Steroid compounds, preparation method therefor and use thereof

Abstract

Disclosed in the present invention are steroid compounds, a preparation method therefor and the use thereof. Particularly disclosed are steroid compounds having a structure shown as formula (I), (II) or (III), etc., or pharmaceutically acceptable salts thereof. The compounds provided by the present invention have SREBP pathway inhibitory activity, and thus can be used for preventing and / or treating obesity, hyperlipidemia, fatty liver, diabetes, atherosclerosis, cardiovascular and cerebrovascular diseases, liver cancer, skin injury and other diseases.

Description

Steroid compounds, preparation methods and applications thereof Technical Field

[0001] The present invention relates to a steroid compound, a preparation method and application thereof. Background Art

[0002] With changing lifestyles, including increased consumption of high-calorie foods and high-sugar beverages, and a lack of exercise and physical activity, metabolic diseases, such as hyperlipidemia, obesity, type 2 diabetes, and fatty liver disease, have become increasingly serious health problems worldwide. Fatty liver disease has become a major cause of chronic liver disease in Europe, America, and affluent regions of my country. The prevalence of simple hepatic lipid accumulation in the general adult population ranges from 10% to 30%, of which 10% to 20% develop steatohepatitis, and the latter leads to a 25% incidence of cirrhosis and liver cancer within 10 years. However, the pathophysiology of fatty liver disease remains incompletely elucidated, and effective and specific therapeutic agents are still lacking. The accumulation of lipids, such as cholesterol and triglycerides, in the blood and liver is known to be the primary cause of hyperlipidemia, which in turn is a key pathogenic factor in atherosclerosis, stroke, and fatty liver disease. Therefore, the development of novel drugs targeting lipid metabolism pathways with the goal of lowering lipids is becoming an increasingly important focus of new metabolic disease drug research and development.

[0003] The lipid synthesis pathway in mammalian cells is known to be a key factor in regulating lipid metabolism. Key factors regulating cholesterol and fatty acid synthesis are transcription factors called sterol-regulatory element binding proteins (SREBPs). Precursors of these proteins are first synthesized in the endoplasmic reticulum (ER). They are transported to the Golgi apparatus by SREBP cleavage-activating protein (SCAP). Subsequently, they are cleaved by two proteases, Site-1 protease (S1P) and Site-2 protease (S2P), releasing their N-terminal active domains. These domains then enter the cell nucleus to act as transcription factors, binding to SREBP response elements (SREs) in target gene promoters and initiating expression of downstream genes. The cleavage and maturation of SREBP proteins are strictly regulated by intracellular levels of sterols (such as cholesterol and 25-hydroxycholesterol). When cells accumulate sufficient cholesterol in the endoplasmic reticulum, cholesterol binds to SCAP and changes the conformation of SCAP, causing the SCAP-SREBP complex to bind to the protein Insig (Insulin-induced gene), thereby blocking the transport of SREBP to the Golgi apparatus and subsequent SREBP activation. Conversely, the active form of SREBP in the nucleus increases, promoting cellular lipid synthesis. In addition to cholesterol, 25-hydroxycholesterol (25-HC) is another potent endogenous inhibitor of the SREBP pathway. Unlike cholesterol, which binds to SCAP, 25-HC directly binds to Insig and induces the binding of SCAP and Insig.

[0004] Previous studies have found that inhibiting the SREBP pathway is an effective strategy and method for preventing and / or treating metabolic diseases such as obesity, hyperlipidemia, fatty liver, atherosclerosis, diabetes, and cardiovascular and cerebrovascular diseases, skin damage, liver cancer and other diseases.

[0005] The pathogenesis of hyperlipidemia is primarily due to increased lipid synthesis or abnormal lipid transport caused by factors such as diet or genetic mutations, leading to excessive accumulation of lipids such as cholesterol and fatty acids in the blood. Currently, statins and fibrates are the main lipid-lowering drugs used clinically. Statins work by inhibiting the cellular cholesterol synthesis pathway while promoting reverse cholesterol transport in the blood. This suggests that targeting key factors in the cellular lipid synthesis pathway is an important means of effectively lowering lipid levels.

[0006] To date, there are no approved therapeutics for fatty liver disease, necessitating the identification of therapeutic targets and the development of new, effective therapies. The pathogenesis of fatty liver disease is known to involve multiple risk factors, including the accumulation of triglycerides in lipid droplets, which can trigger steatosis. Abnormally elevated cholesterol and fatty acids in cells can cause endoplasmic reticulum stress and mitochondrial dysfunction, leading to cell death, inflammation, and fibrosis. Free cholesterol accumulation has been reported to be a key driver of the transition from simple steatosis to aggressive steatohepatitis. Furthermore, in the establishment of a mouse model of fatty liver disease, a simple cholesterol-free, high-fat diet, even after prolonged feeding, only induces steatosis, while supplementing the diet with 1-2% cholesterol is essential for inflammation and fibrosis. Therefore, cholesterol reduction may represent a novel therapeutic strategy for fatty liver disease. Studies have shown that abnormal activation of SREBPs is observed in patients with fatty liver disease and in mouse models of fatty liver disease. Deletion or knockout of the liver-specific gene Scap in mice can abolish the activation of all SREBPs, thereby preventing the development of fatty liver and hyperlipidemia. Furthermore, recent studies have shown that ER stress-induced abnormal activation of SREBPs promotes lipogenesis and fatty liver. Therefore, these evidences suggest that lowering hepatic triglyceride and cholesterol levels by inhibiting the SREBP pathway is an effective strategy for preventing and / or treating metabolic disorders, including fatty liver.

[0007] Summary of the Invention

[0008] The technical problem to be solved by the present invention is to provide a new compound having inhibitory activity on the SREBP pathway.

[0009] The present invention provides a compound represented by formula I or a pharmaceutically acceptable salt thereof:

[0010] in,

[0011] R 4a H; R 4b is halogen, CN, -CH2-CN, -CH2-OH, -CH(CH3)-OH, -COOH, -CH2-COOH, C1-C6 haloalkyl, -CH2-OAc or NH2; or, R 4a and R 4b and the carbon atoms to which they are attached together to form

[0012] When there is a single bond between carbon atoms 7 and 8, R 7a and R 7bare independently H, halogen, CN, -CH2-OH, -COOH, -CH2-COOH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, or -CH2-CN; or, R 7a and R 7b and the carbon atoms to which they are attached together to form R 8a is H;

[0013] When there is a double bond between carbon atoms 7 and 8, R 7a Does not exist, R 7b is halogen; R 8a does not exist;

[0014] R 21 for

[0015] n1 and n3 are independently 2, 3, 4 or 5;

[0016] m1 and m3 are independently 0, 1, 2, 3, 4 or 5;

[0017] Ring A and Ring C are independently C6-C 10 Aryl, "5-10 membered heteroaryl group wherein the heteroatoms are 1, 2 or 3 selected from N, O and S" or C3-C6 cycloalkyl;

[0018] R A and R C are independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy;

[0019] R 1 for or NR 1a R 1b ;

[0020] R 1a and R 1b are independently H or C1-C6 alkyl;

[0021] The carbon atom with "*" indicates that when it is a chiral carbon atom, it is in R configuration, S configuration or a mixture of the two;

[0022] The carbon atom with “#” indicates that when it is a chiral carbon atom, it is in R configuration, S configuration or a mixture of the two;

[0023] The carbon atom with "&" indicates that when it is a chiral carbon atom, it is independently in R configuration, S configuration or a mixture of the two;

[0024] The compound shown in formula I is not the following compound:

[0025] and its isomers.

[0026] In certain preferred embodiments of the present invention, certain groups in the compound or its pharmaceutically acceptable salt are defined as follows. The unmentioned groups are the same as those described in any embodiment of the present invention (referred to as "in some embodiments"), R 4b wherein the halogen is independently F, Cl, Br or I; for example, Br.

[0027] In some embodiments, R 4b wherein the C1-C6 haloalkyl groups are independently CHF2, CH2F or CF3.

[0028] In some embodiments, R 7a and R 7b wherein the halogen is independently F, Cl, Br or I; preferably F.

[0029] In some embodiments, R 7a and R 7b wherein the C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0030] In some embodiments, R 7a and R 7b wherein the C1-C6 haloalkyl group is independently CHF2, CH2F or CF3, for example CHF2.

[0031] In some embodiments, in Ring A and Ring C, the C6-C 10 Aryl is independently phenyl or naphthyl, preferably phenyl.

[0032] In some embodiments, in Ring A and Ring C, the “5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S” is independently “a 5-6 membered or 9-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S”, for example, pyridyl (e.g. ).

[0033] In some embodiments, in Ring A and Ring C, the C3-C6 cycloalkyl group is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0034] In some embodiments, R A and R C wherein the halogen is independently F, Cl, Br or I; preferably F or Cl, such as F.

[0035] In some embodiments, R A and R C wherein the C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0036] In some embodiments, R A and R C wherein the C1-C6 haloalkyl groups are independently CHF2, CH2F or CF3.

[0037] In some embodiments, R A and R C wherein the C1-C6 alkoxy groups are independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy or ethoxy.

[0038] In some embodiments, R A and R C wherein the C1-C6 haloalkoxy group is independently -OCHF2, -OCH2F or -OCF3; preferably -OCF3.

[0039] In some embodiments, R 1a and R 1b wherein the C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl.

[0040] In some embodiments, in Formula I, a carbon atom with a "*" indicates that when it is a chiral carbon atom, it is in the S configuration.

[0041] In some embodiments, in Formula I, for

[0042] In some embodiments, R 4a H; R 4b is halogen (e.g., Br), CN, -CH2-CN, -CH2-OH, -CH(CH3)-OH, -COOH, -CH2-COOH, -CH2-OAc, or NH2; or, R 4a and R 4b and the carbon atoms to which they are attached together to form For example, R 4a H; R 4b is Br, CN, -CH2-CN, -CH2-OH, -CH(CH3)-OH, -COOH, -CH2-OAc or NH2; or, R 4a and R4b and the carbon atoms to which they are attached together to form

[0043] In some embodiments, when there is a single bond between carbon atoms 7 and 8, R 7a and R 7b are independently H or halogen (such as F), preferably, R 7a and R 7b is H or halogen (e.g., F) at the same time;

[0044] When there is a double bond between carbon atoms 7 and 8, R 7a Does not exist, R 7b is halogen (such as F); R 8a Does not exist.

[0045] In some embodiments, R 21 for For example

[0046] In some embodiments, Ring A and Ring C are independently C6-C 10 Aryl or "a 5- to 10-membered heteroaryl group wherein the heteroatoms are 1, 2 or 3 selected from the group consisting of N, O and S, and the number of heteroatoms is 1, 2 or 3".

[0047] In some embodiments, R A and R C are independently halogen, C1-C6 alkoxy or C1-C6 haloalkoxy.

[0048] In some embodiments, n1 is 3.

[0049] In some embodiments, n3 is 3.

[0050] In some embodiments, ml is 0, 1, 2, or 3.

[0051] In some embodiments, m3 is 0, 1, 2, or 3.

[0052] In some embodiments, for

[0053] In some embodiments, for

[0054] In some embodiments, for

[0055] In some embodiments, R 21 for

[0056] The present invention also provides a compound represented by Formula II or a pharmaceutically acceptable salt thereof:

[0057] in,

[0058] R 4c H; R 4d is H or OH;

[0059] R 7c H, R 7d are independently CN, -CH2-OH, -COOH, C1-C6 alkyl, C1-C6 haloalkyl, -CH2-COOH, NH2, -CH2-CN or Cl; or, R 7c and R 7d and the carbon atoms to which they are attached together to form

[0060] R 22 for

[0061] n2 is 2, 3, 4 or 5;

[0062] m2 is 0, 1, 2, 3, 4 or 5;

[0063] Ring B is C6-C 10 Aryl, "5-10 membered heteroaryl group wherein the heteroatoms are 1, 2 or 3 selected from N, O and S" or C3-C6 cycloalkyl;

[0064] R B are independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy;

[0065] The carbon atom with "*" indicates that when it is a chiral carbon atom, it is in R configuration, S configuration or a mixture of the two;

[0066] The carbon atom with “#” indicates that when it is a chiral carbon atom, it is in R configuration, S configuration or a mixture of the two;

[0067] The carbon atom with "&" indicates that when it is a chiral carbon atom, it is in R configuration, S configuration or a mixture of the two;

[0068] The compound shown in formula II is not the following compound:

[0069] and its isomers.

[0070] In some embodiments, R 7c and R 7d wherein the C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0071] In some embodiments, R 7c and R 7d wherein the C1-C6 haloalkyl group is independently CHF2, CH2F or CF3, for example CHF2.

[0072] In some embodiments, in Ring B, the C6-C 10 Aryl is phenyl or naphthyl, preferably phenyl.

[0073] In some embodiments, in ring B, the “heteroatoms selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3, 5-10 membered heteroaryl group” is “heteroatoms selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1 or 2, 5-6 membered or 9-10 membered heteroaryl group”, for example, pyridyl (for example ).

[0074] In some embodiments, in ring B, the C3-C6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0075] In some embodiments, R B wherein the halogen is independently F, Cl, Br or I; preferably F or Cl, such as F.

[0076] In some embodiments, R B wherein the C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0077] In some embodiments, R B wherein the C1-C6 haloalkyl groups are independently CHF2, CH2F or CF3.

[0078] In some embodiments, R B wherein the C1-C6 alkoxy groups are independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy or ethoxy.

[0079] In some embodiments, R Bwherein the C1-C6 haloalkoxy group is independently -OCHF2, -OCH2F or -OCF3; preferably -OCF3.

[0080] In some embodiments, in Formula II, the carbon atom with "*" indicates that when it is a chiral carbon atom, it is in the S configuration.

[0081] In some embodiments, in Formula II, a carbon atom with a "#" indicates that when it is a chiral carbon atom, it is in the R configuration.

[0082] In some embodiments, in Formula II, for

[0083] In some embodiments, R 7c H, R 7d are independently CN, -CH3, -CH2-OH, -COOH, -CHF2, -CH2-COOH, NH2, -CH2-CN or Cl; or, R 7c and R 7d and the carbon atoms to which they are attached together to form For example, R 7c H, R 7d are independently CN, -CH2-OH, -CH3, NH2, -CH2-CN, -CF2H, -COOH, or R 7c and R 7d and the carbon atoms to which they are attached together to form

[0084] In some embodiments, R 22 for

[0085] In some embodiments, Ring B is C6-C 10 Aryl or "a 5- to 10-membered heteroaryl group wherein the heteroatoms are 1, 2 or 3 selected from the group consisting of N, O and S, and the number of heteroatoms is 1, 2 or 3".

[0086] In some embodiments, R B are independently halogen, C1-C6 alkoxy or C1-C6 haloalkoxy.

[0087] In some embodiments, n2 is 3.

[0088] In some embodiments, m2 is 0, 1, 2, or 3.

[0089] In some embodiments, for

[0090] In some embodiments, R 22 for

[0091] In some embodiments, in Formula II, for

[0092] The present invention also provides a compound represented by formula III or a pharmaceutically acceptable salt thereof:

[0093] in,

[0094] R 3a is H or C1-C6 alkyl;

[0095] R 3b -O-(CH2)nR 3-1 NR 3-2 R 3-3 or OH; when R 3b When OH, R 3a is a C1-C6 alkyl group;

[0096] n is 1, 2, 3 or 4; R 3-1 OH or -C(O)OR 3-1a ; R 3-1a is H or C1-C6 alkyl;

[0097] R 3-2 and R 3-3 are independently H or -S(O)2R 3-2a ; R 3-2a is C1-C6 haloalkyl or C1-C6 alkyl;

[0098] R 4e H; R 4f H, OH or -O-(CH2)mOR 4-1 ; or R 4e and R 4f and the carbon atoms to which they are attached together to form m is 1 or 2; R 4-1 is a C1-C6 alkyl group;

[0099] The carbon atom with "*" indicates that when it is a chiral carbon atom, it is in R configuration, S configuration or a mixture of the two;

[0100] The carbon atom with “#” indicates that when it is a chiral carbon atom, it is in R configuration, S configuration or a mixture of the two;

[0101] The compound shown in formula III is not the following compound:

[0102] and its isomers.

[0103] In some embodiments, R 3a wherein the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl.

[0104] In some embodiments, R 3-1a wherein the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example tert-butyl.

[0105] In some embodiments, R 3-2a wherein the C1-C6 haloalkyl group is CHF2, CH2F or CF3, for example CF3.

[0106] In some embodiments, R 4-1 wherein the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, ethyl.

[0107] In some embodiments, in Formula III, for

[0108] In some embodiments, n is 1, 2, or 3.

[0109] In some embodiments, R 3-2 H, R 3-3 is -S(O)2R 3-2a .

[0110] In some embodiments, m is 1.

[0111] In some embodiments, R 3a H, R 3b for Or, R 3a is methyl, R 3b For OH.

[0112] In some embodiments, R 4e H; R 4f H, OH or or R 4e and R 4f and the carbon atoms to which they are attached together to form

[0113] In some embodiments, in Formula III, for

[0114] The present invention also provides any of the following compounds or pharmaceutically acceptable salts thereof:

[0115] The present invention also provides a pharmaceutical composition comprising the compound according to any one of the present invention or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient.

[0116] The present invention also provides a use of a compound according to any one of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of the present invention, in the preparation of a medicament for preventing and / or treating a disease, wherein the disease is obesity, hyperlipidemia, fatty liver, diabetes, atherosclerosis, cardiovascular and cerebrovascular diseases, liver cancer, or skin damage.

[0117] The present invention also provides a use of the compound according to any one of the present invention or a pharmaceutically acceptable salt thereof or the pharmaceutical composition described above in the preparation of a drug for inhibiting the SREBP pathway.

[0118] The present invention also provides a method for inhibiting the SREBP pathway, comprising administering an effective amount of the compound as described above or a pharmaceutically acceptable salt thereof to a subject.

[0119] The present invention also provides a method for preventing and / or treating a disease, comprising administering an effective amount of a compound according to any one of the present invention or a pharmaceutically acceptable salt thereof to a subject, wherein the disease is obesity, hyperlipidemia, fatty liver, diabetes, atherosclerosis, cardiovascular and cerebrovascular diseases, liver cancer, or skin damage.

[0120] Definition and Description

[0121] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0122] As used herein, the term "substituted" or "substituent" refers to the replacement of a hydrogen atom in a group with a specified group. When the position of substitution is not specified, substitution can be made at any position, but only if a stable or chemically feasible compound is formed. Examples are as follows: The structure shows that the hydrogen atoms on ring A are replaced by m1 R A When there are multiple R A When each R A Same or different.

[0123] When any variable (such as R A ) occurs more than once in the composition or structure of a compound, its definition is independent on each occurrence.

[0124] As used herein, the term "alkyl" refers to a saturated, linear or branched, monovalent hydrocarbon group. A C1-C6 alkyl group represents an alkyl group having 1 to 6 carbon atoms. In some embodiments, the C1-C6 alkyl group may be a C1-C4 alkyl group. C1-C4 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0125] As used herein, the term "haloalkyl" refers to a group in which one or more hydrogen atoms in an alkyl group are replaced by a halogen, wherein the definition of alkyl is as described above. Examples of haloalkyl groups include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, and the like.

[0126] As used herein, the term "alkoxy" refers to an -O-alkyl group, where alkyl is as defined above. A C1-C4 alkoxy group refers to an -O-(C1-C4 alkyl group), where C1-C4 alkyl is as defined above, i.e., the C1-C4 alkoxy group can specifically be a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, or a tert-butoxy group.

[0127] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., cyclic, spirocyclic, or bridged) cyclic hydrocarbon group. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. C 3-6 The cycloalkyl group may specifically be a C3, C4, C5, or C6 cycloalkyl group. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is polycyclic (e.g., cyclic, spirocyclic, or bridged).

[0128] In this article, the term “C 6-10 "Aryl" means phenyl or naphthyl.

[0129] As used herein, the term "heteroaryl" refers to an aromatic monocyclic or fused ring group formed by carbon atoms and at least one heteroatom, wherein the heteroatoms are independently selected from one, two, or three of N, O, and S. A 5-10 membered heteroaryl group may specifically be a 5-, 6-, 7-, 8-, 9-, or 10-membered heteroaryl group, such as a 5-6 membered heteroaryl group or an 8-10 membered fused heteroaryl group. A 5-6 membered heteroaryl group is monocyclic, and specific examples include, but are not limited to, pyrrole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, pyridine, pyrimidine, and pyrazine. Examples of 8-10 membered fused heteroaryl groups include, but are not limited to, benzopyrrole, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzopyrazole, benzimidazole, benzopyridine, benzopyrimidine, benzopyrazine, thiazolothiazole, pyridopyridine, pyridopyrazine, pyridopyrimidine,

[0130] In this article, the chemical structure Indicates the connection location. Contained in a cyclic group and not specified When the ring atoms are connected, Attachment to any ring atom is permitted but is permitted only if it results in a stable or chemically feasible compound.

[0131] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed with a suitable non-toxic organic acid, inorganic acid, organic base, or inorganic base and a compound, which retains the biological activity of the compound. The organic acid may be any organic acid conventional in the art that can form a salt. The inorganic acid may be any inorganic acid conventional in the art that can form a salt. The organic base may be any organic base conventional in the art that can form a salt. The inorganic base may be any inorganic base conventional in the art that can form a salt.

[0132] In chemical structures, solid wedge-shaped bonds are used and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed bond Indicates the relative configuration of the stereocenter. The configuration is not specified, i.e. if there are configurational isomers in the chemical structure, the bond Can be or include both Two configurations (e.g. The ratio is 1:1). When the specific configuration of a carbon-carbon double bond is not specified, it may be E or Z. Stereoisomers can be synthesized using chiral starting materials, prepared by chiral resolution, or resolved using conventional techniques such as, but not limited to, high performance liquid chromatography (HPLC) using a chiral column.

[0133] As used herein, the term "subject" includes any animal, preferably a mammal, more preferably a human.

[0134] As used herein, the term "effective amount" refers to a non-toxic amount of a drug or pharmaceutical agent sufficient to achieve the desired effect. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0135] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0136] The reagents and raw materials used in the present invention are commercially available.

[0137] The positive progress of the present invention is that the present invention provides a new class of compounds that have inhibitory activity on the SREBP pathway and can be used to prevent and / or treat diseases such as obesity, hyperlipidemia, fatty liver, diabetes, atherosclerosis, cardiovascular and cerebrovascular diseases, liver cancer, and skin damage. DETAILED DESCRIPTION

[0138] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0139] Preparation of key intermediates

[0140] Examples I & II

[0141] Intermediate I (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]hexanal I

[0142] Preparation of Intermediate II (5R)-5-[(3aS,5aR,5bR,7aR,8R,10aR,12aR,12bR)-11-fluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,12,12a,12b-tetradecahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxolan-8-yl]hexanal II

[0143] Step 1: Dissolve (22E,24S)-stigmaster-6(5),22(23)-diene-3β-ol I-1 (5.00 g, 12.11 mmol, 1.0 eq) in dichloromethane (50 mL), place the reaction system in an ice-water bath, and cool to about 5°C. Add acetic anhydride (3.4 mL, 36.35 mmol, 3.0 eq), 4-dimethylaminopyridine (300 mg, 2.42 mmol, 0.2 eq) and triethylamine (8 mL, 60.57 mmol, 5.0 eq) to the reaction system in sequence, and stir the reaction system at room temperature for 2 hours. After the reaction was completed as monitored by TLC (petroleum ether: ethyl acetate = 10:1), the reaction solution was quenched with methanol (20 mL), and the reaction solution was washed once with saturated sodium bicarbonate (~50 mL) and water (~50 mL), dried over anhydrous sodium sulfate, and concentrated. When the concentration was almost dry, methanol (~20 mL) was added, and the mixture was stirred in an ice bath for 30 minutes. The mixture was filtered, and the filter cake was rinsed with a small amount of methanol. The filter cake was dried to obtain a white solid acetic acid-(1R,3aS,3bS, 7S,9aR,9bS,11aR)-1-[(2R,3E,5S)-5-ethyl-6-methylhept-3-en-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester I-2 (5.30 g, purity 90.0%, yield 86.58%). 1 H NMR (400MHz, CDCl3) δ5.37(d,J=4.8Hz,1H),5.09(ddd,J=56.1,15.2,8.6Hz,2H),4.61(ddd,J=15.9,9.0,4.2Hz,1H),2.32(d,J=7.3Hz,2H),2.03(s ,3H),2.01–1.92(m,2H),1.87(dd,J=8.9,6.6Hz,2H),1.73–1.40(m,12H), 1.30–1.07(m,6H),1.02(t,J=3.3Hz,6H),0.87–0.79(m,9H),0.70(s,3H).

[0144] Step 2: Weigh out 10.0 g, 22 mmol, 1 eq of (1R, 3aS, 3bS, 7S, 9aR, 9bS, 11aR)-1-[(2R, 3E, 5S)-5-ethyl-6-methylhept-3-en-2-yl]-9a, 11a-dimethyl-2, 3, 3a, 3b, 4, 6, 7, 8, 9, 9a, 9b, 10, 11, 11a-tetrahydro-1H-cyclopenta[1, 2-i]phenanthrene-7-yl acetate I-2 and dissolve it in tetrahydrofuran (200 mL) and water (20.0 mL). Add pyridine (4.5 mL) at room temperature. L, 55mmol, 2.5eq), N-methylmorpholine oxide (10.30g, 88mmol, 4eq), potassium osmate (0.81g, 2.2mmol, 0.1eq), stirred at room temperature overnight, TLC (petroleum ether: ethyl acetate = 3:1) monitoring, some starting materials remained, and an intermediate (vicinal diol was generated), then sodium periodate (18.80g, 88mmol, 4eq) was added to the reaction solution at 0°C, stirred at room temperature for 1 hour, TLC (petroleum ether: ethyl acetate = 3:1) monitoring, some starting materials remained, and the intermediate was converted to the product. Then, 50 mL of water was added, and 50 mL of ethyl acetate was used for extraction three times. The mixture was dried and concentrated, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate=60:1) to obtain acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R,3E,5S)-5-ethyl-6-methylhept-3-en-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1, 2-i] phenanthrene-7-yl ester I-3 (3.3 g, purity 60%, yield 19.8%) white solid acetate-(1R,3aS,3bS,7S,9aR,9bS,11aS)-1-[(1S)-1-formylethyl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester (1.9 g, purity 90.0%, yield 21.20%). 1 H NMR (400MHz, CDCl3) δ9.50(d,J=3.3Hz,1H),5.31(d,J=5.1Hz,1H),4.54(dd,J=6.4,4.2Hz,1H),2.34–2.23(m,3H),1.96(s ,3H),1.89(dt,J=6.6,3.6Hz,2H),1.83–1.72(m,3H),1.66–1.09(m,14H),1.06(d,J=6.8Hz,3H),0.96(s,3H),0.66(s,3H).

[0145] Step 3: (Methoxymethyl)triphenylphosphonium chloride (55.21 g, 161.052 mmol, 5.0 eq) was dissolved in anhydrous tetrahydrofuran (100 mL). The system was cooled to -10°C in a dry ice ethyl acetate bath. Sodium bis(trimethylsilyl)amide (80.526 mL, 1 mol / L, 2.5 eq) was added. After stirring in the dry ice ethyl acetate bath for 30 minutes, acetic acid-(1R,3aS,3bS,7S,9aR,9bS, 1-[(1S)-1-formylethyl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl]-1-[(11a ... 100 mL of saturated sodium bicarbonate solution was slowly added to the reaction system, extracted with ethyl acetate (100 mL × 3), the collected organic phase was washed with water (100 mL × 2), washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was concentrated to give yellow solid acetate-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2S,3E)-4-methoxybut-3-en-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester I-4 (8 g, purity 90.0%, yield 65.0%), and the crude product was directly used for the next reaction.

[0146] Step 4: (1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2S,3E)-4-methoxybut-3-en-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate I-4 (8 g, 12.5 mmol, 1.0 eq) was dissolved in tetrahydrofuran (100 mL). Dilute hydrochloric acid (5 mol / L, 50 mL) was slowly added, and the reaction mixture was stirred at room temperature for 30 minutes. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 10:1). After the reaction was complete, 80 mL of water was added to the reaction mixture, and the reaction solution was extracted with ethyl acetate (50 mL × 3), washed with saturated brine (20 mL × 3), dried over anhydrous sulfuric acid, and the organic phase was collected and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50:1 to 30:1 to 4:1) and concentrated to obtain (1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-1-formylpropan-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate I-5 as a white solid (6.3 g, purity 90%, yield 48.63%). 1 H NMR (400MHz, CDCl3) δ9.76 (dd, J=3.3, 1.3Hz, 1H), 5.37 (d, J=4.9Hz, 1H), 4.65–4.5 5(m,1H),2.46(dd,J=15.6,2.8Hz,1H),2.32(d,J=7.0Hz,2H),2.22–2.14(m,1H),2 .03(s,3H),2.03–1.93(m,2H),1.89–1.78(m,3H),1.66–1.40(m,9H),1.17(dddd,J =16.5,14.2,10.9,7.1Hz,6H),1.03(dd,J=7.5,3.5Hz,6H),0.73(d,J=5.3Hz,3H).

[0147] Step 5: (The reactant acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-1-formylpropyl-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester I-5 (10.00 g, 25.87 mmol, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (150 mL) To the mixture, (triphenyl-λ5-methylphosphine) methyl acetate (51.89 g, 155.21 mmol, 6.0 eq) was added, and the reaction system was stirred at 90 ° C for 18 h. The reaction raw materials were consumed by nuclear magnetic resonance monitoring. 100 mL of water was added to the reaction system, and ethyl acetate (100 mL × 3) was used for extraction. The organic phase was collected and washed with water (100 mL × 2), washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was collected and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 60: 1 to The reaction mixture was purified by filtration (30:1) to give (2E,5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hex-2-enoic acid methyl ester I-6 (9.0 g, purity 90%, yield 71.1%) as a white solid. 1 H NMR (400MHz, CDCl3) δ6.95 (ddd, J=15.4, 8.7, 6.4Hz, 1H), 6.26 (d, J=11.6Hz, 0H), 5.82 ( d,J=15.5Hz,1H),5.37(d,J=4.9Hz,1H),4.60(tdd,J=10.9,6.6,4.2Hz,1H),3.72(d,J=1 0.2Hz,3H),2.35–2.24(m,3H),2.03(s,3H),2.01–1.91(m,3H),1.90–1.78(m,3H),1.68 –1.40(m,8H),1.31–1.07(m,5H),1.02(s,3H),0.95(d,J=6.7Hz,3H),0.72–0.68(m,3H).

[0148] Step 6: Methyl (2E,5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hex-2-enoate I-6 (10 g, 22.59 mmol, 1.0 eq) was dissolved in a mixture of tetrahydrofuran (100 mL) and methanol (50 mL). Nickel chloride (2.93 g, 22.59 mmol, 1.0 eq) was added, followed by the slow addition of sodium borohydride (1.28 g, 33.89 mmol). The reaction system was stirred at room temperature for 1 h. NMR monitoring indicated that the starting material was consumed. 100 mL of water was added to the reaction system, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phase was collected, washed with water (100 mL × 2), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 60:1 to 30:1) to obtain (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester I-7 (9 g, purity 90%, yield 80.6%) as a white solid. 1 H NMR(400MHz, CDCl3)δ5.37(d,J=4.9Hz,1H),4.66–4.54(m,1H),3.67(s,3H),2.29(dd d,J=15.9,11.9,6.6Hz,4H),2.03(s,3H),2.02–1.93(m,2H),1.82(ddd,J=13.0,10.8, 8.3Hz,3H),1.62–1.38(m,11H),1.19(dddd,J=32.6,25.0,13.7,6.9Hz,9H),1.01(d, J=5.8Hz,3H),0.93(d,J=6.6Hz,3H),0.87(tdd,J=10.2,4.8,2.0Hz,4H),0.67(s,3H).

[0149] Step 7: In a 250 mL round-bottom flask at room temperature, (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester I-7 (2.5 g, 5.62 mmol) was dissolved in chloroform (80 mL). N-methylmorpholine (1.71 g, 16.87 mmol) and selenium dioxide (1.56 g, 14.06 mmol) were added at room temperature, followed by stirring at 70°C for 18 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 10:1). After the reaction, the reaction mixture was quenched with water (100 mL) and extracted with dichloromethane (80 mL × 3). The organic phase was washed with saturated brine (150 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain (5R)-5-[(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-7-acetoxy-6-hydroxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester I-8 (1.4 g, purity: 90%, yield: 48.65%) as a white solid. 1 H NMR (400MHz, CDCl3) δ=5.75–5.65(m,1H),4.80–4.65(m,1H),4.25(d,J=2.6,1H),3.67(s,3H),2.33–2.22(m,2H),2. 10(s,3H),2.07–1.98(m,2H),1.92–1.36(m,17H),1.22(s,3H),1.19–1.06(m,5H),0.93(d,J=6.6,3H),0.68(s,3H).

[0150] Step 8: Dissolve the reactant (5R)-5-[(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-7-acetoxy-6-hydroxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester I-8 (5 g, 11.5 mmol, 1.0 eq) in methanol (150 mL). Add potassium carbonate (6.37 g, 46 mmol, 4.0 eq) and stir the reaction system at room temperature for 30 min. Monitor the reaction by TLC (petroleum ether:ethyl acetate = 5:1). Stop the reaction when the starting material is consumed. Add water (100 mL) to the reaction system, and extract the aqueous layer with ethyl acetate (3 × 50 mL). The ethyl acetate layers were combined and washed with saturated brine (3×50 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give crude (5R)-5-[(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-6,7-dihydroxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester I-9, which was used directly in the next reaction.

[0151] Step 9: Dissolve the reactant (5R)-5-[(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-6,7-dihydroxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester I-9 (5 g, 11.9 mmol, 1 eq) in acetone (150 mL). Add p-toluenesulfonic acid (1.59 g, 8.4 mmol, 0.7 eq) and 4A molecular sieves. Stir the reaction at room temperature for 1 h. Monitor the reaction by TLC (petroleum ether:ethyl acetate = 10:1). Once the starting material is consumed, quench the reaction with saturated sodium sulfite. 100 mL of water was added to the reaction system, extracted with ethyl acetate (50 mL × 3), and the organic phase was collected, dried over anhydrous sodium sulfate, and the organic phase was vacuum-dried to obtain a crude product. The crude product was dissolved in ethyl acetate and purified by column chromatography (petroleum ether:ethyl acetate = 95:5) to obtain a white solid (5R)-5-[(3aR,3R,5aS,9aS,9bS)-7-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-3a,6,6-trimethyl-2,3,3a,4,5,5a,6,9,9a,9b-decahydro-1H-cyclopenta[1,2-a]naphthalen-3-yl]hexanoic acid methyl ester I-10 (3.8 g, purity 90%, yield 62%). 1H NMR (400MHz, CDCl3) δ5.80(d,J=2.9Hz,1H),4.41(d,J=5.8Hz,1H),4.10(dd ,J=13.5,6.5Hz,1H),3.67(s,3H),2.35–2.20(m,2H),2.14–1.98(m,2H),1. 87–1.56(m,10H),1.53(s,3H),1.45–1.37(m,3H),1.35(s,3H),1.28–1.21( m,1H),1.16(s,3H),1.14–0.97(m,6H),0.93(d,J=6.5Hz,3H),0.69(s,3H).

[0152] Step 10: Compound (5R)-5-[(3aR,3R,5aS,9aS,9bS)-7-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-3a,6,6-trimethyl-2,3,3a,4,5,5a,6,9,9a,9b-decahydro-1H-cyclopenta[1,2-a]naphthalen-3-yl]hexanoic acid methyl ester I-10 (3.8 g, 8. 2mmol, 1.0eq) was dissolved in acetone (50mL), and N-hydroxyphthalimide (0.54g, 3.3mmol, 0.8eq), tert-butyl hydroperoxide (12mL, 66mmol, 8.0eq), and anhydrous cobalt(II) acetate (0.29g, 1.6mmol, 0.2eq) were added. The resulting mixture was stirred at 25°C under N2 for 18 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 10:1). After the starting material was essentially consumed, the reaction was quenched with saturated sodium sulfite. Water (10mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3×15mL). The organic layers were combined, washed with saturated brine (15mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 87:13) to give (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-11-oxyylidene-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetradecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]hexanoic acid methyl ester I-11 (2.5 g, purity 95%, yield 60%) as a white solid. 1 H NMR (400MHz, CDCl3) δ5.85 (s, 1H), 4.45 (d, J = 6.4Hz, 1H), 4.26 (dd, J = 11.3, 5.5 Hz,1H),3.60(s,3H),2.34–2.25(m,2H),1.86–1.70(m,2H),1.58(dddd,J=16.6, 11.8,6.3,2.3Hz,5H),1.50(s,3H),1.40(ddd,J=16.5,9.3,3.9Hz,4H),1.30(s ,3H),1.26(s,4H),1.12–0.97(m,4H),0.87(d,J=6.6Hz,3H),0.66–0.59(m,3H).

[0153] Step 11: Compound (5R)-5-[(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-7-acetoxy-6-hydroxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester I-11 (2.4 g, 5.1 mmol, 1.0 eq) was dissolved in methanol (100 mL) and ethyl acetate (50 mL). Palladium on carbon (1.2 g, 11 mmol, 2.2 eq) was then added, and the reaction system was replaced with a hydrogen atmosphere. The reaction system was stirred at room temperature for 1 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1) to confirm complete consumption of the starting material. The reaction system was filtered, and the organic phase was collected and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 90:10) to give (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-2,2,5a,7a-tetramethyl-11-oxyylidene-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]hexanoic acid methyl ester I-12 (1.7 g, purity 95%, yield 67%) as a white solid. 1H NMR (400MHz, CDCl3) δ4.00–3.87(m,2H),3.60(s,3H),2.75–2.66(m,1H),2.36(t ,J=11.3Hz,1H),2.25–2.09(m,4H),1.85(dddd,J=28.9,13.2,6.5,3.1Hz,3H),1 .62(dddd,J=20.4,14.3,6.7,3.3Hz,4H),1.46(s,3H),1.43–1.26(m,5H),1.23( s,6H),0.98(ddt,J=14.4,11.7,7.4Hz,5H),0.86(d,J=6.6Hz,3H),0.59(s,3H).

[0154] Step 12: Compound (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-2,2,5a,7a-tetramethyl-11-oxylidene-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]hexanoate I-12 (1.7 g, 3.6 mmol) was dissolved in diethylaminosulfur trifluoride (10 mL). The resulting mixture was stirred at 80°C for 1 h. The reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 10:1). The reaction solution was cooled to room temperature, and dichloromethane (50 mL) was added to dilute the reaction system. Ice water was carefully added dropwise to quench the reaction. The organic phase was collected and separated, and the aqueous layer was extracted with dichloromethane (3×30 mL). The combined organic phases were washed with saturated brine (40 mL), filtered and concentrated to obtain a crude product. The crude product was added to a silica gel column (petroleum ether: ethyl acetate = 93:7) to obtain a colorless transparent solid (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]hexanoic acid A mixture of methyl ester I-13 and (5R)-5-[(3aS,5aR,5bR,7aR,8R,10aR,12aR,12bR)-11-fluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,12,12a,12b-tetradecahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxolan-8-yl]hexanoic acid methyl ester II-1 (1.4 g, I-13 purity 95%, yield calculated based on I-13: 74%).

[0155] Compound I-13: 1 H NMR(400MHz, CDCl3)δ4.02(d,J=15.0Hz,2H),3.67(s,2H),2.33–2.23(m,2H),2.18–1.58(m,6H),1.51(s,2H), 1.46–1.34(m,2H),1.30(s,2H),1.13(dd,J=17.2,7.0Hz,1H),1.07(s,1H),0.93(d,J=6.3Hz,2H),0.68(s,3H).

[0156] In the thirteenth step, the compound (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]hexanoic acid methyl ester I-13 and (5R)-5-[(3aS,5aR,5bR,7aR,8R,1 A mixture of methyl (1.3 g, 2.6 mmol, 1.0 eq) (0aR,12aR,12bR)-11-fluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,12,12a,12b-tetradecahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxolan-8-yl]hexanoate II-1 was dissolved in tetrahydrofuran (50 mL). Lithium aluminum tetrahydride (0.3 g, 7.8 mmol, 3 eq) was added, and the resulting mixture was stirred at 25°C for 1 h. The reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 10:1). The reaction mixture was quenched with sodium sulfate decahydrate, filtered and concentrated to give (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]hexan-1-ol as a white solid. I-14 and the crude product of (5R)-5-[(3aS,5aR,5bR,7aR,8R,10aR,12aR,12bR)-11-fluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,12,12a,12b-tetradecahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxolan-8-yl]hexanoate II-12 (0.9 g, purity 96%, yield: 92%) were directly used for the next step.

[0157] Step 14: Compound (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]hexan-1-ol I-14 and (5R)-5-[(3aS,5aR,5bR,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]hexan-1-ol I-14 A mixture of methyl (aR,12aR,12bR)-11-fluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,12,12a,12b-tetradecahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxolan-8-yl]hexanoate II-2 (1.3 g, 2.7 mmol, 1.0 eq) was dissolved in dichloromethane (50 mL), and Dess-Martin reagent (2.3 g, 5.5 mmol, 2 eq) was added. The resulting mixture was stirred at 25°C under N2 for 1 h. The reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 10:1). Saturated sodium bicarbonate (10 mL) was added to the reaction system, and the organic phase was extracted with saturated sodium sulfite (3×30 mL). The organic phase was collected and concentrated. Purification by silica gel column chromatography (petroleum ether:ethyl acetate = 92:8) gave a white solid (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolane- A mixture of (5R)-5-[(3aS,5aR,5bR,7aR,8R,10aR,12aR,12bR)-11-fluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,12,12a,12b-tetradecahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxolan-8-yl]hexanal II (0.95 g, purity of I 90%, yield based on I 66%).

[0158] Compound I: 1H NMR (400MHz, CDCl3) δ9.70 (t, J = 1.7Hz, 1H), 3.98–3.91 (m, 2H), 2.39–2.25 (m, 2H), 1. 96–1.86(m,1H),1.81–1.71(m,2H),1.64(ddd,J=10.7,10.3,4.7Hz,1H),1.57–1.52(m ,1H),1.44(s,2H),1.38–1.28(m,2H),1.23(s,1H),1.18(d,J=9.1Hz,1H),1.08–1.02( m,1H),1.00(s,1H),0.87(d,J=6.5Hz,2H),0.83–0.77(m,1H),0.60(d,J=12.0Hz,2H).

[0159] Example III

[0160] Preparation of Intermediate III (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetradecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]hexanal (III)

[0161] Step 1: Compound (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetradecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]hexanoate I-10 (1 g, 2.18 mmol, 1.0 eq) was dissolved in tetrahydrofuran (50 mL). After nitrogen purge, lithium aluminum tetrahydride (0.12 g, 3.270 mmol, 1.5 eq) was added and stirred at 25°C for 1 h. The reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 5:1), indicating complete consumption of the starting material. The reaction mixture was quenched with sodium sulfate decahydrate, filtered, and the filtrate concentrated to yield the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 80:20) to afford (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetradecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]hexan-1-ol III-1 as a white solid (1 g, purity: 90%, yield: 96%). 1 H NMR (400 MHz, CDCl 3 )δ5.80(d,J=2.6Hz,1H),4.41(d,J =5.8Hz,1H),4.09(m,1H),3.64(t,J=6.5Hz,2H),2.08(m,2H),1.84(tt,J=18.5,7.8Hz,2H),1.67(m,8H),1.41(td,J =12.7,6.2Hz,4H),1.35(s,3H),1.24(m,2H),1.17(s,4H),1.08(m,5H),0.93(d,J=6.5Hz,4H),0.69(d,J=4.6Hz,3H).

[0162] Step 2: Compound (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetradecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]hexan-1-ol III-1 (1 g, 90% purity, 2.09 mmol) was dissolved in dichloromethane (50 mL). Dess-Martin periodinane (1.18 g, 2.79 mmol) was added and stirred at 25°C for 1 h. Reaction progress and starting material consumption were monitored by TLC (petroleum ether:ethyl acetate = 5:1). The mixture was quenched with saturated sodium sulfite, water (10 mL) was added to the reaction system, and the aqueous layer was extracted with dichloromethane (3×50 mL). The organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 90:10) to give (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetradecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]hexanal III (750 mg, 1.58 mmol, purity: 90%, yield: 68%) as a white solid. 1 H NMR (400MHz, CDCL3) δ9.76 (s, 1H), 5.80 (d, J = 2.7Hz, 1H), 4.41 (d, J = 5.8Hz, 1H ),4.10(dd,J=13.6,6.3Hz,1H),2.39(m,2H),2.12(m,1H),2.01(m,1H),1.83(m ,1H),1.66(m,10H),1.53(s,4H),1.42(dd,J=12.5,4.2Hz,3H),1.35(s,3H),1 .17(s,3H),1.10(m,4H),0.92(dd,J=18.2,5.8Hz,4H),0.71(d,J=12.1Hz,3H).

[0163] Examples 9 & 10

[0164] Compound 9 3β-[(2-hydroxyethyl)oxy]-5α-cholest-25-ol and

[0165] Compound 10 {[(1R,3aS,3bR,5aS,7S,9aS,9bS,11aR)-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-7-yl]oxy}acetate-2-methylpropan-2-yl ester

[0166] Step 1: Dissolve (1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-6-methoxy-6-oxyylidenehexan-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate I-7 (80 mg, 0.180 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL), add Pd(OH)2 (20 mg, 0.142 mmol), replace the atmosphere with hydrogen three times, stir at 40 ° C for 48 hours, and monitor by HNMR. The reaction solution was filtered and the filtrate was concentrated to give (1R,3aS,3bR,7S,9aS,9bS,11aR)-1-[(2R)-6-methoxy-6-oxyylidenehexan-2-yl]-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate 9-1 (80 mg, 0.170 mmol, 94.57%) as an off-white solid. 1 HNMR(399MHz,cdcl3)δ4.74–4.58(m,1H),3.64(s,3H),2.32–2.17(m,2H),2.00(s,3H),1. 92(d,J=12.7Hz,1H),1.78(d,J=9.5Hz,2H),1.73–1.61(m,3H),1.53(d,J=10.1Hz,3H),1.4 8–1.40(m,3H),1.33(dd,J=23.5,11.4Hz,4H),1.24(d,J=9.9Hz,4H),1.20–1.12(m,3H),1 .10–1.02(m,3H),0.96(d,J=15.7Hz,2H),0.89(d,J=6.3Hz,3H),0.79(s,3H),0.62(s,3H).

[0167] Step 2: Dissolve (1R,3aS,3bR,7S,9aS,9bS,11aR)-1-[(2R)-6-methoxy-6-oxyidenehexan-2-yl]-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl methyl acetate 9-1 (80 mg, 0.179 mmol) in tetrahydrofuran (3 mL). The atmosphere was purged with nitrogen three times, the temperature was lowered to -78°C, methyllithium (0.560 mL, 0.896 mmol) was added, and the mixture was stirred at room temperature for 3 hours. TLC (petroleum ether:ethyl acetate = 10:1) was used for monitoring. The reaction mixture was quenched with water (15 mL) and extracted with ethyl acetate (10 mL x 3). The mixture was washed once with brine, dried over anhydrous sodium sulfate, and concentrated to yield 80 mg of crude product. Cholesteryl-3β,25-diol 9-2 (20 mg, 0.040 mmol, 22.08%) was obtained by column chromatography (DCM:MeOH=300:1-100:1). 1 H NMR(399MHz, CDCl3)δ5.32(s,0H),3.56(s,1H),1.93(d,J=12.9Hz,1H),1.75(s,2H),1.70–1.60(m,2H),1.55(s,3H),1.43(s,3H),1.35(s,3H), 1.28(s,3H),1.24(s,3H),1.23(s,3H),1.19(s,6H),1.11–1.01(m,4H), 0.95(d,J=10.9Hz,3H),0.89(d,J=6.5Hz,3H),0.77(s,3H),0.62(s,3H). 13 CNMR(101MHz, CDCl3)δ77.31,77.20,77.00,76.68,71.35,71.10,56.45,56.16,54.30,44.81,44.39,42.58,40.00,38.19,36.97,36.39 ,35.73,35.47,35.43,32.06,31.50,30.95,29.33,29.18,28.71,28.25,27.19,24.19,21.23,20.74,18.61,12.31,12.06.LC-MS:[M+Na] + =427.15.

[0168] Step 3: Dissolve 5α-cholest-3β,25-diol (10 mg, 0.025 mmol) in toluene (3 mL). Add potassium tert-butoxide (14.03 mg, 0.125 mmol). Stir at room temperature for 1 hour. Add tert-butyl bromoacetate (24.38 mg, 0.125 mmol). Stir at room temperature for 2 hours. Monitor by TLC (petroleum ether:ethyl acetate = 3:1). The reaction solution was directly concentrated to give 40 mg of crude product, which was purified by column chromatography (ethyl acetate:petroleum ether = 30%) to give 2-methylpropan-2-yl {[(1R,3aS,3bR,5aS,7S,9aS,9bS,11aR)-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthr-7-yl]oxy}acetate 10 (3 mg, 0.005 mmol, 22.23%) as a white solid.

[0169] Compound 10: 1 HNMR(399MHz,Chloroform-d)δ3.98(s,2H),3.29(dt,J=11.2,6.2Hz,1H),1.90(dd,J =30.3,12.5Hz,2H),1.79–1.67(m,2H),1.62(d,J=13.0Hz,4H),1.51(d,J=7.2Hz,5H), 1.45(s,9H),1.42(d,J=2.1Hz,5H),1.36–1.29(m,6H),1.19(s,6H),1.04(dt,J=20.1 ,9.4Hz,6H),0.89(d,J=6.5Hz,3H),0.84(d,J=14.0Hz,2H),0.77(s,3H),0.62(s,3H).

[0170] Step 4: 2-Methylpropan-2-yl {[(1R,3aS,3bR,5aS,7S,9aS,9bS,11aR)-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthr-7-yl]oxy}acetate 10 (20 mg, 0.039 mmol) was dissolved in tetrahydrofuran (5 mL). Lithium aluminum tetrahydride (4.39 mg, 0.116 mmol) was added and stirred at room temperature for 1 hour. TLC (petroleum ether:ethyl acetate = 3:1) was used for monitoring. The reaction mixture was concentrated to give 10 mg of crude product, which was purified by column chromatography (ethyl acetate:petroleum ether = 40%) to give 3β-[(2-hydroxyethyl)oxy]-5α-cholest-25-ol 9 (10 mg, 0.021 mmol, 54.92%) as a white solid.

[0171] Compound 9: 1H NMR(399MHz,Chloroform-d)δ3.69(t,J=4.5Hz,2H),3.55(td,J=4.5,2.2Hz,2H),3.29–3.20(m,1H),2.10–1.91(m ,2H),1.87–1.75(m,2H),1.71(dd,J=13.4,3.9Hz,1H),1.62(d,J=3.3Hz,2H),1.52(s,1H),1.49–1.39(m,3H),1.3 7(s,2H),1.31(d,J=6.6Hz,2H),1.27(d,J=4.6Hz,2H),1.23(d,J=7.1Hz,3H),1.19(s,6H),1.13–1.02(m,4H),1.0 1–0.91(m,3H),0.89(d,J=6.6Hz,3H),0.88–0.79(m,2H),0.78(s,3H),0.63(s,3H),0.58(dd,J=10.7,4.0Hz,1H). 13 C NMR (101MHz, CDCl3) δ79.02,71.10,68.82,62.11,56.46,56.18,54.35,44.78,44.39,42.59,40.00,36.91,36.40 ,35.73,35.46,34.79,32.07,29.32,29.17,28.81,28.24,24.18,21.20,20.74,18.61,12.26,12.0.LCMS:[M+Na] + =458.39.

[0172] Example 12

[0173] Compound 12 (5R)-5-[(1R,3aS,3bR,5aS,9aS,9bS,11aR)-7-amino-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester

[0174] Step 1: Dissolve (1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-6-methoxy-6-oxyylidenehexan-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate I-7 (1 g, 2.249 mmol) in tetrahydrofuran (5 mL) and methanol (5 mL). Add potassium carbonate (3.11 g, 22.489 mmol). Stir at 40°C for 5 hours and monitor by TLC (petroleum ether:ethyl acetate = 3:1). Concentrate the reaction mixture to obtain 5 g of the crude product. Purification by column chromatography (ethyl acetate / petroleum ether = 40%) gave (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-hydroxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester 12-1 (0.8 g, 1.888 mmol, 83.94%) as a white solid. 1 H NMR(399MHz,Chloroform-d)δ5.33(d,J=5.1Hz,1H),3.65(s,3H),3.54–3.47(m,1H),2.33–2.17(m,5H), 2.00–1.92(m,2H),1.90–1.74(m,4H),1.67(d,J=7.9Hz,1H),1.53–1.46(m,5H),1.43(dd,J=11.2,4.6Hz ,3H),1.40–1.32(m,2H),1.27–1.12(m,4H),1.07(dd,J=12.8,7.1Hz,4H),1.03(d,J=4.8Hz,1H),0.99(s ,3H),0.95(d,J=5.9Hz,1H),0.92(d,J=6.6Hz,3H),0.85(dd,J=24.1,6.0Hz,1H),0.66(d,J=2.2Hz,3H).

[0175] Step 2: In a 50 mL round-bottom flask at room temperature, (5R)-methyl 5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-hydroxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoate 12-1 (250 mg, 0.62 mmol) was dissolved in ethyl acetate (10 mL). Acetic acid (0.2 mL) and platinum dioxide (125 mg) were added at room temperature. The mixture was stirred under a hydrogen atmosphere at room temperature for 16 hours. TLC (ethyl acetate / petroleum ether = 5:1) indicated the formation of a new compound. After the reaction, the reaction solution was diluted with ethyl acetate (30 mL), filtered through celite, and the organic phase was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give (5R)-5-[(1R,3aS,3bR,5aS,7S,9aS,9bS,11aR)-7-hydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoic acid methyl ester 12-2 (240 mg, purity: 90%, yield: 85.97%) as a white solid. 1 H NMR (400MHz, CDCl3) δ3.66(s,3H),3.62–3.54(m,1H),2.32–2.21(m,2H),1.84–1.75(m,3H),1.74–1.61(m,5H) ),1.58–1.46(m,5H),1.42–1.22(m,11H),1.14–1.04(m,5H),0.91(d,J=6.5Hz,3H),0.80(s,3H),0.64(s,3H).

[0176] Step 3: In a 50 mL round-bottom flask at room temperature, (5R)-methyl 5-[(1R,3aS,3bR,5aS,7S,9aS,9bS,11aR)-7-hydroxy-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoate 12-2 (230 mg, 0.57 mmol) was dissolved in 1,2-dichloroethane (10 mL). Dess-Martin periodinane (362 mg, 0.85 mmol) was added at room temperature and stirred at 45°C for 3 hours. The reaction was monitored by TLC (ethyl acetate / petroleum ether = 10:1). After the reaction, the reaction solution was diluted with dichloromethane (10 mL), and saturated aqueous sodium sulfite solution (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL) were added to quench the reaction. The mixture was extracted with dichloromethane (20 mL × 3), and the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The organic phase was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give (5R)-5-[(1R,3aS,3bR,5aS,9aS,9bS,11aR)-9a,11a-dimethyl-7-oxoylidehexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester 12-3 (220 mg, purity: 90%, yield: 86.52%). 1 H NMR (400MHz, CDCl3) δ = 3.67 (s, 3H), 2.42–2.22 (m, 5H), 2.10–1.96 (m, 3H), 1.85–1.77 (m, 1H), 1.73–1.65 (m, 2H),1.60–1.48(m,6H),1.43–1.30(m,7H),1.27–1.04(m,6H),1.00(s,3H),0.92(d,J=6.5,3H),0.67(s,3H). 13 C NMR (101MHz, CDCl3) δ=212.15,174.33,56.27,55.93,53.78,51.43,46.70,44.73,42.61,39.87,38.56,38.1 9,35.65,35.51,35.40,35.39,34.52,31.70,29.70,28.96,28.16,24.20,21.55,21.43,18.55,12.04,11.46.

[0177] Step 4: In a 50 mL round-bottom flask at room temperature, (5R)-5-[(1R,3aS,3bR,5aS,9aS,9bS,11aR)-9a,11a-dimethyl-7-oxoylidenehexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoate 12-3 (190 mg, 0.47 mmol) was dissolved in tetrahydrofuran (3 mL) and methanol (6 mL). Ammonium acetate (363 mg, 4.70 mmol) and a catalytic amount of acetic acid (0.20 mL) were added, and the mixture was stirred at room temperature for 2 hours. Sodium cyanoborohydride (297 mg, 4.70 mmol) was then added to the reaction mixture, and the mixture was stirred at room temperature for 14 hours. The reaction was monitored by TLC (dichloromethane / methanol = 10:1). After the reaction, the reaction solution was diluted with dichloromethane (20 mL), and saturated aqueous sodium bicarbonate solution (30 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (20 mL × 3), and the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The organic phase was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to give (5R)-5-[(1R,3aS,3bR,5aS,9aS,9bS,11aR)-7-amino-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester 12-4 (160 mg, purity: 90%, yield: 75.59%) as a white solid. 1 H NMR (400MHz, DMSO) δ7.68 (s, 2H), 3.57 (s, 3H), 2.94 (dd, J = 25.9, 13.9Hz, 1H), 2.32–2.16 (m, 2H),1.98–1.88(m,1H),1.80–0.95(m,27H),0.88(d,J=6.4Hz,3H),0.76(s,3H),0.62(s,3H).

[0178] Step 5: In a 50 mL round-bottom flask at room temperature, (5R)-5-[(1R,3aS,3bR,5aS,9aS,9bS,11aR)-7-amino-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoic acid methyl ester 12-4 (160 mg, 0.396 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL). The reaction mixture was cooled to 0°C under nitrogen protection, and 3 mol / L methyl magnesium bromide tetrahydrofuran solution (1.321 mL, 3. 963 mmol), then stirred at room temperature for 2 hours, and the reaction was monitored by TLC (dichloromethane: methanol = 8: 1). After the reaction, the system was cooled to 0°C and quenched with saturated aqueous ammonium chloride solution (20 mL), extracted with ethyl acetate (15 mL × 3), and the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (dichloromethane: methanol = 8: 1) to give 3-amino-5α-cholest-25-ol as a white solid (130 mg, purity: 80%, yield: 64.99%). In a 50 mL round-bottom flask at room temperature, (5R)-5-[(1R,3aS,3bR,5aS,9aS,9bS,11aR)-7-amino-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoic acid methyl ester (160 mg, 0.396 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL). The reaction was cooled to 0°C under nitrogen protection, and 3 mol / L methyl magnesium bromide tetrahydrofuran solution (1 0.321 mL, 3.963 mmol), then stirred at room temperature for 2 hours. The reaction was monitored by TLC (dichloromethane:methanol = 8:1). After the reaction, the system was cooled to 0°C and quenched with saturated aqueous ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (15 mL × 3). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (dichloromethane:methanol = 8:1) to obtain 3-amino-5α-cholest-25-ol 12 as a white solid (130 mg, purity: 80%, yield: 64.99%). (ESI-MS (M+H)+: 404.4. 1 H NMR (400MHz, DMSO) δ7.61(s,2H),4.03(s,1H),2.93(m,1H),1.93(d,J=12.0Hz,1H),1.70(s,4H),1.47(d,J=13.4Hz,4H),1.31(dd,J =13.5,6.9Hz,6H),1.18(m,10H),1.05(s,6H),0.99(m,4H),0.89(d,J=6.5Hz,3H),0.82(d,J=12.6Hz,1H),0.76(s,3H),0.63(s,3H).

[0179] Example 14

[0180] Preparation of compound 14 1,1,1-trifluoro-N-[(1R,3aS,3bR,5aS,9aS,9bS,11aR)-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-7-yl]methanesulfonamide.

[0181] Step 1: In a 50 mL round-bottom flask, 3-amino-5α-cholest-25-ol 12 (20 mg, 0.050 mmol) was dissolved in dichloromethane (1 mL). Triethylamine (15 mg, 0.15 mmol) was added at room temperature. Trifluoromethanesulfonic anhydride (17 mg, 0.059 mmol) was added dropwise at 0°C. The reaction was stirred at 0°C for 1 hour. The reaction was monitored by TLC (ethyl acetate / petroleum ether = 3:1). After the reaction, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL×3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The organic phase was purified by silica gel column chromatography (petroleum ether:ethyl acetate=3:1) to give 1,1,1-trifluoro-N-[(1R,3aS,3bR,5aS,9aS,9bS,11aR)-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-7-yl]methanesulfonamide 14 as a white solid (5 mg, purity: 91.44%, yield: 17.23%).

[0182] Compound 14: 1 H NMR(400MHz,)δ4.53(d,J=8.7Hz,1H),3.46(d,J=8.1Hz,1H),1.94(dd,J=17.4,13.9Hz,2H),1.77(dd,J=14.2,11.3Hz,2H),1.66( d,J=10.3Hz,2H),1.45(d,J=4.9Hz,3H),1.33(m,15H),1.21(s,6H),1.05(m,7H),0.91(d,J=6.5Hz,3H),0.79(s,3H),0.65(s,3H). 19 F NMR(377MHz, CDCl3)δ-77.92(s,3F).

[0183] Example 18

[0184] Preparation of Compound 18 3β-[(3-hydroxypropyl)oxy]-5α-cholest-25-ol

[0185] Step 1: Dissolve 5α-cholesta-3β,25-diol 9-2 (200 mg, 0.494 mmol) in toluene (10 mL). Add potassium tert-butoxide (277.28 mg, 2.471 mmol) and stir at room temperature for 1 hour. Add allyl bromide (298.95 mg, 2.471 mmol) and stir at room temperature for 2 hours. Monitor by TLC (petroleum ether:ethyl acetate = 3:1). The reaction mixture is concentrated to give 40 mg of crude product, which is purified by column chromatography (ethyl acetate:petroleum ether = 30%) to give 3β-(prop-2-enyloxy)-5α-cholesta-25-ol 18-1 (70 mg, 0.150 mmol, 30.26%) as a white solid. 1 H NMR(399MHz,Chloroform-d)δ5.91(ddt,J=16.2,10.7,5.6Hz,1H),5.29–5.09(m,2H),3.99(dd,J=5.6,1.7Hz,2H), 3.25(dt,J=11.2,6.1Hz,1H),1.94(d,J=12.4Hz,1H),1.87–1.74(m,2H),1.74–1.57(m,4H),1.50(d,J=15.1Hz,4H) ,1.47–1.39(m,4H),1.36(d,J=9.0Hz,4H),1.31(s,3H),1.19(s,6H),1.08(d,J=8.3Hz,2H),1.03(d,J=9.1Hz,3H), 0.95(d,J=10.6Hz,2H),0.89(d,J=6.4Hz,3H),0.87–0.79(m,2H),0.77(s,3H),0.62(s,3H),0.57(d,J=13.1Hz,1H).

[0186] Step 2: Dissolve 3β-(prop-2-enyloxy)-5α-cholest-25-ol 18-1 (60 mg, 0.135 mmol) in tetrahydrofuran (3 mL). Add borane (1.349 mL, 1.349 mmol) and stir at room temperature for 1 hour. Add sodium hydroxide (0.899 mL, 2.698 mmol) and hydrogen peroxide (152.94 mg, 1.349 mmol) and stir at room temperature for 2 hours. Monitor by TLC (petroleum ether:ethyl acetate = 1:1). The reaction mixture is concentrated to give 400 mg of crude product, which is purified by column chromatography (ethyl acetate:petroleum ether = 50%) to give 3β-[(3-hydroxypropyl)oxy]-5α-cholest-25-ol 18 (20 mg, 0.041 mmol, 30.43%) as a white solid.

[0187] Compound 18: 1H NMR(400MHz,Chloroform-d)δ3.76(t,J=5.4Hz,2H),3.65(tq,J=5.5,3.2Hz,2H),3.21(dt,J=11.1,6.0Hz,1H),1. 94(dt,J=12.8,3.3Hz,1H),1.86–1.82(m,1H),1.81–1.78(m,2H),1.77–1.66(m,3H),1.62(ddd,J=12.6,6.5,3.1Hz ,2H),1.57–1.46(m,2H),1.42(d,J=11.5Hz,2H),1.38–1.30(m,5H),1.27–1.22(m,4H),1.19(s,6H),1.13–1.06(m, 2H),1.05–0.91(m,5H),0.89(d,J=6.4Hz,3H),0.82(d,J=8.4Hz,1H),0.77(s,3H),0.62(s,3H),0.60–0.54(m,1H). 13 C NMR (100MHz, cdcl3) δ79.053,77.192,71.095,67.771,62.813,56.447,56.162,54.332,44.758,44.385,42.577,39.988,36.886,36.389,35. 721,35.441,34.722,32.068,29.327,29.168,28.789,28.240,28.199,24.174,21.191,20.738,18.609,12.267,12.043. HPLC: 92.13% (CAD).

[0188] .

[0189] Example 19

[0190] Preparation of compound 19 {[(1R,3aS,3bR,5aS,7S,9aS,9bS,11aR)-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-7-yl]oxy}acetic acid.

[0191] Step 1: Dissolve 2-methylpropan-2-yl {[(1R,3aS,3bR,5aS,7S,9aS,9bS,11aR)-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthr-7-yl]oxy}acetate (140 mg, 0.270 mmol) in dichloromethane (3 mL). Add formic acid (6 mL, 0.010 mmol) and stir at room temperature for 1 hour. Monitor by TLC (petroleum ether:ethyl acetate = 3:1). The reaction mixture was directly concentrated to give crude {[(1R,3aS,3bR,5aS,7S,9aS,9bS,11aR)-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-7-yl]oxy}acetic acid 19 (140 mg, 0.121 mmol, 44.85%) as a light yellow solid. Compound 19: 1 H NMR (400MHz, Methanol-d4) δ4.08 (s, 2H), 3.33 (t, J = 5.0Hz, 1H), 2.01–1.96 (m, 1H), 1.84 (d, J=13.6Hz,2H),1.76–1.61(m,3H),1.58–1.48(m,2H),1.42(d,J=8.9Hz,3H),1.35(d,J=20.6H z,4H),1.29(d,J=9.8Hz,5H),1.21(s,1H),1.14(s,6H),1.13–1.06(m,4H),1.04–0.97(m,3H ),0.92(d,J=6.6Hz,3H),0.87(s,1H),0.82(s,3H),0.67(s,3H),0.65–0.59(m,1H).LCMS:[M] + =462.37.

[0192] Example 23

[0193] Preparation of Compound 23 3β,25-dihydroxycholest-4β-carboxylic acid

[0194] Step 1: In a 50 mL round-bottom flask at room temperature, acetic acid-[(1R,3aS,3bS,5aS,7S,9aR,9bS,11aR)-7-hydroxy-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6-yl]methyl ester 13 (220 mg, 0.46 mmol) was dissolved in dichloromethane (10 mL). Imidazole (157 mg, 2.31 mmol) and tert-butyldimethylsilyl chloride (348 mg, 2.31 mmol) were added at room temperature, and the mixture was stirred at room temperature for 16 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1). After completion of the reaction, the reaction was quenched with water (50 mL), extracted with ethyl acetate (30 mL×3), the organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated. The organic phase was purified by silica gel column chromatography (petroleum ether:ethyl acetate=5:1) to give white solid acetate-[(1R,3aS,3bS,5aS,7S,9aR,9bS,11aR)-7-{[dimethyl(2-methylprop-2-yl)silyl]oxy}-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthren-6-yl]methyl ester 23-1 (180 mg, purity: 90%, yield: 59.40%). 1 H NMR(400MHz, CDCl3)δ=4.24–4.05(m,2H),3.71–3.59(m,1H),1.95(s,3H),1.82–1.20(m,25H),1.17(s, 6H),1.10–0.93(m,5H),0.87(d,J=6.5,3H),0.84(s,9H),0.69(s,3H),0.59(s,3H),0.00(d,J=1.3,6H).

[0195] Step 2: In a 50 mL round-bottom flask, acetic acid [(1R,3aS,3bS,5aS,7S,9aR,9bS,11aR)-7-{[dimethyl(2-methylpropan-2-yl)silyl]oxy}-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthren-6-yl]methyl ester 23-1 (140 mg, 0.24 mmol) was dissolved in tetrahydrofuran (6 mL). 1 M lithium aluminum tetrahydride solution in tetrahydrofuran (0.28 mL, 0.28 mmol) was added at room temperature, and the mixture was stirred at room temperature for 0.5 h. The reaction was monitored by TLC (ethyl acetate / petroleum ether = 3:1). After the reaction, the reaction was quenched with water (50 mL), extracted with ethyl acetate (30 mL × 3), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give a white solid 3β-{[dimethyl(2-methylprop-2-yl)silyl]oxy}-4-(hydroxymethyl)-5α-cholest-25-ol 23-2 (100 mg, purity: 90%, yield: 69.21%). 1 H NMR(400MHz, CDCl3)δ=4.02(t,J=10.1,1H),3.95–3.87(m,1H),3.58(d,J=10.8,1H),2.15–1.63(m,16H),1.62–1.3 2(m,14H),1.25(s,9H),1.21(s,6H),1.13–0.94(m,7H),0.91(d,J=6.5,3H),0.68(s,3H),0.63(s,3H),0.00(s,6H).

[0196] Step 3: In a 50 mL round-bottom flask, 3β-{[dimethyl(2-methylpropan-2-yl)silyl]oxy}-4-(hydroxymethyl)-5α-cholest-25-ol 23-2 (50 mg, 0.091 mmol) was dissolved in tetrahydrofuran (1.5 mL) and dichloromethane (1.5 mL). Dess-Martin reagent (58 mg, 0.14 mmol) was added at room temperature and stirred at room temperature for 2 hours. The reaction was monitored by TLC (ethyl acetate / petroleum ether = 4:1). After the reaction, the mixture was quenched with water (20 mL), extracted with ethyl acetate (10 mL × 3), and the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The organic phase was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4: 1) to give 3β-{[dimethyl(2-methylprop-2-yl)silyl]oxy}-25-hydroxy-5α-cholest-4-carboxaldehyde 23-3 as a white solid (15 mg, purity: 90%, yield: 27.10%). 1H NMR(400MHz, CDCl3)δ=9.99(s,1H),3.60–3.53(m,1H),2.61–2.56(m,1H),2.03–1.93(m,2H),1.91–1.72(m,8H),1.69– 1.40(m,12H),1.26(s,9H),1.21(s,6H),1.13–0.99(m,8H),0.91(d,J=6.3,3H),0.76(s,3H),0.64(s,3H),0.00(s,6H).

[0197] Step 4: In a 50 mL round-bottom flask at room temperature, 3β-{[dimethyl(2-methylprop-2-yl)silyl]oxy}-25-hydroxycholest-4β-carbaldehyde 23-3 (12 mg, 0.022 mmol) was dissolved in tert-butanol (1 mL) and tetrahydrofuran (0.5 mL). 2-Methylbut-2-ene (10 mg, 0.13 mmol), sodium dihydrogen phosphate (8 mg, 0.066 mmol), sodium chlorite (7 mg, 0.077 mmol), and water (0.25 mL) were added at 0°C, followed by stirring at room temperature for 16 hours. The reaction was monitored by TLC (dichloromethane:methanol = 10:1). After the reaction, the reaction was quenched with saturated aqueous sodium sulfite solution (20 mL), extracted with dichloromethane and methanol (dichloromethane: methanol = 10: 1, 10 mL × 3), and the organic phase was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by silica gel column chromatography (dichloromethane: methanol = 10: 1) to give 3β,25-dihydroxycholest-4β-carboxylic acid 23 as a white solid (3.65 mg, purity: 100%, yield: 37.09%).

[0198] Compound 23: 1 H NMR (400MHz, DMSO) δ=11.86(s,1H),4.49(s,1H),4.03(s,1H),3.50–3.43(m,1H),2.55(d,J=5.2,1H),2.25–2.03(m,2H),1.92(d,J= 12.0,1H),1.87–1.69(m,2H),1.65(d,J=13.0,2H),1.58–1.19(m,21H),1.05(s,6H),0.88(d,J=6.4,3H),0.83(s,3H),0.61(s,1H). 13C NMR(101MHz, DMSO)δ=71.37,69.23,56.19,55.54,54.29,52.79,50.66,47.76,44.60,42.52,38.01,36.64,36.13,35.69,35.46 ,32.81,31.76,29.88,29.70,28.28,28.01,27.88,24.33,23.18,21.75,20.94,20.72,18.98,13.22,12.32.LC-MS:[M+H-2H2O] + =413.35

[0199] Example 24

[0200] Compound 24 Preparation of 24,24-difluorocholest-6(5)-ene-3β,25-diol.

[0201] In the first step, zinc (0.61 g, 9.312 mmol) was dissolved in THF (15 mL), and then refluxed with stirring under nitrogen for 1 hour. Acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-1-formylprop-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester A mixture of 1-[(2R)-1-formylpropan-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester I-5 (1.2 g, 3.104 mmol) and BrCF2CO2Et (1.89 g, 9.312 mmol) was dissolved in THF (3 mL) and then added dropwise to the above zinc solution. The reaction was refluxed for 0.5 h. The reaction of the raw material was completed as monitored by TLC (petroleum ether:ethyl acetate = 5:1). The reaction solution was poured into water and extracted with ethyl acetate (20 mL x 2). The organic phases were combined and concentrated, and the crude product was separated and purified by flash chromatography (petroleum ether:ethyl acetate = 95:5 to 80:20) to give (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-2,2-difluoro-3-hydroxyhexanoic acid ethyl ester 24-1 (700 mg, purity: 90%, yield: 39.74%) as a white solid. 1 H NMR(400MHz, CDCl3)δ5.37(d,J=4.5Hz,1H),4.68–4.52(m,1H),4.47–4.28(m,2H),4 .12(d,J=7.0Hz,1H),2.32(d,J=7.1Hz,2H),2.08–1.94(m,5H),1.86(d,J=9.6Hz,3H ),1.69(d,J=13.0Hz,2H),1.60(td,J=16.9,6.6Hz,4H),1.47(dd,J=15.7,11.6Hz,3 H),1.37(t,J=7.1Hz,3H),1.29–1.09(m,6H),1.07–0.94(m,8H),0.75–0.67(m,3H).

[0202] In the second step, (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2,2-difluoro-3-hydroxyhexanoic acid ethyl ester 24-1 (300 mg, 0.587 mmol) was dissolved in dichloromethane (10 mL), and then di(imidazol-1-yl)methanone (314.08 mg, 1.762 mmol) and DMAP (14.35 mg, 0.117 mmol) were added sequentially. The reaction was refluxed for 12 hours and monitored by TLC (petroleum ether:ethyl acetate = 3:1). The reaction solution was poured into water and extracted with ethyl acetate (20 mL x 2). The organic phases were combined and concentrated, and the crude product was separated and purified by flash chromatography (petroleum ether:ethyl acetate = 95:5 to 60:40) to give a colorless oily liquid (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-2,2-difluoro-3-{[(imidazol-1-yl)sulfanylidenemethyl]oxy}hexanoic acid ethyl ester 24-2 (250 mg, purity: 90%, 61.69%). 1 H NMR (400MHz, CDCl3) δ8.47(d,J=9.6Hz,1H),7.67(d,J=11.0Hz,1H),7.14(d,J=6.8Hz,1 H),6.32–6.12(m,1H),5.37(d,J=4.8Hz,1H),5.30(s,2H),4.68–4.54(m,1H),4.32(q,J =7.2Hz,2H),2.32(d,J=6.8Hz,2H),2.11(s,1H),2.06–1.93(m,5H),1.85(d,J=10.4Hz, 3H),1.73–1.39(m,9H),1.35–1.24(m,5H),1.22–0.94(m,13H),0.68(t,J=18.8Hz,3H).

[0203] In the third step, ethyl (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-2,2-difluoro-3-{[(imidazol-1-yl)sulfanylidenemethyl]oxy}hexanoate 24-2 (200 mg, 0.322 mmol) was dissolved in toluene (5 mL). Benzoic acid peroxyanhydride (15.61 mg, 0.064 mmol) and triethylsilyl hydrochloride (299.69 mg, 2.577 mmol) were added sequentially. The reaction was refluxed for 18 hours. The reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 8:1). The reaction solution was poured into water and extracted with ethyl acetate (20 mL x 2). The organic phases were combined and concentrated. The crude product was separated and purified by flash chromatography (petroleum ether:ethyl acetate = 95:5) to give (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-2,2-difluorohexanoic acid ethyl ester 24-3 (90 mg, purity: 90%, 50.83%), which was directly used in the next step.

[0204] Step 4: (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2,2-difluorohexanoic acid ethyl ester 24-3 (70 mg, 0.142 mmol) was dissolved in THF (4 mL) and the temperature was lowered to 0 0 C, slowly add 3.0 M MeMgBr (0.28 mL) dropwise, and stir at 0 °C for 0.5 h after the addition is complete. After the reaction was completed as monitored by TLC (petroleum ether:ethyl acetate = 5:1), the mixture was quenched with water (10 mL), extracted with ethyl acetate (10 mL x 2), and concentrated. The crude product was separated and purified by flash chromatography (petroleum ether:ethyl acetate = 95:5 to 90:10) to give (1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-5,5-difluoro-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate 24-4 (50 mg, 90%, 69.83%) as a white solid.1 H NMR (400MHz, CDCl3) δ5.46–5.27(m,1H),4.76–4.47(m,1H),2.33(s,2H),2.08–1.95(m,5H),1.86(d,J=12.4Hz,3H),1.51(d t,J=12.4,7.9Hz,13H),1.31(s,8H),1.14(s,3H),1.02(s,4H),0.94(d,J=6.6Hz,3H),0.87(d,J=11.6Hz,1H),0.69(s,3H).

[0205] Step 5: Acetate (1R, 3aS, 3bS, 7S, 9aR, 9bS, 11aR) -1- [(2R) -5,5-difluoro-6-hydroxy-6-methylhept-2-yl] -9a, 11a-dimethyl-2,3,3a, 3b, 4,6,7,8,9,9a, 9b, 10,11, 11a-tetradecahydro-1H-cyclopenta [1,2-i] phenanthrene-7-yl ester 24-4 (60 mg, 0.125 mmol) was dissolved in MeOH (5 mL) and water (1 mL), and K2CO3 (34.5 mg, 0.25 mmol) was added. The reaction was allowed to proceed at room temperature for 1 hour. TLC (petroleum ether: ethyl acetate = 3:1) was used to monitor the generation of new spots. The reaction solution was poured into water and extracted with ethyl acetate (20 mL x 2). The organic phases were combined and concentrated. The crude product was separated and purified by flash chromatography (petroleum ether: ethyl acetate = 95:5 to 60:40) to obtain a white solid 24,24-difluorocholest-6(5)-ene-3β,25-diol 24 (30 mg, 0.065 mmol, 52.05%).

[0206] Compound 24: 1 H NMR(400MHz, CDCl3)δ5.35(d,J=5.2Hz,1H),3.52(dd,J=10.3,5.6Hz,1H),2.34–2.18(m,2H),2.07–1.92(m,3H),1.86(dt,J=13.9,4.8Hz,3H),1.74–1 .62(m,2H),1.49(ddt,J=18.0,14.7,8.8Hz,7H),1.37–1.24(m,9H),1.18– 1.04(m,4H),1.05–0.98(m,4H),0.97–0.89(m,4H),0.67(d,J=12.8Hz,3H). 13C NMR (101MHz, CDCl3) δ140.76,121.70,71.81,56.72,55.71,50.01,42.36,42.30,39.75,37.21,36.46,35. 37,31.90,31.89,31.66,28.03,27.32,26.87,24.12,23.60,21.08,19.40,18.46,11.79.LC-MS: [M+H-H2O] + =421.55

[0207] Example 25

[0208] Preparation of compound 25 24,24-difluoro-5α-cholesta-3β,25-diol.

[0209] In the first step, the obtained white solid (1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-5,5-difluoro-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate 24-4 (40 mg, 0.083 mmol) was dissolved in methanol (4 mL) and Pd / C (40 mg) was added. After the addition was complete, the mixture was stirred at room temperature for 3 hours. After the reaction was complete as monitored by TLC (petroleum ether:ethyl acetate = 2:1), the mixture was filtered and the crude product was used directly in the next step: (1R,3aS,3bR,5aS,7S,9aS,9bS,11aR)-1-[(2R)-5,5-difluoro-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate 25-1 (40 mg, 90%, 89.62%).

[0210] In the second step, (1R,3aS,3bR,5aS,7S,9aS,9bS,11aR)-1-[(2R)-5,5-difluoro-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate 25-1 (40 mg, 0.083 mmol) was dissolved in methanol (5 ml) and water (0.5 ml), and then potassium carbonate (34.36 mg, 0.249 mmol) was added. The reaction was reacted at room temperature for 1 hour. TLC (petroleum ether:ethyl acetate = 3:1) was used to monitor the generation of new spots. The reaction solution was poured into water and extracted with ethyl acetate (20 ml x 2). The organic phases were combined and concentrated. The crude product was separated and purified by flash chromatography (petroleum ether:ethyl acetate = 95:5 to 60:40) to obtain 24,24-difluoro-5α-cholest-3β,25-diol 25 (10 mg, 0.020 mmol, 24.65%) as a white solid. 1 H NMR(400MHz, CDCl3) δ3.59(s,1H),1.95(d,J=12.6Hz,2H),1.71(ddd,J=27.4,24.6,6.5Hz,6H),1.53–1.42(m, 4H),1.41–1.22(m,14H),1.17–0.95(m,6H),0.91(t,J=8.9Hz,4H),0.80(s,3H),0.66(s,4H).LC-MS: [M+H-H2O] + =423.55

[0211] Example 26

[0212] Compound 26 Preparation of 4β-hydroxy-3β-hydroxy-24-(hydroxycyclopropyl)-5α-cholan-7-one.

[0213] Step 1: Dissolve (5R)-5-[(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-7-acetoxy-6-hydroxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester I-8 (300 mg, 0.65 mmol) in dichloromethane (20 mL). Add 4-dimethylaminopyridine (39.81 mg, 0.03 mmol), triethylamine (197.70 mg, 1.95 mmol), and acetic anhydride (79.78 mg, 0.78 mmol) and react at room temperature for 2 h. The reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 5:1). The product was washed with dichloromethane and water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate ~20:1) to give (5R)-5-[(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-6,7-diacetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester 26-1 (230 mg, 0.441 mmol, 62.2%) as a white solid. 1 H NMR(399MHz,Chloroform-d)δ5.81–5.76(m,1H),5.48(d,J=3.4Hz,1H),3.64(s,3H),2.35–2.18(m,2H),2.04(s,3H),1.99(s,3H),1.87(dt,J=13.8 ,3.7Hz,2H),1.56(dd,J=6.7,4.2Hz,2H),1.50–1.42(m,4H),1.39–1.33(m ,2H),1.24–1.17(m,2H),1.11(s,3H),0.91(d,J=6.4Hz,3H),0.65(s,3H).

[0214] Step 2: Methyl (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoate 26-1 (100.00 mg, 0.23 mmol) was dissolved in acetone (3.0 mL) under nitrogen atmosphere. N-hydroxyphthalimide (3.25 mg, 0.02 mmol) and cobalt acetate (0.35 mg, 0.01 mmol) were then added, followed by tert-butyl peroxide (85 mg, 0.90 mmol). The mixture was allowed to react at room temperature for 16 h. The reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 10:1). Sodium thiosulfate was added to quench the reaction, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography using petroleum ether:ethyl acetate (100% to 20%) to give (5R)-5-[(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-6,7-diacetoxy-9a,11a-dimethyl-4-oxyylidene-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester 26-2 (40 mg, 0.07 mmol, 35.0%). 1 H NMR(399MHz,Chloroform-d)δ5.90(s,1H),5.60–5.56(m,1H),4.80–4.74(m,1H),3. 64(d,J=0.8Hz,3H),2.38–2.22(m,4H),2.07(d,J=0.8Hz,3H),2.06–2.02(m,1H),2.0 0(s,3H),1.98–1.85(m,2H),1.77(dd,J=13.0,4.0Hz,1H),1.47–1.32(m,3H),1.29( s,3H),1.23(d,J=8.5Hz,2H),1.14–1.04(m,3H),0.92(d,J=6.5Hz,3H),0.65(s,3H).

[0215] Step 3: Methyl (5R)-5-[(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-6,7-diacetoxy-9a,11a-dimethyl-4-oxyylidene-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoate 26-2 (300 mg, 0.65 mmol) was dissolved in methanol (10.0 mL), Pd / C 10% (20 mg, 0.19 mmol), purged with hydrogen three times, reacted at room temperature for 1 h, and monitored by TLC (petroleum ether: ethyl acetate = 5:1) for completion of the reaction. Filter through celite, rinse with methanol, concentrate, and perform column chromatography with petroleum ether:ethyl acetate (100% to 20%) to obtain (5R)-5-[(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-6,7-diacetoxy-9a,11a-dimethyl-4-oxyylidenehexahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoic acid methyl ester 26-3 (50 mg) as a white solid, which was directly used in the next step. 1 H NMR (399MHz, Chloroform-d) δ5.15 (s, 1H), 4.76 (dt, J = 12.3, 4.2Hz, 1H), 3.65 (s, 3H), 2.49 (t, J = 13. 5Hz,1H),2.33–2.16(m,4H),2.09(s,3H),2.06(dd,J=13.0,3.1Hz,1H),1.96(s,3H),1.92(d,J=3.7H z,1H),1.90–1.80(m,3H),1.74–1.63(m,3H),1.49(dd,J=9.8,6.4Hz,3H),1.37(td,J=11.7,11.3,7. 0Hz,3H),1.26(s,3H),1.17(d,J=12.5Hz,2H),1.12–1.03(m,5H),0.91(d,J=6.4Hz,3H),0.62(s,3H).

[0216] Step 4: Dissolve (5R)-5-[(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-6,7-diacetoxy-9a,11a-dimethyl-4-oxoylidenehexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester 26-3 (50 mg, 0.10 mmol) in toluene (5 mL). Add ethylene glycol (0.05 mL, 0.96 mmol) and anhydrous p-toluic acid (7.3 mg, 0.05 mmol). Heat under reflux with stirring for 1 h. Monitor the reaction by TLC (petroleum ether:ethyl acetate = 2:1). Water was added, extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography with petroleum ether:ethyl acetate (100% to 20%) to give (5R)-5-[(1'R,3a'S,3b'S,6'R,7'S,9a'R,9b'S,11a'R)-6',7'-diacetoxy-9a',11a'-dimethyl-1',2',3',3a',3b',5',5a',6',7',8',9',9a',9b',10',11',11a'-hexahydrospiro[1,3-dioxolane-2,4'-cyclopenta[1,2-a]phenanthrene]-1'-yl]hexanoic acid methyl ester 26-4 (8 mg, 0.01 mmol, 17.2%) as a white solid. 1 H NMR(399MHz,Chloroform-d)δ5.14(s,1H),4.76(dt,J=12.0,4.3Hz,1H),3.97–3.84(m,5H ),3.63(s,3H),2.05(s,3H),1.94(s,2H),1.02(s,3H),0.90(d,J=6.5Hz,3H),0.62(s,3H)

[0217] Step 5: Compound (5R)-5-[(1'R,3a'S,3b'S,6'R,7'S,9a'R,9b'S,11a'R)-6',7'-diacetoxy-9a',11a'-dimethyl-1',2',3',3a',3b',5',5a',6',7',8',9',9a',9b',10',11',11a'-hexahydrospiro[1,3-dioxolane-2,4'-cyclopenta[1,2-a]phenanthrene]-1'-yl]hexanoic acid methyl ester 26-4 (20 mg, 0.04 mmol) was dissolved in tetrahydrofuran (5 mL), tetraisopropyl titanate (95.6 mg, 0.67 mmol) was added at room temperature, the mixture was purged with nitrogen three times, the temperature was lowered to 0°C and ethylmagnesium chloride (0.62 mL) was added dropwise. The mixture was stirred at room temperature for 1 h and monitored by TLC (petroleum ether:ethyl acetate=3:1). The reaction mixture was quenched by adding brine at low temperature, diluted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography with petroleum ether:ethyl acetate (100%-50%) to give (1'R,3a'S,3b'S,5a'R,6'R,7'S,9a'R,9b'S,11a'R)-1'-[(2R)-5-(hydroxycyclopropyl)pentan-2-yl]-9a',11a'-dimethyl-1',2',3',3a',3b',5',5a',6',7',8',9',9a',9b',10',11',11a'-hexahydrospiro[1,3-dioxolane-2,4'-cyclopenta[1,2-a]phenanthrene]-6',7'-diol 26-5 (15.0 mg, 0.03 mmol, 33.6%) as a white solid. 1 H NMR(399MHz,Chloroform-d)δ3.96(d,J=5.9Hz,4H),3.67(s,1H),1.94(d,J=12.9Hz,2H),1.80(d,J=13.0Hz,5H),1.73(d,J=10.9Hz,5H),1.4 4(d,J=7.8Hz,6H),1.35(s,8H),1.24(s,3H),1.04(s,3H),0.92(d,J=6 .2Hz,3H),0.84(t,J=7.8Hz,4H),0.71(s,2H),0.64(s,3H),0.42(s,2H)

[0218] Step 5: (1'R,3a'S,3b'S,5a'R,6'R,7'S,9a'R,9b'S,11a'R)-1'-[(2R)-5-(hydroxycyclopropyl)pentan-2-yl]-9a',11a'-dimethyl-1',2',3',3a',3b',5',5a',6',7',8',9',9a',9b',10',11',11a'-hexahydrospiro[1,3-dioxolane-2,4'-cyclopenta[1,2-a]phenanthrene]-6',7'-diol 26-5 (10 mg, 0.02 mmol) was dissolved in methanol (3.0 mL). Acetic acid (2 mL, 34.94 mmol) was added at room temperature and stirred at room temperature for 1 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 1:1) to ensure completion. The mixture was quenched by adding brine at low temperature, diluted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using petroleum ether:ethyl acetate (100%-50%) to give 4β-hydroxy-3β-hydroxy-24-(hydroxycyclopropyl)-5α-cholan-7-one 26 (3 mg, 0.01 mmol, 19.3%).

[0219] Compound 26: 1 H NMR (399MHz, Chloroform-d) δ3.70 (s, 1H), 3.57 (d, J = 10.6Hz, 1H), 2.86 (t, J = 13.5Hz, 1H), 2. 37(t,J=11.3Hz,1H),2.21(d,J=12.1Hz,1H),2.14–2.02(m,2H),1.97(d,J=13.1Hz,1H),1.79( ddt,J=45.8,32.3,14.7Hz,4H),1.58–1.38(m,9H),1.27(s,6H),1.11–0.96(m,6iH),0.91(t,J =6.0Hz,3H),0.84(t,J=7.4Hz,2H),0.71(d,J=5.4Hz,2H),0.63(s,3H),0.43(t,J=3.3Hz,2H). 13C NMR(101MHz,cdcl3)δ212.83,77.31,77.20,76.99,76.67,74.71,73.76,7 1.92,55.93,55.76,54.82,50.03,48.95,43.78,42.51,38.80,38.60,36.5 2,36.06,35.89,35.88,35.62,35.55,31.03,29.68,28.40,25.58,24.99, 22.29,21.09,18.74,14.16,13.57,13.48,12.04,7.80,1.00.LC-MS:[M+H] + =433.3.

[0220] Example 27

[0221] Preparation of Compound 27 3-{[(1R,3aS,3bR,5aS,7S,9aS,9bS,11aR)-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-7-yl]oxy}propanoic acid.

[0222] Step 1: Dissolve 3β-[(3-hydroxypropyl)oxy]-5α-cholest-25-ol 18 (70 mg, 0.151 mmol) in dichloromethane (5 mL). Add Dess-Martin periodinane (64.16 mg, 0.151 mmol) and stir at room temperature for 1 hour. Monitor by TLC (petroleum ether:ethyl acetate = 1:1). The reaction mixture is concentrated to give 100 mg of crude product, which is then purified by column chromatography (ethyl acetate:petroleum ether = 30%) to afford 3-{[(1R,3aS,3bR,5aS,7S,9aS,9bS,11aR)-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthren-7-yl]oxy}propanal 27-1 (50 mg, 0.103 mmol, 68.15%) as a white solid. 1H NMR(399MHz,Chloroform-d)δ9.77(t,J=2.0Hz,1H),3.78(td,J=6.3,3.1Hz,2H),3.22(dt,J=11.5,6.2H z,1H),2.63(td,J=6.2,2.0Hz,2H),1.94(d,J=12.5Hz,1H),1.81(d,J=13.9Hz,2H),1.73–1.60(m,3H),1. 58–1.44(m,3H),1.36(q,J=13.9,12.9Hz,5H),1.12(d,J=26.3Hz,2H),1.04(t,J=9.5Hz,3H),0.96(d,J= 20.8Hz,2H),0.89(d,J=6.3Hz,3H),0.82(dd,J=16.9,8.3Hz,2H),0.76(s,3H),0.62(s,3H),0.59(s,1H).

[0223] Step 2: 3-{[(1R,3aS,3bR,5aS,7S,9aS,9bS,11aR)-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthren-7-yl]oxy}propanal 27-1 (45 mg, 0.098 mmol) was dissolved in tert-butanol (4 mL) and water (0.5 mL). Sodium dihydrogen phosphate (43.19 mg, 0.360 mmol), 2-methyl-2-butene (137.01 mg, 1.953 mmol), and sodium chlorite (26.50 mg, 0.293 mmol) were added, and the mixture was stirred at room temperature for 1 hour. TLC (dichloromethane:methanol = 20:1) was used for monitoring. The mixture was diluted with water and extracted three times with ethyl acetate. The organic phase was washed once with brine, dried over anhydrous sodium sulfate, and concentrated to give 20 mg of a solid. Column chromatography (methanol / dichloromethane = 10%) gave 3-{[(1R,3aS,3bR,5aS,7S,9aS,9bS,11aR)-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-7-yl]oxy}propanoic acid 27 (24 mg, 0.048 mmol, 48.97%) as a white solid. Compound 27: 1H NMR (400MHz, Methanol-d4) δ3.71(t,J=6.3Hz,2H),3.25(d,J=10.9Hz,1H),2.48(t,J=6.3Hz,2H),2.02–1.95(m,1H ),1.88–1.77(m,2H),1.76–1.64(m,2H),1.64–1.55(m,2H),1.50(dd,J=13.2,4.1Hz,1H),1.42(d,J=8.9Hz,2H),1. 38(t,J=4.0Hz,2H),1.35–1.32(m,2H),1.27(t,J=12.4Hz,5H),1.19(d,J=10.9Hz,2H),1.14(s,6H),1.13–1.07(m, 3H),1.07–0.94(m,4H),0.92(d,J=6.6Hz,3H),0.90–0.83(m,1H),0.80(s,3H),0.67(s,3H),0.62(d,J=16.2Hz,1H). 13 C NMR(101MHz,cd3od) δ174.242,78.790,70.026,63.304,56.451,56.228,54.382,44.646,43.843,42.334,39.970,36.684,36.350,35.704,35.429,35.3 78,34.873,34.432,31.875,28.548,27.897,27.806,27.780,27.664,23.804,20.894,20.416,17.736,11.265,11.060.LCMS:[Ms-H] - =475.45.

[0224] Example 29

[0225] Preparation of Compound 29 3β-[(2-hydroxyethyl)oxy]-5α-cholest-4β,25-diol

[0226] Step 1: Weigh acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-6-methoxy-6-oxyidenehexan-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester I-7 (77 mg, 0.17 mol, 1.0 eq.) and dissolve it in tetrahydrofuran (2 mL). After nitrogen replacement, dry ice -Acetone was cooled to -78 ° C, methyl lithium (0.54 mL, 0.87 mmol) was added, and then the temperature was raised to room temperature with stirring and monitored by TLC (petroleum ether: ethyl acetate = 10: 1). After the reaction was completed, 6 mL of water was added to quench the reaction, and 5 mL of ethyl acetate was used for extraction. The organic phase was dried and concentrated. The crude product was purified by column chromatography (dichloromethane: methanol = 300: 1 to 100: 1) to obtain cholester-5 (6) -ene-3β, 25-diol 29-1 (35 mg, 0.083 mmol, 47.66%) as a white solid. 1 HNMR(399MHz,cdcl3)δ5.32(s,1H),3.50(s,1H),2.24(m,2H),1.98(dd,J=18.6,10 .9Hz,2H),1.82(d,J=10.3Hz,3H),1.53(d,J=10.0Hz,3H),1.46(d,J=7.2Hz,3H),1 .42(d,J=10.1Hz,3H),1.36(d,J=12.5Hz,4H),1.21(s,3H),1.19(s,6H),1.12(dd, J=14.4,7.2Hz,2H),1.03(m,4H),0.99(s,3H),0.91(d,J=6.6Hz,3H),0.66(s,3H). 13 C NMR (100MHz, cdcl3) δ140.72,121.68,77.31,77.00,76.68,71.76,71.11,56.70,56.00,50.05,44.38,42.57,42.29,42.25,39 .72,37.20,36.46,36.39,35.72,31.87,31.85,31.61,29.34,29.17,28.70,28.23,24.26,21.04,20.72,19.38,18.66,11.84.

[0227] Step 2: Dissolve cholest-5(6)-ene-3β,25-diol 29-1 (1280 mg, 3.179 mmol, 1.0 eq.) in toluene (50 mL), add potassium tert-butoxide (3567.00 mg, 31.789 mmol, 10.0 eq.), and stir at room temperature for 1 hour. Then, add tert-butyl bromoacetate (6200.69 mg, 31.789 mmol, 10.0 eq.), and stir at room temperature for 2 hours. Monitor by TLC (petroleum ether:ethyl acetate = 3:1). The reaction solution was directly concentrated to give a crude product, which was purified by column chromatography (ethyl acetate:petroleum ether = 30%) to give 2-methylpropan-2-yl {[(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-7-yl]oxy}acetate 29-2 (950 mg, 1.746 mmol, 54.93%) as a white solid. 1 H NMR(399MHz,Chloroform-d)δ5.33(d,J=5.0Hz,1H),3.98(s,2H),3.27–3.15(m,1H),2.4 2–2.33(m,1H),2.24(t,J=12.2Hz,1H),1.95(q,J=12.5Hz,3H),1.86–1.73(m,2H),1.62– 1.50(m,3H),1.48(s,2H),1.45(s,9H),1.43–1.41(m,3H),1.39–1.33(m,5H),1.19(s,7H ),1.15–1.08(m,2H),1.07–1.00(m,3H),0.98(s,3H),0.91(d,J=6.5Hz,3H),0.65(s,3H).

[0228] Step 3: 2-Methylpropan-2-yl {[(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthr-7-yl]oxy}acetate 29-2 (950 mg, 1.746 mmol, 54.93%) (950 mg, 1.838 mmol, 1.0 eq.) was dissolved in dichloromethane (15 mL), and pyridine (0.740 mL, 9.191 mmol, 5.0 eq.) and acetyl chloride (0.392 mL, 5.515 mmol, 3.0 eq.) were added. The mixture was stirred at 40°C for 5 hours. TLC (petroleum ether:ethyl acetate = 5:1) was used for monitoring. The reaction mixture was concentrated to obtain a crude product, which was then purified by column chromatography (ethyl acetate:petroleum ether = 20%) to obtain 2-methylpropan-2-yl {[(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-6-acetoxy-6-methylhept-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-7-yl]oxy}acetate 29-3 (760 mg, 1.292 mmol, 70.28%) as a white solid. 1 H NMR(399MHz,Chloroform-d)δ5.33(s,1H),3.98(s,2H),3.26–3.16(m,1H),2.41–2.32(m,1H),2.24(t ,J=12.4Hz,1H),2.00(d,J=3.9Hz,1H),1.95(s,3H),1.88(d,J=15.1Hz,1H),1.83–1.70(m,2H),1.68–1 .61(m,1H),1.59–1.49(m,4H),1.45(d,J=1.8Hz,9H),1.40(s,6H),1.37–1.30(m,3H),1.29–1.17(m,2 H),1.17–1.09(m,2H),1.04(dd,J=12.3,10.5Hz,3H),0.98(s,3H),0.89(d,J=6.3Hz,3H),0.65(s,3H).

[0229] Step 4: 2-Methylpropan-2-yl {[(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-6-acetoxy-6-methylhept-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-7-yl]oxy}acetate 29-3 (760 mg, 1.360 mmol, 1.0 eq.) was dissolved in chloroform (5 mL), and N-methylmorpholine (825.36 mg, 8.160 mmol, 6.0 eq.) and selenium dioxide (198.55 mg, 1.789 mmol, 5.0 eq.) were added. The mixture was stirred at 75°C for 18 hours. The reaction mixture was monitored by TLC (petroleum ether:ethyl acetate = 5:1). The reaction mixture was concentrated to give a crude product, which was then purified by column chromatography (ethyl acetate:petroleum ether = 40%) to give 2-methylpropan-2-yl {[(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-1-[(2R)-6-acetoxy-6-methylhept-2-yl]-6-hydroxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-7-yl]oxy}acetate 29-4 (320 mg, 0.529 mmol, 38.89%) as a white solid. 1 H NMR(399MHz,Chloroform-d)δ5.68(d,J=4.5Hz,1H),4.19–4.11(m,2H),3.93(d,J=16.8 Hz,1H),3.26(d,J=11.6Hz,1H),2.10–2.03(m,1H),1.99(d,J=12.5Hz,2H),1.95(s,3H), 1.83(d,J=14.2Hz,2H),1.66(d,J=14.3Hz,3H),1.52(d,J=11.1Hz,3H),1.46(s,9H),1.40(s,6H),1.34(d,J=6.7Hz,2H),1.24(d,J=8.7H z,1H),1.18(s,3H),1.12(t,J=14.3Hz,2H),1.06–1.01(m,2H),1.00–0.93(m,2H),0.89(d,J=6.4Hz,3H),0.88–0.79(m,1H),0.65(s,3H).

[0230] Step 5: 2-Methylpropan-2-yl {[(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-1-[(2R)-6-acetoxy-6-methylhept-2-yl]-6-hydroxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-7-yl]oxy}acetate 29-4 (320 mg, 0.557 mmol, 1.0 eq.) was dissolved in ethyl acetate (10 mL) and acetic acid (2 mL), and platinum dioxide (160 mg, 0.705 mmol, 1.3 eq.) was added. The mixture was stirred at 40°C for 15 min under a hydrogen atmosphere. The mixture was monitored by TLC (petroleum ether:ethyl acetate = 5:1). The reaction solution was filtered and the filtrate was concentrated to give a crude product, which was purified by column chromatography (ethyl acetate:petroleum ether = 30%) to give 2-methylpropan-2-yl {[(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-1-[(2R)-6-acetoxy-6-methylhept-2-yl]-6-hydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthr-7-yl]oxy}acetate 29-5 (200 mg, 0.329 mmol, 59.17%) as a white solid. 1 H NMR(400MHz,Chloroform-d)δ4.15(d,J=16.6Hz,1H),3.90(d,J=16.8Hz,1H),3.74(s,1H),3.22(d,J=11.4Hz,1H),1.95 (d,J=1.1Hz,3H),1.90(d,J=12.8Hz,1H),1.80(d,J=13.4Hz,2H),1.73(dd,J=13.3,8.3Hz,4H),1.63(dd,J=11.8,7.8Hz, 3H),1.59–1.48(m,2H),1.45(d,J=1.2Hz,9H),1.39(d,J=1.2Hz,6H),1.34(d,J=3.7Hz,5H),1.27–1.21(m,3H),1.16–1.0 6(m,2H),1.02(s,3H),0.99–0.91(m,3H),0.88(d,J=6.4Hz,3H),0.80(d,J=14.0Hz,1H),0.63(s,3H),0.57–0.49(m,1H).

[0231] Step 6: 2-Methylpropan-2-yl {[(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-1-[(2R)-6-acetoxy-6-methylhept-2-yl]-6-hydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthren-7-yl]oxy}acetate 29-5 (40 mg, 0.069 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (5 mL), and lithium aluminum tetrahydride (13.16 mg, 0.347 mmol, 5.0 eq.) was added. The mixture was stirred at room temperature for 1 h. TLC (petroleum ether:ethyl acetate = 5:1) was used for monitoring. The reaction mixture was quenched with water, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by column chromatography (ethyl acetate:petroleum ether = 50%) to obtain 3β-[(2-hydroxyethyl)oxy]-5α-cholest-4β,25-diol 29 (20 mg, 0.041 mmol, 58.96%) as a white solid. Compound 29: 1 H NMR(399MHz,Chloroform-d)δ3.88(s,1H),3.73(q,J=3.8,3.3Hz,2H),3.62(t,J=4.6Hz,2H),3.25(dt,J= 11.9,4.3Hz,1H),1.94(d,J=12.3Hz,1H),1.83–1.73(m,5H),1.70(s,6H),1.54(d,J=9.1Hz,1H),1.41(s,2 H),1.36(d,J=13.0Hz,5H),1.30–1.22(m,2H),1.19(s,6H),1.07(d,J=5.7Hz,2H),1.02(s,3H),0.95(d,J =17.5Hz,2H),0.90(d,J=6.5Hz,3H),0.88–0.80(m,1H),0.63(s,3H),0.60–0.51(m,1H).LCMS:[M-OH-H2O] + =429.40; CAD:92.03%.

[0232] Example 31

[0233] Compound 31 Preparation of 25-hydroxy-3β-[(2-hydroxyethyl)oxy]-5α-cholest-4-one.

[0234] Step 1: Dissolve 3β-[(2-hydroxyethyl)oxy]-5α-cholest-4β,25-diol 29 (86 mg, 0.185 mmol, 1.0 eq.) in dichloromethane (5 mL). Add imidazole (62.99 mg, 0.925 mmol, 5.0 eq.) and tert-butyldimethylsilyl chloride (83.67 mg, 0.555 mmol, 3.0 eq.). Stir at room temperature for 2 h. Monitor by TLC (petroleum ether:ethyl acetate = 5:1). The reaction mixture is concentrated to obtain a crude product, which is then purified by column chromatography (ethyl acetate:petroleum ether = 20%) to afford 3β-[(4,4,5,5-tetramethyl-3-oxa-4-silanhex-1-yl)oxy]-5α-cholest-4β,25-diol 31-1 (65 mg, 0.107 mmol, 57.63%) as a white solid. 1 H NMR(400MHz,Chloroform-d)δ3.84(s,1H),3.72(dq,J=11.5,6.8,6.4Hz,2H),3.55(d ,J=10.4Hz,2H),3.22(d,J=11.1Hz,1H),1.93(d,J=12.3Hz,1H),1.74(dt,J=24.6,12 .8Hz,5H),1.36(s,5H),1.23(s,2H),1.19(s,6H),1.06(s,3H),1.01(s,3H),0.95(d, J=14.0Hz,2H),0.91–0.87(m,12H),0.63(s,3H),0.54(d,J=3.1Hz,1H),0.05(s,6H).

[0235] Step 8: Dissolve 3β-[(4,4,5,5-tetramethyl-3-oxa-4-silanol-1-yl)oxy]-5α-cholest-4β,25-diol 31-1 (60 mg, 0.104 mmol, 1.0 eq.) in dichloromethane (1 mL) and add Dess-Martin periodinane (43.95 mg, 0.104 mmol, 1.0 eq.). Stir at room temperature for 1 h. Monitor by TLC (petroleum ether:ethyl acetate = 5:1). The reaction mixture is concentrated to obtain a crude product, which is then purified by column chromatography (ethyl acetate:petroleum ether = 20%) to afford 25-hydroxy-3β-[(4,4,5,5-tetramethyl-3-oxa-4-silanol-1-yl)oxy]-5α-cholest-4-one 31-2 (50 mg, 0.082 mmol, 79.44%) as a white solid. 1H NMR(399MHz,Chloroform-d)δ4.01(dd,J=12.1,7.1Hz,1H),3.83–3.73(m,3H),3.44(dt,J=11.3,5.2Hz,1H),2 .25(s,1H),2.02(dd,J=38.0,12.2Hz,2H),1.83(dd,J=37.0,11.2Hz,3H),1.72(d,J=13.6Hz,3H),1.50(d,J=2 0.7Hz,4H),1.38(dd,J=18.2,9.9Hz,4H),1.25(d,J=10.6Hz,3H),1.20(s,6H),1.15–1.06(m,2H),1.06–0.95( m,3H),0.91–0.88(m,3H),0.87(s,9H),0.78(d,J=3.9Hz,1H),0.70(s,3H),0.63(s,3H),0.04(d,J=2.8Hz,6H).

[0236] Step 9: Dissolve 25-hydroxy-3β-[(4,4,5,5-tetramethyl-3-oxa-4-silanhex-1-yl)oxy]-5α-cholest-4-one 31-2 (40 mg, 0.069 mmol, 1.0 eq.) in tetrahydrofuran (2 mL) and add tetrabutylammonium fluoride (0.5 mL, 0.500 mmol, 7.2 eq.). Stir at room temperature for 1 h. Monitor by TLC (petroleum ether:ethyl acetate = 3:1). The reaction mixture is added with water and extracted three times with ethyl acetate. The organic phase is dried and concentrated to obtain the crude product. Purification by column chromatography (methanol / ethyl acetate = 5%) affords 25-hydroxy-3β-[(2-hydroxyethyl)oxy]-5α-cholest-4-one 31 (12 mg, 0.025 mmol, 35.54%) as a white solid.

[0237] Compound 31: 1H NMR(400MHz, Methanol-d4)δ4.08(dd,J=11.8,7.2Hz,1H),3.70–3.59(m,3H),3.52(dd,J=9.3,3.4Hz,1H),2. 35–2.22(m,2H),2.20–1.96(m,2H),1.95–1.77(m,2H),1.76–1.61(m,2H),1.55(dq,J=19.4,6.4Hz,4H),1.40 (d,J=9.3Hz,3H),1.34–1.30(m,3H),1.27(d,J=4.0Hz,3H),1.19(d,J=12.7Hz,1H),1.15(s,6H),1.08(d,J=1 3.2Hz,2H),1.03–0.96(m,2H),0.93(d,J=6.4Hz,3H),0.90–0.80(m,2H),0.69(d,J=11.8Hz,6H).LCMS:[M+H] + =463.40; CAD:80.15%.

[0238] Example 33

[0239] Preparation of Compound 33 [(1R, 3aS, 3bS, 5aS, 7S, 9aR, 9bS, 11aR)-7-hydroxy-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1, 2-a]phenanthrene-6-yl]acetonitrile

[0240] Step 1: 4-(Hydroxymethyl)-5α-cholest-3β,25-diol 13-1 (120 mg, 0.28 mmol) was dissolved in 1,2-dichloroethane (5 mL) in a 50 mL round-bottom flask at room temperature. Triethylamine (170 mg, 1.68 mmol), 4-dimethylaminopyridine (34 mg, 0.28 mmol) and p-toluenesulfonyl chloride (107 mg, 0.56 mmol) were added at room temperature, and then stirred at 50 ° C for 8 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 2:1). After completion of the reaction, the mixture was quenched with water (30 mL) and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to give 4-methylbenzenesulfonic acid-[(1R,3aS,3bS,5aS,7S,9aR,9bS,11aR)-7-hydroxy-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6-yl]methyl ester 33-1 as a white solid (60 mg, purity: 90%, yield: 36.36%). 1 HNMR (400MHz, CDCl3) δ = 7.80 (d, J = 8.2, 2H), 7.34 (d, J = 8.1, 2H), 4.33–4.22 (m, 1H), 4.19–4.11 (m, 1H), 3.79–3.71 (m, 1H), 2.45 (s, 3H), 2. 15(d,J=4.7,1H),2.04(s,1H),1.94(d,J=12.4,1H),1.84–1.24(m,22 H),1.21(s,6H),1.13–0.93(m,6H),0.90(d,J=6.4,3H),0.61(s,6H).

[0241] Step 2: In a 50 mL round-bottom flask at room temperature, 4-methylbenzenesulfonic acid-[(1R,3aS,3bS,5aS,7S,9aR,9bS,11aR)-7-hydroxy-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6-yl]methyl ester 33-1 (40 mg, 0.068 mmol) was dissolved in N,N-dimethylformamide (1 mL), and sodium cyanide (20 mg, 0.41 mmol) was added at room temperature. The mixture was then stirred at 100°C for 16 hours and monitored by TLC (petroleum ether:ethyl acetate = 3:1). After the reaction was completed, the reaction was quenched with water (20 mL), extracted with ethyl acetate (10 mL×3), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The organic phase was purified by silica gel column chromatography (petroleum ether:ethyl acetate=3:1) to obtain a white solid [(1R,3aS,3bS,5aS,7S,9aR,9bS,11aR)-7-hydroxy-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6-yl]acetonitrile 33 (15.71 mg, purity: 77.49%, yield: 40.39%).

[0242] Compound 33: 1 H NMR (400MHz, CDCl3) δ = 4.97 (s, 1H), 4.56 (s, 1H), 3.92 (dd, J = 11.4, 5.2, 1H), 1.95–1.88 (m, 2H), 1 .81–1.24(m,23H),1.14(s,6H),1.08–0.93(m,6H),0.85(d,J=6.5,3H),0.62(s,3H),0.58(s,3H). 13 C NMR (101MHz, CDCl3) δ = 153.33, 102.36, 73.37, 71.13, 56.28, 56.23, 54.49, 49.90, 44.42, 42.62, 40.08, 38.62, 37.27, 36. 43,35.76,35.26,33.05,31.61,29.36,29.21,28.28,24.27,24.21,21.72,20.78,18.64,12.94,12.07.LC-MS: [M+H-2H2O] + =408.3

[0243] Example 34

[0244] Compound 34 Preparation of 24,24-difluoro-5α-cholesta-3β,4β,25-triol.

[0245] In the first step, (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-2,2-difluorohexanoic acid ethyl ester 24-3 (300 mg, 0.606 mmol, 1 eq) was dissolved in chloroform (10 mL). Selenium dioxide (201.8 mg, 1.82 mmol, 3 eq) and N-methylmorpholine (153.2 mg, 1.52 mmol, 2.5 eq) were added to the solution and stirred at room temperature for 20 hours. After the reaction was completed, 30 mL of water was added and the mixture was extracted with ethyl acetate (30 mL*3). The obtained organic phase was dried over anhydrous sodium sulfate and then spin-dried to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give (5R)-5-[(1R, 3aS, 3bS, 6R, 7S, 9aR, 9bS, 11aR)-7-acetoxy-6-hydroxy-9a, 11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2,2-difluorohexanoic acid ethyl ester 34-1 (155 mg, 0.304 mmol, yield: 50%). 1 H NMR(400MHz, CDCl3)δ5.70(d,J=3.4Hz,1H),4.72(dt,J=12.1,4.0Hz,1H),4.36–4.30(m,2H),4.25(d,J =2.7Hz,1H),2.10(s,3H),2.04–1.92(m,3H),1.89–1.83(m,2H),1.72–1.64(m,2H),1.57(dd,J=10.2,4. 9Hz,4H),1.49–1.43(m,3H),1.36(d,J=7.1Hz,3H),1.27(dd,J=9.3,2.5Hz,2H),1.22(s,3H),1.17–1.09 (m,3H),1.07–0.99(m,2H),0.94(d,J=6.5Hz,3H),0.87(dd,J=19.1,8.6Hz,1H),0.70(d,J=12.6Hz,3H).

[0246] Step 2: (5R)-5-[(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-7-acetoxy-6-hydroxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2,2-difluorohexanoic acid ethyl ester 34-1 (155 mg, 0.304 mmol, 1 eq) was dissolved in ethyl acetate (15 mL), and then added Platinum dioxide (50%) (75 mg) was added and stirred at room temperature for 12 hours. After the reaction was completed, the mixture was filtered and the organic solvent was dried to obtain the product (5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-7-acetoxy-6-hydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2,2-difluorohexanoic acid ethyl ester 34-2 (70 mg, 0.137 mmol, yield: 46%) as an oily compound. 1 H NMR(400MHz,cdcl3)δ4.69–4.61(m,1H),4.25(q,J=7.1Hz,2H),3.76(s,1H),2.02(s,3H),1 .89–1.76(m,3H),1.72–1.66(m,3H),1.59(dd,J=12.6,3.7Hz,1H),1.46(dd,J=32.8,19.9H z,5H),1.28(s,3H),1.16(dd,J=22.6,9.6Hz,3H),1.08–1.01(m,3H),0.98(s,3H),0.96–0. 87(m,2H),0.85(d,J=6.6Hz,3H),0.81(d,J=4.7Hz,1H),0.58(s,3H),0.54(d,J=3.0Hz,1H).

[0247] In the third step, compound (5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-7-acetoxy-6-hydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2,2-difluorohexanoic acid ethyl ester 34-2 (70 mg, 0.137 mmol, 1 eq) was dissolved in tetrahydrofuran (5 mL). After nitrogen was replaced, methylmagnesium bromide (2.4 M, 0.6 mL, 10 eq) was slowly added dropwise. The mixture was stirred at room temperature for 3 hours and monitored by TLC (petroleum ether:ethyl acetate = 1:1). The reaction was complete. After completion, water was added to quench the reaction mixture, followed by extraction with ethyl acetate (50 mL). The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product, which was then separated and purified on silica gel (petroleum ether:ethyl acetate = 1:1) to obtain (1R,3aS,3bR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 34 (11 mg, 0.024 mmol, yield: 18%).

[0248] Compound 34: 1 H NMR (400MHz, CDCl3) δ3.67(s,1H),3.54–3.44(m,1H),1.94–1.85(m,2H),1.79–1.52(m,16H),1.43–1.30(m,5H),1.23(s,6H) ,1.07–0.98(m,4H),0.95(s,3H),0.91(d,J=6.1Hz,2H),0.85(d,J=6.6Hz,3H),0.81(s,1H),0.59(s,3H),0.56–0.49(m,1H). 13 C NMR (101MHz, CDCl3) δ74.84, 73.69,72.30,64.38,59.40,59.37,58.07,56.53,55.82,48.83,42.65,42.63,39.88,36.88, 35.50,35.40,35.38,34.55,28.09,25.86,24.18,23.60,20.59,18.78,18.48,14.67,12.09.

[0249] Examples 41 & 65

[0250] Compound 41 (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-9a, 11a-dimethyl-1-[(2R)-7,7,7-trifluoro-6-hydroxyhept-2-yl] hexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0251] Preparation of compound 65 (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-9a,11a-dimethyl-1-[(2R)-7,7,7-trifluoro-6-hydroxyhept-2-yl]-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol.

[0252] Step 1: (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]hexanal I and (5R)-5-[(3aS,5aR,5bR,7aR,8R,10aR,12bR)-11-fluoro-2,2,5a,7a-tetramethyl A mixture of 4,5,5a,5b,6,7,7a,8,9,10,10a,12,12a,12b-tetrahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxolan-8-yl]hexanal II (70 mg, 0.150 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 mL). After complete dissolution, cesium fluoride (11.39 mg, 0.075 mmol, 0.5 eq) and (trifluoromethyl)trimethylsilane (106.7 mg, 0.750 mmol, 5 eq) were added to the reaction system in sequence. After the addition was completed, the atmosphere was replaced with nitrogen three times and stirred at room temperature for 1 hour. After the reaction was complete, as monitored by TLC (petroleum ether:ethyl acetate = 5:1), tetrabutylammonium fluoride (1 mL, 1 mmol, 1 mol / L) was added. After the addition was complete, the atmosphere was replaced with nitrogen three times and stirred at room temperature for 1 hour. After the reaction was complete, as monitored by TLC (petroleum ether:ethyl acetate = 5:1), the mixture was quenched with water (10 mL). The reaction solution was washed three times with water (~10 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product.The crude product was separated and purified by flash chromatography (petroleum ether:ethyl acetate = 95:5 to 85:15) to give white solids (6R)-6-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1,1,1-trifluoroheptan-2-ol 41-1 and (6R)-1 ,1,1-trifluoro-6-[(3aS,5aR,5bR,7aR,8R,10aR,12aR,12bR)-11-fluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,12,12a,12b-tetradecahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxolan-8-yl]heptan-2-ol 65-1 mixture (50 mg, 0.089 mmol, purity 80.0%, yield 59.62% calculated based on 41-1).

[0253] Compound 41-1: 1 HNMR(400MHz, CDCl3)δ3.94(dt,J=8.3,6.2Hz,2H),2.11–1.95(m,1H),1.93–1.85(m,2H) ,1.83–1.71(m,4H),1.66–1.50(m,6H),1.49–1.43(m,5H),1.41–1.27(m,5H),1.23(d,J=3 .4Hz,3H),1.19(dd,J=9.0,5.3Hz,2H),1.05(dd,J=10.5,7.0Hz,2H),1.01(s,3H),0.98– 0.90(m,1H),0.87(t,J=5.8Hz,3H),0.82(dd,J=13.7,3.1Hz,1H),0.60(d,J=12.1Hz,3H).

[0254] Step 2: (6R)-6-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1,1,1-trifluoroheptan-2-ol 41-1 and (6R)-1,1,1-trifluoro-6-[(3aS,5a A mixture of (R,5bR,7aR,8R,10aR,12aR,12bR)-11-fluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,12,12a,12b-tetradecahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxolan-8-yl]heptan-2-ol 65-1 (50 mg, 0.093 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 mL). Hydrochloric acid (1 mL, 3 mol / L) was slowly added dropwise. The atmosphere was replaced with nitrogen three times and stirred at room temperature for 1 hr. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 1:1). The reaction solution was washed with saturated sodium bicarbonate solution (3 × 5 mL). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated and purified by flash chromatography (petroleum ether: ethyl acetate = 90: 10 to 80: 20). (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-9a, 11a-dimethyl-1-[(2R)-7,7,7-trifluoro-6-hydroxyhept-2-yl] hexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 41 and (1R, 3aR, 5aR, 6 A mixture of 65 R,7S,9aR,9bR,11aR)-4-fluoro-9a,11a-dimethyl-1-[(2R)-7,7,7-trifluoro-6-hydroxyhept-2-yl]-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol (40 mg, yield 69.16% based on 41) was directly used for the next step.

[0255] Step 3: Compounds (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(2R)-7,7,7-trifluoro-6-hydroxyhept-2-yl]hexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 41 and (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-9a,11a-dimethyl-1-[(2R)-7,7,7-trifluoro-6-hydroxyhept-2-yl]hexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 42 A mixture of a,6,7,8,9,9a,9b,10,11,11a-tetrahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol (23 mg, 0.046 mmol, 1.0 eq) was added to a reaction flask containing dichloromethane (2 mL), and triethylamine (0.045 mL, 0.324 mmol, 7.0 eq) and benzoyl chloride (0.027 mL, 0.232 mmol, 5.0 eq) were added, and the mixture was stirred at room temperature (20°C) for 18 hr; the reaction was monitored by TLC (dichloromethane:methanol = 20:1). The reaction solution was added with water (20 mL), extracted with ethyl acetate (20 mL * 2), and the organic phases were combined, washed with water (20 mL * 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under reduced pressure (water pump, 45 ° C) to obtain a crude product, which was separated and purified by prep-TLC (dichloromethane: methanol = 20:1) and SFC separation (instrument: Waters Acquity UPCC; chromatographic column: Daicel CHIRALPAK ID_3, 3.0*150mm, 3um; mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 75 / 25; flow rate: 2.0 ml / min; column temperature: 37 degrees) to obtain the product 41-2-benzoic acid-(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-6-hydroxy-9a,11a-dimethyl-1-[(2R)-7,7,7-trifluoro-6-hydroxyhept-2-yl]hexahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester (20 mg, 0.030 mmol, 64.70%, retention time t R =1.096min) as a white solid. Product 65-2: Benzoic acid-(1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-6-hydroxy-9a,11a-dimethyl-1-[(2R)-7,7,7-trifluoro-6-hydroxyhept-2-yl]-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester (10 mg, 0.010 mmol, 22.38%, retention time t R=1.280 min) as a white solid.

[0256] Compound 41-2: 1 H NMR (400MHz, CDCl3) δ8.08(d,J=7.6Hz,2H),7.62(t,J=7.4Hz,1H),7.48(t,J=7.7Hz,2H),5.61–5.48(m,1H) ,3.73(s,1H),3.59(d,J=10.7Hz,1H),2.28–2.13(m,1H),2.12–2.07(m,1H),1.94(m,1H),1.88(m,1H),1.83( m,2H),1.80(m,3H),1.75–1.69(m,2H),1.69–1.63(m,1H),1.56(m,1H),1.46(m,3H),1.40–1.34(m,3H),1.33 –1.29(m,2H),1.21(m,1H),1.13–1.06(m,2H),1.05(s,3H),0.98(m,2H),0.87(d,J=6.4Hz,3H),0.64(s,3H). 19 F NMR (377MHz, CDCl3) δ-76.92,-77.02,-88.65,-89.28,-110.63,-111.26.

[0257] Compound 65-2: 19 F NMR(377MHz, CDCl3)δ-76.91,-77.04,-109.74.

[0258] Step 4: Compound benzoic acid-(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-6-hydroxy-9a,11a-dimethyl-1-[(2R)-7,7,7-trifluoro-6-hydroxyhept-2-yl] hexahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 41-2 (20 mg, 0.033 mmol, 1.0 eq) was added to a reaction bottle containing methanol (0.5 mL) and tetrahydrofuran (1 mL), and a solution of lithium hydroxide (13.97 mg, 0.333 mmol) in water (0.5 mL) was added, and the temperature was raised to 40 ° C. and stirred for 2 hours; TLC (petroleum ether: ethyl acetate = 1:1) monitoring of the reaction showed that the starting material disappeared and there was a polarity change. A large main point was generated; water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with water (20 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under reduced pressure (water pump, 45°C) to give a crude product, which was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:0-2:1) to give the product (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(2R)-7,7,7-trifluoro-6-hydroxyhept-2-yl]hexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 41 (16.40 mg, 0.033 mmol, 99.21%) as a white solid.

[0259] Compound 41: 1 H NMR (400MHz, CDCl3) δ3.91 (m, 1H), 3.74 (s, 1H), 3.60 (dt, J = 11.3, 4.1Hz, 1H), 2.21 (m,1H),1.98(m,2H),1.86(m,3H),1.81–1.75(m,2H),1.74–1.71(m,1H),1.70–1.62 (m,3H),1.57(m,2H),1.46(m,3H),1.41–1.37(m,2H),1.35–1.28(m,2H),1.25(m,1H ),1.11(m,2H),1.06(s,3H),1.04–0.95(m,2H),0.93(d,J=6.5Hz,3H),0.67(s,3H). 19 F NMR(377MHz, CDCl3)δ-80.03,-88.64,-89.27,-110.64,-111.26. 19 F NMR (377MHz, CDCl3) δ-76.92,-77.02,-88.65,-89.28,-110.63,-111.26.

[0260] Compound benzoic acid-(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4-fluoro-6-hydroxy-9a,11a-dimethyl-1-[(2R)-7,7,7-trifluoro-6-hydroxyhept-2-yl]hexahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 65-2 (10 mg, 0.017 mmol, 1.0 eq) was added to a reaction flask containing methanol (0.5 mL) and tetrahydrofuran (1 mL), and a solution of lithium hydroxide (7.20 mg, 0.172 mmol) in water (0.5 mL) was added, and the temperature was raised to 40°C and stirred for 2 hours; the reaction was monitored by TLC (petroleum ether:ethyl acetate = 1:1); water (20 mL) was added to the reaction solution, and ethyl acetate (2 The organic phases were combined, washed with water (20 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure (water pump, 45°C) to give a crude product, which was separated and purified by column chromatography (petroleum ether:ethyl acetate=1:0-2:1) to give the product (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-9a,11a-dimethyl-1-[(2R)-7,7,7-trifluoro-6-hydroxyhept-2-yl]-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 65 (1.89 mg, 0.004 mmol, 21.44%) as a white solid.

[0261] Compound 65: 1 H NMR (400MHz, CDCl3) δ3.91 (s, 1H), 3.85 (s, 1H), 3.59 (d, J = 11.0Hz, 1H), 2.66 ( t,J=12.5Hz,1H),2.07–1.98(m,2H),1.94(d,J=16.5Hz,2H),1.88–1.82(m,3H ),1.80–1.71(m,3H),1.68(m,1H),1.63–1.59(m,3H),1.55(m,2H),1.48(m,2H ),1.45(m,3H),1.13(m,4H),1.05(s,3H),0.94(d,J=6.5Hz,3H),0.65(s,3H). 19 F NMR(376MHz, CDCl3)δ-80.03,-109.71. 19 F NMR(377MHz, CDCl3)δ-76.91,-77.04,-109.74.

[0262] Example 53

[0263] Preparation of Compound 53 4-(1-hydroxyethyl)-5α-cholest-3β,25-diol

[0264] Step 1: In a 50 mL round-bottom flask at room temperature, 3β-{[dimethyl(2-methylprop-2-yl)silyl]oxy}-25-hydroxy-5α-cholest-4-carbaldehyde 23-3 (23 mg, 0.042 mmol) was dissolved in anhydrous tetrahydrofuran (1.5 mL). The reaction mixture was cooled to 0°C under nitrogen protection, and a 3 mol / L methylmagnesium bromide solution in tetrahydrofuran (0.07 mL, 0.021 mmol) was added dropwise. The mixture was then stirred at room temperature for 2 hours. TLC (petroleum ether:ethyl acetate = 4:1) was performed. Monitor the reaction. After the reaction is completed, the system is cooled to 0°C and quenched with saturated aqueous ammonium chloride solution (20 mL). The mixture is extracted with ethyl acetate (10 mL × 3). The organic phase is washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain 3β-{[dimethyl(2-methylprop-2-yl)silyl]oxy}-4-(1-hydroxyethyl)-5α-cholest-25-ol 53-1 as a white solid (17 mg, purity: 90%, yield: 64.64%). 1 HNMR(400MHz, CDCl3)δ=4.20-4.11(m,1H),3.85–3.70(m,1H),2.04–1.65(m,7H),1.60–1.46(m,6H) ,1.39–1.29(m,5H),1.21(s,6H),0.94(s,3H),0.91(dd,J=6.9,4.1,12H),0.64(s,3H),0.06(s,6H).

[0265] Step 2: In a 50 mL round-bottom flask, 3β-{[dimethyl(2-methylprop-2-yl)silyl]oxy}-4-(1-hydroxyethyl)-5α-cholest-25-ol 53-1 (17 mg, 0.03 mmol) was dissolved in a 1 M tetrabutylammonium fluoride solution in tetrahydrofuran (0.5 mL) at room temperature and stirred for 2 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 1:1). After completion of the reaction, the system was cooled to 0°C and quenched with saturated aqueous ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (5 mL x 3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 4-(1-hydroxyethyl)-5α-cholest-3β,25-diol 53 as a white solid (5.09 mg, purity: 95.12%, yield: 35.73%).

[0266] Compound 53: 1H NMR(400MHz, CDCl3)δ=4.19–4.08(m,1H),3.83–3.71(m,1H),1.96–1.65(m,7H),1.56–1.47(m,5H), 1.42–1.17(m,18H),1.14(s,6H),1.07–0.92(m,5H),0.88(s,3H),0.84(d,J=6.5,3H),0.57(s,3H). 13 C NMR(101MHz, CDCl3)δ=104.61,103.05,101.06,71.13,69.23,56.48,56.37 ,56.18,44.43,42.48,39.95,38.55,36.44,35.88,35.75,35.73,33.64,33. 59,31.45,30.97,30.36,29.37,29.21,29.04,28.26,26.29,25.61,24.80, 24.27,21.07,20.99,20.92,20.78,18.64,14.96,12.01.LC-MS: [M+H-2H2O] + =413.55

[0267] Example 55

[0268] Preparation of Compound 55 4-Bromo-5α-cholest-3β,25-diol

[0269] In a 100 mL round-bottom flask, (5R)-methyl 5-[(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-7-acetoxy-6-hydroxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoate I-8 (500 mg, 1.09 mmol) was dissolved in ethyl acetate (30 mL). 10% palladium on carbon (250 mg) and acetic acid (0.3 mL) were added at room temperature. The mixture was stirred under a hydrogen atmosphere at room temperature for 5 hours. The reaction was monitored by TLC (ethyl acetate / petroleum ether = 8:1). After the reaction, the reaction solution was diluted with ethyl acetate (60 mL), filtered through celite, and the organic phase was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=8:1) to give (5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-7-acetoxy-6-hydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester 55-1 (390 mg, purity: 90%, yield: 62.72%) as a white solid. 1 H NMR (400MHz, CDCl3) δ4.75–4.69(m,1H),3.83(s,1H),3.66(s,3H),2.35–2.20(m,2H ),2.08(s,3H),2.03–1.05(m,27H),1.05(s,3H),0.92(d,J=6.5Hz,3H),0.64(s,3H).

[0270] Step 2: In a 50 mL round-bottom flask at room temperature, (5R)-5-[(1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-7-acetoxy-6-hydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoic acid methyl ester 55-1 (250 mg, 0.54 mmol) was dissolved in 1,2-dichloroethane (10 mL). A solution of triphenylphosphine (142 mg, 0.54 mmol) in 1,2-dichloroethane (0.6 mL) was added at 0°C, and the reaction solution was stirred at room temperature for 10 minutes. A solution of carbon tetrabromide (180 mg, 0.54 mmol) in 1,2-dichloroethane (0.9 mL) was added to the reaction solution at 0°C, and the reaction solution was then warmed to room temperature and stirred at 50°C for 16 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1). After completion of the reaction, the mixture was quenched with water (30 mL) and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated. The organic phase was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain (5R)-5-[(1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-7-acetoxy-6-bromo-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester 55-2 (150 mg, purity: 90%, yield: 47.57%) as a white solid. 1 H NMR (400MHz, CDCl3) δ = 4.97 (s, 1H), 4.32 (s, 1H), 3.67 (s, 3H), 2.34–2.18 (m, 3H), 2.05 (s, 3H), 1.97 (dd ,J=8.0,4.4,2H),1.89–1.36(m,19H),1.18–1.03(m,5H),0.98(s,3H),0.92(d,J=6.5,3H),0.64(s,3H).

[0271] Step 3: Dissolve the reactant (5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-7-acetoxy-6-bromo-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester 55-2 (150 mg, 0.337 mmol, 1 eq) in tetrahydrofuran (10 mL), and replace the reaction system with a nitrogen atmosphere. After cooling the reaction system to 0°C, methylmagnesium chloride (1.124 mL, 3.373 mmol, 1 mol / L) was slowly added and stirred at room temperature for 1 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1). 20 mL of water was added to the reaction system, and the mixture was extracted with ethyl acetate (25 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, and then evaporated to dryness in vacuo to obtain the crude product. The crude product was dissolved in ethyl acetate and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 88:12) to give 4-bromo-5α-cholesta-3β,25-diol 55 (16 mg, purity: 90.51%, yield: 10.66%).

[0272] Compound 55: 1 H NMR(400MHz,cdcl3)δ4.37(d,J=2.6Hz,1H),3.87(s,1H),2.41–2.30(m,1H),2 .00–1.94(m,1H),1.87–1.73(m,4H),1.64(dd,J=12.9,4.0Hz,1H),1.54(dd,J =9.0,3.4Hz,6H),1.49–1.34(m,9H),1.22(s,6H),1.17–1.04(m,4H),1.02(s, 3H),0.99–0.95(m,1H),0.92(d,J=6.5Hz,3H),0.87–0.72(m,2H),0.65(s,3H).

[0273] Example 56

[0274] Compound 56 Preparation of 4β-[(ethoxymethyl)oxy]-3-methyl-5α-cholesta-3,25-diol.

[0275] Step 1: Dissolve (1R,7S,9aR,11aR)-6-hydroxy-1-[(2R)-6-methoxy-6-oxyidenehexan-2-yl]-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate 55-1 (100 mg, 0.216 mmol) in N,N-diisopropylethylamine (5 mL), add [(chloromethyl)oxy]ethane (204.21 mg, 2.16 mmol), react at 130 ° C for 1.5 h, monitor by TLC (petroleum ether: ethyl acetate = 5:1) and NMR. The raw material was washed with ethyl acetate and water, dried over anhydrous sodium sulfate, and concentrated. The product was purified by column chromatography (petroleum ether:ethyl acetate = 100:1 to 20:1) to give (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6-[(ethoxymethyl)oxy]-1-[(2R)-6-methoxy-6-oxyidenehexan-2-yl]-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate 56-1 (60 mg, 0.106 mmol, 49.04%) as a white solid. 1 HNMR(399MHz,Chloroform-d)δ4.71–4.60(m,3H),3.70(d,J=8.7Hz,1H),3.65( s,3H),2.23(tq,J=16.8,9.6,9.1Hz,2H),2.03(s,3H),1.91(t,J=12.5Hz,2H),1 .53(s,3H),1.39–1.30(m,4H),1.26(d,J=14.6Hz,2H),1.17(d,J=7.3Hz,3H),1 .13(s,1H),1.10–1.01(m,4H),0.99(s,4H),0.90(d,J=6.6Hz,3H),0.62(s,3H).

[0276] Step 2: Dissolve (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6-[(ethoxymethyl)oxy]-1-[(2R)-6-methoxy-6-oxyylidenehexan-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate 56-1 (60 mg, 0.115 mmol) in methanol (5 mL), add potassium carbonate (158.70 mg, 1.150 mmol) at room temperature, stir at room temperature for 5 h, and analyze the product by TLC (petroleum ether: acetic acid). After the reaction, water and ethyl acetate were added for extraction. The organic phase was separated and the crude product was dried. It was then purified by column chromatography (petroleum ether:ethyl acetate = 60:1 to 3:1) to obtain (5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6-[(ethoxymethyl)oxy]-7-hydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester 56-2 (40 mg, 0.079 mmol, 58.89%) as a white solid. 1 H NMR(399MHz,Chloroform-d)δ4.80(d,J=6.7Hz,1H),4.53(d,J=6.7Hz,1H),3.76(dq,J=9.5,7.1Hz,1H),3.65( s,3H),3.60–3.49(m,2H),3.39(s,1H),2.31–2.19(m,2H),1.96–1.90(m,1H),1.68(s,2H),1.57–1.44(m,2H), 1.42–1.32(m,3H),1.31–1.25(m,2H),1.22(t,J=7.1Hz,5H),1.14(d,J=9.5Hz,1H),1 .11–1.02(m,4H),1.01–0.95(m,1H),0.93(s,3H),0.90(d,J=6.6Hz,3H),0.62(s,3H).

[0277] Step 3: Methyl (5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6-[(ethoxymethyl)oxy]-7-hydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoate 56-2 (20 mg, 0.042 mmol) was dissolved in dichloromethane (5 mL), and N-methylmorpholine oxide (7.34 mg, 0.063 mmol) and tetrapropylammonium perruthenate (1.47 mg, 0.004 mmol) were added at room temperature. The mixture was stirred for 1 h and monitored by TLC (petroleum ether:ethyl acetate = 5:1). After the reaction, the mixture was filtered through celite, the filtrate was concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 60:1 to 3:1) to give (5R)-5-[(1R,3aS,3bS,5aR,6R,9aR,9bS,11aR)-6-[(ethoxymethyl)oxy]-9a,11a-dimethyl-7-oxoylidenehexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester 56-3 (15 mg, 0.029 mmol, 69.08%) as a white solid. 1 H NMR(399MHz,Chloroform-d)δ4.65–4.52(m,2H),3.65(s,3H),3.60–3.48(m,3H),2.29–2.13(m,3H),1.37(d,J=19.8Hz,7H),1 .24(s,2H),1.18(d,J=4.7Hz,3H),1.15(d,J=7.3Hz,3H),1.11–1.03(m,3H),0.96(s,1H),0.90(d,J=6.6Hz,3H),0.65(s,4H).

[0278] Step 4: (5R)-5-[(1R,3aS,3bS,5aR,6R,9aR,9bS,11aR)-6-[(ethoxymethyl)oxy]-9a,11a-dimethyl-7-oxoylidene hexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester 56-3 (20 mg, 0.042 mmol) was dissolved in tetrahydrofuran (3 mL), and methyl lithium (9.22 mL) was added dropwise under nitrogen protection at zero temperature. g, 0.42 mmol), and stirred at room temperature for 2 h, monitored by TLC (petroleum ether: ethyl acetate = 2:1); after the reaction, water and ethyl acetate were added for extraction, the organic phase was separated and the crude product was dried, and purified by column chromatography (petroleum ether: ethyl acetate = 50:1 to 1:1) to obtain 4β-[(ethoxymethyl)oxy]-3-methyl-5α-cholesta-3,25-diol 56 (10 mg, 0.019 mmol, 45.90%) as a white solid.

[0279] Compound 56: 1HNMR(400MHz,Chloroform-d)δ4.78(d,J=6.6Hz,1H),4.60(d,J=6.6Hz,1H),3.73–3.57(m,2H),3. 15(s,1H),1.94(d,J=12.6Hz,1H),1.74(t,J=14.7Hz,3H),1.65(m,2H),1.53-1.61(m,5H),1.43(d ,J=15.2Hz,3H),1.36(d,J=10.6Hz,3H),1.29(d,J=22.8Hz,3H),1.23(s,3H),1.22–1.16(m,12H), 1.12–1.05(m,2H),1.01(dd,J=19.5,8.8Hz,3H),0.94(s,3H),0.89(d,J=6.5Hz,3H),0.62(s,3H). 13 CNMR(101MHz,Chloroform-d)δ98.16,90.81,71.10,70.96,64.32,56.48,56.12,47.42,44.37,42.57,39.86,36.1 3,35.73,35.47,32.89,32.31,29.18,28.23,26.75,24.55,24.18,20.75,18.60,15.09,12.02.ELSD-MS:[Ms+NH4] + =491.42; [Ms-H2O-OH] + =493.42.HPLC:94.97% (CAD).

[0280] Example 59

[0281] Compound 59 Preparation of 3-methyl-5α-cholesta-4β,3,25-triol.

[0282] 4β-[(Ethoxymethyl)oxy]-3-methyl-5α-cholesta-3,25-diol 56 (50 mg, 0.101 mmol) was dissolved in tetrahydrofuran (3 mL), and p-toluenesulfonic acid (174.08 mg, 1.014 mmol) was added at room temperature. The mixture was heated at 40°C with stirring for 1 h and monitored by TLC (petroleum ether:ethyl acetate = 1:1). After the reaction, water and ethyl acetate were added for extraction. The organic phase was separated, and the crude product was dried over anhydrous sodium sulfate and purified by column chromatography (petroleum ether:ethyl acetate = 50:1 to 1:1) to obtain 3-methyl-5α-cholesta-4β,3,25-triol 59 (20 mg, 0.044 mmol, 45.35%) as a white solid.

[0283] Compound 59:1 H NMR(399MHz,Chloroform-d)δ3.32(s,1H),2.18(s,1H),1.94(d,J=12.8Hz,1H),1.63(s,1H),1.76(s,3H),1.53(s,4H),1.42(d,J=13.9Hz,3 H),1.39–1.32(m,5H),1.31(s,3H),1.23(s,3H),1.19(s,6H),1.04(dd,J=11.3,6.8Hz,4H),1.00(s,3H),0.89(d,J=6.5Hz,3H),0.62(s,3H). 13 C NMR(100MHz,Chloroform-d)δ72.14,71.09,56.54,56.13,55.50,46.96,44.38,42.58,39.86,36.39,36.23,35.78,35.7 2,35.45,32.41,31.57,29.34,29.17,28.23,26.06,24.80,24.18,20.74,20.54,18.61,14.64,12.05.ELSD-MS:[Ms+NH4] + =433.38; [Ms-H2O-OH] + =435.38.HPLC:93.78%(CAD).

[0284] Example 60

[0285] Compound 60 Preparation of 24-fluoro-5α-cholesta-3β,4β,25-triol.

[0286] Step 1: Weigh out (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6-hydroxy-1-[(2R)-6-methoxy-6-oxyidenehexan-2-yl]-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate IV-1 (300 mg, 0.65 mol, 1.0 eq.) and dissolve it in anhydrous methanol (5 mL). Potassium carbonate (897 mg, 6.5 mmol) was added, and the temperature was raised to 25 ° C. and stirred for 16 hours. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 2:1) after completion of the reaction. The reaction solution was filtered and concentrated, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 0-50%) to give (5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6,7-dihydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester IV-2 (210 mg, 0.5 mmol, 76.9%) as a white solid. 1H NMR(399MHz,Chloroform-d)δ3.71(d,J=3.1Hz,1H),3.65(s,3H),3.53(dt,J=11.3,4.4Hz,1H),2.33–2.18(m,2H),1.97–1.84(m,2H),1.83–1.60 (m,8H),1.42–1.28(m,5H),1.28–1.15(m,3H),1.11–1.01(m,4H),1.00( s,3H),0.90(d,J=6.5Hz,4H),0.62(s,3H),0.57(td,J=11.4,4.2Hz,1H).

[0287] Step 2: Weigh (5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6,7-dihydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoic acid methyl ester IV-2 (250 mg, 0.59 mmol) and dissolve it in acetone (20 mL). Add 4A molecular sieves (250 mg) and p-toluenesulfonic acid (203 mg, 1.18 mmol) and stir at room temperature. Monitor by TLC (petroleum ether: ethyl acetate = 2:1). After the reaction, the insoluble matter was removed by filtration. The filtrate was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 0-30%) to give (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]hexanoic acid methyl ester IV-3 (220 mg, 0.48 mmol, 81.3%) as a white solid. 1 H NMR(399MHz,Chloroform-d)δ3.97(dt,J=8.8,5.7Hz,2H),3.65(s,3H),2.25(ddd,J=10.5,8.5,6.7Hz,2 H),1.97–1.90(m,1H),1.76(td,J=11.5,6.6Hz,3H),1.71–1.63(m,3H),1.58–1.52(m,1H),1.49(s,4H), 1.47–1.32(m,6H),1.28(s,3H),1.23(ddd,J=14.1,8.9,5.6Hz,3H),1.08(td,J=10.7,9.2,3.7Hz,3H),1 .02(s,3H),0.98–0.93(m,1H),0.90(d,J=6.4Hz,3H),0.86–0.80(m,2H),0.64(s,3H),0.61–0.54(m,1H).

[0288] Step 3: In a three-necked flask, (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]hexanoate IV-3 (370 mg, 0.803 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (7 mL), and trimethylsilyl chloride (0.440 mL, 2.409 mmol, 3.0 eq.) was added. Replace the flask with a nitrogen atmosphere, cool to -78°C, and add lithium diisopropylamide (172.08 mg, 1.606 mmol, 2.0 eq.). The reaction mixture is then warmed to 0°C and stirred for 15 minutes. A solution of N-fluorobisbenzenesulfonamide (506.50 mg, 1.606 mmol, 2.0 eq.) in tetrahydrofuran (1 mL) is added. The reaction mixture is warmed to room temperature and stirred for 1 hour. Monitor by TLC (petroleum ether:ethyl acetate = 10:1). Once the starting materials have reacted completely, quench the reaction mixture with water. The resulting mixture was extracted three times with ethyl acetate, and the combined organic phases were washed once with brine, dried over anhydrous sodium sulfate, and concentrated to give a crude product, which was purified by column chromatography (ethyl acetate / petroleum ether = 0–20%) to give (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-2-fluorohexanoic acid methyl ester as a white solid 60-1 (200 mg, 0.397 mmol, 49.42%). 1H NMR(399MHz,Chloroform-d)δ4.14(ddd,J=48.5,18.2,10.2Hz,1H),3.71(d,J=3.0Hz,1H),3.53(dt,J=11.4,4.3Hz,1H) ,1.94(dt,J=12.5,3.5Hz,1H),1.82(dd,J=9.0,5.3Hz,2H),1.76–1.71(m,3H),1.70–1.62(m,3H),1.59–1.46(m,2H),1.3 7(ddd,J=19.3,12.0,4.8Hz,4H),1.30–1.21(m,3H),1.19(d,J=5.0Hz,6H),1.13–1.02(m,4H),0.99(s,3H),0.94(dd,J=8 .7,4.3Hz,2H),0.90(dd,J=6.5,2.0Hz,3H),0.87–0.79(m,1H),0.63(s,3H),0.57(td,J=11.4,4.2Hz,1H).LC-MS:[M-HF] + =458.45;

[0289] Step 4: Methyl (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-2-fluorohexanoate 60-1 (100 mg, 0.209 mmol, 1 eq.) was dissolved in tetrahydrofuran (5 mL). The mixture was cooled to 0°C under a nitrogen atmosphere, and methyllithium (0.653 mL, 1.045 mmol, 5.0 eq.) was added. The mixture was warmed to room temperature and stirred for 1 hour. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 10:1). After completion of the reaction, a small amount of water was added to quench the reaction, and the mixture was concentrated to obtain the crude product, which was then purified by column chromatography (ethyl acetate / petroleum ether = 0–30%) to afford (6R)-6-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-3-fluoro-2-methylheptan-2-ol as a white solid 60-2 (75 mg, 0.149 mmol, 71.24%). 1H NMR(399MHz,Chloroform-d)δ4.14(ddd,J=48.4,18.5,10.3Hz,1H),4.01–3.92(m,2H),1.94(d,J =12.2Hz,1H),1.79(s,2H),1.64(dd,J=15.6,12.1Hz,4H),1.54(s,5H),1.49(s,3H),1.44(d,J=14 .1Hz,6H),1.28(s,3H),1.24(d,J=11.6Hz,3H),1.19(d,J=4.9Hz,6H),1.07(d,J=11.1Hz,4H),1.0 2(s,3H),0.97(s,1H),0.92–0.88(m,3H),0.87–0.79(m,2H),0.65(s,3H),0.58(t,J=10.2Hz,1H).

[0290] Step 5: (6R)-6-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-3-fluoro-2-methylheptan-2-ol 60-2 (75 mg, 0.157 mmol) was dissolved in tetrahydrofuran (5 mL), and hydrochloric acid (2 mL, 4.000 mmol, 25.5 eq.) was added. The mixture was stirred at room temperature for 1 hour and monitored by TLC (petroleum ether:ethyl acetate = 5:1). The reaction mixture was diluted with water and extracted three times with ethyl acetate. The organic phases were combined, washed once with brine, and dried over anhydrous sodium sulfate. The crude product was concentrated and purified by column chromatography (ethyl acetate / petroleum ether = 0-60%) to give 24-fluoro-5α-cholesta-3β,4β,25-triol 60 as a white solid (40 mg, 0.087 mmol, 55.29%).

[0291] Compound 60: 1H NMR(399MHz,Chloroform-d)δ4.14(ddd,J=48.5,18.2,10.2Hz,1H),3.71(d,J=3.0Hz,1H),3.53(dt,J=11.4,4.3Hz,1H),1. 94(dt,J=12.5,3.5Hz,1H),1.82(dd,J=9.0,5.3Hz,2H),1.76–1.71(m,3H),1.70–1.62(m,3H),1.59–1.46(m,2H),1.37(ddd ,J=19.3,12.0,4.8Hz,4H),1.30–1.21(m,3H),1.19(d,J=5.0Hz,6H),1.13–1.02(m,4H),0.99(s,3H),0.94(dd,J=8.7,4.3H z, 2H), 0.90 (dd, J=6.5, 2.0Hz, 3H), 0.87–0.79 (m, 1H), 0.63 (s, 3H), 0.57 (td, J=11.4, 4.2Hz, 1H). LC-MS: [M+Na]+ = 461.45.

[0292] Example 61

[0293] Preparation of compound 61,3,25-dihydroxy-3-methyl-5α-cholest-4-one.

[0294] 3-Methyl-5α-cholesta-4β,3,25-triol 59 (20 mg, 0.046 mmol) was dissolved in dichloromethane (3 mL), and N-methylmorpholine oxide (8.08 mg, 0.069 mmol) and tetrapropylammonium perruthenate (1.61 mg, 0.005 mmol) were added at room temperature. The mixture was stirred at room temperature for 1 h and monitored by TLC (petroleum ether:ethyl acetate = 2:1). After the reaction, the mixture was filtered through celite, and the filtrate was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 50:1 to 1:1) to obtain 3,25-dihydroxy-3-methyl-5α-cholesta-4-one 61 (10 mg, 0.020 mmol, 85.85%) as a white solid.

[0295] Compound 61: 1HNMR(399MHz,Chloroform-d)δ2.33–2.37(m,1H),2.07–1.96(m,2H),1.85–1.71(m,4H), 1.46–1.40(m,4H),1.38(s,3H),1.37–1.31(m,3H),1.24(d,J=12.6Hz,5H),1.19(s,6H), 1.17–1.10(m,2H),1.10–1.04(m,2H),1.01(d,J=8.9Hz,2H),0.97–0.93(m,1H),0.90(d, J=6.5Hz,3H),0.80(dt,J=13.1,8.9Hz,1H),0.69(s,3H),0.63(s,3H).ELSD-MS:[M+NH4] + =433.38; [M-H2O-OH] + =435.38.

[0296] Example 66

[0297] Compound 66: Preparation of (1R,3aR,7S,9aS,9bR,11aR)-4-fluoro-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol.

[0298] Step 1: Dissolve (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoic acid methyl ester I-7 (1 g, 2.25 mmol, 1 eq) in tetrahydrofuran (10 mL), add cobalt acetate (80 mg, 0.45 mmol, 0.2 eq), N-hydroxyphthalimide (0.15 g, 0.90 mmol, 0.4 eq), tert-butyl peroxide (1.01 g, 11.25 mmol, 5 eq) to the solution and stir at room temperature for 20 hours. After the reaction was complete, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL*3). The resulting organic phase was dried over anhydrous sodium sulfate and then spin-dried to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-4-oxyylidene-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester 66-1 (0.6 g, 1.31 mmol, yield: 58%). 1 H NMR (400MHz, CDCl3) δ5.70 (d, J=1.5Hz, 1H), 4.80–4.64 (m, 1H), 3.67 (s, 3H), 2.48 (dddd, J=15.6, 12.1,9.1,2.4Hz,3H),2.25(ddd,J=22.3,12.9,5.3Hz,3H),2.05(s,3H),2.01–1.95(m,2H),1.93 –1.84(m,1H),1.79–1.65(m,2H),1.65–1.46(m,5H),1.40(ddd,J=11.6,8.9,4.3Hz,2H),1.28(dd d,J=10.9,10.5,5.9Hz,3H),1.21(s,3H),1.18–1.05(m,3H),0.94(d,J=6.5Hz,3H),0.68(s,3H).

[0299] Step 2: Compound (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-4-oxy-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester 66-1 (0.6 g, 1.31 mmol, 1 eq) was dissolved in ethyl acetate (15 mL), and then Palladium on carbon (10%) (120 mg) was added thereto, and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, the mixture was filtered, and the organic solvent was then dried to give the product (5R)-5-[(1R, 3aS, 3bR, 7S, 9aS, 9bS, 11aR)-7-acetoxy-9a, 11a-dimethyl-4-oxyylidenehexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester 66-2 (450 mg, 0.977 mmol, yield: 75%) as an oily compound. 1 H NMR(400MHz,cdcl3)δ5.36–5.24(m,1H),4.30(s,3H),3.00–2.81(m,5H),2.70–2.58(m, 5H),2.55–2.47(m,2H),2.42(dt,J=13.4,3.5Hz,1H),2.35–2.26(m,2H),2.22–2.10(m,6 H),2.09–1.99(m,3H),1.86(d,J=12.4Hz,1H),1.76(s,1H),1.73(s,1H),1.73(s,3H),1. 70(s,1H),1.69(d,J=3.3Hz,1H),1.67–1.60(m,1H),1.56(d,J=6.5Hz,3H),1.28(s,3H).

[0300] Step 3: Compound (5R)-5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-4-oxyylidene hexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester 66-2 (150 mg, 0.326 mmol, 1.0 eq) and DAST (157 mg, 0.977 mmol, 3 eq) were dissolved in tetrahydrofuran (5 mL) and stirred at 80 ° C for 3 hours. After TLC detection, water was added to quench the reaction, and then extracted with ethyl acetate (50 mL). The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried to obtain a crude product, which was then separated and purified by silica gel (petroleum The reaction mixture was stirred at 4 ℃ for 1 hr (10 min) for 1 hr. The mixture was stirred at 4 ℃ for 2 hr. The mixture was stirred at 4 ℃ for 3 hr. The mixture was stirred at 4 ℃ for 1 hr. The mixture was stirred at 5 ℃ for 3 hr. The mixture was stirred at 5 ℃ for 1 hr. The mixture was stirred at 5 ℃ for 2 hr. The mixture was stirred at 5 ℃ for 3 hr. The mixture was stirred at 5 ℃ for 3 hr. The mixture was stirred at 5 ℃ for 4 hr. The mixture was stirred at 5 ℃ for 3 hr. The mixture was stirred at 5 ℃ for 5 hr. The mixture was stirred at 5 ℃ for 3 hr. The mixture was stirred at 5 ℃ for 3 hr. The mixture was stirred at 5 ℃ for 4 hr.

[0301] Compound 66-3': 1 H NMR (400MHz, CDCl3) δ4.75–4.63(m,1H),3.66(s,3H),2.34–2.22(m,2H),2.10–1.91(m,5H),1.84(ddd,J=9.3,7.6,3.7Hz,3H),1.78–1.65(m,5H) ),1.57–1.49(m,3H),1.45–1.22(m,7H),1.09(ddd,J=28.8,14.4,9.4Hz,5H),0.94(t,J=5.4Hz,3H),0.85(d,J=11.0Hz,3H),0.71–0.62(m,3H).

[0302] Step 4: (R)-5-((3S, 5R, 9R, 10S, 13R, 14R, 17R)-3-acetoxy-7-fluoro-10,13-dimethyl-2,3,4,5,6,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)hexanoic acid methyl ester 66-3 and (R)-5-((3S, 5R, 8R, 9S, 10S, 13R, 14S, 17R)-3-acetoxy-7-fluoro-10,13-dimethyl-2,3,4,5,6,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)hexanoate 66-3 A mixture of methyl 7,7-difluoro-10,13-dimethylhexahydro-1H-cyclopentyl[a]phenanthrene-17-yl) hexanoate 66-3' (70 mg, 0.145 mmol, 1 eq) was dissolved in tetrahydrofuran (5 mL). After nitrogen was replaced, methylmagnesium bromide (2.4 M) (0.6 mL, 10 eq) was slowly added dropwise. The mixture was stirred at room temperature for 3 hours and monitored by TLC. After the reaction was completed, water was added to quench the reaction, and then the mixture was extracted with ethyl acetate (50 mL). The organic phase was taken, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried to give a crude product, which was then separated and purified on silica gel (petroleum ether: ethyl acetate = 1:1) to give (3S, 5R, 9R, 10S, 13R, 14R, 17R)-7-fluoro-17-((R)-6-hydroxy-6-methylheptane-2-yl)-10,13-dimethyl-2,3,4,5,6,9,10,11,12,13,14,15,16 A mixture of 17-tetrahydro-1H-cyclopenta[a]phenanthrene-3-ol 66-4 and (3S, 5R, 8R, 9S, 10S, 13R, 14S, 17R)-7,7-difluoro-17-((R)-6-hydroxy-6-methylheptane-2-yl)-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-3-ol 66-4' (22 mg, 0.05 mmol, yield calculated based on 66-4': 34%) was directly used for the next step.

[0303] Step 5: A mixture of (3S, 5R, 9R, 10S, 13R, 14R, 17R)-7-fluoro-17-((R)-6-hydroxy-6-methylheptane-2-yl)-10,13-dimethyl-2,3,4,5,6,9,10,11,12,13,14,15,16,17-tetrahydro-1H-cyclopentadien[a]phenanthrene-3-ol 66-4 and (3S, 5R, 8R, 9S, 10S, 13R, 14S, 17R)-7,7-difluoro-17-((R)-6-hydroxy-6-methylheptane-2-yl)-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-3-ol 66-4' (1.3 g, 2.95 mmol, 1 eq) was added. The product was dissolved in dichloromethane (25 mL) and triethylamine (1.19 g, 11.80 mmol, 4 eq) was slowly added dropwise. DMAP (0.29 g, 2.36 mmol, 0.8 eq) was then added dropwise. Benzoyl chloride (1.04 g, 7.38 mmol, 2.5 eq) was then slowly added dropwise at room temperature. The mixture was stirred at room temperature for 1 hour and monitored by TLC. After completion of the reaction, water was added to quench the reaction, followed by extraction with ethyl acetate (50 mL). The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried to dryness to obtain the crude product. The product was then separated and purified on silica gel (petroleum ether:ethyl acetate = 1:1) to obtain a mixture of 66-5 and 66-5' (1.5 g, 2.82 mmol, yield: 95%). After SFC separation (instrument: Waters Acquity UPCC; column: Daicel CHIRALPAK OZ3, 3*150 mm, 3 μm; mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 70 / 30; flow rate: 2.0 ml / min; column temperature: 37 degrees), (6R)-6-[(1R, 3aS, 3bR, 7S, 9aS, 9bS, 11aR)-7-(benzyloxy)-4,4-difluoro-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-2-methylheptan-2-ol 66-5' (1 g, retention time t R =1.178 min) and (1R,3aR,7S,9aS,9bR,11aR)-4-fluoro-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 66-5 (200 mg, retention time t R =1.601min).

[0304] Compound 66-5: 1HNMR(400MHz, CDCl3)δ8.07–7.99(m,2H),7.55(t,J=7.4Hz,1H),7.43(t,J=7.6H z,2H),4.96(d,J=5.0Hz,1H),1.22(s,6H),0.96–0.85(m,6H),0.72–0.64(m,3H). 19 F NMR (377MHz,CDCl3)δ-110.61.

[0305] Compound 66-5': 19 F NMR (377MHz, CDCl3) δ-88.95,-89.58,-110.84,-111.47.

[0306] Step 6: Compound (1R,3aR,7S,9aS,9bR,11aR)-4-fluoro-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 66-5 (100 mg, 0.2 mmol, 1 eq) was dissolved in tetrahydrofuran (4 mL) and methanol (2 ml), and lithium hydroxide monohydrate (82 mg, 2 mmol, 10 eq) was added. The mixture was stirred at 40 degrees for 3 hours and detected by TLC. After the reaction was completed, the mixture was added The reaction mixture was quenched with water, extracted with ethyl acetate (50 mL), and the organic phase was washed twice with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and dried to give a crude product, which was then separated and purified on silica gel (petroleum ether:ethyl acetate = 1:1) to give (1R,3aR,7S,9aS,9bR,11aR)-4-fluoro-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 66 (70 mg, 0.16 mmol, yield: 85%).

[0307] Compound 66: 1H NMR(400MHz, CDCl3)δ3.60(t,J=4.4Hz,1H),2.08–1.90(m,3H),1.83(dddd,J=19.8,15.3,9.9,5.8Hz,6H),1.63(s,1H), 1.56–1.38(m,10H),1.35–1.25(m,3H),1.22(s,6H),1.18–1.03(m,4H),0.94(d,J=6.5Hz,3H),0.82(s,3H),0.64(s,3H).

[0308] Example 79

[0309] Preparation of compound 79(1R,3aR,5aR,7S,9aR,9bR,11aR)-4-fluoro-7-hydroxy-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-6-one.

[0310] Step 1: In a 100 mL round-bottom flask at room temperature, (5R)-5-[(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-7-acetoxy-6-hydroxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoic acid methyl ester I-8 (1 g, 2.17 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). The reaction mixture was cooled to 0°C under nitrogen protection, and methylmagnesium bromide (7.23 mL, 21.70mmol), then stirred at room temperature for 2 hours, and the reaction was monitored by TLC (petroleum ether: ethyl acetate = 2: 1). After the reaction, the system was cooled to 0°C and quenched with saturated aqueous ammonium chloride solution (60mL), extracted with ethyl acetate (50mL×3), and the organic phase was washed with saturated brine (80mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain cholest-6(5)-ene-3β,4β,25-triol 79-1 (800mg, purity: 90%, yield: 79.38%) as a white solid. 1H NMR(400MHz, CDCl3)δ5.68(d,J=3.3Hz,1H),4.14(s,1H),3.56(d,J=11.1Hz,1H),2.22–1.72(m,7H), 1.72–1.31(m,13H),1.21(s,6H),1.18(s,3H),1.15–1.00(m,5H),0.93(d,J=6.5Hz,3H),0.68(s,3H).

[0311] Step 2: Cholest-6(5)-ene-3β,4β,25-triol 79-1 (400 mg, 0.96 mmol) was dissolved in tetrahydrofuran (15 mL) in a 100 mL round-bottom flask at room temperature. Triethylamine (2.9 g, 28.8 mmol), 4-dimethylaminopyridine (117 mg, 0.96 mmol) and acetic anhydride (980 mg, 9.6 mmol) were added at room temperature. The mixture was stirred at 80 ° C for 24 hours and monitored by TLC (petroleum ether: ethyl acetate = 10:1). After the reaction was completed, the mixture was quenched with water (50 mL) and extracted with ethyl acetate (30 mL × 3). The organic phase was saturated with water. The reaction mixture was washed with brine (50 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated. The mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give (6R)-6-[(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-6,7-diacetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2-methylhept-2-yl acetate 79-2 (415 mg, purity: 90%, yield: 71.76%) as a white solid. 1 H NMR(400MHz, CDCl3)δ=5.84–5.79(m,1H),5.50(d,J=2.5,1H),4.74(dt,J=7.8,4.1,1H),2.07(s,3H),2.05–2.02(m,1H),2.01(s,3H),1.97(s, 3H),1.93–1.54(m,10H),1.54–1.44(m,3H),1.42(s,6H),1.39–1.15(m ,7H),1.13(s,3H),1.10–0.96(m,4H),0.92(d,J=6.5,3H),0.67(s,3H).

[0312] Step 3: In a 100 mL round-bottom flask at room temperature, (6R)-6-[(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-6,7-diacetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2-methylhept-2-yl acetate 79-2 (400 mg, 0.73 mmol) was dissolved in acetone (15 mL). N-hydroxyphthalimide (24 mg, 0.15 mmol), cobalt acetate (13 mg, 0.073 mmol) and tert-butyl hydroperoxide (265 mg, 2.94 mmol) were added at room temperature, and then stirred at room temperature for 36 hours. TLC (stone) showed that the product had a yellow solid. The reaction was monitored with petroleum ether:ethyl acetate = 10:1. After completion of the reaction, the product was quenched with water (50 mL) and extracted with ethyl acetate (40 mL × 3). The organic phase was washed with saturated brine (60 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give (6R)-6-[(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-6,7-diacetoxy-9a,11a-dimethyl-4-oxyylidene-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-2-methylhept-2-yl acetate 79-3 (300 mg, purity: 90%, yield: 65.81%) as a white solid. 1 H NMR (400MHz, CDCl3) δ5.92(s,1H),5.61(d,J=2.3Hz,1H),4.80(dt,J=7.8,4.2Hz,1H),2.34(dt,J=22.4,9.8Hz,2H),2.10(s,3H),2.03(s, 3H),1.97(s,3H),1.92–1.52(m,10H),1.42(s,6H),1.39–1.34(m,2H),1.32(s,3H),1.29–1.00(m,8H),0.93(d,J=6.5Hz,3H),0.68(s,3H). 13C NMR (101MHz, CDCl3) δ202.20,170.06,169.47,158.31,131.14,73.61,71.51,71.12,54.68,50.80,49.91,45.95,44.37, 43.06,38.53,37.93,36.42,35.80,35.69,29.31,29.27,28.52,26.20,22.21,21.15,20.99,20.78,18.83,17.91,11.92.

[0313] Step 4: In a 50 mL round-bottom flask at room temperature, (6R)-6-[(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-6,7-diacetoxy-9a,11a-dimethyl-4-oxyylidene-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-2-methylhept-2-yl acetate 79-3 (300 mg, 0.54 mmol) was dissolved in ethyl acetate (10 mL) and tetrahydrofuran (10 mL). 10% Pd / C (150 mg) was added to the mixture, and the mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. The reaction was monitored by TLC (ethyl acetate / petroleum ether = 15:1). After the reaction, the reaction solution was diluted with ethyl acetate (20 mL), filtered through celite, and the organic phase was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to give (6R)-6-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6,7-diacetoxy-9a,11a-dimethyl-4-oxyylidenehexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-2-methylhept-2-yl acetate 79-4 (200 mg, purity: 90%, yield: 59.60%) as a white solid. 1 H NMR(400MHz, CDCl3)δ5.17(s,1H),4.83–4.74(m,1H),2.58–2.46(m,1H),2. 37–2.28(m,1H),2.25–2.17(m,1H),2.11(s,3H),2.07–2.02(m,1H),1.97(d, J=4.3Hz,6H),1.94–1.81(m,3H),1.80–1.46(m,9H),1.40–1.31(m,5H),1.28 (s,3H),1.26(s,6H),1.16–1.01(m,5H),0.91(d,J=6.5Hz,3H),0.64(s,3H). 13C NMR (101MHz, CDCl3)δ=210.87,170.51,170.19,82.52,72.07,71.97,55.16,54.96,49.99,48.91,48.58,42.77,42.53,41.15,38.5 0,36.17,35.78,35.52,31.93,29.70,28.38,26.05,25.06,22.69,22.51,21.13,20.97,20.91,20.32,18.70,14.12,13.65,12.04.

[0314] Step 5: In a 50 mL round-bottom flask at room temperature, (6R)-6-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6,7-diacetoxy-9a,11a-dimethyl-4-oxyylidene hexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-2-methylhept-2-yl acetate 79-4 (200 mg, 0.36 mmol) was dissolved in diethylaminosulfur trifluoride (3 mL) and stirred at 40 ° C for 6 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 10:1). After the reaction was completed, the reaction solution was quenched by adding ice water (30 mL) and extracted with ethyl acetate (20 mL×3). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The organic phase was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain a white solid ethyl acetate. (6R)-6-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6,7-diacetoxy-4,4-difluoro-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-2-methylhept-2-yl acetate 79-5A and (6R)-6-[(1R,3aR,5aR,6R,7S,9aR,9bS,11aR)-6,7-diacetoxy-4,4-difluoro-9a,11a-dimethylheptadecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-2-methylhept-2-yl acetate bR,11aR)-6,7-diacetoxy-4-fluoro-9a,11a-dimethyl-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2-methylhept-2-yl ester mixture 79-5B mixture (120 mg, purity: 90%. Yield calculated based on 79-5A: 51.55%).

[0315] Compound 79-5A: 1H NMR(400MHz,CDCl3)δ5.20(s,1H),4.79(dd,J=8.3,4.0Hz,1H),2.10(s,3H),1.97(d,J=3.6Hz,6H),1.92–1.59(m,21H),1.42(s,6H),1.19–1.09(m,6H),1.05(s,3H),0.91(d,J=6.5Hz,3H),0.66(s,3H). 13 C NMR(101MHz,CDCl3)δ170.25,82.53,72.01,71.84,55.25,43.05,41.15,39.11,36.14,35.61,29.70,26.05,22.67,22.50,20.98,20.92,20.55,20.36,18.66,13.25,11.83.

[0316] Step 6: Acetic acid-(6R)-6-[(1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-4,4-difluoro-6,7-dihydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2-methylhept-2-yl ester 79-5A and acetate-(6R)-6-[(1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-6,7-diacetoxy-4-fluoro-9a,11 A mixture of a-dimethyl-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2-methylhept-2-yl ester 79-5B (385 mg, 0.77 mmol) was dissolved in tetrahydrofuran (5 mL) and methanol (5 mL), and lithium hydroxide monohydrate (324 mg, 7.72 mmol) and water (3 mL) were added at room temperature, followed by stirring at 45° C. for 16 hours. TLC (petroleum ether:ethyl acetate= After the reaction was completed, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (40 mL × 3). The organic phase was washed with saturated brine (80 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain a white solid (1R,3aS,3bS,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene- A mixture of 6,7-diol 79-6A and (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 79-6B (340 mg, purity: 90.18%, yield: 86.97% based on 79-6A).

[0317] Compound 79-6A: 1 H NMR (400MHz, CDCl3) δ = 3.74 (s, 1H), 3.63–3.57 (m, 1H), 2.32–1.72 (m, 15H), 1. 57–1.25(m,14H),1.21(s,6H),1.06(s,3H),0.93(d,J=6.5,3H),0.67(s,3H).

[0318] Step 7: In a 50 mL round-bottom flask at room temperature, (1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 79-6A and (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetrahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 79 were added. A mixture of -6B (1.41 g, 3.09 mmol) was dissolved in dichloromethane (30 mL), and triethylamine (0.94 g, 9.26 mmol), 4-dimethylaminopyridine (0.3 g, 2.47 mmol) and benzoyl chloride (0.65 g, 4.63 mmol) were added at room temperature, followed by stirring at room temperature for 20 minutes. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 4:1). After the reaction was completed, the mixture was quenched with water (100 mL), extracted with ethyl acetate (60 mL×3), and the organic phase was washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, and concentrated. The organic phase was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain a white solid (1.5 g). The product was chirally separated (instrument: Waters Acquity UPCC; column: REGIS CHIRAL (S, S)-whey O1 4.6*150 mm, 3.5 μm; mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 50 / 50; flow rate: 1.5 ml / min; column temperature: 37 degrees) to give a white solid (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-7-(benzyloxy)-4,4-difluoro-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthren-6-ol 79-7A (1.04 g, purity: 95%, yield: 58.52%, retention time t R =2.597 min) and (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-7-(benzyloxy)-4-fluoro-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-6-ol 79-7B (0.24 g, purity: 95%, yield: 14.02%, retention time t R =2.963min).

[0319] Compound 79-7A: 1 H NMR (400MHz, CDCl3) δ=8.11–7.97(m,2H),7.58(t,J=7.4,1H),7.46(t,J=7.7,2H),4.99(dt,J=7.3,3.9,1H),3 .98(s,1H),2.46–1.23(m,25H),1.22(s,6H),1.14(s,3H),1.12–0.97(m,3H),0.94(d,J=6.5,3H),0.68(s,3H). 19 F NMR (376MHz, CDCl3) δ = -89.02 (d, J = 236.3, 1F), -110.79 (d, J = 236.2, 1F).

[0320] Compound 79-7B: 1 H NMR (400MHz, CDCl3) δ = 8.05 (t, J = 6.1, 2H), 7.58 (t, J = 7.4, 1H), 7.46 (t, J = 7.7, 2H), 5.03–4.95 (m, 1H), 4.10 (d, J = 15 .7,1H),2.73(dd,J=16.8,8.5,1H),2.40–1.29(m,26H),1.22(s,6H),1.13(s,3H),0.95(d,J=6.4,3H),0.65(s,3H). 19 F NMR (376MHz, CDCl3) δ = -109.82 (s, 1F).

[0321] Step 8: In a 50 mL round-bottom flask at room temperature, (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-7-(benzyloxy)-4-fluoro-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-6-ol 79-7B (100 mg, 0.19 mmol) was dissolved in dichloromethane (10 mL). Dess-Martin periodinane (242 mg, 0.57 mmol) was added and stirred at room temperature for 2 hours. The reaction was monitored by TLC (ethyl acetate / petroleum ether = 4:1). After the reaction, saturated aqueous sodium sulfite solution (5 mL) and saturated aqueous sodium bicarbonate solution (5 mL) were added to quench the reaction, and the mixture was extracted with dichloromethane (10 mL×3). The organic phase was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=4:1) to give (1R,3aR,5aR,7S,9aR,9bR,11aR)-7-(benzyloxy)-4-fluoro-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-6-one 79-8 (81 mg, purity: 80%, yield: 65.05%) as a white solid. 1 H NMR (400MHz, CDCl3) δ = 8.10 (d, J = 7.4, 2H), 7.58 (t, J = 7.4, 1H), 7.45 (t, J = 7.7, 2H), 5.48–5.41 (m, 1H ),2.64–2.33(m,3H),2.26–1.30(m,23H),1.22(s,6H),0.95(d,J=6.5,3H),0.82(s,3H),0.64(s,3H). 13 C NMR (101MHz, CDCl3) δ = 203.65, 165.72, 133.24, 129.90, 128.38, 71.12, 54.36, 53.16, 52.49, 48.80, 44.37, 43.60, 41.83, 41. 17,39.43,36.44,36.19,35.61,29.41,29.37,29.22,28.49,28.34,25.12,25.03,23.37,22.28,20.84,18.97,14.97,12.61. 19 F NMR (376MHz, CDCl3) δ = -110.02 (s, 1F).

[0322] Step 9: In a 50 mL round-bottom flask at room temperature, (1R,3aR,5aR,7S,9aR,9bR,11aR)-7-(benzyloxy)-4-fluoro-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-6-one 79-8 (80 mg, 0.15 mmol) was dissolved in tetrahydrofuran (2 mL) and methanol (2 mL). Potassium carbonate (105 mg, 0.76 mmol) and water (1 mL) were added at room temperature, followed by stirring at room temperature for 4 hours. The mixture was detected by TLC (petroleum ether:ethyl acetate = 3:1). The reaction was continued for 2 h. After completion of the reaction, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL×3). The organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=3:1) to give a white solid (1R,3aR,5aR,7S,9aR,9bR,11aR)-4-fluoro-7-hydroxy-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-6-one 79 (15.55 mg, purity: 100%, yield: 23.47%).

[0323] Compound 79: 1 H NMR (400MHz, CDCl3) δ = 4.13 (dd, J = 17.4, 7.6, 1H), 2.60–2.35 (m, 3H), 2.19 –1.27(m,24H),1.22(s,6H),0.94(d,J=6.3,3H),0.74(s,3H),0.64(s,3H). 13 C NMR(101MHz, CDCl3)δ=210.89,74.90,71.11,54.35,52.51,52.30,52.21,48.94,48.87,44.37,43.65,41.71,39.42,36.43,36.17 ,35.03,32.02,30.13,29.71,29.43,29.21,28.48,28.46,25.10,25.02,23.40,23.10,22.24,22.23,20.82,18.96,15.04,12.60. 19 F NMR (376MHz, CDCl3) δ = -110.10 (s, 1F). LC-MS: [M+Na] +=457.1

[0324] Example 85 & 86

[0325] Compound 85 or 86 7β-fluoro-5α-cholest-3β,25-diol

[0326] Preparation of compound 86 or 85 7α-fluoro-5α-cholesta-3β,25-diol.

[0327] In the first step, (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoic acid methyl ester I-7 (1 g, 2.25 mmol, 1 eq) was dissolved in tetrahydrofuran (10 mL). Cobalt acetate (80 mg, 0.45 mmol, 0.2 eq), N-hydroxyphthalimide (0.15 g, 0.90 mmol, 0.4 eq) and tert-butyl peroxide (1.01 g, 11.25 mmol, 5 eq) were added to the solution and stirred at room temperature for 20 hours. After the reaction was completed, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL*3). The obtained organic phase was dried over anhydrous sodium sulfate and then spin-dried to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give (5R)-5-[(1R, 3aS, 3bS, 7S, 9aR, 9bS, 11aR)-7-acetoxy-9a, 11a-dimethyl-4-oxyylidene-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoic acid methyl ester 72-1 (0.6 g, 1.31 mmol, yield: 58%). 1H NMR (400MHz, CDCl3) δ5.70 (d, J=1.5Hz, 1H), 4.80–4.64 (m, 1H), 3.67 (s, 3H), 2.48 (dddd, J=15.6, 12.1,9.1,2.4Hz,3H),2.25(ddd,J=22.3,12.9,5.3Hz,3H),2.05(s,3H),2.01–1.95(m,2H),1.93 –1.84(m,1H),1.79–1.65(m,2H),1.65–1.46(m,5H),1.40(ddd,J=11.6,8.9,4.3Hz,2H),1.28(dd d,J=10.9,10.5,5.9Hz,3H),1.21(s,3H),1.18–1.05(m,3H),0.94(d,J=6.5Hz,3H),0.68(s,3H).

[0328] In the second step, compound (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-4-oxyylidene-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetrahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoic acid methyl ester 72-1 (0.6 g, 1.31 mmol, 1 eq) was dissolved in ethyl acetate (15 mL), and then palladium carbon (10%) (120 mg) was added thereto and stirred at room temperature for 12 hours. After filtration, the organic solvent was dried and the product (5R)-5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-4-oxoylidenehexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester 72-2 (450 mg, 0.977 mmol, yield: 75%) was obtained as an oily compound. 1 H NMR(400MHz,cdcl3)δ5.36–5.24(m,1H),4.30(s,3H),3.00–2.81(m,5H),2.70–2.58(m, 5H),2.55–2.47(m,2H),2.42(dt,J=13.4,3.5Hz,1H),2.35–2.26(m,2H),2.22–2.10(m,6 H),2.09–1.99(m,3H),1.86(d,J=12.4Hz,1H),1.76(s,1H),1.73(s,1H),1.73(s,3H),1. 70(s,1H),1.69(d,J=3.3Hz,1H),1.67–1.60(m,1H),1.56(d,J=6.5Hz,3H),1.28(s,3H).

[0329] Step 3: Methyl (5R)-5-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-4-oxoylidenehexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoate 72-2 (300 mg, 0.65 mmol, 1 eq) was dissolved in methanol (10 mL). Sodium borohydride (30 mg, 0.78 mmol, 1.2 eq) was added to the solution and stirred at room temperature for 1 hour. After the reaction was completed, 30 mL of water was added and the mixture was extracted with ethyl acetate (30 mL*3). The obtained organic phase was dried over anhydrous sodium sulfate and then spin-dried to give the crude product of (5R)-5-[(1R,3aS,3bR,5aS,7S,9aS,9bS,11aR)-7-acetoxy-4-hydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoic acid methyl ester 85-1 (240 mg, 0.52 mmol, yield: 80%), which was directly used for the next step.

[0330] In the fourth step, compound (5R)-5-[(1R,3aS,3bR,5aS,7S,9aS,9bS,11aR)-7-acetoxy-4-hydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoic acid methyl ester 85-1 (240 mg, 0.52 mmol, 1 eq) was dissolved in ultra-dry pyridine (5 mL), and then 4-methylbenzenesulfonyl chloride (824 mg, 4.32 mmol, 10 eq) was added thereto. The mixture was stirred at room temperature for 5 days. After the reaction was completed, 30 ml of 3M aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate (30 mL*3). The organic solvent was then dried to obtain a crude product. The crude product was separated and purified by silica gel (petroleum ether: ethyl acetate = 10:1) to obtain the product, which was separated by SFC (instrument: Waters Acquity UPCC; chromatographic column: Daicel CHIRALPAK IB 4.6*250mm, 5um; mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 60 / 40; flow rate: 1.5 ml / min; column temperature: 37 degrees) to obtain 85-2 (60 mg, 0.1 mmol, yield: 22.5%, retention time t R =1.769 min) and 86-1 (70 mg, 0.13 mmol, yield: 30%, retention time t R =2.792min) was an oily compound.

[0331] Compound 85-2: 1H NMR (400MHz, CDCl3) δ7.76(d,J=8.1Hz,1H),7.31(d,J=8.1Hz,1H),4.67–4.57(m,0H),4.46(td,J=10. 4,5.1Hz,0H),3.67(s,3H),2.44(s,3H),2.26(dd,J=15.3,8.2Hz,2H),2.00(s,3H),1.96(d,J=13.0Hz ,1H),1.81(d,J=15.1Hz,3H),1.73–1.63(m,4H),1.53(s,3H),1.47(d,J=9.6Hz,2H),1.41–1.32(m,4H ),1.28–1.17(m,5H),1.14–0.99(m,4H),0.91(d,J=6.4Hz,3H),0.81(s,3H),0.76(s,1H),0.62(s,3H).

[0332] Compound 86-1: 1 H NMR (400MHz, CDCl3) δ7.78(d,J=8.1Hz,2H),7.35(d,J=8.0Hz,2H),4.76(s,1H),4.62–4.46(m,1H ),3.68(s,3H),2.45(s,3H),2.26(dt,J=15.7,7.7Hz,2H),2.00(s,3H),1.90(d,J=13.0Hz,1H),1. 79(d,J=13.2Hz,1H),1.69(d,J=12.4Hz,2H),1.46(dd,J=17.7,12.2Hz,6H),1.38(d,J=13.0Hz,3 H),1.29–1.17(m,6H),1.08(dt,J=22.8,12.9Hz,6H),0.90(d,J=6.3Hz,3H),0.77(s,3H),0.60(s, 3H).

[0333] Step 5: 85-2 (60 mg, 0.1 mmol, 1.0 eq) and TBAF (38 mg, 0.146 mmol, 1.5 eq) were dissolved in tetrahydrofuran (2 mL) and stirred at 65°C for 12 hours. The reaction was detected by TLC. After completion, water was added to quench the reaction, followed by extraction with ethyl acetate (50 mL). The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried to give a crude product. The crude product was then separated and purified on silica gel (petroleum ether:ethyl acetate = 1:1) to give 85-3 (20 mg, 0.145 mmol, yield: 44%), which was directly used for the next step.

[0334] Step 6: 85-3 (20 mg, 0.043 mmol, 1 eq) was dissolved in tetrahydrofuran (2 mL). After nitrogen was replaced, methylmagnesium bromide (2.4 M) (0.6 mL, 10 eq) was slowly added dropwise. The mixture was stirred at room temperature for 3 hours and monitored by TLC. After completion of the reaction, water was added to quench the reaction, followed by extraction with ethyl acetate (50 mL). The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried to give the crude product. The crude product was then separated and purified on silica gel (petroleum ether:ethyl acetate = 4:1) to give 85 (6 mg, 0.014 mmol, yield: 33%).

[0335] Compound 85: 1 H NMR (400MHz, CDCl3) δ4.63(d,J=49.6Hz,1H),3.63(s,1H),1.95(d,J=12.6Hz,1H ),1.88–1.80(m,2H),1.76–1.68(m,3H),1.63(d,J=13.2Hz,2H),1.52(dd,J=11.0 ,8.1Hz,6H),1.39(dd,J=12.3,9.6Hz,7H),1.29–1.25(m,4H),1.21(s,6H),1.10 (ddd,J=14.2,10.1,5.1Hz,4H),0.92(d,J=6.5Hz,3H),0.80(s,3H),0.65(s,3H). 19 F NMR (376 MHz, CDCl3) δ-196.28.

[0336] Similar operation is performed to replace raw material 85-2 with 86-1 to obtain 86.

[0337] Compound 86: 1 H NMR (400MHz, CDCl3) δ4.28–4.09(m,1H),3.65–3.54(m,1H),2.00(dd,J=9.4, 3.4Hz,1H),1.86–1.70(m,5H),1.59(d,J=11.5Hz,2H),1.52(d,J=12.9Hz,2H) ,1.45(d,J=10.9Hz,4H),1.35(dd,J=12.4,4.5Hz,5H),1.30–1.23(m,3H),1.2 1(s,6H),1.17–1.03(m,5H),0.92(d,J=6.5Hz,3H),0.86(s,3H),0.68(s,3H). 19 F NMR (376MHz,CDCl3)δ-167.50.

[0338] Example 94

[0339] Preparation of Compound 94 (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-1-[(2R)-5,5-difluoro-6-hydroxy-6-methylhept-2-yl]-4,4-difluoro-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0340] In the first step, (R)-5-((3S,4R,8S,9S,10R,13R,14S,17R)-3-acetoxy-4-hydroxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2,2-difluorohexanoic acid ethyl ester 34-1 (450 mg, 0.88 mmol) was dissolved in anhydrous tetrahydrofuran (12 mL) at room temperature. Under nitrogen protection, the temperature was lowered to 0°C, and methylmagnesium bromide (3 M in ) was added dropwise. 2-Me-THF, 2.9 mL, 8.8 mmol), and then stirred at room temperature for 2 hours. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 2: 1). After the reaction was completed, the system was cooled to 0 ° C and quenched with saturated aqueous ammonium chloride (30 mL). It was extracted with ethyl acetate (30 mL × 2), and the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4: 1) to obtain a white solid The product (3S,4R,8S,9S,10R,13R,14S,17R)-17-((R)-5,5-difluoro-6-hydroxy-6-methylheptan-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3,4-diol 94-1 (195 mg, purity: 95%, yield: 49%). 1 H NMR (400MHz, CDCl3) δ5.68 (d, J=3.4Hz, 1H), 4.14 (d, J=3.4Hz, 1H), 3.57 (dd, J= 7.7,4.0Hz,1H),2.14–1.94(m,4H),1.94–1.79(m,4H),1.74(d,J=18.2Hz,1H), 1.68–1.53(m,6H),1.52–1.40(m,4H),1.31(s,6H),1.18(s,3H),1.16–1.07(m, 3H),1.05–0.98(m,1H),0.94(d,J=6.6Hz,3H),0.90–0.82(m,1H),0.69(s,3H).

[0341] In the second step, 3S,4R,8S,9S,10R,13R,14S,17R)-17-((R)-5,5-difluoro-6-hydroxy-6-methylheptane-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopentadien[a]phenanthrene-3,4-diol 94-1 (193 mg, 0.4 2mmol, 1.0eq) was dissolved in tetrahydrofuran (10mL), and triethylamine (6.37g, 63.0mmol, 150eq), 4-dimethylaminopyridine (154mg, 1.26mmol, 3.0eq) and acetic anhydride (2.14g, 21.0mmol, 50eq) were added at room temperature, followed by stirring at 80°C for 24 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 1:1). After the reaction, the mixture was quenched with ice water (50 mL) and extracted with ethyl acetate (30 mL × 2). The organic phase was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to give (3S, 4R, 8S, 9S, 10R, 13R, 14S, 17R)-17-((R)-6-acetoxy-5,5-difluoro-6-methylheptan-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3,4-diyl diacetate 94-2 (182 mg, purity: 90%, yield: 74.59%) as a white solid.

[0342] 1 H NMR (400MHz, CDCl3) δ5.84–5.79(m,1H),5.50(d,J=2.6Hz,1H),4.74(dt,J=12.4,4.1H z,1H),2.15–2.08(m,1H),2.07(s,3H),2.03(s,3H),2.01(s,3H),1.97–1.65(m,6H),1. 60(s,6H),1.48(d,J=9.6Hz,3H),1.27(d,J=12.1Hz,7H),1.23–1.16(m,2H),1.13(s,3H ),1.13–0.97(m,3H),0.95(d,J=6.5Hz,3H),0.88(dd,J=13.4,7.8Hz,1H),0.69(s,3H).

[0343] Step 3: (3S,4R,8S,9S,10R,13R,14S,17R)-17-((R)-6-acetoxy-5,5-difluoro-6-methylheptane-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopentadienyl[a]phenanthrene-3,4-diyl diacetate 94-2 (182 mg, 0.31 mmol, 1.0 eq) was dissolved in acetone (8 mL) at room temperature, and N-hydroxyphthalimide (10 mg, 0.062 mmol, 0.2 eq), cobalt acetate (5.5 mg, 0.031 mmol, 0.1 eq) and tert-butyl hydroperoxide (5 M in 1% acetone) were added at room temperature. hexane, 0.25 mL, 1.24 mmol, 4.0 eq), and then stirred at room temperature for 36 hours. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 10:1). After the reaction was completed, it was quenched with water (30 mL), extracted with ethyl acetate (20 mL × 2), and the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15:1) to obtain a white solid (3S, 4 R,8S,9S,10R,13R,14S,17R)-17-((R)-6-acetoxy-5,5-difluoro-6-methylheptan-2-yl)-10,13-dimethyl-7-oxy-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3,4-diyl diacetate 94-3 (120 mg, purity: 90%, yield: 65.22%). 1 H NMR (400MHz, CDCl3) δ5.93(s,1H),5.61(d,J=2.7Hz,1H),4.80(dt,J=12.2,4.0Hz,1H),2.43–2.26(m,2H),2.09(d,J=5.7Hz,4H),2.04(d ,J=5.4Hz,7H),2.00–1.87(m,3H),1.85–1.66(m,3H),1.59(s,6H),1.48(s,2H),1.39–1.04(m,12H),0.96(d,J=6.5Hz,3H),0.70(s,3H). 19 F NMR(376MHz, CDCl3)δ-113.92–-117.67(m,2F).

[0344] Step 4: (3S,4R,8S,9S,10R,13R,14S,17R)-17-((R)-6-acetoxy-5,5-difluoro-6-methylheptan-2-yl)-10,13-dimethyl-7-oxy-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3,4-diyl diacetate 94-3 (120 mg, 0.20 mmol) was dissolved in ethyl acetate (3 mL) and tetrahydrofuran (3 mL). 10% Pd / C (60 mg) was added at room temperature, and the mixture was stirred under a hydrogen atmosphere at room temperature for 6 hours. The reaction was monitored by TLC (ethyl acetate / petroleum ether = 1:4). After the reaction, the reaction solution was diluted with ethyl acetate (20 mL), filtered through celite, the organic phase was concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15:1) to give a white solid (3S, 4R, 5R, 8S, 9S, 10R, 13R, 14S, 17R)-17-((R)-6-acetoxy-5,5-difluoro-6-methylheptane-2-yl)-10,13-dimethyl-7-oxohexadecahydro-1H-cyclopenta[a]phenanthrene-3,4-diyl diacetate 94-4 (53 mg, purity: 90%, yield: 44.54%). 1 H NMR(400MHz, CDCl3)δ5.17(s,1H),4.78(dd,J=12.1,3.6Hz,1H),2.52(t,J=13.5Hz,1H), 2.34(t,J=11.4Hz,1H),2.27–2.18(m,1H),2.12(s,3H),2.10–2.05(m,1H),2.03(s,3H), 1.98(s,3H),1.96–1.82(m,4H),1.71(t,J=12.8Hz,4H),1.59(s,6H),1.44(ddd,J=18.3, 17.6,6.7Hz,4H),1.35–1.24(m,6H),1.19–1.04(m,4H),1.01–0.91(m,4H),0.66(s,3H).

[0345] Step 5: (3S, 4R, 5R, 8S, 9S, 10R, 13R, 14S, 17R)-17-((R)-6-acetoxy-5,5-difluoro-6-methylheptane-2-yl)-10,13-dimethyl-7-oxohexadecahydro-1H-cyclopentadienyl[a]phenanthrene-3,4-diyl diacetate 94-4 (53 mg, 0.089 mmol) was dissolved in diethylaminosulfur trifluoride (2 mL) at room temperature and stirred at 70 ° C for 2 hours. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 4:1). After the reaction was completed, the reaction solution was diluted with ethyl acetate and slowly added dropwise to ice water (20 mL). ) and extracted with ethyl acetate (15 mL×2). The organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to give a white solid (3S,4R,5R,8S,9S,10R,13R,14S,17R)-17-((R)-6-acetoxy-5,5-difluoro-6-methylheptane-2-yl)-7,7-difluoro-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-3,4-diyl diacetate 94-5 (45 mg, purity: 90%, yield: 81.82%). 1 H NMR(400MHz, CDCl3)δ5.21(s,1H),4.83–4.76(m,1H),2.10(s,3H),2.03(s,3H) ,1.98(s,3H),1.83(dd,J=14.1,10.0Hz,5H),1.76–1.67(m,4H),1.59(s,6H),1 .46(dd,J=18.1,9.1Hz,4H),1.30(dd,J=15.2,7.1Hz,4H),1.14(d,J=12.8Hz,3 H),1.06(s,3H),0.99(s,1H),0.95(d,J=6.5Hz,3H),0.88(s,1H),0.68(s,3H). 19 F NMR (377MHz, CDCl3) δ-89.25 (d, J=238.2Hz, 1F), -110.61 (d, J=237.8Hz, 1F), -114.63–-116.99 (m, 2F).

[0346] Step 6: At room temperature, (3S, 4R, 5R, 8S, 9S, 10R, 13R, 14S, 17R)-17-((R)-6-acetoxy-5,5-difluoro-6-methylheptane-2-yl)-7,7-difluoro-10,13-dimethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-3,4-diyl diacetate 94-5 (45 mg, 0.073 mmol, 1.0 eq) was dissolved in tetrahydrofuran (1 mL) and methanol (1 mL). Lithium hydroxide monohydrate (15 mg, 0.365 mmol, 5.0 eq) and water (0.5 mL) were added at room temperature, followed by stirring at room temperature for 30 min. TLC (petroleum ether: acetic acid) was performed. After completion of the reaction, the mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL×2), the organic phase was washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=2:1) ​​to give (3S,4R,5R,8S,9S,10R,13R,14S,17R)-17-((R)-5,5-difluoro-6-hydroxy-6-methylheptane-2-yl)-7,7-difluoro-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-3,4-diol 94-6 (28 mg, purity: 90%, yield: 77.78%) as a white solid. 1 H NMR(400MHz, CDCl3)δ3.74(s,1H),3.66–3.56(m,1H),2.32–2.11(m,1H),1.9 8(d,J=12.5Hz,2H),1.91–1.77(m,6H),1.76–1.64(m,6H),1.44(dd,J=17.3,4 .5Hz,5H),1.30(s,6H),1.12(dd,J=17.0,12.1Hz,3H),1.06(d,J=5.4Hz,3H), 1.00(d,J=4.0Hz,1H),0.94(d,J=6.5Hz,3H),0.90–0.83(m,1H),0.68(s,3H).

[0347] Step 7: (3S,4R,5R,8S,9S,10R,13R,14S,17R)-17-((R)-5,5-difluoro-6-hydroxy-6-methylheptane-2-yl)-7,7-difluoro-10,13-dimethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-3,4-diol 94-6 (28 mg, 0.057 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL) and tetrahydrofuran (1 mL) at room temperature, and triethylamine (35 mg, 0.34 mmol, 6.0 eq) was added at room temperature. , 4-dimethylaminopyridine (7 mg, 0.057 mmol, 1.0 eq) and benzoyl chloride (24 mg, 0.17 mmol, 3.0 eq), and then stirred at room temperature for 8 hours. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 1: 1). After the reaction was completed, it was quenched with water (10 mL), extracted with ethyl acetate (10 mL × 2), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) and SFC separation (instrument: Waters Acquity UPCC; chromatographic column: Daicel CHIRALPAK IB 4.6*250mm, 5um; mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 60 / 40; flow rate: 1.5 ml / min; column temperature: 37 degrees) to give a white solid (3S,4R,5R,8S,9S,10R,13R,14S,17R)-17-((R)-5,5-difluoro-6-hydroxy-6-methylheptane-2-yl)-7,7-difluoro-4-hydroxy-10,13-dimethylhexahydro-1H-cyclopentyl[a]phenanthrene-3-ylbenzoate 94-7 (15 mg, purity: 95%, yield: 44.12%, retention time t R =1.225min). 1 H NMR (400MHz, CDCl3) δ8.04(d,J=7.3Hz,2H),7.58(t,J=7.4Hz,1H),7.46(t,J=7. 6Hz,2H),4.99(d,J=12.0Hz,1H),3.99(s,1H),2.37–2.16(m,1H),2.15–1.96(m, 3H),1.83(d,J=9.5Hz,7H),1.76(s,3H),1.51–1.42(m,3H),1.32(s,3H),1.31(s ,6H),1.14(s,2H),1.14(s,3H),1.03(s,2H),0.94(d,J=6.5Hz,3H),0.69(s,3H).

[0348] Step 8: (3S, 4R, 5R, 8S, 9S, 10R, 13R, 14S, 17R)-17-((R)-5,5-difluoro-6-hydroxy-6-methylheptane-2-yl)-7,7-difluoro-4-hydroxy-10,13-dimethylhexahydro-1H-cyclopentyl[a]phenanthrene-3-ylbenzoate 94-7 (15 mg, 0.025 mmol, 1.0 eq) was dissolved in tetrahydrofuran (0.5 mL) and methanol (0.5 mL) at room temperature, and lithium hydroxide monohydrate (11 mg, 0.25 mmol, 10.0 eq) and water (0.2 mL) were added at room temperature, followed by stirring at room temperature for 30 min. The mixture was purified by TLC (petroleum ether: ethyl acetate). After completion of the reaction, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL×2). The organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=4:1) to give (3S,4R,5R,8S,9S,10R,13R,14S,17R)-17-((R)-5,5-difluoro-6-hydroxy-6-methylheptan-2-yl)-7,7-difluoro-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-3,4-diol 94 (6.23 mg, purity: 100%, yield: 50.89%) as a white solid.

[0349] Compound 94: 1 H NMR (400MHz, CDCl3) δ3.76–3.72(m,1H),3.64–3.56(m,1H),2.27–2.12(m,1H), 2.02–1.94(m,2H),1.89–1.83(m,2H),1.82–1.78(m,2H),1.77–1.67(m,5H),1.6 7–1.57(m,3H),1.48–1.39(m,3H),1.38–1.33(m,2H),1.32–1.27(m,7H),1.17–1 .09(m,2H),1.06(s,3H),1.02–0.97(m,1H),0.94(d,J=6.5Hz,3H),0.68(s,3H). 19 F NMR (377MHz, CDCl3) δ-88.97 (d, J=235.8Hz, 1F), -110.95 (d, J=235.7Hz, 1F), -114.05–-117.90 (m, 2F).

[0350] Example 103

[0351] Preparation of Compound 103 3β,25-dihydroxy-5α-cholestane-7-carbonitrile

[0352] In the first step, (1R,3aS,3bR,7S,9aS,9bS,11aR)-4-hydroxy-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (200 mg, 0.432 mmol, 1 eq) was dissolved in ultra-dry pyridine (5 mL), and then 4-methylbenzenesulfonyl chloride (824 mg, 4.32 mmol, 10 eq) was added thereto. The mixture was stirred at room temperature for 5 days. After the reaction was completed, 30 ml of 4-methylbenzenesulfonyl chloride was added. The mixture was stirred for 2 h, and the mixture was stirred for 3 hours. The mixture was stirred for 2 hours. The mixture was stirred for 3 hours. The mixture was stirred for 3 hours. The mixture was stirred for 2 hours. The mixture was stirred for 3 hours. The mixture was stirred for 3 hours. The mixture was stirred for 2 hours. The mixture was stirred for 3 hours. The mixture was stirred for 3 hours. The mixture was stirred for 2 hours. The mixture was stirred for 3 hours. The mixture was stirred for 3 hours. The mixture was stirred for 2 hours.

[0353] 1 H NMR (400MHz, CDCl3) δ7.77 (t, J=7.9Hz, 2H), 7.33 (dd, J=17.9, 8.2Hz, 2H), 4. 76–4.44(m,2H),2.44(s,3H),2.00(s,3H),1.77(ddd,J=32.4,24.9,8.1Hz,8 H),1.52–1.32(m,13H),1.29–1.24(m,4H),1.22(d,J=4.4Hz,6H),1.15–1.02 (m,5H),0.90(d,J=6.4Hz,3H),0.79(d,J=15.5Hz,3H),0.62(d,J=7.6Hz,3H).

[0354] In the second step, compound 4-methylbenzenesulfonic acid-(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-7-acetoxy-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-i]phenanthrene-4-yl ester 103-1 (60 mg, 0.1 mmol, 1.0 eq) and sodium cyanide (20 mg, 0.4 mmol, 4 eq) were dissolved in DMF (2 mL) and stirred at 65 ° C for 12 hours, monitored by TLC (petroleum ether: ethyl acetate = 1:1). After the reaction was completed, water was added. The reaction mixture was quenched and then extracted with ethyl acetate (50 mL). The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to give a crude product, which was then separated and purified on silica gel (petroleum ether: ethyl acetate = 1:1) to give (1R, 3aS, 3bR, 7S, 9aS, 9bS, 11aR)-4-cyano-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate 103-2 (25 mg, 0.05 mmol, yield: 55%). The crude product was directly used in the next step.

[0355] In the third step, the compound (1R,3aS,3bR,7S,9aS,9bS,11aR)-4-cyano-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate 103-2 (25 mg, 0.05 mmol, 1 eq) was dissolved in methanol (2 mL), and potassium carbonate (29 mg, 0.212 mmol, 4 eq) was added. The mixture was stirred at room temperature for 3 hours and monitored by TLC (petroleum ether: ethyl acetate = 4:1). After the reaction was completed, water was added to quench the reaction, followed by extraction with ethyl acetate (50 mL). The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to give the crude product, which was then separated and purified on silica gel (petroleum ether: ethyl acetate = 4:1) to give 3β,25-dihydroxycholest-7-carbonitrile 103 (16 mg, 0.037 mmol, yield: 70%).

[0356] Compound 103: 1H NMR (400MHz, CDCl3) δ3.67(s,1H),2.84(s,1H),2.00–1.95(m,1H),1.92–1.81(m,2H),1.75–1.67(m,2H),1.59(s,2H),1.54(s,2H),1.46 –1.37(m,8H),1.33–1.27(m,5H),1.22(s,6H),1.19(s,1H),1.13–1.01(m,5H),0.92(d,J=6.5Hz,3H),0.81(d,J=4.2Hz,3H),0.66(s,3H). 13 C NMR (101MHz, CDCl3) δ121.18,71.10,70.63,55.76,52.83,49.11,44.38,42.74,40.40,39.01,37.16,36.36 ,36.28,35.61,35.49,32.36,31.14,30.80,29.29,29.27,28.04,23.60,20.89,20.66,18.57,12.03,11.92.

[0357] Example 106

[0358] Preparation of Compound 106 24-[Hydroxy(2-methoxyphenyl)methyl]-7-methylidene-5α-cholane-3β,4β-diol

[0359] Step 1: Dissolve the raw material 1-bromo-2-methoxybenzene (7.64 g, 40.82 mmol, 3.5 eq) in anhydrous tetrahydrofuran (50 mL), cool the system to -78°C, add n-butyl lithium (14.0 mL, 34.99 mmol, 3.0 eq), and maintain the temperature and stir for 30 minutes. Compound (R)-5-(((3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-3a,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetrahydro-4H-cyclopentyl[7,8]phenanthrene[1,2-d][1,3]dioxy-8-yl)hexanal III (5 g, 11.66 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 mL) and added to the above reaction solution. The system was stirred at -78°C for 30 minutes. TLC (petroleum ether: ethyl acetate = 5:1) monitored the reaction progress and the starting material was completely consumed. 10 mL of water was added to the reaction system, extracted with ethyl acetate (100 mL × 3), the combined organic phases were washed with saturated sodium chloride (100 mL), the combined organic phases were dried, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 90:10) to obtain a white solid (5R)-5-[(3aS, 5aR, 5bS, 7aR, 8R, 10aS, 10bS, 12bR) -2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetrahydro-3aH-cyclopentadieno[1',2':1,2]phenanthrene[7,8-d][1,3]dioxetyl]-1-(2-methoxyphenyl)hexan-1-ol 106-1 (4.9 g, purity 90%, yield 70.43%). 1 H NMR (400MHz, CDCl3) δ7.32–7.28(m,1H),7.26–7.20(m,1H),7.02–6.82(m,2H),5.80(d,J=2.7Hz,1H) ,4.85(dt,J=9.9,5.8Hz,1H),4.41(d,J=5.8Hz,1H),4.10(dd,J=13.6,6.4Hz,1H),3.84(d,J=10.0Hz, 3H),2.19–1.98(m,3H),1.82–1.72(m,3H),1.63(dd,J=13.2,8.6Hz,5H),1.53(s,4H),1.43(s,3H),1. 35(s,3H),1.28–1.23(m,1H),1.16(s,4H),1.13–1.01(m,25H),0.95–0.88(m,4H),0.72–0.64(m,3H).

[0360] Step 2: In a 200 mL round-bottom flask at room temperature, (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetrahydro-3aH-cyclopentadienyl[1',2':1,2]phenanthrene[7,8-d][1, 3]-dioxetyl]-1-(2-methoxyphenyl)hexan-1-ol 106-1 (4.9 g, 9.13 mmol) was dissolved in dichloromethane (70 mL). tert-Butyldimethylsilyl chloride (4.13 g, 27.39 mmol), 4-dimethylaminopyridine (450 mg, 3.65 mmol), and imidazole (2.49 g, 36.51 mmol) were added at room temperature. The mixture was then stirred at room temperature for 2 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1). After completion of the reaction, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The organic phase was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain (9R)-9-[(3aS, 5aR, 5bS, 7aR, 8R, 10aS, 10bS, 12bR) as a white solid. )-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetrahydro-3aH-cyclopentadienyl[1',2':1,2]phenanthrene[7,8-d][1,3]dioxetane-8-yl]-5-(2-methoxyphenyl)-2,3,3-tetramethyl-4-oxo-3-siladecane 106-2 (4.9 g, purity: 90%, yield: 74%). 1H NMR(400MHz,CDCl3)δ7.60(d,J=7.6Hz,1H),7.36–7.27(m,1H),7.11–7.01(m,1H),6.95(d,J=8.1Hz,1H),5.94(d,J=2.7Hz,1H),5.21(dt,J=7.5,3.9Hz,1H),4.55(d,J=5.8Hz,1H),4.25(t,J=5.8Hz,1H),3.95(s,3H),2.30–2.20(m,1H),2.20–2.11(m,2H),1.96(ddd,J=13.1,7.8,3.9Hz,1H),1.91–1.60(m,13H),1.58–1.45(m,7H),1.41(dd,J=13.1,6.0Hz,3H),1.36–1.26(m,5H),1.26–1.09(m,5H),1.08–1.01(m,12H),1.01–0.90(m,1H),0.87–0.78(m,3H),0.21–0.15(m,3H).

[0361] Step 3: In a 250 mL round-bottom flask at room temperature, (9R)-9-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetrahydro-3aH-cyclopentadienyl[1',2':1,2]phenanthrene[7,8-d][1,3]dioxetane-8- [4.9 g, 7.53 mmol]-5-(2-methoxyphenyl)-2,3,3-tetramethyl-4-oxo-3-siladecane 106-2 was dissolved in acetone (100 mL), and N-hydroxyphthalamide (370 mg, 2.26 mmol), cobalt acetate (200 mg, 1.13 mmol), and tert-butyl hydroperoxide (3.39 g, 37.63 mmol) were added at room temperature, followed by stirring at room temperature for 36 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 10:1). After completion of the reaction, the mixture was quenched with water (50 mL) and extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated brine (60 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain (3aS, 5aR, 5bS, 7aR, 8R, 10aS, 10bS, 12bR)-8-[(9R)]-4-[(9R) ...3aS, 5aR, 5bS, 7aR, 8R, 10aS, 10bS, 12bR)-8-[(9R)-4-[ -5-(2-methoxyphenyl)-2,2,3,3-tetramethyl-4-oxo-3-silyl]-2,2,5a,7a,7a-tetramethyl-4,5,5a,5b,6,7,8,9,10,10a,10b,11,12b-tetrahydro-3aH-cyclopenteno[1':1,2]phenanthrene[7,8-d][1,3]dioxy-11,5-one 106-3 (2.6 g, purity: 90%, yield: 46.75%). 1 H NMR(400MHz, CDCl3)δ7.59(d,J=7.5Hz,1H),7.37–7.27(m,1H),7.08(t,J=7.4Hz,1H),6.95(d,J=8.2Hz,1H ),6.06(s,1H),5.22(dd,J=7.0,3.3Hz,1H),4.66(d,J=6.4Hz,1H),4.47(q,J=5.5Hz,1H),3.95 (s,3H),2.55–2.43(m,2H),2.24–2.14(m,1H),2.05–1.93(m,2H),1.81–1.67(m,11H),1.55–1 .39(m,15H),1.31–1.18(m,3H),1.06–0.99(m,13H),0.87–0.80(m,3H),0.16(q,J=7.4Hz,3H).

[0362] Step 4: (3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-8-[(9R)-5-(2-methoxyphenyl)-2,2,3,3-tetramethyl-4-oxa-3-siladec-9-yl]-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetradecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-11-one 106-3 (2.1 g, 3.158 mmol) was dissolved in methanol (30 mL), Pd / C (1.08 g, 5.052 mmol) was added, the system was replaced with hydrogen, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was filtered through celite, and the filtrate was dried and purified by silica gel column chromatography to give (3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-8-[(9R)-5-(2-methoxyphenyl)-2,2,3,3-tetramethyl-4-oxa-3-siladec-9-yl]-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxolan-11-one 106-4 (1.1 g, 1.402 mmol, 44.39%) as a white solid. 1H NMR(400MHz,CDCl3)δ7.45(d,J=7.6Hz,1H),7.22–7.14(m,1H),6.94(t,J=7.4Hz,1H),6.81(d,J=8.0Hz,1H),5.06(s,1H),4.01(s,1H),4.00–3.93(m,1H),3.81(s,3H),2.77(s,1H),2.42(s,1H),2.19(dd,J=12.7,2.6Hz,2H),1.98(d,J=12.9Hz,1H),1.93–1.82(m,2H),1.79–1.67(m,2H),1.63(dd,J=14.5,3.1Hz,2H),1.55(s,4H),1.48(d,J=3.6Hz,2H),1.45–1.34(m,4H),1.30(s,6H),1.21(s,2H),1.06(dt,J=11.1,8.1Hz,4H),0.99(d,J=5.6Hz,1H),0.96(d,J=6.7Hz,1H),0.88(s,9H),0.64(d,J=5.5Hz,3H),0.02(d,J=1.8Hz,3H),-0.00(s,3H),-0.14(s,3H).

[0363] Step 5: Place methyltriphenylphosphonium bromide (696.19 mg, 1.949 mmol) in a two-necked flask (50 mL), replace with nitrogen, add ultra-dry tetrahydrofuran (15 mL), stir at 0°C and add potassium tert-butoxide in tetrahydrofuran (1.949 mL, 1.949 mmol) dropwise. Continue stirring at 0°C for 10 minutes. (3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-8-[(9R)-5-(2-methoxyphenyl)-2,2,3,3-tetramethyl-4-oxa-3-siladec-9-yl]-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxolan-11-one 106-4 (260 mg, 0.390 mmol) was dissolved in ultra-dry tetrahydrofuran (5 mL) and added dropwise to the reaction flask. The reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with 5% sodium dihydrogen phosphate solution, extracted with ethyl acetate, and the organic phase was purified by silica gel column chromatography (petroleum ether / dichloromethane = 2 / 1) to obtain (9R)-9-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-2,2,5a,7a-tetramethyl-11-methylidene-4,5,5a,5b,6,7,7a,8,9, 10,10a,10b,11,12,12a,12b-Hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-5-(2-methoxyphenyl)-2,2,3,3-tetramethyl-4-oxa-3-siladecane 106-5 (210 mg, 0.253 mmol, 64.81%) was a colorless transparent oil. 1H NMR (400MHz, CDCl3) δ7.60(d,J=7.6Hz,1H),7.36–7.28(m,1H),7.08(t,J=7.4Hz,1H),6.95(d,J=8.1Hz,1H),5.21(dt,J=7 .8,4.1Hz,1H),4.85(s,1H),4.73(s,1H),4.21–4.16(m,1H),4.16–4.07(m,1H),3.95(s,3H),2.53(t,J=12.8Hz,1H),2.24 (d,J=10.4Hz,2H),2.12(t,J=14.2Hz,3H),2.04–1.90(m,3H),1.79(ddd,J=14.0,11.9,3.6Hz,3H),1.72(s,2H),1.66(s,4 H),1.58–1.49(m,J=9.1,3.9Hz,6H),1.45(s,3H),1.41–1.37(m,2H),1.31(s,3H),1.24(dd,J=11.4,7.0Hz,2H),1.18–1.11 (m,2H),1.03(s,9H),0.93–0.86(m,1H),0.82(s,3H),0.15(dd,J=7.9,2.2Hz,4H),-0.00(s,3H).

[0364] Step 6: (9R)-9-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-2,2,5a,7a-tetramethyl-11-methylidene-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8 [-d] [1,3]dioxolan-8-yl]-5-(2-methoxyphenyl)-2,2,3,3-tetramethyl-4-oxa-3-siladecane 106-5 (18 mg, 0.027 mmol) was dissolved in tetrahydrofuran (1 mL), and hydrochloric acid (2.520 mL, 7.560 mmol) was added. The mixture was stirred at 40°C for 3 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 1:1). The reaction mixture was added with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and dried by rotary evaporation. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain 2,4-[hydroxy(2-methoxyphenyl)methyl]-7-methylidene-5α-cholane-3β,4β-diol 106 (6 mg, 0.011 mmol, 41.24%) as a white solid.

[0365] Compound 106: 1H NMR (400MHz, CDCl3) δ7.30(d,J=5.8Hz,1H),7.24(d,J=7.8Hz,1H),6.97(dd,J=15.5,8.1Hz,1H),6.88(d,J=8.3Hz,1H),4.91–4.8 0(m,1H),4.65(d,J=42.3Hz,2H),3.86(s,3H),3.79(s,1H),3.61–3.49(m,1H),2.49(t,J=12.8Hz,1H),2.09–1.92(m,5H),1.84(d d,J=23.5,14.4Hz,2H),1.78–1.66(m,5H),1.40(d,J=2.7Hz,3H),1.34–1.28(m,2H),1.25(s,2H),1.18(s,1H),1.15(s,3H),1.11 (d,J=11.3Hz,3H),1.01–0.96(m,1H),0.92(dd,J=6.4,3.9Hz,3H),0.75(t,J=9.3Hz,1H),0.67(d,J=2.5Hz,3H).LC-MS:[M+H-H2O] + =493.45

[0366] Example 109

[0367] Preparation of Compound 109 3β,25-dihydroxy-5α-cholestane-4-carbonitrile

[0368] Step 1: In a 50 mL round-bottom flask at room temperature, 3β-{[dimethyl(2-methylprop-2-yl)silyl]oxy}-25-hydroxycholest-6(5)-ene-4-carbaldehyde 23-3 (90 mg, 0.17 mmol) was dissolved in acetonitrile (6 mL), and sodium acetate (230 mg, 2.8 mmol), hydroxylamine hydrochloride (115 mg, 1.7 mmol) and water (2 ml) were added at room temperature. The mixture was then stirred at room temperature for 30 hours and monitored by TLC (petroleum ether: ethyl acetate = 4:1). After the reaction was completed, the mixture was quenched with water (20 mL), extracted with ethyl acetate (20 mL × 3), and the organic phase was washed with saturated brine (30 mL). The reaction mixture was washed with water and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=4:1) to give [(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-{[dimethyl(2-methylprop-2-yl)silyl]oxy}-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-6-yl]methanealdehyde oxime 109-1 (53 mg, purity: 90%, yield: 51.58%) as a white solid. 1 H NMR(400MHz, CDCl3)δ=7.59(d,J=9.2,1H),3.75(dd,J=15.4,5.9,1H),2.61–2.54(m,1H),2.01–1.27(m,25H),1 .21(s,6H),1.11–1.00(m,5H),0.91(d,J=6.5,3H),0.85(s,9H),0.79(s,3H),0.62(s,3H),0.03(d,J=3.0,6H).

[0369] Step 2: In a 50 mL round-bottom flask at room temperature, [(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-{[dimethyl(2-methylpropyl-2-yl)silyl]oxy}-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-6-yl]methanealdehyde oxime 109-1 (43 mg, 0.077 mmol) was dissolved in tetrahydrofuran (2.5 mL). Diphenyl disulfide (67 mL) was added at room temperature. g, 0.31 mmol), tributylphosphine (62 mg, 0.31 mmol), and then stirred at room temperature for 6 hours. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 8: 1). After the reaction was completed, it was quenched with water (10 mL), extracted with ethyl acetate (10 mL × 3), and the organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8: 1) to give 3β-{[dimethyl(2-methylprop-2-yl)silyl]oxy}-25-hydroxycholest-4-carbonitrile 109-2 (31 mg, purity: 90%, yield: 67.04%) as a white solid. 1 H NMR (400MHz, CDCl3) δ=3.61–3.50(m,1H),2.69(t,J=4.7,1H),1.95–1.21(m,26H),1.14( s,6H),1.01(s,3H),0.98–0.88(m,3H),0.84(d,J=5.0,12H),0.58(s,3H),-0.00(s,6H). 13 C NMR (101MHz, CDCl3) δ142.57,119.68,71.12,70.74,56.45,56.12,55.12,45.76,44.41,42.55,40.84,39.80,36.60,36.41,36 .14,35.71,35.19,31.90,31.52,29.71,29.40,29.20,29.07,28.22,27.08,25.71,24.17,20.72,18.64,18.02,13.09,12.05.

[0370] Step 3: In a 50 mL round-bottom flask at room temperature, 3β-{[dimethyl(2-methylprop-2-yl)silyl]oxy}-25-hydroxycholestane-4-carbonitrile 109-2 (31 mg, 0.057 mmol) was dissolved in a 1 mol / L tetrabutylammonium fluoride solution in tetrahydrofuran (2 mL). The mixture was stirred at room temperature for 2 hours and the reaction was monitored by TLC (petroleum ether:ethyl acetate = 4:1). After the reaction was completed, the mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain 3β,25-dihydroxy-5α-cholestane-4-carbonitrile 109 as a white solid (18.02 mg, purity: 100%, yield: 73.59%). 1 H NMR (400MHz, CDCl3) δ=3.73–3.63(m,1H),2.95(t,J=4.3,1H),2.03–1.25(m,26H ),1.21(s,6H),1.09(s,3H),1.07–0.95(m,4H),0.91(d,J=6.5,3H),0.65(s,3H). 13 C NMR (101MHz, CDCl3) δ119.61,71.13,70.24,56.38,56.12,54.98,45.71,44.40,42.54,40.17,39.73,36.66,36. 40,36.13,35.71,35.17,31.83,29.71,29.39,29.20,28.71,28.21,27.11,24.16,20.74,18.64,13.06,12.05.. LC-MS: [M+H-H2O] + =412.5.

[0371] Example 114

[0372] Preparation of Compound 114 24-[Hydroxy(2-methoxyphenyl)methyl]-7-(hydroxymethyl)-5α-cholane-3β,4β-diol

[0373] Step 1: (9R)-9-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-2,2,5a,7a-tetramethyl-11-methylidene-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1 ,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-5-(2-methoxyphenyl)-2,2,3,3-tetramethyl-4-oxa-3-siladecane 106-5 (180 mg, 0.271 mmol) was dissolved in ultra-dry tetrahydrofuran (5 mL), replaced with nitrogen, and borane dimethyl sulfide (0.406 mL, 0.812 mmol) was added under an ice-water bath. The mixed solution was stirred at room temperature for 2 hours. Subsequently, aqueous sodium hydroxide solution (0.162 mL, 1.624 mmol) and hydrogen peroxide (184.09 mg, 1.624 mmol) were added dropwise to the reaction solution. The mixed solution was stirred at room temperature overnight. The reaction solution was quenched with aqueous sodium bisulfite solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and dried by vortexing. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give [(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-8-[(9R)-5-(2-methoxyphenyl)-2,2,3,3-tetramethyl-4-oxa-3-siladec-9-yl]-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-11-yl]methanol 114-1 (90 mg, 0.112 mmol, 41.38%) as a white solid. 1H NMR(400MHz,cdcl3)δ7.60(d,J=7.6Hz,1H),7.36–7.29(m,1H),7.09(d,J=6.9Hz,1H),6.95(d,J=8.2Hz,1H),5.21(dt,J=7.6,3.9Hz,1H),4.14(s,2 H),3.96(d,J=3.3Hz,3H),3.90(s,1H),3.83(s,1H),2.05(s,2H),1.93(dt ,J=8.5,4.3Hz,5H),1.87–1.83(m,1H),1.81(d,J=2.3Hz,1H),1.75(dd,J= 13.1,3.3Hz,3H),1.71–1.67(m,2H),1.66(s,4H),1.53(ddd,J=15.3,9.1, 3.3Hz,5H),1.44(s,3H),1.42(d,J=2.8Hz,1H),1.41–1.38(m,3H),1.23(s ,3H),1.18(d,J=9.5Hz,2H),1.03(d,J=2.9Hz,9H),1.01(d,J=2.2Hz,2H), 0.98–0.91(m,1H),0.78(s,3H),0.19–0.11(m,4H),0.00(d,J=0.9Hz,3H).

[0374] Step 2: [(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-8-[(9R)-5-(2-methoxyphenyl)-2,2,3,3-tetramethyl-4-oxa-3-silanadecan-9-yl]-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a ,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-11-yl]methanol 114-1 (20 mg, 0.029 mmol) was dissolved in tetrahydrofuran (1 mL), hydrochloric acid (2 mL, 6.000 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and dried by rotary evaporation. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:4) to obtain 24-[hydroxy(2-methoxyphenyl)methyl]-7-(hydroxymethyl)-5α-cholane-3β,4β-diol 114 as a white solid (4 mg, 0.007 mmol, 23.26%)

[0375] Compound 114: 1H NMR (400MHz, CDCl3) δ7.27(s,1H),7.25(s,1H),6.96(s,1H),6.89(d,J=8.2Hz,1H),4.83(d,J=7.0Hz,1H),3. 86(s,3H),3.77(d,J=6.9Hz,1H),3.73(s,1H),3.67(t,J=10.6Hz,1H),3.58(d,J=10.9Hz,1H),1.88(d,J=12. 5Hz,5H),1.76–1.63(m,7H),1.39(dd,J=13.8,7.3Hz,3H),1.34–1.24(m,5H),1.07(s,3H),1.00(d,J=13.9Hz ,3H),0.93–0.87(m,3H),0.81(dd,J=13.8,9.3Hz,2H),0.63(d,J=2.3Hz,3H),0.07(s,2H).LC-MS:[M+H-2H2O] + =493.45.

[0376] Example 118

[0377] Preparation of Compound 118 4-(Hydroxymethyl)-5α-cholest-3β,25-diol

[0378] Step 1: Compound (5R)-5-[(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-7-acetoxy-6-hydroxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester I-8 (150 mg, 0.326 mmol, 1.0 eq) was dissolved in ethyl acetate (5 mL). Platinum dioxide (36.97 mg, 0.163 mmol, 0.5 eq) was added, and the resulting mixture was stirred in H2 at 25°C for 3 h. The reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 3:1), indicating complete consumption of the starting material. The mixture was filtered and the filtrate was concentrated to give a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 80:20) to give (5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-7-acetoxy-6-hydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoic acid methyl ester IV-1 (100 mg, 0.195 mmol, 59.74%) as a white solid. 1H NMR (400MHz, CDCl3) δ4.72(m,1H),3.83(s,1H),3.66(s,3H),2.27(dd,J=16.4,8.7Hz,2H),2.10(d,J=8. 1Hz,3H),1.79(dddd,J=37.0,16.1,10.1,3.7Hz,8H),1.29(m,8H),0.99(m,14H),0.62(d,J=14.3Hz,4H).

[0379] Step 2: In a 50 mL round-bottom flask, (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-6-hydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester IV-1 (200 mg, 0.43 mmol) was dissolved in dichloromethane (10 mL). N-methylmorpholine oxide (76 mg, 0.65 mmol), tetrapropylammonium perruthenate (30 mg, 0.086 mmol), and tetra-A molecular sieves (190 mg, 0.43 mmol) were added at room temperature. The mixture was stirred at room temperature for 24 hours. The reaction was monitored by TLC (petroleum ether / ethyl acetate = 10 / 1). After the reaction, the reaction solution was added to water (50 mL) and extracted with ethyl acetate (30 mL × 3). The extracted organic solution was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified and separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to obtain (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-6-oxoylidenehexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester 118-1 (170 mg, purity: 90%, yield: 76.83%). 1 H NMR(400MHz, CDCl3)δ5.16(dd,J=12.0,7.5Hz,1H),3.67(s,3H),2.31–2.18(m,4H),2.1 5(d,J=3.2Hz,3H),2.01–1.00(m,25H),0.92(d,J=6.6Hz,3H),0.75(s,3H),0.65(s,3H). 13C NMR(101MHz, CDCl3)δ=205.71,174.32,170.18,76.20,57.39,56.06,55.90,54.24,51.44,42.67,42.55,39.80,3 5.93,35.48,35.36,34.91,34.50,30.23,28.50,28.12,24.10,21.70,21.52,20.75,20.17,18.54,13.69,12.03.

[0380] Step 3: In a 50 mL round-bottom flask, methyltriphenylphosphonium bromide (388 mg, 1.09 mmol) was suspended in tetrahydrofuran (4 mL) at room temperature. A 1 M / L solution of potassium tert-butoxide in tetrahydrofuran (1.09 mL, 1.09 mmol) was added dropwise at 0°C. The mixture was stirred at room temperature for 2 hours. A solution of methyl (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-6-oxoylidenehexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoate 118-1 (100 mg, 0.22 mmol) in tetrahydrofuran (1 mL) was added dropwise at 0°C. The mixture was stirred at room temperature for 5 hours. The reaction was monitored by TLC (petroleum ether / ethyl acetate = 10 / 1). After the reaction, the reaction solution was added to water (30 mL) and extracted with ethyl acetate (20 mL × 3). The extracted organic solution was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified and separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to obtain (5R)-5-[(1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-6-methylidene hexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester 118-2 (64 mg, purity: 90%, yield: 57.85%) as a white solid. 1 H NMR(400MHz, CDCl3)δ5.20(d,J=11.1Hz,1H),4.69(s,1H),4.59(s,1H),3.66(s,3H),2.31–2.25(m,3H),2.13(s, 3H),2.06–1.64(m,9H),1.60–1.29(m,13H),1.12–1.02(m,5H),0.96(s,3H),0.91(d,J=6.5Hz,3H),0.65(s,3H). 13C NMR(101MHz, CDCl3)δ=174.35,170.56,147.24,129.65,115.27,103.83,74.35,56.35,55.90,54.43,52.43,51.44,42.52,39 .90,39.43,37.97,35.49,35.39,34.99,34.53,31.34,30.49,28.16,24.12,23.47,21.53,21.00,20.90,18.55,13.22,12.05.

[0381] Step 4: In a 50 mL round-bottom flask at room temperature, (5R)-5-[(1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-6-methylidene hexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester 118-2 (68 mg, 0.15 mmol) was dissolved in anhydrous tetrahydrofuran (4 mL). The reaction mixture was cooled to 0°C under nitrogen protection, and 3 mol / L methyl magnesium bromide tetrahydrofuran solution (0.50 mL, The mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate=4:1). After the reaction, the system was cooled to 0°C and quenched with saturated aqueous ammonium chloride (15 mL). The mixture was extracted with ethyl acetate (10 mL×3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether:ethyl acetate=4:1) to obtain 4-methylidenecholesta-3β,25-diol 118-3 as a white solid (34 mg, purity: 90%, yield: 46.46%). 1 H NMR (400MHz, CDCl3) δ=4.83(dd,J=115.4,50.6,2H),4.07–3.81(m,1H),2.27(dt,J=16.4,8.4,1H),1.97(dd,J=10.2,3 .8,2H),1.85–1.72(m,4H),1.63–1.32(m,20H),1.26(s,3H),1.21(s,6H),1.12–1.00(m,6H),0.91(s,3H),0.66(s,3H). 13C NMR (101MHz, CDCl3) δ152.30,151.31,102.19,101.34,72.35,71.24,70.11,55.38,55.24,55.2 0,55.13,54.36,53.48,53.45,48.86,43.40,41.58,41.50,39.04,38.94,38.63,37.58,36.75,3 6.23,35.39,34.72,34.22,33.99,32.02,30.56,29.46,28.68,28.34,28.32,28.19,27.25,23.23,23.18,23.13,22.44,21.67,20.69,19.98,19.75,17.61,13.11,12.30,11.91,11.05,11.04.

[0382] Step 5: In a 50 mL round-bottom flask, 4-methylidenecholest-3β,25-diol 118-3 (34 mg, 0.082 mmol) was dissolved in tetrahydrofuran (4 mL) at room temperature. A 2M solution of borane dimethyl sulfide complex in tetrahydrofuran (0.12 mL, 0.24 mmol) was added dropwise at 0°C. The mixture was stirred at room temperature for 3 hours. A 10M aqueous sodium hydroxide solution (0.049 mL, 0.49 mmol) and a 30% aqueous hydrogen peroxide solution (56 mg, 0.49 mmol) were then added dropwise at 0°C. The mixture was stirred at room temperature for 16 hours. The reaction was monitored by TLC (petroleum ether / ethyl acetate = 2 / 1). After completion of the reaction, the reaction mixture was added to water (10 mL) and extracted with ethyl acetate (10 mL x 3). The extracted organic solution was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified and separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain 4-(hydroxymethyl)-5α-cholest-3β,25-diol 118 as a white solid (22.27 mg, purity: 73.65%, yield: 46.05%). 1 H NMR (400MHz, CDCl3) δ = 4.26 (t, J = 10.3, 1H), 3.84 (dd, J = 11.2, 5.1, 1H), 3.60–3.53 (m, 1H), 2.35–2.27 (m, 1H),2.05–1.66(m,15H),1.59–1.33(m,16H),1.21(s,6H),0.91(d,J=6.5,3H),0.81(s,3H),0.65(s,3H). 13C NMR (101MHz, DMSO)δ=99.99,68.64,66.35,59.50,51.76,51.45,49.90,42.50,39.68,37.77,36.43,35.21,33.06,31.69,3 1.01,30.32,28.83,26.77,24.96,24.60,24.47,23.51,19.38,18.86,17.78,16.05,13.89,8.16,7.33.LC-MS: [M+H-2H2O] + =399

[0383] Example 13

[0384] Compound 13 Preparation of [(1R,3aS,3bS,5aS,7S,9aR,9bS,11aR)-7-hydroxy-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6-yl]methyl acetate and [(1R,3aS,3bS,5aS,7S,9aR,9bS,11aR)-7-acetoxy-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6-yl]methyl acetate

[0385] Step 1: 4-(Hydroxymethyl)-5α-cholesta-3β,25-diol 118 (180 mg, 0.41 mmol) was dissolved in dichloromethane (2 mL) and tetrahydrofuran (2 mL) in a 50 mL round-bottom flask at room temperature. Triethylamine (126 mg, 1.24 mmol), 4-dimethylaminopyridine (5 mg, 0.041 mmol) and acetic anhydride (42 mg, 0.41 mmol) were added at room temperature. The mixture was then stirred at room temperature for 1 hour and the reaction was monitored by TLC (petroleum ether:ethyl acetate = 3:1). After completion of the reaction, the reaction was quenched with water (30 mL), extracted with ethyl acetate (20 mL×3), the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=3:1) to give acetic acid-[(1R,3aS,3bS,5aS,7S,9aR,9bS,11aR)-7-hydroxy-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6-yl]methyl ester 13 (180 mg, purity: 90%, yield: 82.06%) as a white solid.

[0386] Compound 13: 1H NMR (400MHz, CDCl3)δ=4.34–4.18(m,2H),3.81–3.72(m,1H),2.04(s,3H),1.99– 1.93(m,1H),1.82–1.69(m,4H),1.68–1.51(m,9H),1.44–1.33(m,8H),1.29–1.24(m ,4H),1.21(s,6H),1.09–0.95(m,5H),0.91(d,J=6.5,3H),0.73(s,3H),0.63(s,3H). 13 C NMR (101MHz, CDCl3)δ=171.05,73.11,71.12,61.73,56.46,56.14,55.32,47.67,46.37,44.42,42.51,39.84,37.20 ,36.42,35.73,35.55,32.54,29.37,29.20,28.23,26.91,26.76,24.23,21.25,20.89,20.77,18.63,14.03,12.01.

[0387] Example 119

[0388] Preparation of Compound 119 4β-hydroxy-3β-hydroxy-24-[hydroxy(2-methoxyphenyl)methyl]-5α-cholane-7-carboxylic acid

[0389] Step 1: [(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-8-[(9R)-5-(2-methoxyphenyl)-2,2,3,3-tetramethyl-4-oxa-3-silanadecan-9-yl]-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12 a,12b-Hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-11-yl]methanol 114-1 (70 mg, 0.102 mmol) was dissolved in 99.9% dichloromethane (3 mL). N-methylmorpholine oxide (21 mg, 0.179 mmol), tetrapropylammonium perruthenate (14 mg, 0.040 mmol), and molecular sieves were added. The mixture was stirred at room temperature for 30 minutes. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then spin-dried. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give (3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-8-[(9R)-5-(2-methoxyphenyl)-2,2,3,3-tetramethyl-4-oxa-3-siladec-9-yl]-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxolan-11-carbaldehyde 119-1 (60 mg, 0.075 mmol, 73.08%) as a white solid. 1H NMR(400MHz,CDCl3)δ9.95(s,1H),7.45(d,J=7.7Hz,1H),7.18(s,1H),6.94(s,1H),6.81(d,J=8.2Hz,1H),5.07(d,J=3.6Hz,1H),4.00(s,2H),3.81(d,J=3.4Hz,3H),2.59(s,1H),1.97(d,J=12.8Hz,1H),1.85(d,J=5.4Hz,6H),1.63(d,J=18.7Hz,5H),1.50(s,3H),1.43(s,3H),1.35(d,J=15.3Hz,3H),1.30(s,3H),1.27– 1.19(m,3H),1.18–1.10(m,3H),1.07(s,3H),1.04(s,2H),0.97(d,J=6.6Hz,1H),0.89(s,9H),0.67(s,2H),0.02(t,J=2.7Hz,3H),0.00(d,J=3.3Hz,6H).

[0390] Step 2: (3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-8-[(9R)-5-(2-methoxyphenyl)-2,2,3,3-tetramethyl-4-oxa-3-silanadecan-9-yl]-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10 b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxolane-11-carbaldehyde 119-1 (55 mg, 0.081 mmol) was dissolved in tert-butanol (1 mL). 2-Methyl-2-butene (33.98 mg, 0.485 mmol) was added under ice-water bath and stirred for 1 minute. Subsequently, an aqueous solution of sodium chlorite (25.56 mg, 0.283 mmol) and an aqueous solution of sodium dihydrogen phosphate (2.62 mg, 0.022 mmol) were added. The mixture was brought to room temperature and stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then spin-dried. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give (3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-8-[(9R)-5-(2-methoxyphenyl)-2,2,3,3-tetramethyl-4-oxa-3-siladec-9-yl]-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxolane-11-carboxylic acid 119-2 (50 mg, 0.062 mmol, 76.39%) as a white solid. 1H NMR (400MHz, CDCl3) δ7.45(d,J=7.6Hz,1H),7.17(t,J=7.7Hz,1H),6.93(t,J=7.5Hz,1H),6.80(d,J=8.2Hz,1H),5.06(dd,J=7.1,3 .0Hz,1H),3.99(ddd,J=14.2,10.0,5.0Hz,2H),3.80(s,3H),2.79(s,1H),2.09(dd,J=13.4,5.7Hz,1H),1.93(d,J=11.3Hz,1H),1.8 3(dd,J=13.9,11.3Hz,4H),1.69(dd,J=28.9,9.6Hz,4H),1.63–1.53(m,8H),1.47(s,2H),1.37(dd,J=21.0,11.0Hz,4H),1.29(s,3H ),1.19(d,J=15.1Hz,2H),1.16–1.08(m,3H),1.06(s,3H),1.03–0.92(m,3H),0.88(s,9H),0.64(s,3H),0.01(s,3H),-0.15(s,3H).

[0391] Step 3: (3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-8-[(9R)-5-(2-methoxyphenyl)-2,2,3,3-tetramethyl-4-oxa-3-siladec-9-yl]-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxolane-11-carboxylic acid 119-2 (50 mg, 0.072 mmol) was dissolved in tetrahydrofuran (2 mL) and hydrochloric acid (1 mL, 3.000 mmol) was added. The mixture was stirred at 40°C for 2.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and spin-dried. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 90%-100%) to afford 4β-hydroxy-3β-hydroxy-24-[hydroxy(2-methoxyphenyl)methyl]-5α-cholane-7-carboxylic acid 119 (11.5 mg, 0.015 mmol, 20.68%) as a white solid.

[0392] Compound 119: 1H NMR (400MHz, DMSO) δ11.71(s,1H),7.38(d,J=7.6Hz,1H),7.17(t,J=7.2Hz,1H),6.92(dd,J=7.5,3.9Hz,2H),4.85(s,2H),4.33(d,J=5 .8Hz,1H),3.98(d,J=2.7Hz,1H),3.75(s,3H),3.40(s,1H),3.28(s,1H),2.54(s,1H),2.02(td,J=13.3,5.9Hz,1H),1.87(d,J=11.1Hz, 1H),1.78–1.68(m,1H),1.58(dd,J=11.4,5.7Hz,2H),1.48(s,3H),1.40(dd,J=22.5,13.8Hz,8H),1.32–1.25(m,2H),1.23(s,1H),1.2 1–1.11(m,2H),1.09–0.97(m,4H),0.96(s,3H),0.90(d,J=13.1Hz,1H),0.84(d,J=6.2Hz,3H),0.59(d,J=2.3Hz,3H).LC-MS: [M+H-H2O] + =525.40.

[0393] Examples 121 & 122 & 125

[0394] Compound 121: [(1R,3aS,3bS,5aS,7S,9aS,9bS,11aR)-4,4-difluoro-7-hydroxy-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6-yl]acetonitrile,

[0395] Compound 122: Preparation of (1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-6-methylidene hexahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol and Compound 125: (1R,3aS,3bS,5aS,7S,9aS,9bS,11aR)-4,4-difluoro-6-(hydroxymethyl)-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0396] Step 1: In a 50 mL round-bottom flask at room temperature, (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-7-(benzyloxy)-4,4-difluoro-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-6-ol 79-7A (790 mg, 1.445 mmol) was dissolved in 1,2-dichloroethane (60 mL). Dess-Martin periodinane (1838.04 mg, 4.335 mmol) was added and stirred at room temperature for 2 hours. The reaction was monitored by TLC (ethyl acetate / petroleum ether = 4:1). After the reaction, saturated aqueous sodium sulfite solution (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL) were added to quench the reaction, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phase was washed with saturated brine (80 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to give (1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-7-(benzyloxy)-4,4-difluoro-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6-one 121-1 (750 mg, purity: 90%, yield: 85.76%) as a white solid. 1 H NMR (400MHz, CDCl3) δ = 8.09 (d, J = 7.5, 2H), 7.58 (t, J = 7.4, 1H), 7.45 (t, J = 7.7, 2H), 5.44 (dd, J = 12.0, 7.4, 1H), 2.63 (d,J=12.3,1H),2.47–2.37(m,1H),2.23–1.23(m,25H),1.22(s,6H),0.94(d,J=6.5,3H),0.85(s,3H),0.68(s,3H). 19 F NMR (376MHz, CDCl3) δ = -90.57 (d, J = 240.1, 1F), -111.72 (d, J = 240.0, 1F).

[0397] Step 2: In a 50 mL round-bottom flask, methyltriphenylphosphonium bromide (1.3 g, 3.67 mmol) was dissolved in tetrahydrofuran (20 mL) at room temperature. A 1 M / L solution of potassium tert-butoxide in tetrahydrofuran (3.67 mL, 3.67 mmol) was added dropwise at 0°C, and the mixture was stirred at room temperature for 2 hours. A solution of (1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-7-(benzyloxy)-4,4-difluoro-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthren-6-one 121-1 (400 mg, 0.73 mmol) in tetrahydrofuran (5 mL) was added dropwise at room temperature, and the mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC (petroleum ether / ethyl acetate = 8 / 1). After completion of the reaction, the reaction solution was added to water (30 mL) and extracted with ethyl acetate (20 mL × 3). The extracted organic solution was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to obtain (6R)-6-[(1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-7-(benzyloxy)-4,4-difluoro-9a,11a-dimethyl-6-methylidenehexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-2-methylheptan-2-ol 121-2 as a white solid (158 mg, purity: 90%, yield: 35.68%). 1 H NMR (400MHz, CDCl3) δ=8.18–8.06(m,2H),7.59(q,J=7.4,1H),7.48(t,J=7.7,2H),5.47(d,J=11.3,1H),4.77(s,1H ),4.73(s,1H),2.45–2.34(m,2H),2.18–1.34(m,25H),1.21(s,6H),1.06(s,3H),0.93(d,J=6.5,3H),0.68(s,3H). 19 F NMR (376MHz, CDCl3) δ = -89.23 (d, J = 238.5, 1F), -110.87 (d, J = 238.4, 1F).

[0398] Step 3: In a 50 mL round-bottom flask at room temperature, (6R)-6-[(1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-7-(benzyloxy)-4,4-difluoro-9a,11a-dimethyl-6-methylidene hexahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2-methylheptan-2-ol 121-2 (158 mg, 0.29 mmol) was dissolved in tetrahydrofuran (2 mL) and methanol (2 mL), and lithium hydroxide monohydrate (73 mg, 1.74 mmol) and water (1 mL) were added at room temperature, followed by stirring at room temperature for 2 hours. TLC (petroleum ether:ethyl acetate) was performed. =5:1 to monitor the reaction. After the reaction, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL×3). The organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=5:1) to obtain (1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-6-methylidenehexahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 122 (120 mg, purity: 95%, yield: 86.52%) as a white solid.

[0399] Compound 122: 1 H NMR(400MHz, CDCl3)δ=4.93(d,J=1.2,1H),4.79(d,J=1.4,1H),3.91(d,J=11.0,1H),2.54–2.44(m,1H ),2.38–2.20(m,2H),2.08–1.24(m,25H),1.21(s,6H),0.95(s,3H),0.93(d,J=6.5,3H),0.68(s,3H). 13 C NMR(101MHz, CDCl3)δ=151.10,104.32,71.25,71.13,55.20,50.57,50.22,48.51,44.39,43.05,41.65,3 9.31,38.82,37.29,36.40,35.70,30.17,29.31,29.24,28.49,25.37,20.95,20.75,18.73,12.37,11.87. 19 F NMR (376MHz, CDCl3) δ = -89.00 (d, J = 237.7, 1F), -110.95 (d, J = 237.6, 1F). LC-MS: [M+H-2H2O] + =417.35.

[0400] Step 4: In a 50 mL round-bottom flask, (1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-6-methylidene hexahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 122 (213 mg, 0.47 mmol) was dissolved in tetrahydrofuran (12 mL) at room temperature, and dihydrogen 2-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-6-methylidene hexahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 122 (213 mg, 0.47 mmol) was added dropwise at 0°C. A tetrahydrofuran solution of borane dimethyl sulfide complex (0.71 mL, 1.41 mmol) was added. The mixture was stirred at room temperature for 3 hours. A 10-mol sodium hydroxide solution (0.28 mL, 2.82 mmol) and a 30% hydrogen peroxide solution (320 mg, 2.82 mmol) were then added dropwise at 0°C. The mixture was stirred at room temperature for 16 hours. The reaction was monitored by TLC (petroleum ether / ethyl acetate = 2 / 1). After completion of the reaction, the reaction solution was added to water (20 mL) and extracted with ethyl acetate (20 mL x 3). The extracted organic solution was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified and separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain a white solid (1R,3aS,3bS,5aS,7S,9aS,9bS,11aR)-4,4-difluoro-6-(hydroxymethyl)-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 125 (184 mg, purity: 95%, yield: 78.92%). 1 H NMR (400MHz, CDCl3) δ = 4.25 (t, J = 10.6, 1H), 3.82 (dd, J = 11.1, 5.3, 1H), 3.63 (dd, J = 10.9, 4.2, 1H), 2.47–2.33 (m, 2H), 2.06–1.93(m,2H),1.88–1.39(m,21H),1.21(s,6H),1.16–1.01(m,5H),0.93(d,J=6.5,3H),0.85(s,3H),0.67(s,3H). 19 F NMR (376MHz, CDCl3) δ = -88.57 (d, J = 237.7, 1F), -110.59 (d, J = 237.6, 1F). 13C NMR (101MHz, CDCl3) δ72.09,71.11,69.65,66.63,65.39,64.38,64.05,63.39,56.85,55.25,53.89,50.87,48.88,46. 80,44.39,43.03,40.85,39.27,35.71,30.18,29.73,29.34,29.25,28.50,23.39,20.76,18.73,11.86.LC-MS: [M+Na] + =493.3,

[0401] Step 5: In a 50 mL round-bottom flask at room temperature, (1R,3aS,3bS,5aS,7S,9aS,9bS,11aR)-4,4-difluoro-6-(hydroxymethyl)-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 125 (159 mg, 0.34 mmol) was dissolved in 1,2-dichloroethane (8 mL). Triethylamine (205 mg, 2.04 mmol), 4-dimethylaminopyridine (41 mg, 0.34 mmol) and p-toluenesulfonyl chloride (129 mg, 0.68 mmol) were added at room temperature, and the mixture was stirred at 50 ° C for 16 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 3:1). After completion of the reaction, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL×3). The organic phase was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=3:1) to give 4-methylbenzenesulfonic acid-[(1R,3aS,3bS,5aS,7S,9aS,9bS,11aR)-4,4-difluoro-7-hydroxy-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6-yl]methyl ester 121-3 as a white solid (155 mg, purity: 90%, yield: 66.09%). 1 H NMR (400MHz, CDCl3) δ = 7.80 (d, J = 8.3, 2H), 7.36 (d, J = 8.1, 2H), 4.29 (dd, J = 9.8, 4.2, 1H), 4.16 (t, J = 9.8, 1H), 3.72 (dd, J = 11.8, 5.1, 1 H),2.45(s,3H),2.37–2.19(m,2H),2.02–1.33(m,22H),1.22(s,6H),1.16–0.99(m,5H),0.93(d,J=6.5,3H),0.83(s,3H),0.65(s,3H). 19F NMR (376MHz, CDCl3) δ = -88.75 (d, J = 238.4, 1F), -110.46 (d, J = 238.3, 1F).

[0402] Step 6: In a 50 mL round-bottom flask at room temperature, 4-methylbenzenesulfonic acid-[(1R,3aS,7S,9aS,11aR)-4,4-difluoro-7-hydroxy-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6-yl]methyl ester 121-3 (45 mg, 0.072 mmol) was dissolved in N,N-dimethylformamide (2 mL), and sodium cyanide (18 mg, 0.36 mmol) was added at room temperature. The mixture was then stirred at 100°C for 16 hours and the reaction was monitored by TLC (petroleum ether:ethyl acetate = 4:1). After completion of the reaction, the reaction was quenched with water (10 mL), extracted with ethyl acetate (10 mL×3), the organic phase was washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=4:1) to give [(1R,3aS,3bS,5aS,7S,9aS,9bS,11aR)-4,4-difluoro-7-hydroxy-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6-yl]acetonitrile 121 (7.27 mg, purity: 100%, yield: 21.04%) as a white solid.

[0403] Compound 121: 1 H NMR (400MHz, CDCl3) δ = 4.93 (s, 0.5H), 4.79 (s, 0.5H), 4.53 (dd, J = 8.6, 1.6, 0.5H), 4.28 (t, J = 8.0, 0.5H), 3.91 (d, J=10.5,0.5H),3.37–3.29(m,0.5H),2.55–1.33(m,29H),1.21(d,J=1.1,6H),0.98–0.90(m,4.5H),0.68(s,4.5H). 19 F NMR (376MHz, CDCl3) δ = -88.87 (d, J = 136.8, 0.5F), -89.50 (d, J = 136.6, 0.5F), -110.96 (d, J = 237.7, 0.5F), -112.82 (d, J = 237.5, 0.5F). 13C NMR (101MHz, CDCl3)δ=104.31,84.94,71.11,55.20,50.67,48.68,44.40,43.08,43.05,40.40,39.42,39.31,38.82,36.40,35.72,33.50,31.61 ,30.17,29.32,29.25,28.49,25.48,25.44,24.39,21.92,20.98,20.96 ,20.87,20.77,20.75,19.07,18.98,18.73,12.37,12.05,11.90,11.87.

[0404] Example 123

[0405] Compound 123: Preparation of 4-methylidene-5α-cholest-3β,25-diol

[0406] Step 1: Dissolve the reactant (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester I-7 (500 mg, 1.124 mmol, 1.0 eq) in tetrahydrofuran (40 mL). After cooling the reaction system to 0°C, methylmagnesium chloride (3.75 mL, 11.24 mmol, 3 mol / L, 10 eq) was slowly added. The reaction system was stirred at room temperature for 2 h. The reaction was monitored by TLC plate (petroleum ether:ethyl acetate = 5:1). The reaction was stopped when the starting material was consumed. 20 mL of water was added to the reaction system, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was collected and dried over anhydrous sodium sulfate. The organic phase was vacuum-dried to obtain a crude product. The crude product was dissolved in ethyl acetate and purified by column chromatography (petroleum ether:ethyl acetate = 80:20) to obtain cholest-6(5)-ene-3β,4β,19,25-tetrol 123-1 (450 mg, purity: 90%, yield: 89.45%). 1H NMR(400MHz, CDCl3) δ5.38–5.32(m,1H),3.51(dd,J=11.6,6.8Hz,1H),2.33 –2.19(m,2H),2.06–1.92(m,2H),1.88–1.78(m,3H),1.63–1.46(m,6H),1.42 –1.31(m,4H),1.27(dd,J=7.9,4.1Hz,2H),1.21(s,6H),1.08(ddd,J=16.7,1 3.5, 6.3Hz, 5H), 1.01 (s, 3H), 0.93 (d, J = 6.6Hz, 3H), 0.66 (d, J = 12.7Hz, 3H).

[0407] Step 2: Cholest-6(5)-ene-3β,4β,19,25-tetrol 123-1 (450 mg, 1.118 mmol, 1.0 eq) was dissolved in dichloromethane (20 mL), and acetic anhydride (0.315 mL, 3.354 mmol, 3.0 eq), 4-dimethylaminopyridine (27.32 mg, 0.224 mmol, 0.2 eq) and triethylamine (0.777 mL, 5.590 mmol, 5.0 eq) were added in sequence. The mixture was stirred at room temperature for 3 hours and the reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1). After the reaction was completed, the reaction solution was quenched with methanol, washed once with saturated sodium bicarbonate (10 mL) and water (10 mL), dried over anhydrous sodium sulfate, and concentrated to dryness. Column chromatography (petroleum ether:ethyl acetate = 90:10) gave (1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate 123-2 (450 mg, 0.911 mmol, purity: 90%, yield: 81.49%) as a white solid. 1 H NMR (400MHz, CDCl3) δ5.38–5.32(m,1H),4.64-4.60(m,1H),2.33–2.19(m ,2H),2.06–1.92(m,3H),1.88–1.78(m,3H),1.63–1.46(m,6H),1.42–1.31 (m,4H),1.27(dd,J=7.9,4.1Hz,2H),1.21(s,6H),1.08(ddd,J=16.7,13. 5, 6.3Hz, 5H), 1.01 (s, 3H), 0.93 (d, J = 6.6Hz, 3H), 0.66 (d, J = 12.7Hz, 3H).

[0408] Step 3: Acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 123-2 (450 mg, 1.012 mmol, 1.0 eq) was dissolved in chloroform (20 mL) under nitrogen protection. Selenium dioxide (281 mg, 2.53 mmol, 2.5 eq) and N-methylmorpholine (307.07 mg, 3.036 mmol) were added. The reaction was heated to 75 degrees and stirred for 48 hours. TLC (petroleum ether:ethyl acetate = 3: 1) The reaction was monitored and the starting material was essentially gone. The reaction was cooled to room temperature and quenched with water. The reaction was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate = 70:30) to give (1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-6-hydroxy-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate 123-3 (310 mg, 0.606 mmol, purity: 90%, yield: 59.85%) as a white solid. 1 H NMR (400MHz, CDCl3) δ5.75-5.70(m,1H),4.80-4.70(m,1H),4.28-4.23(m ,1H),2.33–2.19(m,2H),2.06–1.92(m,3H),1.88–1.78(m,3H),1.63–1.46 (m,6H),1.42–1.31(m,4H),1.27(dd,J=7.9,4.1Hz,2H),1.21(s,6H),1.10 -1.06(m,5H),1.01(s,3H),0.93(d,J=6.6Hz,3H),0.66(d,J=12.7Hz,3H).

[0409] Step 4: Compound 123-3 (40 mg, 0.087 mmol, 1.0 eq) was dissolved in ethyl acetate (25 mL) with (1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-6-hydroxy-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate. Platinum dioxide (30 mg, 0.13 mmol, 1.5 eq) was then added, and the reaction system was replaced with a hydrogen atmosphere. The reaction system was stirred at room temperature for 24 h. Reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 3:1), indicating complete consumption of the starting material. The reaction system was filtered, and the organic phase was collected and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 82:18 to 81:19) to give (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6-hydroxy-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate 123-4 (35 mg, purity 90%, yield 78.4%) as a white solid. 1 H NMR (400MHz, CDCl3) δ4.72 (dd, J=8.2, 3.9Hz, 1H), 3.83 (s, 1H), 2.09 (s, 3H), 1.93(dd,J=25.6,12.8Hz,2H),1.78(t,J=11.4Hz,4H),1.67(d,J=12.4Hz,1H ),1.46–1.30(m,9H),1.29–1.24(m,2H),1.21(s,6H),1.14–1.08(m,3H),1.0 5(s,4H),1.02–0.95(m,2H),0.91(d,J=6.5Hz,3H),0.65(s,3H),0.61(s,1H).

[0410] Step 5: Compound (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6-hydroxy-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate 123-4 (25 mg, 0.054 mmol) was dissolved in dichloromethane (5 mL). Under nitrogen, tetrapropylammonium perruthenate (5.69 mg, 0.016 mmol), N-methylmorpholine oxide (9.49 mg, 0.081 mmol), and 4A molecular sieves were added sequentially. The mixture was stirred at room temperature and the reaction was monitored by TLC (petroleum ether:ethyl acetate = 3:1). Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with EA (3 × 25 mL). The ethyl acetate layers were combined and washed with saturated brine (3 × 10 mL). The ethyl acetate layers were dried over Na2SO4, filtered, and concentrated to obtain a crude product. After the reaction, the reaction solution was filtered, the filtrate was washed with water, the organic phase was dried, concentrated, and the crude product was purified by flash column chromatography (petroleum ether:ethyl acetate = 81:19) to obtain (1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-6-oxoylidenehexahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate 123-5 (25 mg, 90% purity, 90% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δ5.16(dd,J=12.2,7.4Hz,1H),2.22(dd,J=19.4,6.6Hz,2H),2.15(s,3H),2.02–1.71(m,5H),1.60(dd, J=18.1,14.5Hz,3H),1.46–1.24(m,11H),1.21(s,6H),1.14–1.00(m,4H),0.92(d,J=6.5Hz,3H),0.75(s,3H),0.65(s,3H).

[0411] Step 6: In a 50 mL round-bottom flask, methyltriphenylphosphonium bromide (4.65 g, 13.02 mmol) was suspended in tetrahydrofuran (50 mL) at room temperature, and 1 M / L potassium tert-butoxide tetrahydrofuran solution (13.02 mL, 13.02 mmol) was added dropwise at 0°C. After the mixture was stirred at room temperature for 2 hours, a solution of (1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-6-oxoylidenehexahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate 123-5 (1.2 g, 2.60 mmol) in tetrahydrofuran (10 mL) was added dropwise at room temperature, and the mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC (petroleum ether / ethyl acetate = 10 / 1). After completion of the reaction, the reaction solution was added to water (50 mL) and extracted with ethyl acetate (40 mL × 3). The extracted organic solution was washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified and separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to obtain (1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-6-methylidene hexadecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate 123-6 as a white solid (612 mg, purity: 95%, yield: 48.66%). 1 H NMR (400MHz, CDCl3) δ = 5.11 (dd, J = 11.8, 5.3, 1H), 4.86 (s, 1H), 4.59 (s, 1H), 2.12 (s, 3H), 2.04 –1.24(m,24H),1.21(s,6H),1.16–1.00(m,5H),0.92(d,J=6.6,3H),0.71(s,3H),0.65(s,3H).

[0412] Step 7: In a 50 mL round-bottom flask at room temperature, (1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-6-methylidene hexahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate 123-6 (700 g, 1.53 mmol) was dissolved in tetrahydrofuran (10 mL) and methanol (10 mL), and lithium hydroxide monohydrate (385 mg, 9.16 mmol) and water (5 mL) were added at room temperature, followed by stirring at room temperature for 1 hour, and the reaction was monitored by TLC (petroleum ether:ethyl acetate = 4:1). After the reaction, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated brine (60 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to give 4-methylidene-5α-cholest-3β,25-diol 123 as a white solid (614 mg, purity: 97%, yield: 93.67%).

[0413] Compound 123: 1 H NMR (400MHz, CDCl3) δ = 5.04 (s, 1H), 4.63 (s, 1H), 3.99 (dd, J = 11.4, 5.4, 1H), 1.99 (ddd, J = 11.8, 8.5, 3.3 ,2H),1.89–1.27(m,23H),1.21(s,6H),1.14–1.00(m,5H),0.92(d,J=6.5,3H),0.69(s,3H),0.65(s,3H). 13 C NMR (101MHz, CDCl3) δ = 153.33, 102.35, 73.37, 71.13, 56.28, 56.24, 54.49, 49.90, 44.42, 42.62, 40.08, 38.61, 37.27, 36. 43,35.76,35.26,33.05,31.61,29.36,29.21,28.28,24.27,24.21,21.72,20.78,18.63,12.93,12.07.LC-MS: [M+H-2H2O] + =381.3.

[0414] Example 137:

[0415] Compound 137: Preparation of 24-[Hydroxy(2-methoxyphenyl)methyl]-7-methyl-5α-cholane-3β,4β-diol

[0416] Step 1: (9R)-9-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-2,2,5a,7a-tetramethyl-11-methylidene-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1 137-1 (20 mg, 25 mg, 0.038 mmol) was dissolved in methanol (5 mL) and Pd / C (13 mg, 0.061 mmol) was added. The atmosphere was replaced with hydrogen, and the mixture was stirred at 40°C for 1 hour. The mixture was filtered through Celite overnight and dried to give the crude product 137-1 (20 mg), which was used directly in the next step.

[0417] Step 2: (9R)-9-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-2,2,5a,7a,11-pentamethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2 ':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-5-(2-methoxyphenyl)-2,2,3,3-tetramethyl-4-oxa-3-siladecane 137-1 (20 mg, 0.030 mmol) was dissolved in tetrahydrofuran (2 mL), and hydrochloric acid (1 mL, 3.000 mmol) was added. The mixture was reacted at 40°C for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and spin-dried to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to afford 2,4-[hydroxy(2-methoxyphenyl)methyl]-7-methyl-5α-cholane-3β,4β-diol 137 as a white solid (4.5 mg, 0.007 mmol, 17.32% yield over two steps).

[0418] Compound 137: 1H NMR (400MHz, CDCl3) δ7.32–7.27(m,1H),7.25–7.21(m,1H),6.95(t,J=7.4Hz,1H),6.88(d,J=8.2Hz,1H),4.85(dt,J=9.6,5. 8Hz,1H),3.86(s,3H),3.71(d,J=2.2Hz,1H),3.68–3.64(m,0H),3.60–3.51(m,1H),1.96(d,J=13.0Hz,1H),1.74(dd,J=15.3 ,5.3Hz,4H),1.67–1.60(m,4H),1.54(dd,J=20.4,7.7Hz,3H),1.49–1.42(m,2H),1.41–1.30(m,5H),1.27(d,J=12.7Hz,3H), 1.13–1.05(m,4H),1.03(s,1H),1.00(d,J=6.0Hz,3H),0.98(s,3H),0.92–0.87(m,3H),0.66–0.62(m,3H).LC-MS: [M+H-H2O] + =477.50.

[0419] Example 138:

[0420] Compound 138: Preparation of (1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-5,5-difluoro-6-hydroxy-6-methylhept-2-yl]-4,4-difluoro-7-hydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6-one

[0421] Step 1: Compound (1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-7-(benzyloxy)-1-[(2R)-5,5-difluoro-6-hydroxy-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6-ol 94-7 (110 mg, 0.189 mmol, 1 eq) was dissolved in dichloromethane (5 mL), and Dess-Martin periodinane (160 mg, 0.378 mmol, 2 eq) was slowly added. The mixture was stirred at room temperature for 3 hours and monitored by TLC (petroleum ether:ethyl acetate = 4:1). After the reaction was completed, water was added to quench the reaction, and then the mixture was extracted with ethyl acetate (50 mL). The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product. The crude product was separated and purified by flash chromatography (petroleum ether:ethyl acetate = 100:0 to 3:1) to obtain (1R,3aS,3bS,7S,9aR,9bS,11aR)-7-(benzyloxy)-1-[(2R)-5,5-difluoro-6-hydroxy-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6-one as a white solid 138-1 (109 mg, purity: 97%, yield: 73%). 1 H NMR (400MHz, CDCl3) δ8.12–8.05(m,2H),7.58(t,J=7.4Hz,1H),7.45(t,J=7.7Hz,2H ),5.44(dd,J=11.9,7.5Hz,1H),2.63(d,J=13.8Hz,1H),2.42(s,1H),2.14–1.99(m,6 H),1.96–1.82(m,4H),1.79–1.60(m,7H),1.49(dd,J=11.0,6.9Hz,3H),1.36(d,J=5. 9Hz, 5H), 1.31 (s, 6H), 1.29 (s, 2H), 0.95 (d, J = 6.5Hz, 3H), 0.85 (s, 3H), 0.69 (s, 3H).

[0422] Step 2: (1R,3aS,3bS,7S,9aR,9bS,11aR)-7-(benzyloxy)-1-[(2R)-5,5-difluoro-6-hydroxy-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6-one 138-1 (15 mg, 0.025 mmol, 1.0 eq) was dissolved in tetrahydrofuran (0.5 mL) and methanol (0.5 mL) at room temperature. Lithium hydroxide monohydrate (11 mg, 0.25 mmol, 10.0 eq) and water (0.2 mL) were added, followed by stirring at room temperature for 30 min. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 10:1). After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 2), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated. The crude product was separated and purified by flash chromatography (petroleum ether: ethyl acetate = 100:0 to 3:1) to give (1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-5,5-difluoro-6-hydroxy-6-methylhept-2-yl]-4,4-difluoro-7-hydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6-one 138 (6.2 mg, purity 100%, yield 52%) as a white solid.

[0423] Compound 138: 1 H NMR (400MHz, CDCl3) δ4.15(t,J=8.2Hz,1H),3.49(d,J=3.4Hz,1H),2.55–2.42(m,2H),2.11(d,J=8.9Hz,1H) ,2.02(d,J=12.5Hz,2H),1.91(d,J=13.0Hz,2H),1.84(d,J=5.5Hz,1H),1.73(s,2H),1.67(s,1H),1.62(d,J =11.8Hz,2H),1.55(d,J=9.3Hz,2H),1.48(d,J=7.5Hz,2H),1.37(s,1H),1.33(s,1H),1.31(s,6H),1.29(s, 2H), 1.15 (t, J = 9.3Hz, 2H), 0.94 (d, J = 6.5Hz, 3H), 0.88 (t, J = 6.7Hz, 1H), 0.77 (s, 3H), 0.69 (d, J = 7.5Hz, 3H). 19 F NMR(377MHz, CDCl3)δ-90.22,-90.85,-111.49,-112.12,-115.16,-115.81,-116.09,-116.74.LC-MS:[MH]+ =489.35.

[0424] Example 139:

[0425] Compound 139: Preparation of (1R,3aR,7S,9aR,9bR,11aR)-1-[(2R)-5,5-difluoro-6-hydroxy-6-methylhept-2-yl]-4-fluoro-9a,11a-dimethyl-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0426] Step 1: At room temperature, (3S, 4R, 5R, 8S, 9S, 10R, 13R, 14S, 17R)-17-((R)-6-acetoxy-5,5-difluoro-6-methylheptane-2-yl)-10,13-dimethyl-7-oxohexadecahydro-1H-cyclopentadienyl[a]phenanthrene-3,4-diyl diacetate 94-4 (53 mg, 0.089 mmol) was dissolved in diethylaminosulfur trifluoride (2 mL) and stirred at 70 ° C for 2 hours. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 4:1). After the reaction was completed, the reaction solution was diluted with ethyl acetate and slowly added dropwise to ice water (20 mL) for quenching. The mixture was extracted with ethyl acetate (15 mL × 2) and the mixture was quenched. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The organic phase was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give (6R)-6-[(1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-6,7-diacetoxy-4-fluoro-9a,11a-dimethyl-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-3,3-difluoro-2-methylhept-2-yl acetate 139-1 (4.5 mg, purity: 90%, yield: 8.2%) as a white solid.

[0427] Step 2: At room temperature, a white solid (6R)-6-[(1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-6,7-diacetoxy-4-fluoro-9a,11a-dimethyl-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetrahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-3,3-difluoro-2-methylhept-2-yl acetate 139-1 (45 mg, 0.073 mmol, 1.0 eq) was obtained. The product was dissolved in tetrahydrofuran (1 mL) and methanol (1 mL), and lithium hydroxide monohydrate (15 mg, 0.365 mmol, 5.0 eq) and water (0.5 mL) were added at room temperature, followed by stirring at room temperature for 30 min. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 10:1). After the reaction was completed, the product was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 2), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1). As a white solid, (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-1-[(2R)-5,5-difluoro-6-hydroxy-6-methylhept-2-yl]-4-fluoro-9a,11a-dimethyl-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 139-2 (28 mg, purity: 90%, yield: 77.78%) was obtained.

[0428] Step 3: (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-1-[(2R)-5,5-difluoro-6-hydroxy-6-methylhept-2-yl]-4-fluoro-9a,11a-dimethyl-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 139-2 (28 mg, 0.057 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL) and tetrahydrofuran (1 mL) at room temperature, and triethylamine (35 mg) was added. , 0.34 mmol, 6.0 eq), 4-dimethylaminopyridine (7 mg, 0.057 mmol, 1.0 eq) and benzoyl chloride (24 mg, 0.17 mmol, 3.0 eq), and then stirred at room temperature for 8 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate=1:1). After the reaction was completed, the product was quenched with water (10 mL) and extracted with ethyl acetate (10 mL×2). The organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1) and SFC (Instrument:Waters Acquity UPCC, Column:Daicel CHIRALPAK IC_3,3.0*150 mm,3 um, Mobile Phase:A / B:CO2 / MeOH(0.1%DEA)=50 / 50, Flow rate:1.5 ml / min, Column Temp: 37 degrees) was split to give a white solid (benzoic acid-(1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-1-[(2R)-5,5-difluoro-6-hydroxy-6-methylhept-2-yl]-4-fluoro-6-hydroxy-9a,11a-dimethyl-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 139-3 (15 mg, purity: 95%, yield: 44.12%, retention time t R =1.624min). 1H NMR (400MHz, CDCl3) δ8.04(d,J=8.1Hz,2H),7.58(t,J=7.2Hz,1H),7.45(t,J=7.7Hz, 2H),4.99(dd,J=8.3,3.6Hz,1H),3.98(s,1H),2.25(dd,J=34.8,4.1Hz,1H),2.08–1.9 5(m,3H),1.89–1.71(m,9H),1.59–1.44(m,6H),1.31(s,6H),1.26(s,1H),1.17(d,J= 13.4Hz, 2H), 1.14 (s, 3H), 1.02 (t, J = 10.2Hz, 1H), 0.95 (d, J = 6.5Hz, 3H), 0.69 (s, 3H).

[0429] Step 4: (1R,3aR,7S,9aR,9bR,11aR)-7-(benzyloxy)-1-[(2R)-5,5-difluoro-6-hydroxy-6-methylhept-2-yl]-4-fluoro-9a,11a-dimethyl-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-6-ol 139-3 (15 mg, 0.025 mmol, 1.0 eq) was dissolved in tetrahydrofuran (0.5 mL) at room temperature. ) and methanol (0.5 mL), lithium hydroxide monohydrate (11 mg, 0.25 mmol, 10.0 eq) and water (0.2 mL) were added at room temperature, followed by stirring at room temperature for 30 min, and the reaction was monitored by TLC (petroleum ether: ethyl acetate = 10:1). After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (10 mL×2), the organic phase was washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated, and the crude product was separated and purified by flash chromatography (petroleum ether: ethyl acetate = 100:0 to The reaction mixture was stirred for 1 h at 37 ℃ for 2 h (3:1) to give (1R,3aR,7S,9aR,9bR,11aR)-1-[(2R)-5,5-difluoro-6-hydroxy-6-methylhept-2-yl]-4-fluoro-9a,11a-dimethyl-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol as a white solid 139 (10 mg, purity 100%, yield 79%).

[0430] Compound 139: 1H NMR (400MHz, CDCl3) δ3.85 (s, 1H), 3.60 (d, J = 11.0Hz, 1H), 2.66 (t, J = 12.4Hz, 1H), 2.14 (s, 1H),2.01(t,J=11.5Hz,3H),1.89(s,2H),1.85(d,J=4.1Hz,1H),1.77(s,2H),1.71(s,1H), 1.63–1.55(m,4H),1.47–1.44(m,2H),1.37(s,1H),1.33(s,1H),1.30(s,6H),1.28(s,2H), 1.13–1.08(m,2H),1.05(s,3H),0.95(d,J=6.5Hz,3H),0.88(t,J=6.6Hz,1H),0.65(s,3H). 19 F NMR(377MHz, CDCl3)δ-109.66,-115.15,-115.80,-116.12,-116.77.LC-MS:[MH] + =471.35.

[0431] Example 143:

[0432] Compound 143: Preparation of 7-amino-24-[hydroxy(2-methoxyphenyl)methyl]-5α-cholane-3β,4β-diol

[0433] Step 1: Compound (3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-8-[(9R)-5-(2-methoxyphenyl)-2,2,3,3-tetramethyl-4-oxa-3-siladecan-9-yl]-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxolane-11-one 1 06-4 (50 mg, 0.075 mmol, 1.0 eq) was dissolved in a mixture of tetrahydrofuran (2 mL) and methanol (1 mL). Catalytic amounts of acetic acid (0.001 mL, 0.014 mmol) and ammonium acetate (57.81 mg, 0.750 mmol, 10 eq) were added. The resulting mixture was stirred at 25°C under N2 for 1 h. Subsequently, sodium cyanoborohydride (reducing agent) (47.13 mg, 0.750 mmol, 10 eq) was added and stirring continued for 2 h. The reaction progress was monitored by TLC (dichloromethane:methanol = 10:1). The reaction was quenched with water, and the aqueous layer was extracted with dichloromethane (3 × 10 mL). The dichloromethane layers were combined and washed with saturated brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a crude product, which was purified by silica gel column chromatography (dichloromethane: methanol = 10:1) to give (3aS, 5aR, 5bS, 7aR, 8R, 10aS, 10bS, 12aR, 12bR)-8-[(9R)-5-(2-methoxyphenyl)-2,2,3,3-tetramethyl-4-oxa-3-silicon]-4-nitropropene] ...4-tetramethyl-4-oxa-3-silicon]-4-nitropropene]-2,2,3,4- [9-hexadecyl]-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxolan-11-amine 143-1 (30 mg, 0.043 mmol, purity: 90%, yield: 56.87%). LC-MS: [M+H] + =668.4.

[0434] Step 2: Compound (3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-8-[(9R)-5-(2-methoxyphenyl)-2,2,3,3-tetramethyl-4-oxa-3-silanadecan-9-yl]-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,1 2a,12b-Hexadecahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxolan-11-amine 143-1 (30 mg, 0.05 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 mL). Dilute hydrochloric acid (0.05 mL) was added and stirred at 25°C for 1 hour and then for 2 hours. The reaction progress was monitored by TLC (dichloromethane:methanol = 5:1). The reaction was quenched with water, and the aqueous layer was extracted with dichloromethane (3 × 10 mL). The dichloromethane layers were combined and washed with saturated brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to give 7-amino-24-[hydroxy(2-methoxyphenyl)methyl]-5α-cholane-3β,4β-diol 143 (17.79 mg, 0.034 mmol, purity: 97.15%, yield: 74.92%) as a white solid.

[0435] Compound 143: 1 H NMR (400MHz, DMSO) δ7.55 (s, 1H), 7.38 (m, 1H), 7.18 (t, J = 7.8Hz, 1H), 6.92 (m, 2H), 4.86 (s, 2H) ,4.42(d,J=5.8Hz,1H),4.17(t,J=6.3Hz,1H),3.75(d,J=3.0Hz,3H),3.44(d,J=22.4Hz,1H),3. 26(m,1H),1.94(dd,J=27.6,11.7Hz,2H),1.75(m,3H),1.59(t,J=12.9Hz,4H),1.43(s,5H),1. 25(m,7H),1.00(s,6H),0.96(s,4H),0.86(d,J=5.8Hz,3H),0.61(d,J=2.5Hz,3H).LC-MS:[M+H] + =427.3.

[0436] Example 144:

[0437] Compound 144: Preparation of 4-methyl-5α-cholest-3β,25-diol

[0438] Step 1: Dissolve (3S,5R,8S,9S,10R,13R,14S,17R)-17-((R)-6-hydroxy-6-methylheptan-2-yl)-10,13-dimethyl-4-methylenehexahydro-1H-cyclopenta[a]phenanthren-3-ol 123 (25 mg, 0.060 mmol, 1 eq) in dichloromethane (2 mL) at room temperature. Add DMAP (2 mg, 0.016 mmol, 0.3 eq) and triethylamine (36 mg, 0.36 mmol, 6 eq). Cool to 0°C in an ice bath, and slowly add a solution of acetic anhydride (12 mg, 0.12 mmol, 2 eq) in dichloromethane (0.5 mL) dropwise. After 10 min, warm to room temperature and stir for 6 h. Quench the reaction with water and extract with dichloromethane (10 mL x 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude product. The crude product was separated by column chromatography (4 g, 0-10% EtOAc / PE, 20 mL / min) to afford (R)-6-((3S,5R,8S,9S,10R,13R,14S,17R)-3-acetoxy-10,13-dimethyl-4-methylenedecadecahydro-1H-cyclopentylphenanthren-17-yl)-2-methylhept-2-yl acetate 144-1 (10 mg, purity: 90%, yield: 43.3%). 1 H NMR (400MHz, CDCl3) δ5.11(d,J=6.7Hz,1H),4.86(s,1H),4.59(s,1H),2.12(s,3H),2.05–1.89(m,3H),1.77(dd,J=27.1,12.6Hz,5H),1.56(d,J= 12.7Hz,3H),1.47–1.31(m,10H),1.21(s,6H),1.09(dd,J=24.8,14.8Hz, 5H),0.92(d,J=6.3Hz,3H),0.88–0.76(m,2H),0.71(s,3H),0.65(s,3H).

[0439] Step 2: (R)-6-((3S,5R,8S,9S,10R,13R,14S,17R)-3-acetoxy-10,13-dimethyl-4-methylenedecadecahydro-1H-cyclopentylphenanthren-17-yl)-2-methylhept-2-yl acetate 144-1 (10 mg, 0.020 mmol, 1 eq) was dissolved in ethyl acetate (3 mL) at room temperature. 10% Pd / C (20 mg) and acetic acid (0.1 mL) were added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 16 h. The reaction was monitored by H NMR. After the reaction, the reaction solution was diluted with ethyl acetate (10 mL), filtered through celite, and the filtrate was washed with saturated sodium bicarbonate solution (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give (6R)-6-((3S, 5S, 8S, 9S, 10R, 13R, 14S, 17R)-3-acetoxy-4,10,13-trimethylhexahydro-1H-cyclopentadienylphenanthren-17-yl)-2-methylheptane-2-yl acetate 144-2 (5 mg, purity: 90%, yield: 44.8%) as a white solid. 1 H NMR (400MHz, CDCl3) δ4.89–4.27(m,1H),2.10(s,1H),2.04(d,J=4.5Hz,1H),1.97(s,1H),1.71(d,J=10.9Hz,3H), 1.42(d,J=3.9Hz,6H), 1.04(dd,J=15.6,9.8Hz,7H), 0.85(ddd,J=20.0,11.2,5.5Hz,11H), 0.64(d,J=4.9Hz,3H).

[0440] Step 3: At room temperature, (6R)-6-((3S, 5S, 8S, 9S, 10R, 13R, 14S, 17R)-3-acetoxy-4,10,13-trimethylhexahydro-1H-cyclopentadienylphenanthren-17-yl)-2-methylheptane-2-yl acetate 144-2 (5 mg, 0.010 mmol, 1.0 eq) was dissolved in tetrahydrofuran (0.5 mL) and methanol (0.5 mL), and lithium hydroxide monohydrate (8 mg, 0.19 mmol, 19.2 eq) and water (0.2 mL) were added at room temperature, followed by stirring at room temperature for 2 hours and in an oil bath at 60°C for 3 hours. The reaction was detected to be complete by TLC plate (petroleum ether: ethyl acetate = 4:1, phosphomolybdic acid baking plate). After the reaction, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 2), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The organic phase was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give 4-methyl-5α-cholesta-3β,25-diol 144 as a white solid (3.07 mg, purity: 99.6%, yield: 38.3%).

[0441] Compound 144: 1 H NMR (400MHz, CDCl3) δ3.79–2.95(m,1H),1.95(d,J=12.7Hz,1H),1.82–1.66(m,3H),1.58(d,J=8.3Hz,4H),1.48–1.32(m,10H),1.27(d,J=12.2 Hz,3H),1.21(s,6H),1.12–0.98(m,5H),0.96–0.87(m,7H),0.83(d,J=6 .3Hz,3H),0.80–0.67(m,1H),0.64(d,J=4.9Hz,3H),0.62–0.55(m,1H).

[0442] Example 158 & 159:

[0443] Preparation of compound 158 [(1R,3aS,3bS,4Z,6R,7S,9aR,9bS,11aR)-6,7-dihydroxy-1-[(2R)-6-hydroxy-6-(2-methoxyphenyl)hexan-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthren-4-ylidene]acetonitrile and compound 159 [(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-6,7-dihydroxy-1-[(2R)-6-hydroxy-6-(2-methoxyphenyl)hexan-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthren-4-yl]acetonitrile.

[0444] Step 1: In an ice-water bath, n-butyl lithium (0.180 mL, 0.450 mmol) solution was added dropwise to a solution of diethyl cyanomethylphosphonate (87.63 mg, 0.495 mmol) in tetrahydrofuran (5 mL). After stirring for 30 minutes, (3aS, 5aR, 5bS, 7aR, 8R, 10aS, 10bS, 12aR, 12bR)-8-[(9R)-5-(2-methoxyphenyl)-2,2,3,3-tetramethyl-4-oxa- 3-Siladecan-9-yl]-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxolan-11-one 106-4 (30 mg, 0.045 mmol) was dissolved in tetrahydrofuran and added dropwise to the reaction flask. The mixture was stirred at room temperature for 2 hours. The reaction solution was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain the crude product. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 8%) to give [(3aS,5aR,5bS,7aR,8R,10aS,10bS,11Z,12aR,12bR)-8-[(9R)-5-(2-methoxyphenyl)-2,2,3,3-tetramethyl-4-oxa-3-siladec-9-yl]-2,2,5a,7a-tetramethyl -4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-Hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-11-ylidene]acetonitrile as a colorless transparent solid 159-1 (45 mg, 0.055 mmol, 61.62%). 1H NMR(400MHz,CDCl3)δ7.45(d,J=7.6Hz,1H),7.18(s,1H),6.95(d,J=7.4Hz,1H),6.81(d,J=8.2Hz,1H),5.14–4.99(m,2H),4.12(d,J=7.1Hz,1H),4.07–3.97(m,1H),3.81(s,3H),2.83(dd,J=12.8,2.4Hz,1H),2.44(s,1H),2.28(s,1H),2.02(d,J=13.0Hz,1H),1.93–1.77(m,4H),1.73–1.59(m,3H),1.52(s,4H),1.42(ddd,J=23.0,18.0,9.9Hz,7H),1.32(s,3H),1.26(dd,J=6.3,3.5Hz,3H),1.21(s,3H),1.09(d,J=8.8Hz,2H),1.06–0.96(m,3H),0.89(s,9H),0.82(dd,J=12.0,7.0Hz,2H),0.67(d,J=6.0Hz,3H),0.02(t,J=3.0Hz,3H),-0.14(s,3H).

[0445] Step 2: [(3aS,5aR,5bS,7aR,8R,10aS,10bS,11Z,12bR)-8-[(9R)-5-(2-methoxyphenyl)-2,2,3,3-tetramethyl-4-oxa-3-silanadecan-9-yl]-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b, 11,12,12a,12b-Hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-11-ylidene]acetonitrile 159-1 (40 mg, 0.058 mmol) was dissolved in methanol (5 mL). Pd / C (20 mg, 0.094 mmol) was added, and the atmosphere was replaced with hydrogen. The mixture was stirred at 40°C for 2 hours. TLC (petroleum ether / ethyl acetate = 5 / 1) revealed complete reaction of the starting material, with the presence of a new spot of increased polarity. The Pd / C was filtered through celite and dried in a vacuum. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 10%) to give [(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-8-[(9R)-5-(2-methoxyphenyl)-2,2,3,3-tetramethyl-4-oxa-3-siladec-9-yl]-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-11-yl]acetonitrile 159-2 as a white solid (20 mg, 0.025 mmol, 42.35%). 1 H NMR (400MHz, CDCl3) δ7.60(d,J=7.6Hz,1H),7.32(s,1H),7.09(d,J=7.4Hz,1H),6.95(d,J=8.1Hz,1H),5.26–5.16 (m,1H),4.20–4.07(m,2H),3.95(s,3H),2.69(s,2H),2.14(d,J=12.6Hz,1H),2.02–1.78(m,7H),1.70(d,J=15.0H z,6H),1.65(s,3H),1.57(s,1H),1.55–1.46(m,5H),1.45(s,3H),1.41(d,J=12.9Hz,3H),1.34–1.23(m,3H),1.18 (s,3H),1.13(dd,J=16.0,8.1Hz,2H),1.03(s,9H),0.99(s,2H),0.83(d,J=5.8Hz,3H),0.16(s,3H),-0.00(s,3H).

[0446] Step 3: [(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-8-[(9R)-5-(2-methoxyphenyl)-2,2,3,3-tetramethyl-4-oxa-3-siladec-9-yl]-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-11-yl]acetonitrile 159-2 (35 mg, 0.051 mmol) was dissolved in tetrahydrofuran (3 mL), hydrochloric acid (2 mL, 6.000 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and then spin-dried. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 50%) to give [(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-6,7-dihydroxy-1-[(2R)-6-hydroxy-6-(2-methoxyphenyl)hexan-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthren-4-yl]acetonitrile 159 (5 mg, 0.008 mmol, 15.63%) as a white solid.

[0447] Compound 159: 1 H NMR (400MHz, CDCl3) δ7.31–7.27(m,1H),7.26–7.21(m,1H),6.96(t,J=7.4Hz,1H),6.88(d,J=8.2Hz,1H),4.89–4.80(m,1H),3. 86(s,3H),3.74(s,1H),3.56(d,J=10.7Hz,1H),2.54(d,J=4.5Hz,2H),1.99(d,J=12.1Hz,2H),1.86(t,J=10.0Hz,2H),1.76(d, J=10.3Hz,3H),1.69–1.63(m,3H),1.51(dd,J=12.3,7.2Hz,3H),1.43–1.32(m,6H),1.27(d,J=12.7Hz,3H),1.10(dd,J=17.6,8 .8Hz,4H),1.03(s,3H),0.97(dd,J=14.0,3.6Hz,1H),0.90(dd,J=6.4,3.6Hz,3H),0.69(d,J=2.6Hz,3H).LCMS(ESI)[M+H-H2O] + =520.45,t R =6.941min.

[0448] Step 4: [(3aS,5aR,5bS,7aR,8R,10aS,10bS,11Z,12bR)-8-[(9R)-5-(2-methoxyphenyl)-2,2,3,3-tetramethyl-4-oxa-3-silanadecan-9-yl]-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a, 10b,11,12,12a,12b-Hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-11-ylidene]acetonitrile 159-1 (40 mg, 0.058 mmol) was dissolved in tetrahydrofuran (3 mL). Hydrochloric acid (2 mL, 6.000 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 50%) to give [(1R,3aS,3bS,4Z,6R,7S,9aR,9bS,11aR)-6,7-dihydroxy-1-[(2R)-6-hydroxy-6-(2-methoxyphenyl)hexan-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthren-4-ylidene]acetonitrile 158 (15 mg, 0.024 mmol, 42.03%) as a white solid.

[0449] Compound 158: 1 H NMR (400MHz, CDCl3) δ7.33–7.27(m,1H),7.26–7.20(m,1H),6.96(t,J=7.5Hz,1H),6.89(d,J=8.2Hz,1H),5.06(s,1H),4.85 (dt,J=9.6,5.8Hz,1H),3.86(s,4H),3.62–3.52(m,1H),2.73(dd,J=12.7,2.3Hz,1H),2.55(t,J=13.0Hz,1H),2.24(t,J=10 .9Hz,1H),2.01(d,J=12.6Hz,2H),1.85(d,J=6.6Hz,2H),1.78–1.67(m,4H),1.43(dd,J=15.2,4.9Hz,5H),1.32–1.22(m,4H ),1.19(s,3H),1.15–1.05(m,3H),1.04–0.95(m,2H),0.92(dd,J=6.4,4.0Hz,3H),0.84–0.78(m,1H),0.67(d,J=2.4Hz,3H). 13C NMR (101MHz, CDCl3) δ156.57,132.56,128.27,127.01,126.88,120.76,117.66,11 0.57,90.13,74.06,71.84,71.35,70.95,56.44,55.28,54.96,51.72,49.47,43.80 ,42.94,38.33,37.74,37.55,36.48,36.28,35.99,35.79,35.61,35.47,35.40,31. 54,28.06,25.64,25.07,22.70,22.56,18.74,12.13,-0.01.LCMS(ESI)[M+H-2H2O] + =500.37,t R =5.860min.

[0450] Example 160:

[0451] Compound 160 Preparation of 25-hydroxy-4β-hydroxy-3β-hydroxy-5α-cholest-7-carbonitrile.

[0452] Step 1: At room temperature, (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-2,2,5a,7a-tetramethyl-11-oxy-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1 Methyl ',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]hexanoate I-12 (200 mg, 0.421 mmol, 1 eq) was dissolved in methanol (5 mL) and cooled to 0°C under nitrogen. Sodium borohydride (24 mg, 0.632 mmol, 1.5 eq) was added and then stirred at room temperature for 2 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 2:1). After the reaction was completed, the product was quenched with water (30 mL) and extracted with ethyl acetate (30 mL × 2). The organic phase was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The organic phase was dried to obtain a white solid (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11-hydroxy-2,2,5 a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]hexanoic acid methyl ester 160-1 (200 mg, purity: 95%, yield: 99%) was directly added to the rear.

[0453] Step 2: Methyl (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11-hydroxy-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]hexanoate 160-1 (200 mg, 0.42 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) at room temperature. The mixture was cooled to 0°C under nitrogen protection and methylmagnesium bromide (3 M in ) was added dropwise. 2-Me-THF, 0.86 mL, 4.19 mmol, 10 eq), and then stirred at room temperature for 2 hours. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 2: 1). After the reaction was completed, the system was cooled to 0°C and quenched with saturated aqueous ammonium chloride (30 mL). The mixture was extracted with ethyl acetate (30 mL × 2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4: 1) to obtain a white solid (3aS, 5aR, 5bS, 7aR, 8R,10aS,10bS,12aR,12bR)-8-[(2R)-6-hydroxy-6-methylhept-2-yl]-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxol-11-ol 160-2 (139 mg, purity: 95%, yield: 67%). 1 H NMR (400MHz, CDCl3) δ4.05–3.92(m,3H),1.98–1.89(m,2H),1.80(dd,J=14.1,7.2Hz,3H),1.75–1.54(m,6H),1 .48–1.33(m,13H),1.30(s,3H),1.27(dd,J=9.8,2.6Hz,4H),1.21(s,6H),1.19–1.10(m,4H),1.05(d,J=7.6Hz, 3H), 0.92 (d, J = 6.5Hz, 3H), 0.68 (d, J = 8.2Hz, 3H).

[0454] Step 3: (3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-8-[(2R)-6-hydroxy-6-methylhept-2-yl]-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[ 1',2':7,8]phenanthro[1,2-d][1,3]dioxol-11-ol 160-2 (130 mg, 0.273 mmol, 1.0 eq) was dissolved in tetrahydrofuran (10 mL), and Dess-Martin periodinane (424 mg, 0.545 mmol, 2 eq) was added at room temperature. The mixture was stirred at room temperature for 1 hour and monitored by TLC (petroleum ether:ethyl acetate = 2:1). After the reaction was completed, the mixture was quenched with ice water (50 mL) and extracted with ethyl acetate (30 mL × 2). The organic phase was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain (3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-8-[(2R)-6-hydroxy-1 ... -6-methylhept-2-yl]-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxolan-11-one 160-3 (110 mg, purity: 95%, yield: 85%). 1 H NMR (400MHz, CDCl3) δ4.06–3.95(m,2H),2.78(t,J=13.5Hz,1H),2.43(t,J=11. 3Hz,1H),2.27–2.17(m,2H),1.99(dd,J=9.6,3.3Hz,1H),1.92–1.83(m,2H),1. 78–1.61(m,4H),1.53(s,3H),1.50–1.35(m,8H),1.30(s,6H),1.26(dd,J=6.8, 4.5Hz, 2H), 1.21 (s, 6H), 1.13–0.99 (m, 5H), 0.92 (d, J = 6.4Hz, 3H), 0.66 (s, 3H).

[0455] Step 4: Potassium tert-butoxide (106 mg, 1.95 mmol, 1.0 eq) was dissolved in dimethylformamide (3 mL) at room temperature, and p-toluenesulfonylmethyl isocyanide (79 mg, 0.38 mmol, 1.5 eq) was added at room temperature, followed by stirring at room temperature for 5 minutes and methanol (8.1 mg, 0.25 mmol, 1 eq) was added, and stirred at room temperature for 10 minutes and then (3aS, 5aR, 5bS, 7aR, 8R, 10aS, 10b S,12aR,12bR)-8-[(2R)-6-hydroxy-6-methylhept-2-yl]-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxolan-11-one 160-3 (120 mg, 0.253 mmol) , 1.0eq), stirred at room temperature for 12 hours, and the reaction was monitored by TLC (petroleum ether: ethyl acetate = 3:1). After the reaction was completed, the reaction was quenched with water (30 mL), extracted with ethyl acetate (20 mL × 2), and the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15:1) to obtain a white solid (3aS, 5aR, 5bS, 7aR, 8R, 10aS, 10bS, 12aR ,12bR)-8-[(2R)-6-hydroxy-6-methylhept-2-yl]-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxolane-11-carbonitrile 160-4 (30 mg, purity: 90%, yield: 25%). Compound 160-4: 1 H NMR (400MHz, CDCl3) δ4.05 (dt, J=8.4, 5.1Hz, 2H), 2.93 (dd, J=6.6, 4.4Hz, 1H), 2.00–1.95 (m, 2H), 1.82–1.60 (m, 10H), 1.50 (s, 3H), 1.38(ddd,J=15.5,11.4,5.4Hz,10H),1.30(s,3H),1.25(s,5H),1.22(s,6H),1.05(s,3H),0.93(t,J=6.0Hz,3H),0.75–0.62(m,3H).

[0456] Step 5: (3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-8-[(2R)-6-hydroxy-6-methylhept-2-yl]-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxolane-11-carbonitrile 160-4 (30 mg, 0.06 mmol, 1e q) was dissolved in tetrahydrofuran (3 mL) and 3 M hydrochloric acid (1 ml), followed by stirring at room temperature for 30 min. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 1:1). After completion of the reaction, the product was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 2). The organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to give 25-hydroxy-4β-hydroxy-3β-hydroxy-5α-cholest-7-carbonitrile 160-5 as a white solid (15 mg, purity: 80%, yield: 50%). 1 H NMR(400MHz, CDCl3)δ3.76(s,1H),3.69–3.61(m,1H),2.93(s,1H),2.27–2. 18(m,1H),2.12–1.96(m,4H),1.89(d,J=9.6Hz,2H),1.73(dd,J=21.6,11.8H z,6H),1.61(dd,J=11.3,6.6Hz,6H),1.46(s,2H),1.37(s,3H),1.28(s,2H) ,1.25(s,3H),1.22(s,3H),1.04(s,3H),0.92(d,J=6.5Hz,3H),0.66(s,3H).

[0457] Step 6: 25-Hydroxy-4β-hydroxy-3β-hydroxy-5α-cholestane-7-carbonitrile 160-6 (10 mg, 0.022 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL) at room temperature. Triethylamine (7 mg, 0.07 mmol, 3.0 eq), 4-dimethylaminopyridine (2.2 mg, 0.018 mmol, 0.8 eq) and benzoyl chloride (5 mg, 0.034 mmol, 1.5 eq) were added at room temperature. The mixture was stirred at room temperature for 1 hour and monitored by TLC (petroleum ether:ethyl acetate = 1:1). After the reaction was completed, the mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL × 2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The organic phase was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) and chiral separation (instrument: Waters Acquity UPCC, column: Daicel CHIRALPAK IB) was performed. The column was purified by chromatography (4.6*250mm, 5um, mobile phase: CO2 / MeOH (0.1% DEA) = 60 / 40, flow rate: 1.5ml / min, column temperature: 37 degrees) to obtain a white solid benzoic acid-(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4-cyano-6-hydroxy-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 160-6 (8 mg, purity: 95%, yield: 80%, retention time: 1.595 min). 1 H NMR (400MHz, CDCl3) δ8.04(d,J=7.3Hz,2H),7.57(d,J=7.4Hz,1H),7.45(t,J=7.7Hz,2H) ,5.11–4.94(m,1H),4.02(s,1H),2.94(s,1H),2.24–2.09(m,2H),1.99(d,J=12.5Hz,2H) ,1.87–1.79(m,3H),1.70(d,J=14.1Hz,3H),1.38(dd,J=18.1,12.4Hz,7H),1.26(d,J=2. 3Hz, 6H), 1.22 (s, 6H), 1.10 (d, J = 9.7Hz, 4H), 0.91 (dd, J = 16.7, 6.4Hz, 4H), 0.67 (s, 3H).

[0458] Step 7: At room temperature, white solid benzoic acid-(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4-cyano-6-hydroxy-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 160-6 (20 mg, 0.045 mmol, 1 eq) was dissolved in tetrahydrofuran (0.5 mL) and methanol (0.5 mL), and lithium hydroxide monohydrate (11 mg, 0.25 mmol, 10.0eq) and water (0.2 mL), followed by stirring at room temperature for 30 min. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 10:1). After completion of the reaction, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 2). The organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give 25-hydroxy-4β-hydroxy-3β-hydroxy-5α-cholestan-7-carbonitrile 160 as a white solid (12 mg, purity: 98.73%, yield: 60%).

[0459] Compound 160: 1 H NMR (400MHz, CDCl3) δ3.76(s,1H),3.66(s,1H),2.93(dd,J=4.5,2.3Hz,1H),2.28(dd,J=37.9,7. 5Hz,2H),2.16–2.04(m,2H),2.04–1.94(m,3H),1.89(dd,J=8.1,4.5Hz,1H),1.73(dd,J=8.7,4.9H z,3H),1.66–1.58(m,4H),1.49–1.40(m,6H),1.33(s,4H),1.22(s,6H),1.09(dd,J=12.7,5.1Hz,2 H), 1.04 (s, 3H), 0.92 (d, J = 6.5Hz, 3H), 0.89 (d, J = 6.7Hz, 2H), 0.66 (s, 3H). LC-MS: [MH]+ = 445.36.

[0460] Effect Example 1 Inhibitory Effect of the Compounds of the Present Invention on SREBP Pathway

[0461] 1.1: SREBP luciferase reporter gene system

[0462] Huh-7 / SRE-luc cells were incubated in sterol-deficient medium (5% delipidated serum, 2 μM lovastatin, 10 μM mevalonic acid) and treated with the corresponding concentrations of compounds for 16 hours. Among them, Huh-7 / SRE-luc cells are cells stably expressing LDLR promotor-luciferase and green fluorescent protein (GFP) in the human hepatoma cell line Huh-7. The cells were obtained by transfecting Huh-7 with pLDLR-promotor-luciferase and pEGFP-N1 plasmids and screening with G418 antibiotic selection pressure. Among them, Huh-7 cells were purchased from ATCC, the pLDLR-promotor-luciferase plasmid was obtained by molecular cloning, and the pEGFP-N1 plasmid was purchased from Addgene.

[0463] After compound treatment, cells were lysed with lysis buffer (E397A, Promega) and luciferase substrate (E1500, Promega) was added. The activity of SRE-driven luciferase was measured using a BioTek Synergy HTX microplate reader (including but not limited to such an instrument). The fluorescence intensity of green fluorescent protein (EGFP) was also measured using the aforementioned BioTek microplate reader (including but not limited to such an instrument) and used as an internal control. The ratio of SRE-driven luciferase activity divided by the fluorescence intensity of green fluorescent protein was used as an indicator of SREBP pathway activity. The test data of each test compound were analyzed using Prism software (the compound inhibition rate was calculated using the DMSO-treated group as a reference, and the Prism log (inhibitor) vs. response--Variable slope (four-parameter) model was used for fitting, with the calculation formula: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC50-X)*HillSlope))) to obtain the IC50 parameter of the compound.

[0464] 1.2 Inhibitory effect of the compounds of the present invention on the SREBP pathway

[0465] The inhibitory effect of the compounds of the present invention on the SREBP pathway was tested by the method of biological test example 1.1, and the concentration gradient of each compound was designed to be 0.01, 0.03, 0.1, 0.3, 1.0, 3.0, and 10 μM, and the control was the solvent DMSO. IC of some compounds 50 The values ​​are shown in Table 1.

[0466] Table 1

[0467] Effect Example 2: Mouse Liver Microsome Metabolic Stability Experiment

[0468] Prepare PB solution (100 mM), MgCl2 solution (300 mM), NADPH solution (2.04 mM), and mouse liver microsome (SHQY Catalog No.: M1000, Lot No.: 2110330) solution (1.00 mg / mL). Prepare stock solutions of the compound and testosterone (positive control, half-life 3.1 minutes) in dimethyl sulfoxide (DMSO). Dilute to 100 μM in methanol for sample incubation and store at -10 to -30°C. Then, add 100 μL of the mouse liver microsomal solution to a 96-well plate. For the 0-min sample, first add acetonitrile solution containing the internal standard, then 2 μL of the 100 μM working solution, and finally 98 μL of 2.04 mM NADPH preheated to 37°C. For samples at 5, 15, 30, 45, and 60 min, 2 μL of a 100 μM working solution was first added. The reaction was then initiated by adding 98 μL of 2.04 mM NADPH preheated to 37°C. At the corresponding time points, the reaction was terminated by adding an acetonitrile solution containing an internal standard. For NCF60 samples, 2 μL of a 100 μM working solution was first added. The reaction was then initiated by adding 98 μL of PB preheated to 37°C. At the corresponding time points, the reaction was terminated by adding an acetonitrile solution containing an internal standard. Samples were incubated in a 37°C water bath throughout the experiment. All samples were shaken at 800 rpm for 10 min and then centrifuged at 3200 g for 20 min. The supernatant was aspirated, diluted with deionized water in the appropriate ratio, and analyzed by LC-MS / MS. The residual rate of the compound at each time point was obtained by dividing the peak area ratio of the compound at 5, 15, 30, 45 and 60 min by the peak area ratio at 0 min, and then the half-life (T1 / 2) of the compound was calculated using Excel.

[0469] Table 2: Mouse liver microsome stability results of some compounds in the examples

[0470] Effect Example 3: Testing the solubility of the compound of the present invention in fasting state simulated intestinal fluid (FaSSIF)

[0471] Dissolve the compound powder in DMSO and prepare it into a 10.0mM stock solution for use. Weigh 0.021g NaOH, 0.198g NaH2PO4 and 0.309g NaCl, add them to 50.0mL of ultrapure water, mix and adjust the pH to 6.5 with HCl or NaOH, then add 0.112g of FaSSIF powder, and let it stand at room temperature for 2 hours after complete dissolution. Take a certain volume of compound stock solution and add it to a certain volume of FaSSIF to prepare a 300μM sample solution. Mix it at room temperature and 1000rpm for 1 hour. After 1 hour, centrifuge the sample and take a certain volume of supernatant, add stop solution, precipitate the sample, mix and centrifuge for 20 minutes. Then take the supernatant and dilute it with diluent and analyze it by liquid chromatography-tandem mass spectrometry (LC-MS / MS). The concentration of the test compound in the sample is quantitatively determined by LC-MS / MS.

[0472] Table 3: FASSIF solubility results of some compounds in the examples

[0473] Effect Example 4: Inhibition experiment of compound on FASN gene expression

[0474] Huh-7 cells (purchased from ATCC) were cultured in Dulbecco's Modified Eagle's Medium (DMEM) (Lonsera S711-001S) supplemented with 10% fetal bovine serum (FBS) at 37°C in a 5% CO2 incubator. After 24 hours, the medium was aspirated and replaced with DMEM starvation medium (5% lipoprotein-depleted serum (LPDS), 2 μM lovastatin, and 10 μM mevalonate). Dimethyl sulfoxide (DMSO) was added to the control group, while compound-treated groups were treated with various concentrations of compound. The highest concentration was 3000 nM, and the cells were diluted three-fold for a total of five concentrations. The cells were cultured for 16 hours. Cell lysis and cell-to-cDNA reverse transcription were performed, and qPCR was used to measure the expression of the SREBP target gene fatty acid synthase (FASN) (forward primer sequence: 5'-AAGGACCTGTCTAGGTTTGATGC-3', reverse primer sequence: 5'-TGGCTTCATAGGTGACTTCCA-3'). IC50 values ​​were calculated. Data for each test compound were analyzed using Prism software (inhibition percentage was calculated using the DMSO-treated group as the reference, using the Prism log(inhibitor) vs. response—variable slope (four-parameter) model fit (Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC50-X)*HillSlope)))) to determine the compound's IC50 value.

[0475] Table 4: Inhibition results of FASN gene expression by compounds of some examples

[0476] In the present invention, the structure of comparative compound 1 is

[0477] Although the above describes specific embodiments of the present invention, it should be understood by those skilled in the art that these are merely illustrative and that various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A compound of formula I, II or III or a pharmaceutically acceptable salt thereof: in, R 4a H; R 4b is halogen, CN, -CH2-CN, -CH2-OH, -CH(CH3)-OH, -COOH, -CH2-COOH, C1-C6 haloalkyl, -CH2-OAc or NH2; or, R 4a and R 4b and the carbon atoms to which they are attached together form When there is a single bond between carbon atoms 7 and 8, R 7a and R 7b are independently H, halogen, CN, -CH2-OH, -COOH, -CH2-COOH, NH2, C1-C6 alkyl, C1-C6 haloalkyl or -CH2-CN; or, R 7a and R 7b and the carbon atoms to which they are attached together form R 8a is H; When there is a double bond between carbon atoms 7 and 8, R 7a Does not exist, R 7b is halogen; R 8a does not exist; R 21 for n1 and n3 are independently 2, 3, 4 or 5; m1 and m3 are independently 0, 1, 2, 3, 4 or 5; Ring A and Ring C are independently C6-C 10 The aryl group, the heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 5-10 membered heteroaryl" or C3-C6 cycloalkyl; R A and R C are independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; R 1 for or NR 1a R 1b ; R 1a and R 1b are independently H or C1-C6 alkyl; R 4c H; R 4d is H or OH; R 7c For H, R 7d are independently CN, -CH2-OH, -COOH, C1-C6 alkyl, C1-C6 haloalkyl, -CH2-COOH, NH2, -CH2-CN or Cl; or, R 7c and R 7d and the carbon atoms to which they are attached together form R 22 for n2 is 2, 3, 4 or 5; m2 is 0, 1, 2, 3, 4 or 5; Ring B is C6-C 10 Aryl, "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S" or a C3-C6 cycloalkyl group; R B are independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; R 3a is H or C1-C6 alkyl; R 3b -O-(CH2)nR 3-1 NR 3-2 R 3-3 or OH; when R 3b When OH, R 3a is a C1-C6 alkyl group; n is 1, 2, 3 or 4; R 3-1 OH or -C(O)OR 3-1a ; R 3-1a is H or C1-C6 alkyl; R 3-2 and R 3-3 are independently H or -S(O)2R 3-2a ; R 3-2a is C1-C6 haloalkyl or C1-C6 alkyl; R 4e H; R 4f H, OH or -O-(CH2)mOR 4-1 ; or R 4e and R 4f and the carbon atoms to which they are attached together form m is 1 or 2; R 4-1 is a C1-C6 alkyl group; The carbon atom with "*" indicates that when it is a chiral carbon atom, it is independently in R configuration, S configuration or a mixture of the two; The carbon atom with "#" indicates that when it is a chiral carbon atom, it is independently in R configuration, S configuration or a mixture of the two; The carbon atom with "&" indicates that when it is a chiral carbon atom, it is independently in R configuration, S configuration or a mixture of the two; The compound shown in formula I is not the following compound: and its isomers; The compound shown in formula II is not the following compound: and its isomers; The compound shown in formula III is not the following compound: and its isomers.

2. The compound of formula I, II or III or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: One or more of the following conditions are met: (1)R 4b wherein the halogen is independently F, Cl, Br or I; for example, Br; (2)R 4b wherein the C1-C6 haloalkyl group is independently CHF2, CH2F or CF3; (3)R 7a and R 7b wherein the halogen is independently F, Cl, Br or I; preferably F; (4)R 7a and R 7b wherein the C1-C6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (5)R 7a and R 7b wherein the C1-C6 haloalkyl group is independently CHF2, CH2F or CF3, for example CHF2; (6) In ring A and ring C, the C6-C 10 Aryl is independently phenyl or naphthyl, preferably phenyl; (7) In Ring A and Ring C, the "heteroatoms selected from 1, 2 or 3 of N, O and S, 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms" is independently "heteroatoms selected from 1, 2 or 3 of N, O and S, 5-6 membered or 9-10 membered heteroaryl group having 1 or 2 heteroatoms", for example, pyridyl (e.g. )； (8) In Ring A and Ring C, the C3-C6 cycloalkyl group is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (9)R A and R C wherein the halogen is independently F, Cl, Br or I; preferably F or Cl, such as F; (10)R A and R C wherein the C1-C6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (11)R A and R C wherein the C1-C6 haloalkyl group is independently CHF2, CH2F or CF3; (12)R A and R C In the above, the C1-C6 alkoxy groups are independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy or ethoxy; (13)R A and R C In the above, the C1-C6 haloalkoxy group is independently -OCHF2, -OCH2F or -OCF3; preferably -OCF3; (14)R 1a and R 1b wherein the C1-C6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl; (15) In formula I, the carbon atom with "*" indicates that when it is a chiral carbon atom, it is in S configuration; (16)R 7c and R 7d wherein the C1-C6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (17)R 7c and R 7d wherein the C1-C6 haloalkyl group is independently CHF2, CH2F or CF3, for example CHF2; (18) In ring B, the C6-C 10 Aryl is phenyl or naphthyl, preferably phenyl; (19) In ring B, the "heteroatoms selected from 1, 2 or 3 of N, O and S, 5-10 membered heteroaryl group" is "heteroatoms selected from 1, 2 or 3 of N, O and S, 5-6 membered or 9-10 membered heteroaryl group", for example, pyridyl (for example )； (20) In ring B, the C3-C6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (21)R B wherein the halogen is independently F, Cl, Br or I; preferably F or Cl, such as F; (22)R B wherein the C1-C6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (23)R B wherein the C1-C6 haloalkyl group is independently CHF2, CH2F or CF3; (24)R B In the above, the C1-C6 alkoxy groups are independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy or ethoxy; (25)R B In the above, the C1-C6 haloalkoxy group is independently -OCHF2, -OCH2F or -OCF3; preferably -OCF3; (26) In formula II, the carbon atom with "*" indicates that when it is a chiral carbon atom, it is in S configuration; (27) In formula II, the carbon atom with "#" indicates that when it is a chiral carbon atom, it is in R configuration; (28)R 3a wherein the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl; (29)R 3-1a wherein the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example tert-butyl; (30)R 3-2a wherein the C1-C6 haloalkyl is CHF2, CH2F or CF3, such as CF3; and (31)R 4-1 In the above, the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, ethyl.

3. The compound of formula I, II or III or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: One or more of the following conditions are met: (1) In formula I, for (2)R 4a H; R 4b is halogen (e.g., Br), CN, -CH2-CN, -CH2-OH, -CH(CH3)-OH, -COOH, -CH2-COOH, -CH2-OAc, or NH2; or, R 4a and R 4b and the carbon atoms to which they are attached together form (3) When there is a single bond between carbon atoms 7 and 8, R 7a and R 7b are independently H or halogen (such as F), preferably, R 7a and R 7b is H or halogen (e.g. F); (4) When there is a double bond between carbon atoms 7 and 8, R 7a Does not exist, R 7b is halogen (such as F); R 8a does not exist; (5)R 21 for (6) Ring A and Ring C are independently C6-C 10 Aryl or "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S"; (7)R A and R C are independently halogen, C1-C6 alkoxy or C1-C6 haloalkoxy; (8) n1 is 3; (9) n3 is 3; (10) m1 is 0, 1, 2 or 3; (11) m3 is 0, 1, 2 or 3; (12) In formula II, for (13)R 7c For H, R 7d are independently CN, -CH3, -CH2-OH, -COOH, -CHF2, -CH2-COOH, NH2, -CH2-CN or Cl; or, R 7c and R 7d and the carbon atoms to which they are attached together form (14)R 22 for (15) Ring B is C6-C 10 Aryl or "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S"; (16)R B are independently halogen, C1-C6 alkoxy or C1-C6 haloalkoxy; (17) n2 is 3; (18) m2 is 0, 1, 2 or 3; (19) In formula III, for (20) n is 1, 2 or 3; (21)R 3-2 For H, R 3-3 is -S(O)2R 3-2a ;and (22)m is 1.

4. The compound of formula I, II or III or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: One or more of the following conditions are met: (1)R 4a H; R 4b is Br, CN, -CH2-CN, -CH2-OH, -CH(CH3)-OH, -COOH, -CH2-OAc or NH2; or, R 4a and R 4b and the carbon atoms to which they are attached together form (2) When there is a single bond between carbon atoms 7 and 8, R 7a and R 7b is H or halogen (e.g. F); (3)R 7c For H, R 7d are independently CN, -CH2-OH, -CH3, NH2, -CH2-CN, -CF2H, -COOH, or R 7c and R 7d and the carbon atoms to which they are attached together form (4)R 3a For H, R 3b for -NH2、 Or, R 3a is methyl, R 3b is OH; and (5)R 4e H; R 4f H, OH or or R 4e and R 4f and the carbon atoms to which they are attached together form 5. The compound of formula I, II or III or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: One or more of the following conditions are met: (1) for (2) for (3) In formula (1), for (4) for (5) In formula II, for (6) In formula III, for 6. The compound of formula I, II or III or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: One or more of the following conditions are met: (1)R 21 for (2)R 22 for 7. The compound of formula I, II or III or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: Any of the following compounds or pharmaceutically acceptable salts thereof:

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient.

9. Use of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 8 in the preparation of a medicament for preventing and / or treating a disease, wherein the disease is obesity, hyperlipidemia, fatty liver, diabetes, atherosclerosis, cardiovascular and cerebrovascular diseases, liver cancer or skin damage.

10. Use of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 8 in the preparation of a medicament for inhibiting the SREBP pathway.

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