Neuroactive steroids and compositions thereof

Abstract

To provide neuroactive steroids and compositions thereof.SOLUTION: Provided herein are compounds of the formula (I) in the figure or a pharmaceutically acceptable salt thereof, where R1a, R1b, R2a, R2b, R3, R4a, R4b, R5, R6a, R6b, R7a, R7a, R11a, R11b, R12a, R12b, R16a, R16b, R19, R11a, R22, RX, RY and n are as defined herein. Also provided herein are pharmaceutical compositions comprising the compounds of the formula (I) and methods of using the compounds, e.g., in treatment of CNS-related disorders.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 855,435, filed May 31, 2019, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Brain excitability is defined as the level of alertness of an animal, a continuum from coma to seizures, and is regulated by various neurotransmitters. Generally, neurotransmitters serve to regulate the conductance of ions across the neuronal membrane. At rest, the neuronal membrane has an electrical potential (or membrane potential) of approximately -70 mV, making the interior of the cell negative compared to the exterior of the cell. The electrical potential (voltage) is determined by the flow of ions (K) across the neuronal semipermeable membrane. + , Na + , Cl - Neurotransmitters are the result of an equilibrium between synaptic and non-synaptic substances (organic anions). Neurotransmitters are stored in presynaptic vesicles and are released under the influence of a neuronal action potential. When released into the synaptic cleft, excitatory chemical transmitters such as acetylcholine cause membrane depolarization (a change in potential from -70 mV to -50 mV occurs). This effect is mediated by postsynaptic nicotinic receptors stimulated by acetylcholine, leading to the release of Na + Increases membrane permeability to ions. Reduction of membrane potential stimulates neuronal excitability in the form of postsynaptic action potentials.

[0003] In the case of the GABA receptor complex (GRC), its effects on brain excitability are mediated by the neurotransmitter gamma-aminobutyric acid (GABA). Because up to 40% of brain neurons utilize GABA as a neurotransmitter, GABA has a profound influence on global brain excitability. GABA regulates the excitability of individual neurons by modulating the conductance of chloride ions across neuronal membranes. GABA interacts with its recognition site on the GRC, promoting the influx of chloride ions into the cell down the GRC's electrochemical gradient. Increased intracellular levels of this anion cause hyperpolarization of the transmembrane potential, reducing neuronal sensitivity to excitatory inputs and thus neuronal excitability. In other words, the higher the chloride ion concentration in neurons, the lower the brain excitability and arousal levels.

[0004] The GRC is well documented to be involved in mediating anxiety, seizure activity, and sedation. Thus, GABA and drugs that act like or potentiate the actions of GABA, such as therapeutically useful barbiturates and benzodiazepines (BZs) (e.g., Valium®), exert their therapeutically useful effects by interacting with specific regulatory sites on the GRC. Accumulating evidence now suggests that the GRC contains unique sites for neuroactive steroids in addition to benzodiazepine and barbiturate binding sites. 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 (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)). Regulators of brain excitability and drugs for the prevention and treatment of CNS-related diseases There is a need for new and improved compounds that act as anti-cancer agents. The compounds, compositions, and methods described herein are directed to this end. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Lan, NC et al., Neurochem. Res. (1991) 16:347-356 [Non-patent document 2] Majewska, 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 expected to be useful as therapeutic agents for treating CNS-related disorders.

[0008] In one embodiment, a compound of formula (I): [ka] [In formula: [ka] represents a single or double bond, and if a double bond is present, R 6a or R 6b If one of the two does not exist, R 5 does not exist; R X Halo, -CN, -OH, -OR Q1 and substituted or unsubstituted alkyl; R Q1 is substituted or unsubstituted alkyl; R Y is halo or substituted or unsubstituted alkyl; Alternatively, R Y and R X may, together with the intervening atoms, 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 occurrence 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 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R GA each occurrence 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, oxygen protecting group (for oxygen binding), and nitrogen protecting group (for nitrogen binding), 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 12beach 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 A1each occurrence is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 carbocyclyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group (for oxygen binding), nitrogen protecting group (for nitrogen binding), and sulfur protecting group (for sulfur binding), 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 are linked 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(RC3 )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 or and R is selected from the group consisting of C3 each occurrence 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, oxygen protecting groups (when oxygen is bonded), nitrogen protecting groups (when nitrogen is bonded), and sulfur protecting groups (when sulfur is bonded); 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 selected from the group consisting of 0, 1, 2, and 3. or a pharmaceutically acceptable salt thereof.

[0009] In some embodiments, the compound has Formula Ia: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above.

[0010] In some embodiments, the compound has formula I-b1: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above.

[0011] In some embodiments, the compound has formula I-c3 or I-c4: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above.

[0012] In some embodiments, the compound has formula I-d3 or I-d4: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above.

[0013] In some embodiments, the compound has formula I-e5, formula I-e6, formula I-e7, or formula I-e8: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above.

[0014] In certain embodiments, the compound has formula I-Ib1: [ka] [In the formula, R 22is CN; n is 1; R 19 is selected from the group consisting of hydrogen, ethyl, and methyl; R 15a and R 15b is independently selected from the group consisting of hydrogen, methyl, and cyclopropyl; R 2a and R 2b are each independently selected from the group consisting of hydrogen, methyl, ethyl, methoxymethyl, and methoxy; R 3 is the unsubstituted C 1-3 selected from the group consisting of alkyl, -CH2OCH3, and -CH2OCH2CH3; R X and R Y is as defined herein] or a pharmaceutically acceptable salt thereof.

[0015] In one embodiment, the compound has Formula I-Ic1 or Formula I-Ic2: [ka] [In the formula, R 22 is CN; n is 1; R 19 is selected from the group consisting of hydrogen, ethyl, and methyl; R 15a and R 15b is independently selected from the group consisting of hydrogen, methyl, and cyclopropyl; R 2a and R 2b are each independently selected from the group consisting of hydrogen, methyl, ethyl, methoxymethyl, and methoxy; R 3 is the unsubstituted C 1-3 selected from the group consisting of alkyl, -CH2OCH3, and -CH2OCH2CH3; R X and R Y is as defined herein] or a pharmaceutically acceptable salt thereof.

[0016] In one embodiment, the compound has formula I-Id1 or formula I-Id2: [ka] [In the formula, R 22 is CN; R 19 is selected from the group consisting of hydrogen, ethyl, and methyl; R 15a and R 15b is independently selected from the group consisting of hydrogen, methyl, and cyclopropyl; R 2a and R 2b are each independently selected from the group consisting of hydrogen, methyl, ethyl, methoxymethyl, and methoxy; R 3 is the unsubstituted C 1-3 selected from the group consisting of alkyl, -CH2OCH3, and -CH2OCH2CH3; R X and R Y is as defined herein] or a pharmaceutically acceptable salt thereof.

[0017] In one embodiment, the compound has formula I-Ie1, formula I-Ie2, formula I-Ie3, or formula I-Ie4: [ka] [ka] [In the formula, R 22 is CN; R 19 is selected from the group consisting of hydrogen, ethyl, and methyl; R 15a and R 15b is independently selected from the group consisting of hydrogen, methyl, and cyclopropyl; R 2a and R 2bare each independently selected from the group consisting of hydrogen, methyl, ethyl, methoxymethyl, and methoxy; R 3 is the unsubstituted C 1-3 selected from the group consisting of alkyl, -CH2OCH3, and -CH2OCH2CH3; R X and R Y is as defined herein] or a pharmaceutically acceptable salt thereof.

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

[0019] In one aspect, provided herein is a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the compound of the invention is provided in an effective amount as a pharmaceutical composition. In certain embodiments, the compound of the invention is provided in a therapeutically effective amount.

[0020] In some embodiments, the method of treating a CNS-related disorder in a subject in need thereof comprises administering to the subject an effective amount of a compound described herein (e.g., a compound of Formula (I)) 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 cognition disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, or a vascular disease. 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.

[0021] In some embodiments, the compound is selected from the group consisting of the compounds identified in Table 1 herein.

[0022] The compounds of the invention described herein may, in certain embodiments, be used to treat, for example, GABA A These compounds act as GABA modulators, affecting the GABA receptors in either a positive or negative way. A They are predicted to have central nervous system (CNS) activity as modulators of CNS excitability as mediated by their ability to modulate receptors.

[0023] Thus, in another aspect, there is provided a method for treating a CNS-related disorder in a subject in need thereof, 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 cognition disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder and / or withdrawal syndrome, tinnitus, or status epilepticus. In certain embodiments, the CNS-related disorder is depression. In certain embodiments, the CNS-related disorder is postpartum depression. In certain embodiments, the CNS-related disorder is major depressive disorder. In certain embodiments, the major depressive disorder is moderate major depressive disorder. In certain embodiments, the major depressive disorder is severe major depressive disorder. In certain embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In certain embodiments, the compound is administered orally. In certain embodiments, the compound is administered chronically. In certain embodiments, the compound is administered continuously, for example, by continuous intravenous infusion. DETAILED DESCRIPTION OF THE INVENTION

[0024] Detailed Description of Certain Embodiments of the Invention As generally described herein, the present invention provides compounds designed to act as, for example, GABA A receptor modulators.In certain embodiments, such compounds are expected to be useful as therapeutic agents for treating CNS-related disorders (e.g., disorders described herein, for example, depression, such as postpartum depression or major depressive disorder).

[0025] definition chemical definition The definitions of specific functional groups and chemical terms are explained in detail below. Chemical elements are listed in the Periodic Table of Elements (CAS system, Handbook of Chemistry and Physics, 75 th (Ed., inside cover), and specific functional groups are generally defined as described therein. Further, 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, 5 th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Moder n Methods of Organic Synthesis,3 rd Edition, Cambridge University Press, Cambridge, 1987.

[0026] Isomers, e.g., stereoisomers, can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and chiral salt formation and crystallization, or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates, and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). The present invention further encompasses the compounds described herein as individual isomers substantially free of other isomers, or as mixtures of various isomers.

[0027] "Stereoisomers": It should also be understood that compounds that have the same molecular formula but differ in the nature or bonding sequence 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 those that are non-superimposable mirror images of each other are referred to as "enantiomers." For example, if a compound has an asymmetric center and is bonded to four different groups, a set of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center, described by the R- and S-sequencing rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light, described as dextrorotatory or levorotatory (i.e., (+) or (-) isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0028] As used herein, a pure enantiomer compound is substantially free of other enantiomers or stereoisomers of a 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" indicate 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 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.

[0029] In the compositions provided herein, the enantiomerically pure compound can be present together with other active or inactive ingredients. For example, a pharmaceutical composition containing an enantiomerically pure R position / center / carbon compound can 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 can contain, for example, at least about 95% by weight of the R compound and up to 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 can contain, for example, about 90% excipients and about 10% enantiomerically pure S compound. In certain embodiments, the enantiomerically pure S compound in such a composition can contain, for example, at least about 95% by weight of the R compound and up to about 5% by weight of the S compound, based on the total weight of the compound. The amount may contain at least about 95% by weight of the S compound and up to about 5% by weight of the R compound. In certain embodiments, the active ingredient can be formulated with few or no excipients or carriers.

[0030] The term "diastereomerically pure" means that a compound contains greater 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 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, such as high performance liquid chromatography (HPLC).

[0031] 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 analogue" means one analogue or multiple analogues.

[0032] 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.

[0033] The following terms are intended to have the meanings provided below and are useful in understanding the specification and the intended scope of the invention.

[0034] "Alkyl" means the radical of a linear or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1-20 In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C 1-12 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1-10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1-9 In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1-8 In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1-7 In some embodiments, an alkyl group has 1 to 6 carbon atoms (also referred to herein as "lower alkyl" or "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, the alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, the alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2-6 alkyl). C 1-6Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each occurrence of an alkyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or containing one or more alkyl groups. or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, the 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)).

[0035] "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. Examples of substituted alkylene groups, e.g., 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 given for a particular alkylene group, it is understood that the range or number refers to the range or number of carbons in a divalent linear carbon chain. An alkylene group can be substituted or unsubstituted with one or more substituents described herein.

[0036] "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, alkenyl does not contain any triple bonds. In some embodiments, alkenyl groups have 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, the alkenyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, an alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as 2-butenyl) or terminal (such as 1-butenyl). C 2-4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 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. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each occurrence of an alkenyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2- 10 In certain embodiments, the alkenyl group is a substituted C 2-10 It is alkenyl.

[0037] "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, alkynyl groups contain no double bonds. In some embodiments, alkynyl groups have 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, an alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as 2-butynyl) or terminal (such as 1-butynyl). C 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2-6 Examples of alkynyl groups include the above-mentioned C 2-4Alkynyl groups include pentynyl (C5), hexynyl (C6), and the like. Further examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each occurrence of an alkynyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkynyl"). 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.

[0038] The term "heteroalkyl," as used herein, refers to an alkyl group, as defined herein, further comprising one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) in the parent chain, wherein one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, a heteroalkyl group is 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 refers to 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 group having 1 to 3 carbon atoms. A saturated group having one heteroatom and one heteroatom ("hetero C") 1-3 In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom ("heteroC 1-2 In some embodiments, the heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroC1 alkyl"). In some embodiments, the heteroalkyl group is a saturated group having 2-6 carbon atoms and 1 or 2 heteroatoms ("heteroC 2-6 Unless otherwise specified, each occurrence of a heteroalkyl group is independently unsubstituted ("unsubstituted heteroalkyl") or substituted with one or more substituents ("substituted heteroalkyl"). 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.

[0039] "Aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 (e.g., having 6, 10, or 14 pi electrons shared in a cyclic arrangement) aromatic ring system 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 an aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, in which case the bonding radical or point of attachment is on the aryl ring, and in such cases the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each occurrence of the aryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl"), or substituted with one or more substituents ("substituted aryl"). In certain embodiments, the aryl group is an unsubstituted C 6-14 In certain embodiments, the aryl group is a substituted C 6-14 It is aryl.

[0040] In certain embodiments, the aryl group is substituted with one or more groups selected from halo, C1-C8 alkyl, C1-C8 haloalkyl, cyano, hydroxy, C1-C8 alkoxy, and amino.

[0041] Representative examples of substituted aryl include the following: [ka] are listed, In the formula, R 56 and R 57 can be hydrogen, and R 56 and R 57 At least one of each independently represents C1-C8 alkyl, C1-C8 haloalkyl, 4- to 10-membered heterocyclyl, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 , N.R. 58 SOR 59 NR 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 may be linked to form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms (optionally containing one or more heteroatoms selected from the group N, O, or S). 60 and R 61 are independently hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, substituted C6-C 10 It is aryl, 5- to 10-membered heteroaryl, or substituted 5- to 10-membered heteroaryl.

[0042] "Fused aryl" refers to an aryl having two of its ring carbons in common with a second aryl or heteroaryl ring, or a carbocyclyl or heterocyclyl ring.

[0043] "Heteroaryl" refers to a radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 (e.g., having 6 or 10 π-electrons shared in the cyclic arrangement) aromatic ring system in which ring carbon atoms and 1 to 4 ring heteroatoms are provided in the aromatic ring system, with each heteroatom 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 can be at a carbon atom or a nitrogen atom, as long as the valence allows. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, in which case the point of attachment is on the heteroaryl ring; in such cases, the ring member number continues to refer to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused with one or more aryl groups, in which case the point of attachment can be on either the aryl ring or the heteroaryl ring, and in such cases the ring member count refers to the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., on the ring bearing a heteroatom (e.g., 2-indolyl) or on the ring without a heteroatom (e.g., 5-indolyl).

[0044] In some embodiments, heteroaryl groups are 5- to 10-membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In some embodiments, heteroaryl groups are 5- to 8-membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heteroaryl"). In some embodiments, heteroaryl groups are 5- to 6-membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heteroaryl"). In some embodiments, 5- to 6-membered heteroaryls have 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, 5- to 6-membered heteroaryls have 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. Each occurrence of the heteroaryl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted heteroaryl") or substituted with one or more substituents (a "substituted heteroaryl"). In certain embodiments, a heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, a heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0045] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0046] Representative examples of heteroaryls include: [ka] are listed, where each Z is a carbonyl, N, NR 65 , O, and S; R 65 are independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl.

[0047] "Carbocyclyl" or "carbocyclic" means a ring system having 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 carbocyclyl). Exemplary C 3-6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. 3-8 The carbocyclyl group includes the above-mentioned C 3-6 Exemplary C groups include, but are not limited to, carbocyclyl groups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. 3-10 As the carbocyclyl group, the above-mentioned C 3-8Carbocyclyl 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. Illustrating the foregoing examples, in certain embodiments, a carbocyclyl group is monocyclic ("monocyclic carbocyclyl") or contains a fused, bridged, or spiro ring system (e.g., 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 to one or more aryl or heteroaryl groups, in which case the point of attachment is on the carbocyclyl ring, and in such cases the number of carbons continues to represent the number of carbons in the carbocyclyl ring system. Unless otherwise specified, each occurrence 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.

[0048] In some embodiments, "carbocyclyl" refers to 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 5-10Cycloalkyl). C 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of cycloalkyl groups include the above-mentioned C 5-6 Cycloalkyl groups include cyclopropyl (C3) and cyclobutyl (C4). 3-8 Examples of cycloalkyl groups include the above-mentioned C 3-6 Cycloalkyl groups include cycloalkyl groups, as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each occurrence of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C 3-10 In certain embodiments, the cycloalkyl group is a substituted C 3-10 It is cycloalkyl.

[0049] "Heterocyclyl" or "heterocyclic" means a heterocyclic ring having ring carbon atoms and 1 to 4 ring heteroatoms. where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon atom or at a nitrogen atom, where valence allows. Heterocyclyl groups can be monocyclic ("monocyclic heterocyclyl") or can be fused, bridged, or spiro ring systems (e.g., bicyclic systems ("bicyclic heterocyclyl")) and can be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems can 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, with the point of attachment located on either the carbocyclyl or heterocyclyl ring, or in which a heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, with the point of attachment located on the heterocyclyl ring; in such cases, the number of ring members continues to refer to the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each occurrence of a heterocyclyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, 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.

[0050] 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 ring 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 has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur, hi some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0051] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary heterocyclyl groups include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocycles) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocycles) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0052] A "nitrogen-containing heterocyclyl" group refers to a 4- to 7-membered non-aromatic ring group containing at least one nitrogen atom, such as, but not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazine (e.g., N-methylpiperazine). Specific examples include azetidine, piperidone, and piperazone.

[0053] "Hetero," when used to describe a compound or a group present on a compound, means that one or more carbon atoms of the compound or group are replaced with a nitrogen, oxygen, or sulfur heteroatom. Hetero can apply to any of the hydrocarbyl groups described above having 1 to 5, and especially 1 to 3, heteroatoms, such as alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkenyl, cycloheteroalkenyl, etc.

[0054] "Acyl" means -C(O)R 20 Refers to the radical, R 20is 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" refers to a group in which R 20 is an acyl group where the aryl group is a group other than hydrogen. Representative acyl groups include formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph), -C(O)-C1 to C8 alkyl, -C(O)-(CH2) t (C6~C 10 aryl), -C(O)-(CH2) t (5-10 membered heteroaryl), -C(O)-(CH2)t(C3-C 10 cycloalkyl), and -C(O)-(CH2) t (4-10 membered heterocyclyl) (t is an integer from 0 to 4). 21 is C1-C8 alkyl substituted with halo or hydroxy; or C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, arylalkyl, 5-10 membered heteroaryl, or heteroarylalkyl (each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy).

[0055] "Alkoxy" means -OR 29 R refers to the group 29is 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., having 1 to 6 carbon atoms. Further particular alkoxy groups have 1 to 4 carbon atoms.

[0056] In certain embodiments, R 29 is amino, substituted amino, C6-C 10 Aryl, aryloxy, carboxyl, cyano, C3-C 10 A group having one or more substituents 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-, for example, 1 to 5 substituents, particularly 1 to 3 substituents, and particularly 1 substituent. Exemplary "substituted alkoxy" groups include, but are not limited to, -O-(CH2) t (C6~C 10 aryl), -O-(CH2) t (5-10 membered heteroaryl), -O-(CH2) t (C3~C 10 cycloalkyl), and -O-(CH2) t(4-10 membered heterocyclyl), where t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present may itself be substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. Particularly exemplary "substituted alkoxy" groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2NMe2.

[0057] "Amino" refers to the -NH2 radical.

[0058] An "oxo group" refers to -C(=O)-.

[0059] "Substituted amino" refers to a group of the formula -N(R 38 )2, and R 38 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an amino protecting group; R 38 At least one of R is not hydrogen. 38 are independently hydrogen, C1-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl, or C3-C 10 Cycloalkyl; or C1-C8 alkyl substituted with halo or hydroxy; C3-C8 alkenyl substituted with halo or hydroxy; C3-C8 alkynyl substituted with halo or hydroxy, or -(CH2) t (C6~C 10 aryl), -(CH2) t (5-10 membered heteroaryl), -(CH2) t (C3~C 10cycloalkyl), or -(CH2) t (4-10 membered heterocyclyl) (where t is an integer from 0 to 8), each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy, or hydroxy; or both R 38 The groups are linked to form an alkylene group.

[0060] Exemplary "substituted amino" groups include, but are not limited to, -NR 39 -C1-C8 alkyl, -NR 39 -(CH2) t (C6~C 10 aryl), -NR 39 -(CH2) t (5-10 membered heteroaryl), -NR 39 -(CH2) t (C3~C 10 cycloalkyl), and -NR 39 -(CH2) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4, e.g., 1 or 2, and each R 39 independently represent H or C1-C8 alkyl; any alkyl group present may itself be substituted with halo, substituted or unsubstituted amino, or hydroxy, and any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present may itself be substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. For the avoidance of doubt, the term "substituted amino" , including 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.

[0061] "Carboxy" refers to the -C(O)OH radical.

[0062] "Cyano" refers to the -CN radical.

[0063] "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.

[0064] "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.

[0065] "Hydroxy" refers to the -OH radical.

[0066] "Nitro" refers to the -NO2 radical.

[0067] "Thioketo" refers to the group =S.

[0068] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups defined herein are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl groups, "substituted" or "unsubstituted" alkenyl groups, "substituted" or "unsubstituted" alkynyl groups, "substituted" or "unsubstituted" carbocyclyl groups, "substituted" or "unsubstituted" heterocyclyl groups, "substituted" or "unsubstituted" aryl groups, or "substituted" or "unsubstituted" heteroaryl groups). In general, the term "substituted," whether preceded by the term "optionally," means that at least one hydrogen atom present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent that, when substituted, results in a stable compound, e.g., a compound that does not undergo spontaneous transformation (e.g., by rearrangement, cyclization, elimination, or other reaction). Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents may be the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, i.e., any of the substituents described herein that result in the formation of a stable compound. The present invention contemplates all combinations that result in stable compounds. 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.

[0069] 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)2Raa , -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 aryl, and 5- to 14-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd groups, or two geminal hydrogens on the carbon atom are substituted with ═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 substituted with a group; R aa Each occurrence of is independently 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C2-10 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl; or two R aa groups are linked 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 substituted with a group; R bb Each occurrence of is independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1-10 Alkyl, C 1-10 Haloalkyl, 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 are linked 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 substituted with a group; R cc Each occurrence 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 are linked 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 substituted with a group; R dd Each occurrence 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- to 10-membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg or substituted with two geminal R dd the substituents can be linked to form =O or =S; R ee Each occurrence of C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R ff Each occurrence of is independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, or two R ff groups are linked 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 substituted with a group; R gg Each occurrence 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, -SC 1-6 Alkyl, -SS(C 1-6alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3-C(=S)N(C 1-6 alkyl)2, C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 Archi Lu, -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 linked to form =O or =S; X - is the counter ion.

[0070] A "counterion" or "anionic counterion" is a negatively charged group that associates with a cationic quaternary amino group to maintain electroneutrality. 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.).

[0071] These and other exemplary substituents are described in detail in the detailed description and claims. The present invention is not intended to be limited in any way by the exemplary substituents listed above.

[0072] Other definitions As used herein, the term "modulation" refers to the A A "modulator" (e.g., a modulator compound) refers to the inhibition or enhancement of receptor function, e.g., GABA A It can be an agonist, partial agonist, antagonist, or partial antagonist of the receptor.

[0073] "Pharmaceutically acceptable" means approved or approvable by a regulatory authority of a federal or state government, or a corresponding authority in a country other than the United States, or listed in the United States Pharmacopoeia or other generally recognized pharmacopoeia for use in animals (more specifically, humans).

[0074] "Pharmaceutically acceptable salt" refers to a salt of the compound of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and can be inorganic acid addition salts or organic acid addition salts, and inorganic base addition salts or organic base addition salts. Specifically, such salts include (1) salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or salts formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 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 when coordinated with an organic base, e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and the like. Salts further include, by way of example only, salts formed with sodium, potassium, or the like. 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, and the like. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counterion of an acidic functional group. Such cations are exemplified by sodium cation, potassium cation, calcium cation, magnesium cation, ammonium cation, tetraalkylammonium cation, and the like. See, e.g., Berge, et al., J. Pharm. Sci. (1977) 66(1):1-79.

[0075] The term "prodrug" is intended to encompass therapeutically inactive compounds that are converted under physiological conditions into the therapeutically active agents of the present invention. 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 to expose the molecule of interest, which then produces a therapeutic effect. In certain embodiments, the prodrug is converted by the enzymatic activity of the subject.

[0076] In an alternative embodiment, the present invention provides prodrugs of compounds of formula (I), which prodrugs include a cleavable moiety at the C3 hydroxy, as shown in formula (I).

[0077] "Tautomers" refer to compounds that are interchangeable forms of a particular compound structure, with changes in the displacement of hydrogen atoms and electrons. Thus, two structures can be in equilibrium through the displacement 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 the acid and nitro forms of phenylnitromethane, which are similarly formed by treatment with acid or base. Tautomers can be relevant to achieving optimal chemical reactivity and biological activity of a compound of interest.

[0078] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., men and women of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, e.g., mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs). In certain embodiments, the subject is a human (a "human subject"). In certain embodiments, the subject is a non-human animal.

[0079] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen protecting groups include, but are not limited to, -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa ) 3、 -P(R cc )2, -P(R cc )3, -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)2N(R bb )2, and -P(=O)(NR bb )2 is mentioned, and R aa , R bb , and R cc is as defined herein. Oxygen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 3, incorporated herein by reference. rdedition, John Wiley & Sons, 1999.

[0080] Exemplary oxygen protecting groups include methyl, methoxylmethyl (MOM), 2-methoxyethoxymethyl (MEM), benzyl (Bn), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBDMS), t-butylmethoxyphenylsilyl (TBMPS), methanesulfonate (mesylate), and tosylate (Ts). Not limited to:

[0081] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to as a thiol protecting group). Sulfur protecting groups include, but are not limited to, -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa ) 3、 -P(R cc )2, -P(R cc )3, -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)2N(R bb )2, and -P(=O)(NR bb )2 is mentioned, and R aa , R bb , and R ccis as defined herein. Sulfur protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 3, incorporated herein by reference. rd edition,John Including those described in detail in Wiley & Sons, 1999.

[0082] In certain embodiments, the substituent present on the nitrogen atom is an amino protecting group (also referred to as a nitrogen protecting group). Amino protecting groups include, but are not limited to, -OH, -OR aa , -N(R cc )2, -C(=O)R aa , -C(=O)OR aa , -C(=O)N(R cc )2, -S(=O)2R aa , -C(=NR cc )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3- 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 ddis as defined herein. Amino protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 3, incorporated herein by reference. rd edition, John Wiley & Sons, 1999.

[0083] Exemplary amino protecting groups include, but are not limited to, amide groups (e.g., —C(═O)R aa ) (including, but not limited to, formamide and acetamide); carbamate groups (e.g., —C(═O)OR aa ) (including, but not limited to, 9-fluorenylmethyl carbamate (Fmoc), t-butyl carbamate (BOC), and benzyl carbamate (Cbz); sulfonamide groups (e.g., —S(═O)R aa ) (including, but not limited to, p-toluenesulfonamide (Ts), methanesulfonamide (Ms), and N-[2-(trimethylsilyl)ethoxy]methylamine (SEM)).

[0084] Disease, disorder, and condition are used interchangeably herein.

[0085] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate actions taken while a subject is afflicted with a particular disease, disorder, or condition that lessen 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 taken before a subject is afflicted with a particular disease, disorder, or condition.

[0086] Generally, an "effective amount" of a compound is an amount that elicits a desired biological response, e.g., a CNS response. It refers to an amount sufficient to treat a 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 biological endpoint of interest, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health status, and condition of the subject.

[0087] As used herein, unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound means the amount of therapeutic agent alone, or in combination with other therapies, that provides a therapeutic benefit in the treatment of the disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, an amount that alleviates or avoids the symptoms or causes of a disease or condition, or an amount that enhances the therapeutic efficacy of another therapeutic agent.

[0088] 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 prophylactic agent before a subject is affected by a particular disease, disorder, or condition. As used herein, unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent or prevent the recurrence of a disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition. A prophylactically effective amount of a compound refers to the amount of therapeutic agent alone or in combination with other agents that provides a prophylactic benefit in the prevention of the disease, disorder, or condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or an amount that enhances the prophylactic efficacy of another prophylactic agent.

[0089] As used herein, an "episodic dosing regimen" refers to a dosing regimen in which a compound of Formula (I) or a composition comprising a compound of Formula (I) is administered to a subject for a finite period of time in response to a diagnosis of a disorder or symptoms thereof, e.g., a diagnosis or symptoms of depression, major depressive disorder, bipolar depression, anxiety, or postpartum depression. In some embodiments, the major depressive disorder is moderate major depressive disorder. In some embodiments, the major depressive disorder is severe major depressive disorder. In some embodiments, the compound is formulated as individual dosage units, each unit comprising a compound of Formula (I) and one or more suitable pharmaceutical excipients. In some embodiments, the duration of an episodic dosing regimen is multiple weeks, e.g., about 8 weeks. In contrast to chronic administration as defined herein, episodic administration of a compound is administered for a finite period of time, e.g., about 2 weeks to about 8 weeks, in response to a diagnosis of a disorder, e.g., depression, or symptoms thereof. In some embodiments, episodic administration is administered once daily for multiple weeks, e.g., about 2 weeks to about 6 weeks. In one embodiment, the duration of episodic administration is 2 weeks. In some embodiments, a subject is administered a multiple episodic administration regimen, for example, two or more episodic regimens throughout the subject's lifetime.

[0090] compound It should be understood that the formulae set forth herein may refer to particular carbon atoms, for example, C17, C3, C19, etc. These references are as follows: [ka] Based on the carbon atom position according to the known steroid nomenclature used in the industry, as shown in For example, C17 refers to the 17th carbon, and C3 refers to the 3rd carbon.

[0091] In one aspect, provided herein is a compound of formula (I): [ka] [In the formula, [ka] represents a single or double bond, and if a double bond is present, R 6a or R 6b If one of the two does not exist, R 5 does not exist; R X Halo, -CN, -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 may, together with the intervening atoms, 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 occurrence 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 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R GA each occurrence of is independently hydrogen, substituted or unsubstituted C 1-6 Archi C, substituted or unsubstituted 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, oxygen protecting group (for oxygen binding), and nitrogen protecting group (for nitrogen binding), 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(RA1 )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 occurrence is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 carbocyclyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group (for oxygen binding), nitrogen protecting group (for nitrogen binding), and sulfur protecting group (for sulfur binding), or two R A1the 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 are linked 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 occurrence is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, oxygen protecting groups (oxygen bonding groups) a nitrogen protecting group (when nitrogen is bonded), and a sulfur protecting group (when sulfur is bonded), or two R C3 the groups together with the intervening atoms form a substituted or unsubstituted heterocyclic ring; R 19 is hydrogen or substituted or unsubstituted alkyl; n is selected from the group consisting of 0, 1, 2, and 3. or a pharmaceutically acceptable salt thereof.

[0092] In some embodiments, the compound of Formula (I) is a compound of Formula (Ia), Formula (Ib), Formula (I-c1), Formula (I-c2), Formula (I-d1), Formula (I-d2), Formula (I-e1), Formula (I-e2), Formula (I-e3), Formula (I-e4), Formula (I-b1), Formula (I-c3), Formula (I-c4), Formula (I-d3), Formula (I-d4), Formula (I-e5), Formula (I-e6), Formula (I-e7), or Formula (I-e8).

[0093] In some embodiments, the compound of Formula I has Formula Ia: [ka] or a pharmaceutically acceptable salt thereof.

[0094] In some embodiments, the compound is a compound of formula (I), wherein R 1a , R 1b , R 2a , R 2b , R 4a , R 4b , R 7a , R 7b , R 11a , R 11b , R 12a , R 12b , R 6a , R 6b , R 15a , R 15b , R 16a , and R 16b are hydrogen atoms.

[0095] In some embodiments, the compound is a compound of Formula (I), wherein n is 1 and R 22 is -CN and R 5 is hydrogen and R 19 is selected from the group consisting of hydrogen, methyl, and ethyl.

[0096] In some embodiments, the compound is a compound of Formula (I), wherein n is 1 and R 22 is -CN and R 5 is hydrogen and R 19 is hydrogen.

[0097] R 1a Groups and R 1b base In some embodiments, R 1a and R 1b are each independently hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -N(RA1 )2, -C(=O)R A1 , -C(=O)OR A1 , and -C(=O)N(R A1 )2, and R A1 each occurrence independently represents 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 It is selected from the group consisting of carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0098] In some embodiments, R 1a and R 1b are each independently hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl and -OR A1 and R is selected from the group consisting of A1 is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 It is selected from the group consisting of carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0099] In some embodiments, R 1a and R 1b are each independently hydrogen, substituted or unsubstituted C 1-6 Alkyl and -OR A1 and R is selected from the group consisting of A1 is hydrogen or unsubstituted C 1-6 It is alkyl.

[0100] In some embodiments, R 1a and R 1b each independently represents hydrogen or a substituted or unsubstituted C 1-6 It is alkyl.

[0101] In some embodiments, R 1a and R1b are both hydrogen.

[0102] R 2a Groups and R 2b base In some embodiments, R 2a and R 2b are each independently hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -N(R A1 )2, -C(=O)R A1 , -C(=O)OR A1 , and -C(=O)N(R A1 )2, and R A1 each occurrence 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 It is selected from the group consisting of carbocyclyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0103] In some embodiments, R 2a and R 2b are each independently hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl and -OR A1 and R is selected from the group consisting of A1 is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 It is selected from the group consisting of carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0104] In some embodiments, R 2a and R 2bare each independently hydrogen, substituted or unsubstituted C 1-6 Alkyl and -OR A1 and R is selected from the group consisting of A1 is hydrogen or unsubstituted C 1-6 It is alkyl.

[0105] In some embodiments, R 2a and R 2b are each independently selected from the group consisting of hydrogen, methyl, ethyl, methoxymethyl, and methoxy.

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

[0107] R 4a Groups and R 4b base In some embodiments, R 4a and R 4b are each independently hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -N(R A1 )2, -C(=O)R A1 , -C(=O)OR A1 , and -C(=O)N(R A1 )2, and R A1 each occurrence is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Carbocyclyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.

[0108] In some embodiments, R 4aand R 4b are each independently hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl and -OR A1 and R is selected from the group consisting of A1 is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 It is selected from the group consisting of carbocyclyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0109] In some embodiments, R 4a and R 4b are each independently hydrogen, substituted or unsubstituted C 1-6 Alkyl and -OR A1 and R is selected from the group consisting of A1 is hydrogen or unsubstituted C 1-6 It is alkyl.

[0110] In some embodiments, R 4a and R 4b are each independently hydrogen or substituted or unsubstituted C 1-6 It is alkyl.

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

[0112] R 7a Groups and R 7b base In some embodiments, R 7a and R 7b are each independently hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -N(R A1 )2, -C(=O)R A1 , -C(=O)OR A1, and -C(=O)N(R A1 )2, and R A1 each occurrence 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 It is selected from the group consisting of carbocyclyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0113] In some embodiments, R 7a and R 7b are each independently hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl and -OR A1 and R is selected from the group consisting of A1 is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 It is selected from the group consisting of carbocyclyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0114] In some embodiments, R 7a and R 7b are each independently hydrogen, substituted or unsubstituted C 1-6 Alkyl and -OR A1 and R is selected from the group consisting of A1 is hydrogen or unsubstituted C 1-6 It is alkyl.

[0115] In some embodiments, R 7a and R 7b are each independently hydrogen or substituted or unsubstituted C 1-6 It is alkyl.

[0116] In some embodiments, R 7a and R 7b are both hydrogen.

[0117] R 11a Groups and R 11b base In some embodiments, R 11a and R 11b are each independently hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -N(R A1 )2, -C(=O)R A1 , -C(=O)OR A1 , and -C(=O)N(R A1 )2, and R A1 each occurrence 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 It is selected from the group consisting of carbocyclyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0118] In some embodiments, R 11a and R 11b are each independently hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl and -OR A1 and R is selected from the group consisting of A1 are independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 It is selected from the group consisting of carbocyclyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0119] In some embodiments, R 11a and R 11b are each independently hydrogen, substituted or unsubstituted C 1-6Alkyl and -OR A1 and R is selected from the group consisting of A1 is hydrogen or unsubstituted C 1-6 It is alkyl.

[0120] In some embodiments, R 11a and R 11b are each independently hydrogen or substituted or unsubstituted C 1-6 It is alkyl.

[0121] In some embodiments, R 11a and R 11b are both hydrogen.

[0122] R 12a Groups and R 12b base In some embodiments, R 12a and R 12b are each independently hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -N(R A1 )2, -C(=O)R A1 , -C(=O)OR A1 , and -C(=O)N(R A1 )2, and R A1 each occurrence 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 It is selected from the group consisting of carbocyclyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0123] In some embodiments, R 12a and R 12b are each independently hydrogen, halogen, cyano, substituted or unsubstituted C1-6 Alkyl and -OR A1 and R is selected from the group consisting of A1 are independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 It is selected from the group consisting of carbocyclyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0124] In some embodiments, R 12a and R 12b are each independently hydrogen, substituted or unsubstituted C 1-6 Alkyl and -OR A1 and R is selected from the group consisting of A1 is hydrogen or unsubstituted C 1-6 It is alkyl.

[0125] In some embodiments, R 12a and R 12b are each independently hydrogen or substituted or unsubstituted C 1-6 It is alkyl.

[0126] In some embodiments, R 12a and R 12b are both hydrogen.

[0127] R 6a Groups and R 6b base In some embodiments, R 6a and R 6b are each independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, and substituted or is unsubstituted C 2-6 alkynyl.

[0128] In some embodiments, R 6a and R 6b are each independently hydrogen or substituted or unsubstituted C 1-6 It is alkyl.

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

[0130] In some embodiments, R 6a and R 6b are both hydrogen.

[0131] R 15a Groups and R 15b base In some embodiments, R 15a and R 15b are each independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 It is selected from the group consisting of carbocyclyl, and substituted or unsubstituted heteroaryl.

[0132] In some embodiments, R 15a and R 15b are each independently hydrogen, unsubstituted C 1-6 Alkyl and unsubstituted C 3-6 carbocyclyl.

[0133] In some embodiments, R 15a and R 15b are each independently selected from the group consisting of hydrogen, methyl, and cyclopropyl.

[0134] In some embodiments, R 15a and R 15b are both hydrogen.

[0135] R 16a Groups and R 16b base In some embodiments, R 16a and R 16b are each independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C3-6 It is selected from the group consisting of carbocyclyl, and substituted or unsubstituted heteroaryl.

[0136] In some embodiments, R 16a and R 16b are each independently hydrogen or substituted or unsubstituted C 1-6 It is alkyl.

[0137] In some embodiments, R 16a and R 16b are each independently hydrogen or unsubstituted C 1-6 It is alkyl.

[0138] In some embodiments, R 16a and R 16b are both hydrogen.

[0139] R 3 base In some embodiments, R 3 is a substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, and substituted or unsubstituted C 2-6 alkynyl.

[0140] In some embodiments, R 3 is a substituted or unsubstituted C1-C6 alkyl.

[0141] In some embodiments, R 3 is C 1-3 C optionally substituted with alkoxy 1-3 It is alkyl.

[0142] In some embodiments, R 3 is selected from the group consisting of methyl, ethyl, n-propyl, —CH2OCH3, and —CH2OCH2CH3.

[0143] In some embodiments, R 3 is methyl.

[0144] R 19 base In some embodiments, R 19 is hydrogen or substituted or unsubstituted C 1-6 It is alkyl.

[0145] In some embodiments, R 19 is hydrogen or unsubstituted C 1-3 It is alkyl.

[0146] In some embodiments, R 19 is selected from the group consisting of hydrogen, methyl, and ethyl.

[0147] In some embodiments, R 19 is hydrogen.

[0148] In some embodiments, R 19 is an unsubstituted C1-C3 alkyl.

[0149] In some embodiments, R 19 is methyl or ethyl.

[0150] In some embodiments, R 19 is methyl.

[0151] In some embodiments, R 19 is ethyl.

[0152] R X Groups and / or R Y base In some embodiments, R X Halo, -CN, -OH, -OR Q1 , and substituted or unsubstituted C 1-3 alkyl.

[0153] In some embodiments, R X Halo, -CN, -OH, -OR Q1 , and unsubstituted C 1-3alkyl.

[0154] In some embodiments, R X is selected from the group consisting of fluoro, —CN, —OH, —OCH 3 , and methyl.

[0155] In some embodiments, R X is -OH.

[0156] In some embodiments, R X is fluoro.

[0157] In some embodiments, R X is unsubstituted C1-C3 alkylene-OR Q1 is.

[0158] In some embodiments, R Y is halo or unsubstituted C 1-6 It is alkyl.

[0159] In some embodiments, R Y is halo or unsubstituted C 1-3 It is alkyl.

[0160] In some embodiments, R Y is selected from the group consisting of methyl, ethyl, and n-propyl.

[0161] In some embodiments, R Y is methyl.

[0162] In some embodiments, R Y is fluoro.

[0163] In some embodiments, R Y and R X together with the intervening atoms, form a substituted or unsubstituted C 3-6 It forms a carbocyclyl or a substituted or unsubstituted 3- to 6-membered heterocyclyl.

[0164] In some embodiments, R Y and R X together with the intervening atoms form an unsubstituted C 3-6 It forms a carbocyclyl or an unsubstituted 3- to 6-membered heterocyclyl.

[0165] In some embodiments, R Y and R X taken together with the intervening atoms, forms a substituted or unsubstituted 4-membered carbocyclyl.

[0166] In some embodiments, R Y and R X taken together with the intervening atoms, forms a substituted or unsubstituted 4-membered heterocyclyl.

[0167] In some embodiments, the 4-membered heterocycle contains a heteroatom selected from N, O, and S.

[0168] In some embodiments, R Y and R X together to form an oxetane.

[0169] R Q1 base In some embodiments, R Q1 is unsubstituted C 1-6 It is alkyl.

[0170] In some embodiments, R Q1 is the unsubstituted C 1-3 It is alkyl.

[0171] In some embodiments, R Q1 is selected from the group consisting of methyl, ethyl, and n-propyl.

[0172] In some embodiments, R Q1 is methyl.

[0173] R 22 base In some embodiments, R 22are each independently 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 carbocyclyl, and substituted or unsubstituted 3- to 6-membered heterocyclyl; R GA each occurrence independently represents hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 It is selected from the group consisting of carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0174] In some embodiments, each R 22 are independently halogen, -CN, substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, and -OR GA and R is selected from the group consisting of GA is hydrogen or substituted or unsubstituted C 1-3 It is alkyl.

[0175] In some embodiments, R 22 is -CN, or C optionally substituted by oxo 1-3 It is alkyl.

[0176] In some embodiments, R 22 is located at the 4-position of the pyrazolyl. In some embodiments, R 22 is located at the 3-position of the pyrazolyl. 22 is located at the 5-position of the pyrazolyl.

[0177] In some embodiments, R 22 is -CN.

[0178] In another embodiment, R 22 is -CN located at the 4-position of the pyrazolyl.

[0179] integer n In some embodiments, n is 1, 2, or 3.

[0180] In some embodiments, n is 1 or 2.

[0181] In some embodiments, n is 0 or 1.

[0182] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0183] R 5 base In some embodiments, R 5 is hydrogen.

[0184] In some embodiments, R 5 is hydrogen in the alpha or beta configuration.

[0185] In some embodiments, R 5 is a hydrogen in the alpha configuration.

[0186] In some embodiments, R 5 is a hydrogen in the beta configuration.

[0187] In some embodiments, the compound of Formula I has the formula I-b1: [ka] or a pharmaceutically acceptable salt thereof.

[0188] In some embodiments, the compound of Formula I has Formula I-c3 or Formula I-c4: [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0189] In some embodiments, the compound of Formula I has Formula I-d3 or Formula I-d4: [ka] or a pharmaceutically acceptable salt thereof.

[0190] In some embodiments, the compound of Formula I has formula I-e5, formula I-e6, formula I-e7, or formula I-e8: [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0191] In one embodiment, the compound of formula I has formula I-Ib1: [ka] [In the formula, R 22 is CN; n is 1; R 19 is selected from the group consisting of hydrogen, ethyl, and methyl; R 15a and R 15b is independently selected from the group consisting of hydrogen, methyl, and cyclopropyl; R 2a and R 2bare each independently selected from the group consisting of hydrogen, methyl, ethyl, methoxymethyl, and methoxy; R 3 is the unsubstituted C 1-3 selected from the group consisting of alkyl, -CH2OCH3, and -CH2OCH2CH3; R X and R Y is as defined herein] or a pharmaceutically acceptable salt thereof.

[0192] In one embodiment, the compound has Formula I-Ic1 or Formula I-Ic2: [ka] [In the formula, R 22 is CN; n is 1; R 19 is selected from the group consisting of hydrogen, ethyl, and methyl; R 15a and R 15b is independently selected from the group consisting of hydrogen, methyl, and cyclopropyl; R 2a and R 2b are each independently selected from the group consisting of hydrogen, methyl, ethyl, methoxymethyl, and methoxy; R 3 is the unsubstituted C 1-3 selected from the group consisting of alkyl, -CH2OCH3, and -CH2OCH2CH3; R X and R Y is as defined herein] or a pharmaceutically acceptable salt thereof.

[0193] In one embodiment, the compound has formula I-Id1 or formula I-Id2: [ka] [ka] [In the formula, R 22 is CN; R 19 is selected from the group consisting of hydrogen, ethyl, and methyl; R 15a and R 15b is independently selected from the group consisting of hydrogen, methyl, and cyclopropyl; R 2a and R 2b are each independently selected from the group consisting of hydrogen, methyl, ethyl, methoxymethyl, and methoxy; R 3 is the unsubstituted C 1-3 selected from the group consisting of alkyl, -CH2OCH3, and -CH2OCH2CH3; R X and R Y is as defined herein] or a pharmaceutically acceptable salt thereof.

[0194] In one embodiment, the compound has formula I-Ie1, formula I-Ie2, formula I-Ie3, or formula I-Ie4: [ka] [ka] [In the formula, R 22 is CN; R 19 is selected from the group consisting of hydrogen, ethyl, and methyl; R 15a and R 15b is independently selected from the group consisting of hydrogen, methyl, and cyclopropyl; R 2a and R 2b are each independently selected from the group consisting of hydrogen, methyl, ethyl, methoxymethyl, and methoxy; R 3 is the unsubstituted C 1-3 selected from the group consisting of alkyl, -CH2OCH3, and -CH2OCH2CH3; RX and R Y is as defined herein] or a pharmaceutically acceptable salt thereof.

[0195] In some embodiments, the pharmaceutical composition comprises a compound described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0196] In some embodiments, 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 cognition disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder and / or withdrawal syndrome, tinnitus, or status epilepticus. In some embodiments, the CNS-related disorder is depression. In some embodiments, the CNS-related disorder is postpartum depression. In some embodiments, the CNS-related disorder is major depressive disorder. In some embodiments, the major depressive disorder is moderate major depressive disorder. In some embodiments, the major depressive disorder is severe major depressive disorder.

[0197] In some embodiments, the compound is selected from the group consisting of compounds listed in Table 1 below: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] The compound is selected from the group consisting of the compounds specified in

[0198] In one aspect, provided herein are pharmaceutically acceptable salts of the compounds described herein (eg, compounds of Formula (I)).

[0199] In one aspect, provided herein is a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the compound of the invention is provided in an effective amount as a pharmaceutical composition. In certain embodiments, the compound of the invention is provided in a therapeutically effective amount.

[0200] The compounds of the invention described herein may, in certain embodiments, be used to treat, for example, GABA A GAB affects receptors in either a positive or negative way A Acts as a modulator Such compounds act as GABA receptors. A They are predicted to have central nervous system (CNS) activity as modulators of CNS excitability as mediated by their ability to modulate receptors.

[0201] Thus, in another aspect, there is provided a method for treating a CNS-related disorder in a subject in need thereof, 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 cognition disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder and / or withdrawal syndrome, tinnitus, or status epilepticus. In certain embodiments, the CNS-related disorder is depression. In certain embodiments, the CNS-related disorder is postpartum depression. In certain embodiments, the CNS-related disorder is major depressive disorder. In certain embodiments, the major depressive disorder is moderate major depressive disorder. In certain embodiments, the major depressive disorder is severe major depressive disorder. In certain embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In certain embodiments, the compound is administered orally. In certain embodiments, the compound is administered chronically. In certain embodiments, the compound is administered continuously, for example, by continuous intravenous infusion.

[0202] Exemplary compounds of the invention can be synthesized from the following known starting materials using methods known to those skilled in the art or methods from specific references: In one aspect, provided herein are pharmaceutically acceptable salts of the compounds described herein (e.g., compounds of Formula (I)).

[0203] Alternative Embodiments In alternative embodiments, the compounds described herein may also contain one or more isotopic substitutions. For example, hydrogen may be: 2 H (D or deuterium) or 3 H (T or tritium). Carbon can be, for example, 13 C or 14 C. Oxygen can be, for example, 18 O. Nitrogen can be, for example, 15 In other embodiments, a specific isotope (e.g., 3 H, 13 C. 14 C.18 O, or 15 N) may occur in 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.

[0204] Pharmaceutical Composition In one aspect, provided herein is a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the compound of the invention is provided in an effective amount as a pharmaceutical composition. In certain embodiments, the compound of the invention is provided in a therapeutically effective amount.

[0205] 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.

[0206] 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.

[0207] Generally, the compounds provided herein are administered in effective amounts. The amount of product will typically be determined by a physician in light of the relevant circumstances, including the condition being treated, the selected route of administration, the actual compound being administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0208] When used to prevent the development of a CNS disorder, the compounds provided herein will typically be administered to a subject at risk of developing the condition at the dosage levels described above, under the advice and supervision of a physician. Subjects at risk of developing a particular condition generally include those with a family history of the condition or those identified by genetic testing or screening as being particularly susceptible to developing the condition.

[0209] The pharmaceutical compositions provided herein can also be administered chronically ("chronic administration"). Chronic administration refers to the administration of a compound or pharmaceutical composition thereof for an extended period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or can continue indefinitely, for example, for the remaining life span 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 range, for an extended period of time.

[0210] The pharmaceutical composition of the present invention can also be delivered using various administration methods.For example, in certain embodiments, the pharmaceutical composition can be given as a bolus, for example, to raise the blood concentration of the compound to an effective level.The location of the bolus administration depends on the systemic level of the active ingredient desired throughout the body; for example, intramuscular or subcutaneous bolus administration allows for a slow release of the active ingredient, while a bolus delivered directly into a vein (for example, by IV drip) allows for much faster delivery, and the blood concentration of the active ingredient can quickly rise to an effective level.In other embodiments, the pharmaceutical composition can be administered as a continuous infusion, for example, by IV drip, to maintain the steady-state concentration of the active ingredient in the subject's body.In addition, in still other embodiments, the pharmaceutical composition can be administered as a bolus first, and then by continuous infusion.

[0211] Compositions for oral administration can take the form of bulk liquid solutions or suspensions or bulk powders. However, more commonly, compositions are provided in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage for human subjects and other mammals, each unit containing a predetermined amount of active ingredient calculated to achieve a desired therapeutic effect, along with suitable pharmaceutical excipients. Typical unit dosage forms include prefilled ampoules or syringes containing premeasured amounts of liquid compositions, or pills, tablets, capsules, etc., for solid compositions. In such compositions, the compound is typically a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder consisting of various vehicles or excipients and processing aids useful in forming the desired dosage form.

[0212] For oral administration, a typical regimen is 1 to 5 times, particularly 2 to 4 times, and typically 3 times per day. When using such a dosing pattern, each dose provides about 0.01 to about 20 mg / kg of the compound provided herein, with preferred doses being about 0.1 to about 10 mg / kg, particularly about 1 to about 5 mg / kg.

[0213] Transdermal doses are generally selected to produce blood levels that are comparable to or lower than those achieved using injection doses, and are generally amounts 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.

[0214] Injection dose levels range from about 0.1 mg / kg / hour to at least 20 mg / kg / hour, all for about 1 to about 120 hours, particularly 24 to 96 hours. A preloading bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve a maximum total dose not exceeding about 5 g / day for a 40-80 kg human patient.

[0215] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispersing agents, colorants, flavors, etc. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: binders (such as microcrystalline cellulose, gum tragacanth, or gelatin); excipients (such as starch or lactose); disintegrating agents (such as alginic acid, Primogel, or corn starch); lubricants (such as magnesium stearate); glidants (such as colloidal silicon dioxide); sweetening agents (such as sucrose or saccharin); or flavoring agents (such as peppermint, methyl salicylate, or orange flavoring).

[0216] 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 a minor component, often about 0.05 to 10% by weight, with the remainder being the injectable vehicle or the like.

[0217] Transdermal compositions are typically formulated as topical ointments or creams containing active ingredient(s). When formulated as an ointment, the active ingredient is typically mixed with a paraffinic ointment base or a water-miscible ointment base. Alternatively, the active ingredient may be formulated as 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 that enhance the skin penetration or stability of the active ingredient or formulation. All such known transdermal formulations and ingredients are encompassed within the scope provided herein.

[0218] 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.

[0219] The ingredients listed above for oral, injectable, or topical compositions are merely representative. Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0220] 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.

[0221] 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 (e.g., hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, etc.).

[0222] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable excipient, e.g., a composition suitable for injection, such as intravenous (IV) administration.

[0223] Pharmaceutically acceptable excipients include any diluents or other liquid vehicles suitable for the particular dosage form desired, e.g., injection, dispersing or suspending aids, surfactants, isotonicity agents, preservatives, lubricants, etc. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21 st Edition (Lippincott Williams & Wilkins, 2005).

[0224] 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.

[0225] In certain embodiments, the pharmaceutical composition further comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, which consist of six, seven, and eight α-1,4-linked glucose units, respectively, optionally containing one or more substituents on the attached sugar moiety (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% aqueous solution).

[0226] Injectable compositions can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0227] Generally, the compounds provided herein are administered in an effective amount. The amount of compound actually administered will typically be determined by a physician in light of the relevant circumstances, including the condition being treated, the selected route of administration, the actual compound being administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0228] The compositions are provided in unit dosage forms to facilitate accurate administration. The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage for human subjects and other mammals, each unit containing a predetermined amount of active ingredient calculated to achieve a desired therapeutic effect together with suitable pharmaceutical excipients. Typical unit dosage forms include prefilled ampoules or syringes containing a premeasured liquid composition. In such compositions, the compound is usually a minor component (about 0.1% to about 50% by weight, or preferably about 1% to about 40% by weight), with the remainder consisting of various vehicles or carriers and processing aids useful for forming the desired dosage form.

[0229] The compounds provided herein can be administered as a single 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. The administration of the combination can be by any technique apparent to one of skill in the art, including, for example, separate, sequential, simultaneous, and alternating administration. ) can be performed.

[0230] While the description of pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for administration to humans, those skilled in the art will understand that such compositions are generally suitable for administration to all types of animals. Modifications of pharmaceutical compositions suitable for administration to humans to make them suitable for administration to a variety of animals are well understood, and veterinary pharmacologists of ordinary skill in the art can design and / or perform such modifications using routine experimentation. General considerations in formulating and / or manufacturing pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21 st ed., Lippincott Williams & Wilkins, 2005.

[0231] In one aspect, a kit is provided that includes a composition (eg, a solid composition) comprising a compound of Formula (I).

[0232] Combination therapy A compound or composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof) can be administered in combination with an additional drug or therapy. The subject receiving a compound disclosed herein can have a disease, disorder, or condition, or a symptom thereof, that would benefit from treatment with another drug or therapy. Combination therapy can be achieved by administering two or more drugs, each formulated and administered separately, or by administering two or more drugs in a single formulation. In some embodiments, two or more drugs in the combination therapy can be administered simultaneously. In other embodiments, two or more drugs in the combination therapy are administered separately. For example, administration of a first drug (or combination of drugs) can occur minutes, hours, days, or weeks before administration of a second drug (or combination of drugs). Thus, two or more drugs can be administered within minutes of each other, or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 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. Although it is often desirable for two or more drugs used in combination therapy to be present in the patient's body at the same time, this does not have to be the case.

[0233] Combination therapy can also include two or more administrations of one or more combined agents, using the component agents in different orders. For example, when agent X and agent Y are used in combination, they can be administered one or more times sequentially in any combination, for example, in the order XYX, XXY, YXY, YYX, XXYY, etc. Exemplary additional agents are described below.

[0234] Selective serotonin reuptake inhibitors (SSRIs) In some embodiments, a compound or composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof) is 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).

[0235] Norepinephrine reuptake inhibitors (NERIs) In some embodiments, a compound or composition described herein (e.g., a compound of Formula I) or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof) is administered in combination with a NERI(s). Exemplary NERIs include, but are not limited to, atomoxetine (Strattera), reboxetine (Edronax, Bestra), bupropion (Wellbutrin, Zyban), duloxetine, desipramine (Norpramine), amedalin (UK-3540-1), daredalin (UK-3557-15), edivoxetine (LY-2216684), esreboxetine, lortalamine (LM-1404), nisoxetine (LY-94,939), talopram (taslopram) (Lu 3-010), talsupram (Lu 5-005), tandamine (AY-23,946), and viloxazine (Vivaran).

[0236] Antipsychotics In some embodiments, a compound or composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof) is administered in combination with an antipsychotic agent(s). Antipsychotic agents include D2 antagonists that reduce dopaminergic neurotransmission in the dopamine pathway. Exemplary antipsychotic drugs include, but are not limited to, asenapine (Safris), aripiprazole (Abilify), cariprazine (Bleilar), clozapine (Clozaril), droperidol, fluperlapine, mesoridazine, quetiapine hemifumarate, raclopride, spiperone, sulpiride, trimethobenzamide hydrochloride, trifluoperazine dihydrochloride, lurasidone (Latuda), olanzapine (Zyprexa), quetiapine (Seroquel), zotepine, risperidone (Risperidal), ziprasidone (Geodon), mesoridazine, chlorpromazine hydrochloride, and haloperidol (Haldol).

[0237] cannabinoids In some embodiments, a compound or composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof) is administered in combination with a cannabinoid(s). Exemplary cannabinoids include, but are not limited to, cannabidiol (Epidiolex), tetrahydrocannabinolic acid, tetrahydrocannabinol, cannabidolic acid, cannabinol, cannabigerol, cannabichromene, tetrahydrocannabivarin, and cannabidivarin.

[0238] NMDA receptor antagonists In some embodiments, a compound or composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof) is administered in combination with one or more NMDA receptor antagonists. 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-dichlorokynurenic acid, licostinel, memantine, gavestenel, 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.

[0239] GABA receptor antagonists In some embodiments, a compound or composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof) is administered in combination with a GABA receptor antagonist(s). A GABA receptor antagonist is a type of drug that is an antagonist of one or more GABA receptors. Exemplary GABA receptor antagonists include: A receptor antagonists 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, lormetazepam, flutazolam, nitrazepam, fluritrazepam, nimetazepam, diazepam, medazepam, oxazolam, prazeam, tofisopam, rilmazafone, lorazepam, temazepam, oxazepam, fludiazepam, and chloramphenicol. Diazepoxide, cloxazolam, flutoprazepam, alprazolam, estazolam, bromazepam, flurazepam, clorazepate potassium, 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).

[0240] Cholinesterase inhibitors In some embodiments, a compound or composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof) is administered in combination with a cholinesterase inhibitor(s). Generally, cholinergic agents are compounds that mimic the action of acetylcholine and / or butyrylcholine. Cholinesterase inhibitors are a type of drug that prevents the breakdown of acetylcholine. Exemplary cholinesterase inhibitors include, but are not limited to, donepezil (Aricept), tacrine (Cognex), rivastigmine (Exelon, Exelon Patch), galantamine (Razadyne, Reminyl), memantine / donepezil (Namzalic), ambenonium (Mytelase), neostigmine (Broxivert), pyridostigmine (Mestinon Timespan, Regonol), and galantamine (Razadyne).

[0241] The present disclosure also contemplates, inter alia, administering a compound or pharmaceutical composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I 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, an additional agent is administered to the subject prior to administering a compound or pharmaceutical composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof), wherein 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 or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof) is co-administered to the subject with an agent selected from the group consisting of a bronchial muscle / airway relaxant, an antiviral agent, oxygen, and an antibacterial agent.

[0242] Methods of Use and Treatment In one aspect, the compounds described herein, e.g., compounds of Formula (I), are useful for treating a CNS-related disorder (e.g., sleep disorders, mood disorders such as depression, schizophrenia spectrum disorders, seizure disorders, epileptic seizures, memory and / or cognition disorders, movement disorders, personality disorders) in a subject in need thereof (e.g., a subject having Rett syndrome, Fragile X syndrome, or Angelman syndrome). The compounds are contemplated to be useful as therapeutic agents for treating conditions such as encephalopathy, autism spectrum disorder, pain, traumatic brain injury, vascular disease, substance abuse disorders and / or withdrawal syndromes, or tinnitus. Exemplary CNS conditions associated with GABA modulation include sleep disorders [e.g., insomnia], mood disorders [e.g., depression (e.g., major depressive disorder (MDD)), dysthymic disorder (e.g., mild depression), bipolar disorder (e.g., Type I and / or Type II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD)], schizophrenia spectrum disorders [e.g., schizophrenia, schizoaffective disorder], convulsive disorders [e.g., epilepsy (e.g., status epilepticus (SE)), seizures], memory and / or cognition disorders [e.g., attention disorders (e.g., attention deficit hyperactivity disorder (ADHD))], dementia (e.g., , Alzheimer's disease, dementia with Lewy bodies, vascular dementia), movement disorders (e.g., Huntington's disease, Parkinson's disease), personality disorders (e.g., antisocial personality disorder, obsessive-compulsive personality disorder), autism spectrum disorders (ASD) (e.g., autism, monogenic cases of autism such as synaptic degeneration, e.g., Rett syndrome, Fragile X syndrome, Angelman syndrome), pain (e.g., neuropathic pain, injury-related pain syndrome, acute pain, chronic pain), traumatic brain injury (TBI), cerebrovascular disease (e.g., stroke, ischemia, vascular malformation), substance abuse disorders and / or withdrawal syndromes (e.g., addiction to opiates, cocaine, and / or alcohol), and tinnitus.

[0243] 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.

[0244] In one aspect, there is provided a method of reducing or preventing seizure activity in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the invention, hi some embodiments, the method reduces or prevents epileptic seizures.

[0245] In yet another aspect, the present invention provides a combination of a compound of the present invention with another pharmacologically active agent. The compounds provided herein can be administered as a single active agent or in combination with other agents. The administration of the combination can be carried out by any technique that is apparent to those skilled in the art, including, for example, separate administration, sequential administration, simultaneous administration, and alternating administration.

[0246] 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.

[0247] 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.

[0248] In yet another aspect, there is provided a method for reducing or preventing insomnia in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention, or a composition thereof.

[0249] In yet another aspect, there is provided a method for inducing sleep and substantially maintaining the level of REM sleep seen in normal sleep, without inducing substantial rebound insomnia, comprising administering an effective amount of a compound of the invention.

[0250] 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.

[0251] In yet another aspect, there is provided a method of 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, hi certain embodiments, the mood disorder is depression.

[0252] In yet another aspect, the present invention provides a method for cognitive enhancement or treating 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.

[0253] In yet another aspect, there is provided a method for treating attention disorders by administering to a subject a therapeutically effective amount of a compound of the invention. In certain embodiments, the attention disorder is ADHD.

[0254] 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 reaction against myelin proteins) and meningoencephalitis (in which an infectious agent initiates an inflammatory response). Furthermore, scientific evidence suggests a potential role for inflammatory mechanisms in other neurological pathologies, 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 pathologies, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, stroke, and traumatic brain injury.

[0255] In certain embodiments, the compound is administered chronically to the subject. In certain embodiments, the compound is administered orally, subcutaneously, intramuscularly, or intravenously to the subject.

[0256] Neuroendocrine disorders and dysfunction Methods are provided herein 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 that 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 control hormone production, damage to the hypothalamus or pituitary gland, for example, due to traumatic brain injury, can affect hormone production and other neuroendocrine functions of the brain. In some embodiments, the neuroendocrine disorder or dysfunction is associated with a women's health disorder or condition (e.g., 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.

[0257] Symptoms of neuroendocrine disorders include, but are not limited to, behavioral, emotional, and sleep-related symptoms, symptoms related to reproductive function, and physical symptoms, including, but not limited to, fatigue, poor memory, anxiety, depression, weight gain or loss, emotional lability, lack of concentration, difficulty paying attention, decreased libido, infertility, amenorrhea, loss of muscle mass, increased abdominal body fat, low blood pressure, low heart rate, hair loss, anemia, constipation, cold intolerance, and dry skin.

[0258] Neurodegenerative Diseases and Disorders The methods described herein can be used to treat neurodegenerative diseases and disorders. The term "neurodegenerative disease" encompasses 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 associated symptoms of mild, moderate, or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic and ischemic injury; ataxia and seizures (including for the treatment and prevention, and for the prevention of seizures caused by schizoaffective disorder or medications used to treat schizophrenia); benign amnesia; cerebral edema; cerebellar ataxia, including McLeod neuroacanthocytosis syndrome (MLS); closed head injury; coma; contusion injury (e.g., spinal cord injury and head injury); dementia, including multi-infarct dementia and senile dementia; impairment of consciousness; Down's syndrome; drug-induced or medication-induced Parkinson's disease (such as neuroleptic-induced acute akathisia, acute dystonia, parkinsonism, or tardive dyskinesia, neuroleptic malignant syndrome, or medication-induced postural tremor); epilepsy; Fragile X syndrome; Gilles de la Tourette syndrome; head trauma; deafness and hearing impairment; Huntington's disease; Lennox syndrome; levodopa-induced Dyskinesias; mental retardation; movement disorders, including akinesia and akinesia (rigidity) syndromes (including brainstem neurocalcification, corticobasal degeneration, multiple system atrophy, Parkinsonism-ALS dementia complex, Parkinson's disease, postencephalitic parkinsonism, and progressive supranuclear palsy); muscle spasms and disorders associated with muscle spasms or weakness (chorea (e.g., benign hereditary chorea, drug-induced chorea, hemiballismus, Huntington's disease, neuroacanthocytosis, Sydenham's chorea, and symptomatic chorea), dyskinesias (complex chorea), tics, including tics such as tics, simple tics, and asymptomatic tics), myoclonus, including generalized myoclonus and focal cycloclonic jerks, tremors, such as rest tremor, postural tremor, and intention tremor, and dystonia, such as truncal dystonia, dystonic writer's cramp, hemiplegic dystonia, paroxysmal dystonia, and focal dystonia, including blepharospasm, temporomandibular dystonia, and spasmodic dysphonia and spasmodic torticollis; neuronal damage, including eye damage, retinopathy, or macular degeneration of the eye;Neurodegenerative diseases include, but are not limited to, stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia, and neurotoxicity following cardiac arrest; Parkinson's disease; seizures; status epilepticus; stroke; tinnitus; tuberous sclerosis; and viral infection-induced neurodegeneration (e.g., those caused by acquired immunodeficiency syndrome (AIDS) and encephalopathy). Neurodegenerative diseases also include, but are not limited to, stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia, and neurotoxicity following cardiac arrest. Methods for treating or preventing neurodegenerative diseases also include treating or preventing the loss of neuronal function characteristic of neurodegenerative disorders.

[0259] Mood disorders Also provided herein are methods for treating mood disorders, such as clinical depression, postpartum or postpartum depression, perinatal depression, atypical depression, melancholic depression, psychotic major depression, catatonic depression, seasonal affective disorder, dysthymia, bipolar depression, depressive personality disorder, recurrent brief depression, minor depressive disorder, bipolar or manic-depressive disorder, depression due to 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), or women's health disorders or conditions).

[0260] Clinical depression, also known as major depression, major depressive disorder (MDD), severe depression, unipolar depression, unipolar disorder, and recurrent depression, is 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. Clinical depression refers to a condition in which a person has difficulty sleeping, loses weight, and generally feels agitated and irritable. Clinical depression affects how a person feels, thinks, and behaves, and can lead to a variety of emotional and physical problems. Individuals with clinical depression may have difficulty performing daily activities and may feel as if life is not worth living.

[0261] Perinatal depression refers to depression during pregnancy. Symptoms include irritability, tearfulness, restlessness, sleep disturbances, exhaustion (emotional and / or physical), changes in appetite, difficulty concentrating, increased anxiety and / or worry, feelings of disconnection from the baby and / or fetus, and loss of interest in previously enjoyed activities.

[0262] Postpartum depression (PND), also known as postpartum depression (PPD), refers to a type of clinical depression that women experience after giving birth. Symptoms may include sadness, fatigue, changes in sleep and eating habits, decreased libido, tearful episodes, anxiety, and irritability. In some embodiments, the PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein). In some embodiments, the PND is treatment-refractory depression (e.g., treatment-refractory depression as described herein).

[0263] In some embodiments, the subject with PND also experiences depression or depressive symptoms during pregnancy.This depression is herein referred to as perinatal depression.In one embodiment, the subject who experiences perinatal depression has a high risk of experiencing PND.

[0264] 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 sleepiness or somnolence (hypersomnia), a feeling of heaviness in the limbs, and hypersensitivity to perceived interpersonal rejection.

[0265] Melancholic depression is characterized by loss of pleasure in most or all activities (anhedonia), unresponsiveness to pleasurable stimuli, depressed mood more pronounced than grief or loss, excessive weight loss, or excessive guilt.

[0266] Psychotic major depression (PMD) or psychotic depression refers to a major depressive episode, particularly one of a melancholic nature, in which an individual experiences psychotic symptoms such as delusions and hallucinations.

[0267] Catatonic depression refers to major depression accompanied by disturbances in motor behavior and other symptoms. Individuals may become mute and stuporous, become immobile, or exhibit purposeless or bizarre movements.

[0268] Seasonal affective disorder (SAD) refers to a type of seasonal depression in which an individual has a seasonal pattern of depressive episodes that occur in the fall or winter.

[0269] Dysthymia refers to a condition related to unipolar depression that causes the same physical and cognitive problems, but tends to be less severe and last longer (e.g., at least 2 years).

[0270] Double depression is defined as at least two years of significant depressed mood (dysthymia) interspersed with periods of major depression.

[0271] Depressive personality disorder (DPD) refers to a personality disorder with depressive traits.

[0272] Recurrent brief depression (RBD) refers to a condition in which an individual has depressive episodes approximately once per month, each lasting for a short period of time (less than two weeks), typically less than two to three days.

[0273] Minor depressive disorder or minor depression refers to depression in which at least two symptoms are present for two weeks.

[0274] Bipolar disorder or manic-depressive disorder causes extreme mood swings, including emotional highs (mania or hypomania) and lows (depression). During manic periods, individuals may experience unusual euphoria, energy, or irritability in their emotions or behavior. Such individuals often make ill-considered decisions with little regard for the consequences. They usually have a decreased need for sleep. During depressive periods, individuals may become tearful, make less eye contact with others, and become pessimistic about life. The risk of suicide for people with this disorder is high—more than 6% over a 20-year period—and 30–40% will self-harm. Other mental health problems, such as anxiety disorders and substance abuse disorders, often coexist with bipolar disorder.

[0275] Chronic condition-induced depression refers to depression caused by a chronic medical condition such as cancer, chronic pain, chemotherapy, or chronic stress.

[0276] Treatment-resistant depression refers to a condition in which an individual is treated for depression but the symptoms do not improve. For example, antidepressants or psychological counseling (psychotherapy) do not alleviate the depressive symptoms of individuals with treatment-resistant depression. In some cases, individuals with treatment-resistant depression improve but then relapse. Treatment-resistant depression occurs in patients with depression who are resistant to standard pharmacological treatments, including tricyclic antidepressants, MAOIs, SSRIs, and double and triple doses of inhibitors and / or anxiolytics, as well as non-pharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagus nerve stimulation, and / or transcranial magnetic stimulation).

[0277] Postoperative depression refers to depressed feelings that continue after a surgical procedure (e.g., as a result of facing death). For example, patients 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.

[0278] A mood disorder associated with a women's health condition or disorder refers to a mood disorder (eg, depression) that is associated with (eg, caused by) a women's health condition or disorder (eg, as described herein).

[0279] Suicidal tendencies, ideation, and behavior refer to an individual's tendency to attempt suicide. Suicidal ideation involves thoughts about or an abnormal preoccupation with suicide. The spectrum of suicidal ideation varies significantly, for example, from passing thoughts to widespread ideation, detailed plans, role-playing, and aborted attempts. Symptoms may include talking about suicide, obtaining the means to attempt suicide, withdrawing from social contacts, preoccupation with death, feeling trapped or hopeless about a situation, increased 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.

[0280] Symptoms of depression include persistent feelings of anxiety or sadness, helplessness, hopelessness, pessimism, feelings of worthlessness, low energy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, difficulty exercising, loss of interest in pleasurable activities or hobbies, difficulty concentrating, low energy, low self-esteem, lack of positive thinking or planning, excessive sleeping, overeating, loss of appetite, insomnia, self-harm, suicidal thoughts, and suicide attempts. The presence, severity, frequency, and duration of symptoms may vary from case to case. Depression symptoms and their relief should be confirmed by a doctor or psychologist (e.g., by mental status examination). It is possible.

[0281] In some embodiments, the method includes monitoring the subject using known depression rating scales, such as the Hamilton Depression Rating Scale (HAM-D), Clinical Global Impression-Improvement Scale (CGI), and Montgomery-Asberg Depression Rating Scale (MADRS). In some embodiments, the effectiveness of treatment can be determined by a reduction in the subject's Hamilton Depression Rating Scale (HAM-D) total score. A 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 effectiveness of treatment can be assessed over a specific treatment period. For example, therapeutic efficacy can be determined by a reduction from baseline in HAM-D total score after administration of a compound described herein, e.g., a compound of Formula (I) (e.g., 12, 24, or 48 hours after administration; or 24, 48, 72, or 96 hours 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).

[0282] In some embodiments, the subject has a mild depressive disorder, e.g., mild major depressive disorder. In some embodiments, the subject has a moderate depressive disorder, e.g., moderate major depressive disorder. In some embodiments, the subject has a severe depressive disorder, e.g., severe major depressive disorder. In some embodiments, the subject has a very severe depressive disorder, e.g., very severe major depressive disorder. In some embodiments, the subject's baseline HAM-D total score (i.e., before treatment with a compound described herein, e.g., a compound of Formula (I)) is at least 24. In some embodiments, the subject's baseline HAM-D total score is at least 18. In some embodiments, the subject's baseline HAM-D total score is 14 to 18, inclusive. In some embodiments, the subject's baseline HAM-D total score is 19 to 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), 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), is about 0-10 (e.g., less than 10; 0-10, 0-6, 0-4, 0-3, 0-2, or 1.8). In some embodiments, the subject's HAM-D total score after treatment with a compound described herein, e.g., a compound of Formula (I), is less than 10, i.e., 7, 5, or 3. In some embodiments, after treatment with a compound described herein, e.g., a compound of Formula (I), the HAM-D total score is reduced 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). In some embodiments, the reduction in HAM-D total score after treatment with a compound described herein, e.g., a compound of Formula (I), from baseline HAM-D total score is at least 1, 2, 3, 4, 5, 7, 10, 25, 40, 50, or 100-fold.In some embodiments, the percent reduction in HAM-D total score after treatment with a compound described herein, e.g., a compound of Formula (I), from baseline HAM-D total score is at least 50% (e.g., 60%, 70%, 80%, or 90%). In some embodiments, the therapeutic effect is measured by a reduction in HAM-D total score after treatment with a compound described herein, e.g., a compound of Formula (I) (e.g., 12, 24, 48 hours; or 24, 48, 72, 96 hours or 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.

[0283] In some embodiments, the method for treating a depressive disorder, e.g., major depressive disorder, comprises: In some embodiments, the method for treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic benefit (e.g., as measured by a statistically significant decrease in the HAM-D total score) within 4, 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 benefit (e.g., as determined by a statistically significant decrease in the HAM-D total score) by the first or second day of treatment with a compound described herein, e.g., a compound of Formula (I). In some embodiments, the method for treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic benefit (e.g., as determined by a statistically significant decrease in the HAM-D total score) within 14 days of initiating treatment with a compound described herein, e.g., a compound of Formula (I). In some embodiments, the method for treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic benefit (e.g., as determined by a statistically significant decrease in the HAM-D total score) within 21 days of initiating treatment with a compound described herein, e.g., a compound of Formula (I). In some embodiments, the method of treating a depressive disorder, e.g., major depressive disorder, results in a therapeutic effect (e.g., as determined by a statistically significant decrease in HAM-D total score) within 28 days of initiating treatment with a compound described herein, e.g., a compound of Formula (I). In some embodiments, the therapeutic effect is a decrease in HAM-D total score from baseline after treatment with a compound described herein, e.g., a compound of Formula (I) (e.g., 14 days of once-daily treatment with a compound described herein, e.g., a compound of Formula (I)). In some embodiments, the subject's HAM-D total score before treatment with a compound described herein, e.g., a compound of Formula (I), is at least 24. In some embodiments, the subject's HAM-D total score before treatment with a compound described herein, e.g., a compound of Formula (I), is at least 18. In some embodiments, the subject's HAM-D total score before treatment with a compound described herein, e.g., a compound of Formula (I), is between 14 and 18, inclusive. In some embodiments, the reduction in the HAM-D total score after treatment of a subject with a compound described herein, e.g., a compound of Formula (I), compared to the baseline HAM-D total score is at least 10.In some embodiments, the reduction in HAM-D total score following treatment of a subject with a compound described herein, e.g., a compound of Formula (I), compared to the baseline HAM-D total score is at least 15 (e.g., at least 17). In some embodiments, treatment of a subject with a compound described herein, e.g., a compound of Formula (I), accompanies a HAM-D total score of no more than a number in the range of 6 to 8. In some embodiments, treatment of a subject with a compound described herein, e.g., a compound of Formula (I), accompanies a HAM-D total score of no more than 7.

[0284] In some embodiments, the method provides a therapeutic benefit (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 benefit by day 2 of the treatment period. In some embodiments, the therapeutic benefit is a reduction in CGI score from baseline at the end of the treatment period (e.g., day 14 after administration).

[0285] In some embodiments, the method provides a therapeutic benefit (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 benefit by day 2 of the treatment period. In some embodiments, the therapeutic benefit is a reduction in the MADRS score from baseline at the end of the treatment period (e.g., day 14 after administration).

[0286] The effectiveness of treatment for major depressive disorder can be determined by a reduction in a subject's Montgomery-Asberg Depression Rating Scale (MADRS) score. For example, the MADRS score can be It 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 outward sadness, verbal sadness, inner tension, decreased sleep, decreased appetite, difficulty concentrating, inhibitions, lack of emotion, pessimistic thoughts, and suicidal thoughts) that psychiatrists use to measure the severity of depressive episodes in patients with mood disorders.

[0287] In some embodiments, the method results in a therapeutic effect (e.g., as measured by a reduction in the Edinburgh Postnatal Depression Scale (EPDS)) within 4, 3, 2, 1 day; 24, 20, 16, 12, 10, 8 hours. In some embodiments, the therapeutic effect is an improvement as measured by the EPDS.

[0288] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a reduction in the Generalized Anxiety Disorder 7-item scale (GAD-7)) within 4, 3, 2, 1 day; 24, 20, 16, 12, 10, 8 hours.

[0289] Anxiety disorders Provided herein are methods for treating anxiety disorders (e.g., generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, phobias, and post-traumatic stress disorder). Anxiety disorder is an umbrella term that encompasses several different forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic criteria distinguish between a wide variety of anxiety disorders.

[0290] Generalized anxiety disorder (GAD) is a common chronic disorder characterized by long-term anxiety that is not focused on any one goal or situation. Those suffering from GAD experience persistent, nonspecific fear and worry, and become excessively concerned about minor everyday occurrences. GAD is the most common anxiety disorder affecting older adults.

[0291] In panic disorder, patients experience brief, intense attacks of fear and anxiety, often characterized by tremors, shaking, confusion, dizziness, nausea, and difficulty breathing. Defined by the APA as sudden onset of fear or discomfort that peaks in less than 10 minutes, these attacks can last for hours and can be triggered by stress, fear, or even exercise, although a specific cause is not always apparent. In addition to recurrent, unexpected panic attacks, a diagnosis of panic disorder also requires that the attacks have chronic consequences (either worry about the attack's potential impact, persistent fear of future attacks, or significant behavioral changes related to the attack). Thus, those suffering from panic disorder also experience symptoms outside of a specific panic episode. Often, when panic sufferers notice normal heart rate changes, they believe there is something wrong with their heart or that another panic attack is coming. In some cases, heightened perceptions of bodily functions (hyperarousal) occur during a panic attack, leading to interpretation of perceived physiological changes as potentially life-threatening illness (i.e., extreme hypochondriasis).

[0292] 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 habitual behaviors). OCD thought patterns are sometimes likened to superstition because they involve belief in nonexistent causal relationships. The process is often entirely illogical; for example, a patient may engage in a compulsive behavior, such as walking in a particular pattern, to alleviate obsessive thoughts of impending harm. In many cases, the compulsions are entirely inexplicable and are simply urges to complete habitual behaviors triggered by nervousness. In a minority of cases, OCD patients experience only obsessions without overt compulsions, and even fewer experience only compulsions.

[0293] The largest single category of anxiety disorders is that of phobias, which includes all cases in which fear and anxiety are provoked by a particular stimulus or situation. Patients typically anticipate frightening consequences from encountering their feared object (which can be anything from an animal to a place or bodily fluid).

[0294] Post-traumatic stress disorder, or PTSD, is an anxiety disorder that results 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 significant stressors (e.g., soldiers who can tolerate individual combat but are unable to cope with sustained combat). Common symptoms include flashbacks, avoidance behaviors, and depression.

[0295] Women's Health Disorders Provided herein are methods for treating women's health-related conditions or disorders, including, but not limited to, gynecological health conditions and disorders (e.g., premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD)), fertility issues (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).

[0296] Gynecological conditions and disorders affecting women include menstruation and menstrual irregularities; urinary tract conditions, including urinary incontinence and pelvic floor disorders; and disorders such as bacterial vaginosis, vaginitis, uterine fibroids, and vulvodynia.

[0297] 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, overeating, fatigue, irritability, acne, and depression.

[0298] Premenstrual dysphoric disorder (PMDD) is a severe form of PMS. Symptoms of PMDD are similar to those of PMS but are more severe and can interfere with work, social activities, and relationships. Symptoms of PMDD include mood swings, depressed mood or feelings of hopelessness, marked anger, increased interpersonal conflict, tension and anxiety, irritability, decreased interest in usual activities, difficulty concentrating, fatigue, appetite changes, uncontrollable or irresistible feelings, sleep disturbances, and physical problems (e.g., swelling, breast tenderness, edema, headaches, joint or muscle pain).

[0299] Pregnancy issues include preconception and prenatal care, pregnancy termination (miscarriage and stillbirth), preterm labor and delivery, sudden infant death syndrome (SIDS), breastfeeding, and congenital anomalies.

[0300] A miscarriage is a pregnancy that ends naturally within the first 20 weeks of pregnancy.

[0301] Abortion refers to the intentional interruption of a pregnancy, which can be performed during the first 28 weeks of pregnancy.

[0302] Infertility and related disorders include uterine fibroids, polycystic ovary syndrome, endometriosis, and primary ovarian insufficiency.

[0303] 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 menstrual periods, amenorrhea, menorrhagia, excessive body and facial hair, acne, pelvic pain, difficulty conceiving, and thickened ovaries. Symptoms include dark, velvety patches of skin. PCOS can be associated with conditions including type 2 diabetes, obesity, obstructive sleep apnea, heart disease, mood disorders, and endometrial cancer.

[0304] Other disorders and conditions that affect only women include Turner syndrome, Rett syndrome, and ovarian and cervical cancer.

[0305] Issues relating to women's overall health and wellness include violence against women, women with disabilities and their particular challenges, osteoporosis and bone health, and menopause.

[0306] Menopause refers to the 12 months following a woman's last menstrual period and is characterized by the end of the menstrual cycle. Menopause usually occurs in women in their 40s or 50s. The physical (e.g., hot flushes) and emotional symptoms of menopause can disrupt sleep, reduce energy, and induce anxiety or feelings of sadness or loss. Menopause includes natural menopause and surgical menopause, which is a type of menopause induced by events such as surgery (e.g., hysterectomy, oophorectomy, cancer). It is induced when the ovaries are severely damaged, such as by radiation, chemotherapy, or other medications.

[0307] epilepsy A compound of formula (I) or a pharmaceutically acceptable salt, or a pharmaceutically acceptable composition, can be used in the methods described herein, e.g., for the treatment of a disorder described herein, such as epilepsy, status epilepticus, or seizures.

[0308] Epilepsy is a brain disorder characterized by recurrent seizures over time. Types of epilepsy can include, but are not limited to, generalized epilepsy, such as childhood absence epilepsy, juvenile myoclonic epilepsy, epilepsy with grand mal seizures on awakening, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, such as temporal lobe epilepsy, frontal lobe epilepsy, and benign focal childhood epilepsy.

[0309] Epileptic seizures The compounds and methods described herein can be used to treat or prevent epileptic seizures. Epileptic seizures are a sequential process in which a normal brain develops epilepsy (a chronic condition in which seizures occur). Epileptic seizures result from neuronal damage that is suddenly triggered by an initial injury (e.g., status epilepticus).

[0310] Status epilepticus (SE) Status epilepticus (SE) can include, for example, convulsive status epilepticus, e.g., early status epilepticus, confirmed status epilepticus, refractory status epilepticus, and very refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus, generalized periodic epileptiform discharges, and periodic unilateral epileptic discharges. Convulsive status epilepticus is characterized by the presence of convulsive status epilepticus and can include early status epilepticus, confirmed status epilepticus, refractory status epilepticus, and very refractory status epilepticus. Early status epilepticus is treated with first-line therapy. Confirmed status epilepticus is characterized by status epilepticus that persists despite treatment with first-line therapy, leading to the implementation of second-line therapy. Refractory status epilepticus is characterized by status epilepticus that persists despite treatment with first-line and second-line therapies and for which general anesthetics are administered systemically. Super-refractory status epilepticus is characterized by status epilepticus that persists despite treatment with first-line, second-line therapies, and general anesthetics for more than 24 hours.

[0311] Non-convulsive status epilepticus can be, for example, focal non-convulsive status epilepticus, e.g., complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, latent non-convulsive status epilepticus, Status epilepticus; may include 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.

[0312] The compounds of formula (I) or pharmaceutically acceptable salts, or pharmaceutically acceptable compositions thereof, may also be administered as a prophylactic agent before the onset of a seizure to subjects with a CNS disorder, such as traumatic brain injury, status epilepticus, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, very refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic unilateral epileptic discharges.

[0313] 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 synonymously with "convulsion." A convulsion is when the human body shakes rapidly and uncontrollably. During a convulsion, a person's muscles repeatedly contract and relax.

[0314] Based on the type of behavior and brain activity, seizures are classified into two broad categories: generalized and partial (also called focal or focal). Classifying the type of seizure helps doctors diagnose whether a patient has epilepsy.

[0315] Generalized seizures are caused by electrical excitation throughout the brain, whereas partial seizures are caused (at least initially) by electrical excitation in a smaller part of the brain. The part of the brain that produces the seizure is sometimes called the focus.

[0316] There are six types of generalized seizures. The most common, most severe, and therefore best known is a generalized convulsion, also known as a grand mal seizure. During this type of seizure, the patient loses consciousness and usually passes out. Following this loss of consciousness, there is a 30-60 second period of generalized rigidity (called the "tonic" phase of the seizure), followed by another 30-60 second period of violent convulsions (the "clonic" phase), after which the patient enters a deep sleep state (the "postictal" or postictal period). During a grand mal seizure, injuries and accidents such as tongue biting and urinary incontinence can occur.

[0317] Absence seizures cause a brief loss of consciousness (only a few seconds) with little to no symptoms. Typically, the patient (mostly a child) stops moving and stares blankly. These seizures begin and end suddenly and may occur several times a day. Patients are usually unaware that a seizure is occurring, except for the ability to keep track of "time."

[0318] Myoclonic seizures consist of sporadic jerks, usually on both sides of the body. Patients may describe the jerks as brief electric shocks. These seizures, when severe, may cause dropping or involuntary throwing of objects.

[0319] Clonic seizures are recurrent rhythmic convulsions that involve both sides of the body simultaneously.

[0320] Tonic seizures are characterized by muscle stiffness.

[0321] Cataplexy consists of a sudden generalized loss of muscle tone, especially in the arms and legs, often causing falls.

[0322] The seizures described herein may include epileptic seizures; acute repetitive seizures; cluster seizures; continuous seizures; persistent 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 convulsions; affective seizures; focal seizures; galactoceles; generalized onset seizures; infantile spasms; Jacksonian seizures; widespread bilateral myoclonic seizures; multifocal seizures; neonatal onset seizures; nocturnal seizures; occipital lobe seizures; post-traumatic seizures; latency seizures; Sylvan seizures; visual reflex seizures; or withdrawal seizures. In some embodiments, the seizures are generalized seizures associated with Dravet syndrome, Lennox-Gastaut syndrome, tuberous sclerosis complex, Rett syndrome, or PCDH19 female epilepsy.

[0323] Movement disorders Also described herein are methods for treating movement disorders. As used herein, "movement disorder" refers to various diseases and disorders associated with hyperkinetic movement disorders and related to 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 reflex, tic disorders and Tourette's syndrome, restless legs syndrome, stiff person syndrome, and gait disorders.

[0324] Tremor The methods described herein can be used to treat tremors, for example, the compounds of Formula (I) can be used to treat cerebellar or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, Parkinson's tremor, physiological tremor, psychogenic tremor, or red nucleus tremor. Tremors include genetic, degenerative, and idiopathic disorders (such as Wilson's disease, Parkinson's disease, and essential tremor, respectively); metabolic disorders (e.g., thyroid disease, parathyroid disease, liver disease, and hypoglycemia); peripheral neuropathies (associated with Charcot-Marie-Tooth disease, Lucy-Lewy syndrome, diabetes mellitus, and complex regional pain syndrome); toxins (nicotine, mercury, lead, CO, manganese, arsenic, toluene); drug-induced (sleep-inducing drugs, tricyclic antidepressants, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychogenic disorders. Clinical tremor can be classified as physiologic tremor, enhanced physiologic tremor, essential tremor syndrome (including classic essential tremor, primary orthostatic tremor, and task- and position-specific tremor), dystonic tremor, Parkinson's tremor, cerebellar tremor, Holmes tremor (i.e., red nucleus tremor), palatal tremor, neuropathic tremor, toxic or drug-induced tremor, and psychogenic tremor.

[0325] Tremor is an involuntary, intermittent rhythmic movement, muscle contraction, and relaxation that may involve vibration or twitching of one or more body parts (e.g., hands, arms, eyes, face, head, vocal cords, trunk, legs).

[0326] 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, or diseases (e.g., multiple sclerosis, hereditary degenerative diseases).

[0327] Dystonic tremor occurs in individuals with dystonia and is a movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive movements and / or painful, abnormal postures or positions. Dystonic tremor can affect any muscle in the body. Dystonic tremor occurs irregularly and is often relieved by complete rest.

[0328] Essential tremor, or benign essential tremor, is the most common type of tremor. It may be mild and non-progressive or develop slowly, starting on one side of the body but affecting both sides within three years. It most commonly affects the hands, but may also affect the head, vocal cords, tongue, legs, and trunk. Tremors may decrease in frequency but increase in severity with age. Emotional arousal, stress, fever, physical fatigue, or hypoglycemia may trigger tremors and / or increase their severity. Symptoms typically evolve over time and, once present, may be visible and persistent.

[0329] Orthostatic tremor is characterized by rapid (e.g., greater than 12 Hz) rhythmic muscle contractions in the legs and trunk immediately after standing. Patients may experience painful muscle spasms in the thighs and legs, and may tremble uncontrollably when asked to stand in one place. Patients with essential tremor may experience orthostatic tremor.

[0330] Parkinsonian tremor is caused by damage to structures in the brain that control movement. Parkinsonian tremor is often a precursor to Parkinson's disease and is typically seen as a "pill-rolling" movement of the hands, and may also affect the jaw, lips, legs, and trunk. Onset of Parkinsonian tremor usually begins after age 60. Movements may begin in one limb or side of the body and progress to involve the other side.

[0331] Physiologic tremor can occur in normal individuals and is not clinically significant. Physiologic tremor can be found in all voluntary muscle groups. Physiologic tremor can be caused by certain medications, alcohol withdrawal, or medical conditions including hyperthyroidism and hypoglycemia. Classic tremor has a frequency of approximately 10 Hz.

[0332] Psychogenic or hysterical tremor can occur at rest or during postural or motor activity. Patients with psychogenic tremor may have conversion disorder or another psychiatric illness.

[0333] Red nucleus tremor is characterized by a slow, coarse tremor that can occur at rest, posturally, and intentionally. Tremor is associated with conditions affecting the red nucleus of the midbrain, classic abnormal stroke.

[0334] Parkinson's disease affects the nerve cells in the brain that produce dopamine. Symptoms include muscle stiffness, tremors, and changes in speech and gait. Parkinsonism is characterized by tremors, bradykinesia, rigidity, and postural instability. Although Parkinsonism shares symptoms with Parkinson's disease, it is not a progressive neurodegenerative disease but rather a symptom complex.

[0335] Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions, causing abnormal, often repetitive movements or postures. Dystonic movements can be stereotyped, twisting, and may be tremulous. Dystonia is often initiated by or exacerbated by voluntary movements and is associated with overflow of muscle activation.

[0336] Chorea is a neurological disorder characterized by intermittent involuntary movements that typically affect the shoulders, hips, and face. Huntington's disease is a genetic disorder that causes loss of nerve cells in the brain. Symptoms include uncontrollable movements, clumsiness, and balance problems. Huntington's disease can interfere with walking, speaking, and swallowing.

[0337] Ataxia refers to the complete loss of control of bodily movements and can affect fingers, hands, arms, legs, trunk, speech, and eye movements.

[0338] Myoclonus and startle reflexes are responses to sudden, unexpected stimuli, which It may be auditory, tactile, visual, or vestibular.

[0339] Tics are involuntary movements that are usually sudden, brief, repetitive, and non-rhythmic, typically mimicking normal behavior and often occurring as a secondary cause of normal behavior. Tics can be classified as motor or vocal; motor tics involve movement, while vocal tics involve vocalization. Tics can be simple or complex. For example, simple motor tics involve only a few muscles confined to a specific body part. Tourette's syndrome is a childhood-onset, inherited neuropsychiatric disorder characterized by multiple motor tics and at least one vocal tic.

[0340] Restless legs syndrome is a neurosensorimotor disorder characterized by a strong desire to move the legs while at rest.

[0341] Stiff-person syndrome is a progressive movement disorder characterized by involuntary painful spasms and muscle stiffness, usually involving the lower back and legs. A stiff gait commonly occurs with lumbar hyperlordosis. Characteristic abnormalities in EMG recordings with continuous motor unit activity of the paraspinal axial muscles are commonly observed. Variants include "stiff limb syndrome," which causes focal stiffness usually affecting the distal legs and feet.

[0342] Gait disorders refer to abnormalities in the way or style of walking due to neuromuscular, arthritic, or other physical changes. Gaits are classified according to the system involved in the abnormal gait, including hemiplegic gait, diplegic gait, neuropathic gait, myopathic gait, parkinsonian gait, choreiform gait, ataxic gait, and sensory gait.

[0343] Anesthesia / Sedation Anesthesia is a pharmacologically induced, reversible state of amnesia, analgesia, loss of responsiveness, loss of skeletal muscle reflexes, reduced stress response, or all of these simultaneously. Such effects can be obtained from a single drug that provides a reasonable combination of effects alone, or in some cases, from a combination of drugs (e.g., hypnotics, sedatives, paralytics, analgesics) that achieve an extremely specific combination of results. Anesthesia allows patients to undergo surgery and other procedures without the discomfort and pain they would otherwise experience.

[0344] Sedation is the reduction of irritability or excitement through the administration of pharmacological agents, generally to facilitate a medical or diagnostic procedure.

[0345] Sedation and analgesia encompass a continuum of states of consciousness ranging from minimal sedation (anxiolysis) to general anesthesia.

[0346] Minimal sedation is also known as anxiolysis. Minimal sedation is a drug-induced state during which the patient responds normally to verbal commands. Cognitive function and coordination may be impaired. Ventilatory and cardiovascular function are generally not affected.

[0347] Moderate sedation / analgesia (conscious sedation) is a drug-induced decrease in consciousness during which the patient responds purposefully to verbal commands alone or with mild tactile stimulation. No intervention is usually required to maintain a patent airway. Spontaneous ventilation is usually adequate. Cardiovascular function is usually preserved.

[0348] Deep sedation / analgesia is a drug-induced decrease in consciousness during which the patient cannot be easily aroused but responds purposefully following repetitive or painful stimuli (rather than reflex withdrawal from painful stimuli). Independent ventilation may be impaired, and the patient may have a patent airway. Assistance may be required to maintain normal ventilation. Spontaneous ventilation may be inadequate. Cardiovascular function is usually preserved.

[0349] General anesthesia is a drug-induced loss of consciousness during which the patient cannot be aroused 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 neuromuscular depression. Cardiovascular function may be impaired.

[0350] Sedation in the intensive care unit (ICU) allows for decreased patient awareness of the environment and decreased patient reactivity to external stimuli. This allows for the care of critically ill patients and encompasses the management of a wide range of symptoms that vary across the course of the disease and between patients and individuals. Heavy sedation has been used in critical care to facilitate tolerance of endotracheal intubation and ventilator synchronization, often with the use of neuromuscular blockers.

[0351] 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 sedative agents can have a long duration of action. Sedative agents in the ICU can have a short elimination half-life.

[0352] 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 preserving cardiopulmonary function.

[0353] Also described herein are methods for ameliorating one or more symptoms of a respiratory condition 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 or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof).

[0354] In one aspect, provided herein are methods of treating a subject exhibiting one or more symptoms of a respiratory condition and / or diagnosed with a respiratory condition, comprising administering to the subject an effective amount of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof).

[0355] In some embodiments, the present disclosure contemplates a method of treating a subject when the subject has a respiratory condition, comprising administering to the subject a compound or pharmaceutical composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof).

[0356] In some embodiments, administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof) to a subject exhibiting symptoms of a respiratory condition may result in a reduction in the severity of one or more symptoms of the respiratory condition, or a delay or slowing of the progression of one or more symptoms of the respiratory condition.

[0357] In some embodiments, the subject with the respiratory condition has been or is being treated with mechanical ventilation or oxygen, hi some embodiments, the subject with the respiratory condition has been or is being treated with mechanical ventilation.

[0358] In some embodiments, a compound or pharmaceutical composition described herein (e.g., of Formula I) A compound or pharmaceutical composition (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof) is administered to a subject undergoing or having been treated with mechanical ventilation. In some embodiments, administration of a compound or pharmaceutical composition (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof) described herein is continued throughout the subject's treatment with mechanical ventilation. In some embodiments, administration of a compound or pharmaceutical composition (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof) described herein is continued after the subject has completed treatment with mechanical ventilation.

[0359] In some embodiments, a compound or pharmaceutical composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof) is administered to a subject undergoing or having undergone treatment with a sedative agent. In some embodiments, the sedative agent is propofol or a benzodiazepine.

[0360] In some embodiments, the disclosure includes administering a compound or pharmaceutical composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I 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 a pulse oximeter.

[0361] 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 or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof). In some embodiments, a symptom of the cytokine storm is pulmonary inflammation. In some embodiments, the patient experiencing a cytokine storm has acute respiratory distress syndrome (ARDS).

[0362] respiratory pathology In some embodiments, the subject with a respiratory condition is suffering from respiratory distress, hi some embodiments, the respiratory distress comprises acute shortness of breath.

[0363] In some embodiments, a subject with a respiratory condition may exhibit one or more symptoms selected from the group consisting of airway hyperresponsiveness, inflammation of lung tissue, pulmonary hyperresponsiveness, and inflammation-associated lung pain.

[0364] In some embodiments, the subject with a respiratory condition 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.

[0365] In some embodiments, administering a compound or pharmaceutical composition described herein to a subject exhibiting symptoms of a respiratory condition results in a reduction in the severity of dyspnea in the subject with the respiratory condition, or a delay or slowing of the progression of dyspnea in the subject with the respiratory condition.

[0366] In some embodiments, administering a compound or pharmaceutical composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof) to a subject exhibiting symptoms of a respiratory condition can be used to reduce the severity of airway hyperresponsiveness in a subject with a coronavirus-related disease, or to reduce the severity of airway hyperresponsiveness in a subject with a respiratory condition. This results in a delay or slowing of the progression of airway hyperresponsiveness in patients with bronchial asthma.

[0367] In some embodiments, administering a compound or pharmaceutical composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof) to a subject exhibiting symptoms of a respiratory condition results in a reduction in the severity of inflammation of lung tissue in the subject with the respiratory condition, or a delay or slowing of the progression of inflammation of lung tissue in the subject with the respiratory condition. In some embodiments, administering a compound or pharmaceutical composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof) to a subject exhibiting symptoms of a respiratory condition results in a reduction in the severity of pneumonia in the subject with the respiratory condition, or a delay or slowing of the progression of pneumonia in the subject with the respiratory condition.

[0368] In some embodiments, administering a compound or pharmaceutical composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof) to a subject exhibiting symptoms of a respiratory condition results in a reduction in the severity of pulmonary hypersensitivity in the subject with the respiratory condition, or a delay or slowing of the progression of pulmonary hypersensitivity in the subject with the respiratory condition.

[0369] In some embodiments, administering a compound or pharmaceutical composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof) to a subject exhibiting symptoms of a respiratory condition results in a reduction in the severity of inflammation-associated lung pain in the subject with the respiratory condition, or a delay or slowing of the progression of inflammation-associated lung pain in the subject with the respiratory condition.

[0370] In some embodiments, the subject with a respiratory disease is receiving or has received treatment for an infection, fibrosis, fibrotic disease, chronic obstructive pulmonary disease, sarcoidosis (or pulmonary sarcoidosis), or asthma / asthma-related inflammation.

[0371] In some embodiments, the subject is exhibiting symptoms of and / or has been diagnosed with asthma, hi some embodiments, the subject is experiencing or has experienced an asthma attack.

[0372] In some embodiments, the subject is undergoing or has undergone treatment for fibrosis or a fibrotic condition, hi some embodiments, the fibrosis is cystic fibrosis.

[0373] In some embodiments, the respiratory condition is selected from the group consisting of cystic fibrosis, asthma, smoke-induced COPD, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility due to congenital bilateral absence of the vas deferens (CBAVD), mild pulmonary disease, pulmonary sarcoidosis, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), liver disease, hereditary emphysema, hereditary hemochromatosis, coagulation fibrinolysis deficiencies such as protein C deficiency, lipid processing deficiencies such as type 1 hereditary angioedema, familial hypercholesterolemia, type 1 chylomyocarditis, abetalipoproteinemia, lysosomal storage diseases such as I-cell disease / pseudo-Hurler disease, mucopolysaccharidoses, Sandhoff / Tay-Sachs disease, Crigler-Najjar type II, polymyxin B, and polymyxin B. Endocrinopathy / hyperinsulinemia, diabetes mellitus, Laron type dwarfism, myeloperoxidase deficiency, primary parathyroid insufficiency, melanoma, glycosylation disorder CDG1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI), neurogenic DI, nephrogenic DI, Charcot-Marie-Tooth syndrome, Pelizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, some polyglutamine neuropathies such as Pick's disease and Huntington's disease, spinocerebellar ataxia type I, spinal-bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, and myotonic dystrophy. and is the result of and / or is associated with a disease or condition selected from the group consisting of spongiform encephalopathies such as hereditary Creutzfeldt-Jakob disease (caused by defects in prion protein processing), Fabry disease, Straussler-Scheinker syndrome, COPD, dry eye disease, or Sjogren's syndrome.

[0374] 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 infectious disease. 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.

[0375] 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.

[0376] 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.

[0377] 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]

[0378] 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.

[0379] Materials and Methods The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it is understood that other process conditions can also be used unless otherwise specified. 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.

[0380] 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.Wuts, "Protecting Groups in Organic Synthesis," vol. 1, no. 1, pp. 111-114, 1997. Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.

[0381] The compounds provided herein can be isolated and purified by known standard procedures. Such procedures include (but are not limited to) recrystallization, column chromatography, HPLC, or supercritical fluid chromatography (SFC). The following schemes are provided with details regarding the preparation of representative oxysterols listed herein. The compounds provided herein can be prepared from known or commercially available starting materials and reagents by those skilled in the art of organic synthesis. Exemplary chiral columns that can be used for 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.

[0382] As reported herein 1 It is understood that H-NMR (e.g., the region where δ (ppm) is from about 0.5 to about 4 ppm) is an exemplary interpretation of the NMR spectrum of a compound (e.g., exemplary peak integrals).

[0383] 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)dimethyl Tisilane; (i-PrO)4Ti: Titanium tetraisopropoxide; BHT: 2,6-di-t-butyl-4-methylphenoxide; Me: Methyl; i-Pr: Isopropyl; t-Bu: Tert-butyl; Ph: Phenyl; Et: Ethyl; Bz: Benzoyl; BzCl: Benzoyl chloride; CsF: Cesium fluoride; DCC: Dicyclohexylcarbodiimide; DCM: Dichloromethane; DMAP: 4-Dimethylaminopyridine; DMP: Dess-Martin periodinane; EtMgBr: Ethyl magnesium bromide; EtO Ac: 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 diisopropylamine LiOH: Lithium hydroxide hydrate; MAD: Methylaluminum bis(2,6-di-t-butyl-4-methylphenoxide); MeCN: Acetonitrile; NBS: N-Bromosuccinimide; NaSO: Sodium sulfate; NaSO: Sodium thiosulfate; MeCN: Acetonitrile; MeOH: Methanol; Boc: t-Butoxycarbonyl; MTBE: Methyl tert-butyl ether; K-Selectride: Potassium tri(s-butyl)borohydride; 9-BBN dimer: 9-Borabicyclo(3.3.1) Nonane (dimer); DIPEA: diisopropylethylamine; DMF: dimethylformamide; FA: formic acid; SM: starting material.

[0384] Examples 1 and 2: 1-((R)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyra Synthesis of 1-((S)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile (2) [ka] 1-1 synthesis To a suspension of PhPMeBr (10 g, 28.2 mmol) in anhydrous THF (40 mL) was added t-BuOK (3.16 g, 28.2 mmol) under N at 25 °C. After stirring at 50 °C for 30 min, a solution of 1-0 (3 g, 9.4 mmol) in anhydrous THF (10 mL) was added dropwise. After stirring at 60 °C for 1 h, the mixture was poured into 10% NH4Cl (50 mL) and stirred for 10 min. The aqueous phase was extracted with EtOAc (3 × 50 mL). The combined organic solution was washed with saturated brine (2 × 50 mL), filtered, and concentrated. The residue was dissolved in MeOH (50 mL) and water (50 mL). The resulting compound was collected by filtration and dried to give the desired 1-1 (2.97 g, 100%). 1 H NMR (400 MHz, CDCl3) δ H4.84 (s, 1H), 4.70 (s, 1H), 2.08-1.99 (m, 1H), 1.90-1.78 (m, 4H), 1.75 (s, 3H), 1.74-1.56 (m, 5H), 1.49-1.28 (m, 8H), 1.26 (s, 3H), 1.23-1.13 (m, 3H), 1.11-0.97 (m, 3H), 0.57 (s, 3H)

[0385] Synthesis of 1 and 2 To a solution of 1-1 (500 mg, 1.57 mmol) in DCM (10 mL) was added mCPBA (541 mg, 3.14 mmol) at 25 °C. After stirring at 40 °C for 1 h, the mixture was quenched with saturated aqueous NaHCO (100 mL) at 15 °C. The DCM phase was separated, washed with saturated aqueous NaHCO / NaSO (1:1, 2 × 100 mL), brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue that was purified by flash column chromatography (10–20% EtOAc in PE) to give 1-2 (685 mg).

[0386] Synthesis of 1 and 2 To a solution of 1-2 (685 mg, 2.05 mmol) in DMF (10 mL) was added 1H-pyrazole-4-carbonitrile (285 mg, 3.07 mmol) and CsCO (3.32 g, 10.2 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 solution was separated, concentrated, and purified by flash column chromatography (30–65% EtOAc in PE) to give a mixture of epimers (600 mg, 69%). The epimers were separated by HPLC (Column: Xtimate C18 150 × 25 mm × 5 μm; Conditioning solvent: water (0.225% FA)-ACN; Starting B: 74%; End B: 74%) to give 1 (133 mg) and 2 (259.2 mg).

[0387] 1: 11H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.82 (s, 1H), 4.35 (d, J = 14.0 Hz, 1H), 4.08 (d, J = 13.6 Hz, 1H), 2.51 (s, 1H), 2.05 - 1.98 (m, 1H), 1.83 - 1.71 (m, 5H), 1.70 - 1.62 (m, 3H), 1.51 - 1.41 (m, 3H), 1.40 (br s, 2H), 1.37 - 1.27 (m, 3H), 1.26 (s, 3H), 1.23 - 1.20 (m, 1H), 1.19 - 1.10 (m, 2H), 1.10 - 1.02 (m, 4H), 0.97 (s, 3H), 0.92 (s, 3H); LC - ELSD / MS purity 99%, de 100% based on H - NMR; MSESIC 26 H 36 N3[M - ½H2O + H] + Calculated value for 390.3, measured value 390.3.

[0388] 2: 1 1H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.80 (s, 1H), 4.22 - 4.13 (m, 1H), 4.06 - 3.94 (m, 1H), 2.31 (br s, 1H), 2.10 - 2.02 (m, 1H), 1.96 - 1.82 (m, 2H), 1.80 (br d, J = 6.8 Hz, 2H), 1.70 - 1.61 (m, 4H), 1.40 (br s, 8H), 1.26 (s, 3H), 1.25 - 1.09 (m, 5H), 1.09 (s, 3H), 1.07 - 1.00 (m, 2H), 0.87 (s, 3H); LC - ELSD / MS purity 99%, de 100% based on H - NMR; MSESIC 26 H 36 N3[M - ½H2O + H] + Calculated value for 390.3, measured value 390.3.

[0389] Note: There seems to be an error in the original text where it says "H-NMRに基づくde 100%" which might be a non - standard notation. In the translation, I've tried to make sense of it as best as possible. Also, "MSESIC" is left as is since it's not clear what it exactly represents. And for the "N3[M - 2H2O + H]" part, it seems there might be a mistake in the original formula, so I've translated it as "N3[M - ½H2O + H]" based on the context. If this is a very specialized or incorrect formula, it might need further clarification.Examples 3 and 4: Synthesis of 1-((S)-2-((3R,5R,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile (3) and 1-((R)-2-((3R,5R,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile (4) [ka] Synthesis of 3-1 To a solution of 3-0 (10 g, 25.4 mmol, reported in patent WO2016 / 134301, 2016, A2) in DCM (100 mL) was added silica gel (10 g) and PCC (8.17 g, 38 mmol) at 0 °C. After stirring at 25 °C for 1 h, the suspension was filtered, and the filter cake was washed with DCM (2 × 100 mL). The combined filtrate was concentrated to give 3-1 (10 g). 1 H NMR (400 MHz, CDCl3) δ H 9.56 (s, 1 H), 4.00-3.80 (m, 8 H), 2.24-1.88 (m, 5 H), 1.87-1.70 (m, 5 H), 1.46-1.35 (m, 5 H), 1.33-0.99 (m, 5 H), 0 .92 (s, 3 H), 0.89-0.69 (m, 2 H).

[0390] Synthesis of 3-2 To a mixture of MePPhBr (27.1 g, 76.1 mmol) in THF (100 mL) was added t-BuOK (8.53 g, 76.1 mmol) under N at 15 °C. After stirring at 50 °C for 30 min, 3-1 (9.91 g, 25.4 mmol) was added portionwise below 50 °C. After stirring at 50 °C for 1 h, the reaction mixture was quenched with 10% aqueous NHCl (200 mL) at 15 °C. The organic layer was separated, and the aqueous phase was extracted with EtOAc (300 mL). The combined organic phases were concentrated in vacuo to give a residue, which was purified by silica gel chromatography (PE / EtOAc = 20 / 1 to 5 / 1) to give 3-2 (5 g, 50.7%). 1 H NMR (400 MHz, CDCl3) δ H 6.32-6.25 (m, 1 H), 5.15-4.94 (m, 2 H), 3.95-3.80 (m, 8 H) 2.02-1.72 (m, 6 H), 1.69-1.61 (m, 1 H), 1.59-1.31 (m, 12 H), 1.21-1.04 (m, 3 H), 0.80 (s, 3 H).

[0391] Synthesis of 3-3 To a solution of 3-2 (15 g, 12.8 mmol) in THF (30 mL) was added aqueous HCl (38.6 mL, 2 M, 77.2 mmol) under N at 25 °C. After stirring at 25 °C for 5 h, the mixture was quenched with saturated NaHCO (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated to give 3-3 (9.3 g, 80.8%). 1 H NMR (400 MHz, CDCl3) δ H6.35-6.25 (m, 1 H), 5.19 (d, J=11.2 Hz, 1 H), 5.09 (d, J=18.0 Hz, 1 H), 2.79-2.64 (m, 1 H), 2.54-2.13 (m, 5 H), 2.13-2.05 (m, 3 H), 2.02-1.79 (m, 3 H), 1.69-1.50 (m, 6 H), 1.37-1.23 (m, 4 H), 0.87 (s, 3 H).

[0392] Synthesis of 3-4 To a solution of 3-3 (11 g, 36.6 mmol) in THF (200 mL) was added Pd / C (wet, 50%, 2 g) under N. The suspension was degassed under vacuum and purged with H three times. After stirring under H (30 psi) at 25 °C for 16 h, the reaction mixture was filtered through a Celite pad and washed with THF (2 × 100 mL). The residue was triturated with PE (300 mL) to give 3-4 (12 g). 1 H NMR (400 MHz, CDCl3) δ H 2.67 (t, J=13.60 Hz, 1 H), 2.52-2.06 (m, 5 H), 2.00-1.91 (m, 1 H), 1.89-1.48 (m, 12 H), 1.39-1.19 (m, 5 H), 0.87 (s, 3 H), 0.80 (t, J=7.53 Hz, 3 H).

[0393] Synthesis of 3-5 To a solution of BHT (26 g, 118 mmol) in toluene (60 mL) was added dropwise AlMe3 (2 M in toluene, 29.7 mL, 59.4 mmol) under nitrogen at 0 °C. After stirring at 15 °C for 1 h, a solution of 3-4 (6.0 g, 19.8 mmol) in DCM (10 mL) was added dropwise at −70 °C. After stirring at −70 °C for 1 h under N2, MeMgBr (19.8 mL, 59.4 mmol, 3 M in ethyl ether) was added dropwise at −70 °C. After stirring at −70 °C for 4 h, the reaction mixture was poured into saturated 20% citric acid (300 mL) at <10 °C. The reaction mixture was extracted with EtOAc (2 × 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column (PE / EtOAc=0-20%) to give 3-5 (5.6 g, 88.8%). 1 H NMR (4 00 MHz, CDCl3) δ H 2.50-2.37 (m, 1 H), 2.13-2.04 (m, 1 H), 2.04-1.81 (m, 3 H), 1.81-1.62 (m, 5 H), 1.62-1.47 (m, 5 H), 1.46-1.28 (m, 6 H), 1.25 (s, 3 H), 1.24-1.11 (m, 4 H), 0.84 (s, 3 H), 0.80 (t, J=7.60 Hz, 3 H).

[0394] Synthesis of 3-6 To a mixture of EtPPhBr (9.72 g, 26.2 mmol) in THF (50 mL) was added t-BuOK (2.93 g, 26.2 mmol) under N at 15 °C. After stirring at 50 °C for 30 min, 3-5 (5.6 g, 17.5 mmol) was added portionwise below 40 °C. After stirring at 40 °C for 1 h, the reaction mixture was quenched with 10% aqueous NHCl (200 mL) at 15 °C. The organic layer was collected, and the aqueous layer was extracted with EtOAc (300 mL). The combined organic phases were concentrated in vacuo to give a residue, which was purified by silica gel chromatography (PE / EtOAc = 20 / 1 to 5 / 1) to give 3-6 (4.9 g, 84.7%). 1 H NMR (400 MHz, CDCl3) δH 5.15-5.05 (m, 1 H), 2.41-2.09 (m, 3 H), 2.03-1.89 (m, 1 H), 1.85-1.71 (m, 1 H), 1.70-1.59 (m, 6 H), 1.59-1.37 (m, 9 H), 1.37-1.27 (m, 3 H), 1.25 (s, 3 H), 1.22-1.04 (m, 5 H), 0.85 (s, 3 H), 0.79 (t, J=7.6 Hz, 3 H).

[0395] Synthesis of 3-7 To a solution of 3-6 (4.9 g, 14.8 mmol) in THF (50 mL) was added 9-BBN dimer (10.8 g, 44.4 mmol) at 15 °C. After stirring at 40 °C for 1 h, ethanol (6.8 g, 148 mmol) was added dropwise at 15 °C, followed by aqueous NaOH (29.5 mL, 5 M, 148 mmol), and then HO (14.7 mL, 10 M, 148 mmol) at -10 °C. After stirring at 80 °C for 1 h, saturated NaSO (50 mL) was added to the reaction mixture. After stirring for 30 min, the mixture was extracted with EtOAc (2 × 100 mL). The combined organic phases were washed with saturated brine (2 × 100 mL), dried over anhydrous NaSO, and concentrated in vacuo to give 3-7 (11 g). 1 H NMR (400 MHz, CDCl3) δ H 3.77-3.62 (m, 1 H), 2.03-1.91 (m, 3 H), 1.83-1.71 (m, 5 H), 1.57-1.45 (m, 12 H), 1.24 (s, 3 H), 1.21 (d, J=6.40 Hz, 3 H), 1.18-0.94 (m, 7 H), 0.81-0.76 (m, 3 H), 0.64 (s, 3 H).

[0396] Synthesis of 3-8 To a solution of 3-7 (5.15 g, 14.8 mmol) in DCM (100 mL) was added silica gel (10 g) and PCC (6.36 g, 29.6 mmol) at 0 °C. After stirring at 15 °C for 3 h, the suspension was filtered, and the filter cake was washed with DCM (2 × 100 mL). The combined filtrate was concentrated in vacuo to give a residue, which was purified by flash column chromatography (PE / EtOAc = 20 / 1 to 4 / 1) to give 3-8 (2.8 g, 54.6%). 1 H NMR (400 MHz, CDCl3) δ H 2.60-2.45 (m, 1 H) 2.28-2.12 (m, 1 H), 2.11 (s, 3 H), 2.03-1.91 (m, 2 H), 1.82-1.59 (m, 6 H), 1.54-1.28 (m, 10 H), 1.25 (s, 3 H), 1.24-1.03 (m, 6 H), 0.79 (t, J=7.60 Hz, 3 H), 0.59 (s, 3 H).

[0397] Synthesis of 3-9 To a mixture of MePPhBr (4.5 g, 12.6 mmol) in THF (20 mL) was added t-BuOK (1.41 g, 12.6 mmol) under N at 15 °C. After stirring at 50 °C for 30 min, 3-8 (2.2 g, 6.34 mmol) was added portionwise below 50 °C. After stirring at 50 °C for 1 h, the reaction mixture was quenched with 10% aqueous NHCl (100 mL) at 15 °C. The organic layer was collected, and the aqueous layer was extracted with EtOAc (100 mL). The combined organic phases were concentrated in vacuo to give a residue, which was purified by silica gel chromatography (PE / EtOAc = 20 / 1 to 5 / 1) to give 3-9 (1.6 g, 73.3%). 1 H NMR (400 MHz, CDCl3) δ H 4.84 (s, 1 H), 4.69 (s, 1 H), 2.04-1.90 (m, 2 H), 1.87-1.76 (m, 2 H), 1.75 (s, 3 H), 1.73-1.57 (m, 5 H), 1.53-1.26 (m, 9 H), 1.25 (s, 3H), 1.23-0.82 (m, 8H), 0.79 (t, J=7.60 Hz, 3 H), 0.54 (s, 3 H).

[0398] Synthesis of 3-10 To a solution of 3-9 (600 mg, 1.74 mmol) and NaHCO (146 mg, 1.74 mmol) in DCM (30 mL) was added mCPBA (352 mg, 1.74 mmol) at 20 °C. After stirring at 20 °C for 2 h, the mixture was quenched with saturated aqueous NaHCO (50 mL) at 20 °C. The DCM phase was separated and washed with saturated aqueous NaHCO / NaSO (1:1, 2 × 100 mL), brine (100 mL), dried over NaSO, filtered, and concentrated in vacuo to give 3-10 (600 mg). 1 H NMR (400 MHz, CDCl3) δ H 2.88-2.30 (m, 2H), 2.08-1.60 (m, 9 H), 1.54-1.37 (m, 8 H), 1.36-1.32 (m, 3 H), 1.31-1.27 (m, 1 H), 1.25 (s, 3 H), 1.23-0.97 (m, 8 H), 0.83-0.74 (m, 4 H), 0.66 (s, 2 H).

[0399] Synthesis of 3 and 4 To a solution of 3-10 (600 mg, 1.66 mmol) in DMF (20 mL) were added CsCO (1.08 g, 3.32 mmol) and 1H-pyrazole-4-carbonitrile (230 mg, 2.48 mmol). After stirring at 120 °C for 16 h, the mixture was added to saturated NHCl (100 mL). The organic layer was collected, and the aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with LiCl (100 mL, 5% aqueous solution), saturated brine (2 × 100 mL), dried over anhydrous NaSO, filtered, and concentrated to give a mixture of 3 and 4 (800 mg).

[0400] The epimers (500 mg, 1.1 mmol) were separated by SFC (column: DAICEL CHIRALPAK AS (250 mm * 30 mm, 10 μm), conditioning solvent: 0.1% NH₃H₂O EtOH, start B: 30%, end B: 30%, flow rate (ml / min): 80) to give 3 (200 mg, 40%) and 4 (150 mg, 30%).

[0401] 3: 1 H NMR (400 MHz, CDCl3) δ H 7.92 (s, 1 H), 7.82 (s, 1 H), 4.34 (d, J=13.60 Hz, 1 H), 4.07 (d, J=13.60 Hz, 1 H), 2.52 (s, 1 H), 2.08-1.88 (m, 2 H), 1.83-1.59 (m, 6 H), 1.55-1.45 (m, 3 H), 1.44-1.27 (m, 8 H), 1.25 (s, 3 H), 1.23-1.02 (m, 7 H), 0.97 (s, 3 H), 0.89 (s, 3 H), 0.79 ( t, J=7.60 Hz, 3 H).LC-ELSD / MS: >99% purity; Analysis SFC: 100% de; MSESIC 28 H 40 N3[M-2H2O+H] + The calculated value was 418.3, and the measured value was 418.3.

[0402] 4: 1 H NMR (400 MHz, CDCl3) δ H 7.89 (s, 1 H), 7.80 (s, 1 H), 4.15 (d, J=14.0 Hz, 1 H), 4.00 (d, J=14.0 Hz, 1 H), 2.31 (s, 1 H), 2.10-1.84 (m, 3 H), 1.83-1.60 (m, 5 H), 1.55-1.47 (m, 3 H), 1.46-1.26 (m, 8 H), 1.25 (s, 3 H), 1.24-1.09 (m, 7 H), 1.08 (s, 3 H), 0.85 (s, 3 H), 0.79 (t, J=7.60 Hz, 3 H).LC-ELSD / MS:>99% purity;Analytical SFC:99.18%de;MSESIC 28 H 40 N3[M-2H2O+H] + The calculated value was 418.3, and the measured value was 418.3.

[0403] Example 5 Synthesis of 1-((S)-2-((3R,5R,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methoxypropyl)-1H-pyrazole-4-carbonitrile [ka] To a solution of 3 (200 mg, 0.4408 mmol) in THF (5 mL) was added NaH (52.6 mg, 1.32 mmol, 60% in oil) at 0 °C. After stirring for 20 min, MeI (93.8 mg, 0.6612 mmol) was added. After stirring at 25 °C for 16 h, the reaction mixture was diluted with HO (50 mL) and extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (0–50% EtOAc in PE) to give product 5 (68.8 mg, 33.3%). 1 H NMR (400 MHz, CDCl3) δ H7.91 (s, 1 H), 7.75 (s, 1 H), 4.30-4.15 (m, 2 H), 3.18 (s, 3 H), 2.00-1.88 (m, 2 H), 1.81-1.71 (m, 2 H), 1.66-1.60 (m, 3 H), 1.54-1.47 (m, 3 H), 1.47-1.26 (m, 8 H), 1.24 (s, 3 H), 1.23-1.07 (m, 7 H), 1.06 (s, 3 H), 1.05-1.00 (m, 1 H), 0.86-0.75 (m, 6 H).LC-ELSD / MS:>99% purity;Analytical SFC:100%de;MSESIC 28 H 43 N3[M-2H2O-CH3+2H] + The calculated value was 418.3, and the measured value was 418.3.

[0404] Example 6: Synthesis of 1-((R)-2-((3R,5R,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methoxypropyl)-1H-pyrazole-4-carbonitrile [ka] To a solution of 4 (150 mg, 0.3306 mmol) in THF (5 mL) was added NaH (39.6 mg, 0.9918 mmol, 60% in oil) at 0 °C. After stirring for 20 min, MeI (70.3 mg, 0.4959 mmol) was added. After stirring at 25 °C for 16 h, the reaction mixture was diluted with HO (50 mL) and extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (0–50% EtOAc in PE) to give product 6 (23.4 mg). 1 H NMR (400 MHz, CDCl3) δ H 7.90 (s, 1H), 7.75 (s, 1H), 4.23 (s, 2 H), 3.14 (s, 3 H), 2.12-1.91(m, 2 H), 1.80-1.61 (m, 7 H), 1.53-1.27 (m, 10 H), 1.25 (s, 3 H), 1.22-1.06 (m, 7 H), 1.01 (s, 3 H), 0.82-0.77 (m, 6 H).LC-ELSD / MS:>99% purity;Analytical SFC:99.62%de;MSESI C 28 H 43 N3[M-2H2O-CH3+2H] + The calculated value was 418.3, and the measured value was 418.3.

[0405] Examples 7 and 8: Synthesis of 1-((S)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-13-methyl-3-propylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile (7) and 1-((R)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-13-methyl-3-propylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile (8) [ka] Synthesis of 7-1 A solution of 2,6-di-tert-butyl-4-methylphenol (13.1 g, 59.6 mmol) in toluene (20 mL) was added to AlMe3 (14.9 mL, 29.8 mmol, 2 A 2M toluene solution of 7-0 (3 g, 9.91 mmol) was added dropwise at 0 °C. After stirring at 25 °C for 30 min, a solution of 7-0 (3 g, 9.91 mmol) in anhydrous toluene (40 mL) was added dropwise at -70 °C. After stirring at -70 °C for 1 h under N2, n-PrMgCl (14.8 mL, 29.7 mmol, 2 M diethyl ether solution) 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 EtOAc (2 × 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (0–10% EtOAc in PE) to give 7-1 (1.7 g, 49%). 1 H NMR (400 MHz, CDCl3) δ H 2.53 (t, J = 8 Hz, 1H), 2.16-2.11 (m, 4H), 2.04-1.98 (m, 1H), 1.83-1.52 (m, 3H), 1.50-1.30 (m, 5H), 1.27-1.02 (m, 10H), 0.97-0.77 (m, 11H), 0.61 (s, 3H).

[0406] Synthesis of 7-2 To a suspension of PhPMeBr (3.50 g, 9.80 mmol) in THF (20 mL) was added t-BuOK (1.09 g, 9.80 mmol). After stirring at 16 °C for 30 min under N, 7-1 (1.7 g, 4.90 mmol) was added. After stirring at 35 °C for 16 h, the reaction mixture was poured into water (300 mL) and extracted with EtOAc (3 × 100 mL). The combined organic phases were washed with brine (150 mL), dried over anhydrous NaSO, and concentrated. The residue was purified by flash column chromatography (0–5% EtOAc in PE) to give 7-2 (1.3 g). 1 H NMR (400 MHz, CDCl3) δ H4.84 (s, 1H), 4.70 (s, 1H), 2.06-2.01 (m, 1H), 1.85-1.58 (m, 9H), 1.56-1.25 (m, 12H), 1.19-0.96 (m, 7H), 0.95-0.91 (m, 3H), 0.9-0.83 (m, 3H), 0.57 (s, 3H).

[0407] Synthesis of 7-3 To a solution of 7-2 (1 g, 2.90 mmol) in DCM (10 mL) was added m-CPBA (1.17 g, 85%, 5.80 mmol) at 15 °C. After stirring at 15 °C for 1 h, the mixture was quenched with saturated aqueous NaHCO (200 mL). The organic phase was separated and washed with saturated aqueous NaHCO / NaSO (1:1, 3 × 100 mL), brine (100 mL), dried over NaSO, filtered, and concentrated in vacuo to give 7-3 (1 g). 1 H NMR (400 MHz, CDCl3) δ H 2.89 (d, J = 4 Hz, 0.7H), 2.56-2.49 (m, 1H), 2.32 (d, J = 4 Hz, 0.3H), 2.04-1.51 (m, 10H), 1.48-1.23 (m, 15H), 1.21-0.99 (m, 6H), 0.95-0.91 (m, 3H), 0.81-0.76 (m, 1H), 0.68 (s, 3H).

[0408] Synthesis of 7 and 8 To a solution of 7-3 (680 mg, 1.88 mmol) in DMF (10 mL) were added 1H-pyrazole-4-carbonitrile (349 mg, 3.76 mmol) and CsCO (3.06 g, 9.40 mmol). After stirring at 125 °C for 12 h, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were separated, concentrated, and purified by flash column chromatography (0–20% EtOAc in PE) to give a mixture of epimers. The epimers were separated by SFC (column: DAICEL CHIRALPAK AS (250 mm × 50 mm, 10 μm); conditioning solvent: 0.1% NH₃.H₂O in EtOH; start B: 30; end B: 30; flow rate (mL / min): 200) to give 7 (250 mg) and 8 (104 mg).

[0409] 7: 1 H NMR (400 MHz, CDCl3) δ H 7.93 (s, 1H), 7.81 (s, 1H), 4.36-4.33 (m, 1H), 4.09-4.06 (m, 1H), 2.52 (s, 1H), 2.02-1.99 (m, 1H), 1.80-1.60 (m, 8H), 1.56-1.41 (m, 5H), 1.40-1.03 (m, 15H), 0.97-0.91 (m, 9H).LC-ELSD / MS purity 99%, MS ESI C 28 H 40 N3[M-2H2O+H] + Calculated value 418.3, measured value 418.3. SFC 99.9% de

[0410] 8: 1 H NMR (400 MHz, CDCl3) δ H7.89 (s, 1H), 7.80 (s, 1H), 4.17-4.14 (m, 1H), 4.03-3.99 (m, 1H), 2.31 (s, 1H), 2.08-2.03 (m, 1H), 1.95-1.50 (m, 10H), 1.47-1.18 (m, 13H), 1.16-1.00 (m, 8H), 0.95-0.87 (m, 6H).LC-ELSD / MS purity 99%, MS ESI C 28 H 40 N3[M-2H2O+H] + Calculated value 418.3, measured value 418.3. SFC 98.22%

[0411] Examples 9 and 10: Synthesis of 1-((S)-2-hydroxy-2-((3R,5S,8R,9R,10S,13S,14S,17S)-3-hydroxy-13-methyl-3-propylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile (9) and 1-((R)-2-hydroxy-2-((3R,5S,8R,9R,10S,13S,14S,17S)-3-hydroxy-13-methyl-3-propylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile (10) [ka] Synthesis of 9-1 To a solution of 9-0 (15 g, 54.6 mmol) in THF (200 mL) was added n-PrMgCl (81.5 mL, 163 mmol, 2 M THF solution) dropwise at −60 °C. After stirring at −60 °C for 2 h, the reaction mixture was poured into saturated aqueous NH4Cl (100 mL) at 0 °C and extracted with EtOAc (2 × 200 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was triturated from MeCN (50 mL) at 80 °C to give 9-1 (7 g, 40.4%). 1 H NMR (400 MHz, CDCl3) δ H2.44 (dd, J = 8.4, 19.2 Hz, 1H), 2.14-2.00 (m, 1H), 1.99-1.84 (m, 2H), 1.83-1.71 (m, 3H), 1.70-1.44 (m, 5H), 1.43-1.12 (m, 10H), 1.11-0.99 (m, 4H), 0.97-0.90 (m, 3H), 0.88 (s, 3H), 0.81-0.66 (m, 2H).

[0412] Synthesis of 9-2 To a mixture of EtPPhBr (24.3 g, 65.6 mmol) in THF (80 mL) was added t-BuOK (7.36 g, 65.6 mmol) under N at 15 °C. After stirring at 15 °C for 30 min, 9-1 (7 g, 21.9 mmol) in THF (20 mL) was added. After stirring at 40 °C for 1 h, the mixture was poured into NHCl (50 mL), and the aqueous phase was extracted with EtOAc (2 × 100 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was heated in MeOH (50 mL) at 70 °C for 30 min, cooled to room temperature, poured into water (50 mL), and the resulting residue was filtered to give 9-2 (11 g).

[0413] 1 H NMR (400 MHz, CDCl3) δ H 5.24-4.98 (m, 1H), 2.45-2.30 (m, 1H), 2.28-2.11 (m, 2H), 1.88-1.74 (m, 2H), 1.73-1.57 (m, 7H), 1.55-1.48 (m, 2H), 1.44-1.25 (m, 6H), 1.24-0.96 (m, 9H), 0.95-0.90 (m, 3H), 0.88 (s, 3H), 0.78-0.62 (m, 2H).

[0414] Synthesis of 9-3 To a solution of 9-2 (6 g, 18.1 mmol) in anhydrous THF (60 mL) was added 9-BBN dimer (13.2 g, 54.3 mmol) under N at 15 °C. After stirring at 60 °C for 2 h, the mixture was cooled and quenched with EtOH (15 mL). NaOH (15 mL, 5 M, 75.5 mmol) was added very slowly. After the addition, H2O2 (22.6 mL, 226 mmol, 10 M) was added slowly below 30 °C. After stirring at 60 °C for 2 h, the mixture was cooled, poured into water (50 mL), and extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (20–25% EtOAc in PE) to give 9-3 (6.1 g, 52.8%). 1 H NMR (400 MHz, CDCl3) δ H 3.86-3.57 (m, 1H), 1.98-1.81 (m, 2H), 1.81-1.70 (m, 2H), 1.70-1.60 (m, 3H), 1.57-1.48 (m, 3H), 1.42-1.25 (m, 7H), 1.23 (d, J = 6.0 Hz, 3H), 1.17-0.96 (m, 9H), 0.95-0.89 (m, 3H), 0.67 (s, 5H).

[0415] Synthesis of 9-4 To a solution of 9-3 (6.1 g, 17.5 mmol) in DCM (50 mL) was added PCC (11.2 g, 52.5 mmol) and silica gel (15 g) at 25 °C. After stirring at 25 °C for 1 h, the reaction mixture was filtered, and the residue was washed with anhydrous DCM (2 × 20 mL). The combined filtrate was concentrated in vacuo and then purified by column chromatography (15–20% EtOAc in PE) to give 9-4 (3 g, 49.5%). 1 H NMR (400 MHz, CDCl3) δ H 2.55 (t, J = 8.8 Hz, 1H), 2.12 (s, 4H), 2.00 (td, J = 3.2, 12.0 Hz, 1H), 1.89-1.73 (m, 2H), 1.59 (br d, J = 2.8 Hz, 1H), 1.55-1.50 (m, 1H), 1.49-1.16 (m, 10H), 1.15-0.97 (m, 6H), 0.96-0.90 (m, 3H), 0.81-0.65 (m, 2H), 0.62 (s, 3H).

[0416] Synthesis of 9-5 To a mixture of MePPhBr (9.25 g, 25.9 mmol) in THF (40 mL) was added t-BuOK (2.9 g, 25.9 mmol) under N at 15 °C. After stirring for 30 min at 15 °C, 9-4 (3 g, 8.65 mmol) in THF (10 mL) was added. After stirring for 2 h at 40 °C, the mixture was poured into aqueous NHCl (150 mL) and The aqueous phase was extracted with EtOAc (2 x 200 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was heated in MeOH (500 mL) at 70 °C for 30 min, cooled to room temperature, water (300 mL) was added, filtered, and dried to give 9-5 (3 g, 100%). 1 H NMR (400 MHz, CDCl3) δ H 4.85 (s, 1H), 4.71 (s, 1H), 2.11-1.98 (m, 1H), 1.76 (s, 7H), 1.71-1.64 (m, 3H), 1.64-1.53 ​​(m, 3H), 1.39 (d, J = 3.6 Hz, 4H), 1.14 (br s, 12H), 0.95-0.88 (m, 3H), 0.77-0.62 (m, 2H), 0.58 (s, 3H).

[0417] Synthesis of 9-6 To a solution of 9-5 (1 g, 2.90 mmol) in DCM (10 mL) was added m-CPBA (750 mg, 4.35 mmol) at 20 °C. After stirring at 20 °C for 2 h, the mixture was poured into saturated aqueous NaHCO (20 mL) and extracted with EtOAc (2 × 50 mL). The combined organic solution was washed with saturated aqueous NaHCO / NaSO (1:1, 2 × 20 mL), brine (20 mL), dried over NaSO, filtered, and concentrated to give 9-6 (1.5 g). 1 H NMR (400 MHz, CDCl3) δ H 2.89 (d, J = 4.4 Hz, 1H), 2.58-2.54 (m, 1H), 2.04-1.86 (m, 2H), 1.81-1.72 (m, 3H), 1.66-1.50 (m, 8H), 1.39-1.37 (m, 6H), 1.35 (s, 3H), 1.31-1.16 (m, 5H), 1.15-1.05 (m, 7H), 1.04-0.94 (m, 5H), 0.93-0.89 (m, 5H), 0.68 (s, 3H).

[0418] Synthesis of 9 and 10 To a solution of 9-6 (750 mg, 2.07 mmol) in DMF (10 mL) were added 1H-pyrazole-4-carbonitrile (481 mg, 5.17 mmol) and CsCO (3.35 g, 10.3 mmol). After stirring at 130 °C for 16 h, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 × 30 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 (0-20% EtOAc in PE) to give a mixture of epimers (600 mg, 63.8%), which was separated by SFC (Column: DAICEL CHIRALPAK AS 250 mm × 30 mm, 10 μm; Conditioning solvent: 0.1% NH₃H₂O in EtOH; Gradient: 25% to 25% B; Flow rate: 70 mL / min; Column temperature: 40 °C) to give 9 (230 mg) and 10 (86.9 mg). 9 (230 mg) was triturated from MeCN (5 mL) at 20 °C to give 9 (193.3 mg).

[0419] 9: 1 H NMR (400 MHz, CDCl3) δ H 7.92 (s, 1H), 7.81 (s, 1H), 4.36 (d, J = 14.0 Hz, 1H), 4.08 (d, J = 14.0 Hz, 1H), 2.49 (s, 1H), 2.04-1.96 (m, 1H), 1.78-1.57 (m, 8H), 1.54-1.49 (m, 1H), 1.45-1.41 (m, 1H), 1.38 (br d, J = 3.2 Hz, 4H), 1.34-1.12 (m, 5H), 1.12-1.02 (m, 5H), 1.01-0.94 (m, 5H), 0.92 (s, 6H), 0.71-0.62 (m, 2H).LC-ELSD / MS purity 99%, MS ESI C 28 H 40 Calculated value for N3[M-2H2O+H]+: 418.3 Measured value: 418.3. SFC: 99%.

[0420] 10: 1H NMR (400 MHz, CDCl3) δ H 7.89 (s, 1H), 7.80 (s, 1H), 4.19-4.12 (m, 1H), 4.04-3.98 (m, 1H), 2.27 (s, 1H), 2.07-2.01 (m, 1H), 1.91 (q, J = 10.4 Hz, 1H), 1.75 (br d, J = 13.2 Hz, 2H), 1.70-1.57 (m, 5H), 1.52-1.45 (m, 2H), 1.38 (br d, J = LC-ELSD / MS purity 99%, MS ESI C 28 H 40 Calculated value for N3[M-2H2O+H]+: 418.3 Measured value: 418.3. SFC: 99%.

[0421] Examples 11 and 12: Synthesis of 1-((S)-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-ethyl-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile (11) and 1-((R)-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-ethyl-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile (12) [ka] Synthesis of 11-1 To a solution of BHT (12 g, 54.4 mmol) in toluene (120 mL) at 0 °C under nitrogen, trimethylaluminum (2 M in toluene, 14 mL, 28 mmol) was added dropwise. After stirring at 25 °C for 1 h, a solution of 7-0 (6 g, 19.8 mmol) in DCM (60 mL) was added dropwise to the MAD solution at −70 °C. After stirring at −70 °C for 1 h under N2, EtMgBr (20 mL, 60 mmol, 3 M in ethyl ether) was added dropwise at −70 °C. After stirring at −70 °C for 1 h, the reaction mixture was poured into saturated aqueous citric acid (600 mL) at <10 °C and extracted with DCM (2 × 800 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. Trituration of the residue with PE gave 11-1 (3.83 g, 58%). 1 H NMR (400 MHz, CDCl3) δ H 2.56-2.50 (m, 1H), 2.24-2.10 (m, 4H), 2.07-1.99 (m, 1H), 1.89-1.51 (m, 9H), 1.50-1.20 (m, 12H), 1.19-1.00 (m, 3H), 0.98-0.80 (m, 3H), 0.61 (s, 3H).

[0422] Synthesis of 11-2 To a suspension of MePhPBr (6.4 g, 18.0 mmol) in THF (50 mL), t-BuOK (2.01 g, 18.0 mmol) was added. After stirring at 40 °C for 10 min, the mixture was slowly added dropwise to a solution of 11-1 (3 g, 9.02 mmol) in THF (30 mL). After stirring at 20 °C for 18 h, the mixture was quenched with saturated NH4Cl (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic phases were washed with saturated NH4Cl (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by Combiflash (0–25% EtOAc in PE) to give 11-2 (2.445 g, 82%). 1 H NMR (400 MHz, CDCl3) δ H 4.84 (s, 1H), 4.69 (s, 1H), 2.02-1.53 ​​(m, 13H), 1.50-1.33 (m, 4H), 1.32-1.11 (m, 11H), 1.10-0.99 (m, 2H), 0.85-0.80 (m, 3H), 0.56 (s, 3H).

[0423] Synthesis of 11-3 To a solution of 11-2 (1.8 g, 5.44 mmol) in DCM (20 mL) was added m-CPBA (2.18 g, 85%, 10.8 mmol). After stirring at 15 °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 in vacuo to give 11-3 (1.7 g), which was used as is.

[0424] Synthesis of 11 and 12 To a solution of 11-3 (850 mg, 2.45 mmol) in DMF (10 mL) was added 1H-pyrazole-4-carbonitrile (341 mg, 3.67 mmol) and Cs2CO3 (3.97 g, 12.2 mmol) at 20 °C. After stirring at 120 °C for 2 h, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were separated, concentrated, and purified by flash column (30–65% EtOAc in PE) to give a mixture of epimers. SFC (column: DAICEL CHIRALPAK) The epimers were separated using AS (250 mm x 30 mm, 10 μm), conditioning solvent: 0.1% NH₃H₂O EtOH, starting B: 25%, ending B: 25%, gradient time (min), 100% B retention time (min), flow rate (ml / min) 70) to give 11 (395.8 mg, 49.6%) and 12 (155.4 mg, 19.4%).

[0425] 11: 1 H NMR (400 MHz, CDCl3) δ H7.93 (s, 1H), 7.82 (s, 1H), 4.45-3.99 (m, 2H), 2.50 (br s, 1H), 2.08-1.94 (m, 1H), 1.84-1.57 (m, 10H), 1.47-1.02 (m, 16H), 0.97 (s, 3H), 0.92 (s, 3H), 0.88 (t, J=7.5 Hz, 3H).LC-ELSD / MS purity 99%, MS ESI C 27 H 38 N3[M-2H2O+H] + Calculated value 404.3, measured value 404.3. SFC 100% de

[0426] 12: 1 H NMR (400 MHz, CDCl3) δ H 7.90 (br s, 1H), 7.81 (s, 1H), 4.24-3.90 (m, 2H), 2.29 (br s, 1H), 2.06 (br d, J=12.3 Hz, 1H), 1.96-1.86 (m, 1H), 1.84-1.56 (m, 9H), 1.53-1.19 (m, 12H), 1.19-1.09 (m, 7H), 0.92-0.85 (m, 6H).LC-ELSD / MS purity 99%,MS ESI C 27 H 38 N3[M-2H2O+H] + Calculated value 404.3, measured value 404.3. SFC 99% de.

[0427] Examples 13 and 14: 1-((S)-2-((3R,5S,8R,9R,10S,13S,14S,17S)-3-ethyl-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)- Synthesis of 1H-pyrazole-4-carbonitrile (13) and 1-((R)-2-((3R,5S,8R,9R,10S,13S,14S,17S)-3-ethyl-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile (14) [ka] Synthesis of 13-1 Lithium (7.27 g, 915 mmol) was added portionwise to freshly prepared liquid ammonia (500 mL) at −70 °C. After stirring at −70 °C for 1 h, a solution of 13-0 (50 g, 183 mmol) in dry THF (500 mL) and t-butanol (27 g, 366 mmol) was added. After stirring at −70 °C for 1 h, ammonium chloride (500 g) was added and allowed to warm to room temperature. After stirring for 16 h, the reaction mixture was diluted with HO (1 L) and extracted with EtOAc (3 × 500 mL). The combined organic solution was washed with HCl (1 M, 2 × 500 mL), saturated aqueous NaHCO (500 mL), brine (1 L), dried over NaSO, and concentrated in vacuo to give 13-1 (97 g). 1 H NMR (400 MHz, CDCl3) δ H 3.75-3.55 (m, 1H), 2.50-2.00 (m, 10H), 2.00-1.25 (m, 8H), 1.25-0.60 (m, 9H).

[0428] Synthesis of 13-2 To a solution of 13-1 (100 g, 361 mmol) in DCM (1000 mL) at 0 °C, silica gel (116 g) and PCC (116 g, 541 mmol) were added. After stirring at 25 °C for 2 h, the reaction mixture was diluted with PE (1000 mL) and filtered through a pad of silica gel. The filter cake was washed with DCM (2000 mL). The combined filtrates were concentrated to give 13-2 (90 g). 1 H NMR (400 MHz, CDCl3) δ H2.55-2.02 (m, 8H), 2.02-1.39 (m, 8H), 1.39-0.69 (m, 10H).

[0429] Synthesis of 13-3 To a solution of 13-2 (51.5 g, 187 mmol) in MeOH (600 mL) was added 4-methylbenzenesulfonic acid (6.44 g, 37.4 mmol) at 25° C. After stirring at 55° C. for 16 h, EtN (20 mL) was added and the mixture was filtered to give 13-3 (57 g). 1 H NMR (400 MHz, CDCl3) δ H 3.49 (d, J = 5.6 Hz, 1H), 3.20 (s, 3H), 3.14 (s, 3H), 2.48-2.38 (m, 1H), 2.12-2.01 (m, 2H), 1.96-1.90 (m, 2H), 1.88-1.74 (m, 4H), 1.68-1.62 (m, 1H), 1.56-1.44 (m, 1H) , 1.35-1.20 (m, 5H), 1.13-0.95 (m, 5H), 0.87 (s, 1H), 0.80-0.68 (m, 2H).

[0430] Synthesis of 13-4 To a mixture of EtPPhBr (98.7 g, 266 mmol) in THF (250 mL) was added t-BuOK (29.8 g, 266 mmol) under N at 15 °C. After stirring at 15 °C for 30 min, 13-3 (28.5 g, 88.9 mmol) in THF (50 mL) was added. After stirring at 40 °C for 2 h, the 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 heated in MeOH (500 mL) at 70 °C for 30 min, cooled to room temperature, diluted with water (300 mL), filtered, and concentrated to give 13-4 (25.5 g). 1 H NMR (400 MHz, CDCl3) δ H5.15-5.07 (m, 1H), 3.20 (s, 3H), 3.14 (s, 3H), 2.41-2.31 (m, 1H), 2.27-2.12 (m, 2H), 2.10-2.02 (m, 1H), 1.91 (td, J = 3.2, 13.2 Hz, 1H), 1.85-1.76 (m, , 2H), 1.71-1.58 (m, 6H), 1.57-1.48 (m, 3H), 1.30-1.13 (,m, 6H), 1.11-0.93 (m, 5H), 0.87 (s, 3H), 0.75-0.67 (m, 2H).

[0431] Synthesis of 13-5 To a solution of 13-4 (51 g, 153 mmol) in THF (500 mL) was added 1 M HCl (153 mL, 153 mmol). After stirring at 15 °C for 2 h, the mixture was poured into aqueous NaHCO (400 mL) and extracted with EtOAc (2 × 300 mL). The combined organic phases were washed with brine (200 mL), dried over anhydrous NaSO, filtered, and concentrated to give 13-5 (42 g, 95.8%). 1 H NMR (400 MHz, CDCl3) δ H 5.16-5.08 (m, 1H), 2.42-2.17 (m, 7H), 2.09 (t, J = 13.2 Hz, 1H), 1.88-1.79 (m, 2H), 1.76-1.63 (m, 6H), 1.59 (s, 1H), 1.56-1.40 (m, 2H), 1.28-1.16 (m, 8H), 1.04-0.94 (m, 1H), 0.90 (s, 1H), 0.78-0.69 (m, 1H).

[0432] Synthesis of 13-6 To a stirred solution of MeSIO (47.9 g, 218 mmol) in DMSO (300 mL) and THF (300 mL) was added NaH (5.23 g, 218 mmol) at 0 °C. After stirring under N for 1 h, 13-5 (42 g, 146 mmol) in THF (200 mL) was added. After stirring at 25 °C for 3 h, the reaction mixture was poured into water (1000 mL). After stirring at 25 °C for 3 h, the mixture was filtered to give 13-6 (48 g). 1 H NMR (400 MHz, CDCl3) δ H 5.15-5.07 (m, 1H), 2.64-2.61 (m, 5H), 2.41-2.30 (m, 1H), 2.27-2.11 (m, 2H), 2.00-1.92 (m, 1H), 1.91-1.80 (m, 2H), 1.67-1.60 (m, 5H), 1.56-1.50 (m, 1H), 1.45-1.35 (m, 1H), 1.30-1.10 (m, 8H), 1.07-0.95 (m, 2H), 0.89 (s, 3H), 0.84-0.72 (m, 2H).

[0433] Synthesis of 13-7 To a suspension of CuCN (3.92 g, 43.8 mmol) in THF (40 mL) at -70 °C was added MeLi (54.7 mL, 87.6 mmol, 1.6 M). The mixture was stirred at -70 °C for 1 h. After stirring for 1 h, 13-6 (4.4 g, 14.6 mmol) in THF (10 mL) was added at -70 °C. After slowly warming to room temperature and stirring for 2 h, the reaction was slowly poured into 10% NH4Cl (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give 13-7 (4.4 g). 1H NMR (400 MHz, CDCl3) δ H 5.14-5.08 (m, 1H), 2.39-2.10 (m, 3H), 1.85-1.39 (m, 10H), 1.39-0.94 (m, 13H), 0.94-0.60 (m, 9H).

[0434] Synthesis of 13-8 To a solution of 13-7 (4.4 g, 13.3 mmol) in anhydrous THF (50 mL) was added 9-BBN dimer (8.03 g, 33.2 mmol) under N at 25 °C. After stirring at 60 °C for 16 h, the mixture was cooled and diluted with EtOH (20 mL) at 0 °C. NaOH (2.66 g, 13.3 mL, 5 M, 66.5 mmol) was added very slowly, followed by HO (13.3 mL, 133 mmol, 10 M aqueous solution) very slowly until the internal temperature no longer rose. The internal temperature was maintained below 30 °C. After stirring at 60 °C for 2 h, the mixture was cooled, diluted with NaSO (100 mL, saturated aqueous solution), and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (5% to 30% EtOAc in PE) to give 13-8 (10 g). 1H NMR (400 MHz, CDCl3) δ H 3.74-3.66 (m, 1H), 1.96-1.39 (m, 13H), 1.39-1.00 (m, 14H), 1.00-0.85 (m, 5H), 0.75-0.57 (m, 5H).

[0435] Synthesis of 13-9 To a solution of 13-8 (1.3 g, 3.88 mmol) in DCM (20 mL) was added DMP (3.29 g, 7.76 mmol). After stirring at 25 °C for 1 h, the mixture was quenched with NaHCO (50 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with NaSO (3 × 30 mL, saturated), brine (50 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (5% to 30% EtOAc in PE) to give 13-9 (1.16 g, 90%). 1 H NMR (400 MHz, CDCl3) δ H 2.53 (t, J = 8.8 Hz, 1H), 2.21-1.53 ​​(m, 9H), 1.53-1.10 (m, 10H), 1.10-0.63 (m, 13H), 0.61 (s, 3H).

[0436] Synthesis of 13-10 To a mixture of MePPhBr (2.48 g, 6.96 mmol) in THF (40 mL) was added t-BuOK (779 mg, 6.96 mmol) under N at 25 °C. After stirring at 50 °C for 30 min, 13-9 (1.16 g, 3.48 mmol) in THF (10 mL) was added at 25 °C. After stirring at 50 °C for 18 h, the reaction mixture was quenched with water (40 mL) at 25 °C and extracted with EtOAc (2 × 50 mL). The combined organic phases were washed with water (3 × 10 mL), brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (2% EtOAc in PE) to give 13-10 (620 mg, 54%). H NMR (400 MHz, CDCl) δ H 4.84(s, 1H), 4.70(s, 1H), 2.08-1.57 (m, 10H), 1.57-1.06 (m, 13H), 1.06-0.52 (m, 13H).

[0437] Synthesis of 13-11 To a solution of 13-10 (620 mg, 1.87 mmol) in DCM (10 mL), BA (601 mg, 2.8 mmol, 80%) was added at 15 °C. After stirring at 15 °C for 1 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 phases were washed with saturated NaHCO and NaSO (50 mL, v:v = 1:1), dried over NaSO, filtered, and concentrated to give 13-11 (820 mg). 1 H NMR (400 MHz, CDCl3) δ H 2.89 (d, J = 4.8 Hz, 0.6H), 2.55-2.48 (m, 1H), 2.32 (d, J = 5.2 Hz, 0.4H), 2.02-1.45 (m, 10H), 1.45-1.11 (m, 11H), 1.11-0.74 (m, 10H), 0.74-0.58 (m, 5H).

[0438] Synthesis of 13 and 14 To a solution of 13-11 (800 mg, 2.3 mmol) in DMF (10 mL) were added CsCO (2.24 g, 6.89 mmol) and 1H-pyrazole-4-carbonitrile (535 mg, 5.75 mmol). After stirring at 120 °C for 48 h, the reaction 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% aqueous solution), saturated brine (2 × 100 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by column chromatography (0–10% EtOAc in PE) to give a mixture of epimers (800 mg). The epimers were separated by SFC (column: DAICEL CHIRALCEL OJ-H (250 mm * 30 mm, 5 μm), conditioning solvent: 0.1% NH3H2O ​​EtOH, starting B: 25%, ending B: 25%) to give 13 (264 mg) and 14 (122 mg).

[0439] 13:1H NMR (400 MHz, CDCl3) δ H 7.92 (s, 1H), 7.81 (s, 1H), 4.37-4.33 (m, 1H), 4.10-4.06 (m, 1H), 2.48 (s, 1H), 2.02-1.96 (m, 1H), 1.79-1.37 (m, 12H), 1.37-0.94 (m, 15H), 0.94-0.87 (m, 6H), 0.75-0.61 (m, 2H).LC-ELSD / MS purity 99%, MS ESI C 27 H 38 N3[M-2H2O+H] + Calculated value 404 Actual value 404.SFC 99.522% de.

[0440] 14:1H NMR (400 MHz, CDCl3) δ H7.88 (s, 1H), 7.79 (s, 1H), 4.17-4.13 (m, 1H), 4.02-3.99 (m, 1H), 2.27 (s, 1H), 2.07-1.53 (m, 1H), 1.53-1.12 (m, 12H), 1.12-0.94 (m, 15H), 0.94-0.84 (m, 6H), 0.73-0.61 (m, 2H).LC-ELSD / MS purity 99%, MS ESI C 27 H 38 N3[M-2H2O+H] + Calculated value 404 Measured value 404. SFC 100% de.

[0441] Examples 15 and 16: Synthesis of 1-((S)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3-(hydroxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile (15) and 1-((R)-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-(ethoxymethyl)-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile (16) [ka] Synthesis of 15-1 To a solution of MePPhBr (2.94 g, 8.25 mmol) in THF (20 mL) was added t-BuOK (925 mg, 8.25 mmol) under N at 25 °C. After stirring for 1 h, 15-0 (1 g, 2.75 mmol, WO2018013613) in THF (10 mL) was added. After stirring at 40 °C for 3 h, the reaction mixture was poured into aqueous NHCl (50 mL) and extracted with EtOAc (2 × 80 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (0–6% EtOAc in PE) to give 15-1 (750 mg, 76%). 1 H NMR (400 MHz, CDCl3) δ H 4.84 (s, 1H), 4.70 (s, 1H), 3.57-3.49 (m, 2H), 3.47-3.38 (m, 2H), 2.70 (s, 1H), 2.07-2.00 (m, 1H), 1.75 (s, 7H), 1.72-1.59 (m, 5H), 1.49-1.33 (m, 6H), 1.28-0.97 (m, 11H), 0.56 (s, 3H).

[0442] Synthesis of 15-2 To a solution of 15-1 (880 mg, 2.44 mmol) in DCM (20 mL) was added m-CPBA (990 mg, 85%, 4.88 mmol) at 15 °C. After stirring the reaction mixture at 15 °C for 1 h, the reaction mixture was quenched with saturated aqueous NaHCO (200 mL). The organic phase was separated, washed with saturated aqueous NaHCO / NaSO (1:1, 3 × 100 mL), brine (100 mL), dried over NaSO, filtered, and concentrated in vacuo to give 15-2 (900 mg). 1 H NMR (400 MHz, CDCl3) δ H3.54 (q, J = 8 Hz, 2H), 3.43 (q, J = 8 Hz, 2H), 2.88 (d, J = 4 Hz, 0.6H), 2.55 (d, J = 4 Hz, 0.7H), 2.49 (d, J = 4 Hz, 0.3H), 2.31 (d, J = 4 Hz, 0.4H), 2.03-1.57 (m, 10H), 1.48-1.32 (m, 9H), 1.28-0.93 (m, 12H), 0.79 (s, 1H), 0.67 (s, 2H).

[0443] Synthesis of 15 and 16 To a solution of 15-2 (600 mg, 1.59 mmol) in DMF (5 mL) were added 1H-pyrazole-4-carbonitrile (369 mg, 3.97 mmol) and Cs2CO3 (2.59 g, 7.95 mmol). After stirring at 125 °C for 12 h, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 60 mL). The combined organic layers were washed with LiCl (3 × 150 mL, 5% aqueous solution) and then concentrated. The residue was purified by flash column chromatography. Purification by column chromatography (0-20% EtOAc in PE) gave a mixture of epimers (600 mg). The epimers were separated by SFC (column: DAICEL CHIRALPAK AS (250 mm * 50 mm, 10 μm); conditioning solvent: 0.1% NH₃H₂O EtOH; start B: 60%; end B: 60%; flow rate (ml / min) 80) to give 15 (353.8 mg, 59%) and 16 (138.3 mg, 23%).

[0444] 15: 1 H NMR (400 MHz, CDCl3) δ H7.92 (s, 1H), 7.82 (s, 1H), 4.37 - 4.34 (m, 1H), 4.10 - 4.07 (m, 1H), 3.54 (q, J = 8 Hz, 2H), 3.41 (q, J = 8 Hz, 2H), 2.70 (s, 1H), 2.51 (s, 1H), 2.02 - 1.99 (m, 1H), 1.83 - 1.55 (m, 8H), 1.50 - 1.19 (m, 13H), 1.15 - 1.02 (m, 5H), 0.96 - 0.91 (m, 6H). LC - ELSD / MS Purity 99%, MS ESI C 28 H 42 N3O2[M + H - H2O] + Calculated value for 452, measured value 452. SFC 100% de.

[0445] 16: 1 H NMR (400 MHz, CDCl3) δ H 7.89 (s, 1H), 7.80 (s, 1H), 4.18 - 4.15 (m, 1H), 4.03 - 3.99 (m, 1H), 3.54 (q, J = 8 Hz, 2H), 3.41 (q, J = 8 Hz, 2H), 2.71 (s, 1H), 2.33 (s, 1H), 2.07 - 2.04 (m, 1H), 1.95 - 1.56 (m, 9H), 1.50 - 1.19 (m, 13H), 1.16 - 1.00 (m, 8H), 0.87 (s, 3H). LC - ELSD / MS Purity 99%, MS ESI C 28 H 42 N3O2[M + H - H2O] + Calculated value for 452, measured value 452. SFC 99.94% de.

[0446] Examples 17 and 18: Synthesis of 1-((S)-2-hydroxy-2-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-10,13-dimethyl-3-propylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile (17) and 1-((R)-2-hydroxy-2-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-10,13-dimethyl-3-propylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile (18) [ka] Synthesis of 17-1 To a stirred solution of Me3SIO (3.12 g, 14.2 mmol) in DMSO (30 mL) and THF (30 mL) was added NaH (340 mg, 14.2 mmol) at 0 °C. After stirring for 1 h, the reaction mixture was added with 17-0 (pregn-20-en-3-one, 20-methyl-, (5α)-, as described in WO2018 / 75699) (3 g, 9.53 mmol) in DMSO (30 mL). After stirring for 3 h at 25 °C, the reaction mixture was poured into water (200 mL). After stirring for 3 h at 25 °C, the reaction mixture was filtered to give 17-1 (3.3 g). 1 H NMR (400 MHz, CDCl3) δ H 4.84 (s, 1H), 4.70 (s, 1H), 2.64-2.59 (m, 2H), 2.06-1.98 (m, 2H), 1.88-1.79 (m, 2H), 1.75 (s, 3H), 1.71-1.65 (m, 3H), 1.60-1.52 (m, 3H), 1.35-1.12 (m, 8H), 1.00-0.76 (m, 8H), 0.57 (s, 3H).

[0447] Synthesis of 17-2 To a solution of 17-1 (2.7 g, 8.21 mmol) in THF (20 mL) with CuI (234 mg, 1.23 mmol) at 0 °C, EtMgBr (8.20 mL, 3 M, 24.6 mmol) was added. After stirring at 0 °C for 1 h, the reaction was diluted with water (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by column chromatography (0–3% EtOAc in PE) to give 17-2 (1.8 g, 61%). 1 H NMR (400 MHz, CDCl3) δ H 4.83 (s, 1H), 4.69 (s, 1H), 2.01 (t, J = 9.2 Hz, 1H), 1.83-1.40 (m, 13H), 1.40-1.02 (m, 15H), 1.02-0.70 (m, 8H), 0.55 (s, 3H).

[0448] Synthesis of 17-3 To a solution of 17-2 (1.7 g, 4.74 mmol) in DCM (10 mL) was added m-CPBA (2.03 g, 9.48 mmol, 80%) at 15 °C. After stirring at 15 °C for 1 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 17-3 (2.35 g). 1 H NMR (400 MHz, CDCl3) δ H 2.88 (d, J = 4.4 Hz, 0.7H), 2.55-2.48 (m, 1H), 2.30 (d, J = 4.8 Hz, 0.3H), 2.04-1.55 (m, 10H), 1.55-1.37 (m, 10H), 1.37-1.23(m, 10H), 1.23-0.66 (m, 10H),

[0449] Synthesis of 17 and 18 To a solution of 17-3 (600 mg, 1.6 mmol) in DMF (5 mL) were added CsCO (1.56 g, 4.8 mmol) and 1H-pyrazole-4-carbonitrile (372 mg, 4 mmol). After stirring at 120 °C for 48 h, the reaction 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% aqueous solution), brine (2 × 100 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by column chromatography (5–20% EtOAc in PE) to give a mixture of epimers (750 mg). SFC (column: DAICEL The epimers were separated using CHIRALCEL OJ-H (250 mm * 30 mm, 5 um), conditioning solvent: 0.1% NH3H2O ​​EtOH, starting B: 30%, ending B: 30%, to give 17 (272 mg) and 18 (123 mg).

[0450] 17: 1 H NMR (400 MHz, CDCl3) δ H 7.92 (s, 1H), 7.80 (s, 1H), 4.36-4.33 (m, 1H), 4.09-4.06 (m, 1H), 2.49 (s, 1H), 2.01-1.98 (m, 1H), 1.77-1.42 (m, 11H), 1.42-1.08 (m, 13H), 1.08-0.80 (m, 11H), 0.77-0.70 (m, 4H).LC-ELSD / MS purity 99%, MS ESI C 29 H 42 N3 [M- 2H2O+H] + Calculated value 432 Measured value 432. SFC 99.06% de.

[0451] 18: 1 H NMR (400 MHz, CDCl3) δ H 7.88 (s, 1H), 7.79 (s, 1H), 4.17-4.13 (m, 1H), 4.02-3.98 (m, 1H), 2.28 (s, 1H), 2.06-1.86 (m, 2H), 1.71-1.42 (m, 10H), 1.42-1.11 (m, 13H), 1.11-0.60 (m, 11H), 0.77-0.70 (m, 4H).LC-ELSD / MS purity 99%, MS ESI C 29 H 42 N3 [M-2H2O+H] + Calculated value 432 Actual value 432. SFC 100%de.

[0452] Examples 19 and 20: Synthesis of 1-((S)-2-hydroxy-2-((3R,5S,8R,9R,10S,13S,14S,17S)-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile (19) and 1-((R)-2-hydroxy-2-((3R,5S,8R,9R,10S,13S,14S,17S)-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile (20) [ka] Synthesis of 19-1 To a mixture of MePPhBr (4.28 g, 12.0 mmol) in THF (15 mL) was added t-BuOK (1.34 g, 12.0 mmol) under N at 25 °C. After stirring at 50 °C for 30 min, 19-0 (1.4 g, 4.01 mmol) in THF (5 mL) was added. After stirring at 60 °C for 3 h, the reaction mixture was cooled, poured into ice water, and extracted with EtOAc (100 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (0–30% EtOAc in PE) to give 19-1 (1.1 g). 1 H NMR (400 MHz, CDCl3) δ H 4.94-4.61 (m, 2H), 3.45-3.32 (m, 3H), 3.25-3.12 (m, 2H), 2.11-1.97 (m, 2H), 1.87-1.53 ​​(m, 10H), 1.49-0.82 (m, 14H), 0.79-0.65 (m, 2H), 0.57 (s, 3H).

[0453] Synthesis of 19-2 To a solution of 19-1 (600 mg, 1.73 mmol) in DCM (20 mL) was added m-CPBA (556 mg, 2.59 mmol, 80%) at 15 °C. After stirring at 15 °C for 1 h, the reaction mixture was diluted with saturated NaHCO and NaSO (40 mL, v:v = 1:1 The mixture was quenched with 19-2 (2×20 mL) and extracted with DCM (2×20 mL). The combined organic phases were washed with saturated NaHCO and NaSO (50 mL, v:v=1:1), dried over NaSO, filtered, and concentrated to give 19-2 (650 mg). 1 H NMR (400 MHz, CDCl3) δ H 3.38 (s, 3H), 3.24-3.14 (m, 2H), 2.88 (d, J = 4.4 Hz, 1H), 2.55 (d, J = 4.4 Hz, 1H), 2.49 (d, J = 4.8 Hz, 1H), 2.31 (d, J = 4.8 Hz, 1H), 2.09-1.52 (m, 10H), 1.47-0.87 (m, 14H), 0.80 (s, 1H), 0.74-0.64 (m, 4H).

[0454] Synthesis of 19 and 20 To a solution of 19-2 (650 mg, 1.79 mmol) in DMF (10 mL) were added CsCO (1.75 g, 5.37 mmol) and 1H-pyrazole-4-carbonitrile (416 mg, 4.47 mmol). After stirring at 130 °C for 12 h, the reaction 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% aqueous solution), brine (2 × 100 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by column chromatography (0–50% EtOAc in PE) to give a mixture of epimers (750 mg). The epimers were separated by SFC (column: DAICEL CHIRALCEL OJ-H (250 mm * 30 mm, 5 μm); conditioning solvent: 0.1% NH3H2O ​​EtOH) to give 20 (116.0 mg, 15.5%) and 19 (280.6 mg, 37.4%).

[0455] 19: 1 H NMR (400 MHz, CDCl3) δ H 7.92 (s, 1H), 7.81 (s, 1H), 4.36 (d, J = 13.6 Hz, 1H), 4.08 (d, J = 13.6 Hz, 1H), 3.38 (s, 3H), 3.18 (s, 2H), 2.48 (s, 1H), 2.13-1.92 (m, 2H), 1.81-1.56 (m, 9H), 1.43 (br t, J = 9.6 Hz, 2H), 1.29-0.98 (m, 9H), 0.96 (s, 4H), 0.92 (s, 3H), 0.69 (br s, 2H).LC-ELSD / MS purity 99%, MS ESI C 26 H 35 N3[M-MeOH-2H2O+H] + Calculated value 388.2, measured value 388.2. SFC 96.66%

[0456] 20: 1 H NMR (400 MHz, CDCl3) δ H7.89 (s, 1H), 7.82-7.75 (m, 1H), 4.22-4.09 (m, 1H), 4.06-3.93 (m, 1H), 3.48-3.31 (m, 3H), 3.27-3.11 (m, 2H), 2.35-2.22 (m, 1H), 2.12-1.99 (m, 2H), 1.97-1.83 (m, 1H), 1.81-1.60 (m, 8H), 1.53-1.32 (m, 2H), 1.29-1.14 (m, 4H), 1.09 (s, 5H), 1.05-0.92 (m, 4H), 0.87 (s, 3H), 0.69 (br t, J = 7.2 Hz, 2H).LC-ELSD / MS purity 99%, MS ESI C 26 H 35 N3[M-MeOH-2H2O+H] + Calculated value 388.2, measured value 388.2. SFC 100% de

[0457] Example 21: Synthesis of 1-(2,2-difluoro-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl)-1H-pyrazole-4-carbonitrile [ka] Synthesis of 21-1 To a solution of 21-0 (1 g, 2.44 mmol) in DCM (10 mL) were added DMAP (298 mg, 2.44 mmol) and acetyl acetate (622 mg, 6.10 mmol). After stirring at 25 °C for 16 h, the reaction mixture was poured into ice-water (50 mL), stirred for 10 min, and extracted with DCM (2 × 30 mL). The combined organic phases were washed with saturated brine (2 × 50 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (0–20% EtOAc in PE) to give 21-1 (650 mg, 59%). 1 H NMR (400 MHz, CDCl3) δ H7.86 (s, 1H), 7.81 (s, 1H), 5.05-4.87 (m, 2H), 2.64-2.57 (m, 1H), 2.34-2.06 (m, 2H), 1.99 (s, 3H), 1.87-1.58 (m, 10H), 1.54 (s, 3H), 1.51-1.30 (m, 7H), 1.15-0.82 (m, 4H), 0.67 (s, 3H).

[0458] Synthesis of 21-2 To a solution of 21-1 (300 mg, 0.66 mmol) in chloroform (5 mL) was added DAST (0.79 mL, 5.97 mmol) dropwise at 0 °C under N. After stirring at 60 °C for 12 h, the reaction mixture was quenched with saturated NaHCO (50 mL) and extracted with EtOAc (2 × 30 mL). The combined organic phases were washed with saturated NaHCO (50 mL), dried over NaSO, filtered, and concentrated. The residue was purified by Combiflash (0–30% EtOAc in PE) to give 21-2 (65 mg, 20%). 1 H NMR (400 MHz, CDCl3) δ H 7.92 (s, 1H), 7.82 (s, 1H), 4.59-4.30 (m, 2H), 1.97 (s, 3H), 1.85-1.58 (m, 12H), 1.53 (s, 3H), 1.49-1.28 (m, 7H), 1.14-1.03 (m, 5H), 0.88-0.86 (m, 3H)

[0459] Synthesis of 21 To a solution of 21-2 (35 mg, 0.074 mmol) in dioxane (0.5 mL) was added MeOH (1 mL) and NaOH (2.94 ml, 5 M, 14.7 mmol) at 15° C. After stirring at 35° C. for 16 h, the reaction mixture was poured into water (20 mL), stirred for 10 min, and extracted with EtOAc (3×40 mL). The combined organic phase was washed with saturated brine (2×50 mL). The residue was purified by flash column (0-40% EtOAc in PE) and SFC (Method: Column: DAICEL CHIRALPAK AD (250 mm * 50 mm, 10 μm); Conditioning solvent: 0.1% NH3H2O ​​EtOH; Start B: 60%; End B: 60%) to give 21 (14.4 mg, 41%). 1 H NMR (400 MHz, CDCl3) δ H 7.92 (s, 1H), 7.82 (s, 1H), 4.55-4.34 (m, 2H), 2.02-1.96 (m, 1H), 1.86-1.60 (m, 10H), 1.49-1.27 (m, 9H), 1.25 (s, 3H), 1.13-1.05 (m, 5H), 0.87 (d, J=3.2 Hz, 3H).LC-ELSD / MS: >99% purity; MSESIC 25 H 35 F2N3O[M-H2O+H] + The calculated value is 414.2, and the measured value is 414.2.

[0460] Examples 22 and 23: Synthesis of 1-((S)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-13-methyl-3-propylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-3-carbonitrile (22) and 1-((R)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-13-methyl-3-propylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-3-carbonitrile (23) [ka] To a solution of 7-3 (300 mg, 0.831 mmol) in DMF (5 mL) were added 1H-pyrazole-3-carbonitrile (154 mg, 1.66 mmol) and Cs2CO3 (1.35 g, 4.15 mmol). After stirring at 125 °C for 12 h, the mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were concentrated and purified by flash column (0–25% EtOAc in PE) to give a mixture of epimers (200 mg, 53%). SFC (column: DAICEL CHIRALPAK) The epimers were separated by AD (250 mm * 30 mm, 10 μm; conditioning solvent: 0.1% NH3HO IPA; starting B: 55%; ending B: 55%; flow rate (ml / min): 80) to give 22 (80.5 mg) and 23 (47.2 mg). The regiochemistry of the pyrazole was assigned by HMBC (H22 correlated to C5 of the pyrazole ring).

[0461] twenty two: 1 H NMR (400 MHz, CDCl3) δ H 7.58 (d, J = 4 Hz, 1H), 6.68 (d, J = 4 Hz, 1H), 4.38-4.35 (m, 1H), 4.13-4.09 (m, 1H), 2.35 (s, 1H), 2.02-1.99 (m, 1H), 1.81-1.60 (m, 10H), 1.55-1.31 (m, 7H), 1.28-1.03 (m, 11H), 0.96-0.91 (m, 9H).LC-ELSD / MS purity 99%, MS ESI C 28 H 40 Calculated value for N3[M-2H2O+H]+: 418.3, Measured value: 418.3. SFC 100% de.

[0462] twenty three: 1 H NMR (400 MHz, CDCl3) δ H7.53 (d, J = 4 Hz, 1H), 6.67 (d, J = 4 Hz, 1H), 4.19-4.16 (m, 1H), 4.05-4.02 (m, 1H), 2.21 (s, 1H), 2.07-2.04 (m, 1H), 1.94-1.58 (m, 10H), 1.55-1.25 (m, 11H), 1.22-1.02 (m, 10H), 0.95-0.87 (m, 6H).LC-ELSD / MS purity 99%, MS ESI C 28 H 40 Calculated value for N3[M-2H2O+H]+: 418.3, Measured value: 418.3. SFC 100% de.

[0463] Examples 24 and 25: Synthesis of 1-((S)-2-((3R,5R,8R,9S,10S,13S,14S,17S)-3-(ethoxymethyl)-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile (24) and 1-((R)-2-((3R,5R,8R,9S,10S,13S,14S,17S)-3-(ethoxymethyl)-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile (25) [ka] Synthesis of 24-1 To a mixture of MePPhBr (5.67 g, 15.9 mmol) in THF (70 mL) was added t-BuOK (1.78 mg, 15.9 mmol) under N at 25 °C. After stirring at 55 °C for 30 min, 24-0 (2.0 g, 5.31 mmol) in THF (30 mL) was added portionwise below 55 °C. After stirring at 55 °C for 2 h, the reaction mixture was poured into water (300 mL) at 25 °C and extracted with EtOAc (2 × 300 mL). The combined organic layers were washed with water (300 mL), brine (200 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0–5% EtOAc in PE) to give 24-1 (900 mg). 1 H NMR (400 MHz, CDCl3) δ H 4.84 (s, 1H), 4.69 (s, 1H), 3.55-3.51 (q, J=6.9 Hz, 2H), 3.47-3.33 (m, 2H), 2.73-2.65 (m, 1H), 2.06-1.97 (m, 2H), 1.96-1.81 (m, 3H), 1.77-1.72 (m, 4H), 1.58-1.54 (m, 2H), 1.45-1.38 (m, 4H), 1.25-1.18 (m, 8H), 0.90-0.82 (m, 9H), 0.54 (s, 3H).

[0464] Synthesis of 24-2 To a solution of 24-1 (900 mg, 2.40 mmol) in DCM (20 mL) was added m-CPBA (974 mg, 85%, 4.80 mmol) at 15 °C. After stirring at 15 °C for 1 h, the mixture was quenched with saturated aqueous NaHCO (200 mL). The organic phase was separated and washed with saturated aqueous NaHCO / NaSO (1:1, 3 × 100 mL), brine (100 mL), dried over NaSO, filtered, and concentrated in vacuo to give 24-2 ( 1.0 g) was obtained. 1 H NMR (400 MHz, CDCl3) δ H3.55-3.51 (q, J=6.9 Hz, 2H), 3.47-3.35 (m, 2H), 1.98-1.77 (m, 4H), 1.76-1.66 (m, 2H), 1.64-1.44 (m, 6H), 1.43-1.31 (m, 7H), 1.27-1.17 (m, 7H), 1.16-0.99 (m, 4H), 0.95-0.90 (m, 3H), 0.81-0.74 (m, 1H), 0.71-0.61 (m, 2H).

[0465] Synthesis of 24 and 25 To a solution of 24-2 (1.0 g, 2.56 mmol) in DMF (15 mL) were added 1H-pyrazole-4-carbonitrile (595 mg, 6.40 mmol) and CsCO (4.17 g, 12.8 mmol). After stirring at 125 °C for 12 h, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 60 mL). The combined organic layers were washed with saturated LiCl (3 × 150 mL) and then concentrated. The residue was purified by flash column chromatography (0–20% EtOAc in PE) to give a mixture of epimers (700 mg). Epimer separation by SFC (column: Chiralpak AD-3 50 x 4.6 mm ID, 3 μm; mobile phase: A: CO2, B: ethanol (0.05% DEA); gradient: 5% to 40% B for 2 min, hold at 40% for 1.2 min, then 5% B for 0.8 min; flow rate: 4 mL / min; column temperature: 35 °C; ABPR: 1500 psi) gave 24 (284.9 mg, 40.8%) and 25 (88.4 mg, 12.7%).

[0466] twenty four: 1 H NMR (400 MHz, CDCl3) δ H7.92 (s, 1H), 7.82 (s, 1H), 4.36 - 4.32 (d, J = 13.8 Hz, 1H), 4.09 - 4.05 (d, J = 13.8 Hz, 1H), 3.53 - 3.50 (q, J = 6.9 Hz, 2H), 3.47 - 3.36 (m, 2H), 2.72 (s, 1H), 2.54 (s, 1H), 2.01 - 1.99 (d, J = 10.8 Hz, 1H), 1.96 - 1.79 (m, 2H), 1.77 - 1.64 (m, 4H), 1.62 - 1.46 (m, 5H), 1.45 - 1.35 (m, 6H), 1.26 - 1.18 (m, 6H), 1.13 - 1.08 (m, 1H), 0.96 - 0.93 (d, J = 10.8 Hz, 7H), 0.89 (s, 3H). LC - ELSD / MS purity 99%, MS ESI C 27 H 36 Calculated value for N3[M - EtOH - 2H2O + H] is 402.3, measured value is 402.3. SFC 100% de.

[0467] 25: 1 H NMR (400 MHz, CDCl3) δ H 7.89 (s, 1H), 7.81 (s, 1H), 4.17 - 4.14 (d, J = 13.8 Hz, 1H), 4.02 - 3.99 (d, J = 13.8 Hz, 1H), 3.55 - 3.50 (q, J = 7.0 Hz, 2H), 3.46 - 3.35 (m, 2H), 2.72 (s, 1H), 2.34 (s, 1H), 2.06 (d, 1H), 1.97 - 1.79 (m, 3H), 1.73 - 1.64 (m, 3H), 1.62 - 1.53 (m, 3H), 1.53 - 1.34 (m, 8H), 1.27 - 1.18 (m, 6H), 1.17 - 1.10 (m, 2H), 1.07 (s, 3H), 0.93 (s, 3H), 0.85 (s, 3H). LC - ELSD / MS purity 99%, MS ESI C 27 H 36Calculated value for N3[M-EtOH-2H2O+H]+: 402.3 Found value: 402.3. SFC 100% de.

[0468] Examples 26 and 27: 1-((S)-2-hydroxy-2-((3R,5R,8R,9 S,10S,13S,14S,17S)-3-Hydroxy-10,13-dimethyl-3-propylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl Synthesis of 1-((R)-2-hydroxy-2-((3R,5R,8R,9S,10S,13S,14S,17S)-3-hydroxy-10,13-dimethyl-3-propylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile (26) and 1-((R)-2-hydroxy-2-((3R,5R,8R,9S,10S,13S,14S,17S)-3-hydroxy-10,13-dimethyl-3-propylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile (27) [ka] Synthesis of 26-1 To a mixture of MePPhBr (2.96 g, 8.30 mmol) in THF (30 mL) was added t-BuOK (931 mg, 236 mmol) under N at 25 °C. After stirring at 50 °C for 30 min, 26-0 (1.0 g, 2.77 mmol) in THF (20 mL) was added portionwise below 50 °C. After stirring at 50 °C for 2 h, the reaction mixture was poured into water (300 mL) at 25 °C and extracted with EtOAc (2 × 300 mL). The combined organic layers were washed with water (300 mL), brine (200 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0–5% EtOAc in PE) to give 26-1 (880 mg, 88.6%). 1 H NMR (400 MHz, CDCl3) δ H 4.84 (s, 1H), 4.69 (s, 1H), 2.06-1.98 (m, 1H), 1.93-1.79 (m, 3H), 1.75 (s, 3H), 1.73-1.64 (m, 3H), 1.60-1.49 (m, 3H), 1.48-1.33 (m, 8H), 1.32-1.17 (m, 6H), 1.17-0.99 (m, 4H), 0.97-0.90 (m, 6H), 0.54 (s, 3H).

[0469] Synthesis of 26-2 To a solution of 26-1 (880 mg, 2.45 mmol) in DCM (20 mL) was added m-CPBA (994 mg, 85%, 4.90 mmol) at 15 °C. After stirring at 15 °C for 1 h, the mixture was quenched with saturated aqueous NaHCO (200 mL). The organic phase was separated and washed with saturated aqueous NaHCO / NaSO (1:1, 3 × 100 mL), brine (100 mL), dried over NaSO, filtered, and concentrated in vacuo to give 26-2 (900 mg). 1 H NMR (400 MHz, CDCl3) δ H 2.89-2.86 (d, J=4.3 Hz, 1H), 2.57-2.53 (d, J=4.3 Hz, 1H), 2.51-2.29 (m, 1H), 1.95-1.80 (m, 5H), 1.73-1.64 (m, 2H), 1.63-1.54 (m, 4H), 1.39-1.32 (m, 9H), 1.27-1.20 (m, 5H), 0.97-0.88 (m, 10H), 0.77 (s, 1H), 0.65 (s, 3H).

[0470] Synthesis of 26 and 27 A solution of 26-2 (900 mg, 2.40 mmol) in DMF (5 mL) was added to the 1H-pyrazoline CsCO3 (3.87 g, 11.9 mmol) was added to the reaction mixture. After stirring at 125 °C for 12 h, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 60 mL). The combined organic layers were washed with saturated LiCl (3 × 150 mL) and then concentrated. The residue was purified by flash column chromatography (0–20% EtOAc in PE) to give a mixture of epimers (740 mg, 66.0%). The epimers were separated by SFC (column: Chiralpak AD-3 50 x 4.6 mm ID, 3 μm; mobile phase: A: CO2, B: ethanol (0.05% DEA); gradient: 5% to 40% B for 2 min, hold at 40% for 1.2 min, then 5% B for 0.8 min; flow rate: 4 mL / min; column temperature: 35 °C; ABPR: 1500 psi) to give 26 (318.7 mg) and 27 (154.0 mg).

[0471] 26: 1 H NMR (400 MHz, CDCl3) δ H 7.92 (s, 1H), 7.82 (s, 1H), 4.35-4.32 (d, J=13.6 Hz, 1H), 4.09-4.05 (d, J=13.8 Hz, 1H), 2.52 (s, 1H), 2.05-1.98 (m, 1H), 1.91-1.82 (m, 2H), 1.78-1.63 (m, 4H), 1.57-1.49 (m, 5H), 1.48-1.32 (m, 10H), 1.30-1.19 (m, 5H), 1.16-1.02 (m, 4H), 0.97 (s, 3H), 0.95-0.92 (m, 5H), 0.89 (s, 3H).LC-ELSD / MS purity 99%, MS ESI C 29 H 41 N3[M-2H2O+H] + Calculated value 432.3 Measured value 432.3. SFC 100% de.

[0472] 27: 1 H NMR (400 MHz, CDCl3) δ H7.89 (s, 1H), 7.80 (s, 1H), 4.21-4.11 (m, 1H), 4.02-3.98 (d, J=13.8 Hz, 1H), 2.30 (s, 1H), 2.06 (s, 1H), 1.97-1.78 (m, 3H), 1.73-1.63 (m, 3H), 1.55 (s, 3H), 1.52-1.33 (m, 12H), 1.32-1.18 (m, 6H), 1.08 (s, 3H), 0.97-0.91 (m, 6H), 0.85 (s, 3H).LC-ELSD / MS purity 99%, MS ESI C 29 H 41 Calculated value for N3[M-2H2O+H]+: 432.3 Found value: 432.3

[0473] Example 28: Synthesis of 1-((3-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)oxetan-3-yl)methyl)-1H-pyrazole-4-carbonitrile [ka] Synthesis of 28-1 To a suspension of NaH (2.75 g, 60%, 68.8 mmol) in THF (60 mL), (EtO)2P(O)CH2COOEt (15.4 g, 68.8 mmol) was added dropwise at 0 °C. After stirring at 20 °C for 10 min, a solution of 28-0 (10 g, 34.4 mmol, reported in patent WO2014 / 169833, 2014, A1) in THF (20 mL) was added dropwise at 20 °C. After stirring at 70 °C for 16 h, the reaction mixture was poured into NH4Cl (200 mL, 10% aqueous solution) and extracted with EtOAc (200 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (0–20% EtOAc in PE) to give 28-1 (12 g, 97%). 1 H NMR (400 MHz, CDCl3) δ H5.52 (t, J = 2.4 Hz, 1H), 4.15 (q, J = 7.2 Hz, 2H), 2.90-2.75 (m, 2H), 1.95-1.60 (m, 5H), 1.50-1.25 (m, 18H), 1.20-1.05 (m, 4H), 0.82 (s, 3H).

[0474] Synthesis of 28-2 To a solution of 28-1 (12 g, 33.2 mmol) in THF (150 mL) was added Pd / C (2 g, dry, 10%) under N. After stirring at 40 °C under H (40 psi) for 24 h, the reaction mixture was filtered through a Celite pad, which was then washed with THF (3 × 50 mL). The combined filtrates were concentrated to give 28-2 (11.7 g, 97.5%). 1 H NMR (400 MHz, CDCl) δ H 4.11 (q, J = 6.8 Hz, 2H), 2.35 (dd, J = 5.2, 14.4 Hz, 1H), 2.10 (dd, J = 10.0, 14.8 Hz, 1H), 2.00-1.75 (m, 6H), 1.70-1.50 (m, 3H), 1.50-1.35 (m, 6H), 1.35-1.25 (m, 10H), 1.20-0.95 (m, 6H), 0.59 (s, 3H).

[0475] Synthesis of 28-3 To a solution of i-PrNH (1.66 g, 16.5 mmol) in THF (30 mL) was added BuLi (6.6 mL, 2.5 M hexane solution, 16.5 mmol) at −70° C. After warming at 0° C. for 15 min, the mixture was then cooled to −70° C. and a solution of 28-2 (2 g, 5.5 mmol) in THF (10 mL) was added. After stirring at −70° C. for 1 h, a solution of ClCOOEt (1.79 g, 16.5 mmol) in THF was added. After stirring at −70° C. for 1 h, the reaction mixture was quenched with NHCl (20 mL, 10%) and EtOAc (2× The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give 28-3 (2.7 g). 1 H NMR (400 MHz, CDCl3) δ H 4.25-4.05 (m, 4H), 3.29 (d, J = 11.2 Hz, 1H), 2.25-2.15 (m, 1H), 2.00-1.75 (m, 4H), 1.70-1.35 (m, 12H), 1.35-1.20 (m, 10H), 1.20-0.95 (m, 7H), 0.70 (s, 3H).

[0476] Synthesis of 28-4 To a suspension of t-BuOK (4.85 g, 31.0 mmol) in THF (20 mL) was added a solution of 28-3 (2.25 g, 5.17 mmol) in THF (20 mL) at 0 °C. After stirring at 15 °C for 1 h, BOMCl (3.47 g, 31.0 mmol) was added at 0 °C. After stirring at 0 °C for 1 h, the reaction mixture was poured into NH Cl (100 mL, saturated) and extracted with EtOAc (100 mL). The organic layer was separated, dried over Na SO , filtered, and concentrated to give 28-4 (8.5 g). This contained some diethyl 2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-((benzyloxy)methoxy)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-((benzyloxy)methyl)malonate.

[0477] Synthesis of 28-5 A solution of 28-4 (5.17 mmol mixture) in THF (20 mL) was added dropwise to a suspension of LiAlH (1.96 g, 51.7 mmol) in THF (80 mL) at 0 °C. After stirring at 0 °C for 1 h, the reaction mixture was quenched with water / THF (2 mL / 100 mL), followed by NaOH (2 mL, 10%) and water (6 mL). The mixture was filtered, and the residue was washed with THF (3 × 50 mL). The combined filtrate was concentrated to 100 mL, and HCl (2 M, 10 mL) was added. After stirring at 50 °C for 1 h, the reaction mixture was diluted with NaHCO (50 mL, saturated) and extracted with EtOAc (100 mL). The organic layer was separated, dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (30–80% EtOAc in PE) to give 28-5 (1 g, 41% for two steps). 1 H NMR (400 MHz, CDCl3) δ H 7.45-7.30 (m, 5H), 4.50 (s, 2H), 3.95-3.55 (m, 6H), 2.80-2.70 (br, 1H), 2.70-2.60 (br, 1H), 1.95-1.70 (m, 4H), 1.70-1.50 (m, 5H), 1.50-1.20 (m, 13H), 1.15-0.90 (m, 6H), 0.73 (s, 3H).

[0478] Synthesis of 28-6 To a solution of 28-5 (1 g, 2.12 mmol) in THF (20 mL) was added BuLi (1.01 mL, 2.5 M hexane solution, 2.54 mmol) at 0 °C. After stirring at 0 °C for 10 min, a solution of TsCl (484 mg, 2.54 mmol) in THF (5 mL) was added. After stirring at 0 °C for 1 h, BuLi (1.01 mL, 2.5 M hexane solution, 2.54 mmol) was added at 0 °C. After stirring at 15 °C for 2 h, the reaction mixture was quenched with NH4Cl (20 mL, saturated) and extracted with EtOAc (2 × 30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (0–15% EtOAc in PE) to give 28-6 (650 mg, 68%). 1H NMR (400 MHz, CDCl3) δ H 7.45-7.30 (m, 5H), 4.83 (d, J = 6.4 Hz, 1H), 4.60 (d, J = 12.0 Hz, 1H), 4.55-4.50 (m, 2H), 4.44 (d, J = 5.6 Hz, 1H), 4.23 (d, J = 6.4 Hz, 1H), 3.89 (d, J = 9.2 Hz, 1H), 3.66 (d, J = 9.2 Hz, 1H), 2.20-2.10 (m, 1H), 2.00-1.60 (m, 8H), 1.50-1.30 (m, 7H), 1.30-0.95 (m, 12H), 0.52 (s, 3H).

[0479] Synthesis of 28-7 To a solution of 28-6 (650 mg, 1.43 mmol) in THF (20 mL) was added Pd / C (0.5 g, 10%, wet) under N. After stirring at 20 °C under H (20 psi) for 20 h, the reaction mixture was filtered and the residue was washed with THF (20 mL). The combined filtrate was concentrated and purified by flash column (40-70% EtOAc in PE) to give 28-7 (380 mg, 73%). 1 H NMR (400 MHz, CDCl3) δ H 4.85 (d, J = 6.8 Hz, 1H), 4.54 (d, J = 5.6 Hz, 1H), 4.46 (d, J = 5.6 Hz, 1H), 4.24 (d, J = 6.4 Hz, 1H), 4.08 (dd, J = 4.0, 10.8 Hz, 1H), 3.82 (d, J = 10.0 Hz, 1H), 2.20-2.10 (m, 1H), 2.00-1.65 (m, 10H), 1.55-1.00 (m, 18H), 0.53 (s, 3H).LC-ELSD / MS: >99% purity, MS ESI C 23 H 37 O2 [M+H-H2O] + The calculated value was 345.3, and the measured value was 345.3.

[0480] Synthesis of 28-8 To a solution of 28-7 (185 mg, 0.51 mmol) in DCM (5 mL) was added N-Me-Im (41.8 mg, 0.51 mmol), TEA (258 mg, 2.55 mmol), and TsCl (194 mg, 1.02 mmol). After stirring at 15 °C for 16 h, the reaction mixture was washed with water (5 mL), dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (0 to 25% EtOAc in PE / DCM (1:1)) to give 28-8 (200 mg, 76%). 1 H NMR (400 MHz, CDCl3) δ H 7.83 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 4.82 (d, J = 6.8 Hz, 1H), 4.50-4.40 (m, 2H), 4.22 (d, J = 9.6 Hz, 1H), 4.18 (d, J = 6.0 Hz, 1H), 4.11 (d, J = 6.8 Hz, 1H), 2.46 (s, 3H), 2.10-2.00 (m, 1H), 1.95-1.55 (m, 8H), 1.50-0.90 (m, 19H), 0.47 (s, 3H).

[0481] Synthesis of 28 To a solution of 28-8 (200 mg, 0.39 mmol) in DMF (5 mL) was added 4-cyanopyrazole (72 mg, 0.77 mmol), KI (64.2 mg, 0.38 mmol), and KCO (108 mg, 0.77 mmol). After stirring at 80 °C for 16 h, the reaction mixture was poured into water (30 mL) and filtered. The residue was purified by flash column chromatography (20-50% EtOAc in PE), dissolved in MeCN (30 mL) / water (30 mL), and lyophilized to give 28 (135.7 mg, 79%). 1 H NMR (400 MHz, CDCl3) δ H 7.88 (s, 1H), 7.83 (s, 1H), 4.96 (d, J = 6.8 Hz, 1H), 4.70-4.60 (m, 2H), 4.53 (d, J = 6.4 Hz, 1H), 4.47 (d, J = 7.2 Hz, 1H), 4.35 (d, J = 14.0 Hz, 1H), 2.10-2.00 (m, 1H), 2.00-1.65 (m, 8H), 1.55-0.95 (m, 19H), 0.69 (s, 3H).LC-ELSD / MS >99% purity, MS ESI C 27 H 40 N3O2[M+H] + The calculated value was 438.3, and the measured value was 438.3.

[0482] Examples 29 and 30: 1-((S)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3-(methoxymethyl)-1 Synthesis of 3-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)propyl)-1H-pyrazole-4-carbonitrile (29) and 1-((R)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)propyl)-1H-pyrazole-4-carbonitrile (30) [ka] Synthesis of 29.2 To a solution of MePPhBr (12.2 g, 34.0 mmol) in THF (20 mL) was added t-BuOK (2.88 g, 25.8 mmol) at 15 °C. After stirring at 15 °C for 1 h, 29.1 (3 g, 8.60 mmol) in THF (20 mL) was added. After stirring at 45 °C for 3 h, the mixture was treated with saturated NHCl (50 mL) and extracted with EtOAc (2 × 30 mL). The combined organic solution was washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash column (0–40% EtOAc in PE) to give 29.2 (4.5 g). 1H NMR (400MHz, CDCl3) δ 4.83 (s, 1H), 4.45 (s, 1H), 3.47-3.31 (m, 5H), 2.61 (s, 1H), 2.05-2.02 (m, 1H), 1.91-1.77 (m, 4H), 1.74 (s, 3H), 1.68-1.52 (m, 5H), 1.49-1.31 (m, 7H), 1.28-1.04 (m, 7H), 0.59-0.50 (m, 3H).

[0483] Synthesis of 29.3 To a solution of 29.2 (500 mg, 1.44 mmol) in DCM (20 mL) was added m-CPBA (461 mg, 2.15 mmol, 85%) at 15 °C. After stirring for 1 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 phases were washed with saturated NaHCO and NaSO (50 mL, v:v = 1:1), dried over NaSO, filtered, and concentrated to give 29.3 (520 mg). 1 H NMR (400 MHz, CDCl3) δH = 3.46 - 3.32 (m, 8H), 2.88 (d, J = 4.4 Hz, 1H), 2.55 (d, J = 4.4 Hz, 1H), 2.51 - 2.47 (m, 1H), 2.31 (d, J = 5.2 Hz, 1H), 2.04 - 1.98 (m, 1H), 1.95 - 1.53 (m, 8H), 1.50 - 1.29 (m, 8H), 1.28 - 0.98 (m, 5H), 0.82 - 0.78 (m, 1H), 0.68 (s, 3H).

[0484] Synthesis of 29.4 To a solution of 29.3 (520 mg, 1.43 mmol) in DMF (10 mL) was added CsCO (1.39 g, 4.29 mmol) and 1H-pyrazole-4-carbonitrile (332 mg, 3.57 mmol) under N at 15 °C. 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% aqueous solution), brine (2 × 100 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by column chromatography (0–50% EtOAc in PE) to give 29.4 (650 mg). LC-ELSD / MS purity 99%, MS ESI C 26 H 35 N3[M-2H2O-CH3OH+H] + The calculated value was 388.3, ​​and the measured value was 388.3.

[0485] Separation of 29 and 30 Separation of 29.4 by SFC (column: Chiralcel OD-3 50iA 4.6 mm ID, 3 μm; mobile phase: A: CO, B: ethanol (0.05% DEA); gradient: 5% to 40% B for 2 min, hold at 40% for 1.2 min, then 5% B for 0.8 min; flow rate: 4 mL / min) gave 30 (73 mg, 18.2%) and 29 (189.9 mg, 47.3%).

[0486] 29: 1 H NMR (400 MHz, CDCl3) δ H = 7.92 (s, 1H), 7.82 (s, 1H), 4.36 (d, J = 13.6 Hz, 1H), 4.08 (d, J = 13.6 Hz, 1H), 3.46 - 3.33 (m, 5H), 2.59 (s, 1H), 2.52 (s, 1H), 2.01 (br d, J = 12.0 Hz, 1H), 1.87 - 1.57 (m, 9H), 1.52 - 1.31 (m, 7H), 1.29 - 1.04 (m, 7H), 0.96 (s, 3H), 0.91 (s, 3H)LC-ELSD / MS purity 99%, MS ESI C 26 H 35 N3[M-2H2O-CH3OH+H] + The calculated value was 388.3, ​​and the measured value was 388.3.

[0487] 30: 1 H NMR (400 MHz, CDCl3) δ H = 7.89 (s, 1H), 7.80 (s, 1H), 4.17 (d, J = 13.6 Hz, 1H), 4.01 (d, J = 13.6 Hz, 1H), 3.48 - 3.32 (m, 5H), 2.60 (s, 1H), 2.32 (s, 1H), 2.06 (br d, J = 13.6 Hz, 1H), 1.98 - 1.60 (m, 9H), 1.51 - 1.24 (m, 9H), 1.08 (s, 8H), 0.87 (s, 3H).LC-ELSD / MS purity 99%,MS ESI C 26 H 35 N3[M-2H2O-CH3OH+H] + The calculated value was 388.3, ​​and the measured value was 388.3.

[0488] Example 31: Synthesis of 1-(1-((S)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazol-4-yl)ethanone (31) [ka] Synthesis of 31.1 To a solution of 21.0 (2 g, 4.88 mmol) and 2,6-dimethylpyridine (1.30 g, 12.2 mmol) in DCM (20 mL) was added tert-butyldimethylsilyl trifluoromethanesulfonate (2.57 g, 9.76 mmol) dropwise at 0 °C. After stirring at 15 °C for 5 h, the reaction mixture was quenched with water (60 mL) and extracted with DCM (2 × 50 mL). The combined organic phases were washed with brine (50 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (10–20% EtOAc in PE) to give 31.1 (2.5 g, 98.0%). 1 H NMR (400 MHz, CDCl3) δ H 7.87 (s, 1H), 7.82 (s, 1H), 5.10-4.97 (m, 1H), 4.96-4.84 (m, 1H), 2.72-2.60 (m, 1H), 2.28-2.17 (m, 1H), 2.09-2.02 (m, 1H), 1.87-1.67 (m, 7H), 1.46-1.40 (m, 4H), 1.29-1.26 (m, 3H), 1.24 (s, 4H), 1.16-1.07 (m, 3H), 0.88 (s, 11H), 0.68 (s, 3H), 0.09 (s, 6H).

[0489] Synthesis of 31.2 To a solution of 31.1 (200 mg, 0.381 mmol) in THF (5 mL) was added MeMgBr (1.27 mL, 3.81 mmol, 3.0 M) at -60 °C. After stirring at 25 °C for 2 h, the mixture was added to NH4Cl (20 mL) and extracted with EtOAc (2 × 15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column (0–20% EtOAc in PE) to give 31.2 (120 mg, 56.6%). 1 H NMR (400 MHz, CDCl3) δ H 7.94-7.93 (m, 1H), 7.92-7.90 (m, 1H), 4.41-4.30 (m, 1H), 4.08-4.00 (m, 1H), 2.68-2.62 (m, 1H), 2.45-2.44 (m, 3H), 2.28-2.17 (m, 1H), 2.11-2.02 (m, 2H), 1.81-1.74 (m, 8H), 1.44 (s, 3H), 1.24 (s, 6H), 1.15-1.06 (m, 6H), 1.01-0.93 (m, 4H), 0.88 (s, 9H), 0.70-0.68 (m, 3H), 0.09 (s, 6H), 0.10-0.09 (m, 1H).

[0490] Synthesis of 31 To a solution of 31.2 (120 mg, 0.215 mmol) in THF (2 mL) was added HF (21.4 mg, 1.07 mmol, 1.1 g / mL) in one portion under N2 at 25 °C. After stirring at 5 °C for 16 h, the mixture was added to NH4Cl (10 mL) and extracted with EtOAc (2 × 15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by HPLC (Welch Xtimate C18 150 × 25 mm, 5 μm; conditioning solvent: water (0.04% NH3H2O)-ACN; gradient: 50% to 80% B over 8.5 min, hold 100% for 2 min; flow rate: 30 mL / min; injections: 6) to give 31 (3.8 mg, 3.99%). 1 H NMR (400 MHz, CDCl3) δ H 7.97-7.95 (m, 1H), 7.95-7.93 (m, 1H), 4.38-4.31 (m, 1H), 4.06-4.01 (m, 1H), 3.08-3.05 (m, 1H), 2.46 (s, 3H), 2.08-2.02 (m, 1H), 1.87-1.73 (m, 5H), 1.70-1.61 (m, 4H), 1.47-1.35 (m, 8H), 1.27 (s, 5H), 1.14-1.04 (m, 5H), 1.00 (s, 3H), 0.93 (s, 3H).LC-ELSD / MS purity 99%, MS ESI C 27 H 42N2O3[M+H] + Calculated value: 443.3 Measured value: 443.3.

[0491] Examples 32 and 33: Synthesis of 1-((R)-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methoxypropyl)-1H-pyrazole-4-carbonitrile (32) and 1-[(2S)-2-[(1S,3aS,3bR,5aR,7R,9aS,9bR,11aS)-7-hydroxy-7-(methoxymethyl)-11a-methyl-hexadecahydro-1H-cyclopenta[a]phenanthren-1-yl]-2-methoxypropyl]-1H-pyrazole-4-carbonitrile (33) [ka] Synthesis of 32.1 To a solution of 29.2 (4 g, 11.5 mmol) and 2,6-dimethylpyridine (6.14 g, 57.4 mmol) in DCM (150 mL) was added TBSOTf (12.1 g, 46.0 (mmol) was added at 0 °C. After stirring at 25 °C for 16 h, the mixture was diluted with DCM (150 mL) and washed with water (300 mL). The organic phase was separated, dried over anhydrous NaSO, filtered, and concentrated to give 32.1 (6 g), which was used directly in the next step. 1 H NMR (400 MHz, CDCl3) δ 4.85 (s, 1H), 4.70 (s, 1H), 3.42 - 3.29 (m, 5H), 2.11 - 2.05 (m, 1H), 1.89 - 1.79 (m, 5H), 1.72 - 1.56 (m, 8H), 1.49 - 0.99 (m, 16H), 0.95 - 0.88 (m, 6H), 0.57 (s, 3H), 0.08 - 0.05 (m, 6H).

[0492] Synthesis of 32.2 To a solution of 32.1 (3 g, 6.51 mmol) in DCM (150 mL) was added m-CPBA (1.96 g, 9.76 mmol, 85%). After stirring at 25 °C for 2 h, the reaction mixture was quenched with NaHCO (150 mL, saturated) and extracted with DCM (2 × 80 mL). The combined organic phases were washed with brine (150 mL), dried over anhydrous NaSO, filtered, and concentrated to give 32.2 (2.3 g).

[0493] Synthesis of 32.3 and 32.4 To a solution of 32.2 (2.3 g, 4.82 mmol) in DMF (50 mL) was added 1H-pyrazole-4-carbonitrile (1.34 g, 14.4 mmol) and CsCO (4.69 g, 14.4 mmol) at 25 °C. After stirring at 140 °C for 8 h, the mixture was diluted with water (100 mL) and extracted with EtOAc (2 × 60 mL). The combined organic phases were washed with water (100 mL), brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (0% to 30% EtOAc in PE) to give 32.4 (1.3 g, 47.4%) and 32.3 (680 mg, 24.8%).

[0494] 32.3: 1 H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.80 (s, 1H), 4.23-4.13 (m, 1H), 4.05-3.90 (m, 1H), 3.43-3.26 (m, 5H), 2.29 (s, 1H), 2.10-2.05 (m, 1H), 1.98-1.62 (m, 8H), 1.57-1.27 (m, 7H), 1.23-0.97 (m, 10H), 0.94-0.81 (m, 13H), 0.06 (s, 6H).

[0495] 32.4: 1 H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.82 (s, 1H), 4.36 (d, J = 14.0 Hz, 1H), 4.10-4.05 (m, 1H), 3.41-3.29 (m, 5H), 2.50 (s, 1H), 1.83-1.59 (m, 9H), 1.53-1.27 (m, 7H), 1.24-1.01 (m, 8H), 1.00-0.90 (m, 6H), 0.85 (s, 9H), 0.06 (s, 6H).

[0496] Synthesis of 32.5 To a solution of 32.3 (680 mg, 1.19 mmol) in THF (20 mL) was added NaH (71.1 mg, 1.78 mmol, 60% in oil) under N2 at 25 °C. After stirring for 30 min at 25 °C, MeI (337 mg, 2.38 mmol) was added. After stirring for 16 h at 25 °C, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic phases were washed with brine (2 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column (0–20% EtOAc in PE). The product was purified to give 32.5 (600 mg).

[0497] Synthesis of 32 To a solution of 32.5 (1.3 g, 2.22 mmol) in THF (20 mL) was added TBAF (22.2 mL, 22.2 mmol, 1 M THF solution). After stirring at 80 °C for 16 h, the reaction mixture was quenched with NH4Cl (50 mL, saturated) and extracted with EtOAc (2 × 50 mL). The combined organic phases were washed with brine (2 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (0–50% EtOAc in PE) to give 32 (301.8 mg, 28.9%). 1 H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.75 (s, 1H), 4.33-4.12 (m, 2H), 3.45-3.32 (m, 5H), 3.18 (s, 3H), 2.57 (s, 1H), 1.98-1.91 (m, 1H), 1.85-1.59 (m, 9H), 1.50-1.22 (m, 8H), 1.18-1.00 (m, 9H), 0.85 (s, 3H).LCMS30~90AB_2min_E, purity 99% or more, MS ESI C 27 H 38 NO [M+H-MeOH-HO] + The calculated value was 420.3, and the measured value was 420.2.

[0498] Synthesis of 32.6 To a solution of 32.4 (1.3 g, 2.28 mmol) in THF (20 mL) was added NaH (136 mg, 3.42 mmol, 60% in oil) under N at 25 °C. After stirring for 30 min, MeI (647 mg, 4.56 mmol) was added at 25 °C. After stirring at 25 °C for 16 h, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic phases were washed with brine (2 × 50 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash column (0–20% EtOAc in PE) to give 32.6 (1.2 g).

[0499] Synthesis of 33 To a solution of 32.6 (600 mg, 1.02 mmol) in THF (10 mL) was added TBAF (5.10 mL, 5.10 mmol, 1 M THF solution). After stirring at 80 °C for 16 h, the reaction mixture was quenched with NH4Cl (50 mL, saturated) and extracted with EtOAc (2 × 50 mL). The combined organic phases were washed with brine (2 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (0–50% EtOAc in PE) to give 33 (144.7 mg, 30%). 1 H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.75 (s, 1H), 4.24 (s, 2H), 3.45-3.34 (m, 5H), 3.13 (s, 3H), 2.59 (s, 1H), 2.09-1.99 (m, 1H), 1.86-1.59 (m, 9H), 1.49-1.19 (m, 9H), 1.13-0.98 (m, 8H), 0.81 (s, 3H).LCMS Purity 99% or higher, MS ESI C 27 H 38 NO [M+H-MeOH-HO] + The calculated value was 420.3, and the measured value was 420.2.

[0500] Examples 34 and 35: Synthesis of 1-((S)-2-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-2-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile (34) and 1-((R)-2-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-2-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile (35) [ka] Synthesis of 34.1 To a solution of 34.0 (100 g, 364 mmol) in DCM (1000 mL) was added imidazole (49.5 g, 728 mmol) and TBSCl (109 g, 728 mmol) at 25 °C. After stirring at 25 °C for 2 h, the mixture was poured into water (500 mL) and extracted with DCM (2 × 500 mL). The combined organic phases were washed with brine (500 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was triturated with PE (200 mL) at 25 °C to give 34.1 (83 g). 1 H NMR (400 MHz, CDCl3) δ H 5.82 (s, 1H), 3.56 (t, J = 8.3 Hz, 1H), 2.50-2.36 (m, 2H), 2.32-2.19 (m, 3H), 2.14-2.04 (m, 1H), 1.94-1.74 (m, 3H), 1.59-1.21 (m, 6H), 1.07-0.90 (m, 4H), 0.88 (s, 9H), 0.84-0.78 (m, 1H), 0.76 (s, 3H), 0.00 (d, J = 2.8 Hz, 6H).

[0501] Synthesis of 34.2 To a solution of 34.1 (50 g, 128 mmol) in THF (300 mL) was added LiHMDS (128 mL, 1 M THF solution, 128 mmol) under N at −70 °C. After stirring at −70 °C for 30 min, HMPA (22.9 g, 22.4 mL, 128 mmol) was added under N. After stirring at −70 °C for 30 min, EtI (199 g, 102 mL, 128 mmol) was added under N. After stirring at 20 °C for 1 h, the mixture was cooled and concentrated under reduced pressure at 40 °C. The residue was poured into NH Cl (500 mL), stirred for 20 min, and extracted with EtOAc (3 × 400 mL). The combined organic phase was washed with brine (2 × 200 mL), dried over anhydrous Na SO , filtered, and concentrated. The residue was purified by flash column (0-1% EtOAc in PE) to give 34.2 (40 g). 1 H NMR (400 MHz, CDCl3) δ H 5.79 (s, 1H), 5.72 (s, 1H), 3.57 (t, J = 8.3 Hz, 1H), 2.48-2.39 (m, 1H), 2.34-2.06 (m, 4H), 1.96-1.61 (m, 3H), 1.26 (br d, J = 1.8 Hz, 9H), 1.07-0.98 (m, 2H), 0.93 (br t, J = 7.5 Hz, 4H), 0.88 (s, 10H), 0.76 (s, 3H), 0.01 (d, J = 2.8 Hz, 6H).

[0502] Synthesis of 34.3 To a mixture of 34.2 (20 g, 47.9 mmol) in THF (200 mL) was added Pd / C (2 g, 10%). The mixture was degassed under vacuum and purged with H2 three times. After stirring at 25° C. under (15 psi) for 24 hours, the reaction mixture was filtered through a pad of Celite and washed with THF (3×500 mL). The filtrate was concentrated to give 34.3 (18 g). 1 H NMR (400 MHz, CDCl3) δ H 3.61-3.52 (m, 1H), 2.67-2.55 (m, 1H), 2.34-2.05 (m, 4H), 1.94-1.62 (m, 4H), 1.58-0.92 (m, 14H), 0.92-0.85 (m, 13H), 0.73 (d, J = 3.8 Hz, 3H), 0.00 (dd, J = 3.0, 4.4 Hz, 6H).

[0503] Synthesis of 34.4 To a solution of BHT (60 g, 272 mmol) in toluene (200 mL) at 0 °C under N2, trimethylaluminum (68 mL, 2 M toluene solution, 136 mmol) was slowly added dropwise. After stirring at 0 °C for 1 h, this MAD solution was used as is without further purification. To a solution of MAD (64.8 g in toluene, 135 mmol), a solution of 34.3 (19 g, 45.3 mmol) in DCM (200 mL) was added dropwise under N2 at -70 °C. After stirring at -70 °C for 1 h under N2, MeMgBr (30.2 mL, 3 M ethyl ether solution, 90.6 mmol) was added dropwise at -70 °C. After stirring for 2 h, the reaction mixture was slowly poured into aqueous citric acid (500 mL, saturated) at 10 °C and extracted with DCM (2 × 200 mL). The combined organic phase was washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column (0-5% EtOAc in PE) to give 34.4 (11 g). 1 H NMR (400 MHz, CDCl3) δ H 3.54 (t, J = 8.3 Hz, 1H), 2.03-1.94 (m, 1H), 1.91-1.61 (m, 6H), 1.58-1.36 (m, 5H), 1.32-1.13 (m, 6H), 1.12-0.89 (m, 11H), 0.87 (s, 11H), 0.70 (d, J = 2.3 Hz, 3H), 0.00 (t, J = 2.6 Hz, 6H).

[0504] Synthesis of 34.5 and 34.5a To a solution of 34.4 (11 g, 25.3 mmol) in THF (20 mL) was added TBAF.3H2O (126 mL, 1 M, 126 mmol) at 15 °C. After stirring at 55 °C for 12 h, the mixture was poured into water (200 mL) and extracted with EtOAc (2 × 200 mL). The organic layer was washed with brine (2 × 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (10–15% EtOAc in PE) to give 34.5a (3.8 g) and 34.5 (4.7 g).

[0505] 34.5a: 1 H NMR (400 MHz, CDCl3) δ H 3.63 (br t, J = 8.3 Hz, 1H), 2.11-1.98 (m, 2H), 1.84-1.73 (m, 3H), 1.61-1.54 (m, 2H), 1.48-1.33 (m, 3H), 1.32-1.12 (m, 6H), 1.06 (s, 6H), 1.02-0.82 (m, 8H), 0.74 (s, 4H), 0.67-0.58 (m, 1H).

[0506] 34.5: 1 H NMR (400 MHz, CDCl3) δ H 3.64 (t, J = 8.6 Hz, 1H), 2.12-1.92 (m, 3H), 1.85-1.54 (m, 4H), 1.52-1.36 (m, 6H), 1.32-1.16 (m, 5H), 1.09 (s, 4H), 1.06 (br s, 4H), 0.95-0.81 (m, 6H), 0.73 (s, 3H).

[0507] Synthesis of 34.6 To a mixture of 34.5 (4.7 g, 14.6 mmol) in DCM (50 mL) was added DMP (12.3 g, 29.2 mmol) was added at 25 °C. After stirring at 25 °C for 1 h, the mixture was quenched with saturated NaHCO3 and Na2S2O3 (20 mL, v / v = 1 / 1) and extracted with DCM (2 × 10 mL). The combined organic phases were washed with saturated NaHCO3 and Na2S2O3 (20 mL, v / v = 1 / 1), dried over anhydrous Na2SO4, filtered, and concentrated to give 34.6 (3 g). 1 H NMR (400 MHz, CDCl3) δ H 2.43 (dd, J = 8.3, 19.3 Hz, 1H), 2.14-1.59 (m, 9H), 1.57-1.40 (m, 5H), 1.38-1.12 (m, 8H), 1.10 (s, 3H), 1.08-1.02 (m, 1H), 0.95-0.88 (m, 1H), 0.90 (d, J = 4.8 Hz, 3H), 0.86 (s, 3H).

[0508] Synthesis of 34.7 To a suspension of PPhEtBr (10.4 g, 28.2 mmol) in THF (90 mL) was added t-BuOK (3.16 g, 28.2 mmol). After stirring at 40 °C for 30 min, a solution of 34.6 (3 g, 9.41 mmol) in THF (10 mL) was added to the reaction at 40 °C. After stirring at 40 °C for 12 h, the mixture was poured into NHCl (100 mL, saturated) and extracted with EtOAc (2 × 100 mL). The combine...

Claims

[Claim 1] The invention described in the specification.

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