Compositions and methods for treating CNS disorders

Abstract

As used herein, a compound of formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or XI: JPEG2022538299000086.jpg62165 or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, and methods of using the compounds, for example, in the treatment of CNS-related disorders, are provided.

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. Generally, neurotransmitters are responsible for regulating the conduction of ions across the neuronal membrane. At rest, the neuronal membrane has a potential (or membrane voltage) of approximately -70 mV, with the interior of the cell being negative relative to the exterior. The potential (voltage) is determined by the flow of ions (K) across the neuronal semipermeable membrane. + , Na + , Cl - Neurotransmitters are stored in presynaptic vesicles and are released under the influence of an action potential in the neuron. When released into the synaptic cleft, excitatory chemical transmitters such as acetylcholine cause membrane depolarization (a change in potential occurs between -70 mV and -50 mV). This effect is stimulated by acetylcholine and Na + It is mediated by postsynaptic nicotinic receptors, which 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 profoundly influences 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, promoting chloride ions flowing down the GRC's electrochemical gradient into the cell. Intracellular increases in the levels of this anion cause 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 within neurons, the lower the brain's excitability and arousal levels.

[0004] It has been well documented that the GRC mediates anxiety, seizure activity, and sedation. Thus, GABA and drugs that act like GABA or potentiate the effects of GABA (e.g., therapeutically useful barbiturates and benzodiazepines (BZs), e.g., Valium®) exert their therapeutic effects by interacting with specific regulatory sites on the GRC. Accumulating evidence now indicates that, in addition to the binding sites for benzodiazepines and barbiturates, the GRC contains distinct sites for neuroactive steroids. See, e.g., Lan, NC et al., Neurochem. Res. (1991) 16:347-356.

[0005] Neuroactive steroids can occur endogenously. The most potent endogenous neuroactive steroids are 3α-hydroxy-5-reduced pregnan-20-one and 3α-21-dihydroxy-5-reduced pregnan-20-one, which are metabolites of the hormonal steroids progesterone and deoxycorticosterone, respectively. The ability of these steroid metabolites to alter brain excitability was recognized in 1986 (Majewska, MD et al., Science 232:1004-1007 (1986); Harrison, NL et al., J Pharmacol. Exp. Ther. 241:346-353 (1987)). There is a need for new and improved compounds that function as modulators of brain excitability and as agents for the prevention and treatment of CNS-related disorders. The compounds, compositions, and methods described herein are directed toward 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, such compounds are contemplated to be useful as therapeutic agents for treating CNS-related disorders.

[0008] In some embodiments, provided herein are compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof is provided, wherein the variables are as defined herein.

[0009] In some embodiments, provided herein are compounds of formula II: [ka] or a pharmaceutically 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 pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

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

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

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

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

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

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

[0017] In one aspect, provided herein are pharmaceutically acceptable salts of 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 pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the compound of the invention is provided in the pharmaceutical composition in an effective amount. In certain embodiments, the compound of the 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 pharmaceutically acceptable salt thereof. In some embodiments, the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a seizure disorder, a memory and / or 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 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 receptors act 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 treating 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 seizure 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. In certain embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In certain embodiments, the compound is administered orally. In certain embodiments, the compound is administered chronically. In certain embodiments, the compound is administered continuously, for example, by continuous intravenous infusion. DETAILED DESCRIPTION OF THE INVENTION

[0023] As generally described herein, the present invention provides a method for treating GABA- A Provided are compounds that are designed to function as receptor modulators.In certain embodiments, it is envisioned that such compounds are useful as therapeutic agents for treating CNS-related disorders (for example, disorders described herein, for example, 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 Edition, 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 reactivities, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[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. For example, see 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., University 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 the molecule rotates the plane of polarized light and is designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomer, 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 other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, the "S" form of a compound is substantially free of the "R" form of the compound and is thus in enantiomeric excess of the "R" form. The terms "enantiomerically pure" or "pure enantiomer" mean 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 weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0028] In the compositions provided herein, the enantiomerically pure compound may be present together with other active or inactive ingredients. For example, a pharmaceutical composition containing an enantiomerically pure R position / center / carbon compound may contain, for example, about 90% excipients and about 10% enantiomerically pure R compound. In certain embodiments, the enantiomerically pure R compound in such a composition may contain, for example, at least about 95% by weight of the R compound and at most about 5% by weight of the S compound, based on the total weight of the compound. For example, a pharmaceutical composition containing an enantiomerically pure S compound may contain, for example, about 90% excipients and about 10% of the enantiomerically pure S compound. In certain embodiments, the enantiomerically pure S compound in such a composition may contain, for example, at least about 95% by weight of the S compound and at most about 5% by weight of the R compound, based on the total weight of the compound. In certain embodiments, the active ingredient may be formulated with little or no excipients or carriers.

[0029] The term "diastereomerically pure" means that a compound contains more than 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98.5%, 99%, 99.2%, 99.5%, 99.6%, 99.7%, 99.8%, 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 between a compound and 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" refers to C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 , and C 5~6 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 straight-chain or branched saturated hydrocarbon group having from 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 In some embodiments, an 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 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2~6 alkyl). C 1~6Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tertiary butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each example of an alkyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1~10 In certain embodiments, the alkyl group is a substituted C 1~10 Common abbreviations for alkyl include Me(-CH), Et(-CHCH), iPr(-CH(CH)), nPr(-CHCHCH), n-Bu(-CHCHCHCHCH), or i-Bu(-CHCH(CH)).

[0034] "Alkylene" refers to an alkyl group in which two hydrogens are removed to provide a divalent radical, which can be substituted or unsubstituted. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), butylene (-CHCHCHCHCH-), pentylene (-CHCHCHCHCHCH-), hexylene (-CHCHCHCHCHCHCH-), and the like. For example, exemplary substituted alkylene groups substituted with one or more alkyl (methyl) groups include, but are not limited to, substituted methylene (-CH(CH)-, (-C(CH)-), substituted ethylene (-CH(CH)CH-, -CHCH(CH)-, -C(CH)CH-, -CHC(CH)-), substituted propylene (-CH(CH)CHCH-, -CHCH(CH)CH-, -CHCHCH(CH)CH-, -CHCHCH(CH)-, -C(CH)CHCH-, -CHC(CH)CH-, -CHCHC(CH)-), 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 divalent carbon chain. An alkylene group can be unsubstituted or substituted 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, an alkenyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2~8In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). C 2~4 Examples of alkenyl include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 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, an alkynyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). C 2~4 Examples of alkynyl include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4Alkynyl groups include pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent (a "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 an alkyl group, as defined herein, further comprising one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) in the parent chain, wherein one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, a heteroalkyl group refers to a saturated group having 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~10 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 1~6In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms ("heteroC 1~5 In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms ("heteroC 1~4 In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 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 1~2 In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (a "heteroC1 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 2-6 carbon atoms and 1 or 2 heteroatoms (a "heteroC 2~6 Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an "unsubstituted heteroalkyl") or substituted (a "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 heteroC 1~10 It is 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 ("C 6~14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10Aryl"; e.g., 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; in such instances, the number of carbon atoms continues to designate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. In particular, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, 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 selected from 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 57 may be hydrogen, and one of R 56 and R 57 At least one of 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 SO2R 59 , COO alkyl, COO aryl, CONR 58 R 59 ,CONR 58 OR 59 , N.R. 58 R 59 , SO2NR 58 R 59 , S-alkyl, SO alkyl, SO alkyl, S aryl, SO aryl, SO 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. R 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 common to a second aryl or heteroaryl ring, or a carbocyclic or heterocyclic ring.

[0042] "Heteroaryl" refers to the radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, valence permitting. 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; 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 to one or more aryl groups, and the point of attachment can be on either the aryl ring or the heteroaryl ring; 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., the ring with a heteroatom (e.g., 2-indolyl) or the ring without a heteroatom (e.g., 5-indolyl).

[0043] In some embodiments, a heteroaryl group is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In some embodiments, a heteroaryl group is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heteroaryl"). In some embodiments, a heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heteroaryl"). In some embodiments, a 5- to 6-membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 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, benzisofuranyl, 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 a 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" refers to a ring system containing 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, without limitation, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. 3~8 The carbocyclyl group is not limited to the above-mentioned C 3~6 Carbocyclyl groups include cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C 3~10 The carbocyclyl group is not limited to the above-mentioned C 3~8 Carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10), spiro[4.5]decanyl (C 10 ) and the like. Where the foregoing examples illustrate, in certain embodiments, a carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or includes a fused, bridged, or spiro ring system, such as a bicyclic system ("bicyclic carbocyclyl"), and can be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, the point of attachment being on the carbocyclyl ring; 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, a 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 3~6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5~6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5~10 Cycloalkyl). C 5~6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3~6 Examples of cycloalkyl groups include the aforementioned C 5~6Cycloalkyl groups include cyclopropyl (C3) and cyclobutyl (C4). 3~8 Examples of cycloalkyl groups include the aforementioned C 3~6 Cycloalkyl groups include cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each example of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). 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 the radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each 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, valence permitting. 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); 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, a heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, a heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0049] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (a "5- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur (a "5- to 8-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur (a "5- to 6-membered heterocyclyl"). In some embodiments, a 5- to 6-membered heterocyclyl group has 1 to 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, In some embodiments, the 5- to 6-membered heterocyclyl has 1 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. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. 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, and the like.

[0051] A "nitrogen-containing heterocyclyl" group refers to a 4- to 7-membered non-aromatic cyclic group containing at least one nitrogen atom, for example, 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-alkylpiperazines such as N-methylpiperazine. Specific 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, etc., having 1 to 5, especially 1 to 3, heteroatoms.

[0053] "Acyl" is the radical -C(O)R 20 refers to 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, and R 20 is a group other than hydrogen. Representative acyl groups include formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph), --C(O)-C 1~8 Alkyl, -C(O)-(CH2) t (C 6~10 aryl), -C(O)-(CH2) t(5-10 membered heteroaryl), -C(O)-(CH2) t (C 3~10 cycloalkyl), and -C(O)-(CH2) t (4- to 10-membered heterocyclyl), where t is an integer from 0 to 4. In certain embodiments, R 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- to 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 It is 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, tert-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. More particular alkoxy groups have 1 to 4 carbon atoms.

[0055] In certain embodiments, R 29 is amino, substituted amino, C 6~10 Aryl, aryloxy, carboxyl, cyano, C 3~10A group having one or more substituents, for example, 1 to 5 substituents, and particularly 1 to 3 substituents, and particularly 1 substituent, selected from the group consisting of cycloalkyl, 4- to 10-membered heterocyclyl, halogen, 5- to 10-membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2-, and aryl-S(O)2-. Exemplary "substituted alkoxy" groups include -O-(CH2) t (C 6~10 aryl), -O-(CH2) t (5-10 membered heteroaryl), -O-(CH2) t (C 3~10 cycloalkyl), and -O-(CH2) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present may itself be 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. Particular exemplary "substituted alkoxy" groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2NMe2.

[0056] "Amino" refers to the radical -NH2.

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

[0058] "Substituted amino" refers to a group of the formula -N(R 38 )2, where R 38is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted 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- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl, or C 3~10 cycloalkyl; or halo or hydroxy substituted C 1~8 Alkyl; halo or hydroxy substituted C 3~8 C substituted with alkenyl, halo or hydroxy 3~8 Alkynyl, or -(CH2) t (C 6~10 aryl), -(CH2) t (5-10 membered heteroaryl), -(CH2) t (C 3~10 cycloalkyl), or -(CH2) t (4- to 10-membered heterocyclyl), t is an integer from 0 to 8, and each 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 substituted by haloalkoxy or hydroxy, or both R 38 are joined to form an alkylene group.

[0059] Exemplary "substituted amino" groups include -NR 39 -C 1~8 Alkyl, -NR 39 -(CH2) t (C 6~10 aryl), -NR 39 -(CH2) t(5-10 membered heteroaryl), -NR 39 -(CH2) t (C 3~10 cycloalkyl), and -NR 39 -(CH2) t (4-10 membered heterocyclyl), where t is an integer of 0 to 4, for example, 1 or 2, and each R 39 are independently H or C 1~8 alkyl, 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" refers to the radical -NO2.

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

[0067] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups 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 replaced with a permissible substituent, e.g., a substituent that, upon substitution, gives rise to a stable compound, e.g., a compound that does not undergo spontaneous transformation, such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group; and when more than one position in any given structure is substituted, the substituents 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 in order 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, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO2H, -CHO, -C(OR cc)2、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa)2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)2N(R bb )2, -OP(=O)2N(R bb )2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(NR bb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(R cc )3, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 and 5- to 14-membered heteroaryl, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently having 0, 1, 2, 3, 4, or 5 R dd groups, or the two geminal hydrogens on the carbon atom are substituted with groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb , or =NOR cc is replaced by R aa Each instance of is independently C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R aa groups 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, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(=NR cc )2, C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R bbgroups 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 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- to 14-membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R cc groups 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 dd Each example of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff)2, -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)2R ee , -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 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 C 1~6 Alkyl, C 1~6Haloalkyl, 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 alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently having 0, 1, 2, 3, 4, or 5 R gg is substituted with a group, R ff 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 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 gg is substituted with a group, R gg Each example of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6 Alkyl, -ON(C 1~6 alkyl)2, -N(C 1~6 alkyl)2, -N(C 1~6 alkyl)3 + X - , -NH(C 1~6 alkyl)2 + X - , -NH2(C 1~6 alkyl) + X - , -NH3 + X - , -N(OC 1~6 Alkyl)(C 1~6 alkyl), -N(OH)(C 1~6 alkyl), -NH(OH), -SH, -SC1~6 Alkyl, -SS(C 1~6 alkyl), -C(=O)(C 1~6 alkyl), -CO2H, -CO2(C 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -OCO2(C 1~6 alkyl), -C(=O)NH2, -C(=O)N(C 1~6 alkyl)2, -OC(=O)NH(C 1~6 alkyl), -NHC(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(C 1~6 alkyl), -NHCO2(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1~6 alkyl), -OC(=NH)(C 1~6 alkyl), -OC(=NH)OC 1~6 Alkyl, -C(=NH)N(C 1~6 alkyl)2, -C(=NH)NH(C 1~6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1~6 alkyl)2, -OC(NH)NH(C 1~6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1~6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 alkyl), -SO2NH2, -SO2C 1~6 Alkyl, -SO2OC 1~6 Alkyl, -OSO2C 1~6 Alkyl, -SOC 1~6 Alkyl, -Si(C 1~6 alkyl)3, -OSi(C 1~6 alkyl)3, -C(=S)N(C 1~6 alkyl)2, C(=S)NH(C 1~6 alkyl), C(=S)NH2, -C(=O)S(C 1~6alkyl), -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 electron neutrality. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HSO4 - , sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

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

[0071] Other definitions As used herein, the term "modulation" refers to the A "Modulators" (e.g., modulatory compounds) refer to the inhibition or enhancement of receptor function, e.g., GABA receptors. A It can 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 Pharmacopoeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0073] "Pharmaceutically acceptable salts" refers to salts of the compounds of the present invention that are pharmaceutically acceptable and possess the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and can 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 salts formed 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 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 sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., and, if the compound contains a basic functional group, salts of non-toxic organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counterion of an acidic functional group. 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 encompass therapeutically inactive compounds that are converted into the therapeutically active agents of the present invention under physiological conditions. One method for creating a prodrug is to design a selected moiety that is hydrolyzed or cleaved at the target in vivo site of action under physiological conditions, thereby revealing the desired molecule that then produces its therapeutic effect. In certain embodiments, the prodrug is converted by the enzyme activity of the target.

[0075] In an alternative embodiment, the present invention provides prodrugs of the compounds described herein, wherein the prodrugs 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, altered by the displacement of hydrogen atoms and electrons. Thus, two structures can be in equilibrium through the shifting 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, whose acetyl and nitro forms are similarly formed by treatment with acid or base. Tautomeric forms can be relevant to achieving optimal chemical reactivity and biological activity of a desired compound.

[0077] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, e.g., mammals such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human ("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 , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3, -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)2N(R bb )2, and -P(=O)(NR bb ) 2, and 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. Butts, 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 , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3, -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)2N(R bb )2, and -P(=O)(NR bb ) 2, and R aa , R bb , and R cc is 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. Butts, 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)2R aa , -C(=NRcc )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 and 5- to 14-membered heteroaryl groups, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently having 0, 1, 2, 3, 4, or 5 R dd substituted with R aa , R bb , R cc and R dd is as defined herein. Amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Butts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[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); aasulfonamide groups (e.g., —S(═O)R ), including, but not limited to, p-toluenesulfonamide (Ts), methanesulfonamide (Ms), and N-[2-(trimethylsilyl)ethoxy]methylamine (SEM); 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 the specified disease, disorder, or condition and that reduce the severity of the disease, disorder, or condition or delay or slow the progression of the disease, disorder, or condition ("therapeutic treatment"), as well as actions that occur before a subject begins to suffer from the specified disease, disorder, or condition.

[0085] Generally, the "effective amount" of a compound refers to an amount sufficient to induce a desired biological response, for example, to treat a CNS-related disorder, and is sufficient to induce anesthesia or sedation.As will be understood by those skilled in the art, the effective amount of the compound of the present invention can vary depending on factors such as the desired biological endpoint, 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 the 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 encompass 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 a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof, as a preventative 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 the amount of a therapeutic agent that, alone or in combination with other agents, provides a prophylactic benefit in the prevention of a disease, disorder, or condition. The term "prophylactically effective amount" can encompass an amount that improves overall prevention 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 shown below. [ka] For example, C17 refers to the 17th carbon, and C3 refers to the 3rd carbon.

[0089] In one aspect, provided herein are compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, 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 5 Provided that there is no R X Halo, -OH, -ORQ1 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 is independently a halogen, -NO2, -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)2R GA , -S(=O)2OR GA , -OS(=O)2R GA , -S(=O)2N(R GA )2, -N(R GA )S(=O)2R 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, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -N(R A1 )2, -SR A1 , -C(=O)R A1 , -C(=O)OR A1 , -C(=O)SR A1 , -C(=O)N(R A1 )2, -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)N(R A1 )2, -OC(=O)SRA1 , -OS(=O)2R A1 , -OS(=O)2OR A1 , -OS(=O)2N(R A1 )2, -N(R A1 )C(=O)R A1 , -N(R A1 )C(=NR A1 )R A1 , -N(R A1 )C(=O)OR A1 , -N(R A1 )C(=O)N(R A1 )2, -N(R A1 )C(=NR A1 )N(R A1 )2, -N(R A1 )S(=O)2R A1 , -N(R A1 )S(=O)2OR A1 , -N(R A1 )S(=O)2N(R A1 )2, -SC(=O)R A1 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -S(=O)2R A1 , -S(=O)2OR A1 , or -S(=O)2N(R A1 )2, and 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 6bare each independently selected from the group consisting of hydrogen, halogen, cyano, —NO, —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, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR C3 , -N(R C3 )2, -SR C3 , -C(=O)R C3 , -C(=O)OR C3 , -C(=O)SR C3 , -C(=O)N(R C3 )2, -OC(=O)R C3 , -OC(=O)OR C3 , -OC(=O)N(R C3 )2, -OC(=O)SR C3 , -OS(=O)2R C3 , -OS(=O)2OR C3 , -OS(=O)2N(R C3 )2, -N(R C3 )C(=O)R C3 , -N(R C3 )C(=NR C3 )R C3 , -N(R C3 )C(=O)OR C3 , -N(R C3 )C(=O)N(R C3 )2, -N(R C3 )C(=NR C3 )N(R C3 )2, -N(R C3 )S(=O)2R C3 , -N(R C3 )S(=O)2OR C3 , -N(R C3)S(=O)2N(R C3 )2, -SC(=O)R C3 , -SC(=O)OR C3 , -SC(=O)SR C3 , -SC(=O)N(R C3 )2, -S(=O)2R C3 , -S(=O)2OR C3 , or -S(=O)2N(R C3 )2, and 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 are compounds of formula II: [ka] or a pharmaceutically acceptable salt thereof, 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 5 Provided that there is no R X Halo, -OH, -ORQ1 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 is independently a halogen, -NO2, -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)2R GA , -S(=O)2OR GA , -OS(=O)2R GA , -S(=O)2N(R GA )2, -N(R GA )S(=O)2R 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, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -N(R A1 )2, -SR A1 , -C(=O)R A1 , -C(=O)OR A1 , -C(=O)SR A1 , -C(=O)N(R A1 )2, -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)N(R A1 )2, -OC(=O)SRA1 , -OS(=O)2R A1 , -OS(=O)2OR A1 , -OS(=O)2N(R A1 )2, -N(R A1 )C(=O)R A1 , -N(R A1 )C(=NR A1 )R A1 , -N(R A1 )C(=O)OR A1 , -N(R A1 )C(=O)N(R A1 )2, -N(R A1 )C(=NR A1 )N(R A1 )2, -N(R A1 )S(=O)2R A1 , -N(R A1 )S(=O)2OR A1 , -N(R A1 )S(=O)2N(R A1 )2, -SC(=O)R A1 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -S(=O)2R A1 , -S(=O)2OR A1 , or -S(=O)2N(R A1 )2, and 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 6bare each independently selected from the group consisting of hydrogen, halogen, cyano, —NO, —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, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR C3 , -N(R C3 )2, -SR C3 , -C(=O)R C3 , -C(=O)OR C3 , -C(=O)SR C3 , -C(=O)N(R C3 )2, -OC(=O)R C3 , -OC(=O)OR C3 , -OC(=O)N(R C3 )2, -OC(=O)SR C3 , -OS(=O)2R C3 , -OS(=O)2OR C3 , -OS(=O)2N(R C3 )2, -N(R C3 )C(=O)R C3 , -N(R C3 )C(=NR C3 )R C3 , -N(R C3 )C(=O)OR C3 , -N(R C3 )C(=O)N(R C3 )2, -N(R C3 )C(=NR C3 )N(R C3 )2, -N(R C3 )S(=O)2R C3 , -N(R C3 )S(=O)2OR C3 , -N(R C3)S(=O)2N(R C3 )2, -SC(=O)R C3 , -SC(=O)OR C3 , -SC(=O)SR C3 , -SC(=O)N(R C3 )2, -S(=O)2R C3 , -S(=O)2OR C3 , or -S(=O)2N(R C3 )2, and 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; R 18 is substituted or unsubstituted alkyl; n is 0, 1, 2, or 3, but However, R 5 is hydrogen, R 18 is not -CH3.

[0091] In some embodiments, the compound of Formula II is a compound of Formula IIIa or IIIb: [ka] or a pharmaceutically acceptable salt thereof.

[0092] In some embodiments, provided herein are compounds of formula V: [ka] or a pharmaceutically acceptable salt thereof, 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 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 is independently a halogen, -NO2, -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)2R GA , -S(=O)2OR GA , -OS(=O)2R GA , -S(=O)2N(R GA )2, -N(R GA )S(=O)2R 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, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -N(R A1)2, -SR A1 , -C(=O)R A1 , -C(=O)OR A1 , -C(=O)SR A1 , -C(=O)N(R A1 )2, -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)N(R A1 )2, -OC(=O)SR A1 , -OS(=O)2R A1 , -OS(=O)2OR A1 , -OS(=O)2N(R A1 )2, -N(R A1 )C(=O)R A1 , -N(R A1 )C(=NR A1 )R A1 , -N(R A1 )C(=O)OR A1 , -N(R A1 )C(=O)N(R A1 )2, -N(R A1 )C(=NR A1 )N(R A1 )2, -N(R A1 )S(=O)2R A1 , -N(R A1 )S(=O)2OR A1 , -N(R A1 )S(=O)2N(R A1 )2, -SC(=O)R A1 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -S(=O)2R A1 , -S(=O)2OR A1 , or -S(=O)2N(R A1 )2, and 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 are each independently selected from the group consisting of hydrogen, halogen, cyano, —NO, —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, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR C3 , -N(R C3 )2, -SR C3 , -C(=O)R C3 , -C(=O)OR C3 , -C(=O)SR C3 , -C(=O)N(R C3 )2, -OC(=O)R C3 , -OC(=O)OR C3 , -OC(=O)N(R C3 )2, -OC(=O)SR C3 , -OS(=O)2R C3 , -OS(=O)2OR C3 , -OS(=O)2N(R C3 )2, -N(R C3 )C(=O)R C3 , -N(R C3 )C(=NR C3 )R C3 , -N(R C3 )C(=O)OR C3, -N(R C3 )C(=O)N(R C3 )2, -N(R C3 )C(=NR C3 )N(R C3 )2, -N(R C3 )S(=O)2R C3 , -N(R C3 )S(=O)2OR C3 , -N(R C3 )S(=O)2N(R C3 )2, -SC(=O)R C3 , -SC(=O)OR C3 , -SC(=O)SR C3 , -SC(=O)N(R C3 )2, -S(=O)2R C3 , -S(=O)2OR C3 , or -S(=O)2N(R C3 )2, and 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.

[0093] In some embodiments, provided herein are compounds of formula VIa or VIb: [ka] or a pharmaceutically acceptable salt thereof, 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 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 is independently a halogen, -NO2, -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)2RGA , -S(=O)2OR GA , -OS(=O)2R GA , -S(=O)2N(R GA )2, -N(R GA )S(=O)2R 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, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -N(R A1 )2, -SR A1 , -C(=O)R A1 , -C(=O)OR A1 , -C(=O)SRA1 , -C(=O)N(R A1 )2, -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)N(R A1 )2, -OC(=O)SR A1 , -OS(=O)2R A1 , -OS(=O)2OR A1 , -OS(=O)2N(R A1 )2, -N(R A1 )C(=O)R A1 , -N(R A1 )C(=NR A1 )R A1 , -N(R A1 )C(=O)OR A1 , -N(R A1 )C(=O)N(R A1 )2, -N(R A1 )C(=NR A1 )N(R A1 )2, -N(R A1 )S(=O)2R A1 , -N(R A1 )S(=O)2OR A1 , -N(R A1 )S(=O)2N(R A1 )2, -SC(=O)R A1 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -S(=O)2R A1 , -S(=O)2OR A1 , or -S(=O)2N(R A1 )2, and 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 are each independently selected from the group consisting of hydrogen, halogen, cyano, —NO, —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, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR C3 , -N(R C3 )2, -SR C3 , -C(=O)R C3 , -C(=O)OR C3 , -C(=O)SR C3 , -C(=O)N(R C3 )2, -OC(=O)R C3 , -OC(=O)OR C3 , -OC(=O)N(R C3 )2, -OC(=O)SR C3 , -OS(=O)2R C3 , -OS(=O)2OR C3 , -OS(=O)2N(R C3 )2, -N(R C3 )C(=O)R C3 , -N(R C3 )C(=NR C3 )R C3 , -N(RC3 )C(=O)OR C3 , -N(R C3 )C(=O)N(R C3 )2, -N(R C3 )C(=NR C3 )N(R C3 )2, -N(R C3 )S(=O)2R C3 , -N(R C3 )S(=O)2OR C3 , -N(R C3 )S(=O)2N(R C3 )2, -SC(=O)R C3 , -SC(=O)OR C3 , -SC(=O)SR C3 , -SC(=O)N(R C3 )2, -S(=O)2R C3 , -S(=O)2OR C3 , or -S(=O)2N(R C3 )2, and 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; r is 2 or 3; p is 2 or 3; n is 0, 1, 2, or 3.

[0094] In some embodiments, provided herein are compounds of formula VII: [ka] or a pharmaceutically acceptable salt thereof, 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 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 is independently a halogen, -NO2, -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)2R GA , -S(=O)2OR GA , -OS(=O)2R GA , -S(=O)2N(R GA )2, -N(R GA )S(=O)2R 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 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, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -N(R A1 )2, -SR A1, -C(=O)R A1 , -C(=O)OR A1 , -C(=O)SR A1 , -C(=O)N(R A1 )2, -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)N(R A1 )2, -OC(=O)SR A1 , -OS(=O)2R A1 , -OS(=O)2OR A1 , -OS(=O)2N(R A1 )2, -N(R A1 )C(=O)R A1 , -N(R A1 )C(=NR A1 )R A1 , -N(R A1 )C(=O)OR A1 , -N(R A1 )C(=O)N(R A1 )2, -N(R A1 )C(=NR A1 )N(R A1 )2, -N(R A1 )S(=O)2R A1 , -N(R A1 )S(=O)2OR A1 , -N(R A1 )S(=O)2N(R A1 )2, -SC(=O)R A1 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -S(=O)2R A1 , -S(=O)2OR A1 , or -S(=O)2N(R A1 )2, and 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 are each independently selected from the group consisting of hydrogen, halogen, cyano, —NO, —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, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR C3 , -N(R C3 )2, -SR C3 , -C(=O)R C3 , -C(=O)OR C3 , -C(=O)SR C3 , -C(=O)N(R C3 )2, -OC(=O)R C3 , -OC(=O)OR C3 , -OC(=O)N(R C3 )2, -OC(=O)SR C3 , -OS(=O)2R C3 , -OS(=O)2OR C3 , -OS(=O)2N(R C3 )2, -N(R C3 )C(=O)R C3 , -N(R C3 )C(=NR C3 )R C3 , -N(RC3 )C(=O)OR C3 , -N(R C3 )C(=O)N(R C3 )2, -N(R C3 )C(=NR C3 )N(R C3 )2, -N(R C3 )S(=O)2R C3 , -N(R C3 )S(=O)2OR C3 , -N(R C3 )S(=O)2N(R C3 )2, -SC(=O)R C3 , -SC(=O)OR C3 , -SC(=O)SR C3 , -SC(=O)N(R C3 )2, -S(=O)2R C3 , -S(=O)2OR C3 , or -S(=O)2N(R C3 )2, and 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.

[0095] In some embodiments, provided herein are compounds of formula VIII: [ka] or a pharmaceutically acceptable salt thereof, 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 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 is independently a halogen, -NO2, -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)2R GA , -S(=O)2OR GA , -OS(=O)2R GA , -S(=O)2N(R GA )2, -N(R GA )S(=O)2R 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, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -N(R A1 )2, -SR A1 , -C(=O)R A1, -C(=O)OR A1 , -C(=O)SR A1 , -C(=O)N(R A1 )2, -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)N(R A1 )2, -OC(=O)SR A1 , -OS(=O)2R A1 , -OS(=O)2OR A1 , -OS(=O)2N(R A1 )2, -N(R A1 )C(=O)R A1 , -N(R A1 )C(=NR A1 )R A1 , -N(R A1 )C(=O)OR A1 , -N(R A1 )C(=O)N(R A1 )2, -N(R A1 )C(=NR A1 )N(R A1 )2, -N(R A1 )S(=O)2R A1 , -N(R A1 )S(=O)2OR A1 , -N(R A1 )S(=O)2N(R A1 )2, -SC(=O)R A1 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -S(=O)2R A1 , -S(=O)2OR A1 , or -S(=O)2N(R A1 )2, and 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 are each independently selected from the group consisting of hydrogen, halogen, cyano, —NO, —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, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR C3 , -N(R C3 )2, -SR C3 , -C(=O)R C3 , -C(=O)OR C3 , -C(=O)SR C3 , -C(=O)N(R C3 )2, -OC(=O)R C3 , -OC(=O)OR C3 , -OC(=O)N(R C3 )2, -OC(=O)SR C3 , -OS(=O)2R C3 , -OS(=O)2OR C3 , -OS(=O)2N(R C3 )2, -N(R C3 )C(=O)R C3 , -N(R C3 )C(=NR C3 )R C3 , -N(RC3 )C(=O)OR C3 , -N(R C3 )C(=O)N(R C3 )2, -N(R C3 )C(=NR C3 )N(R C3 )2, -N(R C3 )S(=O)2R C3 , -N(R C3 )S(=O)2OR C3 , -N(R C3 )S(=O)2N(R C3 )2, -SC(=O)R C3 , -SC(=O)OR C3 , -SC(=O)SR C3 , -SC(=O)N(R C3 )2, -S(=O)2R C3 , -S(=O)2OR C3 , or -S(=O)2N(R C3 )2, and 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; s is 2, n is 0, 1, 2, or 3.

[0096] In some embodiments, provided herein are compounds of formula IX: [ka] or a pharmaceutically acceptable salt thereof, 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 is independently a halogen, -NO2, -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)2R GA , -S(=O)2OR GA , -OS(=O)2R GA , -S(=O)2N(R GA )2, -N(R GA )S(=O)2R 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, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -N(R A1 )2, -SR A1 , -C(=O)R A1 , -C(=O)OR A1 , -C(=O)SR A1 , -C(=O)N(R A1 )2, -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)N(R A1 )2, -OC(=O)SRA1 , -OS(=O)2R A1 , -OS(=O)2OR A1 , -OS(=O)2N(R A1 )2, -N(R A1 )C(=O)R A1 , -N(R A1 )C(=NR A1 )R A1 , -N(R A1 )C(=O)OR A1 , -N(R A1 )C(=O)N(R A1 )2, -N(R A1 )C(=NR A1 )N(R A1 )2, -N(R A1 )S(=O)2R A1 , -N(R A1 )S(=O)2OR A1 , -N(R A1 )S(=O)2N(R A1 )2, -SC(=O)R A1 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -S(=O)2R A1 , -S(=O)2OR A1 , or -S(=O)2N(R A1 )2, and 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, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR C3 , -N(R C3 )2, -SR C3 , -C(=O)R C3 , -C(=O)OR C3 , -C(=O)SR C3 , -C(=O)N(R C3 )2, -OC(=O)R C3 , -OC(=O)OR C3 , -OC(=O)N(R C3 )2, -OC(=O)SR C3 , -OS(=O)2R C3 , -OS(=O)2OR C3 , -OS(=O)2N(R C3 )2, -N(R C3 )C(=O)R C3 , -N(R C3 )C(=NR C3 )R C3 , -N(R C3 )C(=O)OR C3 , -N(R C3 )C(=O)N(R C3 )2, -N(R C3 )C(=NR C3 )N(R C3 )2, -N(R C3 )S(=O)2R C3 , -N(R C3 )S(=O)2OR C3 , -N(R C3 )S(=O)2N(R C3 )2, -SC(=O)R C3 , -SC(=O)OR C3 , -SC(=O)SR C3 , -SC(=O)N(R C3 )2, -S(=O)2R C3 , -S(=O)2OR C3 , or -S(=O)2N(R C3 )2, and RC3 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.

[0097] In some embodiments, provided herein are compounds of formula X: [ka] or a pharmaceutically acceptable salt thereof, 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 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 is independently a halogen, -NO2, -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)2R GA , -S(=O)2OR GA , -OS(=O)2R GA , -S(=O)2N(R GA )2, -N(R GA )S(=O)2R 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 3~6carbosilyl, 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, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -N(R A1 )2, -SR A1 , -C(=O)R A1 , -C(=O)OR A1 , -C(=O)SR A1 , -C(=O)N(R A1 )2, -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)N(R A1 )2, -OC(=O)SR A1 , -OS(=O)2R A1 , -OS(=O)2OR A1 , -OS(=O)2N(R A1 )2, -N(R A1 )C(=O)R A1 , -N(R A1 )C(=NR A1 )R A1 , -N(R A1 )C(=O)OR A1 , -N(R A1 )C(=O)N(R A1 )2, -N(RA1 )C(=NR A1 )N(R A1 )2, -N(R A1 )S(=O)2R A1 , -N(R A1 )S(=O)2OR A1 , -N(R A1 )S(=O)2N(R A1 )2, -SC(=O)R A1 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -S(=O)2R A1 , -S(=O)2OR A1 , or -S(=O)2N(R A1 )2, and 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 are each independently selected from the group consisting of hydrogen, halogen, cyano, —NO, —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 16beach independently represents hydrogen, halogen, —CN, —NO, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR C3 , -N(R C3 )2, -SR C3 , -C(=O)R C3 , -C(=O)OR C3 , -C(=O)SR C3 , -C(=O)N(R C3 )2, -OC(=O)R C3 , -OC(=O)OR C3 , -OC(=O)N(R C3 )2, -OC(=O)SR C3 , -OS(=O)2R C3 , -OS(=O)2OR C3 , -OS(=O)2N(R C3 )2, -N(R C3 )C(=O)R C3 , -N(R C3 )C(=NR C3 )R C3 , -N(R C3 )C(=O)OR C3 , -N(R C3 )C(=O)N(R C3 )2, -N(R C3 )C(=NR C3 )N(R C3 )2, -N(R C3 )S(=O)2R C3 , -N(R C3 )S(=O)2OR C3 , -N(R C3 )S(=O)2N(R C3 )2, -SC(=O)R C3 , -SC(=O)OR C3 , -SC(=O)SR C3 , -SC(=O)N(R C3 )2, -S(=O)2R C3 , -S(=O)2OR C3 , or -S(=O)2N(R C3 )2, and 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 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 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, or substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0099] In some embodiments, R 1a and R 1beach 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, or substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0100] In some embodiments, R 1a and R 1b each independently represents hydrogen, unsubstituted C 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 R 1b each independently represents hydrogen or a substituted or unsubstituted C 1~6 It is 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, or 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 A1 Each instance of is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0106] In some embodiments, R 2a and R 2b each independently represents hydrogen, unsubstituted C 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 4beach 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, or 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, or substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0111] In some embodiments, R 4a and R 4b each independently represents hydrogen, unsubstituted C 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 R4b are both hydrogen.

[0114] R 7a and R 7b base In some embodiments, R 7a and R 7b 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, or 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, or substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0116] In some embodiments, R 7a and R 7b each independently represents hydrogen, unsubstituted C 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, or 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, R11a and R 11b each independently represents hydrogen, unsubstituted C 1~6 Alkyl, C 1~3 Haloalkyl, or -OR A1 and 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, or 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, or substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0126] In some embodiments, R 12a and R 12b each independently represents hydrogen, unsubstituted C 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 are each 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 are 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 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 a substituted or unsubstituted alkyl.

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

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

[0149] In some embodiments, R 3 is methyl, ethyl, propyl, butyl, -CH2OCH3, or -CH2OCH2CH3.

[0150] In some embodiments, R3 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 a substituted or unsubstituted alkyl.

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

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

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

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

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

[0162] In some embodiments, R 19 is -CH3.

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

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

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

[0169] In some embodiments, R Y is methyl.

[0170] In some embodiments, R X is -OH and RY is the unsubstituted C 1~3 It is 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, form a substituted or unsubstituted C 3~7 Carbocyclic ring, or substituted or unsubstituted C 3~7 A heterocyclic ring can be formed.

[0174] In some embodiments, R Y and R X taken 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 the unsubstituted C 1~6 It is 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, -NO2, -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)2R GA , -S(=O)2OR GA , -OS(=O)2R GA , -S(=O)2N(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, a halogen, -CN, -OR GA , -N(R GA )2, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 3~6 carbosilyl, R GA 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 C1~3 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 alkyl.

[0182] In some embodiments, R 22 is located at the 4-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 a methyl in the alpha or beta configuration.

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

[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 a hydrogen in the alpha configuration.

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

[0205] In some embodiments, the compound of Formula I is a compound of Formula Ia: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0206] In some embodiments, the compound of formula I is a compound of formula Ib: [ka] or a pharmaceutically acceptable salt thereof, wherein 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 pharmaceutically acceptable salt thereof, wherein 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 pharmaceutically acceptable salt thereof, wherein 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 pharmaceutically acceptable salt thereof, wherein 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 pharmaceutically acceptable salt thereof, wherein 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 pharmaceutically acceptable salt thereof, wherein 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 pharmaceutically acceptable salt thereof, wherein 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 pharmaceutically acceptable salt thereof, wherein 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 pharmaceutically 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 pharmaceutically acceptable salts of 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 pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the compound of the invention is provided in the pharmaceutical composition in an effective amount. In certain embodiments, the compound of the invention is provided in a therapeutically effective amount.

[0218] The compounds of the invention described herein may, in certain embodiments, A It acts as a regulator, e.g., GABA A GABA receptors act 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 GABA 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 pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0220] In another aspect, a method for treating 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 seizure 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. In certain embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In certain embodiments, the compound is administered orally. In certain embodiments, the compound is administered chronically. In certain embodiments, the compound is administered continuously, for example, by continuous intravenous infusion.

[0221] Exemplary compounds of the invention can be synthesized from the following known starting materials using methods known to those skilled in the art or certain references: In one aspect, provided herein are pharmaceutically acceptable salts of the compounds described herein (e.g., compounds of Formula I, 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 may 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, and the nitrogen may be, for example, 15 In other embodiments, specific isotopes (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 the element occupying a particular site in the 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 pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the compound of the invention is provided in the pharmaceutical composition in an effective amount. In certain embodiments, the compound of the 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 can be administered by a variety of routes, including, but not limited to, oral (enteral), parenteral (by injection), rectal, transdermal, intradermal, intrathecal, subcutaneous (SC), intravenous (IV), intramuscular (IM), and intranasal administration.

[0226] Generally, 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 onset of CNS disorders, the compounds provided herein are typically administered at the dosage levels described above to subjects at risk of developing the condition under the advice and supervision of a physician. 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 a compound or a pharmaceutical composition thereof for an extended period of time, such as 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 be further delivered using various administration methods.For example, in certain embodiments, the pharmaceutical composition can be given as a bolus, for example, to raise the concentration of the compound in the blood to an effective level.The placement of the bolus dose depends on the systemic level of the active ingredient desired 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 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 can be administered as a continuous infusion, for example, by infusion, to provide maintenance of the steady-state concentration of the active ingredient in the subject's body.In addition, in still other embodiments, the pharmaceutical composition can be initially administered as a bolus dose, followed by continuous infusion.

[0230] Compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. However, more commonly, compositions are presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as single dosages for human subjects and other mammals, each containing a predetermined amount of active agent calculated to produce a desired therapeutic effect in association with a suitable pharmaceutical excipient. 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 typically 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] A typical oral administration regimen is 1 to 5 times, particularly 2 to 4 times, typically 3 times per day. Using these administration patterns, each dose provides about 0.01 to about 20 mg / kg of the compound provided by the present invention, with preferred doses being about 0.1 to about 10 mg / kg, particularly about 1 to about 5 mg / kg.

[0232] The transdermal dose is generally selected to provide similar or lower blood levels than those achieved using an injection dose, and is generally 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. Preloading boluses of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve adequate steady-state levels. The maximum total dose is 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, flavors, etc. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth, or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent 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 vehicles known in the art. As noted 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 an ointment, the active ingredient is typically combined with either a paraffinic or water-miscible ointment base.Alternatively, the active ingredient may be formulated in a cream, for example, with an oil-in-water cream base.Such transdermal formulations are well known in the art and generally contain additional ingredients to enhance the skin penetration of the active ingredient 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. Accordingly, 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-described 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 this invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0240] The present invention also relates to pharmaceutically acceptable acid addition salts of the compounds of the present invention. Acids that can be used to prepare pharmaceutically acceptable salts are those that form non-toxic acid addition salts, i.e., salts containing 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 pharmaceutically acceptable excipient, eg, a composition suitable for injection, such as intravenous (IV) administration.

[0242] Pharmaceutically acceptable excipients include any diluents or other liquid vehicles, dispersing or suspending aids, surfactants, isotonic agents, preservatives, lubricants, etc., that are suitable for the particular dosage form desired, e.g., injection. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 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, e.g., 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 before 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 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 administration. The term "unit dosage form" refers to physically discrete units suitable as single dosages for human subjects and other mammals, each unit containing a predetermined amount of active agent 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 serve to 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 a compound 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 pharmaceutically acceptable salt thereof) can be administered in combination with an additional agent or therapy. The subject to whom the compounds disclosed herein are administered can 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 therapy can be administered simultaneously. In other embodiments, two or more drugs in combination therapy are administered separately. For example, the administration of the first drug (or drug combination) can be carried out minutes, hours, days, or weeks before the administration of the second drug (or drug combination). 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, or 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 that two or more drugs used in combination therapy 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 combination, using different sequences of the constituent drugs. For example, when drug X and drug Y are used in combination, they can be administered one or more times sequentially in any combination, for example, in the order of XYX, XXY, YXY, YYX, XXYY, etc. Exemplary additional drugs 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 pharmaceutically 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 pharmaceutically acceptable salt thereof) is administered in combination with NERI(s). Exemplary NERIs include, but are not limited to, atomoxetine (Strattera), reboxetine (Edronax, Vestra), bupropion (Wellbutrin, Zyban), duloxetine, desipramine (Norpramin), amedalin (UK-3540-1), daredalin (UK-3557-15), edivoxetine (LY-2216684), esreboxetine, lortalamine (LM-1404), nisoxetine (LY-94,939), talopram (taslopram) (Lu 3-010), talspram (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 pharmaceutically 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 composition comprising a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, or a pharmaceutically acceptable salt thereof) may be administered in combination with a cannabinoid(s). Exemplary cannabinoids include, but are not limited to, cannabinoid (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 pharmaceutically 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, licostinel, 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 pharmaceutically acceptable salt thereof) is administered in combination with GABA receptor agonist(s). GABA receptor agonists are a class of drugs that are agonists for one or more 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, prazepam, tofizoam, rilmazafone, lorazepam, temazepam, oxazepam, fludiazepam, chlordiazepine, and the like. Oxide, cloxazolam, flutoprazepam, alprazolam, estazolam, bromazepam, flurazepam, potassium clorazepate, haloxazolam, ethyl loflazepate, quazepam, clonazepam, mexazolam, etizolam, 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 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 pharmaceutically acceptable salt thereof) is administered in combination with a cholinesterase inhibitor(s). Generally, cholinergics are compounds that mimic the actions 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 pharmaceutically 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, the 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 pharmaceutically 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 pharmaceutically 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] Use and Treatment In certain embodiments, a compound described herein, e.g., a compound of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X, is administered to a subject (e.g., a subject in need of treatment for a CNS-related disorder (e.g., a sleep disorder, a mood disorder (e.g., depression, schizophrenia spectrum disorder, seizure 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). It is envisioned that the compounds will be useful as therapeutic agents for doing so in subjects 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 disorders (e.g., mild depression), bipolar disorder (e.g., I and / or II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), and the like. ), 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, Symptoms of tinnitus include, but are not limited to, neurological disorders, autism spectrum disorders (ASDs) (e.g., autism, synaptopathy, monogenic causes of autism such as Rett syndrome, Fragile X syndrome, Angelman syndrome), pain (e.g., neuropathic pain, injury-related pain syndrome, acute pain, chronic pain), traumatic brain injury (TBI), vascular disease (e.g., stroke, ischemia, vascular malformation), 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 seizure 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 a compound of the present invention with another pharmacologically active agent is provided. The compounds provided herein can be administered as the sole active agent or in combination with other agents. Coadministration 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 levels 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 for 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, there is provided a method for treating or preventing a mood disorder in a subject, 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 aspect, there is provided a method for treating cognitive enhancement or memory impairment by administering a therapeutically effective amount of the compound of the present invention to a subject.In certain embodiments, the disorder is Alzheimer's disease.In certain embodiments, the disorder is Rett syndrome.

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

[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 (in which an infectious agent triggers 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 to the subject chronically, hi certain embodiments, the compound is administered to the subject orally, subcutaneously, intramuscularly, or intravenously.

[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 an imbalance in the body's hormone production, which is directly related to the brain. Neuroendocrine disorders involve interactions between the nervous system and the endocrine system. Because the hypothalamus and pituitary gland are two areas of the brain that regulate hormone production, damage to the hypothalamus or pituitary gland, for example, due to traumatic brain injury, can affect hormone production and other neuroendocrine functions of the brain. In some embodiments, the neuroendocrine disorder or dysfunction is associated with a women's health disorder or condition (e.g., a women's health disorder or condition described herein). In some embodiments, the neuroendocrine disorder or dysfunction associated with a women's health disorder or condition is polycystic ovary 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 the progressive loss of neuronal structure or function, or the death of neurons.Neurodegenerative diseases and disorders include Alzheimer's disease (including symptoms associated with mild, moderate, or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic and ischemic injuries; ataxia and convulsions (including the treatment and prevention of seizures caused by schizoaffective disorder or drugs used to treat schizophrenia); benign amnesia; cerebral edema; cerebellar ataxia, including McLeod neurospinal cell syndrome (MLS); closed head injury; coma; contusion (e.g., spinal cord injury and head injury); dementia, including multi-infarct dementia and senile dementia; disorders of consciousness; and Down's syndrome. Drug-induced or medication-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; movement disorders including akinesia and akinesia (rigid) syndrome (basal ganglia calcification, corticobasal degeneration, multiple system atrophy, parkinsonism-ALS dementia complex, Parkinson's disease, postencephalitic parkinsonism) muscle spasms and disorders related to 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 (including tics such as complex tics, simple tics, and symptomatic tics), myoclonus (including generalized myoclonus and focal cycloclonucleus), tremors (such as rest tremor, postural tremor, and intention tremor) and dystonias (axial dystonia, dystonic writer's cramp, hemiplegic dystonia) , paroxysmal dystonia, and focal dystonia, such as blepharospasm, oromandibular dystonia, and spasmodic dystonia and torticollis; eye damage, neurological damage including retinopathy or ocular macular degeneration; stroke, thrombotic 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. Methods for treating or preventing neurodegenerative diseases also include 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, treatment-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 have trouble sleeping, lose weight, and are generally agitated and irritable. Clinical depression affects an individual's emotions, thoughts, and behaviors and can lead to a variety of emotional and physical problems. People with clinical depression may have trouble performing daily activities and feel that life is not worth living.

[0280] Perinatal depression refers to depression during pregnancy. Symptoms include irritability, crying, restlessness, sleep disturbances, extreme fatigue (emotional and / or physical), changes in appetite, difficulty concentrating, increased anxiety and / or worry, 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 described herein). In some embodiments, the PND is a treatment-refractory depression (e.g., a treatment-refractory depression described herein).

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

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

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

[0285] Psychotic major depression (PMD) or psychotic depression refers to major depressive episodes, 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. Individuals may become silent and stuporous, immobile, or exhibit aimless 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 a condition related to unipolar depression that manifests the same physical and cognitive problems, but which tends to be less severe and last longer (e.g., at least 2 years).

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

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

[0291] Recurrent brief depression (RBD) refers to a condition in which an individual has depressive episodes about once a month, each 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, including emotional highs (mania or hypomania) and lows (depression). During manic periods, individuals may feel or act unusually happy, energetic, or irritable. They often make poorly considered decisions with little consideration for the consequences. The need for sleep is usually reduced. During depressive periods, individuals may cry, make less eye contact with others, and have a negative outlook on life. The risk of suicide for individuals with the disorder is high, exceeding 6% over a 20-year period, and self-harm occurs in 30-40% of cases. 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 condition in which an individual has received treatment for depression but their 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 their symptoms, but then return. Treatment-resistant depression occurs in patients with depression that is resistant to standard pharmacological treatments, including tricyclic antidepressants, MAOIs, SSRIs, and dual and triple uptake inhibitors and / or anxiolytics, as well as non-pharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagus nerve stimulation, and / or transcranial magnetic stimulation).

[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 an abnormal preoccupation with suicide. Suicidal ideation can range from momentary thoughts to extensive thinking, detailed plans, role-playing, and aborted attempts. Symptoms may include talking about suicide, obtaining the means to attempt it, withdrawing from social contacts, becoming preoccupied with death, feeling trapped or hopeless in a situation, increasing alcohol or drug use, engaging in risky or self-destructive behavior, 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, despair, pessimism, feelings of 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, lack 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.The symptoms of depression and their alleviation can be confirmed by a doctor or psychologist (for example, 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. The reduction in the HAM-D total score can occur within 4, 3, 2, or 1 day, or within 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, or 8 hours. The therapeutic effect can be evaluated over a specific treatment period. For example, therapeutic efficacy can be determined by a decrease from baseline in HAM-D total score after administration of 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, 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., before 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 before 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 to 10 (e.g., less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 1.8). In some embodiments, the HAM-D total score after treatment with a compound described herein, 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 baseline to 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 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), of at least 10, 15, or 20 points compared to baseline HAM-D total score.

[0302] In some embodiments, the method for treating a depressive disorder, e.g., 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., 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., 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, methods for treating depressive disorders, e.g., major depressive disorder, provide 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, methods for treating depressive disorders, e.g., major depressive disorder, provide 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 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., once daily treatment for 14 days 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 subject's HAM-D total score before 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 before 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 before 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, compared to the 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, compared to the baseline HAM-D total score is at least 15 (e.g., at least 17). In some embodiments, the HAM-D total score associated with 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 a number in the range of 6 to 8 or less. 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, involves a HAM-D total score of 7 or less.

[0303] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a reduction in the Clinical Global Impression (CGI) score) 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 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 the MADRS score from baseline at the end of the treatment period (e.g., 14 days after administration).

[0305] The effectiveness of treatment for major depressive disorder can be determined by a reduction in the subject's Montgomery-Asberg Depression Rating Scale (MADRS) score. For example, the MADRS score may decrease within 4, 3, 2, or 1 day, or within 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, or 8 hours. The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item diagnostic questionnaire (addressing apparent sadness, reported sadness, inner tension, decreased sleep, decreased appetite, difficulty concentrating, fatigue, loss of sensation, pessimistic thoughts, and suicidal ideation) 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, or 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, 24, 20, 16, 12, 10, 8 hours.

[0308] Anxiety disorders Provided herein are methods for treating anxiety disorders (e.g., generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, phobias, post-traumatic stress disorder). Anxiety disorder is an umbrella term that 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 suffering 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 affecting the elderly.

[0310] In panic disorder, individuals experience brief attacks of intense fear and anxiety, often characterized by trembling, shaking, confusion, dizziness, nausea, and difficulty breathing. These panic attacks are defined by the APA as a sudden onset of fear or discomfort that peaks in less than 10 minutes, but can last for several hours and may be triggered by stress, fear, or exercise. However, the specific cause is not always clear. In addition to recurring unexpected panic attacks, a diagnosis of panic disorder also requires the presence of chronic consequences, either worry about the potential impact of the attacks, ongoing fear of future attacks, or significant changes in behavior related to the attacks. Therefore, individuals with panic disorder experience symptoms outside of specific panic episodes. Often, normal changes in heart rate are noticed by panic sufferers, leading them to believe something is wrong with their heart or that another panic attack is imminent. In some cases, heightened awareness of bodily functions (hypervigilance) occurs during panic attacks, and the perceived physiological changes are interpreted as potentially life-threatening illness (i.e., extreme hypochondria).

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

[0312] The single largest category of anxiety disorders 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 prolonged (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 are methods for treating conditions or disorders related to women's health, including, but 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 ovary syndrome (PCOS)), other disorders and conditions, and issues related to women's overall health and wellness (e.g., menopause).

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

[0316] Premenstrual syndrome (PMS) refers to the physical and emotional symptoms that occur one to two weeks before a woman's 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, depressed mood or feelings of hopelessness, noticeable anger, increased interpersonal conflict, tension and anxiety, irritability, decreased interest in usual activities, difficulty concentrating, fatigue, appetite changes, feeling out of control or overwhelming, sleep disturbances, and 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 occur during the first 28 weeks of pregnancy.

[0321] Infertility and related disorders include uterine fibroids, polycystic ovary 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 group of symptoms caused by elevated levels of male hormones in women. Most women with PCOS develop many small cysts on their ovaries. Symptoms of PCOS include irregular or absent menstrual periods, heavy menstrual periods, excess body and facial hair, acne, pelvic pain, difficulty conceiving, 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 the end of a woman's menstrual cycle, occurring 12 months after her last menstrual period. Menopause typically occurs in women in their 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, a type of induced menopause resulting from events such as surgery (e.g., hysterectomy, oophorectomy, cancer). This can be 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 pharmaceutically acceptable salt, or a pharmaceutically 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 recurrent seizures over time. Types of epilepsy include, but are not limited to, generalized epilepsy (e.g., childhood absence epilepsy, juvenile myoclonic epilepsy, epilepsy with grand mal seizures during awakening), West syndrome, Lennox-Gastaut syndrome, partial epilepsy (e.g., temporal lobe epilepsy, frontal lobe epilepsy, and benign focal epilepsy of childhood).

[0328] Epilepsy The compounds and methods described herein can be used to treat or prevent epileptogenesis, a gradual 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, and super-refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus, generalized periodic epileptic-like discharges, and periodic lateralized epileptic-like discharges. Convulsive status epilepticus is characterized by the presence of convulsive status epilepticus episodes 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 persistent status epilepticus episodes despite treatment with first-line therapy, and second-line therapy is administered. Refractory status epilepticus is characterized by persistent seizures of status epilepticus despite treatment with first-line and second-line therapies, typically with general anesthetics. Super-refractory status epilepticus is characterized by persistent seizures of status epilepticus despite treatment with first-line and second-line therapies and general anesthetics for more than 24 hours.

[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 pharmaceutically acceptable salt thereof, or a pharmaceutically 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, very 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 the entire brain, while partial seizures are caused (at least initially) by electrical impulses in a smaller part of the brain. The part of the brain that generates the seizure is sometimes called the focus.

[0335] There are six types of generalized seizures. The most common, dramatic, and therefore best known is the generalized convulsion, also known as a grand mal seizure. In this type of seizure, the patient 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 deep sleep (the "postictal" or postictal phase). Injuries and accidents, such as tongue biting and urinary incontinence, can occur during a grand mal seizure.

[0336] Absence seizures cause a brief loss of consciousness (only a few seconds) with few or no symptoms. Affected individuals, most often children, typically stop their activities and stare blankly. 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 resulting in a fall.

[0341] Seizures as used herein can include epileptic seizures; acute repetitive seizures; cluster seizures; consecutive seizures; discontinuous seizures; prolonged seizures; recurrent seizures; status epilepticus seizures, e.g., refractory convulsive status epilepticus, non-convulsive 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; gibberish 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, compounds of Formula I, II, IIIa, IIIb, V, VIa, VIb, VII, VIII, IX, or X can be used to treat cerebellar or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, Parkinsonian tremor, physiologic tremor, psychogenic tremor, or rubral tremor. Tremors include genetic, degenerative, and idiopathic disorders such as Wilson's disease, Parkinson's disease, and essential tremor, respectively; metabolic diseases (e.g., thyroid and parathyroid disease, liver disease, and hypoglycemia); peripheral neuropathies (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, intensified physiologic tremor, essential tremor syndrome (including classic essential tremor, primary orthostatic tremor, and task- and postural-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 may 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, such as tumors, stroke, and diseases (e.g., multiple sclerosis, hereditary degenerative disorders).

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

[0347] Essential tremor, or benign essential tremor, is the most common type of tremor. Essential tremor can be mild and non-progressive or 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 its severity. Symptoms generally progress over time and may be both noticeable 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 may be felt in the thighs and legs, and patients may sway uncontrollably when asked to stand in one place. Patients with essential tremor may experience orthostatic tremor.

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

[0350] Physiologic tremor can occur in normal individuals and is not clinically significant. It can be seen in all voluntary muscle groups. Physiologic tremor can be caused by certain drugs, alcohol withdrawal, or medical conditions including thyroid overactivity and hypoglycemia. Tremor classically has a frequency of approximately 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, posturally, and at will. The tremor is associated with conditions affecting the red nucleus of the midbrain, a 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 symptoms 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 excessive 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, speaking, 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 usually occur suddenly; they are brief, repetitive, but not rhythmic, typically mimic normal behavior, and often occur against a background of normal activity. Tics can be classified as motor or vocal; motor tics are associated with movement, while vocal tics are associated with sound. Tics can be 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 neurosensorimotor 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 lower back and legs. A stiff-legged gait with exaggerated lumbar hyperlordosis is the typical outcome. Characteristic abnormalities in EMG recordings, involving serial motor unit activity of paraaxial muscles, are typically observed. Variants include "stiff limb syndrome," which produces focal stiffness typically affecting the distal legs and feet.

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

[0362] Anesthesia / Sedation Anesthesia is a pharmacologically induced, reversible state of amnesia, analgesia, loss of responsiveness, loss of skeletal muscle reflexes, decreased stress response, or all of these simultaneously. These effects can be obtained from a single drug that provides the correct combination of effects alone, or occasionally with a combination of drugs (e.g., hypnotics, sedatives, paralysis, 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 encompass a range of states of consciousness from minimal sedation (anxiolysis) to general anesthesia.

[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 adequate. Cardiovascular function is usually preserved.

[0367] Deep sedation / analgesia is a drug-induced decrease in consciousness during which the patient is not easily aroused but responds purposefully after repetitive or painful stimuli (rather than 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, even by painful stimuli. The ability to maintain independent ventilation is often impaired, and assistance is often required to maintain a patent airway. Positive pressure ventilation may be required due to decreased spontaneous ventilation or drug-induced depression of neuromuscular function. Cardiovascular function may be impaired.

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

[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. ICU sedation may have a short elimination half-life.

[0371] Procedural sedation and analgesia, also called conscious sedation, is a technique in which sedative 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] Also described herein are methods 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, 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 pharmaceutically acceptable salt thereof).

[0373] In one aspect, provided herein is a method of treating a subject wherein the subject exhibits one or more symptoms of and / or has been diagnosed with a respiratory disorder, the method 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 pharmaceutically acceptable salt thereof).

[0374] In some embodiments, the present 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 pharmaceutically 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 pharmaceutically 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 pharmaceutically acceptable salt thereof) is administered to a subject who is being treated 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 pharmaceutically 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 pharmaceutically acceptable salt thereof) continues after the 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 pharmaceutically 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 pharmaceutically 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 pharmaceutically acceptable salt thereof). In some embodiments, a symptom of a cytokine storm is pulmonary inflammation. In some embodiments, a patient experiencing 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 hypersensitivity, 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 pharmaceutically acceptable salt thereof) to a subject exhibiting symptoms of a respiratory disease results in a reduction in the severity of airway hyperresponsiveness in the subject with a disease associated with a coronavirus, or delays or slows the progression of airway hyperresponsiveness in the subject with a respiratory disease.

[0386] In some embodiments, 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 pharmaceutically 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 pharmaceutically 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 pharmaceutically 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, 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 pharmaceutically 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-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 fibrosis or a fibrotic episode. In 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 the vas deferens (CBAVD), mild lung disease, pulmonary sarcoidosis, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), liver disease, hereditary emphysema, hereditary hemochromatosis, coagulation fibrosis deficiency (e.g., protein C deficiency), hereditary type 1 vasculitis, and pulmonary edema. tumors, lipid processing defects (e.g., familial hypercholesterolemia), type 1 chylomicronemia, abetalipoproteinemia, hemolytic storage diseases (e.g., I-cell disease / pseudo-Hurler), mucopolysaccharidoses, Sandhoff / Tysachs, Crigler-Najjar type II, polyendocrinopathy / hyperinsulinemia, diabetes mellitus, Laron dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG1 or is the result of, and / or associated with, a disease or condition selected from the group consisting of: congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI), neurophysiologic DI, nephrogenic DI, Charcot-Marie-Tooth syndrome, Pelizaeus-Merzbacher disease, neurodegenerative diseases (e.g., Alzheimer's disease), Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, several polyglutamine neurological disorders (e.g., Huntington's), spinal aneurysm type I, spinal and bulbar muscular atrophy, dentatorubral-pallidoluysian dystrophy, and myotonic dystrophy, as well as spongiform encephalopathies (e.g., hereditary Creutzfeldt-Jakob disease) (due to prion protein processing defects), Fabry disease, Straussler-Scheinker syndrome, COPD, dry eye disease, or Sjogren's disease.

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

[0394] In some embodiments, the viral infection is an infection with a virus selected from the group consisting of 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 subjects 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, hi some embodiments, the Staphylococcus aureus is methicillin-resistant Staphylococcus aureus. [Example]

[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 offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and are not to 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. Where typical or suitable process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it will be understood that other process conditions can also be used unless otherwise 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 those 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, numerous protecting groups and their introduction and removal are described in T.W. Greene and P.G.M. Buts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.

[0400] The compounds provided herein can 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 those skilled in the art of organic synthesis. Exemplary chiral columns available for use in the separation / purification of enantiomers / diastereomers provided herein include, but are not limited to, ChiralPak® AD-10, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ, and CHIRALCEL® OK.

[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 1.2 ml / 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-Bu3P)2: bis(tri-tert-butylphosphine)palladium(0), AcCl: acetyl chloride, i-PrMgCl: isopropylmagnesium chloride; TBSCl: tert-butyl(chloro)dimethylsilane, (i-PrO)4Ti: titanium tetraisopropoxide oxide, 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: ethylmagnesium bromide, EtOAc: ethyl acetate, TEA: triethylamine, AlaOH: alanine, Boc: t-butoxycarbonyl. Py: pyridine, TBAF: tetra-n-butylammonium fluoride, THF: tetrahydrofuran, TBS: t-butyldimethylsilyl, TMS: trimethylsilyl, TMSCF3: (trifluoromethyl)trimethylsilane, Ts: p-toluenesulfonyl, Bu: butyl, Ti(OiPr)4: tetraisopropoxytitanium, LAH: lithium aluminum hydride, LDA: lithium diisopropylamide, LiOH.H2O: lithium hydroxide hydrate, MAD: methylaluminum bis(2,6-di-t-butyl-4-methyl) phenoxide), MeCN: acetonitrile, NBS: N-bromosuccinimide, Na2SO4: sodium sulfate, Na2S2O3: 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 poured into saturated aqueous NH4Cl solution (400 mL) at 0° C. and extracted with EtOAc (2 × 200 mL). The combined organic layers were dried over Na2SO4, 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, CDCl3) 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 for 2 h at −78° C., 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 (3×500 mL). The combined organic layers were washed with brine (1500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to give 1.3 (20 g) as an oil which was used as is.

[0406] Synthesis of 1.4 To a solution of 1.3 (20 g) and DME (200 mL) was added Rh(OAc) (204 mg, 0.462 mmol) 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] 1.5 Synthesis 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 poured into HO (200 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with HCl (1 M, 100 mL), saturated NaHCO (100 mL), brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated. 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, CDCl3) δ H2.62(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[M-HO+H] + MS ESI calculated value 315.2 found value 315.2.

[0408] Synthesis of 1.6 To a suspension of PhPEtBr (10.6 g, 28.8 mmol) in anhydrous THF (50 mL) was added t-BuOK (4.84 g, 43.2 mmol) under N at 15 °C. 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 phases were washed with saturated brine (2 × 200 mL), filtered, and concentrated. The residue was purified by flash column chromatography (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, CDCl3) 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 sequentially with EtOH (6.05 mL, 104 mmol, 0.789 g / mL), dropwise NaOH (20.8 mL, 5 M, 104 mmol), and dropwise HO (11.7 g, 104 mmol, 30% in water) at 0 °C to maintain the internal temperature below 30 °C. After stirring at 50 °C for 1 h, the reaction mixture was quenched with saturated aqueous NaSO (130 mL). After stirring at 0 °C for an additional 1 h, the reaction was checked with potassium iodide-starch test paper to ensure that excess HO was destroyed. The aqueous phase was extracted with DCM (3 × 50 mL). The combined organic phases were washed with saturated NaSO (2 × 100 mL), brine (2 × 100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 1.7 (800 mg) as a solid.

[0410] 1.8 Synthesis 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 (50 mL) and NaSO (50 mL, saturated) and extracted with DCM (2 × 50 mL). The combined organic phase was washed with NaHCO (100 mL), NaSO (100 mL, saturated), and brine (100 mL), dried over anhydrous NaSO, filtered, concentrated, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (0–15% EtOAc in PE) to give 1.8 (740 mg) as an oil. 1 H NMR (400 MHz, CDCl3) 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 added to saturated NH4Cl (100 mL) and extracted with EtOAc (2 × 100 mL). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue (200 mg) was purified by column chromatography (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, CDCl3) 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[M-HO+H] + MS ESI calculated value 343.3 found value 343.3. 1.8b: 1 H NMR (400 MHz, CDCl3) 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[M-HO+H] + MS ESI calculated value 343.3 found value 343.3.

[0412] 1.9 Synthesis To a suspension of MePhPBr (4.31 g, 12.2 mmol) in anhydrous THF (20 mL) was added t-BuOK (1.36 g, 12.2 mmol) under N at 15 °C. After 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 phases were 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 quenched with NaHCO (50 mL, saturated aqueous solution) and NaSO (20 mL, saturated aqueous solution). The organic layer was separated, dried over NaSO, filtered, and concentrated. 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 To a solution of 1.10 (340 mg, 0.908 mmol) in DMF (10 mL) was added 1H-pyrazole-4-carbonitrile (168 mg, 1.81 mmol) and CsCO (593 mg, 1.81 mmol) 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 diastereomeric mixture of 1 and 2 (350 mg) as a solid. The diastereomers were separated by SFC (column DAICEL CHIRALCEL OD-H (250 mm * 30 mm, 5 μm) conditions: 0.1% NH3H2O, EtOH, start B 30%, end B 30%, gradient time (min), 100% B, retention time (min), flow rate (ml / min) 50) to give both 2 (208.9 mg) and 1 (50.2 mg) as solids.

[0415] 1: 1 H NMR (400 MHz, CDCl3) 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 N3[M-2H2O+H] + MS ESI calculated value 432.4 found value 432.4.

[0416] 2: 1 H NMR (400 MHz, CDCl3) δ H7.92(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 N3[M-2H2O+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 To a solution of BHT (144 g, 654 mmol) in toluene (165 mL) was added AlMe (2 M in toluene, 163 mL, 327 mmol) dropwise at 0 °C under nitrogen. After stirring at 25 °C for 1 h, the MAD solution was used without further purification. To the MAD (327 mmol) solution was added a solution of (5β)-estrane-3,17-dione, 6.1 (30 g, 109 mmol) in DCM (100 mL) dropwise at −70 °C. After stirring at −70 °C for 1 h under N, 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 dried over NaSO, 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, CDCl3) 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 (3×400 mL). The combined organic layers were washed with brine, dried over NaSO, and evaporated under reduced pressure. 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, CDCl3) 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] 6.4 Synthesis To a solution of 6.3 (6.0 g, 14.3 mmol) in DME (30 mL) was added Rh(OAc) (94.7 mg, 0.2 mmol) 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] 6.5 Synthesis 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 phases were washed with water (80 mL), brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (15–30% EtOAc in PE) to give 6.5 (3.9 g, 80%) as a solid. 1 H NMR (400 MHz, CDCl3) 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 To a suspension of PhPEtBr (13.5 g, 36.5 mmol) in anhydrous THF (100 mL) was added t-BuOK (5.47 g, 48.8 mmol) under N at 15 °C. 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 phases were 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, CDCl3) 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] 6.7 Synthesis To a solution of 6.6 (3.1 g, 9.4 mmol) in THF (10 mL) was added BH3·Me2S (2.81 mL, 28.1 mmol) 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) sequentially. HO2 (9.38 mL, 93.7 mmol, 1.13 g / mL, 30% in water) was then added slowly until the internal temperature no longer rose, maintaining the internal temperature below 30 °C. After stirring at 50 °C for an additional 1 h, the reaction mixture was quenched with saturated aqueous Na2S2O3 (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.sub.2S.sub.2O.sub.3 (2.times.50 mL), brine (2.times.50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated to give 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) was added MeONa (4.67 g, 86.5 mmol) at 0 °C. After stirring at 70 °C for 16 h, the reaction mixture was added to saturated NH4Cl (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. 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 To a mixture of MePPhBr (3.07 g, 8.63 mmol) in THF (12 mL) was added t-BuOK (966 mg, 8.63 mmol) under N at 15 °C. After stirring at 50 °C for 30 min, 6.8a (1 g, 2.88 mmol) in THF (8 mL) was added portionwise below 50 °C. After stirring at 50 °C for 1 h, the reaction mixture was quenched at 15 °C with 10% aqueous NHCl (30 mL) and extracted with EtOAc (2 × 30 mL). The combined organic phases were 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, CDCl3) δ H 4.80 (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 quenched with saturated NaHCO and NaSO (10 mL, v:v = 1:1) and extracted with DCM (2 × 10 mL). The combined organic phase was washed with saturated NaHCO and NaSO (10 mL, v:v = 1:1), dried over NaSO, filtered, and concentrated to give 6.10 (900 mg) as a solid. 1 H NMR (400 MHz, CDCl3) δ H8.07-8.04 (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) was added CsCO (2.43 g, 7.47 mmol) and 1H-pyrazole-4-carbonitrile (579 mg, 6.22 mmol). After stirring at 130 °C for 12 h, the mixture was added to saturated NHCl (10 mL) 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), dried over anhydrous NaSO, filtered, and concentrated to give a mixture of diastereomers 6 and 7 (670 mg) as a solid. 1 H NMR (400 MHz, CDCl3) 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 separated by SFC (DAICEL CHIRALCEL OJ-H (250 mm * 30 mm, 5 μm), conditions: 0.1% NH3HO EtOH, start B: 25%, end B: 25%, flow rate (ml / min): 60) to give 6 (212.6 mg, 31.8%) and 7 (55 mg) as solids. 7 was further purified by SFC (column: DAICEL CHIRALCEL OJ-H (250 mm * 30 mm, 5 μm), conditions: 0.1% NH3HO EtOH, start B: 25%, end B: 25%, flow rate (ml / min): 60) to give 7 (33.5 mg) as a solid.

[0429] 6: 1 H NMR (400 MHz, CDCl3) 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,6 H),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 N3[M-2H2O+H] + MS ESI calculated value 418 found value 418. SFC 99% de.

[0430] 7: 1 H NMR (400 MHz, CDCl3) 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 N3[M-2H2O+H] + MS ESI calculated value 418 found value 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 To a solution of BHT (96 g, 436 mmol) in toluene (300 mL) was added AlMe (2 M in toluene, 109 mL, 218 mmol) dropwise at 0 °C under nitrogen. After stirring at 25 °C for 1 h, the MAD solution was used directly without further purification. To a freshly prepared solution of MAD (218 mmol), a solution of 6.1 (20 g, 72.8 mmol) in DCM (80 mL) was added dropwise at −70 °C. After stirring at −70 °C for 1 h under N, 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 dried over NaSO, filtered, and concentrated. 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, CDCl3) 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), dried over anhydrous NaSO, filtered, and evaporated under reduced pressure. The residue was purified by flash column chromatography (0–10% EtOAc in PE) to give 8.3 (13 g, 80%) as an oil. 1 H NMR (400 MHz, CDCl3) 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 To a solution of 8.3 (13 g, 30.0 mmol) and DME (150 mL) was added Rh(OAc) (132 mg, 0.3 mmol) 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 poured into HO (200 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with HCl (1 M, 100 mL), saturated NaHCO (100 mL), brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated. 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, CDCl3) 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 To a suspension of PhPEtBr (27.6 g, 74.6 mmol) in anhydrous THF (100 mL) was added t-BuOK (11.1 g, 99.6 mmol) under N at 15 °C. 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 phases were washed with brine (2 × 200 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by trituration with MeOH / HO (1:1, 320 mL) under reflux to give 8.6 (5.3 g, 62%) as a solid. 1 H NMR (400 MHz, CDCl3) δ H5.24-5.00 (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] 8.7 Synthesis To a solution of 8.6 (5.3 g, 15.3 mmol) in THF (100 mL) was added BH3·Me2S (4.58 mL, 45.9 mmol) at 0 °C. After stirring at 15 °C for 16 h, the reaction mixture was cooled (0 °C) and treated slowly dropwise with EtOH (8.91 mL, 203 mmol, 0.789 g / mL), NaOH (30.5 mL, 5 M, 153 mmol), and HO2 (15.3 mL, 153 mmol, 1.13 g / mL, 30% in water) 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 quenched with saturated aqueous Na2S2O3 (130 mL) and stirred at 0 °C for an additional 1 h. The reaction was checked with potassium iodide-starch test paper to ensure that excess HO was destroyed (no blue color). The aqueous phase was extracted with DCM (3 × 50 mL). The combined organic phases were washed with saturated NaSO (2 × 100 mL), brine (2 × 100 mL), dried over anhydrous NaSO, filtered, and concentrated to give 8.7 (4.3 g) as a solid. 1 H NMR (400 MHz, CDCl3) 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, CDCl3) 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 added to saturated NH Cl (10 mL) and extracted with EtOAc (2 × 10 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na SO , filtered, and concentrated to give 8.9 (1.2 g) as a solid. 1 H NMR (400 MHz, CDCl3) 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 To a mixture of MePPhBr (9.46 g, 26.5 mmol) in THF (20 mL) was added t-BuOK (2.96 g, 26.5 mmol) under N at 25 °C. 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, CDCl3) 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 at 25 °C for 2 h, the mixture was quenched with saturated NaHCO and NaSO (40 mL, v:v = 1:1) and extracted with DCM (2 × 20 mL). The combined organic phase was washed with saturated NaHCO and NaSO (50 mL, v:v = 1:1), dried over NaSO, filtered, and concentrated to give 8.11 (520 mg) as a solid. 1 H NMR (400 MHz, CDCl3) 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) was added CsCO (782 mg, 2.40 mmol) and 1H-pyrazole-4-carbonitrile (186 mg, 2.00 mmol). After stirring at 130 °C for 12 h, the mixture was added to saturated NHCl (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with LiCl (100 mL, 5% in water), brine (2 × 100 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (0–50% EtOAc in PE) to give a mixture of diastereomers 8 and 9 (165 mg) as a solid. 1 H NMR (400 MHz, CDCl3) 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 diastereomers were separated by SFC (column DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm); condition 0.1% NH3H2O ​​EtOH; flow rate (ml / min) 70) to give 8 (67.3 mg, 32.2%) and 9 (11 mg) as solids. 9 (11 mg) was further purified by SFC (column DAICEL CHIRALCE OD (250 mm × 30 mm, 10 μm); condition 0.1% NH3H2O ​​EtOH; flow rate (ml / min) 70) to give 9 (6.5 mg) as a solid.

[0443] 8: 1 H NMR (400 MHz, CDCl3) 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 N3[M-2H2O+H] + MS ESI calculated for 432.3, found 432.3. SFC 98.54% de.

[0444] 9: 1 H NMR (400 MHz, CDCl3) 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 N3[M-2H2O+H] + MS ESI calculated value for 432.3, found value 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 at 55 °C for 16 h, the mixture was diluted with EtN (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, CDCl3) δ H 0.73-0.83 (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, 2H), 2.05-2.16 (m, 2H), 2.25-2.35 (m, 3H), 2.38-2.51 (m, 2H), 3.15 (s, 1H), 3.21 (s, 1H), 3.50 (s, 6H).

[0446] 10.3 Synthesis To a solution of 10.2 (4.5 g, 14.0 mmol) and ethyl diazoacetate (7.35 mL, 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 added to NH Cl (200 mL) and extracted with EtOAc (2 × 125 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na SO , filtered, and concentrated. 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, CDCl3) 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 To a solution of 10.3 (57 g, 147 mmol) and DME (500 mL) was added Rh(OAc) (800 mg, 1.81 mmol) 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 poured into HO (500 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with HCl (1 M, 100 mL), saturated NaHCO (100 mL), and brine (200 mL), dried over anhydrous NaSO, filtered, and concentrated. 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, CDCl3) δ H 3.21 (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 To a mixture of EtPPhBr (99.4 g, 268 mmol) in THF (400 mL) was added t-BuOK (30.0 g, 268 mmol) under N at 15 °C. 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 poured into saturated aqueous NHCl (400 mL) and extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous NaSO, filtered, and concentrated to give 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 poured into aqueous NaHCO (200 mL) and extracted with EtOAc (2 × 150 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated. 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, CDCl3) δ H 5.25-5.07 (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 heated at 40 °C for 1 h under N. 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 vacuum to give 10.8 (12.5 g, 85.6%) as a solid. 1 H NMR (400 MHz, CDCl3) 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 slowly poured into 10% NH4Cl (20 mL) and extracted with EtOAc (2×50 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give 10.9 (4.5 g, 86.2%) as a solid. 1 H NMR (400 MHz, CDCl3) δ H5.23-5.05 (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 BH3Me2S (4.97 mL, 49.8 mmol, 10 M) 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 quenched with saturated aqueous Na2S2O3 (30 mL) and extracted with EtOAc (2 × 30 mL). The combined organic phase was washed with brine (2 × 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give 10.10 (5.5 g, 95.1%) as an oil. 1 H NMR (400 MHz, CDCl3) 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 × 20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (15-20% EtOAc in PE) to give 10.11 (4.4 g, 81.4%) as a solid. 1 H NMR (400 MHz, CDCl3) δH 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 added to saturated NH Cl (100 mL) and extracted with EtOAc (2 × 100 mL). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous Na SO , filtered, and concentrated to give 10.12 (1.2 g, 86.3%) as an oil. 1 H NMR (400 MHz, CDCl3) 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 To a mixture of MePPhBr (6.57 g, 18.4 mmol) in THF (40 mL) was added t-BuOK (2.06 g, 18.4 mmol) under N at 15 °C. 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 poured into aqueous NHCl (150 mL) and extracted with EtOAc (2 × 200 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated. 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, CDCl3) 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 quenched with NaHCO (50 mL, saturated aqueous solution) and NaSO (20 mL, saturated aqueous solution). The organic layer was separated, dried over NaSO, filtered, and concentrated under reduced pressure to give 10.14 (360 mg, 76.9%) as a solid. 1 H NMR (400 MHz, CDCl3) 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 To a solution of 10.14 (360 mg, 0.998 mmol) in DMF (10 mL) was added 1H-pyrazole-4-carbonitrile (185 mg, 1.99 mmol) and CsCO (648 mg, 1.99 mmol) 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, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (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, CDCl3) 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] The diastereomers were separated by SFC (column: DAICEL CHIRALCEL OJ-H 250 mm * 30 mm, 5 um; conditions: 0.1% NH3H2O ​​EtOH; gradient: 25% to 25% B; flow rate: 60 mL / min; column temperature: 40 °C) to give 11 (30 mg) and 10 (130.5 mg) as solids. 11 was re-purified by SFC (column: DAICEL CHIRALCEL OJ-H 250 mm * 30 mm, 5 um; conditions: 0.1% NH3H2O ​​EtOH; gradient: 20% to 20% B; flow rate: 60 mL / min; column temperature: 40 °C) to give 11 (16.9 mg) as a solid.

[0460] 10: 1 H NMR (400 MHz, CDCl3) δ H7.93 (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 N3[M - 2H2O + H] + Calculated MS ESI value for 418.3, measured value 418.3 for N3[M - 2H2O + H]. SFC: 95% de.

[0461] 11: 1 1H NMR (400 MHz, CDCl3) δ<0002xx25>7.89 (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, xx3H), 1.11 - 1.05 (m, 1H), 1.02 (s, 3H), 1.01 - 0.93 (m, 5H), 0.93 - 0.89 (m, 4H), xx78 - 0.66 (m, 3H), 0.62 - 0.54 (m, 1H). LC - ELSD / MS purity 99%; C 28 H 40 N3[M - 2H2O + H] + Calculated MS ESI value for 418.3, measured value 418.3 for N3[M - 2H2O + H]. SFC: 99% de.

[0462] It should be noted that there seems to be some potential inaccuracies or unclear parts in the original text (such as "xx3H" and "xx78" in the translated text of ID=14 which might be errors in the original). If possible, it would be beneficial to double - check and correct the original text for a more accurate translation.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 solution of freshly prepared MAD (310 mmol) in toluene (300 mL) was added (5β)-androstane-3,17-dione 12.0 (30 g, 104 mmol) in DCM (100 mL) dropwise at −70 °C. After stirring at −70 °C for 1 h under N2, 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 dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (0–30% EtOAc in PE) to give 12.1 (16 g, 47.7%) as a solid. 1 H NMR (400 MHz, CDCl3) 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 extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous NaSO, filtered, and concentrated. 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, CDCl3) δ H 4.75-4.65(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 To a solution of 12.2 (13 g, 29.1 mmol) in DME (130 mL) was added Rh(OAc) (300 mg, 0.6787 mmol) 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 x 200 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous NaSO, 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, 1 N), saturated NaHCO (200 mL), saturated brine (100 mL), dried over NaSO, filtered, and concentrated to give 12.4 (11 g) as a solid. 1 H NMR (400 MHz, CDCl3) 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 To a mixture of EtPPhBr (38.2 g, 103 mmol) in THF (160 mL) was added t-BuOK (11.5 g, 103 mmol) under N at 20 °C. 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 quenched with saturated aqueous NHCl (150 mL) at 20 °C and extracted with EtOAc (2 × 100 mL). The combined organic phases were 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, CDCl3) 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 MeS (3.51 mL, 10 M, 35.1 mmol). After stirring at 15 °C for 16 h, the reaction was treated sequentially with EtOH (6.73 mL, 117 mmol), dropwise NaOH (4.67 g, 5 M, 117 mmol in 23.4 mL of water), and dropwise HO (11.7 mL, 10 M, 117 mmol) at 0 °C. After stirring at 70 °C for 2 h, the mixture was quenched with NaSO (100 mL, 10%) and extracted with EtOAc (2 × 100 mL). The combined organic layers were separated, dried over NaSO, filtered, and concentrated under reduced pressure to give 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 quenched with NaHCO (100 mL, saturated) and NaSO (100 mL, saturated). The organic layer was separated, dried over NaSO, filtered, and concentrated to give 12.7 (4.0 g) as a solid. 1 H NMR (400 MHz, CDCl3) 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 diluted with saturated NH Cl (100 mL) and extracted with EtOAc (2 × 100 mL). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous Na SO , filtered, and concentrated to give 12.8 (2.2 g, 63.0%) as a solid. 1H NMR(400 MHz, CDCl3)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-HO+H] + MS ESI calculated value for 357.3, found value 357.3.

[0470] 12.9 Synthesis To a mixture of MePPhBr (3.78 g, 10.6 mmol) in THF (16 mL) was added t-BuOK (1.18 g, 10.6 mmol) under N at 20 °C. 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 quenched with saturated aqueous NHCl (150 mL) at 20 °C and extracted with EtOAc (2 × 100 mL). The combined organic phases were 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, CDCl3) 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 quenched with NaHCO (20 mL, saturated) and NaSO (20 mL, saturated). The organic layer was separated, dried over NaSO, filtered, and concentrated to give 12.10 (700 mg) as a solid, which was used as is.

[0472] Synthesis of 12 and 13 To a solution of 12.10 (400 mg, 1.02 mmol) in DMF (20 mL) was added 1H-pyrazole-4-carbonitrile (189 mg, 2.04 mmol) and CsCO (668 mg, 2.04 mmol) at 20 °C. After stirring at 120 °C for 48 h, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (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 separated by SFC (Column: DAICEL CHIRALCEL OJ-H (250 mm * 30 mm * 5 um); Mobile phase: A:CO2B:0.1%NH3HO EtOH; Gradient: 20% to 20%B, Flow rate (ml / min): 60) to give both 12 (41.0 mg, 11.7%) and 13 (98.4 mg, 28.1%) as solids.

[0473] 12: 1 H NMR (400 MHz, CDCl3) 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 N3[M-2H2O+H] + MS ESI calculated value for 446.4, found value 446.4.

[0474] 13: 1 H NMR (400 MHz, CDCl3) 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 N3[M-2H2O+H] + MS ESI calculated value for 446.4, found value 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 solution of freshly prepared MAD (519 mmol) in toluene (1 L) was added dropwise a solution of 12.0 (50.0 g, 173 mmol) in DCM (200 mL) at −70 °C. After stirring at −70 °C for 1 h under N, 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 dried over NaSO, 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, CDCl3) 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 × 100 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous NaSO, filtered, and concentrated. 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, CDCl3) δ H4.69 (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 To a solution of 14.2 (8.0 g) in DME (100 mL) was added Rh(OAc) (211 mg, 0.48 mmol) in one portion at 15 °C. After stirring at 30 °C for 12 h, the mixture was diluted with HO (100 mL) and extracted with EtOAc (3 × 60 mL). The combined organic phases were washed with brine (2 × 30 mL), dried over anhydrous NaSO, 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 (100 mL), brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated to give 14.4 (5.8 g, 93%) as a solid. 1HNMR (400 MHz, CDCl3) 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 To a mixture of PhPEtBr (40.4 g, 109 mmol) in THF (160 mL) was added t-BuOK (12.2 g, 21.8 mmol) under N at 20 °C. After 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 quenched at 20 °C with 10% aqueous NHCl (60 mL) and extracted with EtOAc (2 × 100 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated. 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, CDCl3) 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 BH3.Me2S (4.8 mL, 48 mmol, 10 M) under N2. After stirring at 20 °C for 12 h under N2, 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. H2O2 (28.8 mL, 10 M, 288 mmol) was then added dropwise. After stirring at 70 °C for 2 h, the mixture was cooled, poured into Na2S2O3 (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), dried over anhydrous Na2SO4, filtered, and concentrated to give 14.6 (5.57 g) as a solid. 1 HNMR (400 MHz, CDCl3) 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 quenched with saturated aqueous NaHCO (100 mL). The DCM phase was separated and washed with saturated aqueous NaHCO / NaSO (1:1, 2 × 100 mL), brine (30 mL), dried over NaSO, filtered, and concentrated. 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, CDCl3) δ H2.48-2.25 (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) in one portion under N. After stirring at 80 °C for 48 h, the mixture was diluted with HO (60 mL) and extracted with EtOAc (3 x 70 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated to give 14.8 (3.9 g) as a solid. 1 HNMR (400 MHz, CDCl3) 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 To a mixture of MePPhBr (12.3 g, 34.6 mmol) in THF (50 mL) was added t-BuOK (3.87 g, 34.9 mmol) under N at 20 °C. 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 quenched with 10% aqueous NHCl (100 mL) at 20 °C and extracted with EtOAc (2 × 80 mL). The combined organic phases were washed with brine (40 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash column (0–10% EtOAc in PE) to give 14.9 (1.6 g, 81%) as an oil. 1HNMR (400 MHz, CDCl3) δ H 4.80 (s, 1H), 4.60 (s, 1H), 1.98-1.89 (m, 1H), 1.86-1.74 (m, 3H), 1.69-1.55 (m, 5H), 1.54-1.47 (m, 3H), 1.47-1.36 (m, 5H), 1.30-1.24 (m, 6H), 1.17-0.92 (m, 6H), 0.90 (s, 3H), 0.89-0.84 (m, 3H), 0.80 (s, 3H).

[0484] 14.10 Synthesis To a solution of 14.9 (1.5 g, 4.4 mmol) in DCM (30 mL) was added m-CPBA (1.76 g, 8.7 mmol, 85% purity) under N at 25 °C. After stirring at 25 °C for 4 h, the mixture was quenched with saturated aqueous NaHCO (20 mL) and extracted with DCM (3 × 30 mL). The combined organic solution was washed with saturated aqueous NaHCO / NaSO (1:1, 30 mL), brine (20 mL), dried over NaSO, filtered, and concentrated. The residue was purified by flash column (0–20% EtOAc in PE) to give 14.10 (1.52 g, 97%) as a solid. 1 HNMR (400 MHz, CDCl3) δ H 2.73-2.62 (m, 2H), 1.87-1.72 (m, 5H), 1.68-1.58 (m, 5H), 1.50-1.30 (m, 8H), 1.25 (s, 3H), 1.22 (s, 3H), 1.07-0.96 (m, 2H), 0.93-0.88 (m, 8H), 0.87-0.71 (m, 4H).

[0485] Synthesis of 14 and 15 To a solution of 14.10 (1.52 g, 4.2 mmol) in DMF (30 mL) was added 1H-pyrazole-4-carbonitrile (587 mg, 6.3 mmol) and CsCO (4.10 g, 12.6 mmol) under N. After stirring at 130 °C for 72 h, the mixture was diluted with HO (40 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with HO (4 × 50 mL) and brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (0–35% EtOAc in PE) to give a mixture of diastereomers 14 and 15 (0.85 g) as a solid. 1 HNMR (400 MHz, CDCl3) δ H 7.94-7.88 (m, 1H), 7.81-7.77 (m, 1H), 4.38-4.27 (m, 1H), 4.26-4.19 (m, 1H), 2.36-2.28 (m, 1H), 1.97-1.82 (m, 3H), 1.78-1.74 (m, 2H), 1.74-1.65 (m, 4H), 1.64-1.56 (m, 2H), 1.55-1.32 (m, 10H), 1.31-1.28 (m, 1H), 1.20-1.01 (m, 4H), 0.99-0.93 (m, 7H), 0.91-0.85 (m, 5H).

[0486] Diastereomers 14 and 15 (0.81 g) were separated by SFC (Column: DAICEL CHIRALCEL OD-H (250 mm * 30 mm * 5 um), A: CO; B: 0.1% NH3H2O ​​EtOH; Gradient: 30-30%, Flow rate: 50 mL / min) to give both 14 (112 mg) and 15 (351.4 mg) as solids.

[0487] 14: 1 HNMR (400 MHz, CDCl3) δ H7.89 - 7.87 (m, 1H), 7.87 - 7.86 (m, 1H), 4.33 - 4.23 (m, 1H), 4.03 - 3.90 (m, 1H), 3.07 (s, 1H), 2.44 - 2.36 (m, 1H), 1.95 - 1.86 (m, 1H), 1.84 - 1.65 (m, 4H), 1.51 - 1.44 (m, 3H), 1.43 - 1.34 (m, 5H), 1.29 - 1.20 (m, 6H), 1.20 - 1.16 (m, 4H), 1.07 - 0.99 (m, 2H), 0.99 - 0.89 (m, 5H), 0.89 - 0.83 (m, 4H), 0.83 - 0.66 (m, 3H); LC - ELSD / MS: purity 99%, analytical SFC: 99.74% de; C 28 H 40 N3[M - 2H2O + H] + The calculated value of MS ESI for it is 418.3, the measured value is 418.3.

[0488] 15:<​​​​​​​​​​​​Examples 16 and 17: Synthesis of 1-((S)-2-hydroxy-2-((1S,4aS,4bR,6aS,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,6aS,8R,10aS,10bS,12aS)-8-hydroxy-10a,12a-dimethyl-8-propyloctadecahydrochrysen-1-yl)propyl)-1H-pyrazole-4-carbonitrile [ka] 16.2 Synthesis To a mixture of (3α,5α)3-hydroxy-androstan-17-one, 16.1 (10 g, 34.4 mmol) in THF (100 mL) was added LDA (1 M, 160 mL, 160 mmol) under N at −70° C. After stirring at −70° C. for 2 h, the reaction mixture was quenched with HOAc (10.2 g, 171 mmol) in THF (100 mL) at 0° C. After slowly warming to room temperature overnight, the reaction was diluted with water (400 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous NaSO, and evaporated under reduced pressure to give 16.2 (15 g) as a solid. 1 H NMR (400 MHz, CDCl3) δ H 0.82 (s, 3H), 0.91 (s, 3H), 0.95-1.01 (m, 1H), 1.05-1.15 (m, 2H), 1.26-1.33 (m, 6H), 1.35-1.52 (m, 6H), 1.54-1.73 (m, 6H), 1.74-1.92 (m, 4H), 2.11-2.22 (m, 1H), 3.55-2.60 (m, 1H), 4.20-4.28 (m, 2H), 4.69 (s, 1H).

[0490] 16.3 Synthesis To a solution of 16.2 (10 g, 24.7 mmol) and DME (200 mL) was added Rh(OAc) (196 mg, 0.4445...

Claims

1. Compounds of formula (I): 【Chemistry 54】 or a pharmaceutically acceptable salt thereof, During the ceremony, 【Transformation 55】 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; 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 instance of is independently a halogen, —NO 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 carbocyclyl, 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 carbocyclyl, 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 and 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 groups taken together with said 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 and 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 groups taken together with said 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; The compound, or a pharmaceutically acceptable salt thereof, wherein t is 2.

2. Each instance of R 22 is independently halogen, —NO 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) 2R GA 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R GA is selected from the group consisting of: -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 , unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, and unsubstituted heteroaryl, wherein each instance of R GA is hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl, unsubstituted C 2-6 alkynyl, unsubstituted C 3-6 carbocyclyl, unsubstituted 3-6 membered heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl.

3. R ３ is substituted or unsubstituted C １～６ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: R is alkyl;

4. R ３ But C １～３ C optionally substituted with alkoxy １～３ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: R is alkyl;

5. R ３ is methyl, ethyl, propyl, n-propyl, butyl, -CH ２ OCH ３ , or -CH ２ OCH ２ CH ３ 5. The compound of claim 4, wherein:

6. R １９ is hydrogen or unsubstituted C １～３ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: R is alkyl;

7. R １９ 7. The compound or pharmaceutically acceptable salt of claim 6, wherein is hydrogen or methyl.

8. R １５ａ and R １５ｂ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each of is independently hydrogen or substituted or unsubstituted alkyl.

9. R １５ａ and R １５ｂ 9. The compound or pharmaceutically acceptable salt of claim 8, wherein each of is independently hydrogen or methyl.

10. R １５ａ and R １５ｂ 10. The compound or pharmaceutically acceptable salt of claim 9, wherein each of is hydrogen.

11. R １６ａ and R １６ｂ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each of is hydrogen. 【Request Item 12】 【Chemistry 55】 is a single bond, and R ５ 2. The compound or pharmaceutically acceptable salt of claim 1, wherein is hydrogen or methyl. 【Request Item 13】 【Chemistry 55】 is a single bond, and R ５ 13. The compound or pharmaceutically acceptable salt of claim 12, wherein is hydrogen. 【Request Item 14】 【Chemistry 55】 is a double bond, and R ５ and R ６ａ and R ６ｂ 2. The compound or pharmaceutically acceptable salt of claim 1, wherein one of: is absent.

15. R Ｘ is —OH, and R Ｙ is unsubstituted C １～３ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: R is alkyl;

16. R Ｘ is —OH, and R Ｙ 16. The compound or pharmaceutically acceptable salt of claim 15, wherein is unsubstituted methyl.

17. n is 1 and R ２２ is halogen, -CN, -OR ＧＡ , -N(R ＧＡ ) ２ , substituted or unsubstituted C １～６ Alkyl, or substituted or unsubstituted C ３～６ carbocyclyl, where R ＧＡ Each instance of is independently hydrogen, or substituted or unsubstituted C １～３ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: R is alkyl;

18. R ２２ 18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein: is located at the 4-position of the pyrazolyl.

19. R ２２ 18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein: is located at the 3-position of the pyrazolyl.

20. R ２２ 18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein: is located at the 5-position of the pyrazolyl.

21. 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 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each of is hydrogen.

22. The compound of formula (I) is a compound of formula (I-a) or (I-b): 【Transformation 56】 or 【Transformation 56】 2. The compound of claim 1, which is: or a pharmaceutically acceptable salt thereof.

23. The compound of formula (I-a) is a compound of formula (I-c): 【Transformation 56】 23. The compound of claim 22, which is: or a pharmaceutically acceptable salt thereof.

24. The compound of formula (I-b) is a compound of formula (I-d): 【Transformation 73】 23. The compound of claim 22, which is: or a pharmaceutically acceptable salt thereof.

25. Compound of Formula VIa: 【Chemistry 74】 or a pharmaceutically acceptable salt thereof, During the ceremony, 【Transformation 62】 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; R ３ 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; R ５ is hydrogen or methyl, R ２２ Each instance of is independently a halogen, —NO 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 carbocyclyl, 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 carbocyclyl, 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 groups taken together with said 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 and 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 groups, together with said 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 and 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 groups taken together with said intervening atoms form a substituted or unsubstituted heterocyclic ring; R １９ is hydrogen, or substituted or unsubstituted alkyl; r is 2, The compound, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.

26. R ３ is substituted or unsubstituted C １～６ 26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein: R is alkyl;

27. R ３ But C １～３ C optionally substituted with alkoxy １～３ 27. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein: R is alkyl;

28. R ３ is methyl, ethyl, propyl, n-propyl, butyl, -CH ２ OCH ３ , or -CH ２ OCH ２ CH ３ 28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein:

29. R １９ is hydrogen or unsubstituted C １～３ 26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein: R is alkyl;

30. R １９ 30. The compound or pharmaceutically acceptable salt of claim 29, wherein is hydrogen or methyl.

31. R １５ａ and R １５ｂ 26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein each of is independently hydrogen or substituted or unsubstituted alkyl.

32. R １５ａ and R １５ｂ 32. The compound or pharmaceutically acceptable salt of claim 31, wherein each of is independently hydrogen or methyl.

33. R １５ａ and R １５ｂ 33. The compound or pharmaceutically acceptable salt of claim 32, wherein each of is hydrogen.

34. R １６ａ and R １６ｂ 26. The compound or pharmaceutically acceptable salt of claim 25, wherein each of is hydrogen. 【Request Item 35】 【Transformation 55】 is a single bond, and R ５ 26. The compound or pharmaceutically acceptable salt of claim 25, wherein is hydrogen or methyl. 【Request Item 36】 【Chemistry 55】 is a single bond, and R ５ 36. The compound or pharmaceutically acceptable salt of claim 35, wherein is hydrogen. 【Request Item 37】 【Chemistry 55】 is a double bond, and R ５ and R ６ａ and R ６ｂ 26. The compound or pharmaceutically acceptable salt of claim 25, wherein one of: is absent.

38. R Ｘ is —OH, and R Ｙ is unsubstituted C １～３ 26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein: R is alkyl;

39. R Ｘ is —OH, and R Ｙ 39. The compound of claim 38, or a pharmaceutically acceptable salt thereof, wherein is unsubstituted methyl.

40. n is 1 and R ２２ is halogen, -CN, -OR ＧＡ , -N(R ＧＡ ) ２ , substituted or unsubstituted C １～６ Alkyl, or substituted or unsubstituted C ３～６ carbocyclyl, where R ＧＡ Each instance of is independently hydrogen, or substituted or unsubstituted C １～３ 26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein: R is alkyl;

41. R ２２ 41. The compound of claim 40, or a pharmaceutically acceptable salt thereof, wherein: is located at the 4-position of the pyrazolyl.

42. R ２２ 41. The compound or pharmaceutically acceptable salt of claim 40, wherein: is located at the 3-position of the pyrazolyl.

43. R ２２ 41. The compound of claim 40, or a pharmaceutically acceptable salt thereof, wherein: is located at the 5-position of the pyrazolyl.

44. The compound of formula (VIa) is a compound of formula (VIa-a): 【Chemistry 75】 26. The compound of claim 25, which is: or a pharmaceutically acceptable salt thereof.

45. The compound of formula (VIa-a) may be a compound of formula (VIa-b): 【Transformation 76】 45. The compound of claim 44, which is: or a pharmaceutically acceptable salt thereof.

46. The compound of formula (VIa-b) is a compound of formula (VIa-c) or (VIa-d): 【Chemical 77】 46. ​​The compound of claim 45, which is: or a pharmaceutically acceptable salt thereof.

47. The compound of formula (VIa) is a compound of formula (VIa-e): 【Transformation 78】 26. The compound of claim 25, which is: or a pharmaceutically acceptable salt thereof.

48. Compound of formula (VIb): 【Chemistry 79】 or a pharmaceutically acceptable salt thereof, During the ceremony, 【Transformation 62】 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; R ３ 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; R ５ is hydrogen or methyl, R ２２ Each instance of is independently a halogen, —NO 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 carbocyclyl, 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 carbocyclyl, 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 groups taken together with said 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 and 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 groups, together with said 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 and 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 groups taken together with said intervening atoms form a substituted or unsubstituted heterocyclic ring; R １９ is hydrogen, or substituted or unsubstituted alkyl; p is 2, The compound, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.

49. R ３ is substituted or unsubstituted C １～６ 49. The compound of claim 48, or a pharmaceutically acceptable salt thereof, which is alkyl.

50. R ３ But C １～３ C optionally substituted with alkoxy １～３ 50. The compound of claim 49, or a pharmaceutically acceptable salt thereof, wherein: R is alkyl;

51. R ３ is methyl, ethyl, propyl, n-propyl, butyl, -CH ２ OCH ３ , or -CH ２ OCH ２ CH ３ 51. The compound of claim 50, or a pharmaceutically acceptable salt thereof:

52. R １９ is hydrogen or unsubstituted C １～３ 49. The compound of claim 48, or a pharmaceutically acceptable salt thereof, which is alkyl.

53. R １９ 53. The compound or pharmaceutically acceptable salt of claim 52, wherein is hydrogen or methyl.

54. R １５ａ and R １５ｂ 49. The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein each of is independently hydrogen or substituted or unsubstituted alkyl.

55. R １５ａ and R １５ｂ 55. The compound or pharmaceutically acceptable salt of claim 54, wherein each of is independently hydrogen or methyl.

56. R １５ａ and R １５ｂ 56. The compound or pharmaceutically acceptable salt of claim 55, wherein each of is hydrogen.

57. R １６ａ and R １６ｂ 49. The compound or pharmaceutically acceptable salt of claim 48, wherein each of is hydrogen. [Request Item 58] [Transformation 55] is a single bond, and R ５ 49. The compound or pharmaceutically acceptable salt of claim 48, wherein is hydrogen or methyl. 【Request Item 59】 【Chemistry 55】 is a single bond, and R ５ 59. The compound or pharmaceutically acceptable salt of claim 58, wherein is hydrogen. [Request Item 60] [Chemistry 55] is a double bond, and R ５ and R ６ａ and R ６ｂ 49. The compound or pharmaceutically acceptable salt of claim 48, wherein one of: is absent.

61. R Ｘ is —OH, and R Ｙ is unsubstituted C １～３ 49. The compound of claim 48, or a pharmaceutically acceptable salt thereof, which is alkyl.

62. R Ｘ is —OH, and R Ｙ 62. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein is unsubstituted methyl.

63. n is 1 and R ２２ is halogen, -CN, -OR ＧＡ , -N(R ＧＡ ) ２ , substituted or unsubstituted C １～６ Alkyl, or substituted or unsubstituted C ３～６ carbocyclyl, where R ＧＡ Each instance of is independently hydrogen, or substituted or unsubstituted C １～３ 49. The compound of claim 48, or a pharmaceutically acceptable salt thereof, which is alkyl.

64. R ２２ 64. The compound of claim 63, or a pharmaceutically acceptable salt thereof, wherein: is located at the 4-position of the pyrazolyl.

65. R ２２ 64. The compound of claim 63, or a pharmaceutically acceptable salt thereof, wherein: is located at the 3-position of the pyrazolyl.

66. R ２２ 64. The compound of claim 63, or a pharmaceutically acceptable salt thereof, wherein: is located at the 5-position of the pyrazolyl.

67. The compound of formula (VIb) is a compound of formula (VIb-b): 【Chemistry 80】 49. The compound of claim 48, which is: or a pharmaceutically acceptable salt thereof.

68. The compound of formula (VIb-b) is a compound of formula (VIb-c) or (VIb-d): 【Chemistry 81】 68. The compound of claim 67, which is: or a pharmaceutically acceptable salt thereof.

69. The compound of formula (VIb) is a compound of formula (VIb-e): 【Chemistry 82】 49. The compound of claim 48, which is: or a pharmaceutically acceptable salt thereof.

70. Compound of Formula VII: 【Transformation 63】 or a pharmaceutically acceptable salt thereof, During the ceremony, 【Chemistry 64】 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; R ３ 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; R ５ is hydrogen or methyl, R ２２ Each instance of is independently a halogen, —NO 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 carbocyclyl, 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 carbocyclyl, 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 groups taken together with said 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 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 and 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 groups taken together with said 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 and 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 groups taken together with said intervening atoms form a substituted or unsubstituted heterocyclic ring; R １９ is hydrogen, or substituted or unsubstituted alkyl; The compound, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.

71. R ３ is substituted or unsubstituted C １～６ 71. The compound of claim 70, or a pharmaceutically acceptable salt thereof, which is alkyl.

72. R ３ But C １～３ C optionally substituted with alkoxy １～３ 72. The compound of claim 71, or a pharmaceutically acceptable salt thereof, wherein: R is alkyl;

73. R ３ is methyl, ethyl, propyl, n-propyl, butyl, -CH ２ OCH ３ , or -CH ２ OCH ２ CH ３ 73. The compound of claim 72, or a pharmaceutically acceptable salt thereof, wherein:

74. R １９ is hydrogen or unsubstituted C １～３ 71. The compound of claim 70, or a pharmaceutically acceptable salt thereof, which is alkyl.

75. R １９ 75. The compound or pharmaceutically acceptable salt of claim 74, wherein is hydrogen or methyl.

76. R １５ａ and R １５ｂ 71. The compound of claim 70, or a pharmaceutically acceptable salt thereof, wherein each of is independently hydrogen or substituted or unsubstituted alkyl.

77. R １５ａ and R １５ｂ 77. The compound or pharmaceutically acceptable salt of claim 76, wherein each of is independently hydrogen or methyl.

78. R １５ａ and R １５ｂ 78. The compound or pharmaceutically acceptable salt of claim 77, wherein each of is hydrogen.

79. R １６ａ and R １６ｂ 71. The compound or pharmaceutically acceptable salt of claim 70, wherein each of is hydrogen. [Request Item 80] [Chemistry 55] is a single bond, and R ５ 71. The compound or pharmaceutically acceptable salt of claim 70, wherein is hydrogen or methyl. 【Request Item 81】 【Chemistry 55】 is a single bond, and R ５ 81. The compound or pharmaceutically acceptable salt of claim 80, wherein is hydrogen. 【Request Item 82】 【Chemistry 55】 is a double bond, and R ５ and R ６ａ and R ６ｂ 71. The compound or pharmaceutically acceptable salt of claim 70, wherein one of: is absent.

83. R Ｘ is —OH, and R Ｙ is unsubstituted C １～３ 71. The compound of claim 70, or a pharmaceutically acceptable salt thereof, which is alkyl.

84. R Ｘ is —OH, and R Ｙ 84. The compound of claim 83, or a pharmaceutically acceptable salt thereof, wherein is unsubstituted methyl.

85. n is 1 and R ２２ is halogen, -CN, -OR ＧＡ , -N(R ＧＡ ) ２ , substituted or unsubstituted C １～６ Alkyl, or substituted or unsubstituted C ３～６ carbocyclyl, where R ＧＡ Each instance of is independently hydrogen, or substituted or unsubstituted C １～３ 71. The compound of claim 70, or a pharmaceutically acceptable salt thereof, which is alkyl.

86. R ２２ 86. The compound of claim 85, or a pharmaceutically acceptable salt thereof, wherein: is located at the 4-position of the pyrazolyl.

87. R ２２ 86. The compound of claim 85, or a pharmaceutically acceptable salt thereof, wherein: is located at the 3-position of the pyrazolyl.

88. R ２２ 86. The compound of claim 85, or a pharmaceutically acceptable salt thereof, wherein: is located at the 5-position of the pyrazolyl.

89. The compound of formula (VII) is a compound of formula (VII-a): 【Chemical 85】 or a pharmaceutically acceptable salt thereof.

90. The compound of formula (VII) is a compound of formula (VII-b): 【Chemical 86】 or a pharmaceutically acceptable salt thereof.

91. The compound of formula (VII-b) is a compound of formula (VII-c): 【Transformation 87】 91. The compound of claim 90, which is: or a pharmaceutically acceptable salt thereof.

92. The compound is 【Transformation 70】 【Chemistry 71】 【Chemistry 72】 A compound selected from the group consisting of:

93. Structural formula 【Chemical 88】 93. The compound of claim 92, having the formula:

94. Structural formula 【Chemical 89】 93. The compound of claim 92, having the formula:

95. Structural formula [Chemical 90] 93. The compound of claim 92, having the formula:

96. Structural formula 【Chemistry 91】 93. The compound of claim 92, having the formula:

97. Structural formula 【Chemistry 92】 93. The compound of claim 92, having the formula:

98. Structural formula 【Chemistry 93】 93. The compound of claim 92, having the formula:

99. Structural formula 【Chemical 94】 93. The compound of claim 92, having the formula:

100. Structural formula 【Chemical 95】 93. The compound of claim 92, having the formula:

101. Structural formula 【Chemistry 96】 93. The compound of claim 92, having the formula:

102. Structural formula 【Chemistry 97】 93. The compound of claim 92, having the formula:

103. Structural formula 【Chem.98】 93. The compound of claim 92, having the formula:

104. Structural formula 【Chem.99】 93. The compound of claim 92, having the formula:

105. Structural formula 【Chemistry 100】 93. The compound of claim 92, having the formula:

106. Structural formula 【Chemistry 101】 93. The compound of claim 92, having the formula:

107. Structural formula 【Chemical Engineering 102】 93. The compound of claim 92, having the formula:

108. Structural formula 【Chemistry 103】 93. The compound of claim 92, having the formula:

109. Structural formula 【Chemical 104】 93. The compound of claim 92, having the formula:

110. Structural formula 【Chemistry 105】 93. The compound of claim 92, having the formula:

111. Structural formula 【Chemistry 106】 93. The compound of claim 92, having the formula:

112. Structural formula 【Chemistry 107】 93. The compound of claim 92, having the formula:

113. Structural formula 【Chemistry 108】 93. The compound of claim 92, having the formula:

114. Structural formula 【Chemistry 109】 93. The compound of claim 92, having the formula:

115. Structural formula 【Chemical 110】 93. The compound of claim 92, having the formula:

116. Structural formula 【Chemistry 111】 93. The compound of claim 92, having the formula:

117. Structural formula 【Chemistry 112】 93. The compound of claim 92, having the formula:

118. Structural formula 【Chemistry 113】 93. The compound of claim 92, having the formula:

119. Structural formula 【Chemistry 114】 93. The compound of claim 92, having the formula:

120. Structural formula 【Chemical 115】 93. The compound of claim 92, having the formula:

121. Structural formula 【Chemistry 116】 93. The compound of claim 92, having the formula:

122. A pharmaceutically acceptable salt of the compound of any one of claims 92 to 121.

123. 122. A pharmaceutical composition comprising a compound according to any one of claims 1 to 121 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

124. Each instance of R 22 is independently halogen, —NO 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) 2R GA 71. The compound or pharmaceutically acceptable salt of any one of claims 25, 48, or 70, wherein R GA is selected from the group consisting of -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 , unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, and unsubstituted heteroaryl, wherein each instance of R GA is hydrogen, unsubstituted C 1-6 alkyl, unsubstituted C 2-6 alkenyl, unsubstituted C 2-6 alkynyl, unsubstituted C 3-6 carbocyclyl, unsubstituted 3-6 membered heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl.

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