RU2810331C2 - Compositions and methods of treatment of diseases of central nervous system - Google Patents

Abstract

FIELD: organic chemistry; pharmaceuticals.

SUBSTANCE: compound of formula (II-I) having the properties of an inhibitor of GABA receptor function, a pharmaceutical composition based on it, a method of treating a disease of the central nervous system (CNS) associated with GABA function, and a method of inducing sedation and/or anesthesia with their use. In the general formula (II-I) t is 1; n is 0 or 1; R¹⁹ represents unsubstituted C₂-C₆-alkyl, unsubstituted C₂-C₆-alkenyl; R⁵ represents a hydrogen atom; R³ represents either a hydrogen atom or a C_1-6 alkyl, optionally substituted with one or more C_1-3 alkoxy; R^6a and R^6b each represent a hydrogen atom; R¹ is a C_1-6 alkyl, optionally substituted by one or more –OH, a 5-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N or O, and optionally substituted by one or more substituents independently selected from unsubstituted C_1-6 alkyl, phenyl, optionally substituted with one or more halogens, or –S(O)₂CH₃, phenyl, optionally substituted with one or more unsubstituted C_1-6 alkyls, 5-10 membered heteroaryl containing 1-4 atoms N and optionally substituted with one or more substituents independently selected from unsubstituted C_1-6 alkyl, –CN or C_1-6 alkoxy, or -N(R^A1)₂ where R^A1 represents a hydrogen atom or phenyl, optionally substituted with one or several substituents independently selected from unsubstituted C_1-6 alkyl or –CN; R^2a, R^2b, R^4a, R^4b, R^7a, R^7b, R^11a, R^11b, R^12a, R^12b or R^17b each represents a hydrogen atom; each of R^15a, R^15b, R^16a and R^16b represents a hydrogen atom; and moreover represents a single bond.

EFFECT: effective treatment of diseases of the central nervous system (CNS) associated with GABA function and inducing sedation and/or anesthesia.

31 cl, 50 ex

Description

Cross reference to related applications

[ 0001 ] This application claims the benefit of US Patent Application Number (USSN) 62/734,718, filed September 21, 2018, USSN 62/722.78, filed August 24, 2018, USSN 62/620,095, filed January 22, 2018, USSN 62/611,983, filed December 29, 2017, and USSN 62/610,069, filed December 22, 2017, the contents of each of which are incorporated herein by reference in their entirety.

Field of technology to which the invention relates

[ 0002 ] Brain excitability is defined as the animal's level of activation, a continuum that ranges from coma to convulsions, and is regulated by a variety of neurotransmitters. Typically, neurotransmitters are responsible for regulating the conduction of ions across neuronal membranes. At rest, the neuron membrane has a potential (or membrane voltage) of approximately -70 mV, and the inside of the cell is negatively charged relative to the environment surrounding the cell. Potential (voltage) is the result of ionic (K ⁺ , Na ⁺ , Cl ^- , organic anions) balance on either side of the neuronal semipermeable membrane. Neurotransmitters are contained in presynaptic vesicles and are released under the influence of the action potential of the neuron. When they are released into the synaptic cleft, the potential changes from -70 mV to -50 mV. This effect is mediated by postsynaptic nicotinic receptors, which are stimulated by acetylcholine to increase membrane permeability to Na ⁺ ions. The decreased membrane potential stimulates neuron excitability in the form of a neuron action potential.

[ 0003 ] In the case of the GABA receptor complex (GRC), the effect on brain excitability is determined by the neurotransmitter γ-aminobutyric acid (GABA). GABA has a strong effect on overall brain excitability because up to 40% of neurons use GABA as a neurotransmitter. GABA controls the excitability of individual neurons by regulating the conductance of chloride ions across the neuronal membrane. GABA interacts with its recognition site on the GRC, facilitating the flow of chloride ions into the cell to reduce the electrochemical gradient of the GRC. Increasing levels of this anion within the cell causes hyperpolarization of the transmembrane potential, making neurons less sensitive to excitatory inputs, i.e. , reducing neuronal excitability. In other words, the higher the concentration of chloride ions in a neuron, the lower the brain's excitability and level of arousal.

[ 0004 ] It is well documented that GRC is responsible for alleviating anxiety, seizure activity, and sedation. Thus, GABA and drugs that act like GABA or enhance the effects of GABA (eg, therapeutically acceptable barbiturates and benzodiazepines (BZs) such as Valium®) exert their therapeutically beneficial effects by interacting with specific regulatory sites on the GRC. Evidence accumulated to date suggests that, in addition to benzodiazepine and barbiturate binding sites, the GRC contains a distinct site for neuroactive steroids. For example, see the work of the authors Lan, NC et al., Neurochem. Res., (1991) vol. 16: pp. 347-356.

[ 0005 ] Neuroactive steroids can occur endogenously. The most potent endogenous neuroactive steroids are 3α-hydroxy-5(H)-pregnanone-20-one and 3α-21-dihydroxy-5(H)-pregnanone-20-one, metabolites of the steroid hormones progesterone and deoxycorticosterone, respectively. The ability of these steroid metabolites to alter brain excitability was identified in 1986 (Majewska, MD , et al., Science, vol. 232: pp. 1004-1007 (1986); Harrison, NL , et al., J. Pharmacol. Exp. Ther., volume 241: pp. 346-353 (1987))

[ 0006 ] New and improved compounds are needed that act as modulating agents for brain excitability, as well as drugs for the prevention and treatment of CNS-related diseases. The compounds, compositions and methods described herein are intended to achieve this goal.

The essence of the invention

[ 0007 ] Presented herein are compounds intended to act as GABA modulators. In some embodiments, such compounds are useful as therapeutic agents for the treatment of CNS-related diseases.

[ 0008 ] Compounds of Formula ( IX ) are presented here:

[ 0009 ] or pharmaceutically acceptable salts thereof. Also presented here are compounds of Formula ( II ):

[ 0010 ] or pharmaceutically acceptable salts thereof.

[ 0011 ] In some embodiments, a compound of Formula ( II-I ) is provided herein

or a pharmaceutically acceptable salt thereof.

[ 0012 ] In some embodiments, the compound of Formula ( II-I ) is a compound of Formula ( II-Ia )

or a pharmaceutically acceptable salt thereof.

[ 0013 ] In some embodiments, the compound of Formula ( II-I ) is a compound of Formula ( II-Ib )

or a pharmaceutically acceptable salt thereof.

[ 0014 ] In some embodiments, the compound of Formula ( II-I ) is a compound of Formula

or a pharmaceutically acceptable salt thereof.

[ 0015 ] In some embodiments, the compound of Formula ( II-I ) is a compound of Formula

or a pharmaceutically acceptable salt thereof.

[ 0016 ] In some embodiments, the compound of Formula ( II-I ) is a compound of Formula

or a pharmaceutically acceptable salt thereof.

[ 0017 ] In some embodiments, the compound of Formula ( II-I ) is a compound of Formula

or a pharmaceutically acceptable salt thereof.

[ 0018 ] In some embodiments, the compound of Formula ( II-I ) is a compound of Formula

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

[ 0020 ] In some embodiments, a compound of Formula ( III-I ) is provided herein

or a pharmaceutically acceptable salt thereof.

[ 0021 ] In some embodiments, a compound of Formula ( III-II ) is provided herein

or a pharmaceutically acceptable salt thereof.

[ 0022 ] In some embodiments, the compound of Formula ( III-I ) or ( III-II ) is a compound of Formula ( III-Ia )

or a pharmaceutically acceptable salt thereof.

[ 0023 ] In some embodiments, the compound of Formula ( III-I ) or ( III-II ) is a compound of Formula ( III-Ib )

or a pharmaceutically acceptable salt thereof.

[ 0024 ] In some embodiments, the compound of Formula ( III-I ) or ( III-II ) is a compound of Formula ( III-Ie )

or a pharmaceutically acceptable salt thereof.

[ 0025 ] In some embodiments, the compound of Formula ( III-I ) or ( III-II ) is a compound of Formula ( III-Ig )

or a pharmaceutically acceptable salt thereof.

[ 0026 ] In some embodiments, the compound of Formula ( III-I ) or ( III-II ) is a compound of Formula ( III-Ih )

or a pharmaceutically acceptable salt thereof.

[ 0027 ] In some embodiments, the compound of Formula ( III-I ) or ( III-II ) is a compound of Formula ( III-Ii )

or a pharmaceutically acceptable salt thereof.

[ 0028 ] In some embodiments, the pharmaceutical composition includes a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[ 0029 ] In some embodiments, a method of treating a CNS-related disease 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, mood disorder, schizophrenia spectrum disorder, seizure disorder, memory and/or cognitive impairment, movement disorder, personality change, autism spectrum disorder, pain, traumatic brain injury, vascular disease, Substance abuse disorders, and/or withdrawal symptoms, tinnitus, or status epilepticus. In some embodiments, the CNS-related disease is depression. In some embodiments, the CNS-related disease is postpartum depression. In some embodiments, the CNS-related disease is major depressive disorder. In some embodiments, the major depressive disorder is a moderate form of major depressive disorder. In some embodiments, the major depressive disorder is a severe form of major depressive disorder.

[ 0030 ] In some embodiments, the compound is selected from the group consisting of compounds listed herein in Table I-1 , Table II-1 , or Table III-1 .

[ 0031 ] In one aspect, provided herein is a pharmaceutically acceptable salt of a compound described herein ( eg , a compound of Formula (IX , II , II-I , III-I , or III-II).

[ 0032 ] In one aspect, provided herein is a pharmaceutical composition comprising a compound described herein ( e.g. , a compound of Formula (IX , II , II-I , III-I , or III-II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, a compound of the present invention is included in a pharmaceutical composition in an effective amount. In certain embodiments, a compound of the present invention is included in a therapeutically effective amount. In certain embodiments, a compound of the present invention is included in a prophylactically effective amount.

[ 0033 ] The compounds of the present invention, as described herein, act, in certain embodiments, as GABA modulators, for example , by affecting the GABA _A receptor in a positive or negative manner. As modulators of central nervous system (CNS) excitability, facilitated by their ability to modulate the GABA _A receptor, such compounds are proposed to have CNS activity.

Thus, in yet another aspect, methods are provided for treating a CNS-related disease 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 cognitive impairment, a movement disorder, personality changes, an autism spectrum disorder, pain, traumatic brain injury, vascular disease, Substance abuse disorders, and/or withdrawal symptoms, tinnitus, or status epilepticus. In certain embodiments, the CNS-related disease is depression. In certain embodiments, the CNS-related disease is postpartum depression. In certain embodiments, the CNS-related disease is major depressive disorder. In certain embodiments, the major depressive disorder is a moderate form of major depressive disorder. In certain embodiments, the major depressive disorder is a severe form of 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, such as by continuous intravenous infusion.

Detailed Description of Certain Embodiments of the Invention

[ 0034 ] As generally described herein, the present invention provides compounds intended, for example, to act as GABA modulators. In certain embodiments, such compounds are useful as therapeutic agents for the treatment of a CNS-related disease (eg, a disorder described herein, eg, depression, such as postpartum depression or major depressive disorder).

Definitions

Chemical definitions

[ 0035 ] Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics , 75th edition, inside cover, and specific functional groups are generally defined as described therein. In addition, the general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry , University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry , 5th edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations , VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis , 3rd edition, Cambridge University Press, Cambridge, 1987.

[ 0036 ] Isomers, eg , stereoisomers, can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be obtained by asymmetric synthesis. For example, see Jacques et al. , Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al. , Tetrahedron, vol. 33: p. 2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, p. 268 (E.L. Eliel, editor, Univ. of Notre Dame Press, Notre Dame, IN 1972). The invention further covers the compounds described herein as individual isomers, substantially free of other isomers, and, alternatively, as mixtures of different isomers.

[ 0037 ] As used herein, a pure enantiomeric compound is substantially free of other enantiomers or stereoisomers of the compound ( ie , in enantiomeric excess). In other words, the "S" form of the compound is substantially free of the "R" form of the compound, and is thus in enantiomeric excess relative to the "R" form. The term "enantiomerically pure" or "pure enantiomer" means that the compound is greater than 75% by weight, greater than 80% by weight, greater than 85% by weight, greater than 90% by weight, greater than 91% by weight, greater than 92% by weight , more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight , more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight, or more than 99.9% by weight, enantiomer. In certain embodiments, the weight amounts are based on the total weight of all enantiomers or stereoisomers of the compound.

[ 0038 ] In the compositions provided herein, the enantiomerically pure compound may be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure compound with an R-position of the central carbon atom may contain, for example, about 90% excipient and about 10% enantiomerically pure R-compound. In certain embodiments, the enantiomerically pure R compound in such compositions may include, for example, at least about 95% by weight of the R compound and no more than about 5% by weight of the S compound, based on the total weight of the compound. For example, a pharmaceutical composition containing an enantiomerically pure S-compound may comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S compound in such compositions may include, for example, at least about 95 weight percent S compound and no more than about 5 weight percent R compound, based on the total weight of the compound. In certain embodiments, the active ingredient may be formulated with little or no excipient or carrier.

[ 0039 ] The term "diastereomerically pure" means that the compound contains more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more 99.2% by weight, greater than 99.5% by weight, greater than 99.6% by weight, greater than 99.7% by weight, greater than 99.8% by weight, or greater than 99.9% by weight, of one diastereomer . Methods for determining diastereomeric and enantiomeric purity are well known in the art. Diastereomeric purity can be determined by any analytical method capable of quantitatively distinguishing a compound and its diastereomers, such as high performance liquid chromatography (HPLC).

[ 0040 ] “Stereoisomers”: It will also be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonds between their atoms, or the arrangement of their atoms in space, are called “isomers”. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereomers", and those that are non-superimposed mirror images are called "enantiomers". When a compound has an asymmetric center, for example where four different groups are linked, it is possible to form a pair of enantiomers. An enantiomer can be characterized by the absolute configuration of its asymmetric center, and is described by the R- and S-sequence rules of Cahn and Prelog, or by the way in which the molecule rotates the plane of polarized light and is designated as dextrorotatory or levorotatory ( that is , as (+)- or (-)-isomers, respectively). A chiral compound can exist either as an individual enantiomer or as a mixture of both. A mixture containing equal amounts of enantiomers is called a "racemic mixture".

[ 0041 ] The articles "a" and "an" may be used here to refer to one or more ( that is , at least one) grammatical object of the article. By way of example, “analogue” means one analogue or more than one analogue.

[ 0042 ] When a range of values is listed, it is intended to include each value and subrange within the range. For example, "C _1-6 -alkyl" is intended to include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C _1-6 , C _1-5 , C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-5 , C 2-4, C _2-3 , C _3-6 , C _3-5 , C _3-4 , C _4-6 , _{C 4-5 ,} and C _5-6 -alkyl.

[ 0043 ] The following terms are intended to have the meanings given to them below and are useful for understanding the description and intended scope of the present invention.

[ 0044 ] "Alkyl" means a radical with a straight-chain or branched hydrocarbon group having from 1 to 20 carbon atoms ("C _1-20 -alkyl"). In some embodiments, the alkyl group has from 1 to 12 carbon atoms (“C _1-12 alkyl”). In some embodiments, the alkyl group has from 1 to 10 carbon atoms (“C _1-10 -alkyl”). In some embodiments, the alkyl group has from 1 to 9 carbon atoms (“C _1-9 -alkyl”). In some embodiments, the alkyl group has 1 to 8 carbon atoms (“C _1-8 alkyl”). In some embodiments, the alkyl group has 1 to 7 carbon atoms (“C _1-7 alkyl”). In some embodiments, the alkyl group has 1 to 6 carbon atoms (“C _1-6 alkyl,” also referred to herein as “lower alkyl”). In some embodiments, the alkyl group has 1 to 5 carbon atoms (“C _1-5 alkyl”). In some embodiments, the alkyl group has 1 to 4 carbon atoms (“C _1-4 alkyl”). In some embodiments, the alkyl group has 1 to 3 carbon atoms (“C _1-3 alkyl”). In some embodiments, the alkyl group has 1 to 2 carbon atoms (“C _1-2 alkyl”). In some embodiments, the alkyl group has 1 carbon atom (“C ₁ -alkyl”). In some embodiments, the alkyl group has 2 to 6 carbon atoms (“C _2-6 alkyl”). Examples of _C1-6 alkyl groups include methyl ( _C1 ), ethyl ( _C2 ), n-propyl ( _C3 ), isopropyl ( _C3 ), n-butyl ( _C4 ), tert-butyl ( _C4 ) , sec-butyl ( _C4 ), isobutyl ( _C4 ), n-pentyl ( _C5 ), 3-pentyl ( _C5 ), amyl ( _C5 ), neopentyl ( _C5 ), 3-methyl-2-butyl ( _C5 ), tertiary amyl ( _C5 ), and n-hexyl ( _C6 ). Additional examples of alkyl groups include n-heptyl (C ₇ ), n-octyl (C ₈ ) and the like. Unless otherwise specified, the alkyl group in each instance is independently optionally substituted, that is , unsubstituted (“unsubstituted alkyl”) or substituted (“substituted alkyl”) with one or more substituents; for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is an unsubstituted C _1-10 alkyl ( eg, -CH ₃ ). In certain embodiments, the alkyl group is a substituted C _1-10 -alkyl. Common abbreviations for alkyl groups include Me (-CH ₃ ), Et (-CH ₂ CH ₃ ), i-Pr (-CH(CH ₃ ) ₂ ), n-Pr (-CH ₂ CH ₂ CH ₃ ), n- Bu (-CH ₂ CH ₂ CH ₂ CH ₃ ), or i-Bu (-CH ₂ CH(CH ₃ ) ₂ ).

[ 0045 ] "Alkylene" means an alkyl group in which two hydrogen atoms have been removed to form a divalent radical, and which may be substituted or unsubstituted. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH ₂ -), ethylene (-CH ₂ CH ₂ -), propylene (-CH ₂ CH ₂ CH ₂ -), butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -), pentylene (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -), hexylene (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -), and the like. Exemplary substituted alkylene groups, such as those substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted methylene (-CH(CH ₃ )-, (-C(CH ₃ ) ₂ -), substituted ethylene (- CH(CH ₃ )CH ₂ -,-CH ₂ CH(CH ₃ )-, -C(CH ₃ ) ₂ CH ₂ -,-CH ₂ C(CH ₃ ) ₂ -), substituted propylene (-CH(CH ₃ )CH ₂ CH ₂ -, -CH ₂ CH(CH ₃ )CH ₂ -, -CH ₂ CH ₂ CH(CH ₃ )-, -C(CH ₃ ) ₂ CH ₂ CH ₂ -, -CH ₂ C(CH ₃ ) ₂ CH ₂ -, -CH ₂ CH ₂ C(CH ₃ ) ₂ -), and the like.When a number or range of carbon atoms is given for a particular alkylene group, this means the range or number of carbon atoms in a linear divalent carbon chain. Alkylene groups may be substituted or unsubstituted with one or more substituents as described herein.

[ 0046 ] "Alkenyl" means a straight-chain or branched hydrocarbon group radical having from 2 to 20 carbon atoms, with one or more carbon-carbon double bonds ( for example , with 1, 2, 3 or 4 carbon-carbon double bonds), and optionally with one or more carbon-carbon triple bonds ( e.g. 1, 2, 3 or 4 carbon-carbon triple bonds) (“C _2-20 -alkenyl”). In certain embodiments, alkenyl does not contain any triple bonds. In some embodiments, the alkenyl group has from 2 to 10 carbon atoms (“C _2-10 -alkenyl”). In some embodiments, the alkenyl group has from 2 to 9 carbon atoms (“C _2-9 -alkenyl”). In some embodiments, the alkenyl group has 2 to 8 carbon atoms (“C _2-8 -alkenyl”). In some embodiments, the alkenyl group has from 2 to 7 carbon atoms (“C _2-7 alkenyl”). In some embodiments, the alkenyl group has 2 to 6 carbon atoms (“C _2-6 -alkenyl”). In some embodiments, the alkenyl group has 2 to 5 carbon atoms (“C _2-5 alkenyl”). In some embodiments, the alkenyl group has 2 to 4 carbon atoms (“C _2-4 -alkenyl”). In some embodiments, the alkenyl group has 2 to 3 carbon atoms (“C _2-3 -alkenyl”). In some embodiments, the alkenyl group has 2 carbon atoms (“C ₂ -alkenyl”). One or many carbon-carbon double bonds may be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C _2-4 alkenyl groups include ethenyl (C ₂ ), 1-propenyl (C ₃ ), 2-propenyl (C ₃ ), 1-butenyl (C ₄ ), 2-butenyl (C ₄ ), butadienyl (C ₄ ), and the like. Examples of C _2-6 alkenyl groups include the above C _2-4 alkenyl groups, as well as pentenyl (C ₅ ), pentadienyl (C ₅ ), hexenyl (C ₆ ), and the like. Additional examples of alkenyl groups include heptenyl (C ₇ ), octenyl (C ₈ ), octatrienyl (C ₈ ), and the like. Unless otherwise stated, the alkenyl group in each instance is independently optionally substituted, that is , unsubstituted (“unsubstituted alkenyl”) or substituted (“substituted alkenyl”) with one or more substituents; for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkenyl group is an unsubstituted C _2-10 -alkenyl. In certain embodiments, the alkenyl group is a substituted C _2-10 -alkenyl.

[ 0047 ] "Alkynyl" means a radical with a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, with one or more carbon-carbon triple bonds ( for example , with 1, 2, 3 or 4 carbon-carbon triple bonds), and optionally with one or more carbon-carbon double bonds ( e.g. 1, 2, 3 or 4 carbon-carbon double bonds) (“C _2-20 -kynyl”). In some embodiments, the alkynyl group does not contain any double bonds. In some embodiments, the alkynyl group has from 2 to 10 carbon atoms (“C _2-10 -alkynyl”). In some embodiments, the alkynyl group has from 2 to 9 carbon atoms (“C _2-9 -alkynyl”). In some embodiments, the alkynyl group has 2 to 8 carbon atoms (“C _2-8 -alkynyl”). In some embodiments, the alkynyl group has from 2 to 7 carbon atoms (“C _2-7 -alkynyl”). In some embodiments, the alkynyl group has 2 to 6 carbon atoms (“C _2-6 -alkynyl”). In some embodiments, the alkynyl group has 2 to 5 carbon atoms (“C _2-5 -alkynyl”). In some embodiments, the alkynyl group has 2 to 4 carbon atoms (“C _2-4 -alkynyl”). In some embodiments, the alkynyl group has 2 to 3 carbon atoms (“C _2-3 -alkynyl”). In some embodiments, the alkynyl group has 2 carbon atoms (“C ₂ -alkynyl”). One or many carbon-carbon triple bonds may be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C _2-4 alkynyl groups include ethynyl (C ₂ ), 1-propynyl (C ₃ ), 2-propynyl (C ₃ ), 1-butynyl (C ₄ ), 2-butynyl (C ₄ ), and the like . Examples of C _2-6 alkynyl groups include the above C _2-4 alkynyl groups, as well as pentynyl (C ₅ ), hexynyl (C ₆ ), and the like. Additional examples of alkynyl groups include heptynyl (C ₇ ), octinyl (C ₈ ), and the like. Unless otherwise stated, the alkynyl group in each instance is independently optionally substituted, that is , unsubstituted (“unsubstituted alkynyl”) or substituted (“substituted alkynyl”) with one or more substituents; for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkynyl group is an unsubstituted C _2-10 -alkynyl. In certain embodiments, the alkynyl group is a substituted C _2-10 -alkynyl.

[ 0048 ] The term “heteroalkyl” as used herein means an alkyl group, as defined herein, which further includes 1 or more ( e.g. , 1, 2, 3, or 4) heteroatoms ( e.g. , oxygen, sulfur, nitrogen, boron, silicon , phosphorus) within the main chain, with one or more heteroatoms introduced between adjacent carbon atoms within the main chain, and/or one or more heteroatoms introduced between the carbon atom and the main chain, that is , between points of attachment. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1, 2, 3 or 4 heteroatoms (“hetero-C _1-10 -alkyl”). In some embodiments, a heteroalkyl group is a saturated group having from 1 to 9 carbon atoms and 1, 2, 3 or 4 heteroatoms (“hetero-C _1-9 -alkyl”). In some embodiments, a heteroalkyl group is a saturated group having from 1 to 8 carbon atoms and 1, 2, 3 or 4 heteroatoms (“hetero-C _1-8 -alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“hetero-C _1-7 -alkyl”). In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“hetero-C _1-6 -alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“hetero-C _1-5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms (“hetero-C _1-4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having from 1 to 3 carbon atoms and 1 heteroatom (“hetero-C _1-3 -alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (“hetero-C _1-2 -alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“hetero-C ₁ -alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms (“hetero-C _2-6 -alkyl”). Unless otherwise specified, the heteroalkyl group in each instance is independently optionally unsubstituted (“unsubstituted heteroalkyl”) or substituted (“substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted C _1-10 heteroalkyl. In certain embodiments, the heteroalkyl group is a substituted C _1-10 heteroalkyl.

[ 0049 ] "Aryl" means a radical of a monocyclic or polycyclic ( e.g. , bicyclic or tricyclic) 4n+2-aromatic ring system ( e.g. , having 6, 10, or 14 π electrons shared in a ring structure) having 6-14 carbon atoms in the ring and zero heteroatoms introduced into the aromatic ring system (“C _6-14 -aryl”). In some embodiments, the aryl group has six carbon atoms in the ring ("C ₆ -aryl"; e.g. , phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C ₁₀ -aryl"; e.g. , naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen carbon atoms in the ring ("C ₁₄ -aryl"; e.g. anthracenyl). "Aryl" also includes cyclic systems in which an aryl ring, as defined above, is fused to one or more carbocyclic or heterocyclic groups, the radical or point of attachment being on the aryl ring, and in such cases the number of carbon atoms continues to mean the number of carbon atoms in aryl cyclic system. Typical aryl groups include, but are not limited to, those derived from aceanthrylene, acenaphthylene, acephenanthrilene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, asym-indacene, sym-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentafene, perylene, phenalene, phenanthrene, picene, pleiadiene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Specific aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, the aryl group in each instance is independently optionally substituted, that is , unsubstituted (“unsubstituted aryl”) or substituted (“substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is unsubstituted C _6-14 -aryl. In certain embodiments, the aryl group is a substituted C _6-14 -aryl.

[ 0050 ] In certain embodiments, the aryl group substituted with one or more groups is selected from groups such as halogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl, cyano, hydroxyl, C ₁ -C ₈ -alkoxy group, and amino group.

[ 0051 ] Examples of representative substituted aryl groups include the following:

in which one of R⁵⁶ and R⁵⁷ may represent a hydrogen atom, and at least one of R⁵⁶ and R⁵⁷, in each case independently, selected from C₁-C₈-alkyl, C₁-C₈-haloalkyl, 4-10 membered heterocyclic fragment, alkanoyl, C₁-C₈-alkoxy groups, heteroaryloxy groups, alkylamino groups, arylamino groups, heteroarylamino groups, NR⁵⁸COR⁵⁹, NR⁵⁸SOR⁵⁹ NR⁵⁸SO₂R⁵⁹, COO-alkyl, COO-aryl, CONR⁵⁸R⁵⁹,CONR⁵⁸OR⁵⁹, NR⁵⁸R⁵⁹,SO₂NR⁵⁸R⁵⁹, S-alkyl, SO-alkyl, SO₂-alkyl, S-aryl, SO-aryl, SO₂-arila; or R⁵⁶ and R⁵⁷ may be combined to form a cyclic structure (saturated or unsaturated) of 5-8 atoms, optionally containing one or more heteroatoms selected from the group N, O, or S. R⁶⁰ and R⁶¹ independently represent a hydrogen atom, C₁-C₈-alkyl, C₁-C₄-haloalkyl, C₃-C₁₀-cycloalkyl, 4-10 membered heterocyclic fragment, C₆-C₁₀-aryl substituted with C₆-C₁₀-aryl, 5-10 membered heteroaryl, or substituted 5-10 membered heteroaryl.

[ 0052 ] "Fused aryl" means an aryl having two of its carbon atoms in common structure with a second aryl or heteroaryl ring, or with a carbocyclic or heterocyclic ring.

[ 0053 ] "Heteroaryl" means a radical of a 5-10 membered monocyclic or bicyclic 4n+2-aromatic ring system ( e.g. having 6 or 10 π electrons shared in a ring structure) having carbon atoms in the ring and 1-4 heteroatoms in a ring included in an aromatic ring system in which each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). In a heteroaryl group that contains one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems may include one or many heteroatoms in one or both rings. "Heteroaryl" includes cyclic systems in which the heteroaryl ring, as defined above, is fused to one or more carbocyclic or heterocyclic groups in which the point of attachment is on the heteroaryl ring, and in such cases the number of ring members continues to denote the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes cyclic systems in which the heteroaryl ring, as defined above, is fused to one or more aryl groups in which the point of attachment is on either the aryl or heteroaryl ring, and in such cases the number of ring members refers to the number of ring members in a fused (aryl/heteroaryl) ring system. Bicyclic heteroaryl groups, in which one ring does not contain a heteroatom ( for example , indolyl, quinolinyl, carbazolyl, and the like), the point of attachment can be on any ring, that is , either on a ring containing a heteroatom ( for example , 2-indolyl), or on a ring that does not contain a heteroatom ( for example , 5-indolyl).

[ 0054 ] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms included in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms included in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur (“5 -8-membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms included in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5 -6-membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen and sulfur. Unless otherwise specified, a heteroaryl group in each instance is independently optionally substituted, that is , unsubstituted (“unsubstituted heteroaryl”) or substituted (“substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[ 0055 ] 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, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[ 0056 ] Examples of exemplary heteroaryls include the following:

in which each Z is selected from carbonyl, N, NR ⁶⁵ , O, and S; and R ⁶⁵ independently represents a hydrogen atom, C ₁ -C ₈ -alkyl, C ₃ -C ₁₀ -cycloalkyl, 4-10 membered heterocyclyl, C ₆ -C ₁₀ -aryl, and 5-10 membered heterocyclic moiety.

[ 0057 ] "Carbocyclyl" or "carbocyclic" refers to the radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 carbon atoms in the ring ("C _3-10 -carbocyclyl"), and containing no heteroatoms in the non-aromatic cyclic system. In some embodiments, the carbocyclyl group has from 3 to 8 carbon atoms in the ring (“C _3-8 -carbocyclyl”). In some embodiments, the carbocyclyl group has from 3 to 6 carbon atoms in the ring (“C _3-6 -carbocyclyl”). In some embodiments, the carbocyclyl group has from 3 to 6 carbon atoms in the ring (“C _3-6 -carbocyclyl”). In some embodiments, the carbocyclyl group has from 5 to 10 carbon atoms in the ring (“C _5-10 -carbocyclyl”). Exemplary _C3-6 carbocyclyl groups include, but are not limited to, cyclopropyl ( _C3 ), cyclopropenyl ( _C3 ), cyclobutyl ( _C4 ), cyclobutenyl ( _C4 ), cyclopentyl ( _C5 ), cyclopentenyl ( _C5 ), cyclohexyl (C ₆ ), cyclohexenyl (C ₆ ), cyclohexadienyl (C ₆ ), and the like. Exemplary _C3-8 carbocyclyl groups include, but are not limited to, the aforementioned _C3-6 carbocyclyl groups, as well as cycloheptyl ( _C7 ), cycloheptenyl ( _C7 ), cycloheptadienyl ( _C7 ), cycloheptatrienyl ( _C7 ), cyclooctyl ( C ₈ ), cyclooctenyl (C ₈ ), bicyclo[2.2.1]heptyl (C ₇ ), bicyclo[2.2.2]octyl (C ₈ ), and the like. Exemplary C _3-10 -carbocyclyl groups include, but are not limited to, the aforementioned C _3-8 -carbocyclyl groups, as well as cyclononyl (C ₉ ), cyclononenyl (C ₉ ), cyclodecyl (C ₁₀ ), cyclodecenyl (C ₁₀ ), octahydro- 1 H -indenyl (C ₉ ), decahydronaphthalenyl (C ₁₀ ), spiro[4.5]decyl (C ₁₀ ), and the like. As illustrated in the above examples, in certain embodiments, the carbocyclyl group is either monocyclic ("monocyclic carbocyclyl"), or contains a fused, bridged or spirocyclic system, such as a bicyclic system ("bicyclic carbocyclyl"), and may be saturated, or may be partially unsaturated. "Carbocyclyl" also includes cyclic systems in which the carbocyclic ring, as defined above, is fused to one or more aryl or heteroaryl groups, the point of attachment being on the carbocyclic ring, and in such cases the number of carbon atoms continues to denote the number of carbon atoms in the carbocyclic ring system. Unless otherwise specified, the carbocyclic group in each instance is independently optionally substituted, that is , unsubstituted (“unsubstituted carbocyclyl”) or substituted (“substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C _3-10 -carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C _3-10 -carbocyclyl.

[ 0058 ] In some embodiments, "carbocyclyl" is a monocyclic, saturated carbocyclyl group having from 3 to 10 carbon atoms in the ring ("C _3-10 -cycloalkyl"). In some embodiments, the cycloalkyl group has from 3 to 8 carbon atoms in the ring (“C _3-8 -cycloalkyl”). In some embodiments, the cycloalkyl group has from 3 to 6 carbon atoms in the ring (“C _3-6 -cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 6 carbon atoms in the ring (“C _5-6 -cycloalkyl”). In some embodiments, the cycloalkyl group has from 5 to 10 carbon atoms in the ring (“C _5-10 -cycloalkyl”). Examples of C _5-6 cycloalkyl groups include cyclopentyl (C ₅ ) and cyclohexyl (C ₆ ). Examples of C _3-6 cycloalkyl groups include the above-mentioned C _5-6 cycloalkyl groups, as well as cyclopropyl (C ₃ ) and cyclobutyl (C ₄ ). Examples of C _3-8 cycloalkyl groups include the above-mentioned C _3-6 cycloalkyl groups, as well as cycloheptyl (C ₇ ) and cyclooctyl (C ₈ ). Unless otherwise specified, the cycloalkyl group in each case is independently unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl") with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C _3-10 -cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C _3-10 -cycloalkyl.

[ 0059 ] "Heterocyclyl" or "heterocyclic" refers to a radical 3-10 membered non-aromatic cyclic system having carbon atoms in the ring and from 1 to 4 heteroatoms in the ring, each heteroatom independently selected from nitrogen, oxygen, sulfur, boron , phosphorus and silicon (“3-10 membered heterocyclyl”). In heterocyclic groups that contain one or many nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence permits. The heterocyclyl group can be either monocyclic ("monocyclic heterocyclyl") or a fused, bridged or spirocyclic system such as bicyclic ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may include one or many heteroatoms in one or both rings. "Heterocyclyl" also includes cyclic systems in which the heterocyclyl ring, as defined above, is fused to one or more carbocyclic groups in which the point of attachment is on either the carbocyclyl or heterocyclyl ring, or cyclic systems in which the heterocyclyl ring, as defined above, fused with one or more aryl or heteroaryl groups, the point of attachment being on the heterocyclyl ring, and in such cases the number of ring members continues to denote the number of ring members in the heterocyclyl ring system. Unless otherwise specified, heterocyclyl is in each case independently unsubstituted ("unsubstituted heterocyclyl") or substituted ("substituted heterocyclyl") with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-10 membered heterocyclyl.

[ 0060 ] In some embodiments, the heterocyclyl group is a 5-10 membered non-aromatic cyclic system having carbon atoms in the ring and 1-4 heteroatoms in the ring, each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon (“5-10 membered heterocyclyl”). In some embodiments, the heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 heteroatoms per ring, each heteroatom independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl” ). In some embodiments, the heterocyclyl group is a 5-6 membered non-aromatic cyclic system having carbon atoms in the ring and 1-4 heteroatoms in the ring, each heteroatom independently selected from nitrogen, oxygen and sulfur ("5-6 membered heterocyclyl" ). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[ 0061 ] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, 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. Examples of 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. Examples of 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl and thianyl. Examples of 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, dioxanyl. Examples of 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Examples of 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanil, oxepanyl, and tiepanil. Examples of 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Examples of 5-membered heterocyclyl groups fused to a C ₆ -aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) 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 a 6,6-bicyclic heterocyclyl ring) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[ 0062 ] "Nitrogen-containing heterocyclyl" group means a 4-7 membered non-aromatic cyclic group containing at least one nitrogen atom, such as, but not limited to, morpholine, piperidine ( e.g. 2-piperidinyl, 3-piperidinyl and 4-piperidinyl) , pyrrolidine ( eg 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine and N-alkylpiperazines such as N-methylpiperazine. Specific examples include azetidine, piperidone and piperazone.

[ 0063 ] "Hetero" when used to describe a compound or group present in a compound means that one or more carbon atoms in the compound or group have been replaced by a heteroatom of nitrogen, oxygen or sulfur. "Hetero" can be applied to any of the hydrocarbon groups described above, such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. heterocyclyl, aryl, e.g. heteroaryl, cycloalkenyl, e.g. cycloheteroalkenyl, and the like, having from 1 to 5, and in particular 1 to 3 heteroatoms.

[ 0064 ] "Acyl" refers to the radical -C(O)R ²⁰ , where R ²⁰ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl as defined herein. "Alkanoyl" is an acyl group in which R ²⁰ represents a group other than hydrogen. Exemplary acyl groups include, but are not limited to, formyl (-CHO), acetyl (-C(=O)CH ₃ ), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O) )CH ₂ Ph), -C(O)-C ₁ -C ₈ -alkyl, -C(O)-(CH ₂ ) _t (C ₆ -C ₁₀ -aryl), -C(O)-(CH ₂ ) _t (5-10-membered heteroaryl), -C(O)-(CH ₂ ) _t (C ₃ -C ₁₀ -cycloalkyl) and -C(O)-(CH ₂ ) _t (4-10-membered heterocyclyl ), in which t represents an integer from 0 to 4. In certain embodiments, R ²¹ represents C ₁ -C ₈ -alkyl substituted with halogen or hydroxy; or C ₃ -C ₁₀ -cycloalkyl, 4-10 membered heterocyclyl, C ₆ -C ₁₀ -aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted by unsubstituted C ₁ -C ₄ -alkyl, halogen , unsubstituted C ₁ -C ₄ -alkoxy group, unsubstituted C ₁ -C ₄ -haloalkyl, unsubstituted C ₁ -C ₄ -hydroxyalkyl or unsubstituted C ₁ -C ₄ -haloalkoxy group or hydroxy group.

[ 0065 ] "Alkoxy" refers to the group -OR ²⁹ , where R ²⁹ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Specific alkoxy groups are methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, t-butoxy group, sec-butoxy group, n-pentoxy group, n-hexoxy group and 1,2-dimethylbutoxy group. Specific alkoxy groups are lower alkoxy groups, that is , those with a number of carbon atoms from 1 to 6. Additional specific alkoxy groups have from 1 to 4 carbon atoms.

[ 0066 ] In certain embodiments, R ²⁹ is a group that has 1 or more substituents, such as 1 to 5 substituents, and in particular 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of an amino group , substituted amino group, C ₆ -C ₁₀ -aryl, aryloxy group, carboxyl, cyano group, C ₃ -C ₁₀ -cycloalkyl, 4-10-membered heterocyclyl, halogen, 5-10-membered heteroaryl, hydroxyl, nitro group, thioalkoxy group, thioaryloxy group, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O) ₂ -, and aryl-S(O) ₂ -. Exemplary "substituted alkoxy groups" include, but are not limited to, -O-(CH ₂ ) _t (C ₆ -C ₁₀ -aryl), -O-(CH ₂ ) _t (5-10 membered heteroaryl), -O- (CH ₂ ) _t (C ₃ -C ₁₀ -cycloalkyl) and -O-(CH ₂ ) _t (4-10 membered heterocyclyl), in which t represents an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl or heterocyclyl groups may themselves be substituted by unsubstituted C ₁ -C ₄ -alkyl, halogen, unsubstituted C ₁ -C ₄ -alkoxy, unsubstituted C ₁ -C ₄ -haloalkyl, unsubstituted C ₁ -C ₄ -hydroxyalkyl or unsubstituted C ₁ - With a ₄ -haloalkoxy group or hydroxy group. Specific exemplary "substituted alkoxy groups" are -OCF ₃ , -OCH ₂ CF ₃ , -OCH ₂ Ph, -OCH ₂ -cyclopropyl, -OCH ₂ CH ₂ OH and -OCH ₂ CH ₂ NMe ₂ .

[ 0067 ] "Amino" refers to the radical -NH ₂ .

[ 0068 ] "Oxo group" means -C(=O)-.

[ 0069 ] "Substituted amino group" refers to an amino group of formula -N(R ³⁸ ) ₂ where R ³⁸ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an amino protecting group, wherein at least one R ³⁸ is not hydrogen. In certain embodiments, each R ³⁸ is independently selected from hydrogen, C ₁ -C ₈ -alkyl, C ₃ -C ₈ -alkenyl, C ₃ -C ₈ -alkynyl, C ₆ -C ₁₀ -aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl or C ₃ -C ₁₀ -cycloalkyl; or C ₁ -C ₈ -alkyl substituted with halogen or hydroxy group; C ₃ -C ₈ -alkynyl substituted with halogen or hydroxy group, or -(CH ₂ ) _t (C ₆ -C ₁₀ -aryl), -(CH ₂ ) _t (5-10-membered heteroaryl), -(CH ₂ ) _t (C ₃ -C ₁₀ -cycloalkyl) or -(CH ₂ ) _t (4-10 membered heterocyclyl), in which t represents an integer from 0 to 8, each of which is substituted with an unsubstituted C ₁ -C ₄ -alkyl, halogen, unsubstituted C ₁ -C ₄ -alkoxy group, unsubstituted C ₁ -C ₄ -haloalkyl, unsubstituted C ₁ -C ₄ -hydroxyalkyl or unsubstituted C ₁ -C ₄ -haloalkoxy group or hydroxy group; or both R ³⁸ groups are combined to form an alkylene group.

[ 0070 ] Exemplary "substituted amino groups" include, but are not limited to, -NR ³⁹ -C ₁ -C ₈ -alkyl, -NR ³⁹ -(CH ₂ ) _t (C ₆ -C ₁₀ -aryl), -NR ³⁹ - (CH ₂ ) _t (5-10 membered heteroaryl), -NR ³⁹ -(CH ₂ ) _t (C ₃ -C ₁₀ -cycloalkyl) and -NR ³⁹ -(CH ₂ ) _t (4-10 membered heterocyclyl) wherein t is an integer from 0 to 4, for example 1 or 2, each R ³⁹ independently represents H or C ₁ -C ₈ alkyl; and any alkyl groups present may themselves be substituted by halogen, substituted or unsubstituted amino group or hydroxy group; and any aryl, heteroaryl, cycloalkyl or heterocyclyl groups present may themselves be substituted by unsubstituted C ₁ -C ₄ -alkyl, halogen, unsubstituted C ₁ -C ₄ -alkoxy, unsubstituted C ₁ -C ₄ -haloalkyl, unsubstituted C ₁ -C ₄ -hydroxyalkyl or unsubstituted C ₁ -C ₄ -haloalkoxy group or hydroxy group. For the avoidance of doubt, the term "substituted amino group" includes an alkylamino group, a substituted alkylamino group, an alkylaryl amino group, a substituted alkylaryl amino group, an arylamino group, a substituted arylamino group, a dialkylamino group, and a substituted dialkylamino group, as defined below. The substituted amino group includes both monosubstituted amino groups and disubstituted amino groups.

[ 0071 ] "Carboxy" refers to the radical -C(O)OH.

[ 0072 ] "Cyano" refers to the radical -CN.

[ 0073 ] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). In certain embodiments, the halogen group is either fluorine or chlorine.

[ 0074 ] "Haloalkyl" means an alkyl radical in which the alkyl group is replaced by one or more halogen atoms. Typical haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromomethyl, tribromomethyl, tetrafluoroethyl, and the like.

[ 0075 ] "Hydroxy" refers to the radical -OH.

[ 0076 ] "Nitro" refers to the radical -NO ₂ .

[ 0077 ] "Tioketo" belongs to the =S group.

[ 0078 ] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups as defined herein are optionally substituted ( for example , "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 group). In general, the term "substituted", whether preceded by the term "optionally" or not, means that at least one present hydrogen in a group (such as at a carbon or nitrogen atom) is replaced by an acceptable substituent, e.g. a substituent that, when substituted, results in a stable compound, e.g. a compound that does not spontaneously undergo transformations such as rearrangement, cyclization, cleavage, or other reactions. Unless otherwise specified, a "substituted" group contains a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is at either the same or a different position. The term "substituted" is intended to include the substitution of all permissible substituents on organic compounds, any of the substituents described herein that result in the formation of a stable compound. The present invention contemplates any and all such combinations that result in a stable compound. For purposes of the present invention, heteroatoms, such as nitrogen, may be substituted with hydrogen atoms and/or any suitable substituent as described herein that satisfy the valences of the heteroatoms and result in the formation of a stable residue.

[ 0079 ] Exemplary substituents on the carbon atom include, but are not limited to, halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ^aa , -ON(R ^bb ) ₂ , -N(R ^bb ) ₂ , -N(R ^bb ) ₃ ⁺ X-, -N(OR ^cc )R ^bb , -SH, -SR ^aa , -SSR ^cc , -C(=O)R ^aa , -CO ₂ H, -CHO, -C(OR ^cc ) ₂ , -CO ₂ R ^aa , -OC(=O)R ^aa , -OCO ₂ R ^aa , -C(=O)N(R ^bb ) ₂ , -OC(=O)N(R ^bb ) ₂ , -NR ^bb C(=O)R ^aa , -NR ^bb CO ₂ R ^aa , -NR ^bb C(=O)N(R ^bb ) ₂ , -C (=NR ^bb )R ^aa , -C(=NR ^bb )OR ^aa , -OC(=NR ^bb )R ^aa , -OC(=NR ^bb )OR ^aa , -C(=NR ^bb )N(R ^bb ) ₂ , -OC(=NR ^bb )N(R ^bb ) ₂ , -NR ^bb C(=NR ^bb )N(R ^bb ) ₂ , -C(=O)NR ^bb SO ₂ R ^aa , -NR ^bb SO ₂ R ^aa , -SO ₂ N(R ^bb ) ₂ , -SO ₂ R ^aa , -SO ₂ OR ^aa , -OSO ₂ R ^aa , -S(=O)R ^aa , -OS(=O)R ^aa , - Si(R ^aa ) ₃ , -OSi(R ^aa ) ₃ , -C(=S)N(R ^bb ) ₂ , -C(=O)SR ^aa , -C(=S)SR ^aa , -SC(= S)SR ^aa , -SC(=O)SR ^aa , -OC(=O)SR ^aa , -SC(=O)OR ^aa , -SC(=O)R ^aa , -P(=O) ₂ R ^aa , -OP(=O) ₂ R ^aa , -P(=O)(R ^aa ) ₂ , -OP(=O)(R ^aa ) ₂ , -OP(=O)(OR ^cc ) ₂ , -P( =O) ₂ N(R ^bb ) ₂ , -OP(=O) ₂ N(R ^bb ) ₂ , -P(=O)(NR ^bb ) ₂ , -OP(=O)(NR ^bb ) ₂ , - NR ^bb P(=O)(OR ^cc ) ₂ , -NR ^bb P(=O)(NR ^bb ) ₂ , -P(R ^cc ) ₂ , -P(R ^cc ) ₃ , -OP(R ^cc ) ₂ , -OP(R ^cc ) ₃ , -B(R ^aa ) ₂ , -B(OR ^cc ) ₂ , -BR ^aa (OR ^cc ), C _1-10 -alkyl, C _1-10 -haloalkyl, C _{2- 10} -alkenyl, C _2-10 -alkynyl, C _3-10 -carbocyclyl, 3-14-membered heterocyclyl, C _6-14 -aryl and 5-14-membered heteroaryl, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl , aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ^dd groups; or two geminal hydrogen atoms on a carbon atom are replaced by a group =O, =S, =NN(R ^bb ) ₂ , =NNR ^bb C(=O)R ^aa , =NNR ^bb C(=O)OR ^aa , =NNR ^bb S (=O) ₂ R ^aa , =NR ^bb , or =NOR ^cc ;

[ 0080 ] R ^aa in each case is independently selected from C _1-10 -alkyl, C _1-10 -haloalkyl, C _2-10 -alkenyl, C _2-10 -alkynyl, C _3-10 -carbocyclyl, 3-14- membered heterocyclyl, C _6-14 -aryl and 5-14 membered heteroaryl, or two R ^aa -groups are combined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl , heterocyclyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ^dd groups;

[ 0081 ] R ^bb is in each case independently selected from hydrogen, -OH, -OR ^aa , -N(R ^cc ) ₂ , -CN, -C(=O)R ^aa , -C(=O)N(R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -C(=NR ^cc )OR ^aa , -C(=NR ^cc )N(R ^cc ) ₂ , -SO ₂ N(R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C(=S)N(R ^cc ) ₂ , -C(=O)SR ^cc , -C(=S)SR ^cc , -P( =O) ₂ R ^aa , -P(=O)(R ^aa ) ₂ , -P(=O) ₂ N(R ^cc ) ₂ , -P(=O)(NR ^cc ) ₂ , C _1-10 - alkyl, C _1-10 -haloalkyl, C _2-10 -alkenyl, C _2-10 -alkynyl, C _3-10 -carbocyclyl, 3-14 membered heterocyclyl, C _6-14 -aryl and 5-14 membered heteroaryl , or two R ^bb groups are combined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl being independently substituted with 0, 1, 2, 3, 4 or 5 R ^dd -groups;

[ 0082 ] R ^cc is in each case independently selected from hydrogen, C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3 -14-membered heterocyclyl, C _6-14 -aryl and 5-14 membered heteroaryl, or two R ^cc -groups are combined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ^dd groups;

[ 0083 ] R ^dd is in each case independently selected from halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ^ee , -ON(R ^ff ) ₂ , - N(R ^ff ) ₂ , -N(R ^ff ) ₃ ⁺ X-, -N(OR ^ee )R ^ff , -SH, -SR ^ee , -SSR ^ee , -C(=O)R ^ee , -CO ₂ H, -CO ₂ R ^ee , -OC(=O)R ^ee , -OCO ₂ R ^ee , -C(=O)N(R ^ff ) ₂ , -OC(=O)N(R ^ff ) ₂ , - NR ^ff C(=O)R ^ee , -NR ^ff CO ₂ R ^ee , -NR ^ff C(=O)N(R ^ff ) ₂ , -C(=NR ^ff )OR ^ee , -OC(=NR ^ff ) R ^ee , -OC(=NR ^ff )OR ^ee , -C(=NR ^ff )N(R ^ff ) ₂ , -OC(=NR ^ff )N(R ^ff ) ₂ , -NR ^ff C(=NR ^ff ) N(R ^ff ) ₂ , -NR ^ff SO ₂ R ^ee , -SO ₂ N(R ^ff ) ₂ , -SO ₂ R ^ee , -SO ₂ OR ^ee , -OSO ₂ R ^ee , -S(=O)R ^ee , -Si(R ^ee ) ₃ , -OSi(R ^ee ) ₃ , -C(=S)N(R ^ff ) ₂ , -C(=O)SR ^ee , -C(=S)SR ^ee , - SC(=S)SR ^ee , -P(=O) ₂ R ^ee , -P(=O)(R ^ee ) ₂ , -OP(=O)(R ^ee ) ₂ , -OP(=O)(OR ^ee ) ₂ , C _1-6 -alkyl, C _1-6 -haloalkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, C _3-10 -carbocyclyl, 3-10-membered heterocyclyl, C _6-10 -aryl, 5-10 membered heteroaryl, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R ^gg groups, two geminal R ^dd substituents can be combined to form =O or =S;

[ 0084 ] R ^{ee is} in each case independently selected from C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, C _6-10 -aryl, 3-10 membered heterocyclyl and 3-10 membered heteroaryl, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl being independently substituted with 0, 1, 2, 3, 4 or 5 R ^gg groups;

[ 0085 ] R ^ff is in each case independently selected from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, 3 -10-membered heterocyclyl, C _6-10 -aryl and 5-10 membered heteroaryl, or two R ^ff -groups are attached to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ^gg groups; And

[ 0086 ] R ^gg in each case independently represents halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OC _1-6 -alkyl, -ON(C _{1- 6} -alkyl) ₂ , -N(C _1-6 -alkyl) ₂ , -N(C _1-6 -alkyl) ₃ ⁺ X-, -NH(C _1-6 -alkyl) ₂ ⁺ X-, -NH ₂ (C _1-6 -alkyl) ⁺ X-, -NH ₃ ⁺ X-, -N(OC _1-6 -alkyl)(C _1-6 -alkyl), -N(OH)(C _1-6 - alkyl), -NH(OH), -SH, -SC _1-6 -alkyl, -SS(C _1-6 -alkyl), -C(=O)(C _1-6 -alkyl), -CO ₂ H , -CO ₂ (C _1-6 -alkyl), -OC(=O)(C _1-6 -alkyl), -OCO ₂ (C _1-6 -alkyl), -C(=O)NH ₂ , - C(=O)N(C _1-6 -alkyl) ₂ , -OC(=O)NH(C _1-6 -alkyl), -NHC(=O)(C _1-6 -alkyl), -N( C _1-6 -alkyl)C(=O)(C _1-6 -alkyl), -NHCO ₂ (C _1-6 -alkyl), -NHC(=O)N(C _1-6 -alkyl) ₂ , -NHC(=O)NH(C _1-6 -alkyl), -NHC(=O)NH ₂ , -C(=NH)O(C _1-6 -alkyl), -OC(=NH)(C _{1 -6} -alkyl), -OC(=NH)OC _1-6 -alkyl, -C(=NH)N(C _1-6 -alkyl) ₂ , -C(=NH)NH(C ₁ - ₆ -alkyl ), -C(=NH)NH ₂ , -OC(=NH)N(C _1-6 -alkyl) ₂ , -OC(NH)NH(C _1-6 -alkyl), -OC(NH)NH ₂ , -NHC(NH)N(C _1-6 -alkyl) ₂ , -NHC(=NH)NH ₂ , -NHSO ₂ (C _1-6 -alkyl), -SO ₂ N(C _1-6 -alkyl) ₂ , -SO ₂ NH(C _1-6 -alkyl), -SO ₂ NH ₂ , -SO ₂ C _1-6 -alkyl, -SO ₂ OC _1-6 -alkyl, -OSO ₂ C _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)NH ₂ , -C(=O)S(C _1-6 -alkyl), -C(=S)SC _1-6 -alkyl , -SC(=S)SC _1-6 -alkyl, -P(=O) ₂ (C _1-6 -alkyl), -P(=O)(C _1-6 -alkyl) ₂ , -OP(= O)(C _1-6 -alkyl) ₂ , -OP(=O)(OC _1-6 -alkyl) ₂ , C _1-6 -alkyl, C _1-6 -haloalkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, C _3-10 -carbocyclyl, C _6-10 -aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R ^gg substituents can be combined to form =O or =S; wherein X ^- represents a counterion.

[ 0087 ] A "counterion" or "anionic counterion" is a negatively charged group bonded to a cationic quaternary amino group in order to maintain electrical neutrality. Exemplary counterions include halide ions ( e.g. , F ^- , Cl ^- , Br ^- , I ^- ), NO ₃ ^- , ClO ₄ ^- , OH ^- , H ₂ PO ₄ ^- , HSO ₄ ^- , sulfonate ions ( e.g. methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid 5-sulfonate, ethane-1-sulfonic acid 2-sulfonate, and the like), and carboxylate ions ( e.g. acetate , ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate and the like).

[ 0088 ] These and other exemplary substituents are described in more detail in the Detailed Description section and in the Claims . The invention is in no way intended to be limited by the above exemplary list of substituents.

Other definitions

[ 0089 ] As used herein, the term "modulation" refers to inhibition or potentiation of GABA receptor function. A "modulator" ( eg , a modulatory compound) may be, for example, an agonist, partial agonist, antagonist, or partial antagonist of the GABA receptor.

[ 0090 ] "Pharmaceutically acceptable" means approved or approved by a federal or state regulatory agency or an appropriate agency in countries other than the United States of America, or one that is listed in the United States Pharmacopoeia or other generally accepted pharmacopoeias for use in animals, and more specifically, in people.

[ 0091 ] "Pharmaceutically acceptable salt" refers to a salt of a compound of the invention that is pharmaceutically acceptable and that has the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and may be inorganic or organic acid addition salts and base addition salts. More specifically, such salts include: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed by organic acids such as acetic acid, propionic acid, caproic 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 acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4 -toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2,2,2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid , glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like; or (2) salts formed when the acid proton present in the parent compound is also replaced by a metal ion, for example an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and the like. In addition, salts include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and the like; and when the compound contains the basic functionality, 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. Examples of such cations are sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like. See, for example , the work of the authors Berge, et al., J. Pharm. Sci., (1977) vol. 66 (no. 1): pp. 1-79.

[ 0092 ] The term “prodrug” is intended to include therapeutically inactive compounds that, under physiological conditions, are converted to therapeutically active agents according to the present invention. One way to produce a prodrug is to select certain moieties that are hydrolyzed or cleaved at the target site in vitro under physiological conditions to release the desired molecule, which then exerts its therapeutic effect. In certain embodiments, the prodrug is converted as a result of enzymatic activity of the subject.

[ 0093 ] In an alternative embodiment, the present invention provides prodrugs of a compound of Formula (IX , II , II-I , III-I , or III-II) , wherein the prodrug includes a leaving moiety on the C3-hydroxy group as depicted in a compound of Formula (IX , II , II-I , III-I , or III-II). “Tautomers” refer to compounds that are interconvertible forms of the structure of a particular compound, and that change when hydrogen atoms and electrons move around. Thus, two structures can be in equilibrium through the movement of π electrons and an atom (usually H). For example, enols and ketones are tautomers because they quickly transform into each other in the presence of an acid or base. Another example of tautomerism is the acy and nitro forms of phenylnitromethane, which are similarly formed in the presence of an acid or base. Tautomeric forms may be important in achieving optimal chemical reactivity and biological activity of the compound in question.

[ 0094 ] The “subject” to which administration is intended includes, but is not limited to, humans ( i.e. , male or female of any age group, e.g. , a pediatric subject ( e.g. , infants, children, adolescents) or an adult subject ( e.g. , young adults, middle-aged adults or older adults)), and/or non-human animals, e.g. mammals such as primates (e.g. cynomolgus, rhesus macaques), cattle, pigs, horses, sheep, goats, rodents, cats and/or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.

[ 0095 ] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also called 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 , -CO ₂ R ^aa , -C( =O)N(R ^bb ) ₂ , -C(=NR ^bb )R ^aa , -C(=NR ^bb )OR ^aa , -C(=NR ^bb )N(R ^bb ) ₂ , -S(=O) R ^aa , -SO ₂ R ^aa , -Si(R ^aa ) _3, -P(R ^cc ) ₂ , -P(R ^cc ) ₃ , -P(=O) ₂ R ^aa , -P(=O)( R ^aa ) ₂ , -P(=O)(OR ^cc ) ₂ , -P(=O) ₂ N(R ^bb ) ₂ and -P(=O)(NR ^bb ) ₂ , where R ^aa , R ^bb and R ^cc are as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis , TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

[ 0096 ] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), 2-methoxyethoxymethyl (MEM), benzyl (Bn), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), tert-butylmethoxyphenylsilyl ( TBMPS), methanesulfonate (mesylate) and tosylate (Ts).

[ 0097 ] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also called a thiol protecting group). Protecting groups for sulfur include, but are not limited to, -R ^aa , -N(R ^bb ) ₂ , -C(=O)SR ^aa , -C(=O)R ^aa , -CO ₂ R ^aa , -C( =O)N(R ^bb ) ₂ , -C(=NR ^bb )R ^aa , -C(=NR ^bb )OR ^aa , -C(=NR ^bb )N(R ^bb ) ₂ , -S(=O) R ^aa , -SO ₂ R ^aa , -Si(R ^aa ) _3, -P(R ^cc ) ₂ , -P(R ^cc ) ₃ , -P(=O) ₂ R ^aa , -P(=O)( R ^aa ) ₂ , -P(=O)(OR ^cc ) ₂ , -P(=O) ₂ N(R ^bb ) ₂ and -P(=O)(NR ^bb ) ₂ , in which R ^aa , R ^bb and R ^cc are as defined herein. Protecting groups for sulfur are well known in the art, and include those described in detail in Protecting Groups in Organic Synthesis , TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

[ 0098 ] In certain embodiments, the substituent present on the nitrogen atom is an amino protecting group (also referred to herein as a nitrogen protecting group). Amine 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) ₂ R ^aa , -C(=NR ^cc )R ^aa , -C(=NR ^cc )OR ^aa , -C(=NR ^cc )N(R ^cc ) ₂ , - SO ₂ N(R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C(=S)N(R ^cc ) ₂ , -C(=O)SR ^cc , -C( =S)SR ^cc , C _1-10 -alkyl, C _2-10 -alkenyl, C _2-10 -alkynyl, C _3-10 -carbocyclyl, 3-14-membered heterocyclyl, C _6-14 -aryl and 5- 14-membered heteroaryl groups wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted with 0, 1, 2, 3, 4 or 5 R ^dd groups, and where R ^aa , R ^bb , R ^cc and R ^dd are as defined herein. Amine protecting groups are well known in the art, and include those described in detail in Protecting Groups in Organic Synthesis , TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

[ 0099 ] Exemplary amino protecting groups include, but are not limited to, amide groups ( eg , -C(=O)R ^aa ), which include, but are not limited to, formamide and acetamide; carbamate groups ( eg -C(=O)OR ^aa ), which include, but are not limited to, 9-fluorenylmethylcarbamate (Fmoc), tert-butylcarbamate (BOC) and benzylcarbamate (Cbz); sulfonamide groups ( eg -S(=O) _2R ^aa ), which include, but are not limited to, p-toluenesulfonamide (Ts), methanesulfonamide (Ms) and N- [2-(trimethylsilyl)ethoxy]methylamine (SEM) .

[ 0100 ] Disease, disorder and condition are used interchangeably herein.

[ 0101 ] As used herein, and unless otherwise specified, the terms “treat”, “treatment” and “treatment” consider an action that occurs while a subject is suffering from a specified disease, disorder or condition that reduces the severity of the disease, disorder or condition, or delays or slows the progression of the disease, disorder or condition. Generally, an "effective amount" of a compound means an amount sufficient to achieve a desired biological response, e.g. , for the treatment of a CNS-related disorder, sufficient to induce anesthesia or sedation. As will be appreciated by those of ordinary skill in the art, the effective amount of a compound of the invention may vary depending on factors such as the desired biological end result, the pharmacokinetics of the compound, the disease being treated, the route of administration, and the age, weight, health and condition of the subject. .

[ 0102 ] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic effect in treating a disease, disorder or condition, or to delay or minimize one or more symptoms associated with a disease, disorder or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic effect in treating a disease, disorder or condition. The term "therapeutically effective amount" may include an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic effectiveness of another therapeutic agent.

[ 0103 ] In an alternative embodiment, the present invention contemplates administering compounds, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable composition thereof, of the present invention for prophylaxis before a subject begins to suffer from said disease, disorder or condition. As used herein, and unless otherwise specified, a “prophylactically effective amount” of a compound is an amount sufficient to prevent the disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or to prevent recurrence thereof. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic effect in preventing a disease, disorder or condition. The term “prophylactically effective amount” may encompass an amount that improves overall prophylaxis or enhances the prophylactic effectiveness of another prophylactic agent.

[ 0104 ] As used herein, an "occasional dosing regimen" is a dosage regimen in which a compound of Formula (IX , II , II-I , III-I , or III-II) or a composition comprising a compound of Formula (IX , II , II-I , III-I , or III-II) is administered to a subject for a limited period of time in response to a diagnosis of a disease or symptom thereof, such as a diagnosis or symptom of depression, an episode of major depressive disorder, bipolar depression, anxiety, or postpartum depression . In some embodiments, the major depressive disorder is a moderate major depressive disorder. In some embodiments, the major depressive disorder is a severe major depressive disorder. In some embodiments, the compound is formulated as individual dosages, each dosage comprising a compound of Formula (IX , II , II-I , III-I , or III-II) and one or more pharmaceutically acceptable excipients. In some embodiments, the episodic dosing regimen has a duration of many weeks, for example, about 8 weeks. In contrast to chronic administration as defined herein, episodic dosing of a compound is administered over a limited period of time, for example, about 2 weeks to about 8 weeks, in response to a diagnosis of a disease, such as depression, or a symptom thereof. In some embodiments, episodic dosing is administered once daily for many weeks, such as about 2 weeks to about 6 weeks. In one embodiment, episodic dosing has a two-week duration. In some embodiments, a subject is prescribed more than one dosing episode, such as two or more dosing episodes over the course of the subject's lifetime.

Connections

[ 0105 ] It will be understood that specific carbon atoms such as C17, C3, C10, etc. may be mentioned in the formulas described herein. These references are based on the position of the carbon atoms according to the steroid nomenclature known and used in the industry, as shown below:

For example, C17 refers to the carbon atom at position 17, and C3 refers to the carbon atom at position 3.

[ 0106 ] As described herein, in one aspect, the present invention provides compounds of Formula ( IX ):

or pharmaceutically acceptable salts thereof,

in which: p is 0, 1 or 2; R ¹⁹ represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; R ¹ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, -SR ^X1 , -N(R ^X1 ) ₂ ,-OC(=O)R ^X1 , -OC(=O)OR ^X1 , -OC(=O)SR ^X1 , -OC(=O)N(R ^X1 ) ₂ , -SC(=O)R ^X2 , -SC(=O)OR ^X1 , -SC(=O)SR ^X1 , -SC(=O)N(R ^X1 ) ₂ , -NHC(=O)R ^X1 , -NHC(=O)OR ^X1 , - NHC(=O)SR ^X1 , -NHC(=O)N(R ^X1 ) ₂ , -OS(=O) ₂ R ^X2 , -OS(=O) ₂ OR ^X1 , -SS(=O) ₂ R ^X2 , -SS(=O) ₂ OR ^X1 , -S(=O)R ^X2 , -SO ₂ R ^X2 , or -S(=O) ₂ OR ^X1 , wherein R ^X1 , in each case independently, represents a hydrogen atom, 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, protecting group for oxygen when attached to an oxygen atom, protecting group for sulfur when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R ^X1 groups are combined to form a substituted or unsubstituted heterocyclic or heteroaryl ring; and R ^X2 is, in each instance independently, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ^3a is substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, or substituted or unsubstituted C _3-6 carbocyclyl; R ^2a represents a hydrogen atom, halogen, substituted or unsubstituted C _1-6 -alkyl, substituted or unsubstituted C _2-6 -alkenyl, substituted or unsubstituted C _2-6 -alkynyl, or substituted or unsubstituted C _3-6 -carbocyclyl, or -OR ^A2 , wherein R ^A2 represents a hydrogen atom or substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, or substituted or unsubstituted C _3-6 - carbocyclyl; R ^11a represents a hydrogen atom or -OR ^A3 , wherein R ^A3 represents a hydrogen atom or substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, or substituted or unsubstituted C _3-6 -carbocyclyl, and R ^11b represents a hydrogen atom; or R ^11a and R ^11b are combined to form an oxo group (=O); and R ^6a and R ^6b , in each case independently, represent a hydrogen atom or substituted or unsubstituted C _1-6 alkyl, or halogen.

[ 0107 ] It should be understood that the stereochemical configuration at C17 could be depicted in any of the following but equivalent ways:

[ 0108 ] In certain embodiments, R ¹⁹ represents a hydrogen atom in the compound of Formula ( I - X ); in certain embodiments, R ¹⁹ is methyl in the compound of Formula ( I - X ).

[ 0109 ] In certain embodiments, R ¹ represents a substituted or unsubstituted alkyl in the compound of Formula ( IX ).

[ 0110 ] In certain embodiments, R ¹ is substituted or unsubstituted heteroaryl in the compound of Formula ( IX ).

[ 0111 ] In certain embodiments, R ¹ is substituted or unsubstituted heteroaryl, wherein the heteroaryl contains at least one nitrogen atom in the compound of Formula ( IX ).

[ 0112 ] In certain embodiments, R ¹ is substituted or unsubstituted heteroaryl, wherein the heteroaryl is bicyclic in the compound of Formula ( IX ).

[ 0113 ] In one aspect, the present invention provides compounds of the 19-unsubstituted C3,3-disubstituted C21-pyrazolyl derivative of Formula ( II ):

and a pharmaceutically acceptable salt thereof, wherein: R ^3a represents substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, or substituted or unsubstituted C _3-6 - carbocyclyl; R ^2a represents a hydrogen atom, halogen, substituted or unsubstituted C _1-6 -alkyl, substituted or unsubstituted C _2-6 -alkenyl, substituted or unsubstituted C _2-6 -alkynyl, or substituted or unsubstituted C _3-6 -carbocyclyl, or -OR ^A2 , wherein R ^A2 represents a hydrogen atom or substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, or substituted or unsubstituted C _3-6 - carbocyclyl; R ^11a represents a hydrogen atom or -OR ^A3 , wherein R ^A3 represents a hydrogen atom or substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, or substituted or unsubstituted C _3-6 -carbocyclyl, and R ^11b represents a hydrogen atom; or R ^11a and R ^11b are combined to form an oxo group (=O); R ^6a and R ^6b , in each case independently, represent a hydrogen atom, substituted or unsubstituted C _1-6 -alkyl, or halogen; R ^m , R ⁿ , and R ^x , in each case independently, represent a hydrogen atom, halogen, -NO ₂ , -CN, -OR ^GA , -N(R ^GA ) ₂ , -C(=O)R ^GA , - C(=O)OR ^GA , -OC(=O)R ^GA , -OC(=O)OR ^GA , -C(=O)N(R ^GA ) ₂ , -N(R ^GA )C(=O) R ^GA , -OC(=O)N(R ^GA ) ₂ , -N(R ^GA )C(=O)OR ^GA , -N(R ^GA )C(=O)N(R ^GA ) _2, -SR ^GA , -S(O)R ^GA , for example, -S(=O)R ^GA , -S(=O) ₂ R ^GA , -S(=O) ₂ OR ^GA , -OS(=O) ₂ R ^GA , -S(=O) ₂ N(R ^GA ) ₂ , -N(R ^GA )S(=O) ₂ R ^GA , substituted or unsubstituted C _1-6 -alkyl, substituted or unsubstituted C _2-6 -alkenyl, substituted or unsubstituted C _2-6 -alkynyl, or substituted or unsubstituted C _3-6 -carbocyclyl, or substituted or unsubstituted 3-6-membered heterocyclyl; and R ^GA in each instance independently represents a hydrogen atom, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, or substituted or unsubstituted C _3-6 - carbocyclyl, or substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group when attached to an oxygen atom, nitrogen protecting group when attached to a nitrogen atom; or two R ^GA groups are linked by common atoms to form a substituted or unsubstituted heterocyclic or heteroaryl ring.

[ 0114 ] In certain embodiments, R ^3a in the unsubstituted at position 19 C3,3-disubstituted C21-pyrazolyl derivative of Formula ( II ) is C _1-6 alkyl, optionally substituted with an alkoxy group or one or two halogen atoms (e.g., fluorine), or at least one of R ^m , R ⁿ , and R ^x is halogen (for example, -F, -Cl, -Br), -NO ₂ , -CN, -OR ^GA , -N(R ^GA ) ₂ , - C(=O)R ^GA , -C(=O)OR ^GA , -SR ^GA , -S(=O) R ^GA , -S(=O) ₂ R ^GA , -S(=O) ₂ OR ^GA , -OS(=O) ₂ R ^GA , -S(=O) ₂ N(R ^GA ) ₂ , substituted or unsubstituted C _1-6 alkyl, (for example, -CH ₃ , -CH ₂ CH ₃ , haloalkyl, for example , -CF ₃ ), wherein R ^GA represents substituted or unsubstituted C _1-2 alkyl.

[ 0115 ] Based on the above description, it is understood that the steroids of Formula ( II ) include 3,3-disubstituted, unsubstituted compounds at position 19, in which the A/B ring system of the compound has a cis configuration (as represented in Formula ( IIA ), in which the A/B cyclic coupling system has a trans configuration (as represented in Formula ( IIB ):

and pharmaceutically acceptable salts thereof.

Formula ( I-X ) or Formula ( I-I ): group R ^3a

[ 0116 ] As generally defined herein, R ^3a is substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-6 alkynyl, or substituted or unsubstituted C _{3- 6} -carbocyclyl.

[0117] In certain versions R^3a represents substituted or unsubstituted C_1-6-alkyl,For example, substituted or unsubstituted C_1-2-alkyl, substituted or unsubstituted C_2-3-alkyl, substituted or unsubstituted C_3-4-alkyl, substituted or unsubstituted C_4-5-alkyl, either substituted or unsubstituted C_5-6-alkyl. Approximate R^3a like C_1-6-alkyl groups include, but are not limited to, substituted or unsubstituted methyl (C₁), ethyl (C₂), n-propyl (C₃), isopropyl (C₃), n-butyl (C₄), tert-butyl (C₄), sec-butyl (C₄), isobutyl (C₄), n-pentyl (C₅), 3-pentyl (C₅), amyl (C₅), neopentyl (C₅), 3-methyl-2-butyl (C₅), tertiary amyl (C₅), n-hexyl (C₆), C_1-6-alkyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more fluorine atoms (For example, -CF₃, -CH₂F, -CHF₂, difluoroethyl, and 2,2,2-trifluoro-1,1-dimethylethyl), C_1-6-alkyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more chlorine atoms (For example, -CH₂Cl, -CHCl₂), and C_1-6-alkyl substituted with alkoxy groups (For example,-CH₂OCH₃ and -CH₂OCH₂CH₃). In certain versions R^3a represents substituted C_1-6-alkyl,For example, R^3ais haloalkyl, alkoxyalkyl, or aminoalkyl. In certain versions R^3a represents Me, Et, n-Pr, n-Bu, i-Bu, fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, difluoroethyl, 2,2,2-trifluoro-1,1-dimethylethyl, methoxymethyl, methoxyethyl or ethoxymethyl.

[ 0118 ] In certain embodiments, R ^3a is unsubstituted C _1-3 alkyl, for example, R ^3a is -CH ₃ , -CH ₂ CH ₃ , or -CH ₂ CH ₂ CH ₃ .

[ 0119 ] In certain embodiments, R ^3a is C _1-6 alkyl substituted with one or more fluorine atoms; for example, R ^3a represents -CH ₂ F, -CHF ₂ , or -CF ₃ . In certain embodiments, R ^3a is C _1-6 alkyl substituted with one or two fluorine atoms; for example, R ^3a represents -CH ₂ F or -CHF ₂ .

[ 0120 ] In certain embodiments, R ^3a is a C _1-6 alkyl substituted with one or more -OR ^A1 groups, wherein R ^A1 is a hydrogen atom or substituted or unsubstituted alkyl. In certain embodiments, R ^3a represents -CH ₂ OR ^A1 , for example, in which R ^A1 represents a hydrogen atom, -CH ₃ , -CH ₂ CH ₃ , or -CH ₂ CH ₂ CH ₃ , for example, to form the group R ^3a with formula -CH ₂ OH, -CH ₂ OCH ₃ , -CH ₂ OCH ₂ CH ₃ , or -CH ₂ OCH ₂ CH ₂ CH ₃ .

[ 0121 ] In certain embodiments, R ^3a is substituted or unsubstituted C _2-6 -alkenyl, for example, substituted or unsubstituted C _2-3 -alkenyl, substituted or unsubstituted C _3-4 -alkenyl, substituted or unsubstituted C _4-5 - alkenyl, or substituted or unsubstituted C _5-6 -alkenyl. In certain embodiments, R ^3a is ethenyl (C ₂ ), propenyl (C ₃ ), or butenyl (C ₄ ), substituted or unsubstituted with one or more substituents selected from the group consisting of alkyl, halogen, haloalkyl, alkoxyalkyl, or hydroxyl. In certain embodiments, R ^3a is ethenyl, propenyl, or butenyl, substituted or unsubstituted with alkyl, halogen, haloalkyl, alkoxyalkyl, or hydroxyl. In certain embodiments, R ^3a is ethenyl.

[ 0122 ] In certain embodiments, R ^3a is substituted or unsubstituted C _2-6 -alkynyl, for example, substituted or unsubstituted C _2-3 -alkynyl, substituted or unsubstituted C _3-4 -alkynyl, substituted or unsubstituted C _4-5 - alkynyl, or substituted or unsubstituted C _5-6 -alkynyl. In certain embodiments, R ^3a is ethynyl, propynyl, or butynyl, substituted or unsubstituted with alkyl, halogen, haloalkyl ( eg, CF ₃ ), alkoxyalkyl, cycloalkyl ( eg, cyclopropyl or cyclobutyl), or hydroxyl. In certain embodiments, R ^3a is selected from the group consisting of trifluoroethynyl, cyclopropylethynyl, cyclobutylethynyl, and propynyl, fluoropropynyl, and chloroethynyl. In certain embodiments, R ^3a is ethynyl (C ₂ ), propynyl (C ₃ ), or butynyl (C ₄ ), substituted or unsubstituted with one or more substituents selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl. In certain embodiments, R ^3a is ethynyl (C ₂ ), propynyl (C ₃ ), or butynyl (C ₄ ) substituted with phenyl. In certain embodiments, the phenyl substituent is further substituted with one or more substituents selected from the group consisting of halogen, alkyl, trifluoroalkyl, alkoxy, acyl, amino, or amide. In certain embodiments, R ^3a is ethynyl (C ₂ ), propynyl (C ₃ ), or butynyl (C ₄ ), substituted with substituted or unsubstituted pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, 1,2,3-triazolyl, 1 ,2,4-triazolyl, oxadiazolyl, thiadiazolyl or tetrazolyl.

[ 0123 ] In certain embodiments, R ^3a is ethynyl, propynyl, or butynyl, unsubstituted or substituted with alkyl, halogen, haloalkyl, alkoxyalkyl, or hydroxyl. In certain embodiments, R ^3a is ethynyl or propynyl, substituted or unsubstituted with aryl. In certain embodiments, R ^3a is ethynyl or propynyl substituted with phenyl, unsubstituted or substituted halogen, alkyl, alkoxy, haloalkyl, trihaloalkyl, or acyl. In certain embodiments, R ^3a is ethynyl or propynyl substituted with unsubstituted or substituted carbocyclyl. In certain embodiments, R ^11a is ethynyl or propynyl substituted with phenyl, unsubstituted or substituted cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In certain embodiments, R ^3a is ethynyl or propynyl substituted with unsubstituted or substituted heteroaryl. In certain embodiments, R ^3a is ethynyl or propynyl substituted with unsubstituted or substituted pyridinyl or pyrimidinyl. In certain embodiments, R ^3a is ethynyl or propynyl substituted with unsubstituted or substituted pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl. In certain embodiments, R ^3a is ethynyl or propynyl substituted with unsubstituted or substituted heterocyclyl. In certain embodiments, R ^3a is ethynyl or propynyl substituted with unsubstituted or substituted pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl. In certain embodiments, R ^3a is propynyl or butynyl substituted with a hydroxyl or alkoxyl group. In certain embodiments, R ^3a is propynyl or butynyl substituted with a methoxy or ethoxy group. In certain embodiments, R ^3a is ethynyl or propynyl substituted with a chlorine atom. In certain embodiments, R ^3a is ethynyl or propynyl substituted with trifluoromethyl.

[ 0124 ] In certain embodiments, R ^3a is a substituted or unsubstituted C _3-6 -carbocyclyl, for example, a substituted or unsubstituted C _3-4 -carbocyclyl, a substituted or unsubstituted C _4-5 -carbocyclyl, or a substituted or unsubstituted C _5-6 - carbocyclyl. In certain embodiments, R ^3a is substituted or unsubstituted cyclopropyl or substituted or unsubstituted cyclobutyl.

Formula (I-X) or Formula (I-1) group R ^2a , R ^11a , R ^11b , R ^6a , And R ^6b

[ 0125 ] As generally defined herein, R ^2a represents a hydrogen atom, halogen, 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 -OR ^A2 , wherein R ^A2 represents a hydrogen atom, 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.

[ 0126 ] In certain embodiments, R ^2a represents a hydrogen atom. In certain embodiments, R ^2a represents a halogen atom, such as fluorine, chlorine, bromine or iodine. In certain embodiments, R ^2a is fluorine or chlorine. In certain embodiments, R ^2a is substituted or unsubstituted C _1-6 alkyl, for example, substituted or unsubstituted C _1-2 alkyl, substituted or unsubstituted C _2-3 alkyl, substituted or unsubstituted C _3-4 alkyl, substituted or unsubstituted C _4-5 -alkyl, or substituted or unsubstituted C _5-6 -alkyl. For example, in some embodiments, R ^2a is C _1-6 alkyl, optionally substituted with a halogen atom ( e.g., bromine, chlorine, fluorine ( i.e., to form the group R ^2a with the formula -CH ₂ F, -CHF ₂ , -CF ₃ )) or -OR ^A2 . In certain embodiments, R ^A2 is -CH ₃ , -CH ₂ CH ₃ , or -CH ₂ CH ₂ CH ₃ , that is, to form a group R ^2a with the formula -OH, -OCH ₃ , -OCH ₂ CH ₃ , or -OCH ₂ CH ₂ CH ₃ . In certain embodiments, R ^2a is substituted or unsubstituted C _2-6 alkenyl. In certain embodiments, R ^2a is substituted or unsubstituted C _2-6 -alkynyl, for example, substituted or unsubstituted C _2-3 -alkynyl, substituted or unsubstituted C _3-4 -alkynyl, substituted or unsubstituted C _4-5 -alkynyl, or substituted or unsubstituted C _5-6 -alkynyl. In certain embodiments, R ^2a is substituted or unsubstituted C _3-6 -carbocyclyl, for example, substituted or unsubstituted C _3-4 -carbocyclyl, substituted or unsubstituted C _4-5 -carbocyclyl, or substituted or unsubstituted C _5-6 -carbocyclyl. In certain embodiments, R ^2a is substituted or unsubstituted cyclopropyl or substituted or unsubstituted cyclobutyl. In certain embodiments, R ^2a is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , or substituted or unsubstituted cyclopropyl. In certain embodiments, R ^2a is -OR ^A2 . In certain embodiments, R ^A2 represents a hydrogen atom. In certain embodiments, R ^A2 is substituted or unsubstituted alkyl, for example, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _1-2 alkyl, substituted or unsubstituted C _2-3 alkyl, substituted or unsubstituted C _{3- 4} -alkyl, substituted or unsubstituted C _4-5 -alkyl, or substituted or unsubstituted C _5-6 -alkyl. In certain embodiments, R ^A2 represents a hydrogen atom, -CH ₃ , -CH ₂ CH ₃ , or -CH ₂ CH ₂ CH ₃ , that is, to form a group R ^2a with the formula -OH, -OCH ₃ , -OCH ₂ CH ₃ , or -OCH ₂ CH ₂ CH ₃ . In certain embodiments, R ^2a represents a non-hydrogen substituent in the alpha configuration. In certain embodiments, R ^2a represents a non-hydrogen substituent in the beta configuration.

[ 0127 ] As generally defined herein, R ^11a represents a hydrogen atom or -OR ^A3 , wherein R ^A3 represents a hydrogen atom or 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, and R ^11b represents a hydrogen atom; or R ^11a and R ^11b are combined to form an oxo group (=O).

[ 0128 ] In certain embodiments, both R ^11a and R ^11b represent a hydrogen atom.

[ 0129 ] In certain embodiments, R ^11a and R ^11b are combined to form an oxo group (=O).

[ 0130 ] In certain embodiments, R ^11a is -OR ^A3 , and R ^11b is a hydrogen atom. In certain embodiments in which R ^11a is -OR ^A3 , R ^11a is in the alpha or beta configuration. In certain embodiments in which R ^11a is -OR ^A3 , R ^11a is in the alpha configuration. In certain embodiments in which R ^11a represents -OR ^A3 , R ^11a is in the beta configuration. In certain embodiments, R ^A3 represents a hydrogen atom. In certain embodiments, R ^A3 is substituted or unsubstituted C _1-6 alkyl, e.g., substituted or unsubstituted C _1-2 alkyl, substituted or unsubstituted C _2-3 alkyl, substituted or unsubstituted C _3-4 alkyl, substituted or unsubstituted C _4-5 -alkyl, or substituted or unsubstituted C _5-6 -alkyl. In certain embodiments, R ^A3 represents a hydrogen atom, -CH ₃ , -CH ₂ CH ₃ , or -CH ₂ CH ₂ CH ₃ , that is, to form the group R ^11a with the formula -OH, -OCH ₃ , -OCH ₂ CH ₃ , or -OCH ₂ CH ₂ CH ₃ .

[ 0131 ] As generally defined herein, R ^6a and R ^6b each independently represent a hydrogen atom, substituted or unsubstituted C _1-6 alkyl, or halogen.

Formula (I-X) group p

[ 0132 ] In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

Formula (I-1) of the groups R ^m , R ⁿ , and R ^x

[ 0133 ] As generally defined herein, R ^m , R ⁿ , and R ^x , in each case independently, represent a hydrogen atom, halogen, -NO ₂ , -CN, -OR ^GA , -N(R ^GA ) ₂ , -C(=O)R ^GA , -C(=O)OR ^GA , -OC(=O)R ^GA , -OC(=O)OR ^GA , -C(=O)N(R ^GA ) ₂ , - N(R ^GA )C(=O)R ^GA , -OC(=O)N(R ^GA ) ₂ , -N(R ^GA )C(=O)OR ^GA , -N(R ^GA )C(=O )N(R ^GA ) _2, -SR ^GA , -S(O)R ^GA , for example, S(=O)R ^GA , -S(=O) ₂ R ^GA , -S(=O) ₂ OR ^GA , -OS(=O) ₂ R ^GA , -S(=O) ₂ N(R ^GA ) ₂ , -N(R ^GA )S(=O) ₂ R ^GA , substituted or unsubstituted 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 3-6-membered heterocyclyl.

[ 0134 ] Additionally, as generally defined herein, R ^GA , in each instance independently, represents a hydrogen atom, 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 3-6-membered heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, oxygen protecting group when attached to an oxygen atom, nitrogen protecting group , when attached to a nitrogen atom, or two R ^GA groups are linked by common atoms to form a substituted or unsubstituted heterocyclic or heteroaryl ring. In certain embodiments, R ^GA , in each instance independently, represents a hydrogen atom, substituted or unsubstituted C _1-6 -alkyl ( for example, substituted or unsubstituted C _1-2 -alkyl, substituted or unsubstituted C _2-3 -alkyl, substituted or unsubstituted C _3-4 -alkyl, substituted or unsubstituted C _4-5 -alkyl, or substituted or unsubstituted C _5-6 -alkyl), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In certain embodiments, R ^GA is, in each case independently, a hydrogen atom, -CH ₃ , -CH ₂ CH ₃ , or substituted or unsubstituted phenyl.

[ 0135 ] In certain embodiments, at least one of R ^m , R ⁿ , and R ^x represents a hydrogen atom. In certain embodiments, at least two of ^Rm , ^Rn , and ^Rx represent a hydrogen atom. In certain embodiments, R ^m , R ⁿ , and R ^x all represent a hydrogen atom to form an unsubstituted pyrazolyl.

[ 0136 ] In certain embodiments, at least one of R ^m , R ⁿ , and R ^x represents a non-hydrogen substituent. As used herein, R ^m , R ⁿ , and R ^x as a “non-hydrogen substituent” means that R ^m , R ⁿ , and R ^x are not hydrogen atoms but are any of halogen, -NO ₂ , -CN, -CF ₃ , -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 , -SR ^GA , -S(O)R ^GA , for example, S(=O)R ^GA , -S(=O) ₂ R ^GA , -S(=O) ₂ OR ^GA , -OS(= O) ₂ R ^GA , -S(=O) ₂ N(R ^GA ) ₂ , or -N(R ^GA )S(=O) ₂ R ^GA ; substituted or unsubstituted C _1-6 -alkyl, substituted or unsubstituted C _2-6 -alkenyl, substituted or unsubstituted C _2-6 -alkynyl, substituted or unsubstituted C _3-6 -carbocyclyl, substituted or unsubstituted 3-6-membered heterocyclyl.

[ 0137 ] In certain embodiments, at least one of ^Rm , ^Rn , and ^Rx is a halogen atom, such as fluorine, bromine, iodine, or chlorine. In certain embodiments, one of R ^m , R ⁿ , and R ^x represents a halogen atom. In certain embodiments, R ^m represents a halogen atom, such as fluorine, bromine, iodine, or chlorine. In certain embodiments, R ⁿ represents a halogen atom, such as fluorine, bromine, iodine, or chlorine. In certain embodiments, R ^x represents a halogen atom, such as fluorine, bromine, iodine, or chlorine.

[ 0138 ] In certain embodiments, at least one of R ^m , R ⁿ , and R ^x is -NO ₂ . In certain embodiments, one of R ^m , R ⁿ , and R ^x is -NO ₂ . In certain embodiments, R ^m is -NO ₂ . In certain embodiments, R ⁿ is -NO ₂ . In certain embodiments, R ^x is -NO ₂ .

[ 0139 ] In certain embodiments, at least one of R ^m , R ⁿ , and R ^x is -CN. In certain embodiments, one of R ^m , R ⁿ , and R ^x is -CN. In certain embodiments, R ^m is -CN. In certain embodiments, R ⁿ is -CN. In certain embodiments, R ^x is -CN.

[ 0140 ] In certain embodiments, at least one of R ^m , R ⁿ , and R ^x is -OR ^GA , for example, wherein R ^GA is a hydrogen atom or a substituted or unsubstituted C _1-6 alkyl ( for example, -CH ₃ or -CF ₃ ). In certain embodiments, one of R ^m , R ⁿ , and R ^x is -OR ^GA , for example, -OH, -OCH ₃ , or -OCF ₃ . In certain embodiments, R ^m is -OR ^GA , for example, -OH, -OCH ₃ , or -OCF ₃ . In certain embodiments, ^Rn is -OR ^GA . In certain embodiments, R ^x is -OR ^GA , such as -OH, -OCH ₃ , or -OCF _3.

[0141] In certain embodiments, at least one of R^m, Rⁿ, and R^x represents -N(R^GA)₂,For example,and R^GA represents a hydrogen atom or substituted or unsubstituted C_1-6-alkyl (For example, -CH₃ or -CF₃). In certain embodiments, one of R^m, Rⁿ, and R^x represents -N(R^GA)₂,eg, -NH₂,-NHCH₃, or -N(CH₃)₂. In certain versions R^m represents -N(R^GA)₂,For example, -NH₂,-NHCH₃, or -N(CH₃)_2. In certain versions Rⁿ represents -N(R^GA)₂,For example, -NH₂,-NHCH₃, or -N(CH₃)_2. In certain versions R^x represents -N(R^GA)₂,For example, -NH₂,-NHCH₃, or -N(CH₃)_2.

[ 0142 ] In certain embodiments, at least one of R ^m , R ⁿ , and R ^x is -C(=O)R ^GA , -C(=O)OR ^GA , or -C(=O)N(R ^GA ) ₂ , for example, in which R ^GA represents a hydrogen atom or substituted or unsubstituted C _1-6 alkyl ( eg -CH ₃ or -CF ₃ ). In certain embodiments, one of R ^m , R ⁿ , and R ^x is -C(=O)R ^GA , for example, -CHO, -C(=O)CH ₃ , or -C(=O)CH ₂ CH ₃ . In certain embodiments, R ^m is -C(=O)R ^GA , such as -CHO, -C(=O)CH ₃ , or -C(=O)CH ₂ CH ₃ . In certain embodiments, R ⁿ is -C(=O)R ^GA , such as -CHO, -C(=O)CH ₃ , or -C(=O)CH ₂ CH ₃ . In certain embodiments, R ^x is -C(=O)R ^GA , such as -CHO, -C(=O)CH ₃ , or -C(=O)CH ₂ CH ₃ . In certain embodiments, one of R ^m , R ⁿ , and R ^x is -C(=O)OR ^GA , for example, -C(=O)OH, -C(=O)OCH ₃ , or -C(=O )OCH ₂ CH ₃ . In certain embodiments, R ^m is -C(=O)OR ^GA , such as -C(=O)OH, -C(=O)OCH ₃ , or -C(=O)OCH ₂ CH _3. In certain embodiments execution R ⁿ represents -C(=O)OR ^GA , for example, -C(=O)OH, -C(=O)OCH ₃ , or -C(=O)OCH ₂ CH ₃ . In certain embodiments, R ^x is -C(=O)OR ^GA , such as -C(=O)OH, -C(=O)OCH ₃ , or -C(=O)OCH ₂ CH _3. In certain embodiments execution one of R ^m , R ⁿ , and R ^x represents -C(=O)N(R ^GA ) ₂ , for example, -C(=O)NH ₂ , -C(=O)NHCH ₃ , or -C( =O)N(CH ₃ ) ₂ . In certain embodiments, R ^m is -C(=O)N(R ^GA ) ₂ , for example, -C(=O)NH ₂ , -C(=O)NHCH ₃ , or -C(=O)N(CH ₃ ) _2. In certain embodiments, R ⁿ is -C(=O)N(R ^GA ) ₂ , for example, -C(=O)NH ₂ , -C(=O)NHCH ₃ , or -C(=O )N(CH ₃ ) _2. In certain embodiments, R ^x is -C(=O)N(R ^GA ) ₂ , for example, -C(=O)NH ₂ , -C(=O)NHCH ₃ , or - C(=O)N(CH ₃ ) ₂ .

[ 0143 ] In certain embodiments, at least one of R ^m , R ⁿ , and R ^x is -OC(=O)R ^GA , -OC(=O)OR ^GA , or -OC(=O)N(R ^GA ) ₂ , for example, in which R ^GA represents a hydrogen atom or substituted or unsubstituted C _1-6 alkyl ( eg -CH ₃ or -CF ₃ ). In certain embodiments, one of R ^m , R ⁿ , and R ^x represents -OC(=O)R ^GA , for example, -OC(=O)CH _3. In certain embodiments, R ^m represents -OC(=O)R ^GA , for example, -OC(=O)CH ₃ . In certain embodiments, R ⁿ is -OC(=O)R ^GA , such as -OC(=O)CH _3. In certain embodiments, R ^x is -OC(=O)R ^GA , such as -OC(=O )CH ₃ . In certain embodiments, one of R ^m , R ⁿ , and R ^x represents -OC(=O)OR ^GA , for example, -OC(=O)OCH ₃ . In certain embodiments, R ^m is -OC(=O)OR ^GA , for example, -OC(=O)OCH ₃ . In certain embodiments, R ⁿ is -OC(=O)OR ^GA , for example, -OC(=O)OCH ₃ . In certain embodiments, R ^x represents -OC(=O)OR ^GA , for example, -OC(=O)OCH ₃ . In certain embodiments, one of R ^m , R ⁿ , and R ^x is -OC(=O)N(R ^GA ) ₂ , for example, -OC(=O)NHCH ₃ or -OC(=O)N(CH ₃ ) ₂ . In certain embodiments, R ^m is -OC(=O)N(R ^GA ) ₂ , for example, -OC(=O)NHCH ₃ or -OC(=O)N(CH ₃ ) ₂ . In certain embodiments, R ⁿ is -OC(=O)N(R ^GA ) ₂ , for example, -OC(=O)NHCH ₃ or -OC(=O)N(CH ₃ ) ₂ . In certain embodiments, R ^x is -OC(=O)N(R ^GA ) ₂ , for example, -OC(=O)NHCH ₃ or -OC(=O)N(CH ₃ ) ₂ .

[ 0144 ] In certain embodiments, at least one of R ^m , R ⁿ , and R ^x is -N(R ^GA )C(=O)R ^GA , -N(R ^GA )C(=O)OR ^GA , or -N(R ^GA )C(=O)N(R ^GA ) ₂ , for example, in which R ^GA represents a hydrogen atom or a substituted or unsubstituted C _1-6 -alkyl ( for example, -CH ₃ or -CF ₃ ). In certain embodiments, one of R ^m , R ⁿ , and R ^x is -N(R ^GA )C(=O)R ^GA , for example, -NHC(=O)CH ₃ . In certain embodiments, R ^m is -N(R ^GA )C(=O)R ^GA , for example, -NHC(=O)CH _3. In certain embodiments, R ⁿ is -N(R ^GA )C(=O) R ^GA , for example, -NHC(=O)CH _3. In certain embodiments, R ^x is -N(R ^GA )C(=O)R ^GA , for example, -NHC(=O)CH _3. In certain embodiments one of R ^m , R ⁿ , and R ^x is -N(R ^GA )C(=O)OR ^GA , for example, -NHC(=O)OCH ₃ . In certain embodiments, R ^m is -N(R ^GA )C(=O)OR ^GA , for example, -NHC(=O)OCH _3. In certain embodiments, R ⁿ is -N(R ^GA )C(=O) OR ^GA , for example, -NHC(=O)OCH _3. In certain embodiments, R ^x is -N(R ^GA )C(=O)OR ^GA , for example, -NHC(=O)OCH _3. In certain embodiments one of R ^m , R ⁿ , and R ^x is -N(R ^GA )C(=O)N(R ^GA ) ₂ , for example -NHC(=O)NH ₂ or -NHC(=O)N(CH ₃ ) ₂ . In certain embodiments, R ^m is -N(R ^GA )C(=O)N(R ^GA ) ₂ , for example, -NHC(=O)NH ₂ or -NHC(=O)N(CH ₃ ) ₂ . In certain embodiments, R ⁿ is -N(R ^GA )C(=O)N(R ^GA ) ₂ , for example, -NHC(=O)NH ₂ or -NHC(=O)N(CH ₃ ) ₂ . In certain embodiments, R ^x is -N(R ^GA )C(=O)N(R ^GA ) ₂ , for example, -NHC(=O)NH ₂ or -NHC(=O)N(CH ₃ ) _2.

[0145] In certain embodiments, at least one of R^m, Rⁿ, and R^x represents -SR^GA, -S(O)R^GA,For example, -S(=O)R^GA, -S(=O)₂R^GA, -S(=O)₂OR^GA, -OS(=O)₂R^GA, -S(=O)₂N(R^GA)₂, or -N(R^GA)S(=O)₂R^GA,For example, in which R^GA represents a hydrogen atom, substituted or unsubstituted C_1-6-alkyl (For example, -CH₃ or -CF₃), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In certain embodiments, one of R^m, Rⁿ, and R^x represents -SR^GA,For example, -SCH₃, or -S-Aryl, wherein Aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, one of R^m, Rⁿ, and R^x represents -S(O)R^GA,For example, -S(=O)R^GA,For example,-S(=O)CH₃, -S(=O)CF₃, or -S(=O)-Aryl, wherein Aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, one of R^m, Rⁿ, and R^x represents -S(=O)₂R^GA,For example, -S(=O)₂CH_3,-S(=O)₂CF₃, or -S(=O)₂-Aryl, wherein Aryl is substituted or unsubstituted aryl or heteroaryl. In certain versions R^m represents -SR^GA,For example, -SCH₃, -SCF₃; -S(O)R^GA,For example,-S(=O)R^GA,For example, -S(=O)CH₃, -S(=O)CF₃; -S(=O)₂R^GA,For example, -S(=O)₂CH₃, -S(=O)₂CF₃, or -S(=O)₂-Aryl, wherein Aryl is substituted or unsubstituted aryl or heteroaryl. In certain versions Rⁿ represents -SR^GA,For example, -SCH₃, -SCF₃; -S(O)R^GA,For example,-S(=O)R^GA,For example, -S(=O)CH₃, -S(=O)CF₃; -S(=O)₂R^GA,For example, -S(=O)₂CH₃, -S(=O)₂CF₃, or -S(=O)₂-Aryl, wherein Aryl is substituted or unsubstituted aryl or heteroaryl. In certain versions R^x represents -SR^GA,For example, -SCH₃, -SCF₃; -S(O)R^GA,For example,S(=O)R^GA,For example, -S(=O)CH₃, -S(=O)CF₃; -S(=O)₂R^GA,For example, -S(=O)₂CH₃, -S(=O)₂CF₃, or -S(=O)₂-Aryl, wherein Aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, one of R^m, Rⁿ, and R^x represents -S(=O)₂OR^GA. In certain versions R^m represents -S(=O)₂OR^GA,For example, -S(=O)₂OCH₃, -S(=O)₂OCF₃, or -S(=O)₂OAryl, in which Aryl is substituted or unsubstituted aryl or heteroaryl. In certain versions Rⁿ represents -S(=O)₂OR^GA,For example, -S(=O)₂OCH₃, -S(=O)₂OCF₃, or -S(=O)₂OAryl, in which Aryl is substituted or unsubstituted aryl or heteroaryl. In certain versions R^x represents -S(=O)₂OR^GA,For example, -S(=O)₂OCH₃, -S(=O)₂OCF₃, or -S(=O)₂OAryl, in which Aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, one of R^m, Rⁿ, and R^x represents -OS(=O)₂R^GA. In certain versions R^m represents -OS(=O)₂R^GA,For example, -OS(=O)₂CH₃, -OS(=O)₂CF₃, or -OS(=O)₂-Aryl, wherein Aryl is substituted or unsubstituted aryl or heteroaryl. In certain versions Rⁿ represents -OS(=O)₂R^GA,For example, -OS(=O)₂CH₃, -OS(=O)₂CF₃, or -OS(=O)₂-Aryl, wherein Aryl is substituted or unsubstituted aryl or heteroaryl. In certain versions R^x represents -OS(=O)₂R^GA,For example, -OS(=O)₂CH₃, -OS(=O)₂CF₃, or -OS(=O)₂-Aryl, wherein Aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, one of R^m, Rⁿ, and R^x represents -S(=O)₂N(R^GA)₂. In certain versions R^m represents -S(=O)₂N(R^GA)₂,For example, -S(=O)₂NHCH₃, -S(=O)₂NHCF₃, or -S(=O)₂-NH-Aryl, in which Aryl is substituted or unsubstituted aryl or heteroaryl. In certain versions Rⁿ represents -S(=O)₂N(R^GA)₂,For example, -S(=O)₂NHCH₃, -S(=O)₂NHCF₃, or -S(=O)₂-NH-Aryl, in which Aryl is substituted or unsubstituted aryl or heteroaryl. In certain versions R^x represents -S(=O)₂N(R^GA)₂,For example, -S(=O)₂NHCH₃, -S(=O)₂NHCF₃, or -S(=O)₂-NH-Aryl, in which Aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, one of R^m, Rⁿ, and R^x represents -N(R^GA)S(=O)₂R^GA. In certain versions R^m represents -N(R^GA)S(=O)₂R^GA,For example, -NHS(=O)₂CH₃, -NHS(=O)₂CF₃, or -NHS(=O)₂-Aryl, wherein Aryl is substituted or unsubstituted aryl or heteroaryl. In certain versions Rⁿ represents -N(R^GA)S(=O)₂R^GA,For example, -NHS(=O)₂CH₃, -NHS(=O)₂CF₃, or -NHS(=O)₂-Aryl, wherein Aryl is substituted or unsubstituted aryl or heteroaryl. In certain versions R^x represents -N(R^GA)S(=O)₂R^GA,For example, -NHS(=O)₂CH₃, -NHS(=O)₂CF₃, or -NHS(=O)₂-Aryl, wherein Aryl is substituted or unsubstituted aryl or heteroaryl.

[ 0146 ] In certain embodiments, at least one of R ^m , R ⁿ , and R ^x is a substituted or unsubstituted C _1-6 alkyl, such as a substituted or unsubstituted C _1-2 alkyl, substituted or unsubstituted C _{2- 3} -alkyl, substituted or unsubstituted C _3-4 -alkyl, substituted or unsubstituted C _4-5 -alkyl, or substituted or unsubstituted C _5-6 -alkyl. Exemplary _C1-2 alkyl groups include, but are not limited to, substituted or unsubstituted methyl ( _C1 ), ethyl ( _C2 ), n-propyl ( _C3 ), isopropyl ( _C3 ), n-butyl ( _C4 ), tert-butyl (C ₄ ), sec-butyl (C ₄ ), isobutyl (C ₄ ), n-pentyl (C ₅ ), 3-pentyl (C ₅ ), amyl (C ₅ ), neopentyl (C ₅ ), 3-methyl-2-butyl (C ₅ ), tertiary amyl (C ₅ ), n-hexyl (C ₆ ), C _1-6 -alkyl, substituted 1, 2, 3, 4, 5, 6, 7 , 8, 9, 10, or more fluorine atoms ( for example, -CF ₃ , -CH ₂ F, -CHF ₂ , difluoroethyl, and 2,2,2-trifluoro-1,1-dimethylethyl), C _1-6 - alkyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more chlorine atoms ( for example, -CH ₂ Cl, -CHCl ₂ ), and C _1-6 alkyl substituted with alkoxy groups ( for example, -CH ₂ OCH ₃ and -CH ₂ OCH ₂ CH ₃ ). In certain embodiments, at least one of R ^m , R ⁿ , and R ^x is a substituted C _1-6 alkyl, for example, at least one of R ^m , R ⁿ , and R ^x is haloalkyl, alkoxyalkyl, or aminoalkyl . In certain embodiments, at least one of R ^m , R ⁿ , and R ^x is Me, Et, n-Pr, n-Bu, i-Bu, fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, difluoroethyl, 2,2 ,2-trifluoro-1,1-dimethylethyl, methoxymethyl, methoxyethyl or ethoxymethyl.

[ 0147 ] In certain embodiments, at least one of R ^m , R ⁿ , and R ^x is substituted or unsubstituted C _2-6 -alkenyl, e.g., substituted or unsubstituted C _2-3 -alkenyl, substituted or unsubstituted C _{3- 4} -alkenyl, substituted or unsubstituted C _4-5 -alkenyl, or substituted or unsubstituted C _5-6 -alkenyl. In certain embodiments, at least one of R ^m , R ⁿ , and R ^x is ethenyl (C ₂ ), propenyl (C ₃ ), or butenyl (C ₄ ), unsubstituted or substituted with one or more substituents selected from the group, consisting of an alkyl, halogen atom, haloalkyl, alkoxyalkyl or hydroxyl. In certain embodiments, at least one of R ^m , R ⁿ , and R ^x is ethenyl, propenyl, or butenyl, unsubstituted or substituted with alkyl, halogen, haloalkyl, alkoxyalkyl, or hydroxyl.

[ 0148 ] In certain embodiments, at least one of R ^m , R ⁿ , and R ^x is a substituted or unsubstituted C _2-6 -alkynyl, such as a substituted or unsubstituted C _2-3 -alkynyl, substituted or unsubstituted C _{3- 4} -alkynyl, substituted or unsubstituted C _4-5 -alkynyl, or substituted or unsubstituted C _5-6 -alkynyl. In certain embodiments, at least one of R ^m , R ⁿ , and R ^x is ethynyl, propynyl, or butynyl, unsubstituted or substituted with alkyl, halogen, haloalkyl ( e.g., CF ₃ ), alkoxyalkyl, cycloalkyl ( e.g., cyclopropyl or cyclobutyl) , or hydroxyl.

[ 0149 ] In certain embodiments, at least one of R ^m , R ⁿ , and R ^x is a substituted or unsubstituted C _3-6 -carbocyclyl, such as a substituted or unsubstituted C _3-4 -carbocyclyl, substituted or unsubstituted C _{4- 5} -carbocyclyl, or substituted or unsubstituted C _5-6 -carbocyclyl. In certain embodiments, at least one of R ^m , R ⁿ , and R ^x is substituted or unsubstituted cyclopropyl or substituted or unsubstituted cyclobutyl.

[ 0150 ] In certain embodiments, at least one of R ^m , R ⁿ , and R ^x is a substituted or unsubstituted 3-6 membered heterocyclyl, e.g., a substituted or unsubstituted 3-4 membered heterocyclyl, substituted or unsubstituted 4-5 -membered heterocyclyl, or substituted or unsubstituted 5-6 membered heterocyclyl.

[ 0151 ] In certain embodiments, at least one of R ^m , R ⁿ , and R ^x is a substituted or unsubstituted C _1-2 alkyl ( eg, -CH ₃ , -CF ₃ ), -CO ₂ R ^GA , - C(=O)R ^GA , -CN, -NO ₂ , or halogen, wherein R ^GA is substituted or unsubstituted C _1-2 alkyl ( eg, -CH ₃ , -CF ₃ ).

[ 0152 ] Exemplary combinations of R ^m , R ⁿ , and R ^x as non-hydrogen substituents are discussed herein.

[ 0153 ] For example, in certain embodiments, C21-pyrazolyl of the formula

is a monosubstituted pyrazolyl ring of the formula

wherein each of ^Rm , ^Rn , and ^Rx is a non-hydrogen substituent as defined herein.

[ 0154 ] In certain embodiments, C21-pyrazolyl of the formula

is a disubstituted pyrazolyl ring of the formula

wherein each of ^Rm , ^Rn , and ^Rx is a non-hydrogen substituent as defined herein.

[ 0155 ] In certain embodiments, C21-pyrazolyl of the formula

is a trisubstituted pyrazolyl ring in which ^Rm , ^Rn , and ^Rx are in each case non-hydrogen substituents as defined herein.

[ 0156 ] For example, in certain embodiments in which R ^2a represents a hydrogen atom or a non-hydrogen alpha substituent, a steroid of Formula ( II-A1 ) or ( II-B1 ) is provided:

or a pharmaceutically acceptable salt thereof. In certain embodiments, R ^3a is -CH _{3 ,} -CH ₂ CH ₃ , -CH ₂ F , -CHF ₂ , -CF ₃ , -CH ₂ OCH ₃ , or substituted or unsubstituted cyclopropyl. In certain embodiments, R ^2a is -OH, -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , substituted or unsubstituted cyclopropyl , fluorine or chlorine atom. In certain embodiments, both R ^11a and R ^11b represent a hydrogen atom. In certain embodiments, R ^11a and R ^11b are combined to form =O (oxo groups). In certain embodiments in which Ring B includes a C5-C6 double bond, R ^6a is a hydrogen atom, a fluorine atom, -CH ₃ , or -CF ₃ . In certain embodiments in which Ring B does not contain a C5-C6 double bond, both R ^6a and R ^6b represent a hydrogen atom. In certain embodiments in which Ring B contains a C5-C6 double bond, both R ^6a and R ^6b are -CH ₃ or -CF ₃ . In certain embodiments in which Ring B does not contain a C5-C6 double bond, both R ^6a and R ^6b are fluorine. In certain embodiments in which Ring B does not contain a C5-C6 double bond, R ^6a represents a non-hydrogen substituent and R ^6b represents a hydrogen atom. In certain embodiments, the C21-pyrazolyl ring is a monosubstituted pyrazolyl. In certain embodiments, the C21-pyrazolyl ring is a disubstituted pyrazolyl. In certain embodiments, at least one of R ^m , R ⁿ , and R ^x is a substituted or unsubstituted C _1-2 alkyl ( eg, -CH ₃ , -CF ₃ ), -CO ₂ R ^GA , -C(= O)R ^GA , -CN, -NO ₂ , or halogen, wherein R ^GA is substituted or unsubstituted C _1-2 alkyl ( eg, -CH ₃ , -CF ₃ ). In certain embodiments, the C21-pyrazolyl ring is an unsubstituted pyrazolyl, in which in each case R ^m , R ⁿ , and R ^x represent a hydrogen atom.

[ 0157 ] In certain embodiments in which R ^2a represents a hydrogen atom or a non-hydrogen beta substituent, a steroid of Formula ( II-A2 ) or ( II-B2 ) is provided:

or a pharmaceutically acceptable salt thereof. In certain embodiments, R ^3a is -CH _{3 ,} -CH ₂ CH ₃ , -CH ₂ F , -CHF ₂ , -CF ₃ , -CH ₂ OCH ₃ , or substituted or unsubstituted cyclopropyl. In certain embodiments, R ^2a is -OH, -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , substituted or unsubstituted cyclopropyl , fluorine or chlorine atom. In certain embodiments, both R ^11a and R ^11b represent a hydrogen atom. In certain embodiments, R ^11a and R ^11b are combined to form =O (oxo groups). In certain embodiments in which Ring B includes a C5-C6 double bond, R ^6a is a hydrogen atom, a fluorine atom, -CH ₃ , or -CF ₃ . In certain embodiments in which Ring B does not contain a C5-C6 double bond, both R ^6a and R ^6b represent a hydrogen atom. In certain embodiments in which Ring B does not contain a C5-C6 double bond, both R ^6a and R ^6b are -CH ₃ or -CF ₃ . In certain embodiments in which Ring B does not contain a C5-C6 double bond, both R ^6a and R ^6b are fluorine. In certain embodiments in which Ring B does not contain a C5-C6 double bond, R ^6a represents a non-hydrogen substituent and R ^6b represents a hydrogen atom. In certain embodiments, the C21-pyrazolyl ring is a monosubstituted pyrazolyl. In certain embodiments, the C21-pyrazolyl ring is a disubstituted pyrazolyl. In certain embodiments, at least one of R ^m , R ⁿ , and R ^x is a substituted or unsubstituted C _1-2 alkyl ( eg, -CH ₃ , -CF ₃ ), -CO ₂ R ^GA , -C(= O)R ^GA , -CN, -NO ₂ , or halogen, wherein R ^GA is substituted or unsubstituted C _1-2 alkyl ( eg, -CH ₃ , -CF ₃ ). In certain embodiments, the C21-pyrazolyl ring is an unsubstituted pyrazolyl, in which in each case R ^m , R ⁿ , and R ^x represent a hydrogen atom.

[ 0158 ] In certain embodiments in which R ^11a represents a hydrogen atom or a non-hydrogen alpha substituent and R ^11b represents a hydrogen atom, a steroid of Formula ( II-A3 ) or ( II-B3 ) is provided:

or a pharmaceutically acceptable salt thereof. In certain embodiments, R ^3a is -CH _{3 ,} -CH ₂ CH ₃ , -CH ₂ F , -CHF ₂ , -CF ₃ , -CH ₂ OCH ₃ , or substituted or unsubstituted cyclopropyl. In certain embodiments, R ^2a is -OH, -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , substituted or unsubstituted cyclopropyl , fluorine or chlorine atom. In certain embodiments, R ^2a represents a non-hydrogen substituent in the alpha configuration. In certain embodiments, R ^2a represents a non-hydrogen substituent in the beta configuration. In certain embodiments in which Ring B includes a C5-C6 double bond, R ^6a is a hydrogen atom, a fluorine atom, -CH ₃ , or -CF ₃ . In certain embodiments in which Ring B does not contain a C5-C6 double bond, both R ^6a and R ^6b represent a hydrogen atom. In certain embodiments in which Ring B does not contain a C5-C6 double bond, both R ^6a and R ^6b are -CH ₃ or -CF ₃ . In certain embodiments in which Ring B does not contain a C5-C6 double bond, both R ^6a and R ^6b are fluorine. In certain embodiments in which Ring B does not contain a C5-C6 double bond, R ^6a represents a non-hydrogen substituent and R ^6b represents a hydrogen atom. In certain embodiments, the C21-pyrazolyl ring is a monosubstituted pyrazolyl. In certain embodiments, the C21-pyrazolyl ring is a disubstituted pyrazolyl. In certain embodiments, at least one of R ^m , R ⁿ , and R ^x is a substituted or unsubstituted C _1-2 alkyl ( eg, -CH ₃ , -CF ₃ ), -CO ₂ R ^GA , -C(= O)R ^GA , -CN, -NO ₂ , or halogen, wherein R ^GA is substituted or unsubstituted C _1-2 alkyl ( eg, -CH ₃ , -CF ₃ ). In certain embodiments, the C21-pyrazolyl ring is an unsubstituted pyrazolyl, in which in each case R ^m , R ⁿ , and R ^x represent a hydrogen atom.

[ 0159 ] In certain embodiments in which R ^11a represents a hydrogen atom or a non-hydrogen beta substituent and R ^11b represents a hydrogen atom, a steroid of Formula ( II-A4 ) or ( II-B4 ) is provided:

or a pharmaceutically acceptable salt thereof. In certain embodiments, R ^3a is -CH _{3 ,} -CH ₂ CH ₃ , -CH ₂ F , -CHF ₂ , -CF ₃ , -CH ₂ OCH ₃ , or substituted or unsubstituted cyclopropyl. In certain embodiments, R ^2a is -OH, -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , substituted or unsubstituted cyclopropyl , fluorine or chlorine atom. In certain embodiments, R ^2a represents a non-hydrogen substituent in the alpha configuration. In certain embodiments, R ^2a represents a non-hydrogen substituent in the beta configuration. In certain embodiments in which Ring B includes a C5-C6 double bond, R ^6a is a hydrogen atom, a fluorine atom, -CH ₃ , or -CF ₃ . In certain embodiments in which Ring B does not contain a C5-C6 double bond, both R ^6a and R ^6b represent a hydrogen atom. In certain embodiments in which Ring B does not contain a C5-C6 double bond, both R ^6a and R ^6b are -CH ₃ or -CF ₃ In certain embodiments in which Ring B does not contain a C5-C6 double bond , both R ^6a and R ^6b are fluorine. In certain embodiments in which Ring B does not contain a C5-C6 double bond, R ^6a represents a non-hydrogen substituent and R ^6b represents a hydrogen atom. In certain embodiments, the C21-pyrazolyl ring is a monosubstituted pyrazolyl. In certain embodiments, the C21-pyrazolyl ring is a disubstituted pyrazolyl. In certain embodiments, at least one of R ^m , R ⁿ , and R ^x is a substituted or unsubstituted C _1-2 alkyl ( eg, -CH ₃ , -CF ₃ ), -CO ₂ R ^GA , -C(= O)R ^GA , -CN, -NO ₂ , or halogen, wherein R ^GA is substituted or unsubstituted C _1-2 alkyl ( eg, -CH ₃ , -CF ₃ ). In certain embodiments, the C21-pyrazolyl ring is an unsubstituted pyrazolyl, in which in each case R ^m , R ⁿ , and R ^x represent a hydrogen atom.

[ 0160 ] In certain embodiments in which R ^11a and R ^11b are combined to form an oxo group, a steroid of Formula ( II-A5 ) or ( II-B5 ) is provided:

or a pharmaceutically acceptable salt thereof. In certain versions R^3a represents -CH_3,-CH₂CH₃, -CH₂F, -CHF₂, -CF₃, -CH₂OCH₃, or substituted or unsubstituted cyclopropyl. In certain versions R^2a represents -OH, -OCH₃, -OCH₂CH₃, -OCH₂CH₂CH₃, -CH₃, -CH₂CH₃, -CH₂CH₂CH₃, substituted or unsubstituted cyclopropyl, fluorine or chlorine atom. In certain versions R^2a represents a non-hydrogen substituent inalpha-configurations. In certain versions R^2a represents a non-hydrogen substituent inbeta-configurations. In certain embodiments in which Ring B includes a C5-C6 double bond, R^6a represents a hydrogen atom, a fluorine atom, -CH₃, or -CF₃. In certain embodiments in which Ring B does not contain a C5-C6 double bond, both of R^6a and R^6b represent a hydrogen atom. In certain embodiments in which Ring B does not contain a C5-C6 double bond, both of R^6a and R^6b represent -CH₃ or -CF₃In certain embodiments in which Ring B does not contain a C5-C6 double bond, both of R^6a and R^6b represent fluorine. In certain embodiments in which Ring B does not contain a C5-C6 double bond, R^6a represents a non-hydrogen substituent, and R^6b represents a hydrogen atom. In certain embodiments, the C21-pyrazolyl ring is a monosubstituted pyrazolyl. In certain embodiments, the C21-pyrazolyl ring is a disubstituted pyrazolyl. In certain embodiments, at least one of R^m, Rⁿ, and R^x represents substituted or unsubstituted C_1-2-alkyl (For example, -CH₃, -CF₃), -CO₂R^GA, -C(=O)R^GA, -CN, -NO₂, or halogen, and R^GA represents substituted or unsubstituted C_1-2-alkyl (For example, -CH₃, -CF₃). In certain embodiments, the C21-pyrazolyl ring is an unsubstituted pyrazolyl, wherein in each case R^m, Rⁿ, and R^x represents a hydrogen atom.

[ 0161 ] In certain embodiments in which R ^6a is a non-hydrogen substituent, a steroid of Formula ( II-A6 ) or ( II-B6 ) is provided:

or a pharmaceutically acceptable salt thereof. In certain embodiments, R ^3a is -CH _{3 ,} -CH ₂ CH ₃ , -CH ₂ F , -CHF ₂ , -CF ₃ , -CH ₂ OCH ₃ , or substituted or unsubstituted cyclopropyl. In certain embodiments, R ^2a is -OH, -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , substituted or unsubstituted cyclopropyl , fluorine or chlorine atom. In certain embodiments, R ^2a represents a non-hydrogen substituent in the alpha configuration. In certain embodiments, R ^2a represents a non-hydrogen substituent in the beta configuration. In certain embodiments, both R ^11a and R ^11b represent a hydrogen atom. In certain embodiments, R ^11a and R ^11b are combined to form =O (oxo groups). In certain embodiments, R ^6a is a fluorine atom, -CH ₃ or -CF ₃ , and R ^6b is a hydrogen atom. In certain embodiments, R ^6b is a fluorine atom, -CH ₃ or -CF ₃ , and R ^6a is a hydrogen atom. In certain embodiments, both R ^6a and R ^6b are -CH ₃ or -CF ₃ . In certain embodiments, both R ^6a and R ^6b are fluorine. In certain embodiments, the C21-pyrazolyl ring is a monosubstituted pyrazolyl. In certain embodiments, the C21-pyrazolyl ring is a disubstituted pyrazolyl. In certain embodiments, at least one of R ^m , R ⁿ , and R ^x is a substituted or unsubstituted C _1-2 alkyl ( eg, -CH ₃ , -CF ₃ ), -CO ₂ R ^GA , -C(= O)R ^GA , -CN, -NO ₂ , or halogen, wherein R ^GA is substituted or unsubstituted C _1-2 alkyl ( eg, -CH ₃ , -CF ₃ ). In certain embodiments, the C21-pyrazolyl ring is an unsubstituted pyrazolyl, in which in each case R ^m , R ⁿ , and R ^x represent a hydrogen atom.

[ 0162 ] In certain embodiments, the Formula ( II-A7 ) or ( II-B7 ) steroid is provided:

or a pharmaceutically acceptable salt thereof. In certain embodiments, R ^3a is -CH _{3 ,} -CH ₂ CH ₃ , -CH ₂ F , -CHF ₂ , -CF ₃ , -CH ₂ OCH ₃ , or substituted or unsubstituted cyclopropyl. In certain embodiments, the C21-pyrazolyl ring is a monosubstituted pyrazolyl. In certain embodiments, the C21-pyrazolyl ring is a disubstituted pyrazolyl. In certain embodiments, at least one of R ^m , R ⁿ , and R ^x is a substituted or unsubstituted C _1-2 alkyl ( eg, -CH ₃ , -CF ₃ ), -CO ₂ R ^GA , -C(= O)R ^GA , -CN, -NO ₂ , or halogen, wherein R ^GA is substituted or unsubstituted C _1-2 alkyl ( eg, -CH ₃ , -CF ₃ ). In certain embodiments, the C21-pyrazolyl ring is an unsubstituted pyrazolyl, in which in each case R ^m , R ⁿ , and R ^x represent a hydrogen atom.

[ 0163 ] In some embodiments, the connection is:

[ 0164 ]

[ 0165 ] In some embodiments, a compound of Formula ( II-I ) is provided here

or a pharmaceutically acceptable salt thereof; in which

t is 1, 2, or 3;

n is 0, 1 or 2;

R ¹⁹ represents substituted or unsubstituted C ₂ -C ₆ -alkyl, substituted or unsubstituted C ₂ -C ₆ -alkenyl, or substituted or unsubstituted C ₂ -C ₆ -alkynyl;

R ⁵ represents a hydrogen atom or methyl, or when represents a double bond, R ⁵ absent;

R ³ represents a hydrogen atom, 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;

each of R ^6a and R ^6b independently represents a hydrogen atom, a halogen, a cyano group, a hydroxyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, or a substituted or unsubstituted alkynyl, or R ^6a and R ^6b are combined to form an oxo group (=O);

R ¹ represents substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, -OR ^A1 , -SR ^A1 , -N( R ^A1 ) ₂ , -N(R ^A1 ), -OC(=O)R ^A1 , -OC(=O)OR ^A1 , -OC(=O)SR ^A1 , -OC(=O)N(R ^A1 ) ₂ , -SC(=O)R ^A2 , -SC(=O)OR ^A1 , -SC(=O)SR ^A1 , -SC(=O)N(R ^A1 ) ₂ , -NHC(=O)R ^A1 , -NHC(=O)OR ^A1 , -NHC(=O)SR ^A1 , -NHC(=O)N(R ^A1 ) ₂ , -OS(=O) ₂ R ^A2 , -OS(=O) ₂ OR ^A1 , -SS(=O) ₂ R ^A2 , -SS(=O) ₂ OR ^A1 , -S(=O)R ^A2 , -SO ₂ R ^A2 , or -S(=O) ₂ OR ^A1 , and R ^A1 , in each instance independently, represents a hydrogen atom, 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, a protecting group for oxygen when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R ^GA groups are combined to form a substituted or unsubstituted heterocyclic or heteroaryl ring; and R ^A2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

each of R ^2a , R ^2b , R ^4a , R ^4b , R ^7a , R ^7b , R ^11a , R ^{11b , R 12a} , R ^12b or ^{R 17b independently} represents a hydrogen atom, a halogen, a cyano group, a hydroxyl, a substituted or unsubstituted alkyl , substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , -N(R ^D1 ) ₂ , or -NR ^D1 C(=O )R ^D1 , wherein ^RD1 , in each case independently, represents a hydrogen atom, 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, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R ^D1 groups combined to form a substituted or unsubstituted heterocyclic ring; or any of R ^2a and R ^2b , R ^4a and R ^4b , R ^7a and R ^7b , R ^11a and R ^11b , and R ^12a and R ^12b are combined to form an oxo group (=O);

each of R^15a, R^15b, R^16a and R^16b, in each occurrence independently, represents a hydrogen atom, halogen, cyano group, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, -OR^A1,-SR^A1, -N(R^A1)₂, -N(R^A1), -CN(R^A1)₂, -C(O)R^A1, -OC(=O)R^A1, -OC(=O)OR^A1, -OC(=O)SR^A1, -OC(=O)N(R^A1)₂, -SC(=O)R^A2, -SC(=O)OR^A1, -SC(=O)SR^A1, -SC(=O)N(R^A1)₂, -NHC(=O)R^A1, -NHC(=O)OR^A1, -NHC(=O)SR^A1, -NHC(=O)N(R^A1)₂, -OS(=O)₂R^A2, -OS(=O)₂OR^A1, -S-S(=O)₂R^A2, -S-S(=O)₂OR^A1, -S(=O)R^A2, -SO₂R^A2, or -S(=O)₂OR^A1, and R^A1, in each occurrence independently, represents a hydrogen atom, 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, oxygen protecting group , when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, -SO₂R^A2, -C(O)R^A2, or two R^A1-groups are combined to form a substituted or unsubstituted heterocyclic or heteroaryl ring; and R^A2 represents 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; And

and represents a single or double bond, provided that if a double bond is present in Ring B, then one of R ^6a or R ^6b and R ⁵ is missing.

[ 0166 ] It should be understood that the stereochemical configuration at C17 could be depicted in any of the following but equivalent ways:

Formula (II-I) Group R ^{2 a} and R ^{2 b}

[ 0167 ] In some aspects, R ^2a and R ^2b are, in each case independently, hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , -N(R ^D1 ) ₂ , or -NR ^D1 C(=O)R ^D1 , wherein R ^D1 , in each case independently, represents a hydrogen atom, 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.

[ 0168 ] In some aspects, R ^2a and R ^2b are, in each case independently, hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , or -N(R ^D1 ) ₂ , wherein ^RD1 is, in each case independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[ 0169 ] In some aspects, R ^2a and R ^2b , each independently, represent a hydrogen atom, substituted or unsubstituted alkyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , -N(R ^D1 ) ₂ , or -NR ^D1 C(=O)R ^D1 , wherein ^RD1 , in each case independently, represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[ 0170 ] In some aspects, both R ^2a and R ^2b represent a hydrogen atom.

[ 0171 ] In some embodiments, R ^2a and R ² are each independently a hydrogen atom or a substituted or unsubstituted alkyl.

[ 0172 ] In some embodiments, R ^2a and R ^2b each independently represent a hydrogen atom, a C ₁ -C ₆ alkyl, a C ₁ -C ₆ haloalkyl, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ haloalkoxy group, or -OH.

[ 0173 ] In some embodiments, R ^2a or R ^2b independently represents -CH ₃ , -CH ₂ CH ₃ , -OH, -OCH ₃ or -CH(CH ₃ ) ₂ .

Formula (II-I): Groups R ^4a and R ^4b

[ 0174 ] In some aspects, R ^4a and R ^4b are, in each case independently, hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkynyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , -N(R ^D1 ) ₂ , or -NR ^D1 C(=O)R ^D1 , wherein R ^D1 , in each case independently, represents a hydrogen atom, 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.

[ 0175 ] In some aspects, R ^4a and R ^4b , each independently, represent a hydrogen atom, a halogen, a cyano group, a hydroxyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , or -N(R ^D1 ) ₂ , wherein ^RD1 is, in each case independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[ 0176 ] In some aspects, R ^4a and R ^4b are, in each case independently, hydrogen, substituted or unsubstituted alkyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , -N(R ^D1 ) ₂ , or -NR ^D1 C(=O)R ^D1 , wherein ^RD1 , in each case independently, represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[ 0177 ] In some aspects, both R ^4a and R ^4b represent a hydrogen atom. In further embodiments, R ^16a and R ^16b , each independently, represent a hydrogen atom or a substituted or unsubstituted alkyl.

[ 0178 ] In some aspects, R ^4a and R ^4b independently represent a hydrogen atom, a C ₁ -C ₆ alkyl, a C ₁ -C ₆ haloalkyl, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ haloalkoxy group, or - HE. In some other aspects, R ^4a and R ^4b are -CH ₃ , -CH ₂ CH ₃ , -OH, -OCH ₃ or -CH(CH ₃ ) ₂ .

Formula (II-I): Groups R ^11a and R ^11b

[ 0179 ] In some embodiments, R ^11a and R ^11b , each independently, represent a hydrogen atom, a halogen, a cyano group, a hydroxyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted alkynyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , -N(R ^D1 ) ₂ , or -NR ^D1 C(=O)R ^D1 , wherein R ^D1 , in each case independently, represents a hydrogen atom, 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.

[ 0180 ] In certain additional embodiments, R ^11a and R ^11b , each independently, represent a hydrogen atom, a halogen, a cyano group, a hydroxyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , or -N(R ^D1 ) ₂ , wherein ^RD1 , in each case independently, represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[ 0181 ] In some aspects, R ^11a and R ^11b , in each case independently, represent a hydrogen atom, substituted or unsubstituted alkyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , -N(R ^D1 ) ₂ , or -NR ^D1 C(=O)R ^D1 , wherein ^RD1 , in each case independently, represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some aspects, both R ^11a and R ^11b represent a hydrogen atom.

[ 0182 ] In some aspects, R ^11a and R ^11b , each independently, represent a hydrogen atom or a substituted or unsubstituted alkyl. In some aspects, R ^11a and R ^11b independently represent a hydrogen atom, a C ₁ -C ₆ alkyl, a C ₁ -C ₆ haloalkyl, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ haloalkoxy group, or -OH.

[ 0183 ] In some aspects, R ^11a and R ^11b are -CH ₃ , -CH ₂ CH ₃ , -OH, -OCH ₃ or -CH(CH ₃ ) ₂ .

[ 0184 ] In some embodiments, R ^11a and R ^11b are combined to form an oxo group (=O).

Formula (II-I): Groups R ^15a and R ^15b

[ 0185 ] In some aspects, R ^15a and R ^15b , each independently, represent a hydrogen atom, a halogen, a cyano group, a hydroxyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted alkynyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , -N(R ^D1 ) ₂ , or -NR ^D1 C(=O)R ^D1 , wherein R ^D1 , in each case independently, represents a hydrogen atom, 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.

[ 0186 ] In some embodiments, R ^15a and R ^15b , each independently, represent a hydrogen atom, a halogen, a cyano group, a hydroxyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , or -N(R ^D1 ) ₂ , wherein ^RD1 is, in each case independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[ 0187 ] In some embodiments, R ^15a and R ^15b , each independently, represent a hydrogen atom, substituted or unsubstituted alkyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , -N(R ^D1 ) ₂ , or -NR ^D1 C(=O)R ^D1 , wherein ^RD1 , in each case independently, represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[ 0188 ] In some additional embodiments, both R ^15a and R ^15b represent a hydrogen atom.

[ 0189 ] In some aspects, R ^15a and R ^15b , each independently, represent a hydrogen atom or a substituted or unsubstituted alkyl. In some aspects, R ^15a and R ^15b independently represent a hydrogen atom, a C ₁ -C ₆ alkyl, a C ₁ -C ₆ haloalkyl, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ haloalkoxy group, or -OH. In some aspects, R ^15a and R ^15b are -CH ₃ , -CH ₂ CH ₃ , -OH, -OCH ₃ or -CH(CH ₃ ) ₂ .

Formula (II-I): Groups R ^16a and R ^16b

[ 0190 ] In some aspects, R ^16a and R ^16b , each independently, represent a hydrogen atom, a halogen, a cyano group, a hydroxyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted alkynyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , -N(R ^D1 ) ₂ , or -NR ^D1 C(=O)R ^D1 , wherein R ^D1 , in each case independently, represents a hydrogen atom, 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.

[ 0191 ] In some embodiments, R ^16a and R ^16b , each independently, represent a hydrogen atom, a halogen, a cyano group, a hydroxyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , or -N(R ^D1 ) ₂ , wherein ^RD1 is, in each case independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[ 0192 ] In some embodiments, R ^16a and R ^16b , each independently, represent a hydrogen atom, substituted or unsubstituted alkyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , -N(R ^D1 ) ₂ , or -NR ^D1 C(=O)R ^D1 , wherein ^RD1 , in each case independently, represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[ 0193 ] In some additional embodiments, both R ^16a and R ^16b represent a hydrogen atom.

[ 0194 ] In some aspects, R ^16a and R ^16b , each independently, represent a hydrogen atom or a substituted or unsubstituted alkyl. In some aspects, R ^16a and R ^16b independently represent a hydrogen atom, a C ₁ -C ₆ alkyl, a C ₁ -C ₆ haloalkyl, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ haloalkoxy group, or -OH.

[ 0195 ] In some aspects, R ^16a and R ^16b are -CH ₃ , -CH ₂ CH ₃ , -OH, -OCH ₃ or -CH(CH ₃ ) ₂ .

Formula (II-I): Groups R ^7a and R ^7b

[ 0196 ] In some aspects, R ^7a and R ^7b , each independently, represent a hydrogen atom, a halogen, a cyano group, a hydroxyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted alkynyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , -N(R ^D1 ) ₂ , or -NR ^D1 C(=O)R ^D1 , wherein R ^D1 , in each case independently, represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or any of R ^7a and R ^7b are combined to form an oxo group (=O).

[ 0197 ] In certain further embodiments, R ^7a and R ^7b are, in each case independently, hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , or -N(R ^D1 ) ₂ , wherein ^RD1 , in each case independently, represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[ 0198 ] In some aspects, R ^7a and R ^7b , in each case independently, represent a hydrogen atom, substituted or unsubstituted alkyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , -N(R ^D1 ) ₂ , or -NR ^D1 C(=O)R ^D1 , wherein ^RD1 , in each case independently, represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[ 0199 ] In some aspects, R ^7a and R ^7b are all hydrogen.

[ 0200 ] In some aspects, R ^7a and R ^7b , each independently, represent a hydrogen atom or a substituted or unsubstituted alkyl. In some aspects, R ^7a and R ^7b independently represent a hydrogen atom, a C ₁ -C ₆ alkyl, a C ₁ -C ₆ haloalkyl, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ haloalkoxy group, or -OH.

[ 0201 ] In some aspects, R ^7a and R ^7b are -CH ₃ , -CH ₂ CH ₃ , -OH, -OCH ₃ or -CH(CH ₃ ) ₂ .

[ 0202 ] In some embodiments, any of R ^7a and R ^7b are combined to form an oxo group (=O).

Formula (II-I): group R ⁵

[ 0203 ] In some aspects, R ⁵ represents a hydrogen atom in the cis position relative to the C19 position. In some other aspects, R ⁵ represents a hydrogen atom in the trans position relative to the C19 position. In some embodiments, R ⁵ is methyl in cis relative to the C19 position. In some additional embodiments, R ⁵ is methyl in the trans position relative to the C19 position.

Formula (II-I): group R ³

[ 0204 ] In some embodiments, R ³ represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.

[ 0205 ] In some embodiments, R ³ is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[ 0206 ] In some embodiments, R ³ is substituted or unsubstituted alkyl.

[ 0207 ] In some embodiments, R ³ represents a hydrogen atom. In some embodiments, R ³ is substituted alkyl (eg, -CH ₂ OMe or -CH ₂ OEt, etc.). In some embodiments, R ³ is unsubstituted alkyl. In some embodiments, R ³ is methyl.

Formula (II-I) group R ¹⁹

[ 0208 ] In some aspects, R ¹⁹ is C ₂ -C ₆ -alkyl. In some aspects, R ¹⁹ is C ₂ -C ₆ alkyl with deuterium substitution.

[ 0209 ] In some embodiments, R ¹⁹ is substituted C ₂ -C ₆ -alkyl. In some embodiments, R ¹⁹ is unsubstituted C ₂ -C ₆ -alkyl.

[ 0210 ] In some embodiments, R ¹⁹ is substituted C ₂ -C ₆ -alkenyl. In some embodiments, R ¹⁹ is unsubstituted C ₂ -C ₆ -alkenyl.

[ 0211 ] In some embodiments, R ¹⁹ is a substituted C ₂ -C ₆ -alkynyl. In some embodiments, R ¹⁹ is unsubstituted C ₂ -C ₆ alkynyl.

[ 0212 ] In some aspects, R ¹⁹ is ethyl.

Formula (II-I): group R ^6a and R ^6b

[ 0213 ] In some embodiments, R ^6a and R ^6b independently represent a hydrogen atom, a halogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, or a substituted or unsubstituted alkynyl.

[ 0214 ] In some embodiments, R ^6a and R ^6b independently represent a hydrogen atom or a substituted or unsubstituted alkyl.

[ 0215 ] In some aspects, R ^6a and R ^6b independently represent a hydrogen atom or a substituted alkyl. In some aspects, R ^6a and R ^6b independently represent a hydrogen atom or unsubstituted alkyl.

[ 0216 ] In some aspects, both R ^6a and R ^6b represent a hydrogen atom. In some aspects, R ^6a is halogen or alkyl, and R ^6b is a hydrogen atom. In some embodiments, both R ^6a and R ^6b are halogen.

[ 0217 ] In some aspects, both R ^6a and R ^6b are alkyl.

[ 0218 ] In some embodiments, R ^6a and R ^6b are combined to form an oxo group.

Formula (II-I) group R ^12a and R ^12b

[ 0219 ] In some aspects, R ^12a and R ^12b , each independently, represent a hydrogen atom, a halogen, a cyano group, a hydroxyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted alkynyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , -N(R ^D1 ) ₂ , or -NR ^D1 C(=O)R ^D1 , wherein R ^D1 , in each case independently, represents a hydrogen atom, 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.

[ 0220 ] In some embodiments, R ^12a and R ^12b , each independently, represent a hydrogen atom, a halogen, a cyano group, a hydroxyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , or -N(R ^D1 ) ₂ , wherein ^RD1 is, in each case independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[ 0221 ] In some embodiments, R ^12a and R ^12b , each independently, represent a hydrogen atom, substituted or unsubstituted alkyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , -N(R ^D1 ) ₂ , or -NR ^D1 C(=O)R ^D1 , wherein ^RD1 , in each case independently, represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[ 0222 ] In some embodiments, both R ^12a and R ^12b represent a hydrogen atom.

[ 0223 ] In certain further embodiments, R ^12a and R ^12b are each independently a hydrogen atom or a substituted or unsubstituted alkyl.

[ 0224 ] In some embodiments, R ^12a and R ^12b are combined to form an oxo group (=O).

Formula (II-I) group R ^17b

[ 0225 ] In some embodiments, R ^17b is fluorine, hydroxyl, methyl, or a hydrogen atom. In some additional embodiments, the hydrogen at R ^17b is replaced by deuterium.

Formula (II-I) t and n

[ 0226 ] In some embodiments, t is 1. In some other embodiments, t is 2. In some other embodiments, t is 3.

[ 0227 ] In some embodiments, n is 1. In some other embodiments, n is 2.

Formula (II-I) group R ¹

[ 0228 ] In some embodiments, R ¹ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[ 0229 ] In some embodiments, R ¹ represents

wherein R ₂₀ is, in each case independently, halogen, -NO ₂ , -CN, -OR ^GA , -N(R ^GA ) ₂ , -C(=O)R ^GA , -C(=O)OR ^GA , - OC(=O)R ^GA , -OC(=O)OR ^GA , -C(=O)N(R ^GA ) ₂ , -N(R ^GA )C(=O)R ^GA , -OC(=O) N(R ^GA ) ₂ , -N(R ^GA )C(=O)OR ^GA , -S(=O) ₂ R ^GA , -S(=O) ₂ OR ^GA , -OS(=O) ₂ R ^GA , -S(=O) ₂ N(R ^GA ) ₂ , or -N(R ^GA )S(=O) ₂ R ^GA ; substituted or unsubstituted C _1-6 -alkyl, substituted or unsubstituted C _2-6 -alkenyl, substituted or unsubstituted C _2-6 -alkynyl, substituted or unsubstituted C _3-4 -carbocyclyl, substituted or unsubstituted 3-4-membered heterocyclyl, substituted or unsubstituted C _5-10 -aryl, substituted or unsubstituted 5-10 membered heteroaryl, or optionally two R ^GA groups are linked by common atoms to form a substituted or unsubstituted 3-4 membered carbocyclic or heterocyclic ring; wherein R ^GA , in each instance independently, represents a hydrogen atom, 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 3-6 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group when attached to an oxygen atom, nitrogen protecting group when attached to a nitrogen atom, or two R ^GA groups linked common atoms to form a substituted or unsubstituted carbocyclic or heterocyclic ring; and e is 0, 1, 2, 3, 4, or 5, or n is 0, 1, 2, 3, 4, or 5.

[ 0230 ] In some embodiments in which R ¹ represents

wherein R ₂₀ is, in each case independently, halogen, -NO ₂ , -CN, -OR ^GA , -N(R ^GA ) ₂ , -C(=O)R ^GA , -C(=O)OR ^GA , - OC(=O)R ^GA , -OC(=O)OR ^GA , -C(=O)N(R ^GA ) ₂ , -N(R ^GA )C(=O)R ^GA , -OC(=O) N(R ^GA ) ₂ , -N(R ^GA )C(=O)OR ^GA , -S(=O) ₂ R ^GA , -S(=O) ₂ OR ^GA , -OS(=O) ₂ R ^GA , -S(=O) ₂ N(R ^GA ) ₂ , or -N(R ^GA )S(=O) ₂ R ^GA ; substituted or unsubstituted C _1-6 -alkyl, substituted or unsubstituted C _2-6 -alkenyl, substituted or unsubstituted C _2-6 -alkynyl, substituted or unsubstituted C _3-4 -carbocyclyl, substituted or unsubstituted 3-4-membered heterocyclyl, substituted or unsubstituted C _5-10 -aryl, substituted or unsubstituted 5-10 membered heteroaryl, or optionally two R ^GA groups are linked by common atoms to form a substituted or unsubstituted 3-4 membered carbocyclic or heterocyclic ring; wherein R ^GA , in each instance independently, represents a hydrogen atom, 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 3-6 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group when attached to an oxygen atom, nitrogen protecting group when attached to a nitrogen atom, or two R ^GA groups linked common atoms to form a substituted or unsubstituted carbocyclic or heterocyclic ring; and e is 0, 1, 2, 3, 4, or 5, and n is 0, 1, 2, 3, 4, or 5.

[ 0231 ] In some embodiments, R ¹ is a substituted carbocyclyl, substituted heterocyclyl, substituted aryl, or substituted heteroaryl, wherein each substituted carbocyclyl, substituted heterocyclyl, substituted aryl, or substituted heteroaryl is independently substituted with a substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[ 0232 ] In some embodiments, the compound of Formula ( II-I ) is a compound of Formula ( II-Ia )

or a pharmaceutically acceptable salt thereof.

[ 0233 ] In some embodiments, the compound of Formula ( II-I ) is a compound of Formula ( II-Ib )

or a pharmaceutically acceptable salt thereof.

[ 0234 ] In some embodiments, the compound of Formula ( II-I ) is a compound of Formula ( II-Ic )

or a pharmaceutically acceptable salt thereof.

[ 0235 ] In some embodiments, the compound of Formula ( II-I ) is a compound of Formula ( II-Ie )

in which m is 0, 1, 2 or 3; p is 0, 1, or 3; each R ₃₂ independently represents halogen, alkyl, hydroxyl or cyano;

or a pharmaceutically acceptable salt thereof.

[ 0236 ] In some embodiments, the compound of Formula ( II-I ) is a compound of Formula ( II-Ig )

wherein u is 0, 1, or 2; each X independently represents -C(R ^N )-, -C(R ^N ) ₂ -, -O-, -S-, -N-, or N(R ^N )-, wherein R ^N independently represents a hydrogen atom substituted or unsubstituted C _1-6 -alkyl, C(=O)R ^GA , -C(=O)OR ^GA , -C(=O)N(R ^GA ) ₂ , -S(=O) ₂ R ^GA , or -S(=O) ₂ N(R ^GA ) ₂ ; and R ^GA , in each instance independently, represents a hydrogen atom, 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 3-6 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group when attached to an oxygen atom, nitrogen protecting group when attached to a nitrogen atom, or two R ^GA groups linked common atoms to form a substituted or unsubstituted heterocyclic or heteroaryl ring; or a pharmaceutically acceptable salt thereof.

[ 0237 ] In some embodiments, the compound of Formula ( II-I ) is a compound of Formula ( II-Iga )

wherein u is 0, 1, or 2; each X independently represents -C(R ^N )-, -C(R ^N ) ₂ -, -O-, -S-, -N-, or N(R ^N )-, wherein R ^N independently represents a hydrogen atom substituted or unsubstituted C _1-6 -alkyl, C(=O)R ^GA , -C(=O)OR ^GA , -C(=O)N(R ^GA ) ₂ , -S(=O) ₂ R ^GA , or -S(=O) ₂ N(R ^GA ) ₂ ; and R ^GA , in each instance independently, represents a hydrogen atom, 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 3-6 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group when attached to an oxygen atom, nitrogen protecting group when attached to a nitrogen atom, or two R ^GA groups linked common atoms to form a substituted or unsubstituted heterocyclic or heteroaryl ring; or a pharmaceutically acceptable salt thereof.

[ 0238 ] In some embodiments, the compound of Formula ( II-I ) is a compound of Formula ( II-Ih )

wherein each R ₃₅ independently represents a halogen, alkyl, hydroxyl or cyano group; and r is 0, 1, 2 or 3; or a pharmaceutically acceptable salt thereof.

[ 0239 ] In some embodiments, the compound of Formula ( II-I ) is a compound of Formula ( II-Ii )

in which s is 0, 1, or 2; each X independently represents -C(R ^N )-, -C(R ^N ) ₂ -, -O-, -S-, -N-, or N(R ^N )-, wherein R ^N independently represents a hydrogen atom substituted or unsubstituted C _1-6 -alkyl, C(=O)R ^GA , -C(=O)OR ^GA , -C(=O)N(R ^GA ) ₂ , -S(=O) ₂ R ^GA , or -S(=O) ₂ N(R ^GA ) ₂ ; And

R ^GA , in each instance independently, represents a hydrogen atom, 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 3-6 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group when attached to an oxygen atom, nitrogen protecting group when attached to a nitrogen atom, or two R ^GA groups linked by common atoms to form a substituted or unsubstituted heterocyclic or heteroaryl ring; or a pharmaceutically acceptable salt thereof.

[ 0240 ] In some embodiments, the compound is selected from the group consisting of compounds identified below in Table II-I :

Connections

[ 0241 ] In some embodiments, a compound of Formula ( III-I ) is presented here

or a pharmaceutically acceptable salt thereof;

in which:

n is 0, 1 or 2;

R ^3a represents substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R ¹⁸ represents substituted alkyl, or unsubstituted C ₂ -C ₆ -alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl;

R ¹⁹ represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted C ₂ -C ₆ -alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl;

R ⁵ represents a hydrogen atom or methyl, or when represents a double bond, R ⁵ absent;

each of R ^6a and R ^6b independently represents a hydrogen atom, a halogen, a cyano group, a hydroxyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, or a substituted or unsubstituted alkynyl, or R ^6a and R ^6b are combined to form an oxo group (=O);

R ¹ represents substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, -OR ^A1 , -SR ^A1 , -N( R ^A1 ) ₂ , -N(R ^A1 ), -OC(=O)R ^A1 , -OC(=O)OR ^A1 , -OC(=O)SR ^A1 , -OC(=O)N(R ^A1 ) ₂ , -SC(=O)R ^A2 , -SC(=O)OR ^A1 , -SC(=O)SR ^A1 , -SC(=O)N(R ^A1 ) ₂ , -NHC(=O)R ^A1 , -NHC(=O)OR ^A1 , -NHC(=O)SR ^A1 , -NHC(=O)N(R ^A1 ) ₂ , -OS(=O) ₂ R ^A2 , -OS(=O) ₂ OR ^A1 , -SS(=O) ₂ R ^A2 , -SS(=O) ₂ OR ^A1 , -S(=O)R ^A2 , -SO ₂ R ^A2 , or -S(=O) ₂ OR ^A1 , and R ^A1 , in each occurrence independently, represents a hydrogen atom, 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, a protecting group for oxygen when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R ^GA groups are combined to form a substituted or unsubstituted heterocyclic or heteroaryl ring; and R ^A2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

each of 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 ^15a , R ^15b , R ^16a , or ^{R 16b} independently represents a hydrogen atom, halogen, cyano group, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , - N(R ^D1 ) ₂ , or -NR ^D1 C(=O)R ^D1 , wherein R ^D1 , in each case independently, represents a hydrogen atom, 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, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R ^D1 groups combined to form a substituted or unsubstituted heterocyclic core; or any of R ^2a and R ^2b , R ^4a and R ^4b , R ^7a and R ^7b , R ^11a and R ^11b , and R ^12a and R ^12b are combined to form an oxo group (=O); And

and represents a single or double bond, provided that if a double bond is present in Ring B, then one of R ^6a or R ^6b is missing.

[ 0242 ] In some embodiments, a compound of Formula ( III-II ) is presented here

or a pharmaceutically acceptable salt thereof;

with variable values R ¹⁸ , n, R ⁵ , R ¹ , R ^1a , R ^1b , R ^2a , R ^2b , R 4a, R ^4b , R ^6a , R ^6b , R ^7a , ^{R 7b ,} R ^11a , R ^11b , R ^12a , R ^12b , R ^15a , R ^15b , R ^16a and R ^16b are defined as above in Formula III-I ; And

R ^3a represents a hydrogen atom, 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; And

R ¹⁹ represents a hydrogen atom, substituted C ₁ -C ₆ -alkyl, unsubstituted C ₂ -C ₆ -alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl;

provided that if n is 0, R ¹ is methyl, and R ^1a , R ^1b , R ^2a , R ^2b , R ^4a , R ^4b , R 6a, R ^6b , R ^7a , ^{R 7b ,} R ^11a , R ^11b , R ^12a , R ^12b , R ^15a , R ^15b , R ^16a and R ^16b represent a hydrogen atom, then R ¹⁸ represents a substituted C ₁ -C ₆ alkyl, unsubstituted C ₃ -C ₆ alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and if R ¹⁸ is substituted methyl, then the methyl is substituted with a halogen atom, -CN, -NO ₂ , -SO ₂ H, -SO ₃ H, -OR ^aa , -ON(R ^bb ) ₂ , - N(R ^bb ) ₂ , -C(=O)R ^aa , -C(O)H, -CO ₂ H, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein R ^aa is, in each case independently, selected from C _{1 -10} -alkyl, C _1-10 -haloalkyl, C _2-10 -alkenyl, C _2-10 -alkynyl, C _3-10 -carbocyclyl, 3-14-membered heterocyclyl, C _6-14 -aryl, and 5- 14-membered heteroaryl, or two R ^aa groups are combined to form a 3-14 membered heterocyclyl, or 5-14 membered heteroaryl, and R ^bb , in each case independently, is selected from hydrogen, -OH, -OR ^aa . -N(R ^cc ) ₂ , -CN, -C(=O)R ^aa , -C(=O)N(R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , or -C(= NR ^cc )OR ^aa .

Formula (III-I) and Formula (III-II) Group R ¹⁸

[ 0243 ] In some aspects, R ¹⁸ is alkyl substituted with a halogen atom, cyano group, -CO ₂ H or phenyl.

[ 0244 ] In some embodiments, R ¹⁸ is substituted or unsubstituted C _2-6 alkyl.

[ 0245 ] In some embodiments, R ¹⁸ is -CH(CH ₃ ) ₂ .

[ 0246 ] In some embodiments, R ¹⁸ is substituted alkyl. In some embodiments, the alkyl is substituted with a -OCH ₃ , -CH ₂ CN, or -OCH(CH ₃ ) ₂ group.

[ 0247 ] In some embodiments, R ¹⁸ is propyl, butyl, t-butyl, or isopropyl, or ethyl.

Formula (III-I) and Formula (III-II) Groups R ^1a and R ^1b

[ 0248 ] In some aspects, R ^1a and R ^1b , each independently, represent a hydrogen atom, a halogen, a cyano group, a hydroxyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted alkynyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , -N(R ^D1 ) ₂ , or -NR ^D1 C(=O)R ^D1 , wherein R ^D1 , in each case independently, represents a hydrogen atom, 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.

[ 0249 ] In some aspects, R ^1a and R ^1b , each independently, represent a hydrogen atom, a halogen, a cyano group, a hydroxyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , or -N(R ^D1 ) ₂ , wherein ^RD1 is, in each case independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[ 0250 ] In some aspects, R ^1a and R ^1b , in each case independently, represent a hydrogen atom, substituted or unsubstituted alkyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , -N(R ^D1 ) ₂ , or -NR ^D1 C(=O)R ^D1 , wherein ^RD1 , in each case independently, represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[ 0251 ] In some aspects, both R ^1a and R ^1b represent a hydrogen atom.

[ 0252 ] In some embodiments, R ^1a and R ^1b , each independently, represent a hydrogen atom or a substituted or unsubstituted alkyl.

[ 0253 ] In some embodiments, R ^1a and R ^1b independently represent a hydrogen atom, a C ₁ -C ₆ alkyl, a C ₁ -C ₆ haloalkyl, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ haloalkoxy group, or -HE.

In some embodiments, R ^1a and R ^1b are -CH ₃ , -CH ₂ CH ₃ , -OH, -OCH ₃ or -CH(CH ₃ ) ₂ .

Formula (III-I) and Formula (III-II) Groups R ^2a and R ^2b

[ 0254 ] In some aspects, R ^2a and R ^2b are, in each instance independently, a hydrogen atom, a halogen, a cyano group, a hydroxyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted alkynyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , -N(R ^D1 ) ₂ , or -NR ^D1 C(=O)R ^D1 , wherein R ^D1 , in each case independently, represents a hydrogen atom, 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.

[ 0255 ] In some aspects, R ^2a and R ^2b are, in each case independently, a hydrogen atom, a halogen, a cyano group, a hydroxyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , or -N(R ^D1 ) ₂ , wherein ^RD1 is, in each case independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[ 0256 ] In some aspects, R ^2a and R ^2b , each independently, represent a hydrogen atom, substituted or unsubstituted alkyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , -N(R ^D1 ) ₂ , or -NR ^D1 C(=O)R ^D1 , wherein ^RD1 , in each case independently, represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[ 0257 ] In some aspects, both R ^2a and R ^2b represent a hydrogen atom.

[ 0258 ] In some embodiments, R ^2a and R ^2b , each independently, represent a hydrogen atom or a substituted or unsubstituted alkyl.

[ 0259 ] In some embodiments, R ^2a and R ^2b independently represent a hydrogen atom, a C ₁ -C ₆ alkyl, a C ₁ -C ₆ haloalkyl, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ haloalkoxy group, or -HE.

[ 0260 ] In some embodiments, R ^2a and R ^2b are -CH ₃ , -CH ₂ CH ₃ , -OH, -OCH ₃ or -CH(CH ₃ ) ₂ .

Formula (III-I) and Formula (III-II) Groups R ^4a and R ^4b

[ 0261 ] In some aspects, R ^4a and R ^4b , each independently, represent a hydrogen atom, a halogen, a cyano group, a hydroxyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted heterocyclyl, or a substituted or unsubstituted alkynyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , -N(R ^D1 ) ₂ , or -NR ^D1 C(=O)R ^D1 , wherein R ^D1 , in each case independently, represents a hydrogen atom, 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.

[ 0262 ] In some aspects, R ^4a and R ^4b are, in each case independently, hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , or -N(R ^D1 ) ₂ , wherein ^RD1 is, in each case independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[ 0263 ] In some aspects, R ^4a and R ^4b are, in each case independently, hydrogen, substituted or unsubstituted alkyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , -N(R ^D1 ) ₂ , or -NR ^D1 C(=O)R ^D1 , wherein ^RD1 , in each case independently, represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[ 0264 ] In some aspects, both R ^4a and R ^4b represent a hydrogen atom. In further embodiments, R ^4a and R ^4b , each independently, represent a hydrogen atom or a substituted or unsubstituted alkyl.

[ 0265 ] In some aspects, R ^4a and R ^4b independently represent a hydrogen atom, a C ₁ -C ₆ alkyl, a C ₁ -C ₆ haloalkyl, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ haloalkoxy group, or - HE. In certain other aspects, R ^4a and R ^4b are -CH ₃ , -CH ₂ CH ₃ , -OH, -OCH ₃ or -CH(CH ₃ ) ₂ .

Formula (III-I) and Formula (III-II) Groups R ^11a and R ^11b

[ 0266 ] In some embodiments, R ^11a and R ^11b , each independently, represent a hydrogen atom, a halogen, a cyano group, a hydroxyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted heterocyclyl, or a substituted or unsubstituted alkynyl, - OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , -N(R ^D1 ) ₂ , or -NR ^D1 C(=O)R ^D1 , wherein R ^D1 , in each case independently, represents a hydrogen atom 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.

[ 0267 ] In certain additional embodiments, R ^11a and R ^11b are, in each case independently, hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , or -N(R ^D1 ) ₂ , wherein ^RD1 , in each case independently, represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[ 0268 ] In some aspects, R ^11a and R ^11b , in each case independently, represent a hydrogen atom, substituted or unsubstituted alkyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , -N(R ^D1 ) ₂ , or -NR ^D1 C(=O)R ^D1 , wherein ^RD1 , in each case independently, represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some aspects, both R ^11a and R ^11b represent a hydrogen atom.

[ 0269 ] In some aspects, R ^11a and R ^11b , each independently, represent a hydrogen atom or a substituted or unsubstituted alkyl. In some aspects, R ^11a and R ^11b independently represent a hydrogen atom, a C ₁ -C ₆ alkyl, a C ₁ -C ₆ haloalkyl, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ haloalkoxy group, or -OH.

[ 0270 ] In certain other aspects, R ^11a and R ^11b are -CH ₃ , -CH ₂ CH ₃ , -OH, -OCH ₃ or -CH(CH ₃ ) ₂ .

[ 0271 ] In some embodiments, R ^11a and R ^11b are combined to form an oxo group (=O).

Formula (III-I) and Formula (III-II) Groups R ^15a and R ^15b

[ 0272 ] In some embodiments, R ^15a and R ^15b , each independently, represent a hydrogen atom, a halogen, a cyano group, a hydroxyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted heterocyclyl, or a substituted or unsubstituted alkynyl, - OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , -N(R ^D1 ) ₂ , or -NR ^D1 C(=O)R ^D1 , wherein R ^D1 , in each case independently, represents a hydrogen atom 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.

[ 0273 ] In some embodiments, R ^15a and R ^15b , each independently, represent a hydrogen atom, a halogen, a cyano group, a hydroxyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , or -N(R ^D1 ) ₂ , wherein ^RD1 is, in each case independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[ 0274 ] In some embodiments, R ^15a and R ^15b , each independently, represent a hydrogen atom, substituted or unsubstituted alkyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , -N(R ^D1 ) ₂ , or -NR ^D1 C(=O)R ^D1 , wherein ^RD1 , in each case independently, represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[ 0275 ] In some additional embodiments, both R ^15a and R ^15b represent a hydrogen atom.

[ 0276 ] In some aspects, R ^15a and R ^15b , each independently, represent a hydrogen atom or a substituted or unsubstituted alkyl. In some aspects, R ^15a and R ^15b independently represent a hydrogen atom, a C ₁ -C ₆ alkyl, a C ₁ -C ₆ haloalkyl, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ haloalkoxy group, or -OH. In some aspects, R ^15a and R ^15b are -CH ₃ , -CH ₂ CH ₃ , -OH, -OCH ₃ or -CH(CH ₃ ) ₂ .

Formula (III-I) and Formula (III-II) Groups R ^16a and R ^16b

[ 0277 ] In some aspects, R ^16a and R ^16b , each independently, represent a hydrogen atom, a halogen, a cyano group, a hydroxyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted heterocyclyl, or a substituted or unsubstituted alkynyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , -N(R ^D1 ) ₂ , or -NR ^D1 C(=O)R ^D1 , wherein R ^D1 , in each case independently, represents a hydrogen atom, 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.

[ 0278 ] In some embodiments, R ^16a and R ^16b , each independently, represent a hydrogen atom, a halogen, a cyano group, a hydroxyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , or -N(R ^D1 ) ₂ , wherein ^RD1 is, in each case independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[ 0279 ] In some embodiments, R ^16a and R ^16b , each independently, represent a hydrogen atom, substituted or unsubstituted alkyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , -N(R ^D1 ) ₂ , or -NR ^D1 C(=O)R ^D1 , wherein ^RD1 , in each case independently, represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[ 0280 ] In some additional embodiments, both R ^16a and R ^16b represent a hydrogen atom.

[ 0281 ] In some aspects, R ^16a and R ^16b , each independently, represent a hydrogen atom or a substituted or unsubstituted alkyl. In some aspects, R ^16a and R ^16b independently represent a hydrogen atom, a C ₁ -C ₆ alkyl, a C ₁ -C ₆ haloalkyl, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ haloalkoxy group, or -OH.

[ 0282 ] In some aspects, R ^16a and R ^16b are -CH ₃ , -CH ₂ CH ₃ , -OH, -OCH ₃ or -CH(CH ₃ ) ₂ .

Formula (III-I) and Formula (III-II) Groups R ^7a and R ^7b

[ 0283 ] In some embodiments, R ^7a and R ^7b , each independently, represent a hydrogen atom, a halogen, a cyano group, a hydroxyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted heterocyclyl, or a substituted or unsubstituted alkynyl, - OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , -N(R ^D1 ) ₂ , or -NR ^D1 C(=O)R ^D1 , wherein R ^D1 , in each case independently, represents a hydrogen atom substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or any of R ^7a and R ^7b are combined to form an oxo group ( =O).

[ 0284 ] In certain further embodiments, R ^7a and R ^7b are, in each case independently, hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , or -N(R ^D1 ) ₂ , wherein ^RD1 , in each case independently, represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[ 0285 ] In some aspects, R ^7a and R ^7b , in each case independently, represent a hydrogen atom, substituted or unsubstituted alkyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , -N(R ^D1 ) ₂ , or -NR ^D1 C(=O)R ^D1 , wherein ^RD1 , in each case independently, represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[ 0286 ] In some aspects, R ^7a and R ^7b are all hydrogen.

[ 0287 ] In some aspects, R ^7a and R ^7b , each independently, represent a hydrogen atom or a substituted or unsubstituted alkyl. In some aspects, R ^7a and R ^7b independently represent a hydrogen atom, a C ₁ -C ₆ alkyl, a C ₁ -C ₆ haloalkyl, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ haloalkoxy group, or -OH.

[ 0288 ] In some aspects, R ^7a and R ^7b are -CH ₃ , -CH ₂ CH ₃ , -OH, -OCH ₃ or -CH(CH ₃ ) ₂ .

[ 0289 ] In some embodiments, any of R ^7a and R ^7b are combined to form an oxo group (=O).

Formula (III-I) and Formula (III-II) Group R ⁵

[ 0290 ] In some aspects, R ⁵ represents a hydrogen atom in the cis position relative to the C19 position. In some other aspects, R ⁵ represents a hydrogen atom in the trans position relative to the C19 position. In some embodiments, R ⁵ is methyl in cis relative to the C19 position. In some additional embodiments, R ⁵ is methyl in the trans position relative to the C19 position.

Formula (III-I) and Formula (III-II) Group R ^3a

[ 0291 ] In some embodiments, R ^3a represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.

[ 0292 ] In some embodiments, R ^3a is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[ 0293 ] In some embodiments, R ^3a is substituted or unsubstituted alkyl.

[ 0294 ] In some embodiments, R ^3a represents a hydrogen atom. In some embodiments, R ^3a is a substituted alkyl (eg, -CH ₂ OMe or -CH ₂ OEt, etc.). In some embodiments, R ^3a is unsubstituted alkyl. In some embodiments, R ^3a is methyl.

[ 0295 ] In some aspects, R ^3a is not trifluoromethyl.

Formula (III-I) and Formula (III-II) Group R ¹⁹

[ 0296 ] In some aspects, R ¹⁹ is substituted alkyl. In some aspects, R ¹⁹ is unsubstituted alkyl.

[ 0297 ] In some aspects, R ¹⁹ is C ₂ -C ₆ -alkyl. In some embodiments, R ¹⁹ represents a hydrogen atom. In some aspects, R ¹⁹ is C ₂ -C ₆ alkyl with deuterium substitution.

[ 0298 ] In some embodiments, R ¹⁹ is substituted C ₂ -C ₆ -alkyl. In some embodiments, R ¹⁹ is unsubstituted C ₂ -C ₆ -alkyl.

[ 0299 ] In some embodiments, R ¹⁹ is substituted C ₂ -C ₆ -alkenyl. In some embodiments, R ¹⁹ is unsubstituted C ₂ -C ₆ -alkenyl.

[ 0300 ] In some embodiments, R ¹⁹ is a substituted C ₂ -C ₆ -alkynyl. In some embodiments, R ¹⁹ is unsubstituted C ₂ -C ₆ alkynyl.

[ 0301 ] In some aspects, R ¹⁹ is ethyl.

Formula (III-I) and Formula (III-II) Groups R ^6a and R ^6b

[ 0302 ] In some embodiments, R ^6a and R ^6b independently represent a hydrogen atom, a halogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, or a substituted or unsubstituted alkynyl.

[ 0303 ] In some aspects, R ^6a and R ^6b independently represent a hydrogen atom or a substituted or unsubstituted alkyl.

[ 0304 ] In some aspects, R ^6a and R ^6b independently represent a hydrogen atom or a substituted alkyl. In some aspects, R ^6a and R ^6b independently represent a hydrogen atom or unsubstituted alkyl.

[ 0305 ] In some aspects, both R ^6a and R ^6b represent a hydrogen atom. In some aspects, R ^6a is halogen or alkyl, and R ^6b is a hydrogen atom. In some embodiments, both R ^6a and R ^6b are halogen.

[ 0306 ] In some aspects, both R ^6a and R ^6b are alkyl.

[ 0307 ] In some embodiments, R ^6a and R ^6b are combined to form an oxo group.

Formula (III-I) and Formula (III-II) Groups R ^12a and R ^12b

[ 0308 ] In some aspects, R ^12a and R ^12b are, in each instance independently, hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkynyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , -N(R ^D1 ) ₂ , or -NR ^D1 C(=O)R ^D1 , wherein R ^D1 , in each case independently, represents a hydrogen atom, 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.

[ 0309 ] In some aspects, R ^12a and R ^12b , each independently, represent a hydrogen atom, a halogen, a cyano group, a hydroxyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , or -N(R ^D1 ) ₂ , wherein ^RD1 is, in each case independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[ 0310 ] In some embodiments, R ^12a and R ^12b , each independently, represent a hydrogen atom, substituted or unsubstituted alkyl, -OR ^D1 , -OC(=O)R ^D1 , -NH ₂ , -N(R ^D1 ) ₂ , or -NR ^D1 C(=O)R ^D1 , wherein ^RD1 , in each case independently, represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[ 0311 ] In some embodiments, both R ^12a and R ^12b represent a hydrogen atom.

[ 0312 ] In certain further embodiments, R ^12a and R ^12b are each independently a hydrogen atom or a substituted or unsubstituted alkyl.

[ 0313 ] In some embodiments, R ^12a and R ^12b are combined to form an oxo group (=O).

Formula (III-I) and Formula (III-II) Groups n

[ 0314 ] In some embodiments, n is 1. In some other embodiments, n is 2.

[ 0315 ] In some embodiments, n is 0. In some embodiments, n is 1. In some other embodiments, n is 2.

Formula (III-I) and Formula (III-II) Groups R ¹

[ 0316 ] In some embodiments, R ¹ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[ 0317 ] In some embodiments, R ¹ represents

wherein R ₂₀ is, in each case independently, halogen, -NO ₂ , -CN, -OR ^GA , -N(R ^GA ) ₂ , -C(=O)R ^GA , -C(=O)OR ^GA , - OC(=O)R ^GA , -OC(=O)OR ^GA , -C(=O)N(R ^GA ) ₂ , -N(R ^GA )C(=O)R ^GA , -OC(=O) N(R ^GA ) ₂ , -N(R ^GA )C(=O)OR ^GA , -S(=O) ₂ R ^GA , -S(=O) ₂ OR ^GA , -OS(=O) ₂ R ^GA , -S(=O) ₂ N(R ^GA ) ₂ , or -N(R ^GA )S(=O) ₂ R ^GA ; substituted or unsubstituted C _1-6 -alkyl, substituted or unsubstituted C _2-6 -alkenyl, substituted or unsubstituted C _2-6 -alkynyl, substituted or unsubstituted C _3-6 -carbocyclyl, substituted or unsubstituted 3-6-membered heterocyclyl, substituted or unsubstituted C _5-10 -aryl, substituted or unsubstituted 5-10 membered heteroaryl, or optionally two R ^GA groups are linked by common atoms to form a substituted or unsubstituted 3-4 membered carbocyclic or heterocyclic ring; wherein R ^GA , in each instance independently, represents a hydrogen atom, 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 3-6 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group when attached to an oxygen atom, nitrogen protecting group when attached to a nitrogen atom, or two R ^GA groups linked common atoms to form a substituted or unsubstituted carbocyclic or heterocyclic ring; and e is 0, 1, 2, 3, 4, or 5, or n is 0, 1, 2, 3, 4, or 5.

[ 0318 ] In some embodiments in which R ¹ represents

wherein R ₂₀ is, in each case independently, halogen, -NO ₂ , -CN, -OR ^GA , -N(R ^GA ) ₂ , -C(=O)R ^GA , -C(=O)OR ^GA , - OC(=O)R ^GA , -OC(=O)OR ^GA , -C(=O)N(R ^GA ) ₂ , -N(R ^GA )C(=O)R ^GA , -OC(=O) N(R ^GA ) ₂ , -N(R ^GA )C(=O)OR ^GA , -S(=O) ₂ R ^GA , -S(=O) ₂ OR ^GA , -OS(=O) ₂ R ^GA , -S(=O) ₂ N(R ^GA ) ₂ , or -N(R ^GA )S(=O) ₂ R ^GA ; substituted or unsubstituted C _1-6 -alkyl, substituted or unsubstituted C _2-6 -alkenyl, substituted or unsubstituted C _2-6 -alkynyl, substituted or unsubstituted C _3-6 -carbocyclyl, substituted or unsubstituted 3-6-membered heterocyclyl, substituted or unsubstituted C _5-10 -aryl, substituted or unsubstituted 5-10 membered heteroaryl, or optionally two R ^GA groups are linked by common atoms to form a substituted or unsubstituted 3-4 membered carbocyclic or heterocyclic ring; wherein R ^GA , in each instance independently, represents a hydrogen atom, 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 3-6 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group when attached to an oxygen atom, nitrogen protecting group when attached to a nitrogen atom, or two R ^GA groups linked common atoms to form a substituted or unsubstituted carbocyclic or heterocyclic ring; and e is 0, 1, 2, 3, 4, or 5.

[ 0319 ] In some embodiments, the compound of Formula ( III-I ) or ( III-II ) is a compound of Formula ( III-Ia )

or a pharmaceutically acceptable salt thereof.

[ 0320 ] In some embodiments, the compound of Formula ( III-I ) or ( III-II ) is a compound of Formula ( III-Ib )

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula ( III-I ) or ( III-II ) is a compound of Formula ( III-Ie )

in which m is 0, 1, 2 or 3;

p is 0, 1, or 3;

each R ₃₂ independently represents halogen, alkyl, hydroxyl or cyano;

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula ( III-I ) or ( III-II ) is a compound of Formula ( III-Ig )

wherein u is 0, 1, or 2; each X independently represents -C(R ^N )-, -C(R ^N ) ₂ -, -O-, -S-, -N-, or N(R ^N )-, wherein R ^N independently represents a hydrogen atom substituted or unsubstituted C _1-6 -alkyl, C(=O)R ^GA , -C(=O)OR ^GA , -C(=O)N(R ^GA ) ₂ , -S(=O) ₂ R ^GA , or -S(=O) ₂ N(R ^GA ) ₂ ; and R ^GA , in each instance independently, represents a hydrogen atom, 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 3-6 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group when attached to an oxygen atom, nitrogen protecting group when attached to a nitrogen atom, or two R ^GA groups linked common atoms to form a substituted or unsubstituted heterocyclic or heteroaryl ring;

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula ( III-I ) or ( III-II ) is a compound of Formula ( III-Ih )

wherein each R ₃₅ independently represents a halogen, alkyl, hydroxyl or cyano group; and r is 0, 1, 2 or 3;

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula ( III-I ) or ( III-II ) is a compound of Formula ( III-Ii )

in which s is 0, 1, or 2; each X independently represents -C(R ^N )-, -C(R ^N ) ₂ -, -O-, -S-, -N-, or N(R ^N )-, wherein R ^N independently represents a hydrogen atom substituted or unsubstituted C _1-6 -alkyl, C(=O)R ^GA , -C(=O)OR ^GA , -C(=O)N(R ^GA ) ₂ , -S(=O) ₂ R ^GA , or -S(=O) ₂ N(R ^GA ) ₂ ; And

R ^GA , in each instance independently, represents a hydrogen atom, 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 3-6 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group when attached to an oxygen atom, nitrogen protecting group when attached to a nitrogen atom, or two R ^GA groups linked by common atoms to form a substituted or unsubstituted heterocyclic or heteroaryl ring;

or a pharmaceutically acceptable salt thereof.

[ 0321 ] In some embodiments, the compound is selected from the group consisting of the compounds identified herein below in Table III-I :

[ 0322 ] In one aspect, provided herein is a pharmaceutically acceptable salt of a compound described herein ( e.g. , a compound of Formula (IX , II , II-I , III-1, or III-2)

[ 0323 ] In one aspect, provided herein is a pharmaceutically acceptable composition comprising a compound described herein ( e.g. , a compound of Formula (IX , II , II-I , III-I, or III-II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient .

[ 0324 ] In certain embodiments, a compound of the present invention is included in a pharmaceutical composition in an effective amount. In certain embodiments, a compound of the present invention is administered in a therapeutically effective amount. In certain embodiments, a compound of the present invention is administered in a prophylactically effective amount.

[ 0325 ] The compounds of the present invention, as described herein, act, in certain embodiments, as GABA _A modulators, for example , by affecting the GABA _A receptor in a positive or negative manner. As modulators of central nervous system (CNS) excitability, facilitated by their ability to modulate the GABA _A receptor, such compounds are proposed to have CNS activity.

[ 0326 ] Thus, in yet another aspect, methods are provided for treating a CNS-related disease 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 cognitive impairment, a movement disorder, personality changes, an autism spectrum disorder, pain, traumatic brain injury, vascular disease, Substance abuse disorders, and/or withdrawal symptoms, tinnitus, or status epilepticus. In certain embodiments, the CNS-related disease is depression. In certain embodiments, the CNS-related disease is postpartum depression. In certain embodiments, the CNS-related disease is major depressive disorder. In certain embodiments, the major depressive disorder is a moderate form of major depressive disorder. In certain embodiments, the major depressive disorder is a severe form of 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, such as by continuous intravenous infusion.

[ 0327 ] Exemplary compounds of the invention can be synthesized from the following known starting materials using methods known to one skilled in the art or by following certain literature. In one aspect, provided herein is a pharmaceutically acceptable salt of a compound described herein ( eg , a compound of Formula (IX , II , II-I , III-I , or III-II).

Alternative embodiments of the invention

[ 0328 ] In one alternative embodiment, the compounds described herein may also include one or more isotopic substituents. For example, hydrogen may be ² H (D, or deuterium) or ³ H (T, or tritium), for example, carbon may be ¹³ C or ¹⁴ C; for example, oxygen can be ¹⁸ O; for example, nitrogen may be ¹⁵ N, and the like. In other embodiments, a particular isotope (for example, ³ H, ¹³ C, ¹⁴ C, ¹⁸ O, or ¹⁵ N) may be present in an amount of 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 composition of the element that occupies a given location in the compound.

Pharmaceutical compositions

[ 0329 ] In one aspect, provided herein is a pharmaceutical composition comprising a compound described herein ( e.g. , a compound of Formula (IX , II , II-I , III-I , or III-II )) , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient . In certain embodiments, a compound of the present invention is included in a pharmaceutical composition in an effective amount. In certain embodiments, a compound of the present invention is administered in a therapeutically effective amount. In certain embodiments, a compound of the present invention is administered in a prophylactically effective amount.

[ 0330 ] In certain embodiments, the pharmaceutical composition includes an effective amount of an active ingredient. In certain embodiments, the pharmaceutical composition includes a therapeutically effective amount of an active ingredient.

[ 0331 ] The pharmaceutical composition provided herein can be administered by a variety of routes, including, but not limited to, oral (enteral) administration, parenteral (injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration , intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration.

[ 0332 ] Typically, the compounds presented herein are administered in an effective amount. The amount of compound actually administered will generally be determined by the physician, taking into account relevant circumstances, including the condition being treated, the route of administration chosen, the actual compound administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.

[ 0333 ] When used to prevent the onset of a CNS disorder, the compounds presented herein will be administered to a subject at risk of developing the condition, typically under the advice and supervision of a physician at the dosage levels described above. Subjects at risk for developing a particular condition typically include those who have a family history of the condition or those who have been identified by genetic testing or screening as particularly susceptible to developing the condition.

[ 0334 ] The pharmaceutical compositions presented herein can also be administered over a long period of time (“chronic administration”). Chronic administration refers to the administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g. , for 3 months, 6 months, 1 year, 2 years, 3 years, 5 years , etc. , or may continue indefinitely, e.g. , for the rest of the subject's life. In certain embodiments, chronic administration is contemplated to provide a constant blood level of the compound, eg , within a therapeutic window, over an extended period of time.

[ 0335 ] In addition, the pharmaceutical compositions provided herein can be delivered using a variety of dosing methods. For example, in certain embodiments, the pharmaceutical composition may be given as a bolus, for example , to increase the concentration of a compound in the blood to an effective level. The placement of a bolus dose depends on the systemic levels of active ingredient desired by the body, for example , an intramuscular or subcutaneous bolus dose allows for slow release of the active ingredient, whereas bolus delivery directly into a vein ( eg , intravenous (IV) infusion) allows for significantly faster delivery. , which quickly increases the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition may be administered by continuous infusion, for example , intravenously through an IV, to ensure that a steady-state concentration of the active ingredient is maintained in the subject. Additionally, in other additional embodiments, the pharmaceutical composition may be administered first as a bolus dose and then as a continuous infusion. Compositions for oral administration may be in the form of bulk liquid solutions or suspensions or bulk powders. More commonly, however, the compositions are provided in unit dosage forms to facilitate accurate dosing. The term "unit dosage forms" refers to physically discrete units suitable as unit dosages for human patients and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect, in combination with a suitable pharmaceutical excipient. Typical unit dosage forms include ampoules or syringes pre-filled with liquid compositions of a predetermined volume, or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the compound typically constitutes a minor component (from about 0.1 to about 50% by weight, or preferably from about 1 to about 40% by weight), with the balance being comprised of various carriers or excipients and processing aids. to form the desired dosage form.

[ 0336 ] For oral administration, typical regimens are one to five, particularly two to four, and typically three oral doses per day. When using such dosage regimens, each dose delivers from about 0.01 to about 20 mg/kg of the compound provided herein, with preferred doses delivering in each case from about 0.1 to about 10 mg/kg, and in particular, from about 1 to about 5 mg/kg.

[ 0337 ] Transdermal dosages are generally selected to achieve similar or lower blood levels than those achieved using injections, typically in 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.

[ 0338 ] Dose levels administered by injection range from about 0.1 mg/kg/hour to at least 10 mg/kg/hour, all over about 1 hour to about 120 hours, and especially from 24 to 96 hours. Also, a preloading bolus of about 0.1 mg/kg to about 10 mg/kg or more can be administered to achieve adequate steady-state levels. It is suggested that the maximum total dose does not exceed about 5 g/day for a sick person weighing 40 to 80 kg.

[ 0339 ] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous carrier with buffers, suspending and dispersing agents, dyes, flavors, and the like. Solid forms may include, for example, any of the following ingredients or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrant such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate; a flow control agent (glidant), such as colloidal silica; a sweetener such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavor.

[ 0340 ] Injectable compositions are typically based on sterile injectable saline or phosphate buffered saline, or other injectable excipients known in the art. As before, the active compound in such compositions is typically the minor component, often ranging from about 0.05 to 10% by weight, with the remainder being injectable excipient and the like.

[ 0341 ] Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s). When formulated as an ointment, the active ingredients will usually be combined in either a paraffin or water-miscible ointment base. Alternatively, the active ingredients may be formulated as a cream, for example an oil-in-water cream. Such transdermal formulations are well known in the art and typically include additional ingredients to enhance skin penetration or persistence of the active ingredients or formulation. All such known transdermal drugs and ingredients are included within the scope of the present invention.

[ 0342 ] The compounds presented herein can also be administered via a transdermal device. Accordingly, transdermal administration can be accomplished using a patch or reservoir, or a porous membrane or various solid matrices.

[ 0343 ] The above components for compositions administered orally, by injection or by topical application are indicative only. Other materials, as well as processing methods and the like, are set forth in Part 8 of Remington's Pharmaceutical Sciences , 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[ 0344 ] The compounds of the present invention may also be administered in delayed release forms, or from sustained release drug delivery systems. A description of typical sustained release materials can be found in Remington's Pharmaceutical Sciences .

[ 0345 ] The present invention also provides a pharmaceutically acceptable acid addition salt of a compound of the present invention. An acid that can be used to prepare a pharmaceutically acceptable salt is one that forms a non-toxic acid addition salt, that is , a salt containing pharmacologically acceptable anions such as hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, p-toluenesulfonate, and the like.

[ 0346 ] In another aspect, the invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, for example , a composition suitable for injection, such as intravenous (IV) administration.

[ 0347 ] Pharmaceutically acceptable excipients include any and all diluents or other liquid carriers, dispersants or suspending auxiliaries, surfactants, isotonic solutions, preservatives, lubricants, and the like as are suitable for the particular dosage form desired, e.g. injections. General considerations regarding the formulation and/or preparation of agents for pharmaceutical compositions can be found, for example, in Remington's Pharmaceutical Sciences , sixteenth edition, E.W. Martin (Mack Publishing Co., Easton, PA, 1980), and Remington: The Science and Practice of Pharmacy , 21st edition (Lippincott Williams & Wilkins, 2005).

[ 0348 ] For example, injectable preparations, such as sterile aqueous injectable suspensions, can be formulated according to known technology using suitable dispersants and wetting agents and suspending agents. Exemplary excipients that may be used include, but are not limited to, water, sterile saline or phosphate buffered saline or Ringer's solution.

[ 0349 ] In certain embodiments, the pharmaceutical composition further includes a cyclodextrin derivative. The most common cyclodextrins are α-, β- and γ-cyclodextrins, consisting of 6, 7 and 8 α-1,4-linked glucose units, respectively, optionally including one or many substituents on the linked carbohydrate moieties, which include, but are not limited to by this, substituents introduced by methylation, hydroxyalkylation, acylation and the introduction of sulfoalkyl ether. In certain embodiments, the cyclodextrin is a β-cyclodextrin sulfoalkyl ether, such as β-cyclodextrin sulfobutyl ether, also known as CAPTISOL®. See, for example, US Patent 5,376,645. In certain embodiments, the composition includes hexapropyl-β-cyclodextrin. In a more specific embodiment, the composition includes hexapropyl-β-cyclodextrin (10-50% in water).

[ 0350 ] The injectable composition may be sterilized, for example, by filtration through a bacteria-retaining filter, or by administering sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable media prior to use.

[ 0351 ] Typically, the compounds presented herein are administered in an effective amount. The actual amount of compound administered will generally be determined by the physician, taking into account the relevant circumstances, including the condition being treated, the route of administration chosen, the actual compound administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.

[ 0352 ] The compositions are presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage forms" refers to physically discrete units suitable as unit dosages for human patients and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect, in combination with a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled ampoules or syringes with liquid compositions of a predetermined volume. In such compositions, the compound typically constitutes a minor component (from about 0.1% to about 50% by weight, or preferably from about 1% to about 40% by weight), with the balance being various carriers or excipients and processing aids excipients for the formation of the desired dosage form.

[ 0353 ] The compounds presented herein may be administered as the sole active agent, or they may be administered in combination with other active agents. In one aspect, the present invention provides a combination of a compound of the present invention and another pharmacologically active agent. Administration in the combination may be accomplished in any manner apparent to those skilled in the art, including, for example, separate, sequential, simultaneous, or alternating administration.

[ 0354 ] Although the descriptions of pharmaceutical compositions presented herein are in principle directed to pharmaceutical compositions that are suitable for administration to humans, one skilled in the art will appreciate that such compositions are generally suitable for administration to mammals of all species. Modification of pharmaceutical compositions suitable for administration to humans to make the compositions suitable for administration to various mammals is well known, and a veterinarian of ordinary skill can develop and/or carry out such modification by simple experimentation. General information regarding the formulation and/or preparation of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy , 21st edition, Lippincott Williams & Wilkins, 2005.

[ 0355 ] In one aspect, a kit is provided including a composition ( eg , a solid composition) containing a compound of Formula (IX , II , II-I , III-I, or III-II).

Methods of application and treatment

[ 0356 ] In one aspect, the compounds described herein, for example , compounds of Formula (IX , II , II-I , III-I or III-II) , are useful as therapeutic agents for the treatment of a CNS-related disease ( eg , sleep disorders, mood disorders such as depression, schizophrenia spectrum disorder, seizure disorder, epileptogenesis, memory and/or cognitive impairment, movement disorder, personality changes, autism spectrum disorder, pain, traumatic brain injury, vascular disease, substance abuse disorder, and /or withdrawal symptoms or tinnitus) in a subject in need ( eg , Rett syndrome, fragile X syndrome, or Angelman syndrome). Exemplary CNS conditions associated with GABA modulation include, but are not limited to, sleep disorders [ eg , insomnia], mood disorders [ eg , depression ( eg , major depressive disorder (MDD)), dysthymic disorder ( eg , mild depression), bipolar disorder ( eg , I and/or II), anxiety disorders ( eg , generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), compulsive disorders ( eg , obsessive-compulsive disorder (OCD)], schizophrenia spectrum disorders [ eg , schizophrenia, schizoaffective disorder], seizure syndromes [ eg , epilepsy ( eg , status epilepticus (SE)), seizures], memory and/or cognitive disorders [ eg , attention disorders ( e.g. attention deficit hyperactive disorder (ADHD)), dementia ( e.g. Alzheimer's dementia, dementia with Lewy bodies, vascular dementia), movement disorders [ e.g. Huntington's disease, Parkinson's disease], personality disorders [ e.g. antisocial disorder personality, obsessive-compulsive personality disorder], autism spectrum disorder (ASD) [ e.g. autism, monogenic causes of autism such as synaptopathic, e.g. Rett syndrome, fragile X syndrome, Angelman syndrome], pain [ e.g. neuropathic pain, trauma-related pain syndromes, acute pain, chronic pain], traumatic brain injury (TBI), vascular disorders [ eg , stroke, ischemia, vascular disease], substance abuse disorders and/or withdrawal syndromes [ eg , addiction opiates, cocaine and/or alcohol] and tinnitus.

[ 0357 ] In certain embodiments, the CNS related disorder is a sleep disorder, mood disorder, schizophrenia spectrum disorder, seizure disorder, memory and/or cognitive impairment, movement disorder, personality change, autism spectrum disorder, pain, traumatic brain injury, vascular disease, substance use disorder, and/or withdrawal syndrome, tinnitus, or status epilepticus. In certain embodiments, the CNS-related disease is depression. In certain embodiments, the CNS-related disease is postpartum depression. In certain embodiments, the CNS-related disease is major depressive disorder. In certain embodiments, the major depressive disorder is a moderate form of major depressive disorder. In certain embodiments, the major depressive disorder is a severe form of major depressive disorder.

[ 0358 ] In one aspect, a method is provided for mitigating or preventing seizure activity in a subject, comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention. In some embodiments, the method mitigates or prevents epileptogenesis.

[ 0359 ] In yet another aspect, a combination of a compound of the present invention and another pharmacologically active agent is provided. The compounds presented herein may be administered as a single active agent, or they may be administered in combination with other agents. Administration in the combination may be accomplished in any manner apparent to those skilled in the art, including, for example, separate, sequential, simultaneous, or alternating administration.

[ 0360 ] In yet another aspect, a method is provided for treating or preventing cerebral excitability in a subject susceptible to or suffering from a condition associated with cerebral excitability, comprising administering to the subject an effective amount of a compound of the present invention.

[ 0361 ] In yet another aspect, the present invention provides a method of treating or preventing stress or anxiety in a subject, comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention, or a composition therewith.

[ 0362 ] In yet another further aspect, there is provided a method of treating 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 therewith.

[ 0363 ] In yet another further aspect, a method of inducing sleep and maintaining substantially the level of REM sleep found during normal sleep without causing significant relapse of insomnia is provided, comprising administering an effective amount of a compound of the present invention.

[ 0364 ] In yet another aspect, there is provided a method of treating or preventing premenstrual syndrome (PMS) or postpartum depression (PND) in a subject, comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention.

[ 0365 ] In yet another further aspect, there is provided a method of treating or preventing mood disorders in a subject, comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention. In certain embodiments, the mood disorder is depression.

[ 0366 ] In yet another further aspect, there is provided a method of improving cognition or treating a memory disorder by administering to a subject a therapeutically effective amount of a compound of the present invention. In certain embodiments, the disorder is Alzheimer's disease. In certain embodiments, the disorder is Rett syndrome.

[ 0367 ] In yet another further aspect, there is provided a method of treating attention disorders by administering to a subject a therapeutically effective amount of a compound of the present invention. In certain embodiments, the attention disorder is ADHD.

[ 0368 ] In certain embodiments, the compound is administered to a subject chronically. In certain embodiments, the compound is administered to the subject orally, subcutaneously, intramuscularly, or intravenously.

Neuroendocrine diseases and dysfunction

[ 0369 ] Presented herein are methods that can be used to treat neuroendocrine diseases and dysfunction. As used herein, "neuroendocrine disease" or "neuroendocrine dysfunction" refers to various conditions caused by imbalances in the body's production of hormones directly related to the brain. Neuroendocrine diseases involve interactions between the nervous system and the endocrine system. Because the hypothalamus and pituitary gland are two areas of the brain that regulate hormone production, damage to the hypothalamus or pituitary gland, such as in the case of traumatic brain injury, can interfere with hormone production and other neuroendocrine functions of the brain. In some embodiments, the neuroendocrine disease or dysfunction is associated with a female health disorder or condition ( eg , a female health disorder or condition described herein). In some embodiments, the neuroendocrine disease or dysfunction associated with a health disorder or condition in women is polycystic ovary syndrome.

[ 0370 ] Symptoms of a neuroendocrine disease include, but are not limited to, behavioral, emotional and sleep-related symptoms, reproductive symptoms, and physical symptoms including, but not limited to, fatigue, poor memory, anxiety, depression, enlargement or weight loss, emotional lability, lack of concentration, difficulty paying attention, decreased libido, infertility, amenorrhea, decreased muscle mass, increased belly fat, low blood pressure, decreased heart rate, hair loss, anemia, constipation, cold intolerance, and dryness skin.

Neurodegenerative diseases and disorders

[ 0371 ] The methods described herein can be used to treat neurodegenerative diseases and disorders. The term "neurodegenerative disease" includes diseases and disorders that are associated with the progressive loss of neuronal structure or function, or the death of neurons. Neurodegenerative diseases and disorders include, but are not limited to, Alzheimer's disease (including associated symptoms of mild, moderate or severe cognitive impairment); amyotrophic lateral sclerosis (ALS), hypoxia injury and ischemic injury; ataxia and convulsions (including for the treatment and prevention of seizures that are caused by schizoaffective illness or medications used to treat schizophrenia); benign forgetfulness; cerebral edema; cerebellar ataxia, including McLeod neuroacanthocytosis syndrome (MLS); closed craniocerebral injury; soma; concussion injuries ( eg spinal cord injuries or head injuries); dementias, including multi-infarct dementia and senile dementia; blackout; Down syndrome; drug- or treatment-induced parkinsonism (such as neuroleptic-induced acute akathisia, acute dystonia, parkinsonism or tardive dyskinesia, neuroleptic malignant syndrome, or treatment-induced postural tremor); epilepsy; fragile X syndrome; Gilles de la Tourette syndrome; head injury; deterioration and loss of hearing; Huntington's disease; Lennox syndrome; levodopa-induced dyskinesia; oligophrenia; movement disorders, including akinesia and akinetic (rigid) syndromes (including basal ganglia calcification, corticobasal degeneration, multiple system atrophy, parkinsonism-ALS dementia complex, Parkinson's disease, postencephalitic parkinsonism and progressive supranuclear palsy); myotonic spasms and disorders associated with muscle spasticity, or weakness, including chorea (such as benign hereditary chorea, drug-induced chorea, hemiballismus, Huntington's disease, neuroacanthocytosis, Sydenham's chorea and symptomatic chorea), dyskinesia (including tics, such as complex tics , simple tics and symptomatic tics), myoclonus (including generalized myoclonus and focal dystonia), tremor (such as resting tremor, orthostatic tremor and intention tremor) and dystonia (including axial dystonia, writers' dystonia, hemiplegic dystonia, paroxysmal dystonia and focal dystonia such as blepharospasm, oromandibular dystonia and spastic dystonia and torticollis); neuronal damage, including eye damage, retinopathy, or macular degeneration; neurotoxic damage, which is caused by cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest; Parkinson's disease; seizure; status epilepticus; hit; noise in ears; tubular sclerosis and viral infection-induced neurodegeneration ( for example , caused by acquired immunodeficiency syndrome (AIDS) and encephalopathies). Neurodegenerative diseases also include, but are not limited to, neurotoxic damage that follows cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest. Methods for treating or preventing a neurodegenerative disease also include treating or preventing the loss of neuronal function that characterizes the neurodegenerative disorder.

Mood disorders

[ 0372 ] Also provided herein are methods of treating a mood disorder such as, for example, clinical depression, postnatal depression or postpartum depression, perinatal depression, atypical depression, melancholic depression, psychotic major depression, catatonic depression, seasonal affective disorder, dysthymia, double depression, depressive disorder personality disorder, recurrent depression, minor depressive disorder, bipolar disorder or manic-depressive disorder, depression due to chronic illness, treatment-resistant depression, refractory depression, suicidality, suicidal ideation, or suicidal behavior. In some embodiments, the method described herein provides a therapeutic effect to a subject suffering from depression ( eg , moderate or severe depression). In some embodiments, the mood disorder is associated with a disease or disorder described herein ( e.g. , neuroendocrine diseases or disorders, neurodegenerative diseases or disorders ( e.g. , epilepsy), movement disorders, tremor ( e.g. , Parkinson's disease), women's health or condition).

[ 0373 ] Clinical depression is also known as major depression, major depressive disorder (MDD), major depression, unipolar depression, unipolar disorder and recurrent depression, and refers to a mental disorder characterized by profound and persistent low mood that is accompanied by low self-esteem and loss of interest or pleasure from normal pleasurable activities. Some people with clinical depression have trouble sleeping, losing weight, and generally feeling agitated and irritable. Clinical depression affects both an individual's feelings and thoughts as well as behavior, and can lead to a range of emotional and physical problems. Individuals with clinical depression may have anxiety in daily activities and develop a feeling that life is not worth living.

[ 0374 ] Peripartum depression refers to depression during pregnancy. Symptoms include irritability, tearfulness, feeling restless, trouble sleeping, severe exhaustion (emotional and/or physical), changes in appetite, distraction, increased restlessness and/or agitation, feelings of disconnection from the baby and/or fetus, and loss of interest in previously enjoyable activity.

[ 0375 ] Postpartum depression (PND), also referred to as peripartum depression (PPD) , is a type of clinical depression that affects women after childbirth. Symptoms may include sadness, fatigue, changes in sleep and eating habits, decreased sexual desire, crying episodes, anxiety and irritability. In some embodiments, the PND is treatment-resistant depression ( eg , refractory depression, as described herein).

[0376] In some embodiments, the subject having PND also experiences depression, or a symptom of depression during pregnancy. This depression is called here asperinatal depression.In one version a subject experiencing perinatal depression is at high risk of experiencing PND.

[ 0377 ] Atypical depression (AD) is characterized by mood reactivity ( eg , paradoxical anhedonia) and positivity, significant weight gain, or increased appetite. AD patients may also experience excessive sleep or sleepiness (hypersomnia), a feeling of heavy limbs, and significant social impairment as a result of hypersensitivity to perceived rejection in interpersonal relationships.

[ 0378 ] Melancholic depression is characterized by loss of pleasure (anhedonia) in most or all activities, failure to respond to pleasant stimuli, depressed mood more severe than with grief or loss, excessive weight loss, or excessive feelings of guilt.

[ 0379 ] Psychotic major depression (PMD), or psychotic depression, refers to a major depressive episode, particularly of a melancholic nature, where the individual experiences psychotic symptoms such as delusions and hallucinations.

[ 0380 ] Catatonic depression refers to major depression that includes disturbances in motor behavior and other symptoms. The individual may become mute and stuporous and either motionless or make aimless and strange movements.

[ 0381 ] Seasonal affective disorder (SAD) refers to a type of seasonal depression in which an individual has a seasonal pattern of depressive episodes occurring in the fall or winter.

[ 0382 ] Dysthymia refers to a condition related to unipolar depression, where the same physical and cognitive problems are evident. They are not severe, and tend to be of long duration ( eg , at least 2 years).

[ 0383 ] Double depression refers to low depressed mood (dysthymia) that lasts for at least 2 years and is punctuated by periods of major depression.

[ 0384 ] Depressive personality disorder (DPD) refers to a personality disorder with depressive features.

[ 0385 ] Recurrent brief depression (RBD) refers to a condition in which individuals have depressive episodes approximately once a month, with each episode lasting 2 weeks or less, and usually less than 2-3 days.

[ 0386 ] Minor depressive disorder, or minor depression, refers to depression in which at least 2 symptoms occur within 2 weeks.

[ 0387 ] Bipolar disorder, or manic-depressive disorder, causes extreme mood swings that include emotional highs (mania or hypomania) and lows (depression). During periods of mania, an individual may feel or act abnormally happy, energetic, or irritable. They often make bad decisions with little regard for the consequences. The need for sleep usually decreases. During periods of depression, they may be whiny, have poor visual contact with others, and have a negative outlook on life. Among people with this disorder, the risk of suicide is high, over 6% in people over 20 years of age, while self-harm occurs in 30-40%. Other mental health problems, such as anxiety disorders and substance misuse, are commonly associated with bipolar disorder.

[ 0388 ] Depression caused by chronic medical conditions refers to depression caused by chronic diseases such as cancer or chronic pain, chemotherapy, chronic stress.

[ 0389 ] Treatment-resistant depression refers to a condition where individuals are treated for depression but symptoms do not improve. For example, antidepressants or counseling (psychotherapy) do not relieve symptoms in individuals with treatment-resistant depression. In some cases, in individuals with treatment-resistant depression, symptoms improve but return. Refractory depression occurs in patients suffering from depression who are resistant to standard pharmacological treatment, including tricyclic antidepressants, monoamine oxidase inhibitor (MAOI), serotonin reuptake inhibitors (SSRIs), and double and triple doses of inhibitors and/or anxiolytic drugs, and also to non-pharmacological treatments ( eg psychotherapy, electroconvulsive therapy, vagus nerve stimulation and/or transcranial magnetic stimulation).

[ 0390 ] Postoperative depression refers to the feeling of depression that occurs after surgery ( eg , as a result of being near death). For example, individuals may feel sad or persistently return to a depressed mood, experience a loss of pleasure or interest in normally attractive hobbies and activities, or a persistent feeling of worthlessness or hopelessness.

[ 0391 ] Mood disorder associated with women's health conditions or disorders refers to mood disorders ( eg , depression) associated with ( eg , caused by) a women's health condition or impairment ( eg , as described herein).

[ 0392 ] Suicidality, suicidal ideation, suicidal behavior refers to an individual's tendency to commit suicide. Suicidal ideation refers to thinking about suicide or being unusually interested in suicide. The scope of suicidal ideation varies widely from, for example , fleeting thoughts to extensive thoughts, detailed planning, acting out, and incomplete attempts. Symptoms include talking about suicide, acquiring means to commit suicide, withdrawing from social contact, preoccupying yourself with thoughts of death, feeling overwhelmed or hopeless in a situation, increasing use of alcohol or drugs, engaging in dangerous or suicidal behavior, talking goodbye to people as if they were won't see each other again.

[ 0393 ] Symptoms of depression include persistent feelings of fear or sadness, feelings of helplessness, hopelessness, pessimism, worthlessness, low energy, restlessness, poor sleep, insomnia, irritability, fatigue, movement problems, loss of interest in enjoyable activities or hobbies, loss of concentration, loss energy, low self-esteem, lack of positive thoughts or plans, excessive sleepiness, 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. Symptoms of depression and their nature can be determined by a doctor or psychologist ( for example , by checking your mental state).

[ 0394 ] In some embodiments, the therapeutic effect can be determined by monitoring the subject according to a known depression scale, for example , the Hamilton Depression Scale (HAM-D), the improved Clinical Global Impression (CGI), and the Montgomery-Asberg Depression Rating Scale (MADRS). . In some embodiments, the therapeutic effect may be determined by a reduction in the subject's total score on the Hamilton Depression Inventory (HAM-D). Decrease in HAM-D total score may occur within 4, 3, 2, or 1 day; or 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, 8 hours or less. The therapeutic effect can be assessed over a given treatment period. For example, a therapeutic effect may be determined by a decrease in baseline HAM-D total score following administration of a compound described herein, e.g., a compound of Formula (IX , II , II-I , III-I, or III-II) ( eg , after 12, 24 , or 48 hours after administration; or after 24, 48, 72, or 96 hours or more; or after 1 day, 2 days, 14 days, 21 days, or 28 days; or after 1 week, 2 weeks, 3 weeks, or 4 weeks; or after 1 month, 2 months, 6 months, or 10 months; or after 1 year, 2 years, or throughout life).

[ 0395 ] In some embodiments, the subject has a mild depressive disorder, such as mild major depressive disorder. In some embodiments, the subject has a mild depressive disorder, such as moderate major depressive disorder. In some embodiments, the subject has a severe depressive disorder, such as severe major depressive disorder. In some embodiments, the subject has a very severe depressive disorder, such as very severe major depressive disorder. In some embodiments, the baseline of the subject's total HAM-D score (i.e., prior to treatment with a compound described herein, e.g. , a compound of Formula (IX , II , II-I , III-I, or III-II) ) is at least 24 In some embodiments, the baseline of the subject's total HAM-D score is at least 18. In some embodiments, the baseline of the subject's total HAM-D score is between 14 and 18, inclusive. In some embodiments, the baseline of the subject's total HAM-D score is between 19 and 22, inclusive. In some embodiments, the baseline of the subject's total HAM-D score before treatment with a compound described herein, e.g. , a compound of Formula (IX , II , II-I , III-I, or III-II) , is greater than or equal to 23. In some embodiments, the baseline score is at least 10, 15, or 20. In some embodiments, the subject's total HAM-D score after treatment with a compound described herein, for example , a compound of Formula (IX , II , II-I , III-I, or III- ii) ), is from about 0 to 10 ( e.g. less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 1.8). In some embodiments, the subject's total HAM-D score after treatment with a compound described herein, e.g. , a compound of Formula (IX , II , II-I , III-I, or III-II) ), is less than 10, 7, 5, or 3. In some embodiments, reducing the total HAM-D score from a base score of about 20 to 30 ( e.g. , 22 to 28, 23 to 27, 24 to 27, 25 to 27, 26 to 27) to a total HAM- D is from about 0 to 10 ( e.g., less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 1.8) after treatment with a compound described herein, e.g. , a compound of Formula (IX , II , II-I , III-I or III-II) . In some embodiments, the baseline reduction in HAM-D total score following treatment with a compound described herein, e.g. , a compound of Formula (IX , II , II-I , III-I, or III-II) , is 1-, 2-, 3-, 4-, 5-, 7-, 10-, 25-, 40-, 50-, or 100 times the value). In some embodiments, the percentage reduction in baseline HAM-D total score following treatment with a compound described herein, e.g. , a compound of Formula (IX , II , II-I , III-I, or III-II) , is at least 50% ( e.g. 60%, 70%, 80%, or 90%). In some embodiments, the therapeutic effect, measured by the reduction in the total HAM-D score after treatment with a compound described herein, e.g. , a compound of Formula (IX , II , II-I , III-I, or III-II) , relative to a baseline total HAM-D score D ( eg , 12, 24, 48 hours after administration; or 24, 48, 72, 96 hours or more; or 1 day, 2 days, 14 days, or more) is at least 10, 15, or 20 points.

[0396] In some embodiments, a method of treating a depressive disorder,For example, major depressive disorder, provides a therapeutic effect (For example, as measured by the Hamilton Depression Rating (HAM-D) within 14, 10, 4, 3, 2, or 1 day, or 24, 20, 16, 12, 10, or 8 hours or less. In some embodiments, a method of treating a depressive disorder,For example, major depressive disorder, provides a therapeutic effect (For example, determined by a statistically significant decrease in the total HAM-D score) within the first or second day of treatment with a compound described herein,For example, compound Formula(IX,II,II-I,III-I orIII-II). In some embodiments, a method of treating a depressive disorder,For example, major depressive disorder, provides a therapeutic effect (For example, defined as a statistically significant decrease in the total HAM-D score) within a period less than or equal to 14 days from the start of treatment with the compound described herein,For example, compound Formula(IX,II,II-I,III-I orIII-II). In some embodiments, a method of treating a depressive disorder,For example, major depressive disorder, provides a therapeutic effect (For example, defined by a statistically significant decrease in the total HAM-D score) within a period less than or equal to 21 days from the start of treatment with a compound described herein,For example, compound Formula(IX,II,II-I,III-I orIII-II). In some embodiments, a method of treating a depressive disorder,For example, major depressive disorder, provides a therapeutic effect (For example, defined by a statistically significant decrease in the HAM-D total score) within a period less than or equal to 28 days from the start of treatment with a compound described herein,For example, compound Formula(IX,II,II-I,III-I orIII-II). In some embodiments, the therapeutic effect is manifested as a decrease from baseline in the total HAM-D score after treatment with a compound described herein,For example, compound Formula(IX,II,II-I,III-I orIII-II) (For example, treatment with a compound described herein,For example, compound Formula(IX,II,II-I,III-I orIII-II)once a day for 14 days. In some embodiments, the subject's total HAM-D score before treatment with a compound described herein,For example, compound Formula(IX,II,II-I,III-I orIII-II)is at least 24. In some embodiments the subject's total HAM-D score before treatment with the compound described herein,For example, compound Formula(IX,II,II-I,III-I orIII-II)is at least 18. In some embodiments the subject's total HAM-D score before treatment with the compound described herein,For example, compound Formula(IX,II,II-I,III-I orIII-II),is between 14 and 18 inclusive. In some embodiments, a decrease in the total HAM-D score following treatment of a subject with a compound described herein,For example, compound Formula(IX,II,II-I,III-I orIII-II),relative to baseline, the HAM-D total score is at least 10. In some embodiments, a decrease in the HAM-D total score following treatment of a subject with a compound described herein,For example, compound Formula(IX,II,II-I,III-I orIII-II),relative to baseline, the HAM-D total score is at least 15 (For example, at least 17). In some embodiments, the total HAM-D score associated with treatment of a subject with a compound described herein isFor example, compound Formula(IX,II,II-I,III-I orIII-II),is no more than a number in the range of 6 to 8. In some embodiments, the total HAM-D score associated with treatment of a subject with a compound described herein isFor example, compound Formula(IX,II,II-I,III-I orIII-II),is no more than 7.

[ 0397 ] In some embodiments, the method provides a therapeutic effect ( for example , measured by a decrease in an improved Clinical Global Impression (CGI) score of 14, 10, 4, 3, 2, or 1 day, or 24, 20, 16, 12, 10, or 8 hours or less. In some embodiments, the CNS-related disease is a depressive disorder, such as major depressive disorder. In some embodiments, a method of treating a depressive disorder, such as major depressive disorder, provides a therapeutic effect within a second day of the treatment period. In some embodiments, the therapeutic effect is manifested by a decrease in the baseline CGI score at the end of the treatment period ( eg , 14 days after administration).

[ 0398 ] In some embodiments, the method provides a therapeutic effect ( for example , measured by a reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) score within 14, 10, 4, 3, 2, or 1 day, or 24, 20, 16, 12, 10, or 8 hours or less. In some embodiments, the CNS-related disease is a depressive disorder, such as major depressive disorder. In some embodiments, a method of treating a depressive disorder, such as major depressive disorder, provides a therapeutic effect in within the second day of the treatment period. In some embodiments, the therapeutic effect is manifested by a decrease in the baseline MADRS score at the end of the treatment period ( eg , 14 days after administration).

[ 0399 ] Therapeutic effect on major depressive disorder can be determined by the subject's reduction in Montgomery-Asberg Depression Rating Scale (MADRS) score. For example, the MADRS score may be reduced by 4, 3, 2, or 1 day; or 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, 8 hours or less. The Montgomery-Asberg Depression Rating Scale (MADRS) is a ten-item diagnostic questionnaire (regarding apparent sadness, marked sadness, inner discord, reduced sleep, decreased appetite, difficulty concentrating, apathy, inability to feel, pessimistic thoughts, and suicidal ideation). ), which doctors use to measure the severity of depressive episodes in patients with mood disorders.

[ 0400 ] In some embodiments, the method provides a therapeutic effect (eg, as measured by the Edinburgh Postnatal Depression Scale (EPDS)) within 4, 3, 2, or 1 day; 24, 20, 16, 12, 10, 8 hours or less. In some embodiments, the therapeutic effect is manifested as improvement as measured by the EPDS.

[ 0401 ] In some embodiments, the method provides a therapeutic effect (eg, as measured by the Generalized Anxiety Disorder 7-Item (GAD-7) questionnaire) within 4, 3, 2, 1 day; 24, 20, 16, 12, 10, 8 hours or less.

Anxiety disorders

[ 0402 ] Provided herein is a method of treating anxiety disorders ( eg , generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, phobia, post-traumatic stress disorder). Anxiety disorder is an umbrella term that covers several different forms of abnormal and pathological fear and anxiety. Modern medical diagnostic criteria recognize a wide range of anxiety disorders.

[ 0403 ] Generalized anxiety disorder is a common, chronic disorder characterized by long-lasting anxiety that is not focused on any one object or situation. Individuals suffering from generalized anxiety experience nonspecific persistent fear and worry and become overly concerned about everyday things. Generalized anxiety disorder is the most common anxiety disorder affecting older adults.

[ 0404 ] In panic disorder, a person suffers from short-term attacks of intense terror and apprehension, often marked by shaking, chills, confusion, dizziness, nausea, and difficulty breathing. Such panic attacks are defined by the American Psychological Association (APA) as fear or discomfort that suddenly appears and peaks in less than ten minutes, can last for several hours, and can be triggered by stress, fear, or quiet exercise, although a specific cause is not always apparent. . In addition to recurrent, unexpected panic attacks, a diagnosis of panic disorder also requires that said attacks have lasting effects: either anxiety about possible attacks, persistent fear of future attacks, or significant changes in behavior associated with attacks. Accordingly, people suffering from panic disorder experience symptoms even outside of specific panic episodes. Often, panic sufferers notice normal changes in their heart rate, leading them to think something is wrong with their heart or to consider having another panic attack. In some cases, during panic attacks there is a heightened awareness (hypervigilance) of the body's functioning, where any perceived physiological change is interpreted as a possible life-threatening illness (ie, extreme hypochondriasis).

[ 0405 ] Obsessive-compulsive disorder is a type of anxiety disorder characterized primarily by recurring obsessions (distressing, persistent, and intrusive thoughts and images) and compulsive urges (urges to perform specific actions or rituals). The pattern of thinking in OCD may be similar to superstition in that it involves a belief in a cause-and-effect relationship where in reality none exists. Often the process is completely counterintuitive; for example, a compulsive urge to walk in a certain pattern can be used to alleviate the obsession with impending trouble. And in many cases, the compulsive urge is completely inexplicable, simply an urge to complete the ritual, triggered by nervousness. In a minority of cases, OCD sufferers may experience only obsessions without overt compulsive impulses; a significantly smaller number of patients experience only compulsive urges.

[ 0406 ] The single largest category of anxiety disorders is phobia , which includes all cases in which fear and anxiety are triggered by a specific stimulus or situation. Sufferers typically anticipate dire consequences from confronting the object of their fear, which can be anything from an animal to a disposition to bodily fluids.

[ 0407 ] Post-traumatic stress disorder, or PTSD, is an anxiety disorder that results from exposure to trauma. PTSD can be the result of an extreme situation such as a fight, rape, hostage situation, or even a serious accident. It can also result from long-term (chronic) exposure to a severe stressor, such as in soldiers who survive isolated battles but cannot cope with continuous combat. Common symptoms include vivid memories of the past, avoidance reactions, or depression.

Health disorders in women

[ 0408 ] Presented herein is a method of treating conditions or disorders relevant to women's health. Conditions or disorders relevant to women's health include, but are not limited to, gynecological health and disorders ( eg , premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD), pregnancy problems ( eg , miscarriage, abortion), infertility, and related disorders ( eg polycystic ovary syndrome (PCOS)), other disorders and conditions, and problems related to a woman's general health and well-being ( eg menopause).

[ 0409 ] Gynecological health and disorders of concern to women include menstruation and menstrual irregularities; urinary tract health, including urinary incontinence and pelvic floor disorders; and disorders such as bacterial vaginosis, vaginitis, uterine fibroids, and vulvodynia.

[ 0410 ] Premenstrual syndrome (PMS) refers to physical and emotional symptoms that occur one to two weeks before the menstrual cycle. Symptoms vary but may include bleeding, mood swings, swollen breasts, hunger, fatigue, irritability, acne, and depression.

[ 0411 ] Premenstrual dysphoric disorder (PMDD) is a severe form of PMS. The symptoms of PMDD are similar to 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, anger, increased interpersonal conflict, tension and anxiety, irritability, feelings of control or overwhelm, trouble sleeping, physical problems ( eg , bloating, breast tenderness, swelling, headaches). pain, joint or muscle pain).

[ 0412 ] Pregnancy problems include preconception care and prenatal care, miscarriage (miscarriage and stillbirth), preterm labor and preterm birth, sudden infant death syndrome (SIDS), breastfeeding, and birth trauma.

[ 0413 ] Miscarriage refers to a pregnancy that spontaneously ends within the first 20 weeks of gestation.

[ 0414 ] Abortion refers to the intentional termination of a pregnancy, which may be performed during the first 28 weeks of gestation.

[ 0415 ] Infertility and related disorders include uterine fibroids, polycystic ovary syndrome, endometriosis and primary ovarian failure.

[ 0416 ] Polycystic ovary syndrome (PCOS) is related to endocrine system disorders among women of reproductive age. PCOS is a set of symptoms caused by elevated levels of male hormones in women. Most women with PCOS develop numerous small cysts on their ovaries. Symptoms of PCOS include irregular or absent menstrual cycles, heavy periods, excessive body and facial hair growth, acne, pelvic pain, inability to become pregnant, and patches of thick, dark, velvety skin. PCOS may be associated with conditions including type 2 diabetes, obesity, sleep apnea, heart disease, mood disorders, and endometrial cancer.

[ 0417 ] Other disorders and conditions that affect only women include Turner syndrome, Rett syndrome, and ovarian and cervical cancers.

[ 0418 ] Issues related to women's general health and well-being include violence against women, women with disabilities and their unique challenges, osteoporosis and bone health, and menopause.

[ 0419 ] Menopause refers to the 12 months after a woman's last menstrual period, and marks the end of menstrual cycles. Menopause usually occurs in women between the ages of 40 and 50. Physical symptoms such as hot flashes and emotional symptoms of menopause can disrupt sleep, reduce energy, cause anxiety, or feelings of sadness or loss. Menopause includes natural menopause and surgical menopause, which is a type of induced menopause due to an event such as surgery ( eg , hysterectomy, ovary removal, cancer). It is caused when the ovaries are seriously damaged, such as by radiation, chemotherapy, or other medical treatments.

Epilepsy

[ 0420 ] A compound of Formula (IX , II , II-I , III-I or III-II), or a pharmaceutically acceptable salt, or a pharmaceutically acceptable composition thereof, can be used in the method described herein, for example, in the treatment of the disorders described herein, such as epilepsy, status epilepticus or seizure disorder.

[ 0421 ] Epilepsy is a brain disorder characterized by recurrent seizures at unspecified times. Types of epilepsy may include, but are not limited to, generalized epilepsy, e.g. childhood absence epilepsy, juvenile myoclonic epilepsy, grand mal epilepsy, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, e.g. temporal lobe epilepsy, frontal lobe epilepsy, benign focal epilepsy of childhood.

Epileptogenesis

[ 0422 ] The compounds and methods described herein can be used to treat or prevent epileptogenesis. Epileptogenesis is a gradual process in which a normal brain develops epilepsy (a chronic condition in which epileptic seizures occur). Epileptogenesis is caused by neuronal damage caused by the initial manifestation of the stroke ( eg , status epilepticus).

Status epilepticus (SE)

[ 0423 ] Status epilepticus (SE) may include, for example , convulsive status epilepticus, eg , early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, eg generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges and periodic lateralized epileptiform discharges. Convulsive status epilepticus is characterized by the presence of convulsive epileptic seizures and can include early status epilepticus, established status epilepticus, refractory status epilepticus, and super-refractory status epilepticus. Early status epilepticus is treated with first-line therapy. Established status epilepticus is characterized by epileptic seizures that persist despite treatment with first-line therapy and second-line therapy is prescribed. Refractory status epilepticus is characterized by seizures that persist despite treatment with first-line and second-line therapy, and general anesthetics are usually prescribed. Super-refractory status epilepticus is characterized by seizures that persist, despite treatment with first-line therapy, second-line therapy, and general anesthetics, for 24 hours or longer.

[ 0424 ] Nonconvulsive status epilepticus may include, for example , focal nonconvulsive status epilepticus, eg complex partial status epilepticus; simple partial nonconvulsive status epilepticus, subtle nonconvulsive status epilepticus; generalized nonconvulsive status epilepticus, eg late absence nonconvulsive status epilepticus, atypical absence nonconvulsive status epilepticus, or typical absence nonconvulsive status epilepticus.

[ 0425 ] A compound of Formula (IX , II , II-I , III-I , or III-II) , or a pharmaceutically acceptable salt, or a pharmaceutically acceptable composition thereof, may also be administered as a prophylactic agent to a subject having a CNS disorder, e.g. , traumatic brain damage, status epilepticus, e.g. convulsive status epilepticus, e.g. early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, eg generalized non-convulsive status epilepticus, eg complex partial status epilepticus; generalized periodic epileptiform discharges and periodic lethalized epileptiform discharges, before the onset of the attack.

Epileptic seizure

[ 0426 ] A seizure is a physical manifestation or behavioral change that occurs following an episode of abnormal electrical activity in the brain. The term "seizure" is often used interchangeably with the term "convulsion". Seizures are a condition in which a person's body shakes quickly and uncontrollably. During seizures, a person's muscles contract and relax repeatedly.

[ 0427 ] Based on the type of behavior and brain activity, seizures are divided into two broad categories: generalized and partial (also called localized or focal). Seizure type classification helps doctors diagnose whether a patient has epilepsy or not.

[ 0428 ] Generalized seizures are initiated by electrical impulses from an entire area of the entire brain, while partial seizures are initiated (at least initially) by electrical impulses in a relatively small part of the brain. The part of the brain that generates seizures is sometimes called the focus.

[ 0429 ] There are six types of generalized seizures. The most common and dramatic, and therefore the most commonly known, is a generalized seizure, also called a grand mal seizure. In this type of seizure, the patient becomes unconscious and usually falls. Loss of consciousness is followed by a generalized rigidity of the body (called the "tonic" phase of the seizure) for 30-60 seconds, then a sharp start ("clonic" phase) for 30-60 seconds, after which the patient falls into deep sleep ("postictal" or postictal phase). During grand mal seizures, damage and trauma such as tongue biting and urinary incontinence may occur.

[ 0430 ] Absence seizures cause a brief loss of consciousness (just a few seconds) with few or no symptoms. The patient, most often a child, usually stops activity and becomes indifferent. These seizures begin and end suddenly and may occur several times a day. Patients are usually unaware that they are having a seizure, except that they may be aware of a “loss of time.”

[ 0431 ] Myoclonic seizures involve sporadic jerking, usually on both sides of the body. Patients sometimes describe the twitching as electric shocks. These seizures, when severe, can lead to falling or unintentionally throwing objects.

[ 0432 ] Clonic seizures are repeated rhythmic jerks that affect both sides of the body at the same time.

[ 0433 ] Tonic seizures are characterized by muscle rigidity.

[ 0434 ] Atonic seizures involve a sudden and general loss of muscle tone, especially in the arms and legs, which often results in falling.

[ 0435 ] The seizures described here may include epileptic seizures; acute recurrent seizures; cluster seizures; continuous seizures; persistent seizures; prolonged seizures; recurrent seizures; seizures of status epilepticus, for example , refractory convulsive status epilepticus, seizures of non-convulsive status epilepticus; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; complex partial seizures; secondary generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign rolandic seizures; febrile seizures; emotional attacks; focal seizures; gelastic seizures; generalized initial seizures; infantile spasms; Jacksonian seizures; severe bilateral myoclonic seizures; multifocal seizures; neonatal initial seizures; nocturnal seizures; occipital seizures; post-traumatic seizures; subtle seizures; Sylvan's seizures; visual reflex seizures or withdrawal seizures. In some embodiments, the seizure is a generalized onset seizure associated with Dravet syndrome, Lennox-Gastaut syndrome, tuberous sclerosis complex, Rett syndrome, or female childhood epilepsy caused by a mutation of the PCDH19 gene.

Traffic violation

[ 0436 ] Treatments for movement disorders are also described herein. As used herein, “movement disorders” refer to a variety of diseases and disorders that are associated with hyperkinetic movement disorders and related abnormalities in muscle control. Exemplary movement disorders include, but are not limited to, Parkinson's disease and parkinsonism (defined in particular by slowness of movement (bradykinesia)), dystonia, chorea and Huntington's disease, ataxia, tremor ( eg , idiopathic tremor), myoclonus and startle, tics and Tourette's syndrome, restless legs syndrome, stiff muscle syndrome, and gait disorders.

Tremor

[ 0437 ] The methods described herein can be used to treat tremor, for example, compounds of Formula (IX , II , II-I , III-I or III-II) can be used to treat cerebellar tremor or dynamic tremor, dystonic tremor, essential tremor , orthostatic tremor, parkinsonian tremor, physiological tremor, psychogenic tremor, or rubral tremor. Tremor includes hereditary, degenerative, and idiopathic disorders such as Wilson's disease, Parkinson's disease, and essential tremor, respectively; metabolic disorders ( eg, thyroid-parathyroid, liver disease and hypoglycemia); peripheral neuropathies (associated with Charcot-Marie-Tooth disease, Roussy-Lévy syndrome, diabetes mellitus, complex regional pain syndrome); toxins (nicotine, mercury, lead, CO, manganese, arsenic, toluene); drug-induced (narcoleptics, tricyclic antidepressants, lithium, cocaine, alcohol, epinephrine, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychogenic disorders. The clinical presentation of tremor can be classified into physiological tremor, enhanced physiological tremor, essential tremor syndromes (including classic essential tremor, primary orthostatic tremor, and task- and position-specific tremor), dystonic tremor, parkinsonian tremor, cerebellar tremor, Holmes tremor ( that is, rubral tremor), palatal tremor, neuropathic tremor, toxin- or drug-induced tremor, and psychogenic tremor.

[ 0438 ] Tremor is an involuntary, rhythmic contraction and relaxation of muscles that may involve vibrations or jerking of one or more parts of the body ( eg , hands, shoulders, eyes, face, head, vocal cords, torso, legs).

[ 0439 ] Cerebellar tremor, or intention tremor, is a slow, widespread tremor of the limbs that occurs after purposeful movement. Cerebellar tremor is caused by lesions or damage to the cerebellum resulting from, for example , a tumor, stroke, disease ( eg multiple sclerosis, hereditary degenerative disorder).

[ 0440 ] Dystonic tremor occurs in individuals affected by dystonia, a movement disorder in which prolonged involuntary muscle contractions cause twisting and repetitive body movements and/or painful and abnormal body positions or positions. Dystonic tremors can affect any muscle in the body. Dystonic tremors occur irregularly and can often be relieved by adequate rest.

[ 0441 ] Essential tremor, or benign essential tremor, is the most common type of tremor. Essential tremor may be mild and non-progressive in some, and may progress slowly, starting on one side of the body, but affecting both sides within 3 years. The hands are most commonly affected, but the head, voice, tongue, legs and trunk may also be affected. The frequency of tremors may decrease as a person ages, but the severity may increase. Increased anxiety, stress, nervous agitation, physical exhaustion, or low blood sugar can trigger tremors and/or increase their severity. Symptoms usually develop over time and can be either visible or long-lasting once they begin.

[ 0442 ] Orthostatic tremor is characterized by rapid ( eg , greater than 12 Hz) rhythmic muscle contractions that occur in the legs and torso immediately after standing. Spasms are felt in the thighs and legs, and the patient may shake uncontrollably when asked to stand in one place. Orthostatic tremor may occur in patients with essential tremor.

[ 0443 ] Parkinsonian tremors are 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 "circling" movement of the hands, which can also affect the chin, lips, legs and torso. Typically, parkinsonian tremor appears after the age of 60. The movement begins in one limb or on one side of the body and can progress to include the other side.

[ 0444 ] Physiological tremor may occur in healthy individuals and is not of clinical significance. It can be seen in all voluntary muscle groups. Physiological tremors can be caused by certain medications, hangovers, or medical conditions including an overactive thyroid gland and hypoglycemia. Tremor classically has a frequency of approximately 10 Hz.

[ 0445 ] Psychogenic tremor, or hysterical tremor, can occur at rest or during postural or kinetic movement. A patient with psychogenic tremor may have conversion disorder or another mental illness.

[ 0446 ] Rubral tremor is characterized by a large-scale weak trembling that can be present at rest, during posture and action. Tremor is associated with conditions affecting the red nuclei in the midbrain, classic unusual seizures.

[ 0447 ] Parkinson's disease affects the nerve cells in the brain that produce dopamine. Symptoms include muscle rigidity, tremors, changes in speech and gait. Parkinsonism is characterized by tremor, bradykinesia, rigidity, and postural instability. Parkinsonism exhibits symptoms common to Parkinson's disease, but is a complex of symptoms rather than a progressive neurodegenerative disease.

[ 0448 ] Dystonia is a movement disorder that is characterized by prolonged or intermittent muscle contractions, resulting in abnormal, frequently repetitive movements or positions. Dystonia is often initiated or worsened by deliberate actions and is associated with excessive muscle activation.

[ 0449 ] Chorea is a neurological disorder that is characterized by jerking, involuntary movements typically occurring in the shoulders, hips, and face. Huntington's disease is a congenital disorder that causes the death of nerve cells in the brain. Symptoms include uncontrolled movements, clumsiness, and balance problems. Huntington's disease can affect walking, speaking, and swallowing.

[ 0450 ] Ataxia refers to the loss of complete control over body movements, and can affect the fingers, hands, arms, legs, body, speech, and eye movements.

[ 0451 ] Myoclonus and Startle is a response to a sudden and unexpected stimulus, which may be auditory, tactile, visual, or vestibular.

[ 0452 ] Tics are involuntary movements that usually occur suddenly, are brief, are repeated but are not rhythmic, usually mimic normal behavior, and often occur in the context of normal activities. Tics can be classified as motor or vocal motor tics, which are related to movement, whereas vocal tics are related to sound. Tics can be characterized as simple or complex. For example, simple motor tics affect only certain muscles limited to a specific part of the body. Tourette syndrome is a congenital neuropsychiatric disorder of childhood onset that is characterized by multiple motor tics and at least one vocal tic.

[ 0453 ] Restless legs syndrome is a neurological sensorimotor disorder characterized by an irresistible urge to move the legs while at rest.

[ 0454 ] Stiff muscle syndrome is a progressive movement disorder characterized by involuntary, painful spasms and stiffness of muscles typically found in the lower back and legs. This typically results in a stiff-legged gait with severe lumbar hyperlordosis. There is usually a characteristic abnormality on electromyograms (EMG) with continuous motor activity of the paraspinal axial muscles. Variants include “stiff limb syndrome,” which creates focal stiffness usually affecting the ends of the legs and feet.

[ 0455 ] Gait disorders refer to abnormalities in the nature and style of walking that are caused by neuromuscular, arthritic, and other changes in the body. Gait is classified according to the system responsible for abnormal locomotion and includes hemiplegic gait, diplegic gait, neuropathic gait, myopathic gait, parkinsonian gait, choreic gait, ataxic gait, and sensory gait.

Anesthesia/Sedation

[ 0456 ] Anesthesia is a pharmacologically induced and reversible state of amnesia, analgesia, sensory loss, loss of skeletal muscle reflexes, impaired stress response, or all of them. Such effects can be obtained from a single drug, which alone provides the right combination of effects, or sometimes from a combination of drugs ( eg , hypnotics, sedatives, paralytics, analgesics) to achieve a very specific combination of results. Anesthesia allows patients to undergo surgery and other procedures without the distress and pain they might otherwise experience.

[ 0457 ] Sedation is the reduction of irritability or agitation by the administration of a pharmacological agent, typically to facilitate a medical or diagnostic procedure.

[ 0458 ] Sedation and analgesia include a continuum of states of consciousness ranging from minimal sedation (anxiolysis) to general anesthesia.

[ 0459 ] 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 deteriorate. Respiratory and cardiovascular function are usually not affected.

[ 0460 ] Moderate sedation/analgesia (conscious sedation) is a drug-induced depression of consciousness during which the patient responds purposefully to a verbal command or one or accompanied by light-tactile stimulation. There is usually no need to maintain the patient's airway. Typically spontaneous breathing is adequate. Cardiovascular function is usually preserved.

[ 0461 ] Deep sedation/analgesia is a drug-induced depression of consciousness during which the patient cannot rise easily but responds purposefully (without loss of reflex to a painful stimulus) after repeated or painful stimulation. Independent respiratory function may deteriorate and the patient may require assistance to maintain his or her own airway. Spontaneous breathing may be inadequate. Cardiovascular function is usually preserved.

[ 0462 ] General anesthesia is a drug-induced loss of consciousness during which the patient cannot respond even to a painful stimulus. The ability to maintain independent respiratory function is often impaired, and assistance is usually required to maintain the patient's airway. Positive pressure breathing may be required due to suppressed spontaneous respiration or drug-induced depression of neuromuscular function. Cardiovascular function may deteriorate.

[ 0463 ] Sedation in the intensive care unit (ICU) can suppress the patient's awareness of the environment and reduce the patient's response to external stimulation. This may play a role in the treatment of a critically ill patient and covers a wide range of symptom control that will vary from patient to patient and within individual patients throughout the course of their illness. Deep sedation in intensive care is used to facilitate endotracheal tube tolerance and respiratory synchronization, often with neuromuscular blockers.

[ 0464 ] In some embodiments, sedation ( eg , long-term sedation, continuous sedation) is induced and maintained in the ICU for an extended period of time ( eg , 1 day, 2 days, 3 days, 5 days, 1 week, 2 weeks, 3 weeks , 1 month, 2 months). Long-term sedation agents may have a long-lasting effect. Sedatives in the ICU may have a short half-life.

[ 0465 ] Procedural sedation and analgesia, also referred to as conscious sedation, is a method of administering sedatives or dissociative agents with or without analgesics to induce a state that allows the subject to tolerate unpleasant procedures with preservation of cardiopulmonary function.

Examples

[ 0466 ] In order that the invention described herein may be more fully understood, the following examples are provided. The synthetic and biological examples described in this application are presented to illustrate the compounds, pharmaceutical compositions and methods presented herein, and should in no way be construed as limiting its scope.

Materials and methods

[ 0467 ] The compounds presented herein can be prepared from readily available starting materials using the following general methods and techniques. It will be understood that where typical or preferred process conditions are given ( i.e. , reaction temperatures, durations, reactant molar ratios, solvents, pressure , etc. ), other process conditions may also apply unless otherwise noted. Optimal reaction conditions may vary due to the particular reactants or solvents used, but such conditions can be determined by routine experimental optimization by one skilled in the art.

[ 0468 ] In addition, as will be apparent to those skilled in the art, conventional protecting groups may be needed to prevent certain functional groups from participating in undesired reactions. The selection of a suitable protecting group for a particular functional group, as well as suitable conditions for its introduction and removal, are well known in the art. For example, many protecting groups and their introduction and removal are described in TW Greene and PGM Wuts, Protecting Groups in Organic Synthesis , second edition, Wiley, New York, 1991, and the references cited therein.

[ 0469 ] The compounds presented herein can be isolated and purified by known standard procedures. Such procedures include, but are not limited to, column chromatography, high pressure liquid chromatography (HPLC), or supercritical fluid chromatography (SFC). The following schemes are presented with details of the preparation of the representative oxysterols that have been listed here. The compounds presented herein can be prepared by one skilled in the art of organic synthesis technology from known or commercially available starting materials and reagents. Exemplary chiral columns listed herein available for use in enantiomer/diastereomer separation/purification 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.

[ 0470 ] The ¹ H-NMR data given here ( e.g. , for the region between δ (ppm, ^ppm ) from about 0.5 to about 4 ^ppm ) will imply an approximate interpretation of the NMR spectrum ( e.g., integration of the approximate peak) connections.

[ 0471 ] Approximate general method for preparative HPLC: column: Waters RBridge prep., 10 µm C18, 19*250 mm. Mobile phase: acetonitrile, water (NH ₄ HCO ₃ ) (30 l of water, 24 g of NH ₄ HCO ₃ , 30 ml of NH ₃ ·H ₂ O). Flow rate: 25 ml/min.

[ 0472 ] Example general analytical HPLC method: Mobile phase: A: water (10 mM NH ₄ HCO ₃ ), B: acetonitrile, gradient: 5%-95% B in 1.6 or 2 min. Flow rate: 1.8 or 2 ml/min; column: XBridge C18, 4.6*50 mm, 3.5 µm at 45°C.

[ 0473 ] Approximate general preparative HPLC method: column: Waters Xbridge Column 150*25 5 µm, conditions: water (10 mM NH4HCO3)-ACN, start: B 85, end: B 100, gradient time (minutes) 6.5, retention time 100% B (minutes) 1, flow rate (ml/min) 25, injections: 4).

[ 0474 ] Approximate general method for SFC: column: CHIRALPAK® AD CSP (250 mm*30 mm, 10 µm), gradient: 45% B, A=NH ₃ H ₂ O, B=MeOH, flow rate: 60 ml/ min. For example, AD_3_EtOH_DEA_5_40_25 ml would indicate: “column: Chiralpak AD-3 150 x 4.6 mm internal diameter (ID), 3 µm, mobile phase: A: CO2 B: ethanol (0.05% DEA), gradient: from 5 % to 40% B for up to 5 minutes, and hold at 40% for 2.5 minutes, then 5% B for 2.5 minutes, flow rate: 2.5 ml/min, column temperature: 35°C.”

[0475] Approximate general method for standard LC-ELSD: 30-90AB_2 min_E. (mobile phase: 1.5 ml/4 L TFA in water (solvent A) and 0.75 ml/4 L TFA in acetonitrile (solvent B), using a 30%-90% elution gradient (solvent B) for 0.9 minutes and hold at 90% for 0.6 minutes at a flow rate of 1.2 ml/min; column: Xtimate C18 2.1*30 mm, 3 µm; wavelength: UV 220 nm; column temperature: 50°C; MS ionization: ESI; detector: PDA&ELSD.

[ 0476 ] Approximate general method for SFC: Column: CHIRALPAK® AD CSP (250 mm*30 mm, 10 µm), Gradient: 45% B, A=NH ₃ H ₂ O, B=MeOH, Flow Rate: 60 ml/ min. For example, AD_3_EtOH_DEA_5_40_25 ml would indicate: “column: Chiralpak AD-3 150 x 4.6 mm internal diameter (ID), 3 µm, mobile phase: A: CO2 B: ethanol (0.05% DEA), gradient: from 5 % to 40% B for up to 5 minutes, and hold at 40% for 2.5 minutes, then 5% B for 2.5 minutes, flow rate: 2.5 ml/min, column temperature: 35°C.”

Formula (I-X) or Formula (I-I) Abbreviations:

[ 0477 ] PE: petroleum ether; EtOAc: ethyl acetate; THF: tetrahydrofuran; PCC: pyridinium chlorochromate; TLC: thin layer chromatography; PCC: pyridinium chlorochromate; t-BuOK: potassium tert-butoxide; 9-BBN: 9-borabicyclo[3.3.1]nonane; Pd( t -Bu ₃ P) ₂ : bis(tri-tert-butylphosphine)palladium(0); AcCl: acetyl chloride; i -PrMgCl: isopropyl magnesium chloride; TBSCl: tert-butyl(chloro)dimethylsilane; ( i- PrO) _4Ti : titanium tetraisopropoxide; BHT: 2,6-di-tert-butyl-4-methylphenoxide; Me: methyl; i -Pr: isopropyl; t -Bu: tert-butyl; Ph: phenyl; Et: ethyl; Bz: benzoyl; BzCl: benzoyl chloride; CsF: cesium fluoride; DAST: diethylaminosulfur trifluoride, DCC: dicyclohexylcarbodiimide; DCM: dichloromethane; DMAP: 4-dimethylaminopyridine; DMP: Dess-Martin periodinan; EtMgBr: ethyl magnesium bromide; EtOAc: ethyl acetate; TEA: triethylamine; AlaOH: alanine; Boc: tert-butoxycarbonyl; Py: pyridine; TBAF: tetra-n-butylammonium fluoride; THF: tetrahydrofuran; TBS: tert-butyldimethylsilyl; TMS: trimethylsilyl; TMSCF ₃ : (trifluoromethyl)trimethylsilane; Ts: para-toluenesulfonyl; Bu: butyl; Ti(OiPr) ₄ : tetraisopropoxytitanium; LAH: lithium aluminum hydride; LDA: lithium diisopropylamide; LiOH·H ₂ O: lithium hydroxide hydrates; MAD: methyl aluminum bis(2,6-di-tert-butyl-4-methylphenoxide); MeCN: acetonitrile; NBS: N-bromosuccinimide; Na ₂ SO ₄ : sodium sulfate; Na ₂ S ₂ O ₃ : sodium thiosulfate; PE: petroleum ether; MeCN: acetonitrile; MeOH: methanol ; Boc: tert-butoxycarbonyl; MTBE: methyl tert-butyl ether; K-selectride: potassium tri(sec-butyl)borohydride.

[ 0478 ] EXAMPLE I-1: Synthesis of 1-((3R,5R,8S,9S,10R,13S,14S,17S)-3-hydroxy-3,5,10,13-tetramethylhexadecahydro-1H-cyclopenta[a] phenanthrene-17-yl)-2-(methyl(phenyl)amino)ethan-1-one (I-A2)

[ 0479 ] To a solution of DIPEA (78.9 mg, 0.611 mmol) in DMF (10 ml) was added N-methylaniline (100 mg, 0.94 mmol) at 10°C. After stirring at 10°C for 10 minutes , I-A1 (200 mg, 0.47 mmol, described below in EXAMPLE I-4) was added. The mixture was stirred at 40°C for 16 hours. The mixture was evaporated to give an oil, which was purified using HPLC to give I-A2 (21 mg, 10%) as a solid.

[0480] ¹ H-NMR(400 MHz, CDCl₃) δ 7.24-7.15 (m, 2H), 6.75-6.70 (m, 1H), 6.65-6.55 (m, 2H), 4.13-3.93 (m , 2H), 3.00 (s, 3H), 2.63-2.54 (m, 1H), 2.27-2.09 (m, 2H), 2.03-1.95 (m, 1H ), 1.74-1.53 (m, 6H), 1.50-1.42 (m, 6H), 1.38-1.32 (m, 5H), 1.24-1.11 (m , 4H), 1.06-0.98 (m, 1H), 0.93 (s, 3H), 0.81 (s, 3H), 0.65 (s, 3H); LC ELSD purity 99%, MS ESI calculated for C_thirtyH₄₆NO₂ [M+H]⁺ 452, 452 found.

[ 0481 ] EXAMPLE I-2: Synthesis of 1-((3R,5R,8S,9S,10R,13S,14S,17S)-3-hydroxy-3,5,10,13-tetramethylhexadecahydro-1H-cyclopenta[a] phenanthrene-17-yl)-2-(phenylamino)ethan-1-one (I-A3)

[ 0482 ] To a solution of DIPEA (78.9 mg, 0.611 mmol) in DMF (10 ml) was added aniline (100 mg, 0.94 mmol) at 10°C. After stirring at 10°C for 10 minutes , I-A1 (200 mg, 0.47 mmol) was added. The mixture was stirred at 40°C for 16 hours. The mixture was evaporated to give an oil, which was purified using HPLC to give I-A3 (5 mg, 2%) as a solid.

[ 0483 ] ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 7.23-7.16 (m, 2H), 6.75-6.70 (m, 1H), 6.63-6.58 ( m, 2H), 4.00-3.86 (m, 2H), 2.60-2.56 (m, 1H), 2.29-2.18 (m, 2H), 2.04-1, 94 (m, 2H), 1.78-1.71 (m, 2H), 1.52-1.43 (m, 7H), 1.42-1.38 (m, 2H), 1.36 ( s, 4H), 1.29-1.23 (m, 3H), 1.20-1.15 (m, 2H), 1.06-0.99 (m, 1H), 0.94 (s, 3H), 0.90-0.85 (m, 1H), 0.80 (s, 3H), 0.62 (s, 3H); LC-ELSD purity 99%; MS ESI calculated for C ₂₉ H ₄₄ NO ₂ [M+H] ⁺ 438, found 438.

[ 0484 ] EXAMPLE I-3: Synthesis of 1-((3R,5R,8S,9S,10R,13S,14S,17S)-3-hydroxy-3,5,10,13-tetramethylhexadecahydro-1H-cyclopenta[a] phenanthrene-17-yl)ethan-1-one (I-B6)

Synthesis of I-B1

[ 0485 ] Si(OEt) ₄ (132 g, 636 mmol) and a catalytic amount of TsOH (4.91 g, 28.6 mmol) were added to a solution of progesterone (100 g, 318 mmol) in ethylene glycol (2 L). After stirring at 25°C for 5 hours, the reaction mixture was poured into NaHCO ₃ solution (aq, 1.5 L), filtered, washed with water (2 L x 3), filtered, air dried, and triturated with MTBE/PE (50 ml/2.5 L) to form I-B1 (95.0 g, 83%) as a solid.

[0486] ¹ H-NMR(400 MHz, CDCl₃) δ_H 5.72 (s, 1H), 4.05-3.80 (m, 4H), 2.45-2.25 (m, 4H), 2.10-2.00 (m, 2H), 1. 90-1.57 (m, 5H), 1.56-1.40 (m, 3H), 1.29 (s, 3H), 1.22-1.13 (m, 5H), 1.10- 0.85 (m, 4H), 0.81 (s, 3H).

Synthesis of I-B2

[ 0487 ] To a solution of I-B1 (10 g, 27.8 mmol) and nickel (2+) diacetylacetonate (1.42 g, 5.56 mmol) in THF (300 ml) was added AlMe ₃ (41.7 ml, 83.4 mmol, 2 M in toluene) at 0°C under N ₂ . After addition, the reaction mixture was stirred at 0°C for 2 hours. The mixture was filled with 50% NH ₄ Cl solution (500 ml), diluted with EtOAc (300 ml), and then filtered. The organic layer was separated and the aqueous phase was extracted with EtOAc (200 ml). The combined organic phase was washed with brine (500 ml), dried over Na ₂ SO ₄ , filtered, evaporated and purified using Combi-flash (0-15% EtOAc in PE) to give I-B2 (6 g, 57%) as solid matter.

Synthesis of I-B3

[ 0488 ] To a suspension of MePh ₃ PBr (17 g, 48 mmol) in THF (80 ml) was added t-BuOK (5.37 g, 48 mmol). After stirring at 40°C for 20 minutes, a solution of I-B2 (6 g, 16 mmol) in THF (20 ml) was added dropwise at 40°C. After addition, the mixture was filled with 50% NH ₄ Cl solution (300 ml) and extracted with EtOAc (2×100 ml). The combined organic phase was dried over Na ₂ SO ₄ , filtered, evaporated and purified using Combi-flash (0-5% EtOAc in PE) to give I-B3 (5 g, 83%) as a solid.

[0489] ¹ H-NMR(400 MHz, CDCl₃) δ_H 4.66-4.61 (m, 1H), 4.58-4.51 (m, 1H), 4.03-3.82 (m, 4H), 2.87-2.79 (m, 1H ), 2.20-1.91 (m, 3H), 1.83-1.77 (m, 1H), 1.75-1.58 (m, 5H), 1.54 (s, 3H), 1.48-1.31 (m, 5H), 1.29 (s, 3H), 1.23-1.01 (m, 5H), 0.82-0.78 (m, 5H), 0. 74 (s, 3H).

Synthesis of I-B4

[ 0490 ] To a solution of I-B3 (5 g, 13.4 mmol) in DCM (100 ml) was added K ₂ CO ₃ (9.27 g, 67 mmol) and meta- chloroperoxybenzoic acid ( m- CPBA) (6, 91 g, 40.1 mmol). After stirring at 20°C for 30 minutes, the reaction mixture was poured with a saturated solution of Na ₂ S ₂ O ₃ (300 ml). After stirring at 20°C for 10 minutes, the organic phase was separated, dried over Na ₂ SO ₄ , filtered and evaporated to give I-B4 (5 g) as a solid.

[0491] ¹ H-NMR(400 MHz, CDCl₃) δ_H 4.03-3.83 (m, 4H), 2.69-2.46 (m, 3H), 2.09-1.89 (m, 2H), 1.82-1.76 (m, 1H ), 1.75-1.62 (m, 4H), 1.62-1.47 (m, 2H), 1.46-1.33 (m, 4H), 1.29 (s, 3H), 1.26-0.98 (m, 8H), 0.96-0.93 (m, 2H), 0.89-0.82 (m, 3H), 0.74 (s, 3H), 0. 61-0.50 (m, 1H).

Synthesis of I-B5 and I-B8

[ 0492 ] To a solution of I-B4 (300 mg, 0.772 mmol) in THF (30 ml) was added LiAlH ₄ (293 mg, 7.72 mmol) in portions over 10 minutes. After stirring at 20°C for 30 minutes, the mixture was poured with 50% NH ₄ Cl solution (60 ml) and extracted with EtOAc (3×30 ml). The combined organic phase was washed with 50% NH ₄ Cl (100 ml), dried over Na ₂ SO ₄ , filtered, evaporated and purified using Combi-flash (0-15% EtOAc in PE) to give I-B5 (210 mg, 69%) and I-B8 (40 mg, 13%) as a solid.

[0493]I-B5: ¹ H-NMR(400 MHz, CDCl₃) δ_H 4.04-3.81 (m, 4H), 2.11-2.00 (m, 2H), 1.84-1.58 (m, 5H), 1.52-1.39 (m, 3H ), 1.39-1.34 (m, 2H), 1.33-1.29 (m, 4H), 1.28-1.23 (m, 3H), 1.22-1.16 (m , 4H), 1.16-1.02 (m, 7H), 1.00-0.87 (m, 2H), 0.83 (s, 3H), 0.73 (s, 3H).

[0494]I-B8: ¹ H-NMR(400 MHz, CDCl₃) δ_H 4.02-3.82 (m, 4H), 2.26-2.19 (m, 1H), 2.05-2.00 (m, 1H), 1.82-1.75 (m, 1H ), 1.74-1.62 (m, 3H), 1.57-1.49 (m, 2H), 1.48-1.37 (m, 7H), 1.33 (s, 3H), 1.28 (s, 3H), 1.24-1.09 (m, 5H), 1.08-0.98 (m, 3H), 0.91 (s, 3H), 0.79 (s, 3H), 0.72 (s, 3H).

Synthesis of I-B6

[ 0495 ] To a solution of I-B5 (210 mg, 0.537 mmol) in MeOH (8 ml) was added HCl (5.35 ml, 10.7 mmol, 2 M in water). After stirring at 20°C for 5 minutes, the mixture was diluted with water (50 ml) and filtered, dried in vacuum to form I-B6 (150 mg, 80%) as a solid. The stereochemical assignment was confirmed by X-ray crystallography.

[0496] ¹ H-NMR(400 MHz, CDCl₃) δ_H 2.56-2.47 (m, 1H), 2.26-2.12 (m, 2H), 2.10 (s, 3H), 2.04-1.97 (m, 1H), 1. 74-1.53 (m, 5H), 1.52-1.38 (m, 7H), 1.37-1.33 (m, 4H), 1.29-1.10 (m, 5H), 1.05-0.98 (m, 1H), 0.92 (s, 3H), 0.79 (s, 3H), 0.57 (s, 3H).

[ 0497 ] EXAMPLE I-4: Synthesis of 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-3-hydroxy-3,5,10,13-tetramethylhexadecahydro-1H-cyclopent [a]phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (I-A4)

Synthesis of I-A1

[ 0498 ] To a solution of I-B6 (1.2 g, 3.46 mmol) in MeOH (30 ml) add one drop of HBr (55.9 mg, 0.692 mmol) and Br ₂ (829 mg, 5.19 mmol) . After stirring at 20°C for 1 hour, the mixture was poured into 50% NaHCO ₃ solution (50 ml) and extracted with EtOAc (2×30 ml). The combined organic layer was washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered, evaporated to give I-AI (1.4 g, 95%) as a solid.

[0499] ¹ H-NMR(400 MHz, CDCl₃) δ_H 3.95-3.85 (m, 2H), 2.85-2.77 (m, 1H), 2.27-2.12 (m, 2H), 1.96-1.88 (m, 1H ), 1.80-1.68 (m, 2H), 1.56-1.39 (m, 10H), 1.35 (s, 3H), 1.34-1.11 (m, 6H), 1.06-0.99 (m, 1H), 0.93 (s, 3H), 0.79 (s, 3H), 0.61 (s, 3H).

Synthesis of I-A4

[ 0500 ] To a solution of I-AI (100 mg, 0.235 mmol) in acetone (2 ml) was added 1H-pyrazole-4-carbonitrile (32.7 mg, 0.352 mmol) and K ₂ CO ₃ (64.8 mg, 0 .47 mmol). After stirring at 20°C for 16 hours, the reaction mixture was filtered and purified by preparative HPLC to give I-A4 (46 mg, 45%) as a solid.

[0501] ¹ H-NMR(400 MHz, CDCl₃) δ_H 7.85 (s, 1H), 7.81 (s, 1H), 5.05-4.85 (m, 2H), 2.64-2.54 (m, 1H), 2.29-2, 15 (m, 2H), 2.09-1.99 (m, 1H), 1.80-1.71 (m, 2H), 1.51-1.38 (m, 9H), 1.38- 1.33 (m, 5H), 1.32-1.21 (m, 3H), 1.20-1.12 (m, 2H), 1.07-1.00 (m, 1H), 0. 94 (s, 3H), 0.80 (s, 3H), 0.64 (s, 3H);LC-ELSD purity 99%;MS ESI calculated for C₂₇H₃₈N₃O[M+H-H₂O]⁺ 420, 420 found.

[ 0502 ] EXAMPLE I-5: Synthesis of 1-((3S,5R,8S,9S,10R,13S,14S,17S)-3-hydroxy-3,5,10,13-tetramethylhexadecahydro-1H-cyclopenta[a] phenanthrene-17-yl)-ethan-1-one (I-A5)

[ 0503 ] To a solution of I-B8 (40 mg, 0.102 mmol) in MeOH (2 ml) was added HCl (1.02 ml, 2 M in water). After stirring at 20°C for 5 minutes, the mixture was diluted with water (20 ml) and filtered, dried in vacuum to form A5 (20 mg, 56%) as a solid.

[0504] ¹ H-NMR(400 MHz, CDCl₃) δ_H 2.57-2.48 (m, 1H), 2.20-1.98 (m, 6H), 1.74-1.57 (m, 4H), 1.56-1.42 (m, 5H ), 1.41-1.30 (m, 5H), 1.21 (s, 3H), 1.20-1.13 (m, 2H), 1.13-1.03 (m, 6H), 0.98-0.92 (m, 1H), 0.83 (s, 3H), 0.58 (s, 3H).

[ 0505 ] EXAMPLE I-6 and I-7: synthesis of 1-((3R,5R,8S,9S,10R,13S,14S,17S)-3-hydroxy-3,5,10,13-tetramethylhexadecahydro-1H- cyclopenta[a]phenanthrene-17-yl)-2-(2H-pyrazolo[3,4-c]pyridin-2-yl)ethan-1-one (I-A6) and 1-((3R,5R,8S ,9S,10R,13S,14S,17S)-3-hydroxy-3,5,10,13-tetramethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(1H-pyrazolo[3,4- c]pyridin-2-yl)ethan-1-one (I-A7)

[ 0506 ] To a mixture of I-AI (200 mg, 0.47 mmol) and K ₂ CO ₃ (129 mg, 0.94 mmol) in acetone (5 ml) was added 1H-pyrazolo[3,4-c]pyridine ( 83.9 mg, 0.705 mmol) at 25°C. After stirring at 25°C for 16 hours, the reaction mixture was filtered and the filtrate was evaporated in vacuo to give the product, which was purified by preparative HPLC, and the eluates were washed with saturated NaHCO ₃ solution, dried over Na ₂ SO ₄ , filtered and evaporated to form I- A6 (25 mg) and I-A7 (40 mg) as a solid, which was further purified by preparative TLC (DCM:acetone=2:3) to give pure I-A6 (4 mg, 1.8%) and I- A7 (20 mg, 9%) as a solid.

[0507]I-A6: ¹ H-NMR(400 MHz, CDCl₃) δ 9.26 (s, 1H), 8.19-8.14 (m, 1H), 7.98 (s, 1H), 7.55-7.50 (m, 1H), 5.35-5 .18 (m, 2H), 2.70-2.61 (m, 1H), 2.29-2.09 (m, 3H), 1.84-1.71 (m, 2H), 1.55 -1.40 (m, 10H), 1.38-1.35 (m, 4H), 1.31-1.22 (m, 3H), 1.20-1.11 (m, 2H), 1 .08-1.00 (m, 1H), 0.94 (s, 3H), 0.81 (s, 3H), 0.70 (s, 3H);LC-ELSDpurity 99%;MS ESI calculated for C₂₉H₄₂N₃O₂ [M+H]⁺ 464, 464 found.

[0508]I-A7: ¹ H-NMR(400 MHz, CDCl₃) δ 8.79 (s, 1H), 8.36-8.31 (m, 1H), 8.09 (s, 1H), 7.67-7.62 (m, 1H), 5.31-5 .19 (m, 2H), 2.70-2.62 (m, 1H), 2.29-2.11 (m, 3H), 1.81-1.69 (m, 2H), 1.64 -1.60 (m, 1H), 1.53-1.39 (m, 9H), 1.36 (s, 3H), 1.35-1.21 (m, 4H), 1.20-1 .13 (m, 2H), 1.08-1.01 (m, 1H), 0.94 (s, 3H), 0.82 (s, 3H), 0.72 (s, 3H);LC-ELSDpurity 99%;MS ESI calculated for C₂₉H₄₂N₃O₂ [M+H]⁺ 464, 464 found.

[ 0509 ] EXAMPLE I-8 and I-9: synthesis of 1-((3R,5R,8S,9S,10R,13S,14S,17S)-3-hydroxy-3,5,10,13-tetramethylhexadecahydro-1H- cyclopenta[a]phenanthrene-17-yl)-2-(5-methyl-1H-tetrazol-1-yl)ethan-1-one (I-A8) and 1-((3R,5R,8S,9S,10R ,13S,14S,17S)-3-hydroxy-3,5,10,13-tetramethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(5-methyl-2H-tetrazol-2-yl) ethan-1-one (I-A9)

[ 0510 ] To a mixture of I-AI (200 mg, 0.5 mmol) and K ₂ CO ₃ (129 mg, 0.9 mmol) in acetone (5 ml) at 15°C was added 5-methyl-2H-1, 2,3,4-tetrazole (59.2 mg, 0.7 mmol). The reaction mixture was stirred at 15°C for 16 hours. The reaction mixture was filled with water (20 ml) and extracted with EtOAc (2×20 ml). The combined organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and evaporated in vacuo to give the product, which was purified by flash column chromatography (EtOAc in PE, 50%~80%) to give I-A8 (65 mg, 32% ) as a solid and I-A9 (45 mg, 22%) as a solid.

[ 0511 ] I-A8: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 5.21-4.97 (m, 2H), 2.68-2.59 (m, 1H), 2.47 (s , 3H), 2.30-2.03 (m, 3H), 1.86-1.67 (m, 2H), 1.65-1.57 (m, 2H), 1.53-1.38 (m, 9H), 1.37 (s, 3H), 1.32-1.11 (m, 5H), 1.08-1.01 (m, 1H), 0.95 (s, 3H), 0.81 (s, 3H), 0.66 (s, 3H); LC ELSD purity 99%; MS ESI calculated for C ₂₅ H ₃₉ N ₄ O [M+HH ₂ O] ⁺ 411, found 411

[ 0512 ] I-A9: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 5.40-5.29 (m, 2H), 2.65-2.53 (m, 4H), 2.29-2 .15 (m, 2H), 2.12-2.04 (m, 1H), 1.84-1.71 (m, 2H), 1.66-1.57 (m, 2H), 1.52 -1.39 (m, 7H), 1.39-1.33 (m, 5H), 1.29-1.11 (m, 5H), 1.07-0.99 (m, 1H), 0 .94 (s, 3H), 0.81 (s, 3H), 0.69 (s, 3H); LC-ELSD purity 99%; MS ESI calculated for C ₂₅ H ₃₉ N ₄ O [M+HH ₂ O] ⁺ 411, found 411.

[ 0513 ] Formula II, abbreviations : PE: petroleum ether; EtOAc: ethyl acetate; THF: tetrahydrofuran; PCC: pyridinium chlorochromate; TLC: thin layer chromatography; PCC: pyridinium chlorochromate; t-BuOK: potassium tert-butoxide; 9-BBN: 9-borabicyclo[3.3.1]nonane; Pd( t -Bu ₃ P) ₂ : bis(tri-tert-butylphosphine)palladium(0); AcCl: acetyl chloride; i -PrMgCl: isopropyl magnesium chloride; TBSCl: tert-butyl(chloro)dimethylsilane; ( i- PrO) _4Ti : titanium tetraisopropoxide; BHT: 2,6-di-tert-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 periodinan; EtMgBr: ethyl magnesium bromide; EtOAc: ethyl acetate; TEA: triethylamine; AlaOH: alanine; Boc: tert-butoxycarbonyl; Py: pyridine; TBAF: tetra-n-butylammonium fluoride; THF: tetrahydrofuran; TBS: tert-butyldimethylsilyl; TMS: trimethylsilyl; TMSCF ₃ : (trifluoromethyl)trimethylsilane; Ts: para-toluenesulfonyl; Bu: butyl; Ti(OiPr) ₄ : tetraisopropoxytitanium; LAH: lithium aluminum hydride; LDA: lithium diisopropylamide; LiOH·H ₂ O: lithium hydroxide hydrates; MAD: methyl aluminum bis(2,6-di-tert-butyl-4-methylphenoxide); MeCN: acetonitrile; NBS: N-bromosuccinimide; Na ₂ SO ₄ : sodium sulfate; Na ₂ S ₂ O ₃ : sodium thiosulfate; PE: petroleum ether; MeCN: acetonitrile; MeOH: methanol ; Boc: tert-butoxycarbonyl; MTBE: methyl tert-butyl ether; K-selectride: potassium tri(sec-butyl)borohydride.

General schemes

Scheme II -1

Scheme II -2

Scheme II -3

Scheme II -4

Scheme II -5

Scheme II -6

Scheme II -7

[ 0514 ] Example II-1: Synthesis of ((3R,5R,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene- 17-yl)((S)-3-phenylpyrrolidin-1-yl)methanone (II-1)

[ 0515 ] Experimental data on intermediate II-G2 can be found in Example II- 10.

A solution of II-G2 (50 mg, 0.143 mmol), EDCI (54.9 mg, 0.287 mmol) and (3S)-3-phenylpyrrolidine (25.3 mg, 0.172 mmol) in pyridine (2 ml) was stirred at 35°C within 18 hours. The mixture was treated with water (5 ml), extracted with EtOAc (2×8 ml). The organic layers were washed with brine (2×10 ml), dried over Na ₂ SO ₄ , filtered, and evaporated in vacuo to form an oil (35 mg). The product was purified by preparative HPLC (instrument: BF; column: Agela DuraShell 150 mm_25 mm_5 μm; conditions: water (0.225% FA)-ACN, start B: 69, end B: 99, gradient time (minutes): 8.5, time retention 100% B (minutes): 2; flow rate (ml/min): 30; injection: 7) to form II-1 (20 mg, 29%) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ_H 7.37-7.29 (m, 2H), 7.26-7.19 (m, 3H), 4.11-3.97 (m, 1H), 3.94-3.85 (m, 0 ,5H), 3.81-3.71 (m, 0.5H), 3.58-3.26 (m, 3H), 2.60-2.48 (m, 1H), 2.40-2 .16 (m, 2H), 2.09-1.88 (m, 2H), 1.87-1.61 (m, 6H), 1.59-1.47 (m, 4H), 1.45 -1.28 (m, 8H), 1.27-1.09 (m, 8H), 0.85-0.72 (m, 6H).

LC-ELSD/MS retention time (Rt) = 1.252 min in 2 min chromatography, 30-90AB_2MIN_E.M, 99% purity, MS ESI calculated for C ₃₂ H ₄₈ NO ₂ [M+H] ⁺ 478, found 478.

(Mobile phase: 1.5 ml/4 L TFA in water (solvent A) and 0.75 ml/4 L TFA in acetonitrile (solvent B), using a 30%-90% elution gradient (solvent B) for 0.9 minutes and hold at 90% for 0.6 minutes at a flow rate of 1.2 ml/min; column: Xtimate C18 2.1*30 mm, 3 µm; wavelength: UV 220 nm; column temperature: 50^oC; MS ionization: ESI; detector: PDA&ELSD).

[ 0516 ] Example II-2: Synthesis of 1-((3R,5S,8S,9S,10R,13S,14S,17S)-3-hydroxy-3,13-dimethyl-10-vinylhexadecahydro-1H-cyclopenta[a] phenanthrene-17-yl)ethan-1-one (II-A4)

[ 0517 ] Synthesis II-A2

To a suspension of methyltriphenylphosphonium bromide (16.27 g, 45.45 mmol) in anhydrous THF (30 ml) was added KOtBu (5.15 g, 45.9 mmol) under nitrogen (N ₂ ) atmosphere. The mixture was heated at reflux for 1 hour. Compound II-A1 (5.0 g, 15.15 mmol) in anhydrous THF (15 ml) was then added to the above refluxing solution, and stirred at reflux for 3 hours. After cooling to room temperature, the solution was poured into brine (100 ml). The aqueous solution was extracted with ethyl acetate (50 ml×3). The extracts were washed with brine (50 ml x 2), dried over Na ₂ SO ₄ , filtered, evaporated and purified by silica gel column chromatography (petroleum ether/ethyl acetate 20/1 to 10/1) to give 3.82 g (11.65 mmol, yield 76.90%) II-A2 as a solid.

Connection II-A2 :

¹ H-NMR(500 MHz, CDCl₃) δ_H (million^-1): 5.88 (1H, dd, J=11.0 Hz, J=17.0 Hz), 5.33 (1H, dd, J=1.5 Hz, J=11.5 Hz), 5. 10 (1H, t×d, J=2.0 Hz, J=7.5 Hz), 5.00 (1H, dd, J=1.5 Hz, J=11.5 Hz), 1.63 ( 3H, t×d, J=2.0 Hz, 7.0 Hz), 1.15 (3H, s), 0.78 (3H, s).

[ 0518 ] Synthesis II-A3

To a solution of compound II-A2 (3.82 g, 11.65 mmol) in anhydrous THF (50 ml) was added borane-tetrahydrofuran complex (15 ml of 1.0 M solution in THF), and the reaction mixture was stirred at ambient temperature in for 3 hours, and 10% aqueous NaOH solution (5 ml) was slowly added. The mixture was cooled in ice and a 30% aqueous solution of H ₂ O ₂ (10 ml) was slowly added. The mixture was stirred at ambient temperature for 1 hour, and then extracted with CH ₂ Cl ₂ (3×50 ml). The combined CH ₂ Cl ₂ extracts were washed with a 10% aqueous solution of Na ₂ S ₂ O ₃ (2×20 ml), then directly used in the next step without further purification.

[ 0519 ] Synthesis II-A4

CompoundII-A3from the last stage dissolved in 100 ml of dichloromethane, cooled to 0°C, and 4.0 g of PCC was added at 0°C. The mixture was then stirred for 6 hours. The mixture was filtered, evaporated and purified by flash silica gel eluting chromatography using (petroleum ether/ethyl acetate=12/1~6/1) to give 3.15 g (9.15 mmol, 78.54%, two steps) of compoundII-A4in the form of a solid.

¹ H-NMR(500 MHz, CDCl₃) δ_H (million^-1): 5.85 (1H, dd, J=11.5 Hz, J=17.5 Hz), 5.32 (1H, dd, J=2.0 Hz, J=11.5 Hz), 4, 98 (1H, dd, J=2.0 Hz, J=11.5 Hz), 2.51 (1H, t, J=9.5 Hz), 2.10 (3H, s), 1.15 ( 3H, s), 0.51 (3H, s).LC-MS:rt=1.88 min,m/z=327.0 [M-H₂O+H]⁺, m/z=345.1 [M+H]⁺.

[0520] Example II-3: Synthesis of 1-((3R,5S,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a] phenanthrene-17-yl)ethan-1-one (II-A5)

Compound II-A4 (1.0 g, 2.91 mmol) was dissolved in 20 ml anhydrous MeOH, and 100 mg Pd/C was added. The reaction mixture was stirred at room temperature under H ₂ from a balloon overnight, filtered, the resulting solution was evaporated and purified by silica gel column chromatography (petroleum ether/ethyl acetate 12/1 to 6/1) to give 896 mg (2.59 mmol , yield 89.0%) of compound II-A5 in the form of a solid.

¹ H-NMR(500 MHz, CDCl₃) δ_H (million^-1): 2.52 (1H, t, J=8.5 Hz), 2.11 (3H, s), 1.20 (3H, s), 0.93 (3H, t, J=7.0 Hz ), 0.63 (3H, s).

[0521] Example II-4: Synthesis of 1-((3R,5S,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a] phenanthrene-17-yl)-2-(1H-pyrazol-1-yl)ethan-1-one (II-A7)

[0522] Synthesis II-A6:

Compound II-A5 (100 mg, 0.29 mmol) was dissolved in 10 ml anhydrous MeOH, and 3 drops of Br ₂ and 2 drops of aqueous HBr were added. The reaction mixture was stirred at room temperature for three hours, then the solution was poured into ice water (30 ml). The aqueous solution was extracted with ethyl acetate (20 ml×2). The extracts were dried over MgSO ₄ , filtered, and evaporated to yield 94 mg of compound II-A6 as a solid.

[0523] Synthesis II-A7

64 mg (0.15 mmol) of compound I-A6 was dissolved in 8 ml of anhydrous THF and 100 mg (0.77 mmol) K ₂ CO ₃ , 100 mg (1.47 mmol) pyrazole were added. The reaction mixture was stirred at room temperature overnight. The solution was then diluted with ethyl acetate (100 ml). The resulting solution was washed with brine (100 ml), dried over sodium sulfate and evaporated in vacuo . The residue was purified by reverse phase preparative HPLC to yield 20 mg (0.05 mmol, 32.36%) of compound II-A7 as a solid.

¹ H-NMR(500 MHz, CDCl₃) δ_H (million^-1): 7.54 (1H, d, J=2.0 Hz), 7.40 (1H, d, J=2.0 Hz), 6.33 (1H, t, J=2.0 Hz), 4.95 (1H, AB, J=18.0 Hz), 4.87 (1H, AB, J=17.5 Hz), 2.57 (1H, t, J=9.0 Hz), 1, 20 (3H, s), 0.93 (3H, t, J=7.5 Hz), 0.70 (3H, s).

[0524] Example II-5: Synthesis of 1-((3R,5S,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a] phenanthrene-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one (II-A8) and 1-((3R,5S,8S,9S,10S,13S ,14S,17S)-10-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(2H-1,2,3-triazol-1-yl) ethan-1-one (II-A8a)

To II-A6 (120 mg, 0.28 mmol) dissolved in THF (8 ml) was added K ₂ CO ₃ (200 mg, 1.54 mmol) and 1H-1,2,3-triazole (0.5 ml, 8.6 mmol). The reaction mixture was stirred at room temperature overnight. The solution was then diluted with ethyl acetate (100 ml). The resulting solution was washed with brine (100 ml), dried over sodium sulfate and evaporated in vacuo . The residue was purified by reverse phase preparative HPLC to yield II-A8 ( 24 mg, 0.06 mmol, 20.75% yield) and II-A8a (23 mg, 0.06 mmol, 19.89% yield) as solids.

II-A8 :

¹ H-NMR(500 MHz, CDCl₃) δ_H (million^-1): 7.75 (1H, s), 7.64 (1H, s), 5.26 (1H, AB, J=18.0 Hz), 5.13 (1H, AB, J=18.0 Hz ), 2.64 (1H, t, J=8.5 Hz), 1.21 (3H, s), 0.94 (3H, t, J=7.5 Hz), 0.69 (3H, s );LC-MS: rt=2.25 min, m/z=414.4 [M+H]⁺.

II-A8a :

¹ H-NMR(500 MHz, CDCl₃) δ_H (million^-1): 7.68 (2H, s), 5.25 (1H, AB, J=17.0 Hz), 5.21 (1H, AB, J=17.5 Hz), 2.57 (1H, t , J=9.0 Hz), 1.21 (3H, s), 0.94 (3H, t, J=7.5 Hz), 0.73 (3H, s);LC-MS: rt=2.40 min, m/z=414.4 [M+H]⁺.

[0525] Example II-6: Synthesis of 1-((3R,5S,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a] phenanthrene-17-yl)-2-morpholinoethan-1-one (II-A9)

To compound II-A6 (90 mg, 0.21 mmol) dissolved in THF (8 ml) was added K ₂ CO ₃ (100 mg, 0.77 mmol) and morpholine (0.5 ml, 5.74 mmol). The reaction mixture was stirred at room temperature overnight. The solution was diluted with ethyl acetate (100 ml). The resulting solution was washed with brine (100 ml), dried over sodium sulfate and evaporated in vacuo . The residue was purified by reverse phase preparative HPLC to yield 50 mg (0.11 mmol, 55.24%) of product II-A9 as a solid.

¹ H-NMR(500 MHz, CDCl₃) δ_H (million^-1): 3.75 (4H, t, J=4.5 Hz), 3.18 (1H, AB, J=17.5 Hz), 3.17 (1H, AB, J=17.5 Hz), 2.56 (1H, t, J=8.5 Hz), 2.51-2.45 (4H, m), 1.20 (3H, s), 0.93 (3H, t, J=7, 5 Hz), 0.64 (3H, s);LC-MS: rt=2.40 min, m/z=432.4 [M+H]⁺.

[0526] Example II-7: Synthesis of 1-((3R,5S,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a] phenanthrene-17-yl)-2-(4-(methylsulfonyl)piperazin-1-yl)ethan-1-one (II-A10)

To compound II-A6 (150 mg, 0.35 mmol) dissolved in THF (8 ml) was added K ₂ CO ₃ (160 mg, 1.15 mmol) and 1-(methylsulfonyl)piperazine (150 mg, 0.92 mmol ). The reaction mixture was stirred at room temperature overnight. The solution was diluted with ethyl acetate (100 ml), and the resulting solution was washed with brine (100 ml), dried over sodium sulfate and evaporated in vacuo . The residue was purified by reverse phase preparative HPLC to yield 33 mg (0.06 mmol, 18.56%) of product II-A10 as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ_H (million^-1): 3.30 (4H, t, J=4.0 Hz), 3.25 (2H, s), 2.78 (3H, s), 2.64~2.57 (4H, m), 2 .51 (1H, t, J=9.2 Hz), 1.21 (3H, s), 0.93 (3H, t, J=7.2 Hz), 0.64 (3H, s);LC-MS: rt=2.33 min, m/z=509.4 [M+H]⁺.

[0527] Example II-8: Synthesis of 1-((3R,5S,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a] phenanthrene-17-yl)-2-hydroxyethan-1-one (II-A11)

Triethylamine (1 ml) and 2,2,2-trifluoroacetic acid (0.5 ml) were added to compound II-A6 (300 mg, 0.71 mmol) dissolved in THF (8 ml). The mixture was heated at reflux for 1 hour, then 400 mg (2.9 mmol) of sodium 2,2,2-trifluoroacetate was added and the resulting solution was refluxed overnight, then the solution was poured into ice water (50 ml). The aqueous solution was extracted with ethyl acetate (30 ml×2). The extracts were dried over MgSO ₄ and evaporated in vacuo . The residue was purified by reverse phase preparative HPLC to yield 88 mg (0.24 mmol, 34.23%) of product II-A11 as a solid.

¹ H-NMR(500 MHz, CDCl₃) δ_H (million^-1): 4.20 (1H, AB×d, J=4.0 Hz, J=19.0 Hz), 4.15 (1H, AB×d, J=4.0 Hz, J=19.0 Hz ), 3.28 (1H, t, J=4.0 Hz), 2.44 (1H, t, J=9.0 Hz), 2.20 (1H, dd, J=11.0 Hz, J =20.5 Hz,), 1.20 (3H, s), 0.93 (3H, AB, J=7.5 Hz), 0.68 (3H, s).

[0528] Example II-9: Synthesis of 1-((3R,5R,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a] phenanthrene-17-yl)ethan-1-one (II-E12)

[0529] Synthesis II-E2

To a solution of II-E1 (226 g, 742 mmol) in DCM (1000 ml) was added 1H-imidazole (125 g, 1.85 mol) and tert-butylchlorodimethylsilane (200 g, 1.33 mol) at 25°C under N ₂ . After stirring at 25°C for 4 hours, the mixture was poured with water (500 ml). The organic layer was separated. The aqueous phase was extracted with DCM (2×300 ml). The combined organic phase was washed with saturated brine (500 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated in vacuo. The residue was purified by silica gel chromatography (PE/EtOAc=100/1 to 20/1) to give product II-E2 (240 g, 77%) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ_H 3.80-3.75 (m, 1H), 3.60-3.50 (m, 1H), 2.65-2.50 (m, 1H), 2.48-2.40 (m, 1H ), 2.40-2.25 (m, 3H), 2.20-1.65 (m, 7H), 1.65-1.10 (m, 9H), 0.81-0.80 (m , 13H), 0.00 (m, 6H).

[0530] Synthesis II-E3

To a solution of BHT (753 g, 3.42 mol) in toluene (2000 ml) under nitrogen at 0° C., a solution of trimethylaluminum (855 ml, 2 M, 1.71 mol) was added dropwise. After stirring at 0°C for 30 minutes, the solution was cooled to -78°C, followed by the dropwise addition of a solution of II-E2 (240 g, 573 mmol) in toluene (500 ml) at -78°C. After stirring at -78°C for 1 hour, a solution of MeMgBr (476 ml, 1.43 mol, 3 M in diethyl ether) was added dropwise at -78°C. The resulting solution was stirred at a temperature from -78°C to -60°C for 2 hours. The reaction mixture was poured at -60°C into a saturated solution of citric acid (3000 ml). After stirring at 25°C for 25 minutes, the aqueous layer was extracted with ethyl acetate (3×1000 ml). The combined organic layer was dried over Na ₂ SO ₄ and evaporated in vacuo to give an oil, which was purified on a silica gel column (PE:EtOAc=50:1, 30:1, 15:1, 10:1, 5:1) to give II-E3 (60 g, 24%) as a solid and II-E3 (1.2 kg).

¹ H-NMR(400 MHz, CDCl₃) δ_H 3.80-3.75 (m, 1H), 3.45-3.35 (m, 1H), 2.55-2.40 (m, 1H), 2.25-1.65 (m, 7H ), 1.65-1.35 (m, 6H), 1.35-1.15 (m, 12H), 0.90-0.75 (m, 12H), 0.05 (m, 6H).

[0531] Synthesis II-E4

To a suspension of MePPh ₃ Br (170 g, 460 mmol) in THF (200 ml) was added t -BuOK (51.6 g, 460 mmol) at 25°C. After addition, the reaction mixture was heated to 45°C and stirred for 1 hour. A solution of II-E3 (50 g, 115 mmol) in THF (50 ml) was then added and the reaction mixture was stirred at 45°C for 16 hours. The mixture was treated with NH ₄ Cl solution (100 ml, saturated, aqueous). The organic layer was separated. The aqueous phase was extracted with EtOAc (2×100 ml). The combined organic phase was washed with saturated brine (2×50 ml), dried over anhydrous Na ₂ SO ₄ , filtered, and evaporated. The residue was purified by flash column chromatography (0~10% EtOAc in PE) to give II-E4 (48 g, 93%) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ_H 5.25-5.05 (m, 1H), 3.80-3.75 (m, 1H), 3.45-3.35 (m, 1H), 2.45-2.35 (m, 1H ), 2.35-2.15 (m, 2H), 2.00-1.80 (m, 2H), 1.75-1.35 (m, 13H), 1.35-1.05 (m , 11H), 0.95-0.80 (m, 9H), 0.80-0.75 (m, 3H), 0.05 (m, 6H).

[0532] Synthesis II-E5

To a solution of II-E4 (48 g, 107 mmol) in THF (500 ml) at 0° C. was added 9-BBN dimer (104 g, 428 mmol) under N ₂ . The solution was stirred at 65°C for 2 hours. After cooling to 0°C, EtOH (49.2 g, 1.07 mol) was added. NaOH solution (214 mL, 5 M, 1.07 mol) was then added very slowly. After the addition, H ₂ O ₂ (121 g, 1.07 mol, 30% in water) was added slowly and the internal temperature was maintained below 10°C. The mixture was stirred at 75°C under N ₂ for 1 hour. The mixture was re-cooled to 25°C. Then water (300 ml) was added. The organic layer was separated. The aqueous phase was extracted with EtOAc (3×100 ml). The combined organic phase was washed with saturated brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated in vacuo. The residue was recrystallized from THF/H ₂ O (100 ml/1500 ml) at 25°C and purified on a flash chromatography column (0~20% EtOAc in PE) to give II-E5 (45 g, 82%) as solid matter.

¹ H-NMR(400 MHz, CDCl₃) δ_H 3.80-3.75 (m, 1H), 3.75-3.55 (m, 1H), 3.45-3.35 (m, 1H), 2.04 (s, 4H), 2. 01-1.75 (m, 4H), 1.75-1.55 (m, 3H), 1.55-1.25 (m, 12H), 1.25-1.05 (m, 8H), 0.89 (s, 9H), 0.63 (s, 3H), 0.05-0.01 (m, 6H).

[0533] Synthesis II-E6

To a solution of II-E5 (15 g, 32.2 mmol) in pyridine (200 ml) was added benzoyl chloride (22.6 g, 161 mmol) and DMAP (392 mg, 3.22 mmol). After stirring at 80°C for 4 hours, the reaction mixture was poured into water (1000 ml). The mixture was stirred for 10 minutes, filtered and the filter cake dissolved in EtOAc (200 ml). The solution was washed with brine (2×50 ml), dried over Na ₂ SO ₄ , filtered, and evaporated. The residue was purified by flash column chromatography (0~10% EtOAc in PE) to give II-E6 (19 g, 84%) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ_H 8.05-8.00 (m, 4H), 7.65-7.50 (m, 2H), 7.45-7.35 (m, 4H), 5.25-5.15 (m, 1H ), 3.80-3.75 (m, 1H), 3.45-3.35 (m, 1H), 2.30-2.20 (m, 1H), 2.25-2.00 (m , 2H), 1.95-1.75 (m, 4H), 1.75-1.25 (m, 5H), 1.25-1.00 (m, 13H), 0.95-0.75 (m, 13H), 0.70 (s, 3H), 0.06 (m, 6H).

[0534] Synthesis II-E7

To a solution of II-E6 (18.9 g, 28.0 mmol) in acetone (200 ml) was added p -TsOH (10.4 g, 56.0 mmol). The reaction mixture was stirred at 25°C for 5 hours, filled with water (200) and extracted with EtOAc (2×200 ml). The combined organic extracts were washed with NaHCO ₃ solution (50 ml, 10%) and brine (50 ml), and dried over Na ₂ SO ₄ , filtered and evaporated to give II-E7 (15 g) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ_N 8.05-8.00 (m, 4H), 7.65-7.50 (m, 2H), 7.45-7.35 (m, 4H), 5.25-5.15 (m, 1H ), 4.00-3.90 (m, 1H), 3.65-3.50 (m, 1H), 2.30-2.20 (m, 1H), 2.20-1.75 (m , 7H), 1.75-1.25 (m, 6H), 1.25-1.05 (m, 12H), 0.91 (s, 4H), 0.70 (s, 3H).

[0535] Synthesis II-E8

To a solution of II-E7 (15 g, 26.8 mmol) in DCM (100 ml) at 25°C was added PCC (11.5 g, 53.6 mmol) and silica gel (10 g). After stirring at 25°C for 2 hours, the reaction mixture was filtered and the residue was washed with anhydrous DCM (2×50 ml). The combined filtrate was evaporated in vacuo. The residue was purified by flash column chromatography (0~10% EtOAc in PE) to give II-E8 (7 g, 58%) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ_N 0.97 (s, 1H) 8.05-8.00 (m, 4H), 7.65-7.50 (m, 2H), 7.45-7.35 (m, 4H), 5.25 -5.15 (m, 1H), 2.30-2.20 (m, 1H), 2.20-1.75 (m, 12H), 1.75-1.01 (m, 14H), 1 .01-0.80 (m, 4H) 0.78 (s, 3H).

[0536] Synthesis II-E9

t -BuOK (3.45 g, 30.8 mmol) was added to a suspension of PPh ₃ EtBr (17.9 g, 30.8 mmol) in THF (100 ml) at 25°C. After stirring at 45°C for 1 hour, a solution of II-E8 (7 g, 15.4 mmol) in THF (20 ml) was added at 40°C. The reaction mixture was stirred at 40°C for 10 minutes and treated with a saturated solution of NH ₄ Cl (50 ml) and EtOAc (50 ml). The organic layer was separated and the aqueous phase was extracted with EtOAc (2×50 ml). The combined organic phase was washed with saturated brine (2×30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated. The residue was purified by flash column chromatography (0~20% EtOAc in PE) to give II-E9 (4.8 g, 90%) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ_H 8.05-8.00 (m, 4H), 7.65-7.50 (m, 2H), 7.45-7.35 (m, 4H), 6.40-6.25 (m, 1H ), 5.20-4.95 (m, 3H), 2.30-2.20 (m, 1H), 2.15-1.75 (m, 9H), 1.75-1.05 (m , 15H), 1.05-0.80 (m, 4H), 0.69 (s, 3H).

[0537] Synthesis II-E10

To a solution of II-E9 (2.5 g, 4.50 mmol) in THF (30 ml) was added Pd-C (dry, 10%, 0.2 g) under N ₂ . The suspension was degassed in vacuum and purged with hydrogen three times. The mixture was stirred under H ₂ (30 psi, (0.21 MPa)) at 25°C for 16 hours to form a slurry. The reaction mixture was filtered through a pad of Celite and washed with THF (3×20 ml). The filtrate was evaporated to give II-E10 (2.4 g, 96%) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ_H 8.05-8.00 (m, 4H), 7.65-7.50 (m, 2H), 7.45-7.35 (m, 4H), 5.20-5.10 (m, 1H ), 2.30-2.20 (m, 1H), 2.10-1.75 (m, 6H), 1.75-1.30 (m, 13H), 1.30-1.05 (m , 11H), 0.85-0.75 (m, 3H), 0.70 (s, 3H).

[0538] Synthesis II-E11

To a solution of II-E10 (2.4 g, 0.875 mmol) in THF (10 ml) and MeOH (10 ml) was added NaOH (1.72 g, 43.1 mmol) and H ₂ O (4 ml) at 25° WITH. the solution was stirred at 25°C for 48 hours. The residue was poured into water (30 ml). The mixture was extracted with EtOAc (2×20 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated in vacuo to give the product, which was triturated with MeCN (10 ml) to give the desired product II-E11 (1.6 g) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ_H 3.75-3.65 (m, 1H), 2.05-1.75 (m, 4H), 1.75-1.35 (m, 13H), 1.35-1.05 (m, 16H ), 0.85-0.75 (m, 3H), 0.64 (s, 3H).

[0539] Synthesis II-E12

To a solution of II-E11 (1.6 g, 4.59 mmol) in DCM (20 ml) was added PCC (1.97 g, 1.51 mmol) and silica gel (1 g) at 25°C. After stirring at 25°C for 3 hours, the reaction mixture was filtered and the residue was washed with anhydrous DCM (2×10 ml). The combined filtrate was evaporated in vacuo. The residue was purified by flash column chromatography (0~50% EtOAc in PE) to give II-E12 (1.4 g, 88%) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ_H 2.60-2.50 (m, 1H), 2.25-2.05 (m, 4H), 2.05-1.90 (m, 2H), 1.80-1.65 (m, 6H ), 1.65-0.30 (m, 8H), 1.30-1.05 (m, 11H), 0.85-0.70 (m, 3H), 0.59 (s, 3H).

LC-ELSD/MS Rt=1.223 min in 2 min chromatography, 30-90AB_2MIN_E, 99% purity, MS ESI calculated for C ₂₃ H ₃₇ O [M+HH ₂ O] ⁺ 329, found 329.

(Mobile phase: 1.5 ml/4 L TFA in water (solvent A) and 0.75 ml/4 L TFA in acetonitrile (solvent B), using a 30%-90% elution gradient (solvent B) for 0.9 minutes and hold at 90% for 0.6 minutes at a flow rate of 1.2 ml/min; column: Xtimate C18 2.1*30 mm, 3 µm; wavelength: UV 220 nm; column temperature: 50°C; MS ionization: ESI; detector: PDA&ELSD).

[0540] Example II-10: Synthesis of (3R,5R,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3,13-dimethyl-N-phenylhexadecahydro-1H-cyclopenta[a ]phenanthrene-17-carboxamide (II-G3)

[0541] Experimental data on II -E12 can be found in Example II-8.

[0542] Synthesis II-G2

Liquid bromine (2.28 g, 14.3 mmol) was slowly added to a vigorously stirred aqueous sodium hydroxide solution (5.73 mL, 3 M, 17.2 mmol) at 0°C. When all the bromine had dissolved, the mixture was diluted with cold dioxane (10 ml), and slowly added to a stirred solution of II-E12 (500 mg, 1.44 mmol) in dioxane (10 ml) and water (10 ml), and a precipitate formed, and the reaction mixture was stirred at 20°C for 16 hours. The remaining oxidizing reagent was quenched with an aqueous solution of Na ₂ S ₂ O ₃ (20 ml), and then the mixture was heated at 80°C until the solid material dissolved. Acidification of the solution with hydrochloric acid (3N) led to the formation of a precipitate. The solid was filtered and washed with water (3×20 ml) to form a solid, which was dried in vacuo to give II-G2 (450 mg) as a solid.

[0543] Synthesis II-G3

To a solution of II-G2 (100 mg, 0.2869 mmol) in pyridine (5 ml) was added EDCI (82.4 mg, 0.4303 mmol). After stirring at 20°C for 10 minutes, aniline (29.3 mg, 0.3155 mmol) was added. The mixture was stirred at 20°C for 16 hours. Water (20 ml) was added to the reaction mixture and stirred for 30 minutes. The suspension was filtered and recrystallized from MeCN (5 ml) at 20°C to form II-G3 (63 mg, 52%) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ_H 7.60-7.45 (m, 2H), 7.35-7.27 (m, 2H), 7.20-7.05 (m, 1H), 6.93 (s, 1H), 2. 35-2.25 (m, 2H), 2.10-1.95 (m, 2H), 1.90-1.50 (m, 6H), 1.50-1.05 (m, 19H), 0.85-0.75 (m, 3H), 0.73 (s, 3H).

LC-ELSD/MS purity 99%, MS ESI calculated for C ₂₈ H ₄₂ NO ₂ [M+H] ⁺ 424, found 424.

[0544] Example II-11: Synthesis of 1-((3R,5R,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a] phenanthren-17-yl)-2-(6-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)ethan-1-one (II-M2), 1-((3R, 5R,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(5-methoxy-1H -benzo[d][1,2,3]triazol-1-yl)ethan-1-one (II-M2a) and 1-((3R,5R,8S,9S,10S,13S,14S,17S)- 10-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(5-methoxy-2H-benzo[d][1,2,3]triazol-2 -yl)ethan-1-one (II-M2b)

[0545] Experimental data on II-E12 can be found in Example II- 8.

Synthesis II-M1

[0546] To a solution of II-E12 (500 mg, 1.44 mmol) in MeOH (10 ml) was added HBr (58.2 mg, 0.288 mmol, 40% in water) and Br ₂ (241 mg, 1.51 mmol ) at 25°C. After stirring at 25°C for 2 hours, the mixture was poured with a saturated aqueous solution of NaHCO ₃ (20 ml). The mixture was extracted with EtOAc (2×20 ml). The combined organic phase was washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ , filtered, evaporated in vacuo to give II-M1 (610 mg) as a solid, which was used directly in the next step.

Synthesis of II-M2, II-M2a, II-M2b

[0547] To a solution of II-M1 (510 mg, 1.19 mmol) in acetone (10 ml) was added K ₂ CO ₃ (245 mg, 1.78 mmol) and 5-methyl-2H-tetrazole (211 mg, 1 .42 mmol) at 20°C. The mixture was stirred at 20°C for 16 hours. The reaction mixture was treated with water (20 ml). The mixture was extracted with EtOAc (2×20 ml). The combined organic phase was washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ , filtered, and evaporated in vacuo. The residue was purified using HPLC (column: YMC-Actus Triart C18 100*30mm*5μm), gradient: 75-95% B (water (0.05% HCl)-ACN), flow rate: 25 ml/min) to obtain a mixture of II-M2 and II-M2a (peak 1, 320 mg) as a solid, and II-M2b (peak 2, 50 mg) as a solid.

A mixture of II-M2 and II-M2a (320 mg) was purified using SFC (column: DAICEL CHIRALCEL OJ-H (250 mm*30 mm, 5 μm)), gradient: 35-35% B (0.1% NH ₃ H ₂ O, B=EtOH), flow rate: 200 ml/min) to obtain II-M2 (peak 1, 49 mg, 8%) as a solid, and II-M2a (peak 2, 62 mg, 10% ) in the form of a solid.

The residue II-M2b (50 mg) was dissolved in MeCN (5 ml) at 25°C and evaporated in vacuo to give II-M2b (45 mg, 8%) as a solid.

II-M2:

¹ H-NMR(400 MHz, CDCl₃) δ_H 7.90-7.80 (m, 1H), 7.05-6.95 (m, 1H), 6.75-6.55 (m, 1H), 5.45-5.25 (m, 2H ), 3.86 (s, 3H), 2.75-5.60 (m, 1H), 2.25-2.05 (m, 2H), 2.01-1.85 (m, 1H), 1.80-1.50 (m, 6H), 1.50-1.05 (m, 19H), 0.80-0.75 (m, 3H), 0.72 (s, 3H);MS ESI calculated for C_thirtyH₄₄N₃O₃ [M+H]⁺ 494, 494 found.

II-M2a:

¹ H-NMR(400 MHz, CDCl₃) δ 7.40-7.35 (m, 1H), 7.25-7.15 (m, 1H), 7.15-7.05 (m, 1H), 5.40-5.30 (m , 2H), 3.89 (m, 3H), 2.65-2.55 (m, 1H), 2.25-2.05 (m, 3H), 2.05-1.80 (m, 1H ), 1.75-1.50 (m, 7H), 1.50-1.30 (m, 7H), 1.30-1.05 (m, 10H), 0.85-0.75 (m , 3H), 0.70 (s, 3H);MS ESI calculated for C_thirtyH₄₄N₃O₃ [M+H]⁺ 494, 494 found.

II-M2b:

¹ H-NMR(400 MHz, CDCl₃) δ_H 7.5-7.70 (m, 1H), 7.15-7.05 (m, 2H), 5.55-5.35 (m, 2H), 3.88 (m, 3H), 2. 65-2.55 (m, 1H), 2.25-2.05 (m, 2H), 2.05-1.80 (m, 1H), 1.80-1.50 (m, 7H), 1.50-1.30 (m, 8H), 1.30-1.05 (m, 10H), 0.85-0.75 (m, 3H), 0.72 (s, 3H);MS ESI calculated for C_thirtyH₄₄N₃O₃ [M+H]⁺ 494, 494 found.

[0548] Example II-12-II-14

The following examples were made from II-M1 as in Example II-11, replacing 5-methyl-2H-tetrazole with the indicated nucleophiles.

Example No. Nucleophile Name ¹ H-NMR (400 MHz, CDCl3) MS ESI II-12 1H-pyrazole-4-carbo-nitrile 1-((3R,5R,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3,13-dimethylhexadeca-hydro-1H-cyclopenta[a]phenanthrene-17-carbonyl)- 1H-pyrazole-4-carbonitrile ( II-12 ) δ _H 7.85-7.75 (m, 2H), 5.05-4.80 (m, 2H), 2.60-2.50 (m, 1H), 2.25-2.10 (m , 1H), 2.10-1.90 (m, 2H), 1.75-1.50 (m, 6H), 1.50-1.25 (m, 8H), 1.25-1.05 (m, 11H), 0.85-0.70 (m, 3H), 0.65 (s, 3H) calculated for C ₂₇ H ₃₈ N ₃ O [M+H-H2O] ⁺ 420, found 420 II-13 2H -1,2,3-triazole 1-((3R,5R,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3,13-dimethylhexadeca-hydro-1H-cyclopenta[a]phenanthrene-17-yl)- 2-(2H-1,2,3-triazol-2-yl)ethan-1-one ( II-13 ) δ _H 7.67 (s, 2H), 5.28-5.17 (m, 2H), 2.56 (t, J =7.2 Hz, 1H), 2.24-2.14 (m, 1H), 2.10-2.04 (m, 1H), 1.99-1.90 (m, 1H), 1.80-1.50 (m, 9H), 1.47-1.36 ( m, 5H), 1.35-1.12 (m, 11H), 0.79 (t, J =7.2 Hz, 3H), 0.68 (s, 3H). calculated for C ₂₅ H ₃₉ N ₃ O ₂ [M+H] ⁺ 413.3, found 414.3. II-13a 2H -1,2,3-triazole 1-((3R,5R,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3,13-dimethylhexadeca-hydro-1H-cyclopenta[a]phenanthrene-17-yl)- 2-(1H-1,2,3-triazol-1-yl)ethan-1-one ( II-13a ) δ _H 7.76 (d, J =0.8 Hz, 1H), 7.64 (d, J =0.8 Hz, 1H), 5.20 (dd, J =18.0, 54.8 Hz , 2H), 2.64 (t, J =8.8 Hz, 1H), 2.27-2.16 (m, 1H), 2.13-2.05 (m, 1H), 2.01- 1.92 (m, 1H), 1.82-1.58 (m, 6H), 1.55-1.38 (m, 8H), 1.36-1.13 (s, 11H), 0. 80 (t, J =7.6 Hz, 3H), 0.65 (s, 3H). calculated for C ₂₅ H ₃₉ N ₃ O ₂ [M+H] ⁺ 413.3, found 414.3. II-14 5-methyl-1H-1,2,3,4-tetrazole 1-((3R,5R,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3,13-dimethylhexadeca-hydro-1H-cyclopenta[a]phenanthrene-17-yl)- 2-(5-methyl-2H-tetrazol-2-yl)ethan-1-one ( II-14 ) δ _H 5.34 (s, 2H), 2.65-2.58 (m, 1H), 2.56 (s, 3H), 2.21 (brd, J=10.4 Hz, 1H) , 2.10-1.91 (m, 2.5H), 1.82-1.60 (m, 6.5H), 1.49-1.29 (m, 10H), 1.26 (s, 10H), 0.80 (t, J=7.2 Hz, 3H), 0.69 (s, 1H). calculated for C ₂₅ H ₃₉ N ₄ O [MH ₂ O+H] ⁺ 411, found 411. II-14a 5-methyl-1H-1,2,3,4-tetrazole 1-((3R,5R,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3,13-dimethylhexadeca-hydro-1H-cyclopenta[a]phenanthrene-17-yl)- 2-(5-methyl-1H-tetrazol-1-yl)ethan-1-one ( II-14a ) δ _H 5.18-5.01 (m, 2H), 2.68-2.62 (m, 1H), 2.47 (s, 3H), 2.20 (bd, J = 9.2 Hz, 1H), 2.10-2.03 (m, 1H), 2.02-1.92 (m, 1H), 1.80-1.62 (m, 6H), 1.52-1, 32 (m, 9H), 1.27 (s, 10H), 0.81 (t, J =7.2 Hz, 3H), 0.66 (s, 3H) calculated for C ₂₅ H ₃₉ N ₄ O [MH ₂ O+H] ⁺ 411, found 411.

[0549] Example II-20-II-22

[0550] The following examples were made from II-G2 as in Example II-1, replacing (3S)-3-phenylpyrrolidine with the indicated nucleophile (amine).

Example No. Amine Name ¹ H-NMR (400 MHz, CDCl ₃ ) MS ESI II-20 ( 2S )-2-methyl-piperidine ((3R,5R,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)((S)- 2-methylpiperidin-1-yl)methanone ( II-20 ) δ _H 5.00-4.90 (m, 0.88H), 4.60-4.45 (m, 0.35H), 4.30-4.25 (m, 0.33H), 3.80 -3.75 (s, 0.90H), 3.10-2.95 (m, 1H), 2.70-2.55 (m, 1.70H), 2.40-2.20 (m, 1.40H), 2.05-1.80 (m, 1H), 1.80-1.50 (m, 4H), 1.50-1.30 (m, 9H), 1.30-1. 20 (m, 9H), 1.20-1.05 (m, 10H), 0.80-0.75 (m, 5H), 0.71 (s, 3H) calculated for C ₂₈ H ₄₈ NO ₂ [M+H] ⁺ 430, found 430. II-21 2-ethyl-piperidine ((3R,5R,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)((S)- 2-ethylpiperidin-1-yl)methanone ( II-21 ) δ 4.78-4.50 (m, 1H), 3.95-3.75 (m, 1H), 3.12-2.80 (m, 1H), 2.76-2.50 (m, 1H), 2.30-2.10 (m, 1H), 2.09-1.87 (m, 1H), 1.83-1.70 (m, 2H), 1.68-1.49 ( m, 17H), 1.40-1.27 (m, 6H), 1.27-1.10 (m, 10H), 0.89-0.75 (m, 6H), 0.72 (s, 2H). calculated for C ₂₉ H ₅₀ NO ₂ [M+H] ⁺ 444, found 444 II-21a 2-ethyl-piperidine ((3R,5R,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)((R)- 2-ethylpiperidin-1-yl)methanone ( II-21a ) δ 4.82-4.56 (m, 1H), 4.05-3.85 (m, 1H), 3.04-2.95 (m, 0.5H), 2.73-2.54 ( m, 1H), 2.53-2.38 (m, 0.5H), 2.37-2.30 (m, 1H), 1.99-1.92 (m, 1H), 1.68- 1.49 (m, 11H), 1.59-1.49 (m, 12H), 1.40-1.10 (m, 11H), 0.86-0.75 (m, 6H), 0. 72-0.68 (m, 3H). calculated for C ₂₉ H ₅₀ NO ₂ [M+H] ⁺ 444, found 444 II-22 Ammonium chloride (3R,5R,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide ( II-22 ) δ _H 5.24 (broadband, J = 11.6 Hz, 2H), 2.21-2.08 (m, 2H), 2.02-1.91 (m, 2H), 1.84- 1.59 (m, 6H), 1.51-1.30 (m, 8H), 1.29-1.09 (m, 11H), 0.79 (t, J = 7.6 Hz, 3H) , 0.70 (s, 3H). calculated for C ₂₂ H ₃₈ NO ₂ [M+H] ⁺ 348, found 348

[ 0551 ] Example II-30: Synthesis of ((3R,5R,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene- 17-yl)(o-tolyl)methanone (II-G5)

Synthesis II-G4

[0552] To the solutionII-G2(100 mg, 0.3 mmol) in DMF (3 ml) added HATU (163 mg, 0.4 mmol), TEA (57.9 mg, 0.6 mmol) and N, O-dimethylhydroxylamine hydrochloride (26.2 mg, 0.4 mmol) at 25°C. The mixture was stirred at 25°C for 16 hours. The reaction mixture was poured into water (50 ml) and extracted with DCM (2×50 ml). The combined organic phase was washed with brine (50 ml), dried over anhydrous Na₂SO₄, filtered and evaporated in vacuo to obtain a product, which was washed with LiCl solution (2x50 ml), brine (2x20 ml), dried over anhydrous Na₂SO₄, filtered, evaporated and purified on a flash chromatography column (0~20% EtOAc in PE) to give (95 mg, 95%) asII-G4 in the form of a solid.

¹ H-NMR(400 MHz, CDCl₃) δ_H 3.67 (s, 3H), 3.19 (s, 3H), 1.92 (t,J=8.0 Hz, 1H), 1.55-1.45 (m, 7H), 1.45-1.10 (m, 18H), 0.90-0.80 (m, 3H), 0, 78 (t,J=8.0 Hz, 3H), 0.72 (s, 3H).

[ 0553 ] Synthesis II-G5

To a solution of 1-bromo-2-methylbenzene (700 mg, 4.1 mmol) in THF (2 ml) was added t-BuLi (5.53 ml, 1.3 M, 7.2 mmol) at -70°C. The result was a suspension. The resulting mixture was stirred at -70°C for 15 minutes. II-G4 (80 mg, 0.2 mmol) in THF (2 ml) was added to a suspension of (2-methylphenyl)lithium at -70°C. The reaction mixture was stirred at 0°C for 10 minutes. The mixture was extracted with ethyl acetate (3×50 ml). The combined organic phase was washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated in vacuo to give a solid (95 mg). The material (20 mg) was purified by preparative HPLC to yield II-G5 (12 mg, 0.028 mmol) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ_H7.47 (d, 1H), 7.40-7.30 (m, 1H), 7.25-7.20 (m, 2H), 3.30 (t,J=8.0 Hz, 1H), 2.39 (s, 3H), 2.35-2.25 (m, 1H), 1.91 (t,J=8.0 Hz, 1H), 1.75-1.05 (m, 26H), 0.76 (t,J=8.0 Hz, 3H), 0.64 (s, 3H);MS ESI calculated for C29H43O2 [M+H]⁺ 423, 423 found.

[ 0554 ] EXAMPLE II-35: Synthesis of 1-((3R,5R,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H- cyclopenta[a]phenanthrene-17-yl)ethan-1-one (II-B9)

Synthesis II-B2

[ 0555 ] To a suspension of PPh ₃ MeBr (548 g, 1536 mmol) in THF (1000 ml) was added t -BuOK (172 g, 1536 mmol) at 15°C. After stirring at 45°C for 1 hour, a solution of II-B1 (200 g, 512 mmol, described in patent document "WO2016/134301, 2016, A2") in THF (500 ml) was added at 45°C, and the reaction the mixture was stirred at 45°C for 10 minutes. A saturated solution of NH ₄ Cl (500 ml) and EtOAc (500 ml) was added to the reaction mixture. The organic layer was separated and the aqueous phase was extracted with EtOAc (2×300 ml). The combined organic phase was washed with saturated brine (2×300 ml), dried over anhydrous Na ₂ SO ₄ , filtered, evaporated and triturated with MeOH/H ₂ O (1000 ml/1000 ml) at 15°C, and purified by chromatography on silica gel ( PE/EtOAc=50/1 to 20/1) to form II-B2 (137 g, 69%) as an oil.

¹ H-NMR(400 MHz, CDCl₃) δ 6.40-6.25 (m, 1H), 5.15-5.00 (m, 2H), 3.95-3.75 (m, 9H), 2.10-1.65 (m , 9H), 1.65-1.25 (m, 5H), 1.25-1.05 (m, 6H), 0.85-0.75 (m, 4H).

Synthesis II-B3

[ 0556 ] To a solution of II-B2 (70 g, 180 mmol) in THF (1000 ml) was added Pd-C (dry, 10%, 10 g) under N ₂ . The suspension was degassed in vacuum and purged with hydrogen three times. The mixture was stirred under H ₂ (30 psi (0.21 MPa)) at 25°C for 16 hours. The reaction mixture was filtered through a pad of Celite and washed with THF (3×500 ml). The filtrate was evaporated with the 2nd batch (70 g of II-B2) to form II-B3 (141 g) as an oil.

¹ H-NMR(400 MHz, CDCl₃) δ 3.95-3.75 (m, 9H), 2.10-1.90 (m, 2H), 1.90-1.65 (m, 8H), 1.65-1.25 (m , 4H), 1.25-1.05 (m, 8H), 0.80-0.45 (s, 7H).

Synthesis II-B4

[ 0557 ] To a solution of II-B3 (141 g, 361 mmol) in THF (1000 ml) was added aqueous HCl (361 ml, 4 M, 1444 mmol). The mixture was stirred at 25°C for 16 hours. The mixture was poured into water (500 ml). The organic phase was separated and the aqueous layer was extracted with ethyl acetate (EA) (2×300 ml). The combined organic solutions were washed with saturated aqueous NaHCO ₃ (500 ml), H ₂ O (2×300 ml), brine (200 ml), dried over Na ₂ SO ₄ , filtered, evaporated in vacuum and triturated with PE (300 ml) at 15°C to form II-B4 (82 g, 73%) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ 2.80-2.70 (m, 1H), 2.55-2.45 (m, 3H), 2.45-2.15 (m, 1H), 2.15-2.00 (m , 3H), 2.00-1.90 (m, 1H), 1.90-1.65 (m, 6H), 1.65-1.30 (m, 2H), 1.30-1.10 (m, 7H), 0.88 (s, 3H), 1.85-0.75 (m, 3H).

Synthesis II-B5

[ 0558 ] To a stirred solution of trimethylsulfonium iodide (22.2 g, 109 mmol) in DMSO/THF (100 ml/500 ml) was added NaH (4.35 g, 109 mmol, 60% in oil) at 0°C for 1 hour under N ₂ . The mixture was added to a solution of II-B4 (30 g, 99.1 mmol) in DMSO (100 ml) at 15°C for 4 hours. The reaction mixture was treated with water (200 ml). The mixture was extracted with EtOAc (2×100 ml). The combined organic phase was washed with water (2×100 ml), brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated in vacuo to give II-B5 (35 g) as an oil.

Synthesis II-B6

[ 0559 ] Na (9.83 g, 410 mmol) was added in ten portions to anhydrous methanol (300 ml) at 15°C. The reaction mixture was stirred at 65°C for 1 hour. II-B5 (13 g, 41.0 mmol) in anhydrous methanol (50 ml) was added to a suspension of sodium methoxide at 65°C. The reaction mixture was stirred at 65°C for 16 hours. Add water (500 ml). The reaction mixture was evaporated to remove most of the solvent. The mixture was extracted with EtOAc (2×200 ml). The combined organic phase was washed with brine (2×100 ml), dried over anhydrous Na ₂ SO ₄ , filtered, and evaporated. The residue was purified by flash column chromatography (0~20% EtOAc in PE) to give II-B6 (7 g) as an oil and II-B6a .

II-B6:

¹ H-NMR(400 MHz, CDCl₃) δ 3.45-3.30 (m, 5H), 2.50-2.30 (m, 1H), 2.15-1.95 (m, 2H), 1.95-1.80 (m , 2H), 1.80-1.50 (m, 5H), 1.50-1.30 (m, 7H), 1.30-1.05 (m, 8H), 0.90-0.65 (m, 6H).

Synthesis II-B7

[ 0560 ] To a suspension of bromo(ethyl)triphenylphosphorane (29.6 g, 80.0 mmol) in THF (200 ml) was added t -BuOK (8.96 g, 80.0 mmol) at 15°C under N ₂ . The mixture was heated to 45°C and stirred for 1 hour. A solution of II-B6 (7 g, 20.0 mmol) in THF (50 ml) was added. The mixture was stirred at 45°C for 16 hours. The mixture was treated with NH ₄ Cl solution (100 ml). The organic layer was separated. The aqueous phase was extracted with EtOAc (2×50 ml). The combined organic phase was washed with brine (2×30 ml), dried over anhydrous Na ₂ SO ₄ , filtered, and evaporated in vacuo. The residue was triturated with MeOH/H ₂ O (50 ml/50 ml) at 15°C to form II-B7 (7.5 g) as a solid.

Synthesis II-B8

[ 0561 ] To a solution of II-B7 (5 g, 13.8 mmol) in THF (50 ml) was added 9-BBN dimer (6.73 g, 27.6 mmol) at 15°C. The mixture was stirred at 15°C for 48 hours. After cooling to 0°C, ethanol (6.34 g, 138 mmol) and NaOH solution (27.6 mL, 5 M, 138 mmol) were added very slowly to the reaction mixture. After addition was complete, H ₂ O ₂ (13.8 mL, 138 mmol, 30%) was added slowly and the internal temperature was maintained below 15°C. The resulting solution was stirred at 75°C for 1 hour. A saturated aqueous solution of Na ₂ S ₂ O ₃ (50 ml) was added and the mixture was stirred at 0° C. for an additional 1 hour. The reaction mixture was tested using potassium iodide and starch paper to confirm the decomposition of excess H ₂ O ₂ . The mixture was cooled and added to water (500 ml). The mixture was filtered. The filter cake was dissolved in EtOAc (100 ml). The organic phase was washed with brine (30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated in vacuo to give II-B8 (7 g) as an oil.

Synthesis II-B9

[ 0562 ] To a solution of II-B8 (7 g, 18.4 mmol) in DCM (100 ml) at 15°C was added PCC (7.91 g, 36.8 mmol) and silica gel (8 g). The solution was stirred at 15°C for 3 hours. The reaction mixture was filtered and the residue was washed with anhydrous DCM (2×100 ml). The combined filtrate was evaporated in vacuo. The residue was purified by flash column chromatography (0~50% EtOAc in PE) to give II-B9 (3.8 g, 55%) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ 3.45-3.30 (m, 5H), 2.63 (s, 1H), 2.60-2.45 (m, 1H), 2.20-2.05 (m, 4H), 2.05-1.80 (m, 2H), 1.80-1.50 (m, 7H), 1.50-1.30 (m, 7H), 1.30-1.05 (m, 7H ), 0.80-0.65 (m, 3H), 0.58 (s, 3H);MS ESI calculated for C₂₄H₃₉O₂ [M+H-H₂O]⁺ 359, 359 found.

[ 0563 ] Example II-36: Synthesis of ((3R,5R,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[ a]phenanthren-17-yl)((S)-2-methylpiperidin-1-yl)methanone (II-B11)

Synthesis II-B10

[ 0564 ] Liquid bromine (1.05 g, 6.60 mmol) was added slowly at 0°C to a vigorously stirred aqueous solution of sodium hydroxide (5.26 mL, 3 M, 15.8 mmol). When all the bromine had dissolved, the mixture was diluted with cold dioxane (5 ml) and slowly added to a stirred solution of II-B9 (500 mg, 1.32 mmol) in dioxane (10 ml) and water (5 ml), and a precipitate formed, and the reaction the mixture was stirred at 15°C for 16 hours. The remaining oxidizing agent was quenched with aqueous Na ₂ SO ₃ (30 ml) and the mixture was then heated at 80° C. until the solid material dissolved. Acidification of the solution with hydrochloric acid (3N) led to the formation of a precipitate. EtOAc (20 ml) was added to the suspension. The organic phase was separated. The aqueous phase was extracted with EtOAc (2×20 ml). The combined organic solution was washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated in vacuo to give II-B10 (550 mg) as a solid.

Synthesis II-B11

[ 0565 ] To a solution of II-B10 (500 mg, 1.32 mmol) in pyridine (10 ml) was added EDCI (1.01 g, 5.28 mmol) and stirred at 25°C for 10 minutes. (2S)-2-methylpiperidine (143 mg, 1.45 mmol) was added. The mixture was stirred at 25°C for 16 hours. Water (20 ml) and EtOAc (20 ml) were added to the reaction mixture. The organic layer was separated. The aqueous phase was extracted with EtOAc (2×10 ml). The combined organic phase was washed with brine (2×10 ml), dried over anhydrous Na ₂ SO ₄ , filtered, evaporated and purified using HPLC ((column: YMC-Actus Triart C18 100 * 30 mm * 5 μm), gradient: 85- 100% B (A=water (0.05% HCl)-ACN), B=MeCN, flow rate: 25 ml/min) to form II-B11 (136 mg, 22%) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ 5.00-4.80 (m, 0.7H), 4.65-4.45 (m, 0.3H), 4.35-4.25 (m, 0.3H), 3.80 -3.70 (m, 0.7H), 3.40-3.25 (m, 5H), 3.10-2.95 (m, 1H), 2.75-2.60 (m, 2H) , 2.35-2.15 (m, 1H), 2.00-1.80 (m, 1H), 1.80-1.55 (m, 12H), 1.55-1.30 (m, 8H), 1.30-1.05 (m, 11H), 0.80-0.65 (m, 6H);MS ESI calculated for C₂₉H₅₀NO₃ [M+H]⁺ 460, 460 found.

[ 0566 ] Example II-40: Synthesis of 1-((3R,5R,8S,9S,10S,13S,14S,17S)-3-(ethoxymethyl)-10-ethyl-3-hydroxy-13-methylhexadecahydro-1H- cyclopenta[a]phenanthrene-17-yl)ethan-1-one (II-C4)

Synthesis II-C1

[ 0567 ] To anhydrous EtOH (200 ml) at 15°C was added Na (25.4 g, 1107 mmol) in ten portions. The reaction mixture was stirred at 75°C for 1 hour. II-B5 (22 g, 69.5 mmol) in anhydrous ethanol (50 ml) was added to a suspension of sodium ethoxide at 75°C. The reaction mixture was stirred at 75°C for 16 hours. Water (500 ml) was added at 15°C. The reaction mixture was evaporated to remove most of the solvent. The mixture was extracted with EtOAc (2×200 ml). The combined organic phase was washed with saturated brine (2×100 ml), dried over anhydrous Na ₂ SO ₄ , filtered, and evaporated. The residue was purified by flash column chromatography (0~20% EtOAc in PE) to give II-C1 (12 g) as an oil, and II-C1a (7 g, 28%) as a solid.

II-C1:

¹ H-NMR(400 MHz, CDCl₃) δ_H 3.60-3.45 (m, 2H), 3.45-3.30 (m, 2H), 2.45-2.30 (m, 1H), 2.10-1.90 (m, 4H ), 1.90-1.55 (m, 5H), 1.55-1.30 (m, 7H), 1.30-1.10 (m, 11H), 0.90-0.80 (m , 3H), 0.80-0.60 (m, 3H).

II-C1a:

¹ H-NMR(400 MHz, CDCl₃) δ_H3.55-3.46 (m, 2H), 3.25-3.15 (m, 2H), 2.47-2.35 (m, 1H), 2.10-1.95 (m, 4H ), 1.95-1.85 (m, 1H), 1.85-1.60 (m, 5H), 1.55-1.35 (m, 6H), 1.35-1.15 (m , 11H), 0.90-0.80 (m, 6H)

Synthesis II-C2

[ 0568 ] To a suspension of bromo(ethyl)triphenylphosphorane) (48.9 g, 132 mmol) in THF (200 ml) was added t -BuOK (14.7 g, 132 mmol) at 15°C under N ₂ . The mixture was heated to 45°C and stirred for 1 hour. At 45°C, a solution of II-C1 (12 g, 33.0 mmol) in THF (20 ml) was added. The mixture was stirred at 45°C for 16 hours. The mixture was treated with NH ₄ Cl solution (100 ml). The organic layer was separated. The aqueous phase was extracted with EtOAc (2×50 ml). The combined organic phase was washed with brine (2×40 ml), dried over anhydrous Na ₂ SO ₄ , filtered, and evaporated in vacuo. The residue was triturated with MeOH/H ₂ O (50 ml/50 ml) at 20°C to give II-C2 (17 g) as an oil.

Synthesis II-C3

[ 0569 ] To a solution of II-C2 (17 g, 45.3 mmol) in THF (100 ml) was added 9-BBN dimer (22.1 g, 90.6 mmol) at 15°C. The mixture was stirred at 15°C for 16 hours. After cooling to 0°C, ethanol (20.8 g, 453 mmol) and NaOH solution (90.6 mL, 5 M, 453 mmol) were added very slowly to the reaction mixture. After addition was complete, H ₂ O ₂ (45.3 mL, 453 mmol, 30%) was added slowly and the internal temperature was maintained below 15°C. The resulting solution was stirred at 75°C for 1 hour. A saturated aqueous solution of Na ₂ S ₂ O ₃ (100 ml) was added and the mixture was stirred at 0°C for 1 hour. The reaction mixture was tested using potassium iodide and starch paper to confirm the decomposition of excess H ₂ O ₂ . The mixture was cooled and added to water (2 L). The mixture was filtered. The combined oil filtrate was dissolved in EtOAc (200 ml). The organic phase was washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated in vacuo to give II-C3 (18 g) as an oil.

Synthesis II-C4

[ 0570 ] To a solution of II-C3 (18 g, 45.8 mmol) in DCM (200 ml) at 15°C was added PCC (19.6 g, 91.6 mmol) and silica gel (15 g). The solution was stirred at 15°C for 3 hours. The reaction mixture was filtered and the residue was washed with anhydrous DCM (2×100 ml). The combined filtrate was evaporated in vacuo. The residue was purified by flash column chromatography (0~20% EtOAc in PE) to give II-C4 (8 g, 45%) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ_H 3.60-3.50 (m, 2H), 3.50-3.30 (m, 2H), 2.74 (s, 1H), 2.60-2.45 (m, 1H), 2. 20-2.05 (m, 4H), 2.05-1.75 (m, 2H), 1.75-1.50 (m, 7H), 1.50-1.30 (m, 7H), 1.30-1.05 (m, 10H), 0.80-0.65 (m, 3H), 0.59 (s, 3H); MS ESI calculated for C₂₅H₄₁O₂ [M+H-H₂O]⁺ 373, 373 found.

Example II-43-II-51

[ 0571 ] The following examples were made from II-C5 as in Example II-41, replacing 1,3-dimethyl-1H-pyrazol-5-amine with the listed amine and a suitable coupling reagent (oxalic acid dichloride, EDCI, HATU, and etc.).

Example No. Amine Name ¹ H-NMR (400 MHz, CDCl ₃ )/ ¹⁹ F-NMR (376.5 MHz, CDCl3) MS ESI II-43 4-amino-3-methylbenzo-nitrile (3R,5R,8S,9S,10S,13S,14S,17S)-N-(4-cyano-2-methylphenyl)-3-(ethoxymethyl)-10-ethyl-3-hydroxy-13-methylhexadecahydro-1H- cyclopenta[a]phenanthrene-17-carboxamide ( II-43 ) _δH 8.40-8.30 (m, 1H), 7.50-7.48 (m, 1H), 7.48-7.40 (m, 1H), 6.95 (s, 1H), 3.65-3.48 (m, 2H), 3.48-3.30 (m, 2H), 2.74 (s, 1H), 2.35-2.20 (m, 5H), 2. 10-1.50 (m, 9H), 1.50-1.25 (m, 7H), 1.25-1.10 (m, 10H), 0.80-0.75 (m, 3H), 0.72 (s, 3H) calculated for C ₃₂ H ₄₇ N ₂ O ₃ [M+H] ⁺ 507, found 507 II-44 (2S)-2-methylpiperidine ((3R,5R,8S,9S,10S,13S,14S,17S)-3-(ethoxymethyl)-10-ethyl-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)( (S)-2-methylpiperidin-1-yl)methanone ( II-44 ) _δH 4.94 (s, 0.5H), 4.59-4.48 (m, 0.25H), 4.35-4.28 (m, 0.25H), 3.82 (d, J=12.0 Hz, 0.5H), 3.54 (kv, J=7.2 Hz, 2H), 3.40 (kv, J=13.6 Hz, 2H), 3.10-3, 00 (m, 0.5H), 2.69-2.62 (m, 2H), 2.36-2.15 (m, 1H), 1.94 (t, J=12.0 Hz, 1H) , 1.83-1.58 (m, 10H), 1.55-1.36 (m, 11H), 1.30-1.10 (m, 14H), 0.65-0.33 (m, 6H) MS ESI calculated for C ₃₀ H ₅₂ NO ₃ [M+H] ⁺ 474, found 474 II-45 (2R)-2-methylpiperidine ((3R,5R,8S,9S,10S,13S,14S,17S)-3-(ethoxymethyl)-10-ethyl-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)( (R)-2-methylpiperidin-1-yl)methanone ( II-45 ) δ _H 5.10-5.05 (m, 0.5H), 4.56-4.48 (m, 0.5H), 4.40-3.30 (br.s, 0.5H), 3.92-3.84 (m, 0.5H), 3.54 (kv, J =7.2 Hz, 2H), 3.40 (kv, J =13.6 Hz, 2H), 3.12 -3.05 (m, 0.5H), 2.69 (s, 2.5H), 2.38-2.30 (m, 1H), 1.94 (t, J =12.0 Hz, 1H ), 1.83-1.58 (m, 12H), 1.45-1.09 (m, 21H), 0.77 (t, J =7.6 Hz, 3H), 0.69 (d, J =4.0 Hz, 3H). calculated for C ₃₀ H ₅₂ NO ₃ [M+H] ⁺ 474, found 474 II-46 aniline (3R,5R,8S,9S,10S,13S,14S,17S)-3-(ethoxymethyl)-10-ethyl-3-hydroxy-13-methyl-N-phenylhexadecahydro-1H-cyclopenta[a]phenanthrene-17- carboxamide ( II-46 ) δ _H 7.51 (d, J =8.0 Hz, 2H), 7.31 (t, J =8.0 Hz, 2H), 7.08 (t, J =7.6 Hz, 1H), 6.94 (s, 1H), 3.55 (kv, J =7.2 Hz, 2H), 3.42 (kv, J =9.6 Hz, 2H), 2.74 (br.s, 1H ), 2.38-2.18 (m, 2H), 2.06-1.90 (m, 2H), 1.88-1.58 (m, 8H), 1.53-1.51 (m , 1H), 1.50-1.28 (m, 9H), 1.30-1.15 (m, 6H), 0.78 (t, J =7.6 Hz, 3H), 0.73 ( s, 3H) calculated for C30H46NO3 [M+H] ⁺ 468, found 468 II-47 2-methyl-aniline (3R,5R,8S,9S,10S,13S,14S,17S)-3-(ethoxymethyl)-10-ethyl-3-hydroxy-13-methyl-N-(o-tolyl)hexadecahydro-1H-cyclopenta[a ]phenanthrene-17-carboxamide ( II-47 ) δ _H 7.95 (d, J = 8.0 Hz, 1H), 7.23-7.14 (m, 2H), 7.08-7.00 (m, 1H), 6.80 (s, 1H), 3.55 (kv, J =7.2 Hz, 2H), 3.47-3.36 (m, 2H), 2.73 (s, 1H), 2.37-2.21 (m , 5H), 2.13-2.03 (m, 1H), 2.00-1.90 (m, 1H), 1.88-1.57 (m, 8H), 1.53-1.31 (m, 8H), 1.28-1.15 (m, 8H), 0.83-0.72 (m, 6H). calculated for C ₃₁ H ₄₈ NO ₃ [M+H] ⁺ 482, found 482 II-48 Ammonium chloride (3R,5R,8S,9S,10S,13S,14S,17S)-3-(ethoxymethyl)-10-ethyl-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide ( II- 48 ) _δH 5.27 (d, J =26.8 Hz, 2H), 3.58-3.50 (m, 2H), 3.46-3.35 (m, 2H), 2.74 (s, 1H), 2.20-2.10 (m, 2H), 1.98-1.90 (m, 2H), 1.80-1.56 (m, 7H), 1.56-1.15 ( m, 17H), 0.80-0.74 (m, 3H), 0.70 (s, 3H) calculated for C ₂₄ H ₃₂ NO ₃ [M+H] ⁺ 392, found 392 II-50 (R)-2-(4-fluorophenyl)-piperidine ((3R,5R,8S,9S,10S,13S,14S,17S)-3-(ethoxymethyl)-10-ethyl-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)( (R)-2-(4-fluorophenyl)piperidin-1-yl)methanone ( II-50 ) δ _H 7.12 (br.s, 2H), 7.01 (br.s, 2H), 6.10-5.95 (m, 1H), 3.99-3.82 (m, 1H), 3.54 (kV, J=7.2 Hz, 2H), 3.46-3.35 (m, 2H), 2.98-2.85 (m, 1H), 2.82-2.73 ( m, 1H), 2.70 (br.s, 1H), 2.37 (br.d, J=14.0 Hz, 2H), 1.63 (br.s, 12H), 1.52-1 .14 (m, 19H), 0.85-0.73 (m, 6H).
_δF -117.23. calculated for C ₃₅ H ₅₃ FNO ₃ [M+H] ⁺ 554, found 554 II-51 (S)-2-(4-fluorophenyl)-piperidine ((3R,5R,8S,9S,10S,13S,14S,17S)-3-(ethoxymethyl)-10-ethyl-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)( S)-2-(4-fluorophenyl)piperidin-1-yl)methanone ( II-51 ) δH 7.21 (s, 1H), 7.11 (s, 2H), 7.03 (d, J=8.0 Hz, 2H), 6.10-5.95 (m, 0.5H), 5.35-5.25 (m, 0.5H), 4.65 (d, J=12.0 Hz, 0.5H), 3.92 (d, J=13.2 Hz, 0.5H) , 3.53 (kv, J=6.8 Hz, 2H), 3.40 (kv, J=15.2 Hz, 2H), 2.95-2.80 (m, 1H), 2.72- 2.61 (m, 1H), 2.59-2.48 (m, 1H), 2.43-2.23 (m, 2H), 1.95-1.55 (m, 12H), 1. 49-1.12 (m, 18H), 0.778 (m, 6H).
_δF -116.27, -117.01 calculated for C ₃₅ H ₅₃ FNO ₃ [M+H] ⁺ 554, found 554

[ 0572 ] Example II-61: Synthesis of 1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-(ethoxymethyl)-10-ethyl-3-hydroxy-13-methylhexadecahydro-1H- cyclopenta[a]phenanthrene-17-yl)ethan-1-one (II-D9)

Synthesis II-D2

[ 0573 ] To a suspension of MePPh ₃ Br (50.3 g, 141 mmol) in THF (200 ml) at 15°C was added t-BuOK (15.8 g, 141 mmol). After stirring at 45°C for 0.5 hour, a solution of II-D1 (18.5 g, 47.3 mmol) in THF (100 ml) was added at 45°C and the reaction mixture was stirred at 45°C for 1 hours. A saturated solution of NH ₄ Cl (200 ml) was added to the mixture, and the organic layer was separated. The aqueous layer was extracted with EtOAc (2×100 ml). The combined organic layers were washed with saturated brine (200 ml), filtered and evaporated under reduced pressure. The residue was purified by column chromatography (PE/EtOAc=10/1~4/1) to obtain II-D2 (13.6 g, 74.3%) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ_H 5.88 (dd,J=10.8, 17.6 Hz, 1H), 5.35 (dd,J=11.2 Hz, 1H), 5.02 (dd,J=1.2, 18.0 Hz, 1H), 4.00-3.82 (m, 8H), 2.20-2.12 (m, 1H), 2.00-1.90 (m, 1H ), 1.85-1.12 (m, 18H), 1.07-0.92 (m, 1H), 0.90-0.80 (m, 1H), 0.74 (s, 3H).

II-D3 synthesis

[ 0574 ] To a solution of II-D2 (13.6 g, 35.0 mmol) in THF (80 ml) was added 12 M HCl (29.1 ml, 350 mmol). The reaction mixture was stirred at 15°C for 16 hours. The reaction mixture was diluted with water (50 ml) and the pH was adjusted to pH=9 with solid Na ₂ CO ₃ (20 g). The aqueous layer was extracted with EtOAc (3×200 ml). The combined organic layers were washed with saturated brine (200 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated to give the product (10.5 g). The product was purified by flash column chromatography (15~20% EtOAc in PE) to give II-D3 (8.0 g, 76.9%) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ_H 6.03 (dd,J=11.2, 18.0 Hz, 1H), 5.52 (d,J=11.2 Hz, 1H), 5.20 (d,J=18.0 Hz, 1H), 2.55-2.40 (m, 3H), 2.32-1.55 (m, 13H), 1.55-1.15 (m, 4H), 1, 10-0.95 (m, 1H), 0.93-0.83 (m, 1H), 0.80 (s, 3H).

II-D4 synthesis

[ 0575 ] To a mixture of II-D3 (8.0 g, 26.6 mmol) in THF (200 ml) was added Pd-C (wet, 50%, 2.0 g) under Ar. The suspension was degassed in vacuum and purged with hydrogen three times. The resulting solution was maintained at a hydrogen pressure of 30 psi (0.21 MPa) at 25°C for 16 hours. The reaction mixture was filtered through a pad of Celite and washed with THF (2×200 ml). The filtrate was evaporated under reduced pressure. The product was purified by flash column chromatography (15~20% EtOAc in PE) to give II-D4 (8.0 g, 99.5%) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ_H 2.55-2.25 (m, 5H), 2.15-1.15 (m, 17H), 1.10 (t,J=8.0 Hz, 3H), 1.05-0.95 (m, 1H), 0.91 (s, 3H), 0.85-0.65 (m, 1H);MS ESI calculated for C₂₀H₃₁O₂ [M+H]⁺ 303, 303 found.

Synthesis II-D5

[ 0576 ] To a stirred solution of Me ₃ SIO (4.35 g, 19.8 mmol) in DMSO (30 ml) and THF (30 ml) was added NaH (791 mg, 19.8 mmol, 60%) in portions at 0°C In oil). The reaction mixture was stirred for 1 hour under N ₂ . The mixture was added to a solution of II-D4 (5.0 g, 16.5 mmol) in DMSO (30 ml). The reaction mixture was stirred at 15°C for 16 hours. The reaction mixture was poured into ice water (300 ml). The mixture was extracted with EtOAc (2×100 ml). The combined organic phase was washed with water (2×100 ml) and brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated to give product II-D5 (5.0 g) as an oil (selectively obtaining the structure with equatorial methylene).

¹ H-NMR(400 MHz, CDCl₃) δ_H 2.61 (s, 2H), 2.42 (dd,J=8.8, 19.6 Hz, 1H), 2.15-1.40 (m, 11H), 1.35-1.05 (m, 8H), 1.02-0.70 (m, 10H ).

Synthesis II-D6

[ 0577 ] To a freshly prepared solution of sodium ethoxide (31.5 ml, 31.5 mmol, 1 M in EtOH) at 75°C was added a solution of II-D5 (1.0 g, 3.15 mmol) in anhydrous ethanol (20 ml ). The reaction mixture was stirred at 75°C for 16 hours. Add water (50 ml). The reaction mixture was evaporated to remove most of the solvent. The mixture was extracted with EtOAc (2×30 ml). The combined organic phase was washed with saturated brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated. The residue was purified by silica gel chromatography (0-40% EtOAc in PE) to give II-D6 (512 mg, 44.9%) as an oil.

II-D6:

¹ H-NMR(400 MHz, CDCl₃) δ_H 3.52 (sq.J=6.8 Hz, 2H), 3.21 (s, 2H), 2.42 (dd,J=8.8, 19.6 Hz, 1H), 2.15-1.50 (m, 9H), 1.50-1.10 (m, 15H), 1.05-0.99 (m, 1H ), 0.95 (t,J=7.6 Hz, 3H), 0.90-0.65 (m, 4H);MS ESI calculated for C₂₃H₃₈O₃Na[M+Na]⁺ 385, 385 found.

[ 0578 ] Synthesis II-D7

To a suspension of bromo(ethyl)triphenylphosphorane (22.4 g, 60.4 mmol) in THF (100 ml) was added t-BuOK (6.76 g, 60.4 mmol) at 15°C under N ₂ . The mixture was heated to 45°C and stirred for 1 hour. A solution of II-D6 (5.5 g, 15.1 mmol) in THF (100 ml) was added at 45°C. The mixture was stirred at 45°C for 16 hours. The mixture was treated with NH ₄ Cl solution (300 ml). The organic layer was separated. The aqueous phase was extracted with EtOAc (2×150 ml). The combined organic phase was washed with brine (2×100 ml), dried over anhydrous Na ₂ SO ₄ , filtered, and evaporated in vacuum. The residue was purified by flash column chromatography (0~15% EtOAc in PE) to give II-D7 (5.0 g, 88%) as an oil.

¹ H-NMR(400 MHz, CDCl₃) δ_H5.15-5.05 (m, 1H), 3.52 (kv,J=6.8 Hz, 2H), 3.21 (s, 2H), 2.40-2.10 (m, 4H), 1.85-1.75 (m, 1H), 1.70-1, 40 (m, 7H), 1.35-1.10 (m, 14H), 1.10-0.80 (m, 11H).

[ 0579 ] Synthesis II-D8

To a solution of II-D7 (3.0 g, 8.0 mmol) in THF (50 ml) was added 9-BBN dimer (3.90 g, 16.0 mmol) at 15°C. The mixture was stirred at 15°C for 16 hours. After cooling to 0°C, ethanol (3.68 g, 80.0 mmol) and NaOH solution (16 mL, 5 M, 80.0 mmol) were added very slowly to the mixture. After addition was complete, H ₂ O ₂ (8.01 mL, 80.0 mmol, 30%) was added slowly and the internal temperature was maintained below 15°C. The resulting solution was stirred at 75°C for 1 hour. The solution was processed and purified along with another batch obtained in a similar way. A saturated aqueous solution of Na ₂ S ₂ O ₃ (300 ml) was added and the mixture was stirred at 0°C for an additional 1 hour. The reaction mixture was tested using potassium iodide and starch paper to confirm the decomposition of excess H ₂ O ₂ . The mixture was cooled and added to water (200 ml). The mixture was extracted with EtOAc (3×100 ml), washed with saturated brine (200 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated in vacuo to give II-D8 (5.0 g) as an oil.

¹ H-NMR(400 MHz, CDCl₃) δ_H 3.75-3.65 (m, 1H), 3.51 (kv,J=6.8 Hz, 2H), 3.20 (s, 2H), 1.95-1.75 (m, 12H), 1.74-1.40 (m, 13H), 1.39-0, 95 (m, 8H), 0.92 (t,J=7.6 Hz, 3H), 0.66 (s, 3H).

Synthesis II-D9

[ 0580 ] To a solution of II-D8 (0.8 g, 2.0 mmol) in DCM (20 ml) at 18°C was added PCC (872 mg, 4.1 mmol) and silica gel (1 g). The solution was stirred at 18°C for 3 hours. The reaction mixture was filtered and the residue was washed with anhydrous DCM (2×50 ml). The combined filtrate was evaporated in vacuo. The residue was purified by flash column chromatography (0~20% EtOAc in PE) to give II-D9 (0.75 g, 94.6%) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ_H 3.52 (sq.J=6.8 Hz, 2H), 3.21 (s, 2H), 2.52 (t,J=8.8 Hz, 1H), 2.25-2.10 (m, 5H), 2.05-1.95 (m, 1H), 1.90-1.80 (m, 1H), 1, 75-1.65 (m, 4H), 1.55-1.05 (m, 18H), 1.00-0.80 (m, 5H), 0.62 (s, 3H);MS ESI calculated for C₂₅H₄₁O₂ [M-H₂O+H]⁺ 373, 373 found.

[ 0581 ] Example II-62: Synthesis of ((3R,5S,8S,9S,10S,13S,14S,17S)-3-(ethoxymethyl)-10-ethyl-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[ a]phenanthren-17-yl)((S)-2-methylpiperidin-1-yl)methanone (II-D11)

Synthesis II-D10

[ 0582 ] Liquid bromine (1.22 g, 7.7 mmol) was slowly added to a vigorously stirred aqueous solution of sodium hydroxide (10.2 mL, 3 M, 30.7 mmol) at 0°C. When all the bromine had dissolved, the mixture was slowly added to a stirred solution of II-D9 (1.0 g, 2.6 mmol) in dioxane (18 ml) and water (6 ml). The reaction mixture was stirred at 15°C for 16 hours. The remaining oxidizing reagent was quenched with an aqueous solution of Na ₂ SO ₃ (30 ml). Acidification of the solution with hydrochloric acid (3N) led to the formation of a precipitate. EtOAc (50 ml) was added to the suspension. The organic phase was separated. The aqueous phase was extracted with EtOAc (2×50 ml). The combined organic layers were washed with saturated brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated in vacuo to give II-D10 (0.8 g, 80%) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ_H 3.71 (s, 1H), 3.52 (kv,J=6.8 Hz, 2H), 3.21 (s, 2H), 2.37 (t,J=9.2 Hz, 1H), 2.15-2.00 (m, 3H), 1.90-1.70 (m, 2H), 1.60-1.10 (m, 20H), 1, 00-0.65 (m, 5H), 0.74 (s, 3H).

Synthesis II-D11

[ 0583 ] To a solution of II-D10 (200 mg, 0.5 mmol) in DMF (5 ml) was added HATU (382 mg, 1.0 mmol), TEA (256 mg, 2.5 mmol) and (2S)- 2-methylpiperidine (100 mg, 1.0 mmol) at 20°C. The mixture was stirred at 20°C for 16 hours to form a brown solution. The reaction mixture was poured into water (50 ml) and extracted with EtOAc (2×20 ml). The combined organic phase was washed with saturated brine (2×20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated in vacuo. The residue was purified by flash column chromatography (10~20% EtOAc in PE) to give the product. The product was purified by preparative HPLC (column: Agela DuraShell 150 mm_25 mm_5 μm; conditions: water (10 mM NH ₄ HCO ₃ )-ACN; start B: 83; end B: 99; gradient time (minutes): 8.5; retention time 100% B (minutes): 2) to form II-D11 (53.3 mg, 22%) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ_H 5.00-4.90 (m, 1H), 4.60-4.25 (m, 1H), 3.82 (d,J=11.6 Hz, 1H), 3.52 (kv,J=6.8 Hz, 2H), 3.21 (s, 2H), 3.03 (t,J=12.0 Hz, 1H), 2.63 (t,J=8.8 Hz, 1H), 2.40-2.15 (m, 1H), 2.12 (s, 1H), 1.90-1.80 (m, 2H), 1.65-1, 60 (m, 5H), 1.58-1.40 (m, 10H), 1.38-1.00 (m, 15H), 0.95-0.65 (m, 8H);MS ESI calculated for C_thirtyH₅₂NO₃ [M+H]⁺ 474, 474 found.

The following example was made from II-D10 as in Example II -62, replacing (2S)-2-methylpiperidine with the listed amine and a suitable coupling reagent (oxalic acid dichloride, EDCI, HATU, etc.).

Example No. Amine Name ¹ H-NMR (400 MHz, CDCl ₃ ) MS ESI II-63 4-amino-3-methyl-benzo-nitrile (3R,5S,8S,9S,10S,13S,14S,17S)-N-(4-cyano-2-methylphenyl)-3-(ethoxymethyl)-10-ethyl-3-hydroxy-13-methylhexa-decahydro- 1H-cyclopenta[a]-phenanthrene-17-carboxamide ( II-63 ) _δH 8.33 (d, J =8.4 Hz, 1H), 7.49 (d, J =8.4 Hz, 1H), 7.45 (s, 1H), 6.98 (s, 1H ), 3.52 (kV, J =6.8 Hz, 2H), 3.21 (s, 2H), 2.40-2.20 (m, 5H), 2.15 (s, 1H), 2 .05-1.95 (m, 1H), 1.90-1.65 (m, 5H), 1.60-1.10 (m, 18H), 1.00-0.80 (m, 5H) , 0.76 (s, 3H). calculated for C ₃₂ H ₄₇ N ₂ O ₃ [M+H] ⁺ 507, found 507

[ 0584 ] Example II-70: Synthesis of 1-((3R,5S,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H- cyclopenta[a]phenanthrene-17-yl)ethan-1-one (II-E4)

Synthesis II-E1

[ 0585 ] Fresh Na (1.45 g, 63 mmol) was carefully added in portions to MeOH (63 ml) at 0°C. After stirring at 20°C for 3 hours, Na was completely dissolved. To a solution of MeONa (63 mL, 63.0 mmol, 1 M in MeOH) was added II-D5 (2.0 g, 6.3 mmol) in anhydrous MeOH (40 mL) at 65°C. The reaction mixture was stirred at 65°C for 2 hours. Water (100 ml) was added to the above mixture. The reaction mixture was evaporated to remove most of the solvent. The aqueous layer was extracted with EtOAc (2×100 ml). The combined organic phase was washed with saturated brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography (15~20% EtOAc in PE) to give II-E1 (0.8 g, 37%) as an oil and II-E1a .

II-E1:

¹ H-NMR(400 MHz, CDCl₃) δ_H 3.39 (s, 3H), 3.18 (s, 2H), 2.43 (dd,J=8.4, 19.2 Hz, 1H), 2.15-1.86 (m, 4H), 1.85-1.75 (m, 3H), 1.75-1.45 (m, 6H ), 1.44-1.13 (m, 10H), 1.12-0.93 (m, 4H), 0.92-0.82 (m, 3H).

Synthesis II-E2

[ 0586 ] To a suspension of bromo(ethyl)triphenylphosphorane (3.4 g, 9.2 mmol) in THF (10 ml) was added t-BuOK (1.0 g, 9.2 mmol) at 15°C under N ₂ . The mixture was heated to 60°C and stirred for 1 hour. A solution of II-E1 (0.8 g, 2.3 mmol) in THF (5 ml) was added at 60°C. The mixture was stirred at 60°C for 16 hours. The mixture was treated with NH ₄ Cl solution (20 ml). The organic layer was separated. The aqueous phase was extracted with EtOAc (3×20 ml). The combined organic phase was washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography (0~15% EtOAc in PE) to give II-E2 (630 mg, 76%) as an oil.

¹ H-NMR(400 MHz, CDCl₃) δ_H5.12 (sq.J=6.8 Hz, 1H), 3.38 (s, 3H), 3.18 (s, 2H), 2.45-2.12 (m, 3H), 1.88 (d,J=12.8 Hz, 1H), 1.77-1.40 (m, 12H), 1.39-1.08 (s, 11H), 0.95 (t,J=7.6 Hz, 3H), 0.93-0.80 (m, 4H).

Synthesis II-E3

[ 0587 ] To a solution of II-E2 (630 mg, 1.7 mmol) in THF (10 ml) was added 9-BBN-dimer (849 mg, 3.5 mmol) at 15°C. The mixture was stirred at 15°C for 16 hours. After cooling to 0°C, ethanol (800 mg, 17.4 mmol) and 5 M NaOH solution (3.47 mL, 17.4 mmol) were slowly added to the mixture. After addition was complete, H ₂ O ₂ (1.74 mL, 17.4 mmol, 30%) was added slowly and the internal temperature was maintained below 15°C. The resulting solution was stirred at 75°C for 1 hour. The aqueous layer was extracted with EtOAc (3×20 ml). The combined organic layer was washed with saturated brine (20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography (30%~50% EtOAc in PE) to give II-E3 (540 mg, 82%) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ_H 3.77-3.15 (m, 1H), 3.38 (s, 3H), 3.18 (s, 2H), 1.95-1.80 (m, 3H), 1.70-1. 40 (m, 11H), 1.40-1.00 (m, 15H), 0.98-0.90 (m, 3H), 0.89-0.77 (m, 1H), 0.76 ( s, 1H), 0.64 (s, 2H).

Synthesis II-E4

[ 0588 ] To a solution of II-E3 (0.54 g, 1.4 mmol) in DCM (10 ml) was added PCC (610 mg, 2.8 mmol) and silica gel (1 g) at 18°C. The solution was stirred at 18°C for 1 hour. The reaction mixture was filtered and the residue was washed with DCM (2×50 ml). The combined filtrate was evaporated under reduced pressure to give II-E4 (534 mg) as an oil. Purification by chromatography gave pure II-E4 .

¹ H-NMR(400 MHz, CDCl₃) δ_H 3.38 (s, 3H), 3.18 (s, 2H), 2.52 (t,J=8.4 Hz, 1H), 2.20-2.08 (m, 4H), 2.05-1.95 (m, 2H), 1.93-1.83 (m, 1H), 1, 77-1.55 (m, 4H), 1.54-1.08 (m, 15H), 1.05-0.82 (m, 5H), 0.62 (s, 3H);MS ESI calculated for C₂₄H₄₀O₃Na[M+Na]⁺ 399, 399 found.

[ 0589 ] Example II-71: Synthesis of (3R,5S,8S,9S,10S,13S,14S,17S)-N-(4-cyano-2-methylphenyl)-10-ethyl-3-hydroxy-3-( methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide (II-E6)

Synthesis II-E5

[ 0590 ] Liquid bromine (127 mg, 0.8 mmol) was slowly added to a vigorously stirred aqueous solution of sodium hydroxide (1.05 ml, 3 M, 3.2 mmol) at 0°C. When all the bromine had dissolved, the mixture was slowly added to a stirred solution of II-E4 (100 mg, 0.3 mmol) in dioxane (6 mL) and water (2 mL). The reaction mixture was stirred at 15°C for 16 hours. The remaining oxidizing reagent was quenched with an aqueous solution of Na ₂ SO ₃ (3 ml), and acidification of the solution with hydrochloric acid (5 ml, 3N) led to the formation of a precipitate. EtOAc (10 ml) was added to the suspension. The organic layer was separated. The aqueous phase was extracted with EtOAc (2×10 ml). The combined organic phase was washed with saturated brine (30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated in vacuo to give II-E5 (120 mg) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ_H 3.38 (s, 3H), 3.18 (s, 2H), 2.37 (t,J=9.2 Hz, 1H), 2.12-1.99 (m, 2H), 1.93-1.64 (m, 5H), 1.62-1.40 (m, 5H), 1, 36-1.09 (m, 11H), 1.07-0.79 (m, 6H), 0.73 (s, 3H).

Synthesis II-E6

[ 0591 ] To a solution of II-E5 (110 mg, 0.3 mmol) in pyridine (5 ml) was added EDCI (167 mg, 0.9 mmol) and stirred for 10 minutes. 4-amino-3-methylbenzonitrile (76.7 mg, 0.6 mmol) was added. The mixture was stirred at 80°C for 16 hours to form a brown solution. The reaction mixture was poured into water (50 ml) and extracted with EtOAc (2×20 ml). The combined organic phase was washed with saturated brine (2×20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated in vacuo. The residue was purified by silica gel chromatography (0-50% EtOAc in PE) to give product II-E6 (51.1 mg, 36%) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ_H 8.35 (d,J=8.8 Hz, 1H), 7.53-7.48 (m, 1H), 7.45 (s, 1H), 6.95 (s, 1H), 3.39 (s, 3H), 3 .19 (s, 2H), 2.36-2.23 (m, 5H), 2.06-1.99 (m, 2H), 1.91-1.67 (m, 5H), 1.65 -1.56 (m, 2H), 1.53-1.41 (m, 3H), 1.36-1.13 (m, 10H), 1.02-0.85 (m, 5H), 0 .76 (s, 3H);MS ESI calculated for C₃₁H₄₅N₂O₃ [M+H]⁺ 493, 493 found.

Example II-72: Synthesis of 1-(2-((3R,5S,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H- cyclopenta[a]phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile (II-E8)

Synthesis II-E7

[ 0592 ] To a solution of II-E4 (100 mg, 0.27 mmol) in MeOH (5 ml) was added HBr (10.7 mg, 0.05 mmol, 40%) and Br ₂ (46.6 mg, 0. 3 mmol) at 15°C. The reaction mixture was stirred at 15°C for 1 hour. A saturated NaHCO ₃ solution (10 ml) and a saturated Na ₂ SO ₃ solution (10 ml) were added to the mixture. The aqueous layer was extracted with EtOAc (3×10 ml). The combined organic layers were washed with saturated brine (10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated to give II-E7 (120 mg) as an oil.

Synthesis II-E8

[ 0593 ] To a solution of II-E7 (120 mg, 0.26 mmol) in acetone (3 ml) at 15°C was added K ₂ CO ₃ (54.6 mg, 0.4 mmol) and 1H-pyrazole-4- carbonitrile (36.7 mg, 0.4 mmol). The reaction mixture was stirred at 15°C for 16 hours. The reaction mixture was evaporated and purified by flash column chromatography (20-40% EtOAc in PE) to give II-E8 (46 mg, 39%) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ_H 7.46 (d,J=2.4 Hz, 1H), 6.70 (d,J=2.0 Hz, 1H), 4.96 (dd,J=18.0, 42.8 Hz, 2H), 3.37 (s, 3H), 3.17 (s, 2H), 2.58 (t,J=8.8 Hz, 1H), 2.24-2.00 (m, 3H), 1.86 (d,J=12.4 Hz, 1H), 1.80-1.43 (m, 9H), 1.42-1.10 (m, 10H), 1.05-0.85 (m, 5H), 0, 66 (s, 3H);MS ESI calculated for C₂₈H₄₁N₃O₃Na[M+Na]⁺ 490, 490 found.

[ 0594 ] Example II-73: Synthesis of 1-(2-((3R,5S,8S,9S,10S,13S,14S,17S)-3-(ethoxymethyl)-10-ethyl-3-hydroxy-13-methylhexadecahydro -1H-cyclopenta[a]phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile (II-D13)

Synthesis II-D12

[ 0595 ] To a solution of II-D5 (150 mg, 0.38 mmol) in MeOH (5 ml) was added HBr (15.3 mg, 0.077 mmol, 40%) and Br ₂ (67.5 mg, 0.42 mmol ) at 15°C. The reaction mixture was stirred at 15°C for 16 hours. The reaction mixture was added to saturated NaHCO ₃ solution (20 ml), then extracted with EtOAc (3×20 ml). The combined organic layer was washed with saturated brine (50 ml), dried over Na ₂ SO ₄ , filtered and evaporated to give II-D12 (165 mg) as an oil.

¹ H-NMR(400 MHz, CDCl₃) δ_H 4.00-3.85 (m, 2H), 3.52 (kv,J=6.8 Hz, 2H), 3.21 (s, 2H), 2.80 (t,J=9.2 Hz, 1H), 2.25-2.10 (m, 1H), 1.90-1.80 (m, 2H), 1.75-1.40 (m, 10H), 1, 40-1.10 (m, 12H), 1.00-0.80 (m, 6H), 0.65 (s, 3H).

Synthesis II-D13

[ 0596 ] To a solution of II-D12 (165 mg, 0.4 mmol) in acetone (5 ml) at 15°C was added K ₂ CO ₃ (96.9 mg, 0.7 mmol) and 1H-pyrazole-4- carbonitrile (65.4 mg, 0.7 mmol). The reaction mixture was stirred at 15°C for 16 hours. The reaction mixture was added to a saturated solution of NH ₄ Cl (20 ml). The aqueous layer was extracted with EtOAc (3×20 ml). The combined organic layer was washed with saturated brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated to give the product. The residue was purified using Combi-flash (0-20% EtOAc in PE) to yield II-D13 (74.6 mg, 44.1%) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ_H 7.47 (d,J=2.4 Hz, 1H), 6.72 (d,J=2.4 Hz, 1H), 4.96 (dd,J=17.6, 51.2 Hz, 2H), 3.52 (kv,J=6.8 Hz, 2H), 3.21 (s, 2H), 2.59 (t,J=8.8 Hz, 1H), 2.25-2.10 (m, 2H), 1.90-1.60 (m, 6H), 1.55-1.10 (m, 18H), 1, 05-0.80 (m, 5H), 0.68 (s, 3H);MS ESI calculated for C₂₉H₄₂N₃O₂ [M-H₂O+H]⁺ 464, 464 found.

[ 0597 ] Example II-74: Synthesis of 1-(2-((3R,5R,8S,9S,10S,13S,14S,17S)-3-(ethoxymethyl)-10-ethyl-3-hydroxy-13-methylhexadecahydro -1H-cyclopenta[a]phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (II-C8)

Synthesis II-C7

[ 0598 ] To a solution of II-C4 (500 mg, 1.3 mmol) in MeOH (10 ml) at 15°C was added HBr (10 mg, 40%) and Br ₂ (224 mg, 1.4 mmol). The reaction mixture was stirred at 15°C for 16 hours. The reaction mixture was added to saturated NaHCO ₃ solution (50 ml). The aqueous layer was extracted with EtOAc (3×50 ml). The combined organic layer was washed with saturated brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated to give II-C7 (220 mg) as an oil.

¹ H-NMR(400 MHz, CDCl₃) δ_H 3.95-3.88 (m, 2H), 3.54 (kv,J=6.8 Hz, 2H), 3.41 (kv,J=11.2 Hz, 2H), 2.85-2.75 (m, 1H), 2.74-2.60 (m, 1H), 2.25-2.10 (m, 1H), 1, 95-1.81 (m, 2H), 1.78-1.59 (m, 9H), 1.38-1.10 (m, 13H), 0.98-0.78 (m, 2H), 0.78 (t,J=6.8 Hz, 3H), 0.62 (s, 3H).

Synthesis II-C8

[ 0599 ] To a solution of II-C7 (70 mg, 0.15 mmol) in acetone (5 ml) at 15°C was added K ₂ CO ₃ (41 mg, 0.3 mmol) and 1H-pyrazole-4-carbonitrile ( 28 mg, 0.3 mmol). The reaction mixture was stirred at 15°C for 16 hours. The reaction mixture was added to saturated NH ₄ Cl solution (50 ml) and the aqueous layer was extracted with EtOAc (3×50 ml). The combined organic layer was washed with saturated brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated to give the product. The residue was purified using Combi-flash (0-20% EtOAc in PE) to give II-C8 (45 mg, 63%) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ_H 7.85 (s, 1H), 7.81 (s, 1H), 5.02 (d,J=18.0 Hz, 2H), 4.89 (d,J=18.0 Hz, 2H), 3.54 (kv,J=6.8 Hz, 2H), 3.41 (kv,J=9.2 Hz, 2H), 2.75 (s, 1H), 2.63-2.53 (m, 1H), 2.25-2.10 (m, 1H), 2.09-1, 85 (m, 2H), 1.80-1.58 (m, 7H), 1.51-1.25 (m, 11H), 1.24-1.10 (m, 6H), 0.78 ( T,J=7.2 Hz, 3H), 0.64 (s, 3H);MS ESI calculated for C₂₉H₄₂N₃O₂[M+H-H₂O]⁺ 464, 464 found.

Examples II-75 to II-79

Examples II-75 to II-76 were made from α-haloketone ( II-C7) , Examples II-77 to II-70 were made from α-haloketone II-D12 ), as in Examples II-72 to II-74 , with the replacement of 1H-pyrazole-4-carbonitrile with the listed nucleophiles.

Example No. Nucleophile Name ¹ H-NMR (400 MHz, CDCl ₃ ) MS ESI II-75 1,2,3-triazole 1-((3R,5R,8S,9S,10S,13S,14S,17S)-3-(ethoxymethyl)-10-ethyl-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl )-2-(2H-1,2,3-triazol-2-yl)ethan-1-one ( II-75 ) δ _H 7.68 (s, 2H), 5.23 (s, 2H), 3.54 (kv, J =6.8 Hz, 2H), 3.41 (kv, J =9.2 Hz, 2H ), 2.73 (s, 1H), 2.56 (t, J =9.6 Hz, 1H), 2.24-2.15 (m, 1H), 2.09-2.05 (m, 1H), 1.97-1.88 (m, 2H), 1.78-1.69 (m, 5H), 1.56-1.53 (m, 5H), 1.41-1.38 ( m, 3H), 1.23-1.20 (m, 6H), 0.89-0.86 (m, 4H), 0.78 (t, J = 7.6 Hz, 3H), 0.68 (c, 3H). calculated for C ₂₇ H ₄₄ N ₃ O ₃ [M+H] ⁺ 458, found 458 II-76 1,2,3-triazole 1-((3R,5R,8S,9S,10S,13S,14S,17S)-3-(ethoxymethyl)-10-ethyl-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl )-2-(1H-1,2,3-triazol-1-yl)ethan-1-one ( II-76 ) δ _H 7.76 (s, 1H), 7.64 (s, 1H), 5.27 (d, J =18.0 Hz, 1H), 5.12 (d, J =18.0 Hz, 1H ), 3.54 (kv, J =6.8 Hz, 2H), 3.40 (kv, J =9.2 Hz, 2H), 2.74 (s, 1H), 2.64 (t, J =6.6 Hz, 1H), 2.26-2.17 (m, 1H), 2.11-2.04 (m, 1H), 1.94 (t, J =13.2, 1H), 1.78-1.71 (m, 3H), 1.66-1.61 (m, 3H), 1.57-1.48 (m, 6H), 1.43-1.38 (m, 3H ), 1.32-1.27 (m, 3H), 1.24-1.20 (m, 5H), 0.94-0.85 (m, 1H), 0.78 (t, J =11 .6 Hz, 3H), 0.65 (s, 3H). calculated for C ₂₇ H ₄₄ N ₃ O ₃ [M+H] ⁺ 458, found 458 II-77 5-methyl- 2H -tetrazole 1-((3R,5R,8S,9S,10S,13S,14S,17S)-3-(ethoxymethyl)-10-ethyl-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl )-2-(5-methyl-2H-tetrazol-2-yl)ethan-1-one ( II-77 ) δ _H 5.35-5.25 (m, 2H), 3.53 (kv, J =6.8 Hz, 2H), 3.21 (s, 2H), 2.65 (t, J =8, 8 Hz, 1H), 2.56 (s, 3H), 2.25-2.05 (m, 3H), 1.90-1.65 (m, 6H), 1.60-1.10 (m , 17H), 1.05-0.85 (m, 5H), 0.72 (s, 3H). calculated for C ₂₇ H ₄₅ N ₄ O ₃ [M+H] ⁺ 473, found 473 II-78 5-methyl- 2H -tetrazole 1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-(ethoxymethyl)-10-ethyl-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl )-2-(5-methyl-1H-tetrazol-1-yl)ethan-1-one ( II-78 ) _δH 5.09 (dd, J =18.4, 36.4 Hz, 2H), 3.53 (kv, J =6.8 Hz, 2H), 3.22 (s, 2H), 2.70 -2.60 (m, 3H), 2.48 (s, 3H), 2.25-1.40 (m, 10H), 1.35-1.10 (m, 13H), 1.05-0 .65 (m, 5H), 0.70 (s, 3H) calculated for C ₂₇ H ₄₅ N ₄ O ₃ [M+H] ⁺ 473, found 473 II-79 1H-pyrazole-3-carbo-nitrile 1-(2-((3R,5R,8S,9S,10S,13S,14S,17S)-3-(ethoxymethyl)-10-ethyl-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene- 17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile ( II-79 ) δ _H 7.48 (d, J =2.4 Hz, 1H), 6.73 (d, J =2.4 Hz, 1H), 5.03 (d, J =17.6 Hz, 1H), 4.91 (d, J =17.6 Hz, 1H), 3.54 (kv, J =6.8 Hz, 2H), 3.41 (kv, J =9.6 Hz, 2H), 2, 75 (s, 1H), 2.63-2.53 (m, 1H), 2.25-2.10 (m, 1H), 2.09-2.03 (m, 1H), 2.00- 1.85 (m, 1H), 1.80-1.40 (m, 11H), 1.39-1.10 (m, 13H), 0.78 (t, J = 7.2 Hz, 3H) , 0.65 (s, 3H) calculated for C ₂₉ H ₄₂ N ₃ O ₂ [M+HH ₂ O] ⁺ 464, found 464

EXAMPLE II-80: Synthesis of 1-((3R,5R,8S,9S,10R,13S,14S,17S)-3-hydroxy-10-((R)-1-methoxyethyl)-3,13-dimethylhexadecahydro-1H -cyclopenta[a]phenanthrene-17-yl)ethan-1-one (II-E10)

Synthesis II-E2

[ 0600 ] To a solution of II-E2 (6 g, 19.7 mmol) in toluene (100 ml) was added pyridine hydrochloride (453 mg, 3.94 mmol) and ethane-1,2-diol (6.1 g, 98 .4 mmol). After stirring at 130°C for 16 hours, the mixture was evaporated in vacuo. The residue was purified on a silica gel column, eluting with a mixture of (PE/EtOAc=5/1) to give II-E2 (5.4 g, 66%) as a solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.98-3.80 (m, 9H), 3.58-3.55 (m, 1H), 2.10-2.01 (m, 1H) , 1.99-1.91 (m, 2H), 1.84-1.60 (m, 5H), 1.59-1.33 (m, 10H), 1.30-1.17 (m, 4H), 1.15-1.02 (m, 1H), 0.82 (s, 3H).

Synthesis II-E3

[ 0601 ] PCC (4.34 g, 20.2 mmol) was added to a solution of II-E2 (5.3 g, 13.5 mmol) in DCM (60 ml) at 25°C. After stirring at 25°C for 30 minutes, the solution was filtered and the filter cake was washed with DCM (2×100 ml). The combined filtrate was washed with saturated NaHCO ₃ solution (100 ml) and brine (100 ml), dried over Na ₂ SO ₄ , filtered and evaporated in vacuum. The residue was purified on a silica gel column, eluting with a mixture of (PE/EtOAc=8/1) to give II-E3 (3.1 g, 53%) as an oil. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.58 (s, 1H), 4.00-3.84 (m, 8H), 2.25-2.15 (m, 1H), 2.03 -1.88 (m, 2H), 1.84-1.59 (m, 7H), 1.56-1.32 (m, 10H), 1.30-1.17 (m, 1H), 1 .13-0.99 (m, 1H), 0.92 (s, 3H).

Synthesis II-E4

[ 0602 ] To a solution of II-E4 (3 g, 7.68 mmol) in THF (50 ml) at 0°C was added MeMgBr (5.1 ml, 15.3 mmol, 3 M in dimethyl ether). After stirring at 25°C for 2 hours, the reaction mixture was poured into water (100 ml) and extracted with EtOAc (2×100 ml). The combined organic solution was washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and evaporated in vacuo to give II-E4 (2.8 g, 81%) as an oil.

¹ H-NMR(400 MHz, CDCl₃) δ 4.42 (m, 1H), 3.97-3.81 (m, 8H), 2.03-1.92 (m, 2H), 1.90-1.74 (m, 5H), 1.71-1.64 (m, 1H), 1.60-1.34 (m, 9H), 1.30-1.22 (m, 4H), 1.21-1.11 (m, 5H ), 0.87 (s, 3H).

Synthesis II-E5

[ 0603 ] To a solution of II-E4 (2.7 g, 6.64 mmol) in DMF (20 ml) was added NaH (795 mg, 19.9 mmol, 60%) at 25°C. After stirring at 50°C for 30 minutes, MeI (2.82 g, 19.9 mmol) was added dropwise to the reaction mixture. After stirring at 50°C for 2 hours, additional MeI (2.82 g, 19.9 mmol) was added dropwise. After stirring at 50°C for 1 hour, the mixture was poured into ice water (50 ml) and extracted with EtOAc (2×60 ml). The combined organic solution was washed with saturated brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated in vacuo. The residue was purified by a silica gel column (PE/EtOAc=10/1) to give II-E5 (2 g, 64%) as a solid. ^1H -NMR (400 MHz, CDCl ₃ ) δ 3.97-3.83 (m, 8H), 3.79-3.74 (m, 1H), 3.29 (s, 3H), 2.08 -1.93 (m, 2H), 1.91-1.75 (m, 3H), 1.73-1.57 (m, 3H), 1.54-1.36 (m, 8H), 1 .31-1.05 (m, 9H), 0.88 (s, 3H).

Synthesis II-E6

[ 0604 ] To a solution of II-E5 (2 g, 4.75 mmol) in THF (30 mL) was added aqueous HCl (4.75 mL, 4 M, 19 mmol). After stirring at 25°C for 16 hours, the mixture was poured into water (100 ml) and extracted with EtOAc (2×50 ml). The combined organic solution was washed with saturated aqueous NaHCO ₃ (50 ml), brine (50 ml), dried over Na ₂ SO ₄ and evaporated in vacuo to give II-E6 (1.4 g, 80%) as a solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.86-3.82 (m, 1H), 3.31 (s, 3H), 2.77-2.67 (m, 1H), 2.54 -2.43 (m, 1H), 2.32-2.19 (m, 3H), 2.16-1.94 (m, 4H), 1.91-1.78 (m, 3H), 1 .75-1.60 (m, 4H), 1.55-1.35 (m, 2H), 1.30-1.16 (m, 4H), 1.10-1.05 (m, 3H) , 0.93 (s, 3H).

Synthesis II-E7

[ 0605 ] To a solution of BHT (5.56 g, 25.2 mmol) in toluene (50 ml) was added AlMe ₃ (6.3 ml, 12.6 mmol, 2 M in toluene) dropwise at 0°C. After stirring at 25°C for 1 hour, a solution of II-E6 (1.4 g, 4.21 mmol) in toluene (20 ml) was added dropwise to the mixture at -65°C. After stirring at -65°C for 1 hour, MeMgBr (4.19 ml, 12.6 mmol, 3 M in diethyl ether) was added dropwise at -65°C. After stirring at -65°C for 3 hours, the reaction mixture was poured with a saturated aqueous solution of NH ₄ Cl (50 ml) at -65°C. After stirring at 25°C for 0.5 hour, the resulting mixture was filtered through a pad of celite and the layer was washed with EtOAc (100 ml). The combined organic solution was separated, washed with brine (2×100 ml), dried over Na ₂ SO ₄ and evaporated in vacuum. The residue was purified on a silica gel column, eluting with PE/EtOAc=5/1 to give II-E7 (1.1 g, 68%) as a solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.80-3.75 (m, 1H), 3.29 (s, 3H), 2.48-2.41 (m, 1H), 2.15 -2.02 (m, 1H), 2.00-1.77 (m, 4H), 1.74-1.63 (m, 4H), 1.57-1.33 (m, 7H), 1 .29-1.13 (m, 9H), 1.08 (d, J =6.4 Hz, 3H), 0.89 (s, 3H); LC-ELSD/MS purity 99%, MS ESI calculated for C ₂₁ H ₃₁ O [M+HH ₂ O-MeOH] ⁺ 299, found 299.

Synthesis II-E8

[ 0606 ] To a solution of PPh ₃ EtBr (3.18 g, 8.58 mmol) in THF (15 ml) was added t -BuOK (962 mg, 8.58 mmol) at 25°C. After stirring at 60°C for 1 hour, a solution of II-E7 (1 g, 2.86 mmol) in THF (5 ml) was added dropwise. After stirring at 60°C for 16 hours, the mixture was poured into ice water (100 ml) and extracted with EtOAc (2×50 ml). The combined organic solution was washed with brine (50 ml), dried over Na ₂ SO ₄ and filtered, evaporated in vacuum. The residue was purified on a silica gel column, eluting with PE/EtOAc=15/1 to give II-E8 (1 g, 78%) as a solid. ^1H -NMR (400 MHz, CDCl ₃ ) δ 5.18-4.99 (m, 1H), 3.83-3.71 (m, 1H), 3.30 (s, 3H), 2.45 -2.09 (m, 3H), 2.01-1.81 (m, 3H), 1.68-1.58 (m, 6H), 1.58-1.37 (m, 7H), 1 .31-1.12 (m, 10H), 1.08-1.03 (m, 3H), 0.91 (s, 3H).

Synthesis II-E9

[ 0607 ] To a solution of II-E8 (1 g, 2.77 mmol) in THF (20 ml) a solution of BH ₃ -Me ₂ S (2.77 ml, 27.7 mmol) was added dropwise at 0°C. After stirring at 25°C for 16 hours, the solution was cooled to 0°C and NaOH solution (9.23 ml, 3 M) was added very slowly. After addition was complete, H ₂ O ₂ (4.5 mL, 33%) was added slowly and the internal temperature was maintained below 10°C. After stirring at 25°C for 2 hours, the resulting solution was extracted with EtOAc (2×20 ml). The combined organic solution was washed with saturated aqueous Na ₂ S ₂ O ₃ (2×50 ml), brine (50 ml), dried over Na ₂ SO ₄ , filtered and evaporated in vacuum to form II-E9 (0.9 g) in as a solid, which was used for the next step without further purification.

Synthesis II-E10

[ 0608 ] To a solution of II-E9 (800 mg, 2.11 mmol) in DCM (10 ml) was added PCC (907 mg, 4.22 mmol) at 25°C. After stirring at 25°C for 2 hours, the solution was filtered and the filter cake was washed with DCM (2×50 ml). The combined filtrate was evaporated in vacuo. The residue was purified on a silica gel column, eluting with a mixture of (PE/EtOAc=5/1) to give II-E10 (600 mg, 68%) as a solid. ^1H -NMR (400 MHz, CDCl ₃ ) δ 3.78-3.74 (m, 1H), 3.27 (s, 3H), 2.56-2.51 (m, 1H), 2.22 -2.16 (m, 1H), 2.12 (s, 3H), 2.06-1.94 (m, 2H), 1.91-1.79 (m, 1H), 1.74-1 .61 (m, 6H), 1.50-1.32 (m, 6H), 1.29-1.10 (m, 10H), 1.06 (d, J =6.0 Hz, 3H), 0.64 (s, 3H); LC-ELSD/MS purity 99%, MS ESI calculated for C ₂₃ H ₃₅ O [M+HH ₂ O-MeOH] ⁺ 327, found 327.

EXAMPLE II-81: Synthesis of 1-((3R,5R,8S,9S,10R,13S,14S,17S)-3-hydroxy-10-((R)-1-methoxyethyl)-3,13-dimethylhexadecahydro-1H -cyclopenta[a]phenanthrene-17-yl)-2-(5-methyl-2H-tetrazol-2-yl)ethan-1-one (II-E12) and 1-((3R,5R,8S,9S, 10R,13S,14S,17S)-3-hydroxy-10-((R)-1-methoxyethyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(5-methyl -1H-tetrazol-1-yl)ethan-1-one (II-E13)

Synthesis II-E11

[ 0609 ] To a solution of II-E10 (300 mg, 0.796 mmol) and HBr (0.1 ml, 48% in water) in MeOH (5 ml) was added dropwise bromine (190 mg, 1.19 mmol). After stirring at 25°C for 2 hours, the reaction mixture was filled with saturated aqueous NaHCO ₃ solution (20 ml), and the pH was adjusted to 7~8. The mixture was extracted with EtOAc (2×30 ml). The combined organic solution was washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and evaporated in vacuo. The residue was purified on a silica gel column, eluting with a mixture of (PE/EtOAc=8/1) to give II-E11 (240 mg, 60%) as a solid. ^1H -NMR (400 MHz, CDCl ₃ ) δ 3.98-3.86 (m, 2H), 3.77-3.73 (m, 1H), 3.26 (s, 3H), 2.85 -2.83 (m, 1H), 2.27-2.13 (m, 1H), 2.02-1.83 (m, 3H), 1.77-1.61 (m, 5H), 1 .54-1.33 (m, 7H), 1.31-1.11 (m, 8H), 1.08-1.02 (m, 3H), 0.91-0.80 (m, 2H) , 0.67 (s, 3H).

Synthesis of II-E12 and II-E13

[ 0610 ] To a solution of II-E11 (120 mg, 0.263 mmol) in acetone (3 ml) was added K ₂ CO ₃ (72.5 mg, 0.526 mmol) and 5-methyl-2H-tetrazole (44.2 mg, 0.526 mmol) at 25°C. After stirring at 25°C for 16 hours, the mixture was poured into water (30 ml) and extracted with EtOAc (2×30 ml). The combined organic solution was washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and evaporated in vacuo. The residue was purified by preparative HPLC separation (column: Boston Green ODS 150*30 5 µm, gradient: 60-90% B (A=0.05% HCl-ACN, B=acetonitrile), flow rate: 25 ml/min) with forming II-E12 (15 mg, 12%) and II-E12 (32 mg, 27%), both as solids.

II-E12: ^1H -NMR (400 MHz, CDCl ₃ ) δ 5.43-5.29 (m, 2H), 3.79-3.74 (m, 1H), 3.27 (s, 3H) , 2.65-2.60 (m, 1H), 2.57 (s, 3H), 2.30-2.16 (m, 1H), 2.11-2.08 (m, 1H), 2 .01-1.95 (m, 1H), 1.76-1.65 (m, 1H), 1.80-1.63 (m, 6H), 1.52-1.34 (m, 6H) , 1.33-1.10 (m, 10H), 1.07 (d, J =6.4 Hz, 3H), 0.74 (s, 3H); LC-ELSD/MS purity 99%, MS ESI calculated for C ₂₆ H ₄₁ N ₄ O ₂ [M+HH ₂ O] ⁺ 441, 441 found.

II-E13: ^1H -NMR (400 MHz, CDCl ₃ ) δ 5.21-5.02 (m, 2H), 3.79-3.74 (m, 1H), 3.28 (s, 3H) , 2.71-2.61 (m, 1H), 2.48 (s, 3H), 2.29-2.17 (m, 1H), 2.09-2.06 (m, 1H), 2 .03-1.93 (m, 1H), 1.90-1.87 (m, 1H), 1.83-1.62 (m, 6H), 1.53-1.41 (m, 6H) , 1.39-1.11 (m, 10H), 1.07 (d, J =6.4 Hz, 3H), 0.71 (s, 3H); LC-ELSD/MS purity 99%, MS ESI calculated for C ₂₆ H ₄₁ N ₄ O ₂ [M+HH ₂ O] ⁺ 441, 441 found.

[0611] Formula III, abbreviations: PE: petroleum ether; EtOAc: ethyl acetate; THF: tetrahydrofuran; PCC: pyridinium chlorochromate; TLC: thin layer chromatography; PCC: pyridinium chlorochromate; t-BuOK: potassium tert-butoxide; 9-BBN: 9-borabicyclo[3.3.1]nonane; Pd( t -Bu ₃ P) ₂ : bis(tri-tert-butylphosphine)palladium(0); AcCl: acetyl chloride; i -PrMgCl: isopropyl magnesium chloride; TBSCl: tert-butyl(chloro)dimethylsilane; ( i- PrO) _4Ti : titanium tetraisopropoxide; BHT: 2,6-di-tert-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 periodinan; EtMgBr: ethyl magnesium bromide; EtOAc: ethyl acetate; TEA: triethylamine; AlaOH: alanine; Boc: tert-butoxycarbonyl; Py: pyridine; TBAF: tetra-n-butylammonium fluoride; THF: tetrahydrofuran; TBS: tert-butyldimethylsilyl; TMS: trimethylsilyl; TMSCF ₃ : (trifluoromethyl)trimethylsilane; Ts: para-toluenesulfonyl; Bu: butyl; Ti(OiPr) ₄ : tetraisopropoxytitanium; LAH: lithium aluminum hydride; LDA: lithium diisopropylamide; LiOH·H ₂ O: lithium hydroxide hydrates; MAD: methyl aluminum bis(2,6-di-tert-butyl-4-methylphenoxide); MeCN: acetonitrile; NBS: N-bromosuccinimide; Na ₂ SO ₄ : sodium sulfate; Na ₂ S ₂ O ₃ : sodium thiosulfate; PE: petroleum ether; MeCN: acetonitrile; MeOH: methanol ; Boc: tert-butoxycarbonyl; MTBE: methyl tert-butyl ether; K-selectride: potassium tri(sec-butyl)borohydride.

[ 0612 ] EXAMPLE III-1: Synthesis of 1-((3R,5R,8R,9R,10S,13S,14S,17S)-13-ethyl-3-hydroxy-3-methylhexadecahydro-1H-cyclopenta[a]phenanthrene- 17-yl)ethan-1-one (III-A8)

Synthesis III-A2

[ 0613 ] A solution of III-A1 (described in WO 2013056181) (14 g, 45.9 mmol), TsOH (787 mg, 4.6 mmol) and ethane-1,2-diol (28.4 g, 458 mmol) was added to toluene (200 ml) at 25°C under N ₂ . The mixture was stirred at 120°C for 4 hours. The mixture was poured into water (100 ml) and extracted with ethyl acetate (2×100 ml). The combined organic solution was washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and evaporated in vacuo. The residue was purified by flash column chromatography (5-10% EtOAc in PE) to give III-A2 (8 g, 50%) as a solid.

¹ H-NMR(400 MHz, CDCl3) δ_H 3.93 (s, 4H), 3.76-3.63 (m, 1H), 2.03-1.95 (m, 1H), 1.93-1.80 (m, 4H), 1. 64-1.58 (m, 3H), 1.56-1.48 (m, 2H), 1.44-1.30 (s, 6H), 1.27-0.95 (m, 12H), 0.66 (s, 3H).

Synthesis III-A3

[ 0614 ] To a solution of III-A2 (2 g, 5.7 mmol) in cyclohexane (100 ml), stirred under N ₂ , was added CaCO ₃ (1.71 g, 17.1 mmol), Pb(OAc) ₄ ( 7.58 g, 17.1 mmol), and I ₂ (2.89 g, 11.4 mmol), and irradiated with a high-power tungsten lamp for 130 minutes. During irradiation, the solvent was refluxed. The reaction mixture was left to cool to 25°C, filtered, and the cyclohexane solution was washed with 10% aqueous Na ₂ S ₂ O ₃ solution (30 ml), brine (50 ml), dried over Na ₂ SO ₄ and evaporated. The residue was purified by flash column chromatography (0-15% EtOAc in PE) to give III-A3 (900 mg, 39%) as an oil.

¹ H-NMR(400 MHz, CDCl3) δ_H 5.95 (s, 1H), 4.36-4.27 (m, 1H), 3.93 (s, 4H), 2.38-2.35 (m, 1H), 2.08 (s, 3H), 2.05-1.96 (m, 2H), 1.91-1.73 (m, 4H), 1.70-1.60 (m, 2H), 1.41-1.32 ( m, 4H), 1.31-1.19 (m, 7H), 1.18-0.98 (m, 4H), 0.89-0.80 (m, 3H).

Synthesis III-A4

[ 0615 ] To a solution of PPh ₃ MeBr (5.28 g, 14.8 mmol) in THF (15 ml) was added t-BuOK (1.66 g, 14.8 mmol) at 25°C. After stirring at 50°C for 1 hour, a solution of III-A3 (600 mg, 1.48 mmol) in THF (5 ml) was added dropwise at 50°C. After stirring at 50°C for 3 hours, the mixture was poured into saturated NH ₄ Cl solution (50 ml) and extracted with EtOAc (2×50 ml). The organic layer was washed with brine (100 ml), dried over Na ₂ SO ₄ and filtered, evaporated in vacuum. The residue was purified by flash column chromatography (0~30% EtOAc in PE) to give III-A4 (420 mg, 79%) as an oil.

¹ H-NMR(400 MHz, CDCl3) δ_H 5.84-5.70 (m, 1H), 5.34-5.23 (m, 1H), 5.18-5.13 (m, 1H), 3.94 (s, 4H), 3. 87-3.75 (m, 1H), 2.39-2.34 (m, 1H), 2.03-1.93 (m, 1H), 1.90-1.73 (m, 5H), 1.63-1.56 (m, 4H), 1.44-1.21 (m, 10H), 1.14-1.09 (m, 4H), 1.16-1.09 (m, 1H ), 0.90-0.86 (m, 2H).

Synthesis III-A5

[ 0616 ] To a solution of III-A4 (420 mg, 1.2 mmol) in MeOH (10 ml) was added Pd/C (200 mg, <1% water). The solution was then hydrogenated under 15 psi (0.1 MPa) hydrogen pressure at 25°C for 16 hours. The mixture was filtered through a pad of celite and the filtrate was evaporated in vacuo to give III-A5 (420 mg, 100%) as a solid.

¹ H-NMR(400 MHz, CDCl3) δ_H 3.94 (s, 4H), 3.85-3.82 (m, 1H), 2.15-2.11 (m, 1H), 2.03-1.97 (m, 1H), 1. 90-1.84 (m, 3H), 1.65-1.51 (m, 10H), 1.45-1.31 (m, 6H), 1.28-1.26 (m, 3H), 1.18-1.06 (m, 3H), 0.98-0.89 (m, 2H), 0.84 (t,J=8 Hz, 3H).

Synthesis III-A6

[ 0617 ] To a solution of III-A5 (420 mg, 1.2 mmol) in THF (10 mL) was added aqueous HCl (1.15 mL, 4 M, 4.6 mmol). After stirring at 25°C for 2 hours, the mixture was poured into water (100 ml) and extracted with EtOAc (2×50 ml). The combined organic solution was washed with saturated aqueous NaHCO ₃ (50 mL), brine (50 mL), dried over Na ₂ SO ₄ and evaporated in vacuo to give III-A6 (240 mg, 66%) as a solid.

¹ H-NMR(400 MHz, CDCl3) δ_H 3.87-3.84 (m, 1H), 2.60 (t,J=16 Hz, 1H), 2.29-2.14 (m, 4H), 2.11-2.03 (m, 1H), 1.92-1.84 (m, 1H), 1.75- 1.64 (m, 4H), 1.61-1.56 (m, 3H), 1.54-1.45 (m, 2H), 1.45-1.31 (m, 4H), 1. 29-1.26 (m, 3H), 1.24-1.09 (m, 5H), 1.07-0.92 (m, 2H), 0.87 (t,J=8 Hz, 3H).

Synthesis III-A7

[ 0618 ] To a solution of BHT (1.65 g, 7.52 mmol) in toluene (10 ml) AlMe ₃ (2 M in toluene, 1.88 ml, 3.76 mmol) was added dropwise at 0°C under nitrogen. . The mixture was stirred at 25°C for 1 hour. III-A6 (240 mg, 0.75 mmol) in toluene (5 ml) was added dropwise to the solution at -65°C. After stirring at -65°C for 1 hour, MeMgBr (1 ml, 3.0 mmol, 3 M in diethyl ether) was added dropwise at -65°C. The resulting solution was stirred at -65°C for 1 hour. The reaction mixture was filled with a saturated aqueous solution of NH ₄ Cl (50 ml) at -65°C. After stirring at 25°C for 0.5 hour, the resulting mixture was filtered through a pad of celite and the layer was washed with EtOAc (20 ml). The combined organic layer was separated, washed with brine (2×20 ml), dried over Na ₂ SO ₄ , filtered and evaporated in vacuo. The residue was purified by flash column chromatography (0-30% EtOAc in PE) to give III-A7 (215 mg, 86%) as a solid.

¹ H-NMR(400 MHz, CDCl3) δ_H 3.85-3.81 (m, 1H), 2.15-2.11 (m, 1H), 1.92-1.76 (m, 4H), 1.64-1.61 (m, 1H ), 1.48-1.18 (m, 20H), 1.11-1.04 (m, 4H), 0.98-0.88 (m, 1H), 0.87-0.79 (m , 4H).

Synthesis III-A8

[ 0619 ] To a solution of III-A7 (215 mg, 0.64 mmol) in DCM (5 ml) was added DMP (542 mg, 1.28 mmol). The reaction mixture was stirred at 30°C for 30 minutes. The reaction mixture was poured with saturated aqueous NaHCO ₃ solution (50 ml) until the pH of the aqueous layer reached approximately 9 and filtered. The DCM layer was separated and the aqueous phase was extracted with DCM (10 ml). The combined organic phase was washed with saturated aqueous Na ₂ S ₂ O ₃ (2×20 ml), saturated NaHCO ₃ solution (40 ml), brine (40 ml), dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by flash column chromatography (0-30% EtOAc in PE) to give III-A8 (138 mg, 65%) as a solid.

¹ H-NMR(400 MHz, CDCl3) δ_H 2.46 (t,J=8 Hz, 1H), 2.33-2.21 (m, 2H), 2.20 (s, 3H), 1.87-1.80 (m, 3H), 1.74-1.59 ( m, 4H), 1.52-1.33 (m, 7H), 1.32-1.04 (m, 12H), 0.96-0.81 (m, 1H), 0.62 (t,J=8 Hz, 3H);LC-ELSD/MSpurity 99%,MS ESIcalculated for C₂₂H₃₅O[M-H₂O+H]⁺ 315, 315 found.

[ 0620 ] EXAMPLE III-2: Synthesis of 1-(2-((3R,5R,8R,9R,10S,13S,14S,17S)-13-ethyl-3-hydroxy-3-methylhexadecahydro-1H-cyclopenta[a ]phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (III-A10)

Synthesis III-A9

[ 0621 ] To a solution of III-A8 (107 mg, 0.32 mmol) and concentrated HBr (0.1 ml, 48% in water) in MeOH (2 ml) was added bromine (61.5 mg, 0.39 mmol) . The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was filled with saturated aqueous NaHCO ₃ solution and adjusted to pH 7~8, and extracted with EtOAc (2×30 ml). The combined organic phase was washed with saturated Na ₂ S ₂ O ₃ solution (50 ml) and brine (50), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated in vacuo to give III-A9 (130 mg) as a solid.

¹ H-NMR(400 MHz, CDCl3) δ_H 4.01-3.91 (m, 2H), 2.67 (t,J=8 Hz, 1H), 2.26-2.13 (m, 2H), 1.79-1.71 (m, 4H), 1.67-1.56 (m, 4H), 1.43- 1.29 (m, 8H), 1.22-1.08 (m, 10H), 0.86-0.73 (m, 1H), 0.52 (t,J=8 Hz, 3H).

Synthesis III-A10

[ 0622 ] To a solution of III-A9 (130 mg, 0.32 mmol) in acetone (3 ml) was added K ₂ CO ₃ (108 mg, 0.79 mmol) and 1H-pyrazole-4-carbonitrile (43.9 mg , 0.47 mmol). The mixture was stirred at 25°C for 3 hours. The mixture was poured into water (30 ml) and extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and evaporated in vacuo. The residue was purified by flash column chromatography (15-35% EtOAc in PE) to give III-A10 (43 mg, 32%) as a solid.

¹ H-NMR(400 MHz, CDCl3) δ_H 7.86 (s, 1H), 7.81 (s, 1H), 5.20-4.88 (m, 2H), 2.52-2.46 (m, 1H), 2.36-2, 25 (m, 2H), 1.89-1.62 (m, 7H), 1.51-1.33 (m, 10H), 1.29-1.07 (m, 9H), 0.98- 0.85 (m, 1H), 0.61 (t,J=8 Hz, 3H);LC-ELSD/MSpurity 99%,MS ESI calculated for C₂₆H₃₇N₃O₂Na[M+Na]⁺ 446, 446 found.

[ 0623 ] EXAMPLE III-3: Synthesis of 1-((3R,5S,8R,9R,10S,13S,14S,17S)-13-ethyl-3-hydroxy-3-(methoxymethyl)hexadecahydro-1H-cyclopenta[a ]phenanthrene-17-yl)ethan-1-one (III-A20)

Synthesis III-A12

[ 0624 ] A stirred solution of trimethylsulfonium iodide (880 mg, 4.00 mmol) and t-BuOK (448 mg, 4.00 mmol) in DMSO (10 ml) was heated at 40°C for 1 hour under N ₂ . The reaction mixture was added to III-A11 (1 g, 3.64 mmol, CAS No. 5696-58-2) in DMSO (10 ml) and stirred at 40°C. After 10 minutes, the reaction mixture was treated with water (100 ml), extracted with EtOAc (3×50 ml). The combined organic phase was washed with water (100 ml), brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated in vacuo to give III-A12 (1.8 g) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ_H 2.43 (dd,J=8.3, 19.3 Hz, 1H), 2.13-2.05 (m, 1H), 2.00-1.73 (m, 5H), 1.66-1.28 (m, 6H ), 1.22-0.98 (m, 4H), 0.91-0.72 (m, 4H).

Synthesis III-A13

[ 0625 ] To a solution of III-A12 (1.8 g, 6.24 mmol) in MeOH (20 ml) was added sodium methoxide (1.34 g, 24.9 mmol) at 25°C under N ₂ . After refluxing for 16 hours, the mixture was poured into water (300 ml) and extracted with EtOAc (2×200 ml). The combined organic phase was washed with brine (2×200 ml), dried over Na ₂ SO ₄ , filtered, and evaporated to leave a residue. The residue was purified by silica gel chromatography (0-20% EtOAc in PE) to give III-A13 (900 mg, 45.2%) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ_H 3.38 (s, 3H), 3.19 (s, 2H), 2.52-2.32 (m, 1H), 2.16-2.00 (m, 2H), 1.98-1, 85 (m, 2H), 1.84-1.70 (m, 4H), 1.68-1.62 (m, 2H), 1.55-1.41 (m, 2H), 1.37- 1.18 (m, 5H), 1.15-0.96 (m, 4H), 0.87 (s, 3H), 0.81-0.67 (m, 2H).

Synthesis III-A14

[ 0626 ] To a solution of PPh ₃ EtBr (20.7 g, 56 mmol) in THF (100 ml) was added t-BuOK (6.28 g, 56 mmol) at 25°C. After stirring at 50°C for 1 hour, a solution of III-A13 (9 g, 28 mmol) in THF (50 ml) was added dropwise at 50°C. After stirring at 50°C for 16 hours, the mixture was poured into saturated NH ₄ Cl solution (500 ml) and extracted with EtOAc (2×100 ml). The organic layer was washed with brine (300 ml), dried over Na ₂ SO ₄ , and filtered, evaporated in vacuum. The residue was purified by flash column chromatography (0~30% EtOAc in PE) to give III-A14 (8.5 g, 91.2%) as an oil.

¹ H-NMR(400 MHz, CDCl₃) δ_H 5.14-5.07 (m, 1H), 3.38 (s, 3H), 3.18 (s, 2H), 2.38-2.29 (m, 1H), 2.25-2. 12 (m, 2H), 1.86-1.67 (m, 3H), 1.60-1.49 (m, 4H), 1.33-0.95 (m, 12H), 0.89- 0.83 (m, 6H), 0.75-0.65 (m, 2H).

Synthesis III-A15

[ 0627 ] To a solution of III-A14 (7.5 g, 22.5 mmol) in DMF (100 ml) add NaH (2.68 g, 67.5 mmol, 60% in mineral oil) in three portions at 25°C. . After stirring at 25°C for 30 minutes, BnBr (11.5 g, 67.5 mmol) was added to the solution. After stirring at 25°C for 16 hours, the mixture was poured into ice water (500 ml) and extracted with ethyl acetate (2×200 ml). The combined organic solutions were washed with brine (200 ml), dried over Na ₂ SO ₄ , filtered and evaporated in vacuo. The residue was purified by flash column chromatography (5-10% EtOAc in PE) to give III-A15 (8 g) as an oil.

¹ H-NMR(400 MHz, CDCl₃) δ_H 7.30-7.18 (m, 5H), 5.06-5.01 (m, 1H), 4.50 (s, 1H), 4.44-4.38 (m, 2H), 3. 32-3.24 (m, 5H), 2.31-2.25 (m, 1H), 2.17-1.92 (m, 3H), 1.80-1.52 (m, 9H), 1.45-0.88 (m, 9H), 0.79-0.76 (m, 4H), 0.67-0.65 (m, 2H).

Synthesis III-A16

[ 0628 ] To a solution of III-A15 (8.0 g, 18.9 mmol) in THF (150 ml) was added 9-BBN-dimer (9.22 g, 37.8 mmol) and stirred at 25°C for 12 hours. Ethanol (50 ml) was added to the resulting mixture at 15°C, then an aqueous NaOH solution (37.8 ml, 5.0 M, 189 mmol) was added at 0°C. Hydrogen peroxide (18.9 mL, 10 M, 189 mmol) was added dropwise at 0°C. The reaction mixture was stirred at 78°C for 1 hour. After cooling to 15°C, the mixture was added to water (100 ml) and extracted with EtOAc (2×200 ml). The combined organic layer was washed with Na ₂ S ₂ O ₃ solution (2×100 ml) and brine (200 ml), dried over Na ₂ SO ₄ , filtered and evaporated in vacuum. The residue was purified by flash column chromatography (0-15% EtOAc in PE) to give III-A16 (8.2 g) as an oil. III-A16 (8 g) was further purified by flash column chromatography (0-5% EtOAc in PE) to give III-A16 (5.6 g, 70%) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ_H 7.39-7.29 (m, 4H), 7.26-7.21 (m, 1H), 4.50-4.45 (m, 2H), 3.75-3.66 (m, 1H ), 3.40-3.30 (m, 5H), 2.03-1.96 (m, 1H), 1.93-1.79 (m, 3H), 1.77-1.60 (m , 6H), 1.42-1.18 (m, 8H), 1.17-0.91 (m, 9H), 0.75-0.69 (m, 1H), 0.66 (s, 3H ).

Synthesis III-A17

[ 0629 ] To a solution of III-A16 (1 g, 2.26 mmol) in cyclohexane (100 ml) at 25°C was added CaCO ₃ (677 mg, 6.77 mmol), PhI(OAc) ₂ (2.18 g , 6.77 mmol), I ₂ (1.14 mg, 4.52 mmol). The reaction mixture was heated at reflux (80°C) under irradiation with an infrared lamp (250 W) for 15 minutes in an N ₂ atmosphere, then cooled to ambient temperature. The reaction mixture was poured into a saturated solution of Na ₂ S ₂ O ₃ in ice water (200 ml) and extracted with EtOAc (2×200 ml), the combined organic layers were dried over Na ₂ SO ₄ , evaporated at a temperature below 35 ° C to form III- A17 (1.1 g) as an oil and used directly for the next step.

Synthesis III-A18

[ 0630 ] To a mixture of MePPh ₃ Br (15.7 g, 44.2 mmol) in THF (100 ml) was added t -BuOK (4.95 g, 44.2 mmol) at 25°C under N ₂ . After stirring at 50°C for 30 minutes , III-A17 (2.2 g, 4.42 mmol) was added in portions at temperatures below 50°C. The reaction mixture was stirred at 50°C for 16 hours to form a suspension. The reaction mixture was filled with a 10% aqueous solution of NH ₄ Cl (500 ml). The aqueous solution was extracted with EtOAc (2×300 ml), and the combined organic layers were washed with brine (150 ml), dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by flash column chromatography (0~10% EtOAc in PE) to give III-A18 (1.3 g, 65%) as an oil.

¹ H-NMR(400 MHz, CDCl₃) δ_H 7.38-7.30 (m, 4H), 7.26-7.21 (m, 1H), 5.78 (dd,J=11.2, 18.4 Hz, 1H), 5.32-5.12 (m, 2H), 4.47 (s, 2H), 3.86-3.77 (m, 1H), 3, 37-3.29 (m, 5H), 2.40-2.31 (m, 1H), 2.01-1.94 (m, 1H), 1.85-1.65 (m, 5H), 1.56-1.23 (m, 9H), 1.22-0.93 (m, 10H), 0.78-0.62 (m, 2H).

Synthesis III-A19

[0631] To the solutionIII-A18 (220 mg, 0.49 mmol) in MeOH (10 ml) added Pd/C (500 mg) (10% Pd, 50% water), the mixture was stirred at 25°C under H₂ (15 psi (0.1 MPa)) for 15 hours. The reaction mixture was filtered through a pad of Celite and washed with MeOH (3×10 ml). The filtrate was evaporated to formIII-A19 (170 mg, 96%) as a solid. solid (170 mg) was purified by flash column chromatography (0~20% EtOAc in PE) to giveIII-A19 (140 mg) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ 3.87-3.78 (m, 1H), 3.38 (s, 3H), 3.18 (s, 2H), 2.15-2.08 (m, 1H), 1.93- 1.69 (m, 5H), 1.64-1.58 (m, 5H), 1.46-1.30 (m, 4H), 1.26 (d,J=6.0 Hz, 3H), 1.24-1.15 (m, 3H), 1.13-1.05 (m, 3H), 1.03-0.87 (m, 5H), 0. 84 (t,J=8.0 Hz, 3H), 0.75-0.63 (m, 2H).

LC-ELSD/MS purity 99%, MS ESI calculated for C ₂₃ H ₃₇ O [M-2H ₂ O+H] ⁺ 329.3, found 329.3.

Synthesis III-A20

[ 0632 ] To a solution of III-A19 (1 g, 2.74 mmol) in DCM (20 ml) was added DMP (2.32 g, 5.48 mmol), the mixture was stirred at 25°C for 2 hours. The mixture was poured with a saturated aqueous solution of NaHCO ₃ (150 ml) and an aqueous solution of Na ₂ S ₂ O ₃ (150 ml). The aqueous phase was extracted with DCM (3×100 ml). The combined organic phase was washed with brine (200 ml), dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by flash column chromatography (0~15% EtOAc in PE) to give III-A20 (840 mg, 84.5%) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ 3.38 (s, 3H), 3.18 (s, 2H), 2.46 (t,J=8.8 Hz, 1H), 2.36-2.20 (m, 2H), 2.19 (s, 3H), 1.87-1.60 (m, 7H), 1.58-1, 08 (m, 11H), 1.05-0.86 (m, 4H), 0.81-0.66 (m, 2H), 0.62 (t,J=7.6 Hz, 3H);LC-ELSD/MS 99%,MS ESI calculated for C₂₃H₃₇O₂ [M-H₂O+H]⁺ 345.3, found 345.3.

[ 0633 ] EXAMPLE III-4: Synthesis of 1-((3R,5S,8R,9R,10S,13S,14S,17S)-13-ethyl-3-hydroxy-3-(methoxymethyl)hexadecahydro-1H-cyclopenta[a ]phenanthrene-17-yl)-2-(5-methyl-2H-tetrazol-2-yl)ethan-1-one (III-A22) and 1-((3R,5S,8R,9R,10S,13S, 14S,17S)-13-ethyl-3-hydroxy-3-(methoxymethyl)hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(5-methyl-1H-tetrazol-1-yl)ethane- 1-she (III-A23)

Synthesis III-A21

[ 0634 ] To a solution of III-A20 (150 mg, 0.41 mmol) in MeOH (2 ml) was added HBr (16.7 mg, 0.08 mmol, 40% in water) and Br ₂ (66.1 mg, 0.41 mmol) at 25°C. After stirring at 25°C for 2 hours, the mixture was poured with a saturated aqueous solution of NaHCO ₃ (10 ml), treated with water (30 ml), and extracted with EtOAc (2×50 ml). The combined organic phase was washed with brine (30 ml), dried over anhydrous Na ₂ SO ₄ , filtered, evaporated to give III-A21 (180 mg) as an oil, and used directly for the next step.

¹ H-NMR(400 MHz, CDCl₃) δ 4.01 (s, 2H), 3.39 (s, 3H), 3.18 (s, 2H), 2.74 (t,J=8.8 Hz, 1H), 2.32-2.17 (m, 2H), 1.87-1.69 (m, 4H), 1.61-1.54 (m, 1H), 1, 47-1.15 (m, 13H), 0.96-0.65 (m, 6H), 0.59 (t,J=7.6 Hz, 3H).

Synthesis of III-A22 and III-A23

[ 0635 ] To a solution of III-A21 (180 mg, 0.41 mmol) in THF (3 ml) was added K ₂ CO ₃ (168 mg, 1.22 mmol) and 5-methyl-2 H -1,2,3 ,4-tetrazole (52 mg, 0.62 mmol). After stirring at 25°C for 14 hours, water (20 ml) was added to the mixture and extracted with EtOAc (2×30 ml). The organic layer was separated, dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by flash column chromatography (5~90% EtOAc in PE) to give III-A22 (50 mg) and III-A23 (50 mg).

III-A22 (50 mg) was purified using HPLC to give III-A22 (4 mg, 2.2%) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ 5.54-5.32 (m, 2H), 3.39 (s, 3H), 3.19 (s, 2H), 2.60-2.47 (m, 4H), 2.41- 2.23 (m, 2H), 2.09-1.96 (m, 1H), 1.94-1.61 (m, 7H), 1.49-1.17 (m, 9H), 1. 07-0.90 (m, 4H), 0.84-0.67 (m, 5H);LC-ELSD/MSpurity 99%,MS ESI calculated for C₂₅H₄₀N₄O₃ [M+H]⁺ 445.3, found 445.3.

III-A23 (50 mg) was purified using HPLC to give III-A23 (4 mg, 2.2%) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ_H 5.48-4.89 (m, 2H), 3.39 (s, 3H), 3.19 (s, 2H), 2.45 (t,J=8.4 Hz, 1H), 2.49 (s, 3H), 2.43-2.36 (m, 1H), 2.32-2.22 (m, 1H), 1.95-1, 64 (m, 8H), 1.48-1.18 (m, 8H), 1.11-0.67 (m, 7H), 0.63 (t,J=7.6 Hz, 3H);LC-ELSD/MSpurity 99%,MS ESI calculated for C₂₅H₄₀N₄O₃ [M+H]⁺ 445.3, found 445.3.

[ 0636 ] EXAMPLE III-6: Synthesis of 1-((3R,5R,8R,9S,10S,13S,14S,17S)-13-ethyl-3-hydroxy-3,10-dimethylhexadecahydro-1H-cyclopenta[a] phenanthrene-17-yl)ethan-1-one (III-A30)

Synthesis III-A25

[ 0637 ] To a solution of III-A24 (1.0 g, 2.3 mmol) in cyclohexane (100 ml) at 25°C was added CaCO ₃ (688 mg, 6.89 mmol), PhI(OAc) ₂ (2, 21 g, 6.89 mmol), I ₂ (1.16 g, 4.6 mmol). The reaction mixture was heated at reflux (80°C) under irradiation with an infrared lamp (250 W) for 15 minutes in an N ₂ atmosphere. The reaction mixture was then cooled to ambient temperature. The reaction mixture was poured into a saturated solution of Na ₂ S ₂ O ₃ in ice water (100 ml) and separated. The aqueous layer was extracted with EtOAc (2 x 50 mL) and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , evaporated below 40°C to give III-A25 (2.5 g) as a solid, and used directly to the next stage.

Synthesis III-A26

[ 0638 ] To a mixture of MePPh ₃ Br (9.07 g, 25.4 mmol) in THF (50 ml) was added t-BuOK (2.85 g, 25.4 mmol) at 25°C under N ₂ . After stirring at 50°C for 30 minutes , III-A25 (2.5 g, 5.09 mmol) was added in portions at temperatures below 50°C. After stirring at 50°C for 14 hours, the reaction mixture was filled with a saturated 10% aqueous solution of NH ₄ Cl (100 ml) at 15°C. The mixture was extracted with EtOAc (2×50 ml). The organic layer was separated, dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by flash column chromatography (0~10% EtOAc in PE) to give III-A26 (410 mg, 18.0%) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ_H5.73-5.57 (m, 1H), 5.36-5.25 (m, 1H), 5.23-5.12 (m, 1H), 3.70-3.48 (m, 2H ), 2.54-2.43 (m, 1H), 1.87-1.66 (m, 5H), 1.61-1.44 (m, 6H), 1.40-1.30 (m , 8H), 1.28-1.13 (m, 4H), 1.12-1.08 (m, 3H), 0.90-0.80 (s, 12H), 0.06 (s, 6H ).

Synthesis III-A27

[ 0639 ] To a solution of III-A26 (560 mg, 1.25 mmol) in MeOH (20 ml) was added Pd/C (500 mg, 10%, wet with 50% water). The solution was hydrogenated under 15 psi (0.1 MPa) hydrogen pressure at 25°C for 16 hours. The reaction mixture was filtered through a pad of Celite and washed with THF (3×50 ml). The filtrate was evaporated to give III-A27 (600 mg) as a solid and used directly for the next step.

¹ H-NMR(400 MHz, CDCl₃) δ_H3.81-3.71 (m, 1H), 3.64-3.53 (m, 1H), 2.33-2.18 (m, 1H), 1.90-1.71 (m, 3H), 1.70-1.58 (m, 2H), 1.54-1.14 (m, 14H), 1.14-1.11 (m, 3H), 1.10-1.01 ( m, 3H), 1.00-0.92 (m, 5H), 0.91-0.88 (m, 12H), 0.06 (s, 6H).

Synthesis III-A28

[0640]III-A27 (562 mg, 1.25 mmol) was dissolved in TBAF (6.26 ml, 6.26 mmol, 1 M in THF). The mixture was stirred at 25°C for 16 hours. The mixture was filled with a 10% NH solution₄Cl (30 ml) and extracted with EtOAc (2×10 ml). The combined organic phase was washed with 10% NH solution₄Cl (3x20 ml), dried over Na₂SO₄, filtered and evaporated with educationIII-A28 (400 mg) as oil.

Synthesis III-A29

[ 0641 ] Dess-Martin periodinane (1.14 g, 2.69 mmol) was added to a solution of III-A28 (300 mg, 0.89 mmol) in DCM (5 ml) at 30°C. After stirring at 30°C for 10 minutes, the mixture was poured with a saturated aqueous solution of NaHCO ₃ /Na ₂ S ₂ O ₃ (1:1, 50 ml) at 25°C. The organic phase was separated and washed with saturated aqueous NaHCO ₃ /Na ₂ S ₂ O ₃ solution (1:1, 50 ml), brine (50 ml), dried over Na ₂ SO ₄ , filtered and evaporated in vacuum to form III-A29 ( 230 mg) as a solid and used directly for the next step.

¹ H-NMR(400 MHz, CDCl₃) δ_H 2.74-2.62 (m, 1H), 2.52-2.43 (m, 1H), 2.41-2.23 (m, 3H), 2.21 (s, 3H), 2. 09-0.99 (m, 2H), 1.96-1.78 (m, 2H), 1.72-1.58 (m, 3H), 1.55-1.47 (m, 3H), 1.47-1.37 (m, 1H), 1.37-1.05 (m, 9H), 1.02 (s, 3H), 0.65 (t,J=7.6 Hz, 3H);LC-ELSD/MSpurity 99%,MS ESI calculated for C₂₂H₃₄O₂ [M+H]⁺ 331.2, found 331.2.

Synthesis III-A30

[ 0642 ] To a solution of MAD (3.38 mmol in 3 ml toluene) a solution of III-A29 (280 mg, 0.85 mmol) in DCM (2 ml) was added dropwise at -70°C. After stirring at -70°C for 1 hour under N ₂ , MeMgBr (0.85 ml, 2.55 mmol, 3 M in diethyl ether) was added dropwise at -70°C. The resulting solution was stirred at -70°C for an additional 4 hours. The reaction mixture was poured into saturated aqueous citric acid (50 ml) at a temperature below 10°C, and extracted with EtOAc (2×50 ml). The combined organic layer was dried over Na ₂ SO ₄ , filtered and evaporated in vacuo. The residue was purified by a silica gel column (PE/EtOAc=0-20%) to give III-A30 (110 mg) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ_H2.49-2.39 (m, 1H), 2.36-2.21 (m, 2H), 2.19 (s, 3H), 2.01-1.92 (m, 1H), 1. 91-1.79 (m, 1H), 1.79-1.70 (m, 1H), 1.68-1.57 (m, 3H), 1.53-1.32 (m, 9H), 1.31-1.19 (m, 11H), 1.14-1.00 (m, 3H), 0.93 (s, 3H), 0.62 (t,J=7.6 Hz, 3H);LC-ELSD/MSpurity 99%,MS ESI calculated for C₂₃H₃₈O₂ [M+H]⁺ 329.3, found 329.3.

[ 0643 ] EXAMPLE III-7 and III-8: synthesis of 1-((3R,5R,8R,9S,10S,13S,14S,17S)-13-ethyl-3-hydroxy-3,10-dimethylhexadecahydro-1H- cyclopenta[a]phenanthrene-17-yl)-2-(5-methyl-1H-tetrazol-1-yl)ethan-1-one (III-A32) and 1-((3R,5R,8R,9S,10S ,13S,14S,17S)-13-ethyl-3-hydroxy-3,10-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(5-methyl-2H-tetrazol-2-yl) ethan-1-one (III-A33)

Synthesis III-A31

To a solution of III-A30 (99 mg, 0.28 mmol) in MeOH (2 ml) was added HBr (0.01 ml, 40% in water) and Br ₂ (54.7 mg, 0.3427 mmol) at 25° WITH. After stirring at 25°C for 2 hours, the mixture was poured into a saturated aqueous solution of NaHCO ₃ (10 ml), extracted with EtOAc (2×30 ml). The combined organic phase was washed with brine (30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated in vacuo to give III-A31 (100 mg) as a solid, and used directly for the next step.

Synthesis of III-A32 and III-A33

[ 0644 ] To a solution of III-A31 (100 mg, 0.23 mmol) in acetone (3 ml) was added 1H-pyrazole-4-carbonitrile (23.7 mg, 0.282 mmol) and K ₂ CO ₃ (60.2 mg , 0.47 mmol). After stirring at 25°C for 14 hours, water (20 ml) was added to the mixture and extracted with EtOAc (2×30 ml). The organic layer was separated, dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by flash column chromatography (20~50% EtOAc in PE) to give III-A32 (20 mg, 19.9%) and III-A33 (16.5 mg, 16.5%) as a solid .

III-A32: ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 5.36 (d, J =18.0 Hz, 1H), 4.96 (d, J =18.0 Hz, 1H), 2 .57-2.50 (m, 1H), 2.49 (s, 3H), 2.44-2.17 (m, 2H), 2.03-1.81 (m, 2H), 1.81 -1.62 (m, 3H), 1.51-1.40 (m, 5H), 1.39-1.22 (m, 12H), 1.22-0.99 (m, 4H), 0 .95 (s, 3H), 0.63 (t, J =7.6 Hz, 3H); LC-ELSD/MS purity 99%, MS ESI calculated for C ₂₅ H ₄₀ N ₄ O ₂ [MH ₂ O +H] ⁺ 411.3, found 411.3.

III-A33: ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 5.48 (d, J =17.6 Hz, 1H) 5.37 (d, J =17.6 Hz, 1H), 2, 56 (s, 3H), 2.54-2.47 (m, 1H), 2.41-2.20 (m, 2H), 2.06-1.79 (m, 2H), 1.79- 1.63 (m, 3H), 1.52-1.39 (m, 6H), 1.39-1.20 (m, 14H), 1.19-0.99 (m, 4H), 0. 95 (s, 3H), 0.71 (t, J =7.6 Hz, 3H); LC-ELSD/MS purity 99%, MS ESI calculated for C ₂₅ H ₄₀ N ₄ O ₂ [MH ₂ O +H] ⁺ 411.3, found 411.3.

EXAMPLE III-9: synthesis of 1-((3R,5R,8R,9R,10S,13S,14S,17S)-13-ethyl-3-hydroxy-3-(methoxymethyl)hexadecahydro-1H-cyclopenta[a]phenanthrene- 17-yl)ethan-1-one (III-B15)

Synthesis III-B2

[ 0645 ] To a suspension of bromo(ethyl)triphenylphosphorane (160 g, 432 mmol) in THF (300 ml) was added t-BuOK (48.3 g, 432 mmol) at 25°C under N ₂ . After stirring at 45°C for 1 hour, a solution of III-B1 (30 g, 108 mmol, CAS: 33036-33-8) in THF (100 ml) was added at 45°C. After stirring at 45°C for 16 hours, the mixture was cooled, diluted with saturated NH ₄ Cl solution (1000 ml) and extracted with EtOAc (2×250 ml). The combined organic solution was washed with brine (2×250 ml), dried over anhydrous Na ₂ SO ₄ , filtered, evaporated (30 g), and purified along with two more batches (20 g and 30 g). The residue (80 g) was purified by flash column chromatography (0~25% EtOAc in PE) to give III-B2 (50 g, 63%) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ_H 5.20-5.05 (m, 1H), 3.70-3.60 (m, 1H), 2.40-2.30 (m, 1H), 2.25-2.10 (m, 2H ), 1.95-1.85 (m, 1H), 1.85-1.40 (m, 12H), 1.40-1.05 (m, 11H), 0.87 (s, 3H).

Synthesis III-B3

[ 0646 ] To a solution of III-B2 (15 g, 51.9 mmol) in DMF (100 ml) was added NaH (6.18 g, 155 mmol, 60% in oil) in portions at 25°C. After stirring at 25°C for 30 minutes, BnBr (26.5 g, 155 mmol) was added. After stirring at 25°C for 3 hours, the mixture was poured into ice water (500 ml) and extracted with ethyl acetate (2×100 ml). The combined organic solution was washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated in vacuo. The residue was purified on a flash PE column to give III-B3 (19 g) as an oil. ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 7.43-7.26 (m, 5H), 5.20-5.05 (m, 1H), 4.57 (s, 2H), 3, 45-3.35 (m, 1H), 2.45-2.10 (m, 4H), 2.00-1.93 (m, 1H), 1.85-1.55 (m, 8H), 1.50-1.00 (m, 13H), 0.88 (s, 3H).

Synthesis III-B4

[ 0647 ] To a solution of III-B3 (10 g, 26.4 mmol) in THF (100 ml) at 25°C was added 9-BBN dimer (12.8 g, 52.8 mmol). After stirring at 25°C for 12 hours, the reaction mixture was cooled to 0°C and ethanol (12.1 g, 264 mmol) and NaOH (52.8 ml, 5 M, 264 mmol) were added very slowly. After addition was complete, H ₂ O ₂ (26.4 mL, 264 mmol, 30%) was added slowly while maintaining the internal temperature below 15°C. After stirring at 75°C for 1 hour, a saturated aqueous solution of Na ₂ S ₂ O ₃ (500 ml) was added and the mixture was stirred at 0°C for an additional 1 hour. The mixture was diluted with water (500 ml) and extracted with EtOAc (3×200 ml). The combined organic solution was washed with saturated brine (500 ml), dried over anhydrous Na ₂ SO ₄ , filtered, evaporated (10 g), and purified by flash column chromatography (0-15% EtOAc in PE) to give III-B4 ( 8 g, 80%) as oil. ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 7.42-7.20 (m, 5H), 4.56 (s, 2H), 3.90-3.80 (m, 2H), 3, 75-3.65 (m, 1H), 3.45-3.30 (m, 1H), 2.00-1.75 (m, 9H), 1.70-1.55 (m, 4H), 1.40-0.95 (m, 13H), 0.66 (s, 3H).

Synthesis III-B5

[ 0648 ] To a suspension of III-B4 (2.5 g, 6.3 mmol), PhI(OAc) ₂ (6.08 g, 18.9 mmol) and CaCO ₃ (1.89 g, 18.9 mmol) elemental iodine (3.19 g, 12.6 mmol) was added to cyclohexane (250 ml) at 25°C. After heating to 80°C by irradiation with an infrared lamp (275 W) for 10 minutes, the mixture was added to saturated Na ₂ S ₂ O ₃ solution (500 ml) and extracted with EtOAc (3×50 ml). The combined organic solution was washed with saturated brine (200 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated to give III-B5 (2.85 g) as an oil, which was used directly for the next step without further purification.

Synthesis of III-B6 and III-B7

[ 0649 ] After stirring at 50°C for 1 hour, a suspension of PPh ₃ MeBr (11.2 g, 31.4 mmol) and t-BuOK (3.51 g, 31.4 mmol) in THF (30 ml) was added to a solution of III-B7 (2.85 g, 6.29 mmol) in THF (20 ml). After stirring at 50°C for 12 hours, the mixture was added to saturated NH ₄ Cl solution (100 ml) and extracted with EtOAc (3×50 ml). The combined organic solution was washed with saturated brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated (2.5 g) to an oil, which was purified along with the other three batches (from 2.85 g, 2.85 g and 2.35 g). The residue (9.5 g) was purified by flash column chromatography (0-15% EtOAc in PE) to give a mixture of III-B6 and III-B7 (~1:1) (5 g) as an oil.

Synthesis III-B8

[ 0650 ] To a solution of III-B6 and III-B7 (~1:1) (5.0 g, 12.2 mmol) in DCM (50 ml) added imidazole (2.48 g, 36.5 mmol) and TBSCl (5.50 g, 36.5 mmol) at 25°C. After stirring at 25°C for 12 hours, the mixture was filtered and the filtrate was evaporated. The product was dissolved in DCM (70 ml), washed with saturated aqueous NH ₄ Cl (50 ml), saturated brine (50 ml). The organic solution was dried over sodium sulfate, filtered, and the filtrate was evaporated and purified by flash column chromatography (0-15% EtOAc in PE) to give III-B8 (3.5 g, 55%) and III-B7 (2 g , 40%), both in the form of oils.

III-B8: ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 7.40-7.20 (m, 5H), 5.57 (dd, J = 11.2, 17.6 Hz, 1H), 5.18 (dd, J =1.6, 12.8 Hz, 1H), 4.98 (dd, J =1.6, 18.0 Hz, 1H), 4.55 (s, 2H), 3 .50-3.30 (m, 2H), 2.40-2.25 (m, 1H), 2.05-1.75 (m, 3H), 1.55-1.00 (m, 14H) , 0.95-0.75 (m, 12H), 0.02 (s, 3H), 0.01 (s, 3H).

III-B7: ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 7.40-7.20 (m, 5H), 5.04 (s, 1H), 4.56 (s, 2H), 4. 45-4.35 (m, 1H), 3.45-3.30 (m, 1H), 2.55-2.30 (m, 2H), 2.00-1.45 (m, 15H), 1.44-0.95 (m, 12H).

Synthesis III-B9

[ 0651 ] To a solution of III-B8 (3.5 g, 6.7 mmol) in MeOH (30 ml) was added Pd/C (1 g, 10% Pd, 50% water). After stirring at 25°C under H ₂ (15 psi (0.1 MPa)) for 12 hours, the reaction mixture was filtered through a pad of Celite and washed with MeOH (3×10 ml). The filtrate was evaporated to give III-B9 (2.50 g, 86%) as an oil. ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 3.80-3.73 (m, 1H), 3.65-3.55 (m, 1H), 2.15-2.05 (m, 1H ), 1.95-1.70 (m, 6H), 1.55-1.35 (m, 6H), 1.30-0.95 (m, 15H), 0.90-0.75 (m , 14H), 0.05 (s, 3H), 0.04 (s, 3H).

Synthesis III-B10

[ 0652 ] To a solution of III-B9 (2.5 g, 5.8 mmol) in DCM (20 ml) was added PCC (2.47 g, 11.5 mmol) and silica gel (5 g) at 25°C. After stirring at 25°C for 1 hour, the reaction mixture was filtered and the residue was washed with anhydrous DCM (2×20 ml). The combined filtrate was evaporated in vacuo to give III-B10 (2.2 g, 88%) as a solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 3.85-3.75 (m, 1H), 2.61 (t, J =14.0 Hz, 1H), 2.30-2.10 ( m, 6H), 1.95-1.83 (m, 1H), 1.78-1.60 (m, 2H), 1.50-1.25 (m, 7H), 1.25-0, 95 (m, 11H), 0.90-0.80 (m, 13H), 0.05 (s, 3H), 0.04 (s, 3H).

Synthesis III-B11

NaH (243 mg, 6.1 mmol, 60% in oil) was added to a stirred solution of Me ₃ SI (1.24 g, 6.1 mmol) in DMSO (10 ml) and THF (10 ml) at 0°C. After stirring for 1 hour under _N2 , the mixture was added to a solution of III-B10 (2.2 g, 5.1 mmol) in DMSO (10 ml). After stirring at 25°C for 16 hours, the reaction mixture was poured into ice water (100 ml) and extracted with EtOAc (2×50 ml). The combined organic solution was washed with water (2x50 ml) and brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated to give III-B11 (2 g) as an oil, which was used directly for the next step without further cleaning. ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 3.80-3.70 (m, 1H), 2.65-2.50 (m, 2H), 2.30-2.05 (m, 2H ), 2.00-1.80 (m, 3H), 1.55-1.30 (m, 12H), 1.30-0.75 (m, 24H), 0.05 (s, 3H), 0.04 (s, 3H).

Synthesis III-B12

Fresh Na (1.02 g, 44.7 mmol) was carefully added portionwise to MeOH (44.7 mL). After stirring at 25°C for 3 hours, a solution of III-B11 (2 g, 4.47 mmol) in anhydrous MeOH (30 ml) was added. After stirring at 75°C for 16 hours, the reaction mixture was diluted with water (50 ml), evaporated to remove most of the solvent, and extracted with EtOAc (2×50 ml). The combined organic solution was washed with saturated brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated. The residue was purified by silica gel chromatography (0-20% EtOAc in PE) to give product III-B12 (2 g, 93%) as an oil.

Synthesis of III-B13 and III-B14

[ 0653 ] To a solution of III-B12 (2 g, 4.2 mmol) in THF (30 ml) at 25°C was added TBAF·3H ₂ O (1.95 g, 6.3 mmol). After stirring at 55°C for 12 hours, the mixture was poured into water (50 ml) and extracted with EtOAc (2×30 ml). The organic solution was washed with saturated brine (2×20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated in vacuo. The residue was purified by silica gel chromatography (0-20% EtOAc in PE) to give III-B13 (620 mg, 42%) and III-B14 (570 mg, 38%), both as oils.

III-B13: ¹ H-NMR(400 MHz, CDCl₃) δ_H 3.93-3.76 (m, 1H), 3.48-3.35 (m, 5H), 2.58 (s, 1H), 2.17-2.08 (m, 1H), 1. 93-1.60 (m, 8H), 1.55-1.02 (m, 19H), 1.00-0.78 (m, 5H);LC-ELSD/MSpurity 99%, 100% according to H-NMR. MS ESI calculated for C₂₃H₃₇O [M-H₂O-H₂O+H]⁺ 329.3, found 329.3.

III-B14: ¹ H-NMR(400 MHz, CDCl₃) δ_H 3.93-3.76 (m, 1H), 3.39 (s, 3H), 3.20 (s, 2H), 3.18-3.10 (m, 2H), 2.00 (s, 1H), 1.95-1.82 (m, 1H), 1.75-1.58 (m, 5H), 1.54-0.85 (m, 25H);LC-ELSD/MSpurity 99%, 100% according to H-NMR. MS ESI calculated for C₂₃H₃₇O [M-H₂O-H₂O+H]⁺ 329.3, found 329.3.

Synthesis III-B15

[ 0654 ] To a solution of III-B13 (600 mg, 1.6 mmol) in DCM (20 ml) were added silica gel (1.5 g) and PCC (1.05 g, 4.9 mmol) in portions at 25°C. After stirring at 25°C for 0.5 hour, the mixture was filtered and the filter cake was washed with DCM (30 ml). The combined filtrate was evaporated and purified by silica gel chromatography (0-20% EtOAc in PE) to give III-B15 (550 mg, 93%) as an oil. ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 3.45-2.35 (m, 5H), 2.61 (s, 1H), 2.53-2.42 (m, 1H), 2, 35-2.18 (m, 5H), 1.85-1.10 (m, 22H), 0.96-0.82 (m, 1H), 0.62 (t, J = 7.6 Hz, 3H); LC-ELSD/MS purity 99%, MS ESI calculated for C ₂₃ H ₃₇ O ₂ [MH ₂ O+H] ⁺ 345.3, found 345.3.

EXAMPLE III-10: 1-(2-((3R,5R,8R,9R,10S,13S,14S,17S)-13-ethyl-3-hydroxy-3-(methoxymethyl)hexadecahydro-1H-cyclopenta[a] phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (III-B17)

Synthesis III-B16

[ 0655 ] To a solution of III-B15 (80 mg, 0.22 mmol) in MeOH (5 ml) at 25°C was added HBr (8.80 mg, 0.044 mmol) and Br ₂ (35.2 mg, 0.22 mmol). After stirring at 25°C for 2 hours, the reaction mixture was added to saturated NaHCO ₃ solution (10 ml) and extracted with EtOAc (3×10 ml). The combined organic solution was washed with saturated brine (20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated to give III-B16 (90 mg) as an oil, which was used directly in the next step without further purification.

Synthesis III-B17

[ 0656 ] K ₂ CO ₃ (56, 2 mg, 0.4 mmol). After stirring at 25°C for 2 hours, the reaction mixture was extracted with EtOAc (3×30 ml). The combined organic solution was washed with saturated brine (30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated. The residue was purified by flash column chromatography (0-30% EtOAc in PE) and then by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*30 5 μm; conditions: water (10 mM NH ₄ HCO ₃ )-ACN; Start B: 70 End B: 90 Gradient Time (minutes): 7 100% B Retention Time (minutes): 1) Forming III-B17 (32.6 mg, 53%) as a solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 7.86 (s, 1H), 7.81 (s, 1H), 5.04 (dd, J = 18.0, 95.6 Hz, 2H) , 3.45-3.33 (m, 5H), 2.50 (t, J =8.8 Hz, 1H), 2.40-2.23 (m, 2H), 1.88-1.10 (m, 23H), 1.00-0.83 (m, 1H), 0.60 (t, J =7.6 Hz, 3H); LC-ELSD/MS purity 99%, MS ESI calculated for C ₂₇ H ₃₈ N ₃ O ₂ [MH ₂ O+H] ⁺ 436.3, found 436.3.

EXAMPLE III-11: Synthesis of 1-((3R,5R,8R,9R,10S,13R,14S,17S)-3-hydroxy-13-(methoxymethyl)-3-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-17 -yl)ethan-1-one (III-C11)

III-C2 synthesis

[ 0657 ] To a solution of EtPh ₃ PBr (63.4 g, 171 mmol) in THF (400 ml) at 25°C was added t-BuOK (19.1 g, 171 mmol). After stirring at 50°C for 30 minutes , III-C1 (20 g, 68.8 mmol) was added. After stirring at 50°C for 2 hours, the mixture was added to saturated NH ₄ Cl solution (400 ml) and extracted with EtOAc (3×200 ml). The combined organic solution was washed with saturated brine (500 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated. The residue was recrystallized from MeOH/water (700 ml, 1:1) to give III-C2 (25 g) as an oil. ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 5.25-5.05 (m, 1H), 2.42-2.10 (m, 3H), 1.92-1.55 (m, 7H ), 1.53-1.25 (m, 14H), 1.24-1.06 (m, 6H), 0.87 (s, 3H).

III-C3 synthesis

[ 0658 ] To a mixture of III-C2 (25 g, 82.6 mmol) in DMF (300 ml) was added NaH (8.23 g, 206 mmol, 60%) at 0°C. After stirring at 25°C for 1 hour, BnBr (35.2 g, 206 mmol) was added. After stirring at 60°C for 20 hours, the mixture was added to water (500 ml) and extracted with EtOAc (3×200 ml). The combined organic solution was washed with LiCl solution (2×500 ml, 4% in water), saturated brine (500 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated. The residue was purified by flash column chromatography (100% PE) to give III-C3 (30 g, 93%) as a solid.

¹ H-NMR(400 MHz, CDCl₃) δ_H 7.40-7.27 (m, 5H), 5.15-5.05 (m, 1H), 4.50 (s, 2H), 2.40-2.10 (m, 3H), 1. 99-1.59 (m, 9H), 1.52-1.34 (m, 6H), 1.33 (s, 3H), 1.32-1.05 (m, 8H), 0.87 ( s, 3H).

III-C4 synthesis

[ 0659 ] To a solution of III-C3 (28 g, 71.3 mmol) in THF (300 ml) at 0°C was added 9-BBN dimer (34.3 g, 142 mmol). After stirring at 25°C for 1 hour, ethanol (200 ml) was added at 25°C, and then aqueous NaOH (142 ml, 5 M, 713 mmol) was added dropwise, then H ₂ O ₂ (121 g, 30% , 1069 mmol). After stirring at 70°C for 1 hour, the reaction mixture was diluted with water (300 ml) and stirred at 25°C for 1 hour. The solid was filtered and washed with water (2 x 300 mL), dried in vacuo to give III-C4 (19.1 g, 65%) as a solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 7.45-7.28 (m, 5H), 4.50 (s, 2H), 3.75-3.62 (m, 1H), 2, 00-1.59 (m, 12H), 1.52-1.32 (m, 10H), 1.31-1.00 (m, 9H), 0.67 (s, 3H).

III-C5 synthesis

[ 0660 ] To a solution of III-C4 (3 g, 7.3 mmol) in cyclohexane (300 ml) at 25°C under N ₂ was added CaCO ₃ (2.19 g, 21.9 mmol), PhI(OAc) ₂ (7.05 g, 21.9 mmol), I ₂ (3.70 g, 14.6 mmol). After heating at reflux (80° C.) by irradiation with an infrared lamp (250 W) for 30 minutes, the mixture was added to saturated Na ₂ S ₂ O ₃ solution (500 ml) and extracted with EtOAc (3 x 100 ml). The combined organic solution was washed with saturated brine (500 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated. The residue was purified by flash column chromatography (0-5% EtOAc in PE) to give III-C5 (4.0 g) as an oil. ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 7.40-7.20 (m, 4H), 7.25-7.20 (m, 1H), 6.00 (s, 1H), 5, 07 (s, 1H), 4.50 (s, 2H), 4.40-4.25 (m, 2H), 2.20-2.08 (m, 1H), 2.00-1.65 ( m, 13H), 1.50-1.40 (m, 10H), 1.25-0.95 (m, 5H), 0.85-0.70 (m, 2H).

III-C6 synthesis

[ 0661 ] To a solution of MePh ₃ PBr (30.5 g, 85.7 mmol) in THF (200 ml) was added t-BuOK (9.59 g, 85.7 mmol) at 25°C. After stirring at 50°C for 1 hour, a solution of III-C5 (4 g, 8.6 mmol) in THF (20 ml) was added. After stirring at 50°C for 16 hours, the mixture was added to saturated NH ₄ Cl solution (200 ml) and extracted with EtOAc (3×100 ml). The combined organic solution was washed with saturated brine (200 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated. The residue was triturated with MeOH/water (400 ml, 1:1) at 25°C to give III-C6 (3.6 g) as an oil. ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 7.42-7.27 (m, 5H), 5.85-5.70 (m, 1H), 5.35-5.25 (m, 1H ), 5.20-5.10 (m, 1H), 4.50 (s, 2H), 3.90-3.75 (m, 1H), 2.40-2.30 (m, 1H), 1.95-1.60 (m, 9H), 1.55-1.30 (m, 14H), 1.28-0.90 (m, 7H).

III-C7 synthesis

[ 0662 ] To a solution of III-C6 (3.6 g, 8.5 mmol) in DMF (20 ml) at 25°C was added NaH (1.70 g, 42.5 mmol, 60% in oil). After stirring at 25°C for 1 hour, BnBr (4.36 g, 25.5 mmol) was added. After stirring at 60°C for 16 hours, the mixture was added to water (200 ml) and extracted with EtOAc (3×50 ml). The combined organic solution was washed with LiCl solution (2×100 ml, 4% in water), saturated brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated. The residue was purified by flash column chromatography (0-2% EtOAc in PE) to give III-C7 (1 g, 23%) as an oil. ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 7.45-7.28 (m, 10H), 5.70-5.55 (m, 1H), 5.25-5.15 (m, 1H ), 5.05-4.95 (m, 1H), 4.57-4.45 (m, 3H), 4.33-4.25 (m, 1H), 3.27-3.15 (m , 1H), 2.41-2.32 (m, 1H), 2.15-2.05 (m, 1H), 1.95-1.59 (m, 7H), 1.52-1.25 (m, 11H), 1.20-0.80 (m, 10H).

III-C8 synthesis

[ 0663 ] NaHCO ₃ (1 g, 11.9 mmol) was added to a solution of III-C7 (1 g, 1.9 mmol) in DCM/MeOH (10 ml/10 ml) at 25°C. After stirring under O ₃ (1 atm) for 20 minutes at -70°C, NaBH ₄ (296 mg, 7.8 mmol) was added to the mixture at 0°C. After stirring for 1 hour at 70°C, the mixture was added to saturated NH ₄ Cl solution (100 ml) and extracted with EtOAc (3×50 ml). The combined organic solution was washed with saturated brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated to give III-C8 (300 mg) as an oil, which was used directly for the next step.

III-C9 synthesis

[ 0664 ] NaH (92.6 mg, 2.3 mmol, 60%) was added to a solution of III-C8 (300 mg, 0.58 mmol) in THF (5 ml) at 0°C. After stirring at 25°C for 1 hour, MeI (329 mg, 2.3 mmol) was added. After stirring at 25°C for 1 hour, the mixture was added to saturated NH ₄ Cl solution (100 ml) and extracted with EtOAc (3×50 ml). The combined organic solution was washed with saturated brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated. The residue was purified by flash column chromatography (0-2% EtOAc in PE) to give III-C9 (200 mg) as an oil. ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 7.45-7.28 (m, 8H), 7.25-7.21 (m, 2H), 4.65-4.55 (m, 1H ), 4.50 (s, 2H), 4.40-4.30 (m, 1H), 3.55-3.43 (m, 1H), 3.40-3.30 (m, 1H), 3.21 (s, 3H), 3.15-3.05 (m, 1H), 2.40-2.30 (m, 1H), 2.20-1.59 (m, 11H), 1. 52-1.20 (m, 11H), 1.18-0.80 (m, 7H).

Synthesis III-C10

[ 0665 ] To a solution of III-C9 (200 mg, 0.38 mmol) in MeOH (5 ml) was added Pd/C (50 mg, 10% in water) at 25°C. After stirring at room temperature for 16 hours under H ₂ (50 psi (0.35 MPa)), the mixture was filtered and the mother liquor was evaporated. The residue was purified by flash column chromatography (0-30% EtOAc in PE) to give III-C10 (50 mg, 38%) as an oil. ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 4.20-4.11 (m, 1H), 4.10-4.00 (m, 1H), 3.40-3.25 (m, 5H ), 2.35-2.25 (m, 1H), 1.95-1.80 (m, 4H), 1.78-1.59 (m, 4H), 1.52-1.35 (m , 5H), 1.33-1.23 (m, 7H), 1.30-1.00 (m, 6H), 0.98-0.80 (m, 4H).

Synthesis III-C11

[ 0666 ] A solution of III-C10 (50 mg, 0.14 mmol) and DMP (120 mg, 0.29 mmol) in DCM (2 ml) was stirred at 25°C for 1 hour. The mixture was added to saturated NaHCO ₃ solution (50 ml) and extracted with DCM (3×20 ml). The combined organic solution was washed with saturated Na ₂ S ₂ O ₃ solution (2×50 ml), saturated brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated. The residue was purified by flash column chromatography (0-30% EtOAc in PE) to give III-C11 (30 mg, 60%) as a solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 3.48-3.40 (m, 1H), 3.09 (s, 3H), 2.88-2.80 (m, 1H), 2, 65-2.55 (m, 1H), 2.50-2.40 (m, 1H), 2.38-2.28 (m, 1H), 2.15 (s, 3H), 1.95- 1.59 (m, 7H), 1.52-1.25 (m, 13H), 1.24-1.00 (m, 5H); LC-ELSD/MS purity 99%, MS ESI calculated for C ₂₂ H ₃₇ O ₃ [M+H] ⁺ 349.3, found 349.3.

EXAMPLE III-12: synthesis of 1-(2-((3R,5R,8R,9R,10S,13R,14S,17S)-3-hydroxy-13-(methoxymethyl)-3-methylhexadecahydro-1H-cyclopenta[a] phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (III-C13)

III-C12 synthesis

[0667] To the solutionIII-C11 (25 mg, 0.072 mmol) in MeOH (5 ml) was added HBr (2 mg, 40%) at 25°C, and then Br₂ (11.4 mg, 0.072 mmol) at 0°C. After stirring at 25°C for 5 hours, the mixture was added to a saturated NaHCO solution₃ (50 ml) and extracted with EtOAc (3×20 ml). The combined organic solution was washed with saturated brine (50 ml), dried over anhydrous Na₂SO₄, filtered and evaporated with educationIII-C12 (40 mg) as an oil. ¹ H-NMR(400 MHz, CDCl₃) δ_H 4.05-3.95 (m, 2H), 3.55-3.45 (m, 1H), 3.06 (s, 3H), 2.85-2.75 (m, 2H), 2. 52-2.38 (m, 2H), 1.92-1.59 (m, 5H), 1.52-1.30 (m, 12H), 1.27 (s, 3H), 1.25- 0.80 (m, 5H).

III-C13 synthesis

[ 0668 ] A solution of III-C12 (40 mg, 0.094 mmol), K ₂ CO ₃ (17.4 mg, 0.19 mmol) and 1H-pyrazole-4-carbonitrile (25.8 mg, 0.19 mmol) was stirred at 25°C for 2 hours. The mixture was added to water (100 ml) and extracted with EtOAc (3×20 ml). The combined organic solution was washed with water (2×100 ml), saturated brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated. The residue was purified by flash column chromatography (0-50% EtOAc in PE) to give III-C13 (5 mg, 12%) as a solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 7.82 (s, 1H), 7.80 (s, 1H), 5.28-5.20 (m, 1H), 4.92-4, 85 (m, 1H), 3.55-3.45 (m, 1H), 3.02 (s, 3H), 2.92-2.82 (m, 1H), 2.65-2.35 ( m, 3H), 1.90-1.59 (m, 7H), 1.52-1.30 (m, 11H), 1.28 (s, 3H), 1.25-1.02 (m, 4H); LC-ELSD/MS purity 99%, MS ESI calculated for C ₂₆ H ₃₈ N ₃ O ₃ [M+H] ⁺ 440.3, found 440.3.

EXAMPLE III-13: synthesis of 1-((3R,5R,8R,9R,10S,13R,14S,17S)-3-hydroxy-13-isobutyl-3-(methoxymethyl)hexadecahydro-1H-cyclopenta[a]phenanthrene- 17-yl)ethan-1-one (III-D20)

III-D2 synthesis

[ 0669 ] To a solution of III-D1 (300 g, 1093 mmol) in MeOH (2 L) at 25°C was added 4-methylbenzenesulfonic acid (18.7 g, 109 mmol). After stirring at 65°C for 1 hour, the reaction mixture was cooled and the precipitate was isolated by filtration and washed with methanol (2×300 ml) to form III-D2 (230 g) as a solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 3.19 (s, 3H), 3.14 (s, 3H), 2.60-2.39 (m, 2H), 2.25-2, 00 (m, 2H), 1.97-1.90 (m, 2H), 1.86-1.75 (m, 6H), 1.70-1.60 (m, 5H), 1.56- 1.49 (m, 4H), 1.47-1.35 (m, 10H), 1.30-1.22 (m, 5H), 1.15-1.00 (m, 2H), 0. 86 (s, 3H).

III-D3 synthesis

[ 0670 ] To a suspension of EtPPh ₃ Br (798 g, 2.15 mol) in THF (1.5 L) was added t-BuOK (241 g, 2.15 mol) at 25°C under N ₂ . After stirring at 50°C for 30 minutes, a solution of III-D2 (230 g, 717 mmol) in THF (500 ml) was added at 50°C. After stirring at 50°C for 16 hours, the reaction mixture was cooled to 25°C, diluted with saturated NH ₄ Cl solution (500 ml) and extracted with EtOAc (2×500 ml). The combined organic solution was washed with brine (2×500 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated. The residue was recrystallized from methanol (1 L) and water (1 L) to give III-D3 (290 g) as a solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 3.19 (s, 3H), 3.14 (s, 3H), 2.40-2.10 (m, 4H), 1.95-1, 35 (m, 13H), 1.33-1.05 (m, 10H), 0.87 (s, 3H).

III-D4 synthesis

[ 0671 ] To a solution of III-D3 (275 g, 826 mmol) in THF (2 L) was added 9-BBN dimer (402 g, 1.65 mol) at 25°C. After stirring at 50°C for 2 hours, the reaction mixture was cooled to 0°C and ethanol (379 g, 8.26 mol) and NaOH (1.65 L, 5 M, 8.26 mol) were added very slowly. After addition was complete, H ₂ O ₂ (825 mL, 8.26 mol, 30%) was added slowly while maintaining the internal temperature below 15°C. After stirring at 75°C for 1 hour, the reaction mixture was poured with a saturated aqueous solution of Na ₂ S ₂ O ₃ (260 ml) and stirred at 0°C for 1 hour. The mixture was diluted with water (2 L) and filtered. The filter cake was washed with water (3×700 ml), dried in vacuum to form III-D4 (285 g) as a solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 3.17-3.09 (m, 6H), 1.96-1.77 (m, 8H), 1.64-1.29 (m, 11H ), 1.24-0.91 (m, 10H), 0.63 (s, 3H).

III-D5 synthesis

[ 0672 ] To a solution of III-D4 (285 g, 813 mmol) in THF (3 L) at 20°C was added aqueous HCl (1.62 L, 1.62 mol, 1 M). After stirring for 1 hour, the mixture was diluted with water (700 ml) and extracted with DCM (2×500 ml). The combined organic solution was washed with brine (2×500 ml), dried over anhydrous Na ₂ SO ₄ , filtered, evaporated to give III-D5 (280 g) as a solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 3.75-3.65 (m, 1H), 2.65-2.55 (m, 1H), 2.30-2.10 (m, 1H ), 2.00-1.80 (m, 5H), 1.75-1.42 (m, 10H), 1.40-1.28 (m, 4H), 1.29-1.15 (m , 7H), 0.66 (s, 3H).

III-D6 synthesis

[ 0673 ] To a solution of III-D6 (14 g, 45.9 mmol) in toluene (200 ml) at 25°C was added TsOH (787 mg, 4.6 mmol) and ethane-1,2-diol (28.4 g, 458 mol) under N ₂ . After stirring at 120°C for 4 hours, the mixture was poured into water (100 ml) and extracted with ethyl acetate (2×100 ml). The combined organic solution was washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated in vacuo. The residue was purified by flash column chromatography (5-10% EtOAc in PE) to give III-D6 (8 g, 50%) as a solid. ¹ H-NMR (400 MHz, CDCl3) _δH 3.93 (s, 4H), 3.76-3.63 (m, 1H), 2.03-1.95 (m, 1H), 1.93 -1.80 (m, 4H), 1.64-1.58 (m, 3H), 1.56-1.48 (m, 2H), 1.44-1.30 (s, 6H), 1 .27-0.95 (m, 12H), 0.66 (m, 3H).

Synthesis III-D7

[ 0674 ] To a solution of III-D6 (2.0 g, 5.7 mmol), PhI(OAc) ₂ (5.50 g, 17.1 mmol) and CaCO ₃ (1.71 g, 17.1 mmol) I ₂ (2.89 g, 11.4 mmol) was added to cyclohexane (200 ml) at 25°C. The mixture was heated to 80°C by irradiation with an infrared lamp (200 W) for 10 minutes. The mixture was purified along with another similar reaction mixture (2 g). The mixture was added to saturated Na ₂ S ₂ O ₃ solution (1000 ml) and extracted with EtOAc (3×300 ml). The combined organic solution was washed with saturated brine (1000 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated to give III-D7 (4.6 g) as an oil. ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 5.95 (s, 1H), 4.35-4.40 (m, 1H), 3.92 (s, 4H), 2.40-2, 30 (m, 1H), 2.25-2.05 (m, 3H), 2.00-1.70 (m, 12H), 1.50-1.35 (m, 7H), 1.30- 1.00 (m, 6H), 0.90-0.70 (m, 1H).

Synthesis III-D8

[ 0675 ] To a solution of PPh ₃ MeBr (20.2 g, 56.8 mmol) and t-BuOK (6.36 g, 56.8 mmol) in THF (30 ml), stirred for 1 hour, was added solution III -D7 (2.3 g, 5.7 mmol) in THF (20 ml). After stirring for 12 hours at 50°C, the solution was purified along with another batch (of 2.3 g). The mixture was added to saturated NH ₄ Cl solution (200 ml) and extracted with EtOAc (3×50 ml). The combined organic solution was washed with saturated brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated. The residue was purified by silica gel chromatography (0-20% EtOAc in PE) to give III-D8 (2.3 g) as an oil. ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 5.77 (dd, J = 11.2, 18.0 Hz, 1H), 5.28 (d, J = 10.8 Hz, 1H), 5 .14 (d, J =18.0 Hz, 1H), 3.93 (s, 4H), 3.90-3.85 (m, 1H), 2.40-2.30 (m, 1H), 2.00-1.90 (m, 1H), 1.90-1.65 (m, 6H), 1.60-1.50 (m, 3H), 1.50-1.40 (m, 1H ), 1.35-0.80 (m, 16H).

Synthesis III-D9

[ 0676 ] To a solution of III-D8 (2.0 g, 5.5 mmol) in DMF (20 ml) was added NaH (438 mg, 11.0 mmol, 60% in mineral oil) at 0°C. After stirring at 20°C for 1 hour, BnBr (2.36 g, 13.8 mmol) was added to the mixture at 20°C. After stirring at 60°C for 10 hours, the mixture was poured into water (50 ml) and extracted with EtOAc (2×50 ml). The combined organic solution was washed with brine (3×50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated. The residue was purified by flash column chromatography (0-40% EtOAc in PE) to give III-D9 (2.0 g, 80.3%) as an oil. ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 7.34-7.25 (m, 5H), 5.66-5.56 (m, 1H), 5.27-5.17 (m, 1H ), 5.08-5.01 (m, 1H), 4.57-4.26 (m, 2H), 3.93 (s, 4H), 3.27-3.14 (m, 1H), 2.39-2.34 (m, 1H), 1.96 (s, 2H), 1.90-1.78 (m, 3H), 1.61-1.54 (m, 4H), 1. 48-1.34 (m, 10H), 1.20-1.14 (m, 5H), 1.06-0.99 (m, 2H).

Synthesis III-D10

[ 0677 ] To a solution of III-D9 (2.0 g, 4.4 mmol) in THF (20 ml) was added BH ₃ ·Me ₂ S (2.21 ml, 10 M, 22.1 mmol). After stirring at 25°C for 16 hours, EtOH (2.55 ml, 44.3 mmol) was slowly added, followed by aqueous NaOH (1.77 g in 8.86 ml water, 44.3 mmol) and aqueous H ₂ O ₂ (4.43 ml, 10 M, 44.3 mmol). After stirring at 70°C for 1 hour, the mixture was poured into Na ₂ SO ₃ solution (80 ml, 10%) and extracted with EtOAc (2×100 ml). The combined organic solution was dried over Na ₂ SO ₄ , filtered and evaporated, and purified by flash chromatography (0~30% EtOAc in PE) to give III-D10 (1.4 g, 67.6%) as a solid substances. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.37-7.31 (m, 4H), 7.28-7.24 (m, 1H), 4.66 (d, J = 11.2 Hz , 1H), 4.32 (d, J =11.2 Hz, 1H), 3.93 (s, 4H), 3.68-3.46 (m, 3H), 2.02-1.74 ( m, 6H), 1.70-1.57 (s, 5H), 1.52-1.33 (m, 9H), 1.28-1.23 (m, 2H), 1.21-1. 03 (m, 5H), 1.02-0.92 (m, 3H)

Synthesis III-D11

[ 0678 ] To a solution of III-D10 (1.4 g, 2.98 mmol) in DCM (50 ml) was added DMP (2.52 g, 5.96 mmol). After stirring at 20°C for 1 hour, the mixture was added to saturated NaHCO ₃ solution (200 ml) and extracted with DCM (3×50 ml). The combined organic solution was washed with saturated Na ₂ S ₂ O ₃ solution (2×200 ml), saturated brine (200 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated to give III-D11 (1.4 g) as oils ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 9.66 (s, 1H), 7.40-7.27 (m, 4H), 7.25-7.15 (m, 1H), 4, 56 (d, J =11.6 Hz, 1H), 4.23 (d, J =11.6 Hz, 1H), 3.93 (s, 4H), 3.80-3.70 (m, 1H ), 2.55-2.40 (m, 2H), 2.30-2.20 (m, 1H), 2.10-1.60 (m, 9H), 1.52-1.25 (m , 8H), 1.22 (d, J =6.0 Hz, 3H), 1.20-0.92 (m, 6H).

Synthesis III-D12

[ 0679 ] To a solution of III-D11 (1.4 g, 3.0 mmol) in THF (20 ml) at 0°C was added MeMgBr (5 ml, 3 M in Et ₂ O, 15.0 mmol). After stirring at 20°C for 1 hour, the mixture was added to saturated NH ₄ Cl solution (200 ml) and extracted with EtOAc (3×50 ml). The combined organic solution was washed with saturated brine (200 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated to give III-D12 (1.3 g) as an oil. ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 7.35-7.28 (m, 4H), 7.25-7.16 (m, 1H), 4.61 (d, J =12.0 Hz, 1H), 4.34 (d, J =11.6 Hz, 1H), 3.93 (s, 4H), 3.91-3.75 (m, 1H), 3.54-3.40 (m, 1H), 2.40-2.25 (m, 1H), 2.00-1.60 (m, 8H), 1.52-1.20 (m, 14H), 1.18-0 .80 (m, 10H).

Synthesis III-D13

[ 0680 ] To a solution of III-D12 (1.8 g, 3.7 mmol) in DCM (40 ml) was added Dess-Martin periodinane (DMP) (3.15 g, 7.4 mmol). After stirring at 20°C for 1 hour, the mixture was added to saturated NaHCO ₃ solution (300 ml) and extracted with DCM (3×50 ml). The combined organic solution was washed with saturated Na ₂ S ₂ O ₃ solution (2×300 ml), saturated brine (300 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated to give III-D13 (1.8 g) as oils ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 7.40-7.28 (m, 4H), 7.25-7.16 (m, 1H), 4.51 (d, J =12.0 Hz, 1H), 4.11 (d, J =12.0 Hz, 1H), 3.93 (s, 4H), 3.13-3.02 (m, 1H), 2.44 (d, J =18.4 Hz, 1H), 2.29 (d, J =19.2 Hz, 1H), 2.10-1.78 (m, 8H), 1.76 (s, 3H), 1.52 -1.11 (m, 15H), 1.10-0.75 (m, 4H).

To a solution of MePh ₃ PBr (6.67 g, 18.7 mmol) in THF (30 ml) was added t-BuOK (2.09 g, 18.7 mmol) at 20°C. After stirring at 50°C for 1 hour, a solution of III-D13 (1.8 g, 3.7 mmol) in THF (20 ml) was added to the reaction mixture at a temperature below 50°C. After stirring at 50°C for 16 hours, the mixture was added to saturated NH ₄ Cl solution (200 ml) and extracted with EtOAc (3×50 ml). The combined organic solution was washed with saturated brine (200 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated. The residue was purified by flash column chromatography (0-5% EtOAc in PE) to give III-D14 (1.2 g, 67%) as an oil. ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 7.40-7.28 (m, 4H), 7.25-7.16 (m, 1H), 4.77 (s, 1H), 4, 71 (s, 1H), 4.57 (d, J =11.6 Hz, 1H), 4.34 (d, J =11.2 Hz, 1H), 3.93 (s, 4H), 3, 90-3.75 (m, 1H), 2.36 (d, J =11.6 Hz, 1H), 2.20-1.80 (m, 9H), 1.78-1.59 (m, 4H), 1.52-1.25 (m, 9H), 1.23-1.19 (m, 3H), 1.15-0.80 (m, 6H).

Synthesis of III-D15 and III-D15a

To a solution of III-D14 (1.2 g, 2.5 mmol) in MeOH (20 ml) was added Pd/C (200 mg, 10% in water) at 25°C. After stirring at 25°C for 16 hours under H ₂ (50 psi (0.35 MPa)), the mixture was filtered and the mother liquor was evaporated. The residue was purified by flash column chromatography (0-10% EtOAc in PE) to give III-D15a (400 mg, 41%) and III-D15 (300 mg, 31%), both as oils.

To a solution of III-15a (400 mg, 1.0 mmol) in MeOH (10 ml) was added Pd/C (100 mg, 10% in water) at 25°C. After stirring at 50°C for 16 hours under H ₂ (50 psi (0.35 MPa)), the mixture was filtered and the filter cake was washed with MeOH (3×30 ml). The mother liquor was evaporated to form III-D15 (300 mg) as an oil. ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 3.93 (s, 4H), 3.84-3.71 (m, 1H), 2.25-2.15 (m, 1H), 2, 08-1.60 (m, 8H), 1.52-1.33 (m, 9H), 1.31 (d, J =6.0 Hz, 3H), 1.28-1.02 (m, 10H), 0.97 (d, J =6.4 Hz, 3H), 0.92 (d, J =6.8 Hz, 3H).

Synthesis III-D16

[ 0681 ] A solution of III-D15 (600 mg, 1.5 mmol) and aqueous HCl (3 mL, 2 M, 6.0 mmol) in THF (5 mL) was stirred at 20°C for 1 hour. The mixture was added to saturated NaHCO ₃ solution (150 ml) and extracted with EtOAc (3×50 ml). The combined organic solution was washed with saturated brine (150 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated to give III-D16 (500 mg) as an oil. ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 3.90-3.75 (m, 1H), 2.59 (t, J =14.0 Hz, 1H), 2.35-2.05 ( m, 6H), 2.00-1.60 (m, 5H), 1.50-1.35 (m, 4H), 1.32 (d, J =5.6 Hz, 3H), 1.30 -1.03 (m, 12H), 1.00 (d, J =6.4 Hz, 3H), 0.94 (d, J =6.8 Hz, 3H).

Synthesis III-D17

[ 0682 ] To a solution of t-BuOK (581 mg, 5.2 mmol) and Me ₃ SI (1.05 g, 5.2 mmol) in THF (15 ml) was added III-D16 (600 mg, 1.7 mmol ). After stirring at 20°C for 1 hour, the reaction mixture was diluted with water (200 ml) and extracted with EtOAc (3×50 ml). The combined organic solution was washed with saturated brine (200 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated to give III-D17 (540 mg) as an oil. ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 3.85-3.70 (m, 1H), 2.65-2.55 (m, 2H), 2.30-2.15 (m, 2H ), 2.03-1.59 (m, 9H), 1.52-1.35 (m, 5H), 1.32 (d, J =6.0 Hz, 3H), 1.30-1, 02 (m, 10H), 0.99 (d, J =6.4 Hz, 3H), 0.93 (d, J =6.8 Hz, 3H), 0.91-0.80 (m, 2H ).

Synthesis of III-D18 and III-D19

[ 0683 ] Na (716 mg, 29.8 mmol) was added to MeOH (30 ml) at 20°C. After stirring at 70°C for 3 hours, a solution of III-D17 (540 mg, 1.5 mmol) in MeOH (10 ml) was added. After stirring at 70°C for 5 hours, the mixture was added to saturated NH ₄ Cl solution (150 ml) and extracted with EtOAc (3×50 ml). The combined organic solution was washed with saturated brine (150 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated. The residue was purified by flash column chromatography (0-25% EtOAc in PE) to give III-D18 (150 mg, 26%) and III-D19 (250 mg, 43%), both as oils. The stereochemical configuration at C3 was assigned based on H-NMR.

III-D18 : ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 3.90-3.75 (m, 1H), 3.39 (s, 3H), 3.20 (s, 2H), 2. 25-2.10 (m, 2H), 1.99 (s, 1H), 1.98-1.58 (m, 8H), 1.52-1.34 (m, 6H), 1.31 ( d, J =6.0 Hz, 3H), 1.28-1.02 (m, 12H), 0.98 (d, J =6.4 Hz, 3H), 0.92 (d, J =6 ,8 Hz, 3H).

III-D19 : ^1H -NMR (400 MHz, _CDCl3 ) _δH 3.88-3.72 (m, 1H), 3.48-3.30 (m, 5H), 2.57 (s, 1H ), 2.19 (d, J =9.2 Hz, 1H), 2.00-1.60 (m, 8H), 1.50-1.34 (m, 6H), 1.31 (d, J =5.6 Hz, 3H), 1.28-1.02 (m, 12H), 0.98 (d, J =6.4 Hz, 3H), 0.92 (d, J =6.4 Hz, 3H), 0.90-0.85 (m, 1H); LC-ELSD/MS purity 99%, 100% by H-NMR; MS ESI calculated for C ₂₅ H ₄₁ O [M-2H ₂ O+H] ⁺ 357.3, found 357.3.

Synthesis III-D20

[ 0684 ] To a solution of III-D19 (230 mg, 0.59 mmol) in DCM (10 ml) was added DMP (496 mg, 1.2 mmol). After stirring at 20°C for 1 hour, the mixture was added to saturated NaHCO ₃ solution (100 ml) and extracted with DCM (3×50 ml). The combined organic solution was washed with saturated Na ₂ S ₂ O ₃ solution (2×100 ml), saturated brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated. The residue was purified by flash column chromatography (0-25% EtOAc in PE) to give III-D20 (132 mg, 58%) as a solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 3.45-3.35 (m, 5H), 2.61 (s, 1H), 2.48-2.36 (m, 2H), 2, 30-2.15 (m, 4H), 1.90-1.59 (m, 8H), 1.52-1.32 (m, 7H), 1.30-1.05 (m, 9H), 0.93 (d, J =6.4 Hz, 3H), 0.78 (d, J =6.4 Hz, 3H); LC-ELSD/MS purity 99%, MS ESI calculated for C ₂₅ H ₄₁ O ₂ [MH ₂ O+H] ⁺ 373.3, found 373.3.

EXAMPLE III-14: synthesis of 1-(2-((3R,5R,8R,9R,10S,13R,14S,17S)-3-hydroxy-13-isobutyl-3-(methoxymethyl)hexadecahydro-1H-cyclopenta[a ]phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (III-D22)

Synthesis III-D21

[0685] To the solutionIII-D21 (117 mg, 0.3 mmol) and HBr (11.9 mg, 0.06 mmol, 40%) in MeOH (5 ml) at 0°C added Br₂ (47.9 mg, 0.3 mmol). After stirring at 20°C for 3 hours, the mixture was added to a saturated NaHCO solution₃ (100 ml) and extracted with EtOAc (3×50 ml). The combined organic solution was washed with saturated brine (100 ml), dried over anhydrous Na₂SO₄, filtered and evaporated with educationIII-D21 (180 mg) as oil, used as is.

Synthesis III-D22

[ 0686 ] To a solution of III-D22 (180 mg, 0.38 mmol) in acetone (5 ml) was added 1H-pyrazole-4-carbonitrile (106 mg, 1.1 mmol) and K ₂ CO ₃ (157 mg, 1 .1 mmol). After stirring at 20°C for 16 hours, the mixture was added to saturated NH ₄ Cl solution (100 ml) and extracted with EtOAc (3×30 ml). The combined organic solution was washed with water (2×100 ml), saturated brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated. The residue was purified by flash column chromatography (0-40% EtOAc in PE) to give III-D2 (24.5 mg, 13%) as a solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ _H 7.86 (s, 1H), 7.80 (s, 1H), 5.22 (d, J = 18.0 Hz, 1H), 4.90 (d, J =17.6 Hz, 1H), 3.48-3.35 (m, 5H), 2.50-2.40 (m, 2H), 2.35-2.22 (m, 1H ), 1.95-1.55 (m, 13H), 1.53-1.00 (m, 12H), 0.95 (d, J =6.4 Hz, 3H), 0.67 (d, J =6.4 Hz, 3H); LC-ELSD/MS purity 99%, MS ESI calculated for C ₂₉ H ₄₂ N ₃ O ₂ [MH ₂ O+H] ⁺ 464.3, found 464.3.

Steroid inhibition of TBPS binding

[ 0687 ] [ ³⁵ S]-tert-Butylbicyclophosphorothionate (TBPS) binding assays using rat brain cortical membranes in the presence of 5 μM GABA have been described (Gee et al., J. Pharmacol. Exp. Ther ., 1987, vol. 241 , pp. 346-353; Hawkinson et al., Mol. Pharmacol ., 1994, vol. 46 , pp. 977-985; Lewin AH et al., Mol. Pharmacol ., 1989, vol. 35 , pp. 189-194 ).

[ 0688 ] Briefly, after decapitation under carbon dioxide anesthesia in Sprague-Dawley rats (200-250 g), the cerebral cortex was rapidly removed. The cerebral cortex was homogenized in 10 volumes of ice-cold 0.32 M sucrose solution using a glass/Teflon homogenizer and centrifuged at 1500 x g for 10 min at 4°C. The resulting supernatants are centrifuged at 10,000× g for 20 min at 4°C to form sediments P2. P2 pellets were resuspended in 200 mM NaCl/50 mM Na-K-phosphate buffer, pH 7.4, and centrifuged at 10,000 × g for 10 min at 4°C. This washing procedure is repeated twice, and the pellets are resuspended in 10 volumes of buffer. Aliquots (100 μl) of membrane suspensions are incubated with 3 nM [ ³⁵ S]-TBPS and 5 ml aliquots of the test drug dissolved in dimethyl sulfoxide (DMSO) (0.5% final concentration) in the presence of 5 μM GABA. The incubation mixture is brought to a final volume of 1.0 ml with buffer. Nonspecific binding was determined in the presence of 2 μM unlabeled TBPS and in the range from 15 to 25%. After 90 min of incubation at room temperature, assays are terminated by glass filtration (Schleicher and Schuell, no. 32) using a cell harvester (Brandel) and washed three times with ice-cold buffer. The radioactivity associated with the filter is measured by liquid scintillation spectrometry. Using Prism (GraphPad), a nonlinear curve fit is performed on all data for each drug, averaged at each concentration. Data are fitted to a partial inhibition model instead of a full one if the sum of squares is significantly smaller by the F test. Similarly, data are fit to a two-component inhibition model instead of a single-component inhibition model if the sum of squares is significantly smaller by the F test. The concentration of test compound that produces 50% inhibition (IC ₅₀ ) of specific binding and the maximum degree of inhibition (I _max ) is determined for individual experiments with the same model used for all data, and then the mean±SEM of individual experiments is calculated. Picrotoxin serves as a positive control for such studies as it has been demonstrated to consistently inhibit TBPS binding.

[ 0689 ] Various compounds are or can be screened in vitro to determine their potential as modulators of [ ³⁵ S]-TBPS binding. Such analyzes are or may be performed in accordance with the above.

[ 0690 ] Example I-10: TBPS binding

[ 0691 ] Below in Table I-1 A means TBPS IC ₅₀ (µM) <0.01 µM, B means TBPS IC ₅₀ (µM) from 0.01 µM to <0.1 µM, C means TBPS IC ₅₀ (µM ) from 0.1 μM to <1.0 μM, D is TBPS IC ₅₀ (μM) from 1.0 μM to <10 μM, and E is ≥10 μM.

[ 0692 ]

EXAMPLE II-82

[ 0693 ] Below in Table II-2 A means TBPS IC ₅₀ (µM) <0.01 µM, B means TBPS IC ₅₀ (µM) from 0.01 µM to <0.1 µM, C means TBPS IC ₅₀ (µM ) from 0.1 μM to <1.0 μM, D is TBPS IC ₅₀ (μM) from 1.0 μM to <10 μM, and E is ≥10 μM.

[ 0694 ] EXAMPLE III-14: Biological Data

[ 0695 ] Below in Table III-1 A means TBPS IC ₅₀ (µM) <0.01 µM, B means TBPS IC ₅₀ (µM) from 0.01 µM to <0.1 µM, C means TBPS IC ₅₀ (µM ) from 0.1 μM to <1.0 μM, D means TBPS IC ₅₀ (μM) 1.0 μM to <10 μM, and E means ≥10 μM.

Equivalents and area

[0696] In claims, articles such as "a", "an" and "the" may mean one or more than one thing unless otherwise stated or otherwise obvious from the context. Claims or specifications that include "or" between one or more group members are considered enforceable if one, more than one, or all of the group members are present, in use, or otherwise related to the product or process, unless states otherwise or is otherwise not obvious from the context. The invention includes embodiments in which exactly one member of the group is present, used, or otherwise related to a given product or process. The invention includes embodiments in which more than one or all of the members of the group are present, used or otherwise related to a given product or process.

[ 0697 ] Moreover, the invention covers all variations, combinations and modifications in which one or more of the limitations, elements, clauses and descriptive terms from one or more of the listed claims are introduced into yet another claim. For example, any claim that is dependent on another claim may be modified to include one or more of the limitations found in any other claim that is dependent on the same main claim. Where elements are presented as lists, for example in Markush group format, each subgroup of elements is also disclosed, and any element(s) may be removed from the group. It should be understood that, generally, where an invention, or aspect of an invention, is stated to include particular elements and/or features, certain embodiments or aspects of the invention are, or are substantially composed of, such elements and/or signs. For purposes of simplicity, those embodiments have not been specifically set forth herein in these words . It should also be noted that the terms “including” and “comprising” are intended to be open-ended and allow for the inclusion of additional elements or steps. Where ranges are given, endpoints are included. In addition, unless otherwise stated or otherwise obvious from the context and understood by one of ordinary skill in the art, values that are expressed as ranges may allow for any specific value or subrange within the stated ranges in various embodiments implementation of the invention, to a tenth of a unit of the lower limit of the range, unless the context clearly states otherwise.

[ 0698 ] This application makes reference to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the included references and this description, the description should be relied upon. In addition, any specific embodiment of the present invention that falls within the scope of the prior art may be specifically excluded from any one or more claims. To the extent such embodiments are known to one of ordinary skill in the art, they may be excluded even if the exclusion is not expressly set forth herein. Any particular embodiment of the invention may be excluded from any claim on any basis, whether or not it relates to existing prior art.

[ 0699 ] Those skilled in the art will recognize, or have no difficulty in discovering, using no more than routine experimentation, many equivalent variations of the specific embodiments described herein. The scope of these embodiments described herein is not intended to be limited by the above Description, but rather is as set forth in the appended claims. Those skilled in the art will appreciate that various changes and modifications to this specification may be made without departing from the spirit and scope of the present invention as defined in the following claims.

Claims (66)

1. Compound Formula ( II-I ): in which: t is 1; n is 0 or 1; R ¹⁹ represents unsubstituted C ₂ -C ₆ -alkyl, unsubstituted C ₂ -C ₆ -alkenyl; R ⁵ represents a hydrogen atom; R ³ represents a hydrogen atom or a C _1-6 alkyl, optionally substituted with one or more C _1-3 alkoxy; R ^6a and R ^6b each represent a hydrogen atom; R ¹ is a C _1-6 alkyl, optionally substituted by one or more –OH, a 5-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N or O, and optionally substituted by one or more substituents independently selected from unsubstituted C _1-6 alkyl, phenyl, optionally substituted with one or more halogens, or –S(O) ₂ CH ₃ , phenyl, optionally substituted with one or more unsubstituted C _1-6 alkyls, 5-10 membered heteroaryl containing 1-4 atoms N and optionally substituted with one or more substituents independently selected from unsubstituted C _1-6 alkyl, –CN or C _1-6 alkoxy, or -N(R ^A1 ) ₂ where R ^A1 represents a hydrogen atom or phenyl, optionally substituted with one or several substituents independently selected from unsubstituted C _1-6 alkyl or –CN; R ^2a , R ^2b , R ^4a , R ^4b , R ^7a , R ^7b , R ^11a , R ^11b , R ^12a , R ^12b or R ^17b each represents a hydrogen atom; R ^15a , R ^15b , R ^16a and R ^16b each represent a hydrogen atom; And and represents a single bond. 2. The compound according to claim 1, in which R ⁵ represents a hydrogen atom in the cis position relative to the C19 position. 3. The compound according to claim 1, in which R ⁵ represents a hydrogen atom in the trans position relative to the C19 position. 4. Connection according to any one of paragraphs. 1-3, in which n is 1. 5. Connection according to any one of paragraphs. 1-4, in which R ³ represents a hydrogen atom or unsubstituted methyl. 6. Connection according to any one of paragraphs. 1-5, in which R ¹⁹ represents unsubstituted C _2-6 -alkyl. 7. Connection according to any one of paragraphs. 1-6, in which R ¹⁹ represents unsubstituted ethyl. 8. Connection according to any one of paragraphs. 1-7, in which R ¹ represents , , , , , , , , , , , , , , , , , , , , or . 9. The compound according to claim 1, where the compound of Formula ( II-I ) has Formula ( II-Ia ): Where: n is 0 or 1; R ⁵ represents a hydrogen atom; R ³ represents a hydrogen atom or a C _1-6 alkyl, optionally substituted with one or more C _1-3 alkoxy; R ^6a and R ^6b each represent a hydrogen atom; R ¹ is a C _1-6 alkyl, optionally substituted with one or more –OH, a 5-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N or O, and optionally substituted with one or more substituents independently selected from unsubstituted C _1-6 alkyl, phenyl, optionally substituted with one or more halogens or –S(O) ₂ CH ₃ , phenyl, optionally substituted with one or more unsubstituted C _1-6 alkyls, 5-10 membered heteroaryl containing 1-4 N atoms and optionally substituted with one or more substituents independently selected from unsubstituted C _1-6 alkyl, –CN or C _1-6 alkoxy, or –N(R ^A1 ) ₂ , wherein each R ^A1 independently represents hydrogen or phenyl, optionally substituted with one or several substituents independently selected from unsubstituted C _1-6 alkyl or –CN; R ^12a and R ^12b each represent a hydrogen atom; each of R^16a and R^16b represents a hydrogen atom; And and represents a single bond. 10. The compound according to claim 9, in which R ⁵ represents a hydrogen atom in the cis position relative to the C19 position. 11. The compound according to claim 9, in which R ⁵ represents a hydrogen atom in the trans position relative to the C19 position. 12. Connection according to any one of paragraphs. 9-11, in which R ³ represents methyl, methoxymethyl or ethoxymethyl. 13. The compound according to claim 9, in which R ¹ represents 14. The compound according to claim 9, where the compound of Formula ( II-Ia ) has Formula ( II-Ib ) or Formula ( II-Ic ): 15. The compound according to claim 9, where the compound of Formula ( II-Ia ) has Formula ( II-Ie ): in which m is 0 or 1; p is 0 or 1; R ₃₂ represents a cyano group. 16. The compound according to claim 9, where the compound of Formula ( II-Ia ) has Formula ( II-Ig ): where u is 0 or 1; each X independently represents -C(R ^N )-, -C(R ^N ) ₂ -, -S-, -N-, or N(R ^N )-, where R ^N independently represents a hydrogen atom or OCH ₃ . 17. Connection selected from Compound Structure II-1 II-A4 II-A5 II-A7 II-A8 II-A8a II-A9 II-A10 II-A11 II-E12 II-G3 II-M2 II-M2a II-M2b II-12 II-13 II-13a II-14 II-14a II-20 II-21 II-21a II-22 II-G5 II-B9 II-B11 II-C4 II-43 II-44 II-45 II-46 II-47 II-48 II-50 II-51 II-D9 II-D11 II-63 II-E4 II-E6 II-E8 II-D13 II-C8 II-75 II-76 II-77 II-78 II-79 18. A pharmaceutical composition for treating a CNS disorder associated with GABA function in a subject, comprising an effective amount of a compound according to any one of claims. 1-17 and a pharmaceutically acceptable excipient. 19. A method of treating a CNS disease associated with GABA function in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of claims. 1-17 or the pharmaceutical composition according to claim 18. 20. The method according to claim 19, in which the CNS-related disease is a sleep disorder, mood disorder, schizophrenia spectrum disorder, seizure disorder, memory and/or cognitive impairment, movement disorder, personality change, autism spectrum disorder, pain, traumatic brain damage, vascular disease, substance use disorder and/or withdrawal syndrome, tinnitus or status epilepticus. 21. The method of claim 19, wherein the CNS related disease is depression. 22. The method of claim 20, wherein the CNS-related disease is postpartum depression. 23. The method of claim 22, wherein the CNS-related disease is major depressive disorder. 24. The method of claim 22, wherein the CNS-related disease is major depressive disorder in a moderate form. 25. The method of claim 19, wherein the CNS-related disease is severe major depressive disorder. 26. The method of claim 19, wherein the CNS related disorder is seizures. 27. The method of claim 19, wherein the CNS related disorder is tremor. 28. The method of claim 27, wherein the tremor is an essential tremor. 29. Method according to any one of paragraphs. 19-28, wherein the compound or pharmaceutical composition is administered orally. 30. Method according to any one of paragraphs. 19-29, wherein the compound or pharmaceutical composition is administered continuously. 31. A method of inducing sedation and/or anesthesia in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of claims. 1-17.