10 M, 35.1 mmol) was added. After stirring at 15° C. for 16 h, the reaction was diluted with EtOH (6.73 mL, 117 mmol), dropwise addition of NaOH (4.67 g, 5 M, 117 mmol in 23.4 mL of water) and dropwise addition of H 2 O 2 (11.7 mL, 10 M, 117 mmol) at 0° C. After stirring at 70° C. for 2 h, the mixture was treated with Na 2 SO 3(100 mL, 10%) and extracted with EtOAc (2×100 mL). The combined organic layers were separated and washed with Na 2 SO 4 Dry on a stover, filter, Concentration under reduced pressure gave 12.6 (4.2 g) as a solid which was used as is.

[0468] 12.7 Synthesis To a solution of 12.6 (4.2 g, 11.1 mmol) in DCM (50 mL) was added DMP (9.41 g, 22.2 mmol). After stirring at 20 °C for 1 h, the mixture was diluted with NaHCO 3 (100mL, saturated) and Na 2 S 2 O 3 (100 mL, saturated). The organic layer was separated and 2 SO 4 It was dried over, filtered and concentrated to give 12.7 (4.0 g) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H 2.50-2.24 (m, 1H), 2.16-2.10 (m, 3H), 1.93-1.64 (m, 7H), 1.54-1.43 (m, 6H), 1.39-1.12 (m, 11H), 1.05-0.82 (m, 14H).

[0469] 12.8 Synthesis To a solution of 12.7 (3.5 g, 9.34 mmol) in MeOH (80 mL) was added MeONa (10.0 g, 186 mmol) at 0° C. After stirring at 80° C. for 16 h, the reaction mixture was concentrated. The residue was washed with saturated NH 4 The mixture was diluted with Cl (100 mL) and extracted with EtOAc (2×100 mL). The combined organic phase was washed with saturated brine (100 mL) and anhydrous Na 2 SO 4 The mixture was dried over ice, filtered and concentrated to give 12.8 (2.2 g, 63.0%) as a solid. 1 H NMR (400 MHz, CDCl 3)2.32-2.25(m,1H),2.13(s,3H),1.89-1.75(m,3H),1.74-1.56(m,5H),1.52-1.40(m,6H),1.39-1.17(m, 10H),1.04-0.96(m,2H),0.95-0.92(m,4H),0.91-0.89(m,6H),0.89-0.82(m,1H);LC-ELSD / MS: Purity>99%,C 25 H 41 O[M-H2O+H] + MS ESI calculated value for 357.3, found value 357.3.

[0470] 12.9 Synthesis MePPh in THF (16 mL) 3 A mixture of Br (3.78 g, 10.6 mmol) and t-BuOK (1.18 g, 10.6 mmol) was added to N 2 After stirring at 50° C. for 30 min, 12.8 (1.0 g, 2.66 mmol) was added at 50° C. After stirring at 50° C. for 16 h, the reaction mixture was diluted with saturated NH 4 It was quenched with aqueous Cl (150 mL) at 20° C. and extracted with EtOAc (2×100 mL). The combined organic phase was concentrated. The residue was purified by flash column (0-20% EtOAc in PE) to give 12.9 (700 mg, 70.6%) as a solid. 1 H NMR (400 MHz, CDCl 3 ) δ H 4.80 (s, 1H), 4.60 (d, J=2.0 Hz, 1H), 1.87-1.58 (m, 12H), 1.54-1.23 (m, 17H), 1.12-0.97 (m, 3H), 0.96-0.91 (m, 4H), 0.90 (s, 3H), 0.80 (s, 3H).

[0471] 12.10 Synthesis To a solution of 12.9 (700 mg, 1.87 mmol) in DCM (10 mL) was added m-CPBA (758 mg, 3.74 mmol). After stirring at 20 °C for 1 h, the mixture was diluted with NaHCO 3(20mL, saturated) and Na 2 S 2 O 3 (20 mL, saturated). The organic layer was separated and 2 SO 4 Drying over, filtration and concentration gave 12.10 (700 mg) as a solid which was used as is.

[0472] Synthesis of 12 and 13 A solution of 12.10 (400 mg, 1.02 mmol) in DMF (20 mL) was diluted with 1H-pyrazole-4-carbonitrile (189 mg, 2.04 mmol) and Cs 2 CO 3 (668 mg, 2.04 mmol) was added at 20° C. After stirring at 120° C. for 48 h, The reaction mixture was then diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (50 mL) and diluted with Na 2 SO 4 The mixture was dried over hexane, filtered and concentrated under reduced pressure. The residue was purified by flash column (5-40% EtOAc in PE) to give a mixture of diastereomers 12 and 13 (350 mg, 71.2%) as a solid. 12 and 13 (350 mg, 0.7 mmol) were purified by SFC (column: DAICEL CHIRALCEL OJ-H(250mm*30mm*5um);Mobile phase:A:CO 2 B: 0.1% NH 3 H 2 Separation with 20% to 20% B in O / EtOH; gradient: 20% to 20% B, flow rate (ml / min): 60) afforded both 12 (41.0 mg, 11.7%) and 13 (98.4 mg, 28.1%) as solids.

[0473] 12: 1 H NMR (400 MHz, CDCl 3 ) δ H7.88 (s, 1H), 7.87 (s, 1H), 4.33 - 3.94 (m, 2H), 3.06 (s, 1H), 2.45 - 2.35 (m, 1H), 1.87 - 1.61 (m, 5H), 1.52 - 1.20 (m, 15H), 1.18 (s, 3H), 1.13 - 1.01 (m, 3H), 0.98 (s, 3H), 0.93 (t, J = 7.2 Hz, 4H), 0.87 (s, 3H), 0.85 - 0.66 (m, 3H). LC - ELSD / MS: Purity > 99%, Analytical SFC: 97.84% de; C 30 H 44 N 3 [M - 2H 2 O + H] + The calculated MS ESI value for [M - 2H + O + H] is 446.4, and the measured value is 446.4.

[0474] 13: 1 H NMR (400 MHz, CDCl 3 ) δ H 7.91 (s, 1H), 7.79 (s, 1H), 4.39 - 4.19 (m, 2H), 2.40 (s, 1H), 2.36 - 2.29 (m, 1H), 1.91 - 1.63 (m, 7H), 1.53 - 1.41 (m, 7H), 1.40 - 1.10 (m, 13H), 0.98 (s, 3H), 0.96 - 0.91 (m, 7H), 0.90 - 0.85 (m, 4H); LC - ELSD / MS: Purity > 99%, Analytical SFC: 99.64%, C 30 H 44 N 3 [M - 2H 2 O + H] + The calculated MS ESI value for [M - 2H + O + H] is 446.4, and the measured value is 446.4.

[0475] Examples 14 and 15: Synthesis of 1-((S)-2-hydroxy-2-((1S,4aS,4bR,6aR,8R,10aS,10bS,12aS)-8-hydroxy-8,10a,12a-trimethyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile and 1-((R)-2-hydroxy-2-((1S,4aS,4bR,6aR,8R,10aS,10bS,12aS)-8-hydroxy-8,10a,12a-trimethyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile [ka] 14.1 Synthesis To a freshly prepared solution of MAD (519 mmol) in toluene (1 L) was added a solution of 12.0 (50.0 g, 173 mmol) in DCM (200 mL) dropwise at −70° C. 2 After stirring at −70° C. for 1 h, MeMgBr (173 mL, 519 mmol, 3 M in ethyl ether) was added dropwise at −70° C. After stirring at −70° C. for 2 h, the reaction mixture was poured into saturated aqueous citric acid (1000 mL) at 10° C. and extracted with EtOAc (2×400 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate, filtered and concentrated. The residue was purified by silica gel chromatography (PE / EtOAc=10 / 1 to 3 / 1) to give 14.1 (36 g, 68%) as a solid. 1 HNMR (400 MHz, CDCl 3 ) δ H 2.48-2.38 (m, 1H), 2.13-2.02 (m, 1H), 1.98-1.85 (m, 3H), 1.83-1.69 (m, 2H), 1.63-1.43 (m, 8H), 1.39-1.14 (m, 10H), 1.12-1.02 (m, 1H), 0.97 (s, 3H), 0.84 (s, 3H).

[0476] 14.2 Synthesis To a solution of freshly prepared LDA (82.1 mmol) in THF (100 mL) was added a solution of 14.1 (6 g, 19.7 mmol) and ethyl diazoacetate (12.4 g, 98.4 mmol, 90%) in THF (120 mL) at -70 °C. After stirring at -70 °C for 2 h, the reaction was quenched with acetic acid (5.61 mL, 98.4 mmol) in THF (15 mL), warmed to 20 °C for 16 h, diluted with water (300 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (300 mL) and diluted with anhydrous Na 2 SO 4 The residue was purified by flash column (0-15% EtOAc in PE) to give 14.2 (8.0 g, 97%) as an oil. 1 HNMR (400 MHz, CDCl 3 ) δ H 4.69 (br s, 1H), 4.25 (q, J = 7.2 Hz, 2H), 2.18-2.08 (m, 1H), 2.04 (s, 1H), 2.01-1.93 (m, 1H), 1.91-1.78 (m, 2H), 1.76-1.63 (m, 2H), 1.60-1.38 (m, 9H), 1.35-1.29 (m, 4H), 1.28-1.23 (m, 5H), 1.14-0.98 (m, 4H), 0.94 (s, 3H), 0.89 (s, 3H).

[0477] 14.3 Synthesis A solution of 14.2 (8.0 g) in DME (100 mL) was diluted with Rh 2 (OAc) 4 (211 mg, 0.48 mmol) was added in one portion at 15° C. After stirring at 30° C. for 12 h, the mixture was 2 The mixture was diluted with 2×O (100 mL) and extracted with EtOAc (3×60 mL). The combined organic phase was washed with brine (2×30 mL) and anhydrous Na 2 SO 4 It was dried over, filtered and concentrated to give 14.3 (7.7 g) as an oil. 1 HNMR (400 MHz, CDCl3 ) δ H 12.41 (s, 1H), 4.24-4.15 (m, 2H), 3.74-2.27 (m, 2H), 2.22-2.11 (m, 1H), 1.98-1.69 (m, 5H), 1.57-1.35 (m, 8H), 1.32-1.24 (m, 9H), 1.22-1.01 (m, 7H), 0.96-0.90 (m, 3H).

[0478] 14.4 Synthesis To a solution of 14.3 (7.7 g, 19.7 mmol) in MeOH (100 mL) was added KOH (6.62 g, 118 mmol) at 15° C. After stirring at 70° C. for 1 h, the reaction mixture was poured into saturated brine (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with HCl (1 M, 100 mL), saturated NaHCO 3 (100 mL), brine (100 mL), and anhydrous Na 2 SO 4 Drying over, filtration and concentration gave 14.4 (5.8 g, 93%) as a solid. 1 HNMR (400 MH z, CDCl 3 ) δ H 2.66-2.55 (m, 1H), 2.23-2.16 (m, 1H), 2.09-2.01 (m, 1H), 1.93-1.84 (m, 2H), 1.83-1.72 (m, 3H), 1.67-1.50 (m, 6H), 1.44-1.31 (m, 5H), 1.30-1.13 (m, 7H), 1.09-0.99 (m, 5H), 0.93 (s, 3H).

[0479] 14.5 Synthesis Ph in THF (160 mL) 3 To a mixture of PEtBr (40.4 g, 109 mmol), t-BuOK (12.2 g, 21.8 mmol) was added with N 2After stirring at 40° C. for 1 h, 14.4 (5.8 g, 18.2 mmol) was concentrated. After stirring at 40° C. for 2 h, the reaction mixture was diluted with 10% NH 4 The mixture was quenched with aqueous Cl (60 mL) at 20° C. and extracted with EtOAc (2×100 mL). The combined organic phase was washed with brine (50 mL) and anhydrous Na 2 SO 4 The residue was purified by flash column (0-15% EtOAc in PE) to give 14.5 (5.3 g, 88%) as an oil. 1 HNMR (400 MHz, CDCl 3 ) δ H 5.20-5.09 (m, 1H), 2.55-2.10 (m, 2H), 2.01-1.70 (m, 7H), 1.66-1.58 (m, 3H), 1.53-1.31 (m, 7H), 1.31-1.22 (m, 6H), 1.22-1.01 (m, 5H), 1.00-0.82 (m, 7H).

[0480] 14.6 Synthesis To a solution of 14.5 (5.3 g, 16 mmol) in THF (80 mL) was added BH 3 .Me 2 S (4.8 mL, 48 mmol, 10 M) 2 The N 2 After stirring at 20° C. for 12 h under reduced pressure, the mixture was cooled to 0° C. and EtOH (16.5 mL, 288 mmol) and NaOH (57.6 mL, 5 M, 288 mol) were added. 2 O 2 (28.8 mL, 10 M, 288 mmol) was added dropwise. After stirring at 70° C. for 2 h, the mixture was cooled and 2 S 2 O 3 (500 mL, saturated), stirred for 30 min and extracted with EtOAc (2×200 mL). The combined organic phase was washed with saturated brine (2×100 mL) and anhydrous Na 2 SO 4Drying over, filtering and concentrating gave 14.6 (5.57 g) as a solid. 1 HNMR (400 MHz, CDCl 3 ) δ H 1.97-1.72 (m, 5H), 1.70-1.67 (m, 1H), 1.55-1.34 (m, 8H), 1.31-1.18 (m, 12H), 1.17-0.99 (m, 5H), 0.97-0.85 (m, 8H), 0.79-0.72 (m, 1H).

[0481] 14.7 Synthesis To a solution of 14.6 (5.57 g, 15.9 mmol) in DCM (120 mL) was added DMP (13.4 g, 31.8 mmol) at 20° C. After stirring at 20° C. for 1 h, the mixture was diluted with saturated NaHCO 3 The DCM phase was separated and quenched with saturated NaHCO 3 / Na 2 S 2 O 3 Wash with aqueous solution (1:1, 2×100 mL), brine (30 mL), and Na 2 SO 4 The residue was purified by flash column (0-20% EtOAc in PE) to give 14.7 (4.95 g, 90%) as an oil. 1 HNMR (400 MHz, CDCl 3 ) δ H 2.48-2.25 (m, 1H), 2.13 (d, J = 1.6 Hz, 3H), 1.98-1.87 (m, 1H), 1.86-1.65 (m, 5H), 1.63-1.43 (m, 8H), 1.42-1.28 (m, 5H), 1.24-1.14 (m, 5H), 1.08-0.92 (m, 3H), 0.91- 0.83 (m, 7H).

[0482] 14.8 Synthesis To a solution of 14.7 (4.95 g, 14.2 mmol) in MeOH (80 mL) was added MeONa (15.2 g, 283 mmol)2 After stirring at 80° C. for 48 h, the mixture was 2 The mixture was diluted with 2×O (60 mL) and extracted with EtOAc (3×70 mL). The combined organic phase was washed with brine (50 mL) and anhydrous Na 2 SO 4 It was dried over, filtered and concentrated to give 14.8 (3.9 g) as a solid. 1 HNMR (400 MHz, CDCl 3 ) δ H 2.32-2.24 (m, 1H), 2.13 (s, 3H), 1.97-1.89 (m, 1H), 1.87-1.66 (m, 5H), 1.57-1.32 (m, 9H), 1.31-1.17 (m, 9H), 1.07-0.93 (m, 3H), 0.91-0.86 (m, 7H).

[0483] 14.9 Synthesis MePPh in THF (50 mL) 3 To a mixture of Br (12.3 g, 34.6 mmol), t-BuOK (3.87 g, 34.9 mmol) was added 2 After stirring at 50° C. for 1 h, 14.8 (2.0 g, 5.8 mmol) was added at 50° C. After stirring at 50° C. for 12 h, the reaction mixture was diluted with 10% NH 4 The mixture was quenched with aqueous Cl (100 mL) at 20° C. and extracted with EtOAc (2×80 mL). The combined organic phase was washed with brine (40 mL) and anhydrous Na 2 SO 4 The residue was purified by flash column (0-10% EtOAc in PE) to give 14.9 (1.6 g, 81%) as an oil. 1 HNMR (400 MHz, CDCl 3 ) δ H 4.80 (...

Claims

[Claim 1] The invention described in the specification.

Images