Steroid compound, preparation method therefor, and use thereof

Abstract

Disclosed are a steroid compound having a structure represented by formula (I) or a pharmaceutically acceptable salt thereof, a preparation method therefor, and a use thereof. The compound has SREBP pathway inhibitory activity, and can be used for preventing and / or treating diseases such as obesity, hyperlipidemia, fatty liver, diabetes, atherosclerosis, cardiovascular and cerebrovascular diseases, liver cancer, and skin injury.

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] each are independently a single bond or a double bond;

[0012] R 4a H; R 4b is H or OH; or, R 4a and R 4b and the carbon atoms to which they are attached together to form

[0013] When there is a single bond between carbon atoms 7 and 8, R 7a and R 7b are independently H or halogen; R 8a is H;

[0014] When there is a double bond between carbon atoms 7 and 8, R 7a Does not exist, R7b is halogen; R 8a does not exist;

[0015] R 22 for

[0016] n1, n2, n3, n4 and n5 are independently 2, 3, 4 or 5;

[0017] m1, m2, m3 and m4 are independently 0, 1, 2, 3, 4 or 5;

[0018] Ring A, Ring B, Ring C and Ring D 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;

[0019] R 1 is a C1-C6 alkoxy group, or NR 1a R 1b ;

[0020] R 2 and R 3 are independently H or C1-C6 alkyl;

[0021] R A 、R B 、R C and R D are independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy;

[0022] Ring E is a C3-C6 cycloalkyl group;

[0023] m5 is 0, 1, 2, or 3;

[0024] R E are independently OH, NR e1 R e2 , COOH, C1-C6 alkyl, oxo (=O) or

[0025] R 1a 、R 1b 、R e1 and R e2 are independently H or C1-C6 alkyl;

[0026] 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;

[0027] 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;

[0028] 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;

[0029] The compound shown in formula I is not the following compound: and its isomers.

[0030] In certain preferred embodiments of the present invention, certain groups in the compound of Formula I or a pharmaceutically acceptable salt thereof 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 7a and R 7b wherein the halogen is independently F, Cl, Br or I; preferably F.

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

[0032] In some embodiments, in Ring A, Ring B, Ring C and Ring D, the “5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S” is independently “a 5-6 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S” or “a 9-10 membered heteroaryl group having 1 or 2 heteroatoms selected from O”, and is preferably a pyridyl group (e.g. ), pyrazinyl (e.g. ), pyrimidinyl (e.g. ), triazine groups (e.g. ), thiazolyl (e.g. ), oxazolyl (e.g. )

[0033] In some embodiments, the C3-C6 cycloalkyl groups in Ring A, Ring B, Ring C, and Ring D are independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or bicyclo[1.1.1]pentyl (e.g. ), preferably

[0034] In some embodiments, R 1 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.

[0035] In some embodiments, R 2 and R 3 wherein the C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; preferably methyl.

[0036] In some embodiments, R A 、R B 、R C and R D wherein the halogen is independently F, Cl, Br or I; preferably F or Cl, such as F.

[0037] In some embodiments, R A 、R B 、R C and R D wherein the C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0038] In some embodiments, R A 、R B 、R C and R D wherein the C1-C6 haloalkyl groups are independently CHF2, CH2F or CF3.

[0039] In some embodiments, R A 、R B 、R C and R D 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.

[0040] In some embodiments, R A 、R B 、R C and R D wherein the C1-C6 haloalkoxy group is independently -OCHF2, -OCH2F or -OCF3; preferably -OCF3.

[0041] In some embodiments, in ring E, the C3-C6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or bicyclo[1.1.1]pentyl (e.g. ), preferably cyclopropyl or cyclobutyl.

[0042] In some embodiments, R Ewherein the C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl.

[0043] In some embodiments, R 1a 、R 1b 、R e1 and R e2 wherein the C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl.

[0044] In some embodiments, n1 is 3.

[0045] In some embodiments, n2 is 3.

[0046] In some embodiments, n3 is 2.

[0047] In some embodiments, n4 is 2.

[0048] In some embodiments, n5 is 2.

[0049] In some embodiments, ml is 0, 1, 2, or 3.

[0050] In some embodiments, m2 is 0, 1, 2 or 3, for example, 2.

[0051] In some embodiments, m3 is 1.

[0052] In some embodiments, m4 is 1.

[0053] In some embodiments, m5 is 1 or 2.

[0054] In some embodiments, R A are independently halogen, C1-C6 alkoxy or C1-C6 haloalkoxy.

[0055] In some embodiments, Ring A is phenyl, pyridyl, (e.g. ), pyrazinyl (e.g. ), pyrimidinyl (e.g. ), triazine groups (e.g. ), thiazolyl (e.g. ), oxazolyl (e.g. ),

[0056] In some embodiments, R B and C1-C6 alkoxy and C1-C6 alkoxy are independently halogen, C1-C6 alkoxy or C1-C6 haloalkoxy; for example, halogen or C1-C6 alkoxy.

[0057] In some embodiments, Ring B is phenyl.

[0058] In some embodiments, R 1 Methoxy, or NH2.

[0059] In some embodiments, R C and R D are independently halogen.

[0060] In some embodiments, Ring C is phenyl.

[0061] In some embodiments, Ring D is phenyl.

[0062] In some embodiments, Ring E is cyclopropyl or cyclobutyl.

[0063] In some embodiments, R 1a and R 1b are independently H.

[0064] In some embodiments, R e1 and R e2 are independently C1-C6 alkyl (eg, methyl).

[0065] In some embodiments, a carbon atom with a "*" indicates that when it is a chiral carbon atom, it is in the S configuration.

[0066] In some embodiments, a carbon atom with a "#" indicates that when it is a chiral carbon atom, it is in the R configuration.

[0067] In some embodiments, for Among them, R 4b is H or OH, R 7a and R 7b are independently H or halogen (eg, F); preferably, R 4b OH, R 7a and R 7b is independently halogen (eg, F).

[0068] In some embodiments, for

[0069] In some embodiments, for

[0070] In some embodiments, for Among them, m 1A is 0, 1, 2, 3, or 4; m 1B is independently 0, 1, 2 or 3; m 1C is independently 0, 1 or 2.

[0071] In some embodiments, for Among them, m 2A 0, 1, 2, 3, or 4.

[0072] In some embodiments, for

[0073] In some embodiments, for

[0074] In some embodiments, Independently

[0075] In some embodiments, for

[0076] In some embodiments, R 22 for

[0077] In some embodiments, the compound of formula I is a compound of formula I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9 or I-10:

[0078] Among them, 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;

[0079] Ring A, Ring B, R A 、R B , m1 and m2 are defined as described in any embodiment of the present invention.

[0080] In some embodiments, the compound represented by Formula I is any of the following compounds:

[0081] 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.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] 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.

[0086] Definition and Description

[0087] 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.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] 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).

[0094] In this article, the term “C 6-10 "Aryl" means phenyl or naphthyl.

[0095] 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,

[0096] 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.

[0097] 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.

[0098] 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.

[0099] As used herein, the term "subject" includes any animal, preferably a mammal, more preferably a human.

[0100] 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.

[0101] 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.

[0102] The reagents and raw materials used in the present invention are commercially available.

[0103] 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

[0104] 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.

[0105] In the present invention, the structure of comparative compound 1 is

[0106] Preparation of key intermediates

[0107] Examples I & II

[0108] 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

[0109] 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

[0110] 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).

[0111] 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).

[0112] 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.

[0113] 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 mixture 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, 90% purity, 48.63% yield). 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).

[0114] 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) ), (triphenyl-λ5-methylphosphine) methyl acetate (51.89g, 155.21mmol, 6.0eq) was added, and the reaction system was stirred at 90℃ for 18h. Nuclear magnetic resonance monitoring showed that the reaction raw materials were consumed. 100mL of water was added to the reaction system, extracted with ethyl acetate (100mL×3), the organic phase was collected and washed with water (100mL×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 The mixture was purified by filtration (5% by weight) 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).

[0115] 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 x 3). The organic phase was collected, washed with water (100 mL x 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, 90% purity, 80.6% yield) 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).

[0116] 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).

[0117] 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.

[0118] 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).

[0119] 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, A 1% hydroxybenzoic acid (8.2 mmol, 1.0 eq) was dissolved in acetone (50 mL), and N-hydroxyphthalimide (0.54 g, 3.3 mmol, 0.8 eq), tert-butyl hydroperoxide (12 mL, 66 mmol, 8.0 eq), and anhydrous cobalt(II) acetate (0.29 g, 1.6 mmol, 0.2 eq) 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 (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 × 15 mL). The organic layers were combined, washed with saturated brine (15 mL), 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).

[0120] 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).

[0121] 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%).

[0122] Compound I-3: 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).

[0123] Step 13: 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 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 I-1 as a white solid. The crude product of methyl (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-2 (0.9 g, purity 96%, yield calculated based on I-14: 92%) was directly used for the next step.

[0124] 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 (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-8-[( ... 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 90%. Yield 66% based on compound I).

[0125] 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).

[0126] Example III

[0127] 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)

[0128] 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 (1000 mg, 2.09 mmol, purity: 90%, yield: 96%) as a white solid. 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).

[0129] Step 2: Dissolve 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, 2.32 mmol, 1.0 eq) in dichloromethane (50 mL). Add Dess-Martin periodinane (1.18 g, 2.79 mmol, 1.2 eq) and stir at 25°C for 1 h. Monitor the reaction progress and starting material consumption 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).

[0130] Example IV

[0131] Preparation of Intermediate IV (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]hexanal (IV)

[0132] 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. 1 H 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).

[0133] Step 2: Weigh out acetic acid-(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 ester IV-1 (300 mg, 0.65 mol, 1.0 eq.) and dissolve it in anhydrous methanol (5 mL). Add potassium carbonate (897 mg, 6.5 mmol), then heat the temperature to 25 °C and stir for 16 hours. Monitor by TLC (petroleum ether:ethyl acetate = 2:1) until the reaction is complete. 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).

[0134] Step 3: 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).

[0135] Step 4: Weigh out (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]hexanoate IV-3 (180 mg, 0.39 mmol) and dissolve it in diethyl ether (20 mL). Cool the mixture to -78 ° C with dry ice-acetone, and then add diisobutylaluminum hydride (1 M, 1.17 mL) dropwise. After the addition is complete, warm to room temperature and stir. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 3:1). After completion of the reaction, saturated aqueous ammonium chloride was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was separated, dried, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 0-30%) to obtain (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]hexan-1-ol IV-4 (120 mg, 0.28 mmol, 71.8%) as a white solid. 1 H NMR (399MHz, Chloroform-d) δ3.98 (d, J = 7.6 Hz, 2H), 3.62 (t, J = 6.6 Hz, 2H), 1.94 (d, J = 12. 3Hz,1H),1.76(d,J=10.5Hz,3H),1.65(t,J=13.8Hz,3H),1.54(d,J=9.8Hz,4H),1.49(s,4H ),1.48–1.34(m,7H),1.29(s,3H),1.25(d,J=11.2Hz,6H),1.13–1.05(m,3H),1.02(s,3H), 1.00(d,J=6.1Hz,1H),0.89(d,J=6.2Hz,4H),0.84(s,1H),0.64(s,3H),0.63–0.54(m,1H).

[0136] Step 5: (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]hexan-1-ol IV-4 (100 mg, 0.23 mmol) was dissolved in dichloromethane (10 mL), and Dess-Martin periodinane (195 mg, 0.46 mmol) was added at room temperature. The mixture was then stirred at room temperature and monitored by TLC (petroleum ether:ethyl acetate = 3:1). After the reaction, saturated aqueous sodium bicarbonate solution and ethyl acetate were added for extraction. The organic phase was separated, dried, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 0-30%) to obtain (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]hexanal IV (53 mg, 0.12 mmol, 52.2%) as a white solid. 1 H NMR(399MHz,Chloroform-d)δ9.74(t,J=1.8Hz,1H),3.97(dt,J=8.9,5.7Hz,2H),2.37(tdd,J=8.1,6 .8,1.9Hz,2H),1.94(d,J=12.5Hz,1H),1.76(td,J=10.3,5.3Hz,3H),1.71–1.62(m,3H),1.56(s,3H) ,1.49(s,3H),1.48–1.36(m,5H),1.29(s,3H),1.24(dq,J=12.6,4.6,3.8Hz,5H),1.08(dd,J=11.8,7 .5Hz,3H),1.02(s,3H),0.91(d,J=6.5Hz,3H),0.89–0.83(m,2H),0.64(s,3H),0.58(d,J=2.5Hz,1H).

[0137] Example 1 & 2

[0138] Compound 1(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-{2-[(trifluoromethyl)oxy]phenyl}hexan-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0139] Preparation of compound 2(1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-1-[(2R)-6-hydroxy-6-{2-[(trifluoromethyl)oxy]phenyl}hexan-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.

[0140] In the first step, 1-bromo-2-[(trifluoromethyl)oxy]benzene (126 mg, 0.5 mmol, 3.5 eq) was dissolved in anhydrous tetrahydrofuran (3 mL). The system was cooled to -78°C and n-butyllithium (1.8 mL, 0.45 mmol, 3.0 eq) was added dropwise. The reaction system was stirred at -78°C for 30 min. 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]hexanal I and (5R)-5-[(3aS,5aR,5bR A mixture of (70 mg, 0.15 mmol, 1.0 eq) (7aR,8R,10aR,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 was dissolved in tetrahydrofuran (2 mL) and added to the above reaction solution. The reaction system was stirred at -78°C for 30 min. After completion of the reaction, TLC (petroleum ether:ethyl acetate = 5:1) was used to monitor the reaction. 10 mL of water was added to the reaction system, and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over sodium sulfate, 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 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]dioxolan-8-yl]-1-{2-[(trifluoromethyl)oxy]phenyl}hexane 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]-1-{2-[(trifluoromethyl)oxy]phenyl}hexan-1-ol 2-1 (70 mg, purity 95%, yield 70% based on compound 1-1).

[0141] Compound 1-1: 1 H NMR (400MHz, CDCl3) δ7.54–7.49(m,1H),7.24(dt,J=6.2,4.0Hz,2H),7.15(dd,J=4.7,2.9H z,1H),5.03–4.96(m,1H),3.94(dt,J=8.3,6.2Hz,2H),2.09–1.85(m,3H),1.78–1.51(m,12 H),1.44(s,3H),1.38–1.26(m,5H),1.23(s,3H),1.20–1.10(m,2H),1.05(dd,J=10.9,6.5H z,1H),1.00(s,3H),0.97–0.86(m,2H),0.83(dd,J=6.4,3.9Hz,3H),0.59(t,J=5.9Hz,3H).

[0142] Step 2: Reaction of reactants (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]-1-{2-[(trifluoromethyl)oxy]phenyl}hexan-1-ol 1-1 and (5R)-5-[(3aS,5aR,5bR, A mixture of 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]-1-{2-[(trifluoromethyl)oxy]phenyl}hexan-1-ol 2-1 (70 mg, 0.11 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL). Dilute hydrochloric acid (1 mL, 3 mol / L) was added, and the reaction system was stirred at room temperature for 1 h. The reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 5:1). Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3×10 mL). The ethyl acetate layers were combined and washed with saturated brine (3×10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 70:30) to obtain a white solid, which was then subjected to chiral separation by 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) = 60 / 40; flow rate: 1.5 ml / min; column temperature: 37 degrees) to give (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-{2-[(trifluoromethyl)oxy]phenyl}hexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 1 (33.65 mg, purity 99%, yield 51%, retention time t R=0.793 min) and (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-1-[(2R)-6-hydroxy-6-{2-[(trifluoromethyl)oxy]phenyl}hexan-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 2 (3.29 mg, purity 96%, yield 5%, retention time t R =1.109min).

[0143] Compound 1: 1 H NMR (400MHz, CDCl3) δ7.55–7.49(m,1H),7.28–7.20(m,2H),7.17–7.12(m,1H),5.02–4.96(m,1H),3.67(s,1H),3.56–3.49(m,1H),2.22–2.04(m ,1H),1.90(d,J=12.7Hz,1H),1.83–1.56(m,13H),1.43–1.15(m,10H),0 .99(s,3H),0.95–0.87(m,2H),0.83(dd,J=6.5,3.9Hz,3H),0.59(s,3H). 19 F NMR (377MHz, CDCl3) δ-56.80,-56.81,-88.64,-89.27,-110.64,-111.27.

[0144] Compound 2: 1 H NMR(400MHz, CDCl3)δ7.52(d,J=7.4Hz,1H),7.28–7.21(m,2H),7.15(d,J=7.4H z,1H),4.99(dd,J=11.4,5.4Hz,1H),3.78(s,1H),3.52(d,J=12.0Hz,1H),2.57 (d,J=12.0Hz,1H),1.95(d,J=12.6Hz,1H),1.83–1.50(m,16H),1.41–1.17(m,1 1H),1.06–0.99(m,3H),0.97(s,3H),0.84(dd,J=6.4,4.1Hz,3H),0.56(s,3H). 19 F NMR(377MHz, CDCl3)δ-56.79,-56.81,-109.80.LC-MS:[M-H2O] + =551.80.

[0145] Examples 3 & 4

[0146] Compound 3(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-(2-fluorophenyl)-6-hydroxyhexan-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0147] Preparation of Compound 4(1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-1-[(2R)-6-(2-fluorophenyl)-6-hydroxyhexan-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

[0148] Step 1: Dissolve 1-bromo-2-fluorobenzene (195.96 mg, 1.12 mmol, 1.2 eq) in tetrahydrofuran (30 mL), cool to -78°C in a nitrogen-protected dry ice bath, add 2.5 M n-butyllithium solution in n-hexane (89.67 mg, 1.400 mmol, 1.5 eq), keep warm and stir for 30 minutes, then add (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 (400 mg, 0.933 mmol, 1.0 eq) was added and allowed to warm to room temperature. The reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 5:1). After completion, the reaction was quenched with saturated ammonium chloride, and the aqueous layer was extracted with ethyl acetate (3 × 50 mL). The organic layers were combined and washed with saturated brine (15 mL). The ethyl acetate layer was dried over 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]-1-(2-fluorophenyl)hexan-1-ol 3-1 as a white solid (400 mg, 0.610 mmol, purity: 80%, yield: 65%). 1H NMR (400MHz, CDCL3) δ7.46 (t,J=7.4Hz,1H),7.23(s,1H),7.15(s,1H),7.02(m,1H),5.80(s,1H),5.00(dd,J= 12.0,7.0Hz,1H),4.41(d,J=5.8Hz,1H),4.10(dd,J=13.9,6.1Hz,1H),2.06(dd,J=4 4.2,10.2Hz,3H),1.65(dd,J=30.7,25.0Hz,9H),1.41(d,J=9.7Hz,4H),1.35(s,3H ),1.25(s,3H),1.16(s,3H),1.10(m,6H),0.90(dd,J=6.4,4.0Hz,3H),0.68(m,3H).

[0149] The second step: 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]-1-(2- (400 mg, 0.76 mmol, 1.0 eq) of (1-fluorophenyl)hexan-1-ol 3-1 was dissolved in dichloromethane (20 mL). Acetic anhydride (0.215 mL, 2.29 mmol, 3.0 eq), triethylamine (0.530 mL, 3.81 mmol, 5.0 eq), and 4-dimethylaminopyridine (93.09 mg, 0.76 mmol, 1.0 eq) were added. The resulting mixture was stirred at 25°C for 1 hour. Reaction progress and starting material consumption were monitored by TLC (petroleum ether:ethyl acetate = 5:1). The reaction was quenched with methanol, and water (10 mL) was added to the reaction system. The aqueous layer was extracted with dichloromethane (3 × 20 mL). The organic phases were combined and washed with saturated brine (50 mL), dried over Na2SO4, filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 95:5) 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]-1-(2-fluorophenyl)hexyl acetate 3-2 (400 mg, 0.635 mmol, purity: 90%, yield: 83%) as a white solid. 1H NMR (400MHz, CDCL3) δ7.34(t,J=7.4Hz,1H),7.24(d,J=7.2Hz,1H),7.12(t,J=7.5 Hz,1H),7.03(m,1H),6.01(m,1H),5.80(d,J=2.8Hz,1H),4.41(d,J=5.8Hz,1H),4. 10(dd,J=13.6,6.3Hz,1H),2.08(d,J=2.4Hz,3H),1.61(m,8H),1.43(s,4H),1.34( d,J=6.2Hz,5H),1.26(s,3H),1.16(s,5H),1.02(m,9H),0.86(m,7H),0.67(m,4H).

[0150] The third step: the compound acetic acid-(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]-1-(2-fluorophenyl)- The ester 3-2 (120 mg, 0.21 mmol, 1.0 eq) was dissolved in acetone (5 mL), and N-hydroxyphthalimide (6.92 mg, 0.042 mmol, 0.2 eq), tert-butyl hydroperoxide (0.170 mL, 0.848 mmol, 4.0 eq), and anhydrous cobalt(II) acetate (1.88 mg, 0.011 mmol, 0.05 eq) were added. The resulting mixture was stirred at 25°C for 18 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 10:1). The reaction was quenched with saturated sodium sulfite, and water (10 mL) was added to the reaction system. The aqueous layer was extracted with ethyl acetate (3 × 15 mL). The ethyl acetate layers were combined, washed with saturated brine (15 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 80:20) to give (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-11-oxyidene-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]-1-(2-fluorophenyl)hexyl acetate 3-3 (60 mg, 0.093 mmol, purity: 90%, yield: 44%). 1H NMR (400MHz, CDCL3) δ7.34(t,J=7.3Hz,1H),7.23(m,1H),7.12(t,J=7.5Hz,1H),7.03(m,1H),6. 02(d,J=5.0Hz,1H),5.92(s,1H),4.52(d,J=6.4Hz,1H),4.32(d,J=5.6Hz,1H),2.34(d,J=10.6H z,2H),2.08(s,3H),2.02(m,1H),1.82(dd,J=20.1,10.2Hz,4H),1.57(t,J=12.4Hz,13H),1.34( m,17H),1.07(m,5H),0.87(dd,J=11.7,6.8Hz,4H),0.80(d,J=5.9Hz,1H),0.69(d,J=3.5Hz,3H)

[0151] Step 4: Compound (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-11-oxylidene-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]-1-(2-fluorophenyl)hexyl acetate 3-3 (60 mg, 0.10 mmol) was dissolved in methanol (5 mL), palladium carbon (11 mg, 0.103 mmol) was added, and the atmosphere was replaced with hydrogen three times. The resulting mixture was stirred in the reaction mixture under hydrogen at 25 ° C for 1 h. The reaction progress and starting material consumption were monitored by TLC (petroleum ether:ethyl acetate=3:1). Filtration and concentration were performed to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 80:20) 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]-1-(2-fluorophenyl)hexyl acetate 3-4 (40 mg, 0.062 mmol, purity: 90%, yield: 60%) as a white solid. 1HNMR(400MHz,CDCL3)δ7.34(s,1H),7.23(s,1H),7.12(s,1H),7.03(s,1H),6.01(dd,J=10.9,6.4Hz,1H),3.98(d,J=3.4Hz,2H),2.77(s,1H),2.42(s,1H),2.19(dd,J=12.7,2.7Hz,2H),2.08(s,3H),1.74(m,9H),1.53(s,3H),1.38(dd,J=11.7,7.8Hz,4H),1.28(d,J=17.1Hz,10H),0.95(ddd,J=10.8,9.5,6.5Hz,10H),0.64(d,J=3.2Hz,3H).

[0152] Step 5: 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]-1-(2-fluorophenyl)hexyl acetate 3-4 (250 mg, 0.43 mmol) was dissolved in diethylaminosulfur trifluoride (5 mL), and the resulting mixture was stirred in the reaction solution at 80°C for 1 h. The reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 10:1), indicating complete consumption of the starting material. The reaction solution was cooled to room temperature, and dichloromethane (20 mL) was added to dilute the reaction system. Ice water was carefully added dropwise to quench the reaction. The organic phase was separated and the aqueous layer was extracted with dichloromethane (3 × 10 mL). The combined organic phases were washed with saturated brine (15 mL), filtered, and concentrated to obtain the crude product. The crude product was added to silica gel and passed through a column with petroleum ether: ethyl acetate = 93:7 to obtain a colorless transparent solid acetic acid-(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]-1-(2-fluorophenyl)- A mixture of hexyl ester 3-5 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]-1-(2-fluorophenyl)hexyl acetate 4-1 (210 mg, purity: 90%, yield based on 3-5: 72.85%).

[0153] Compounds 3-5 1H NMR:(400MHz,CDCl3)δ7.34(t,J=7.4Hz,1H),7.24(d,J=6.6Hz,1H),7.12(t,J=7.5Hz,1H),7.06–7.00(m,1H),6.05–5.98(m,1H),4.07–3.98(m,2H),2.08(d,J=1.3Hz,3H),1.98–1.68(m,9H),1.63–1.57(m,2H),1.50(s,3H),1.39(dd,J=10.5,5.0Hz,4H),1.30(s,3H),1.07(s,3H),1.05–0.90(m,4H),0.87(dd,J=6.3,4.7Hz,4H),0.64(dd,J=11.7,3.6Hz,3H).

[0154] Step 6: reacting the reactants (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]-1-(2-fluorophenyl)hexyl acetate 3-5 and (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]-1-(2-fluorophenyl)hexyl acetate 3-5 A mixture of 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]-1-(2-fluorophenyl)hexyl ester (210 mg, 0.34 mmol, 1.0 eq) was dissolved in tetrahydrofuran (10 mL). Dilute hydrochloric acid (1 mL, 3 mol / L) was added, and the reaction system was stirred at room temperature for 1 h. The reaction progress was monitored by TLC plate (petroleum ether:ethyl acetate = 5:1). Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3×25 mL). The EA layers were combined and washed with saturated brine (3×10 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 70:30) to give white solids (5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-6,7-dihydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1-(2-fluorophenyl)hexyl acetate 3-6 and (5R)-5-[(1R ,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-6,7-dihydroxy-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]-1-(2-fluorophenyl)hexyl ester 4-2 (200 mg, purity 95%, yield 96.9% calculated based on 3-6).

[0155] 3-6: 1H NMR(400MHz,CDCl3)δ7.34(t,J=7.4Hz,1H),7.23(s,1H),7.12(t,J=7.5Hz,1H),7.07–6.98(m,1H),6.01(dd,J=11.2,6.4Hz,1H),3.85(s,0H),3.74(s,1H),3.64–3.55(m,1H),2.09(s,3H),1.96(d,J=12.7Hz,1H),1.88–1.67(m,9H),1.49–1.29(m,8H),1.09(d,J=4.6Hz,1H),1.05(s,3H),1.03–0.94(m,2H),0.89–0.84(m,3H),0.63(dd,J=12.0,3.6Hz,3H).

[0156] Step 7: Compounds (5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-6,7-dihydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1-(2-fluorophenyl)hexyl acetate 3-6 and (5R)-5-[(1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4,4-difluoro-6,7-dihydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1-(2-fluorophenyl)hexyl acetate A mixture of α,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]-1-(2-fluorophenyl)hexyl ester 4-2 (50 mg, 0.09 mmol, 1 eq) was dissolved in a mixed solvent of tetrahydrofuran (2 mL) and methanol (2 mL). Potassium carbonate (122 mg, 0.89 mmol, 10 eq) was added, and the resulting mixture was stirred at 25°C for 1 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 1:1). The reaction solution was diluted with ethyl acetate (20 mL), washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 71:29) to obtain a white mixture, which was then subjected to chiral separation to obtain a white solid (instrument: Waters Acquity; UPCC column: REGIS CHIRAL (S, S)-Whelk O1 The column was purified by column chromatography (4.6*150mm, 3.5um; mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 50 / 50; flow rate: 1.5 ml / min; column temperature: 37 degrees) to obtain a white solid (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R)-6-(2-fluorophenyl)-6-hydroxyhexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 3 (25.6 mg, purity: 95.02%, yield 52.56%, retention time t R =1.205min)) and 7(1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-1-[(2R)-6-(2-fluorophenyl)-6-hydroxyhexan-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 4 (3.74 mg, purity: 82.29%, yield 6.89%, retention time t R =1.666min).

[0157] Compound 3: 11H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 7.02 (m, 1H), 5.00 (d, J = 7.1 Hz, 1H), 3.74 (s, 1H), 3.61 (s, 1H), 2.07 (dd, J = 11.2, 9.0 Hz, 2H), 1.95 (s, 1H), 1.79 (m, 6H), 1.67 (m, 4H), 1.37 (m, 10H), 1.10 (d, J = 5.4 Hz, 2H), 1.06 (s, 3H), 1.00 (d, J = 3.4 Hz, 2H), 0.89 (dd, J = 6.5, 4.1 Hz, 3H), 0.65 (d, J = 2.0 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 161.90, 127.19, 124.26, 115.44, 115.19, 112.45, 73.44, 71.86, 68.51, 55.22, 50.95, 48.56, 44.03, 43.15, 39.34, 39.17, 38.55, 38.42, 36.22, 35.63, 35.52, 34.93, 28.46, 25.58, 25.39, 22.36, 22.22, 20.57, 18.66, 15.87, 15.53, 13.78, 11.84, -0.01. 19 19F NMR (377 MHz, CDCl3) δ -88.63, -89.26, -110.63, -111.25, -119.75, -119.78.

[0158] Compound 4: 1 1H NMR (400 MHz, CDCl3) δ 7.46 (t, J = 7.6 Hz, 1H), 7.23 (d, J = 6.0 Hz, 1H), 7.15 (s, 1H), 7.02 (m, 1H), 5.00 (d, J = 7.0 Hz, 1H), 3.85 (s, 1H), 3.59 (d, J = 11.8 Hz, 1H), 2.65 (s, 1H), 2.06 (d, J = 16.1 Hz, 4H), 1.78 (dd, J = 27.9, 5.7 Hz, 6H), 1.60 (s, 3H), 1.44 (s, 3H), 1.26 (s, 7H), 1.09 (d, J = 17.5 Hz, 3H), 1.04 (s, 3H), 0.91 (dd, J = 6.3, 3.8 Hz, 3H), 0.62 (d, J = 1.8 Hz, 3H). 19 19F NMR (377 MHz, CDCl3) δ -109.79, -119.75, -119.78.

[0159] Example 5

[0160] Preparation of Compound 5 24-[Hydroxy(3-methoxyphenyl)methyl]-5α-cholane-3β,4β-diol

[0161] The first step was to weigh m-bromoanisole (109 mg, 0.6 mol, 5.0 eq.) and dissolve it in ultra-dry tetrahydrofuran (5 mL). The mixture was cooled to -78°C with dry ice-acetone. Then, butyl lithium (1.6 M, 0.45 mL) was added dropwise. The mixture was stirred at this temperature for half an hour. Then, (5R)-5-[(3aS, 5aR, 5bS, 7aR, 8R, 10aS] was added to another reaction flask. ,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]hexanal III (50 mg , 0.12mmol), dissolved in ultra-dry tetrahydrofuran (5mL), and then added dropwise to the above solution at -78°C. After completion of the addition, the temperature was gradually raised to room temperature and monitored by TLC (petroleum ether: ethyl acetate = 3:1). After completion of the reaction, saturated aqueous ammonium chloride solution was added to quench the reaction. The organic phase was separated, dried, and concentrated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 0-30%) to give 5R-1-(3-methoxyphenyl)-5-((3aS, 5aR, 5bS, 7aR, 8R, 10aS, 10bS, 12bR)-2,2,5a,7a-tetramethylhexahydro-4H-cyclopenta[7,8]phenanthro[1,2-d][1,3]dioxetane-8-yl)hexan-1-ol 5-1 (30mg, 0.056mmol, 48.0%) as a white solid.

[0162] Step 2: (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]hexanal 5-1 (30 mg, 0.056 mmol) was dissolved in anhydrous methanol (10 mL). 2 M hydrochloric acid (3 mL) was added at room temperature. After the addition, stirring was continued at room temperature. The reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 3:1). Water and ethyl acetate were added for extraction. The organic phase was separated, dried, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 0-50%) to give 24-[hydroxy(3-methoxyphenyl)methyl]-5α-cholane-3β,4β-diol 5 (15 mg, 0.030 mmol, 54.1%) as a white solid.

[0163] Compound 5: 1 H NMR(399MHz,Chloroform-d)δ6.91(d,J=7.1Hz,2H),4.63(q,J=6.3Hz,1H),3.81(s,3H),3.7 3(s,1H),3.55(dd,J=11.5,5.0Hz,1H),1.93(d,J=12.5Hz,1H),1.75(s,2H),1.73–1.67(m,4H ),1.64(s,4H),1.36(s,2H),1.35–1.30(m,3H),1.24(s,2H),1.08(d,J=8.6Hz,1H),1.06–1.0 2(m,3H),1.00(s,3H),0.97–0.91(m,2H),0.86(dd,J=6.5,4.7Hz,3H),0.62(d,J=2.7Hz,3H). 13 C NMR(100MHz,Chloroform-d)δ159.69,129.43,118.22,118.14,112.91,112.86 ,111.31,111.24,74.82,74.58,72.26,56.51,56.13,56.11,55.22,55.18,48.7 7,42.57,39.85,39.52,39.48,36.82,35.67,35.44,35.36,32.36,28.24,25.9 6,25.83,24.18,22.46,22.37,20.55,18.58,18.56,14.66,12.05.LC-MS:[M+H]+ =498.37.

[0164] The synthesis of Examples 6, 7, 8, 20, 28 and 104 was completed using a similar synthesis method to Example 5.

[0165] Structural spectral analysis of compounds 6, 7, 8, 20, 28, and 104

[0166] Example 11

[0167] Preparation of compound 11(1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-(2-fluorophenyl)-6-hydroxyhexan-2-yl]-7-hydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6-one.

[0168] In the first step, 1-bromo-2-fluorobenzene (195.96 mg, 1.12 mmol, 1.2 eq) was dissolved in tetrahydrofuran (30 mL), cooled to -78°C in a dry ice bath under nitrogen protection, and n-butyllithium 2.5 M n-hexane solution (89.67 mg, 1.400 mmol, 1.5 eq) was added. The mixture was stirred for 30 minutes, and then (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 (400 mg, 0.933 mmol, 1.0 eq) was allowed to warm to room temperature. The reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 5:1). After completion, the reaction was quenched with saturated ammonium chloride. The aqueous layer was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined and washed with saturated brine (15 mL). The ethyl acetate layer was dried over 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]-1-(2-fluorophenyl)hexan-1-ol 11-1 as a white solid (400 mg, 0.610 mmol, purity: 80%, yield: 65%). 1 H NMR (400MHz, CDCL3) δ7.46(t,J=7.4Hz,1H),7.23(s,1H),7.15(s,1H),7.02(m,1H),5.80( s,1H),5.00(dd,J=12.0,7.0Hz,1H),4.41(d,J=5.8Hz,1H),4.10(dd,J=13.9,6.1Hz,1H), 2.06(dd,J=44.2,10.2Hz,3H),1.65(dd,J=30.7,25.0Hz,9H),1.41(d,J=9.7Hz,4H),1.35 (s,3H),1.25(s,3H),1.16(s,3H),1.10(m,6H),0.90(dd,J=6.4,4.0Hz,3H),0.68(m,3H).

[0169] In the second step, the 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]-1-(2-fluoro- Phenyl)hexan-1-ol 11-1 (400 mg, 0.76 mmol, 1.0 eq) was dissolved in dichloromethane (20 mL). Acetic anhydride (0.215 mL, 2.29 mmol, 3.0 eq), triethylamine (0.530 mL, 3.81 mmol, 5.0 eq), and 4-dimethylaminopyridine (93.09 mg, 0.76 mmol, 1.0 eq) were added. The resulting mixture was stirred at 25°C for 1 h. The reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 5:1). After the starting material was consumed, the reaction was quenched with methanol, water (10 mL) was added to the reaction system, and the aqueous layer was extracted with dichloromethane (3 × 20 mL). The organic phases were combined and washed with saturated brine (50 mL), dried over Na2SO4, filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 95:5) 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]-1-(2-fluorophenyl)hexyl acetate 11-2 (400 mg, 0.635 mmol, purity: 90%, yield: 83%) as a white solid. 1 H NMR (400MHz, CDCL3) δ7.34(t,J=7.4Hz,1H),7.24(d,J=7.2Hz,1H),7.12(t,J=7.5 Hz,1H),7.03(m,1H),6.01(m,1H),5.80(d,J=2.8Hz,1H),4.41(d,J=5.8Hz,1H),4. 10(dd,J=13.6,6.3Hz,1H),2.08(d,J=2.4Hz,3H),1.61(m,8H),1.43(s,4H),1.34( d,J=6.2Hz,5H),1.26(s,3H),1.16(s,5H),1.02(m,9H),0.86(m,7H),0.67(m,4H).

[0170] In the third step, the compound acetic acid-(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]-1-(2-fluorophenyl)hexyl Ester 11-2 (120 mg, 0.21 mmol, 1.0 eq) was dissolved in acetone (5 mL), and N-hydroxyphthalimide (6.92 mg, 0.042 mmol, 0.2 eq), tert-butyl hydroperoxide (0.170 mL, 0.848 mmol, 4.0 eq), and anhydrous cobalt(II) acetate (1.88 mg, 0.011 mmol, 0.05 eq) were added. The resulting mixture was stirred at 25°C for 18 hours. Reaction progress and starting material consumption were monitored by TLC (petroleum ether:ethyl acetate = 10:1). The reaction was quenched with saturated sodium sulfite, and water (10 mL) was added to the reaction system. The aqueous layer was extracted with ethyl acetate (3 × 15 mL). The ethyl acetate layers were combined, washed with saturated brine (15 mL), dried over Na2SO4, filtered, and concentrated to yield the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 80:20) to give (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-11-oxyidene-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]-1-(2-fluorophenyl)hexyl acetate 11-3 (60 mg, 0.093 mmol, purity: 90%, yield: 44%). 1H NMR (400MHz, CDCL3) δ7.34(t,J=7.3Hz,1H),7.23(m,1H),7.12(t,J=7.5Hz,1H),7.03(m,1H),6. 02(d,J=5.0Hz,1H),5.92(s,1H),4.52(d,J=6.4Hz,1H),4.32(d,J=5.6Hz,1H),2.34(d,J=10.6H z,2H),2.08(s,3H),2.02(m,1H),1.82(dd,J=20.1,10.2Hz,4H),1.57(t,J=12.4Hz,13H),1.34( m,17H),1.07(m,5H),0.87(dd,J=11.7,6.8Hz,4H),0.80(d,J=5.9Hz,1H),0.69(d,J=3.5Hz,3H)

[0171] Step 4: Compound (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-11-oxylidene-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]-1-(2-fluorophenyl)hexyl acetate 11-3 (60 mg, 0.10 mmol) was dissolved in methanol (5 mL), palladium carbon (11 mg, 0.103 mmol) was added, and the atmosphere was replaced with hydrogen three times. The resulting mixture was stirred in the reaction mixture under H2 at 25 °C for 1 h. The reaction progress was monitored by TLC (petroleum ether:ethyl acetate=3:1). The raw material was consumed, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 80:20) 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]-1-(2-fluorophenyl)hexyl acetate 11-4 (40 mg, 0.062 mmol, purity: 90%, yield: 60%) as a white solid. 1HNMR(400MHz,CDCL3)δ7.34(s,1H),7.23(s,1H),7.12(s,1H),7.03(s,1H),6.01(dd ,J=10.9,6.4Hz,1H),3.98(d,J=3.4Hz,2H),2.77(s,1H),2.42(s,1H),2.19(dd,J=12 .7,2.7Hz,2H),2.08(s,3H),1.74(m,9H),1.53(s,3H),1.38(dd,J=11.7,7.8Hz,4H), 1.28(d,J=17.1Hz,10H), 0.95(ddd,J=10.8,9.5,6.5Hz,10H), 0.64(d,J=3.2Hz,3H).

[0172] Step 5: 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]-1-(2-fluorophenyl)hexyl acetate 11-4 (250 mg, 0.43 mmol) was dissolved in diethylaminosulfur trifluoride (5 mL), and the resulting mixture was stirred in the reaction solution at 80° C. for 1 h. The reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 10:1), indicating complete consumption of the starting material. The reaction solution was cooled to room temperature, and dichloromethane (20 mL) was added to dilute the reaction system. Ice water was carefully added dropwise to quench the reaction. The organic phase was separated and the aqueous layer was extracted with dichloromethane (3 × 10 mL). The combined organic phases were washed with saturated brine (15 mL), filtered, and concentrated to obtain the crude product. The crude product was added to silica gel and filtered through a column with petroleum ether:ethyl acetate = 93:7 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]-1-(2-fluorophenyl)hexyl acetate 11-5 (210 mg, purity: 90%, yield: 72.85%) as a colorless, transparent solid. 1H NMR (400MHz, CDCl3) δ7.34(t,J=7.4Hz,1H),7.24(d,J=6.6Hz,1H),7.12(t,J=7.5Hz,1H) ,7.06–7.00(m,1H),6.05–5.98(m,1H),4.07–3.98(m,2H),2.08(d,J=1.3Hz,3H),1.98–1 .68(m,9H),1.63–1.57(m,2H),1.50(s,3H),1.39(dd,J=10.5,5.0Hz,4H),1.30(s,3H),1 .07(s,3H),1.05–0.90(m,4H),0.87(dd,J=6.3,4.7Hz,4H),0.64(dd,J=11.7,3.6Hz,3H).

[0173] Step 6: (5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-6,7-dihydroxy-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1-(2-fluorophenyl)hexyl acetate 11-5 (130 mg, 0.23 mmol, 1.0 eq) was dissolved in dichloromethane (8 mL). The reaction system was placed in an ice-water bath and cooled to about 5°C. Acetic anhydride (0.022 mL, 0.23 mmol, 1.0 eq), 4-dimethylaminopyridine (5.62 mg, 0.046 mmol, 0.2 eq) and triethylamine (0.064 mL, 0.46 mmol, 2.0 eq) were added to the reaction system in sequence, and the reaction system was stirred at room temperature for 1 hour. After the reaction was complete as monitored by TLC (petroleum ether:ethyl acetate = 10:1), the mixture was quenched with methanol (20 mL), washed with water (40 mL × 2), and the aqueous phase was washed with dichloromethane (40 mL × 2). The organic phase was collected and removed in vacuo to afford the crude product. The crude product was purified by flash chromatography (petroleum ether:ethyl acetate = 80:20) to afford (5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-7-acetoxy-4,4-difluoro-6-hydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-1-(2-fluorophenyl)hexyl acetate 11-6 as a white solid (90 mg, 95% purity, 61% yield). 1H NMR (400MHz, CDCl3) δ7.34(t,J=7.4Hz,1H),7.24(d,J=5.8Hz,1H),7.12(t,J=7.5Hz,1H),7.0 2(dd,J=15.2,6.7Hz,1H),6.05–5.97(m,1H),4.73(dd,J=9.2,6.0Hz,1H),3.88(d,J=39.4Hz,1 H),2.30–2.12(m,1H),2.09(s,6H),1.98–1.69(m,10H),1.48–1.29(m,8H),1.16–1.09(m,2H), 1.08(s,3H),1.03(d,J=8.7Hz,3H),0.87(dd,J=6.4,4.1Hz,3H),0.63(dd,J=12.2,3.5Hz,3H).

[0174] Step 7: Compound (5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-7-acetoxy-4,4-difluoro-6-hydroxy-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-1-(2-fluorophenyl)hexyl acetate 11-6 (80 mg, 0.132 mmol) was dissolved in dichloromethane (10 mL) and Dess-Martin periodinane (67 mg, 0.158 mmol). The mixture was stirred at room temperature for 1 hour and 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 ethyl acetate (3 × 25 mL). The ethyl acetate layers were combined and washed with saturated brine (3 × 10 mL). The ethyl acetate layer was dried over Na2SO4, filtered, and concentrated to obtain the crude product. After the reaction was completed, the reaction solution was filtered, the filtrate was washed with water, the organic phase was dried and concentrated, and the crude product was purified by flash column chromatography (petroleum ether: ethyl acetate = 84:16) to give white solid acetate-(5R)-5-[(1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-7-acetoxy-4,4-difluoro-9a,11a-dimethyl-6-oxoylidenehexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-1-(2-fluorophenyl)hexyl ester 11-7 (85 mg, purity 95%, yield 90%). 1H NMR (400MHz, CDCl3) δ7.34(t,J=7.4Hz,1H),7.25(s,1H),7.12(t,J=7.5Hz,1H),7.07– 7.00(m,1H),6.05–5.99(m,1H),5.18(dd,J=12.2,7.4Hz,1H),2.53(t,J=10.2Hz,1H),2 .09(s,3H),2.05(s,4H),1.99–1.56(m,11H),1.38(ddd,J=26.0,14.1,6.7Hz,6H),1.22 –0.99(m,4H),0.89–0.85(m,3H),0.77(d,J=10.9Hz,3H),0.63(dd,J=15.2,3.6Hz,3H).

[0175] Step 8: Compound (5R)-5-[(1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-7-acetoxy-4,4-difluoro-9a,11a-dimethyl-6-oxoylidenehexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-1-(2-fluorophenyl)hexyl acetate 11-7 (87 mg, 0.144 mmol, 1 eq) was dissolved in a mixed solvent of tetrahydrofuran (2.5 mL) and methanol (2.5 mL), and lithium hydroxide aqueous solution (0.5 mL, 3 mol / L) was added, and the resulting mixture was stirred at 25 ° C for 1 h. The reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 1:1). Once the starting material was consumed, the reaction solution was diluted with ethyl acetate (20 mL), washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 76:24). This was followed by SFC separation (instrument: Waters Acquity UPCC; column: REGIS CHIRAL (S,S)-Whelk 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°C; retention time t R =2.417 min) to give a white solid (1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-(2-fluorophenyl)-6-hydroxyhexan-2-yl]-7-hydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6-one 11 (6.04 mg, purity: 95.12%, yield: 8.34%).

[0176] Compound 11: 1H NMR (400MHz, CDCl3) δ7.46(t,J=7.5Hz,1H),7.23(d,J=5.9Hz,1H),7.15(t,J=7.2Hz,1 H),7.05–6.98(m,1H),5.04–4.96(m,1H),4.14(dd,J=11.2,8.1Hz,1H),2.46(ddd,J=1 6.8,12.7,8.3Hz,2H),2.18–2.07(m,1H),1.77–1.50(m,11H),1.27(dddd,J=55.4,28. 2,14.6,6.8Hz,12H),0.90(dd,J=6.4,4.0Hz,3H),0.76(s,3H),0.66(d,J=2.0Hz,3H). 19 F NMR (377MHz, CDCl3) δ-90.21,-90.85,-111.50,-112.14,-119.77,-119.80.

[0177] Examples 15A & 15B

[0178] Compounds 15A & 15B: Preparation of 2-fluoro-N-[(3R)-3-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6,7-dihydroxy-5a,9a,11a-trimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]butyl]-N-methylbenzamide and 2-fluoro-N-[(3R)-3-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6,7-dihydroxy-5a,9a,11a-trimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]butyl]-N-methylbenzamide

[0179] Step 1: (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 (300 mg, 0.776 mmol) was dissolved in tetrahydrofuran (5 mL). Zinc chloride (105.76 mg, 0.776 mmol) and methylamine tetrahydrofuran solution (1.552 mL) were added sequentially at room temperature. The mixture was stirred at room temperature for 30 minutes, and sodium cyanoborohydride (48.77 mg, 0.776 mmol) was then added. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1). After the reaction, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was separated, dried, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to give (1R,3aS,3bS,7S,9aR,9bS,11aR)-9a,11a-dimethyl-1-[(2R)-4-(methylamino)butan-2-yl]-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate 15-1 (220 mg, 0.438 mmol, 56.47%) as a white solid. 1 H NMR (399MHz, Chloroform-d) δ5.35 (d, J = 5.0 Hz, 1H), 4.59 (d, J = 13.0 Hz, 1H), 2.95 (d, J = 36. 8Hz,2H),2.69(s,2H),2.30(d,J=7.3Hz,2H),2.01(s,3H),1.96(d,J=13.5Hz,2H),1.88–1.8 1(m,3H),1.56(d,J=10.6Hz,3H),1.50(d,J=16.6Hz,3H),1.45–1.36(m,2H),1.33–1.24(m, 2H),1.20–1.01(m,5H),0.99(s,3H),0.96(d,J=6.0Hz,3H),0.94–0.84(m,1H),0.68(s,3H).

[0180] Step 2: (1R,3aS,3bS,7S,9aR,9bS,11aR)-9a,11a-dimethyl-1-[(2R)-4-(methylamino)butan-2-yl]-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate 15-1 (60 mg, 0.149 mmol) was dissolved in DCM (5 mL). Diisopropylethylamine (0.074 mL, 0.448 mmol) was added, followed by o-fluorobenzoyl chloride (47.37 mg, 0.299 mmol) with stirring. Stirring was continued at room temperature. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 10:1). After the reaction, water (20 ml) and ethyl acetate (15 ml) were added for extraction. The organic phase was separated, dried, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 30:1 to 5:1) to give (1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-4-{[(2-fluorophenyl)carbonyl](methyl)amino}butan-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 15-2 (40 mg, 0.061 mmol, 40.90%) as a white solid. 1 H NMR(399MHz,Chloroform-d)δ7.32(dt,J=15.8,6.9Hz,2H),7.17(t,J=7.5Hz,1H),7.07(q,J=8.8Hz,1H),5.36(d,J= 5.7Hz,1H),4.58(d,J=6.0Hz,1H),3.20–3.09(m,1H),3.07(s,2H),2.86(d,J=1.5Hz,1H),2.30(t,J=5.8Hz,2H),2.01 (d,J=1.9Hz,4H),1.97–1.87(m,2H),1.83(t,J=9.9Hz,2H),1.51–1.36(m,5H),1.34–1.25(m,2H),1.14(ddd,J=33.9 ,16.5,6.5Hz,5H),1.01(dd,J=14.9,8.0Hz,6H),0.96–0.83(m,2H),0.69(s,1H),0.63(d,J=5.9Hz,2H),0.59(s,2H).

[0181] Step 3: Acetate (1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-4-{[(2-fluorophenyl)carbonyl](methyl)amino}butan-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 15-2 (232 mg, 0.443 mmol) was dissolved in chloroform (10 mL). Selenium dioxide (245.76 mg, 2.215 mmol) and NMM (268.84 mg, 2.658 mmol) were added sequentially under stirring at room temperature. The temperature was then raised to 75 ° C with stirring. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 3:1). After the reaction, the mixture was cooled to room temperature, filtered to obtain the filtrate, and water and dichloromethane were added for extraction. The organic phase was separated, dried, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 5:1) to obtain (1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-1-[(2R)-4-{[(2-fluorophenyl)carbonyl](methyl)amino}butan-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-i]phenanthrene-7-yl acetate 15-3 (136 mg, 0.202 mmol, 45.51%) as a white solid. 1 H NMR(399MHz,Chloroform-d)δ7.32(dt,J=15.9,7.0Hz,2H),7.17(t,J=7.5Hz,1H),7.07(q,J=8.7Hz,1H),5.69(d,J=5.6 Hz,1H),4.69(d,J=11.4Hz,1H),4.22(d,J=4.2Hz,1H),3.67(s,1H),3.43(s,1H),3.15(s,1H),3.07(s,1H),2.86(s,1H), 2.08(s,4H),2.00(s,1H),1.85(q,J=12.1Hz,3H),1.65(d,J=9.2Hz,3H),1.49–1.38(m,3H),1.30(s,3H),1.19(d,J=9.7Hz,3 H),1.11(dd,J=23.4,9.3Hz,3H),1.03(d,J=6.6Hz,2H),0.98–0.80(m,3H),0.69(s,1H),0.64(d,J=5.9Hz,1H),0.59(s,1H).

[0182] Step 4: Acetate (1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-1-[(2R)-4-{[(2-fluorophenyl)carbonyl](methyl)amino}butan-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-i]phenanthrene-7-yl ester 15-3 (136 mg, 0.252 mmol) was dissolved in acetic acid (3 mL). Platinum dioxide (85.83 mg, 0.378 mmol) was added and the atmosphere was replaced with hydrogen. The mixture was then heated to 60°C with stirring and monitored by TLC (petroleum ether:ethyl acetate = 5:1). After the reaction, platinum dioxide was removed by filtration, and the mixture was concentrated to remove most of the acetic acid. Saturated aqueous sodium bicarbonate solution and ethyl acetate were then added for extraction. The organic phase was separated, dried, and concentrated to give crude acetate-(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-1-[(2R)-4-{[(2-fluorophenyl)carbonyl](methyl)amino}butan-2-yl]-6-hydroxy-5a,9a,11a-trimethylhexahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 15-4 (130 mg), which was directly used in the next reaction.

[0183] Step 5: Acetate (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-1-[(2R)-4-{[(2-fluorophenyl)carbonyl](methyl)amino}butan-2-yl]-6-hydroxy-5a,9a,11a-trimethylhexadecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl) ester 15-4 (130 mg, 0.234 mmol) was dissolved in a mixture of methanol (1 mL) and tetrahydrofuran (2 mL). Aqueous lithium hydroxide (2.339 mL) was added, and the mixture was stirred at room temperature. TLC (petroleum ether:ethyl acetate = 2:1) was used for monitoring. After the reaction, water and ethyl acetate were added for extraction, and the organic phase was separated, dried, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 20:1 to 1:1) to obtain 2-fluoro-N-[(3R)-3-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6,7-dihydroxy-5a,9a,11a-trimethylhexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]butyl]-N-methylbenzoyl Amine 15A (14 mg, 0.026 mmol, 10.95%) and 2-fluoro-N-[(3R)-3-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6,7-dihydroxy-5a,9a,11a-trimethylhexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]butyl]-N-methylbenzamide 15B (18 mg, 0.035 mmol, 14.82%)

[0184] 15A: 1 H NMR(399MHz,Chloroform-d)δ7.33(d,J=22.2Hz,2H),7.18(t,J=7.6Hz,1H),7.08(q,J=8.3Hz,1H),4.01(s,1H), 3.88(t,J=11.1Hz,1H),3.67(s,1H),3.44(s,1H),3.17(d,J=14.2Hz,1H),3.08(s,2H),2.87(s,1H),1.99(s,6H), 1.81(d,J=39.6Hz,2H),1.64(s,3H),1.47(s,2H),1.41(d,J=9.7Hz,2H),1.29(d,J=9.4Hz,2H),1.18(d,J=15.9Hz ,3H),1.05(s,2H),1.01(d,J=6.7Hz,3H),0.96(d,J=9.2Hz,3H),0.66(s,1H),0.62(d,J=5.9Hz,1H),0.56(s,2H). 19F NMR(376MHz,Chloroform-d)δ-115.20.LC-MS:[M+H] + =500.35.

[0185] 15B: 1 H NMR(399MHz,Chloroform-d)δ7.39–7.28(m,2H),7.18(d,J=7.7Hz,1H),7.07(q,J=8.4Hz,1H),3.74 (s,1H),3.56(s,1H),3.44(s,1H),3.16(d,J=13.0Hz,1H),3.07(s,2H),2.86(s,1H),2.46(s,4H),1 .95(d,J=13.2Hz,1H),1.73(d,J=12.6Hz,5H),1.48(s,1H),1.33(s,3H),1.10(dd,J=22.5,10.9Hz, 5H), 0.98 (d, J = 9.3Hz, 6H), 0.87 (d, J = 6.3Hz, 3H), 0.65 (s, 1H), 0.61 (d, J = 5.6Hz, 2H), 0.55 (s, 2H). 19 F NMR (376MHz, Chloroform-d) δ-115.13 (d, J=49.4Hz). 13 C NMR(100MHz,Chloroform-d)δ110.00, 77.21,77.01,56.37,55.94,55.59,55.06,48.60,44.95,42.65,42.54,35.31,33 .76,33.40,32.78,32.25,30.96,20.45,18.72,18.43,14.58,11.96.LC-MS:[M+H] + =500.40.

[0186] Example 21

[0187] Preparation of compound 21(1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-1-[(2R)-6-(2,6-difluorophenyl)-6-hydroxyhexan-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.

[0188] Step 1: The reagent 2-bromo-1,3-difluorobenzene (270 mg, 1.40 mmol, 3.0 eq) was dissolved in tetrahydrofuran (5 mL) under nitrogen protection and cooled to -78 °C in a dry ice bath. Then, n-butyl lithium, 2.5 M n-hexane solution (0.67 mL, 1.680 mmol, 3.6 eq) was added and the reaction was continued for about 0.5 h. Then, (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-3 A solution of aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]hexanal III (200 mg, 0.467 mmol, 1.0 eq) in tetrahydrofuran (10 mL) was prepared and the reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1). The starting material was almost gone. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and the crude product was purified by flash column chromatography (petroleum ether:ethyl acetate = 80:20) 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,11,12b-Tetradecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-(2,6-difluorophenyl)hexan-1-ol 21-1 (180 mg, 0.03 mmol, purity: 90%, yield: 63.97%). 1 H NMR(400MHz,)δ7.21(s,1H),6.87(t,J=8.2Hz,2H),5.80(d,J=2.7Hz,1H),5.03(s,1H),4.40(d,J=5.8Hz,1H),4.10(d,J=7.4Hz,1H) ,2.12(m,1H),2.00(d,J=13.4Hz,2H),1.69(m,10H),1.39(m,8H),1.08(m,10H),0.90(dd,J=14.8,8.6Hz,5H),0.68(d,J=3.9Hz,3H).

[0189] 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]-1-(2, 6-difluorophenyl)hexan-1-ol 21-1 (180 mg, 0.332 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), and acetic anhydride (0.093 mL, 0.995 mmol, 3.0 eq), triethylamine (0.230 mL, 1.658 mmol, 5.0 eq) and DMAP (8.10 mg, 0.066 mmol, 0.2 eq) were added. The reaction solution was stirred at 25 ° C for 1 h. The reaction progress was monitored by TLC plate (petroleum ether:ethyl acetate = 5:1). After the starting material was consumed, the mixture was quenched with methanol, washed with saturated sodium bicarbonate, washed with saturated brine (15 mL), dried over Na2SO4, filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 90:10) to obtain acetic acid-(5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12b R)-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]-1-(2,6-difluorophenyl)hexyl ester 21-2 (150 mg, 0.231 mmol, purity: 90%, yield: 69.61%). 1 H NMR (400MHz, CDCl3) δ7.23(m,1H),6.86(t,J=8.0Hz,2H),6.05(t,J=7.5Hz,1H),5 .80(d,J=2.6Hz,1H),4.40(d,J=5.8Hz,1H),4.10(dd,J=13.7,6.2Hz,1H),2.11(d d,J=12.6,4.2Hz,1H),2.06(s,3H),2.01(m,2H),1.77(m,3H),1.61(m,6H),1.41( d,J=12.5Hz,4H),1.30(m,6H),1.06(m,11H),0.87(m,5H),0.67(d,J=4.0Hz,3H).

[0190] The third step: the compound acetate-(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]-1-(2,6-difluorophenyl)hexyl ester Compound 21-2 (150 mg, 0.257 mmol, 1.0 eq) was dissolved in acetone (5 mL), and N-hydroxyphthalimide (8.37 mg, 0.051 mmol, 0.2 eq), tert-butyl hydroperoxide (0.205 mL, 1.026 mmol, 4.0 eq), and anhydrous cobalt(II) acetate (2.27 mg, 0.013 mmol, 0.05 eq) were added. The resulting mixture was stirred at 25°C under N₂ for 18 hr. The reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 10:1). When the starting material was essentially consumed, the reaction was quenched with saturated sodium sulfite. Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with saturated brine (15 mL), dried over Na₂SO₄, filtered, and concentrated to yield the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 80:20) 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]-1-(2,6-difluorophenyl)hexyl acetate 21-3 (90 mg, 0.135 mmol, purity: 90%. Yield: 52.74%). 1 H NMR (400MHz, CDCl3) δ7.23(s,1H),6.86(t,J=8.2Hz,2H),6.04(t,J=7.4Hz,1H),5.92(s,1H),4.52(d,J=6.4Hz,1H ),4.33(d,J=5.6Hz,1H),2.34(d,J=10.5Hz,2H),2.06(s,3H),1.82(m,3H),1.63(dd,J=15.0,9.3Hz,3H),1.56(d, J=5.4Hz,8H),1.37(s,4H),1.28(m,9H),1.07(m,4H),0.87(dd,J=12.8,6.4Hz,4H),0.69(d,J=3.9Hz,3H).

[0191] Step 4: Compound (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-11-oxylidene-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]-1-(2-fluorophenyl)hexyl acetate 21-3 (90 mg, 0.150 mmol) was dissolved in methanol (5 mL), palladium on carbon (10.99 mg) was added, and the atmosphere was replaced with hydrogen three times. The resulting mixture was stirred in the reaction mixture under H2 at 25°C for 1 h. The reaction progress was monitored by TLC plate (petroleum ether:ethyl acetate=3:1). The starting material was consumed, filtered and concentrated to obtain a crude product. The crude product was added to silica gel column chromatography (petroleum ether:ethyl acetate = 80:20) and purified to obtain (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]-1-(2,6-difluorophenyl)hexyl acetate 21-4 (50 mg, 0.067 mmol, purity: 80%, yield: 44.30%). 1 H NMR(400MHz, CDCl3)δ7.34(s,1H),7.23(s,1H),7.12(s,1H),7.03(s,1H),6.01(dd, J=10.9,6.4Hz,1H),3.98(d,J=3.4Hz,2H),2.77(s,1H),2.42(s,1H),2.19(dd,J=12. 7,2.7Hz,2H),2.08(s,3H),1.74(m,9H),1.53(s,3H),1.38(dd,J=11.7,7.8Hz,4H), 1.28(d,J=17.1Hz,10H), 0.95(ddd,J=10.8,9.5,6.5Hz,10H), 0.64(d,J=3.2Hz,3H).

[0192] Step 5: 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]-1-(2,6-difluorophenyl)hexyl acetate 21-4 (800 mg, 1.332 mmol) was dissolved in DAST (30 mL), and the resulting mixture was stirred in the reaction solution under N2 at 80°C for 3 h. The reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 5:1) to confirm complete consumption of the starting material. The reaction solution was cooled to room temperature and carefully added dropwise to an ice-water mixture. The aqueous layer was extracted with ethyl acetate (3 x 100 mL). The ethyl acetate layers were combined and washed with saturated brine (100 mL). The organic phase was dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was monitored by TLC (petroleum ether:ethyl acetate = 1:1). The crude product was added to silica gel and passed through a column with petroleum ether:ethyl acetate = 1:1 to give (5R)-1-(2,6-difluorophenyl)-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]hexyl acetate 21-5 (600 mg, 0.185 mmol, purity: 10%) as a colorless, transparent solid.

[0193] Step 6: Compound (5R)-1-(2,6-difluorophenyl)-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]hexyl acetate 21-5 (600 mg, 0.963 mmol, content 10%) was dissolved in tetrahydrofuran (30 mL), added to 3 mol / L hydrochloric acid solution (5 mL), and the resulting mixture was stirred at 25 ° C for 1 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 1:1). After the starting material was consumed, the reaction solution was diluted with ethyl acetate (20 mL), washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product 4 (petroleum ether:ethyl acetate: 1:1), (5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-6,7-dihydroxy-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1-(2,6-difluorophenyl)hexyl acetate 21-6 (420 mg, 0.649 mmol, purity: 10%).

[0194] Step 7: Compound (5R)-1-(2,6-difluorophenyl)-5-[(1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-6,7-dihydroxy-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]hexyl acetate 21-6 (420 mg, 0.721 mmol, 10%) was dissolved in a mixture of methanol (10 mL) and tetrahydrofuran (10 mL). Lithium hydroxide solution (3 mL) was added, and the resulting mixture was stirred at 25°C for 1 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 1:1), indicating complete consumption of the starting material. Water (5 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 × 100 mL). The ethyl acetate layers were combined and washed with saturated brine (100 mL). The ethyl acetate layer was dried over Na2SO4, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain a crude product, which was then separated by chiral SFC (instrument: Waters Acquity UPCC; column: Daicel CHIRALPAK IC_3, 3.0*150 mm, 3 μm mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 60 / 40; flow rate: 1.5 mL / min, column temperature: 37°C; retention time t R =1.738 min) to give 24-[(2,6-difluorophenyl)(hydroxy)methyl]-7-fluoro-5α-cholane-3β,4β-diol 21 (30 mg, 0.055 mmol, 7.57%) as a white solid. 1 H NMR (400MHz, CDCl3) δ7.20(m,1H),6.88(m,2H),5.03(m,1H),3.85(s,1H),3. 59(dt,J=11.8,4.1Hz,1H),2.66(t,J=12.6Hz,1H),2.01(m,2H),1.83(ddd,J= 33.4,31.9,12.6Hz,13H),1.61(m,2H),1.46(m,3H),1.37(m,3H),1.09(dd,J =12.7,4.5Hz,3H),1.04(s,3H),0.90(t,J=6.0Hz,3H),0.62(d,J=3.8Hz,3H). 13C NMR (101MHz, CDCl3) δ151.96,137.52,128.96,113.27,111.86,111.57,108.65,72.41,72.36,54.20,53.47,52.56,49.59,43 .97,43.45,39.50,36.79,36.09,35.44,34.21,32.98,28.49,27.56,27.30,25.37,22.67,22.50,21.14,18.85,15.11,12.56. 19 F NMR(377MHz, CDCl3)δ-89.26,-109.78,-115.39,-115.45.LC-MS: [M+H-H2O] + =503.7.

[0195] Example 22

[0196] Preparation of Compound 22 24-[Methoxy(2-methoxyphenyl)methyl]-5α-cholane-3β,4β-diol

[0197] In the first step, the reactant (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-2,2,5a,7a-tetramethyl- 0b,11,12,12a,12b-Hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]hexanal III (58 mg, 0.058 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 mL). After cooling the reaction system to 0°C, (2-methoxyphenyl)lithium (1.22 mL, 0.29 mmol, 5 eq) was slowly added. The reaction system was stirred at room temperature for 1 h. TLC (petroleum ether:ethyl acetate = 5:1) monitored the reaction for completion. 20 mL of water was added to the reaction system, and extraction was performed with ethyl acetate (50 mL x 3). The combined organic phases were washed with water (30 mL), dried, and concentrated to yield the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 88:12 to 85:15) 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]-1-(2-methoxyphenyl)hexan-1-ol 22-1 (7 mg, purity 90%, yield 20.14%) as a white solid. 1H NMR(400MHz,CDCl3)δ7.32–7.27(m,1H),7.25–7.21(m,1H),6.95(t,J=7.5Hz,1H),6.88(d,J=8.2Hz,1H),4.85(dt,J=9.9,5.8Hz,1H),4.02–3.94(m,2H),3.85(s,3H),1.95(d,J=12.7Hz,1H),1.81–1.67(m,4H),1.42(s,1H),1.33(s,1H),1.30(s,2H),1.28(s,1H),1.25(s,4H),1.09(dd,J=16.1,9.7Hz,2H),1.04(s,2H),0.89(d,J=4.0Hz,1H),0.83(dd,J=16.6,9.1Hz,1H),0.65(d,J=2.7Hz,1H),0.58(d,J=8.2Hz,1H).

[0198] In the second step, the reactant (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]-1-(2-methoxyphenyl)hexan-1-ol 22-1 (50 mg, 0.093 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (5 mL). The reaction system was replaced with a nitrogen atmosphere. Sodium hydride (11.14 mg, 0.278 mmol, 3.0 eq) was slowly added, and the reaction system was stirred at room temperature for 30 min. Iodomethane (39.51 mg, 0.278 mmol, 3.0 eq) was then added, and the reaction system was stirred at 40°C for 2 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1). The reaction was stopped after the starting material was consumed. Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 × 25 mL). The EA layers were combined and washed with saturated brine (3 × 10 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=94:6) to give (3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-8-[(2R)-6-methoxy-6-(2-methoxyphenyl)hexan-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':1,2]phenanthro[7,8-d][1,3]dioxolan-22-2 (20 mg, purity 95%, yield 88.89%) as a white solid. 1H NMR (400MHz, CDCl3) δ7.34(d,J=7.5Hz,1H),7.24–7.20(m,1H),6.98(t,J=7.7Hz,1H),6.86(d,J=8.2Hz,1H),4.59(dd,J=11.1 ,5.1Hz,1H),4.05–3.91(m,2H),3.82(s,3H),3.22(d,J=1.6Hz,3H),1.95(d,J=12.2Hz,1H),1.76(dd,J=15.0,5.6Hz,3H),1.66 (dd,J=20.4,8.4Hz,4H),1.51(s,3H),1.41(ddd,J=29.3,15.8,6.4Hz,6H),1.30(s,3H),1.28–1.18(m,3H),1.08(d, J=9.2Hz,2H),1.04(s,3H),1.01–0.96(m,2H),0.88(dd,J=6.4,3.6Hz,3H),0.64(t,J=2.5Hz,3H),0.62–0.55(m,1H).

[0199] In the third step, the reactant (3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-8-[(2R)-6-methoxy-6-(2-methoxyphenyl)hexan-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':1,2]phenanthro[7,8-d][1,3]dioxolane 22-2 (45 mg, 0.072 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 mL), and dilute hydrochloric acid (0.5 mL, 3 mol / L) was added. The reaction system was stirred at room temperature for 40 min. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 2:1). The starting material was consumed and the reaction was stopped. Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3×25 mL). The EA layers were combined and washed with saturated brine (3×10 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 73:27) to obtain a white solid 24-[methoxy(2-methoxyphenyl)methyl]-5α-cholane-3β,4β-diol 22 (21.37 mg, purity 91.20%, yield 52.53%). 1H NMR (400MHz, CDCl3) δ7.34(d,J=7.6Hz,1H),7.25–7.19(m,1H),6.98(t,J=7.8Hz,1H),6.86(d,J=8.1Hz,1H),4.5 9(dd,J=11.1,5.1Hz,1H),3.82(s,3H),3.73(s,1H),3.55(d,J=11.2Hz,1H),3.22(d,J=1.5Hz,3H),1.95(d,J=12 .0Hz,1H),1.74(dt,J=15.2,14.2Hz,6H),1.54(dd,J=16.6,7.5Hz,3H),1.43–1.16(m,10H),1.09–1.02(m,4H),1 .01(s,3H),0.98–0.89(m,3H),0.87(dd,J=6.4,3.6Hz,3H),0.63(d,J=1.1Hz,3H),0.57(dd,J=16.8,5.9Hz,1H). 13 C NMR (101MHz, CDCl3) δ157.13,127.87,126.52,126.46,120.68,110.26,74.86,74.57,72.30,56.79,56.57,56.30,55.31, 48.82,42.59,39.90,37.48,37.29,36.85,35.48,35.39,32.39,28.22,25.99,25.86,22.28,20.58,18.57,14.67,12.07.

[0200] Examples 35 & 36

[0201] Compound 35 (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R)-6-(4-fluoro-2-methoxyphenyl)-6-hydroxyhexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0202] Example 36 Preparation of (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-1-[(2R)-6-(4-fluoro-2-methoxyphenyl)-6-hydroxyhexan-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.

[0203] Step 1: Dissolve the raw material 1-bromo-4-fluoro-2-methoxybenzene (107 mg, 0.5 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL). Cool the system to -78°C, add n-butyl lithium (1.8 mL, 0.45 mmol, 3.0 eq), and stir at this temperature for 30 min. 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]hexanal I and (5R)-5-[(3aS,5aR,5bR A mixture of 2,7aR,8R,10aR,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 (70 mg, 0.15 mmol, 1.0 eq) was dissolved in tetrahydrofuran (2 mL) and added to the above reaction solution. The reaction system was stirred at -78°C for 30 min. The completion of the reaction was monitored by TLC plate (petroleum ether:ethyl acetate = 5:1). 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 (10 mL), the combined organic phases were dried, and concentrated to give colorless oily crude products of 35-1 and 36-1 (70 mg,), which were then used directly in the next step.

[0204] Step 2: Reaction of crude (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]-1-(4-fluoro-2-methoxyphenyl)hexan-1-ol 35-1 and (5R)-5-[(3aS,5aR,5bS,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-(4-fluoro-2-methoxyphenyl)hexan-1-ol 35-1 The crude product of (R,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]-1-(4-fluoro-2-methoxyphenyl)hexan-1-ol 36-1 (70 mg, 0.11 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL). Dilute hydrochloric acid (1 mL, 3 mol / L) was added, and the reaction system was stirred at room temperature for 1 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1). The reaction was stopped after the starting material was consumed. Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3×10 mL). The EA layers were combined and washed with saturated brine (3×10 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 65:35) to give a white solid, which was then separated by chiral separation SFC (instrument: Waters Acquity UPCC; chromatographic column: Daicel CHIRALPAK IC_3, 3.0*150mm, 3um; mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 60 / 40; flow rate: 1.5 ml / min; column temperature: 37 degrees) to obtain (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R)-6-(4-fluoro-2-methoxyphenyl)-6-hydroxyhexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 35 (48.95 mg, purity 100%, yield 75%, retention time t R=1.420 min) and (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-1-[(2R)-6-(4-fluoro-2-methoxyphenyl)-6-hydroxyhexan-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 36 (4.64 mg, purity 99%, yield 7%, retention time t R =2.015min).

[0205] Compound 35: 1 H NMR (400MHz, CDCl3) δ7.19–7.16(m,1H),6.62–6.50(m,2H),4.81–4.74(m,1H),3 .75(d,J=13.2Hz,3H),3.67(s,1H),3.56–3.49(m,1H),2.22–2.05(m,1H),1.90( d,J=12.9Hz,1H),1.82–1.56(m,12H),1.43–1.15(m,10H),1.08–1.01(m,2H),0. 99(s,3H),0.95–0.86(m,2H),0.83(dd,J=6.5,4.1Hz,3H),0.59(d,J=1.7Hz,3H). 19 F NMR (376MHz, CDCl3) δ-88.63,-89.25,-110.63,-111.25,-113.00,-113.06.

[0206] Compound 36: 1 H NMR(400MHz, CDCl3)δ7.17(d,J=4.3Hz,1H),6.64–6.47(m,2H),4.82–4.74(m,1 H),3.78(s,1H),3.77(d,J=5.9Hz,3H),3.56–3.49(m,1H),2.59(s,1H),1.96(d, J=11.9Hz,1H),1.90–1.73(m,6H),1.68–1.51(m,11H),1.42–1.16(m,10H),1.0 6–0.99(m,3H),0.97(s,3H),0.84(dd,J=6.5,3.3Hz,3H),0.56(d,J=1.9Hz,3H). 19 F NMR (376MHz, CDCl3) δ-109.80,-113.00,-113.06.

[0207] Examples 37 & 38

[0208] Compound 37 (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-(2-methoxyphenyl)hexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol and

[0209] Preparation of compound 38 (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-1-[(2R)-6-hydroxy-6-(2-methoxyphenyl)hexan-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.

[0210] Step 1: Dissolve 1-bromo-2-methoxybenzene (1309.01 mg, 6.999 mmol, 3.0 eq) in tetrahydrofuran (50 mL). Under nitrogen, cool to -78°C. Add n-butyl lithium, 2.5 M n-hexane solution (3.359 mL, 8.398 mmol, 3.6 eq). Keep warm for 1 hour. Then add (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 (1000 mg, 2.333 mmol, 1.0 eq) was added to a tetrahydrofuran solution (10 mL) and stirred at room temperature for 1 h. 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 saturated ammonium chloride, and the aqueous layer was extracted with ethyl acetate (3 × 20 mL). The organic layers were combined and washed with saturated brine (15 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated to give a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 95:5) 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]-1-(2-methoxyphenyl)hexan-1-ol 37-1 (750 mg, 1.257 mmol, purity: 90%, yield: 53.90%) as a white solid. 1H NMR(400MHz,CDCl3)δ7.30(ddd,J=7.4,3.9,1.6Hz,1H),7.23(m,1H),6.95(t,J=7.4Hz,1H),6.88(d,J=8.2Hz,1H),5.74(dd,J=49.3,2.9Hz,1H),4.85(d,J=7.3Hz,1H),4.40(d,J=5.8Hz,1H),4.14(d,J=3.6Hz,0H),3.85(s,3H),3.56(dd,J=7.3,3.8Hz,1H),2.05(m,3H),1.71(m,10H),1.42(d,J=8.4Hz,4H),1.17(d,J=6.5Hz,4H),1.06(ddd,J=25.8,14.6,5.0Hz,6H),0.90(dt,J=7.5,3.7Hz,4H),0.68(dd,J=4.6,2.7Hz,3H).

[0211] 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]-1-(2-methoxyphenyl)hexan-1-ol 37-1 (750 mg, 1.397 mmol, 1.0 eq) was dissolved in dichloromethane (50 mL), and acetic anhydride (0.197 mL, 2.096 mmol, 1.5 eq), triethylamine (0.388 mL, 2.794 mmol, 2.0 eq) and 4-dimethylaminopyridine (34.14 mg, 0.279 mmol, 0.2 eq) were added. The resulting mixture was stirred in the reaction mixture under N2 at 25 °C for 3 h. The reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 5:1). After the starting material was consumed, the mixture was quenched with methanol, and water (10 mL) was added to the reaction system. The aqueous layer was extracted with dichloromethane (3 × 15 mL). The organic phases were combined and washed with saturated brine (5 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was added to silica gel and filtered through a column with petroleum ether:ethyl acetate = 10:1 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]-1-(2-methoxyphenyl)hexyl acetate 37-2 (750 mg, 1.166 mmol, purity: 90%, yield: 83.46%) as a white solid. 1H NMR(400MHz,CDCl3)δ7.30(d,J=7.6Hz,1H),7.22(dd,J=5.5,4.0Hz,1H),6.94(t,J=7.5Hz,1H),6.86(d,J=8.2Hz,1H),6.16(m,1H),5.80(d,J=2.7Hz,1H),4.40(d,J=5.8Hz,1H),4.11(m,1H),3.84(d,J=6.8Hz,3H),3.55(d,J=12.1Hz,0H),2.09(t,J=3.8Hz,3H),2.00(d,J=12.6Hz,1H),1.77(m,5H),1.62(m,5H),1.53(s,3H),1.35(s,3H),1.26(m,3H),1.16(s,3H),1.02(m,5H),0.86(m,7H),0.67(t,J=3.5Hz,3H).

[0212] The third step: the compound acetate-(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]-1-(2-methoxyphenyl)hexyl ester 37-2 (750 mg, 1.296 mmol, 1.0 eq) was dissolved in acetone (30 mL), and N-hydroxyphthalimide (42.27 mg, 0.259 mmol, 0.2 eq), tert-butyl hydroperoxide (1.037 mL, 5.183 mmol, 4.0 eq), and anhydrous cobalt(II) acetate (11.47 mg, 0.065 mmol, 0.05 eq) were added. The resulting mixture was stirred at 25°C under N₂ for 18 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1). The mixture was diluted with ethyl acetate and quenched with saturated sodium sulfite. The aqueous layer was extracted with ethyl acetate (3 × 10 mL). The ethyl acetate layers were combined and washed with saturated brine (15 mL). The ethyl acetate layer was dried over anhydrous Na₂SO₄, filtered, and concentrated to yield the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 80:20) to give (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-11-oxyidene-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]-1-(2-methoxyphenyl)hexyl acetate 37-3 (340 mg, 0.516 mmol, purity: 90%, yield: 39.84%) as a white solid. 1H NMR (400MHz, CDCl3) δ7.30(d,J=7.5Hz,1H),7.23(d,J=8.3Hz,1H),6.94(t,J=7.5Hz,1H),6.86(d,J=8.2Hz,1H) ,6.16(s,1H),5.92(s,1H),4.52(d,J=6.4Hz,1H),4.33(d,J=5.7Hz,1H),3.84(s,3H),2.35(d,J=10.3Hz,2H),2. 08(d,J=1.8Hz,3H),2.05(s,1H),1.80(m,4H),1.63(dd,J=16.1,10.4Hz,3H),1.57(s,4H),1.42(m,2H),1.37(s, 3H),1.33(s,4H),1.26(m,2H),1.09(dd,J=38.3,9.0Hz,4H),0.88(dt,J=7.8,3.9Hz,3H),0.69(d,J=1.7Hz,3H).

[0213] Step 4: Compound (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-11-oxoylidene-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]-1-(2-methoxyphenyl)hexyl acetate 37-3 (340 mg, 0.574 mmol) was dissolved in methanol (20 mL) and palladium on carbon (100 mg, 0.940 mmol) was added. The resulting mixture was stirred in H2 at 25 °C for 1 h. The reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 5:1). Filtering and concentration afforded the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 80:20) 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]-1-(2-methoxyphenyl)hexyl acetate 37-4 (250 mg, 0.378 mmol, purity: 90%, yield: 65.95%) as a white solid. 1H NMR(400MHz,CDCl3)δ7.29(d,J=7.6Hz,1H),7.23(d,J=8.2Hz,1H),6.94(t,J=7.5Hz,1H),6.86(d,J=8.2Hz,1H),6.16(t,J=6.3Hz,1H),3.99(dt,J=8.4,7.3Hz,2H),3.84(d,J=6.9Hz,3H),2.77(t,J=13.5Hz,1H),2.42(t,J=11.2Hz,1H),2.21(d,J=2.7Hz,1H),2.08(d,J=0.9Hz,3H),1.97(d,J=12.5Hz,1H),1.87(m,2H),1.74(m,3H),1.63(d,J=14.5Hz,2H),1.41(m,5H),1.30(s,6H),1.25(m,3H),1.02(m,6H),0.86(m,7H),0.64(d,J=1.5Hz,3H).

[0214] Step 5: 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]-1-(2-methoxyphenyl)hexyl acetate 37-4 (180 mg, 0.303 mmol) was dissolved in DAST (5 mL, 0.333 mmol), and the resulting mixture was stirred in the reaction solution under N2 at 80°C for 3 h. The reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 5:1). Once the starting material was consumed, the reaction solution was cooled to room temperature, diluted with dichloromethane, and carefully added dropwise to an ice-water mixture. The aqueous layer was extracted with dichloromethane (3 × 25 mL). The dichloromethane was combined and washed with saturated brine (15 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated to give crude acetate-(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]-1-(2-methoxyphenyl)hexyl ester 37-5 and ( The crude product was directly used in the next step without further purification.

[0215] Step 6: Compounds (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]-1-(2-methoxyphenyl)hexyl acetate 37-5 and (5R)-5-[(3aS,5aR A mixture of (120 mg, 0.202 mmol) of (5bR, 7aR, 8R, 10aR, 12aR, 12bR)-11-fluoro-2,2,5a,7a-tetramethyl-3a,5,5a,5b,6,7,7a,8,9,10,10a,12,12a,12b-tetradecahydro-4H-cyclopentyl[7,8]phenanthro[1,2-d][1,3]dihydroxy-8-yl)-1-(2-methoxyphenyl)acetate 38-1 was dissolved in tetrahydrofuran (20 mL), and dilute hydrochloric acid (0.067 mL) was added. The resulting mixture was stirred at 25°C for 3 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1). The reaction was diluted with ethyl acetate, and the aqueous layer was extracted with ethyl acetate (3 × 25 mL). The ethyl acetate layers were combined and washed with saturated brine (15 mL). The ethyl acetate layer was dried over anhydrous Na2SO4, filtered and concentrated to give crude (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]-1-(2-methoxyphenyl)hexyl acetate 37-6 and (5R)-5-[(3S,4R,5R,9R,10R,13R,14R,17 R)-7-fluoro-3,4-dihydroxy-10,13-dimethyl-2,3,4,5,6,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-1-(2-methoxyphenyl)acetate 38-2 mixture (80 mg, 0.111 mmol, 37-6 purity: 80%), the crude product was not further purified and directly used in the next step.

[0216] Step 7: Compounds (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]-1-(2-methoxyphenyl)hexyl acetate 37-6 and (5 A mixture of 38-2 (80 mg, 0.139 mmol) of 5-((3S,4R,5R,9R,10R,13R,14R,17R)-7-fluoro-3,4-dihydroxy-10,13-dimethyl-2,3,4,5,6,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-1-(2-methoxyphenyl)acetate was dissolved in a mixed solvent of methanol (1 mL) and tetrahydrofuran (1 mL). The resulting mixture was stirred at 25°C for 3 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 1:1). The reaction solution was cooled to room temperature and carefully added dropwise to an ice-water mixture. The aqueous layer was extracted with ethyl acetate (3 × 25 mL). The ethyl acetate layers were combined and washed with saturated brine (15 mL). The ethyl acetate layer was dried over anhydrous Na2SO4, filtered and concentrated to obtain the crude product. The crude product was added to silica gel and filtered through a column using petroleum ether and ethyl acetate to obtain a white solid. The solid was then subjected to chiral separation (instrument: Waters Acquity UPCC; column: Daicel CHIRALPAK IC_3, 3.0*150 mm, 3 μm; mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 50 / 50; flow rate: 1.5 ml / min; column temperature: 37°C) to obtain (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-(2-methoxyphenyl)hexan-2-yl]-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 37 (42.6 mg, 0.074 mmol, purity: 93.24%, retention time t R=1.281 min) and (3S,4R,5R,9R,10R,13R,14R,17R)-7-fluoro-17-((2R)-6-hydroxy-6-(2-methoxyphenyl)hexan-2-yl)-10,13-dimethyl-2,3,4,5,6,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopentadien[a]phenanthrene-3,4-diol 38 (8.67 mg, 0.016 mmol, purity: 93.98%, yield: 11.34%, retention time t R =1.748min).

[0217] Compound 37: 1 H NMR (400MHz, CDCl3) δ7.32–7.28(m,1H),7.25–7.21(m,1H),7.00–6.93(m,1H),6.88(dd,J=8.1, 3.7Hz,1H),4.85(dt,J=9.7,5.9Hz,1H),3.86(s,3H),3.74(s,1H),3.64–3.57(m,1H),2.35–1.9 4(m,4H),1.88–1.78(m,5H),1.40(ddd,J=18.9,11.1,7.2Hz,8H),1.27(t,J=14.2Hz,4H),1.16– 1.07(m,3H),1.06(s,3H),1.02–0.93(m,2H),0.90(dd,J=6.4,4.1Hz,3H),0.65(d,J=2.3Hz,3H). 13 C NMR (101MHz, CDCl3) δ161.17,127.21,125.88,124.00,119.66,109.53,72.42,70.88,69.21,54.56,54.25,49.92,49.76,47.44, 42.81,42.20,38.29,36.76,36.68,35.21,34.82,34.63,34.28,33.87,33.47,27.43,24.51,21.51,19.39,17.68,12.64,10.83. 19 F NMR(377MHz, CDCl3)δ-88.63,-89.25,-110.62,-111.25.

[0218] Compound 38: 1H NMR(400MHz, CDCl3)δ7.30(d,J=7.6Hz,1H),7.23(d,J=7.9Hz,1H),6.96(t, J=7.5Hz,1H),6.88(d,J=8.1Hz,1H),4.90–4.81(m,1H),3.86(s,4H),3.63– 3.55(m,1H),2.66(s,1H),2.05–1.68(m,13H),1.49–1.24(m,10H),1.15–1. 07(m,3H),1.04(s,3H),0.91(dd,J=6.5,3.5Hz,3H),0.62(d,J=2.5Hz,3H). 19 F NMR (377MHz,CDCl3)δ-119.83.

[0219] Examples 39 & 40

[0220] Compound 39 (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-(3-methoxyphenyl)hexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0221] Preparation of compound 40 (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-1-[(2R)-6-hydroxy-6-(3-methoxyphenyl)hexan-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.

[0222] Step 1: Dissolve the raw material 1-bromo-3-methoxybenzene (98 mg, 0.5 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL). Cool the system to -78°C, add n-butyl lithium (1.8 mL, 0.45 mmol, 3.0 eq), and maintain the temperature with stirring for 30 min. 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]hexanal I and (5R)-5-[(3aS,5aR,5bR A mixture of (70 mg, 0.15 mmol, 1.0 eq) (7aR,8R,10aR,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 was dissolved in tetrahydrofuran (2 mL) and added to the reaction mixture. The reaction system was stirred at -78°C for 30 min. The reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 5:1), indicating complete consumption of the starting material. 10 mL of water was added to the reaction system, and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated sodium chloride (10 mL), and the combined organic phases were dried and concentrated to give a colorless oily product (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- 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]-1-(3-methoxyphenyl)hexan-1-ol 40-1 (70 mg) was prepared and used directly in the next step.

[0223] Step 2: Reaction of (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]-1-(3-methoxyphenyl)hexan-1-ol 39-1 and (5R)-5-[(3aS,5aR,5bR The crude product of (70 mg, 0.11 mmol, 1.0 eq) (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]-1-(3-methoxyphenyl)hexan-1-ol 40-1 was dissolved in tetrahydrofuran (3 mL) and diluted hydrochloric acid (1 mL, 3 mol / L) was added. The reaction system was stirred at room temperature for 1 h. The reaction progress was monitored by TLC plate (petroleum ether:ethyl acetate = 5:1). The reaction was stopped when the starting material was consumed. Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3×10 mL). The EA layers were combined and washed with saturated brine (3×10 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 65:35) to give a white solid, which was then separated by chiral separation SFC (instrument: Waters Acquity UPCC; chromatographic column: Daicel CHIRALPAK IC_3, 3.0*150mm, 3um; mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 60 / 40; flow rate: 1.5 ml / min; column temperature: 37 degrees) to obtain (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-(3-methoxyphenyl)hexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 39 (48.27 mg, purity 100%, yield 74.12%, retention time t R=2.218 min) and (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-1-[(2R)-6-hydroxy-6-(3-methoxyphenyl)hexan-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 40 (4.18 mg, purity 100%, yield 6%, retention time t R =3.272min).

[0224] Compound 39: 1 H NMR (400MHz, CDCl3) δ7.25 (s, 1H), 6.93 (d, J = 6.9Hz, 2H), 6.82 (dd, J = 8.6, 2.0Hz, 1 H),4.65(dd,J=13.1,6.0Hz,1H),3.83(s,3H),3.75(s,1H),3.64–3.57(m,1H),1.9 7(d,J=12.8Hz,1H),1.87–1.67(m,12H),1.50–1.24(m,10H),1.12(dd,J=13.3,4.4 Hz,2H),1.06(s,3H),1.03–0.94(m,2H),0.92–0.88(m,3H),0.66(d,J=2.3Hz,3H). 19 F NMR (376 MHz, CDCl3) δ -88.64, -89.26, -110.63, -111.26. Compound 40: 1 H NMR (400MHz, CDCl3) δ7.25 (s, 0H), 6.95–6.90 (m, 2H), 6.82 (dd, J = 8.7, 2.0Hz, 1H), 4 .66(dd,J=13.3,6.3Hz,1H),3.86(s,1H),3.83(s,3H),3.63–3.56(m,1H),2.66(t,J =13.5Hz,1H),1.78(dddd,J=45.2,31.3,23.5,11.4Hz,17H),1.49–1.42(m,4H),1.2 8(d,J=11.9Hz,5H),1.05(s,3H),0.91(dd,J=6.4,4.2Hz,3H),0.63(d,J=2.4Hz,3H). 19 F NMR (376MHz,CDCl3)δ-109.78.

[0225] Example 43

[0226] Preparation of Compound 43 24-(Hydroxy{2-[(trifluoromethyl)oxy]phenyl}methyl)-5α-cholan-3β-ol

[0227] In the first step, (1R,3aS,7S,9aR,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 acetate I-7 (1.0 g, 2.2 mmol) was dissolved in a mixed solvent of anhydrous methanol (10 mL) and tetrahydrofuran (5 mL), and 1 M aqueous lithium hydroxide solution (5 mL, 5 mmol) was added. The reaction was reacted at room temperature and monitored by TLC (petroleum ether: ethyl acetate = 10:1) to complete the reaction. The organic solvent was removed by concentration, and the remaining crude product was extracted with water and ethyl acetate. The organic phase was separated, dried, and concentrated to give (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]phenanthrene-1-yl]hexanoic acid 43-1 (800 mg, 2.06 mmol, 91.6%) as a white solid. 1 H NMR(399MHz,Chloroform-d)δ5.33(s,1H),3.49(d,J=12.8Hz,1H),2.36–2.17(m,5H),2.04–1.91(m,3H),1.82(d,J=12.2Hz,3H),1. 42(d,J=5.2Hz,5H),1.20–1.14(m,2H),1.11–1.05(m,3H),0.99(s,3H),0.92(d,J=6.4Hz,3H),0.85(d,J=10.0Hz,3H),0.66(s,3H).

[0228] In the second step, (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]phenanthrene-1-yl]hexanoic acid 43-1 (300 mg, 0.77 mmol) was dissolved in tetrahydrofuran (5 mL) and added. 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (354 mg, 0.93 mmol) and N,N-diisopropylethylamine (300 mg, 2.32 mmol) were added, and stirring was continued at room temperature for 30 minutes. Subsequently, dimethylhydroxylamine hydrochloride (150.2 mg, 1.54 mmol) was added, and stirring was continued at room temperature overnight. TLC (petroleum ether:ethyl acetate = 5:1) monitored the reaction completion. Ethyl acetate and water were added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 0-20%) to give (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]phenanthrene-1-yl]-N-methoxy-N-methylhexanamide 43-2 (100 mg, 0.23 mmol, 30%). 1 H NMR(399MHz,Chloroform-d)δ5.33(d,J=5.1Hz,1H),3.66(s,3H),3.49(dq,J=10.9, 5.6,4.9Hz,1H),3.16(s,3H),2.35(q,J=7.6Hz,2H),2.29–2.15(m,2H),2.01–1.90(m ,2H),1.88–1.76(m,3H),1.46(d,J=8.3Hz,5H),1.43–1.36(m,3H),1.21(ddd,J=26. 0,13.5,5.9Hz,2H),1.15–1.01(m,5H),0.98(s,4H),0.96–0.85(m,5H),0.65(s,3H).

[0229] In the third step, (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]phenanthrene-1-yl]-N-methoxy-N-methylhexanamide 43-2 (200 mg, 0.51 mmol) was dissolved in methanol (5 mL), and Pd / C (20 mg, 10%) was added to replace H2. The mixture was stirred at room temperature overnight and the reaction was monitored to be complete by TLC (petroleum ether:ethyl acetate = 5:1). Ethyl acetate and water were added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 0-20%) 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]-N-methoxy-N-methylhexanamide 43-3 (100 mg, 0.25 mmol, 50%). 1 H NMR(399MHz,Chloroform-d)δ3.66(s,3H),3.57(s,1H),3.16(s,3H),2.35(d,J=7.7Hz,2H),1.92(s,1H),1.71(dt,J=37.0 ,17.5Hz,5H),1.49(d,J=30.3Hz,8H),1.43–1.13(m,11H),1.13–1.00(m,5H),1.00–0.88(m,6H),0.78(s,3H),0.63(s,4H).

[0230] Step 4: (5R)-5-[(1R,3aS,3bR,5aS,7S,9aS,9bS,11aR)-7-hydroxy-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N-methoxy-N-methylhexanamide 43-3 (100 mg, 0.25 mmol) was dissolved in THF (10 mL). The temperature was cooled to -50°C, and DIBAL-H (0.5 mL, 5.0 eq) was added. The mixture was allowed to warm to room temperature and react for 2 h. The reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 5:1). Ethyl acetate and water were added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 0-20%) 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]hexanal 43-4 (60 mg, 0.16 mmol, 64%). 1H NMR(399MHz,Chloroform-d)δ9.74(s,1H),3.57(s,1H),2.37(d,J=6.9Hz,1H),1.96–1.62(m,5H),1.55(s,11 H),1.45–1.21(m,14H),1.07(q,J=8.5,6.5Hz,5H),1.00–0.84(m,7H),0.78(s,3H),0.63(s,3H),0.60(s,1H).

[0231] Step 5: Weigh o-bromotrifluoromethoxybenzene (192.8 mg, 0.8 mmol) and dissolve it in tetrahydrofuran (5 mL). Cool the mixture to -78 °C with dry ice-acetone, then add butyl lithium (1.6 M, 1.15 mmol) dropwise, and continue stirring at -78 °C for one hour. Separately, weigh (5R)-5-[(1R,3aS,3bR,5aS,7S,9aS,9bS,11aR)-7-hydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanal 43-4 (60 mg, 0.16 mmol) and dissolve it in tetrahydrofuran (10 mL). Cool the mixture to -78 °C, then add the above butyl lithium solution dropwise, and then maintain stirring at -78 °C for one hour before slowly warming to room temperature. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1). After completion of the reaction, saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was separated and dried, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 0-20%) to give 24-(hydroxy{2-[(trifluoromethyl)oxy]phenyl}methyl)-5α-cholan-3β-ol 43 (9 mg, 0.016 mmol, 10%) as a white solid. 1 H NMR (399MHz,Chloroform-d)δ7.57(dt,J=6.7,2.3Hz,1H),7.29(td,J=6.8,6.2,3.9Hz,2H),7.22–7.17(m,1H) ,5.04(d,J=6.8Hz,1H),1.93(d,J=12.5Hz,1H),1.77(d,J=11.6Hz,2H),1.73–1.60(m,4H),1.52(s,3H),1. 43(d,J=3.2Hz,1H),1.39(d,J=18.7Hz,4H),1.29(dd,J=18.1,6.2Hz,4H),1.24(d,J=3.9Hz,3H),1.11(s,1 H),1.08–1.03(m,3H),1.02–0.93(m,3H),0.87(dd,J=6.5,4.0Hz,3H),0.78(s,3H),0.62(d,J=1.5Hz,3H). 13C NMR(100MHz,Chloroform-d)δ128.44,128.42,127.40,127.00,119.93,71.3 7,68.11,67.92,56.43,56.17,54.29,44.80,42.57,39.99,38.54,38.42,38. 17,36.96,35.67,35.65,35.62,35.50,35.46,35.42,32.05,31.49,30.95,29.70,28.70,28.19,24.17,22.36,22.23,21.22,18.50,18.47,12.30,12.03. 19 F NMR(376MHz,Chloroform-d)δ-56.84(dd,J=4.0,1.8Hz).LC-MS:[M-OH] + =436.4.

[0232] Examples 44 & 45

[0233] Compound 44 (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R)-6-(3-fluorophenyl)-6-hydroxyhexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0234] Preparation of compound 45 (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-1-[(2R)-6-(3-fluorophenyl)-6-hydroxyhexan-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.

[0235] Step 1: Dissolve the raw material 1-bromo-3-fluorobenzene (92 mg, 0.5 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL). Cool the system to -78°C, add n-butyl lithium (1.8 mL, 0.45 mmol, 3.0 eq), and stir at this temperature for 30 min. 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]hexanal I and (5R)-5-[(3aS,5aR,5bR A mixture of (70 mg, 0.15 mmol, 1.0 eq) (7aR,8R,10aR,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 was dissolved in tetrahydrofuran (2 mL) and added to the reaction solution. The reaction system was stirred at -78°C for 30 min. The reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 5:1, phosphomolybdic acid hotplate), indicating complete consumption of the starting material. 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 (10 mL), the combined organic phases were dried, and concentrated to give colorless oily crude products 44-1 and 45-1 (70 mg), which were then used directly in the next step.

[0236] Step 2: Reaction of (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]-1-(3-fluorophenyl)hexan-1-ol 44-1 and (5R)-5-[(3aS,5aR,5bR The crude product of (70 mg, 0.11 mmol, 1.0 eq) (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]-1-(3-fluorophenyl)hexan-1-ol 45-1 was dissolved in tetrahydrofuran (3 mL) and diluted hydrochloric acid (1 mL, 3 mol / L) was added. The reaction system was stirred at room temperature for 1 h. The reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 5:1, phosphomolybdic acid hotplate). The reaction was stopped when the starting material was consumed. Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3×10 mL). The EA layers were combined and washed with saturated brine (3×10 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 65:35) to give a white solid, which was then separated by chiral separation SFC (instrument: Waters Acquity UPCC; chromatographic column: Daicel CHIRALPAK IC_3, 3.0*150 mm, 3 um; mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 60 / 40; flow rate: 1.5 ml / min; column temperature: 37 degrees) to give (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R)-6-(3-fluorophenyl)-6-hydroxyhexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 44 (42.38 mg, purity 96.53%, yield 62.92%; retention time t R=1.302 min) and (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-1-[(2R)-6-(3-fluorophenyl)-6-hydroxyhexan-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 45 (3.47 mg, purity 91.52%, yield 5%; retention time t R =1.730min).

[0237] Compound 44: 1 H NMR(400MHz, CDCl3) δ7.23(dd,J=13.8,7.9Hz,1H),7.02(dd,J=12.2,9.2Hz,2H),6.89(t,J =8.4Hz,1H),4.60(dd,J=12.9,5.9Hz,1H),3.67(s,1H),3.53(dt,J=11.3,4.1Hz,1H),2.22 –2.02(m,1H),1.90(d,J=12.8Hz,1H),1.80–1.55(m,13H),1.43–1.14(m,10H),1.04(dd,J= 14.1,5.4Hz,2H),0.99(s,3H),0.93–0.86(m,2H),0.84–0.80(m,3H),0.58(d,J=1.7Hz,3H). 19 F NMR (377MHz, CDCl3) δ-88.64,-89.26,-110.63,-111.26,-113.02.

[0238] Compound 45: 1 H NMR(400MHz, CDCl3)δ7.27–7.20(m,1H),7.02(dd,J=12.1,9.3Hz,2H),6.89(t,J=8.4Hz,1H), 4.61(dd,J=12.9,5.9Hz,1H),3.78(s,1H),3.52(dt,J=11.7,4.0Hz,1H),2.58(dd,J=16.6,8.1 Hz,1H),1.95(d,J=12.5Hz,1H),1.67(dddd,J=32.2,23.7,10.5,6.3Hz,17H),1.42–1.16(m,13 H),1.05–0.99(m,4H),0.97(s,3H),0.83(dt,J=6.7,3.4Hz,3H),0.57(dd,J=14.6,4.4Hz,3H). 19F NMR(377MHz, CDCl3)δ-109.76,-113.02.LC-MS: [M+H-H2O] + =485.65.

[0239] Examples 46 & 48

[0240] Compound 46 (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R)-6-(2-methoxy-3-fluorophenyl)-6-hydroxyhexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0241] Preparation of compound 48 (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-1-[(2R)-6-(3-fluoro-2-methoxyphenyl)-6-hydroxyhexan-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.

[0242] Step 1: Dissolve the raw material 1-bromo-3-fluoro-2-methoxybenzene (107 mg, 0.5 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL). Cool the system to -78°C, add n-butyl lithium (1.8 mL, 0.45 mmol, 3.0 eq), and maintain stirring at this temperature for 30 min. 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]hexanal I and (5R)-5-[(3aS,5aR,5bR A mixture of 2,7aR,8R,10aR,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 (70 mg, 0.15 mmol, 1.0 eq) was dissolved in tetrahydrofuran (2 mL) and added to the above reaction solution. The reaction system was stirred at -78°C for 30 min. The reaction progress was monitored by TLC plate (petroleum ether:ethyl acetate = 5:1), 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 (10 mL), the combined organic phases were dried, and concentrated to give colorless oily crude products 46-1 and 48-1 (70 mg), which were then used directly in the next step.

[0243] Step 2: Reaction of (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]-1-(3-fluoro-2-methoxyphenyl)hexan-1-ol 46-1 and (5R)-5-[(3aS,5aR,5bR The crude product of (70 mg, 0.11 mmol, 1.0 eq) (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]-1-(3-fluoro-2-methoxyphenyl)hexan-1-ol 48-1 was dissolved in tetrahydrofuran (3 mL). Dilute hydrochloric acid (1 mL, 3 mol / L) was added, and the reaction system was stirred at room temperature for 1 h. The reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 5:1). The reaction was stopped when the starting material was consumed. Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3×10 mL). The ethyl acetate layers were combined and washed with saturated brine (3×10 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 65:35) to obtain a white solid, which was then separated by chiral separation SFC (instrument: Waters Acquity UPCC; chromatographic column: Daicel CHIRALPAK IC_3, 3.0*150mm, 3um; mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 60 / 40; flow rate: 1.5 ml / min; column temperature: 37 degrees) to obtain (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R)-6-(3-fluoro-2-methoxyphenyl)-6-hydroxyhexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 46 (38.58 mg, purity 100%, yield 53%, retention time t R=1.341min) and (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-(2-methoxy-3-fluorophenyl)-6-hydroxyhexan-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 48 (3.464 mg, purity 95.32%, yield 5%, retention time t R =1.879min).

[0244] Compound 46: 1 H NMR (400MHz, CDCl3) δ7.04 (dd, J=6.5, 3.2Hz, 1H), 6.98–6.89 (m, 2H), 4.88–4.80 (m, 1H ),3.98–3.85(m,3H),3.78(s,1H),3.52(s,1H),2.57(d,J=16.5Hz,1H),1.95(d,J=15.1 Hz,1H),1.83–1.64(m,10H),1.32(ddd,J=59.4,28.0,19.9Hz,12H),1.10–1.00(m,4H), 0.98(s,3H),0.85(dd,J=6.5,3.3Hz,3H),0.82(d,J=8.3Hz,2H),0.56(t,J=4.6Hz,3H). 19 F NMR (376MHz, Chloroform-d) δ -88.63, -89.26, -110.63, -111.26, -130.48, -130.51.

[0245] Compound 48: 1 H NMR (400MHz, CDCl3) δ7.07–6.99(m,1H),6.97–6.88(m,2H),4.84(dt,J=13.2,5.9Hz,1H),3 .90(d,J=1.6Hz,3H),3.67(s,1H),3.53(dt,J=11.3,4.0Hz,1H),2.23–2.04(m,1H),1.90(d ,J=12.8Hz,1H),1.68(dddd,J=19.3,16.3,8.7,3.9Hz,12H),1.40–1.18(m,9H),1.07–1.00 (m,2H),0.99(s,3H),0.97–0.86(m,2H),0.83(dd,J=6.5,3.8Hz,3H),0.59(d,J=2.4Hz,3H). 19F NMR(376MHz,Chloroform-d)δ-109.78, 130.48.LC-MS:[M+H-H2O] + =515.70.

[0246] Example 47

[0247] Preparation of Compound 47 (3S, 4R, 5R, 8S, 9S, 10R, 13R, 14S, 17R, 20R)-N-(2-fluorophenyl)-3, 4-dihydroxy-N-methyl-5α-cholane-24-amide

[0248] In the first step, (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 acetate I-3 (2 g, 5.368 mmol) was dissolved in tetrahydrofuran (30 mL), and methoxyformylmethylenetriphenylphosphine (5.38 g, 16.105 mmol) was added at room temperature. The mixture was then heated to 90 ° C with stirring and monitored by TLC (petroleum ether: ethyl acetate = 10:1) until the reaction was complete. The mixture was cooled to room temperature, and water and ethyl acetate were added for extraction. The organic phase was separated, dried, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 5:1) to give (1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R,3E)-5-methoxy-5-oxopent-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 47-1 (1.4 g, 2.940 mmol, 54.76%) as a white solid. 1H NMR(399MHz,Chloroform-d)δ6.82(dd,J=15.6,9.0Hz,1H),5.72(d,J=15.6Hz,1H),5.35(d,J=5.1Hz,1 H),4.64–4.52(m,1H),3.70(s,3H),2.30(d,J=7.8Hz,2H),2.25(d,J=6.8Hz,1H),2.01(s,3H),1.97(d, J=9.8Hz,2H),1.86–1.81(m,2H),1.72–1.64(m,1H),1.53–1.40(m,5H),1.22(dd,J=8.4,3.8Hz,3H),1. 18–1.09(m,2H),1.07(d,J=6.7Hz,3H),1.00(s,3H),0.98–0.90(m,2H),0.88–0.78(m,1H),0.69(s,3H).

[0249] Step 2: Acetate (1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R,3E)-5-methoxy-5-oxopent-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) 47-1 (1.4 g, 3.266 mmol) was dissolved in a mixture of THF (5 mL) and MeOH (3 mL). Nickel chloride (0.42 g, 3.266 mmol) and sodium borohydride (0.19 g, 4.900 mmol) were added sequentially, and the mixture was stirred at room temperature. TLC (petroleum ether:ethyl acetate = 10:1) was used for monitoring. After the reaction, water and ethyl acetate were added for extraction. The organic phase was separated, dried, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 30:1 to 10:1) to obtain (1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-5-methoxy-5-oxopentan-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 47-2 (1.1 g, 2.171 mmol, 66.47%) as a white solid. 1H NMR(399MHz,Chloroform-d)δ5.35(d,J=5.2Hz,1H),4.58(d,J=9.8Hz,1H),3.64 (s,3H),2.30(d,J=7.6Hz,2H),2.21(td,J=9.8,5.0Hz,1H),2.01(s,3H),1.99–1 .92(m,2H),1.87–1.75(m,4H),1.63–1.55(m,2H),1.49–1.37(m,5H),1.27(d,J= 10.5Hz,3H),1.18–1.02(m,5H),0.99(s,3H),0.90(d,J=6.4Hz,3H),0.66(s,3H).

[0250] Step 3: Acetate (1R, 3aS, 3bS, 7S, 9aR, 9bS, 11aR)-1-[(2R)-5-methoxy-5-oxopentan-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 47-2 (1.1 g, 2.554 mmol) was dissolved in chloroform (10 mL), and selenium dioxide (1.42 g, 12.772 mmol) and NMM (1.55 g, 15.326 mmol) were added in sequence. The temperature was then raised to 75 ° C and stirred. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1). After completion of the reaction, the insoluble solid was removed by filtration through celite, and the filtrate was extracted with water and dichloromethane. The organic phase was separated, dried, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 30:1 to 2:1) to give (1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-6-hydroxy-1-[(2R)-5-methoxy-5-oxopentan-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 47-3 (630 mg, 1.270 mmol, 49.70%) as a white solid. 1H NMR(400MHz,Chloroform-d)δ5.73–5.63(m,1H),4.70(dt,J=12.2,3.9Hz,1H),4.23(d,J=3.2Hz,1H),3. 67(d,J=22.0Hz,3H),2.40–2.14(m,2H),2.09(s,4H),2.05–1.97(m,2H),1.85(d,J=11.8Hz,3H),1.65(d ,J=10.5Hz,1H),1.54–1.52(m,1H),1.47–1.37(m,3H),1.34–1.21(m,4H),1.20(d,J=2.5Hz,3H),1.13(d ,J=15.9Hz,2H),1.09–1.04(m,2H),0.99(t,J=7.2Hz,1H),0.90(d,J=6.3Hz,3H),0.67(d,J=15.0Hz,3H).

[0251] Step 4: Acetic acid-(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-6-hydroxy-1-[(2R)-5-methoxy-5-oxopentan-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 47-3 (30 mg, 0.067 mmol) was dissolved in acetic acid (3 mL). Platinum dioxide (15.25 mg, 0.067 mmol) was added, and the atmosphere was replaced with hydrogen. The temperature was then raised to 40 °C and stirred. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 3:1). After completion of the reaction, the catalyst was removed by filtration, and the mixture was subsequently concentrated to remove most of the acetic acid. The mixture was extracted with saturated sodium bicarbonate and ethyl acetate. The organic phase was separated, dried, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 2:1) to obtain (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6-hydroxy-1-[(2R)-5-methoxy-5-oxopentan-2-yl]-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate 47-4 (8 mg, 0.016 mmol, 23.89%) as a white solid. 1H NMR(399MHz,Chloroform-d)δ4.70(dd,J=11.8,4.1Hz,1H),3.81(s,1H),3.65(s,3H), 2.40–2.17(m,2H),2.07(s,3H),1.97–1.78(m,4H),1.77–1.71(m,3H),1.65(s,2H),1.3 2(dd,J=24.6,13.3Hz,7H),1.08(q,J=9.9,8.1Hz,4H),1.03(s,3H),0.97(d,J=18.7Hz, 1H),0.89(d,J=6.4Hz,3H),0.80(d,J=6.5Hz,1H),0.63(s,3H),0.58(d,J=10.0Hz,1H).

[0252] Step 5: Acetate (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-6-hydroxy-1-[(2R)-5-methoxy-5-oxopentan-2-yl]-9a, 11a-dimethylhexadecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 47-4 (100 mg, 0.223 mmol) was dissolved in a mixed solvent of tetrahydrofuran (3 mL) and methanol (2 mL). Lithium hydroxide (0.669 mL, 0.669 mmol) was added at room temperature, and the mixture was stirred at room temperature and monitored by TLC (petroleum ether: ethyl acetate = 1:1). After the reaction, 1N hydrochloric acid was added to adjust the pH to 3-4, followed by extraction with water and ethyl acetate. The organic phase was separated, dried, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 5:1 to 0:1) to obtain 3β-hydroxy-4β-hydroxy-5α-cholan-24-oic acid 47-5 (70 mg, 0.160 mmol, 72.00%) as a white solid. 1H NMR (400 MHz, Methanol-d4) δ 3.62 (d, J = 3.3 Hz, 1H), 3.50–3.41 (m, 1H), 2.28 (dd, J = 9.8, 5.3 Hz, 1H), 2.22–2.12 (m, 1H), 1.97 (d, J = 12.6 Hz, 1H), 1.81 (dd, J = 14.5, 5.3 Hz, 2H), 1.77–1.63 (m, 4H), 1.55 ( t,J=12.5Hz,2H),1.40(d,J=10.3Hz,3H),1.32(d,J=3.8Hz,3H),1.16–1.03(m,4H),1.01(s,4H),0. 97(d,J=3.8Hz,1H),0.92(d,J=6.6Hz,3H),0.89–0.82(m,1H),0.67(s,3H),0.62(d,J=12.6Hz,1H).

[0253] Step 6: 3β-Hydroxy-4β-hydroxy-5α-cholan-24-oic acid 47-5 (72 mg, 0.183 mmol) was dissolved in dichloromethane (5 mL). Triethylamine (0.076 mL, 0.550 mmol) and DMAP (2.24 mg, 0.018 mmol) were added. Acetic anhydride (0.034 mL, 0.367 mmol) was added with stirring at room temperature. Stirring was continued and the reaction was monitored by TLC (petroleum ether:ethyl acetate = 1:1). After completion of the reaction, water and ethyl acetate were added for extraction. The organic phase was separated, dried, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 3:1) to afford 4β-acetoxy-3β-acetoxy-5α-cholan-24-oic acid 47-6 (81 mg, 0.153 mmol, 83.39%) as a white solid. 1 H NMR(399MHz,Chloroform-d)δ5.18(s,1H),4.77(d,J=12.1Hz,1H),2.44–2.35(m,1H),2.25(q,J=9.7,8.5Hz,2H),2.07(s,3H),1.96(s,3H ),1.92–1.70(m,5H),1.69–1.37(m,7H),1.35–1.25(m,7H),1.09(q,J=18.1,14.6Hz,4H),0.99(s,3H),0.91(d,J=6.4Hz,3H),0.63(s,3H).

[0254] Step 7: 4β-acetoxy-3β-acetoxy-5α-cholan-24-oic acid 47-6 (50 mg, 0.105 mmol) was weighed and dissolved in dichloromethane (5 mL). SOCl2 (0.015 mL, 0.210 mmol) was added dropwise at room temperature, followed by stirring at 40 ° C for 2 hours and monitoring by TLC (petroleum ether: ethyl acetate = 3:1). After the reaction was completed, the solvent was removed by concentration, and the mixture was diluted with dichloromethane and cooled in an ice bath. Diisopropylethylamine (0.017 mL, 0.105 mmol) was added, followed by the dropwise addition of (2-fluorophenyl)(methyl)amine (13.14 mg, 0.105 mmol). After the addition was complete, the temperature was gradually raised to 40 ° C and stirred overnight. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 3:1). After completion of the reaction, the mixture was cooled to room temperature, extracted with water and ethyl acetate, and the organic phase was separated, dried, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 30:1 to 2:1) to give (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6-acetoxy-1-[(2R)-5-[(2-fluorophenyl)(methyl)amino]-5-oxopentan-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate 47-7 (20 mg, 0.031 mmol, 29.39%) as a white solid.

[0255] Step 8: Acetate (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-6-acetoxy-1-[(2R)-5-[(2-fluorophenyl)(methyl)amino]-5-oxopentan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 47-7 (60 mg, 0.103 mmol) was dissolved in a mixed solvent of tetrahydrofuran (2 mL) and methanol (1 mL), and potassium carbonate (28.41 mg, 0.206 The reaction mixture was stirred at room temperature and monitored by TLC (petroleum ether:ethyl acetate = 3:1). After the reaction was completed, water and ethyl acetate were added for extraction. The organic phase was separated, dried, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 1:1) to give (3S,4R,5R,8S,9S,10R,13R,14S,17R,20R)-N-(2-fluorophenyl)-3,4-dihydroxy-N-methyl-5α-cholane-24-amide 47 (40 mg, 0.076 mmol, 74.10%) as a white solid. 1H NMR(399MHz,Chloroform-d)δ7.33(d,J=6.8Hz,1H),7.18(q,J=9.8,9.4Hz,3H),3.71(s,1H),3.53(d,J=10.6 Hz,1H),3.20(s,3H),2.07(s,1H),1.94(s,1H),1.85(d,J=12.6Hz,1H),1.71–1.58(m,6H),1.50(d,J=9.4Hz, 1H),1.35(d,J=13.9Hz,3H),1.28(s,1H),1.21(s,3H),1.06–0.99(m,3H),0.9 8(s,3H),0.97–0.82(m,5H),0.67(d,J=5.6Hz,3H),0.57(s,3H),0.52(s,1H). 19 F NMR(376MHz,Chloroform-d)δ-121.32.LCMS:[M+H] + =500.45.

[0256] Example 49 & 105

[0257] Compound 49 (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R)-6-(2-fluoro-6-methoxyphenyl)-6-hydroxyhexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol and

[0258] Preparation of compound 105 (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-1-[(2R)-6-(2-fluoro-6-methoxyphenyl)-6-hydroxyhexan-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.

[0259] Step 1: Dissolve the raw material 2-bromo-1-fluoro-3-methoxybenzene (107 mg, 0.5 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL). Cool the system to -78°C, add n-butyl lithium (1.8 mL, 0.45 mmol, 3.0 eq), and maintain stirring at this temperature for 30 min. (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, A mixture of (7aR,8R,10aR,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 (70 mg, 0.15 mmol, 1.0 eq) was dissolved in tetrahydrofuran (2 mL) and added to the reaction mixture. The reaction system was stirred at -78°C for 30 min. Reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 5:1), indicating complete consumption of the starting material. 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 (10 mL), the combined organic phases were dried, and concentrated to give colorless oily crude products 49-1 and 105-1 (70 mg), which were then used directly in the next step.

[0260] Step 2: Reaction of reactants (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]-1-(6-fluoro-2-methoxyphenyl)hexan-1-ol 49-1 and (5R)-5-[(3aS,5aR,5bR, A mixture of 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]-1-(2-fluoro-6-methoxyphenyl)hexan-1-ol 105-1 (70 mg, 0.11 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL), and dilute hydrochloric acid (1 mL, 3 mol / L) was added. The reaction system was stirred at room temperature for 1 h. The reaction progress was monitored by TLC plate (petroleum ether:ethyl acetate = 5:1). The reaction was stopped when the starting material was consumed. Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3×10 mL). The EA layers were combined and washed with saturated brine (3×10 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 65:35) to give a white solid, which was then separated by chiral separation SFC (instrument: Waters Acquity UPCC; chromatographic column: Daicel CHIRALPAK IC_3, 3.0*150mm, 3um; mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 60 / 40; flow rate: 1.5 ml / min; column temperature: 37 degrees) to obtain (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R)-6-(2-fluoro-6-methoxyphenyl)-6-hydroxyhexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 49 (44.57 mg, purity 100%, yield 68.30%, retention time t R=1.876min) and (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-1-[(2R)-6-(2-fluoro-6-methoxyphenyl)-6-hydroxyhexan-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 (4.28 mg, purity 93.67%, yield 6.42%, retention time t R =2.785min).

[0261] Compound 49: 1 H NMR(400MHz, CDCl3)δ7.18(td,J=8.3,6.6Hz,1H),6.74–6.67(m,2H),5.01(t,J =6.1Hz,1H),3.89(s,3H),3.75(s,1H),3.64–3.57(m,1H),2.31–2.09(m,2H),2. 02–1.91(m,2H),1.90–1.64(m,10H),1.51–1.22(m,10H),1.15–1.08(m,2H),1.0 6(s,3H),1.03–0.94(m,2H),0.90(dd,J=6.4,4.5Hz,3H),0.66(d,J=4.6Hz,3H). 19 F NMR (377MHz, CDCl3) δ-88.62,-89.25,-110.62,-111.24,-117.19,-117.26.

[0262] Compound 105: 1 H NMR (100MHz, CDCl3) δ7.17 (dd, J=14.9, 8.3Hz, 1H), 6.69 (dt, J=8.6, 4.5Hz, 2H) ,5.01(s,1H),3.88(s,3H),3.85(s,1H),3.63-3.56(m,1H),2.66(dd,J=16.9,8 .6Hz,1H),2.19(s,1H),2.02(t,J=6.0Hz,1H),1.97-1.78(m,7H),1.48–1.24(m ,8H),1.15-1.07(m,3H),1.04(s,3H),0.93–0.88(m,3H),0.62(d,J=5.0Hz,3H). 19 F NMR (376MHz, CDCl3) δ-109.83,-117.20,-117.28.

[0263] Examples 50 & 51

[0264] Compound 50 (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R)-6-(4-methoxyphenyl)-6-hydroxyhexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol and

[0265] Preparation of compound 51 (1R, 3aR, 5aR, 6R, 7S, 9aR, 9bR, 11aR)-4-fluoro-1-[(2R)-6-hydroxy-6-(4-methoxyphenyl)hexan-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.

[0266] Step 1: Dissolve the raw material 4-bromo-1-methoxybenzene (98 mg, 0.5 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL). Cool the system to -78°C, add n-butyl lithium (1.8 mL, 0.45 mmol, 3.0 eq), and stir at this temperature for 30 min. 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]hexanal I and (5R)-5-[(3aS,5aR,5bR A mixture of (70 mg, 0.15 mmol, 1.0 eq) (7aR,8R,10aR,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 was dissolved in tetrahydrofuran (2 mL) and added to the reaction solution. The reaction system was stirred at -78°C for 30 min. The reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 5:1, phosphomolybdic acid hotplate), indicating complete consumption of the starting material. 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 (10 mL), the combined organic phases were dried, and concentrated to give a colorless oily crude product of 50-1 and 51-1 (70 mg), which was then used directly in the next step.

[0267] The second step: reacting the reactants (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]-1-(4-methoxyphenyl)hexan-1-ol 50-1 and (5R)-5-[(3aS,5aR,5bR The crude product of (70 mg, 0.11 mmol, 1.0 eq) (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]-1-(4-methoxyphenyl)hexan-1-ol 51-1 was dissolved in tetrahydrofuran (3 mL). Dilute hydrochloric acid (1 mL, 3 mol / L) was added, and the reaction system was stirred at room temperature for 1 h. The reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 5:1). The reaction was stopped when the starting material was consumed. Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3×10 mL). The EA layers were combined and washed with saturated brine (3×10 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 65:35) to give a white solid, which was then separated by chiral separation SFC (instrument: Waters Acquity UPCC; chromatographic column: Daicel CHIRALPAK IC_3, 3.0*150mm, 3um; mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 60 / 40; flow rate: 1.5 ml / min; column temperature: 37 degrees) to obtain (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-(4-methoxyphenyl)hexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 50 (43.21 mg, purity 100%, yield 66.35%, retention time t R=2.329 min) and (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-1-[(2R)-6-hydroxy-6-(4-methoxyphenyl)hexan-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 51 (3.77 mg, purity 80.81%, yield 4.85%, retention time t R =3.557min).

[0268] Compound 50: 1 H NMR (400MHz, CDCl3) δ7.21 (s, 2H), 6.81 (d, J = 8.6Hz, 2H), 4.54 (dd, J = 12.2, 5.9Hz,1H),3.74(s,3H),3.67(s,1H),3.53(dd,J=7.1,4.2Hz,1H),2.22–1.9 9(m,2H),1.89(d,J=12.6Hz,1H),1.81–1.58(m,10H),1.43–1.12(m,11H),0 .99(s,3H),0.95–0.85(m,2H),0.81(t,J=6.3Hz,3H),0.58(d,J=2.5Hz,3H). 19 F NMR(376MHz, CDCl3)δ-88.64,-89.26,-110.63,-111.26.

[0269] Compound 51:. 1 H NMR (400MHz, CDCl3) δ7.28 (d, J=3.3Hz, 2H), 6.88 (t, J=6.0Hz, 2H), 4.62 (dd, J=12 .8,6.0Hz,1H),3.86(d,J=9.2Hz,1H),3.81(s,3H),3.63–3.55(m,1H),2.66(t,J=1 2.4Hz,1H),1.86(ddt,J=46.3,23.4,12.1Hz,12H),1.64–1.56(m,5H),1.48–1.36 (m,6H),1.14–1.05(m,4H),1.04(s,3H),0.91–0.87(m,3H),0.62(d,J=2.7Hz,3H). 19 F NMR(376MHz, CDCl3)δ-109.79.LC-MS:[M+H-H2O] + =497.60

[0270] Example 54

[0271] Preparation of compound 54 (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-(pyridin-3-yl)hexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol.

[0272] The raw material 3-bromopyridine (169 mg, 1.07 mmol, 5 eq) was dissolved in anhydrous tetrahydrofuran (3 mL), the system was cooled to -78 °C, n-butyl lithium (0.34 mL, 0.86 mmol, 4 eq) was added, and the temperature was maintained and stirred for 30 min. 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]hexanal I (100 mg, 0.214 mmol, 1.0 eq) was dissolved in tetrahydrofuran (2 mL) and added to the reaction mixture. The reaction system was stirred at -78°C for 30 min. The reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 5:1), indicating complete consumption of the starting material. 10 mL of water was added to the reaction system, and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated sodium chloride (10 mL), dried, and concentrated to obtain a white solid 54-1, which was dissolved in anhydrous tetrahydrofuran (3 mL). 3 M aqueous hydrochloric acid solution (1 ml) was slowly added dropwise, and the reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 1:1). 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 (10 mL), the combined organic phases were dried, and concentrated to give a white solid (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-(pyridin-3-yl)hexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 54 (36.95 mg, purity 99.63%, yield 34%).

[0273] Compound 54: 1H NMR (400MHz, CDCl3) δ8.55(dd,J=18.2,3.1Hz,2H),7.71(d,J=7.9Hz,1H),7.29(dd,J=7.8,4.9H z,1H),4.73(d,J=6.5Hz,1H),3.74(s,1H),3.60(d,J=10.9Hz,1H),2.15(s,2H),1.99–1.89(m,2H ),1.85–1.78(m,4H),1.75–1.66(m,4H),1.58(s,3H),1.43–1.29(m,7H),1.22(s,1H),1.11(dd,J =13.1,4.4Hz,2H),1.06(s,3H),1.02–0.92(m,2H),0.89(t,J=6.0Hz,3H),0.65(d,J=2.2Hz,3H). 19 F NMR(376MHz, CDCl3)δ-88.63,-89.26,-110.62,-111.25.

[0274] Example 62

[0275] Preparation of compound 62 (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R)-6-{2-fluoro-4-[(trifluoromethyl)oxy]phenyl}-6-hydroxyhexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol.

[0276] Step 1: Dissolve the raw material 1-bromo-2-fluoro-4-[(trifluoromethyl)oxy]benzene (97 mg, 0.37 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL). Cool the system to -78°C, add n-butyl lithium (1.28 mL, 0.32 mmol, 3.0 eq), and stir at this temperature for 30 min. 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]hexanal I (50 mg, 0.1 mmol, 1.0 eq) was dissolved in tetrahydrofuran (2 mL) and added to the reaction mixture. The reaction system was stirred at -78°C for 30 min. The reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 5:1). 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 (10 mL), the combined organic phases were dried, and concentrated to obtain a colorless oily (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl The crude product (50 mg) of -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-{2-fluoro-4-[(trifluoromethyl)oxy]phenyl}hexan-1-ol 62-1 was directly used in the next step.

[0277] Step 2: Reaction of (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]-1-{2-fluoro-4-[(trifluoromethyl)oxy]phenyl}hexan-1-ol 62-1 (50 mg, 0.1 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL), and dilute hydrochloric acid (1 mL, 3 mol / L) was added. The reaction system was stirred at room temperature for 1 h. TLC (petroleum ether:ethyl acetate = 5:1) monitored the reaction completion. Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The EA layers were combined and washed with saturated brine (3 × 10 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=65:35) to give a white solid, which was subsequently chirally resolved to give (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-{2-fluoro-4-[(trifluoromethyl)oxy]phenyl}-6-hydroxyhexan-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 62 (19.80 mg, purity 95.76%, yield 50.53%).

[0278] Compound 62: 1 H NMR(400MHz, CDCl3) δ7.23(dd,J=13.8,7.9Hz,1H),7.02(dd,J=12.2,9.2Hz,2H),6.89(t,J =8.4Hz,1H),4.60(dd,J=12.9,5.9Hz,1H),3.67(s,1H),3.53(dt,J=11.3,4.1Hz,1H),2.22 –2.02(m,1H),1.90(d,J=12.8Hz,1H),1.80–1.55(m,13H),1.43–1.14(m,10H),1.04(dd,J= 14.1,5.4Hz,2H),0.99(s,3H),0.93–0.86(m,2H),0.84–0.80(m,3H),0.58(d,J=1.7Hz,3H). 19F NMR (376MHz, cdcl3) δ-58.06,-58.07,-58.09,-88.65,-89.28,-110.65,-111.27,-115.89,-115.92.

[0279] Example 63 & 64

[0280] Compound 63 (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R)-6-(2-fluoro-3-methoxyphenyl)-6-hydroxyhexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0281] Preparation of compound 64 (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-1-[(2R)-6-(2-fluoro-3-methoxyphenyl)-6-hydroxyhexan-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.

[0282] Step 1: Dissolve the raw material 1-bromo-2-fluoro-3-methoxybenzene (77 mg, 0.37 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL). Cool the system to -78°C, add n-butyl lithium (1.28 mL, 0.32 mmol, 3.0 eq), and stir at this temperature for 30 min. 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]hexanal I and (5R)-5-[(3aS,5aR,5bS,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 were synthesized. A mixture of (R,7aR,8R,10aR,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 (50 mg, 0.1 mmol, 1.0 eq) was dissolved in tetrahydrofuran (2 mL) and added to the reaction mixture. The reaction system was stirred at -78°C for 30 min. Reaction completion was monitored by TLC (petroleum ether:ethyl acetate = 5:1). 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 (10 mL), the combined organic phases were dried, and concentrated to give colorless oily crude products 63-1 and 64-1 (70 mg), which were then used directly in the next step.

[0283] Step 2: Reaction of (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]-1-(2-fluoro-3-methoxyphenyl)hexan-1-ol 63-1 and (5R)-5-[(3aS,5aR,5 The crude product of (a)-1,2-dioxolan-1-ol (50 mg, 0.1 mmol, 1.0 eq) (50 mg, 0.1 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL) and diluted hydrochloric acid (1 mL, 3 mol / L) was added. The reaction system was stirred at room temperature for 1 h. The reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 5:1). The reaction was stopped when the starting material was consumed. Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3×10 mL). The ethyl acetate layers were combined and washed with saturated brine (3×10 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 65:35) to obtain a white solid, which was then separated by chiral separation SFC (instrument: Waters Acquity UPCC; chromatographic column: Daicel CHIRALPAK IC_3, 3.0*150mm, 3um; mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 70 / 30; flow rate: 2.0 ml / min; column temperature: 37 degrees) to obtain (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R)-6-(2-fluoro-3-methoxyphenyl)-6-hydroxyhexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 63 (29.11 mg, purity 99.70%, yield 77.81%, retention time t R=1.966min) and (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-1-[(2R)-6-hydroxy-6-(2-fluoro-3-methoxyphenyl)hexan-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 64 (2.06 mg, purity 98.77%, yield 5.70%, retention time t R =2.943min).

[0284] Compound 63: 1 H NMR(400MHz, CDCl3)δ7.05(dt,J=13.5,7.9Hz,2H),6.91–6.85(m,1H),5.05–4.98(m,1H), 3.89(s,3H),3.74(s,1H),3.60(dt,J=11.2,4.0Hz,1H),2.29–2.11(m,1H),1.97(d,J=13. 2Hz,1H),1.89–1.63(m,13H),1.39(ddd,J=29.8,17.0,8.6Hz,8H),1.11(dd,J=14.4,5.4H z,2H),1.05(s,3H),1.02–0.93(m,2H),0.89(dd,J=6.4,4.2Hz,3H),0.65(d,J=2.3Hz,3H). 19 F NMR (377MHz, CDCl3) δ-88.64,-89.27,-110.63,-111.26,-142.59,-142.62.

[0285] Compound 64: 1 H NMR (400MHz, CDCl3) δ7.14–7.04(m,2H),6.95–6.89(m,1H),5.06(dd,J=12.2,5.6Hz,1H),3.93(s,3H),3.89(s,1H),3.67–3.59(m,1H),2.68(d ,J=13.8Hz,1H),2.06(d,J=13.5Hz,1H),2.00–1.75(m,10H),1.64(d,J=12.3Hz,4H),1.52–1.44(m,5H),1.14(dd,J=18.2,5.5Hz,4H),1.08(s, 3H), 0.96–0.92 (m, 3H), 0.89 (dd, J=9.0, 5.2Hz, 2H), 0.66 (d, J=2.5Hz, 3H). 19F NMR (377MHz, CDCl3) δ-109.79,-142.59,-142.62.

[0286] Examples 67 & 68

[0287] Compound 67 (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R)-6-(2-fluoro-4-methoxyphenyl)-6-hydroxyhexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0288] Preparation of compound 68 (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-1-[(2R)-6-(2-fluoro-4-methoxyphenyl)-6-hydroxyhexan-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.

[0289] Step 1: Dissolve the raw material 1-bromo-2-fluoro-4-methoxybenzene (76 mg, 0.37 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL), cool the system to -78 ° C, add n-butyl lithium (1.28 mL, 0.32 mmol, 3.0 eq), and stir at the same temperature for 30 minutes. 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 A mixture of (50 mg, 0.1 mmol, 1.0 eq) of (1,8R,10aR,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 was dissolved in tetrahydrofuran (2 mL) and added to the reaction mixture. The reaction system was stirred at -78°C for 30 min. The reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 5:1). 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 (10 mL), the combined organic phases were dried, and concentrated to give colorless oily crude products 67-1 and 68-1 (70 mg), which were then used directly in the next step.

[0290] Step 2: Reaction of (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]-1-(2-fluoro-4-methoxyphenyl)hexan-1-ol 67-1 and (5R)-5-[(3aS,5aR,5bR The crude product of (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]-1-(2-fluoro-4-methoxyphenyl)hexan-1-ol 68-1 (50 mg, 0.1 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL). Dilute hydrochloric acid (1 mL, 3 mol / L) was added, and the reaction system was stirred at room temperature for 1 h. The reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 5:1). Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The EA layers were combined and washed with saturated brine (3×10 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 65:35) to give a white solid, which was then separated by chiral SFC (instrument: Waters Acquity UPCC; column: Daicel CHIRALPAK IC_3, 3.0*150mm, 3um; mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 65 / 35 flow rate: 2.0 ml / min; column temperature: 37 degrees) to obtain (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R)-6-(2-fluoro-4-methoxyphenyl)-6-hydroxyhexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 67 (16 mg, purity 100%, yield 29.77%, retention time t R=1.135min) and (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-1-[(2R)-6-(2-fluoro-4-methoxyphenyl)-6-hydroxyhexan-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 68 (1.17 mg, purity 98.44%, yield 2.57%, retention time t R =1.497min).

[0291] Compound 67: 1 H NMR (400MHz, CDCl3) δ7.33 (td, J=8.6, 1.7Hz, 1H), 6.70 (dd, J=8.6, 2.4Hz, 1H), 6.58(dd,J=12.3,2.5Hz,1H),4.92(m,1H),3.79(s,3H),3.74(s,1H),3.60(m,1 H),2.19(m,1H),1.97(d,J=12.8Hz,1H),1.82(m,5H),1.68(m,4H),1.38(m,10H ),1.08(m,6H),0.96(m,2H),0.89(dd,J=6.4,4.5Hz,3H),0.65(d,J=2.0Hz,3H). 19 F NMR(377MHz, CDCl3)δ-88.64,-89.26,-110.63,-111.25,-117.79,-117.83.LC-MS: [M+1-H2O] + =535.80.

[0292] Compound 68: 1H NMR (400MHz, CDCl3) δ7.33 (td, J=8.6, 2.0Hz, 1H), 6.70 (dd, J=8.5, 2.4Hz, 1H), 6.58 (dd, J=12.3, 2.5Hz, 1H) ,4.92(dd,J=13.1,6.1Hz,1H),3.85(s,1H),3.79(s,3H),3.59(m,1H),2.66(s,1H),2.02(d,J=10.7Hz,1H), 1.92(s,1H),1.86(s,2H),1.81(s,2H),1.74(d,J=9.5Hz,3H),1.61(d,J=11.8Hz,4H),1.45(dd,J=12.6,5.6 Hz, 4H), 1.26 (s, 6H), 1.08 (d, J = 4.5Hz, 2H), 1.04 (s, 3H), 0.90 (dd, J = 6.4, 4.3Hz, 4H), 0.62 (d, J = 2.2Hz, 3H). 19 F NMR (377MHz, CDCl3) δ -109.79, -117.80, -117.83. LC-MS: [M+H-H2O]+ = 515.70.

[0293] Example 69

[0294] Preparation of compound 69(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-(2,4,6-trifluorophenyl)hexan-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol.

[0295] Step 1: Dissolve the raw material 2-bromo-1,3,5-trifluorobenzene (79 mg, 0.37 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL). Cool the system to -78°C, add n-butyl lithium (1.28 mL, 0.32 mmol, 3.0 eq), and maintain the temperature with stirring for 30 min. 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]hexanal I (50 mg, 0.1 mmol, 1.0 eq) was dissolved in tetrahydrofuran (2 mL) and added to the reaction mixture. The reaction system was stirred at -78°C for 30 min. The reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 5:1). 10 mL of water was added to the reaction system, and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated sodium chloride (10 mL), and the combined organic phases were dried and concentrated to obtain a colorless oily product (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7 The crude product of a-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-(2,4,6-trifluorophenyl)hexan-1-ol 69-1 (50 mg) was directly used in the next step.

[0296] Step 2: The reactant (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]-1-(2,4,6-trifluorophenyl)hexan-1-ol 69-1 (50 mg, 0.1 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL), and dilute hydrochloric acid (1 mL, 3 mol / L) was added. The reaction system was stirred at room temperature for 1 h. TLC (petroleum ether: ethyl acetate = 5: 1) monitored the reaction to be complete. Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3×10 mL). The ethyl acetate layers were combined and washed with saturated brine (3×10 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 65: 35) to obtain a white solid, which was then separated by chiral separation SFC (instrument: Waters Acquity UPCC; chromatographic column: Daicel CHIRALPAK IC_3, 3.0*150mm, 3um; mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 70 / 30; flow rate: 2.0 ml / min; column temperature: 37 degrees) to obtain (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-(2,4,6-trifluorophenyl)hexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 69 (13.91 mg, purity 98.75%, yield 24.77%, retention time t R =1.107min).

[0297] Compound 69: 1 H NMR (400MHz, CDCl3) δ6.65(m,2H),4.98(t,J=6.9Hz,1H),3.74(s,1H),3.60(dt,J=11.3,4.2Hz,1H),2.22(m,1H),2.02(m,4H),1.83(m,5H),1.68( ddd,J=13.6,10.8,5.5Hz,3H),1.35(m,9H),1.11(m,2H),1.06(s,3H),0. 98(dd,J=16.3,5.7Hz,2H),0.89(t,J=6.0Hz,3H),0.65(d,J=2.9Hz,3H).19 F NMR (377MHz, CDCl3) δ-88.64,-89.27,-109.16,-110.64,-111.26,-112.09,-112.16.

[0298] Examples 70 & 71

[0299] Compound 70 or 71 (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-1-[(2R, 6S)-6-(2, 3-dimethoxyphenyl)-6-hydroxyhexan-2-yl]-4, 4-difluoro-9a, 11a-dimethylhexahydro-1H-cyclopenta[1, 2-a]phenanthrene-6, 7-diol and

[0300] Preparation of compound 71 or 70 (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-1-[(2R, 6R)-6-(2, 3-dimethoxyphenyl)-6-hydroxyhexan-2-yl]-4, 4-difluoro-9a, 11a-dimethylhexahydro-1H-cyclopenta[1, 2-a]phenanthrene-6, 7-diol.

[0301] Step 1: Dissolve the raw material 1-bromo-2,3-dimethoxybenzene (81.4 mg, 0.38 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL). Cool the system to -78°C, add n-butyl lithium (0.13 mL, 0.32 mmol, 3.0 eq), and maintain stirring at this temperature for 30 min. 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]hexanal I (50 mg, 0.11 mmol, 1.0 eq) was dissolved in tetrahydrofuran (2 mL) and added to the reaction mixture. The reaction system was stirred at -78°C for 30 min. The reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 5:1). 10 mL of water was added to the reaction system, extracted with ethyl acetate (10 mL×3), the combined organic phases were washed with saturated sodium chloride (20 mL), the combined organic phases were dried, and concentrated to give a colorless oily (5R)-5-((3aS, 5aR, 5bS, 7aR, 8R, 10aS, 10bS, 12aR, 12bR)-11,11-difluoro-2,2,5a,7a-tetramethylhexahydro-4H-cyclopentadienyl[7,8]phenanthro[1,2-d][1,3]dioxy-8-yl)-1-(2,3-dimethoxy)-1-[(3aS, 5aR, 5bS, 7aR, 8R, 10aS, 10bS, 12aR, 12bR)-11,11-difluoro-2,2,5a,7a-tetramethylhexahydro-4H-cyclopentadienyl[7,8]phenanthro[1,2-d][1,3]dioxy-8-yl)-1-[ ... The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 90:10) to give a white solid (5R)-5-((3aS, 5aR, 5bS, 7aR, 8R, 10aS, 10bS, 12aR, 12bR)-11,11-difluoro-2,2,5a,7a-tetramethylhexahydro-4H-cyclopentadieno[7,8]phenanthro[1,2-d][1,3]dioxy-8-yl)-1-(2,3-dimethoxyphenyl)hexan-1-ol 70-1 (32 mg, yield 49%).

[0302] Step 2: The reactant (5R)-5-((3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethylhexahydro-4H-cyclopentadieno[7,8]phenanthro[1,2-d][1,3]dioxy-8-yl)-1-(2,3-dimethoxyphenyl)hexan-1-ol 70-1 (32 mg, 0.053 mmol, 1.0 eq) was dissolved in tetrahydrofuran (2 mL). Dilute hydrochloric acid (1 mL, 3 mol / L) was added, and the reaction system was stirred at room temperature for 1 h. The reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 5:1, phosphomolybdic acid hotplate). The reaction was stopped when the starting material was consumed. Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The ethyl acetate layers were combined and washed with saturated brine (3×10 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 75:25) to obtain a white solid, which was then subjected to chiral separation (instrument: Waters Acquity UPCC; column: Daicel CHIRALPAK OZ3, 3*150 mm, 3 um; mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 50 / 50; flow rate: 1.5 ml / min; column temperature: 37 degrees) to obtain 70 (5.68 mg, purity 94%, yield 18%, retention time t R =1.909 min)) and 71 (5.06 mg, purity 95%, yield 16%, retention time t R =2.840min).

[0303] Compound 70: 1 H NMR (400MHz, CDCl3) δ7.05(t,J=7.9Hz,1H),6.94(d,J=6.6Hz,1H),6.85(d,J=8.0Hz,1H),4.91(dd,J= 8.1,5.0Hz,1H),3.88(s,3H),3.87(s,3H),3.76–3.71(m,1H),3.65–3.55(m,1H),2.32–2.11(m,2H),2 .11–2.05(m,1H),2.00–1.94(m,1H),1.86–1.77(m,4H),1.72–1.60(m,4H),1.48–1.37(m,6H),1.30–1 .24(m,3H),1.16–1.08(m,2H),1.07–1.02(m,4H),1.01–0.95(m,1H),0.94–0.85(m,4H),0.65(s,3H). 19F NMR (377MHz, CDCl3) δ-88.94 (d, J = 235.7Hz, 1F), -110.94 (d, J = 236.0Hz, 1F).

[0304] Compound 71: 1 H NMR (400MHz, CDCl3) δ7.05(t,J=7.9Hz,1H),6.94(dd,J=7.8,1.4Hz,1H),6.84(dd,J=8.1,1.4Hz,1H),4.90(t ,J=6.6Hz,1H),3.88(s,3H),3.87(s,3H),3.76–3.71(m,1H),3.63–3.55(m,1H),2.40–2.23(m,1H),2.22–2.0 1(m,2H),2.00–1.93(m,1H),1.88–1.78(m,4H),1.77–1.65(m,5H),1.61–1.50(m,2H),1.50–1.33(m,6H),1.3 2–1.24(m,3H),1.23–1.16(m,1H),1.14–1.03(m,6H),1.01–0.93(m,1H),0.89(d,J=6.5Hz,3H),0.65(s,3H). 19 F NMR (377MHz, CDCl3) δ-88.95 (d, J = 236.5Hz, 1F), -110.94 (d, J = 236.0Hz, 1F).

[0305] Examples 72 & 73

[0306] Preparation of Compound 72 (1R, 3aS, 3bR, 7S, 9aS, 9bS, 11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-(2-methoxyphenyl)hexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0307] Preparation of Compound 73 (1R, 3aR, 5aR, 7S, 9aS, 9bR, 11aR)-4-fluoro-1-[(2R)-6-hydroxy-6-(2-methoxyphenyl)hexan-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-7-ol

[0308] 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]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%). 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).

[0309] 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).

[0310] In the third step, compound (5R)-5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-4-oxoylidenehexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoate 72-2 (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. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1). 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 dried to obtain a crude product, which was then separated and purified on silica gel (petroleum ether:ethyl acetate = 1:1) to obtain (5R)-5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-7-acetoxy-4,4-difluoro-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl] ... A white solid mixture of methyl hexanoate 72-3 and (5R)-5-[(1R,3aR,5aR,7S,9aS,9bR,11aR)-7-acetoxy-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]hexanoate 73-1 (70 mg, 0.145 mmol, yield calculated based on 72-3: 45%). Compound 72-3: 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).

[0311] In the fourth step, the mixture (5R)-5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-7-acetoxy-4,4-difluoro-9a,11a-dimethylhexahydro- A mixture of methyl 1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoate 72-3 and methyl (5R)-5-[(1R,3aR,5aR,7S,9aS,9bR,11aR)-7-acetoxy-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]hexanoate 73-1 (120 mg, 0.249 mmol, 1.0 eq) was dissolved in methanol (5 mL). Potassium carbonate (171 mg, 1.243 mmol, 5.0 eq) was slowly added, and the reaction system was stirred at room temperature for 5 hours. The reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 2:1). Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 × 25 mL). The ethyl acetate layers were combined and washed with saturated brine (3 × 10 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain (5R)-5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-4,4-difluoro-7-hydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoate 72-4 and (5R)-5-[(1R,3aR,5aR,7S,9aS ,9bR,11aR)-4-fluoro-7-hydroxy-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]hexanoic acid methyl ester 73-2 was obtained as a white solid mixture (100 mg, purity 95%, yield 91% based on 72-4), and the crude product was directly used in the next reaction.

[0312] In the fifth step, (5R)-5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-4,4-difluoro-7-hydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoic acid methyl ester 72-4 and (5R)-5-[(1R,3aR,5aR,7S,9aS,9bR,11aR)-4-fluoro-7-hydroxy-9a,11a-dimethyl-2,3,3a,5,5a,6,7,8,9 A mixture of methyl 1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoate 73-2 (1.1 g, 2.496 mmol, 1.0 eq) was dissolved in dimethylformamide (10 mL). Chloro(2-methylprop-2-yl)diphenylsilane (1.72 g, 6.24 mmol, 2.5 eq) and imidazole (0.84 g, 12.48 mmol, 5.0 eq) were added. The reaction system was stirred at 40°C for 12 hours. The reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 5:1). Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 × 25 mL). The ethyl acetate layers were combined and washed with saturated brine (3 × 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain white solids (5R)-5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylprop-2-yl)diphenylsilyl]oxy}hexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester 72-5 and (5R)-5-[(1R,3aR,5 aR,7S,9aS,9bR,11aR)-4-fluoro-9a,11a-dimethyl-7-{[(2-methylprop-2-yl)diphenylsilyl]oxy}-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoic acid methyl ester 73-3 (1.65 g, purity 95%, yield 92% based on 72-5).

[0313] Compound 72-5: 1H NMR(400MHz,CDCl3)δ7.63–7.56(m,4H),7.36–7.26(m,6H),3.55(d,J=27.4Hz,4H),2.25–2.12(m,2H),1.85(d,J=12.7Hz,1H),1.74(dd,J=13.6,6.1Hz,2H),1.65–1.49(m,6H),1.45–1.34(m,5H),1.30(dd,J=15.2,11.1Hz,4H),1.23–1.13(m,5H),1.04–1.00(m,2H),0.97(s,9H),0.84(t,J=5.6Hz,3H),0.76–0.71(m,3H),0.69(d,J=3.3Hz,1H),0.55(d,J=12.1Hz,3H).

[0314] In the sixth step, white solids (5R)-5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylprop-2-yl)diphenylsilyl]oxy}hexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester 72-5 and (5R)-5-[(1R,3aR,5aR,7S,9aS,9bR,11aR)-4-fluoro-9a,11a-dimethyl-7 A mixture of methyl-{[(2-methylprop-2-yl)diphenylsilyl]oxy}-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoate 73-3 (2.5 g, 3.682 mmol, 1.0 eq) was dissolved in tetrahydrofuran (20 mL), and lithium aluminum tetrahydride (0.42 g, 11.05 mmol, 3 eq) was added. The reaction system was stirred at room temperature for 1 hour. The reaction was monitored by TLC plate (petroleum ether:ethyl acetate = 5:1). Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 × 25 mL). The ethyl acetate layers were combined and washed with saturated brine (3 × 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to give white solids (5R)-5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylprop-2-yl)diphenylsilyl]oxy}hexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexan-1-ol 72-6 and (5R)-5-[(1R,3aR, A mixture of (5aR,7S,9aS,9bR,11aR)-4-fluoro-9a,11a-dimethyl-7-{[(2-methylprop-2-yl)diphenylsilyl]oxy}-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexan-1-ol 73-4 (1.7 g, purity 95%, yield 72% based on 72-6).

[0315] Compound 72-6: 1HNMR(400MHz,CDCl3)δ7.70–7.62(m,4H),7.45–7.33(m,6H),3.63(s,3H),1.93(d,J=12.7Hz,1H),1.81(d,J=9.4Hz,2H),1.68–1.60(m,3H),1.54(s,7H),1.38(ddd,J=23.8,18.6,8.6Hz,8H),1.25(d,J=7.1Hz,5H),0.90(d,J=6.5Hz,4H),0.82(s,4H),0.63(s,3H)

[0316] In the seventh step, white solids (5R)-5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylprop-2-yl)diphenylsilyl]oxy}hexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexan-1-ol 72-6 and (5R)-5-[(1R,3aR,5aR,7S,9aS,9bR,11aR)-4-fluoro-9a,11a-dimethyl-7-{ A mixture of [(2-methylpropan-2-yl)diphenylsilyl]oxy}-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexan-1-ol 73-4 (1.6 g, 2.46 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL). Dess-Martin periodinane (2.08 g, 4.92 mmol, 2.0 eq) was added, and the reaction system was stirred at room temperature for 2 hours. TLC (petroleum ether:ethyl acetate = 10:1) monitored the reaction completion. Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 × 25 mL). The ethyl acetate layers were combined and washed with saturated sodium sulfite (3 × 10 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to give white solids (5R)-5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylprop-2-yl)diphenylsilyl]oxy}hexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanal 72-7 and (5R)-5-[(1R,3aR, A mixture of (5aR,7S,9aS,9bR,11aR)-4-fluoro-9a,11a-dimethyl-7-{[(2-methylprop-2-yl)diphenylsilyl]oxy}-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanal 73-5 (1.4 g, purity 95%, yield 87% based on 72-7).

[0317] Compound 72-7: 1H NMR(400MHz,CDCl3)δ9.75(t,J=1.7Hz,1H),7.69–7.63(m,4H),7.44–7.34(m,6H),3.59(td,J=10.5,5.3Hz,1H),2.38(d,J=6.4Hz,2H),1.55(s,6H),1.04(s,10H),0.92(d,J=6.5Hz,3H),0.82(s,3H),0.62(d,J=12.3Hz,3H).

[0318] Step 8: Dissolve the raw material 1-bromo-2-methoxybenzene (173 mg, 0.9 mmol, 4 eq) in anhydrous tetrahydrofuran (3 mL), cool the system to -78°C, add n-butyl lithium (1.8 mL, 0.28 mmol, 3 eq), and stir at the same temperature for 30 min. The white solid (5R)-5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylprop-2-yl)diphenylsilyl]oxy}hexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanal 72-7 and (5R)-5-[(1R,3aR,5aR,7S,9aS,9bR,11aR)-4-fluoro-9a,11a A mixture of 7-dimethyl-7-{[(2-methylpropan-2-yl)diphenylsilyl]oxy}-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthr-1-yl]hexanal 73-5 (150 mg, 0.23 mmol, 1.0 eq) was dissolved in tetrahydrofuran (2 mL) and added to the reaction mixture. The reaction system was stirred at -78°C for 30 min. The reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 5:1). 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 (10 mL), the combined organic phases were dried, and concentrated to give a white solid (5R)-5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylprop-2-yl)diphenylsilyl]oxy}hexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-1-(2-methoxyphenyl)hexane- The crude product (70 mg, 0.11 mmol) of 1-ol 72-8 and (5R)-5-[(1R,3aR,7S,9aS,9bR,11aR)-4-fluoro-9a,11a-dimethyl-7-{[(2-methylprop-2-yl)diphenylsilyl]oxy}-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-1-(2-methoxyphenyl)hexan-1-ol 73-6 was directly used in the next step.

[0319] In the ninth step, white solids (5R)-5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylprop-2-yl)diphenylsilyl]oxy}hexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-1-(2-methoxyphenyl)hexan-1-ol 72-8 and (5R)-5-[(1R,3aR,7S,9aS,9bR,11aR)-4-fluoro-9a,11a-dimethyl A mixture of 7-{[(2-methylpropan-2-yl)diphenylsilyl]oxy}-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-1-(2-methoxyphenyl)hexan-1-ol 73-6 (70 mg, 0.11 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL), and tetrabutylammonium fluoride (1 mL, 1 mol / L) was added. The reaction system was stirred for 12 h over 40 h. TLC (petroleum ether:ethyl acetate = 5:1) monitored the reaction completion. Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The ethyl acetate layers were combined and washed with saturated brine (3 × 10 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 65:35) to give a white solid, which was then separated by chiral separation SFC (instrument: Waters Acquity UPCC; chromatographic column: Daicel CHIRALPAK IE_3, 3.0*150mm, 3um; mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 50 / 50; flow rate: 1.5 ml / min; column temperature: 37 degrees) to give (1R, 3aS, 3bR, 7S, 9aS, 9bS, 11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-(2-methoxyphenyl)hexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthren-7-ol 72 (35 mg, purity 100%, yield 56%, retention time t R =1.682 min) and (1R,3aR,7S,9aS,9bR,11aR)-4-fluoro-1-[(2R)-6-hydroxy-6-(2-methoxyphenyl)hexan-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-7-ol 73 (5 mg, purity 100%, yield 8%, retention time t R =2.241min).

[0320] 72: 1H NMR (400MHz, CDCl3) δ7.32–7.27(m,1H),7.26–7.21(m,1H),7.00–6.84(m,2H),4 .85(dt,J=9.1,5.9Hz,1H),3.85(s,3H),3.68–3.58(m,1H),1.98(d,J=11.4Hz,1H ),1.88–1.69(m,8H),1.64–1.51(m,4H),1.46–1.28(m,9H),1.24–1.11(m,2H),1. 10–0.95(m,4H),0.90(dt,J=7.6,3.8Hz,3H),0.84(s,3H),0.65(d,J=2.3Hz,3H). 19 F NMR (377MHz, CDCl3) δ-88.96,-89.59,-110.85,-111.48.

[0321] 73: 1 H NMR (400MHz, CDCl3) δ7.31–7.28(m,1H),7.24(s,1H),6.92(dd,J=32.7,7.8Hz,2H),4.85(dd,J= 14.9,8.1Hz,1H),3.86(s,3H),3.68–3.54(m,1H),2.02(d,J=11.5Hz,3H),1.81(ddd,J=17.2,12 .6,8.5Hz,6H),1.64(s,2H),1.54(d,J=3.1Hz,4H),1.44(dd,J=13.3,4.6Hz,3H),1.34–1.28(m, 5H),1.13–1.02(m,4H),0.91(dd,J=6.5,3.6Hz,3H),0.80(d,J=10.7Hz,3H),0.71–0.60(m,3H). 19 F NMR (376MHz, CDCl3) δ-106.98,-110.64.

[0322] Examples 74 & 75

[0323] Preparation of Compound 74 (1R, 3aS, 3bR, 7S, 9aS, 9bS, 11aR)-4,4-difluoro-1-[(2R)-6-(2-fluorophenyl)-6-hydroxyhexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0324] Preparation of Compound 75 (1R,3aR,7S,9aS,9bR,11aR)-4-fluoro-1-[(2R)-6-(2-fluorophenyl)-6-hydroxyhexan-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

[0325] Referring to Examples 72 & 73, the 1-bromo-2-methoxybenzene in the eighth step was replaced with 1-bromo-2-fluorobenzene, and chiral separation was performed by SFC (instrument: Waters Acquity UPCC; chromatographic column: Daicel CHIRALPAK IE_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 temperature: 37 degrees) to obtain (1R,3aS,3bR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-(2-fluorophenyl)-6-hydroxyhexan-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthren-7-ol 74 (35 mg, purity 100%, yield 56%, retention time t R =1.167min) and (1R,3aR,7S,9aS,9bR,11aR)-4-fluoro-1-[(2R)-6-(2-fluorophenyl)-6-hydroxyhexan-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 75 (5 mg, purity 100%, yield 8%, retention time t R =1.410min).

[0326] Compound 74: 1 H NMR (400MHz, CDCl3) δ7.32–7.27(m,1H),7.26–7.21(m,1H),7.00–6.84(m,2H),4 .85(dt,J=9.1,5.9Hz,1H),3.85(s,3H),3.68–3.58(m,1H),1.98(d,J=11.4Hz,1H ),1.88–1.69(m,8H),1.64–1.51(m,4H),1.46–1.28(m,9H),1.24–1.11(m,2H),1. 10–0.95(m,4H),0.90(dt,J=7.6,3.8Hz,3H),0.84(s,3H),0.65(d,J=2.3Hz,3H). 19F NMR (376MHz, CDCl3) δ-88.98,-89.60,-110.85,-111.48,-119.75,-119.78.

[0327] Compound 75: 1 H NMR (400MHz, CDCl3) δ7.31–7.28(m,1H),7.24(s,1H),6.92(dd,J=32.7,7.8Hz,2H),4.85(dd,J= 14.9,8.1Hz,1H),3.86(s,3H),3.68–3.54(m,1H),2.02(d,J=11.5Hz,3H),1.81(ddd,J=17.2,12 .6,8.5Hz,6H),1.64(s,2H),1.54(d,J=3.1Hz,4H),1.44(dd,J=13.3,4.6Hz,3H),1.34–1.28(m, 5H),1.13–1.02(m,4H),0.91(dd,J=6.5,3.6Hz,3H),0.80(d,J=10.7Hz,3H),0.71–0.60(m,3H). 19 F NMR (376MHz, CDCl3) δ110.61,105.12,105.11.

[0328] Example 76

[0329] Preparation of compound 76 (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-(pyridin-4-yl)hexan-2-yl]-9a, 11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol.

[0330] Step 1: Dissolve 4-bromo-pyridine (118.50 mg, 0.75 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL). Cool the mixture to -78°C, add n-butyl lithium (2.5 mL, 0.45 mmol, 3.0 eq), and stir at this temperature for 30 min. Dissolve (5R)-5-((3aS, 5aR, 5bS, 7aR, 8R, 10aS, 10bS, 12bR)-11,11-difluoro-2,2,5a,7a-tetramethylhexahydro-4H-cyclopentadieno[7,8]phenanthro[1,2-d][1,3]dihydroxy-8-yl)hexanal I (100 mg, 0.21 mmol, 1.0 eq) in tetrahydrofuran (2 mL) and add the resulting mixture. Stir the reaction at -78°C for 30 min. The reaction was complete as monitored by TLC (petroleum ether:ethyl acetate = 5:1). 10 mL of water was added to the reaction system, and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated sodium chloride (10 mL), dried, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 90:10) to obtain (5R)-5-((3aS, 5aR, 5bS, 7aR, 8R, 10aS, 10bS, 12aR, 12bR)-11,11-difluoro-2,2,5a,7a-tetramethylhexahydro-4H-cyclopenta[7,8]phenanthren[1,2-d][1,3]dioxetyl)-1-(pyridin-4-yl)hexan-1-ol 76-1 (24 mg, 90% purity, 18.8% yield) as a white solid.

[0331] 1 H NMR (400MHz, CDCl3) δ8.59(s,2H),7.39(s,2H),4.75(s,1H),4.02(d,J=15.0Hz,1H),2.20(dd,J=22.6,14.8Hz,1H),2.09–1.93(m,3H),1.82( d,J=7.0Hz,2H),1.76–1.58(m,4H),1.50(s,2H),1.30(s,2H),1.26(s,3H),1.07(s,2H),0.90(dd,J=7.0,3.8Hz,2H),0.65(d,J=11.8Hz,2H).

[0332] Step 2: The reactant (5R)-5-((3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethylhexahydro-4H-cyclopenta[7,8]phenanthren[1,2-d][1,3]dioxetyl)-1-(pyridin-4-yl)hexan-1-ol 76-1 (24 mg, 0.044 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL) and dilute hydrochloric acid (1 mL, 3 mol / L) was added. The reaction system was stirred at room temperature for 1 h. The reaction was monitored for completion by TLC plate (petroleum ether:ethyl acetate = 5:1). Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3×10 mL). The ethyl acetate layers were combined and washed with saturated brine (3×10 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 70:30) to give a white solid, which was then separated by chiral separation (instrument: Waters Acquity UPCC; chromatographic column: Daicel CHIRALPAK IC_3, 3.0*150 mm, 3 um; mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 70 / 30; flow rate: 2.0 ml / min; column temperature: 37 degrees) to give (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-(pyridin-4-yl)hexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 76 (3.04 mg, purity 100%, yield 13.7%, retention time t R =1.965min). Compound 76: 1 H NMR(400MHz, CDCl3)δ8.56(d,J=5.9Hz,2H),7.28(s,2H),4.68(t,J=6.4Hz ,1H),3.73(s,1H),3.64–3.55(m,1H),2.23–2.14(m,1H),1.96(d,J=12.7H z,1H),1.82–1.65(m,10H),1.46–1.23(m,10H),1.09(d,J=6.4Hz,2H),1.0 5(d,J=5.2Hz,3H),1.01–0.92(m,2H),0.88(d,J=6.5Hz,3H),0.65(s,3H). 19 F NMR (377MHz, CDCl3) δ-88.62, -89.25, -109.77, -110.65, -111.24.

[0333] Example 77

[0334] Preparation of compound 77 (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-1-[(2R)-6-(2,2-difluorobenzo[d][1,3]dioxolan-4-yl)-6-hydroxyhexan-2-yl]-4,4-difluoro-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol.

[0335] Step 1: Dissolve the raw material 4-bromo-2,2-difluorobenzo[d][1,3]diazole (177.8 mg, 0.75 mmol, 3.5 eq) in anhydrous tetrahydrofuran (4 mL). Cool the system to -78°C, add n-butyl lithium (0.26 mL, 0.64 mmol, 3.0 eq), and maintain the temperature and stir for 30 minutes. 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]hexanal I (100 mg, 0.21 mmol, 1.0 eq) was dissolved in tetrahydrofuran (2 mL) and added to the above reaction solution. The reaction system was stirred at -78°C for 30 min. The reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 5:1, phosphomolybdic acid hotplate). 20 mL of water was added to the reaction system, and the mixture was extracted with ethyl acetate (20 mL×2). The combined organic phases were washed with saturated sodium chloride (30 mL), dried, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=90:10) to obtain (5R)-5-((3aS, 5aR, 5bS, 7aR, 8R, 10aS, 10bS, 12aR, 12bR)-11,11-difluoro-2,2,5a,7a-tetramethylhexahydro-4H-cyclopenta[7,8]phenanthrene[1,2-d][1,3]dioxol-8-yl)-1-(2,2-difluorobenzo[d][1,3]trioxol-4-yl)hexan-1-ol 77-1 (80 mg, yield 60%) as a white solid.

[0336] Step 2: (5R)-5-((3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethylhexahydro-4H-cyclopenta[7,8]phenanthren[1,2-d][1,3]dioxol-8-yl)-1-(2,2-difluorobenzo[d][1,3]trioxol-4-yl)hexan-1-ol 77-1 (80 mg, 0.13 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL). Dilute hydrochloric acid (1 mL, 3 mol / L) was added, and the reaction system was stirred at room temperature for 1 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1). Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The ethyl acetate layers were combined and washed with saturated brine (3×10 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 80:20) to obtain a white solid, which was then separated by chiral separation (instrument: Waters Acquity UPCC; column: Daicel CHIRALPAK IC_3, 3.0*150mm, 3um; mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 70 / 30; flow rate: 2.0 ml / min; column temperature: 37 degrees) to obtain (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-1-[(2R)-6-(2,2-difluorobenzo[d][1,3]dioxolan-4-yl)-6-hydroxyhexan-2-yl]-4,4-difluoro-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 77 (28.80 mg, purity 97%, yield 38%, retention time t R =0.921min). 1H NMR (400MHz, CDCl3) δ7.13 (dd, J=8.0, 1.8Hz, 1H), 7.07 (t, J=7.9Hz, 1H), 6.97 (d, J=7.3Hz, 1H), 4.94–4.83(m,1H),3.77–3.71(m,1H),3.65–3.54(m,1H),2.30–2.05(m,2H),2.02–1.90(m,2H),1 .89–1.76(m,6H),1.75–1.63(m,3H),1.50–1.39(m,4H),1.38–1.32(m,3H),1.31–1.20(m,2H),1. 16–1.08(m,2H),1.07–1.02(m,4H),1.01–0.94(m,1H),0.92–0.85(m,3H),0.65(d,J=1.9Hz,3H). 19 F NMR (376MHz, CDCl3) δ-49.75 (qd, J=97.3, 9.6Hz, 2F), -88.95 (d, J=235.8Hz, 1F), -110.94 (d, J=235.9Hz, 1F).

[0337] Example 80

[0338] Preparation of compound 80 (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R)-6-(2-fluoropyridin-3-yl)-6-hydroxyhexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol.

[0339] Step 1: Dissolve the raw material 3-bromo-2-methoxypyridine (141 mg, 0.75 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL). Cool the system to -78°C, add n-butyl lithium (0.26 mL, 0.64 mmol, 3.0 eq), and maintain stirring at this temperature for 30 min. 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]hexanal I (100 mg, 0.214 mmol, 1.0 eq) was dissolved in tetrahydrofuran (2 mL) and added to the reaction mixture. The reaction system was stirred at -78°C for 30 min. The reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 5:1). 10 mL of water was added to the reaction system, and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated sodium chloride (10 mL), and the combined organic phases were dried and concentrated to obtain a colorless oily product (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7 The crude product of a-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-(2-fluoropyridin-3-yl)hexan-1-ol 80-1 (50 mg) was directly used in the next step. LC-MS: [M+H-H2O] + =594.3.

[0340] Step 2: The reactant (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]-1-(2-fluoropyridin-3-yl)hexan-1-ol 80-1 (50 mg, 0.086 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL), and dilute hydrochloric acid (1 mL, 3 mol / L) was added. The reaction system was stirred at room temperature for 1 h. The reaction was complete as monitored by TLC (petroleum ether: ethyl acetate = 5:1). Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3×10 mL). The ethyl acetate layers were combined and washed with saturated brine (3×10 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 65:35) to obtain a white solid, which was then separated by chiral separation (instrument: Waters Acquity UPCC; chromatographic column: Daicel CHIRALPAK IC_3, 3.0*150mm, 3um; mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 60 / 40; flow rate: 1.5 ml / min; column temperature: 37 degrees) to obtain (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R)-6-(2-fluoropyridin-3-yl)-6-hydroxyhexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 80 (4.06 mg, purity 100%, yield 8.07%, retention time t R =1.683min).

[0341] Compound 80: 1 H NMR (400MHz, CDCl3) δ8.12(d,J=4.5Hz,1H),7.92(t,J=8.5Hz,1H),7.21(m ,1H),4.95(m,1H),3.74(s,1H),3.60(m,1H),2.17(m,2H),1.97(d,J=12.9H z,4H),1.82(d,J=7.2Hz,7H),1.72(s,4H),1.40(s,4H),1.36(m,2H),1.09( s,2H),1.06(s,3H),0.95(m,3H),0.90(dd,J=6.7,2.3Hz,3H),0.66(s,3H).19 F NMR (377MHz, CDCl3) δ-72.48, -76.69, -88.63, -89.26, -110.61, -111.22.LC-MS: [M+H] + =524.35.

[0342] Example 81 & 83

[0343] Compound 81 (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R)-6-(2-methoxypyridin-3-yl)-6-hydroxyhexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol and

[0344] Preparation of compound 83 (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-1-[(2R)-6-hydroxy-6-(2-methoxypyridin-3-yl)hexan-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.

[0345] Step 1: Dissolve the raw material 3-bromo-2-methoxypyridine (141 mg, 0.75 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL). Cool the system to -78°C, add n-butyl lithium (0.26 mL, 0.64 mmol, 3.0 eq), and maintain stirring at this temperature for 30 min. 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]hexanal I and (5R)-5-[(3aS,5aR,5bR, A mixture of (7aR,8R,10aR,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 (100 mg, 0.214 mmol, 1.0 eq) was dissolved in tetrahydrofuran (2 mL) and added to the above reaction solution. The reaction system was stirred at -78°C for 30 min. The reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 5:1). 10 mL of water was added to the reaction system, and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated sodium chloride (10 mL), dried, and concentrated to obtain a colorless oily crude mixture of 81-1 and 83-1 (80 mg), which was used directly in the next step. LC-MS: ([M+H-H2O] + =594.3.

[0346] Step 2: Reaction of (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aS,12bS)-11,11,12a-trifluoro-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-(2-methoxypyridin-3-yl)hexan-1-ol 81-1 and (5R)-5-[(3aS,5aR,5bR,7aR,8R,10aR,12aR,12bR)-11-fluoro-2,2,5a,7a-tetrafluoroethylene]-1-[(3aS,5aR,5bR,7aR,8R,10aR,12aR,12bR)-11-fluoro-2,2,5a,7a-tetrafluoroethylene]-1-[(3aS,5aR,5bR,7aR,8R,10aR,12aR,12bR)-11-fluoro-2,2,5a,7a-tetrafluoroethylene]-1-[(3aS,5aR,5bR,7aR,8R,10aR,12aR,12b The crude product of methyl-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]-1-(2-methoxypyridin-3-yl)hexan-1-ol 83-1 (80 mg, 0.14 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL). Dilute hydrochloric acid (1 mL, 3 mol / L) was added, and the reaction system was stirred at room temperature for 1 h. The reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 5:1). Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The ethyl acetate layers were combined and washed with saturated brine (3 × 10 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 65:35) to obtain a white solid, which was then separated by chiral separation (instrument: Waters Acquity UPCC; column: Daicel CHIRALPAK IB The column was purified by column chromatography (4.6*250mm, 5um; mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 50 / 50; flow rate: 1.5 ml / min; column temperature: 37 degrees) to obtain (1R,3aS,3bS,5aS,6S,7S,9aR,9bS,11aR)-4,4,5a-trifluoro-1-[(2R)-6-hydroxy-6-(2-methoxypyridin-3-yl)hexan-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 81 (22.46 mg, purity 99.06%, yield 30.11%, retention time t R=1.484 min) and (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-1-[(2R)-6-hydroxy-6-(2-methoxypyridin-3-yl)hexan-2-yl]hexan-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 83 (1.98 mg, purity 89.13%, yield 2.75%, retention time t R =1.986min).

[0347] Compound 81:1H NMR (400MHz, CDCl3) δ8.08(m,1H),7.62(t,J=5.2Hz,1H),6.91(dd,J=7.2,5.1Hz ,1H),4.79(dt,J=13.4,6.7Hz,1H),4.01(s,3H),3.74(s,1H),3.60(m,1H),2.16( m,2H),1.97(d,J=13.2Hz,1H),1.82(m,4H),1.70(m,4H),1.36(m,11H),1.10(s,2 H),1.06(s,3H),0.98(m,2H),0.90(dd,J=6.5,3.3Hz,3H),0.66(d,J=1.8Hz,3H). 19 F NMR(377MHz, CDCl3)δ-88.63,-89.26,-110.63,-111.26.LC-MS:[M+H] + =536.35.

[0348] Compound 83: 1H NMR (400 MHz, CDCl3) δ 8.11 (m, 1H), 7.68 (s, 1H), 6.95 (m, 1H), 4.81 (d, J = 4.9 Hz, 1H), 4.06 (s, 3H), 3.85 (s, 1H), 3.59 (d, J = 11.6 Hz, 1H), 2.66 (s, 1H), 2.02 (d, J = 11.3 Hz, 1H), 1.92 ( s,1H),1.81(dd,J=20.6,13.4Hz,6H),1.77(s,3H),1.61(d,J=9.5Hz,3H),1.44(m,7H),1 .25(s,3H),1.10(m,3H),1.05(s,3H),0.92(dd,J=6.5,2.8Hz,3H),0.63(d,J=1.5Hz,3H). 19 F NMR(377MHz,CDCl3)δ-109.77.LC-MS:[M+H]+ =516.35.

[0349] Example 82 & 87

[0350] Preparation of Compound 87 (1R, 3aS, 3bR, 7S, 9aS, 9bS, 11aR)-1-[(2R)-6-(2,6-difluorophenyl)-6-hydroxyhexan-2-yl]-4,4-difluoro-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0351] Preparation of Compound 82 (1R,3aR,7S,9aS,9bR,11aR)-1-[(2R)-6-(2,6-difluorophenyl)-6-hydroxyhexan-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-7-ol

[0352] Referring to Examples 74 & 75, the 1-bromo-2-methoxybenzene in the eighth step was replaced with 2-bromo-1,3-difluorobenzene, and chiral separation was performed by SFC (instrument: Waters Acquity UPCC; chromatographic column: Daicel CHIRALPAK IB 4.6*250 mm, 5 um; mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 60 / 40; flow rate: 1.5 ml / min; column temperature: 37 degrees) to obtain (1R,3aS,3bR,7S,9aS,9bS,11aR)-1-[(2R)-6-(2,6-difluorophenyl)-6-hydroxyhexan-2-yl]-4,4-difluoro-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthren-7-ol 87 (35 mg, purity 100%, yield 56%, retention time t R =1.293 min) and (1R,3aR,7S,9aS,9bR,11aR)-1-[(2R)-6-(2,6-difluorophenyl)-6-hydroxyhexan-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-7-ol 82 (5 mg, purity 100%, yield 8%, retention time t R =1.646min).

[0353] 87: 1H NMR (400MHz, CDCl3) δ7.25–7.16(m,1H),6.87(t,J=8.3Hz,2H),5.03(t,J=7.2Hz,1H),3.69–3.53(m,1H),2.03–1.92(m,2H),1.86–1.70(m,7 H),1.64–1.49(m,4H),1.47–1.25(m,10H),1.07(ddd,J=27.8,15.1,11.4Hz,5H),0.89(t,J=6.0Hz,3H),0.84(s,3H),0.65(d,J=3.7Hz,3H). 19 F NMR (376MHz, CDCl3) δ-88.97,-89.60,-110.85,-111.48,-115.39,-115.46.

[0354] 82: 1 H NMR (400MHz, CDCl3) δ7.21(t,J=7.4Hz,1H),6.87(t,J=8.2Hz,2H),5.03(s,1H),3.63(d,J=26.3Hz,1H), 2.01(dd,J=11.2,8.9Hz,3H),1.91(s,2H),1.84(s,3H),1.76(s,3H),1.68–1.48(m,6H),1.44(dd,J=10.8 ,5.9Hz,2H),1.38(d,J=5.0Hz,2H),1.30(dd,J=11.6,5.1Hz,4H),1.13(d,J=12.9Hz,1H),1.08(d,J=10.0 Hz,2H),1.02(d,J=11.9Hz,1H),0.92–0.84(m,5H),0.80(d,J=11.0Hz,3H),0.66(dd,J=28.8,3.7Hz,3H). 19 F NMR (376MHz, CDCl3) δ-110.61,-115.39,-115.46.

[0355] Examples 84 & 88

[0356] Compound 84 (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-{3-[(trifluoromethyl)oxy]phenyl}hexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol and

[0357] Preparation of compound 88 (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-1-[(2R)-6-hydroxy-6-{3-[(trifluoromethyl)oxy]phenyl}hexan-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.

[0358] Step 1: Dissolve the raw material 1-bromo-3-[(trifluoromethyl)oxy]benzene (126.7 mg, 0.5 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL). Cool the system to -78°C, add n-butyl lithium (1.8 mL, 0.45 mmol, 3.0 eq), and stir at this temperature for 30 min. 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]hexanal I and (5R)-5-[(3aS,5aR,5bR A mixture of 2,7aR,8R,10aR,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 (70 mg, 0.15 mmol, 1.0 eq) was dissolved in tetrahydrofuran (2 mL) and added to the above reaction solution. The reaction system was stirred at -78°C for 30 min. The reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 5:1). 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 (10 mL), the combined organic phases were dried, and concentrated to obtain a colorless oily crude mixture of 84-1 and 88-1 (70 mg), which was then used directly in the next step.

[0359] Step 2: Reaction of (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]-1-{3-[(trifluoromethyl)oxy]phenyl}hexan-1-ol 84-1 and (5R)-5-[(3aS,5aR,5bR The crude product of (70 mg, 0.11 mmol, 1.0 eq) (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]-1-(3-[(trifluoromethyl)oxy]phenyl)hexan-1-ol 88-1 was dissolved in tetrahydrofuran (3 mL). Dilute hydrochloric acid (1 mL, 3 mol / L) was added, and the reaction system was stirred at room temperature for 1 h. The reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 5:1). Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3×10 mL). The ethyl acetate layers were combined and washed with saturated brine (3×10 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 65:35) to obtain a white solid, which was then separated by chiral separation SFC (Instrument: Waters Acquity UPCC; Column: Daicel CHIRALPAK IC_3, 3.0*150mm, 3um; mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 65 / 35; flow rate: 2.0 ml / min; column temperature: 37 degrees) to obtain (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-{3-[(trifluoromethyl)oxy]phenyl}hexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 84 (33.05 mg, purity 99.04%, yield 49.94%, retention time t R=0.700 min) and (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-1-[(2R)-6-hydroxy-6-(3-[(trifluoromethyl)oxy]phenyl)hexan-2-yl]hexan-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 88 (2.97 mg, purity 97.97%, yield 4.96%, retention time t R =0.927min).

[0360] Compound 84: 1 H NMR (400MHz, CDCl3) δ7.37(t,J=7.9Hz,1H),7.28(s,1H),7.22(s,1H),7.12(d,J=8.0Hz, 1H),4.74–4.65(m,1H),3.74(s,1H),3.60(dt,J=11.0,4.0Hz,1H),2.29–2.07(m,1H),1. 97(d,J=12.9Hz,1H),1.88–1.77(m,8H),1.77–1.60(m,5H),1.50–1.24(m,10H),1.11(dd ,J=14.1,5.1Hz,2H),1.06(s,3H),1.02–0.92(m,2H),0.89(t,J=5.9Hz,3H),0.65(s,3H). 19 F NMR (377MHz, CDCl3) δ-57.72,-88.64,-89.27,-110.64,-111.26.

[0361] Compound 88: 1H NMR (400MHz, CDCl3) δ7.37(t,J=7.9Hz,1H),7.28(s,1H),7.22(s,1H),7.12(d,J=7.9Hz,1H),4.74– 4.67(m,1H),3.85(s,1H),3.63–3.56(m,1H),2.65(t,J=14.8Hz,1H),2.02(d,J=14.1Hz,2H),1.90– 1.66(m,11H),1.61(d,J=12.8Hz,4H),1.45(dd,J=15.3,7.8Hz,4H),1.35–1.22(m,7H),1.09(dd,J= 12.2,4.5Hz,3H),1.04(s,3H),0.90(dd,J=6.4,4.4Hz,3H),0.62(d,J=1.3Hz,3H).LC-MS:[M+1-H2O] + =551.30. 19 F NMR (376MHz, CDCl3) δ-57.72,-109.77.

[0362] Examples 89 & 90

[0363] Compound 89 (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-(1,3-thiazolyl)hexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol and

[0364] Preparation of compound 90 (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-1-[(2R)-6-hydroxy-6-(1,3-thiazolyl-2-yl)hexan-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.

[0365] Step 1: Dissolve the raw material 1,3-thiazolinone (44.7 mg, 0.5 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL), cool the system to -78°C, add n-butyl lithium (1.8 mL, 0.45 mmol, 3.0 eq), and maintain the temperature with stirring for 30 min. (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, A mixture of (7aR,8R,10aR,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 (70 mg, 0.15 mmol, 1.0 eq) was dissolved in tetrahydrofuran (2 mL) and added to the above reaction solution. The reaction system was stirred at -78°C for 30 min. The reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 5:1). 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 (10 mL), the combined organic phases were dried, and concentrated to give colorless oily crude products of 89-1 and 90-1 (70 mg), which were then used directly in the next step.

[0366] Step 2: Reaction of (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]-1-(1,3-thiazolyl)hexan-1-ol 89-1 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-decane] The crude product of tetrahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxolan-8-yl]-1-(3-[(1,3-thiazolyl)hexan-2-yl)hexan-1-ol 90-1 (70 mg, 0.1 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL) and diluted hydrochloric acid (1 mL, 3 mol / L) was added. The reaction system was stirred at room temperature for 1 h. TLC (petroleum ether:ethyl acetate = 5:1) monitored the completion of the reaction. Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3×10 mL). The EA layers were combined and washed with saturated brine (3×10 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 65:35) to obtain a white solid, which was then separated by chiral separation SFC (instrument: Waters Acquity UPCC; chromatographic column: Daicel CHIRALPAK IC_3, 3.0*150mm, 3um; mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 50 / 50; flow rate: 1.5 ml / min; column temperature: 37 degrees) to obtain (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-(1,3-thiazolyl)hexan-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 89 (17.91 mg, purity 93.50%, yield 36.11%, retention time t R=1.209 min) and (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-1-[(2R)-6-hydroxy-6-(1,3-thiazolyl)hexan-2-yl]hexan-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 90 (2.09 mg, purity 98.75%, yield 4.63%, retention time t R =1.618min).

[0367] Compound 89: 1 H NMR (400MHz, DMSO) δ7.72–7.69(m,1H),7.58(dd,J=3.2,1.8Hz,1H),6.05(dd,J=5.2,1.2Hz,1H),4.78 (dt,J=8.0,3.9Hz,1H),4.40(d,J=6.0Hz,1H),4.24(d,J=3.4Hz,1H),3.49(d,J=2.4Hz,1H),3.35(d,J =6.6Hz,1H),2.17–1.97(m,1H),1.91(d,J=12.5Hz,1H),1.85–1.54(m,8H),1.43(d,J=9.9Hz,3H),1.3 7–1.15(m,9H),1.05(t,J=10.5Hz,3H),0.98(s,3H),0.87(d,J=6.4Hz,3H),0.62(s,3H).LC-MS:[M+1] + =512.37. 19 F NMR(377MHz, DMSO)δ-86.66,-87.28,-108.65,-109.27.

[0368] Compound 90: 1H NMR (400MHz, DMSO) δ7.70(d,J=3.2Hz,1H),7.58(dd,J=3.2,1.7Hz,1H),6.06(d,J=5.2Hz,1H),4.7 7(dt,J=8.2,4.8Hz,1H),4.41(d,J=6.0Hz,1H),4.24(d,J=3.4Hz,1H),3.59(d,J=2.8Hz,1H),3.29( d,J=4.2Hz,1H),2.03–1.93(m,2H),1.84–1.56(m,10H),1.47–1.27(m,8H),1.25(d,J=9.6Hz,4H),1 .07(ddd,J=35.6,21.8,13.4Hz,4H),0.95(s,3H),0.88(d,J=6.5Hz,3H),0.57(s,3H).LC-MS:[M+1] + =492.25. 19 F NMR (377MHz,CDCl3)δ-103.90.

[0369] Example 91 & 92

[0370] Compound 91 or 92 (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R, 6S)-6-hydroxy-6-(pyridin-2-yl)hexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol and

[0371] Preparation of compound 92 or 91 (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R, 6R)-6-hydroxy-6-(pyridin-2-yl)hexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol.

[0372] Step 1: Dissolve the raw material 2-bromopyridine (118.50 mg, 0.750 mmol) in anhydrous tetrahydrofuran (5 mL), cool the system to -78°C, add n-butyl lithium (0.257 mL, 0.643 mmol), and maintain stirring at this temperature for 30 minutes. 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]hexanal I (100 mg, 0.214 mmol) was dissolved in tetrahydrofuran (5 mL) and added to the reaction mixture. The reaction system was stirred at -78°C for 30 min. The reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 5:1). 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 (10 mL), the combined organic phases were dried, and concentrated to obtain a colorless oily (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl The crude product of 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-(pyridin-2-yl)hexan-1-ol 91-1 (70 mg, 0.103 mmol, 47.88%) was added.

[0373] Step 2: The reactant (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]-1-(pyridin-2-yl)hexan-1-ol 91-1 (70 mg, 0.11 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL), and dilute hydrochloric acid (1 mL, 3 mol / L) was added. The reaction system was stirred at room temperature for 1 h. The reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 5:1). Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3×10 mL). The EA layers were combined and washed with saturated brine (3×10 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 65:35) to obtain a white solid, which was then subjected to chiral separation (instrument: Waters Acquity UPCC; chromatographic column: Daicel CHIRALPAK IC_3, 3.0*150 mm, 3 μm; mobile phase: A / B:CO2 / MeOH (0.1% DEA) = 65 / 35; flow rate: 2.0 mL / min; column temperature: 37 degrees) to obtain compound 91 (4.46 mg, 0.009 mmol, 6.89%, retention time t R =1.776 min) and compound 92 (5.72 mg, 0.011 mmol, 8.25%, retention time t R =1.986min).

[0374] Compound 91: 1H NMR (400 MHz, CDCl3) δ8.55 (d, J = 4.7 Hz, 1H), 7.71 (td, J = 7.7, 1.4 Hz, 1H), 7.29 (s, 1H), 7.25–7.21 (m, 1H), 4.74 (dd, J = 7.8, 4.4 Hz, 1H), 3.74 (s, 1H), 3.65–3.57 (m, 1H), 2.29–2.09 (m, 1H), 1.96 (dd, J = 9.5, 3 .3Hz,0H),1.85–1.77(m,1H),1.76–1.70(m,1H),1.56–1.45(m,1H),1.40(dd,J=13.6,8.8Hz,1H),1.3 4–1.24(m,2H),1.15–1.08(m,1H),1.06(s,3H),1.01–0.93(m,1H),0.89(t,J=5.2Hz,3H),0.65(s,3H). 19 F NMR (376MHz, CDCl3) δ-88.63, -89.26, -110.62, -111.25.

[0375] Compound 92: 1 H NMR (400MHz, CDCl3) δ8.55(d,J=4.8Hz,1H),7.70(td,J=7.7,1.5Hz,1H),7.22(dd,J=7.2,5.2Hz,1 H),4.74(dd,J=7.7,4.2Hz,1H),3.74(s,1H),3.59(m,1H),2.21(ddd,J=28.4,13.8,7.1Hz,1H),1.9 7(d,J=12.7Hz,1H),1.80(dd,J=16.2,6.4Hz,4H),1.70(m,6H),1.33(ddd,J=20.1,16.0,6.8Hz,11 H),1.11(d,J=5.4Hz,2H),1.05(s,3H),0.97(m,2H),0.90(d,J=6.4Hz,3H),0.63(d,J=11.0Hz,3H). 19 F NMR (376MHz, CDCl3) δ-88.58, -89.21, -110.56, -111.19.

[0376] Example 93

[0377] Preparation of Compound 93 (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R)-5-(hydroxycyclopropyl)pentan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0378] Step 1: Dissolve the reactant (5R)-5-((3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-11,11-difluoro-2,2,5a,7a-tetramethylhexahydro-4H-cyclopentadieno[7,8]phenanthrene[1,2-d][1,3]dihydroxy-8-yl)hexanoate I-13 (400 mg, 0.805 mmol, 1.0 eq) in tetrahydrofuran (6 mL). Add dilute hydrochloric acid (3 mL, 3 mol / L), and stir at room temperature for 1 h. Monitor the reaction progress by TLC (petroleum ether:ethyl acetate = 10:1, phosphomolybdic acid hotplate). Stop the reaction when the starting material is consumed. Add water (30 mL) to the reaction system, and extract the aqueous layer with ethyl acetate (3 × 20 mL). Combine the EA layers and wash with saturated brine (50 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 80:20) to obtain a white solid (5R)-5-((3S,4R,8S,9S,10R,13R,14S,17R)-7,7-difluoro-3,4-dihydroxy-10,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)hexanoic acid methyl ester 93-1 (330 mg, purity 90%, yield 73.42%). Compound 93-1: 1 H NMR (400MHz, CDCl3) δ3.74(s,1H),3.67(s,3H),3.64–3.56(m,1H),2.31–2.23(m,2H),1.97(d,J=12.7Hz,1H),1.89–1.77(m,5H),1.75–1.6 6(m,4H),1.55–1.43(m,4H),1.43–1.33(m,5H),1.15–1.07(m,3H),1.06(s,3H),1.01(d,J=3.0Hz,2H),0.93(d,J=6.5Hz,3H),0.66(s,3H). 19 F NMR (377MHz, CDCl3) δ-88.96 (d, J = 235.9Hz, 1F), -110.94 (d, J = 236.0Hz, 1F).

[0379] Step 2: Compound (5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-6,7-dihydroxy-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoate 93-1 (300 mg, 0.66 mmol, 1.0 eq) was dissolved in tetrahydrofuran (15 mL) at room temperature. Isopropyl titanate (938 mg, 3.30 mmol, 5.0 eq) was added under nitrogen. Ethylmagnesium bromide (1 M in THF, 6.6 mL, 6.60 mmol, 10 eq) was slowly added dropwise, maintaining the temperature at 18-20°C. The mixture was then stirred at room temperature for 1 hour. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 2:1). The mixture was quenched with ammonium chloride solution, and ethyl acetate (30 mL) and water (20 mL) were added. The mixture was filtered through celite, and the aqueous phase was extracted with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to give (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-5-(hydroxycyclopropyl)pentan-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 93-2 as a white solid (185 mg, purity: 90%, yield: 61.67%). 1 H NMR(400MHz, CDCl3)δ3.74(s,1H),3.65–3.56(m,1H),2.27–2.11(m,1H),1.98(d,J =12.9Hz,1H),1.91–1.78(m,5H),1.77–1.65(m,4H),1.54(dd,J=13.4,9.8Hz,3H),1 .49–1.39(m,6H),1.16–1.08(m,3H),1.06(s,3H),1.02–0.97(m,1H),0.94(d,J=6. 5Hz,3H),0.91–0.82(m,2H),0.73(t,J=5.5Hz,2H),0.67(s,3H),0.47–0.41(m,2H).

[0380] Step 3: ((1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-5-(hydroxycyclopropyl)pentan-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 93-2 (185 mg, 0.41 mmol, 1.0 eq) was dissolved in dichloromethane (4 mL) and tetrahydrofuran (2 mL) at room temperature, and triethylamine (41 mg, 1.23 mmol, 3 eq) was added. -dimethylaminopyridine (40 mg, 0.33 mmol, 0.8 eq) and benzoyl chloride (58 mg, 0.62 mmol, 1.5 eq), then stirred at room temperature for 4 hours, the reaction was monitored by TLC (petroleum ether: ethyl acetate = 1: 1), after the reaction was completed, quenched with ice water (20 mL), extracted with ethyl acetate (20 mL × 2), 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 = 10: 1) and SFC separation (instrument: Waters Acquity UPCC column: Daicel CHIRALPAK IH_3, 3.0*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) to obtain a white solid benzoic acid-(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-6-hydroxy-1-[(2R)-5-(hydroxycyclopropyl)pentan-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 93-3 (75 mg, purity: 95%, yield: 32.75%, retention time t R =1.171min). 1 H NMR (400MHz, CDCl3) δ8.04(d,J=7.5Hz,2H),7.58(t,J=7.6Hz,1H),7.46(t,J=7.8Hz,2 H),4.99(d,J=11.2Hz,1H),3.98(s,1H),2.25(d,J=35.4Hz,1H),2.02(dd,J=17.0,8.7H z,2H),1.83(d,J=10.0Hz,7H),1.55(s,6H),1.49–1.32(m,8H),1.14(s,3H),1.09–0.9 8(m,2H),0.95(d,J=6.5Hz,3H),0.74(t,J=5.5Hz,2H),0.68(s,3H),0.50–0.37(m,2H). 19F NMR (376MHz, CDCl3) δ-89.03 (d, J = 236.3Hz, 1F), -110.80 (d, J = 236.4Hz, 1F).

[0381] Step 4: Benzoic acid-(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-6-hydroxy-1-[(2R)-5-(hydroxycyclopropyl)pent-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 93-3 (20 mg, 0.036 mmol, 1.0 eq) was dissolved in tetrahydrofuran (1 mL) and methanol (1 mL) at room temperature, and potassium carbonate (25 mg, 0.18 mmol, 5.0 eq) and water (0.5 mL) were added at room temperature, followed by stirring at room temperature for 4 hours. TLC (petroleum ether:ethyl acetate = 4 :1) monitor the reaction. 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 obtain a white solid ((1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-5-(hydroxycyclopropyl)pentan-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 93 (2.79 mg, purity: 100%, yield: 17.01%). 1 H NMR (400MHz, CDCl3) δ3.76–3.72(m,1H),3.64–3.57(m,1H),2.45–2.25(m,1H),2.22–2.07 (m,1H),2.02–1.95(m,1H),1.91–1.77(m,5H),1.76–1.73(m,2H),1.72–1.64(m,3H),1.49– 1.43(m,3H),1.42–1.36(m,4H),1.33–1.28(m,3H),1.14–1.09(m,2H),1.06(s,3H),1.03– 0.97(m,1H),0.95–0.92(m,3H),0.73(t,J=5.4Hz,2H),0.67(s,3H),0.44(t,J=5.4Hz,2H). 19 F NMR (377MHz, CDCl3) δ-88.95 (d, J = 235.7Hz, 1F), -110.94 (d, J = 235.7Hz, 1F).

[0382] Example 95 & 96

[0383] Compound 95 (4R)-4-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-6,7-dihydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N-(2-fluorophenyl)-N-methylpentanamide and

[0384] Preparation of Compound 96 (4R)-4-[(1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-6,7-dihydroxy-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]-N-(2-fluorophenyl)-N-methylpentanamide

[0385] In the first step, the reactant (4R)-4-((3S,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-cyclopentadienyl[a]phenanthrene-17-yl)pentanoate 47-3 (4.5 g, 10.08 mmol, 1.0 eq) was dissolved in methanol (50 mL). Potassium carbonate (6.95 g, 50.38 mmol, 5.0 eq) was added, and the reaction system was stirred at room temperature for 30 min. The reaction was monitored by TLC plate (petroleum ether:ethyl acetate = 5:1). The reaction was stopped when the starting material was consumed. Water (80 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 × 80 mL). The ethyl acetate layers were combined and washed with saturated brine (3×80 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 77:23 to 75:25) to give (4R)-4-((3S,8S,9S,10R,13R,14S,17R)-3,4-dihydroxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoic acid methyl ester 95-1 (4.0 g, 9.89 mmol, purity 80%, yield 78.5%) as a white solid. 1H NMR(400MHz, CDCl3) δ5.68(d,J=3.7Hz,1H),4.14(d,J=3.3Hz,1H),3.66(s,3H) ,3.56(d,J=11.5Hz,1H),2.39–2.18(m,3H),2.13–1.96(m,3H),1.91–1.77(m,4H ),1.68–1.52(m,5H),1.45(ddd,J=15.1,10.6,4.8Hz,3H),1.30(dd,J=19.1,9.5 Hz,3H),1.18(s,3H),1.09(d,J=9.3Hz,4H),0.92(d,J=6.4Hz,4H),0.68(s,3H).

[0386] In the second step, the reactant (4R)-4-((3S,8S,9S,10R,13R,14S,17R)-3,4-dihydroxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)pentanoate 95-1 (3.95 g, 9.76 mmol, 1 eq) was dissolved in acetone (60 mL). p-Toluenesulfonic acid (1.18 g, 6.83 mmol, 0.7 eq) and 4A molecular sieves were added, and the reaction system was stirred at room temperature for 1 h. The reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 10:1). The reaction was quenched with saturated sodium sulfite. 20mL of water was added to the reaction system, extracted with ethyl acetate (25mL×3), the organic phase was collected, dried over anhydrous sodium sulfate, and the organic phase was spin-dried in vacuo to give a crude product. The crude product was dissolved in ethyl acetate and purified by column chromatography (petroleum ether:ethyl acetate=95:5) to give (R)-4-((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-cyclopentadienyl[7,8]phenanthrene[1,2-d][1,3]dihydroxy-8-yl)valerate 95-2 (3.5 g, 7.87 mmol, purity 90%, yield 72.6%) as a white solid. 1H NMR (400MHz, CDCl3) δ5.80(d,J=2.7Hz,1H),4.41(d,J=5.8Hz,1H),4.15(s,1H),3.66(s,3H),2.43–2.10(m,3H),1.99(s,1 H),1.67–1.58(m,4H),1.53(s,3H),1.35(s,3H),1.26(t,J=7.1Hz,13H),1.16(s,3H),0.93(d,J=6.4Hz,3H),0.69(s,3H).

[0387] In the third step, compound (R)-4-((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-cyclopentadienyl[7,8]phenanthrene[1,2-d][1,3]dihydroxy-8-yl)pentanoic acid methyl ester 95-2(3. 4 g, 7.61 mmol, 1.0 eq) was dissolved in acetone (50 mL), and N-hydroxyphthalimide (0.99 g, 6.12 mmol, 0.8 eq), tert-butyl hydroperoxide (11 mL, 61.88 mmol, 8.0 eq), and anhydrous cobalt(II) acetate (0.27 g, 1.52 mmol, 0.2 eq) were added. The resulting mixture was stirred at 25°C under N₂ for 36 h. The reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 10:1). When the starting material was essentially consumed, the reaction was quenched with saturated sodium sulfite, water (10 mL) was added, and the aqueous layer was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 87:13) to give (R)-methyl 4-((3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-11-oxo-3a,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetrahydro-4H-cyclopenta[7,8]phenanthren[1,2-d][1,3]dioxan-8-yl)pentanoate 95-3 (0.9 g, 1.96 mmol, purity 90%. Yield 23.2%) as a white solid. 1H NMR (400MHz, CDCl3) δ5.93 (s, 1H), 4.53 (d, J = 6.4Hz, 1H), 4.33 (dd, J = 11.3, 5.5Hz ,1H),3.67(d,J=5.3Hz,3H),2.36(ddd,J=15.3,10.0,5.1Hz,3H),2.28–2.18(m,1 H),1.88(dddd,J=16.7,10.3,9.6,3.8Hz,5H),1.59–1.55(m,4H),1.50–1.42(m,2 H),1.33(s,5H),1.18–1.06(m,2H),0.94(t,J=7.6Hz,3H),0.72(d,J=10.0Hz,3H).

[0388] Step 4: Compound (R)-methyl 4-((3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-11-oxo-3a,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetrahydro-4H-cyclopenta[7,8]phenanthren[1,2-d][1,3]dioxan-8-yl)pentanoate 95-3 (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 progress was monitored by TLC (petroleum ether:ethyl acetate = 5:1), and the starting material was completely consumed. The reaction system was filtered, and the organic phase was collected 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 ((4R)-4-[(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]pentanoic acid methyl ester 95-4 (1.7 g, purity 95%, yield 67%).

[0389] 1H NMR(400MHz,CDCl3)δ4.07–4.00(m,1H),4.00–3.95(m,1H),3.66(s,3H),2.81–2.70(m,1H),2.46–2.32(m,3H),2.26–2.17(m,4H),1.98–1.74(m,5H),1.65(ddd,J=14.1,6.7,3.6Hz,3H),1.53(s,5H),1.45–1.37(m,3H),1.32–1.26(m,6H),1.12–1.03(m,4H),0.93–0.82(m,3H),0.66(s,3H).

[0390] Step 5: Methyl (4R)-4-[(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]pentanoate 95-4 (400 mg, 0.87 mmol) was dissolved in diethylaminosulfur trifluoride (5 mL), and the resulting mixture was stirred in the reaction solution at 80°C for 1 h. The reaction progress was monitored by TLC (petroleum ether: ethyl acetate = 10:1). The starting material was completely consumed and a small polar spot was generated. 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 by layers. 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 silica gel and passed through a column with petroleum ether:ethyl acetate = 93:7 to obtain a colorless transparent solid ((4R)-4-[(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]pentanoic acid methyl ester 95% -5 and (4R)-4-[(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]pentanoic acid methyl ester 96-1 (300 mg, 0.62 mmol, purity 90%, yield calculated based on 95-5: 64.3%).

[0391] Compound 95-5: 1H NMR(400MHz,CDCl3)δ4.15–3.95(m,2H),3.66(s,3H),2.29(dddd,J=21.8,15.6,9.8,5.8Hz,2H),2.06–1.78(m,7H),1.72–1.59(m,3H),1.55(s,3H),1.51(s,3H),1.43(ddd,J=20.7,13.3,5.9Hz,3H),1.34–1.25(m,8H),1.14–1.05(m,4H),0.93(t,J=5.8Hz,3H),0.66(d,J=12.0Hz,3H).

[0392] Step 6: ((4R)-4-[(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]pentanoic acid methyl ester 95-5 and (4R)-4-[(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]pentanoate A mixture of methyl (5,5aR,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]pentanoate 96-1 (100 mg, 0.21 mmol) was dissolved in tetrahydrofuran (1 mL) solvent and 1 mol / L was added. L of lithium hydroxide solution (0.5 mL), the resulting mixture was stirred at 25°C for 16 h. The reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 1:1). After the starting material was consumed, the reaction solution was diluted with ethyl acetate (20 mL), washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate: 60:40) to obtain a white solid (4R)-4-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12b (R)-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]pentanoic acid 95-6 and (4R)-4-[(3aS,5aR,5bR,7aR,8R,10aR,12aR,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-tetradecahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxolan-8-yl]pentanoic acid 96-2 (65 mg, 0.14 mmol, purity: 90%, yield 59.4% based on 95-6).

[0393] Compound 95-6: 1<h2 style=";text-align:left;direction:ltr">H NMR (400MHz,CDCl3)δ9.25(s,1H),4.02(s,2H),2.34(ddd,J=25.4,17.2,9.7Hz,2H),1.99(s,2H),1.96–1.57(m,8H),1.51(s,3H),1.40(dd,J=34.3,11.9Hz,6H),1.30(s,3H),1.26(s,3H),1.08(t,J=16.2Hz,4H),0.90(dd,J=28.7,9.1Hz,5H),0.69(s,3H).<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0394] Step 7 (4R)-4-[(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]pentanoic acid 95-6 and (4R)-4-[(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,1 A mixture of 2,12a,12b-tetradecahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxolan-8-yl]pentanoic acid 96-2 (50 mg, 0.11 mmol, 1.0 eq) was dissolved in DMF (3 mL), and HATU (2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate) (50 mg, 0.13 mmol, 1.2 eq) and N,N-diisopropylethylamine (28 mg, 0.22 mmol, 2.0 eq) were added in sequence. The mixture was stirred at room temperature for about 15 minutes, and then o-fluoroaniline (12 mg, 0.11 mmol, 1.0 eq) was added. The mixture was stirred at room temperature for 2 hours and the reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1). After the reaction, the reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 60:40) to obtain (4R)-4-[(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-8-[( ... A mixture of (4R)-4-[(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]-N-(2-fluorophenyl)pentanamide 96-3 (30 mg, 0.053 mmol, purity: 90%, yield: 48.2% based on 95-7).LC-MS:[M+H]。 + =562.3

[0395] In the eighth step, the raw materials (4R)-4-[(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]-N-(2-fluorophenyl)pentanamide 95-7 and (4R)-4-[(3aS,5 A mixture of 2-[(aR,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]-N-(2-fluorophenyl)pentanamide 96-3 (30 mg, 0.053 mmol, 1.0 eq) was dissolved in DMF (2 mL), and the reaction system was replaced with nitrogen atmosphere. After cooling the reaction system to 0°C, sodium hydride (60%, paraffin) (2.26 mg, 0.056 mmol, 1.3 eq) was slowly added. The reaction was then stirred at room temperature for 30 min. Methyl iodide (8.00 mg, 0.056 mmol, 1.3 eq) was then added and stirred at room temperature for 2 h. TLC (petroleum ether:ethyl acetate = 5:1) was used to monitor the reaction completion and terminate the reaction. The system was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product.The crude product was separated and purified by flash chromatography (petroleum ether: ethyl acetate = 90:10 to 80:20) to give white solid (4R)-4-[(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]-N-(2-fluorophenyl)-N-methylpentanamide 95-8 and ( A mixture of 4-[(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]-N-(2-fluorophenyl)-N-methylpentanamide 96-4 (25 mg, 90% purity, 90.3% yield based on 95-8). LC-MS: [M+H]. + =576.4

[0396] In the eighth step, the reactants (4R)-4-[(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]-N-(2-fluorophenyl)-N-methylpentanamide 95-8 and (4R)-4-[(3aS,5aR,5bR,7 A mixture of 2-(aR,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]-N-(2-fluorophenyl)-N-methylpentanamide 96-4 (25 mg, 0.043 mmol, 1.0 eq) was dissolved in tetrahydrofuran (1 mL). Dilute hydrochloric acid (1 mL, 3 mol / L) was added, and the reaction system was stirred at room temperature for 1 h. The reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 5:1). The reaction was stopped when the starting material was consumed. Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3×10 mL). The EA layers were combined and washed with saturated brine (3×10 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 70:30) to give a white solid, which was then separated by chiral separation (instrument: Waters Acquity UPCC; column: REGIS CHIRAL (S, S)-whey O1 4.6*150 mm, 3.5 um; mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 50 / 50; flow rate: 1.5 ml / min; column temperature: 37 degrees) to give (4R)-4-[(1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-6,7-dihydroxy-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-N-(2-fluorophenyl)-N-methylpentanamide 95 (6.60 mg, purity 100%, yield 29%, retention time t R=2.907 min) and (4R)-4-[(1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-6,7-dihydroxy-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]-N-(2-fluorophenyl)-N-methylpentanamide 96 (0.68 mg, purity 97%, yield 3%, retention time t R =3.328min).

[0397] Compound 95: 1 H NMR (400MHz, CDCl3) δ7.35 (dd, J=13.9, 6.3Hz, 1H), 7.26–7.14 (m, 3H), 3.73 (s,1H),3.58(dd,J=11.4,3.6Hz,1H),3.22(s,3H),2.26–2.05(m,2H),2.02– 1.89(m,2H),1.89–1.75(m,6H),1.72–1.60(m,4H),1.45–1.30(m,4H),1.25 (s,3H),1.04(s,3H),1.00–0.86(m,3H),0.72(d,J=5.5Hz,3H),0.60(s,3H). 19 F NMR (377MHz, CDCl3) δ-89.00 (d, J = 235.7Hz, 1F), -110.96 (d, J = 236.0Hz, 1F), -121.27 (d, J = 11.7Hz, 1F).

[0398] Compound 96: 1 H NMR(400MHz, CDCl3)δ7.36(s,1H),7.20(d,J=7.4Hz,3H),3.84(s,1H),3.60(s,1H),3.22(s,3H),2.65(s,1H),2.11(s,1H),2.07(s,1H),1 .96(s,3H),1.82(s,3H),1.75(s,4H),1.43(s,5H),1.08(d,J=13.2Hz,2H),1.02(s,3H),0.88(s,4H),0.73(d,J=5.7Hz,3H),0.57(s,3H). 19 F NMR(377MHz, CDCl3)δ-109.72(s,1F),-121.29(s,1F).

[0399] Example 97

[0400] Preparation of Compound 97 (1R, 3aS, 3bS, 5aR, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-7-hydroxy-1-[(2R)-6-hydroxy-6-{2-[(trifluoromethyl)oxy]phenyl}hexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6-one

[0401] In the first step, (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,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-{2-[(trifluoromethyl)- 1-[(4-(4-(4-(4-(4-oxy)phenyl)hexan-1-ol)-1-one] (220 mg, 0.35 mmol, 1.0 eq)) was dissolved in dichloromethane (10 mL). The reaction system was placed in an ice-water bath and cooled to approximately 5°C. Acetic anhydride (0.1 mL, 1 mmol, 3.0 eq), 4-dimethylaminopyridine (8.55 mg, 0.07 mmol, 0.2 eq), and triethylamine (0.15 mL, 1 mmol, 3.0 eq) were added sequentially to the reaction system. The reaction system was stirred at room temperature for 1 hour. After completion of the reaction, as monitored by TLC (petroleum ether:ethyl acetate = 10:1), the reaction solution was washed with water (10 mL x 2), then washed with saturated sodium bicarbonate (10 mL x 2), and the aqueous phase was washed with dichloromethane (10 mL x 2). The organic phase was then collected and removed in vacuo to yield the crude product. The crude product was separated and purified by flash chromatography (petroleum ether:ethyl acetate = 92:8) to give (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-{2-[(trifluoromethyl)oxy]phenyl}hexyl acetate 97-1 (190 mg, purity 95%, yield 72%) as a white solid. 1H NMR(400MHz, CDCl3)δ7.43(d,J=7.7Hz,1H),7.34–7.27(m,2H),7.23(s,1H),6.08–6.00(m,1 H),4.05–3.98(m,2H),2.13(dd,J=15.2,5.1Hz,1H),1.96(dd,J=12.6,3.5Hz,2H),1.87–1.5 5(m,13H),1.51(s,3H),1.45–1.32(m,6H),1.30(s,3H),1.29–1.21(m,4H),1.12(dd,J=12.9 ,3.9Hz,2H),1.07(s,4H),1.04–0.90(m,4H),0.87(dd,J=6.3,4.3Hz,3H),0.69–0.63(m,3H). 19 F NMR(376MHz, CDCl3)δ-56.48,-89.01,-89.64,-111.37,-112.00.

[0402] In the second step, the reactant (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-{2-[(trifluoromethyl)oxy]phenyl}hexyl acetate 97-1 (190 mg, 0.28 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 mL), and dilute hydrochloric acid (1.5 mL, 3 mol / L) was added, and the reaction system was stirred at room temperature for 1 h. The reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 5:1). The reaction was stopped after the starting material was consumed. Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The ethyl acetate layers were combined and washed with saturated brine (3 × 10 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 70:30) to obtain (5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-6,7-dihydroxy-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-1-{2-[(trifluoromethyl)oxy]phenyl}hexyl acetate 97-2 as a white solid (180 mg, 99% purity, 90% yield). 1H NMR(400MHz, CDCl3)δ7.43(d,J=7.3Hz,1H),7.34–7.27(m,2H),7.26–7.22(m,1H),6.08 –5.98(m,1H),3.74(s,1H),3.60(dd,J=7.1,4.0Hz,1H),2.08(s,3H),2.05(s,2H),1.96 (d,J=12.8Hz,1H),1.89–1.55(m,13H),1.49–1.29(m,9H),1.16–1.08(m,2H),1.05(s,4 H),0.95(ddd,J=12.4,11.2,2.5Hz,3H),0.87(dd,J=6.3,4.5Hz,3H),0.67–0.61(m,3H).

[0403] In the third step, (5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-6,7-dihydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1-{2-[(trifluoromethyl)oxy]phenyl}hexyl acetate 97-2 (180 mg, 0.28 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), and the reaction system was placed in an ice-water bath. Acetic anhydride (0.04 mL, 0.34 mmol, 1.2 eq), 4-dimethylaminopyridine (6.97 mg, 0.06 mmol, 0.2 eq) and triethylamine (0.12 mL, 1 mmol, 3.0 eq) were added to the reaction system in sequence, and the reaction system was stirred at room temperature for 1 hour. After the reaction was complete as monitored by TLC (petroleum ether:ethyl acetate = 10:1), the reaction solution was washed with water (10 mL × 2), and the aqueous phase was washed with dichloromethane (10 mL × 2). The organic phase was collected and removed in vacuo to obtain the crude product. The crude product was separated and purified by flash chromatography (petroleum ether:ethyl acetate = 80:20) to obtain (5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-7-acetoxy-4,4-difluoro-6-hydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-1-{2-[(trifluoromethyl)oxy]phenyl}hexyl acetate 97-3 as a white solid (150 mg, 95% purity, 74% yield). 1H NMR(400MHz, CDCl3)δ7.43(d,J=7.7Hz,1H),7.34–7.27(m,2H),7.23(s,1H),6.08–6.00(m,1 H),4.05–3.98(m,2H),2.13(dd,J=15.2,5.1Hz,1H),1.96(dd,J=12.6,3.5Hz,2H),1.87–1.5 5(m,13H),1.51(s,3H),1.45–1.32(m,6H),1.30(s,3H),1.29–1.21(m,4H),1.12(dd,J=12.9 ,3.9Hz,2H),1.07(s,4H),1.04–0.90(m,4H),0.87(dd,J=6.3,4.3Hz,3H),0.69–0.63(m,3H).

[0404] Step 4: Compound (5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-7-acetoxy-4,4-difluoro-6-hydroxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1-{2-[(trifluoromethyl)oxy]phenyl}hexyl acetate 97-3 (140 mg, 0.2 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), and Dess-Martin reagent (176 g, 0.4 mmol, 2 eq) was added. The resulting mixture was stirred in the reaction mixture under N2 at 25°C for 1 h. The reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 10:1). The starting material was essentially consumed. Saturated sodium bicarbonate (10 mL) was added to the reaction system, and the organic phase was extracted with saturated sodium sulfite (3 × 10 mL). The concentrated organic phase was collected and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 92:8) to afford (5R)-5-[(1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-7-acetoxy-4,4-difluoro-9a,11a-dimethyl-6-oxoylidenehexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-1-{2-[(trifluoromethyl)oxy]phenyl}hexyl acetate 97-4 as a white solid (150 mg, 90% purity, 96% yield). 1HNMR(400MHz, CDCl3)δ7.43(d,J=7.0Hz,1H),7.33–7.27(m,2H),7.25–7.22(m,1H),6 .07–6.00(m,1H),5.18(dd,J=12.2,7.4Hz,1H),2.53(t,J=10.6Hz,1H),2.29–2.23(m, 1H),2.16(d,J=2.8Hz,3H),2.08(s,3H),2.03–1.78(m,8H),1.60(dd,J=23.4,10.1Hz, 5H),1.45–1.00(m,14H),0.88(dd,J=6.4,3.8Hz,3H),0.79(s,3H),0.66–0.60(m,3H).

[0405] Step 5: The reactant, (5R)-5-[(1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-7-acetoxy-4,4-difluoro-9a,11a-dimethyl-6-oxoylidenehexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-1-{2-[(trifluoromethyl)oxy]phenyl}hexyl acetate 97-4 (50 mg, 0.08 mmol, 1.0 eq), was dissolved in methanol (2 mL) and tetrahydrofuran (2 mL). Potassium carbonate (41 mg, 0.3 mmol, 4.0 eq) was added, and the reaction system was stirred at room temperature for 30 min. The reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 5:1). The reaction was terminated when the starting material was consumed. Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The ethyl acetate layers were combined and washed with saturated brine (3×10 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 75:25) to give a white solid, which was then separated by chiral separation (instrument: Waters Acquity UPCC; column: Daicel CHIRALPAK IC_3, 3.0*150mm, 3um; mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 60 / 40; flow rate: 1.5 ml / min; column temperature: 37 degrees) to obtain (1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-4,4-difluoro-7-hydroxy-1-[(2R)-6-hydroxy-6-{2-[(trifluoromethyl)oxy]phenyl}hexan-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6-one 97 (3.74 mg, purity 99.64%, yield 8.52%, retention time t R =1.876min). 1H NMR (400MHz, CDCl3) δ7.62–7.56(m,1H),7.35–7.28(m,2H),7.24–7.19(m,1H),5.11–5.03(m,1H),4.15(dd,J=11.0,8.3Hz,1H),2.55–2.39( m,2H),2.17–1.82(m,7H),1.76–1.51(m,14H),1.50–1.24(m,14H),1.23–1.01(m,4H),0.91(dd,J=6.5,3.8Hz,3H),0.76(s,3H),0.66(s,3H). 19 F NMR (377MHz, CDCl3) δ-56.78,-56.79,-56.81,-90.21,-90.85,-111.50,-112.14.

[0406] Example 98

[0407] Preparation of compound 98 (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-1-[(2R)-6-(4,6-difluoro-2-methoxyphenyl)-6-hydroxyhexan-2-yl]-4,4-difluoro-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol.

[0408] Step 1: Dissolve the raw material 2-bromo-1,5-difluoro-3-methoxybenzene (123 mg, 0.5 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL). Cool the system to -78°C, add n-butyl lithium (0.18 mL, 0.45 mmol, 3.0 eq), and maintain the temperature with stirring for 30 minutes. 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]hexanal I (70 mg, 0.15 mmol, 1.0 eq) was dissolved in tetrahydrofuran (2 mL) and added to the reaction mixture. The reaction system was stirred at -78°C for 30 min. The reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 5:1). 10 mL of water was added to the reaction system, and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated sodium chloride (10 mL), and the combined organic phases were dried and concentrated to obtain a colorless oily product (5R)-5-v[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a- The crude product of 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-(4,6-difluoro-2-methoxyphenyl)hexan-1-ol 98-1 (70 mg) was directly used in the next step.

[0409] Step 2: The reactant (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]-1-(4,6-difluoro-2-methoxyphenyl)hexan-1-ol (70 mg, 0.11 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL), and dilute hydrochloric acid (1 mL, 3 mol / L) was added. The reaction system was stirred at room temperature for 1 h. The reaction was complete as monitored by TLC (petroleum ether:ethyl acetate = 5:1). Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The ethyl acetate layers were combined and washed with saturated brine (3 × 10 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 65:35) to give a white solid, which was then separated by chiral separation (instrument: Waters Acquity UPCC; chromatographic column: Daicel CHIRALPAK IC_3, 3.0*150 mm, 3 um; mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 60 / 40; flow rate: 1.5 ml / min; column temperature: 37 degrees) to give (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-1-[(2R)-6-(4,6-difluoro-2-methoxyphenyl)-6-hydroxyhexan-2-yl]-4,4-difluoro-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 98 (21.58 mg, purity 100%). Yield 32.99%, retention time t R =1.486min).

[0410] Compound 98: 1H NMR(400MHz, CDCl3)δ6.44(dd,J=9.6,8.0Hz,2H),4.98–4.92(m,1H),3.82(d,J=33.4Hz,3 H),3.74(s,1H),3.60(dt,J=11.3,4.1Hz,1H),2.30–2.11(m,2H),1.97(d,J=12.6Hz,2H), 1.83–1.77(m,3H),1.69(ddd,J=20.3,13.9,9.8Hz,5H),1.46–1.24(m,10H),1.11(dd,J=1 2.7, 4.3Hz, 2H), 1.06 (s, 4H), 1.02–0.91 (m, 2H), 0.90–0.85 (m, 3H), 0.65 (d, J = 3.7Hz, 3H). 19 F NMR (377MHz, CDCl3) δ-88.63,-89.25,-110.39,-110.41,-110.43,-110.62,-111.25,-113.84,-113.86,-113.91,-113.93,-114.31,-114.38.

[0411] Example 99

[0412] Preparation of compound 99(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-(1,3-oxazacyclopentan-2-yl)hexan-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol.

[0413] Step 1: Dissolve the raw material 1,3-oxazacyclopentane (51.8 mg, 0.75 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL), cool the system to -78°C, add n-butyl lithium (0.25 mL, 0.64 mmol, 3.0 eq), and maintain the temperature and stir for 30 minutes. 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]hexanal I (100 mg, 0.21 mmol, 1.0 eq) was dissolved in tetrahydrofuran (2 mL) and added to the reaction mixture. The reaction system was stirred at -78°C for 30 min. The reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 5:1). 10 mL of water was added to the reaction system, and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated sodium chloride (10 mL), and the combined organic phases were dried and concentrated to obtain a colorless oily (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetrafluoroethylene]-1,4-difluoro-2,4-difluoro-3,5-difluoro-4,5-difluoro-3 ... The crude product of methyl-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-(1,3-oxazacyclopentan-2-yl)hexan-1-ol 99-1 (70 mg) was directly used for the next step.

[0414] Step 2: (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-3a H-Cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxolan-8-yl]-1-(1,3-oxazacyclopentan-2-yl)hexan-1-ol 99-1 (70 mg, 0.1 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL). Dilute hydrochloric acid (1 mL, 3 mol / L) was added, and the reaction system was stirred at room temperature for 1 h. TLC (petroleum ether:ethyl acetate = 5:1) monitored the reaction completion. Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The ethyl acetate layers were combined and washed with saturated brine (3 × 10 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 65:35) to obtain a white solid, which was then separated by chiral separation (instrument: Waters Acquity UPCC; column: Daicel CHIRALPAK IC_3, 3.0*150mm, 3um; mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 60 / 40; flow rate: 1.5 ml / min; column temperature: 37 degrees) to obtain (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-(1,3-oxazacyclopentan-2-yl)hexan-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 99 (8.64 mg, purity 94.39%, yield 22.04%, retention time t R =1.684min). 1H NMR (400MHz, DMSO) δ8.25 (s, 1H), 7.85 (d, J = 2.6Hz, 1H), 5.11 (dd, J = 5.2, 1.2Hz, 1H), 4. 46(s,1H),4.40(d,J=6.0Hz,1H),4.24(d,J=3.4Hz,1H),3.49(d,J=2.2Hz,1H),3.36(s,1 H),2.19–1.86(m,3H),1.65(ddd,J=31.6,22.1,14.8Hz,9H),1.43(d,J=9.8Hz,3H),1.3 5–1.22(m,8H),1.05(t,J=10.9Hz,3H),0.98(s,3H),0.87(d,J=5.8Hz,3H),0.62(s,3H). 19 F NMR(377MHz,DMSO)δ-86.66,-87.28,-108.65,-109.27.LC-MS:[M+1] + =496.3.

[0415] Examples 100 & 101

[0416] Compound 100 (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R)-6-(4-fluorophenyl)-6-hydroxyhexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol and

[0417] Preparation of compound 101 (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-1-[(2R)-6-(4-fluorophenyl)-6-hydroxyhexan-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.

[0418] Step 1: Dissolve the raw material 4-bromo-1-fluorobenzene (65.7 mg, 0.35 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL). Cool the system to -78°C, add n-butyl lithium (0.128 mL, 0.3 mmol, 3.0 eq), and stir at this temperature for 30 min. 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]hexanal I and (5R)-5-[(3aS,5aR,5bS,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 were synthesized. A mixture of (R,7aR,8R,10aR,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 (50 mg, 0.1 mmol, 1.0 eq) was dissolved in tetrahydrofuran (2 mL) and added to the above reaction solution. The reaction system was stirred at -78°C for 30 min. The reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 5:1, phosphomolybdic acid hotplate), indicating complete consumption of the starting material. 10 mL of water was added to the reaction system, and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated sodium chloride (10 mL), dried, and concentrated to give a colorless oily product (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]] The crude products (70 mg) of [1,3]dioxolan-8-yl]-1-(4-fluorophenyl)hexan-1-ol 100-1 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]-1-(4-fluorophenyl)hexan-1-ol 101-1 were directly used in the next step.

[0419] Step 2: reacting the reactants (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]-1-(4-fluorophenyl)hexan-1-ol 100-1 and (5R)-5-[(3aS,5aR,5bR, The crude product (70 mg, 0.09 mmol, 1.0 eq) of (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]-1-(4-fluorophenyl)hexan-1-ol 101-1 was dissolved in tetrahydrofuran (3 mL). Dilute hydrochloric acid (1.5 mL, 3 mol / L) was added, and the reaction system was stirred at room temperature for 1 h. The reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 5:1). The reaction was stopped when the starting material was consumed. Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3×10 mL). The ethyl acetate layers were combined and washed with saturated brine (3×10 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 65:35) to obtain a white solid, which was then separated by chiral separation SFC (instrument: Waters Acquity UPCC; chromatographic column: Daicel CHIRALPAK IC_3, 3.0*150mm, 3um; mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 65 / 35; flow rate: 2.0 ml / min; column temperature: 37 degrees) to obtain (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R)-6-(4-fluorophenyl)-6-hydroxyhexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 100 (19.06 mg, purity 99.68%, yield 40.91%, retention time t R=1.154min) and (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-1-[(2R)-6-(4-fluorophenyl)-6-hydroxyhexan-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 101 (1.72 mg, purity 100%, yield 3.85%, retention time t R =1.718min).

[0420] Compound 100: 1 H NMR (400MHz, CDCl3) δ7.31 (dd, J=8.6, 5.5Hz, 2H), 7.03 (t, J=8.7Hz, 2H), 4.65 (dd, J=12. 6,5.7Hz,1H),3.74(s,1H),3.60(dt,J=11.4,4.3Hz,1H),2.32–2.14(m,1H),1.96(d,J=1 2.9Hz,1H),1.89–1.77(m,5H),1.76–1.58(m,10H),1.46–1.36(m,5H),1.14–1.07(m,2H) ,1.06(s,3H),0.98(dd,J=16.9,5.9Hz,2H),0.88(t,J=6.3Hz,3H),0.65(d,J=2.2Hz,3H). 19 F NMR (377MHz, CDCl3) δ-88.64,-89.27,-110.63,-111.26,-115.21,-115.27.

[0421] Compound 101: 1 H NMR (400MHz, CDCl3) δ7.31(s,2H),7.03(s,2H),4.66(dd,J=12.7,5.7Hz,1H),3.85(s,1H),3.62–3.56(m,1H),2.66(t,J=12.5Hz,1H),2.05–1.97(m ,2H),1.84(s,12H),1.45(dd,J=12.4,3.8Hz,7H),1.33–1.24(m,10H),1.0 7(d,J=8.8Hz,3H),1.04(s,3H),0.91–0.87(m,3H),0.62(d,J=2.3Hz,3H). 19 F NMR (377MHz, CDCl3) δ-109.78,-115.21,-115.28.

[0422] Example 102

[0423] Preparation of compound 102 (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-1-[(2R)-6-(2,4-difluorophenyl)-6-hydroxyhexan-2-yl]-4,4-difluoro-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol.

[0424] Step 1: Dissolve the raw material 1-bromo-2,4-difluorobenzene (101 mg, 0.5 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL). Cool the system to -78°C, add n-butyl lithium (0.18 mL, 0.45 mmol, 3.0 eq), and stir at this temperature for 30 min. 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]hexanal I (70 mg, 0.15 mmol, 1.0 eq) was dissolved in tetrahydrofuran (2 mL) and added to the reaction mixture. The reaction system was stirred at -78°C for 30 min. The reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 5:1). 10 mL of water was added to the reaction system, and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated sodium chloride (10 mL), and the combined organic phases were dried and concentrated to obtain a colorless oily product (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7 The crude product of a-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-(2,4-difluorophenyl)hexan-1-ol 102-1 (70 mg) was directly used for the next step.

[0425] Step 2: The reactant (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]-1-(2,4-difluorophenyl)hexan-1-ol 102-1 (70 mg, 0.12 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL), and dilute hydrochloric acid (1 mL, 3 mol / L) was added. The reaction system was stirred at room temperature for 1 h. The reaction was complete as monitored by TLC (petroleum ether: ethyl acetate = 5:1). Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3×10 mL). The ethyl acetate layers were combined and washed with saturated brine (3×10 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 65:35) to obtain a white solid, which was then separated by chiral separation (instrument: Waters Acquity UPCC; chromatographic column: Daicel CHIRALPAK IC_3, 3.0*150mm, 3um; mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 60 / 40; flow rate: 1.5 ml / min; column temperature: 37 degrees) to obtain (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-1-[(2R)-6-(2,4-difluorophenyl)-6-hydroxyhexan-2-yl]-4,4-difluoro-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 102 (24.38 mg, purity 100%, yield 37.41%, retention time t R =1.306min).

[0426] Compound 102: 1H NMR(400MHz,,CDCl3)δ7.20(td,J=8.4,4.2Hz,1H),6.91–6.83(m,2H),5.03(t,J=7.0Hz,1H),3.74(s ,1H),3.60(dt,J=11.4,4.2Hz,1H),2.30–2.07(m,2H),1.96(d,J=12.9Hz,2H),1.82(dd,J=21.0,13. 2Hz, 5H), 1.68 (ddd, J=14.8, 7.5, 3.5Hz, 4H), 1.39 (ddd, J=36.8, 16.8, 8.5Hz, 8H), 1.11 (dd, J=13.3, 4.9Hz,3H),1.05(s,3H),0.98(dd,J=17.1,6.1Hz,2H),0.89(t,J=6.0Hz,3H),0.65(d,J=3.7Hz,3H). 19 F NMR (377MHz, CDCl3) δ-88.64,-89.27,-110.63,-111.26,-115.39,-115.46.

[0427] Examples 107 & 108

[0428] Compound 107 (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-1-[(2R)-6-(6-fluoro-2-methoxypyridin-3-yl)-6-hydroxyhexan-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

[0429] and

[0430] Preparation of compound 108 (1R, 3aS, 3bS, 5aR, 6R, 7S, 9aR, 9bS, 11aR)-4,4-difluoro-1-[(2R)-6-(6-fluoro-2-methoxypyridin-3-yl)-6-hydroxyhexan-2-yl]-9a, 11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol.

[0431] Step 1: Dissolve the raw material 3-bromo-6-fluoro-2-methoxypyridine (123.61 mg, 0.6 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL). Cool the system to -78°C, add n-butyl lithium (0.2 mL, 0.45 mmol, 3.0 eq), and maintain stirring at this temperature for 30 min. (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, A mixture of (7aR,8R,10aR,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 (80 mg, 0.17 mmol, 1.0 eq) was dissolved in tetrahydrofuran (2 mL) and added to the above reaction mixture. The reaction system was stirred at -78°C for 30 min. The reaction progress was monitored by TLC (petroleum ether:ethyl acetate = 5:1), indicating complete consumption of the starting material. 10 mL of water was added to the reaction system, and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated sodium chloride (10 mL), dried, and concentrated to obtain the crude product.The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 87:13) to give 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]dioxolan-8-yl]-1-(6-fluoro-2-methoxypyridine- A mixture of (3-yl)hexan-1-ol 108-1 and (5R)-5-((3aS, 5aR, 5bR, 7aR, 8R, 10aR, 12aR, 12bR)-11-fluoro-2,2,5a,7a-tetramethyl-3a, 5,5a, 5b, 6,7,7a, 8,9,10,10a, 12,12a, 12b-tetradecahydro-4H-cyclopentyl[7,8]phenanthren[1,2-d][1,3]dihydroxy-8-yl)-1-(6-fluoro-2-methoxypyridin-3-yl)hexan-1-ol 107-1 (60 mg, purity 95%, yield 56% based on 108-1).

[0432] Compound 108-1: 1 H NMR (400MHz, CDCl3) δ7.70 (td, J=8.0, 4.1Hz, 1H), 6.48 (dd, J=7.9, 2.6Hz, 1H), 4.82 (dd, J=13.1, 7.5Hz,1H),4.05–3.98(m,3H),3.96(s,3H),2.21–2.09(m,1H),1.96(dd,J=14.7,7.9Hz,2H),1.89 –1.55(m,17H),1.51(s,4H),1.44–1.34(m,6H),1.30(s,3H),1.29–1.24(m,5H),1.13(dd,J=13.1 ,4.2Hz,2H),1.07(s,3H),0.95(dd,J=16.5,7.6Hz,2H),0.90(dd,J=6.3,3.2Hz,4H),0.67(s,3H).

[0433] The second step: reacting the reactants (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]-1-(6-fluoro-2-methoxypyridin-3-yl)hexan-1-ol 108-1 and (5R)-5-[(3aS,5aR, A mixture of (5bR,7aR,8R,10aR,12aR,12bR)-11-fluoro-2,2,5a,7a-tetramethyl-3a,5,5a,5b,6,7,7a,8,9,10,10a,12,12a,12b-tetradecahydro-4H-cyclopentyl[7,8]phenanthren[1,2-d][1,3]dihydroxy-8-yl)-1-(6-fluoro-2-methoxypyridin-3-yl)hexan-1-ol 107-1 (60 mg, 0.11 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL), and dilute hydrochloric acid (1.5 mL, 3 mol / L) was added. The reaction system was stirred at room temperature for 1 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1) and the reaction was stopped when the starting material was consumed. Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3×10 mL). The ethyl acetate layers were combined and washed with saturated brine (3×10 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 65:35) to obtain a white solid, which was then separated by chiral separation (instrument: Waters Acquity UPCC, chromatographic column: Daicel CHIRALPAK IC_3, 3.0*150mm, 3um, mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 60 / 40, flow rate: 1.5 ml / min, column temperature: 37 degrees) to obtain (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-(6-fluoro-2-methoxypyridin-3-yl)-6-hydroxyhexan-2-yl]-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 108 (29.91 mg, purity 90.01%, yield 48.12%, SFC retention time t R=1.496 min) and (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-1-[(2R)-6-(6-fluoro-2-methoxypyridin-3-yl)-6-hydroxyhexan-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 107 (2.63 mg, purity 85.01%, yield 4.15%, SFC retention time t R =2.090min).

[0434] Compound 108: 1 H NMR (400MHz, DMSO) δ7.87(t,J=7.8Hz,1H),6.69(dd,J=7.9,2.4Hz,1H),5.16(d,J=4.9Hz,1H),4. 71(s,1H),4.41(d,J=5.9Hz,1H),4.26(d,J=3.2Hz,1H),3.84(s,3H),3.49(s,1H),3.31–3.29(m,1 H),2.13(s,1H),1.97(dd,J=47.3,14.9Hz,2H),1.73–1.54(m,6H),1.42(d,J=10.3Hz,4H),1.36–1 .22(m,9H),1.03(d,J=10.9Hz,3H),0.98(s,3H),0.94(s,1H),0.86(d,J=6.3Hz,3H),0.62(s,3H). 19 F NMR(376MHz, DMSO)δ-74.51,-74.61,-86.66,-87.28,-108.65,-109.27.LC-MS: [M+H] + = 554.35

[0435] Compound 107: 1H NMR (400MHz, DMSO) δ7.85 (t, J=7.8Hz, 1H), 6.68 (dd, J=8.0, 2.5Hz, 1H), 5.1 3(s,1H),4.70(s,1H),4.38(s,1H),4.23(s,1H),3.83(s,3H),3.58(s,1H),3 .20(s,1H),2.02–1.91(m,3H),1.80–1.54(m,10H),1.37(d,J=11.7Hz,6H),1 .13–0.96(m,6H),0.94(s,3H),0.85(d,J=6.3Hz,3H),0.56(d,J=1.9Hz,3H). 19 F NMR(376MHz,DMSO)δ-74.51,-108.66.LC-MS: [M+H-H2O] + =516.35.

[0436] Examples 110 & 111 & 112 & 113

[0437] Compound 110 or 111: (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-1-[(2R,6R)-6-(4-chloro-2-methoxyphenyl)-6-hydroxyhexan-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

[0438] Compound 111 or 110: (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-1-[(2R,6S)-6-(4-chloro-2-methoxyphenyl)-6-hydroxyhexan-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;

[0439] Compound 113 or 112: (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-1-[(2R,6R)-6-(4-chloro-2-methoxyphenyl)-6-hydroxyhexan-2-yl]-4,4-difluoro-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol;

[0440] Compound 112 or 113: Preparation of (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-1-[(2R,6S)-6-(4-chloro-2-methoxyphenyl)-6-hydroxyhexan-2-yl]-4,4-difluoro-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol.

[0441] Step 1: 2-bromo-5-chloroanisole (116.28 mg, 0.525 mmol, 3.5 eq) was dissolved in tetrahydrofuran (5 mL), the reaction system was cooled to -78 ° C, n-butyl lithium (0.180 mL, 0.450 mmol, 2.5 mol / L, 3.0 eq) was added to the reaction system, maintained at -78 ° C, stirred for 30 min, and then (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,11,1 2,12a,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-4,5,5a,5b,6 A mixture of 70 mg, 0.150 mmol, 1 eq, 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 was added. After the addition was complete, the atmosphere was replaced with nitrogen three times and stirred at -78°C for 30 minutes. After the reaction was complete as monitored by TLC (petroleum ether:ethyl acetate = 5:1), the mixture was quenched with water (10 mL), washed three times with w...

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof: in, each are independently a single bond or a double bond; R 4a H; R 4b is H or OH; 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 or halogen; 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 22 for n1, n2, n3, n4 and n5 are independently 2, 3, 4 or 5; m1, m2, m3 and m4 are independently 0, 1, 2, 3, 4 or 5; Ring A, Ring B, Ring C and Ring D are independently C6-C 10 Aryl, "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S" or C3-C6 cycloalkyl; R 1 is C1-C6 alkoxy, or NR 1a R 1b ; R 2 and R 3 are independently H or C1-C6 alkyl; R A , R B , R C and R D are independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; Ring E is C3-C6 cycloalkyl; m5 is 0, 1, 2 or 3; R E OH, NR e1 R e2 , COOH, C1-C6 alkyl, oxo (=O) or R 1a , R 1b , R e1 and R e2 are independently H or C1-C6 alkyl; A 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; A carbon atom with a "#" indicates that when it is a chiral carbon atom, it is in the R configuration, S configuration, or a mixture of the two; A carbon atom with "&" indicates that it is a chiral carbon atom, which is 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.

2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: One or more of the following conditions are met: (1)R 7a and R 7b wherein the halogen is independently F, Cl, Br or I; preferably F; (2) In ring A, ring B, ring C and ring D, the C6-C 10 Aryl is independently phenyl or naphthyl, preferably phenyl; (3) In Ring A, Ring B, Ring C and Ring D, the "5- to 10-membered heteroaryl group having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S" is independently "5- to 6-membered heteroaryl group having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S" or "9- to 10-membered heteroaryl group having 1 or 2 heteroatoms selected from the group consisting of O", and is preferably pyridyl (e.g. ), pyrazinyl (e.g. ), pyrimidine radicals (e.g. ), triazine groups (e.g. ), thiazolyl (e.g. ), oxazolyl (e.g. )or (4) In ring A, ring B, ring C and ring D, the C3-C6 cycloalkyl group is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or bicyclo[1.1.1]pentyl (e.g. ), preferably (5)R 1 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; (6)R 2 and R 3 wherein the C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; preferably methyl; (7)R A , R B , R C and R D wherein the halogen is independently F, Cl, Br or I; preferably F or Cl, such as F; (8)R A , R B , R C and R D wherein the C1-C6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (9)R A , R B , R C and R D wherein the C1-C6 haloalkyl group is independently CHF2, CH2F or CF3; (10)R A , R B , R C and R D 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; (11)R A , R B , R C and R D In the above, the C1-C6 haloalkoxy group is independently -OCHF2, -OCH2F or -OCF3; preferably -OCF3; (12) In ring E, the C3-C6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or bicyclo[1.1.1]pentyl (e.g. ), preferably cyclopropyl or cyclobutyl; (13)R E wherein the C1-C6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl; and (14)R 1a , R 1b , R e1 and R e2 In the above, the C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl.

3. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: One or more of the following conditions are met: (1) n1 is 3; (2) n2 is 3; (3) n3 is 2; (4) n4 is 2; (5) n5 is 2; (6) m1 is 0, 1, 2 or 3; (7) m2 is 0, 1, 2 or 3, for example, 2; (8) m3 is 1; (9) m4 is 1; (10) m5 is 1 or 2; (11)R A are independently halogen, C1-C6 alkoxy or C1-C6 haloalkoxy; (12) Ring A is phenyl, pyridyl, (e.g. ), pyrazinyl (e.g. ), pyrimidine radicals (e.g. ), triazine groups (e.g. ), thiazolyl (e.g. ), oxazolyl (e.g. like )、 (13)R B are independently halogen, C1-C6 alkoxy or C1-C6 haloalkoxy; for example halogen or C1-C6 alkoxy; (14) Ring B is phenyl; (15)R 1 Methoxy, or NH2; (16)R 1a and R 1b independently H; (17)R C and R D are independently halogen; (18) Ring C is phenyl; (19) Ring D is phenyl; (20) Ring E is cyclopropyl or cyclobutyl; (21)R e1 and R e2 are independently C1-C6 alkyl (e.g. methyl); (22) Carbon atoms marked with "*" indicate that when they are chiral carbon atoms, they are in S configuration; and (23) A carbon atom with a "#" indicates that it is in the R configuration when it is a chiral carbon atom.

4. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: One or more of the following conditions are met: (1) for Among them, R 4b is H or OH, R 7a and R 7b are independently H or halogen (such as F); preferably, R 4b For OH, R 7a and R 7b are independently halogen (e.g. F); (2) for Among them, m 1A is 0, 1, 2, 3, or 4; m 1B is independently 0, 1, 2 or 3; m 1C are independently 0, 1 or 2; and (3) for Among them, m 2A Is 0, 1, 2, 3, or 4.

5. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 4, characterized in that: One or more of the following conditions are met: (1) for (2) for (3) for (4) for (5) Independently (6) for 6. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R 22 for 7. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound represented by formula I is a compound represented by formula I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9 or I-10: Wherein, 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; Ring A, Ring B, R A , R B , m1 and m2 are defined as in any one of claims 1-6.

8. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound represented by formula I is any of the following compounds:

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

10. Use of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 9 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.

11. Use of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition as described above in the preparation of a drug for inhibiting the SREBP pathway.

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