OA20991A - Neuroactive steroids and compositions thereof. - Google Patents

Abstract

Provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R1a, R1b, R2a, R2b, R3 , R4a, R4b, R5 , R6a, R6b, R7a , R7a, R11a, R11b , R12a, R12b, R16a, R16b, R19, R11a, R22 , RX, RY and n are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I) and methods of using the compounds, e.g., in the treatment of CNS-related disorders.

Description

Detailed Description of Certain Embodiments of the Invention

As generally described herein, the présent invention provides compounds designed, for example, to act as GABAA receptor modulators. In certain embodiments, such compounds are envisioned to be usefiil as therapeutic agents for treating a CNS-related disorder (e.g., a disorder as described herein, for example dépréssion, such as post-partum dépréssion or major dépressive disorder).

Définitions

Chemical définitions

Définitions of spécifie functional groups and Chemical terms are described in more detail below. The Chemical éléments are identified in accordance with the Periodic Table of the Eléments, CAS version, Handbook of Chemistry and Physics, 75^tb Ed., înside cover, and spécifie functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as spécifie functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March ’s Advanced Organic Chemistry, 5^tb Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modem Methods of Organic Synthesis, 3Edition, Cambridge University Press, Cambridge, 19S7.

Isomers, e.g., stereoisomers, can be isolated from mixtures by methods known to those skilled in the art, including chiral hîgh pressure liquid chromatography (HPLC) and the formation and crystallîzation of chiral salts; or preferred isomers can be prepared by asymmetric synthèses. See, for example, Jacques et al., Enantiomers, Racemates and Résolutions (Wiley

Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, ΓΝ 1972). The invention additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

“Stereoisomers”: It is also to be understood that compounds that hâve the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantîomers.” When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantîomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molécule rotâtes the plane of polarized lîght and désignâted as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantîomers is called a “racemîc mixture”.

As used herein a pure enantiomeric compound is substantially free from other enantîomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an “S” form of the compound is substantially free from the “R” fonn of the compound and is, thus, in enantiomeric excess of the “R” fonn. The tenu “enantîomerically pure” or “pure enantiomer” dénotés that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% b y weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of ail enantîomers or stereoisomers of the compound.

In the compositions provîded herein, an enantîomerically pure compound can be présent with other active or inactive ingrédients. For example, a pharmaceutîcal composition comprising enantîomerically pure R-position/center/ carbon compound can comprise, for example, about 90% excipient and about 10% enantîomerically pure R- compound. In certain embodiments, the enantîomerically pure R-compound in such compositions can, for example, comprise, at least about 95% by weight R-compound and at most about 5% by weight S-compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantîomerically pure S-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound. In certain embodiments, the enantîomerically pure S5 compound in such compositions can, for example, comprise, at least about 95% by weight Scompound and at most about 5% by weight R—compound, by total weight of the compound. In certain embodiments, the active ingrédient can be formulated with little or no excipient or carrier.

The term “diastereomierically pure” dénotés that the compound comprises more than

75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% b y weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of a single diastereomer. Methods for determining dîastereomeric and enantiomeric purity are well-known in the art. Diastereomeric purity can be determined by any analytical method capable of quantitatively distinguishing between a compound and its diastereomers, such as high performance liquid chromatography (HPLC).

The articles “a” and “an” may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. B y way of example “an analogue” means one analogue or more than one analogue.

When a range of values is listed, it is intended to encompass each value and sub-range withîn the range. For example alkyl” is intended to encompass, C], C₂, C₃, C₄, C5, C$, Ci_$,

C[-s, Ci^, Ci-3, Ci-?, C2-6, C2-5, C₂^, C₂_₃, C₃_$, C₃-5, C_M, C^, C4-5, and €5.$ alkyl.

The followîng terms are intended to hâve the meanings presented therewith below and are useful in understanding the description and intended scope of the présent invention.

“Alkyl” refers to a radical of a straight—chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“Ci-20 alkyl”). In some embodiments, an alkyl group has I to 12 carbon atoms (“C|_|₂ alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“Cj_io alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“Cj_₉ alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“Ci-₈ alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C]_₇ alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“Ci-6 alkyl”, also referred to herein as “lower alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“Cj-s alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C_t^ alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“Ci-₃ alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has I carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of Ci-6 alkyl groups include methyl (Ci), ethyl (C₂), n-propyl (C₃), isopropyl (C3), n-butyl (C₄), tert-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), n-pentyl (C₅), 3-pentanyl (C₅), amyl (C₅), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C₅), and n-hexyl (Cé). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C₈) and the like. Unless otherwîse specified, each instance of an alkyl group is independently optionally substituted, Le., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substîtuents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted Ci-io alkyl (e.g., -CH₃). In certain embodiments, the alkyl group is substituted Ci-ιο alkyl. Common alkyl abbreviations include Me (-CH₃), Et (-CH2CH3), iPr (-CH(CH₃)₂), nPr (-CH2CH₂CH₃), n-Bu (-CH2CH2CH2CH3), or iBu (-CH₂CH(CH₃)₂).

“Alkyiene” refers to an alkyl group wherein two hydrogens are removed to provide a divalent radical, and which may be substituted or unsubstituted. Unsubstituted alkyiene groups include, but are not limited to, methyl ene (-CH₂-), ethylene (-CH2CH2-), propylene (CH₂CH₂CH₂-), butylène (-CIT2CH2CH2CH2-), pentylene (-CH₂CH₂CH₂CH₂CH₂-), hexylene (CH2CH₂CH2CH2CH₂CH₂-), and the like. Exemplary substituted alkyiene groups, e.g., substituted with one or more alkyl (methyl) groups, include but are not limited to, substituted methylenc (-CH(CH₃)-, (-C(CH₃)₂-), substituted ethylene (-CH(CH₃)CH₂-,-CH₂CH(CH₃)-, C(CEI₃)₂CH₂-,-CH₂C(CH₃)₂-), substituted propylene (-CH(CH₃)CH₂CH₂-, -CH2CH(CH₃)CH₂-, CH₂CH₂CH(CH₃)-, -C(CH₃)₂CH₂CH₂-, -CH₂C(CH₃)₂CH2-, -CH₂CH₂C(CH3)2-), and the like. When a range or number of carbons is provided for a particular alkyiene group, it is understood that the range or number refers to the range or number of carbons în the linear carbon divalent chain. Alkyiene groups may be substituted or unsubstituted with one or more substituents as described herein.

“Alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carboncarbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) (“C₂_₂q alkenyl”). In certain embodiments, alkenyl does not contain 13 any triple bonds. In some embodiments, an alkenyl group bas 2 to 10 carbon atoms (“C₂-io alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C₂-9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C₂_₈ alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C₂_₆ alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C₂_₅ alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C₂=i alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C₂ alkenyl”). The one or more carbon—carbon double bonds can be internai (such as in 2-butenyl) or terminal (such as in 1-butenyI). Examples of C₂^ alkenyl groups include ethenyl (C₂), 1propenyl (C3), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), and the like. Examples of C₂-& alkenyl groups include the aforementioned C₂^t alkenyl groups as well as pentenyl (C₅), pentadienyl (C5), hexenyl (C₆), and the like. Additional examples of alkenyl include heptenyl (C₇), octenyl (C₈), octatrienyl (C₈), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, Le., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkenyl group is unsubstituted C₂_jo alkenyl. In certain embodiments, the alkenyl group is substituted C₂_]o alkenyl.

“Alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g, 1, 2, 3, or 4 carboncarbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) (“C₂_₂o alkynyl”). In certain embodiments, alkynyl does not contain any double bonds. In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C₂~io alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C₂_₉ alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C₂-s alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C₂_₇ alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C₂^ alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C₂_₃ alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C₂ alkynyl”). The one or more carbon-carbon triple bonds can be internai (such as in 2butynyl) or terminal (such as in 1-butynyl). Examples of C₂^ alkynyl groups include, without limitation, ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), and 14 the like. Examples of C₂-6 alkenyl groups include the aforementioned C₂^i alkynyl groups as well as pentynyl (C₅), hexynyl (C₆), and the like. Additional examples of alkynyl include heptynyl (C₇), octynyl (C₈), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, Le., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkynyl group is unsubstituted C₂-io alkynyl. In certain embodiments, the alkynyl group is substituted C₂-io alkynyl.

The tenn “heteroalkyl,” as used herein, refers to an alkyl group, as defined herein, which further comprises 1 or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, Silicon, phosphorus) within the parent chain, wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molécule, Le., between the point of attachment. In certain embodiments, a heteroalkyl group refers to a safurated group having from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroCi-ιο alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroCi-9 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroCr₈ alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroCi-₇ alkyl”). In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“heteroCi^ alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroC|_5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and lor 2 heteroatoms (“heteroCi^i alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“heteroCi_3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (“heteroCi_₂ alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroCi alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC₂-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an ‘unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCi-io alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroCi-io alkyl.

“Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π électrons shared in a cyclic array) having 6-14 ring carbon atoms and zéro heteroatoms provided in the aromatic ring System (“Cé-^ aryl”). In some embodiments, an aryl group has six ring carbon atoms (“Cé aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1— naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“Ci4 aryl”; e.g., anthracyl). “Aryl” also inciudes ring Systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is unsubstituted Cô-i₄ aryl· In certain embodiments, the aryl group is substituted Cé-i4 aryl.

In certain embodiments, an aryl group substituted with one or more of groups selected from halo, Ci-Cg alkyl, Cj-Cg haloalkyl, cyano, hydroxy, Ci-Cg alkoxy, and amino.

Examples of représentative substituted aryls include the following

wherein one of R’⁶ and R⁵⁷ may be hydrogen and at least one of R⁵⁶ and R⁵⁷ is each independently selected from C|-C'k alkyl, Cj-Cg haloalkyl, 4-10 membered heterocyclyl, alkanoyl, Cj-Cg alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR⁵⁸COR⁵⁹, NR⁵⁸SOR⁵⁹NR⁵⁸SO2R⁵⁹, COOalkyl, COOaryl, CONR⁵⁸R⁵⁹, CONR⁵⁸OR⁵⁹, NR⁵⁸R⁵⁹, SO2NR⁵⁸R⁵⁹, S-alkyl, SOalkyl, SO₂alkyl, Saryl, SOaryl, SO₂aryl; or R⁵⁶ and R⁵⁷maybejoined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O, or S. R⁶⁰ and R⁶¹ are independently hydrogen, Ci-C₈ alkyl, C1-C4 haloalkyl, C3-C10 cycioalkyl, 4-10 membered heterocyclyl, Cg-Ciq aryl, substituted Cé-Cm aryl, 5-10 membered heteroaryl, or substituted 5-10 membered heteroaryl.

“Fused aryl” refers to an aryl having two of its ring carbon in common with a second aryl or heteroaryl ring or with a carbocyclyl or heterocyclyl ring.

“Heteroaryl” refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring System (e.g., having 6 or 10 π électrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring System, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring Systems can include one or more heteroatoms in one or both rings, “Heteroaryl” includes ring Systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate îhe number of ring members in the heteroaryl ring System. “Heteroaryl” also includes ring Systems wherein the heteroaryl ring, as defined above, is fiised with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members désignâtes the number of ring members in the fiised (aryl/heteroaryl) ring System. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quînolînyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indoIyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring System having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1^4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is 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 I ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadîazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazînyl. Exemplary 6meinbered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6bicyclic heteroaryl groups include, without limitation, îndolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazoiyl, îndolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolînyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

Examples of représentative heteroaryls include the foliowing:

wherein each Z is selected from carbonyl, N, NR⁶⁵, O, and S; and R⁶⁵ is independently hydrogen, Cj-C₈ alkyl, C₃-Cjo cycloalkyl, 4-10 membered heterocyclyl, Cs-Cio aryl, and 5-10 membered heteroaryl.

“Carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C₃_|₀ carbocyclyl”) and zéro heteroatoms in the non-aromatic ring System. In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“Cî-s carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C₃-6 carbocyclyl groups include, without limitation, cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C₆), cyclohexenyl (C&), cyclohexadjenyl (C&), and the like. Exemplary C₃__s carbocyclyl groups include, without limitation, the aforementioned C₃„₆ carbocyclyl groups as well as cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C₃_j₀ carbocyclyl groups include, without limitation, the aforementioned C₃_₈ carbocyclyl groups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (Cio), cyclodecenyl (Cio), octahydro-l/f-indenyl (C₉), decahydronaphthalenyl (Cio), spiro[4.5]decanyl (Cio), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring System such as a bicyclic System (“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated. “Carbocyclyl” also includes ring Systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring System. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, Le., unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is unsubstituted C3-10 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-10 carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C₃^ cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“Cs-ιο cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C₅) and cyclohexyl (C5). Examples of C₃_₆ cycloalkyl groups înclude the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C₃) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C₈). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is unsubstituted C₃_io cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C3-10 cycloalkyl.

“Heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 10-membered nonaromatic ring System having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and Silicon (“3-10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can eîther be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring System such as a bicyclic System (“bicyclîc heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring Systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also inciudes ring Systems wherein the heterocyclyl ring, as defïned above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring Systems wherein the heterocyclyl ring, as defïned above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, Le., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 310 membered heterocyclyl.

In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and Silicon (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered nonaromatic ring system having ring carbon atoms and 1—4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is 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.

Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofiiranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothîophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazoünyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl 21 and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a Cf, aryl ring (also referred to herein as a 5,6-bicyclic heterocyclîc ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fiised to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclîc ring) include, without limitation, tetrahydiOquinoIinyl, tetrahydroisoquinolinyl, and the like.

“Nitrogen-containing heterocyclyl” group means a 4- to 7- membered non-aromatic cyclic group containing at least one nitrogen atom, for example, but without limitation, morpholine, piperidine (e.g. 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g. 2pyrrolidinyl and 3-pyrroIîdînyl), azetidine, pyrrolidone, imidazoline, imidazolidînone, 2pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N-methyl piperazine. Particular examples include azetidine, piperidone and piperazone.

“Hetero” when used to describe a compound or a group présent on a compound means that one or more carbon atoms in the compound or group hâve been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl, cycioalkyl, e.g., heterocyclyl, aryl, e.g,. heteroaryl, cycloalkenyl, e.g,. cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.

“Acyl” refers to a radical -C(O)R²⁰, where R²⁰ 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 wherein R²⁰ is a group other than hydrogen. Représentative acyl groups include, but are not limited to, formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph), —C(O)-Ci-C8 alkyl, -C(O)-(CH2)t(C6-C10 aryl), -C(O)-(CH2)t(5-10 membered heteroaryl), -C(O)-(CH2)t(C3-CjQ cycioalkyl), and -C(O)(CH2)t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4. In certain embodiments, R²¹ is Ci-C8 alkyl, substituted with halo or hydroxy; or C3-CK) cycioalkyl, 4-10 membered heterocyclyl, Cô-Ciq aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C;-C₄ hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.

“Alkoxy” refers to the group -OR²⁹ where R²⁹ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Particular alkoxy groups are methoxy, ethoxy, npropoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups hâve between 1 and 4 carbon atoms.

In certain embodiments, R²⁹ is a group that has 1 or more substituents, for instance from 1 to 5 substituents, and parti cul arl y from 1 to 3 substituents, în particular 1 substituent, selected from the group consisting of amino, substituted amino, Cé-Cw aryl, aryloxy, carboxyl, cyano, C₃Cjo cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thîoalkoxy, thioaryloxy, 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-(CH₂)_t(C₆-C|₀ aryl), O-(CH₂)t(5-10 membered heteroaryl), -0-(CH₂)t(C₃-Cio cycloalkyl), and -O-(CH2)t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocyclyl groups présent, may themselves be substituted by unsubstituted C|-C₄ alkyl, halo, unsubstituted C]-C₄ alkoxy, unsubstituted C|-C₄ haloalkyl, unsubstituted Cj-C₄ hydroxyalkyl, or unsubstituted C|-C₄ haloalkoxy or hydroxy. Particular exemplary ‘substituted alkoxy’ groups are -OCF₃, -OCH2CF3, -OCH₂Ph, -OCH₂-cyclopropyl, -OCH₂CH₂OH, and -OCH₂CH₂NMe2.

“Amino” refers to the radical -NH₂.

“Oxo group” refers to -C(=O)-.

“Substituted amino” refers to an amino group of the formula -N(R³⁸)2 wherein R³⁸ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstitued heteroaryl, or an amino protectîng group, wherein at least one of R is not a hydrogen. In certain embodiments, each R is independently selected from hydrogen, C|-Cg alkyl, C₃-C₈ alkenyl, C₃-C_g alkynyl, CsC10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, or C₃-Cio cycloalkyl; or C|-C₈ alkyl, substituted with halo or hydroxy; C₃-C₈ alkenyl, substituted with halo or hydroxy; C₃-Cs alkynyl, substituted with halo or hydroxy, or -(CH₂)_t(C6-Cio aryl), -(CH₂)_t(5-10 membered heteroaryl), -(CH₂)_t(C3-Cio cycloalkyl), or -(CH₂)t(4-10 membered heterocyclyl), wherein t is an integer between 0 and 8, each of which is substituted by unsubstituted Cj-C₄ alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted Ci-C₄ haloalkyl, unsubstituted C]-C₄ hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; or both R³⁸ groups are joined to form an alkylene group.

Exemplary “substituted amino” groups include, but are not limited to, —NR³⁹-Ci-Cg alkyl, -NR³⁹-(CH2)l(C6-Cio aryl), -NR³⁹-(CH2)_t(5-10 membered heteroaryl), -NR³⁹-(CH2)1(C3-CiO cycloalkyl), and -NR³⁹-(CH2)_t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4, for instance 1 or 2, each R³⁹ independently represents H or Cj-Cg alkyl; and any alkyl groups présent, may themselves be substituted by halo, substituted or unsubstituted amino, or hydroxy; and any aryl, heteroaryl, cycloalkyl, or heterocyclyl groups présent, may themselves be substituted by unsubstituted Cj-C₄ alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted Cj-C₄ hydroxyalkyl, or unsubstituted C_rC₄ haloalkoxy or hydroxy. For the avoidance of doubt the tenu ‘substituted amino’ includes the groups alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamîno, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino as defined below. Substituted amino encompasses both monosubstituted amino and disubstituted amino groups.

“Carboxy” refers to the radical -C(O)OH.

“Cyano” refers to the radical -CN.

“Halo” or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, the halo group is either fluoro or chloro.

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

“Hydroxy” refers to the radical -OH.

“Nitro” refers to the radical -NO₂.

“Thioketo” refers to the group =S.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are optionally substituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted”, whether preceded by the term “optionally” or not, means that at least one hydrogen présent on a group (e.g., a carbon or nitrogen atom) is replaced with a pennissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, 24 cyclization, élimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with ail permissible substituants of organic compounds, any of the substituents described herein that results in the formation of a stable compound. The présent invention contemplâtes any and ail such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may hâve hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.

Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, —NO₂, -N₃, -SO₂H, -SO₃H, -OH, -OR^aa, -ON(R^bb)2, -N(R^bb)2, -N(R^bb)3'X“, -N(OR^cc)R^bb, -SH, SR^aa, -SSR^CC, -C(=O)R^aa, -CO2H, -CHO, -C(OR^cc)2, -CO^, -OC(=O)R^aa, -OCO2R^aa, C(=O)N(R^bb)2, -OC(=O)N(R^bb)2, -NR^bbC(=O)R^a\ -NR^bbCO2R^aa, -NR^bbC(=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)2î OC(=NR^bb)N(R^bb)2, -NR^bbC(=NR^bb)N(R^bb)2, -C(=O)NR^bbSO2R^aa, -NR^bbSO2R^aa, -SO2N(R^bb)2, SO2R^aa, -SOzOR³³, -OSO2R^aa, -S(=O)R^aa, -OS(=O)R^aa, -Si(R^aa)3, -OSi(R^aa)3 -C(=S)N(R^bb)2, C(=O)SR^aa, -C(=S)SR^aa, -SC(=S)SR^aa, -SC(=O)SR^aa, -OC(=O)SR^aa, -SC(=O)OR^aa, SC(=O)R^aa, -P(=O)2R^aa, -OP(=O)2R^aa, -P(=O)(R^aa)2, -OP(=O)(R^aa)2, -OP(=O)(OR^CC)2, P(=O)₂N(R^bb)2, -OP(=O)2N(R^bb)2, -P(=O)(NR^bb)2, -OP(=O)(NR^bb)2, -NR^bbP(=O)(OR^cc)2, NR^bbP(=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^ec)2, -BR^OR⁰⁰), Ci-ίο alkyl, Ci-io haloalkyl, C2-io alkenyl, C2_io alkynyl, C3-io carbocyclyl, 3-14 membered heterocyclyl, C$_i4 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1,2, 3, 4, or 5 R^dd groups; or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(R^bb)2, =NNR^bbC(=O)R^aa, =NNR^bbC(=O)OR^aa, =NNR^bbS(=O)₂R^aa, =NR^bb, or =NOR^CC;

each instance of R³³ is, independently, selected from Cj-jq alkyl, C|__t0 haloalkyl, C₂^i₀ alkenyl, C₂~io alkynyl, C₃-io carbocyclyl, 3—14 membered heterocyclyl, C$-i4 aryl, and 5-14 membered heteroaryl, or two R^aa groups arejoîned to form a 3-14 membered heterocyclyl or 514 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1,2, 3, 4, or 5 R^dd groups;

each instance of R^bb is, independently, selected from hydrogen, -OH, -OR^aa, —N(R^CC)2, CN, -C(=O)R^aa, -C(=O)N(R^cc)2, -CO₂R^aa, -SO2R^aa, -C(=NR^cc)OR^aa, -C(=NR^cc)N(R^cc)2, SO₂N(R“)₂, -SO₂R^œ, -SO2OR^CC, -SOR^aa, -C(=S)N(R^CC)2, -C(=O)SR^CC, -C(=S)SR^cc, 25

P(=O)₂R^aa, -P(=O)(R^aa)2, -P(=O)2N(R^CC)2, -P(=O)(NR^cc)₂, Cj_i₀ alkyl, C|_|₀ haloalkyl, C₂-io alkenyl, C₂-io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Cé-u aryl, and 5-14 membered heteroaryl, or two R^bb groups are joined to form a 3-14 membered heterocyclyl or 514 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1,2, 3, 4, or 5 R^dd groups;

each instance of R^cc is, independently, selected from hydrogen, C1-10 alkyl, Ci_ 10 haloalkyl, C₂^_I0 alkenyl, C₂-io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C₆_₁₄ aryl, and 5-14 membered heteroaryl, or two R^cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^dd groups;

each instance of R^dd is, independently, selected from halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR^ee, -ON(R^ff)2, -N(R^ff)2> -N(R^ffVXk -N(OR^ee)R^f\ -SH, -SR^ee, -SSR^ee, C(=O)R^ee, -CO2H, -CO₂R^ee, -OC(=O)R^ee, -OCO2R^ee, -C(=O)N(R^ff)2, -OC(=O)N(Rⁿ)2, NR^ffC(=O)R^ee, -NRAOjRA —NR^ffC(=O)N(R^ff)2, -C(=NR^ft')OR^ee, -OC^NR^RA OC^NR^OR^, -C(=NR^ff)N(R^f% -OC(=NR^ff)N(R^ff)2) -NR^frC(=NR^ff)N(R^iï)2,-NR^ffSO2R^eeî SO₂N(R^îY)2) -SO2R^ee, -SOîORA -OSO2R^ee, -S(=O)R^œ, -Si(R^ee)î, -OSi(R^ee)3, -C(=S)N(R^ff)2î C(=O)SR^ee, -C(=S)SR^ee, -SC(=S)SR^ee, -P(=O)2R^ee, -P(=O)(R^e% -OP(=O)(R^ee)2, OP(=O)(OR^ee)2, Cj-6 alkyl, Cj_₆ haloalkyl, C₂_₆ alkenyl, C₂-6 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C₆_₁₀ aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^Së groups, or two gemmai R^dd substituents can be joined to form =0 or =S;

each instance of R^ee is, independently, selected from Cu,, alkyl, C_{b 6} haloalkyl, C₂-6 alkenyl, C₂-e alkynyl, C310 carbocyclyl, Cô-io ^aryk 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1,2, 3, 4, or 5 R^gs groups;

each instance of R^ff is, independently, selected from hydrogen, Ci-6 alkyl, Cj-6 haloalkyl, C₂-6 alkenyl, C₂-6 alkynyl, €3-10 carbocyclyl, 3-10 membered heterocyclyl, Cé-io aryl and 5-10 membered heteroaryl, or two R groups are joined to form a 3-14 membered heterocyclyl or 514 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R®⁸ groups; and each instance of R^gë is, independently, halogen, -CN, -NO2, -N3, -SO?H, -SO3H, -OH, -OCi_6 alkyl, -ON(C,_6 alkyl)2, -N(Ct_6 alkyl)2, -NfC^ alkylVX’, -NHfC^ alkyl)2⁺X-, NH2(C₁.₆ alkyl) ⁺X“, -ΝΗ3⁺χ·, -N(OCi_6 alkyl)(Ci-₆ alkyl), -N(OH)(C,_₆ alkyl), -NH(OH), 26

SH, -SC|..₆ alkyl, -SS(Ci-₆ alkyl), -C(=O)(Ci_₆ alkyl), -CO₂H, -CO₂(Ci^ alkyl), -OC(=O)(Ci_₆ alkyl), -OCO₂(Ci_₆ alkyl), -C(=O)NH₂, -C(=O)N(Ci-₆ alkyl),, -OC(=O)NH(Ci_₆ alkyl), NHC(=O)( Ci_₆ alkyl), -N(Ci-₆ alkyl)C(=O)( alkyl), -NHCO₂(C^₆ alkyl), —NHC(=O)N(Ci_ ₆ alkyl)₂, -NHC(=O)NH(Ci_₆ alkyl), -NHC(=O)NH₂, -C(=NH)O(C₁_₆ alkyl),-OC(=NH)(Ci_₆ alkyl), -OC(=NH)OCi_₆ alkyl, -C(=NH)N(C₁_₆ alkyl)₂, -C(=NH)NH(C₁_₆ alkyl), -C(=NH)NH₂, -OC(=NH)N(Ci_₆ alkyl),, -OC(NH)NH(C)_₆ alkyl), -OC(NH)NH₂, -NHC(NH)N(C^ alkyl)₂, NHC(=NH)NH₂, -NHSO₂(C]_6 alkyl), -SO₂N(Ci_₆ alkyl)₂, -SO₂NH(C_l_₆ alkyl), -SO₂NH₂ ,SO₂Ci-₆ alkyl, -SO₂OCi_₆ alkyl, -OSOsCm alkyl, -SOCi_₆ alkyl, -81(0^ alkyl)₃, -OSi(C)_₆ alkyl)₃ -C(=S)N(C_W, alkyl)₂, C(=S)NH(Ci-₆ alkyl), C(=S)NH₂, -C(=O)S(C|.₆ alkyl), C(=S)SC|_₆ alkyl, -SC(=S)SC^ alkyl,-P(=O)₂(Ci-₆ alkyl), -P(=O)(C_t_₆ alkyl),, -OP(=O)(C|_₆ alkyl)₂, -OP(=O)(OC_t_₆ alkyl)₂, Ci-₆ alkyl, Ci-₆ haloalkyl, C₂-6 alkenyl, C₂-& alkynyl, C₃_._[0 carbocyclyl, Cs-iq aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R^sg substituents can bejoined to form =0 or =S; wherein X“ is a counterion.

A “counterion” or “anionic counterion” is a negatively charged group associated with a cationic quatemary amino group in order to maintain electronic neutrality. Exemplary counterions include halide ions (e.g,, F”, ΟΓ, Br”, Γ), NO₃“, CIOT, OH”, H₂PO4^-, HSO/, sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toiuenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-l-sulfonic acid-5-sulfonate, ethan-l-sulfonic acid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, and the like).

These and other exemplary substituents are described in more detail in the Detailed Description, and Claims. The invention is not intended to be limited in any manner b y the above exemplary listing of substituents.

Other définitions

As used herein, the term “modulation” refers to the inhibition or potentiation of GABA_a receptor fonction. A “modulator” (e.g., a modulator compound) may be, for example, an agonist, partial agonist, antagonist, or partial antagonist of the GABA_a receptor.

“Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Fédéral or a state govemment or the corresponding agency in countries other than the United States, or that is 1 isted in the U.S. Pharmacopoeia or other general!y recognized phannacopoeia for use in animais, and more particularly, in humans.

“Pharmaceutically acceptable sait” refers to a sait of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity ofthe parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifïcally, 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 with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartane acid, citric acid, benzoic acid, 3-(4hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4—chlorobenzenesulfonic acid, 2-naphthalenesuIfonic acid, 4—toluenesulfonic acid, camphorsulfonic acid, 4-methylbicycIo[2.2.2]-oct—2-ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethyl acetic acid, tertiary butylacetîc acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoîc acid, salicylic acid, stearic acid, muconîc acid, and the like; or (2) salts formed when an acidic proton présent in the parent compound either îs replaced by a métal ion, e.g., an alkali métal ion, an alkaline earth ion, or an alumînum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, tri éthanol amine, Nmethylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnésium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The tenu “pharmaceutically acceptable cation” refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnésium, ammonium, tetraalkylammonium cations, and the like. See, e.g., Berge, et al., J. Pharm. Sci. (1977)66(1): 1-79.

The term “prodrug” is intended to encompass therapeutically inactive compounds that, under physiological conditions, are couverted into the therapeutically active agents of the présent invention. One method for making a prodrug is to design selected moietîes that are hydrolyzed or cteaved at a targeted in vivo site of action under physiological conditions to reveal the desired molécule which then produces its therapeutic effect. In certain embodiments, the prodrug is converted by an enzymatic activity of the subject.

In an altemate embodiment, the présent invention provides prodrugs of compound of Formula (I), wherein the prodrug includes a cleavable moiety on the C3 hydroxy as depîcted in Formula (I).

“Tautomers” refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and électrons. Thus, two structures may be in equilibrium through the movement of π électrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment ofthe optimal Chemical reactivity and biological activity of a compound of interest.

A “subject” to which administration is contemplated încludes, but is not limited to, humans (i.e., a male or female of any âge group, e.g., a pédiatrie subject (e.g, infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or a nonhuman animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhésus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs. In certain embodiments, the subject is a human (“humait subject”). In certain embodiments, the subject is a non-human animal.

In certain embodiments, the substituent présent on an oxygen atom is an oxygen protecting group (also referred to as a hydroxyl proteetîng group). Oxygen protecting groups include, but are not limited to, -R^aa, -N(R^bb)2, -C(=O)SR^aa, -C(=O)R^aa, -CO2R^aa, C(=O)N(R^bb)2, -C(=NR^bb)R^aa, -C(=NR^bb)OR^aa, -C(=NR^bh)N(R^bb)2, -S(=O)R^aa, -SO2R^aa, Si(R^aa)3i -P(R^cc)2, -P(R^cc)3, -P(=O)₂R^aa, -P(=O)(R^aa)2, -P(=O)(OR^ce)2, -P(=O)₂N(R^bb)2, and P(=O)(NR^bb)2, wherein 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, T. W. Greene and P. G. M. Wuts, 3^rd édition, John Wiley & Sons, 1999, incorporated herein b y reference.

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

In certain embodiments, the substituent présent on a sulfur atom is a sulfur protecting group (also referred to as a thiol protecting group). Sulfur protecting groups include, but are not limited to, -R^aa, -N(R^bb)2, -C(=O)SR^aa, -C(=O)R^aa, -CO2R^aa, -C(=O)N(R^bb)2, -C(=NR^bb)R^aa, C(=NR^bb)OR^aa, -C(=NR^bb)N(R^bb)2, -S(=O)R^aa, -SO2R^aa, -Si(R^aa)3j-P(R^CC)2, -P(R^CC)3, P(=O)₂R^aa, -P(=O)(R^aa)2, -P(=O)(OR^CC)2, -P(=O)₂N(R^bb)2, and -P(=O)(NR^bb)2, wherein R^aa, R^bb, and R^cc are as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protectîng Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^rd édition, John Wiley & Sons, 1999, încorporated herein by reference.

In certain embodiments, the substituent présent on a nitrogen atom is an amino protectîng group (also referred to herein as a nitrogen protectîng group). Amino protectîng groups include, but are not limited to, —OH, -OR^aa, —N(R^LC)2, -C(=O)R^aa, -C(=O)OR^aa, -C(=O)N(R^tc)2, S(=O)₂R^aa, -C^NR^R^, -C(=NR^cc)OR^aa, -C(=NR^cc)N(R“)2, -SO2N(R^CC)2, SO₂R“, SO₂OR^CC, -SOR^aa, -C(=S)N(R^cc)2, -C(=O)SR^cc, -C(=S)SR^ce, Ci_10 alkyl, C₂_i₀ alkenyl, C₂_i₀ alkynyl, Cs-m carbocyclyl, 3-14-membered heterocyclyl, C₆-i4 aryl, and 5-14-membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^dd groups, and wherein R^aa, R^bb, R^cc and R^dd are as defined herein. Amino protectîng groups are well known in the art and include those described in detail in Protectîng Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^rd édition, John Wiley & Sons, 1999, încorporated herein by reference.

Exemplary amino protectîng groups include, but are not limited to amide groups (e.g., C(=O)R^aa), which include, but are not limited to, formamide and acetamide; carbamate groups (e.g., -C(=O)OR‘^ia), which include, but are not limited to, 9-lluorenylmethyl carbamate (Fmoc), Abutyl carbamate (BOC), and benzyl carbamate (Cbz); sulfonamide groups (e.g., -S(=O)₂R^aa), which include, but are not limited to, p-toluenesulfonamide (Ts), methanesulfonamide (Ms), and A-[2-(trimethylsilyl)ethoxy]methylamine (SEM).

Disease, dîsorder, and condition are used interchangeably herein.

As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, dîsorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (“therapeutic treatment”), and also contemplâtes an action that occurs before a subject begins to suffer from the specified disease, disorder or condition.

In general, the “effective amount” of a compound refers to an amount suffi ci ent to elîcit the desired biological response, e.g., to treat a CNS-related disorder, is sufficient to induce anesthésia or sédation. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the invention may vary dependîng on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the âge, weight, health, and condition of the subject.

As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, 30 disorder or condition, or to delay or minimize one or more symptoms associated with the disease, dîsorder or condition. A therapeutically effective amounl of a compound means an amount of therapeutic agent, alone or in combination with other thérapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

In an alternate embodiment, the présent invention contemplâtes administration of the compounds of the présent invention or a phannaceutically acceptable sait or a pharmaceutically acceptable composition thereof, as a prophylactic before a subject begins to suffer from the specified disease, disorder or condition. As used herein, and unless otherwise specified, a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its récurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prévention of the disease, disorder or condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efïïcacy of another prophylactic agent.

As used herein, an “episodic dosing regimen” is a dosing regimen wherein a compound of Formula (I) or a composition comprising a compound of Formula (I) is administered to a subject for a fmite period of time in response to the diagnosis of a disorder or symptom thereof, e.g, a diagnosis or symptom of dépréssion, an épisode of major dépressive disorder, bipolar dépréssion, anxiety, or postpartum dépréssion. In some embodiments, the major dépressive disorder is moderate major dépressive disorder. In some embodiments, the major dépressive disorder is severe major dépressive disorder Tn some embodiments, the compound is formulated as individual dosage units, each unit comprising a compound of Formula (I) and one or more suitable pharmaceutical excipients. In some embodiments, the episodic dosing regimen has a duration of a pluralîty of weeks, e.g. about 8 weeks. In contrast with chronic administration as defined herein, episodic dosing of a compound occurs over a imite period of time, e.g., from about 2 weeks to about 8 weeks, in response to a diagnosis of a disorder, e.g., dépréssion, or a symptom thereof. In some embodiments, episodic dosing occurs once per day across a pluralîty of weeks, e.g., from about 2 weeks to about 6 weeks. In one embodiment, the episodic dosing has a duration of two weeks. In some embodiments, more than one episodic dosing regimen is administered to the subject, e.g., two or more episodic regimens throughout the subject’s life.

Compounds

It should be appreciated that formulas described herein may reference particular carbon atoms, such as C17, C3, Cl9, etc. These references are based on the position of carbon atoms according to steroid nomenclature known and used in the industry, as shown below:

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

In an aspect, provided herein is a compound of Formula (I):

or a pharmaceutically acceptable sait thereof;

wherein:

: ~ represents a single or double bond, provided if a double bond is présent, then one of R^6a or R^6b is absent and R⁵ îs absent;

R^x îs selected from the group consisting of halo, -CN, -OH, -OR^¹, and substituted or unsubstîtuted alkyl, wherein R^QI is substituted or unsubstituted alkyl;

R^Y is halo or substituted or unsubstituted alkyl; or

R^Y and R^x may join together with the intervening atoms to form a substituted or unsubstituted carbocyclyl or a substituted or unsubstituted heterocyclyl;

R³ is selected from the group consisting of substituted or unsubstîtuted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

R⁵ is hydrogen or methyl;

each instance of R²² is independently selected from the group consisting of halogen, -NO2, CN, -OR^ga, -N(R^ga)2, -C(=O)R^ga, -C(=O)OR^ga, -OC(=O)R^ga, -OC(=O)OR^ga, C(=O)N(R^ga)2, -N(R^ga)C(=O)R^ga, -OC(=O)N(R^ga)2, -N(R^ga)C(=O)OR^oa, N(R^ga)C(=O)N(R^ga)2,-SR^ga, -S(=O) R^ga, -S(=O)2R^ga, -S(=O)2OR^ga, -OS(=O)2R^GA, S(=O)2N(R^ga)2, -N(R^ga)S(=O)2R^ga, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocylyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein each instance of R^GA is independently selected from the group consisting of hydrogen, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C2-₍; alkenyl, substituted or unsubstituted C₂~₆ alkynyl, substituted or unsubstituted C3.6 carbocylyl, substituted or unsubstituted 3- to 6- membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, and a nitrogen protecting group when attached to nitrogen, or two R^GA groups are taken with the întervening atoms to form a substituted or unsubstîtuted heterocyclyl or heteroaryl ring;

each of R^la, R^lb, R^2a, R^2b, R^4a, R^4b, R^7a, R^7b, R^lla, R^llb, R^l2a, and R^12b is independently selected from the group consisting of hydrogen, halogen, cyano, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR^A1, -N(R^A1)2, -SR^A1, -C(=O)R^AI, C(=O)OR^A1, -C(=O)SR^ai, -C(=O)N(R^a1)2, -OC(=O)R^ai, -OC(=O)OR^a1, -OC(=O)N(R^a1)2, OC(=O)SR^A1, -OS(=O)2R^a1, -OS(=O)2OR^ai, -OS(=O)2N(R^a1)2, -N(R^A1)C(=O)R^Al, N(R^A1)C(=NR^AI)R^A1, -N(R^a1)C(=O)OR^ai, -N(R^A1)C(=O)N(R^Al)2, -N(R^Al)C(=NR^Al) N(R^ai)2, N(R^Al)S(=O)2R^At, -N(R^Al)S(=O)2OR^Al, -N(R^a1)S(=O)2N(R^ai)2, -SC(=O)R^a1, -SC(=O)OR^a1, SC(=O)SR^a1, -SC(=O)N(R^ai)2, -S(=O)2R^ai, -S(=O)2OR^a1, or -S(=O)2N(R^a1)2, wherein each instance of R^ai îs independently selected from the group consisting of hydrogen, substituted or unsubstituted Ci-t,alkyl, substituted or unsubstituted C₂-6alkenyl, substituted or unsubstituted C₂. ôalkynyl, substituted or unsubstituted C3._&carbocyclyl, or substituted or unsubstituted 3-to 6membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur, or two R^A1 groups are taken with the întervening atoms to form a substituted or unsubstituted heterocyclic ring;

each of R^6a and R^6b is independently selected from the group consisting of hydrogen, halogen, cyano, -NO₂, -OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl; or R^6a and R^6b are joined to form an oxo (=0) group;

each of R^l5a, R^15b, R^16a, and R^l6b is independently selected from the group consisting of hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR^C3, -N(R^C3)2, -SR^C3, -C(=O)R^C3, -C(=O)OR^C3, -C(=O)SR^C3, -C(=O)N(R^C3)2, OC(=O)R^C3, -OC(=O)OR^C3, -OC(=O)N(R^C3)2î -OC(=O)SR^C3, -OS(=O)2R^C3, -OS(=O)2OR^C3, OS(=O)2N(R^C3)2î -N(R^CÎ)C(=O)R^C3, -N(R^C3)C(=NR^C3)R^C3, -N(R^C3)C(=O)OR^C3, N(R^C3)C(=O)N(R^C3)2, -N(R^C3)C(=NR^C3) N(R^C3)2, -N(R^C3)S(=O)2R^C3, -N(R^C3)S(=O)2OR^C3, N(R^C3)S(=O)2N(R^C3)2, -SC(=O)R^C3, -SC(=O)OR^C3, -SC(=O)SR^C3, -SC(=O)N(R^C3)2, S(=O)2R^C3, -S(=O)2OR^C3, or -S(=O)2N(R^C3)2, wherein each instance of R^C3 is independently selected from the group consisting of hydrogen, substituted or unsubstituted Ci^alkyl, substituted or unsubstituted C₂-6aIkenyl, substituted or unsubstituted C₂-6alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur, or two R^Cj groups are taken with the intervening atoms to fonn a substituted or unsubstituted heterocyclic ring;

R¹⁹ is hydrogen or substituted or unsubstituted alkyl; and n is selected from the group consisting of 0, 1, 2, and 3.

In some embodiments, the compound of Formula (I) is a compound of Formula (I-a), Formula (I-b), Formula (I-cl), Formula (I-c2), Formula (I-dl), Formula (I-d2), Formula (I-e 1 ), Formula (I-e2), Formula (I-e3), Formula (I-e4), Formula (I-bl), Formula (I-c3), Formula (I-c4), Formula (I-d3), Formula (I-d4), Formula (I-e5), Formula (I-e6), Formula (I-e7), or Formula (Ie8).

In some embodiments, the compound of Formula I is a compound of Formula I-a:

or a phannaceutically acceptable sait thereof.

In some embodiments, the compound is a compound of Formula (I) and each R^,a, R^lb, R^2a, R^2b, R^4a, R^4b, R^7a, R^7b, R^{1 la}, R^{1 ib}, R^12a, R^12b, R^6a, R^6b, R^15a, R^15b, R^16a, and R^16b is hydrogen.

In some embodiments, the compound is a compound of Formula (I) and n is 1, R is CN, R⁵ is hydrogen, and R¹⁹ is selected from the group consisting of hydrogen, methyl, and ethyl.

In some embodiments, the compound is a compound of Fonnula (I) and n is 1, R is CN, R⁵ is hydrogen, and R¹⁹ is hydrogen.

Groups R^!a and R^lh

In some embodiments, each R^la and R^lb is independently selected from the group consisting of hydrogen, halogen, cyano, substituted or unsubstituted Ci-ealkyl, substituted or unsubstituted C3-6carbocyclyl, substituted or unsubstituted 3- to 6- membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR^A1, -N(R^A1)2, C(=O)R^A1, -C(=O)OR^a1, and -C(=O)N(R^A1)2, wherein each instance of R^Al is independently selected from the group consisting of hydrogen, substituted or unsubstituted C].6alkyl, substituted or unsubstituted Ci^alkenyl, substituted or unsubstituted C₂.6alkynyl, substituted or unsubstituted C3.r,carbocyclyl₅ substituted or unsubstituted 3- to 6- membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In some embodiments, each R^la and R^lb is independently selected from the group consisting of hydrogen, halogen, cyano, substituted or unsubstituted Ci^alkyl, and -OR^Al, wherein R^A1 is selected from the group consisting of hydrogen, substituted or unsubstituted C|. salkyl, substituted or unsubstituted C₃-6carbocyclyl, substituted or unsubstituted 3- to 6membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In some embodiments, each R^la and R^lb is independently selected from the group consisting of hydrogen, substituted or unsubstituted Ci-6 alkyl, and -OR^A1, wherein R^A1 is hydrogen or unsubstituted Ci-6alkyl.

In some embodiments, each of R^laand R^,b is independently hydrogen or substituted or unsubstituted Ch, alkyl.

In some embodiments, R^la and R^lb are both hydrogen.

Groups R^2a and R~^b

In some embodiments, each R^2a and R^2b is independently selected from the group consisting of hydrogen, halogen, cyano, substituted or unsubstituted C]-6 alkyl, substituted or unsubstituted C3.6 carbocyclyl, substituted or unsubstituted 3- to 6- membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR^AI, -N(R^A1)2, C(=O)R^A1, -C(=O)OR^ai, and -C(=O)N(R^A1)2, wherein each instance of R^AI is independently selected from the group consisting of hydrogen, substituted or unsubstituted C(_$ alkyl, substituted or unsubstituted C2.₆ alkenyl, substituted or unsubstituted C₂-6alkynyl, substituted or unsubstituted C₃-6 carbocyclyl, or substituted or unsubstituted 3- to 6- membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In some embodiments, each R^2a and R^2b is independently selected from the group consisting of hydrogen, halogen, cyano, substituted or unsubstituted C[_$ alkyl, and -OR^A!, wherein R^A1 is selected from the group consisting of hydrogen, substituted or unsubstituted Cj.₆ alkyl, substituted or unsubstituted C₃.₆ carbocyclyl, substituted or unsubstituted 3- to 6membercd heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In some embodiments, each R^2a and R^2b is independently selected from tire group consisting of hydrogen, substituted or unsubstituted C।_$ alkyl, and -OR^A1, wherein R^A1 is hydrogen or unsubstituted Ci.$ alkyl.

In some embodiments, each R^2a and R^2b is independently selected from the group consisting of hydrogen, methyl, ethyl, methoxymethyl, and methoxy.

In some embodiments, R^2a and R^2b are both hydrogen.

Groups R^4a and R^4b

In some embodiments, each R^4a and R^4b is independently selected from the group consisting of hydrogen, halogen, cyano, substituted or unsubstituted Ci-$ alkyl, substituted or unsubstituted C₃._b carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR^Al, -N(R^A')2, C(=O)R^Al, -C(=O)OR^ai, and -C(=O)N(R^AI)2, wherein each instance of R^A1 is independently selected from the group consisting of hydrogen, substituted or unsubstituted Cj.6alkyl, substituted or unsubstituted C₂.₆ alkenyl, substituted or unsubstituted C₂.₆ alkynyl, substituted or unsubstituted C₃.6 carbocyclyl, or substituted or unsubstituted 3- to 6- membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In some embodiments, each R^4a and R^4b is independently selected from the group consisting of hydrogen, halogen, cyano, substituted or unsubstituted Ci-6 alkyl, and -OR^Al, wherein R^AI is selected from the group consisting of from hydrogen, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C₃.₆ carbocyclyl, or substituted or unsubstituted 3- to 6membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

Tn some embodiments, each R^4a and R^4b is independently selected from the group consisting of hydrogen, substituted or unsubstituted Ci-6alkyl, and -OR^AI, wherein R^AI is hydrogen or unsubstituted Ci.&alkyl.

In some embodiments, each R^4a and R^4b is independently hydrogen or substituted or unsubstituted C].& alkyl.

In some embodiments, R^4a and R^4b are both hydrogen.

Groups R^7a and R^7b

In some embodiments, each R^7a and R^7b is independently selected from the group consisting of hydrogen, halogen, cyano, substituted or unsubstituted C|.6 alkyl, substituted or unsubstituted C3.6 carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR^AI, -N(R^A1)2, C(=O)R^Al, -C(=O)OR^ai, and -C(=O)N(R^A1h, wherein each instance of R^AI is independently selected from the group consisting of hydrogen, substituted or unsubstituted Ci.6 alkyl, substituted or unsubstituted C₂-6 alkenyl, substituted or unsubstituted C₂.₆ alkynyl, substituted or unsubstituted C₃_₆ carbocyclyl, or substituted or unsubstituted 3- to 6- membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In some embodiments, each R^7a and R^7b is independently selected from the group consisting of hydrogen, halogen, cyano, substituted or unsubstituted Ci-6 alkyl, and -OR^A1, wherein R^A1 is selected from the group consisting of from hydrogen, substituted or unsubstituted Ci.6 alkyl, substituted or unsubstituted C₃.6 carbocyclyl, or substituted or unsubstituted 3- to 637 membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In some embodiments, each R^7a and R^7b is independently selected from the group consisting of hydrogen, substituted or unsubstituted Cj.6 alkyl, and -OR^AI, wherein R^AI is hydrogen or unsubstituted Cw alkyl.

In some embodiments, each R^7a and R^7b is independently hydrogen or substituted or unsubstituted C|-6 alkyl.

In some embodiments, R^7a and R^7b are both hydrogen.

Groups R^!ia and R^!lb

In some embodiments, each R^{1 la} and R^{1 lb} is independently selected from the group consisting of hydrogen, halogen, cyano, substituted or unsubstituted Ci.6 alkyl, substituted or unsubstituted C3.6 carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR^Al, -N(R^A1)2, C(=O)R^a1, -C(=O)OR^a1, and -C(=O)N(R^AI)2î wherein each instance of R^A! is independently selected from the group consisting of hydrogen, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C2.₆ alkenyl, substituted or unsubstituted C₂-6 alkynyl, substituted or unsubstituted C3-6 carbocyclyl, or substituted or unsubstituted 3- to 6- membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In some embodiments, each R^lla and R^{1 lb} is independently selected from the group consisting of hydrogen, halogen, cyano, substituted or unsubstituted Ct.6 alkyl, and -OR^Al, wherein R^Al is independently selected from the group consisting of hydrogen, substituted or unsubstituted CP6 alkyl, substituted or unsubstituted C3-6 carbocyclyl, or substituted or unsubstituted 3- to 6- membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In some embodiments, each R^{1 la} and R^{1 lb} is independently selected from the group consisting of hydrogen, substituted or unsubstituted Cj-6 alkyl, and -OR^A1, wherein R^A,is hydrogen or unsubstituted C1-6 alkyl.

In some embodiments, each R^lla and R^{1 lb} is independently hydrogen or substituted or unsubstituted Ci-6 alkyl.

In some embodiments, R^{1 la}and R^l,b are both hydrogen.

Groups R^!2a and R^l2b

In some embodiments, each R^12a and R^12b is independently selected from the group consisting of hydrogen, halogen, cyano, substituted or unsubstituted C].6 alkyl, substituted or unsubstituted Cj.6carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR^A1, -N(R^A1)2, C(=O)R^ai, -C(=O)OR^a1, and -C(=O)N(R^Al)2, wherein each instance of R^A1 is independently selected from the group consisting of hydrogen, substituted or unsubstituted Cb6 alkyl, substituted or unsubstituted C₂.6 alkenyl, substituted or unsubstituted C₂-6 alkynyl, substituted or unsubstituted C₃-s carbocyclyl, or substituted or unsubstituted 3- to 6- membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In some embodiments, each R^12a and R^12b îs independently selected from the group consisting of hydrogen, halogen, cyano, substituted or unsubstituted Cb& alkyl, and -OR^AI, wherein R^A1 is independently selected from the group consisting of hydrogen, substituted or unsubstituted Cb6 alkyl, substituted or unsubstituted C₃.₆ carbocyclyl, or substituted or unsubstituted 3- to 6- membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In some embodiments, each R^12a and R^12b îs independently selected from the group consisting of hydrogen, substituted or unsubstituted Ci-6 alkyl, and -OR^AI, wherein R^A1is hydrogen or unsubstituted C_b& alkyl.

In some embodiments, each R^12a and R^,2b is independently hydrogen or substituted or unsubstituted C1.6 alkyl.

In some embodiments, R^!2a and R^I2b are both hydrogen.

Groups R^6a and R^6b

In some embodiments, each R^6a and R^6b is independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_b6 alkyl, substituted or unsubstituted C₂-6 alkenyl, and substituted or unsubstituted C₂-6 alkynyl.

In some embodiments, each R^6a and R^6b is independently hydrogen or substituted or unsubstituted C 1.6 alkyl.

In some embodiments, each R^6a and R^6b is independently hydrogen or unsubstituted Ci-6 alkyl.

In some embodiments, R^ûa and R^6b are both hydrogen.

Groups R^!5a and R^!5b

In some embodiments, each R^l5a and R^!5b is independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_b6 alkyl, substituted or unsubstituted C₃-6 carbocyclyl, and substituted or unsubstituted heteroaryl.

In some embodiments, each R^l5a and R^l5b is independently selected from the group consisting of hydrogen, unsubstituted Ci-6 alkyl, and unsubstituted C3.6 carbocyclyl.

In some embodiments, each R^l5a and R^!5b is independently selected from the group consisting of hydrogen, methyl, and cyclopropyl.

In some embodiments, R^,5a and R^l5b are both hydrogen.

Groups R^!6a and R^!6b

In some embodiments, each R^16a and R^l6b is independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted Cj.6 alkyl, substituted or unsubstituted C₃.₆ carbocyclyl, and substituted or unsubstituted heteroaryl.

In some embodiments, each R^l6a and R^l6b is independently hydrogen or substituted or unsubstituted C i .6 alkyl.

In some embodiments, each R^l6a and R^,6b is independently hydrogen or unsubstituted Ci. 6 alkyl.

In some embodiments, R^l6a and R^l6b are both hydrogen.

Group R³

In some embodiments, R³ is selected from the group consisting of substituted or unsubstituted Cj.6 alkyl, substituted or unsubstituted C₂-6 alkenyl, and substituted or unsubstituted C₂-₆ alkynyl.

In some embodiments, R³ is substituted or unsubstituted Ci-C^alkyl.

In some embodiments, R³ is C1.3 alkyl optionally substituted with C1.3 alkoxy.

In some embodiments, R³ is selected from the group consisting of methyl, ethyl, npropyl, -CH₂OCH₃, and -CH₂OCH₂CH₃.

In some embodiments, R³ is methyl.

Group R^lÿ

In some embodiments, R¹⁹ is hydrogen or substituted or unsubstituted C|-₆alkyl.

In some embodiments, R¹⁹ is hydrogen or unsubstituted Ci-₃alkyl.

In some embodiments, R¹⁹ is selected from the group consisting of hydrogen, methyl, and ethyl.

ίη some embodiments, R¹⁹ is hydrogen.

In some embodiments, R¹⁹ is unsubstituted Ci-C₃ alkyl.

In some embodiments R¹⁹ is methyl or ethyl.

In some embodiments R¹⁹ is methyl

In some embodiments, R¹⁹ is ethyl.

Group R* and/or Group R^Y

In some embodiments, R^x is selected from the group consisting of halo, -CN, -OH, OR^¹, and substituted or unsubstituted Ci-₃alkyl.

In some embodiments, R^x is selected from the group consisting of halo, -CN, -OH, OR^Q1, and unsubstituted Ci-₃alkyl.

In some embodiments, R^x is selected from the group consisting of fluoro, -CN, -OH, OCH₃, and methyl.

In some embodiments, R is -OH.

In some embodiments, R^x is fluoro.

In some embodiments, R^xis unsubstituted Ci-C₃alkylene-OR^QI

In some embodiments, R^Y is halo or unsubstituted Ci-éalkyl.

In some embodiments, R^Y is halo or unsubstituted C।-₃alkyl.

In some embodiments, R^Y is selected from the group consisting of methyl, ethyl, and npropyl.

In some embodiments, R^Y is methyl.

In some embodiments, R is fluoro.

In some embodiments, R^Y and R^x joîn together with the intervening atoms to form a substituted or unsubstituted C₃-6carbocyclyl or a substituted or unsubstituted 3- to 6- membered heterocyclyl.

In some embodiments R^Y and R^x join together with the intervening atoms to form an unsubstituted C₃-6 carbocyclyl or an unsubstituted 3- to 6- membered heterocyclyl.

In some embodiments, R^Y and R^x join together with the intervening atoms to form a substituted or unsubstituted 4-membered carbocyclyl.

In some embodiments, R^Y and R^x join together with the intervening atoms to form a substituted or unsubstituted 4-membered heterocyclyl.

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

In some embodiments, R^Y and R^x join together to form an oxetane.

Group R~'

In some embodiments, R^Q! is unsubstituted Ci-6alkyl.

In some embodiments, R^Q1 is unsubstituted Ci-₃alkyl.

In some embodiments, R^Ql is selected from the group consisting of methyl, ethyl, and npropyl.

In some embodiments, R^¹ is methyl.

Group R²²

In some embodiments, each R²² is independently selected from the group consisting of halogen, -NO2, -CN, -OR^GA, -N(R^GA)2, -C(=O)R^GA, -C(=O)OR^GA, -N(R^GA)C(=O)R^GA,-SR^GA, S(=O) R^GA, -S(=O)₂R^ga, -S(=O)2OR^ga, -OS(=O)2R^ga, -S(=O)₂N(R^ga)2, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C3.6 carbocylyl, and substituted or unsubstituted 3- to 6- membered heterocyclyl, wherein each instance of R^GA is independently selected from the group consisting of hydrogen, substituted or unsubstituted Ci.6 alkyl, substituted or unsubstituted C3.₆ carbocylyl, substituted or unsubstituted 3- to 6- membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In some embodiments, each R²² is independently selected from the group consisting of halogen, -CN, substituted or unsubstituted C|_3 alkyl, substituted or unsubstituted 3- to 6membered heterocyclyl, and -OR^GA, wherein R^GA is hydrogen or substituted or unsubstituted Ci.3 alkyl.

In some embodiments, R²² is -CN or Ci.₃ alkyl optionally substituted with oxo.

In some embodiments, R²² is located at the 4-position of the pyrazolyl. In some embodiments, R is located at the 3-positîon of the pyrazolyl. In another embodiment, R is located at the 5-position of the pyrazolyl.

In some embodiments, R²² is -CN.

In another embodiment, R²² is -CN located at the 4-position of the pyrazolyl.

Integer n

In some embodiments n is 1, 2, or 3.

In some embodiments, n is 1 or 2.

In some embodiments n is 0 or 1.

In some embodiments n is 0. In some embodiments n is 1. In some embodiments n is 2.

In some embodiments n is 3.

Group R*

In some embodiments, R⁵ is hydrogen.

In some embodiments, R⁵ is a hydrogen in the alpha or beta configuration.

In some embodiments, R⁵ is a hydrogen in the alpha configuration.

In some embodiments, R⁵ is a hydrogen in the beta configuration.

In some embodiments, the compound of Formula I is a compound of Formula I-bl:

or a pharmaceutically acceptable sait thereof.

Tn some embodiments, the compound of Formula I is a compound of Formula I-c3 or

Formula I-c4:

or a pharmaceutically acceptable sait thereof.

In some embodiments, the compound of Formula I is a compound of Formula I-d3 or

or a pharmaceutically acceptable sait thereof.

In some embodiments, the compound of Formula I is a compound of Formula I-e5, Formula I-e6, Formula I-e7, or Formula I-e8:

or a pharmaceutically acceptable sait thereof.

In one embodiment, the compound of Formula I is a compound of Formula 1-lbl:

or a pharmaceutically acceptable sait thereof, wherein R²² is CN;

n is 1;

R¹⁹ is selected from the group consisting of hydrogen, ethyl, and methyl;

R^I5a and R^15b is independently selected from the group consisting of hydrogen, methyl, and cyclopropyl;

R^2a and R^2b is each independently selected from the group consisting of hydrogen, methyl, ethyl, methoxym ethyl, and methoxy;

R³ is selected from the group consisting of unsubstituted C1-3 alkyl, -CH₂OCH₃, and CH2OCH2CH3; and

R^x and R^Y are as defined herein.

In one embodiment, the compound is a compound of Fonnula Hcl or Formula I-Ic2:

or a pharmaceutically acceptable sait thereof, wherein R is CN;

n is 1;

R¹⁹ is selected from the group consisting of hydrogen, ethyl, and methyl;

R^15a and R^l5b îs independently selected from the group consisting of hydrogen, methyl, and cyclopropyl;

R^2a and R^2b is each independently selected from the group consisting of hydrogen, methyl, ethyl, methoxymethyl, and methoxy;

R³ is selected from the group consisting of unsubstituted C_b3 alkyl, -CH₂OCH₃, and CH₂OCH₂CH₃; and

R^x and R^Y are as defined herein.

In one embodiment। the compound is a compound of Formula I-Idl or Formula I-Id2:

Id2), or a pharmaceutically acceptable sait thereof, wherein R²² is CN;

R¹⁹ is selected from the group consisting of hydrogen, ethyl, and methyl;

R^l5a and R^i5b is independently selected from the group consisting of hydrogen, methyl, and cyclopropyl;

R^2a and R^2b îs each independently selected from the group consisting of hydrogen, methyl, ethyl, methoxymethyl, and methoxy;

R³ is selected from the group consisting of unsubstîtuted Ci.3 alkyl, -CH₂OCH₃, and CH₂OCH₂CH₃; and

R^x and R^Y are as defined herein.

In one embodiment, the compound is a compound of Formula 1-Iel, Formula 1-Ie2, Formula I-Ie3, or Formula I-Ie4:

or a pharmaceutically acceptable sait thereof, wherein R²² is CN;

R¹⁹ îs selected from the group consisting of hydrogen, ethyl, and methyl;

R^15a and R^15b is independently selected from the group consisting of hydrogen, methyl, and cyclopropyl;

R^2a and R^2b is each independently selected from the group consisting of hydrogen, methyl, ethyl, methoxymethyl, and methoxy;

R³ is selected from the group consisting of unsubstîtuted C|.₃ alkyl, -CH₂OCH₃, and CH₂OCH₂CH₃; and

R^x and R^Y are as defined herein.

In some embodiments, a pharmaceutical composition comprises a compound described herein or pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable excipient.

In some embodiments, a method of treating a CNS-related dîsorder in a subject in need thereof, comprises administering to the subject an effective amount of a compound described herein or a pharmaceutically acceptable sait thereof. In some embodiments, the CNS-related dîsorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive dîsorder, a disorder of memory and/or cognîtion, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, tinnitus, or status epilepticus. In some embodiments, the

CNS-related disorder is dépréssion. In some embodiments, the CNS-related disorder is postpartum dépréssion. In some embodiments, the CNS-related disorder is major dépressive disorder. In some embodiments, the major dépressive disorder is moderate major dépressive disorder. In some embodiments, the major dépressive disorder is severe major dépressive disorder.

In some embodiments, the compound is selected from the group consisting of the compounds identified in Table 1 below:

Table 1.

3		\PH 1 Γ^Ν-Ν T 7
4	H <5	3i H	OH f Λν-Ν Tl
5
6
7

8	r, OH HO'
9	OH H
10	6 OH OH h
11	a-A ho' H
12	,, OH HO' H

13	OH HO' A
14	,r OH HO' fi
15	HO H
16	,, OH HÔ H
17	HÔ A

28	j 7 Ν~ν A Y1 HO H
29
30
31
32

In one aspect, provided herein is a pharmaceutically acceptable sait of a compound described herein (e.g., a compound of Formula (I)).

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

Compounds of the présent invention as described herein, act, in certain embodiments, as GAB_A modulators, e.g., effecting the GABAa receptor in either a positive or négative manner. As modulators of the excitabilîty of the central nervous system (CNS), as médiated by their abîlity to modulate GABA_a receptor, such compounds are expected to hâve CNS-activity.

Thus, in another aspect, provided are methods of treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the présent invention. In certain embodiments, CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, tinnitus, or status epilepticus. In certain embodiments, the CNS-related disorder is dépréssion. In certain embodiments, the CNS-related disorder is postpartum dépréssion. In certain embodiments, the CNS-related disorder is major dépressive disorder. In certain embodiments, the major dépressive disorder is moderate major dépressive disorder. In certain embodiments, the major dépressive disorder is severe major dépressive 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 adminîstered chronically. In certain embodiments, the compound is adminîstered continuously, e.g., by continuons intravenous infusion.

Exemplary compounds of the invention may be synthesized from the following known starting materials using methods known to one skilled in the art or certain références, In one aspect, provided herein is a pharmaceutically acceptable sait of a compound described herein (e.g., a compound of Formula (I)).

Alternative Embodiments

In an alternative embodiment, compounds described herein may also comprise one or more isotopic substitutions. For example, hydrogen may be ² H (D or deuterium) or ³H (T or tritium); carbon may be, for example, ¹³C or ¹⁴C; oxygen may be, for example, ^l8O; nitrogen may be, for example, ¹⁵N, and the like. In other embodiments, a particular isotope (e.g., ³H, ¹³C, ^l4C, ¹⁸O, or ^l5N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of an element that occupies a spécifie site of the compound.

Pharmaceutical Compositions

In one aspect, provided herein is a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula (I)) or a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the compound of the présent invention is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the compound ofthe présent invention is provided in a therapeutîcally effective amount.

In certain embodiments, the pharmaceutical composition comprises an effective amount of the active ingrédient. In certain embodiments, the pharmaceutical composition comprises a therapeutîcally effective amount of the active ingrédient.

The pharmaceutical compositions provided herein can be adminîstered by a variety of routes includîng, but not limited to, oral (enterai) administration, parentéral (by injection) administration, rectal administration, transdermal administration, intradermal administration, întrathecal administration, subeutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration.

Generally, the compounds provided herein are admînistered in an effective amount. The amount of the compound actually admînistered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound admînistered, the âge, weight, and response of the individual patient, the severity of the patient’s symptoms, and the lîke.

When used to prevent the onset of a CNS-disorder, the compounds provided herein will be admînistered to a subject at rîsk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Subjects at rîsk for developing a particular condition generally include those that hâve a family history of the condition, or those who hâve been identified by genetic testing or screening to be parti cul art y susceptible to developing the condition.

The pharmaceutical compositions provided herein can also be admînistered chronically (“chronic administration”). Chronic administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc, or may be continued indefinitely, for example, for the rest of the subject’s lîfe. In certain embodiments, tire chronic administration is intended to provide a constant level of the compound in the blood, e.g., withîn the therapeutic window over the extended period of time.

The pharmaceutical compositions of the présent invention may be further delivered using a variety of dosing methods. For example, in certain embodiments, the pharmaceutical composition may be given as a bolus, e.g., in order to raise the concentration of the compound in the blood to an effective level. The placement of the bolus dose dépends on the systemic levels of the active ingrédient desired throughout the body, e.g., an intramuscular or subcutaneous bolus dose allows a slow release of the active ingrédient, while a bolus delivered directly to the veins (e.g., through an IV drip) allows a much faster delivery which quickly raises the concentration of the active ingrédient in the blood to an effective level. In other embodiments, the pharmaceutical composition may be admînistered as a continuons infusion, e.g., by IV drip, to provide maintenance of a steady-state concentration of the active ingrédient in the subject’s body. Furthermore, in still yet other embodiments, the pharmaceutical composition may be admînistered as first as a bolus dose, followed by continuous infusion.

The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are présented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrète units suitable as unitary dosages for human subjects and other mammals, each unit 62 containmg a predetennined quantity of active material calculated to produce the desired therapeutic effect, in association with a suîtable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampules or syrînges of the lîquid compositions or pills, tablets, capsules or the like în the case of solid compositions. In such compositions, the compound is usually a minor component (from about O.l to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being varions vehicles or excipients and processing aids helpful for forming the desired dosing form.

With oral dosing, one to five and especially two to four and typically three oral doses per day are représentative regîmens. Using these dosing patterns, each dose provides from about 0.01 to about 20 mg/kg of the compound provided herein, with preferred doses each providing from about 0.1 to about 10 mg/kg, and especially about 1 to about 5 mg/kg.

Transdermal doses are generally selected to provide sîmilar or lower blood levels than are achieved using injection doses, generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.

Injection dose levels range from about 0.1 mg/kg/hour to at least 20 mg/kg/hour, ail for from about 1 to about 120 hours and especially 24 to 96 hours. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adéquate steady state levels. The maximum total dose is not expected to exceed about 5 g/day for a 40 to 80 kg human patient.

Liquid forms suîtable for oral administration may include a suîtable aqueous or nonaqueous vehicle with buffers, suspendîng and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingrédients, or compounds of a sîmilar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid. Primogel, or corn starch; a lubricant such as magnésium stéarate; a glidant such as colloïdal Silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based upon injectable stérile saline or phosphatebuffered saline or other injectable excipients known in the art. As before, the active compound in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable excipient and the like.

Transdermal compositions are typically formulated as a topîcal ointment or cream containing the active ingredient(s). When formulated as an ointment, the active ingrédients will 63 typically be combined with either a paraffinic or a water-miscible ointment base. Alternative!y, the active ingrédients may be formulated in a cream with, for example an oil-in-water créant base. Such transdermal formulations are well-known in the art and generally include additional ingrédients to enhance the dennal pénétration of stability of the active ingrédients or Formulation. Ail such known transdermal formulations and ingrédients are included within the scope provided herein.

The compounds provided herein can also be adininistered by a transdermal device. Accordingly, transdermal administration can be accomplîshed using a patch either of the réservoir or porous membrane type, or of a solid matrix variety.

The above-described components for orally administrable, injectable or topically administrable compositions are merely représentative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington ’s Pharmaceutical Sciences, 17th édition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

The compounds of the présent invention can also be administered in sustained release forms or from sustained release drug delivery Systems. A description of représentative sustained release materials can be found in Remington ’s Pharmaceutical Sciences.

The présent invention also relates to the pharmaceutically acceptable acid addition sait of a compound of the présent invention. The acid which may be used to préparé the pharmaceutically acceptable sait is that which forms a non-toxic acid addition sait, i.e., a sait containing pharmacologicaily acceptable anions such as the hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, and the like.

Tn another aspect, the invention provides a pharmaceutical composition comprising a compound of the présent invention and a pharmaceutically acceptable excipient, e.g., a composition suitable for injection, such as for intravenous (IV) administration.

Pharmaceutically acceptable excipients include any and ail diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonie agents, preservatives, lubricants and the like, as suited to the particular dosage form desired, e.g., injection. General considérations in the formulation and/or manufacture of pharmaceutical compositions agents can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21^sl Edition (Lippincott Williams & Wilkins, 2005).

For example, injectable préparations, such as stérile injectable aqueous suspensions, can be formulated according to the known art using suitabîe dispersîng or wetting agents and suspending agents. Exemplary excipients that can be employed include, but are not limited to, water, stérile saline or phosphate-buffered saline, orRinger’s solution.

In certain embodiments, the pharmaceutical composition further comprises a cyclodextrin derivatîve. The most common cyclodextrins are et-, β- and γ- cyclodextrins consisting of 6, 7 and 8 a-1,4-linked glucose units, respectively, optionally comprising one or more substituents on the lînked sugar moieties, which include, but are not limited to, substituted or unsubstîtuted methylated, hydroxyalkylated, acylated, and sulfoalkylether substitution. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, e.g., for example, sulfobutyl ether β-cyclodextrin, also known as CAPTISOL®. See, e.g·., U.S. 5,376,645. In certain embodiments, the composition comprises hexapropyl-p-cyclodextrin. In a more particular embodiment, the composition comprises hexapropyl-p-cyclodextrin (10-50% in water).

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

Generally, the compounds provided herein are admînistered in an effective amount. The amount of the compound actually admînistered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound admînistered, the âge, weight, response of the individual patient, the severity of the patient’s symptoms, and the like.

The compositions are presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrète units suitabîe as unîtary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitabîe pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampules or syringes of the liquid compositions. In such compositions, the compound is usually a mînor component (from about 0.1% to about 50% by weight or preferably from about 1% to about 40% by weight) with the remainder being varions vehicles or carriers and processing aids helpful for forming the desired dosing form,

The compounds provided herein can be admînistered as the sole active agent, or they can be admînistered in combination with other active agents. In one aspect, the présent invention provides a combination of a compound of the présent invention and another pharmacologically active agent. Administration in combination can proceed by any technique apparent to those of ski II in the art including, for example, separate, sequential, concurrent, and altemating administration.

Although the descriptions of pharmaceutical compositions provided herein are princîpally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animais of ail sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to varions animais is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary expérimentation. General considérations in the formulation and/or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21^st ed., Lippincott Williams & Wilkins, 2005.

In one aspect, provided is a kit comprising a composition (e.g., a solid composition) comprising a compound of Fonnula (I).

Combination Therapy

A compound or composition described herein (e.g., a compound of Formula I, or a pharmaceutical sait thereof, or a composition comprising a compound of Formula I, or a phannaceutically acceptable sait thereof) maybe administered in combination with an additional agent or therapy. A subject to be administered a compound disclosed herein may hâve a disease, disorder, or condition, or a symptom thereof, that would benefit from treatment with another agent or therapy. Combination therapy may be achieved by administering two or more agents, each of which is formulated and administered separately, or by administering two or more agents in a single formulation. In some embodiments, the two or more agents in the combination therapy can be administered simultaneously. In other embodiments, the two or more agents in the combination therapy are administered separately. For example, administration of a first agent (or combination of agents) can précédé administration of a second agent (or combination of agents) by minutes, hours, days, or weeks. Thus, the two or more agents can be administered within minutes of each other or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other or within 2, 3, 4, 5, 6, 7, 8, 9, or weeks of each other. In some cases even longer intervals are possible. While in many cases it is désirable that the two or more agents used in a combination therapy be présent in within the patient's body at the sanie time, this need not be so.

Combination therapy can also include two or more administrations of one or more of the agents used in the combination using different sequencing of the component agents. For example, if agent X and agent Y are used în a combination, one could administer them sequentially in any combination one or more times, e.g., in the order X-Y-X, X-X-Y, Y-X-Y, YY-X, X-X-Y-Y, etc. Exemplary additional agents are described below.

Sélective Serotonin Reuptake Inhibitor (SSRJ)

In some embodiments, the compound or composition described herein (e.g., a compound of Formula I, or a pharmaceutical sait thereof, or a composition comprising a compound of Formula I, or a pharmaceutically acceptable sait thereof) is administered in combination with an SSRI(s). SSRIs include antîdepressants that increase the level of serotonin in the brain. Exemplary SSRIs include, but are not limited to, Citalopram (Celexa), Escitalopram (Lexapro), Fluoxetine (Prozac), Fluvoxamine (Luvox), Paroxetine (Paxil), and Sertraline (Zoloft).

Norepinephrine Reuptake Inhibitor (NER1)

In some embodiments, the compound or composition described herein (e.g., a compound of Formula I, or a pharmaceutical sait thereof, or a composition comprising a compound of Formula I, or a pharmaceutically acceptable sali thereof) is administered in combination with an NERI(s). Exemplary NERIs include, but are not limited to, Atomoxetine (Strattera), Reboxetine (Edronax, Vestra), Bupropion (Wellbutrin, Zyban), Duloxetine, Desipramine (Norpramin), Amedalin (UK-3540-l), Daledalin (UK-3557-15), Edivoxetine (LY-2216684), Esreboxetine, Lortal amine (LM-1404), Nisoxetine (LY-94,939), Talopram (tasulopram) (Lu 3-010), Talsupram (Lu 5-005), Tandamine (AY-23,946), and Viloxazine (Vivalan).

Antipsychotics

In some embodiments, the compound or composition described herein (e.g., a compound of Formula I, or a pharmaceutical sait thereof, or a composition comprising a compound of Formula I, or a pharmaceutically acceptable sait thereof) is administered in combination with an antipsychotic agent(s). Antipsychotics include D2 antagonists, lowering dopaminergic neurotransmission in the dopamine pathways. Exemplary antipsychotics include, but are not limited to, Asenapine (Saphris), Aripiprazole (Abilify), Cariprazine (Vrayar), Clozapine (Clozaril), Droperidol, Fluperlapine, Mesoridazine, Quetiapine Hemifumarate, Raclopride, Spiperone, Sulpiride, Trimethobenzamide hydrochloride, Trifluoperazine Dihydrochloride, 67 lurasidone (Latuda), Olanzapine (Zyprexa), Quetiapine (Seroquei), Zotepine, Rispéridone (Rîsperdal), Ziprasidone (Geodon), Mesotidazine, Chlorpromazine hydrochloride, and Haloperidol (Haldol).

Cannabinoids

In some embodiments, the compound or composition described herein (e.g., a compound of Formula I, or a pharmaceutical sait thereof, or a composition comprising a compound of Formula I, or a pharmaceutically acceptable sait thereof) is administered in combination with a cannabinoid(s). Exemplary cannabinoids include, but are not limited to, Cannabidiol (Epidiolex), Tetrahydrocannabinolic Acid, Tetrahydrocannabinol, Cannabidolic Acid, Cannabinol, Cannabigeroi, Cannabichromene, Tetrahydrocannabivarin, and Cannabidivarin.

NMDA Receptor Antagonists

In some embodiments, the compound or composition described herein (e.g., a compound of Formula I, or a pharmaceutical sait thereof, or a composition comprising a compound of Formula I, or a pharmaceutically acceptable sait thereof) is administered in combination with an NMDA receptor antagonist(s). NMDA receptor antagonists are a class of drugs that inhibit the action of the N-methyl-d-aspartate receptor. Exemplary NMDA antagonists include, but are not limited to, Ketamine, Esketamine, Ketobemidone, Ifendopril, 5,7-Dichlorokynurenic Acid, Licostinel, Memantine, Gavestinel, Phencyclidine, Dextromethorphan, Remacemide, Selfotel, Tiletamine, Dextropropoxyphène, Aptiganel, Dexanabinol, and Amantadîne. NMDA receptor antagonists also include opîoids such as Methadone, Dextropropoxyphène, Pethidine, Levorphanol, Tramadol, Neramexane, and Ketobemidone.

GABA Receptor Agonists

In some embodiments, the compound or composition described herein (e.g., a compound of Formula I, or a pharmaceutical sait thereof, or a composition comprising a compound of Formula I, or a pharmaceutically acceptable sait thereof) is administered in combination with GABA receptor agaonist(s). GABA receptor agonist are a class of drugs that are agonists for one or more of the GABA receptors. Exemplary GABA receptor agonists include, but are not limited to, Clobazam, Topiramate, Muscimol, Progabide, Riluzole, Baclofen, Gabapentin, Vigabatrin, Valproic Acid, Tiagabine, Lamotrigine, Pregabalin, Phenyloin, Carbamazepine, Thiopental, Thiamylal, Pentobarbital, Secobarbital, Hexobarbital, Butobarbital, Amobarbital, Barbital, Mephobarbital, Phénobarbital, Primidone, Midazolam, Triazolam, Lometazepam, Flutazolam, Nitrazepam, Fluritrazepam, Nimetazepam, Diazepam, Medazepam, Oxazolam,

Prazeam, Tofisopam, Rilmazafonoe, Lorazépam, Temazepam, Oxazepam, Fluidazepam, Chlordizaepoxide, Cloxazolam, Flutoprazepam, Alprazolam, Estazolam, Bromazepam, Flurazepam, Clorazepate Potassium, Haloxazolam, Ethyl Loflazepate, Qazepam, Clonazepam, Mexazolam, Etizolam, Brotizolam, Clotizaepam, Propofol, Fospropofol, Zolpidem, Zopîclone, Exzopi clone, Muscimol, TFQP/gaboxadol, Isoguvacine, Kojic amine, GABA, Homotaurine, Homohypotaurine, Trans-aminocycIopentane-3- carboxylic acid, Trans-amÎno-4-crotonic acid, b-guanidinopropionic acid, homo-b-proline, Isonipecotic acid, 3-((ammoiminomethyl)thio)-2propenoic acid (ZAP A), Imîdazoleacetic acid, and Piperidîne-4-suIfonic acid (P4S).

Cholinestérase Inhibltors

In some embodiments, the compound or composition described herein (e.g., a compound of Formula I, or a pharmaceutical sait thereof, or a composition comprising a compound of Formula I, or a pharmaceutically acceptable sait thereof) is administered in combination with a cholinestérase inhibîtor(s). In general, cholinergîcs are compounds which mi mie the action of acétylcholine and/or butyrylcholine. Cholinestérase inhibitors are a class of drugs that prevent the breakdown of acétylcholine. Exemplary cholinestérase inhibitors include, but are not limited to, Donepizil (Aricept), Tacrine (Cognex), Rivastigmine (Exelon, Exelon Patch), Galantamine (Razadyne, Reminyl), Memantine/Donepezil (Namzaric), Ambenonium (Mytelase), Neosfigmine (Bloxiverz), Pyridostigmine (Mestinon Timespan, Regonol), and Galantamine (Razadyne).

The présent disclosure also contemplâtes, among other things administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula 1, or a pharmaceutical sait thereof, or a composition comprising a compound of Formula I, or a pharmaceutically acceptable sait thereof) to a subject has been previously administered an agent selected from the group consisting of a bronchial muscle/airway relaxant, an antiviral, oxygen, an antibody, and an antibacterial. In some embodiments an additional agent is administered to a subject prior to administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula 1, or a pharmaceutical sait thereof, or a composition comprising a compound of Formula I, or a pharmaceutically acceptable sait thereof) and an additional agent is selected from the group consisting of a bronchial muscle/airway relaxant, an antiviral, oxygen, an antibody, and an antibacterial. In some embodiments, a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, or a pharmaceutical sait thereof, or a composition comprising a compound of Formula I, or a pharmaceutically acceptable sait thereof) is co-admînistered with to a subject with an agent selected from a bronchial muscle/airway relaxant, an antiviral, oxygen, and an antibacterial.

Methods ofüse and Treatment

In an aspect, compounds described herein, e.g., compounds of Formula (I), are envisioned to beuseful as therapeutic agents for treatîng a CNS-related disorder (e.g., sleep disorder, a mood disorder such as dépréssion, a schizophrenia spectrum disorder, a convulsive disorder, epileptogenesis, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, or tinnitus) in a subject in need (e.g., a subject with Rett syndrome, Fragile X syndrome, or Angelman syndrome). Exemplary CNS conditions related to GABA-modulation include, but are not limited to, sleep disorders [e.g., insomnia], mood disorders [e.g., dépréssion dépréssion (e.g., major dépressive disorder (MDD)), dysthymie disorder (e.g., mild dépréssion), bipolar disorder (e.g., 1 and/or II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), compulsive disorders (e.g., obsessive compulsive disorder (OCD))]. schizophrenia spectrum disorders [e.g., schizophrenia, schizoaffective disorder], convulsive disorders [e.g., epilepsy (e.g., status epîlepticus (SE)), seizures], disorders of memory and/or cognition [e.g., attention disorders (e.g., attention déficit hyperactivity disorder (ADHD)), dementia (e.g., Alzheimer’s type dementia, Lewis body type dementia, vascular type dementia], movement disorders [e.g., Huntington’s disease, Parkinson’s disease], personality disorders [e.g., anti-social personality disorder, obsessive compulsive personality disorder], autism spectrum disorders (ASD) [e.g., autism, monogenetic causes of autism such as synaptophathy’s, e.g., Rett syndrome, Fragile X syndrome, Angelman syndrome], pain [e.g., neuropathie pain, injury related pain syndromes, acute pain, chronic pain], traumatic brain injury (TBI), vascular diseases [e.g., stroke, ischeinia, vascular malformations], substance abuse disorders and/or withdrawal syndromes [e.g., addition to opiates, cocaine, and/or alcohol], and tinnitus.

In certain embodiments, CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, tinnitus, or status epîlepticus. In certain embodiments, the CNS-related disorder is dépréssion. In certain embodiments, the CNS-related disorder is postpartum dépréssion. In certain embodiments, the CNS-related disorder is major dépressive disorder. In certain embodiments, the major dépressive disorder is moderate major dépressive disorder. In certain embodiments, the major dépressive disorder is severe major dépressive disorder.

In an aspect, provided is a method of alleviating 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 présent invention. In some embodiments, the method alleviates or prevents epileptogenesis.

In y et another aspect, provided is a combination of a compound of the présent invention and another pharmacologically active agent. The compounds provided herein can be administered as the sole active agent or they can be administered in combination with other agents. Administration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent and alternating administration.

In another aspect, provided îs a method of treating or preventing brain excitability in a subject susceptible to or afflicted with a condition associated with brain excitability, comprising administering to the subject an effective amount of a compound of the présent invention to the subject.

In yet another aspect, provided is 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 présent invention, or a composition thereof.

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

In yet another aspect, provided is a method of inducing sleep and maintainîng substantially the level of REM sleep that is found in normal sleep, wherein substantial rebound însomnia is not induced, comprising administering an effective amount of a compound of the présent invention.

In yet another aspect, provided is a method of alleviating or preventing premenstrual syndrome (PMS) or postnatal dépréssion (PND) in a subject, comprising administering to the subject in need of such treatment an effective amount of a compound of the présent invention.

In yet another aspect, provided is 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 présent invention. In certain embodiments the mood disorder is dépréssion.

In yet another aspect, provided is a method of cognition enhancement or treating memory disorder by administering to the subject a therapeutically effective amount of a compound of the présent invention. In certain embodiments, the disorder is Alzheimer’s disease. In certain embodiments, the disorder is Rett syndrome.

In yet another aspect, provided is a method of treating attention disorders by administering to the subject a therapeutîcally effective amount of a compound of the présent invention. In certain embodiments, the attention disorder is ADHD.

Inflammation of the central nervous system (CNS) (neuroinflammation) is recognized to be a feature of ail neurological disorders. Major inflammatory neurological disorders include multiple sclerosis (characterized by an immune-mediated response against myelin proteins), and meningoencephalitis (where infectious agents triggered the inflammatory response). Additional scientific evidence suggests a potential rôle of inflammatory mechanisms in other neurological conditions such as Alzheimer's disease, Parkinson's disease, Huntington' disease, amyotrophie latéral sclerosis, stroke and traumatic brain injuries. In one embodiment, the compounds of the présent invention are useful in treating neuroinflammation. In another embodiment, the compounds of the présent invention are usefiil in treating inflammation in neurological conditions, includîng Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophie latéral sclerosis, stroke, and traumatic brain injuries.

In certain embodiments, the compound is adminîstered to the subject chronically. In certain embodiments, the compound is adminîstered to the subject orally, subcutaneously, intramuscularly, or intravenously.

Neuroendocrine Disorders and Dysfunction

Provided herein are methods that can be used for treating neuroendocrine disorders and dysfunction. As used herein, “neuroendocrine disorder” or “neuroendocrine dysfunction” refers to a variety of conditions caused by imbalances in the body’s hormone production directly related to the brain. Neuroendocrine disorders involve interactions between the nervous system and the endocrine system. Because the hypothalamus and the pituitary gland are two areas of the brain that regulate the production of hormones, damage to the hypothalamus or pituitary gland, e.g., by traumatic brain injury, may impact the production of hormones and other neuroendocrine fonctions of the brain. In some embodiments, the neuroendocrine disorder or dysfunction is associated with a women’s health disorder or condition (e.g., a women’s health disorder or condition described herein). In some embodiments, the neuroendocrine disorder or dysfunction is associated with a women’s health disorder or condition is polycystic ovary syndrome.

Symptoms of neuroendocrine disorder include, but are not limited to, behavioral, emotional, and sleep-related symptoms, symptoms related to reproductive function, and somatic symptoms; including but not limited to fatigue, poor memory, anxiety, dépréssion, weight gain or loss, emotional lability, lack of concentration, attention difficulties, loss of lipido, infertility, amenorrhea, loss of muscle mass, increased beliy body fat, low blood pressure, reduced heart rate, hair loss, anémia, constipation, cold intolérance, and dry skin.

Neurodegenerative Diseases and Disorders

The methods described herein can be used for treating neurodegenerative diseases and disorders. The term “neurodegenerative disease” includes diseases and disorders that are associated with the progressive loss of structure or function of neurons, or death of neurons. Neurodegenerative diseases and disorders include, but are not limited to, Alzheimer’s disease (including the associated symptoms of mild, moderato, or severe cognitive impairment); amyotrophie latéral sclerosis (ALS); anoxie and ischémie injuries; ataxia and convulsion (including for the treatment and prévention and prévention of seizures that are caused by schîzoaffective disorder or by drugs used to treat schizophrenia); benign forgetfulness; brain edema; cerebellar ataxia including McLeod neuroacanthocytosis syndrome (MLS); closed head injury; coma; contusive injuries (e.g., spinal cord injury and head injury); dementias including multi-infarct dementia and senile dementia; disturbances of consciousness; Down syndrome; drug-induced or medication-înduced Parkinsonism (such as neuroleptic-induced acute akathisia, acute dystonia, Parkinsonism, or tardive dyskinesia, neuroleptîc malignant syndrome, or medication-înduced postural tremor); epîlepsy; fragile X syndrome; Gilles de la Tourette’s syndrome; head traurna; hearing impairment and loss; Huntington’s disease; Lennox syndrome; levodopa-induced dyskinesia; mental retardation; movement disorders including akinesîas and akinetic (rigid) syndromes (including basal ganglia calcification, corticobasai degeneration, multiple System atrophy, Parkinsonism-ALS dementia complex, Parkinson’s disease, postencephalitîc parkinsonism, and progressively supranuclear palsy); muscular spasms and disorders associated with muscular spasticity or weakness including chorea (such as benign hereditary chorea, drug-induced chorea, hemiballism, 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 cyloclonus), tremor (such as rest tremor, postural tremor, and intention tremor) and dystonia (including axial dystonia, dystonie writer's cramp, hémiplégie dystonia, paroxysmal dystonia, and focal dystonia such as blepharospasm, oromandibular dystonia, and spasmodic dysphonia and torticollis); neuronal damage including ocular damage, retinopathy or macular degeneratîon of the eye; neurotoxic injury which follows cérébral stroke, thromboembolie stroke, hémorrhagie stroke, cérébral ischemia, cérébral vasospasm, hypoglycemia, amnesîa, hypoxia, anoxîa, périnatal asphyxia and cardiac arrest; Parkinson’s disease; seizure; status epilecticus; stroke; tinnitus; tubular sclerosis, and viral infection induced neurodegeneration (e.g., caused by acquired immunodeficiency syndrome (AIDS) and encéphalopathies). Neurodegenerative diseases also include, but are not limited to, neurotoxic injury which follows cérébral stroke, thromboembolie stroke, hémorrhagie stroke, cérébral ischemia, cérébral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, périnatal asphyxia and cardiac arrest. Methods of treating or preventing a neurodegenerative disease also include treating or preventing loss of neuronal fonction characteristic of neurodegenerative disorder.

Mood disorders

Also provided herein are methods for treating a mood disorder, for example clinical dépréssion, postnatal dépréssion or postpartum dépréssion, périnatal dépréssion, atypîcal dépréssion, melancholic dépréssion, psychotic major dépréssion, cataonic dépréssion, seasonal affective disorder, dysthymia, double dépréssion, dépressive personality disorder, récurrent brief dépréssion, minor dépressive disorder, bipolar disorder or manie dépressive disorder, dépréssion caused by chronic medical conditions, treatment-resistant dépréssion, refractory dépréssion, suicidality, suicidai idéation, or suicidai behavior. In some embodiments, the method described herein provides therapeutic effect to a subject suffering from dépréssion (e.g., moderate or severe dépréssion). In some embodiments, the mood disorder is assocîated with a disease or disorder described herein (e.g., neuroendocrine diseases and disorders, neurodegenerative diseases and disorders (e.g., epilepsy), movement disorders, tremor (e.g., Parkinson’s Disease), women’s health disorders or conditions).

Clinical dépréssion is also known as major dépréssion, major dépressive disorder (MDD), severe dépréssion, unipolar dépréssion, unipolar disorder, and récurrent dépréssion, and refers to a mental disorder characterized by pervasive and persistent low mood that is accompanied by low self-esteem and loss of interest or pleasure in normally enjoyable activities. Some people with clinical dépréssion hâve trouble sleeping, lose weight, and generally feel agitated and irritable. Clinical dépréssion affects how an individual feels, thînks, and behaves and may lead to a variety of emotional and physical problems. Individuals with clinical 74 dépréssion may hâve trouble doing day-to-day activities and make an individual feel as if life is not worth living.

Péripartum dépréssion refers to dépréssion in pregnancy. Symptoms include irritability, crying, feeling restless, trouble sleeping, extreme exhaustion (emotional and/or physical), changes in appetite, difficulty focusing, încreased anxiety and/or worry, disconnected feeling from baby and/or fétus, and losing interest in formerly pleasurable activities.

Postnatal dépréssion (PND) is also referred to as postpartum dépréssion (PPD), and refers to a type of clinical dépréssion that affects women after childbirth. Symptoms can include sadness, fatigue, changes in sleeping and eating habits, reduced sexual desire, crying épisodes, anxiety, and irritability. In some embodiments, the PND is a treatment-resistant dépréssion (e.g., a treatment-resistant dépréssion as described herein). In some embodiments, the PND is refractory dépréssion (e.g., a refractory dépréssion as described herein).

In some embodiments, a subject having PND also experienced dépréssion, or a symptom of dépréssion during pregnancy. This dépréssion is referred to herein as) périnatal dépréssion. In an embodiment, a subject experiencing périnatal dépréssion is at increased risk of experiencing PND.

Atypical dépréssion (AD) is characterized by mood reactivity (e.g., paradoxical anhedonia) and positivity, significant weight gain or increased appetite. Patients suffering from AD also may hâve excessive sleep or somnolence (hypersomnia), a sensation of limb heaviness, and significant social impairment as a conséquence of hypersensitivity to perceived interpersonal rejection.

Melancholic dépréssion is characterized by loss of pleasure (anhedonia) in most or ail activities, failures to react to pleasurable stimuli, depressed mood more pronounced than that of grief or loss, excessive weight loss, or excessive guilt.

Psychotic major dépréssion (PMD) or psychotic dépréssion refers to a major dépressive épisode, in particular of melancholic nature, where the individual expériences psychotic symptoms such as delusions and hallucinations.

Catatonie dépréssion refers to major dépréssion involving disturbances of motor behavîor and other symptoms. An individual may become mute and stuporose, and either îs immobile or exhibits purposeless or bizarre movements.

Seasonal affective disorder (SAD) refers to a type of seasonal dépréssion wherein an individual has seasonal patterns of dépressive épisodes coming on in the fall or winter.

Dysthymia refers to a condition related to unipolar dépréssion, where the same physical and cognitive problems are évident. They are not as severe and tend to last longer (e.g., at least 2 years).

Double dépréssion refers to fairly depressed mood (dysthymia) that lasts for at least 2 years and is punctuated by periods of major dépréssion.

Dépressive Personality Disorder (DPD) refers to a personality disorder with dépressive features.

Récurrent Brief Dépréssion (RBD) refers to a condition in which individuals hâve dépressive épisodes about once per month, each épisode lasting 2 weeks or less and typically less than 2-3 days.

Minor dépressive disorder or minor dépréssion refers to a dépréssion in which at least 2 symptoms are présent for 2 weeks.

Bipolar disorder or manie dépressive disorder causes extreme mood swings that include emotional highs (mania or hypomania) and lows (dépréssion). During periods of mania the individual may feel or act abnormally happy, energetic, or irritable. They often make poorly thought out decisions with little regard to the conséquences. The need for sleep is usually reduced. During periods of dépréssion there may be crying, poor eye contact with others, and a négative outlook on life. The risk of suicide among those with the disorder is high at greater than 6% over 20 years, while self-hann occurs in 30-40%. Other mental health issues such as anxiety disorder and substance use disorder are commenly associâted with bipolar disorder.

Dépréssion caused by chronic medical conditions refers to dépréssion caused by chronic medical conditions such as cancer or chronic pain, chemotherapy, chronic stress.

Treatment-résistant dépréssion refers to a condition where the individuals hâve been treated for dépréssion, but the symptoms do not improve. For example, antidepressants or physchological counseling (psychotherapy) do not case dépréssion symptoms for individuals with treatment-resistant dépréssion. In some cases, individuals with treatment-resistant dépréssion improve symptoms, but corne back. Refractory dépréssion occurs in patients suffering from dépréssion who are résistant to standard pharmacological treatments, including tricyclic antidepressants, MAOIs, SSRIs, and double and triple uptake inhibitors and/or anxiolytic drugs, as well as non-pharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagus nerve stimulation and/or transcranial magnetic stimulation).

Post-surgical dépréssion refers to feelings of dépréssion that follow a surgical procedure (e.g., as a resuit of having to confiront one’s mortality). For example, individuals may feel sadness or empty mood persistently, a loss of pleasure or interest in hobbies and activities normally enjoyed, or a persistent felling of worthlessness or hopelessness.

Mood disorder associated with conditions or disorders of women’s health refers to mood disorders (e.g., dépréssion) associated with (e.g., resulting from) a condition or disorder of women’s health (e.g., as described herein).

Suicidality, suicidai idéation, suicidai behavior refers to the tendency of an individual to commit suicide. Suicidai idéation concems thoughts about or an unusual préoccupation with suicide. The range of suicidai idéation varies greatly, from e.g., fleetîng thoughts to extensive thoughts, detailed planning, rôle playing, incomplète attempts. Symptoms include talking about suicide, getting the means to commit suicide, withdrawing from social contact, being preoccupîed with death, feeling trapped or hopeless about a situation, increasing use of alcohol or drugs, doing risky or self-destructive things, saying goodbye to people as if they won’t be seen again.

Symptoms of dépréssion include persistent anxious or sad feelings, feelings of helplessness, hopelessness, pessimism, worthlessness, low energy, restlessness, difficulty sleeping, sleeplessness, irritability, fatigue, motor challenges, loss of interest in pleasurable activities or hobbies, loss of concentration, loss of energy, poor self-esteem, absence of positive thoughts or plans, excessive sleeping, overeating, appetîte loss, insomnia,self-hann, thoughts of suicide, and suicide attempts. The presence, severity, frequency, and duration of symptoms may vary on a case to case basis. Symptoms of dépréssion, and relief of the same, may be ascertained by a physician or psychologist (e.g., by a mental State examination).

In some embodiments, the method comprises monitoring a subject with a known dépréssion scale, e.g., the Hamilton Dépréssion (HAM-D) scale, the Clinical Global ImpressionImproveinent Scale (CGI), and the Montgomery-Âsberg Dépréssion Rating Scale (MADRS). In some embodiments, a therapeutic effect can be determined by réduction in Hamilton Dépréssion (HAM-D) total score exhibited by the subject. Réduction in the HAM-D total score can happen within 4, 3, 2, or 1 days; or 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, 8 hours or less. The therapeutic effect can be assessed across a specified treatment period. For example, the therapeutic effect can be determined by a decrease from baseline in HAM-D total score after administering a compound described herein, e.g., a compound of Fonnula (I) (e.g., 12, 24, or 48 hours after administration; or 24, 48, 72, or 96 hours or more; or I day, 2 days, 14 days, 21 days, or 28 days; or 1 week, 2 weeks, 3 weeks, or 4 weeks; or 1 month, 2 months, 6 months, or 10 months; or 1 year, 2 years, or for life).

In some embodiments, the subject has a mild dépressive disorder, e.g., mild major dépressive disorder. In some embodiments, the subject has a moderate dépressive disorder, e.g., moderato major dépressive disorder. In some embodiments, the subject has a severe dépressive disorder, e.g., severe major dépressive disorder. In some embodiments, the subject has a very severe dépressive disorder, e.g., very severe major dépressive disorder. In some embodiments, the baseline HAM-D total score of the subject (Le., prior to treatment with a compound described herein, e.g., a compound of Formula (I)) is at least 24. In some embodiments, the baseline HAM-D total score of the subject is at least l S. In some embodiments, the baseline HAM-D total score of the subject is between and including 14 and 18. In some embodiments, the baseline HAM-D total score of the subject is between and including 19 and 22. In some embodiments, the HAM-D total score of the subject before treatment with a compound described herein, e.g., a compound of Formula (I), is greater than or equal to 23. In some embodiments, the baseline score is at least 10, 15, or 20. In some embodiments, the HAM-D total score ofthe subject after treatment with a compound described herein, e.g., a compound of Formula (I), is about 0 to 10 (e.g., less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 1.8). In some embodiments, the HAM-D total score after treatment with a compound described herein, e.g., a compound of Formula (I), is less than 10, 7, 5, or 3. In some embodiments, the decrease in HAM-D total score is from a baseline 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 HAM-D total score at 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 (1). In some embodiments, the decrease în the baseline HAM-D total score to HAM-D total score after treatment with a compound described herein, e.g., a compound of Formula (I), is at least 1, 2, 3, 4, 5, 7, 10, 25, 40, 50, or 100 fold). In some embodiments, the percentage decrease in the baseline HAM-D total score to HAM-D total score after treatment with a compound described herein, e.g., a compound of Formula (I), is at least 50% (e.g., 60%, 70%, 80%, or 90%). In some embodiments, the therapeutic effect is measured as a decrease in the HAM-D total score after treatment with a compound described herein, e.g., a compound of Formula (I), relative to the baseline HAM-D total score (e.g., 12, 24, 48 hours after administration; or 24, 48, 72, 96 hours or more; or 1 day, 2 days, 14 days, or more) îs at least 10, 15, or 20 points.

In some embodiments, the method of treating a dépressive disorder, e.g., major dépressive disorder provides a therapeutic effect (e.g., as measured by réduction in Hamilton Dépréssion Score (HAM-D)) within 14, 10, 4, 3, 2, or I days, or 24, 20, 16, 12, 10, or 8 hours or less. In some embodiments, the method of treating the dépressive disorder, e.g., major 78 depressîve disorder, provides a therapeutic effect (e.g., as determined by a statistically significant réduction in HAM-D total score) within the first or second day of the treatment with a compound described herein, e.g., a compound of Formula (I). In some embodiments, the method of treating the depressîve disorder, e.g., major depressîve disorder, provides a therapeutic effect (e.g., as determined by a statistically significant réduction in HAM-D total score) within less than or equal to 14 days since the beginning of the treatment with a compound described herein, e.g., a compound of Formula (I). In some embodiments, the method of treating the depressîve disorder, e.g., major depressîve disorder, provides a therapeutic effect (e.g., as determined by a statistically significant réduction in HAM-D total score) within less than or equal to 21 days since the beginning of the treatment with a compound described herein, e.g., a compound of Formula (I). In some embodiments, the method of treating the depressîve disorder, e.g., major depressîve disorder, provides a therapeutic effect (e.g., as determined by a statistically significant réduction in HAM-D total score) within less than or equal to 28 days since the beginning of the treatment with a compound described herein, e.g., a compound of Formula (I). In some embodiments, the therapeutic effect is a decrease from baseline in HAM-D total score after treatment with a compound described herein, e.g., a compound of Fonnula (I) (e.g., treatment with a compound described herein, e.g., a compound of Fonnula (I), once a day for 14 days). In some embodiments, the HAM-D total score of the subject before treatment with a compound described herein, e.g., a compound of Formula (I), is at least 24. In some embodiments, the HAM-D total score of the subject before treatment with a compound described herein, e.g., a compound of Fonnula (I), is at least 18. In some embodiments, the HAM-D total score of the subject before treatment with a compound described herein, e.g., a compound of Formula (I), is between and including 14 and 18. In some embodiments, the decrease in HAM-D total score after treating the subject wîth a compound described herein, e.g., a compound of Formula (I), relative to the baseline HAM-D total score is at least 10. In some embodiments, the decrease in HAM-D total score after treating the subject with a compound described herein, e.g., a compound of Fonnula (I), relative to the baseline HAM-D total score is at least 15 (e.g., at least 17). In some embodiments, the HAM-D total score associated with treating the subject with a compound described herein, e.g., a compound of Fonnula (I), is no more than a number ranging from 6 to 8. In some embodiments, the HAM-D total score associated with treating the subject with a compound described herein, e.g., a compound of Formula (I), is no more than 7.

In some embodiments, the method pro vides therapeutic effect (e.g., as measured b y réduction in Clinical Global Impression-Improvement Scale (CGI)) within 14, 10,4, 3, 2, or 1 days, or 24, 20, 16, 12, 10, or 8 hours or less. In some embodiments, the CNS-disorder is a 79 dépressive disorder, e.g,, major dépressive disorder. In some embodiments, the method of treating the dépressive disorder, e.g., major dépressive disorder provides a therapeutic effect within the second day of the treatment period. In some embodiments, the therapeutic effect is a decrease from baseline in CGI score at the end of a treatment period (e.g., 14 days after administration).

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

A therapeutic effect for major dépressive disorder can be determined by a réduction in Montgomery-Âsberg Dépréssion Rating Scale (MADRS) score exhibited by the subject. For example, the MADRS score can be reduced within 4, 3, 2, or 1 days; or 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, 8 hours or less. The Montgomery-Âsberg Dépréssion Rating Scale (MADRS) is a ten-item diagnostic questionnaire (regarding apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidai thoughts) which psychiatrists use to measure the severity of dépressive épisodes in patients with mood disorders.

In some embodiments, the method provides therapeutic effect (e.g., as measured by réduction în Edinburgh Postnatal Dépréssion Scale (EPDS)) within 4, 3, 2, 1 days; 24, 20, 16, 12, 10, 8 hours or less. In some embodiments, the therapeutic effect is an improvement measured by the EPDS.

In some embodiments, the method provides therapeutic effect (e.g., as measured by réduction in Generalized Anxiety Disorder 7-Item Scale (GAD-7)) within 4, 3, 2, 1 days; 24, 20, 16, 12, 10, 8 hours or less.

Anxiety Disorders

Provided herein are methods for treating anxiety disorders (e.g., generalized anxiety disorder, panic disorder, obsessive compulsive disorder, phobia, post-traumatic stress disorder).

Anxiety disorder is a blanket tenu covering several different forms of abnormal and pathological fear and anxiety. Current psychiatrie diagnostic criteria recognize a wide variety of anxiety disorders.

Generalized anxiety disorder is a common chronic disorder characterized by longlasting anxiety that is not focused on any one object or situation. Those suffering front generalized anxiety expérience non-spécifie persistent fear and worry and become overly concemed with everyday matters. Generalized anxiety disorder is the most common anxiety disorder to affect older adults.

In panic disorder, a person suffers from brief attacks of intense terror and appréhension, often marked by trembling, shaking, confusion, dizziness, nausea, difficulty breathing. These panic attacks, defined by the APA as fear or discomfort that abruptly arises and peaks in less than ten minutes, can last for several hours and can be triggered by stress, fear, or even exercise; although the spécifie cause is not always apparent. In addition to récurrent unexpected panic attacks, a diagnosis of panic disorder also requires that said attacks hâve chronic conséquences: either worry over the attacks' potential implications, persistent fear of future attacks, or significant changes in behavior related to the attacks. Accordingly, those suffering from panic disorder expérience symptoms even outside of spécifie panic épisodes. Often, normal changes in heartbeat are noticed by a panic sufferer, leadîng them to think something is wrong with their heart or they are about to hâve another panic attack. In some cases, a heightened awareness (hypervigilance) of body functioning occurs during panic attacks, wherein any perceived physiological change is interpreted as a possible life threatening illness (i.e. extreme hypochondriasis).

Obsessive compulsive disorder is a type of anxiety disorder primarily characterized by répétitive obsessions (distressing, persistent, and intrusive thoughts or images) and compulsions (urges to perfonn spécifie acts or rituals). The OCD thought pattern may be likened to superstitions insofar as it involves a belief in a causative relationship where, in reality, one does not exist. Often the process is entirely illogical; for example, the compulsion of walking in a certain pattern may be employed to alleviate the obsession of împending harm. And in many cases, the compulsion is entirely inexplicable, simply an urge to complété a ritual triggered by nervousness. In a minority of cases, sufferers of OCD may only expérience obsessions, with no overt compulsions; a mu ch smaller number of sufferers expérience only compulsions.

The single largest category of anxiety disorders is that of phobia, which includes ail cases in which fear and anxiety is triggered by a spécifie stimulus or situation. Sufferers typically anticipate terrifying conséquences from encountering the object of their fear, which can be anything from an animal to a location to a bodily fluid.

Post-traumatic stress disorder or PTSD is an anxiety disorder which results from a traumatic expérience. Post-traumatic stress can resuit from an extreme situation, such as combat, râpe, hostage situations, or even serious accident. It can also resuit from long term (chronic) exposure to a severe stressor, for example soldiers who endure individual battles but cannot cope with contînuous combat. Common symptoms include flashbacks, avoidant behaviors, and dépréssion.

Wbmen ’s Health Disorders

Provided herein are methods for treating conditions or disorders related to women’s health. Conditions or disorders related to women’s health include, but are not limited to, gynecologîcal health and disorders (e.g., premenstrual syndrome (PMS), premenstrual dysphorie disorder (PMDD)), pregnancy issues (e.g., miscarriage, abortion), infertility and related disorders (e.g., polycystic ovary syndrome (PCOS)), other disorders and conditions, and issues related to women’s overall health and wellness (e.g., ménopausé).

Gynecologîcal health and disorders affecting women include menstruation and menstrual irregularities; urinary tract health, including urinary incontinence and pelvic floor disorders; and such disorders as bacterial vaginosîs, vaginitis, uterine fïbroids, and vulvodynîa.

Premenstrual syndrome (PMS) refers to physical and emotional symptoms that occur in the one to two weeks before a women’s period. Symptoms vary but can include bleeding, mood swings, tender breasts, food cravings, fatigue, irritability, acné, and dépréssion.

Premenstrual dysphorie disorder (PMDD) is a severe form of PMS. The symptoms of PMDD are similar to PMS but more severe and may interfère with work, social activity, and relationships. PMDD symptoms include mood swings, depressed mood or feelings of hopelessness, marked anger, increased interpersonal conflicts, tension and anxiety, irritability, decreased înterest in usual activities, difficulty concentrating, fatigue, change in appetite, feeling out of control or overwhelmed, sleep problems, physical problems (e.g., bloating, breast tenderness, swelling, headaches, joint or muscle pain).

Pregnancy issues include preconceptîon care and prénatal care, pregnancy loss (miscarriage and stîllbirth), preterm labor and prématuré birth, sudden infant death syndrome (SIDS), breastfeeding, and birth defects.

Miscarriage refers to a pregnancy that ends on its own, within the first 20 weeks of gestation.

Abortion refers to the deliberate termination of a pregnancy, which can be performed during the First 2S weeks of pregnancy.

Infertilîty and related disorders include uterine fibroids, polycystic ovary syndrome, endometrîosis, and primary ovarian insufficiency.

Polycystic ovary syndrome (PCOS) refers to an endocrine system disorder among women of reproductive âge. PCOS is a set of symptoms resulting from an elevated male hormone in women. Most women with PCOS grow many small cysts on their ovaries. Symptoms of PCOS include irregular or no menstrual periods, heavy periods, excess body and facial haïr, acné, pelvic pain, difficulty getting prégnant, and patches of thick, darker, velvety skin. PCOS may be associated with conditions includîng type 2 diabètes, obesity, obstructive sleep apnea, heart disease, mood disorders, and endométrial cancer.

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

Issues related to women’s overall health and wellness include violence against women, women with disabilîties and their unique challenges, osteoporosis and bone health, and ménopausé.

Ménopausé refers to the 12 months after a woman’s last menstrual period and marks the end of menstrual cycles. Ménopausé typically occurs in a woman’s 40s or 50s. Physical symptoms such as hot flashes and emotional symptoms of ménopausé may disrupt sleep, lower energy, or trigger anxiety or feelings of sadness or loss. Ménopausé includes natural ménopausé and surgical ménopausé, which is a type of induced ménopausé due to an event such as surgery (e.g., hysterectomy, oophorectomy; cancer). It is induced when the ovaries are gravely damaged by, e.g., radiation, chemotherapy, or other médications.

Epilepsy

The compound of Formula (I), or pharmaceutically acceptable sait, or a pharmaceutically acceptable composition thereof, can be used in a method described herein, for example in the treatment of a disorder described herein such as epilepsy, status epilepticus, or seizure.

Epilepsy is a brain disorder characterized by repeated seizures over time. Types of epilepsy can include, but are not limited to generalîzed epilepsy, e.g., childhood absence epilepsy, juvénile nyoclonic epilepsy, epilepsy with grand-mal seizures on awakening, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, e.g., temporal lobe epilepsy, frontal lobe epilepsy, benign focal epilepsy of childhood.

Epileptogenesis

The compounds and methods described herein can be used to treat or prevent epileptogenesis. Epileptogenesis is a graduai process by which a normal brain develops epilepsy (a chronic condition în which seizures occur). Epileptogenesis results from neuronal damage precipitated by the initial insult (e.g., status epileptîcus).

Status epileptîcus (SE)

Status epileptîcus (SE) can include, e.g., convulsive status epileptîcus, e.g., early status epileptîcus, established status epileptîcus, refractory status epileptîcus, super-refractory status epileptîcus; non-convulsive status epileptîcus, e.g., generalized status epileptîcus, complex partial status epileptîcus; generalized periodic epileptiform discharges; and periodic lateralized epileptîform discharges. Convulsive status epileptîcus is characterized by the presence of convulsive status epileptic seizures, and can include early status epileptîcus, established status epileptîcus, refractory status epileptîcus, super-refractory status epileptîcus. Early status epileptîcus is treated with a first line therapy. Established status epileptîcus is characterized by status epileptic seizures which persist despite treatment with a first line therapy, and a second line therapy is administered. Refractory status epileptîcus is characterized by status epileptic seizures which persist despite treatment with a first line and a second line therapy, and a general anesthetic is generally administered. Super refractory status epileptîcus is characterized by status epileptic seizures which persist despite treatment with a first line therapy, a second line therapy, and a general anesthetic for 24 hours or more.

Non-convulsive status epileptîcus can include, e.g., focal non-convulsive status epileptîcus, e.g., complex partial non-convulsive status epileptîcus, simple partial non-convulsive status epileptîcus, subtle non-convulsive status epileptîcus; generalized non-convulsive status epileptîcus, e.g., late onset absence non-convulsive status epileptîcus, atypical absence nonconvulsîve status epileptîcus, or typical absence non-convulsive status epileptîcus.

The compound of Formula (I) or pharmaceutically acceptable sait, or a pharmaceutically acceptable composition thereof, can also be administered as a prophylactic to a subject having a CNS disorder e.g., a traumatic brain injury, status epileptîcus, e.g., convulsive status epileptîcus, e.g., early status epileptîcus, established status epileptîcus, refractory status epileptîcus, superrefractory status epileptîcus; non-convulsive status epileptîcus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges; prior to the onset of a seizure.

Seizure

A seizure is the physical findings or changes in behavior that occur after an épisode of abnormal electrical activity in the brain. The term “seizure” is often used interchangeably with “convulsion.” Convulsions are when a person’s body shakes rapidly and uncontrollably. During convulsions, the person’s muscles contract and relax repeatedly.

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

Generalized seizures are produced by electrical impulses from throughout the entire brain, whereas partial seizures are produced (at least initially) by electrical impulses in a relatively small part of the brain. The part of the brain generating the seizures is sometimes called the focus.

There are six types of generalized seizures. The most common and dramatic, and therefore the most well-known, is the generalized convulsion, also called the grand-mal seizure. In this type of seizure, the patient loses consciousness and usually collapses. The loss of consciousness is followed by generalized body stiffening (called the tonie phase of the seizure) for 30 to 60 seconds, then by violent jerking (the clonie phase) for 30 to 60 seconds, after which the patient goes into a deep sleep (the postictal or after-seizure phase). During grandmal seizures, injuries and accidents may occur, such as tongue biting and urinary incontinence.

Absence seizures cause a short loss of consciousness (just a few seconds) with few or no symptoms. The patient, most often a child, typically interrupts an activity and stares blankly. These seizures begin and end abruptly and may occur several times a day. Patients are usually not aware that they are having a seizure, except that they may be aware of losing time.

Myoclonie seizures consist of sporadic jerks, usually on both sides of the body. Patients sometimes describe the jerks as brief electrical shocks. When violent, these seizures may resuit in dropping or involuntarily throwing objects.

Clonie seizures are répétitive, rhythmic jerks that involve both sides of the body at the same time.

Tonie seizures are characterized by stiffening of the muscles.

Atonie seizures consist of a sudden and general loss of muscle tone, particularly in the arms and legs, which often results in a fall.

Seizures described herein can include epîleptic seizures; acute répétitive seizures; cluster seizures; continuons seizures; unremitting seizures; prolonged seizures; récurrent seizures; status epilepticus seizures, e.g., refractory convulsive status epilepticus, non-convulsive status epilepticus seizures; refractory seizures; myoclonie seizures; tonie seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondarily generalized seizures; atypical absence seizures; absence seizures; atonie seizures; benign Rolandic seizures; febrile seizures; emotional seizures; focal seizures; gelastic seizures; generalized onset seizures; infantile spasms; Jacksonian seizures; massive bilateral myoclonus seizures; multifocal seizures; néonatal onset seizures; noctumal seizures; occipital lobe seizures; post traumatic seizures; subtle seizures; Sylvan seizures; visual reflex seizures; or withdrawal seizures. In some embodiments, the seizure is a generalized seizure associated with Dravet Syndrome, LennoxGastaut Syndrome, Tuberous Sclerosîs Complex, Rett Syndrome or PCDH19 Female Pédiatrie Epilepsy.

Movement Disorders

Also described herein are methods for treating a movement disorder. As used herein, “movement disorders” refers 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 particuiarly bybradykinesia), dystonia, chorea and Huntington’s disease, ataxia, tremor (e.g., essential tremor), myoclonus and startle, tics and Tourette syndrome, Restless legs syndrome, stiff person syndrome, and gait disorders.

Tremor

The methods described herein can be used to treat tremor, for example the compound of Formula (I) can be used to treat cerebellar tremor or intention tremor, dystonie tremor, essential tremor, orthostatic tremor, parkinsonian tremor, physîological tremor, psychogenic tremor, or rubral tremor. Tremor includes hereditary, degenerative, and idîopathic disorders such as Wilson’s disease, Parkinson’s disease, and essential tremor, respectively; metabolic diseases (e.g., thyroid-parathyroid-, liver disease and hypoglycemia); peripheral neuropathies (associated with Charcot-Marie-Tooth, Roussy-Levy, diabètes mellitus, complex régional pain syndrome); toxins (nicotine, mercury, lead, CO, Manganèse, arsenic, toluene); drug-induced (narcoleptics, tricyclics, lithium, cocaïne, alcohol, adrénaline, bronchodilators, theophylltne, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychogenic disorders. Clinical tremor can be classified into physiologie tremor, enhanced physiologie tremor, essential tremor 86 syndromes (including classical essential tremor, primary orthostatic tremor, and task- and position-specific tremor), dystonie tremor, parkinsonian tremor, cerebellar tremor, Holmes’ tremor (i.e., rubral tremor), palatal tremor, neuropathie tremor, toxic or drug-induced tremor, and psychogenic tremor,

Tremor is an involuntary, at times rhythmic, muscle contraction and relaxation that can involve oscillations or twitching of one or more body parts (e.g., hands, arms, eyes, face, head, vocal folds, trunk, legs).

Cerebellar tremor or intention tremor is a slow, broad tremor ofthe extremities that occurs after a purposeful movement. Cerebellar tremor is caused by lésions in or damage to the cerebellum resulting from, e.g., tumor, stroke, disease (e.g., multiple sclerosis, an inherited degenerative disorder).

Dystonie tremor occurs in individuals affected by dystonia, a movement disorder in whîch sustained involuntary muscle contractions cause twisting and répétitive motions and/or painful and abnonnal postures or positions. Dystonie tremor may affect any muscle in the body. Dystonie tremors occurs irregularly and often can be relieved by complété rest.

Essential tremor or benign essential tremor is the most common type of tremor. Essential tremor may be mild and nonprogressive in some, and may be slowly progressive, starting on one side of the body but affect both sides within 3 years. The hands are most often affected, but the head, voice, tongue, legs, and trunk may also be involved. Tremor frequency may decrease as the person âges, but severity may increase. Heightened émotion, stress, fever, physical exhaustion, or low blood sugar may trigger tremors and/or increase their severity. Symptoms generally evolve over time and can be both visible and persistent following onset.

Orthostatic tremor is characterized by tast (e.g., greater than 12 Hz) rhythmic muscle contractions that occurs in the legs and trunk immediately after standing. Cramps are felt in the thighs and legs and the patient may shake uncontrollably when asked to stand in one spot. Orthostatic tremor may occurs in patients with essential tremor.

Parkinsonian tremor is caused by damage to structures within the brain that control movement. Parkinsonian tremor is often a precursor to Parkinson’s disease and is typically seen as a “pill-rolling” action of the hands that may also affect the chin, lips, legs, and trunk. Onset of parkinsonian tremor typically begins after âge 60. Movement starts in one limb or on one side of the body and can progress to include the other side.

Physiological tremor can occur in normal individuals and hâve no clinical significance. It can be seen in ail voluntary muscle groups. Physiological tremor can be caused by certain drugs, alcohol withdrawal, or medical conditions including an overactive thyroid and hypoglycemia. The tremor classically has a frequency of about 10 Hz.

Psychogenic tremor or hysterical tremor can occur at rest or during postural or kinetic movement. Patient with psychogenic tremor may hâve a conversion disorder or another psychiatrie disease.

Rubral tremor is characterized by coarse slow tremor which can be présent at rest, at posture, and with intention. The tremor is associated with conditions that affect the red nucléus in the midbraîn, classîcal unusual strokes.

Parkinson’s Disease affects nerve cells in the brain that produce dopamine. Symptoms include muscle rigidity, tremors, and changes in speech and gait. Parkinsonism is characterized by tremor, bradykinesia, rigidity, and postural instability. Parkinsonism shares symptoms found in Parkinson’s Disease, but is a symptom complex rather than a progressive neurodegenerative disease.

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often répétitive movements or postures. Dystonie movements can be patterned, twisting, and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation.

Chorea is a neurological disorder characterized by jerky involuntary movements typically affecting the shoulders, hîps, and face. Huntington’s Disease îs an inherited disease that causes nerve cells in the brain to waste away. Symptoms include uncontrolled movements, clumsiness, and balance problems. Huntington’s disease can hinder walk, talk, and swallowing.

Ataxîa refers to the loss of fiill control of bodily movements, and may affect the fïngers, hands, anns, legs, body, speech, and eye movements.

Myloclonus and Startle is a response to a sudden and unexpected stimulus, which can be acoustic, tactile, visual, or vestibular.

Tics are an involuntary movement usually onset suddenly, brief, répétitive, but nonrhythmical, typically imitating normal behavior and often occurring out of a background of normal activity. Tics can be classîfied as motor or vocal, motor tics associated with movements while vocal tics associated with sound. Tics can be characterized as simple or complex. For example simple motor tics in volve only a few muscles restricted to a spécifie body part. Tourette Syndrome is an inherited neuropsychiatrie disorder with onset in childhood, characterized by multiple motor tics and at least one vocal tic.

Restless Legs Syndrome is a neurologie sensorimotor disorder characterized by an overwhelming urge to move the legs when at rest.

Stiff Person Syndrome is a progressive movemenî disorder characterized by involuntary painful spasms and rigidity of muscles, usually involvîng the lower back and legs. Stiff-legged gaît with exaggerated lumbar hyperlordosis typically results. Characteristic abnormality on EMG recordings with contînuous motor unit activity ofthe paraspinal axial muscles is typically observed. Variants include “stiff-Iimb syndrome” producing focal stiffness typically affecting distal legs and feet.

Gait disorders refer to an abnormality in the manner or style of walking, which results from neuromuscular, arthritic, or other body changes. Gait is classified according to the System responsible for abnormal locomotion, and include hémiplégie gait, diplegic gait, neuropathie gaît, myopathie gait, parkinsonian gait, choreiform gait, ataxie gait, and sensory gait. Anesthésia /Sédation

Anesthésia is a pharmacologically induced and réversible State of amnesia, analgesia, loss of responsiveness, loss of skeletal muscle reflexes, decreased stress response, or ail of these simultaneously. These effects can be obtained from a single drug which alone provides the correct combination of effects, or occasionally with a combination of drugs (e.g., hypnotics, sédatives, paralytics, analgésies) to achieve very spécifie combinations of results. Anesthésia allows patients to undergo surgery and other procedures without the distress and pain they would otherwise expérience.

Sédation is the réduction of irritability or agitation by administration of a pharmacological agent, generally to facilitate a medical procedure or diagnostic procedure.

Sédation and analgesia include a continuum of States of consciousness ranging from minimal sédation (anxiolysis) to general anesthésia.

Minimal sédation is also known as anxiolysis. Minimal sédation is a drug-induced State during which the patient responds normally to verbal commands. Cognitive fonction and coordination may be impaired. Ventilatory and cardiovascular fonctions are typically onaffected.

Moderate sedation analgesia (conscious sédation) is a drog-indoced dépréssion of consciousness during which the patient responds purposefully to verbal command, either alone or accompanied by light tactile stimulation. No interventions are usually necessary to maintain a patent airway. Spontaneous ventilation is typically adéquate. Cardiovascular fonction is usoally maintained.

Deep sedation/analgesia is a drug-induced dépréssion of consciousness during which the patient cannot be easily aroused, but responds purposefully (not a reflex withdrawal from a painful stimulus) following repeated or painful stimulation. Independent ventilatory function 89 may be impaired and the patient may require assistance to maintain a patent airway. Spontaneous ventilation may be inadéquate. Cardiovascular function is usually mamtained.

General anesthésia is a drug-induced loss of consciousness during which the patient is not arousable, even to painful stimuli. The ability to maintain independent ventilatory function is often impaired and assistance is often required to maintain a patent airway. Positive pressure ventilation may be required due to depressed spontaneous ventilation or drug-induced dépréssion of neuromuscular function. Cardiovascular function may be impaired.

Sédation in the intensive care unit (ICU) allows the dépréssion of patients’ awareness of the environment and réduction of their response to extemal stimulation. It can play a rôle in the care of the critically ill patient, and en compassés a wide spectrum of symptom control that will vary between patients, and among individuals throughout the course of their illnesses. Heavy sédation in critical care has been used to facilitate endotrachéal tube tolérance and ventilator synchronization, often with neuromuscular blocking agents.

In some embodiments, sédation (e.g., long-term sédation, continuons sédation) is induced and maîntained in the ICU for a prolonged period of time (e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 week, 3 weeks, 1 month, 2 months). Long-tenu sédation agents may hâve long duration of action. Sédation agents in the ICU may hâve short élimination half-life.

Procédural sédation and analgesia, also referred to as conscious sédation, is a technique of administering sédatives or dissociative agents with or without analgésies to induce a State that allows a subject to tolerate unpleasant procedures while maintaining cardiorespiratory function.

Also described herein are methods of ameliorating one or more symptoms of a respiratory condition in a subject, comprising administering to the subject an effective amount of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, or a pharmaceutical sait thereof, or a composition comprising a compound of Formula I, or a pharmaceutically acceptable sait thereof).

In one aspect, provided herein is a method of treating a subject wherein the subject exhibits one or more symptoms of a respiratory condition and/or has been dîagnosed with a respiratory condition, comprising administering to said subject an effective amount of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, or a pharmaceutical sait thereof, or a composition comprising a compound of Formula I, or a pharmaceutically acceptable sait thereof)·

In some embodiments, the présent disclosure contemplâtes a method of treating a subject comprising administering to said subject a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, or a pharmaceutical sait thereof, or a composition comprising a compound of Formula I, or a pharmaceutically acceptable sait thereof), wherein the subject has a respiratory condition.

In some embodiments, administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, or a pharmaceutical sait thereof, or a composition comprising a compound of Formula I, or a pharmaceutically acceptable sait thereof) to a subject exhibiting symptoms of a respiratory condition, may resuit in the réduction of the severity of one or more symptoms of a respiratory condition or retard or slow the progression of one or more symptoms of a respiratory condition.

In some embodiments, a subject with a respiratory condition has been or is being treated with mechanîcal ventilation or oxygen. In some embodiments, a subject with a respiratory condition has been or is being treated with mechanical ventilation.

In some embodiments, a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, or a pharmaceutical sait thereof, or a composition comprising a compound of Formula I, or a pharmaceutically acceptable sait thereof) is admînistered to a subject that is being or has been treated with mechanical ventilation. In some embodiments, administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, or a pharmaceutical sait thereof, or a composition comprising a compound of Formula I, or a pharmaceutically acceptable sait thereof) continues throughout a subject’s treatment with mechanical ventilation. In some embodiments, administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, or a pharmaceutical sait thereof, or a composition comprising a compound of Formula I, or a pharmaceutically acceptable sait thereof) continues after a subject has ended treatment with mechanical ventilation.

In some embodiments, a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, or a pharmaceutical sait thereof, or a composition comprising a compound of Formula I, or a pharmaceutically acceptable sait thereof) is admînistered to a subject who îs receîving or has received treatment with a sédative. In some embodiments, a sédative is propofol or a benzodiazépine.

In some embodiments, the présent disclosure includes administering to a subject in need thereof a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, or a pharmaceutical sait thereof, or a composition comprising a compound of Fonnula I, or a pharmaceutically acceptable sait thereof) in an amount suffi ci ent to increase oxygen saturation in blood. In some embodiments, oxygen saturation in blood is measured using puise oximetry.

In some embodiments, the présent disclosure contemplâtes a method of treating a cytokine storm in a patient. In some embodiments a method of treating a cytokine storm comprising the step of administering to the patient a compound or pharmaceutical composition described herein (e.g., a compound of Fonnula I, or a pharmaceutical sait thereof, or a composition comprising a compound of Formula I, or a pharmaceutically acceptable sait thereof). In some embodiments, a symptom of a cytokine storm is lung inflammation. In some embodiments, a patient undergoing a cytokine storm has acute respiratory distress syndrome (ARDS).

Respiratory condition

In some embodiments, a subject with a respiratory condition suffers from respiratory distress. In some embodiments, respiratory distress includes acute respiratory distress.

In some embodiments, a subject with a respiratory condition may exhibit one or more symptoms selected from the group consisting of airway hyper-responsiveness, inflammation of lung tissue, lung hypersensitivity, and inflammation-related pulmonary pain.

In some embodiments a subject with a respiratory condition may exhibit inflammation of lung tissue. In some embodiments, inflammation of lung tissue is bronchitis or bronchiectasis. In some embodiments, inflammation of lung tissue is pneumonia. In some embodiments, pneumonia is ventilator-associated pneumonia or hospital-acquîred pneumonia. In some embodiments, pneumonia is ventilator-associated pneumonia.

In some embodiments, administration of the compound or pharmaceutical composition described herein to a subject exhibiting symptoms of a respiratory condition, results in réduction of the severity of respiratory distress in a subject with a respiratory condition or retard or slow the progression of respiratory distress in a subject with a respiratory condition.

In some embodiments, administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, or a pharmaceutical sait thereof, or a composition comprising a compound of Formula I, or a pharmaceutically acceptable sait thereof) to a subject exhibiting symptoms of a respiratory condition, results in réduction of the severity of airway hyper-responsîveness in a subject with a disease associated with a coronavirus or retard or slow the progression of airway hyper-responsiveness in a subject with a respiratory condition.

In some embodiments, administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, or a pharmaceutical sait thereof, or a composition comprising a compound of Formula I, or a pharmaceutically acceptable sait thereof) to a subject exhibiting symptoms of a respiratory condition, results in réduction of the severity of inflammation of lung tissue in a subject with a respiratory condition or retard or slow the progression of inflammation of lung tissue in a subject with a respiratory condition. In some embodiments, administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, or a pharmaceutical sait thereof, or a composition comprising a compound of Formula I, or a pharmaceutically acceptable sait thereof) to a subject exhibiting symptoms of a respiratory condition, results in réduction of the severity of pneumonia in a subject with a respiratory condition or retard or slow the progression of pneumonia in a subject with a respiratory condition.

In some embodiments, administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I, or a pharmaceutical sait thereof, or a composition comprising a compound of Formula I, or a pharmaceutically acceptable sait thereof) to a subject exhibiting symptoms of a respiratory condition, results in réduction of the severity of lung hypersensitivity in a subject with a respiratory condition or retard or slow the progression of lung hypersensitivity in a subject with a respiratory condition.

In some embodiments, administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula 1, or a pharmaceutical sait thereof, or a composition comprising a compound of Formula I, or a pharmaceutically acceptable sait thereof) to a subject exhibiting symptoms of a respiratory condition, results in réduction of the severity of inflammation-related pulmonary pain in a subject with a respiratory condition or retard or slow the progression of inflammation-related pulmonary pain in a subject with a respiratory condition.

In some embodiments, a subject with a respiratory condition is undergoing or has undergone treatment for an infection, fibrosis, a fibrotic épisode, chronic obstructive puimonary disease, Sarcoidosis (or puimonary sarcoidosis) or asthma/asthma-related inflammation.

In some embodiments, a subject exhibits symptoms of and/or has been diagnosed with asthma. In some embodiments, a subject is or has undergone an asthmatic attack.

In some embodiments, a subject is undergoing or has undergone treatment for fibrosis or a fibrotic épisode. In some embodiments, the fibrosis is cystic fibrosis.

In some embodiments, a respiratory condition is the resuit of and/or related to a disease or condition selected from the group consisting of cystic fibrosis, asthma, smoke înduced COPD, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by congénital bilateral absence of the vas deferens (CBAVD), mild puimonary disease, puimonary sarcoidosis, idiopathîc pancreatitis, allergie bronchopulmonary aspergillosis (ΑΒΡΑ), liver disease, hereditary emphysema, hereditary hemochromatosis, coagulationfibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid Processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/pseudo-Hurler, mucopolysacchari doses, Sandhof/Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, Diabètes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, congénital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabètes insipidus (Dl), neurophyseal DI, neprogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus- Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophie latéral sclerosis, progressive supranuclear palsy, Pick's disease, several polyglutamine neurological disorders such as Huntington, spînocerebellar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonie dystrophy, as well as spongiform encéphalopathies, such as hereditary Creutzfeldt-Jakob disease (due to prion protein processing defect), Fabry disease, Straussler-Scheinker syndrome, COPD, dry-eye disease, or Sjogren's disease.

Infections

The présent disclosure contemplâtes, among other things, treatment of a subject who has an infection. The présent disclosure contemplâtes, among other things, treatment of a subject who has a disease associated with an infection. In some embodiments, an infection is a viral infection or a bacterial infection. In some embodiments, an infection îs a viral infection. In some embodiments, an infection is a bacterial infection.

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

The présent disclosure contemplâtes, among other things, treatment of a subject who has a disease associated with coronavîrus. In some embodiments, a disease associated with a coronavîrus is selected from the group consisting of coronavîrus disease 2019 (COVID-19), severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). In some embodiments, a disease associated with a coronavîrus is selected from the group consisting of COVID-19. In some embodiments, a coronavîrus is selected from a group consisting of SARS-CoV-1, SARS-CoV-2, and 2012-nCoV. In some embodiments, a coronavîrus is SARSCoV-2.

In some embodiments, a bacterial infection îs an infection of a bacteria selected from the group consisting of Streptococcus pneumoniae, Chlamydia pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, and Haemophilus influenzae. In some embodiments, Staphylococcus aureus îs methicillin-resistant Staphylococcus aureus.

Examples

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

Materials and Methods

The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It wîll be appreciated that where typical or preferred process conditions (i.e., reaction températures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization.

Additionally, as will be apparent to those skilled in the art, conventîonal protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.

The compounds provided herein may be isolated and purified by known standard procedures. Such procedures include (but are not limited to) trituration, column chromatography, HPLC, or supercritical fluid chromatography (SFC). The following schemes are presented with details as to the préparation of représentative oxysterols that hâve been listed herein. The compounds provided herein may be prepared from known or commercially available starting materiais and reagents by one skilled in the art of organic synthesis. Exemplary chiral columns available for use in the separation/purifi cation of the enantiomers/diastereomers provided herein include, but are not limited to, CHIRALPAK® AD10, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ and CHIRALCEL® OK.

'H-NMR reported herein (e.g., for the région between δ (ppm) of about 0.5 to about 4 ppm) will be understood to be an exemplary interprétation of the NMR spectrum (e.g., exemplary peak integratations) of a compound.

Abbreviations: PE: petroleum ether; EtOAc: ethyl acetate; THF; tetrahydrofuran; PCC: pyridinium chlorochromate; TLC: thin layer chromatography; PCC: pyridinium chiorochromate; t-BuOK: potassium tert-butoxîde; 9-BBN: 9-borabicyclo[3.3.1]nonane; Pd(i-Bu₃P)2: bis(tri-tertbutylphosphine)palladium(O); AcCl: acetyl chloride; LPrMgCl: Isopropylmagnesium chloride; TBSC1: tert-Butyl(chloro)dimethylsilane; (i-PrO^Ti: titanium tetraisopropoxide; BHT: 2,6-di-tbutyl-4-methylphenoxide; Me: methyl; z'-Pr: iso-propyl; r-Bu; tert-butyl; Ph: phenyl; Et: ethyl; Bz: benzoyl; BzCl: benzoyl chloride; CsF: césium fluoride; DCC: dicyclohexylcarbodiimide; DCM: dichloromethane; DMAP: 4-diinethylaminopyridine; DMP: Dess-Martin periodinane; EtMgBr: ethylmagnesium bromide; EtOAc; ethyl acetate; TEA: triethylamine; AlaOH: alanine; Boc: t-butoxycarbonyl. Py: pyridine; TBAF: tetra-n-butylammonium fluoride; THF: tetrahydrofuran; TBS: t-butyldimethylsilyl; TMS: trimethylsilyl; TMSCF₃: (Trifluoromethyl)trimethylsilane; Ts: p-toluenesulfonyl; Bu: butyl; Ti(OiPr)4: tetraisopropoxytitanium; LAH: Lithium Aluminium Hydride; LDA: lithium diisopropylamide; LiOH-HiO: lithium hydroxide hydrates; MAD: methyl aluminum bis(2,6-di-t-butyl-496 methylphenoxide); MeCN: acetonitrile; NBS: N-bromosuccinimide; NaiSCft: sodium sulfate; Na₂S₂O₃: sodium thiosulfate; MeCN: acetonitrile; MeOH: methanol; Boc: t-butoxycarbonyl; MTBE: methyl tert-butyl ether; K-selectride: Potassium tri(s-butyl)borohydride; 9-BBNdimer: 9borabicyclo(3.3.1)nonane(dimer); DIPEA: diisopropylethylamine; DMF: d tm ethyl formamide; FA: fonnic acid; SM: starting material.

EXAMPLE 1 & 2: Synthesis of l-((R)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3hy droxy-3,13-dïniethylhexadecahydro-1 H-cy clopenta [ a] phenanthren-17-y l)p ropy 1)-1Hpyrazole-4-carbonitrile (1) & l-((S)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3hydroxy-3,13-dimethylhexadecahydro-lH-cyclopenta|a]phenanthren-17-yl)propyl)-lHpyrazole-4-carbonitrile (2)

Synthesis of 1-1

To a suspension of PhjPMeBr (10 g, 28.2 mmol) in anhydrous THF (40 mL) was added t-BuOK (3.16 g, 28.2 mmol) at 25°C under N₂. After stirring at 50°C for 30 min, a solution of ΙΟ (3 g, 9.4 mmol) in anhydrous THF (10 mL) was added dropwise. After stirring at 60°C for 1 h, the mixture was poured into 10% NH4G (50 mL) and stirred for 10 min. The aqueous phase was extracted with EtOAc (3 x 50 mL). The combine organic solution was washed with saturated brine (2 x 50 mL), filtered and concentrated. The residue was dissolved in MeOH (50 mL) and water (50 mL). The resulting compound was collected by filtration and dried to give desîred 1-1 (2.97 g, 100%).*H NMR (400 MHz, CDCi₃) δ_Η 4.84 (s, IH), 4.70 (s, IH), 2.08-1.99 (m, IH), 1.90-1.78 (m,4H), 1.75 (s, 3H), 1.74-1.56 (m, 5H), 1.49-1.28 (m, 8H), 1.26 (s, 3H), 1.23-1.13 (m, 3H), 1.11-0.97 (m, 3H), 0.57 (s, 3H)

Synthesis of 1-2

To a solution of 1-1 (500 mg, 1.57 mmol) in DCM (10 mL) was added mCPBA (541 mg, 3.14 mmol) at 25°C. After stirring at 40°C for 1 h, the mixture was quenched with saturated NaHCO₃ aqueous (100 mL) at 15°C. The DCM phase was separated and w'ashed with saturated NaHCO₃/Na₂S2O₃ aqueous (1:1, 2 x 100 mL), brine (100 mL), dried over anhydrous Na₂SO4, 97 filtered and concentrated under vacuum to give a residue, which was purified by flash column (10-20% of EtOAc in PE) to give 1-2 (685 mg).

Synthesis of 1 & 2

To a solution of 1-2 (685 mg, 2.05 mmol) in DMF (10 mL) was added 1 H-pyrazole-4carbonitrile (285 mg, 3.07 mmol) and CS2CO3 (3.32 g, 10.2 mmol) at 20°C, After stirring at 120 °C for 2 h, the mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic solution was separated, concentrated and purified by flash column (30-65% EtOAc in PE) to give a mixture of epimers (600 mg, 69%). The epimers were separated by HPLC (Column: XtimateC18 150*25mm*5pm; Condition: water (0.225% FA)ACN; Begin B: 74%; End B: 74%.) to afford 1 (133 mg) and 2 (259.2 mg).

1: 'H NMR (400 MHz, CDCI3) Ô7.93 (s, lH),7.82(s, 1 H), 4.35 (d, 7=14.0 Hz, 1H),4.O8 (d, 7=13.6 Hz, 1 H), 2.51 (s, 1 H), 2.05-1.98 (m, IH), 1.83-1.71 (m, 5H), 1.70-1.62 (m, 3H), 1.511.41 (m,3H), 1.40 (brs, 2H), 1.37-1.27 (m, 3H), 1.26 (s, 3H), 1.23-1.20 (m, LH), 1.19-1.10 (m, 2H), 1.10-1.02 (m, 4H), 0.97 (s, 3H), 0.92 (s, 3H); LC-ELSD/MS purity 99%, 100% de based on H-NMR; MS ESI calcd. for C₂6H₃₆N₃ [M-2H₂O+H]⁺ 390.3, found 390.3.

2: 'H NMR (400 MHz, CDC1₃) δ7.89 (s, IH), 7.80 (s, IH), 4.22-4.13 (m, IH), 4.06-3.94 (m, IH), 2.31 (brs, IH), 2.10-2.02 (m, IH), 1.96-1.82 (m, 2H), 1.80 (br d, 7=6.8 Hz, 2H), 1.701.61 (m, 4H), 1.40 (br s, 8H), 1.26 (s, 3H), 1.25-1.09 (m, 5H), 1.09 (s, 3H), 1.07-1.00 (m, 2H), 0.87 (s, 3H); LC-ELSD/MS purity 99%, 100% de based on H-NMR; MS ESI calcd. for C₂₆H₃₆N₃ [M-2H₂O+H]⁺ 390.3, found 390.3.

EXAMPLES 3 & 4: Synthesis of l-((S)-2-((3R,5R,8S,9S,10S,13S,14S,17S)-10-ethyl-3hy dr oxy-3,13-dimethylhexadecahydro-1 H-cyclopenta [a | phenanthren- 17-yl)-2hydroxypropyI)-lH-pyrazole-4-carbonitrile (3) & l-((R)-2-((3R,5R,8S,9S,10S,13S,14S,17S)10-ethyl-3-hydr oxy-3,13-diniethylhexadecahydro-l H-cyclopenta [a] phenanthren-17-yl)-2hydroxypropyï)-lH-pyrazole-4-carbonitrile (4)

Synthesis of 3-1

To a solution of 3-0 (10 g, 25.4 mmol, reported in patent ‘WO2016/134301, 2016, A2’) în DCM (100 mL) was added silica gel (10 g) and PCC (8.17 g, 38 mmol) at 0°C. After stirring at 25°C for 1 h, the suspension was fïltered, and the filter cake was washed with DCM (2 x 100 mL). The combined filtrate was concentrated to give 3-1 (10 g), ’h NMR (400 MHz, CDC1₃) δ_Η 9.56 (s, 1 H), 4.00-3.80 (m, 8 H), 2.24-1.88 (m, 5 H), 1.87-1.70 (m, 5 H), 1.46-1.35 (m, 5 H), 1.33-0.99 (m, 5 H), 0.92 (s, 3 H), 0.89-0.69 (m, 2 H).

Synthesis of 3-2

To a mixture of MePPh₃Br (27.1 g, 76.1 mmol) in THF (100 mL) was added t-BuOK (8.53 g, 76.1 mmol) ai 15°C under N₂. After stirring at 50°C for 30 min, 3-1 (9.91 g, 25.4 mmol) was added in portions below 50°C. After stirring at 50°C for 1 h, the reaction mixture was quenched with 10% NH₄C1 aqueous (200 mL) at 15°C. The organic layer was separated and the aqueous was extracted with EtOAc (300 mL). The combined organic phase was concentrated under vacuum to give a residue, which was purified by silica gel chromatography (PE/EtOAc = 20/1 to 5/1) to afford 3-2 (5 g, 50.7%). ’H NMR (400 MHz, CDC1₃) δ_Η 6.32-6.25 (m, 1 H), 5.154.94 (m,2H), 3.95-3.80 (m, 8 H) 2.02-1.72 (m, 6 H), 1.69-1.61 (m, 1 H), 1.59-1.31 (m, 12 H), 1.21-1.04 (m, 3 H), 0.80 (s, 3 H).

Synthesis of 3-3

To a solution of 3-2 (15 g, 12.8 mmol) in THF (30 mL) were added aq. HCl (38.6 mL, 2M, 77.2 mmol) and at 25°C under N₂. After stirring at 25°C for 5 h, the mixture was quenched 99 with saturated NaHCO₃ (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na^SCU, filtered and concentrated to give 3-3 (9.3 g, 80.8%). ^rH NMR (400 MHz, CDCb) Ô_H 6.35-6.25 (m, 1 H), 5.19 (d, >11.2 Hz, 1 H), 5.09 (d, >18.0 Hz, 1 H), 2.79-2.64 (m, 1 H), 2.54-2.13 (m, 5 H), 2.13-2.05 (m, 3 H), 2.02-1.79 (m, 3 H), 1.69-1.50 (m, 6 H), 1.37-1.23 (m, 4 H), 0.87 (s, 3 H).

Synthesis of 3-4

To a solution of 3-3 (11 g, 36.6 mmol) in THF (200 mL) was added Pd/C (wet, 50%, 2 g) under N₂. The suspension was degassed under vacuum and purged with H₂ for three times. After stirring under H₂ (30 psi) at 25°C for 16 h, the reaction mixture was filtered through a pad of Celite and washed with THF (2 x 100 mL). The residue was triturated from PE (300 mL) to give 3-4(12 g). *H NMR (400 MHz, CDC1₃) δ_Η 2.67 (t, >13.60 Hz, 1 H), 2.52-2.06 (m, 5 H), 2.001.91 (m, 1 H), 1.89-1.48 (m, 12 H), 1.39-1.19 (m, 5 H), 0.87 (s, 3 H), 0.80 (t, >7.53 Hz, 3 H).

Synthesis of3-5

To a solution of BHT (26 g, 118 mmol) in toluene (60 mL) under nitrogen at 0°C was added A!Me₃ (2 M in toluene, 29.7 mL, 59.4 mmol) dropwise. After stirring at 15°C for 1 h, a solution of 3-4 (6.0 g, 19.8 mmol) in DCM (10 mL) was added dropwise at -70°C. After stirring at -70°C for 1 h under N₂, MeMgBr (19.8 mL, 59.4 mmol, 3M in ethyl ether) was added dropwise at -70°C. After stirring at -70°C for 4 h, the reaction mixture was poured into saturated 20% citric acid (300 mL) below 10°C. The reaction mixture was extracted with EtOAc (2 x 100 mL). The combined organic layer was dried over Na₂SO4, filtered and concentrated in vacuum. The residue was purified by a silica gel column (PE/EtOAc= 0-20%) to give 3-5 (5.6g, 88.8%). ’H NMR (400 MHz, CDC1₃) δ_Η 2.50-2.37 (m, 1 H), 2.13-2.04 (m, 1 H), 2.04-1.81 (m, 3 H), 1.81-1.62 (m, 5H), 1.62-1.47 (m, 5 H), 1.46-1.28 (m, 6 H), 1.25 (s, 3 H), 1.24-1.11 (m, 4 H), 0.84 (s, 3 H), 0.80 (t, >7.60 Hz, 3 H).

Synthesis of 3-6

To a mixture of EtPPh₃Br (9.72 g, 26.2 mmol) in THF (50 mL) was added t-BuOK (2.93 g, 26.2 mmol) at 15°C under N₂. After stirring at 50°C for 30 min, 3-5 (5.6 g, 17.5 mmol) was added in portions below 40°C. After stirring at 40°C for 1 h, the reaction mixture was quenched

100 with 10% NH4CI aqueous (200 mL) at 15°C. The organic layer was collected and the aqueous layer was extracted with EtOAc (300 mL). The combined organic phase was concentrated under vacuum to give a residue, which was purified by silica gel chromatography (ΡΕ/EtOAc = 20/l to 5/1) to afford 3-6 (4.9g, 84.7%). NMR (400 MHz, CDC1₃) δ_Η 5.15-5.05 (m, 1 H), 2.41-2.09 (m, 3 H), 2.03-1.89 (m, 1 H), 1.85-1.71 (m, 1 H), 1.70-1.59 (m, 6 H), 1.59-1.37 (m, 9 H), 1.371.27 (m, 3 H), 1.25 (s, 3 H), 1.22-1.04 (m, 5 H), 0.85 (s, 3 H), 0.79 (t, 7=7.6 Hz, 3 H).

Synthesîs of 3-7

To a solution of 3-6 (4.9 g, 14.8 mmol) in THF (50 mL) was added 9-BBN dimer (10.8 g, 44.4 mmol) ai 15°C. After stirring at 40°C for 1 h, éthanol (6.8 g, 148 mmol) was added at 15°C foliowed by NaOH aqueous (29.5 mL, 5M, 148 mmol) and then H₂O₂ (14.7 mL, 10 M, 148 mmol) dropwise at -10°C. After stirring at 80°C for 1 h, the reaction mixture was added sat. Na₂S₂O₃ (50 mL). After stirring for 30 min, the mixture was extracted with EtOAc (2 x 100 mL). The combined organic phase was washed with saturated brine (2 x 100 mL), dried over anhydrous Na₂SO₄, and concentrated under vacuum to give 3-7 (11 g). ’H NMR (400 MHz, CDC1₃)Ô_h 3.77-3.62 (m, 1 H), 2.03-1.91 (m, 3 H), 1.83-1.71 (m, 5 H), 1.57-1.45 (m, 12 H), 1.24 (s, 3 H), 1.21 (d, 7=6.40 Hz, 3 H), 1.18-0.94 (m, 7 H), 0.81-0.76 (m, 3 H), 0.64 (s, 3 H).

Synthesîs of 3-8

To a solution of 3-7 (5.15 g, 14.8mmol) in DCM (100 mL) was added silica gel (10 g) and PCC (6.36 g, 29.6 mmol) at 0°C. After stirring at 15°C for 3 h, the suspension was filtered, and the filter cake was washed with DCM (2 x 100 mL). The combined filtrate was concentrated under vacuum to give a residue, which was purified by flash column (ΡΕ/EtOAc = 20/1 to 4/1) to afford 3-8 (2.8 g, 54.6%). ^lH NMR (400 MHz, CDC1₃) δ_Η 2.60-2.45 (m, 1 H) 2.28-2.12 (m, 1 H), 2.11 (s, 3 H), 2.03-1.91 (m, 2 H), 1.82-1.59 (m, 6 H), 1.54-1.28 (m, 10 H), 1.25 (s, 3 H), 1,24-1.03 (m, 6 H), 0.79 (t, 7=7.60 Hz, 3 H), 0.59 (s, 3 H).

Synthesîs of 3-9

To a mixture of MePPh₃Br (4.5 g, 12.6 mmol) in THF (20 mL) was added t-BuOK (1.41 g, 12.6 mmol) at 15°C under N₂. After stirring at 50°C for 30 min, 3-8 (2.2 g, 6.34 mmol) was added in portions below 50°C. After stirring at 50°C for 1 h, the reaction mixture was quenched with 10% NH4CI aqueous (100 mL) at 15°C. The organic layer was collected, and the aqueous layer was extracted with EtOAc (100 mL). The combined organic phase was concentrated under vacuum to give a residue, which was purified by silica gel chromatography (ΡΕ/EtOAc = 20/1 to

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5/1) to afford 3-9 (1.6 g, 73.3%). NMR (400 MHz, CDC1₃) δ_Η 4.84 (s, 1 H), 4.69 (s, 1 H), 2.04-1.90 (m, 2H), 1.87-1.76 (m, 2 H), 1.75 (s, 3 H), 1.73-1.57 (m, 5 H), 1.53-1.26 (m, 9 H), 1.25 (s, 3 H), 1.23-0.82 (m, 8 H), 0.79 (t, 7=7.60 Hz, 3 H), 0.54 (s, 3 H).

Synthesis of 3-10

To a solution of 3-9 (600 mg, 1.74 mmol) and NaHCO₃ (146 mg, 1.74 mmol) in DCM (30 mL) was added mCPBA (352 mg, 1.74 mmol) at 20°C. After stirring at 20°C for 2 h, the mixture was quenched by saturated NaHCO₃ aqueous (50 mL) at 20°C. The DCM phase was separated and washed with saturated NaHCO₃/Na₂S₂O₃ aqueous (1:1, 2 x 100 mL), brine (100 mL), dried over Na₂SO4, filtered and concentrated under vacuum to give 3-10 (600 mg). *H NMR (400 MHz, CDC1₃) δ_Η 2.88-2.30 (m, 2H), 2.08-1.60 (m, 9 H), 1.54-1.37 (m, 8 H), 1.361.32 (m, 3 H), 1.31-1.27 (m, 1 H), 1.25 (s, 3 H), 1.23-0.97 (m, 8 H), 0.83-0.74 (m, 4 H), 0.66 (s, 2 H).

Synthesis of 3 & 4

To a solution of 3-10 (600 mg, 1.66 mmol) in DMF (20 mL) was added Cs₂CO₃ (1.08 g, 3.32 mmol) and lH-pyrazole-4-carbonitrile (230 mg, 2.48 mmol). After stirring at 120 °C for 16 h, the mixture was added into saturated NH4CI (100 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with LiCl (100 mL, 5% in water), saturated brine (2 x 100 mL), dried over anhydrous Na₂SO4, filtered and concentrated to give a mixture of 3 & 4 (800 mg).

The epimers (500 mg, 1.1 mmol) were separated by SFC (Column: DAICEL CHIRALPAK AS (250mm*30mm,10um)), Condition: 0.1%NH₃ H₂O EtOH, Begin B: 30%, End B: 30%, FlowRate (ml/mîn): 80) to afford 3 (200 mg, 40%) and 4 (150 mg, 30%).

3: 'H NMR (400 MHz, CDC1₃) δ_Η 7.92 (s, 1 H), 7.82 (s, 1 H), 4.34 (d, 7=13.60 Hz, 1 H), 4.07 (d, 7=13.60 Hz, 1 H), 2.52 (s, 1 H), 2.08-1.88 (m, 2 H), 1.83-1.59 (m, 6 H), 1.55-1.45 (m, 3 H), 1.44-1.27 (m, 8 H), 1.25 (s, 3 H), 1.23-1.02 (m, 7 H), 0.97 (s, 3 H), 0.89 (s, 3 H), 0.79 (t, 7=7.60 Hz, 3 H). LC-ELSD/MS: purity >99%; analytic SFC:100% de; MS ESI calcd. for C28H40N3 [M-2H₂O+H]⁺ 418.3, found 418.3.

4: 'H NMR (400 MHz, CDC1₃) Ô_H 7.89 (s, 1 H), 7.80 (s, 1 H), 4.15 (d, 7=14.0 Hz, 1 H), 4.00 (d, 7=14.0 Hz, 1 H), 2.31 (s, 1 H), 2.10-1.84 (m, 3 H), 1.83-1.60 (m, 5 H), 1.55-1.47 (m, 3 H), 1.46-1.26 (m, 8 H), 1.25 (s, 3 H), 1.24-1.09 (m, 7 H), 1.08 (s, 3 H), 0.85 (s, 3 H), 0.79 (t,

102 /=7.60 Hz, 3 H). LC-ELSD/MS: purity >99%; analytic SFC:99.18% de;MS ESI calcd. for C28H40N3 [M-2H₂O+H]⁺418.3, found 418.3.

EXAMPLE 5: Synthesis ofl-((S)-2-((3R,5R,8S,9S,10S,13S,14S,17S)-10-ethyI-3-hydroxy3,13-dimethyIhexadecahydro-lH-cyclopenta|a|phenantliren-17-yl)-2-methoxypropyl)-lHpyrazole-4-carbonitrile

To a solution of 3 (200 mg, 0.4408 mmol) in THF (5 mL) was added NaH (52.6 mg, 1.32 mmol, 60% in oil) at 0 °C. After stirring for 20 min, Mel (93.8 mg, 0.6612 mmol) was added. After stirring at 25 °C for 16 h, the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous Na₂SO4, filtered and coneentrated. The residue was purified by flash column (0-50% of EtOAc in PE) to give product 5 (68.8 mg, 33.3%). ^lH NMR (400 MHz, CDCh) Ô_H 7.91 (s, 1 H), 7.75 (s, 1 H), 4.30-4.15 (m, 2 H), 3.18 (s, 3 H), 2.00-1.88 (m, 2 H), 1.81-1.71 (m, 2 H), 1.66-1.60 (m, 3 H), 1.54-1.47 (m, 3 H), 1.47-1.26 (m, 8 H), 1.24 (s, 3 H), 1.23-1.07 (m, 7 H), 1.06 (s, 3 H), 1.05-1.00 (m, 1 H), 0.86-0.75 (m, 6 H). LC-ELSD/MS: purity >99%; analytic SFC:100% de;MS ESI calcd. for C₂8H₄₃N₃ [M-2H₂O-CH₃+2H]^h’ 418.3, found 418.3.

EXAMPLE 6: Synthesis ofl-((R)-2-((3R,5R,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy3,13-dimethyLhexadecahydro-lH-cyclopenta[a]phenanthren-17-yl)-2-methoxypropyl)-lHpyrazole-4-carbonitrile

To a solution of 4 (150 mg, 0.3306 mmol) in THF (5 mL) was added NaH (39.6 mg, 0.9918 mmol, 60% in oil) at 0 °C. After stirring for 20 min, Mel (70.3 mg, 0.4959 mmol) was

103 added. After stirring at 25 °C for 16 h, the reaction mixture was diluted with H₂O (50 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous Na₂SO4, filtered and concentrated. The residue was purified by flash column (0-50% of EtOAc in PE) to give product 6 (23.4 mg). *H NMR (400 MHz, CDCh) δ_Η 7.90 (s, 1 H), 7.75 (s, 1 H), 4.23 (s, 2 H), 3.14 (s, 3 H), 2.12-L91(m, 2 H), 1.80-1.61 (m, 7 H), 1.53-1.27 (m, 10 H), 1.25 (s, 3 H), 1.22-1.06 (m, 7 H), LOI (s, 3 H), 0.82-0.77 (m, 6 H). LC-ELSD/MS: purity >99%; analytic SFC: 99.62% de; MS ESI calcd. for C_2SH₄₃N₃ [M2H₂O-CH₃+2H]⁺ 418.3, found 418.3.

EXAMPLES 7 & 8: Synthesis of l-((S)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3hydroxy-13-methyl-3-propylhexadecahydro-lH-cyclopenta[a]phenanthren-17-yl)propyl)lH-pyrazole-4-carbonitriIe (7) & l-((R)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3hydroxy-13-methyl-3-propyIhexadecahydro-lH-cyclopenta[a]phenanthren-17-yl)propyI)lH-pyrazole-4-carbonitrile (8)

Synthesis of 7-1

To a solution of 2,6-di-tert-butyl-4-methylphenol (13.1 g, 59.6 mmol) in toluene (20 mL) was added AlMe₃(14.9 mL, 29.8 mmol, 2 M in toluene) dropwise at 0°C. After stirring at 25°C for 30 min, a solution of 7-0 (3 g, 9.91 mmol) in anhydrous toluene (40 mL) was added dropwise at -70 °C. After stirring at -70 °C for 1 h under N₂, n-PrMgCl (14.8 mL, 29.7 mmol, 2 M in diethyl ether) was added dropwise at -70°C. After stirring at -70 °C for another 2 h, the reaction mixture was poured into saturated aqueous citric acid (100 mL) below 10°C and extracted with EtOAc (2 x 100 mL). The combined organic layer was dried over Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by flash column (0—10% of EtOAc in PE) to give 7-1 (1.7 g, 49%). *H NMR (400 MHz, CDCI3) Ô_H 2.53 (t,7=8 Hz, IH), 2.16-2.11 (m, 4H),

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2.04-1.98 (m, IH), 1.83-1.52 (m, 3H), 1.50-1.30 (m, 5H), 1.27-1.02 (m, 10H), 0.97-0.77 (m, 1 IH), 0.61 (s, 3H).

Synthesis of 7-2

To a suspension of Ph₃PMeBr (3.50 g, 9.80 mmol) in THF (20 mL) was added t-BuOK (1.09 g, 9.80 mmol). After stirring for 30 min at 16 °C under N₂, 7-1 (1.7 g, 4.90 mmol) was added. After stirring at 35°C for 16 h, the reaction mixture was poured into water (300 mL) and extracted with EtOAc (3 x 100 mL). The combined organic phase was washed with brîne (150 mL), dried over anhydrous Na₂SO4 and concentrated. The residue was purified by flash column (0-5% of EtOAc in PE) to give 7-2 (1.3 g). ‘H NMR (400 MHz, CDC1₃) δ_Η 4.84 (s, IH), 4.70 (s, IH), 2.06-2.01 (m, IH), 1.85-1.58 (m, 9H), 1.56-1,25 (m, 12H), 1.19-0.96 (m, 7H), 0.95-0.91 (m, 3H), 0.9-0.83 (m, 3H), 0.57 (s, 3H).

Synthesis of 7-3

To a solution of 7-2 (1 g, 2.90 mmol) in DCM (10 mL) was added m-CPBA (1.17 g, 85%, 5.80 mmol) at 15°C. After stirring at 15°C for 1 h, the mixture was quenched by saturated NaHCO₃ aqueous (200 mL). The organic phase was separated and washed with saturated NaHCO3/Na2S₂O₃ aqueous (1:1, 3 x 100 mL), brine (100 mL), dried over Na₂SO4, filtered and concentrated under vacuum to give 7-3 (1 g), ’ll NMR (400 MHz, CDC1₃) Ôh 2.89 (d, J= 4 Hz, 0.7H), 2.56-2.49 (m, IH), 2.32 (d, J= 4 Hz, 0.3H), 2.04-1.51 (m, 10H), 1.48-1.23 (m, 15H), 1.21-0.99 (m, 6H), 0.95-0.91 (m, 3H), 0.81-0.76 (m, IH), 0.68 (s, 3H).

Synthesis of 7 & 8

To a solution of 7-3 (680 mg, 1.88 mmol) in DMF (10 mL) was added 1 H-pyrazole-4carbonitrile (349 mg, 3.76 mmol) and Cs₂CO₃ (3.06 g, 9.40 mmol). After stirring at 125°C for 12 h, the reaction mixture was dîluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was separated, concentrated and purified by flash column (0-20% EtOAc in PE) to give a mixture of epimers. The epimers were separated by SFC (Column: DAICEL CHIRALPAK AS (250mm*50mm,10um); Condition: 0.1% NH3H2O EtOH; Bégin B: 30; End B: 30; Flow Rate (mL/min): 200) to give 7 (250 mg) and 8 (104 mg).

7: ^rH NMR (400 MHz, CDC1₃) δ_Η 7.93 (s, IH), 7.81 (s, IH), 4.36-4.33 (m, IH), 4.094.06 (m, IH), 2.52 (s, IH), 2.02-1.99 (m, IH), 1.80-1.60 (m, 8H), 1.56-1.41 (m, 5H), 1.40-1.03

105 (m, 15H), 0.97-0.91 (m, 9H). LC-ELSD/MS purity 99%, MS ESI calcd. for C28H40N3 [M2Η2Ο+ΗΓ 418.3, found 418.3. SFC 99.9% de

8: 'H NMR (400 MHz, CDCI3) Ô_H 7.89 (s, IH), 7.80 (s, IH), 4.17-4.14 (m, IH), 4.033.99 (m, IH), 2.31 (s, IH), 2.08-2.03 (m, IH), 1.95-1.50 (m, 10H), 1.47-1.18 (m, 13H), 1.161.00 (m, 8H), 0.95-0.87 (m, 6H). LC-ELSD/MS purity 99%, MS ESI calcd. for C_2SH₄oN₃ [M2H₂O+H]⁺418.3, found 418.3. SFC 98.22% de

EXAMPLES 9 & 10: Synthesis of l-((S)-2-hydroxy-2-((3R,5S,8R,9R,10S,13S,14S,17S)-3hydroxy-13-methyl-3-propylhexadecahydro-lH-cyclopcnta[a]phenanthren-17-yl)propy])lH-pyrazole-4-carbonitrile (9) & l-((R)-2-hydroxy-2-((3R,5S,8R,9R,10S,13S,I4S,17S)-3hydroxy-13-methyl-3-propylhexade£ahydro-lH-cyclopenta[a]phenanthren-17-yl)propyl)lH-pyrazole-4-carbonitrile (10)

Synthesis of 9-1

To the solution of 9-0 (15 g, 54.6 mmol) in THF (200 mL) was added n-PrMgCl (81.5 mL, 163 mmol, 2M in THF) dropwise at -60°C. After stirring at -60°C for 2 h, the reaction mixture was poured into saturated aqueous NH₄C1 (100 mL) at 0°C and extracted with EtOAc (2 x 200 mL). The combined organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was triturated from MeCN (50 mL) at 80°C to give 9-1 (7 g, 40.4%). ^!H NMR (400 MHz, CDCI3) δ_Η 2.44 (dd, ./=8.4, 19.2 Hz, IH), 2.14-2.00 (m, IH), 1.99-1.84 (m, 2H), 1.831.71 (m, 3H), 1.70-1.44 (m, 5H), 1.43-1.12 (m, 10H), 1.11-0.99 (m, 4H), 0.97-0.90 (m, 3H), 0.88 (s, 3H), 0.81-0.66 (m, 2H).

Synthesis of 9-2

106

To a mixture of EtPPh₃Br (24.3 g, 65.6 mmol) in THF (80 mL) was added t-BuOK (7.36 g, 65,6 mmol) at 15°C under N₂. After stirring at 15°C for 30 min, 9-1 (7 g, 21.9 mmol) in THF (20 mL) was added, After stirring at 40°C for 1 h, the mixture was poured into NH₄C1 (50 mL) and the aqueous phase was extracted with EtOAc (2 x 100 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na₂SO₄, fïltered and concentrated, The residue was heated at 70° C in MeOH (50 mL) for 30 minutes, cooled to room température, poured into water (50 mL) and the resulting residue was fïltered to give 9-2 (11 g).

NMR (400 MHz, CDC1₃) δ_Η 5.24-4.98 (m, IH), 2.45-2.30 (m, IH), 2.28-2.11 (m, 2H), 1.88-1.74 (m, 2FI), 1.73-1.57 (m, 7H), 1.55-1.48 (m, 2H), 1.44-1,25 (m, 6H), 1.24-0.96 (m, 9H), 0.95-0.90 (m, 3H), 0.88 (s, 3H), 0.78-0.62 (m, 2H).

Synthesis of 9-3

To a solution of 9-2 (6 g, 18.1 mmol) in anhydrous THF (60 mL) was added 9-BBN dimer (13.2 g, 54,3 mmol) at 15°C under N₂. After stirring at 60°C for 2 h, the mixture was cooled and quenched by EtOH (15 mL). NaOH (15 mL, 5M, 75,5 mmol) was added very slowly. After the addition, H₂O₂ (22.6 mL, 226 mmol, 10 M) was added slowly below 30°C. After stirring at 60°C for 2 h, the mixture was cooled, poured into water (50 mL) and extracted with EtOAc (2 x 50 mL), The combined organic layer was dried over Na₂SO₄, fïltered and concentrated in vacuum, The residue was purified by column chromatography (20-25% of EtOAc in PE) to give 9-3 (6.1 g, 52.8 %). *H NMR (400 MHz, CDC1₃) 3.86-3.57 (m, IH), 1.98-1.81 (m, 2H), 1.81-1,70 (m, 2H), 1.70-1.60 (m, 3H), 1,57-1.48 (m, 3H), 1.42-1.25 (m, 7H), 1,23 (d, J=6.0 Hz, 3H), 1.17-0,96 (m, 9H), 0,95-0,89 (m, 3H), 0.67 (s, 5H).

Synthesis of 9-4

To a solution of 9-3 (6.1 g, 17.5 mmol) in DCM (50 mL) was added PCC (11.2 g, 52.5 mmol) and silica gel (15 g) at 25°C. After stirring at 25°C for 1 h, the reaction mixture was fïltered and the residue was washed with anhydrous DCM (2 x 20 mL). The combined filtrate was concentrated in vacuum and then purified by column (15- 20% of EtOAc in PE) to give 9-4 (3 g, 49.5%). *H NMR (400 MHz, CDCi₃) δ_Η 2.55 (t, 8.8 Hz, IH), 2.12 (s, 4H), 2.00 (td, J =

3.2, 12.0 Hz, IH), 1.89-1.73 (m, 2H), 1.59 (br d, J = 2.8 Hz, IH), 1.55-1.50 (m, IH), L49-1.16 (m, 10H), 1.15-0.97 (m, 6H), 0.96-0.90 (m, 3H), 0.81-0.65 (m, 2H), 0.62 (s, 3H).

Synthesis of 9-5

107

To a mixture of MePPh₃Br (9.25 g, 25.9 mmol) in THF (40 mL) was added t-BuOK (2.9 g, 25.9 mmol) at 15°C under N₂. After stirring at I5°C for 30 min, 9-4 (3 g, 8.65 mmol) in THF (10 mL) was added. After stirring at 40°C for 2 h, the mixture was poured into NH₄Cl.aq (150 mL) and the aqueous phase was extracted with EtOAc (2 x 200 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na₂SO₄, fïltered and concentrated. The residue was heated in MeOH (500 mL) at 70°C for 30 minutes, cooled to room température, added water (300 mL), fïltered and dried to give 9-5 (3 g, 100%). *H NMR (400 MHz, CDCI₃) S_H 4.85 (s, IH), 4.71 (s, IH), 2.11-1.98 (m, IH), 1.76 (s, 7H), 1.71-1.64 (m, 3H), 1.64-1.53 (m, 3H), 1.39 (d, J= 3.6 Hz, 4H), 1.14 (brs, 12H), 0.95-0.88 (m, 3H), 0.77-0.62 (m, 2H), 0.58 (s, 3H).

Synthesis of 9-6

To a solution of 9-5 (1 g, 2.90 mmol) in DCM (10 mL) was added m-CPBA (750 mg, 4.35 mmol) at 20°C. After stirring at 20°C for 2 h, the mixture was poured into saturated NaHCO₃ aqueous (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic solution was washed with saturated NaHCO₃/Na₂S2O₃ aqueous (1:1, 2 x 20 mL), brine (20 mL), dried over Na₂SO₄, fïltered and concentrated to give 9-6 (1.5 g). ^lH NMR (400 MHz, CDC1₃) δ_Η 2.89 (d, 7=4.4 Hz, IH), 2.58-2.54 (m, IH), 2.04-1.86 (m, 2H), 1.81-1.72 (m. 3H), 1.66-1.50 (m, 8H), 1.39-1.37 (m, 6H), 1.35 (s, 3H), 1.31-1.16 (m, 5H), 1.15-1.05 (m, 7H), 1.04-0.94 (m, 5H), 0.93-0.89 (m, 5H), 0.68 (s, 3H).

Synthesis of 9 & 10

To a solution of 9-6 (750 mg, 2.07 mmol) in DMF (10 mL) was added lH-pyrazole-4carbonitrile (481 mg, 5.17 mmol) and Cs₂CO₃ (3.35 g, 10.3 mmol). After stirring at 130°C for 16 h, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na₂SO₄, fïltered and concentrated. The residue was purified by flash column (0—20% EtOAc in PE) to give a mixture of epimers (600 mg, 63.8%) which were separated SFC (Column: DAICEL CHIRALPAK AS 250mm x 30mm, lOum; Condition: 0.I%NH₃H₂O EtOH; Gradient: from 25% to 25% of B; Flow rate: 70mL/min; Column température: 40°C) to afford 9 (230 mg) and 10 (86.9 mg). 9 (230 mg) was triturated from MeCN (5 mL) at 20°C to give 9 (193.3 mg).

9: ^lH NMR (400 MHz, CDC1₃) δ_Η 7.92 (s, 1H),7.81 (s, IH), 4.36 (d, 7= 14.0 Hz, IH), 4.08 (d, 7= 14.0 Hz, IH), 2.49 (s, IH), 2.04-1.96 (m, IH), 1.78-1.57 (m, 8H), 1.54-1.49 (m, IH),

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1.45-1.41 (m, IH), 1.38 (br d, J= 3.2 Hz, 4H), 1.34-1.12 (m, 5H), 1.12-1.02 (m, 5H), 1.01-0.94 (m, 5H), 0.92 (s, 6H), 0.71-0.62 (m, 2H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₈H₄oN₃ [M-2H₂O+H]+ 418.3 found 418.3. SFC 99%de.

10: ‘H NMR (400 MHz, CDC1₃) Ô_H 7.89 (s, IH), 7.80 (s, IH), 4.19-4.12 (m, IH), 4.043.98 (m, lH),2.27(s, IH), 2.07-2.01 (m, IH), 1.91 (q, J= 10.4 Hz, IH), 1.75 (br d, 7 = 13.2 Hz, 2H), 1.70-1.57 (m, 5H), 1.52-1.45 (m, 2H), 1.38 (br d, 7= 3.2 Hz, 4H), 1.35-1.12 (m, 6H), 1.111.08 (m, 5H), 1.05-0.90 (m, 7H), 0.88 (s, 3H), 0.72-0.63 (m, 2H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₈H₄oN₃ [M-2H₂O+H]+ 41 8.3 found 418.3. SFC 99%de.

EXAMPLES 11 & 12: Synthesîs of l-((S)-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-ethyl-3hydroxy-13-methylhexadecahydro-lH-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)~ lH-pyrazole-4-carbonitrile (11) & l-((R)-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-ethyl-3hydroxy-13-methyIhexadecahydro-lH-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)lH-pyrazole-4-carbonitrile (12)

Synthesîs of 11-1

To a solution of BHT (12 g, 54.4 mmol) in toluene (120 mL) under nitrogen at 0°C was added trimethylaluminum (2 M in toluene, 14 mL, 28 mmol) dropwise. After stirring at 25°C for 1 h, to the MAD solution was added a solution of 7-0 (6 g, 19.8 mmol) in DCM (60 mL) dropwise at -70°C. After stirring at -70°C for 1 h under N₂, EtMgBr (20 mL, 60 mmol, 3M in ethyl ether) was added dropwise at -70°C. After stirring at -70°C for 1 h, the reaction mixture was poured into saturated aqueous citric acid (600 mL) below 10°C and extracted with DCM (2 x 800 mL). The combined organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was triturated by PE to give 11-1 (3.83 g, 58%). ‘H NMR (400 MHz, CDCI3) δ_Η 2.56

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2.50 (m, IH), 2.24-2.10 (m, 4H), 2.07-1.99 (m, IH), 1.89-1.51 (m, 9H), 1.50-1.20 (m, 12H), 1.19-1.00 (m, 3H), 0.98-0.80 (m, 3H), 0.61 (s, 3H).

Synthesis of 11-2

To a suspension of MePh₃PBr (6.4 g, 18.0 mmol) in THF (50 mL) was added t-BuOK (2.01g, 18.0 mmol). After stirring at 40°C for 10 min, the mixture was slowly added dropwise to a solution of 11-1 (3 g, 9.02 mmol) in THF (30 mL). After stirring at 20°C for 18 h, the mixture was quenched with sat. NH4CI (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic phase was washed with sat. NH4CI (100 mL), dried over Na₂SO4, filtered, and concentrated. The residue was purified by combi-flash (0-25% of EtOAc in PE) to give 11-2 (2.445 g, 82%). ’HNMR (400 MHz, CDC1₃) Ô_H 4.84 (s, 1 H), 4.69 (s, IH), 2.02-1.53 (m, 13H), 1.50-1.33 (m, 4H), 1.32-1.11 (m, 11H), 1.10-0.99 (m, 2H), 0.85-0.80 (m, 3H), 0.56 (s, 3H).

Synthesis of 11-3

To a solution of 11-2 (1.8 g, 5.44 mmol) in DCM (20 mL) was added m-CPBA (2.18 g, 85%, 10.8 mmol). After stirring at 15°C for 1 h, the mixture was quenched by NaHCO₃ (50 mL, sat. aq.) and Na₂S₂O₃ (20 mL, sat. aq.). The organic layer was separated, dried over Na₂SO4, filtered and concentrated in vacuum to give 11-3 (1.7 g), which was used as is.

Synthesis of 11 & 12

To a solution of 11-3 (850 mg, 2.45 mmol) in DMF (10 mL) was added lH-pyrazole-4carbonîtrile (341 mg, 3.67 mmol) and Cs₂CO₃ (3.97 g, 12.2 mmol) at 20°C. After stirring at 120°C for 2 h, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was separated, concentrated and purified by flash column (30-65% EtOAc in PE) to give a mixture of epimers. The epimers were separated by SFC (Column DAICEL CHIRALPAK AS (250mm*30mm,10um) Condition 0.1%NH₃ H₂O EtOH Begin B 25% End B 25% Gradient Time(min) 100%B Hold Time(min) FlowRate (ml/min) 70) to give 11 (395.8 mg, 49.6%) and 12 (155.4 mg, 19.4%).

11: ’H NMR (400 MHz, CDC1₃) δ_Η 7.93 (s, IH), 7.82 (s, IH), 4.45-3.99 (m, 2H), 2.50 (brs, 1 H), 2.08-1.94 (m, IH), 1.84-1.57 (m, 10H), 1.47-1.02 (m, 16H),0.97 (s, 3H), 0.92 (s, 3H), 0.88 (t, J=7.5 Hz, 3H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂7H₃₈N₃ [M-2H₂O+H]⁺ 404.3, found 404.3. SFC 100% de

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12: ^fH NMR (400 MHz, CDC1₃) Ô_H 7.90 (br s, IH), 7.81 (s, IH), 4.24-3.90 (m, 2H), 2.29 (brs, IH), 2.06 (br d, J=12.3 Hz, IH), 1.96-1.86 (m, IH), 1.84-1.56 (m, 9H), 1.53-1.19 (m, 12H), 1.19-1.09 (m, 7H), 0.92-0.85 (m, 6H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂7H₃₈N₃ [M-2H₂O+H]⁺ 404.3, found 404.3. SEC 99% de.

Examples 13 & 14: Synthesis of l-((S)-2-((3R,5S,8R,9R,10S,13S,14S,17S)-3-ethyl-3hydroxy-13-methylhexadecahydro-lH-cycIopenta[a]phenanthren-17-yI)-2-hydroxypropyl)lH-pyrazole-4-carbonitrile (13) & l-((R)-2-((3R,5S,8R,9R,10S,13S,14S,17S)-3-ethyl-3hydroxy-13-methylhexadecahydro-lH-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)lH-pyrazole-4-carbonitrile (14)

Synthesis of 13-1

Lithium (7.27 g, 915 mmol) was added to fresh prepared liquid ammonia (500 mL) in portions at -70°C. After stirring at -70°C for 1 hour, a solution of 13-0 (50 g, 183 mmol) in dry THF (500 mL) and t-butanol (27 g, 366 mmol) were added. After stirring at -70°C for 1 h, ammonium chloride (500 g) was added and allowed to warm to room température. After stirring for 16 h, the reaction mixture was diluted with H₂O (1 L) and extracted with EtOAc (3 x 500 mL). The combined organic solution was washed with HCI (1 M, 2 x 500 mL), saturated NaHCO₃ aqueous (500 mL), brine (1 L), dried over Na₂SO₄ and concentrated under vacuum to give 13-1 (97 g). ’H NMR (400 MHz, CDC1₃) δ_Η3.75-3.55 (m, IH), 2.50-2.00 (m, 10H), 2.001.25 (m, 8H), 1.25-0.60 (m, 9H).

Synthesis of 13-2

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To a solution of 13-1 (100 g, 361 mmol) in DCM (1000 mL) ai 0°C was added silica gel (116 g) and PCC (116 g, 541 mmol). After stirring at 25°C for 2 h, the reaction mixture was diluted with PE (1000 mL) and filtered through a pad of silica gel. The filter cake was washed with DCM (2000 mL). The combined filtrate was concentrated to give 13-2 (90 g). *H NMR (400 MHz, CDC1₃) δ_Η 2.55-2.02 (m, 8H), 2.02-1.39 (m, 8H), 1.39-0.69 (m, 10H).

Synthesis of 13-3

To a solution of 13-2 (51.5 g, 187 mmol) in MeOH (600 mL) was added 4methylbenzenesulfonic acid (6.44 g, 37.4 mmol) at 25°C. After stirring at 55°C for 16 h, Et₃N (20 mL) was added and the mixture was filtered to afford 13-3 (57g). NMR (400 MHz, CDC1₃)Ô_H3.49 (d, J=5.6Hz, IH), 3.20 (s, 3H), 3.14 (s, 3H), 2.48-2.38 (m, LH), 2.12-2.01 (m, 2H), 1.96-1.90 (m, 2H), 1.88-1.74 (m, 4H), 1.68-1.62 (m, IH), 1.56-1.44 (m, IH), 1.35-1.20 (m, 5H), 1.13-0.95 (m, 5H), 0.87 (s, IH), 0.80-0.68 (m, 2H).

Synthesis of 13-4

To a mixture of EtPPh₃Br (98.7 g, 266 mmol) in THF (250 mL) was added t-BuOK (29.8 g, 266 mmol) at 15°C under N₂. After stirring at 15°C for 30 min, 13-3 (28.5 g, 88.9 mmol) in THF (50 mL) was added. After stirring at 40°C for 2 h, the mixture was poured into NH₄Cl.aq (150 mL) and extracted with EtOAc (2 x 200 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was heated in MeOH (500 mL) at 70 °C for 30 min, cooled to room température, diluted with water (300 mL), filtered and concentrated to give 13-4 (25.5 g). *H NMR (400 MHz, CDC1₃) δ_Η 5.155.07 (m, IH), 3.20 (s, 3H), 3.14 (s, 3H), 2.41-2.31 (m, IH), 2.27-2.12 (m, 2H), 2.10-2.02 (m, IH), 1.91 (td, ,7=3.2, 13.2 Hz, IH), 1.85-1.76 (m,, 2H), 1.71-1.58 (m, 6H), 1.57-1.48 (m, 3H), 1.30-1.13 (,m, 6H), 1.11-0.93 (m, 5H), 0.87 (s, 3H), 0.75-0.67 (m, 2H).

Synthesis of 13-5

To a solution of 13-4 (51 g, 153 mmol) in THF (500 mL) was added 1 M HCl (153 mL, 153 mmol). After stirring stirred at 15°C for 2 h, the mixture was poured into NaHCO₃.aq (400 mL). and extracted with EtOAc (2 x 300 mL). The combined organic phase was washed with brine (200 mL), dried over anhydrous Na₂SO₄, filtered and concentrated to give 13-5 (42 g, 95.8%). ’H NMR (400 MHz, CDC1₃) δ_Η 5.16-5.08 (m, IH), 2.42-2.17 (m, 7H), 2.09 (t, J = 13.2 Hz, IH), 1.88-1.79 (m, 2H), 1.76-1.63 (m, 6H), 1.59 (s, IH), 1.56-1.40 (m, 2H), 1.28-1.16 (m, 8H), 1.04-0.94 (m, IH), 0.90 (s, IH), 0.78-0.69 (m, IH).

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Synthesis of 13-6

To a stirred solution of Me₃SIO (47.9 g, 218 mmol) in DMSO (300 mL) and THF (300 mL) was added NaH (5.23 g, 218 mmol) at 0°C. After stirring for 1 h under N₂„ 13-5 (42 g, 146 mmol) in THF (200 mL) was added. After stirring at 25°C for 3 h, the reaction mixture was poured into water (1000 mL). After stirring at 25°C for 3 h, the mixture was filtered to give 13-6 (48 g). 'H NMR (400 MHz, CDC1₃) δ_Η 5.15-5.07 (m, IH), 2.64-2.61 (m, 5H), 2.41-2.30 (m, IH), 2.27-2.11 (m, 2H), 2.00-1.92 (m, IH), 1.91-1.80 (m, 2H), 1.67-1.60 (m, 5H), 1.56-1.50 (m, IH), 1.45-1.35 (m, IH), 1.30-1.10 (m, 8H), 1.07-0.95 (m, 2H), 0.89 (s, 3H), 0.84-0.72 (m, 2H).

Synthesis of 13-7

To a suspension of CuCN (3.92 g, 43.8 mmol) in THF (40 mL) at -70°C was added MeLi (54.7 mL, 87.6 mmol, 1.6M). After stirring at -70°C for 1 h, 13-6 (4.4 g, 14.6 mmol) in THF (10 mL) was added at -70°C. After slowly warming to rt and stirring for 2 h, the reaction was slowly poured into 10% NH₄C1 (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO₄, filtered and concentrated to give 13-7 (4.4 g). IH NMR (400 MHz, CDC1₃) 5.14-5.08 (m, IH), 2.39-2.10 (m, 3H), 1.85-1.39 (m, 10H), 1.39-0.94 (m, 13H), 0.94-0.60 (m, 9H).

Synthesis of 13-8

To a solution of 13-7 (4.4 g, 13.3 mmol) in anhydrous THF (50 mL) was added 9-BBN dimer (8.03 g, 33.2 mmol) at 25°C under N₂. After stirring at 60°C for 16 h, the mixture was cooled, and diluted by EtOH (20 mL) at 0°C. NaOH (2.66 g, 13.3 mL, 5M, 66.5 mmol) was added very slowly followed by H₂O₂ (13.3 mL, 133 mmol, 10 M in water) very slowly until the inner température no longer rises and the inner température was maintained below 30°C. After stirring at 60°C for 2 h, the mixture was cooled, diluted with Na₂S₂O₃ (100 mL, sat. aq.) and extracted with EtOAc (3 x 100 mL). The combined organic layer was dried over Na₂SO4, filtered and concentrated in vacuum. The residue was purified by column (5%-30% of EtOAc in PE) to give 13-8 (10 g). IH NMR (400 MHz, CDCft) δ_Η 3.74-3.66 (m, IH), 1.96-1.39 (m, 13H), 1.391.00 (m, 14H), 1.00-0.85 (m, 5H), 0.75-0.57 (m, 5H).

Synthesis of 13-9

To a solution of 13-8(1.3 g, 3.88 mmol) in DCM (20 mL) was added DMP (3.29 g, 7.76 mmol). After stirring at 25°C for 1 h, the mixture was quenched with NaHCO₃ (50 mL) and

113 extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with Na₂S₂O₃ (3 x 30 mL, sat.), brine (50 mL), dried over Na₂SO4, filtered and concentrated in vacuum, The residue was purified by column (5%-30% of EtOAc in PE) to give to give 13-9 (1.16 g, 90%). 'H NMR (400 MHz, CDC1₃)Ô_H2.53 (t,7=8,8 Hz, IH), 2.21-1,53 (m, 9 H), 1.53-1.10 (m, 10H), 1.10-0.63 (m, 13H), 0.61 (s, 3H).

Synthesis of 13-10

To a mixture of MePPh₂Br (2.48 g, 6.96 mmol) in THF (40 mL) was added t-BuOK (779 mg, 6.96 mmol) at 25°C under N₂. After stirring at 50°C for 30 mins. 13-9 (1.16 g, 3.48 mmol) in THF (10 mL) was added at 25°C. After stirring at 50°C for 18 h, the reaction mixture was quenched with water (40 mL) at 25°C and extracted with EtOAc (2 x 50 mL). The combined organic phase was washed with water (3x10 mL), brine (30 mL), dried over anhydrous Na₂SO4, filtered and concentrated in vacuum. The residue was purified by column (2% of EtOAc in PE) to give 13-10 (620 mg, 54%). IH NMR (400 MHz, CDC13) ô_H4.84(s, IH), 4.70(s, IH), 2.081.57 (m, 10H), 1.57-1.06 (m, 13H), 1.06-0.52 (m, 13H).

Synthesis of 13-11

To a solution of 13-10 (620 mg, 1.87 mmol) in DCM (10 mL) was added m-CPBA (601 mg, 2.8 mmol, 80%) at 15°C. After stirring at 15°C for Ih, the mixture was quenched with sat.NaHCO₃ and Na₂S₂O₃ (40 mL, v: v = 1:1) and extracted with DCM (2 x 20 mL). The combined organic phase was washed with sat. NaHCO₃ and Na₂S₂O₃ (50 mL, v: v = 1:1), dried over Na₂SO₄, filtered and concentrated to give 13-11 (820 mg). ’H NMR (400 MHz, CDC1₃) δ_Η 2.89 (d, 7=4.8 Hz, 0.6H), 2.55-2.48 (m, IH), 2.32 (d, 7= 5.2 Hz, 0.4H), 2.02-1.45 (m, 10H), 1.45-1.11 (m, 11 H), 1.11-0.74 (m, 10H), 0.74-0.58 (m, 5H).

Synthesis of 13 & 14

To a solution of 13-11 (800 mg, 2.3 mmol) in DMF (10 mL) were added Cs₂CO₃ (2.24 g, 6.89 mmol) and lH-pyrazole-4-carbonitrile (535 mg, 5.75 mmol). After stirring at I20°C for 48 h, the reaction mixture was added into saturated NH₄C1 (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with LiCl (100 mL, 5% in water), saturated brine (2 x 100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by column (0~10% of EtOAc in PE) to afford a mixture of epimers (800 mg). The epimers were separated by SFC (Column: DAICEL CHIRALCEL OJ-H (250mm*30mm, 5um),

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Condition: 0.1%ΝΗ₃Η₂Ο EtOH, Begin B: 25%, End B: 25%) to give 13 (264 mg) and 14 (122 mg).

13: IH NMR (400 MHz, CDC13)Ô_H7.92 (s, IH), 7.81 (s, 1 H), 4.37-4.33 (m, 1 H), 4.104.06 (m, IH), 2.48 (s, IH), 2.02-1.96 (m, IH), 1.79-1.37 (m, I2H), 1.37-0.94 (m, 15H),0.940,87 (m, 6H), 0.75-0,61 (m, 2H). LC-ELSD/MS purity 99%, MS ESI calcd, for C₂₇H_3SN₃ [M2H₂O+H]⁺ 404found 404. SFC 99.522% de.

14: IH NMR (400 MHz, CDC13) δ_Η 7,88 (s, IH), 7.79 (s, IH), 4.17-4.13 (m, IH), 4.023.99 (m, 1 H), 2.27 (s, IH), 2.07-1.53 (m, IH), 1.53-1.12 (m, 12H), 1.12-0.94 (m, 15H), 0.940.84 (m, 6H), 0.73-0.61 (m, 2H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₇H₃₈N₃ [M2H₂O+H]⁺ 404found 404. SFC100% de.

Examples 15 & 16: Synthesis of l-((S)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3hydroxy-3-(hydroxymethyI)-13-methylhexadecahydro-lH-cyclopenta[a]phenanthren-17yI)propyl)-lH-pyrazole-4-carbonitrile (15) & l-((R)-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3(ethoxyinethyl)-3-hydroxy-13-methylhexadecahydro-lH-cyclopenta[a]phenanthren-17-yl)2-hydroxypropyl)-lH-pyrazole-4-carbonitrîle (16)

Synthesis of 15-1

To a solution of MePPh₃Br (2.94 g, 8.25 mmol) in THF (20 mL) was added t-BuOK (925 mg, 8.25 mmol) under N₂ at 25°C. After stirring for 1 h, 15-0 (1 g, 2.75 mmol, WO 2018013613) in THF (10 mL) was added. After stirring at 40°C for 3 h, the reaction mixture was poured into NH4Cl.aq (50 mL) and extracted with EtOAc (2 x 80 mL). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous Na₂SO₄, fïltered and concentrated.

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The residue was purified by flash column (0-6% of EtOAc in PE) to give 15-1 (750 mg, 76%). *Η NMR (400 MHz, CDC13) Ô_H 4.84 (s, IH), 4.70 (s, IH), 3.57-3.49 (m, 2H), 3.47-3.38 (m, 2H), 2.70 (s, IH), 2.07-2.00 (m, IH), 1.75 (s, 7H), 1.72-1.59 (m, 5H), 1.49-1.33 (m, 6H), 1.280.97 (m, HH), 0.56 (s, 3H).

Synthesis of 15-2

To a solution of 15-1 (880 mg, 2.44 mmol) in DCM (20 mL) was added m-CPBA (990 mg, 85%, 4.88 mmol) at 15°C. After the reaction mixture was stirred at 15°C for 1 h, the reaction mixture was quenched by saturated NaHCOj aqueous (200 mL). The organic phase was separated and washed with saturated NaHCO3/Na₂S₂O3 aqueous (1:1,3 x 100 mL), brine (100 mL), dried over Na₂SO₄, filtered and coneentrated under vacuum to give 15-2 (900 mg). ’H NMR (400 MHz, CDC1₃) δ_Η 3.54 (q, J= 8 Hz, 2H), 3.43 (q, J= 8 Hz, 2H), 2.88 (d, 4 Hz,

0.6H), 2.55 (d, J =4 Hz, 0.7H), 2.49 (d, J= 4 Hz, 0.3H),2.31 (d, 7= 4 Hz, 0.4H), 2.03-1.57 (m, 10H), 1.48-1.32 (m, 9H), 1.28-0.93 (m, 12H), 0.79 (s, IH), 0.67 (s, 2H).

Synthesis of 15 & 16

To a solution of 15-2 (600 mg, 1.59 mmol) in DMF (5 mL) were added 1 H-pyrazole-4carbonitrile (369 mg, 3.97 mmol) and CS2CO3 (2.59 g, 7.95 mmol). After stirring at 125°C for 12 h, the réaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 60 mL). The combined organic layer was washed with LiCl (3x150 mL, 5%, aq.) and then coneentrated. The residue was purified by flash column (0-20% of EtOAc in PE) to give a mixture of epimers (600 mg). The epimers were separated b y SFC (Column: DAICEL CHIRALPAK AS (250mm*50mm,10um); Condition: 0.1% NH₃H₂O EtOH; Begin B: 60%; End B: 60%; Flow Raie (ml/min): 80) to give 15 (353.8 mg, 59%) and 16 (138.3 mg, 23%).

15: 'H NMR (400 MHz, CDC1₃) δ_Η 7.92 (s, IH), 7.82 (s, IH), 4.37-4.34 (m, IH), 4.104.07 (m, IH), 3.54 (q, J= 8 Hz, 2H), 3.41 (q, J= 8 Hz, 2H), 2.70 (s, IH), 2.51 (s, 1 H), 2.02-1.99 (m, IH), 1.83-1.55 (m, 8H), 1.50-1.19 (m, 13H), 1.15-1.02 (m, 5H), 0.96-0.91 (m, 6H). LCELSD/MS purity 99%, MS ESI calcd. for C28H₄2N3O₂[M+H-H₂O]⁺ 452, found 452. SFC 100% de.

16: ’HNMR (400 MHz, CDC1₃)ô_h7.89 (s, IH), 7.80 (s, I H), 4.18-4.15 (m, IH), 4.033.99 (m, IH), 3.54 (q, J= 8 Hz, 2H), 3.41 (q, J = 8 Hz, 2H), 2.71 (s, IH), 2.33 (s, IH), 2.07-2.04 (m , IH), 1.95-1.56 (m, 9H), 1.50-1.19 (m, 13H), 1.16-1.00 (m, 8H), 0.87 (s, 3H). LC-

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ELSD/MS purity 99%, MS ESI calcd. for C28H42N₃O₂[M+H-H2O]⁺ 452, found 452. SFC

99.94% de.

Examples 17 & 18: Synthesis of l-((S)-2-hydroxy-2-((3R,5S,8R,9S,10S,13S,14S,17S)-3hydroxy-10,13-dimethyl-3-pr opylhexadecahydro-1 H-cy cio penta [a|phenanthren-17yl)propyl)-lH-pyrazole-4-carbonîtrile (17) & l-((R)-2-hydroxy-2((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-10,13-dimethyl-3-propylhexadecahydro-lHcyclopenta[a]phenanthren-17-yl)propyl)-lH-pyrazole-4-earbonitrile (18)

Synthesis of 17-1

To a stirred solution of Me₃SIO (3.12 g, 14.2 mmol) in DMSO (30 mL) and THF (30 mL) was added NaH (340 mg, 14.2 mmol) at 0°C. After stirring for 1 h, the reaction mixture was added 17-0 (Pregn-20-en-3-one, 20-methyL, (5α)-, described in WO2018/75699) (3 g, 9.53 mmol) in DMSO (30 mL). After stirring at 25°C for 3 h, the reaction mixture was poured into water (200 mL). After stirring at 25°C for 3 h, the reaction mixture was filtered to give 17-1 (3.3 g). ^lH NMR (400 MHz, CDC1₃) Ô_H4.84(s, IH), 4.70 (s, IH), 2.64-2.59 (m, 2H), 2.06-1.98 (m, 2H), 1.88-1.79 (m, 2H), 1.75 (s, 3H), 1.71-1.65 (m, 3H), 1.60-1.52 (m, 3H), 1.35-1.12 (m, 8H), 1.00-0.76 (m, 8H), 0.57 (s, 3H).

Synthesis of 17-2

To a solution of 17-1 (2.7 g, 8.21 mmol) in THF (20 mL) with Cul (234 mg, 1.23 mmol) at 0°C was added EtMgBr (8.20 mL, 3 M, 24.6 mmol). After stirring at 0°C for 1 h, the reaction was diluted with water (50 mL) and extracted with EtOAc (2x50 mL). The combined organic

117 phase was washed with brine (100 mL), dried over anhydrous Na2SO4, fïltered and concentrated. The residue was purified by column (0-3% of EtOAc in PE) to give 17-2 (1.8 g, 61%). 'H NMR (400 MHz, CDC1₃)Ô_H 4.83 (s, IH), 4.69 (s, 1H),2.O1 (t, 7=9.2 Hz, IH), 1.83-1.40 (m, 13H), 1.40-1.02 (m, 15H), 1.02-0.70 (m, 8H), 0.55 (s, 3H).

Synthesis of 17-3

To a solution of 17-2 (1.7 g, 4.74 mmol) in DCM (10 mL) was added m-CPBA (2.03 g, 9.48 mmol, 80%) at 15°C. After stirring at 15°C for 1 h, the mixture was quenched with sat.NaHCO₃ and Na₂S₂O₃ (40 mL, v: v = 1:1) and extracted with DCM (2 x 20 mL). The combined organic phase was washed with sat. NaHCO₃ and Na2S₂O₃ (50 mL, v: v = 1:1), dried over Na₂SO4, fïltered and concentrated to give 17-3 (2.35 g). *H NMR (400 MHz, CDClj) Ôh 2.88 (d, 7 = 4.4 Hz, 0.7H), 2.55-2.48 (m, IH), 2.30 (d, 7=4.8 Hz, 0.3H), 2.04-1.55 (m, 10H), 1.55-1.37 (m, 10H), 1.37-L23(m, 10H), 1.23-0.66 (m, 10H),

Synthesis of 17 & 18

To a solution of 17-3 (600 mg, 1.6 mmol) in DMF (5 mL) were added Cs₂CO₃ (1.56 g, 4.8 mmol) and 1 H-pyrazoIe-4-carbonitrile (372 mg, 4 mmol). After stirring at 120°C for 48 h, the reaction mixture was added into saturated NH₄C1 (50 mL) and extracted with EtOAc (3 x 50 mL), The combined organic layer was washed with LiCl (100 mL, 5% in water), brine (2 x 100 mL), dried over anhydrous Na2SO4, fïltered and concentrated. The residue was purified by column (5-20% of EtOAc in PE) to afford a mixture of epimers (750 mg). The epîmers were separated by SFC (Column: DAICEL CHIRALCEL OJ-H (250mm*30mm,5um), Condition: 0.1%NH₃H₂O EtOH, Begin B: 30%, End B: 30%) to give 17 (272 mg) and 18 (123 mg).

17: ’HNMR (400 MHz, CDC1₃) δ_Η 7.92 (s, IH), 7.80 (s, IH), 4.36-4.33 (m, IH), 4.094.06 (m, IH), 2.49 (s, 1 H), 2.01-1.98 (m, IH), 1.77-1.42 (m, 1 IH), 1.42-1.08 (m, 13H), 1.080.80 (m, HH), 0.77-0.70 (m, 4H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂9H₄₂N₃ [M2H₂O+H]⁺ 432found 432. SFC 99.06% de.

18: ^lH NMR (400 MHz, CDC1₃) Ôh 7.88 (s, IH), 7.79 (s, IH), 4.17-4.13 (m, IH), 4.023.98 (m, IH), 2.28 (s, IH), 2.06-1.86 (m, 2H), 1.71-1.42 (m, 10H), 1.42-1.11 (m, 13H), 1.110.60 (m, 1 IH), 0.77-0.70 (m, 4H). LC-ELSD/MS purity 99%, MS ESI calcd. for C29H42N3 [M2Η2Ο+ΗΓ 432found 432. SFC 100%de.

118

Examples 19 & 20: Synthesis of l-((S)-2-hydroxy-2-((3R,5S,8R,9R,10S,13S,14S,17S)-3hydroxy-3-(methoxyniethyl)-13-niethylhexadecahydro-lH-cyclopenta[a]phenanthren-17yl)propyl)-lH-pyrazole-4-carbonitrile (19) & l-((R)-2-hydroxy-2((3R,5S,8R,9R,10S,13S,14S,17S)-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro5 lH-cyclopenta[a]phenanthren-17-yI)propyl)-lH-pyrazoIe-4-carbonitrile (20)

Synthesis of 19-1

To a mixture of MePPh₃Br (4,28 g, 12.0 mmol) in THF (15 mL) was added t-BuOK (1.34 g, 12.0 mmol) at 25°C under N₂. After stirring at 50°C for 30 min, 19-0 (1.4 g, 4.01 mmol) 10 in THF (5 mL) was added. After stirring at 60°C for 3 h, the reaction mixture was cooled, poured to ice water, and with EtOAc (100 mL x 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column (0-30% of EtOAc in PE) to give 19-1 (1.1 g). ’H NMR (400 MHz, CDC1₃) Ô_H 4.94-4.61 (m, 2H), 3.45-3.32 (m, 3H), 3.25-3.12 (m, 2H), 2.11-1.97 (m, 2H), 1.87-1.53 (m, 10H), 1.49-0.82 (m, 14H), 0.79-0.65 (m, 2H), 0.57 (s, 3H).

Synthesis of 19-2

To a solution of 19-1 (600 mg, 1.73 mmol) in DCM (20 mL) was added m-CPBA (556 mg, 2.59 mmol, 80%) at 15°C. After stirring at 15°C for I h, the reaction mixture was quenched with sat. NaHCO₃ and Na₂S₂O₃ (40 mL, v: v = 1:1) and extracted with DCM (2 x 20 mL). The combined organic phase was washed with sat. NaHCO₃ and Na₂S₂O₃ (50 mL, v: v = 1:1), dried overNa₂SO4, filtered and concentrated to give 19-2 (650 mg). NMR (400 MHz, CDC1₃) δ_Η 3.38 (s, 3H), 3.24-3.14 (m, 2H), 2.88 (d, J= 4.4 Hz, IH), 2.55 (d, J= 4.4 Hz, IH), 2.49 (d, J = 4.8 Hz, IH), 2.31 (d, J =4.8 Hz, IH), 2.09-1.52 (m, 10H), 1.47-0.87 (m, 14H), 0.80 (s, IH), 0.74-0.64 (m, 4H).

Synthesis of 19 & 20

To a solution of 19-2 (650 mg, 1.79 mmol) in DMF (10 mL) were added Cs₂CO₃ (1.75 g, 5.37 mmol) and lH-pyrazole-4-carbonitrile (416 mg, 4.47 mmol). After stirring at 130°C for 12 h, the reaction mixture was added into saturated NH₄C1 (50 mL) and extracted with EtOAc (3 x

119 mL). The combined organic layer was washed with LiCl (100 mL, 5% in water), brine (2 x 100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column (0-50% of EtOAc in PE) to afford a mixture of epimers (750 mg). The epimers were separated by SFC (Column: DAICEL CHIRALCEL OJ-H (250mm*30mm, 5um); Condition: 0.1%NHjH₂O EtOH) to afford 20(116.0 mg, 15.5%) and 19 (280.6 mg, 37.4%).

19: NMR (400 MHz, CDC1₃) δ_Η 7.92 (s, IH), 7.81 (s, IH), 4.36 (d, J= 13.6 Hz, IH), 4.08 (d, J = 13.6 Hz, IH), 3.38 (s, 3H), 3.18 (s, 2H), 2.48 (s, IH), 2.13-1.92 (m, 2H), 1.81-1.56 (m, 9H), 1.43 (br t, J = 9.6 Hz, 2H), 1.29-0.98 (m, 9H), 0.96 (s, 4H), 0.92 (s, 3H), 0.69 (br s, 2H). LC-ELSD/MS purity 99%, MS ESI calcd for C26H35N3 [M-MeOH-2H₂O+H]⁴' 388.2, found 388.2. SFC 96.66% de

20: ’HNMR (400 MHz, CDCI3) δ_Η 7.89 (s, IH), 7.82-7.75 (m, IH), 4.22-4.09 (m, IH), 4.06-3.93 (m, IH), 3.48-3.31 (m, 3H), 3.27-3.11 (m, 2H), 2.35-2.22 (m, IH), 2.12-1.99 (m, 2H), 1.97-1.83 (m, IH), 1.81-1.60 (m, 8H), 1.53-1.32 (m, 2H), 1.29-1.14 (m, 4H), 1.09 (s, 5H), 1.050.92 (m, 4H), 0.87 (s, 3H), 0.69 (br t, J = 7.2 Hz, 2H). LC-ELSD/MS purity 99%, MS ESI calcd for C26H35N3 [M-MeOH-2H₂O+H]⁺ 388.2, found 388.2. SFC 100% de

Example 21: Synthesis of l-(2,2-difluoro-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy3,13-dÎmethylhexadecahydro-lH-cyclopenta[a]phenanthren-17-yl)ethyl)-lH-pyrazole-4carbonitrile

Synthesis of 21-1

To a solution of 21-0 (1 g, 2.44 mmol) in DCM (10 mL) was added DMAP (298 mg, 2.44 mmol) and acetyl acetate (622 mg, 6.10 mmol). After stirring at 25°C for 16 h, the reaction 120 mixture was poured into ice-water (50 mL), stirred for 10 min, and extracted with DCM (2 x 30 mL). The combined organic phase was washed with saturated brine (2 x 50 mL), dried over anhydrous Na₂SO4, filtered and concentrated. The residue was purified by flash column (0-20% of EtOAc in PE) to give 21-1 (650 mg, 59%). ‘H NMR (400 MHz, CDC1₃) δ_Η 7.86 (s, IH), 7.81 (s, IH), 5.05-4.87 (m, 2H), 2.64-2.57 (m, IH), 2.34-2.06 (m, 2H), 1.99 (s, 3H), 1.87-1.58 (m, 10H), 1.54 (s, 3H), 1.51-1.30 (m, 7H), 1.15-0.82 (m, 4H), 0.67 (s, 3H).

Synthesis of 21-2

To a solution of 21-1 (300 mg, 0.66 mmol) in chloroform (5 mL) was added dropwise DAST (0.79 ml, 5.97 mmol) at 0°C under N₂. After stirring at 60° C for 12h, the reaction mixture was quenched with sat. NaHCO₃ (50 mL) and extracted with EtOAc (2 x 30 mL). The combined organic phase was washed with sat. NaHCO₃ (50 mL), dried over Na₂SO4, filtered, concentrated. The residue was purified by combi-flash (0-30% of EtOAc in PE) to give 21-2 (65 mg, 20%). 'H NMR (400 MHz, CDC1₃) δ_Η 7.92 (s, IH), 7.82 (s, IH), 4.59-4.30 (m, 2H), 1.97 (s, 3H), 1.851.58 (m, 12H), 1.53 (s, 3H), 1.49-1.28 (m, 7H), 1.14-1.03 (m, 5H), 0.88-0.86 (m, 3H)

Synthesis of 21

To a solution of 21-2 (35 mg, 0.074 mmol) in dioxane (0.5 mL) was added MeOH (1 mL) and NaOH (2.94 ml, 5 M, 14.7 mmol) at 15°C. After stirring at 35°C for 16h, the reaction mixture was poured into water (20 mL), stirred for 10 min, and extracted with EtOAc (3 x 40 mL). The combined organic phase was washed with saturated brine (2 x 50 mL), dried over anhydrous Na₂SO4, filtered and concentrated. The residue was purified by flash column (0-40% of EtOAc in PE) and purified by SFC (Method: Column: DAICEL CHIRALPAK AD (250mm*50mm, lOum); Condition: 0.1%NH₃H₂O EtOH; Begin B: 60%; End B: 60%) to afford 21 (14.4 mg, 41%). 'H NMR (400 MHz, CDC1₃) ô_H 7.92 (s, ITl), 7.82 (s, IH), 4.55-4.34 (m, 2H), 2.02-1.96 (m, IH), 1.86-1.60 (m, 10H), 1.49-1.27 (m, 9H), 1.25 (s, 3H), 1.13-1.05 (m, 5H), 0.87 (d, J=32 Hz, 3H). LC-ELSD/MS: purity >99%; MS ESI calcd. for C₂₅H₃₅F₂N₃O [MH₂O+H]⁺414.2, found 414.2.

Example 22 & 23: Synthesis of l-((S)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3hyd roxy- 13-methyl-3-propylhexadecahydro-1 H-cycIopenta [a] phen anthr en-17-yl)propyl)lH-pyrazole-3-carbonitrile (22) & l-((R)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3hyd roxy- 13-methyl-3-propylhexadecahydro-1 H-cyclope nta [ a] phenanthr en- 17-yl)pro py ΟΙ H-pyrazole-3-carbonitrile (23)

121

To a solution of 7-3 (300 mg, 0.831 mmol) in DMF (5 mL) were added lH-pyrazole-3carbonitrile (154 mg, 1.66 mmol) and Cs₂CO₃ (1.35 g, 4.15 mmol). After stirring at 125°C for 12 h, the mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was concentrated and purified by flash column (0-25% of EtOAc in PE) to give mixture of epimers (200 mg, 53%). The epîmers were separated by SFC (Column: DAICEL CHIRALPAK AD (250mm*30mm,l Oum; Condition: 0.1%NH₃H₂O 1PA; Begin: B 55%; End B: 55%; FlowRate (ml/min): 80) to give 22 (80.5 mg) and 23 (47.2 mg). The regiochemistry of pyrazole was assigned by HMBC (H22 correlated with C5 in pyrazole ring).

22: 'H NMR (400 MHz, CDCI₃) δ_Η 7.58 (d, 7= 4 Hz, IH), 6.68 (d,7 = 4Hz, 1 H), 4.384.35 (m, IH), 4.13-4.09 (m, 1H),2.35 (s, IH), 2.02-1.99 (m, IH), 1.81-1.60 (m, 10H), 1.55-1.31 (m, 7H), 1.28-1.03 (m, HH), 0.96-0.91 (m, 9H). LC-ELSD/MS: purity 99%, MS ESI calcd. for C₂₈H_4ÜN₃ [M-2H₂O+H]⁺ 418.3, found 418.3. SFC 100% de.

23: *H NMR (400 MHz, CDC1₃) δ_Η 7.53 (d, 7 = 4 Hz, IH), 6.67 (d, 7 = 4 Hz, IH), 4.194.16 (m, IH), 4.05-4.02 (m, IH), 2.21 (s, IH), 2.07-2.04 (m, IH), 1.94-1.58 (m, 10H), 1.55-1.25 (m, HH), 1.22-1.02 (m, 10H), 0.95-0.87 (m, 6H). LC-ELSD/MS: purity 99%, MS ESI calcd. for C₂₈H₄oN₃ [M-2H₂O+H]⁺ 418.3, found 418.3. SFC 100% de.

Example 24 & 25: Synthesis of l-((S)-2-((3R,5R,8R,9S,10S,13S,14S,17S)-3-(ethoxymethyI)3-hydroxy-10,13-dimethylhexadecahydro-lH-cyclopenta[a]phenanthren-17-yl)-2hydroxypropyl)-lH-pyrazole-4-carbonitrile (24) & l-((R)-2((3R,5R,8R,9S,10S,13S,14S,17S)-3-(ethoxymethyl)-3-hydroxy-10,13dimethylhexadecahydro-1 H-cyclopenta [a ] ph en anth ren-17-yI)-2-hydr oxypr opy 1)-1Hpyrazole-4-carbonitrile (25)

122

Synthesis of 24-1

To a mixture of MePPh₃Br (5.67 g, 15.9 mmol) in THF (70 mL) was added t-BuOK (1.78 mg, 15.9 mmol) at 25°C under N₂. After stirring at 55°C for 30 min, 24-0 (2.0 g, 5.31 mmol) in THF (30 mL) was added in portions blow 55°C. After stirring at 55°C for 2 h, the réaction mixture was poured into water (300 mL) at 25°C and extracted with EtOAc (2 x 300 mL). The combined organic layer was washed with water (300 mL), brine (200 mL), dried over Na₂SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (0-5% EtOAc in PE) to give 24-1 (900 mg). ‘H NMR (400 MHz, CDC1₃) δ_Η 4.84 (s, IH), 4.69 (s, IH), 3.55-3.51 (q, J=6.9 Hz, 2H), 3.47-3.33 (m, 2H), 2.73-2.65 (m, IH), 2.06-1.97 (m, 2H), 1.96-1.81 (m, 3H), 1.77-1.72 (m, 4H), 1.58-1.54 (m, 2H), 1.45-1.38 (m, 4H), 1.25-1.18 (m, 8H), 0.90-0.82 (m, 9H), 0.54 (s, 3H).

Synthesis of 24-2

To a solution of 24-1 (900 mg, 2.40 mmol) in DCM (20 mL) was added m-CPBA (974 mg, 85%, 4.80 mmol) at 15°C. After stirring at 15°C for 1 h, the mixture was quenched with saturated NaHCO₃ aqueous (200 mL). The organic phase was separated and washed with saturated NaHCO₃/Na₂S₂O₃ aqueous (1:1, 3 x 100 mL), brine (100 mL), dried over Na₂SO4, filtered and concentrated under vacuum to give 24-2 (1.0 g). ^lH NMR (400 MHz, CDC1₃) Ô_H 3.55-3.51 (q,J=6.9Hz, 2H), 3.47-3.35 (m, 2H), 1.98-1.77 (m, 4H), 1.76-1.66 (m, 2H), 1.64-1.44 (m, 6H), 1.43-1.31 (m, 7H), 1.27-1.17 (m, 7H), 1.16-0.99 (m, 4H), 0.95-0.90 (m, 3H), 0.81-0.74 (m, IH), 0.71-0.61 (m, 2H).

Synthesis of 24 & 25

123

To a solution of 24-2 (1.0 g, 2.56 mmol) in DMF (15 mL) were added 1 H-pyrazole-4carbonitrile (595 mg, 6.40 mmol) and Cs₂CO₃ (4.17 g, 12.8 mmol). After stirring at 125°C for 12 h, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 60 mL). The combined organic layer was washed with saturated LiCl (3x150 mL) and then concentrated. The residue was purified by flash column (0-20% of EtOAc in PE) to give a mixture of epimers (700 mg). The epimers were separated by SFC (Column: Chiralpak AD-3 50><4.6mm LD., 3um Mobile phase: A: CO₂ B:éthanol (0.05% DEA) Gradient: from 5% to 40% of B in 2 min and hold 40% for 1.2 min, then 5% of B for 0.8 min Flow rate; 4mL/min Column temp.: 35°C ABPR: 1500 psi) afford 24 (284.9 mg, 40.8%) and 25 (88.4 mg, 12.7%).

24: ’HNMR (400 MHz, CDCI3) δ_Η 7.92 (s, IH), 7.82 (s, 1 H), 4.36-4.32 (d, 7=13.8 Hz, IH), 4.09-4.05 (d, 7=13.8 Hz, IH), 3.53-3.50 (q, 7=6.9 Hz, 2H), 3.47-3.36 (m, 2H), 2.72 (s, IH), 2.54 (s, 1 H), 2.01-1.99 (d, 7=10.8 Hz, 1 H), 1.96-1.79 (m, 2H), 1.77-1.64 (m, 4H), 1.62-1.46 (m, 5H), 1.45-1.35 (m, 6H), 1.26-1.18 (m, 6H), 1.13-1.08 (m, IH), 0.96-0.93 (d, 7=10.8 Hz, 7H), 0.89 (s, 3H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₇H₃₆N₃ [M-EtOH-2H₂O +H] 402.3 found 402.3. SFC 100% de.

25: ‘H NMR (400 MHz, CDC1₃) Ô_H7.89 (s, IH), 7.81 (s, IH), 4.17-4.14 (d, 7=13.8 Hz, IH), 4.02-3.99 (d, 7=13.8 Hz, IH), 3.55-3.50 (q, 7=7.0 Hz, 2H), 3.46-3.35 (m, 2H), 2.72 (s, IH), 2.34 (s, IH), 2.06 (d, IH), 1.97-1.79 (m, 3H), 1.73-1.64 (m, 3H), 1.62-1.53 (m, 3H), 1.53-1.34 (m, 8H), 1.27-1.18 (m, 6H), 1.17-1.10 (m, 2H), 1.07 (s, 3H), 0.93 (s, 3H), 0.85 (s, 3H). LCELSD/MS purity 99%, MS ESI calcd. for C₂7H₃₆N₃ [M-EtOH-2H₂O +H]+ 402.3 found 402.3. SFC 100% de.

Example 26 & 27: Synthesis of l-((S)-2-hydroxy-2-((3R,5R,8R,9S,10S,13S,14S,17S)-3hydr oxy-10,13-dimethyl-3-propylhexadecahydro-1 H-cyclopenta ( a] phen an th r en-17yl)propyl)-lH-pyrazole-4-carbonitrile (26) & l-((R)-2-hydroxy-2((3R,5R,8R,9S,10S,13S,14S,17S)-3-hydroxy-10,13-dimethyI-3-propylhexadecahydro-lHcyclopenta[a]phenanthren-17-yl)propyl)-lH-pyrazole-4-carbonitrile (27)

124

Synthesis of 26-1

To a mixture of MePPh₃Br (2.96 g, 8.30 mmol) in THF (30 mL) was added t-BuOK (931 mg, 236 mmol) at 25°C under N₂- After stirring at 50“C for 30 min, 26-0 (LO g, 2.77 mmol) in THF (20 mL) was added in portions blow 50°C. After stirring at 50°C for 2 h, the réaction mixture was poured into water (300 mL) at 25 °C. and extracted with EtOAc (2 x 300 mL). The combined organic layer was washed with water (300 mL), brine (200 mL), dried over Na₂SÛ4 , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (05% EtOAc in PE) to give 26-1 (880 mg, 88.6% ). NMR (400 MHz, CDC1₃) Ô_H 4.84 (s, 1 H), 4.69 (s, IH), 2.06-1.98 (m, IH), 1.93-1.79 (m, 3H), 1.75 (s, 3H), 1.73-1.64 (m, 3H), 1.60-1.49 (m, 3H), 1.48-1.33 (m, 8H), 1.32-1.17 (m, 6H), 1.17-0.99 (m, 4H), 0.97-0.90 (m, 6H), 0.54 (s, 3H).

Synthesis of 26-2

To a solution of 26-1 (880 mg, 2.45 mmol) in DCM (20 mL) was added m-CPBA (994 mg, 85%, 4.90 mmol) at 15°C. After stirring at 15°C for 1 h, the mixture was quenched by saturated NaHCO₃ aqueous (200 mL). The organic phase was separated and washed wîth saturated NaHCO₃/Na₂S₂O₃ aqueous (1:1, 3 x 100 mL), brine (100 mL), dried over Na₂SO4, filtered and concentrated under vacuum to gîve 26-2 (900 mg). ^:Η NMR (400 MHz, CDC1₃) δ_Η 2.89-2.86 (d, 7=4.3 Hz, IH), 2.57-2.53 (d, 7=4.3 Hz, IH), 2.51-2.29 (m, IH), 1.95-1.80 (m, 5H), 1.73-1.64 (m, 2H), 1.63-1.54 (m, 4H), 1.39-1.32 (m, 9H), 1.27-1.20 (m, 5H), 0.97-0.88 (m, 10H), 0.77 (s, IH), 0.65 (s, 3H).

Synthesis of 26 & 27

To a solution of 26-2 (900 mg, 2.40 mmol) in DMF (5 mL) were added 1 H-pyrazole-4carbonitrile (557 mg, 5.99 mmol) and Cs₂CO₃ (3.87 g, 11.9 mmol). After stirring at 125°C for 12

125 h, the reaction mixture was dîluted with water (100 mL) and extracted with EtOAc (3 x 60 mL). The combined organic layer was washed with saturated LiCl (3 x 150 mL) and then concentrated. The residue was purified by flash column (0-20% of EtOAc in PE) to give a mixture of epimers (740 mg, 66.0%). The epimers were separated by SFC (Column; Chiralpak AD-3 50x4.6mm I.D., 3um Mobile phase: A: CO₂ B: éthanol (0.05% DEA) Gradient: from 5% to 40% of B în 2 min and hold 40% for 1.2 min, then 5% of B for 0.8 min Flow rate: 4 mL/min Column temp.: 35°C ABPR: 1500 psi) afford 26 (318.7 mg) and 27 (154.0 mg).

26: *H NMR (400 MHz, CDC1₃) Ô_H7.92 (s, IH), 7.82 (s, IH), 4.35-4.32 (d, 7=13.6 Hz, IH), 4.09-4.05 (d, 7=13.8 Hz, IH), 2.52 (s, IH), 2.05-1.98 (m, IH), 1.91-1.82 (m, 2H), 1.78-1.63 (m, 4H), 1.57-1.49 (m, 5H), 1.48-1.32 (m, 10H), 1.30-1.19 (m, 5H), 1.16-1.02 (m, 4H), 0.97 (s, 3H), 0.95-0.92 (m, 5H), 0.89 (s, 3H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₉H₄iN₃ [M-2H₂O+H]⁺ 432.3 found 432.3. SFC 100% de.

27: *H NMR (400 MHz, CDC1₃) δ_Η 7.89 (s, IH), 7.80 (s, IH), 4.21-4.11 (m, IH), 4.023.98 (d, 7=13.8 Hz, IH), 2.30 (s, IH), 2.06 (s, IH), 1.97-1.78 (m, 3H), 1.73-1.63 (m, 3H), 1.55 (s, 3H), 1.52-1.33 (m, 12H), 1.32-1.18 (m, 6H), 1.08 (s, 3H), 0.97-0.91 (m, 6H), 0.85 (s, 3H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₉H₄iN₃ [M-2H₂O+H]+ 432.3 found 432.3.

Example 28: Synthesis of l-((3-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13dimethylhexadecahydro-lH-cyclopenta[a]phenanthren-17-yI)oxetan-3-yl)methyl)-lHpyrazole-4-carbonitrile

126

Synthesis of 28-1

To a suspension of NaH (2.75 g, 60%, 68.8 mmol) in THF (60 mL) was added (EtO)₂P(O)CH₂COOEt (15.4 g, 68.8 mmol) dropwîse at 0°C. After stirring at 20°C for 10 min, a solution of28-0 (10 g, 34.4 mmol, reported in patent ‘WO2014/169833, 2014, Al’) in THF (20 mL) was added dropwîse at 20°C. After stirring at 70°C for 16 h, the reaction mixture was poured into NH4CI (200 mL, 10% aq) and extracted with EtOAc (200 mL). The organic layer was separated, dried over Na₂SO₄, filtered, concentrated. The residue was purified by flash column (0-20% EtOAc in PE) to give 28-1 (12 g, 97%). H NMR (400 MHz, CDC1₃) δ_Η 5.52 (t, 7=2.4 Hz, 1 H), 4.15 (q,7=7.2 Hz, 2H), 2.90-2.75 (m, 2H), 1.95-1.60 (m, 5H), 1.50-1.25 (m, 18H), 1.20-1.05 (m, 4H), 0.82 (s, 3H).

Synthesis of 28-2

To a solution of 28-1 (12 g, 33.2 mmol) in THF (150 mL) was added Pd/C (2 g, dry, 10%) under N₂. After stirring under H₂ (40 psi) at 40°C for 24 h, the reaction mixture was filtered through a pad of celite which was then washed with THF (3 x 50 mL). The combined filtrate was concentrated to give 28-2 (11.7 g, 97.5%). ‘H NMR(400 MHz, CDClj) δ_Η 4.11 (q, J = 6.8 Hz, 2H), 2.35 (dd, 7= 5.2, 14.4 Hz, IH), 2.10 (dd, 7= 10.0, 14.8 Hz, IH), 2.00-1.75 (m, 6H), 1.70-1.50 (m, 3H), 1.50-1.35 (m, 6H), 1.35-1.25 (m, 10H), 1.20-0.95 (m, 6H), 0.59 (s, 3H).

Synthesis of 28-3

To a solution of i-Pr₂NH (1.66 g, 16.5 mmol) in THF (30 mL) was added BuLi (6.6 mL, 2.5 M in hexane, 16.5 mmol) at -70°C. After wanning to 0°C over 15 min and then cooling to 70°C. a solution of 28-2 (2 g, 5.5 mmol) in THF (10 mL) was added. After stirring at -70°C for 1 h, a solution of CICOOEt (1.79 g, 16.5 mmol) in THF was added. After stirring at -70°C for 1 h, the reaction mixture was quenched with NH4CI (20 mL, 10%) and extracted with EtOAc (2 x 20 mL). The combined organic layer was dried over Na₂SO₄, filtered and concentrated in vacuum to give 28-3 (2.7 g). ^lH NMR (400 MHz, CDClj) δ_Η 4.25-4.05 (m, 4H), 3.29 (d, 7 = 11.2 Hz, IH), 2.25-2.15 (m, 1 H), 2.00-1.75 (m, 4H), 1.70-1.35 (m, 12H), 1.35-1.20 (m, 10H), 1.20-0.95 (m, 7H), 0.70 (s, 3H).

Synthesis of 28-4

To a suspension of t-BuOK (4.85 g, 3 LO mmol) in THF (20 mL) was added a solution of 28-3 (2.25 g, 5.17 mmol) in THF (20 mL) at 0°C. After stirring at 15°C for 1 h, BOMC1 (3.47 g,

127

31.0 mmol) was added at 0°C. After stirring at 0°C for 1 h, the reaction mixture was poured into NH4CI (100 mL, sat.) and extracted with EtOAc (100 mL). The organic layer was separated, dried over Na₂SO₄, filtered and concentrated to give 28-4 (8.5 g) which contain some diethyl 2((3R,5R,8R,9R,10S,13S,!4S,l 7S)-3-((benzyloxy)methoxy)-3,13-dimethylhexadecahydro-lHcyclopenta[a]phenanthren-17-yl)-2-((benzyloxy)methyl)malonate.

Synthesîs of 28-5

To a suspension of L1AIH4 (1.96 g, 51.7 mmol) in THF (80 mL) was added a solution of 28-4 (5.17 mmol mixture) in THF (20 mL) dropwise at 0°C. After stirring at 0°C for 1 h, the reaction mixture was quenched with water/THF (2 mL/100 mL) followed by NaOH (2 mL, 10%) and water (6 mL). The mixture was filtered and the residue was washed with THF (3 x 50 mL). The combined filtrate was concentrated to 100 mL and HCl (2 M, 10 mL) was added. After stirring at 50°C for 1 h, the reaction mixture was diluted with NaHCO₃ (50 mL, sat) and extracted with EtOAc ( 100 mL). The organic layer was separated, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by flash column (30-80% EtOAc in PE) to give 28-5 (1 g, 41% above two steps). ^lH NMR (400 MHz, CDC1₃) Ô_H 7.45-7.30 (m, 5H), 4.50 (s, 2H), 3.95-3.55 (in, 6H), 2.80-2.70 (br, IH), 2.70-2.60 (br, IH), 1.95-1.70 (m, 4H), 1.70-1.50 (m, 5H), 1.50-1.20 (m, 13H), 1.15-0.90 (m, 6H), 0.73 (s, 3H).

Synthesîs of 28-6

To a solution of 28-5 (1 g, 2.12 mmol) in THF (20 mL) was added BuLi (1.01 mL, 2.5 M in hexane, 2.54 mmol) at 0°C. After stirring at 0°C for 10 min, a solution ofTsCl (484 mg, 2.54 mmol) in THF (5 mL) was added. After stirring at 0°C for 1 h, BuLÎ (1.0! mL, 2.5 M in hexane, 2.54 mmol) was added at 0°C. After stirring at 15°C for 2 h, the reaction mixture was quenched with NH4CI (20 mL, sat.) and extracted with EtOAc (2 x 30 mL). The combined organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by flash column (0-15% EtOAc in PE) to give 28-6 (650 mg, 68%). ’H NMR (400 MHz, CDC1₃) δ_Η 7.45-7.30 (m, 5H), 4.83 (d, 7=6.4 Hz, IH), 4.60 (d,7= 12.0 Hz, IH), 4.55-4.50 (m, 2H), 4.44 (d, 7= 5.6 Hz, IH), 4.23 (d,7=6.4 Hz, 1 H), 3.89 (d,7= 9.2 Hz, IH), 3.66 (d,7=9.2 Hz, IH), 2.20-2.10 (m, IH), 2.00-1.60 (m, 8H), 1.50-1.30 (m, 7H), 1.30-0.95 (m, 12H), 0.52 (s, 3H).

Synthesîs of 28-7

To a solution of 28-6 (650 mg, 1.43 mmol) in THF (20 mL) was added Pd/C (0.5 g, 10%, wet) under N₂. After stirring under H₂ (20 psi) at 20°C for 20 h, the reaction mixture was filtered

128 and the residue was washed with THF (20 niL). The combined filtrate was coneentrated and purified by flash column (40-70% EtOAc in PE) to give 28-7 (380 mg, 73%). ⁴Η NMR (400 MHz, CDCh) δ_Η 4.85 (d,/=6.8 Hz, IH), 4.54 (d,/=5.6Hz, IH), 4.46 (d,/=5.6 Hz, IH), 4.24 (d,/=6.4 Hz, IH), 4.08 (dd,/=4.0, 10.8 Hz, IH), 3.82 (d,/ = 10.0 Hz, 1 H), 2.20-2.10 (m, IH), 2.00-1.65 (m, 10H), 1.55-1.00 (m, 18H), 0.53 (s, 3H). LC-ELSD/MS: purity>99%, MS ESI calcd. for C₂₃H₃₇O₂ [M+H-H₂O]⁺ 345.3, found 345.3.

Synthesis of 28-8

To a solution of 28-7 (185 mg, 0.51 mmol) in DCM (5 mL) were added N-Me-Im (41.8 mg, 0.51 mmol), TEA (258 mg, 2.55 mmol) and TsCl (194 mg, 1.02 mmol). After stirring at 15°C for 16 h, the reaction mixture was washed with water (5 mL), dried over Na₂SO₄, filtered, and coneentrated. The residue was purified by flash column (0-25% EtOAc in PE/DCM (1:1)) to give 28-8 (200 mg, 76%). *H NMR (400 MHz, CDC1₃) δ_Η 7.83 (d, / = 8.4 Hz, 2H), 7.37 (d, / = 8.0 Hz, 2H), 4.82 (d,/ = 6.8 Hz, IH), 4.50-4.40 (m, 2H), 4.22 (d,/= 9.6 Hz, IH), 4.18 (d, / = 6.0 Hz, 1 H), 4.11 (d,/=6.8 Hz, 1 H), 2.46 (s, 3H), 2.10-2.00 (m, IH), 1.95-1.55 (m, 8H), 1.500.90 (m, 19H), 0.47 (s, 3H).

Synthesis of 28

To a solution of 28-8 (200 mg, 0.39 mmol) in DMF (5 mL) were added 4-cyano-pyrazole (72 mg, 0.77 mmol), Kl (64.2 mg, 0.38 mmol) and K₂CO₃ (108 mg, 0.77 mmol). After stirring at 80°C for I6h, the reaction mixture was poured into water (30 mL) and filtered. The residue was purified by flash column (20-50% EtOAc in PE), dîssolved în MeCN (30 mL)/water (30 mL) and lyophilized to give 28 (135.7 mg, 79%). NMR (400 MHz, CDCI₃) Ô_H 7.88 (s, IH), 7.83 (s, IH), 4.96 (d,/= 6.8 Hz, 1 H), 4.70-4.60 (m, 2H), 4.53 (d,/=6.4Hz, IH), 4.47 (d, / = 7.2 Hz, IH), 4.35 (d,/ = 14.0 Hz, IH), 2.10-2.00 (m, IH), 2.00-1.65 (m, 8H), 1.55-0.95 (m, 19H), 0.69 (s, 3H). LC-ELSD/MS purity>99%, MS ESI calcd. for C₂₇H₄oN₃02 [M+H] ' 438.3, found 438.3.

EXAMPLE 29 & 30: Synthesis of l-((S)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-lH-cycIopenta[aJphenanthren-17yl)propyI)-lH-pyrazoIe-4-carbonitrile (29 & l-((R)-2-hydroxy-2((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydrolH-cyclopenta[a]phenanthren-17-yl)propyl)-lH-pyrazole-4-carbonitriie (30)

129

Synthesis of 29.2

To a solution of MePPh₃Br (12.2 g, 34.0 mmol) in THF (20 mL) was added t-BuOK (2.88 g, 25.8 mmol) at 15°C. After stirring for 1 h at I5°C, 29.1 (3 g, 8.60 mmol) in THF (20 mL) was added. After stirring at 45°C for 3 h, the mixture was treated with saturated NH₄C1 (50 mL) and extracted with EtOAc (2 x 30 mL). The combined organic solution was washed with brine (100 mL), dried over anhydrous Na2SÛ4, filtered and concentrated. The residue was purified by flash column (0-40% of EtOAc in PE) to give 29.2 (4.5 g), hl NMR (400MHz, CDC1₃) δ 4.83 (s, IH), 4.45 (s, IH), 3.47-3.31 (m, 5H), 2.61 (s, IH), 2.05-2.02 (m, IH), 1.911.77 (m,4H), 1.74 (s, 3H), 1.68-1.52 (m, 5H), 1.49-1.31 (m, 7H), 1.28-1.04 (m, 7H), 0.59-0.50 (m, 3H).

Synthesis of 29.3

To a solution of 29.2 (500 mg, 1.44 mmol) in DCM (20 mL) was added m-CPBA (461 mg, 2.15 mmol, 85%) at 15°C. After stirring for Ih, the mixture was quenched with sat.NaHCO₃ and Na₂S₂O₃ (40 mL, v: v = 1:1) and extracted with DCM (2 x 20 mL). The combined organic phase was washed with sat.NaHCO₃ and Na₂S₂O3 (50 mL, v: v = 1:1), dried over Na₂SO₄, filtered and concentrated to give 29.3 (520 mg). ’H NMR (400 MHz, CDC1₃) ÔH = 3.46 - 3.32 (m, 8H), 2.88 (d, J = 4.4 Hz, IH), 2.55 (d, J = 4.4 Hz, 1 H), 2.51 -2.47 (m, 1 H), 2.31 (d, J = 5.2 Hz, IH), 2.04- 1.98 (m, IH), 1.95 - 1.53 (m, 8H), 1.50- 1.29 (m, 8H), 1.28 - 0.98 (m, 5H), 0.82 -0.78(m, 1 H), 0.68 (s, 3H).

Synthesis of 29.4

To solution of 29.3 (520 mg, 1.43 mmol) in DMF (10 mL) wer added Cs₂CO₃ (1.39 g, 4.29 mmol) and 1 H-pyrazole-4-carbonitrile (332 mg, 3.57 mmol) at 15°C under N₂. After stirring

130 at 130°C for 12 h, the mixture was added into saturated NH4CI (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with LiCl (100 mL, 5% in water), brine (2 x 100 mL), dried over anhydrous Na₂SO4, filtered and concentrated. The residue was purified by column (0-50% of EtOAc in PE) to afford 29.4 (650 mg). LC-ELSD/MS purity 99%, MS ESI calcd for C₂₆H₃₅N₃ [M-2H₂O-CH₃OH+H]⁺ 388.3, found 388.3.

Séparation of 29 & 30

29.4 was separated by SFC (Column: Chiralcel OD-3 50jÂ4.6mm I.D., 3um; Mobile phase: A: CO₂ B:ethanol (0.05% DEA); Gradient: from 5% to 40% of B in 2 min and hold 40% for 1.2 min, then 5% of B for 0.8 min; Flow rate: 4mL/min) to afford 30 (73 mg, 18.2 %) and 29 (189.9 mg, 47.3%).

29: ‘H NMR (400 MHz, CDCI3) δ_Η = 7.92 (s, IH), 7.82 (s, IH), 4.36 (d, J = 13.6 Hz, IH), 4.08 (d, J = 13.6 Hz, 1 H), 3.46 - 3.33 (m, 5H), 2.59 (s, 1 H), 2.52 (s, 1 H), 2.01 (br d, J = 12.0 Hz, IH), 1.87 - 1.57 (m, 9H), 1.52- 1.31 (m, 7H), 1.29 - 1.04 (m, 7H), 0.96 (s, 3H), 0.91 (s, 3H) LC-ELSD/MS purity 99%, MS ESI calcd for C26H35N3 [M-2H₂O-CH₃OH+H]^h 388.3, found 388.3.

30: 'H NMR (400 MHz, CDCfr) Ô_H = 7.89 (s, IH), 7.80 (s, 1H),4.17 (d, J= 13.6 Hz, IH), 4.01 (d, J = 13.6 Hz, IH), 3.48 - 3.32 (m, 5H), 2.60 (s, IH), 2.32 (s, IH), 2.06 (br d, J = 13.6 Hz, IH), 1.98- 1.60 (m, 9H), 1.51-1.24 (m, 9H), 1.08 (s, 8H), 0.87 (s, 3H). LC-ELSD/MS purity 99%, MS ESI calcd for C₂₆H₃₅N3 [M-2H₂O-CH₃OH+Hr 388.3, found 388.3.

EXAMPLE 31: Synthesis of l-(l-((S)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3hydroxy-3,13-dimethylhexadecahydro-lH-cyclopenta[a]phenanthren-17-yl)propyl)-lHpyrazol-4-yi)ethanone (31)

131

Synthesis of 31.1

To a solution of 21.0 (2 g, 4.88 mmol), 2,6-dimethylpyridine (1.30 g, 12.2 mmol) in DCM (20 mL) was added dropwise tert-butyldimethylsilyl trifluoromethanesulfonate (2.57 g, 9.76 mmol) at 0°C. After stirring ai 15°C for 5 hrs, the reaction mixture was quenched with water (60 mL) and extracted with DCM (2 x 50 mL). The combined organic phase washed with brine (50 mL), dried over Na₂SO4, fïltered and concentrated under vacuum. The residue was purified by flash column (10-20% of EtOAc in PE) to afford 31.1 (2.5 g, 98.0%). *H NMR (400 MHz, CDC1₃) ô_h 7.87 (s, IH), 7.82 (s, IH), 5.10-4.97 (m, IH), 4.96-4.84 (m, IH), 2.72-2.60 (m, IH), 2.28-2.17 (m, IH), 2.09-2.02 (m, IH), 1.87-1.67 (m, 7H), 1.46-1.40 (m, 4H), 1.29-1.26 (m, 3H), 1.24 (s,4H), 1.16-1.07 (m, 3H), 0.88 (s, 1 IH), 0.68 (s, 3H), 0.09 (s, 6H).

Synthesis of 31.2

To a solution of 31.1 (200 mg, 0.381 mmol) in THF (5 mL) was added MeMgBr (1.27 mL, 3.81 mmol, 3.0 M) at -60°C. After stirring at 25°C for 2 h, the mixture was added to NH₄C1 (20 mL). and extracted with EtOAc (2x15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na₂SO4, fïltered and concentrated. The residue was purified by flash column (0-20% of EtOAc in PE) to give 31.2 (120 mg, 56.6%). ^lH NMR (400 MHz, CDC13) δ_Η 7.94-7.93 (m, IH), 7.92-7.90 (m, IH), 4.41-4.30 (m, IH), 4.08-4.00 (m, IH), 2.682.62 (m, 1 H), 2.45-2.44 (m, 3H), 2.28-2.17 (m, IH), 2.11-2.02 (m, 2H), 1.81-1.74 (m, 8H), 1.44 (s, 3H), 1.24 (s, 6H), 1.15-1.06 (m, 6H), 1.01-0.93 (m, 4H), 0.88 (s, 9H), 0.70-0.68 (m, 3H), 0.09 (s, 6H), 0.10-0.09 (m, IH).

Synthesis of 31

132

To a solution of 31.2 (120 mg, 0.215 mmol) in THF (2 mL) was added HF (21,4 mg, 1.07 mmol, 1.1 g/m L) in one portion at 25°C under N₂. After stirring at 25°C for 16 h, the mixture was added to NH₄C1 (10 mL) and extracted with EtOAc (2x15 mL), The combined organic layers were washed with brine (15 mL), dried over anhydrous Na₂SO₄, fïltered and concentrated. The residue was purified b y HPLC (Welch Xtimate Cl 8 150 x 25mm, 5um; Condition: water (0.04%NH₃H₂0)-ACN; Gradient: from 50% to 80% of B in 8.5 min and hold 100% for 2 min; Flow rate: 30 mL/min; Injections: 6) to afford 31 (3.8 mg, 3.99 %). ’H NMR (400 MHz, CDC13) S_H 7,97-7.95 (m, IH), 7.95-7.93 (m, IH), 4.38-4.31 (m, IH), 4.06-4.01 (m, IH), 3.08-3.05 (m, IH), 2.46 (s, 3H), 2.08-2.02 (m, IH), 1.87-1.73 (m, 5H), 1.70-1.61 (m, 4H), 1.47-1.35 (m, 8H),

1.27 (s, 5H), 1.14-1.04 (m, 5H), 1.00 (s, 3H), 0.93 (s, 3H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂7H4₂N₂O₃ [M+H]⁺ 443.3 found 443.3.

EXAMPLES 32 & 33: Synthesis of l-((R)-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3( methoxy methy l)-l3-methylhexadecahydro-1H-cyclopen ta] a] phenanthren-17-yl)-215 methoxypropyl)-lH-pyrazole-4-carbonitrile (32) & l-((2S)-2[(lS,3aS,3bR,5aR,7R,9aS,9bR,llaS)-7-hydroxy-7-(methoxymethyl)-lla-methylhex adecahyd ro-1 H-cyclopenta [ a] ph enanthr en- 1-yl] -2-methoxy propyl] -1 H-pyrazo lc-4carbonitrile (33)

133

Synthesis of 32.1

To a solution of29.2 (4 g, II.5 mmol) and 2,6-dimethylpyridine (6.14 g, 57.4 mmol) in DCM (150 mL) was added TBSOTf (12.1 g, 46.0 mmol) at 0°C. After stirring at 25°C for 16 h, the mixture was diluted with DCM (150 mL) and washed with water (300 mL). The organic phase was séparai ed, dried over anhydrous Na?SO4, filtered and concentrated to give 32.1 (6 g), which was used directly for the next step. *H NMR (400 MHz, CDCI3) δ 4.85 (s, IH), 4.70 (s, IH), 3.42-3.29 (m, 5H), 2.11 -2.05 (m, IH), 1.89- 1.79 (m, 5H), 1.72- 1.56 (m, 8H), 1.49 0.99 (m, 16H), 0.95 - 0.88 (m, 6H), 0.57 (s, 3H), 0.08 - 0.05 (m, 6H).

Synthesis of 32.2

To a solution of 32.1 (3 g, 6.51 mmol) in DCM (150 mL) was added m-CPBA (1.96 g, 9.76 mmol, 85%). After stirring at 25°C for 2 h, the reaction mixture was quenched with NaHCO₃ (150 mL, sat.) and extracted with DCM (2 x 80 mL). The combined organic phase was washed with brine (150 mL), dried over anhydrous Na₂SO4, filtered and concentrated to give 32.2 (2.3 g).

Synthesis of 32.3 & 32.4

To a solution of 32.2 (2.3 g, 4.82 mmol) in DMF (50 mL) were added 1 H-pyrazole-4carbonitrile (1.34 g, 14.4 mmol) and CS2CO3 (4.69 g, 14.4 mmol) at 25°C. After stirring at 140°C for 8 h, the mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 60 mL). The combined organic phase was washed with water (100 mL), brine (100 mL), dried over anhydrous Na₂SO4, filtered and concentrated in vacuum. The residue was purified by flash column (0%30% of EtOAc in PE) to give 32.4 (1.3 g, 47.4 %) and 32.3 (680 mg, 24.8%).

32.3: *H NMR (400 MHz, CDC1₃) δ 7.89 (s, IH), 7.80 (s, IH), 4.23-4.13 (m, IH), 4.053.90 (m, IH), 3.43-3.26 (m, 5H), 2.29 (s, IH), 2.10-2.05 (m, 1 H), 1.98-1.62 (m, 8H), 1.57-1.27 (m, 7H), 1.23-0.97 (m, 10H), 0.94-0.81 (m, 13H), 0.06 (s, 6H).

32.4: ^lH NMR (400 MHz, CDCI3) δ 7.93 (s, IH), 7.82 (s, IH), 4.36 (d, J= 14.0 Hz, IH), 4.10-4.05 (m, IH), 3.41-3.29 (m, 5H), 2.50 (s, IH), 1.83-1.59 (m, 9H), 1.53-1.27 (m, 7H), 1.241.01 (m, 8H), 1.00-0.90 (m, 6H), 0.85 (s, 9H), 0.06 (s, 6H).

Synthesis of 32.5

134

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

Synthesis of 32

To a solution of 32.5 (1.3 g, 2.22 mmol) in THF (20 mL) was added TBAF (22.2 mL, 22.2 mmol, IM in THF). After stirring at 80°C for 16 h, the reaction mixture was quenched with NH4CI (50 mL, sat.) and extracted with EtOAc (2x50 mL). The combined organic phase was washed with brine (2 x 50 mL), dried over anhydrous Na₂SO4, filtered and concentrated. The residue was purified by flash column (0-50% of EtOAc in PE) to give 32 (301.8 mg, 28.9%). ’H NMR (400 MHz, CDC1₃) δ 7.91 (s, 11-1),7.75 (s, IH), 4.33-4.12 (m, 2H), 3.45-3.32 (m, 5H), 3.18 (s, 3H), 2.57 (s, IH), 1.98-1.91 (m, IH), 1.85-1.59 (m, 9H), 1.50-1.22 (m, 8H), 1.18-1.00 (m, 9H), 0.85 (s, 3H). LCMS 30-90AB_2min_E, purity>99%, MS ESI calcd. for C₂₇H₃₈N₃O [M+H-MeOH-H₂O]⁺ 420.3, found 420.2.

Synthesis of 32.6

To a solution of 32.4 (1.3 g, 2.28 mmol) in THF (20 mL) was added NaH (136 mg, 3.42 mmol, 60% in oil) at 25°C under N₂. After stirring for 30 min, Mel (647 mg, 4.56 mmol) was added at 25°C. After stirring at 25°C for 16 h, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phase was washed with brine (2 x 50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash column (0-20% of EtOAc in PE) to give 32.6 (1.2 g).

Synthesis of 33

To a solution of 32.6 (600 mg, 1.02 mmol) in THF (10 mL) was added TBAF (5.10 mL, 5.10 mmol, IM in THF). After stirring at 80°C for 16 h, the reaction mixture was quenched with NH4CI (50 mL, sat.) and extracted with EtOAc (2x50 mL). The combined organic phase was washed with brine (2 x 50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash column (0-50% of EtOAc in PE) to give 33 (144.7 mg, 30%). ’H NMR (400 MHz, CDC1₃) δ 7.90 (s, IH), 7.75 (s, IH), 4.24 (s, 2H), 3.45-3.34 (m, 5H), 3.13 (s, 3H), 2.59 (s, IH), 2.09-1.99 (m, IH), 1.86-1.59 (m, 9H), 1.49-1.19(m, 9H), 1.13-0.98 (m, 8H), 135

0.81 (s, 3H). LCMS purity>99%, MS ESI calcd. for C_2JH_!SN,O [M+H-MeOH-H₂Of 420.3, found 420.2.

EXAMPLES 34 & 35: Synthesis of l-((S)-2-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-2-ethyl-3hydroxy-3,13-dimethylhexadecahydro-lH-cyclopenta[a]phenanthren-17-yl)-2hydroxypropyl)-lH-pyrazoIe-4-carbonitrile (34) & l-((R)-2((2S,3S,5R,8R,9R,10S,13S,14S,17S)-2-ethyl-3-hydroxy-3,13-dimethylhcxadecahydro-lHcyclopenta[a|phenanthren-17-yl)-2-hydroxypropyl)-lH-pyrazole-4-carbonitrile (35)

Synthesis of 34.1

To a solution of 34.0 (100 g, 364 mmol) in DCM (1000 mL) were added imidazole (49.5 g, 728 mmol) and TBSC1 (109 g, 728 mmol) at 25°C. After stirring at 25°C for 2 h, the mixture was poured into water (500 mL) and extracted with DCM (2 x 500 mL). The combined organic phase was washed with brine (500 mL), dried over anhydrous Na₂SO4, filtered and concentrated. The residue was triturated from PE (200 mL) at 25°C to give 34.1 (83 g). NMR (400 MHz, CDCfi) δ_Η5.82 (s, IH), 3.56 (t, J= 8.3 Hz, IH), 2.50-2.36 (m, 2H), 2.32-2.19 (m, 3H), 2.14-2.04 (m, IH), 1.94-1.74 (m, 3H), 1.59-1.21 (m, 6H), 1.07-0.90 (m, 4H), 0.88 (s, 9H), 0.84-0.78 (m, IH), 0.76 (s, 3H), 0.00 (d, J = 2.8 Hz, 6H).

Synthesis of 34.2

To a solution of 34.1 (50 g, 128 mmol) in THF (300 mL) was added LÎHMDS (128 mL, 1 M in THF, 128 mmol) at -70°C under N₂. After stirring at -70°C for 30 min, HMPA (22.9 g, 22.4 mL, 128 mmol) was added under N₂. After stirring at -70°C for 30 min, EtI (199 g, 102 mL, 128 mmol) was added under N₂. After stirring at 20°C for 1 h, the mixture was cooled and concentrated with reduced pressure at 40°C. The residue was poured into NH₄C1 (500 mL), 136 stirred for 20 mins, and extracted with EtOAc (3 x 400 mL). The combined organic phase was washed with brine (2 x 200 mL), dried over anhydrous Na₂SO4, filtered and concentrated. The residue was purified by flash column (0-1% of EtOAc in PE) to give 34.2 (40 g). ^fH NMR (400 MHz, CDCI3) δ_Η5.79 (s, IH), 5.72 (s, IH), 3.57 (t, J = 8.3 Hz, IH), 2.48-2.39 (m, IH), 2.34-2.06 (m, 4H), 1.96-1.61 (m, 3H), 1.26 (br d, J = 1.8 Hz, 9H), 1.07-0.98 (m, 2H), 0.93 (br t, 7=7.5 Hz, 4H), 0.88 (s, 10H), 0.76 (s, 3H), 0.01 (d,7= 2.8 Hz, 6H).

Synthesis of 34.3

To a mixture of 34,2 (20 g, 47.9 mmol) in THF (200 mL) was added Pd/C (2 g, 10%). The mixture was degassed under vacuum and purged with H₂ three times. After stirring under H₂ (15 psi) at 25°C for 24 h, the réaction mixture was filtered through a pad of Celite and washed with THF (3 x 500 mL). The filtrate was concentrated to give 34.3 (18 g). ’H NMR (400 MHz, CDCI3) δ_Η 3.61-3.52 (m, IH), 2.67-2.55 (m, IH), 2.34-2.05 (m, 4H), 1.94-1.62 (m, 4H), 1.580.92 (m, 14H), 0.92-0.85 (m, 13H),0.73 (d,7=3.8Hz, 3H), 0.00 (dd,7=3.0, 4.4 Hz, 6H).

Synthesis of 34.4

To a solution of B HT (60 g, 272 mmol) in toluene (200 mL) under N₂ at 0°C was added trimethylaluminum (68 mL, 2 M in toluene, 136 mmol) dropwîse slowly. After stirring at 0°C for 1 h, the MAD solution was used directly without further purification. To the MAD (64.8 g in toluene, 135 mmol) solution was added a solution of 34.3 (19 g, 45.3 mmol) in DCM (200 mL) dropwîse at -70°C under N₂. After stirring ai -70°C for 1 h under N₂, MeMgBr (30.2 mL, 3M in ethyl ether, 90.6 mmol) was added dropwîse at -70°C. After stirring for 2 h, the reaction mixture was poured slowly into aqueous citric acid (500 mL, sat.) at 10°C and extracted with DCM (2 x 200 mL). The combined organic phase was washed with brine (300 mL), dried over anhydrous Na₂SO4, filtered and concentrated. The residue was purified b y flash column (0-5% of EtOAc in PE) to give 34.4 (11 g). *H NMR (400 MHz, CDCI3) δ_Η 3.54 (t,7 = 8.3 Hz, IH), 2.03-1.94 (m, IH), 1.91-1.61 (m, 6H), 1.58-1.36 (m, 5H), 1.32-1.13 (m, 6H), L12-0.89 (m, 11 H), 0.87 (s, 1 IH), 0.70 (d, 7= 2.3 Hz, 3H), 0.00 (t, 7= 2.6 Hz, 6H).

Synthesis of 34.5 & 34.5a

To a solution of 34.4 (11g, 25.3 mmol) in THF (20 mL) was added TBAF.3H₂O (126 ml, IM, 126 mmol) at 15°C. After stirring at 55°C for 12 h, the mixture was poured into water (200 mL) and extracted with EtOAc (2 x 200 mL). The organic layer was washed with brine (2 x

137 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by column (10-15% of EtOAc in PE) to give 34.5a (3.8 g) and 34.5 (4.7 g).

.5a: 'H NMR (400 MHz, CDC1₃) δ_Η 3.63 (br t, 7=8.3 Hz, IH), 2.11-1.98 (m, 2H), 1.84-1.73 (m, 3H), 1.61-1.54 (m, 2H), 1.48-1.33 (m, 3H), 1.32-1.12 (m, 6H), 1.06 (s, 6H), 1.020.82 (m, 8H), 0.74 (s, 4H), 0.67-0.58 (m, IH).

.5: 'H NMR (400 MHz, CDC1₃) 3.64 (t, 7 = 8.6 Hz, IH), 2.12-1.92 (m, 3H), 1.851.54 (m, 4H), 1.52-1.36 (m, 6H), 1.32-1.16 (m, 5H), 1.09 (s, 4H), 1.06 (br s, 4H), 0.95-0.81 (m, 6H), 0.73 (s, 3H).

Synthesis of 34.6

To a mixture of 34.5 (4.7 g, 14.6 mmol) in DCM (50 mL) was added DMP (12.3 g, 29.2 mmol) at 25°C, After stirring at 25°C for 1 h, the mixture was quenched with saturated NaHCO₃ and Na₂S₂O₃ (20 mL, v/v =1/1) and extracted with DCM (2x10 mL). The combined organic phase was washed with saturated NaHCO₃ and Na₂S₂O₃ (20 mL, v/v = 1/1), dried over anhydrous Na₂SO₄, filtered and concentrated to give 34.6 (3 g). *Η NMR (400 MHz, CDC1₃) Oh 2.43 (dd, 7=8,3, 19.3 Hz, IH), 2.14-1.59 (m, 9H), 1.57-1.40 (m, 5H), 1.38-1.12 (m, 8H), 1.10 (s, 3H), 1.08-1.02 (m, IH), 0.95-0.88 (m, IH), 0.90 (d,7 = 4.8 Hz, 3H), 0.86 (s, 3H).

Synthesis of 34.7

To a suspension of PPh₃EtBr (10.4 g, 28.2 mmol) in THF (90 mL) was added t-BuOK (3.16 g, 28.2 mmol). After stirring at 40°C for 30 min, a solution of 34.6 (3 g, 9.41 mmol) in THF ( 10 mL) was added into the reaction at 40°C. After stirring at 40°C for 12 h, the mixture was poured into NH₄C1 (100 mL, sat.) and extracted with EtOAc (2 x 100 mL). The combined organic phase was washed with brine (2 x 100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by flash column (0-5% of EtOAc in PE) to give 34.7 (5 g). ’HNMR (400 MHz, CDC1₃) Ô_H5.10(tq,7= 1.9, 7.2 Hz, IH), 2.40-2.10 (m, 3H), 2.01-1.93 (m, IH), 1.82 (br d, 7 = 6.5 Hz, 2H), 1,65 (td, 7= 2.0, 7.1 Hz, 9H), 1.55-1.37 (m, 5H), 1.22-1.12 (m, 4H), 1.09 (s, 5H), 0.90 (d,7=5.5 Hz, 4H), 0.87 (s, 4H).

Synthesis of 34.8

To a solution of 34.7 (5 g, 15.1 mmol) in THF (100 mL) was added 9-BBN dimer (7.30 g, 30.2 mmol) under N₂. After stirring at 50°C under N₂ for 2 h, the mixture was cooled to 0°C and sequentially treated with EtOH (12.8 mL, 226 mmol), NaOH (45.2 mL, 5M, 226 mmol) and 138

H₂O₂ (22.6 mL, ΙΟ Μ, 226 mmol) dropwise at 15°C. After stirring at 50°C for 2 h, the mixture was cooled, poured into H₂O (500 mL) and extracted with EtOAc (2 x 500 mL). The organic layer was checked by potassium iodide-starch test paper to confirm excess H₂O₂ was destroyed (did not changed to blue). The combined organic phase was washed with aqueous Na₂S₂O₃ (2 x800 mL, sat.) and brine (800 mL), dried over anhydrous Na₂SO₄, fïltered and concentrated. The residue was purified by flash column (0-15% of EtOAc in PE) to give 34.8 (1.8 g). ’H NMR (400 MHz, CDCb) δ_Η 3.75-3.65 (m, IH), 2.00-1.78 (m, 6H), 1.77-1.68 (m, 2H), 1.60-1.25 (m, 13H), 1.22 (d, 7=6.3 Hz, 4H), 1.09 (s, 5H), 0.94-0.80 (m, 6H), 0.66 (s, 3H).

Synthesis of 34.9

To a mixture of 34.8 (1.7 g, 4.87 mmol) in DCM (50 mL) was added DMP (4.13 g, 9.74 mmol) at 25°C. After stirred at 25°C for 1 h, the mixture was quenched with saturated NaHCO₃ and Na₂S₂O₃ (80 mL, v/v = 1/1) and extracted with DCM (2 x lOmL). The combined organic phase was washed with saturated NaHCO₃ and Na₂S₂O₃ (20 mL, v/v = 1/1), dried over anhydrous Na₂SO₄, fïltered and concentrated to give 34.9 (1.8 g). 'H NMR (400 MHz, CDC1₃) ôh 2.59-2.47 (m, 2H), 2.28-2.15 (m, IH), 2.11 (s, 3H), 2.05-1.92 (m, 3H), 1.85-1.80 (m, 2H), 1.76-1.66 (m, IH), 1.50.1.38 (m, 5H), 1.35-1.16 (m, 6H), 1.10 (s, 3H), 1.08-1.01 (m, 2H), 1.081.01 (m, 2H), 0.90 (br d, 7= 4.8 Hz, 5H), 0.60 (s, 3H).

Synthesis of 34.10

To a mixture of MePPh₃Br (5.10 g, 14.3 mmol) in THF (45 mL) was added t-BuOK (1.60 g, 14.3 mmol) at 25°C under N₂. After stirring at 25°C for 30 mins, 34.9 (500 mg, 1.44 mmol) in THF (5 mL) was added at 25°C. After stirring at 60°C for 3 h, the reaction mixture was cooled, poured into NH₄C1 (50 ml) and extracted with EtOAc (2 x 50 mL). The combined organic layer was dried over anhydrous Na₂SO4, fïltered and concentrated. The residue was purified by flash column (0-10% of EtOAc in PE) to give 34.10 (450 mg). 'H NMR (400 MHz, CDCI3) ôh 4.85 (s, IH), 4.70 (s, IH), 2.08-1.93 (m, 2H), 1.89-1.80 (m, 3H), 1.76 (s, 4H), 1.731.60 (m, 2H), 1.55 (s, 2H), 1.52-1.36 (m, 4H), 1.29 (brs, 3H), 1.10 (s, 4H), 1.08-0.98 (m, 3H), 0.90 (br d, 7= 5.0 Hz, 6H), 0.57 (s, 3H).

139

Synthesis of 34.11

To a solution of 34.10 (350 mg, 1.01 mmol) in DCM (20 mL) was added m-CPBA (409 mg, 85%, 2.02 mmol) at 15°C. After stirring at 15°C for 1 h, the mixture was quenched by NaHCO₃ aqueous (50 mL, sat.). The DCM phase was separated and washed with NaHCO₃/Na₂S₂O₃ aqueous (1:1, 3 x 50 mL), brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to give 34.11 (400 mg). NMR (400 MHz, CDC1₃) δ_Η 2.92-2.53 (m, 2H), 2.50.2.27 (m, IH), 2.08-1.69 (m, 2H), 1.35 (s, 11H), 1.25 (br s, 7H), 1.10 (s, 5H), 0.89 (br d, J= 4.8 Hz, 7H), 0.82-0.77 (m, IH), 0.80 (s, IH), 0.73-0.65 (m, 3H).

Synthesis of 34 & 35

To a solution of 34.11 (400 mg, 1.10 mmol) in DMF (15 mL) were added Cs₂CO₃ (1.07 mg, 3.30 mmol) and 1 H-pyrazole-4-carbonitriie (204 mg, 2.20 mmol). After stirring at 130°C for 12 h, the mixture was added into NH₄C1 (50 Ml, sat.) and extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with LiCl (100 mL, 5% in water), brine (2 x 100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash column (0-50% of EtOAc in PE) to give product (450 mg), which was purified by SFC (Column: DAICEL CHIRALCEL OD-H (250 mm x 30 mm, 5 um); Condition; 0.1 %NH₃H₂O ETOH; Begin B:30%; End B:30%) to afford 34 (135.6 mg, 19.5%, Rt = 3.132 min) and 35 (23.8 mg, 47.6%, Rt = 3.383 min).

34: *H NMR (400 MHz, CDC1₃) δ_Η 7.92 (s, IH), 7.82 (s, IH), 4.35 (d, J = 13.8 Hz, IH), 4.08 (d, J= 13.8 Hz, IH), 2.54 (s, IH), 2.07-1.89 (m, 2H), 1.84-1.79 (m, 2H), 1.78-1.71 (m, 3H), 1.68-1.60 (m, 2H), 1.51-1.38 (m, 4H), 1.34-1.15 (m, 7H), 1.09 (s, 4H), 1.08-1.03 (m, 3H), 0.97 (s, 3H), 0.92 (s, 3H), 0.89 (br d, J = 4.0 Hz, 5H). LC-ELSD/MS purity 99%, MS ESI calcd. for C_2SH₄₀N₃ [M-2H₂O+H]+ 418.3 found 418.3. SFC 99% de.

35: ‘H NMR (400 MHz, CDC1₃) 7.89 (s, IH), 7.80 (s, IH), 4.19-4.12 (m, IH), 4.043.97 (m, 1 H), 2.29 (s, IH), 2.08 (br d, J= 12.3 Hz, IH), 1.99-1.89 (m, 2H), 1.82 (br d, J=6.8 Hz, 2H), 1.76-1.60 (m, 5H), 1.52-L38(m, 4H), 1.32-1.18 (m, 6H), 1.10 (d, J = 3.3 Hz, 10H), 0.93-0.84 (m, 8H), LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₈H₄oN₃ [M-2H₂O+H]+ 418.3 found 418.3. SFC 97% de.

EXAMPLES 36 & 37: Synthesis of l-((S)-2-((3R,5R,8R,9R,10S,13S,I4S,I7S)-3-hydroxy-13methyl-3-propylhexadecahydro-lH-cyclopenta[a]phenanthren-17-yl)-2-methoxypropyl)lH-pyrazole-4-carbonitrile (36) & L((R)-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-13

140 methy 1-3-pr opylhexadecahydro-1 H-cyclopenta [ a| phenanthren-17-y l)-2-methoxypr opyl)lH-pyrazole-4-carbonitrile (37)

Synthesis of 36.1

To a solution of 2,6-di-tert-butyl-4-methylphenol (24 g, 108 mmol) in toluène (30 mL) under N₂ at 0°C was added AlMe₃ (2 M in toluene, 27 mL, 54 mmol) dropwise. After stirring at 25°C for 1 h, to the MAD (54 mmol in 30 mL toluene) solution was added a solution of 36.0 (5 g, 18.2 mmol) in toluene (20 mL) dropwise at -60°C. After stirring at -60°C for 1 h under N₂₎ nprMgBr (27.3 mL, 54.6 mmol, 2M in THF) was added dropwise at -60°C. After stirring at -60°C for another 4 h, the reaction mixture was poured into aqueous citric acid (100 mL, sat.) at 10°C and extracted with EtOAc (2 x 100 mL). The combined organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (PE/EtOAc= 0-20%to give 36.1 (3.83 g, 66.1%). ’H NMR (400 MHz, CDC13) δ_Η 2.49-2.37 (m, IH), 2.31-1.98 (m, 2H), 1.97-1.87 (m, IH), 1.86-1.73 (m, 4H), 1.72-1.60 (m, 2H), 1.55-1.45 (m, 5H), 1.45-1.27 (m, 10H), 1.27-1.00 (m, 4H), 0.93 (t, 7=7.2 Hz, 3H), 0.87 (s, 3H).

Synthesis of 36.2

To a mixture of EtPPh₃Br (26.5 g, 71.4 mmol) in THF (50 mL) was added t-BuOK (8.01 g, 71.4 mmol) ai 15°C under N₂. After stirring at 50°C for 30 min, 36.1 (3.8 g, 11.9 mmol) was added in portions below 40°C. After stirring at 40°C for 1 h, the réaction mixture was quenched with 10% NH₄C1 aqueous (100 mL) at 15°C and extracted with EtOAc (500 mL). The combined organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by trituration with MeOH/H₂O (1:1, 300 mL) at reflux to give 36.2 (4.5 g).

141 'H NMR (400 MHz, CDCl3)5_H5.lO (d, J=7.2Hz, IH), 2.41-2.09 (m, 4H), 1.78-1.71 (m, 3H), 1.66-1.63 (m, 3H), 1.56-1.51 (m, 3H), 1.50-1.42 (m, 3H), 1.37-1.29 (m, 6H), 1.21-1.00 (m, 6H), 0.93 (t, >7.28Hz, 3H), 0.87 (s, 3H).

Synthesis of 36.3

To a solution of 36.2 (4.5 g, 13.6 mmol) in THF (50 mL) was added 9-BBN dimer (9.95 g, 40.8 mmol) at 15°C. After stirring at 40°C for 1 h, the mixture was sequentially treated with EtOH (7.9 mL, 135 mmol) at 15°C, NaOH (27 mL, 5M, 135 mmol) at -I0°C, and H₂O₂ (13.5 mL, 10 M, 135 mmol) dropwise. After stirring at 80°C for 1 h, the reaction was quenched with sat. Na₂S₂O₃ (50 mL), stirred for 30 mins and extracted with EtOAc (100 mL). The combined organic phase was washed with saturated brine (2 x 100 mL), dried over anhydrous Na₂SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (ΡΕ/EtOAc = 10 to 20%) to give 36.3 (3.2 g, 67.5%). 'H NMR (400 MHz, CDC13) Ô_H 3.74-3.66 (m, IH), 1.85-1.60 (m, 10H), 1.49-1.29 (m, 13H), 1.22 (d, >6 Hz, 3H), 1.16-1.00 (m, 7H), 0.93 (t, J=1.2 Hz, 3H), 0.66 (s, 3H).LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₃H₄₀O₂ [M+H2H₂O]⁺313.3, found 313.3.

Synthesis of 36.4

To a solution of 36.3 (3.1 g, 8.89 mmol) in DCM (30 mL) was added Dess-martin (7.5 g, 17.7 mmol) at 25°C. After stirring at 25°C for 10 mins, the mixture was quenched by NaHCO₃/Na₂S₂O₃ aqueous (1:1, 375 mL) at 25°C. The organic phase was separated and washed with NaHCO₃/Na₂S₂O₃ aqueous (1:1, 375 mL), brine (200 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to give 36.4 (4 g). *Η NMR (400 MHz, CDC13) Sh 2.40 (d, >12.80Hz, IH), 2.11 (s, 3H), 1.93-1.81 (m, 4H), 1.72-1.63 (m, 8H), 1.50-1.41 (m, 8H), 1.13-1.02 (m, 6H), 0.94-0.91 (m, 3H), 0.62 (s, 3H).

Synthesis of 36.5

To a mixture of MePPh₃Br (12.3 g, 34.5 mmol) in THF (50 mL) was added t-BuOK (3.87 g, 34.5 mmol) at 15°C under N₂. After stirring at 50°C for 30 min, 36.4 (4 g, 11.5 mmol) was added in portions below 50°C. After stirring at 50°C for I h, the reaction mixture was quenched with 10% NH4C1 aqueous (100 mL) at 15°C and extracted with EtOAc (200 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (ΡΕ/EtOAc = 0 to 5%) to give 36.5 (600 mg, 15.1%). NMR (400 MHz, CDCI3) Ô_H 4.84 (s, IH), 4.69 (s, IH) 2.04-1.99 (m,

142

2H), 1.86-1.76 (m, 3H), 1.75 (s, 3 H), 1.74-1.57 (m, 6H), 1.56-1.50 (m, 2H), 1.49-1.28 (m, 10H), 1.23-0.97 (m, 6H), 0.93 (t, J=7.2Hz, 3 H), 0.56 (s, 3H).

Synthesîs of 36.6

To a solution of36.5 (1.7 g, 4.93 mmol) and 2, 6-dimethylpyridine (1.57 g, 14.7 mmol) 5 in DCM (10 mL) was added TBSOTf (1.56 g, 5.91 mmol) at 0°C. After stirring at 25°C for 16 h, the mixture was poured into water (20 mL) and extracted with EtOAc (2x50 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash column (100% of PE) to give 36.6 (2 g, 88.4%).

Synthesîs of 36.7

To a solution of 36.6 (2 g, 4.35 mmol) in DCM (50 mL) was added m-CPBA (1.31 g, 6.52 mmol, 85%) at 25°C. After stirring at 25°C for 2 h, the mixture was poured into NaHCO₃ aqueous (100 mL, sat.) and extracted with EtOAc (2 x 100 mL). The combined organic phase was washed with brine (2 x 100 mL), dried over Na₂SO₄, filtered and concentrated to give 36.7 15 (1.8 g). *Η NMR (400 MHz, CDC1₃) Ô_H 2.96-2.86 (m, 0.7H), 2.62-2.54 (m, 0.7H), 2.52-2.48 (m,

0.3H), 2.52-2.47 (m, 0.3H), 2.34-2.29 (m, IH), 2.10-1.91 (m, 2H), 1.81-1.58 (m, 7H), 1.52-1.34 (m, 1 IH), 1.32-0.96 (m, I3H), 0.86 (d, J = 1.2 Hz, 9H), 0.83-0.75 (m, IH), 0.68 (s, 2H), 0.07 (s, 6H).

Synthesîs of 36.8 & 36.8a

To a solution of 36.7 (900 mg, 1.89 mmol) in DMF (10 mL) were added CS2CO3 (1.48 g,

5.67 mmol) and IH-pyrazole-4-carbontrile (527 mg, 5.67 mmol). After stirring at 130°C for 16 h, the mixture was added into NH₄C1 (100 mL, sat.) and extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with water (100 mL), brine (100 mL), dried over anhydrous Na₂SO4, filtered and concentrated. The residue was purified by flash column (0-15% 25 of EtOAc in PE) to give product (780 mg). The residue was purified by flash column (0-10% of EtOAc in PE) to give 36.8 (350 mg) and 36.8a (230 mg).

36.8: ’H NMR (400 MHz, CDCI3) δ_Η 7.92 (s, IH), 7.84-7.80 (m, IH), 4.37 (d, J = 13.6 Hz, IH), 4.09 (d, J = 13.6 Hz, IH), 2.48 (s, IH), 2.08-1.96 (m, IH), 1.83-1.58 (m, 8H), 1.49-1.21 (m, 16H), 1.20-1.01 (m, 6H), 0.96 (s, 3H), 0.92 (s, 3H), 0.86 (s, 14H), 0.07 (s, 6H).

143

36.8a: 'H NMR (400 MHz, CDC1₃) δ_Η 7.92 (s, IH), 7.89 (s, IH), 4.22-4.11 (m, IH), 4.06-3.95 (m, lH),2.26(s, IH), 2.14-2.02 (m, IH), 1.95-1.87 (m, IH), 1.8l-l.61 (m, 7H), 1.501.24 (ni, 18H), 1.20-0.99 (m, 10H), 0.91-0.87 (m, 9H), 0.07 (d, J = 1.2 Hz, 6H).

Synthesis of 36.9

To a solution of 36.8 (350 mg, 0.6162 mmol) in THF (10 mL) was added NaH (123 mg, 3.08 mmol, 60%) at 0°C under N₂. After stirring for 0.5 h, Mel (874 mg, 6.16 mmol) was added into the reaction mixture at 25C. After stirring at 25°C for another 16 h, the reaction mixture was quenched by ammonia (1 mL), poured into water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phase was washed with brine (2 x 50 mL), dried over anhydrous Na₂SO4, filtered and concentrated. The residue was purified by flash column (0-20% of EtOAc in PE) to give 36.9 (350 mg). ^]H NMR (400 MHz, CDCi₃) δ_Η 7.91 (s, IH), 7.75 (s, 1H),4.344.18 (m, 2H), 3.18 (s, 3H), 2.00-1.93 (m, IH), 1.83-1.58 (m, 11H), 1.48-1.25 (m, 19H), 1.220.97 (m, 15H), 0.86 (s, 22H), 0.07 (s, 6H).

Synthesis of 36.9a

To a solution of 36.8a (230 mg, 0.4049 mmol) in THF (5 mL) was added NaH (80.6 mg, 2.02 mmol, 60%) at 0°C under N₂. After stirring for 0.5 h, Mel (573 mg, 4.04 mmol) was added into the reaction mixture at 25°C. After stirring at 25°C for another 16 h, the reaction mixture was quenched by ammonia (1 mL), poured into water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phase was washed with brine (2 x 50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash column (0-20% of EtOAc in PE) to give 36.9a (230 mg). ‘H NMR (400 MHz, CDCft) δ_Η 7.90 (s, IH), 4.35-4.03 (m, 3H), 3.21-3.05 (m, 3H), 2.11-1.94 (m, 3H), 1.80-1.61 (m, 11H), 1.47-1.27 (m, 18H), 1.21-0.98 (m, 18H), 0.86-0.73 (m, 16H), 0.07 (br s, 6H)

Synthesis of 36

To a solution of 36.9 (350 mg, 0.5993 mmol) in THF (3.5 mL) was added TBAF (5.99 mL, 5.99 mmol, IM in THF). After stirring at 80°C for 16 h, the reaction mixture was quenched with NH₄C1 solution (30 mL, sat.) and extracted with EtOAc (2 x 20 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated to the product (120 mg). The product (130 mg, 0.2779 mmol) was purified by SFC (Column: DAICEL CHIRALPAK AD-H (250 mm * 30 mm, 5 um); Condition: 0.1%NH₃H₂O 1PA; Begin B 35 End B 35; Flow Rate (ml/min) 60) to give 36 (95.4 mg, 73.9%, Rt = 1.459 min). ’H 144

NMR (400 MHz, CDCl₃) δ_Η 7.99-7.86 (m, l H), 7.80-7.67 (m, IH), 4.35-4.13 (m, 2H), 3.25-3.12 (m, 3H), 1.95 (br d, J = 12.8 Hz, IH), 1.83-1.57 (m, 9H), 1.49-1.23 (m, 12H), 1.07 (s, 10H), 0.93 (t, J = 7.2 Hz, 3H), 0.85 (s, 3H). LC-ELSD/MS purity 99%, MS ESI calcd for C28H41N3 [MCH3OH-H2O+H] 418.3, found 418.3. SFC 99% de.

Synthesis of 37

To a solution of 36.9a (230 mg, 0.3938 mmol) in THF (2.3 mL) was added TBAF (1.96 mL, 1.96 mmol, IM in THF). After stirring at 80°C for 16 h, the reaction mixture was quenched with NH₄C1 solution (30 mL, sat.) and extracted with EtOAc (2 x 20 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated to give the product (50 mg). The product was purified by SFC (Column: DAICEL CHIRALPAK AD-H (250 mm * 30 mm, 5 um); Condition: 0.1%ΝΗ₃Η₂Ο IPA; Begin B 35 End B 35; Flow Rate (ml/min) 60) to afford 37 (39.2 mg, 78.5%, Rt = 1.703 min). 'H NMR (400 MHz, CDCft) δ_Η 7.90 (s, 1 H), 7.75 (s, IH), 4.24 (s,2H),3.14 (s, 3H), 2.04 (br d, J = 12.4 Hz, IH), 1.84-1.59 (m, 9H), 1.49-1.05 (m, 18H), 1.02 (s, 4H), 0.93 (t, J = 7.2 Hz, 3H), 0.82 (s, 3H). LC-ELSD/MS purity 99%, MS ESI calcd for C₂₈H₄|N₃ [M-CH₃OH-H₂O+H]⁺ 418.3, found 418.3. SFC 99% de.

EXAMPLE 38: Synthesis of l-(2,2-difluoro-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy3-(methoxymethyl)-13-methylhexadecahydro-lH-cyclopenta[a]phenanthren-17-yl)ethyl)lH-pyrazole-4-carbonitrile (38)

Synthesis of 38.1

To a solution of 38.0 (1.70 g, 4.87 mmol) in MeOH (20 ml) were added HBr (196 mg, 974 pmol, 40% in water) and Br₂ (934 mg, 5.84 mmol) at 25°C. After stirring at 25°C for 2h, the mixture was quenched by NaHCO₃ (10 mL, sat.aq.), treated with water (20 mL), and extracted

145 with EtOAc (2 x 30 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum to afford 38.1 (2.1 g), which was used directly for the next step. IH NMR (400 MHz, CDC1₃) δ_Η 3.96-3.86 (m, 2H), 3.43-3.34 (m, 6H), 2.85-2.76 (m, IH), 2.62 (s, 1 H), 2.22-2.11 (m, IH), 1.95-1.87 (m, 1 H), 1.86-1.67 (m, 7H), 1.58-1.33 (m, 9H), 1.21-0.97 (m, 4H), 0.63 (s, 3H).

Synthesis of 38.2

To a solution of 38.1 (2.1 g, 4.91 mmol) in acetone (30 mL) were added 1 H-pyrazole-4carbonitrile (685 mg, 7.36 mmol) and K₂CO₃ (2.02 g, 14.7 mmol). After stirring at 15°C for 12 h, the mixture was treated with water (30 mL) and extracted with EtOAc (2x30 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash column (0-50% of EtOAc in PE) to gîve 38.2 (1.6 g, 74.4%). IH NMR (400 MHz, CDC1₃) Ô_H 7.85 (s, IH), 7.81 (s, IH), 5.05-4.86 (m, 2H), 3.44-3.38 (m, 5H), 2.67-2.56 (m, 2H), 2.25-2.14 (m, IH), 2.07-2.02 (m, IH), 1.87-1.72 (m, 6H), 1.67-1.59 (m, 2H), 1.53-1.34 (m, 8H), 1.31-1.26 (m, 2H), 1.18-1.05 (m, 3H), 0.67 (s, 3H).

Synthesis of 38.3

To a solution of 38.2(1.6 g, 3.63 mmol) in DCM (30 mL) were added DM AP (442 mg, 3.63 mmol) and acetyl acetate (1.47 g, 14.5 mmol). After stirring at 25°C for 16h, the mixture was poured into îce-water (100 mL), stirred for 10 mins. and extracted with DCM (2 x 50 mL). The combined organic phase was washed with brine (2 x 100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash column (0-20% of EtOAc in PE) to give 38.3 (590 mg, 33.9%). ’H NMR (400 MHz, CDCI3) δ_Η 7.85 (s, IH), 7.81 (s, IH), 5.04-4.86 (m, 2H), 3.86-3.74 (m, 2H), 3.40-3.34 (m, 4H), 2.55-2.66 (m, IH), 2.25-2.15 (m, 2H), 2.03-1.98 (m,4H), 1.90-1.68 (m, 10H), 1.56-1.49 (m, 2H), 1.44-1.31 (m, 6H), 1.15-0.98 (m, 4H), 0.67 (s, 3H).

Synthesis of 38.4

To a solution of 38.3 (290 mg, 600 pmol) in chloroform (4 mL) was added dropwise DAST (1.58 ml, 12 mmol, 1.22g/ml) at 0°C under N₂. After stirring at 60°C for 12h, the mixture was quenched with NaHCO₃ (30 mL) carefully and extracted with EtOAc (2 x 30 mL). The combined organic phase was washed with brine (20 mL), dried over Na₂SO₄, filtered and concentrated. The residue was purified by flash column (0-30% of EtOAc in PE) to give 38.4 (34 mg, 11.2%). 'H NMR (400 MHz, CDC13) δ_Η 7.92 (s, IH), 7.82 (s, IH), 4.50-4.37 (m, IH), 3.84

146

3.75 (m. 2H), 3.36 (s, 3H), 2.02-1.93 (m, 5H), 1.86-1.63 (m, SH), 1.53-1.26 (m, 7H), 1.24-1.00 (m, 7H), 0.86 (m, 4H).

Synthesis of 38

To a solution of 38.4 (24 mg, 47.6 μιηοΐ) in MeOH (1 ml) was added LiOH(l .99 ml, 9.99 mmol, 5M) at 15°C. After stirring at 15°C for 20 h, the mixture was poured into water (20 mL), stirred for 10 min, and extracted with EtOAc (3x5 mL). The combined organic phase was washed with brine (2x5 mL), dried over anhydrous Na2SO₄, filtered and concentrated. The residue was purified by flash column (0-30% of EtOAc in PE) to give 38 (10 mg). ’H NMR (400 MHz, CDC13) Ô_H 7.92 (s, IH), 7.83 (s, IH), 4.52-4.37 (m, 2H), 3,42-3.36 (m, 5H), 2.58 (s, IH), 2.02-1.96 (m, IH), 1.83-1.67 (m, 8H), 1.50-1.34 (m, 7H), 1.25 (s, 3H), 1.15-1.06 (m, 5H), 0.86(d, 7=3.0 Hz, 3H). LC-ELSD/MS 30-90AB_2min_E, purity>99%, MS ESI calcd. for C₂₆H₃₇F₂N₃O₂ [M-H₂O+H]⁺ 444.2, found 444.2.

EXAMPLE 39: Synthesis of l-((l-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13dimethylhexadecahydro-lH-cyclopenta[a]phcnanthren-17-yl)cyclopropyl)methyl)-lHpyrazolc-4-carbonîtrile (39)

Synthesis of 39.1

To a suspension of NaH (2.75 g, 60% in oil, 68.8 mmol) in THF (60 mL) was added (EtO) ₂ P (O) CH₂COOEt (15.4 g, 68.8 mmol) dropwise at 0°C. After stirring at 20°C for 10 min, a solution of 39.0 (10 g, 34.4 mmol) in THF (20 mL) was added dropwise at 20°C. After

147 refluxing at 70°C for 16 h, the mixture was poured into NH4CI (200 mL, 10% aq.) and extracted with EtOAc (200 mL). The combined organic layer was dried over anhydrous Na₂SO4, fïltered and concentrated. The residue was purified by flash column (0~20% of EtOAc in PE) to give 39.1 (12 g, 97%). *H NMR (400 MHz, CDC1₃) δ_Η 5.52 (t, 7=2.4 Hz, IH), 4.15 (q, 7=7.2 Hz, 2H), 2.90-2.75 (m, 2H), 1.95-1.60 (m, 5H), 1.50-1.25 (m, 18H), 1.20-1.05 (m, 4H), 0.82 (s, 3H).

Synthesis of 39.2

To a solution of 39.1 (12 g, 33.2 mmol) in THF (150 mL) was added Pd/C (2 g, dry, 10%) under N₂. The mixture was degassed under vacuum and purged with H₂ three times.After stirring under H₂ (40 psi) at 40°C for 24 h, the mixture was fïltered through a pad of celite and washed with THF (3 x 50 mL). The combined filtrate was concentrated to give 39.2 (11.7 g, 97.5%). 'H NMR(400 MHz, CDCI3) δ_Η 4.11 (q,7=6.8 Hz, 2H), 2.35 (dd,7= 5.2, 14.4 Hz, IH), 2.10 (dd, 7 = 10.0, 14.8 Hz, 1 H), 2.00-1.75 (m, 6H), 1.55.1.50 (m, 3H), 1.50-1.35 (m, 6H), 1.351.25 (m, 10H), 1.20-0.95 (m, 6H), 0.59 (s, 3H).

Synthesis of 39.3

To a suspension of L1AIH4 (6.0 g, 158 mmol) in THF (120 mL) was added a solution of 39.2 (11.1 g, 30.6 mmol) in THF (30 mL) at 0°C under N₂. After stirring at 0°C for 10 min, to the mixture was added water/THF (6 mL/200 mL) dropwise followed by NaOH (6 mL, 10% aq.) and water (18 mL). The mixture was fïltered, and the precipitate was washed with THF (3 x 100 mL). The combined filtrate was concentrated and trîturated from DCM (50 mL) to give 39.3 (9 g, 92%). 'H NMR (400 MHz, CDC1₃) δ_Η 3.75-3.55 (m, 2H), 1.90-1.60 (m, 9H), 1.50-1.15 (m, 16H) 1.15-0.90 (m, 6H), 0.59 (s, 3H).

Synthesis of 39.4

To a solution of 39.3 (3 g, 9.3 mmol) in DCM (80 mL) was added DMP (7.92 g, 18.7 mmol). After stirring at 30°C for Ih, the mixture was washed with a mixed solution of NaHCO₃ (160 mL, aq. sat.) and Na₂S₂O3 (80 mL, aq. sat.) twice, dried over Na₂SO₄, fïltered and concentrated. The residue was purified by flash column (10-30% of EtOAc in PE) to give 39.4 (2.2 g, 74%). 'H NMR (400 MHz, CDC1₃) Ô_H 9.76 (t, 7= 2.4 Hz, IH), 2.55-2.45 (m, IH), 2.302.20 (m, IH), 2.00-1.80 (m, 5H), 1.55.1.55 (m, 4H), 1.50-1.20 (m, 13H), 1.30-1.00 (m, 6H), 0.60 (s, 3H).

Synthesis of 39.5

148

A solution of 39.4 (2 g, 6.27 mmol), HCHO (5.05 g, 37%, 62.6 mmol), Et₃N (1.90 g, 18.8 mmol) in water (10 mL) and dîoxane (20 mL) was stirred at 70^ûC for 16 hs. The mixture was added into water (50 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na₂SO₄, fdtered and concentrated to give 39.5 (1.5 g). *H NMR (400 MHz, CDCft) δ_Η 9.55 (s, IH), 6.27 (s, IH), 6.11 (s, IH), 2.85-2.75 (m, IH), 1.90-1.59 (m, 9H), 1.52-1.28 (m, UH), 1.26 (s, 3H), 1.20-0.85 (m, 4H), 0.52 (s, 3H).

Synthesis of 39.6

To a mixture of 39.5 (1.5 g, 4.53 mmol) and 2-methyl-2-butene (10 mL) in acetone (50 mL) were added a solution of NaClO₂ (2.04 g, 22.6 mmol) and NaH₂PO₄ (2.71 g, 22.6 mmol) in H₂O (25 mL) at 0°C. After stirring at 20°C for 16 h, the reaction mixture was diluted with H₂O (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated to give 39.6 ( 1.9 g). NMR (400 MHz, CDC1₃) Ô_H 6.38 (s, IH), 5.64 (s, IH), 2.81 (t, J= 9.2 Hz, IH), 1.90-1.59 (m, 10H), 1.52-1.28 (m, 9H), 1.26 (s, 3H), 1.24-0.90 (m, 6H), 0.55 (s, 3H).

Synthesis of 39.7

To a solution of 39.6 (1.9 g, 5.48 mmol) in DMF (30 mL) was added K₂CO₃ (1.52 g, 10.9 mmol) at 20°C. After stirring at 20°C for Ih, Mel (1.16 g, 8.22 mmol) was added at 20°C. After stirring at 20°C for another 2 h, the mixture was added into NH₄C1 (150 mL, sat.) and extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with water (2 x 100 mL), brine (150 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash column (0-15% of EtOAc in PE) to give 39.7 (1.26 g, 64%). ¹H NMR (400 MHz, CDCft) Ôh 6.19 (s, IH), 5.50 (s, 1H),3.73 (s, 3H), 2.80 (t, J = 9.2 Hz, IH), 1.90-1.59 (m, 8H), 1.52-1.28 (m, UH), 1.26 (s, 3H), 1.24-0.90 (m, 5H), 0.52 (s, 3H).

Synthesis of 39.8

To a solution of 39.7 (1.25 g, 3.46 mmol) in DMF (30 mL) were added Me₃SI (2.10 g, 10.3 mmol) and t-BuOK (1.15 g, 10.3 mmol). After stirring at 20°C for 16 h, the mixture was added into water (200 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with brine (200 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash column (0-15% of EtOAc in PE) to give 39.8 (350 mg, 27%). ’H NMR (400 MHz, CDC1₃) δ_Η 3.63 (s, 3H), 2.45-2.35 (m, IH), 1.92-1.78 (m, 3H), 1.75-1.59 (m,

149

5H), 1.52-1.28 (m, 9H), 1.26 (s, 3H), 1.25-0.80 (m, 9H), 0.68-0.55 (m, 5H). LC-ELSD/MS 3090AB_2min_E, purity 99%, MS ESI calcd. for C₂₄H₃7O₂ [M-H₂O+Hf 357.3, found 357.3.

Synthesis of 39.9

To a solution of 39.8 (350 mg, 0.93 mmol) in THF (10 mL) was added LiAlH₄ (70.5 mg, 1.86 mmol) at 20°C. After stirring at 20°C for 1 h, water (70 mg) was added to the mixture. The mixture was filtered, and the mother liquid was concentrated to give 39.9 (320 mg, 99%). ’H NMR (400 MHz, CDCI3) Ô_H 3.96 (d, J = 10.8Hz, IH), 3.00 (d,7= 11.2Hz, IH), 2.10-2.00 (m, 2H), 1.92-1.75 (m, 3H), 1.74-1.59 (m, 3H), 1.52-1.28 (m, 11H), 1.26 (s, 3H), 1.25-0.95 (m, 7H), 0.72 (s, 3H), 0.71-0.65 (m, IH), 0.35-0.25 (m, 2H), 0.24-0.11 (m, !H).sLC-ELSD/MS purity 99%, MS ESI calcd. for C₂₃H₃₅ [M-2H₂O+H]⁺ 311.3, found 311.3.

Synthesis of 39.10

To a solution of 39.9 (1.7 g, 4.90 mmol) in DCM (50 mL) were added silica gel (2.10 g) and PCC (2.10 g, 9.80 mmol) at 25°C. After stirring at 25°C for Ih, the mixture was concentrated. The residue was purified by flash column (0-20% of EtOAc in PE) to give 39.10 (1.28 g, 76.1%). *H NMR (400 MHz, CDCI3) Ô_H 9.48 (s, IH), 2.01 (t, 7=8 Hz, IH), 1.72-1.87 (m, 5H), 1.62-1.69 (m, 5H), 1.36-1.50 (m, 8H), 1.26 (s, 4H), 0.91-1.17 (m, 8H), 0.79-0.84 (m, IH), 0.68 (s, 3H).

Synthesis of 39.11

To a solution of 39.10 (1.28 g, 3.71 mmol) in EtOH (30 mL) was added NH₂NH₂H₂O (1.11 g, 22.2 mmol) and Et₃N (749 mg, 7.42 mmol) at 25°C. After stirring at 75°C for 5 h, the mixture was added into water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated to give 39.11 (1.3 g). IH NMR (400 MHz, CDCI3) 8h 7.32 (s, IH), 1.77-1.81 (m, 4H), 1.56-1.66 (m, 12H), 1.35-1.42 (m, 6H), 1.00-1.11 (m, 9H), 0.68 (s, 4H), 0.60-0.63 (m, IH), 0.49-0.54 (m, IH).

Synthesis of 39.12

To a solution of 39.11 (1.3 g, 3.62 mmol) in MeOH (20 mL) was added NaCNBH₃ (2.27 g, 36.2 mmol) at 25°C. After stirring at 70°C for 16 h, the mixture was added into water (100 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated to give 39.12 (1.5 g). IH

150

NMR (400 MHz, CDC1₃) δ_Η 2.51-2.99 (m, 4H), 2.28-2.40 (m, IH), 2.04 (s, 3H), 1.80 (br s, 3H), 1.53-1.72 (m, 4H), 1.29-1.50 (m, 8H), 0.98-1.15 (m, 5H), 0.97-1.18 (m, 5H), 0.74-0.92 (m, 4H), 0.72 (s, IH), 0.44 (br s, 2H), 0.07 (s, 4H).

Synthesîs of 39.13

To a solution of 39.12 (350 mg, 970 μιηοΐ) in EtOH (5 mL) were added Et₃N (979 mg, 9.70 mmol) and 2-(ethoxymethylidene) propanedinitrile (236 mg, 1.94 mmol). After stirring at 75°C for 16 h, the mixture was added into water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash column (20-40% of EtOAc in PE) to give 39.13 (85 mg). NMR (400 MHz, CDC1₃) δ_Η 7.46 (s, IH), 4.27 (s, 2H), 3.93-3.97 (m, IH), 1.92-2.00 (m, 2H), 1.77-1.80 (m, 5H), 1.38-1.42 (m, 9H), 1.04-1.11 (m, 10H), 0.78 (s, 3H), 0.55.0.74 (m, 3H), 0.59 (s, IH), 0.39-0.43 (m, 2H), 0.10-0.13 (m, IH).

Synthesîs of 39

To a solution of 39.13 (50 mg, 114 pmol) in THF (2 mL) was added -BuONO (25 mg, 242 μιηοΐ). After stirring at 70°C for 16 h, the mixture was added into water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na₂SO4, filtered and concentrated. The residue was purified by flash column (15-30% of EtOAc in PE) to give 39 (4.4 mg, 3.23%). 'H NMR (400 MHz, CDCft) δ_Η 7.94 (s, IH), 7.79 (s, IH), 4.69 (d, 7=12.0 Hz, IH), 3.54 (d, 7=12.0 Hz, IH), 1.97-2.02 (m, IH), 1.65-1.87 (m, 7H), 1.34-1.47 (m, 8H), 1.25 (s, 5H), 0.98-1.12 (m, 7H), 0.87-0.90 (m, IH), 0.76 (s, 3H), 0.46-0.55 (m, 2H), 0.36-0.42 (m, IH). LC-ELSD/MS purity>99%, MS ESI calcd. For C₂7H₃₉N₃O [M-H₂O+H] 404.3, found 404.3.

EXAMPLE 40: Synthesîs of l-((3-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3(methoxymethyl)-13-methyIhexadecahydro-lH-cyclopenta[a]phenanthren-17-yI)oxetan-3yl)methyl)-lH-pyrazole-4-carbonitrile (40)

151

Synthesis of 40.1

To a suspension of NaH (2.23 g, 56.0 mmol, 60% in oil) in THF (50 mL) was added (EtO)2 P(O)CH₂COOEt (12.5 g, 56.0 mmol) dropwise at 0°C. After stirring at 20°C for 10 min, a solution of 40.0 (9 g, 28.0 mmol) in THF (90 mL) was added dropwise at 20°C. After refluxing at 70°C for 16 h, the mixture was poured into 10% NH4C1 (200 mL, aq.) and extracted with EtOAc (200 mL x 3). The organic layer was washed with brine (100 mL X 2), dried over Na₂SO₄, filtered and concentrated. The residue was purified by flash column (0-20% of EtOAc in PE) to give 40.1 (9.5 g, 87.1%). 'H NMR (400 MHz, CDC1₃) ) Ô_H 5.46-5.57 (m, IH), 3.864.40 (m, 3H), 3.27-3.51 (m, 5H), 2.71-2.97 (m, 2H), 2.53-2.62 (m, IH), 1.61-1.95 (m, 7H), 1.341.53 (m, 6H), 1.32-1.09 (m, 10H), 0.81 (s, 3H).

Synthesis of 40.2

To a solution of 40.1 (9.5 g, 24.3 mmol) in THF (100 mL) was added Pd/C (1.5 g, dry, 10%) under N₂. The suspension was degassed under vacuum and purged with H₂ for three tîmes. After stirring under H? (40 psi) at 40°C for 24 h, the mixture was filtered through a pad of celite and washed with THF (3 x 100 mL). The combined flltrate was concentrated to give 40,2 (9.3 g, 97.5 %). ‘H NMR (400 MHz, CDC1₃) Ô_H 4.00-4.25 (m, 2H), 3.39 (s, 4H), 3.31-3.46 (m, IH), 2.58 (s, IH), 2.29-2.40 (m, IH), 2.03-2.15 (m, IH), 1.60-1.94 (m, 9H), 1.28-1.58 (m, SH), 1.271.23 (m, 4H), 0.97-1.17 (m, 6H), 0.59 (s, 3H).

Synthesis of 40.3

152

To a solution of i-Pr₂NH (7.16 g, 70.8 mmol) in THF (60 mL) was added n-BuLi (28.3 mL, 2.5 M in hexane, 70.8 mmol) at -70°C. To the mixture was added a solution of 40.2 (9.3 g, 23.6 mmol) in THF (90 mL) at -70°C. After stirring at -70°C for 1 h, to the mixture was added CICOOEt (7.68 g, 70.8 mmol). After stirring at -70^ûC for 1 h, the mixture was quenched by NH₄C1 (200 mL, 10%) and extracted with EtOAc (3 x 150 mL). The combined organic layer was washed with brine (2 x 100 mL), dried over anhydrous NajSOg, filtered and coneentrated in vacuum. The residue was purified by flash column (0-40% of EtOAc in PE) twice to give 40.3 (9.2 g). ‘H NMR (400 MHz, CDC1₃) δ_Η 4.11-4.19 (m, 4H), 3.34-3.45 (m, 5H), 3.32-3.24 (m, IH), 2.57 (s, IH), 2.13-2.27 (m, IH), 1.86-2.00 (m, IH), 1.61-1.85 (m, 5H), 1.31-1.57 (m, 8H), 1.23-1.29 (m, 8H), 0.82-1.20 (m, 7H), 0.70 (s, 3H).

Synthesis of 40.4

To a suspension of t-BuOK (11.1 g, 99.0 mmol) in THF (110 mL) was added a solution of 40.3 (9.2 g, 19.8 mmol) in THF (90 mL) at 0°C. After stirring at 20°C for 1 h, BOMC1 (18.4 g, 118 mmol) was added at 0°C. After stirring at 0°C for 1 h, the mixture was poured into NH4CI (250 mL, sat.) and extracted with EtOAc (100 mL x 3). The combined organic layer was dried over anhydrous Na₂SO₄, filtered and coneentrated to give 40.4 (20.7 g).

Synthesis of 40.5

To a suspension of LAH (7.51 g, 198 mmol) in THF (200 mL) was added a solution of 40.4 (11.5 g, 19.8 mmol) in THF (100 mL) dropwise at 0^ûC. After stirring at 0°C for 1 h, the mixture was quenched sequentially with water/THF (7.5 mL/150 mL), NaOH (7.5 mL, 10%) and water (22.5 mL). The mixture was filtered and the solid was washed with THF (3 x 100 mL). The combined filtrate was coneentrated to 150 mL and HCl (2 M, 40 mL) was added. After stirring at 50°C for 1 h, to the mixture was added NaHCO3 (200 mL, sat) and extracted with EtOAc ( 150 mLx 3). The combined organic layer was dried over Na2SO4, filtered and coneentrated. The residue was purified by flash column (30-100% of EtOAc in PE) twice to give 40.5 (4.8 g). ^lH NMR (400 MHz, CDCft) δΗ 7.27-7.40 (m, 5H), 4.50 (s, 2H), 3.59-3.97 (m, 6H), 3.38 (s, 5H), 2.53-2.81 (m, 3H), 1.66-1.94 (m, 5H), 1.29-1.61 (m, 12H), 0.85-1.23 (m, 7H), 0.73 (s, 3H).

Synthesis of 40.6

To a solution of 40.5 (1 g, 1.99 mmol) in THF (20 mL) was added n-BuLi (0.952 mL, 2.5 M in hexane, 2.38 mmol) at 0°C. After stirring at 0°C for 10 min, to the mixture was added a

153 solution of TsCl (453 mg, 2.38 mmol) in THF (5 mL). After stirring at 0°C for 1 h, to the mixture was added n-BuLi (952 pL, 2.5 M in hexane, 2.38 mmol) at 0°C. After stirring at 15°C for 2 h, the mixture was quenched by NH4CI (20 mL, sat.) and extracted with EtOAc (2 x 30 mL). The combined organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by flash column (0-15% of EtOAc in PE) to give 40.6 (600 mg. 62.5%). ’H NMR (400 MHz, CDCft) Ô_H 7.27-7.41 (m, 5H), 4.78-4.88 (m, IH), 4.41 4.67 (m, 4H), 4.20-4.27 (m, IH), 3.85-3.94 (m, IH), 3.61-3.71 (m, IH), 3.39 (s, 5H), 2.59 (s, IH), 2.05-2.17 (m, IH), 1.58.1.99 (m, 7H), 0.95-1.50 (m, 16H), 0.51 (s, 3H).

Synthesis of 40.7

To a solution of 40.6 (550 mg, 1.13 mmol) in THF (20 mL) was added Pd/C (0.5 g, 10%, wet) under N₂. The mixture was degassed under vacuum and purged with H₂ for three times. After stirring under H₂ (40 psi) at 30°C for 20 h, the mixture was filtered and the solid was washed with THF (20 mL). The combined filtrate was concentrated and purified by flash column (40-70% of EtOAc in PE) to give 40.7 (300 mg, 67.7%). ’H NMR (400 MHz, CDCh) Ô_H 4.85 (d, J= 6.4 Hz, 1 H), 4.55 (d, 7= 6.0 Hz, 1 H), 4.46 (d, 7 =6.0 Hz, IH), 4.24 (d, 7= 6.8 Hz, IH), 4.09 (dd, 7= 6.4, 10.8 Hz, IH), 3.82 (dd, 7= 4.8, 11.2 Hz, IH), 3.39 (s, 5H), 2.59 (s, IH), 2.042.21 (m, IH), 1.59-2.02 (m, 10H), 0.98-1.50 (m, 14H), 0.53 (s, 3H).LC-ELSD/MS purity: 99%, MS ESI calcd. for C₂₄H₄₀O₄ [M+H]⁺ 393.2, found C₂₄H_4ÜO₄ [M+H]⁺ 393.3.

Synthesis of40.8

To a solution of 40.7 (150 mg, 0.3820 mmol) in DCM (5 mL) were added N-Meimidazole (31.3 mg, 0.382 mmol), TEA(193 mg, 1.91 mmol) andTsCI (217 mg, 1.14 mmol). After stirring at 20°C for 1 h, the mixture was concentrated to give 40.8 (340 mg).

Synthesis of 40

To a solution of 40.8 (250 mg, 0.4572 mmol) in DMF (5 mL) were added 4-cyanopyrazole (85.1 mg, 0.9144 mmol), Kl (75.8 mg, 0.4572mmol) and K₂CO₃ (128 mg, 0.9144 mmol). After stirring at 80°C for 16 h, the mixture was washed with water (5 mL) and extracted with EtOAc (50 mL x 3). The combined organic layer was washed with brine (30 mL x 2), dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by Pre-HPLC (column: Welch Xtimate C18 150*25mm*5um; Mobile phase: A: CO₂ B: water (0.225%FA)-ACN; gradient: from 55% to 85% of B, Flow Rate (ml/min): 25) to give 40 (10 mg, 3.44%). ’H NMR (400 MHz, CDCI3) S_H 7.88 (s, IH), 7.84 (s, IH), 4.70-4.55 (d, 7= 6.8 Hz, IH),

154

4.56-4.70 (m, 2H), 4.55-4.45 (m, 2H), 4.38-4.28 (m, IH), 3.39 (s, 5H), 2.57 (s, IH), 1.60-2.15 (m, 1 IH), 0.98-1.50 (m, 13H), 0.69 (s, 3H).LC-ELSD/MS purity: 99%, MS ESI calcd. for C_2gH₄iN₃O₃ [M+H]⁺ 468.3, found C₂₈H₄iN₃O₃ [M+H]⁺ 468.3.

EXAMPLE 41 : Synthesis of l-(2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13dimethylhexadecahydro-lH-cyclopenta[a]phenanthrcn-17-yl)-2-methylpropyl)-lHpyrazole-4-carbonitrile (41)

Synthesis of 41,1

To a suspension of NaH (2.75 g, 60%, 68.8 mmol) in THF (60 mL) was added (EtO)₂P(O)CH₂COOEt (15.4 g, 68.8 mmol) dropwise at 0°C under N₂. After stirring at 20°C for 10 mins, a solution of 41.0 (10 g, 34.4 mmol) in THF (20 mL) was added dropwise at 2Û°C. After refluxing at 70°C for 16 h, the mixture was poured into NH4CI (200 mL, 10% aq) and extracted with EtOAc (200 mL). The organic layer was séparaied, dried over Na₂SÜ4, filtered, concentrated. The residue was purified by flash column (0-20% EtOAc in PE) to give 41.1 (12 g, 97%). ^lH NMR(400 MHz, CDCi₃) δ_Η 5.52 (t, J = 2.4 Hz, IH), 4.15 (q, J = 7.2 Hz, 2H), 2.902.75 (m, 2H), 1.95-1.60 (m, 5H), 1.50-1.25 (m, 18H), 1.20-1.05 (m, 4H), 0.82 (s, 3H).

Synthesis of 41.2

To a solution of 41.1 (12 g, 33.2 mmol) in THF (150 mL) was added Pd/C (2 g, dry, 10%) at 20°C under N₂. After stirring at 40°C under H₂ (40 psi) for 24 h, the mixture was filtered though a pad of celite and washed with THF (3x50 mL). The combined filtrate was concentrated to give 41.2 (11.7 g, 97.5%). ’H NMR(400 MHz, CDC1₃) 8_h 4.11 (q, J = 6.8 Hz,

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2H), 2.35 (dd, 7=5.2, 14.4 Hz, IH), 2.10 (dd, 7= 10.0, 14.8 Hz, IH), 2.00-1.75 (m, 6H), 1.701.50 (m, 3H), 1.50-1.35 (m, 6H), 1.35-1.25 (m, 10H), 1.20-0.95 (m, 6H), 0.59 (s, 3H).

Synthesis of 41.3

To a solution of 41.2 (2.3 g, 6.3 mmol), 2,6-dimethylpyridine (1.69 g, 15.8 mmol) in 5 DCM (20 mL) was added dropwise tert-butyldimethylsilyl trifluoromethanesulfonate (3.33 g, 12.6 mmol) at 0°C. After stirring at 15°C for 18 h, the reaction mixture was quenched with water (30 mL) and extracted with DCM (2 x 20 mL). The combined organic phase washed with brine (50 mL), dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by flash column (0-10% of EtOAc in PE) to afford 41.3 (2.9 g). 'H NMR (400 MHz, CDCI3) 10 δ_Η 4.14-4.08 (m,2H), 2.40-2.32 (m, 1H), 2.15-2.03 (m, IH), 1.95-1.59 (m, 9H), 1.46-1.28 (m, 6H), 1.27-1.21 (m, 8H), 1.20-0.92 (m, 7H), 0.86-0.85 (m, 9H), 0.59 (s, 3H), 0.09-0.05 (m, 6H)

Synthesis of 41.4

To a solution of i-Pr₂NH (2.34 g, 23.2 mmol) in THF (20 mL) was added n-BuLi (11.1 mL, 2.5 M, 27.8 mmol) at -70^ûC under N₂. The mixture was warmed to 0°C and stirred at 0°C for 15 30 mins. To the mixture was added to a stirred solution of 41.3 (3.7 g, 7.7 mmol) in THF (20 mL) at -70°C. After stirring at -70°C for Ih, methyl iodide (6.60 g, 46.5 mmol) was added. After stirring at 20°C for 16 h, the reaction was diluted with water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash column (0-5% 20 of EtOAc in PE) to give 41.4 (2.7 g, 71%). *H NMR (400 MHz, CDCI3) Ô_H 4.20-4.11 (m, 2H), 2.36-2.26 (m, IH), 1.90-1.56 (m, JOH), 1.51-1.29 (m, 8H), 1.28-1.27 (m, 3H), 1.21 (s, 3H), 1.10 (d,7=6.8 Hz, 3H), 1.07-0.87 (m, 6H), 0.86 (s, 9H), 0.69 (s, 3H), 0.06 (s, 6H)

Synthesis of 41.5

To a solution of i-Pr2NH (1.15 g, 11.4 mmol) in THF (10 mL) under N₂ was added n25 BuLi (5.4 mL, 2.5 M, 13.6 mmol) at -70°C. The mixture was warmed to 0°C and stirred at 0°C for 30 min. To the mixture was added to a stirred solution of 41.4 (2.8 g, 5.7 mmol) in THF (10 mL) at -78°C. After stirring at -0°C for 1 h, methyl iodide (4.85 g, 34.2 mmol) was added. After stirring at 20°C for 16 h, the reaction was diluted with water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash column (0-5% of EtOAc in PE) to give 41.5(1.7 g). ’H NMR (400 MHz, CDCI3) Ô_H 4.19-3.98 (m, IH), 1.80

156

1,58 (m, 9H), 1.45-1.29 (m, 9H), 1.23-1.18 (m, 8H), 1.13-0.89 (m, 1 IH), 0.86 (s, 9H), 0.72-0.58 (m, 3H), 0.08-0.06 (m, 6H)

Synthesis of 41.6

To the mixture of 41.5 (1.7 g, 3.4 mmol) in THF (10 mL) was added TBAF (6.7 ml, 1 M, 6.7 mmol). After stirring ai 80°C for 18 h, the mixture cooled to 20°C, diluted with water (10 mL), and extracted with EtOAc (3 x 20 mL). The combined organic phase was washed with brine (2 x 30 mL), dried over anhydrous Na₂SO₄, fïltered, concentrated. The residue was purified by flash column (0-30% of EtOAc in PE) to give 41.6 (870 mg). ’H NMR (400 MHz, CDC1₃) δ_Η 4.09-3.99 (m, IH), 1.80-1.61 (m, 9H), 1.48-1.29 (m, 11H), 1.26-1.24 (m, 4H), 1.19 (d, 7=5.6 Hz, 3H), 1.15-0.90 (m, 10H), 0.83 (d, 7=7.2 Hz, IH), 0.72-0.58 (m, 3H)

Synthesis of 41.7

To a solution of 41.6 (870 mg, 2.3 mmol) in THF (20 mL) was added LiAlH₄ (175 mg, 4.6 mmol) at 25°C. After stirring at 25°C for 16 h, the reaction was quenched with H₂O (0.2 ml) and then HCl (50 mL, 1 M). The mixture was poured into water (30 mL), stirred for 5 min and fïltered. The filter cake was washed with water (2 x 20 mL) and dried to give 41.7 (240 mg, 30%). NMR (400 MHz, CDC1₃) δ_Η 3.42-3.28 (m, 2H), 2.01-1.95 (m, IH), 1.87-1.78 (m, 3H), 1.64-1.57 (m, 4H), 1.52-1.26 (m, I2H), 1.26 (s, 3H), 1.25-1.19 (m, 2H), 1.11-1.01 (m, 4H), 0.99 (s, 3H), 0.90 (s, 3H), 0.77 (s, 3H). LC-ELSD/MS: purity >99%; MS ESI calcd. for C₂₃H₄₀O₂ [M-H₂O+H]⁺ 331.3, found 331.3, MS ESI calcd. for C₂₃H₄₀O₂ [M-H₂O -H₂O +H]⁺ 313.3, found 313.3,

Synthesis of 41.8

To a solution of 41.7 (100 mg, 0.3 mmol) in DCM (3 mL) were added Nmethylimidazole (35.3 mg, 0.4 mmol), TEA (87.0 mg, 0.8 mmol) and TsCl (164 mg, 0.8 mmol). After stirring at 25°C for 2 h, the mixture was poured into water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic phase was washed with water (2 x 20 mL), dried over anhydrous Na₂SO₄, fïltered and concentrated a41.8 (200mg). ‘H NMR (400 MHz, CDC1₃) δ_Η 7.79 (d, 7=8.0 Hz, 2H), 7.35 (d, 7=8.0 Hz, 2H), 3.79-3.66 (m, 2H), 2.46 (s, 3H), 1.85-1.77 (m, 4H), 1.66-1.49 (m, 5H), 1.45-1.27 (m, 9H), 1.26 (s, 3H), 1.23-0.99 (m, 7H), 0.97 (s, 3H), 0.88 (s, 3H), 0.70 (s, 3H)

Synthesis of 41

157

To a solution of 41.8 (200 mg, 0.4 mmol) in DMF (5 mL) were added lH-pyrazole-4carbonitrile (55.5 mg, 0.6 mmol) and Cs₂CO₃ (645 mg, 2.0 mmol) at 25°C under N₂. After stirring at 120°C for 16 h, the mixture was added into water (20 mL), stirred at 25°C for 5 mins and extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine (2 x 100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash column (0-40% of EtOAc in PE) to give 41 (130 mg).

(130 mg) was further purified by HPLC (Method: SAGE-TJF-242-P1A; Column: Welch Xtimate Cl8 150*25mm*5um; Condition: water (0.04%NH3H20)-ACN; Begin B: 70; End B: 100) to afford 41 (15.2 mg, 12%). ^lH NMR (400 MHz, CDC13) δΗ7.78 (s, IH), 7.74 (s, 1 FI), 4,09 (d, 7=13.6 Hz, IH), 3.92 (d, 7=13.6 Hz, IH), 2.00-1.94 (m, IH), 1.87-1.56 (m, 9H), 1.52-1.29 (m, 9H), 1.26 (s, 3H), 1.23-1.02 (m, 6H), 0.99 (s, 3H), 0.94 (s, 3H), 0.82 (s, 3H). LCELSD/MS: purity >99%; MS ESI calcd. for C27H4lN3O [M-H2O+H]⁺ 406.4, found 406.4. MS ESI calcd. for C27H₄iN₃O [M +H]⁺ 424.4, found 424.4.

EXAMPLE 42 & 43: Synthesis of l-((S)-2-((3R,5R,8S,9S,10S,13S,14S,17S)-10-ethyl-3hydr oxy-3-(methoxymethyl)-13-methylhexadecahydro-l H-cyclopenta [ a] phen anth ren-17yl)-2-hydroxypropyl)-lH-pyrazole-4-carbonitrile (42) & l-((R)-2((3R,5R,8S ,9S, l OS, 13S, 14S, 17S)-10-ethyl-3-hy dr oxy-3-(methoxymethyl)-13methylhexadecahydro-lH-cyciopenta[aIphenanthren-17-yI)-2-hydroxypropyI)-lHpyrazole-4-carbonitriIe (43)

Synthesis of 42.1

158

To a stirred solution of trîmethylsulfonium iodide (6.44 g, 31.6 mmol) in DMSO (40 mL) and THF (20 mL) was added NaH (1.26 g, 31.6 mmol, 60 %). After stirring at 0°C for 1.0 h under N₂, he mixture was added to a solution of 42.0 (8 g, 26.4 mmol) in DMSO (20 mL) at 0°C. After stirring at 25°C for 16 h, the reaction was treated with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic phase was washed with water (2 x 100 mL), brine (200 mL), dried over anhydrous Na₂SO₄, fïltered, and concentrated in vacuum. The residue was purified by column (5%-30% of EtOAc in PE) to give 42.1 (5 g). NMR (400 MHz, CDC1₃) δ_Η2.63-2.57 (m, 2H), 2.48-2.33 (m, 2H), 2.13-1.51 (m, 10H), 1.51-0.94 (m, HH), 0.94-0.80 (m, 7H).

Synthesis of 42.2 & 42.2A

To a solution of 42.1 (6.9 g, 21.8 mmol) in MeOH (50 mL) was added CH₃ONa (11.7 g, 218 mmol). After stirring at 65°C for 16 h, the reaction mixture was quenched by addition of H₂O (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic phase was washed with brine (200 mL), dried over anhydrous Na₂SO₄, fïltered and concentrated. The residue was purified by column (2-30% of EtOAc in PE) to give 42.2 (3.7 g, 49%) and 42.2A (2 g, 26%).

.2: ’H NMR (400 MHz, CDC1₃) δ_Η 3.40-3.34 (m, 5H), 2.59 (s, IH), 2.46-2.39 (m, IH), 2.12-1.52 (m, 13H), 1.52-1.14 (m, 10H), 0.84-0.77 (m, 6H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₂H₃₃O [M+H-2H₂O]⁺ 313.2, found 313.2.

.2A:*H NMR (400 MHz, CDCI3) 3.38 (s, 3H), 3.22-3.17 (m, 2H), 2.47-2.40 (m, 2H), 2.10-1.57 (ni, 10H), 1.57-1.48 (m, 3H), 1.48-1.06 (m, 10H), 0.87-0.83 (m, 6H). LCELSD/MS purity 99%, MS ESI calcd. for C₂₂H₃₃O [M+H-2H₂0f 313.2, found 313.2.

Synthesis of 42.3

To a suspension of Ph₃PEtBr (10,8 g, 29.2 mmol) in anhydrous THF (100 mL) was added t-BuOK (3.27 g, 29.2 mmol) at 25°C under N₂. After stirring at 60°C for 30 mins, a solution of 42.2 (3.4 g, 9.75 mmol) in anhydrous THF (50 mL) was added. After stirring at 60°C for 16 h, the mixture was poured into saturated NH₄C1 (100 mL) and extracted with EtOAc (2 x 100 mL). The combine organic phase was washed with brine (200 mL), filtered and concentrated. The residue was purified by column (0-3% of EtOAc in PE) to give 42.3 (3.5 g). ’H NMR (400 MHz, CDCI₃) δ_Η 5.12-4.98 (m, IH), 3.41-3.34 (m, 5H), 2.58 (s, IH), 2.39-2.09 (m, 3H), 1.961.52 (m, 10H), 1.52-1.31 (m, 6H), 1.31-1.03 (m, 8H), 0.84-0.70 (m, 6H).

159

Synthesis of 42.4

To a solution of 42.3 (3.5 g, 9.71 mmol) in anhydrous THF (50 mL) was added 9-BBN dimer (7.04 g, 29,1 mmol) at 25°C under N₂. After stirring at 60°C for 16 h, the mixture was cooled and sequentially treated at 0°C with EtOH (20 mL) and NaOH (9.7 mL, 5M, 48.5 mmol) dropwise. After addition, H₂O₂ (9.7 mL, 97.1 mmol, 10 M in water) was added slowly until the inner température no longer rises and the inner température was maintained below 30°C. The mixture was stirred at 60°C for 2 h. Then the mixture was cooled and quenched with Na₂S₂O3 (100 mL, sat. aq.). The mixture was extracted with EtOAc (2 x 100 mL) and the organic layer was dried over Na₂SO4, filtered and concentrated in vacuum. The residue was purified by column (20% of EtOAc in PE) to give 42.4 (2.2 g). ’H NMR (400 MHz, CDC1₃) δ_Η 3.72-3.58 (m, IH), 3.41-3.34 (m, 4H), 2.59 (s, IH), 2.03-1.46 (m, I6H), 1.46-1.02 (m, 16H), 0.79-0.63 (m, 4H).

Synthesis of 42.5

To a solution of 42.4 (2.1 g, 5.54 mmol) in DCM (30 mL) was added DMP (4.66 g, 11 mmol). After stirring at 25°C for 1 h, the mixture was quenched with NaHCO₃ (50 mL) and extracted with EtOAc (3x30 mL). The combined organic layer was washed with Na₂S₂O₃ (3 x 30 mL, sat.), brine (50 mL), dried over Na₂SÜ4, filtered and concentrated in vacuum to give 42.5 (2.1 g). ‘H NMR (400 MHz, CDC1₃) δ_Η 3.40-3.34 (m, 5H), 2.67-2.50 (m, 2H), 2.04-1.59 (m, Ι0Η), 1.59-1.32 (m, 7H), 1.32-LOS (m, 10H), 0.77 (t, J = 7.6 Hz, 3H), 0.58 (s, 3H).

Synthesis of 42.6

To a suspension of MePh₃BrP (6.93 g, 19.4 mmol) in anhydrous THF (50 mL) was added t-BuOK (2.17 g, 19.4mmol) at 25°C under N₂. After stirring at 60°C for 30 mins, a solution of 42.5 (2.1 g, 5.57 mmol) in anhydrous THF (20 mL) was added at 25°C. After stirring at 60°C for 16 h, the mixture was poured into saturated NH₄C1 (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic phase was washed with brine (200 mL), filtered and concentrated. The residue was purified by column (0-10% of EtOAc in PE) to give 42.6 (1.1 g, 53%). ‘H NMR (400 MHz, CDC1₃) δ_Η4.83 (s, IH), 4.69 (s, IH), 3.41-3.34 (m, 5H), 2.58 (s, IH), 2.041.55 (m, 8H), 1.55-1.30 (m, 10H), 1.30-1.07 (m, 10H), 0.77 (t, J = 7.2 Hz, 3H), 0.54 (s, 3H).

Synthesis of 42.7

160

To a solution of 42.6 (400 mg, 1.06 mmol) in DCM (10 mL) was added m-CPBA (454 mg, 2.12 mmol, 80%) at 25°C. After stirring at 25°C for Ih, the mixture was quenched with sat. NaHCO₃ and Na₂S₂O₃ (40 mL, v: v = 1:1) and extracted with DCM (2 x 20 mL). The combined organic phase was washed with sat. NaHCO₃ and Na₂S₂O₃ (100 mL, v: v = 1:1), dried over Na₂SO₄, filtered and concentrated to give 42.7 (430 mg). *H NMR (400 MHz, CDCI₃) δ_Η 3.403.34 (m, 5H), 2.88 (d, J = 4.4Hz, 0.6 H), 2.62-2.47 (m, 2H),2.31 (d, J = 4.8Hz, 0.4 H), 2.04-1.55 (m, 9H), 1.55-1.29 (m, 10H), 1.29-0.99 (m, 10H), 0.77 (t, J= 7.6 Hz, 3H), 0.65 (s, 2H).

Synthesis of 42.8

To a solution of42.7 (430 mg, 1.1 mmol) in DMF (5 mL) were added Cs₂CO₃ (1.07 g, 3.3 mmol) and lH-pyrazole-4-carbonitriîe (255 mg, 2.75 mmol). After stirring at 120°C for 48 h, the mixture was added into saturated NH₄C1 (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with LiCl (100 mL, 5% in water), brine (2 x 100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by column (10-30% of EtOAc in PE) to afford 42.8 (410 mg).

Séparation of 42 & 43 .8 was separated by SFC (Column: DAICEL CHIRALPAK AD-H (250mm x 30mm, 5um), Condition: 0.1%NH₃H₂O, ETOH, Begin B: 45%, End B: 45%) to give 42 (201.7 mg, 92%, Rt = 2.165 min) and 43 (100 mg, Rt = 5.035 min). 43 (100 mg) was further purified by HPLC séparation (column: Xtimate Cl8 150 x 25mm x 5um, condition: water (0.225%FA)ACN, Begin B: 90, End B: 100) to give 43 (53.4 mg, 53.4%, Rt = 5.016 min).

42: 'H NMR (400 MHz, CDC1₃) Ô_H 7.92 (s, IH), 7.82 (s, IH), 4.35-4.05 (m, 2H), 3.403.34 (m, 5H), 2.61-2.53 (m, 2H), 2.02-1.57 (m, 10H), 1.57-1.18 (m, 10H), 1.18-0.75 (m, 14H), LC-ELSD/MS purity 99%, MS EST calcd. for C₂₉H₄2N₃O [M+H-H₂O]⁺ 448.3, found 448.3. analytic SFC 100% de.

43: NMR (400 MHz, CDC1₃)Ô_H7.88 (s, IH), 7.79 (s, IH), 4.17-3.98 (m, 2H), 3.403.34 (m, 514), 2.62 (s, lH),2.34(s, IH), 2.07-1.59 (m, 10H), 1.59-1.14 (m, 13H), 1.14-1.03 (m, 5H), 0.84-0.75 (m, 6H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₉H₄₂N₃O [M+H-H₂O]⁺ 448.3, found 448.3. analytic SFC 100% de.

Example 44 & 45: Synthesis of l-((S)-2-((3R,5R,8S,9S,10S,I3S,14S,17S)-10-ethyl-3hydroxy-13-methy 1-3-propyl hexadecahydro-1 H-cyclopenta [ a ] phenanthr en-17-yl)-2161 hydroxypropyl)-lH-pyrazole-4-carbonitrile (44) & l-((R)-2((3R,5R,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-13-methyl·3-propylhexadecahydro1 H-cy clopenta [ a] phenanthren-17-yl)-2-hydroxypropyl)-1 H-pyrazoIe-4-carbonitrîle (45)

Synthesis of 44.1

To a solution of 44.0 (400 mg, 1,02 mmol) in DMF (10 mL) were added 1 H-pyrazole-4carbonitrile (237 mg, 2.55 mmol) and Cs₂CO₃(l .66 g, 5.10 mmol) at 20°C under N₂. After stirring at 120°C for 16 h, the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with 5% LiCl (3 x 100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by flash column (0-15% of EtOAc in PE) to give 44.1 (600 mg).

Séparation of 44 & 45

44.1 (600 mg, 1.24 mmol) was separated by SFC (Column: DAICEL CHIRALCEL OD (250mm*30mm,l Oum; Condition: 0.1%NH₃H₂O ETOH; Bégin B: 55; End B: 55; FlowRate(ml/min) : 80) to give 44 (233.8 mg, Rt = 0.641 min) and 45 (107.5 mg, Rt= 1.929 min).

44: ^lH NMR (400 MHz, CDCi₃) δ_Η7.92 (s, IH), 7.81 (s, IH), 4.35-4.31 (m, IH), 4.084.05 (m, lH),2.52(s, IH), 2.04-1.97 (m, IH), 1.90-1.57 (m, 10H), 1.57-1.30 (m, 10H), 1.301.00 (m, 9H), 1.00-0.85 (m, 9H), 0.78 (t, J = 7.6 Hz, 3H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₃₀H₄4N₃ [M+H-2H₂0f 446.3, found 446.3. SFC 100%de.

45: ’HNMR (400 MHz, CDC1₃)Ô_H7.88 (s, IH), 7.80 (s, 1 H), 4.17-4.13 (m, 1 H), 4.023.99 (m, IH), 2.30(s, IH), 2.07-2.00 (m, IH), 1.94-1.52 (m, 10H), 1.52-1.23 (m, 13H), 1.231.02 (m, 9H), 0.94 (t, 7 = 7.2Hz, 3H), 0.85 (s, 3H), 0.78 (t, J = 7.6 Hz, 3H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₃₀H44N₃ [M+H-2H₂O]⁺ 446.3, found 446.4. SFC 100%de.

162

EXAMPLE 46 & 47: Synthesis of l-((R)-2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-lH-cyclopenta[a]phenanthren-I7-yl)2-hydroxypropyl)-lH-pyrazole-4-carbonitrile (46) & l-((S)-2((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13dimethylhexadecahyd r ο-1 H-cy clopenta |a] phen anthren- 17-yI)-2-hydr oxy pr opyl)-1Hpyrazole-4-carbonitrile (47)

Synthesis of 46.1

To a solution oft-BuOK (6.17 g, 55.0 mmol) in THF (150 mL) was added 46.0 (8 g, 27.5 mmol) at 25°C under N₂. After stirring at 25°C for 10 min, methyl benzenesulfinate (8.59 g, 55.0 mmol) was added. After stirring at 30°C for another 30 min, the mixture was quenched with H₂O (200 mL) and extracted with EtOAc (200 x 3 mL). The organic layer was dried over Na₂SO₄, filtered and concentrated in vacuum to give 46.1 (16 g). 'H NMR (400 MHz, CDC1₃) Ôh 7.747.44 (m, 8H),3.53-3.44 (m, 1H),3.26 (dd,7=8.2, 9.9 Hz, IH), 2.41-2.35 (m, IH), 1.81 (brs, IH), 1.56-1.30 (m, 15H), 1.23-1.01 (m, 4H), 0.98 (s, 1 H), 0.93 (s, 2H).

Synthesis of 46.2

To a mixture of 46.1 (16 g, 38.5 mmol) in xylene (200 mL) was added Na₂CO₃ (61.1 g, 577 mmol) in portions. After stirring at 140°C under N₂ for 12 h, the mixture was filtered and concentrated. The residue was purified by flash column (0-15% of EtOAc in PE) to give 46.2 (4.3 g). ’H NMR (400 MHz, CDC1₃) δ_Η 7.55-7.51 (m, IH), 6.03 (dd, 7= 3.1, 5.9 Hz, 1H),2.37

163 (brd, J= 10.3 Hz, IH), 1.85 (br s, 5H), 1.72 (br s, 2H), 1.62-1.34 (m, 9H), 1.33-1.23 (m, 6H), 1.08 (s,3H).

Synthesis of 46.3

To a solution of bromo (cyclopropyl) magnésium (6.14 g, 84.6 ml, 42.3 mmol, 0.5 M in THF) in THF (150 mL) was added Cul (8.05 g, 42.3 mmol) at 0°C under N₂. After stirring at 0°C for 1 h, 46.2 (3.5 g, 12.1 mmol) was added. After stirring at 0°C for another 3 h, the residue was poured into NH₄C1 (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phase was washed with brine (2 x 50 mL), dried over anhydrous Na₂SO₄, filtered, coneentrated. The residue was purified by flash column (0-30% of EtOAc in PE) to give 46.3 (3.8 g). 'H NMR (400 MHz, CDC1j)ô_h 2.47-2.39 (m, IH), 2.38-2.27 (m, IH), 1.96-1.69 (m, 8H), 1.63-1.48 (m, 6H), 1.45-1.43 (m, IH), 1.40-1.31 (m, 3H), 1.30-1.27 (m, 4H), 1.26-1.18 (m, IH), 1.11 (s, 4H), 0.95 (brd,/=8.3 Hz, IH), 0.70-0.62 (m, IH), 0.47 (s, IH), 0.24-0.03 (m, 2H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₂H33N₃O[M-H₂O+H]⁺ 313.3, found 313.3.

Synthesis of 46.4

To a mixture of EtPPh₃Br (20.6 g, 55.5 mmol) in THF (100 mL) was added t-BuOK (6.22 g, 55.5 mmol) at 25°C under N₂. After stirring at 45°C for 30 min, 46.3 (3.7 g, 11.1 mmol) was added below 45°C. After stirring at 45°C for another 16 h, the reaction mixture was quenched with 10% NH4CI aqueous (40 mL) ai 25°C and extracted with EtOAc (2 x 30 mL). The combined organic phase was dried over Na₂SÛ4, filtered, coneentrated. The residue was purified by flash column (0-20% of EtOAc in PE) to give 46.4 (3.7 g). *Η NMR (400 MHz, CDCI3) δ_Η 5.18-5.07 (m, IH), 2.46-2.36 (m, IH), 2.31-2.15 (m, 2H), 1.84 (br d,/= 6.8 Hz, 4H), 1.77-1.63 (m, 4H), 1.59-1.30 (m, 12H), 1.29-1.27 (m, 4H), 1.19-1.08 (m, 5H), 0.86-0.77 (m, IH), 0.58-0.49 (m, IH), 0.40-0.31 (m, 1 H), 0.13-0.00 (m, 2H).

Synthesis of 46.5

To a solution of 46.4 (700 mg, 2.04 mmol) in anhydrous THF (15 mL) was added BH3 Me₂S (1.01 ml, 10.2 mmol) at 25°C under N₂. After stirring at 25°C for 12 h, the resulting mixture was treated sequentially with éthanol (3.09 mL, 61.2 mmol) at 25°C, NaOH aqueous (12.2 mL, 5.0 M, 61.2 mmol) and H₂O₂ (6.13 mL, 30% in water, 61.2 mmol) dropwise at 0°C. After stirring at 50°C for I h, the mixture was cooled, poured into Na₂S₂0a (50 mL, sat. aq.) and extracted with EtOAc (2 x 50 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered and coneentrated in vacuum. The residue was

164 purified by flash column (15—25% of EtOAc in PE) to give 46.5 (560 mg). ¹H NMR (400 MHz, CDC1₃) δ_Η 3.82-3.74 (m, IH), 2.24 (td, J = 9.2, 13.5 Hz, IH), 2.02 (s, IH), 1.85 (brd,7=6.5 Hz, 5H), 1.92-1.58 (m, IH), 1.92-1.58 (m, IH), 1.41 (brd,7=3.3 Hz, 9H), 1.28 (s, 5H), 1.24 (d,7 = 6.3 Hz, 4H), 1.18-1.01 (m, 4H), 0.92-0.78 (m, 4H), 0.57 (br dd, 7= 3.9, 7.7 Hz, IH), 0.42-0.32 (m, IH), 0.16-0.02 (m, 2H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₄H₃₇ [M2H₂O+H]⁺ 325.3, found 325.3.

Synthesis of 46,6

To a mixture of 46.5 (460 mg, 1.27 mmol) in DCM (30 mL) was added DMP (1.61 g, 3.81 mmol) in portions. After stirring at 20°C for 30 min, the mixture was quenched with NaHCO₃ (20 mL) and Na₂S₂O₃ (20 mL) and extracted with DCM (2x30 mL) The organic phase was washed with Na₂S₂O₃ (2 x 20 mL, sat.), brine (30 mL, sat), dried over Na₂SO₄, filtered and concentrated. The residue was purified by flash column (0-15% of EtOAc in PE) to give 46.6 (310 mg). 'H NMR (400 MHz, CDC1₃) δ_Η 2.44 (dd,7= 8.8, 10.5 Hz, 1H),2.14 (s, 4H), 2.021.92 (m, 3H), 1.85 (br d, 7= 6.8 Hz, 2H), 1.76-1.65 (m, 2H), 1.38 (br s, 12H), 1.29 (s, 4H), 1.171.04 (m, 2H), 0.87-0.77 (m, 1 H), 0.85 (s, 3H), 0.62-0.52 (m, IH), 0.46-0.35 (m, IH), 0.17-0.01 (m, 2H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₄H₃₇O [M-H₂O+H]⁺ 341.3, found 341.3.

Synthesis of 46.7

To a suspension of Ph₃PMeBr (3.08 g, 8.64 mmol) in THF (20 mL) was added t-BuOK (969 mg, 8.64 mmol) at 20°C under N₂. After stirring for 30 min at 50 °C, a solution of 46.6 (310 mg, 0.864 mmol) in THF (5 mL) was added dropwise to the resulting suspension. After stirring at 50°C for 2 h under N₂, the reaction mixture was poured into 10% NH₄C1 (50 mL) and extracted with EtOAc (40 mL x 3). The combined organic phase was washed with brine (40 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash column (0-10% of EtOAc in PE) to give 46.7 (300 mg). ’H NMR (400 MHz, CDCft) ôh 4.86 (s, IH), 4.74 (s, IH), 2.03-1.79 (m, 7H), 1.78 (s, 3H), 1.76-1.60 (m, 3H), 1.51-1.27 (m, 13H), 1.23-0.98 (m, 4H), 0.78 (s, 4H), 0.58 (br s, IH), 0.45-0.32 (m, IH), 0.17-0.03 (m, IH), 0.17-0.03 (m, IH).

Synthesis of 46.8

To a solution of 46.7 (200 mg, 0.560 mmol) in DCM (20 mL) was added m-CPBA (223 mg, 1.11 mmol, 85%) at 0°C. After stirring at 0°C for 1 h to give coiorless suspension, the

165 mixture was quenched with NaHCO₃ and Na₂S₂O₃ (40 mL, v: v = 1:1, sat.) and extracted with DCM (2 x 40 mL). The combined organic phase was washed with NaHCO₃ and Na₂S₂O₃ (60 mL, v: v = 1:1, sat.), dried over Na₂SO₄, filtered and concentrated to give 46.8 (250 mg). ’H NMR (400 MHz, CDC1₃) δ_Η 3.01-2.62 (m, IH), 2.59-2.30 (m, 1 H), 2.03-1.60 (m, 3H), 1.51-1.34 (m, 12H), 1.33-1.24 (m, 10H), 1.16-1.04 (m, 3H), LOI (s, IH), 0.95-0.72 (m, 4H), 0.61-0.51 (m, IH), 0.41-0.30 (m, IH), 0.14-0.06 (m, 3H).

Synthesis of 46.9

To solution of 46.8 (250 mg, 0.670 mmol) in DMF (5 mL) were added Cs₂CO₃ (655 mg, 2.01 mmol) and 1 H-pyrazole-4-carbonitrile (155 mg, 1.67 mmol). After stirring at 130°C for 12 h, the mixture was added into saturated NH₄C1 (50 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with LiCl (50 mL, 5% in water), brine (2 x 20 mL), dried over anhydrous Na₂SO₄, filtered, concentrated and purified by column (0-30% of EtOAc in PE) to afford 46.9 (300 mg).

Séparation of 46 & 47

46.9 was separated by SFC (Column: DAICEL CHIRALCEL OD-H (25 Omm* 3 0mm,5um); Condition:0.I%NH₃H₂O ETOH; Begîn B:35%; End B:35%) to afford 46 (24.4 mg, 7.82%, Rt = 1.708 min) and 47 (83.7 mg, 26.8%, Rt = 1.847 min).

46: *H NMR (400 MHz, CDC13) δ_Η 7.92 (s, IH), 7.81 (s, IH), 4.28-3.97 (m, IH), 4.283.97 (m, IH), 2.30 (s, IH), 1.84 (br d, ./=6.5 Hz, 7H), 1.76-1.60 (m, 2H), 1.40 (br d, J = 4.8 Hz, 9H), 1.32-1.23 (m, 6H), 1.22-1.16 (m, IH), 1.09 (d, 1.5 Hz, 8H), 0.90-0.78 (m, IH), 0.65-

0.55 (m, IH), 0.46-0.36 (m, IH), 0.19-0.02 (m, 2H). LC-ELSD/MS purity 99%, MS ESI calcd. for C29H40N3 [M-2H2O+H]+ 430.3, found 430.3. SFC 100% de

47: ’H NMR (400 MHz, CDC1₃) Ô_H 7.94 (s, IH), 7.83 (s, IH), 4.37-4.06 (m, 2H), 2.59 (s, IH), 2.01 (brd, J= 12.0 Hz, 3 H), 1.84 (br d, J =6.8 Hz, 6H), 1.52-1.33 (m, 8H), 1.32-1.14 (m, 9H), 1.12 (s, 3H), 1.03 (s, 4H), 0.89-0.79 (m, IH), 0.64-0.55 (m, IH), 0.46-0.35 (m, IH), 0.190.03 (m, 2H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₉H₄₀N₃ [Μ-2Η2Ο+ΗΓ 430.3, found 430.3. SFC 99% de.

EXAMPLE 48 & 49: Synthesis of l-((S)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)3-hy droxy-3,13,15-trimethylhexadecahydro-1 H-cy clopenta[ a] phenanthr en-17-yl)propyl)166 lH-pyrazole-4-carbonitrile (48) & l-((R)-2-hydroxy-2((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-lHcyclopenta[a]phenanthren-l7-yl)propyI)-lH-pyrazole-4-carbonitrile (49)

Synthesis of 48.1

To a solution of MeMgBr (2.3 mL, 6.92 mmol, 3M) in THF (10 mL) was added Cul (988 mg, 5.19 mmol) at 0°C. After stirring at 0°C for 1 h, 46.2 (500 mg, 1.73 mmol) in THF (5 mL) was added ai 0°C. After stirring at 0°C for 3 h, the mixture was poured into saturated NH₄C1 (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na?SO₄, filtered and concentrated. The residue was purified by flash column (10%~25% of EtOAc in PE) to give 48.1 (360 mg, 68.4%, 35.2 mg). ’H NMR (400 MHz, CDCft) Ô_H2.51 - 2.39 (m, 2H), 2.29 - 2.19 (m, IH), 1.91 - 1.80 (m, 3H), 1.78 - 1.62 (m,4.5H), 1.53 - 1.46 (m, 2.5H), 1.44- 1.31 (m, 7H), 1.28 (s, 5H), 1.24- 1.20 (m, IH), 1.10 (d, J = 7.6 Hz, 3H), 1.03 (s, 3H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₀H₃iO [MH₂O+H]“ 287.2, found 287.2.

Synthesis of 48.2

To a mixture of EtPPhjBr (18.2 g, 49.2 mmol) in THF (40 mL) was added t-BuOK (5.52 g, 49.2 mmol) at 20°C under N₂. After stirring at 40°C for 30 min, 48.1 (2.5 g, 8.21 mmol) in THF (30 mL) was added in portions below 40°C. After stirring at 40°C for 16 h, the reaction mixture was quenched with 10% NH₄C1 aqueous (200 mL) at 15°C and extracted with EtOAc (3 x 200 mL). The combined organic phase was washed with brine (2 x 150 mL), filtered, concentrated under vacuum. The residue was purified by flash column (0-30% ethyl acetate in PE) to give 48.2 (3.1 g). ’H NMR (400 MHz, CDCb) Ô_H 5.18-5.07 (m, 1 H), 2.63-2.50 (m, IH), 2.33-2.23 (m, 3H), 2.22-2.06 (m, 3H), 1.91-1.79 (m, 3H), 1.66 (s, 7H), 1.61-1.31 (m, 11H), 1.251.13 (m, 7H), 1.09 (s, 3H), 0.93 (m, 3H).

167

Synthesîs of 48.3

To a solution of 48.2 (2.6 g, 8.21 mmol) in anhydrous THF (30 mL) was added 9-BBN dimer (4.00 g, 16.4 mmol) at 25°C under N₂. After stirring at 40°C for 16 h, to the resulting mixture was added éthanol (4.53g, 98.5 mmol) at 25°C, followed by NaOH aqueous (19.7 mL, 5.0 M, 98.5 mmol) and H₂O₂ (9.85 mL, 10 M, 98.5 mmol) dropwise at 0°C. After stirring at 80°C for 1 h, the mixture was cooled, poured into Na₂S₂O₃ (100 mL, sat. aq.) and extracted with EtOAc (2 xl50 mL). The organic phase was washed with brine (2 x 100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by flash column (15-40% EtOAc in PE) to give 48.3 (2.6 g, 94.8 %) *Η NMR (400 MHz, CDC1₃) 5h 3.86-3.65 (m, IH), 2.38-2.26 (m, IH), 2.20-2.07 (m, IH), 1.91-1.52 (m, 11H), 1.50-1.37 (m, 6H), 1.29-1.24 (m, 8H), i. 19-0.98 (m, 5H), 0.93 (m, 3H), 0.82 (s, 3H).

Synthesîs of 48.4

To a solution of 48.3 (2.6 g, 7.77 mmol) in DCM (30 mL) was added Dess-martin (6.57 g, 15.5 mmol) at 25°C. After stirring at 25°C for 10 min, the mixture was quenched with saturated NaHCO₃ aqueous (100 mL) at 10°C. The DCM phase was separated and washed with saturated NaHCO₃/Na₂S₂O₃ aqueous (1:1, 3 x 100 mL), brine (2 x 50 mL), dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by flash column (0-30% of EtOAc inPE)to give 48.4 (1 g, 38.7 %). ’H NMR (400 MHz, CDC1₃)Ô_H2.49 (dd, 7=8.8, 10.8 Hz, IH), 2.22-2.13 (m, IH), 2.11 (s, 3H), 2.09-2.00 (m, IH), 1.97-1.79 (m, 5H), 1.75-1.59 (m, 3H), 1.51-1.29 (m, 9H), 1.28 (s, 4H), 1.25-0.99 (m, 3H), 0.96 (d,7=7.2Hz, 3H), 0.78 (s, 3H). LC-ELSD/MS purity: 99%, MS ESI calcd. for C₂₂H₃6O₂ [M-H₂O+H]⁺ 315.3, found C₂₂H₃₆O₂ [M-H₂O+H]⁺ 315.2.

Synthesîs of 48.5

To a mixture of MePPh₃Br (2.24 g, 6.30 mmol) in THF (27 mL) was added t-BuOK (706 mg, 6.30 mmol) at 20°C under N₂. After stirring at 50°C for 30 min, 48.4 (700 mg, 2.10 mmol) in THF (3 mL) was added in portions below 50°C. After stirring at 50°C for 16 h, the reaction mixture was quenched with 10% NH₄C1 aqueous (20 mL) at 15°C and extracted with EtOAc (3 x 20 mL). The combined organic phase was washed with brine (2 x 20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by flash column (0-20% of ethyl acetate in PE) to give 48.5 (620 mg, 89.3 %). ^lH NMR (400 MHz, CDC1₃) δ_Η 4.84 (s, 1 H), 4.71 (s, IH), 2.16-1.95 (m, 3H), 1.91-1.77 (m, 4H), 1.76 (s, 3H), 1.69-1.58 (m, 3H),

168

1,49-1.39 (m, 5H), 1.37-1.28 (m, 4H), 1.27 (s, 4H), 1.24-0.99 (m, 6H), 0.95 (d,7=7.2 Hz, 3H), 0.91-0.82 (m, 2H), 0.72 (s, 3H).

Synthesis of 48.6

To a solution of 48.5 (200 mg, 0.6050 mmol) in DCM (3 ml) was added m-CPBA (194 mg, 0.9074 mmol). After stirring at 20°C for 20 min, saturated aqueous NaHCO₃ (30 mL) and Na₂S₃O₃ (30 mL) were added. After stirring for another 5 min, the aqueous phase was extracted with DCM (3 x 30 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na₂SO₄, fïltered and concentrated to give 48.6 (240 mg). ^JH NMR (400 MHz, CDC1₃) δ_Η2.91 (d, J= 4.4 Hz, IH), 2.54 (d, 7= 4.4 Hz, IH), 1.76-2.16 (m, 10H), 1.51-1.73 (m, UH), 1.39-1.49 (m, 6H), 1.34-1.37 (m, 4H), 1.27 (s, 5H), 1.00-1.24 (m, 8H), 0.95 (s, IH), 0.940.96 (m, IH), 0.88-0.93 (m, 5H), 0.85 (s, 3H).

Synthesis of 48 & 49

To a solution of 48.6 (340 mg, 0.9810 mmol) in DMF (5 mL) were added 1 H-pyrazoIe-4carbonitrile (273 mg, 2.94 mmol) and Cs₂CO₃ (963 mg, 2.94 mmol) at 25°C. After stirring at 120°C for 16 h, the mixture was added water (20 mL) and extracted with EtOAc (120 mL). The combined organic solution was washed with brine (70 mL), dried over anhydrous Na₂SO₄, fïltered, concentrated in vacuum. The residue was purified by column (0%-55% of EtOAc in PE) to give a mixture of diastereomers, which was separated by SFC (column: DAICEL CHIRALPAK AS (250mm*30min, lOum); Mobile phase: A: CO₂ B: 0.1%NH₃H₂O ETOH; gradient: from 25% to 25% of B, Flow Rate (ml/min): 70) to give 48 (158.2 mg, 93%) and 49 (73.8 mg, 43%).

48: ^lH NMR (400 MHz, CDC1₃) δ_Η 7.92 (s, IH), 7.82 (s, IH), 4.44-3.93 (m, 2H), 2.54 (s, 1 H), 2.25-2.07 (m, 2H), 2.00-1.92 (m, IH), 1.90-1.77 (m, 3H), 1.74-1.56 (m, 3H), 1.54-1.29 (m, 9H), 1.27 (s, 4H), 1.26-1.25 (m, IH), 1.25-1.09 (m, 4H), 1.06 (s, 4H), 1.00 (s, 3H), 0.96 (d, 7 = 6.8 Hz, 3H).LC-ELSD/MS purity: 99%, MS ESI calcd. for C₂₇H₄iN₃O₂ [M-2H₂O+Hf 404.3, found C27H_4IN₃O₂ [M-2H₂O+H]⁺ 404.3.

49: ^]H NMR (400 MHz, CDC13) δΗ 7.89 (s, IH), 7.80 (s, IH), 4.28-3.96 (m, 2H), 2.27 (s, IH), 2.22-1.96 (m, 3H), 1.91-1.78 (m, 3H), 1.75-1.56 (m, 4H), 1.53-1.30 (m, 8H), 1.27 (s, 4H), 1.26-1.10 (m, 4H), 1.07 (s, 4H), 1.03 (s, 3H), 0.97 (d, 7= 6.4 Hz, 3H)LC-ELSD/MS purity: 99%, MS ESI calcd. for C27H4|N3O2 [M-2H2O+H]⁺ 404.3, found C27H₄iN₃O₂ [M-2H₂O+H]⁺ 404.3.

169

EXAMPLE 50 & 51: Synthesis of l-((S)-2-hydroxy-2-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3hydroxy-2,3,13-trimethylhexadecahydro-lH-cyclopenta[a]phenanthren-17-yl)propyl)-lHpyrazole-4-carbonitrile (50) & l-((R)-2-hydroxy-2-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3hydroxy-2,3,13-trimethylhexadecahydro-lH-cyclopenta[a]phenanthren-17-yl)propyl)-lHpyrazole-4-carbonitrile (51)

Synthesis of 50.1

To a solution of 34.1 (50 g, 128 mmol) in THF (300 mL) was added LiHMDS (115 mL, 1 M in THF, 115 mL) at-70^ûC under N₂. After stirring at-70°C for 1 h, HMPA (27,4 g, 153 mmol) was added, After stirring at-70°C for 30 minutes, Mel (109 g, 768 mmol) was added, After stirring at 25°C for 1 h, the mixture was quenched with NH₄C1 (200 mL, sat.) and extracted with EtOAc (300 mL). The combined organic layer was separated, dried over Na₂SO₄, filtered and concentrated. The residue was purified by flash column (0-3% of EtOAc in PE) to give 50.1 (6 g, 11.6%). ‘H NMR (400 MHz, CDCfi) δ_Η 5.73 (s, IH), 3.57 (t, J = 8.4 Hz, IH), 2.47-2.34 (m, 2H), 2.29-2.19 (m, IH), 2.17-2,09 (m, IH), 1.99-1.74 (m, 5H), 1.58-1.40 (m, 2H), 1.35-1.25 (m, 4H), 1.10 (d, J= 7.2 Hz, 3H), 1.05-0.91 (m, 4H), 0.88 (s, 9H), 0.76 (s, 3H), 0.01 (d, J= 2.8 Hz, 6H).

Synthesis of 50.2

To a mixture of 50.1 (16 g, 2.48 mmol) in pyridine (200 mL) was added Pd/C (2 g, 10%). After hydrogenating under 15 psi of hydrogen at 25°C for 24 h, the reaction mixture was filtered through a pad of Celite and washed with pyridine (3 x 150 mL). The filtrate was concentrated and washed with IM HCl (200 mL). The aqueous phase was extracted with EtOAc (2 x 150 170 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated to give 50.2 (16 g). 'H NMR (400 MHz, CDC1₃) δ_Η 3.58 (t, J = 8.8 Hz, IH), 2.66-2.57 (m, IH), 2.38-2.30 (m, IH), 2.22-2.14 (m, 2H), 2.09-2.04 (m, IH), 1.94-1.84 (m, IH), 1.82-1.77 (m, IH), 1.76-1.63 (m, 2H), 1.53-1.13 (m, 9H), 1.13-0.99 (m, 4H), 0.97 (d, J = 6.8 Hz, 3H), 0.88 (s, 9H), 0.74 (s, 3H), 0.01 (d, J = 2.8 Hz, 6H).

Synthesis of 50.3

To a solution of BHT (30 g, 136 mmol) in toluene (150 mL) under nitrogen at -70°C in three-necked flask (1000 mL) was added trimethylaluminum (34 mL, 2 M in toluene, 68 mmol) dropwise. After stirring at -70°C for 1 h, to the MAD (56.7 g in toluene, 118 mmol) solution was added a solution of 50.2 (16 g, 39.5 mmol) in toluene (100 mL) and DCM (100 mL) dropwise at70°C under N₂. After stirring at-70°C for 1 h, MeMgBr (39.3 mL, 3M, 118 mmol) was added dropwise at-70°C. After stirring for 2 h, he reaction mixture was poured slowly into saturated aqueous citric acid (500 mL) at 10°C. The aqueous phase was extracted with DCM (2 x 400 mL). The combined organic phase was washed with brine (300 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by flash column (0-2% of EtOAc in PE) to give 50.3 (7.87 g, 44.7%). *H NMR (400 MHz, CDC1₃) Ô_H 3.55 (t, J= 8.0 Hz, IH), 1.92-1.79 (m, 3H), 1.77-1.71 (m, 2H), 1.68-1.63 (m, IH), 1.62-1.58 (m, IH), 1.53-1.48 (m, IH), 1.47-1.36 (m, 4H), 1.30-1.23 (m, 5H), 1.10 (s, 3H), 1.07-0.95 (m, 6H), 0.87 (s, 9H), 0.86-0.84 (m, 3H), 0.69 (s, 3H), 0.00 (d, J = 2.4 Hz, 6H).

Synthesis of 50,4

To a solution of 50.3 (12.25 g, 30.1 mmol) in THF (150 mL) was added TBAF (3.93 g, 120 mmol). After stirring at 80°C for 3 h, the mixture was poured into water (200 mL) and extracted with EtOAc (2 x 200 mL). The combined organic phase was washed with brine (200 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by flash column (0-15% of EtOAc in PE) to give 50.4 (8 g, 91.5%). ^fH NMR (400 MHz, CDC1₃) Ô_H 3.64 (t,7=8.0 Hz, 1 H),2.10-2.02 (m, IH), 1.83-1.68 (m, 3H), 1.51-1.45 (m, 2H), 1.44-1.36 (m, 4H), 1.32-1.23 (m, 7H), 1.10 (s, 3H), 1.08-1.02 (m, 5H), 0.86 (d, 7 = 6.8 Hz, 5H), 0.74 (s, 3H).

Synthesis of 50.5

To a solution of 50.4 (6.2 g, 20.2 mmol) in DCM (100 mL) was added DMP (17.1 g, 40.4 mmol) at 25°C under N₂. After stirring at 25°C for 2 h, the mixture was quenched with NaHCO₃/NaS₂SO₃ (v:v=l:l) (200 mL) and extracted with DCM (2 x 100 mL). The combined

171 organic phase was washed with brine ( 100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by flash column (0-10%-20% of EtOAc in PE) to give 50.5 (5.9 g, 95.9%). ^lH NMR (400 MHz, CDC1₃) δ_Η2.44 (dd, 7= 8.4, 19.6 Hz, IH), 2.13-2.03 (m, IH), 1.97-1.89 (m, IH), 1.84-1.71 (m, 4H), 1.69-1.61 (m, IH), 1.53-1.40 (m, 3H), 1.38-1.24 (m, 7H), 1.23-1.15 (m, 2H), 1.11 (s, 3H), 0.90-0.83 (m, 9H).

Synthesis of 50.6

To a solution EtPPh₃Br (21.4 g, 57.9 mmol) in THF (50 mL) was added t-BuOK (6.49 g, 57.9 mmol) at 25°C under N₂. After stirring at 25°C for 30 min, 50.5 (5.9 g, 19.3 mmol) in THF (50 mL) was added. After stirring at 45°C for 16 h, the mixture was poured into NH₄C1 (100 mL) and extracted with EtOAc (2 x 150 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash column (0-8% of EtOAc in PE) to give 50.6 (7 g). NMR (400 MHz, CDCi₃) Ôh 5.155.07 (m, IH), 2.41-2.31 (m, IH), 2.28-2.13 (m, 2H), 1.84-1.80 (m, 2H), 1.78-1.68 (m, 3H), 1.671.62 (m, 4H), 1.55-1.50 (m, 2H), 1.49-1.45 (m, IH), 1.42 (s, IH), 1.40-1.29 (m, 3H), 1.26 (t, 7 = 7.2 Hz, 3H), 1.21-1.14 (m, 2H), 1.10 (s, 3H), 1.09-1.06 (m, 2H), 0.87-0.85 (m, 6H).

Synthesis of 50.7

To a solution of 50.6 (7 g, 22.1 mmol) in THF (100 mL) was added 9-BBN dimer (10.6 g, 44.2mmol) under N₂. After stirring at 40°C for 1 h, the mixture was cooled to room température, and sequentially treated with EtOH (12.6 mL, 221 mmol) and NaOH (44.2 mL, 5M, 221 mmol). H₂O₂ (22.1 mL, 10M, 221 mmol) was then added very slowly, keeping the inner température below 15°C. After diluting with saturated aqueous Na₂S₂O₃ (150 mL), the mixture was stirred at 25°C for 1 h. The reaction was checked by potassium iodide-starch test paper to confirm excess H₂O₂ was destroyed. The reaction mixture was filtered to give 50.7 (12.3 g). ^lH NMR (400 MHz. CDC1₃) δ_Η 3.75-3.65 (m, IH), 1.95-1.80 (m, 4H), 1.76-1.70 (m, IH), 1.66-1.60 (m, 3H), 1.58-1.45 (m, 4H), 1.43-1.32 (m, 3H), 1.30 (s, 2H), 1.24-1.21 (m, 4H), 1.16-1.11 (m, 2H), 1.10 (s, 4H), 1.08-0.96 (m, 4H), 0.86 (d,7^r = 6.8 Hz, 3H), 0.66 (s, 3H).

Synthesis of 50.8

To a solution of 50.7 (12.3 g, 36.7 mmol) in DCM (200 mL) was added DMP (46.6 g, 110 mmol) in portions. After stirring at 25°C for 3 h, the mixture was poured into NaS₂SO₃/NaHCO₃ (v:v,l:l, 1000 mL) and extracted with DCM (2 x 500 mL). The combined organic phase was washed with brine (200 mL), dried over anhydrous Na₂SO₄, filtered and

172 concentrated to give 50.8 (4.6 g, 37.7%). 'H NMR (400 MHz, CDC13) ôh 2.53 (t, J - 9.2 Hz, IH), 2.20-2.12 (m, 1 H), 2.11 (s, 3H), 2.04-1.97 (m, IH), 1.82 (d, J= 6.4 Hz, 2H), 1.76-1.68 (m, 2H), 1.67-1.52 (m, 6H), 1.44-1.37 (m, 3H), 1.36-1.28 (m, 2H), 1.26-1.13 (m, 3H), 1.11 (s, 3H), 1.09-1.01 (m, 3H), 0.87 (d, J-6.8 Hz, 3H), 0.61 (s, 3H).

Synthesis of 50.9

To a solution of MePPh₃Br (14.7 g, 41.4 mmol) in THF (30 mL) was added t-BuOK (4.64 g, 41.4 mmol) at 25°C under N₂. After stirring at 25°C for 1 h, a solution of 50.8 (4.6 g, 13.8 mmol) in THF (20 mL) was added. After stirring at 40°C for 2 h, the reaction was poured into water (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na₂SO₄, fïltered and concentrated. The residue was purified by flash column (0-10% of EtOAc in PE) to give 50.9 (2.7 g, 39.9%). *H NMR (400 MHz, CDC1₃) δ_Η 4.84 (s, IH), 4.70 (s, IH), 2.07-1.99 (m, IH), 1.88-1.80 (m, 3H), 1.75 (s, 4H), 1.73-1.48 (m, 8H), 1.47-1.13 (m, 8H), 1.11-1.09 (m, 3H), 1.07-0.98 (m, 3H), 0.86 (d, J= 6.8 Hz, 3H), 0.57 (s, 3H).

Synthesis of 50.10

To a solution of 50.9 (250 mg, 0.7563 mmol) in DCM (5 mL) was added m-CPBA (260 mg, 1.51 mmol) at 25°C. After stirring at 25°C for 1 h, the mixture was poured into water (20 mL) and extracted with DCM (2 x 20mL). The combined organic phase was washed with NaHCOj/NaS₂SO₃ (1:1) (2 x 20 mL), dried over anhydrous Na₂SO₄, fïltered and concentrated. The residue was purified by flash column (5%~15% of EtOAc in PE) to give 50.10 (290 mg). ’H NMR (400 MHz, CDC1₃) Ô_H 2.88 (d, J= 4.8 Hz, 1H),2.55 (d, J=4.0Hz, IH), 2.49 (d, J=4.8 Hz, 0.5H), 2.32 (d, J = 4.8 Hz, 0.5H), 1.96-1.85 (m, 2H), 1.76-1.61 (m, 5H), 1.51-1.45 (m, 2H), 1.35 (s, 3H), 1.31-1.24 (m,4H), 1.23-1.13 (m, 3H), 1.10 (s, 4H), 1.08-1.01 (m, 5H), 0.86 (d, J= 6.8 Hz, 4H), 0.68 (s, 3H).

Synthesis of 50.11

To a solution of 50.10 (290 mg, 0.8368 mmol) in DMF (5 mL) were added IH-pyrazole4-carbonitrile (155 mg, 1.67 mmol) and Cs₂CO₃ (817 mg, 2.51 mmol) at 20°C under N₂. After stirring at 130°C for 16 h, the mixture was poured into saturated H₂O (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄, fïltered, and concentrated. The residue was purified by flash column (0-20% of EtOAc in PE) to give 50.11 (250 mg, 68.1%). *H NMR (400 MHz, CDC1₃) δ_Η 7.93 (s, IH),

173

7.82 (s, IH), 4.35 (d, J = 14.0 Hz, IH), 4.08 (d, J = 13.6 Hz, IH), 2.51 (s, IH), 2.04-1.98 (m, IH), 1.83-1.79 (m,2H), 1.78-1.60 (m, 3H), 1.53-1.45 (m, 3H), 1.44-1.35 (m, 4H), 1.33-1.24 (m, 3H), 1.22-1.13 (m, 3H), 1.10 (s, 4H), 1.09-1.03 (m, IH), 0.97 (s, 3H), 0.91 (s, 3H), 0.86 (d, 7 = 6.4 Hz, 6H).

Séparation of 50 & 51 .11 (250 mg, 0.5686 mmol) was separated by SFC (Column: DA1CEL CHIRALPAK AD 250mmx30mm, lOum; Condition: 0.1%NH₃H₂O ETOH; Gradient: from 45% to 45% of B; Flow rate: 80mL/min; Column température; 40°C) and then further purified by HPLC (Column: Phenomenex Gemini-NX 80mm x 40mm, 3um; Condition: water(0.05%NH₃H₂0+10mM NH₄HCO₃)-ACN); Gradient: from 57% to 87% of B in 8min and hold 100% for 1.4 min; Fiow rate: 30mL/min) to afford 51 (10.3 mg, 10.3%) and 50 (76.3 mg, 30.6%).

50: 'H NMR (400 MHz, CDC1₃) δ_Η7.93 (s, IH), 7.82 (s, 1 H), 4.35 (d,7= 13.2 Hz, IH), 4.08 (d,7 = 14.0 Hz, lH),2.50(s, IH), 2.04-1.98 (m, IH), 1.84-1.79 (m, 2H), 1.77-1.60 (m, 6H), 1.52-1.35 (m, 5H), 1.31-1.17 (m, 5H), 1.10 (s, 4H), 1.09-1.03 (m, 4H), 0.97 (s, 3H), 0.91 (s, 3H), 0.86 (d, 7 = 6.8 Hz, 3H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₇H_3SN₃ [M-2H₂O+H]⁺ 404.3, found 404.3. SFC 99% de.

51: 'H NMR (400 MHz, CDC1₃) δ_Η7.89 (s, IH), 7.80 (s, IH), 4,19-4.13 (m, IH), 4.043.98 (m, IH), 2.30 (s, IH), 2.09-2.02 (m, IH), 1.96-1.86 (m, IH), 1.84-1.79 (m, 2H), 1.75-1.61 (m, 5H), 1.53-1.45 (m, 3H), 1.43-1.35 (m, 2H), 1.32-1.14 (m, 5H), 1.11-1.03 (m, HH), 0.880.85 (m, 6H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₇H₃₈N₃ [M-2H₂O+H]⁺ 404.3, found 404.3 SFC 100% de.

EXAMPLES 52 & 53: Synthesis of l-((S)-2-hydroxy-2-((2R,3S,5R,8R,9R,10S,13S,14S,17S)-3hydroxy-2,3,13-trîmethyIhexadecahydro-lH-cyclopenta|a]phenanthren-17-yl)propyl)-lHpyrazole-4-carbonitrile (52) & l-((R)-2-hydroxy-2-((2R,3S,5R,8R,9R,10S,13S,14S,17S)-3hydr oxy-2,33 3-trimethy ïhexadecahydr ο-1 H-cy clopenta ( a] phen anthren-17-yl)propyl)- 1Hpyrazole-4-carbonitrile (53)

174

Synthesis of 52.1

To a solution of 52.0 (14.0 g, 51.0 mmol) in anhydrous THF (140 mL) was added a solution of LiAlH(OtBu)3 (23.3 g, 91.8 mmol) in anhydrous THF (70 mL) dropwise at -40°C over a period of 30 mins under N₂. After stirring at -40°C for 2 h a suspension resulted, and the reaction mixture was poured into saturated NH₄C1 (150 mL) at 0°C, stirred for 30 mins and extracted with EtOAc (3 x 150 mL). The combined organic phase was washed with brine (300 mL), dried over anhydrous Na₂SO₄, filtered and coneentrated to give 52.1 (13.92 g). *H NMR (400 MHz, CDCI3) δ_Η 0.87 (s, 3H) 1.001.33 (m, 8H) 1.33-1.49 (m, 4H) 1.52-1.58 (m, 3H) 1.66-1.72 (m, 2H) 1.75-1.84 (m, 3H) 1.89-1.98 (m, 2H) 2.05-2.14 (m, IH) 2.39-2.49 (m, IH) 3.63 (br s, IH).

Synthesis of 52.2

To a solution of 52.1 (13.0 g, 47.0 mmol) in DCM (130 mL) was added 1 -methyl- 1Himidazole (7.70 g, 94.0 mmol) and TEA (9.49 g, 94.0 mmol) at 25°C, followed by TsCl (17.9 g, 94.0 mmol). After stirring at 25°C for 2 h, the residue was poured into ice-water (250 mL) and stirred for 20 mins. The aqueous phase was extracted with EtOAc (2 x 200 mL). The combined organic phase was washed with brine (2 x 250 mL), dried over anhydrous Na₂SO4, filtered and coneentrated under vacuum to give 52.2 (16.0 g).*H NMR (400 MHz, CDCI3) δ_Η 0.84 (s, 3H) 0.93-0.93 (m, IH) 0.95175

1.16 (m,3H) 1.17-1.36 (m, 5H) 1.38-1.58 (m, 4H) 1.76-2.00 (m, 4H) 2.02-2.27 (m, 3H) 2.36-2.37 (m, IH) 2.39-2.43 (m. 1 H) 2.44 (s, 3H) 2.45-2.63 (m, 1 H) 4.40-4.55 (m, IH) 7.32 (d, 7= 8.13Hz, 2H) 7.74-7.84 (m, 2H).

Synthesis of 52.3 & 52.3A

To 52.2 (16.0 g, 37.1 mmol) was added coliidine (150 mL, 37.1 mmol) at 25°C under N₂. After stirring at 140^ûC for 16 h a solution resulted. The mixture was poured into water (500 mL), extracted with EtOAc (3 x 400 mL). The combined organic phase was washed with water (3 x 100 mL), brine (200 mL), dried over anhydrous Na₂SO4, fdtered and concentrated under vacuum. The residue was purified by flash column (0-20% of EtOAc in PE) to give a mixture of 52.3 and 52.3 A (8.6g).'HNMR (400 MHz, CDC1₃) δ_Η 0.87 (s, 1H)O.91 (s, IH) 0.94-1.10 (m, 2H) 1.10-1.33 (m, 6H) 1.53 (br dd, 7=6.02, 2.76 Hz, 7H) 1.67-1.83 (m, 3 H) 1.83-1.97 (m, 3H) 2.28-2.72 (m, 3H) 5.31-5.55 (m, 1 H) 5.60 (brs, IH).

Synthesis of 52.4 & 52.4A

To a mixed solution of 52.3 and 52.3A (7.5 g, 29.0 mmol) in DCM (90 mL) was added mCPBA (8.8 g, 43.5 mmol) at 0°C under N₂. After stirring at 25°C for 2 h, the mixture was quenched with saturated NaHCO₃ (100 mL) and the mixture was extracted with DCM (2 x 150 mL). The organic layer was washed with Na₂S₂O₃ (2 x 100 mL, sat.), brine (2 x 100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by flash column (0-20% of EtOAc in PE) to give a mixture of 52.4 and 52.4A (7 g).'H NMR (400 MHz, CDC1₃) δ_Η 3.34-2.78 (m, 2H), 2.54-2.33 (m, IH), 2.20-2.02 (m, 2H), 1.96-1.49 (m, UH), 1.39-0.97 (m, 7H), 0.91-0.81 (m, 3H)

Synthesis of 52.5 & 52.5A

To a suspension of PhjPEtBr (24.2 g, 65.3 mmol) in anhydrous THF (100 mL) was added tBuOK (7.32 g, 65.3 mmol) at 15°C under N₂ and the mixture was stirred at 45 °C for 30 min. A mixture of 52,4 and 52.4A (6.0 g, 21.8 mmol) in anhydrous THF (15 mL) was then added dropwise. After stirring for 16 h the mixture was cooled and poured into ice-water (50 mL) and stirred for 10 min. The aqueous phase was extracted with EtOAc (2 x 50 mL) and the combined organic phase was washed with brine (2 x 50 mL), filtered, concentrated and purified by flash column (0-10% of EtOAc in PE) to give a mixture of 52,5 and 52.5A (5.5 g, 88%).

176

Synthesis of 52.6

To a suspension of Cul (1.80 g, 9.48 mmol) in THF (10 mL) was added MeLi (7.75 mL, 1.6 Μ, 12.4 mmol) at 0°C. After stirring at 0°C for 1 h, a mixture of 52.5 and 52.5A (0.3 g, 1.04 mmol) in THF (10 mL) was added at 0°C. After stirring at 15°Cfor 16 h the mixture was poured into water (50 mL) and the aqueous phase was extracted with EtOAc (2 x 50 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na₂SÛ4, filtered, concentrated and purified by flash column (0-15% of EtOAc in PE) to give 52.6 (100 mg, 31.8%). ’H NMR (400 MHz, CDC1₃) δ_Η 5.12 (q, J=7.0 Hz, IH), 3.55 (br s, IH), 2.48-2.10 (m, 4H), 1.98-1.68 (m, 4H), 1.68-1.65 (m, 4H), 1.551.11 (m, 13H), 1.06-0.97 (m, 4H), 0.89 (s, 3H).

Synthesis of 52.7

To a solution of 52.6 (100 mg, 0.3305 mmol) in THF (10 mL) was added 9-BBN dimer (159 mg, 0.661 mmol) under N₂. The reaction mixture was stirred at 50°C under N₂ for 2 h to give a colorless mixture. The mixture was cooled to 0°C, where éthanol (0.288 mL, 4.95 mmol) and NaOH (0.99 mL, 5 M, 4.95 mmol) were added, resulting in the mixture tuming clear. H₂O₂ (560 mg, 30%, 4.95 mmol) was added dropwîse at I5°C. After stirring ai 50°C for 2 h saturated aqueous Na₂S₂O₃ (50 mL) was added and the mixture was stirred at 0°C for another 1 h. The reaction was checked by potassium iodide-starch test paper to confirm excess H₂O₂ was destroyed (did not changed to blue). The aqueous phase was extracted with EtOAc (3 x 40 mL) and the combined organic phase was washed with brine (2 x 50 mL), dried over anhydrous Na₂SO4, filtered and concentrated to give 52.7 (800 mg).

Synthesis of 52.8

To a solution of 52.7 (900 mg, 2.80 mmol) in DCM (40 mL) was added DMP (4.74 g, 12.4 mmol) under N₂. After stirring at 15°C under N₂ for 2 h a colorless mixture resulted, and saturated aqueous NaHCO₃ (50 mL) and saturated aqueous Na₂S₂O₃ (50 mL) were added. The aqueous phase was extracted with DCM (3 x 40 mL). The combined organic phase was washed with brine (2x50 mL), dried over anhydrous Na₂SO4, filtered, concentrated and purified by flash column (0-20% of EtOAc in PE) to give 52.8 (550 mg, 62%). 'H NMR (400 MHz, CDCfi) δ_Η 2.62-2.31 (m, 4H), 2.121.95 (m, 7H), 1.90-1.56 (m, 3H), 1.53-1.39 (m, 2H), 1.33-1.09 (m, 6H), 1.05 (d, J=6.8 Hz, 3H), 1.030.85 (m, 4H), 0.66 (s, 3H)

177

Synthesis of 52.9

To a solution of BHT (2.26 g, 10.3 mmol) in toluene (10 mL) under nitrogen at 0°C was added AlMe₃ (2 M in toluene, 2.57 mL, 5.15 mmol) dropwise. The mixture was stirred at 20°C for 1 h to give the MAD solution. To the MAD solution (4.71 mmol in 10 mL toluene) was added a solution of 52.8 (500 mg, 1.57 mmol) in anhydrous DCM (5 mL) dropwise at -70°C. After stirring at 70°C for 1 h under N₂, MeMgBr (4.16 mL, 12.5 mmol, 3 M in ethyl ether) was added drop wise at 70C. The resulting solution was stirred at -70°C for 3 h. The reaction mixture was poured into citric acid (30 mL, 20% aq.) at below 10°C and extracted with EtOAc (2 x 30 mL). The combined organic layer was dried over Na₂SO₄, filtered, concentrated and purified by silica gel chromatography (0-30% of EtOAc in PE) to give 52.9 (300 mg, 57.4%). 'H NMR (400 MHz, CDC1₃) δ_Η 2.54 (br t, J=8.9 Hz, IH), 2.23-2.13 (m, 1H),2.12 (s, 3H), 2.05-1.94 (m, IH), 1.89-1.56 (m, 12H), 1.52-1.36 (m, 3H), 1.28 (s, 3H), 1.25-1.09 (m, 6H), 1.08-0.94 (m, 5H), 0.63 (s, 3H).

Synthesis of 52.10

To a solution of MePPh₃Br (1.61 g, 4.51 mmol) in THF (40 mL) was added t-BuOK (0.506 g, 4.51 mmol) at 15°C under N₂. After stirring at 15°C for 1 h, 52.9 (0.3 g, 0.9021 mmol) in THF (10 mL) was added. After stirring at 4O‘’C for 2 h, the mixture was poured into water (20 mL) and the aqueous phase was extracted with EtOAc (2 x 50mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, concentrated and purified by flash column (0-10% of EtOAc in PE) to give 52.10 (180 mg, 60.4%).*H NMR (400 MHz, CDC1₃) δ_Η 4.85 (s, IH), 4.71 (s, IH), 2.10-1.99 (m, IH), 1.87-1.78 (m, 4H), 1.76 (s, 3H), 1.73-1.57 (m, 7H), 1.49-1.38 (m, 2H), 1.28 (s, 3H), 1.24-1.07 (m, 7H), 1.02 (d, J=7.0 Hz, 3H), 0.99-0.80 (m, 3H), 0.58 (s, 3H).

Synthesis of 52.11

To a solution of 52.10 (90 mg, 0.2722 mmol) in DCM (10 mL) was added m-CPBA (110 mg, 0.54 mmol, 85%) at 0°C under N₂. After stirring at 15°C for 2 h, the mixture was quenched with saturated NaHCO₃ (10 mL). The mixture was extracted with DCM (2x10 mL), the organic layer was washed with Na₂S₂O₃ (2x10 mL, sat.), brine (2x10 mL), dried over anhydrous Na₂SO₄, filtered and concentrated to give 52.11 (100 mg).

Synthesis of 52 & 53

To a solution of 52.11 (100 mg, 0.2885 mmol) in DMF (5 mL) was added 1 H-pyrazole-4

178 carbonitrile (53.7 mg, 0.577 mmol) and Cs₂CO₃ (187 mg, 0.577 mmol) at 20°C under N₂. After stirring at 130°C for 16 h, the mixture was poured into H₂O (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na₂SÛ4, fïltered, concentrated and purified by SFC (Column DAICEL CHIRALPAK AS(250mm*30mm,10um) Condition 0.1%NH3H2O ETOH Begin B 20 End B 20 Gradient Time(mîn) 100%B Hold Time(min) FlowRate(ml/min) 60 Injections 170) to afford 52 (19.1 mg, 15.1%) and 53 (14.7 mg, 11.6%).

: ’H NMR (400 MHz, CDC1₃) δ_Η 7.93 (s, IH), 7.82 (s, IH), 4.36 (d, 1=13.8 Hz, IH), 4.09 (d, J=13.8Hz, IH), 2.51 (s, IH), 2.01 (brd, J=11.3 Hz, IH), 1.87-1.56 (m, 1 IH), 1.42 (br t, J=9.7 Hz, 5H), 1.28 (s, 3H), 1.25-1.04 (m, 7H), 1.00 (brd, J=7.0 Hz, 3H), 0.98 (s, 3H), 0.93 (s, 3H). LCELSD/MS purity 99%, MS ESI calcd. For C₂7H3₈N₃ [M-2H₂O+H]⁺ 404.3, found 404.3.

: *H NMR (400 MHz, CDCI₃) Ô_H 7.82 (s, IH), 7.73 (s, IH), 4.13-4.03 (m, IH), 3.99-3.87 (m, IH), 2.20 (s, IH), 2.02-1.93 (m, IH), 1.80-1.53 (m, 9H), 1.44-1.25 (m, 9H), 1.20 (s, 3H), 1.15 (brs, 4H), 1.02 (s, 3H), 0.93 (br d, J=7.3 Hz, 3H), 0.81 (s, 3H). LC-ELSD/MS purity 99%, MS ESI calcd. For C₂₇H_3SN₃ [M-2H₂O+H]⁺ 404.3, found 404.3.

EXAMPLES 54 & 55: Synthesis of H(S)-2-((3R,5R,8R,9S,10S,13S,14S,17S)-3-hydroxy-3(inethoxymetliyl)-10,13-dimcthylhexadecahydro-lH-cyclopenta[a]phenanthren-17-yl)-2methoxypropyl)-lH-pyrazole-4-carbonitrile (54) & l-((R)-2-((3R,5R,8R,9S,10S,13S,14S,17S)-3hydroxy-3-(methoxymethyl)-10,13-dimethylhexadecahydro-lH-cycIopenta[a]phenanthren-17yl)-2 -methoxy p r opyl)-1 H-py r azole-4-carbonitrile (55)

179

Synthesîs of 54.1

To a mixture of MePPhjBr (10.4 g, 28.8 mmol) in THF (20 mL) was added t-BuOK (3.7 g, 33.0 mmol) at 25°C under N₂. The resulting mixture was stirred at 45°C for 30 min. 54.0 (8.0 g, 22.0 mmol) was added in portions below 45°C. After stirring at 55°C for 3 h a suspension resulted. The reaction mixture was quenched with 10% NH₄C1 aqueous (40 mL) at 25°C. The aqueous layer was extracted with EtOAc (2 x 40 mL) and the combined organic phase was separated, dried over Na₂SO4, filtered, concentrated and purified by flash column (15-35% of EtOAc in PE) to give 54.1 (3.1g, 39%). *H NMR (400 MHz, CDCI3) Ô_H 4.82-4.89 (m, 1 H), 4.50-4.73 (m, I H), 3.36-3.42 (m, 4 H), 2.56-2.61 (m, 1 H), 1.77-2.03 (m, 4 H), 1.74 (s, 3 H), 1.63-1.72 (m, 3 H), 1.31-1.60 (m, 9 H), 1.09-1.29 (m, 7 H), 0.91-0.95 (m, 3 H), 0.78-0.89 (m, 1 H), 0.54 (s, 2 H).

Synthesîs of 54.2

To a solution of 54.1 (710 mg, 1.96 mmol), 2,6-dimethylpyridine (1.04 g, 9.79 mmol) in DCM (7 mL) was added drop-wise tertbutyldimethylsilyl trifluoromethanesulfonate (2.07 g, 7.84 mmol) at 0°C. After stirring at 25°C for 36 h the reaction mixture was quenched with water (15 mL) and extracted with DCM (2x15 mL). The combined organic phase washed with brine (15 mL), dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by flash column (0-5% of EtOAc in PE) to afford 54.2 (290 mg, 31%).^ NMR (400 MHz, CDCI3), δ_Η 4.85 (s, 1 H), 4.70 (s, 1 H), 3.38-3.42 (m, I H), 3.35 (s, 3 H), 3.28-3.31 (m, 1 H), 1.65-1.85 (m, 12 H), 1.31-1.47 (m, 10 H), 1.09-1.28 (m, 9 H), 0.92 (s, 3 H), 0.86-0.87 (m, 9 H), 0.55 (s, 3 H), 0.07-0.10 (m, 7 H),

Synthesîs of 54.3

To a solution of 54.2 (700 mg, 1.47 mmol) in DCM (10 mL) was added m-CPBA (596 mg, 85%, 2.94 mmol). After stirring at 15°C for 0.5 h a colorless solution resulted. The mixture was quenched with saturated aq. NaHCO₃ (100 mL). The DCM phase was separated and washed with saturated NaHCO₃/Na₂S₂O3 aqueous (1:1, 3 x 100 mL), brine (100 mL), dried over Na₂SO₄, filtered and concentrated under vacuum to give 54.3 (800 mg).¹H NMR (400 MHz, CDCI3), δ h 3.42-3.28 (m, 5H), 2.88-2.87 (m, 0.6H), 2.56-2.49 (m, IH), 2.32-2.31 (m, 0.4H), 2.06-1.51 (m, 4H), 1.49-1.31 (m, Ι0Η), 1.26-0.91 (m, 12 H), 0.86-0.66 (m, 15H), 0.08-0.07 (m, 6 H).

Synthesîs of 54.4 & 55.1

To a solution of 54.3 (800 mg, 1.62 mmol) in DMF (20 mL), was added 1 H-pyrazole-4carbonitrile (451 mg, 4.86 mmol) and Cs₂CO₃ (1.58 g, 4.86 mmol). After stirring at 130°C for 16 h

180 the réaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with 5% LiCl (3 x 100 mL) and coneentrated. The residue was purified by flash column (0 ~ 12% of EtOAc in PE) to give 54.4 (340 mg) and 55.1 (380 mg).

54.4: *H NMR (400 MHz, CDC1₃), 7.92 (s, IH), 7.81 (s, IH), 4.37-4.34 (m, IH), 4.11-

4.07 (m, IH), 3.41-3.27 (m, 5H), 2.49 (s, IH), 2.03-2.01 (m, IH), 1.85-1.62 (m, 7H), 1.56-1.26 (m, 8H), 1.23-0.94 (m, 13 H), 0.91-0.86 (m, 8H), 0.85-0.82 (m, 4H), 0.08-0.07 (m, 6 H).

55,1: 'H NMR (400 MHz, CDCI3), δ_Η 7.86-7.81 (m, IH), 7.74-7.72 (m, IH), 4.11-3.91 (m, 2H), 3.34-3.20 (m, 5H), 2.02-1.56 (m, 8H), 1.44-1.07 (m, 13H), 1.06-0.78 (m, 15H), 0.77-0.69 (m, 6H), 0.01-0.00 (m, 6H).

Synthesis of 54.5

To a solution of 54.4 (310 mg, 0.530 mmol) in THF (10 mL) was added NaH (211 mg, 5.30 mmol, 60%) at 0°C under N₂ in 100 mL three-neck flask. After stirring at 25 °C for 0.5 h, Mel (752 mg, 5.30 mmol) was added into the reaction mixture. After stirring at 25°C for 16 h, the reaction mixture was quenched by ammonia (1 mL) and poured into water (50 mL). The aqueous phase was extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with brine (2 x 50 mL), dried over anhydrous Na₂SO₄, filtered and coneentrated to give 54.5 (470 mg).’H NMR (400 MHz, CDCI3), δ_Η 7.91 (s, IH), 7.75 (s, IH), 4.30-4.18 (m, 2H), 3.41-3.27 (m, 5H), 3.17 (s, 3H), 1.98-1.59 (m, 10H), 1.41-1.29 (m, 7H), 1.25-1.17 (m, 5H), 1.14-1.05 (m, 4H), 0.91-0.83 (m, 15H), 0.07-0.06 (m, 6 H).

Synthesis of 54

To a solution of 54.5 (470 mg, 0.786 mmol) in THF (20 mL) was added TB AF (1.63 g, 6.28 mmol). After stirring at 80°C for 16 h a solution resulted, and the reaction mixture was quenched with saturated aq. NH₄C1 solution (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with saturated brine (100 mL), dried over anhydrous Na₂SO₄, filtered and coneentrated to give a residue, which was purified by flash column (0-50% of EtOAc in PE) to give 54 (150 mg), which was further purified by SFC (Column DAICEL CHIRALCEL OD-H (250 mm * 30 mm, 5 um); Condition 0.1% NH3H2O EtOH; Bégin B 50%; End B 50%; Flow Rate (ml/min) 80; Injections 45) to provide 54 (95.9 mg, 64%).'H NMR (400 MHz, CDCI3), ô_H 7.90 (s, IH), 7.75 (s, IH), 4.28-4.17 (m,2H), 3.41-3.34 (m, 5H), 3.17 (s, 3H), 2.56 (s, IH), 1.98-1.58 (m, 6H), 1.50-1.10 (m, 13H), 1.09-0.93 (m, 10H), 0.82 (s, 3 H). LC-ELSD/MS purity 99%, MS ESI calcd. For C₂7H₃₇N₃

181

[M-2MeOH-H,O+H]+ 402.3 found 402.3.

Synthesis of 55.2

To a solution of55.1 (310mg, 0.530 mmol) in THF (10 mL) was added NaH (211 mg, 5.30 mmol, 60%) at 0°C under N₂ in 100 mL three-neck flask. After stirring at 25 °C for 0.5 h, Mel (752 mg, 5.30 mmol) was added into the reaction mixture. After stirring at 25 °C for 16 h, the reaction mixture was quenched by ammonia (1 mL) and poured into water (50 mL). The aqueous phase was extracted with EtOAc (2 x 50 mL) and the combined organic phase was washed with brine (2 x 50 mL), dried over anhydrous Na₂SO4, filtered and concentrated to give 55.2 (500 mg).¹!! NMR (400 MHz, CDC1₃), δ_Η 7.90 (s, IH), 7.75 (s, IH), 4.35-4.24 (m, 2H), 3.41-3.27 (m, 5H), 3.15 (s, 3H), 2.071.60 (m, 7H), 1.39-1.25 (m, 8H), 1.24-1.07 (m, 7H), 1.05-0.90 (m, 4H), 0.89-0.83 (m, 7H), 0.82-0.78 (m, 8H), 0.08-0.07 (m, 6H).

Synthesis of 55

To a solution of 55.2 (500 mg, 0.836 mmol) in THF (20 mL) was added TBAF (1.74 g, 6.68 mmol). After stirring at 80°C for 16 h a solution resulted, and the reaction mixture was quenched with saturated aq. NH4CI solution (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous Na₂SO4, filtered and concentrated to give a residue, which was purified by flash column (0-50% of EtOAc in PE) to give 55 (250 mg), which was further purified by SFC (Column DAICEL CHIRALCEL OD-H (250 mm * 30 mm, 5um); Condition 0.1 % NH₃H₂O ETOH; Begin B 50%; End B 50%; Flow Rate (ml/min) 80; Injections 60), to provide 55 (71.2 mg, 28.5%).^lH NMR (400 MHz, CDC1₃), ôh 7.90 (s, IH), 7.75 (s, IH), 4.27-4.20 (m, 2H), 3.42-3.35 (m, 5H), 2.58 (s, 3H), 2.05-1.57 (m, 7H), 1.51-1.06 (m, 15H), 1.000.93 (m, 8H), 0.79 (s, 3 H). LC-ELSD/MS purity 99%, MS ESI calcd. For C₂₇H₃₇N₃ [M-2MeOHH₂O+H]+ 402.3 found 402.3.

EXAMPLE 56: Synthesis of l-(2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3(methoxymethyl)-13-niethylhexadecahydro-lH-cyclopenta[a]phenanthren-17-yi)-2methylpropyl)-lH-pyrazoie-4-carbonitriie (56)

182

Synthesis of 56.1

To a solution of EtPhjPBr (41.5 g, 112 mmol) in THF (110 mL) was added t-BuOK (12.5 g, 112 mmol) at 25°C. The mixture was stirred at 50°C for 1 h where a solution of 40.0 (12.0 g, 37.4 mmol) in THF (50 mL) was added into the reaction mixture below 50°C. After stirring at 40°C for 16 h the mixture was added into saturated NH4CI (100 mL). The aqueous layer was extracted with EtOAc (3 x 150 mL) and the combined organic layer was washed with saturated brine (100 mL), dried over anhydrous Na2SÛ4, fïltered and concentrated. The residue was purified by flash column (0-30% of EtOAc in PE) to give 56.1 (14.0 g).’H NMR (400 MHz, CDCI3) δ_Η 5.15-5.05 (m, IH), 3.42-3.37 (m, 5H), 2.41-2.30 (m, IH), 2.27-2.11 (m, 2H), 1.88-1.80 (m, IH), 1.74-1.68 (m, IH), 1.661.63 (m,3H), 1.63-1.59 (m, 2H), 1.56-1.53 (m, IH), 1.52-1.45 (m, 2H), 1.44-1.35 (m, 5H), 1.35-1.18 (m, 5H), 1.17-1.02 (m, 4H), 0.87 (s, 3H)

Synthesis of 56.2

To a mixture of 56.1 (14.0 g, 42.1 mmol) in DMF (150 mL) was added NaH (6.71 g, 168 mmol, 60% in minerai oil) at 0°C. The mixture was stirred at 25^rtC for 1 h and BnBr (28.7 g, 168 mmol) was added. After stirring at 60° C for 20 h triethylamine (50 mL) was added and the mixture was stirred at 60°C for another 30 min. The mixture was added into NH4CI (100 mL) and the aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic phase was washed with saturated brine (2 x 100 mL), dried over anhydrous Na2SÛ4, fïltered and concentrated. The residue was purified by flash column (0-20% of EtOAc in PE) to give 56.2 (18.8 g).*H NMR (400 MHz, CDCI3) 5h7.37-7.37 (m, IH), 7.36 (s, IH), 7.33 (s, IH), 7.31 (s, IH), 7.29 (s, IH), 5.17-5.05 (m, IH), 4.57 (s, 2H), 3.58 (d, J=4.0 Hz, 2H), 3.38 (s, 3H), 2.42-2.31 (m, IH), 2.28-2.11 (m, 2H), 1.94-1.83

183 (m, IH), 1.79-1.70 (m, 2H), 1.69-1.63 (m, 4H), 1.62-1.57 (m, 2H), 1.54-1.51 (m, IH), 1.50-1.37 (m, 4H), 1.37-1.31 (m, IH), 1.30-1.21 (m, 3H), 1.18-0.99 (m, 4H), 0.88 (s, 3H).

Synthesis of 56.3

To a solution of 56.2 (18.8 g, 44.4 mmol) in THF (200 mL) was added 9-BBN dimer (32.4 g, 133 mmol) at 25°C. The mixture was stirred at 40°C for 1 h, To the resulting mixture was added éthanol (10.2 g, 222 mmol) at 0°C. Then aqueous NaOH (44.4 mL, 5M) was added at 0°C followed by H₂O₂ (22.2 mL, 10M, 222 mmol) dropwise. After the addition, the mixture was stirred at 80°C for 1 h. Sat. Na₂S₂O3 (100 mL) was added and the mixture stirred for 30 mins. The aqueous layer was extracted with EtOAc (200 mL), washed with saturated brine (2 x 100 mL), dried over anhydrous Na₂SO₄ and the combined organic phase was concentrated under vacuum to give 56.3 (13.0 g).

Synthesis of 56.4

To a solution of 56.3 (3.0 g, 6.8 mmol) in DCM (30 mL) was added silica gel (6.6 g) and PCC (4.38 g, 20.4 mmol) at 25°C. After stirring at 25°C for 25 min the suspension was filtered, and the filter cake was washed with DCM (2 X 50 mL). The combined filtrate was concentrated, and the residue was purified by silica gel chromatography (0-20% of EtOAc in PE) to give 56.4 (2.6 g, 87.2%).*H NMR (400 MHz, CDCfi) Ô_H7.40-7.29 (m, 4H), 7.25-7.21 (m, IH), 4.58 (s, 2H), 3.59 (d, J=3.6 Hz, 2H), 3.38 (s, 3H), 2.55 (t, J=8.4 Hz, 1 H), 2.19-2.13 (m, 1 H), 2.11 (s, 3H), 2.03-1.96 (m, IH), 1.92-1.79 (m, 3H), 1.77-1.59 (m, 5H), 1.54-1.32 (m, 7H), 1.31-1.03 (m, 6H), 0.61 (s, 3H).

Synthesis of 56.5

To a stirred solution of t-BuOK (1.01 g, 9.08 mmol) in t-BuOH (10 mL) was added a solution of 56.4 (1.0 g, 2.27 mmol) in DME (10 mL) and a solution of Tosmic (886 mg, 4.54 mmol) in DME (10 mL) under N₂. After stirring at 25°C for 72 h the mixture was quenched by aq.NH₄Cl (40 mL, sat.) and extracted with EtOAc (2 x 50 mL). The combined organic layer was dried over Na₂SO₄, filtered, concentrated and purified by flash column chromatography on silica gel (0-15% EtOAc in PE) to give 56.5 (LO g, 98%).'H NMR (400 MHz, CDC1₃) δ_Η 7.29-7.39 (m, 4 H) 7.20-7.25 (m, 1 H) 4.58 (s, 2 H) 3.53-3.64 (m, 2 H) 3.38 (s, 3 H) 2.25-2.70 (m, 2 H) 1.60-2.08 (m, 10 H) 1.26-1.45 (m, 9 H) 0.89-1.22 (m, 7 H) 0.73 (d, .7=2.00 Hz, 3 H)

Synthesis of 56,6

To a solution of D1PEA (3.12 mL, 22.2 mmol) in THF (50 mL) under N₂ was added n-BuLi

184 (10.6 mL, 2.5 M in hexane, 26.6 mmol) at -70°C. The mixture was warmed to 0°C and stirred for 0.5 h under N₂. The freshly prepared LDA (2.37 g, 22.2 mmol) was added to a stirred solution of 56.5 (1.0 g, 2.22 mmol) under N₂ in THF (50 mL) at -70°C. The mixture was stirred at -70°C for 1 h where methyl iodide (3.15 g, 22.2 mmol) was added under N₂ and the mixture was then warmed to 20°C for 16 h. Water (50 mL) was added and the aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, concentrated and purified by flash column (0—2% of EtOAc in PE) to afford 56.6 (900 mg).¹!! NMR (400 MHz, CDC1₃) δ_Η 7.35-7.20 (m, 4H), 7.20-7.05 (m, IH), 4.55-4.45 (m, 2H), 3.55-3.45 (m, 2H), 3.30 (s, 3H), 2.00-1.90 (m, IH), 1.90-1.65 (m, 9H), 1.65-1.50 (m, 3H), 1.50-1.40 (m, 2H), 1.36-1.27 (m, 13H), 1.27-1.15 (m, 6H), 1.15-0.95 (m, 2H), 0.87-0.80 (m, 4H), 0.80-0.75 (m, 3H).

Synthesis of 56.7

To a solution of 56.6 (900 mg, 1.88 mmol) in DCM (10 mL) a solution of D1BAL-H (9.40 mL, 9.40 mmol, 1 M in toluene) was added slowly at -70°C. After stirring for 30 mins at -70°C, HCl (4 ml, 0.468 Μ, 1.88 mmol) was added. After stirring at 25°C for another 10 mins the mixture was carefully poured into H₂O (30 mL), extracted with EtOAc (2 x 30 mL), dried over Na₂SO4, filtered and concentrated to give 56.7 (800 mg)?H NMR (400 MHz, CDC1₃) Ô_H 9.70 (s, IH), 7.45-7.30 (m, 4H), 7.30-7.20 (ni, IH), 4.65-4.50 (m, 2H), 3.65-3.50 (m, 2H), 3.40 (s, 3H), 2.00-1.85 (m, 2H), 1.851.60 (m, 10H), 1.60-1.55 (m, 2H), 1.56-1.35 (m, 5H), 1.34-1.21 (m, 14H), 1.20-1.15 (m, 3H), 1.140.95 (m, 8H), 0.90-0.88 (m, 8H), 0.87-0.75 (m, 6H), 0.70 (s, 2H).

Synthesis of 56.8

To a suspension of 56.7 (800 mg, 1.71 mmol) in anhydrous MeOH (20 mL) was added NaBH₄ (323 mg, 8.55 mmol) slowly at 0°C. After stirring at 20°C for 30 min a colorless mixture resulted. The mixture was poured into H₂O (20 mL) slowly and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, concentrated and purified by flash column (0-7% of EtOAc in PE) to give 56.8 (500 mg, 62%).*H NMR (400 MHz, CDCft) δ_Η 7.40-7.30 (m, 4H), 7.25-7.20 (m, IH), 4.55-4.50 (m, 2H), 3.70-3.55 (m, 2H), 3.45-3.25 (m, 5H), 2.05-1.95 (m, IH), 1.90-1.75 (m, 4H), 1.70-1.52 (m, 7H), 1.50-1.35 (m, 5H), 1.32-1.20 (m, 6H), 1.20-0.95 (m, 5H), 0.99 (s, 3H), 0.90 (s, 3H).

Synthesis of 56.9

To a solution of 56.8 (500 mg, 1.06 mmol) in MeOH (20 mL) was added Pd/C (50 mg)

185 under N₂. After hydrogénation at 50°C under 50 psi for 16 h, the reaction mixture was filtered through a pad of Celite and washed with EtOAc (3x50 mL). The filtrate was concentrated to give 56.9 (270 mg).*HNMR (400 MHz, CDC1₃) δ_Η3.50-3.35 (m, 7H), 2.58 (s, IH), 2.10-1.95 (m, IH), 1.90-1.75 (m, 4H), 1.70-1.55 (m, 3H), 1.50-1.35 (m, 8H), 1.30-1.20 (m, 4H), 1.15-1.10 (m, 4H), LOI (s, 3H), 0.92 (s, 3H), 0.78 (s, 3H).

Synthesis of 56.10

To a solution of 56.9 (50 mg, 0.132 mmol) in DCM (10 mL) was added 1-methyl-1Himidazol (21.6 mg, 0.264 mmol), TEA (0.0365ml, 0.264 mmol) and TsCi (25.1 mg, 0.132 mmol). After stirring at 20°C for 1 h, the mixture was washed with water (5 mL) and the aqueous layer was extracted with DCM (3 x 20 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated to give 56.10 (50 mg).

Synthesis of 56

To a solution of 56.10 (200 mg, 0.375 mmol) in DMF (20 mL) was added Cs₂CO₃ (244 mg, 0.750 mmol) and 4-cyano-pyrazole (104 mg, 1.12 mmol) at 25°C. After stirring at 120°C for 12 h, the mixture was washed with water (10 mL) and the aqueous phase was extracted with EtOAc (2x10 mL). The combined organic phase was washed with brine (2x10 mL), dried over anhydrous Na₂SO₄, filtered, concentrated and purified by HPLC (Column:Chiralcel OD-3 150^K4.6mm I.D., 3um); Condition: water(Û.05% NH₃H₂O+10 mM NH₄HCO₃)-ACN; Gradient: from 64% to 94% of B; Flow rate: 30 mL/min; Injections: 4; Column température: 35°C) to afford 56 (50 mg, 20.0%). The compound 56 (50 mg, 0.110 mmol) was purified by flash column (0-20% of EtOAc in PE) to give 56 (7.8 mg, 15.6%).’fl NMR (400 MHz, CDCi₃) δ_Η 7-80 (s, IH), 7.40 (s, IH), 4.15-4.00 (m, IH), 3.953.85 (m, IH), 3.45-3.30 (m, 6H), 2.56 (s, IH), 2.00-1.90 (m, 1H)„ 1.85-1.65 (m, 4H), 1.64-1.55 (m, 5H), 1.54-1.45 (m, IH), 1.44-1.30 (m, 5H), 1.29-1.15 (m, 4H), 1.14-1.00 (m, 4H), 0.98 (s, 3H), 0.93 (s, 3H), 0.82 (s, 3H). LC-ELSD/MS purity 99%, MS ESI calcd. For C₂₈H₄₂N₃O [M-H₂O+H]⁺ 436.4 found 436.4.

EXAMPLE 57: Synthesis of l-((S)-2-cyano-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13dimethy lhexadecahydro-1 H-cyclopenta [ a | ph en anthr en-17-yI) pr opyl)-1 H-py r azole-4carbonitrile (57)

186

Synthesis of 57.1

To a solution of 39.0 (3 g, 10.3 mmol) in toluene (50 mL) was added acetic acid amine (2.38 g, 30.9 mmol), acetic acid (6.18 g, 103 mmol) and ethyl-l,2-isocyanoacetate (2.33 g, 20.6 mmol) at 25°C under N₂. After stirring at 140°C for 18 h the reaction mixture was quenched with saturated NH4CI aqueous (50 mL) at 20°C. The aqueous was extracted with EtOAc (2x50 mL) and the combined organic phase were concentrated. The residue was purified by flash column (0-20% of EtOAc in PE) to give 57.1 (3.5 g).^JH NMR (400 MHz, CDCI3) δ_Η4.20-4.31 (m, 2H), 3.07-3.23 (m, IH), 2.68-3.02 (m, 2H), 1.72-1.92 (m, 5H), 1.38-1.69 (m, HH), 1.23-1.36 (m, 12H), 1.10-1.22 (m, 3H), 1.01 (s, 3H),

Synthesis of 57.2

To a solution of 57.1 (500 mg, 1.29 mmol) in EtOH (5 mL) was added NaBH₄ (12.2 mg, 0.3225 mmol) at 0°C under N₂. After stirring at 0°C for 0.5 h the reaction mixture was quenched with saturated aqueous NH4CI (10 mL). The aqueous was extracted with EtOAc (2 x 10 mL) and the combined organic phase was concentrated. The residue was purified by flash column (0-20% of EtOAc in PE) to give 57.2 (500 mg).¹H NMR (400 MHz, CDCI3) δ_Η 4.09-4.29 (m, 2H), 3.23-3.42 (m, IH), 1.98-2.24 (m, 2H), 1.63-1.89 (m, 6H), 1.36-1.51 (m, 7H), 1.26 (m, 10H), 0.95-1.23 (m, 6H), 0.76 (d, J=4.4 Hz, 3H).

Synthesis of 57.3

To a solution of 57.2 (400 mg, 1.03 mmol) in acetone (10 mL), Mel (2.93 mL, 46.3 mmol) and K2CO3 (1.44 g, 10.3 mmol) were added into the reaction mixture at 25°C. After stirring for 16 h at 25°C the residue was poured into water (20 mL). The aqueous phase was extracted with EtOAc (2 x 20 mL) and the combined organic phase was washed with water (2 x 20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated to give 57.3 (350 mg, 85%). H NMR (400 MHz, CDCR) Ô_H 4.18

187

4.28 (m, 2H), l.76-2.01 (m, 8H), 1.63-1.72 (m, 3H), 1.46-1.51 (m, 2H), 1.35 (m, 9H), 1.26 (m, 7H), 1.00-1.10 (m, 5H), 0.94 (s, 3H).

Synthesis of 57.4

To a solution of 57.3 (350 mg, 0.8715 mmol) in EtOH (10 mL) was added NaBH₄ (491 mg, 13.0 mmol) at 25°C under N₂. After stirring at 25°C for 18 h the reaction mixture was quenched with saturated NH₄C1 aqueous (20 mL) at 25°C. The aqueous was extracted with EtOAc (2 x 20 mL) and the combined organic phase was concentrated. The residue was purified by flash column (0-20% of EtOAc in PE) to give 57.4 (310 mg, 99%).*H NMR (400 MHz, CDC1₃) δ_Η 3.91-3.99 (m, IH), 3.513.60 (m, IH), 1.58-1.98 (m, HH), 1.36-1.44 (m, 8H), 1.21-1.30 (m, 8H), 1.01-1.16 (m, 5H), 0.94 (s, 3H).

Synthesis of 57.5

To a solution of 57.4 (310 mg, 0.8621 mmol) in DCM (20 mL) was added N-Me-Im (87.2 mg, 0.8621 mmol), TEA (436 mg, 4.31 mmol) and TsCl (985 mg, 5.17 mmol). After stirring at 20°C for 2 h the mixture was washed with water (40 mL), dried over Na₂SO₄, fdtered and concentrated. The residue was purified by column (0%-40% of EtOAc in PE) to give 57.5 (260 mg, 58.8%).'H NMR (400 MHz, CDCl₃) Ô_H 7.79-7.85 (m, 2H), 7.36-7.40 (m, 2H), 4.19-4.24 (m, IH), 3.95-4.00 (m, IH), 2.47 (s, 3H), 1.59-1.90 (m, 10H), 1.54 (s, 3H), 1.33-1.50 (m, 12H), 0.98-1.15 (m, 6H), 0.84 (s, 3H).

Synthesis of 57

To a solution of 57.5 (260 mg, 0.51 mmol) in DMF (5 mL) was added Cs₂CO₃ (331 mg, 1.00 mmol), 4-cyano-pyrazole (94.0 mg, 1.01 mmol) and Kl (83.9 mg, 0.51 mmol) at 25°C. After stirring ai 120°C for 18 h the mixture was washed with water (10 mL) and the aqueous phase was extracted with EtOAc (2x10 mL). The combined organic phase was washed with saturated brine (2 x 10 mL), dried over anhydrous Na₂SO₄, filtered, concentrated and purified by flash column (60-80% of EtOAc in PE) to give 57 (130 mg, 59%). 57 (110 mg, 0.2530 mmol, SFC spectra: SAGE-LXM-138-P1A K3) was purified by SFC (Phenomenex-Cellulose-2 (250mm*30mm, 10um)); Mobile phase: A: CO₂ B: 0.1%NH₃H₂O EtOH; gradient: from 55% to 55% of B, FlowRate(ml/mm): 80) providing 57 (68.0 mg, 62%). *H NMR (400 MHz, CDC1₃) Ô_H 8.10 (s, IH), 7.83 (s, IH), 4.66 (d, J=13.6 Hz, IH), 4.16 (d, J=14.0Hz, IH), 1.95-2.03 (m, 2H), 1.64-1.88 (m, 7H), 1.54 (s, 3H), 1.44-1.45 (m, IH), 1.38-1.52 (m, 5H), 1.24-1.32 (m, 7H), 1.18 (s, 3H), 1.08-1.14 (m, 3H), 1.04 (s, 3H). LC-ELSD/MS 30188

90AB_2min_E, purity 99%,; MS ESI calcd. for C27H38N4O [M+Hf 435.3, found 435.3.

EXAMPLES 58 & 59: Synthesis of l-((S)-2-hydroxy-2-((2R,3S,5R,8R,9R,10S,13S,14S,17S)3-hydroxy-2-(mcthoxymethyl)-3,13-dimethylhexadecahydro-lHcyclopenta[a]phenanthren-17-yl)propyl)-lLLpyrazole-4-carbonitriIe (58) & l-((R)-2hydroxy-2-((2R,3S,5R,8R,9R, 10S,13S,14S,17S)-3-hydroxy-2-(methoxymethyl)-3,135 dimethylhexadecahydro-lH-cyclopenta[a]phenanthren-17-yl)propyl)-lH-pyrazole-4carbonitriie (59) & l-((S)-2-hydroxy-2-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2(methoxymethyI)-3,13-dimethylhexadecahydro-lH-cyclopenta[a]phenanthren-17yl)propyl)-lH-pyrazole-4-carbonitrile (58A) &l-((R)-2-hydroxy-2((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2-(methoxymethyI)-3,1310 dimethyIhexadecahydro-lH-cyclopenta[a]phenanthren-17-yl)propyl)-lH-pyrazole-4carbonitrile (59A)

Synthesis of 58.2

1S9

To a mixture of 58.1 (380 mg, 1.12 mmol) in DCM (10 mL) was added DMP (950 mg, 2.24 mmol) in portions. After stirring at 20°C for 2 h, the mixture was quenched with NaHCO₃ (30 mL) and Na₂S₂O₃ (30 mL) then extracted with DCM (2 x 20 mL). The organic layer was washed with Na₂S₂O₃ (2 x 100 mL, sat.), brine (300 mL, sat.), dried over Na₂SO₄, filtered and concentrated to give 58.2 (600 mg). ^]H NMR (400 MHz, CDC1₃) δ_Η 3.70-3.66 (m, IH), 3.423.23 (m, 4H), 2.47-2.40 (m, IH), 2.18-1.60 (m, 8H), 1.57-1.14 (m, 14H), 1.13-0.86 (m, 6H).

Synthesis of 58.3

To a suspension of Ph₃PEtBr (3.97 g, 10.7 mmol) in THF (20 mL) was added t-BuOK (1.20 g, 10.7 mmol). After stirring at 40°C for 30 min under N₂, 58.2 (600 mg, 1.79 mmol) in THF (20 mL) was added, then the resulting mixture was stirred at 40°C for 16 h under N₂. The reaction mixture was poured into water (90 mL). The aqueous phase was extracted with EtOAc (2 xlOO mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The product was purified by flash column (0-10% EtOAc in PE) to give 58.3 (350 mg). *Η NMR (400 MHz, CDC1₃) δ_Η 5.14-5.09 (m, IH), 3.843.74 (m, IH), 3.42-3.29 (m, 5H), 2.38-2.13 (m, 3H), 1.96-1.51 (m, 7H), 1.49-1.03 (m, 15H), 1.01-0.86 (m, 6 H).

Synthesis of 58.4

To a solution of 58.3 (380 mg, 1.09 mmol) in THF (30 mL) was added 9-BBN dimer (797 mg, 3.27 mmol) at 25°C under N₂. After stirring at 40°C for 16 hours, the reaction mixture was cooled down and quenched with EtOH (0.8 mL, 13.0 mmol) at 0°C, followed by slow addition ofNaOH (2.6 mL, 5M, 13.0 mmol). Then H₂O₂ (1.63 mL, 16.3 mmol, 10 M in water) was added slowly maintaining the température below 30°C. The mixture was stirred at 70°C for another 1 h. The aqueous phase was extracted with ethyl acetate (3 x 100 mL). The combine organic phase was washed with saturated Na₂S₂O₃ (2 x 100 mL), brine (100 mL), drive over anhydrous Na₂SO₄, filtered and concentrated in vacuum to give a residue, which was purified by flash column (0-20% of EtOAc in PE) to give 58.4 (250 mg). 'H NMR (400 MHz, CDC1₃) δ h 3.84-3.67 (m, 2H), 3.41-3.29 (m, 5H), 1.95-1.59 (m, 8H), 1.53-1.18 (m, 13H), 1.16-0.75 (m, 9H), 0.66-0.65 (m, 3H).

Synthesis of 58.5

To a solution of 58.4 (250 mg, 0.685 mmol) in DCM (10 mL) was added DMP (576 mg, 1.36 mmol) at 25°C. After stirring at 25°C for 60 min, the mixture was quenched with NaHCO₃ 190 (300 mL) and Na₂S₂O₃ (300 mL) then extracted with DCM (2 x 100 mL). The organic layer was washed with Na₂S₂O₃ (2 x 100 mL, sat.), brine (300 mL, sat.), dried over Na₂SO₄, filtered and concentrated in vacuum to give 58.5 (400 mg). NMR (400 MHz, CDC1₃) Ôh 3.78-3.71 (m, IH), 3.45-3.32 (m, 5H), 2.56-2.50 (m, 2H), 2.26-1.85 (m, 7H), 1.83-1.54 (m, 6H), 1.53-1.29 (m, 6H), 1.25-0.79 (m, 7H), 0.63-0.60 (m, 4H).

Synthesis of 58.6

To a suspension of Ph₃PMeBr (1.57 g, 4.40 mmol) in THF (20 mL) was added t-BuOK (493 mg, 4.40 mmol) at 25°C under N₂. After stirring at 50°C for 30 min, a solution of 58.5 (400 mg, 1.10 mmol) in THF (20 mL) was added dropwise to the resulting suspension, and then the mixture was stirred at 50°C for 2h under N₂. The reaction mixture was poured into 10% aq. NH₄C1 (100 mL). The aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The product was purified by flash column (0-10% of EtOAc in PE) to give 58.6 (200 mg). ‘H NMR (400 MHz, CDC1₃) Ô_H 4.84 (s, IH), 4.70 (s, IH), 3.87-3.75 (m, IH), 3.423.31 (m, 5H), 2.04-1.56 (m, 9H), 1.51-1.18 (m, 12H), 1.15-0.83 (m, 8H), 0.57 (s, 3H).

Synthesis of 58.7

To a solution of 58.6 (170 mg, 0.47Immol) in DCM (10 mL) was added m-CPBA (190 mg, 85%, 0.94 mmol) at 15°C and stirred for 0.5 h. The mixture was quenched with saturated aq. NaHCO₃ (100 mL). The DCM phase was separated and washed with saturated aq. NaHCO₃/Na₂S₂O₃ (1:1, 3 x 100 mL), brine (100 mL), dried over Na₂SO₄, filtered and concentrated under vacuum to give 58.7 (250 mg). NMR (400 MHz, CDC1₃) 6h 3.92-3.72 (m, IH), 3.42-3.30 (m, 5H), 2.88-2.87 (m, 0.7H), 2.56-2.49 (m, IH), 2.32-2.31 (m, 0.3H), 2.051.52 (m, 7 H), 1.48-1.20 (m, 12H), 1.18-0.81 (m, 10H), 0.79-0.67 (m, 3H).

Synthesis of 58 & 59 & 58A & 59A

To a solution of 58.7 (250 mg, 0.663 mmol) in DMF (10 mL) was added lH-pyrazole-4carbonitrile (184 mg, 1.98 mmol) and Cs₂CO₃ (645 mg, 1.98 mmol). After stirring at 130°C for 16 hours, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with 5% LiCl (3 x 100 mL) and concentrated. The residue was purified by flash column (0—12% of EtOAc in PE) to give 200 mg of compound, which was purified by SFC (Column DAICEL CHIRALPAK IG

191 (250mm*30mm,10um); Condition 0.1% NH₃H₂O ETOH; Begin B 60%; End B 60%) to give 58 (8.9 mg, 6%), 59 (10.1 mg, 6%), 58A (46.7 mg, 31%), 59A (22.2 mg, 14%).

58: ^JH NMR (400 MHz, CDC1₃) Ô_H 7.92 (s, IH), 7.81 (s, IH), 4.36-4.33 (m, IH), 4.094.06 (m, IH), 3.84 (s, IH), 3.40-3.29 (m, 4H), 2.49 (s, 1 H), 2.02-1.56 (m, 8H), 1.49-1.12 (m, 12H), 1.11-0.91 (m, 13 H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₇H₃₆N₃ [M-2H₂OMeOH+H]+ 402.3 found 402.3.

59: ‘H NMR (400 MHz, CDC1₃) δ_Η 7.88 (s, IH), 7.80 (s, IH), 4.18-4.15 (m, IH), 4.023.99 (m, IH), 3.85 (s, IH), 3.40-3.29 (m, 6H), 2.32 (s, IH), 2.07-1.58 (m, 5H), 1.50-1.18 (m, 1 IH), 1.16-0.85 (m, 15 H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₇H₃₆N₃ [M-2H₂OMeOH+H]+ 402.3 found 402.3.

58A: ’H NMR (400 MHz, CDCI3) Ô_H 7.92 (s, IH), 7.81 (s, IH), 4.36-4.32 (m, 1H),4.1O4.07 (m, IH), 3.71 (t, J=9.2Hz, IH), 3.41-3.34 (m, 4H), 3.22 (s, IH), 2.50 (s, IH), 2.04-2.00 (m, IH), 1.88-1.57 (m, 9H), 1.46-1.14 (m, 10H), 1.11-0.85 (m, I2H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₇H₃₆N₃ [M-2H₂O-MeOH+H]⁺ 402.3 found 402.3.

59A: ^rH NMR (400 MHz, CDCI3) δ_Η 7.88 (s, 1 H), 7.80 (s, IH), 4.18-4.14 (m, 1H),4.O23.99 (m, IH), 3.71 (t, J=8.8Hz, IH), 3.41-3.34 (m, 4H), 3.24 (s, 1H),2.28 (s, IH), 2.08-1.57 (m, 9H), 1.52-1.12 (m, 1 IH), 1.09-0.88 (m, 12H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₇H₃₆N₃ [M-2H₂O-MeOH+H]⁺ 402.3 found 402.3.

EXAMPLES 60 & 61: Synthesîs of l-((S)-2-hydroxy-2-((2R,3S,5R,8R,9R,10S,13S,14S,17S)3-hydroxy-2-methoxy-3,13-dimethylhexadecahydro-lH-cyclopenta[a]phenanthren-17yl)propyl)-lH-pyrazole-4-carbonitrile (60) & l-((R)-2-hydroxy-2((2R,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2-methoxy-3,13-dmiethylhexadecahydrolH-cyelopenta[a)phenanthren-17-yl)propyI)-lH-pyrazole-4-carbonitrile (61)

192

Synthesis of 60.1A & 60.IB

Compound 52.2 (16.0 g, 37.1 mmol) was added to collidine (150 mL, 37.1 mmol) at 25°C under N₂. The mixture was stirred at 140°C for 16 hours to give a solution, The mixture was poured into water (500 mL), extracted with EtOAc (3 x 400 mL). Tire combined organic phase was washed with water (3 x 100 mL), brine (200 mL), dried over anhydrous Na₂SO4, fïltered and concentrated under vacuum. The residue was purified by flash column (0-20% of EtOAc in PE) to give 60.1A and 60.1B (8.60 g). 'H NMR (400 MHz, CDC1₃) δ_Η 0.87 (s, IH) 0.91 (s, IH) 0.94-1.10 (m, 2H) 1.10-1,33 (m, 6H) 1.53 (br dd, J=6.02, 2.76 Hz, 7H) 1.67-1.83 (m, 3 H) 1.83-1.97 (m, 3H) 2.28-2.72 (m, 3H) 5.31-5.55 (m, 1 H) 5.60 (br s, IH).

Synthesis of 60.2A & 60.2B

To a mixed solution 60.1 A and 60.1 B (8.60 g, 33.2 mmol) in DCM (90 mL) was added m-CPBA (10.0 g, 49,8 mmol) at 0°C under N₂. After stirring at 25°C for 2 h, the mixture was quenched with saturated NaHCO₃ (100 mL) and extracted with DCM (2 x 150 mL). The organic 15 layer was washed with Na₂S₂O₃ (2 x 100 mL, sat.), brine (2 x 100 mL), dried over anhydrous

Na₂SO4, fïltered and concentrated in vacuum. The residue was purified by flash column (0-20% of EtOAc in PE) to give 60.2A and 60.2B (4.60 g). *H NMR (400 MHz, CDC1₃) 30.64-0,82

193 (m, IH) 0.71-0.89 (m, 1 H) 0.82-0.86 (m, IH)0.87(brs, IH) 0.9-1.12 (m, 2H) 1.12-1.33 (m, 4H) 1.30-1.44 (m, 3H) 1.44-1.65 (m, 3H) 1.65-1.76 (ni, 2H) 1.76-1.89 (m, 2H) 1.89-2.09 (ni, 3H) 2.09-2.74 (m, 2H) 2.76-3.31 (m, IH).

Synthesis of 60.3A & 60.3B

To a solution of the mixture of 60.2A and 60.2B (4.80 g, 17.4 mmol) in MeOH (50 mL) was treated with 0.5 mL of H₂SO₄ (98%) at 25 °C for 3 hours. The reaction mixture was treated with saturated NaHCO₃ (200 mL). The mixture was extracted with EtOAc (2 x 300 mL). The organic layer was washed with brine (2 x 200 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The product was purified by flash column chromatography on silica gel (0-15% of EtOAc in PE) to give 60.3A and 60.3B (4.30 g). 'H NMR (400 MHz, CDCI₃) δ_Η 0.87 (s, 3H) 0.87-0.89 (m, IH) 0.91-1.13 (m, 3H) 1.14-1.35 (m, 6H) 1.35-1.60 (m, 4H) 1.70-2.01 (m, 4H) 2.06-2.65 (m, 3H) 2.96-3.24 (m, IH) 3.33 (s, IH) 3.37 (s, IH) 3.40 (s, 2H) 3.60-3.77 (m, IH).

Synthesis of 60.4A & 60.4B

To a solution of 60.3A and 60.3B (500 mg, 1.63 mmol) in DCM (10 mL) was added DMP (1.38 g, 3.26 mmol) at 25°C under N₂. After stirring at 25°C for 1 h, another batch of DMP (1.38 g, 3.26 mmol) was added to the reaction mixture at 25°C under N₂. After stirring at 35°C for 2 h, the mixture was quenched with saturated aqueous NaHCO₃ and saturated aqueous Na₂S₂O₃ (50 mL, 1:1). The mixture was extracted with DCM (2 x 100 mL). The combined organic phase was washed with a mixture of saturated aqueous NaHCO₃ and saturated aqueous Na₂S₂O₃ (150 mL, 1:1), The combined organic phase was washed with brine (2 x 100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by pre-HPLC (Column:Welch Xtimate C18 150*25mm*5um; Condition: water (0.225%FA)-ACN; Begin B:70%; End B: 100%) to afford 60.4A (50 mg, 10.0 %) and 60.4B (430 mg).

.4A: NMR (400 MHz, CDC1₃) δ_Η 5.70-5.65 (m, 1H), 5.42-5.36 (m, IH), 3.93-3.89 (m, IH), 3.60-3.56 (m, IH), 2.58-2.48 (m, 2H), 2.24-1.90 (m, 6H), 1.80-1.10 (m, 16H), 1.000.87 (m, IH), 0.60 (s, 3H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₎₉H₂₉O₃ [M+H]⁺ 305.2 found 305.2.

.4B: ’H NMR (400 MHz, CDC1₃) δ_Η 0.70 (s, IH) 0.83-0.91 (m, 3H) 0.92-1.08 (m, IH) 1.08-1.26 (m, IH) 1.26-1.50 (m, 4H) L65-L76 (m, 3H) 1.76-1.90 (m, 2H) 1.90-2.02 (m, 2H) 2.05 (br d, 7=8.78 Hz, 2H) 2.12-2.27 (m, IH) 2.27-2.36 (m, IH) 2.45 (br dd, 7=19.20, 8.66

194

Hz, IH) 2.66-2.80 (m, IH) 3.01 (t,/=13.80 Hz, IH) 3.25 (s, 1 H) 3.26 (s, IH) 3.27-3.28 (m, IH) 3.48 (brd,/=3.51 Hz, IH).

Synthesis of 60.5

To a solution of 60.4A (350 mg, 1.14 mmol) in THF (10 mL) was added MeMgBr (1.9 mL, 3 M in ethyl ether, 5.70 mmol) dropwise at -70°C and the mixture was stirred for 2 h. The reaction mixture was slowly poured into saturated aqueous citric acid (20 mL) at below 10°C. The aqueous phase was extracted with EtOAc (2 x 20 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered and coneentrated to afford 60.5 (450 mg). NMR (400 MHz, CDC1₃) δ_Η 3.37 (s, 3H), 3.05 (s, IH), 3.01 (br s, IH), 2.43 (dd,/=8.2, 19.2 Hz, IH), 2.28-2.17 (m, IH), 2.13-2.06 (m, IH), 1.92-1.75 (m, 5H), 1.55-1.33 (m, 8H), 1.22 (s, 3H), 1.21-1.03 (m, 5H), 0.87 (s, 3H).

Synthesis of 60.6

To a suspension of EtPh₃PBr (2.59 g, 7.00 mmol) in anhydrous THF (20 mL) was added t-BuOK (784 mg, 7.00 mmol) at 25°C under N₂ and stirred at 45°C for 30 min. Then a solution of 60.5 (450 mg, 1.40 mmol) in anhydrous THF (10 mL) was added dropwise. The reaction mixture was stirred for 16 h. The mixture was cooled and poured into water (25 mL) and stirred for 10 min. The aqueous phase was extracted with EtOAc (2 x 30 mL). The combine organic phase was washed with brine (2 x 50 mL), filtered, dried over anhydrous Na₂SO₄, and coneentrated. The residue was purified by flash column (0-15% of EtOAc in PE) to give 60.6 (350 mg, 75.2%). 'H NMR (400 MHz, CDC1₃) δ_Η 5.21-5.02 (m, IH), 3.39 (s, 3H), 3.09 (s, IH), 3.00 (br s, 1 H), 2.45-2.09 (m, 4H), 1.98-1.87 (m, IH), 1.86-1.77 (m, 2H), 1.70-1.57 (m, 6H), 1.54-1.31 (m, 6H), 1.22 (s, 3H), 1.20-1.04 (m, 4H), 0.97-0.89 (m, 1H),O.88 (s, 3H).

Synthesis of 60.7

To a solution of 60.6 (350 mg, 1.05 mmol) in THF (20 mL) was added 9-BBN (8.4 ml, 4.20 mmol, 0.5 M in THF) under N₂. The reaction mixture was stirred at 50°C under N₂ for 2 h. The mixture was cooled to 0°C. Then éthanol (0.902 mL, 15.7 mmol) and NaOH (3.13 mL, 5 M, 15.7 mmol) were added to the reaction mixture. Subsequently, H₂O₂ (1.56 mL, 10 M, 15.7 mmol) was added dropwise at 0°C. The mixture was stirred at 50°C for 2 hours. Saturated aqueous Na₂S₂O₃ (50 mL) was added and the mixture was stirred at 0°C for another 1 hour. The reaction was checked with potassium iodide-starch test paper to confirm excess H₂O₂ was destroyed. The aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic 195 layer was washed with brine (2x50 mL), dried over anhydrous Na₂SO4, filtered and concentrated to give 60.7 (350 mg).

Synthesis of 60.8

To a solution of 60.7 (350 mg, 0.998 mmol) in DCM (30 mL) was added DMP (I.69 g, 3.99 mmol) at 25°C under N₂. After stirring at 25°C for 0.5 h, the resulting mixture was quenched with NaHCO₃ and Na₂S₂O₃ (50 mL, 1:1). The mixture was extracted with DCM (2 x 50 mL). The combined organic phase was washed with a mixture of NaHCO₃ and Na₂S₂O₃ (50 mL, 1:1). The combined organic layer was washed with brine (2x30 mL), dried over anhydrous Na₂SO4, filtered and concentrated. The residue was purified by flash column (0-30% of EtOAc in PE) to give 60.8 (260 mg, 74.9%). ‘H NMR (400 MHz, CDC1₃) δ_Η 3.40 (s, 3H), 3.07 (s, IH), 3.02 (brs, 1 H), 2.54 (brt, 7=8.7 Hz, 1 H), 2.30-2.13 (m, 2H),2.12 (s, 3H), 2.04-1.97 (m, IH), 1.92-1.77 (m, 3H), 1.68-1.59 (m, 3H), 1.51-1.26 (m, 7H), 1.22 (s, 3H), 1.20-1.00 (m, 4H), 0.960.81 (m, IH), 0.61 (s, 3H).

Synthesis of 60.9

To a suspension of MePh₃PBr (675 mg, 1.89 mmol) in anhydrous THF (15 mL) was added t-BuOK (212 mg, 1.89 mmol) at 15°C under N₂ and stirred at 60°C for 30 min. Then a solution of 60.8 (220 mg, 0.63 mmol) in anhydrous THF (5 mL) was added dropwise. The reaction mixture was stirred for 1 h. The mixture was cooled and poured into ice-water (50 mL) stirred for 10 min. The aqueous phase was extracted with EtOAc (2 x 50 mL). The combine organic phase was washed with brine (2 x 50 mL), filtered and concentrated. The residue was purified by flash column (0-10% of EtOAc in PE) to give 60.9 (200 mg, 91.7%). ^lH NMR (400 MHz, CDC1₃) δ_Η 4.84 (s, IH), 4.70 (s, 1 H), 3.40 (s, 3H), 3.09 (s, 1 H), 3.00 (brs, IH), 2.30-2.18 (m, IH), 1.96-1.77 (m, 4H), 1.76 (s, 3H), 1.73-1.59 (m, 3H), 1.53-1.31 (m, 6H), 1.22 (s, 3H), 1.20-1.00 (m, 5H), 0.91-0.78 (m, 3H), 0.57 (s, 3H).

Synthesis of 60.10

To a solution of 60.9 (110 mg, 0.3174 mmol) in DCM (10 mL) was added m-CPBA (128 mg, 0.64 mmol, 85%) and NaHCO₃ (53.3 mg, 0.64 mmol) at 0°C under N₂. Then the mixture was stirred at 15°C for 2 h. The mixture was quenched with saturated NaHCO₃ (10 mL) and extracted with DCM (2 x 10 mL). The organic layer was washed with Na₂S₂O₃ (2x10 mL, sat.),

196 brine (2x10 mL), dried over anhydrous Na₂SO4, filtered and concentrated to give 60.10 (100 mg).

Synthesis of 60 & 61

To a solution of 60.10 (100 mg, 0.28 mmol) in DMF (5 mL) was added lH-pyrazole-4carbonitrile (51.3 mg, 0.55 mmol) and Cs₂CO₃ (179 mg, 0.55 mmol) at 20°C under N₂. After stirring at 130°C for 16 hours, the mixture was poured into H₂O (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash column (0-30% of EtOAc in PE), which was purified by SFC (Column:DAICEL CHIRALPAK AD(250mm*30mm,10um); Condition:0.1%NH₃H₂O IPA; Begin B:60%; End B:60%) to afford 60 (26.1 mg, Rt = 2.091 min, 26.1%) and 61 (7.2 mg, Rt = 2.275 min, 7.22%).

60: ‘H NMR (400 MHz, CDC1₃) δ_Η 7.94 (d,7=2.5 Hz, 1 H), 7.83 (d,7=2.5 Hz, IH), 4.42-4.02 (m, 2H), 3.39 (d, J= 2.8 Hz, 3H), 3.11-2.95 (m, 2H), 2.53 (d, J = 2.8 Hz, IH), 2.301.99 (m, IH), 2.30-1.99 (m, 2H), 1.97-1.80 (m, 2H), 1.70-1.32 (m, 9H), 1.23 (brs, 10H), 0.99 (d, 7= 2.5 Hz, 3H), 0.93 (d, 7= 2.3 Hz, 4H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₇H₃₈N₃O [M-2H₂O+H]⁺ 420.3 found 420.3.

61: 'H NMR (400 MHz, CDC1₃) δ_Η 7.90 (s, IH), 7.81 (s, IH), 4.24-3.93 (m, 2H), 3.39 (s, 3H), 3.14-2.94 (m, 2H), 2.29 (s, 4H), 1.95-1.60 (m, 4H), 1.54-1.28 (m, 8H), 1.24-1.06 (m, HH), 0.91-0.86 (m, IH), 0.89 (s, 4H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₇H₃₈N₃O [M2H₂O+H]⁺ 420.3 found 420.3.

Steroid Inhibition of TBPS Binding

[³⁵S]-t-Butylbicyclophosphorothionate (TBPS) binding assays using rat brain cortical membranes in the presence of 5 mM GABA has been described (Gee et al, J. Pharmacol. Exp. Ther. 1987, 241, 346-353; Hawkinson et al, Mol. Pharmacol. 1994, 46, 977-985; Lewin, A.H et al., Mol. Pharmacol. 1989, 35, 189-194).

Briefly, cortices are rapidly removed following décapitation of carbon dioxideanesthetized Sprague-Dawley rats (200-250 g). The cortices are homogenized in 10 volumes of ice-cold 0.32 M sucrose using a glass/teflon homogenizer and centrifuged at 1500 x g for 10 min at 4 °C. The résultant supematants are centrifuged at 10,000 x g for 20 min at 4 °C to obtain the P2 pellets. The P2 pellets are resuspended in 200 mM NaCl/50 mM Na-K phosphate pH 7.4

197 buffer and centrifuged at 10,000 x g for 10 min at 4 ^ÛC. This washing procedure is repeated twice and the pellets are resuspended in 10 volumes of buffer. Aliquots ( 100 mL) of the membrane suspensions are incubated with 3 nM [³⁵S]-TBPS and 5 mL aliquots of test drug dissolved in dimethyl sulfoxide (DMSO) (final 0.5%) in the presence of 5 mM GABA. The incubation is brought to a final volume of 1.0 mL with buffer. Nonspecific binding is detennined in the presence of 2 mM unlabeled TBPS and ranged from 15 to 25 %. Following a 90 min incubation at room temp, the assays are terminated by filtration through glass fiber filters (Schleicher and Schuell No. 32) using a cell harvester (Brandel) and rinsed three times with icecold buffer. Filter bound radioactivity is measured by liquid scintillation spectrometry. Non- linear curve fitting of the overall data for each drug averaged for each concentration is done using Prism (GraphPad). The data are fit to a partial instead of a full inhibition mode! if the sum of squares is significantly lower by F-test. Similarly, the data are fit to a two component instead of a one component inhibition mode! if the sum of squares is significantly lower by F-test. The concentration of test compound producing 50% inhibition (IC50) of spécifie binding and the maximal extent of inhibition (I_max) are detennined for the individual experiments with the same mode! used for the overall data and then the means + SEM.s of the individual experiments are calculated. Picrotoxin serves as the positive control for these studies as it has been demonstrated to robustly inhibit TBPS binding,

Various compounds are or can be screened to détermine their potential as modulators 20 of [³⁵S]-TBPS binding in vitro. These assays are or can be performed in accordance with the above

In Table 2 below, A indicates a TBPS IC50 (μΜ) <0.1 μΜ, B indicates a TBPS IC50 (pM)ofO.l μΜ to < LO μΜ, C indicates a TBPS lC₅₀(pM)of> 1.0 μΜ.

198

2	ι h σ'	^QH 1 Λ^Ν'Ν Ab 9 -i+r 1 O N	A
3	HO	\PH F t N~N γΦ b a T a m O1 N H	A
4	% PH i Λ'ν-ν î Ht? H	A
5		A
6		A

199

7		A
	Π n w N H
8	HO	H	, OH	B
9	OH	H	A s ii	B
10	OH	H		C
			r'R»
11	/< HO	„ N w H	b H W N	A

200

12	,, OH HO' H	B
13	OH HO' A	B
14	,, OH HO' fi	C
15	î HO H	A
16	HÔ H	A

201

17	HO' fi	B
18	OH ... ΜίϊΛ HÔ A
19	OH HÔ H	A
20	,, OH HÔ H	B
21	F F HO' H	A

202

22		A
23		B
24	\PH vn Ύ R [ I ii HO h	A
25	OH hO h	B
26	^OH HO H	A

203

27	, OH HÔ H	B
28	HO' H	A
29		A
30		B
31		A

204

32	xo ZA» Ζί ï HO	B
33	. h' ' HO H	B
34	HQ H pYj N^Z^N J T H J H HO H	A
35	HO HφHJY N^Z^N ζ X H T H HÔ H	B
36	xp HÔ H	B

205

206

207

208

52	HQ H \ H T>	A
	H J H
HO H
53	h HO h	HO ζ^.υ+ __ 1 ΓΗΧ> n^-^n A T A	B
54	HÔ H	B
55	0^ 1 1 H I) NV 5n —°vJ^I^ HÔ H	B
56	Z / *7--\X / T A-χ --L i£ \ T A—4*1 X ΓΌ J X O 1	A

209

57	ï t h [ h î y ν+/'+:ν f H T H HÔ H	A
58	HQ u 1 I H J H HÔ H	A
59	HÔ 1-	HO i ΓΗΤγ H T A d	B
58A	h HÔ h	HO t ΓΗΧ) Nv^n HJ A 1	A
59A	HO H fH L 1 H J H HÔ H	B

210

Equivalents and Scope

In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise évident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or ail of the group members are présent in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise évident from the context. The invention includes embodiments in which exactly one member of the group is présent in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or ail of the group members are présent in, employed in, or otherwise relevant to a given product or process.

Furthermore, the invention encompasses ail variations, combinations, and permutations in which one or more limitations, éléments, clauses, and descriptive tenus from one or more of the listed claims is introduced into another claim. For example, any claim that is dépendent on another claim can be modified to include one or more limitations found in any other claim that is dépendent on the saine base claim. Where éléments are presented as lîsts, e.g., in Markush group format, each subgroup of the éléments is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular éléments and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such

211 éléments and/or features. For purposes of simplicity, those embodiments hâve not been specifically set forth in haec verba herein. It is also noted that the tenns “comprising” and “containing” are intended to be open and permits the inclusion of additional éléments or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indîcated or otherwise évident from the context and understandmg of one of ordinary skill in the art, values that are expressed as ranges can assume any spécifie value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictâtes otherwise.

This application refers to various îssued patents, published patent applications, journal articles, and other publications, ail of which are incorporated herein by reference. If there is a conflict between any of the incorporated référencés and the instant spécification, the spécification shall control. In addition, any parti cul ar embodiment of the présent invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any parti cul ar embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using no more than routine expérimentation many équivalents to the spécifie embodiments described herein. The scope of the présent embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art w^rifi appreciate that various changes and modifications to this description may be made without departîng from the spirit or scope of the présent invention, as defined in the following claims.

Claims (96)

1. A compound of Formula (I):

or a pharmaceutically acceptable sait thereof;

wherein:

represents a single or double bond, provided if a double bond is présent, then one of R^6a or R⁶⁵ is absent and R⁵ is absent;

R^x is selected from the group consisting of halo, -CN, -OH, -OR^Q1, and substituted or unsubstituted alkyl, wherein R⁰¹ is substituted or unsubstituted alkyl;

R^Y is halo or substituted or unsubstituted alkyl; or

R^Y and R^x may join together with the intervening atoms to form a substituted or unsubstituted carbocyclyl or a substituted or unsubstituted heterocyclyl;

R³ is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

R⁵ is hydrogen or methyl;

each instance of R²² is independently selected from the group consisting of halogen,

-NO₂, -CN, -OR^ga, -N(R^ga)2, -C(=O)R^ga, -C(=O)OR^qa, -OC(=O)R^ga, -OC(=O)OR^ga, -C(=O)N(R^ga)2, -N(R^ga)C(=O)R^ga, -OC>O)N(R^ga)2, -N(R^ga)C(=O)OR^ga, -N(R^ga)C(=O)N(R^ga)2.-SR^ga, -S(=O) R^ga, -S(=O)2R^ga, -S(=O)2OR^ga, -OS(=O)2R^ga, -S(=O)2N(R^ga)2, -N(R^ga)S(=O)2R^ga, substituted or unsubstituted alkyl, substituted or unsubstituted

213 alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocylyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein each instance of R^GA is independently selected from the group consisting of hydrogen, substituted or unsubstituted C]_₆ alkyl, substituted or unsubstituted C₂.₆ alkenyl, substituted or unsubstituted C₂.₆ alkynyl, substituted or unsubstituted Cj.₆ carbocylyl, substituted or unsubstituted 3- to 6- membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, and a nitrogen protecting group when attached to nitrogen, or two R^GA groups are taken with the intervening atoms to form a substituted or unsubstituted heterocyclyl or heteroaryl ring;

each of R^,a, R^lb, R^2a, R^2b, R^4a, R^4b, R^7a, R^7b, R^,la, R^,lb, R^12a, and R^12b is independently selected from the group consisting of hydrogen, halogen, cyano, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR^AI, -N(R^A,)2, -SR^AI, -C(=O)R^AI, -C(=O)OR^ai, -C(=O)SR^ai, -C(=O)N(R^ai)2, -OC(=O)R^a1, -OC(=O)OR^a1, -OC(=O)N(R^a1)2j -OC(=O)SR^ai, -OS(=O)2R^ai, -OS(=O)2OR^a!, -OS(=O)2N(R^a1)2, -N(R^a1)C(=O)R^a!, -N(R^ai)C(=NR^a1)R^a1, -N(R^a1)C(=O)OR^a1, -N(R^a1)C(=O)N(R^a1)2, -N(R^a,)C(=NR^a1) N(R^a1)2, -N(R^a1)S(=O)2R^ai, -N(R^a ^5(=0 )2OR^ai, -N(R^ai)S(-O)2N(R^a1)2, -SC(=O)R^ai, -SC(=O)OR^ai, -SC(=O)SR^a1, -SC(=O)N(R^a,)2, -S(=O)2R^a1, -S(=O)2OR^ai, or -S(=O)2N(R^A1)2, wherein each instance of R^a1 is independently selected from the group consisting of hydrogen, substituted or unsubstituted Cj._s alkyl, substituted or unsubstituted C₂_6 alkenyl, substituted or unsubstituted

C₂.₆ alkynyl, substituted or unsubstituted C₃.₆ carbocyclyl, or substituted or unsubstituted 3- to 6membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur, or two R^Ai groups are taken with the intervening atoms to form a substituted or unsubstituted heterocyclic ring;

each of R^6a and R^6b is independently selected from the group consisting of hydrogen, halogen, cyano, -NO₂, -OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl; or R^6a and R^6b are joined to form an oxo (=0) group;

each of R^lîa, R^lîb, R^lûa,and R^1Sb is independently selected from the group consisting of hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR^C3, -N(R^C3)2, -SR^C3, C(=O)R^C3, -C(=O)OR^a, -C(=O)SR^C3, -C(=O)N(R^C3)2, -OC(=O)R^C3, -OC(=O)OR^C3, -OC(=O)N(R^C3)2, -OC(=O)SR^C3, -OS(=O)2R^C3, -OS(=O)2OR^C3,

214

-OS(=O)₂N(R^C3)2, -N(R^C3)C(=0)R^o -N(R°)C(=NR^C3)R^C3, -N(R^C3)C(=O)OR°, -N(R^C3)C(=O)N(R^C3)z, -N(R^C3)C(=NR^C3)N(R^C3)2î -N(R^C3)S(=O)2R^C3, -N(R^cj)S(=O)2OR^C3, -N(R^C3)S(=O)3N(R^C3)2, -SC(=O)R^C3, -SC(=O)OR^c\ -SCfoOjSR⁰, -SC(=O)N(R^C3)2,

-S(=O)₂R^C3, -S(=O)2OR^C3, or -S(=O)2N(R^C3)2j wherein each instance of R^C3 is independently selected from the group consisting of hydrogen, substituted or unsubstîtuted Ci.6 alkyl, substituted or unsubstîtuted C₃.₆ alkenyl, substituted or unsubstîtuted C₂,₆ alkynyl, substituted or unsubstîtuted aryl, substituted or unsubstîtuted heteroaryl, substituted or unsubstîtuted carbocyclyl, or substituted or unsubstîtuted heterocyclyl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, and a sulfur protecting group when attached to sulfur, or two R^C3 groups are taken with the intervening atoms to form a substituted or unsubstîtuted heterocyclic ring;

R¹⁹ is hydrogen or substituted or unsubstîtuted alkyl; and n is selected from the group consisting of 0, 1, 2, and 3.

2. The compound or pharmaceutically acceptable sait of claim 1, wherein the compound ofFormula (I) is a compound ofFormula (I-a):

or a pharmaceutically acceptable sait thereof.

3. The compound or pharmaceutically acceptable sait of claim 1 or 2, wherein R^uand R^lb are both hydrogen,

4. The compound or pharmaceutically acceptable sait of any one of daims 1-3, wherein each R^2a and R^2b is independently selected from the group consisting of hydrogen, substituted or unsubstîtuted C,.₆ alkyl, and -OR^A1, wherein R^A1 is hydrogen or unsubstîtuted alkyl.

215

5. The compound or pharmaceutically acceptable sait of any one of daims 1 -4, wherein each R^2a and R^2b is independently selected from the group consisting of hydrogen, methyl, ethyl, methoxymethyl, and methoxy.

6. The compound or pharmaceutically acceptable sait of any one of daims 1 -5, wherein R^2a and R^2b are both hydrogen.

7. The compound or pharmaceutically acceptable sait of any one of daims 1 -6, wherein R^4a and R^4b are both hydrogen.

8. The compound or pharmaceutically acceptable sait of any one of daims 1 -7, wherein R^7a and R^7b are both hydrogen.

9. The compound or pharmaceutically acceptable sait of any one of daims 1 -8, wherein R^{1 la} and R^llb are both hydrogen.

10. The compound or pharmaceutically acceptable sait of any one of daims 1-9, wherein R^l2a and R^12b are both hydrogen.

11. The compound or pharmaceutically acceptable sait of any one of daims 1-10, wherein R^6a and R^6b are both hydrogen.

12. The compound or pharmaceutically acceptable sait of any one of daims 1-11, wherein each R¹⁵⁰ and R^l5b is independently selected from the group consisting of hydrogen, unsubstituted alkyl, and unsubstituted C₃.6 carbocyclyl.

13. The compound or pharmaceutically acceptable sait of any one of daims 1-12, wherein each R^15a and R^,5b is independently selected from the group consisting of hydrogen, methyl, and cyclopropyl.

14. The compound or pharmaceutically acceptable sait of any one of daims 1-13, wherein R^15a and R^l5b are both hydrogen.

216

15. The compound or phannaceuticaily acceptable sait of any one of claims 1-14, wherein R^l6a and R^l6b are both hydrogen.

16. The compound or phannaceuticaily acceptable sait of any one of claims 1-15, wherein R³ is substituted or unsubstituted C]_₆ alkyl.

17. The compound or phannaceuticaily acceptable sait of any one of claims 1-16, wherein R³ is Ci_₃ alkyl optionally substituted with C].₃ alkoxy.

18. The compound or phannaceuticaily acceptable sait of any one of claims 1-17, wherein R³ is selected from the group consisting of methyl, ethyl, n-propyl, -CH₂OCH₃, and -CH2OCH2CH3.

19. The compound or phannaceuticaily acceptable sait of any one of claims 1-18, wherein R³ is methyl.

20. The compound or phannaceuticaily acceptable sait of any one of claims 1-19, wherein R¹⁹ is hydrogen or unsubstituted C|.₃ alkyl.

21. The compound or phannaceuticaily acceptable sait of any one of claims 1-20, wherein R¹⁹ is selected from the group consisting of hydrogen, methyl, and ethyl.

22. The compound or phannaceuticaily acceptable sait of any one of claims 1-21, wherein R¹⁹ is hydrogen.

23. The compound or phannaceuticaily acceptable sait of any one of claims 1-22, wherein R^x is selected from the group consisting of halo, -CN, -OH, -OR^Q1, and unsubstituted Cj.3 alkyl.

24. The compound or phannaceuticaily acceptable sait of any one of claims 1-23, wherein R⁰¹ is unsubstituted C1.3 alkyl.

217

25. The compound or pharmaceutically acceptable sait of any one of daims l-24, wherein R^Ql is selected from the group consisting of methyl, ethyl, and n-propyl.

26. The compound or phannaceutically acceptable sait of any one of daims 1-25, wherein R'¹ is methyl.

27. The compound or phannaceutically acceptable sait of any one of daims 1-23, wherein R^x is selected from the group consisting of fluoro, -CN, -OH, -OCH_J: and methyl.

28. The compound or phannaceutically acceptable sait of any one of daims 1 -23 or 27, wherein R^x is -OH.

29. The compound or pharmaceutically acceptable sait of any one of daims 1-28, wherein R' is halo or unsubstituted C1.5 alkyl.

30. The compound or pharmaceutically acceptable sait of any one of daims 1-29, wherein R^Y is selected from the group consisting of methyl, ethyl, and n-propyl.

3 ]. The compound or pharmaceutically acceptable sait of any one of daims 1-30, wherein R^Yis methyl.

32. The compound or phannaceutically acceptable sait of any one of daims 1-29, wherein R^Y is fluoro.

33, The compound or pharmaceutically acceptable sait of any one of daims 1 -22, wherein R^Y and R^x join together with the intervening atoms to form an unsubstituted carbocyclyl or an unsubstituted 3- to 6- membered heterocyclyl.

34. The compound or phannaceutically acceptable sait of any one of daims 1-22, wherein R^Y and R^x join together with the intervening atoms to form a substituted or unsubstituted 3-membered carbocyclyl.

218

35, The compound or pharmaceutically acceptable sait of any one of daims l -22, wherein R^Y and R^x join together with the intervening atoms to form a substituted or unsubstituted 4-membered heterocyclyl.

36. The compound or pharmaceutically acceptable sait of claim 35, wherein the 4-membered heterocyclyl contains a heteroatom selected from N, O, and S.

37. The compound or phannaceutically acceptable sait of daim 36, wherein R^Y and R^x join together to form an oxetane.

3S. The compound or pharmaceutically acceptable sait of any one of daims l-37, wherein n is l, and wherein R²² is selected from the group consisting of halogen, -CN, substituted or unsubstituted Ci.3 alkyl, substituted or unsubstituted 3- to 6- membered heterocyclyl, and -OR^GA, wherein R^GA is hydrogen or substituted or unsubstituted alkyl.

39. The compound or pharmaceutically acceptable sait of any one of daims l -38, wherein R²² is -CN or C^j alkyl optionally substituted with oxo.

40. The compound or pharmaceutically acceptable sait of any one of daims l -39, wherein R²² is CN.

41. The compound or pharmaceutically acceptable sait of any one of daims l-40, wherein R²² is -CN located at the 4-position of the pyrazolyl.

42. The compound or phannaceutically acceptable sait of any one of daims l-41, wherein R⁵ is hydrogen.

43. The compound or pharmaceutically acceptable sait of any one of daims 1-42, wherein each R^la, R^,b, R^2a, R^2b, R^4a, R^4b, R^7a, R^7b, R¹¹*, R^,lb, R^,2a, R^l2b, R^6a, R^bb, R^15a, R^15b, R^16a, and R^l6b is hydrogen.

219

44. The compound or pharmaceuticaliy acceptable sait of claim 1, wherein the compound of Formula (I) is a compound of Formula (I-bl):

or a pharmaceuticaliy acceptable sait thereof.

45. The compound or pharmaceuticaliy acceptable sait of claim 1, wherein the compound of Formula (I) is a compound of Formula (I-c3) or Formula (I-c4):

10 or a pharmaceuticaliy acceptable sait thereof.

46. The compound or pharmaceuticaliy acceptable sait of claim 1, wherein the compound of Formula (I) is a compound of Formula (I-d3) or Formula (I-d4):

220 or a pharmaceutically acceptable sait thereof.

47. The compound or pharmaceutically acceptable sait of claim 1, wherein the compound of Formula (I) is a compound of Fonnula (I-e5), Fonnula (I-e6), Formula (I-e7), or Fonnula (I-e8):

(I-e6),

(Le8), or a pharmaceutically acceptable sait thereof.

48. The compound or pharmaceutically acceptable sait of claim 1, wherein the compound of Formula (ï) is a compound of Fonnula (I-Ibl):

or a pharmaceutically acceptable sait thereof,

221 wherein R²² is CN;

n is l;

R¹⁹ is selected from the group consisting of hydrogen, ethyl, and methyl;

R^lîa and R^l5b is independently selected from the group consisting of hydrogen, methyl, and cyclopropyl;

R^2aand R^2b is each independently selected from the group consisting of hydrogen, methyl, ethyl, methoxymethyl, and methoxy;

R³ is selected from the group consisting of unsubstituted Ci.₃ alkyl, -CH₂OCH₃, and CH₂OCH₂CH₃;

R^x is selected from the group consisting of halo, -CN, -OH, -OR^QI, and substituted or unsubstituted alkyl, wherein R¹ is substituted or unsubstituted alkyl; and

R^v is halo or substituted or unsubstituted alkyl; or

R^Yand R^x may join together with the intervening atoms to form a substituted or unsubstituted carbocyclyl or a substituted or unsubstituted heterocyclyl.

49. The compound or pharmaceutically acceptable sait of claim 1, wherein the compound of Formula (I) is a compound of Formula (I-Icl) or Formula (I-Ic2):

N , p ₂ 2\ pY \ fl to )n R^x / ^r2\ ^r11 / RA T A? _ pi 5a R³ H or a pharmaceutically acceptable sait thereof, wherein R²² is -CN; n is 1; R¹⁹ is hydrogen, ethyl, or methyl; pY \ n W R^x j N---' ^r2\ ^r1i JL / R Π T As ni 5a HO'A^A^A ^r (I-Icl), r³ H (I-Ic2),

222

Each of R^l5a and R^15b is independently selected from the group consisting of hydrogen, methyl, and cyclopropyl;

Each of R^2aand R^2b is independently selected from the group consisting of hydrogen, methyl, ethyl, methoxymethyl, and methoxy;

R³ is unsubstituted Ci.₃ alkyl, -CH₂OCH₃, and -CH₂OCH₂CH₃;

R^x is selected from the group consisting of halo, -CN, -OH, -OR^Q!, and substituted or unsubstituted alkyl, wherein R'¹ is substituted or unsubstituted alkyl;

R^Y is halo or substituted or unsubstituted alkyl; or

R^Y and R^x may join together with the intervening atoms to form a substituted or unsubstituted 10 carbocyclyl or a substituted or unsubstituted heterocyclyl.

50. The compound or pharmaceutically acceptable sait of claim 1, wherein the compound of Formula (I) is a compound of Formula (I-Idl) or Formula (I-Id2):

R^2a'

HO

R²³HO' ^_Rl5b _R ¹5a or a pharmaceutically acceptable sait thereof, wherein R²² is -CN;

R¹⁹ is hydrogen, ethyl, or methyl;

223

Each of R^Ha and R^15b is îndependently selected from the group consistùig of hydrogen, methyl, and cyclopropyl;

Each of R^2aand R^2b is îndependently selected from the group consisting of hydrogen, methyl, ethyl, methoxymethyl, and methoxy;

5 R³ is unsubstituted Cp₃ alkyl, -CH₂OCH₃, or -CH₂OCH₂CH₃;

R^x is selected from the group consisting of halo, -CN, -OH, -OR^Ql, and substituted or unsubstituted alkyl, wherein R⁰¹ is substituted or unsubstituted alkyl;

R^Y is halo or substituted or unsubstituted alkyl; or

R^Y and R^x may join together with the intervening atoms to form a substituted or unsubstituted 10 carbocyclyl or a substituted or unsubstituted heterocyclyl.

51. The compound or phannaceuticaily acceptable sait of claim 1, wherein the compound of Fonnula (I) is a compound of Fonnula (I-Iel), Fonnula (I-Ie2), Fonnula (I-Ie3), or Fonnula (I-Ie4):

or a phannaceuticaily acceptable sait thereof, wherein

224

R²² is -CN;

R¹⁹ is hydrogen, ethyl, or methyl;

Each of R^ba and R^,Sb is independently selected from the group consîsting of hydrogen, methyl, and cyclopropyl;

5 Each of R^2a and R^2b is each independently selected from the group consîsting of hydrogen, methyl, ethyl, methoxymethyl, and methoxy;

R² is Ci.j alkyl, -CH₂OCH₃, or -CH₂OCH₂CH₃;

R^x is selected from the group consîsting of halo, -CN, -OH, -OR^Q1, and substituted or unsubstituted alkyl, wherein R^Q1 is substituted or unsubstituted alkyl; and

10 R^Y is halo or substituted or unsubstituted alkyl; or

R^Y and R^x may join together with the intervening atoms to form a substituted or unsubstituted carbocyclyl or a substituted or unsubstituted heterocyclyl.

52. A compound selected from the group consîsting of:

225

226

227

228

229

230

53. The compound or pharmaceutically acceptable sait of claim 52, wherein the compound of is selected from the group consisting of:

232

Compound No. Structure

6 HO' h

7 HO H

11 HO' H

15 OH T HO H

16 ,, OH HO H

233

234

235

236

237

238

or a pharmaceutically acceptable sait thereof.

54. A compound of the formula:

55. A pharmaceutically acceptable sait of the formula:

239

56. A compound ofthe formula:

57. A pharmaceutically acceptable sait of the formula:

58. A compound of the formula:

59. A pharmaceutically acceptable sait ofthe formula:

240

60. A compound of the formula:

61. A pharmaceutically acceptable sait of the formula:

62. A compound of the formula:

63. A pharmaceutically acceptable sait of the formula:

64. A compound of the formula:

241

65. A pharmaceutically acceptable sait of the formula:

66. A compound of the formula:

67. A pharmaceutically acceptable sait of the formula:

68. A compound of the formula:

69. A pharmaceutically acceptable sait of the formula:

242

70. A compound of the formula:

71. A phannaceutically acceptable sait ofthe formula:

72. A pharmaceutical composition comprising a compound or pharmaceutically acceptable sait of any one ofclaims 1-71 or 85-104 and a pharmaceutically acceptable excipient.

73. A compound or pharmaceutically acceptable sait of any one ofclaims 1-71 or 85-104, or a pharmaceutical composition of claim 72, for use in modulating a GABA_a receptor in a subject in need thereof.

74. A compound or pharmaceutically acceptable sait ofany one ofclaims 1-71 or 85-104, or a pharmaceutical composition of daim 72, for use in treatîng a CNS-related disorder in a subject in need thereof.

75. The compound or pharmaceutically acceptable sait ofany one ofclaims 1-71 or 85-104, or the pharmaceutical composition of daim 72, for use according to daim 74, wherein the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive

243 disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, auttsm spectrum disorder, pain, traumatic brain injury, a vascular disease. a substance abuse disorder and/or withdrawal syndrome, tinnîtus, or status epilepticus.

5

76. The compound or pharmaceutically acceptable sait ofany one of daims 1-71 or 85-104, or the pharmaceutical composition of claim 72, for use according to claim 74, wherein the CNS-related disorder is dépréssion.

77. The compound or pharmaceutically acceptable sait ofany one of daims 1-71 or 85-104, or the ¹ ° pharmaceutical composition of daim 72, for use according to claim 76, wherein the dépréssion is postpartum dépréssion.

78. The compound or pharmaceutically acceptable sait ofany one ofdaims 1-71 or 85-104, or the pharmaceutical composition of daim 72, for use according to claim 74, wherein the CNS-related

15 disorder is tremor.

79. The compound or pharmaceutically acceptable sait ofany one of daims 1-71 or 85-104, or the pharmaceutical composition of daim 72, for use according to daim 78, wherein the tremor is essential tremor.

80. The compound or pharmaceutically acceptable sait ofany one of daims 1-71 or 85-104, or the pharmaceutical composition of daim 72, for use according to claim 74, wherein the CNS-related disorder is seizure.

81. The compound or pharmaceutically acceptable sali of any one of daims 1-71 or 85-104, or the pharmaceutical composition of daim 72, for use according to daim 74, wherein the CNS-related disorder is epilepsy or status epilepticus.

82. Fhe compound or pharmaceutically acceptable sait of any one of daims 1-7] or 85-104, or the pharmaceutical composition of daim 72, for use according to daim 81, wherein the status epilepticus is convulsive status epilepticus or non-convulsive status epilepticus.

244

83. The compound or pharmaceutically acceptable sait ofany one of daims l-7l or 85-104, or the pharmaceutical composition of claim 72, for use in inducing sédation and/or anesthésia in a subject in need thereof.

84. A kit comprising a solid composition comprising a compound or pharmaceutically acceptable sait of any one of daims i-71 or 85-104 and a serial diluent.

85. A compound of the formula:

86. A pharmaceutically acceptable sait of the formula:

87. A compound of the formula:

88. A pharmaceutically acceptable sait of the formula:

245

89. A compound of the formula:

90. A pharmaceutically acceptable sait of the formula:

92. A pharmaceutically acceptable sait of the formula:

246

93.

A compound of the formula:

94. A pharmaceutically acceptable sait ofthe formula:

95. A compound of the formula:

96. A pharmaceutically acceptable sait ofthe formula:

97. A compound of the formula:

247

98. A pharmaceutically acceptable sait ofthe formula:

99, A compound of the formula:

100, A pharmaceutically acceptable sait ofthe formula;

101. A compound of the formula:

248

102. A pharmaceutically acceptable sait ofthe formula:

103. A compound of the formula:

104. A pharmaceutically acceptable sait ofthe formula: