Steroidal compounds, methods of making and using the same

Abstract

The application discloses a kind of steroidal compounds, its preparation method and application.It is specifically disclosed that the steroidal compound or its pharmaceutically acceptable salt of structure as shown in formula I etc..The compound of the application has SREBP pathway inhibitory activity, and can be used for preventing and / or treating obesity, hyperlipidemia, fatty liver, diabetes, atherosclerosis, cardiovascular and cerebrovascular diseases, liver cancer, skin damage and other diseases.

Description

[0001] This application claims priority to Chinese Patent Application No. 2023109336322, filed on July 27, 2023, Chinese Patent Application No. 2024102813448, filed on March 12, 2024, and Chinese Patent Application No. 2024108908992, filed on July 3, 2024. This application incorporates the entire contents of the above-mentioned Chinese patent applications by reference. TECHNICAL FIELD

[0002] The present application relates to a steroid compound, a preparation method and application thereof. BACKGROUND

[0003] With the change of lifestyle, including high-calorie food and high-sugar beverage intake, lack of exercise and physical activity, etc., metabolic diseases represented by hyperlipidemia, obesity, type 2 diabetes and fatty liver have become a growing health problem worldwide. Among them, fatty liver has become an important cause of chronic liver disease in rich areas of Europe and China. The prevalence of simple liver lipid accumulation in the general adult population is 10% to 30%, of which 10% to 20% are fatty hepatitis, and the incidence of liver cirrhosis and liver cancer within 10 years is as high as 25%. However, as of now, the pathophysiological mechanism of fatty liver disease has not been fully elucidated, and there is still a lack of effective and specific therapeutic drugs in clinical practice. It is known that the accumulation of cholesterol, triglycerides and other lipids in the blood and liver is the main cause of hyperlipidemia, and hyperlipidemia is an important pathogenic factor for atherosclerosis, stroke and fatty liver disease. Therefore, targeting lipid metabolism regulation pathways, developing new drugs to reduce lipids, is becoming an important direction for the development of new metabolic disease drugs.

[0004] It is known that the lipid synthesis pathway of mammalian cells is an important factor in regulating the balance of lipid metabolism. The key factor regulating cholesterol and fatty acid synthesis is a class of transcription factor proteins, sterol regulatory element binding proteins (SREBP). The precursor of this class of proteins is first synthesized in the endoplasmic reticulum (ER), and the precursor is transported to the Golgi by SREBP cleavage-activating protein (SCAP), and then cleaved by two proteases (Site-1 protease (S1P) and Site-2 protease (S2P)) to release the active domain of its N terminus into the nucleus to play a transcription factor role. The SREBP protein cleavage and maturation are strictly regulated by the intracellular sterol (such as cholesterol, 25-hydroxycholesterol) level. When the cell accumulates sufficient cholesterol in the endoplasmic reticulum, cholesterol and SCAP bind and change 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 and subsequent activation of SREBP. On the contrary, the increase of active form of SREBP in the nucleus promotes the synthesis of cell lipids. In addition to cholesterol, 25-hydroxycholesterol (25-HC) is another potent endogenous inhibitor of the SREBP pathway. Unlike cholesterol binding to SCAP, 25-HC directly binds to Insig and induces SCAP and Insig binding.

[0005] 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.

[0006] For hyperlipidemia, its pathogenesis is mainly caused by factors such as increased lipid synthesis or abnormal lipid transport caused by diet or gene mutation, leading to excessive accumulation of blood cholesterol and fatty acids and other lipids. Currently, statins and fibrates are the main lipid-lowering drugs in clinical practice, and the mechanism of action of statins is to inhibit the cellular cholesterol synthesis pathway while promoting the reverse transport of blood cholesterol. This indicates that targeting key factors of the cellular lipid synthesis pathway is an important means to effectively reduce lipid levels.

[0007] So far, no approved therapeutic drug for fatty liver disease, so it is very important to identify therapeutic targets and develop new effective therapies. The pathogenesis of fatty liver disease is known to involve multiple risk factors, such as steatosis that can be triggered by accumulation of triglycerides in the form of lipid droplets, abnormal increase of cholesterol and fatty acids in cells, which can cause endoplasmic reticulum stress and mitochondrial dysfunction, leading to cell death, inflammation and fibrosis. Among them, free cholesterol accumulation is reported to be a key driver of the transition from simple steatosis to aggressive steatohepatitis. Second, a fatty liver mouse model is established, and a simple cholesterol-free high-fat diet can only induce steatosis even after a long feeding period, and the addition of 1-2% cholesterol in the diet is a necessary condition to achieve inflammation and fibrosis. Therefore, reducing cholesterol can be a new treatment strategy for fatty liver disease. Studies have shown that SREBP is abnormally activated in fatty liver patients and fatty liver mouse models; deletion or knockout of Scap in mouse liver can eliminate the activation of all SREBPs, thereby preventing the occurrence of fatty liver and hyperlipidemia. In addition, recent studies have shown that endoplasmic reticulum stress-induced SREBP abnormal activation promotes lipogenesis and fatty liver. Therefore, these evidences suggest that reducing liver triglyceride and cholesterol levels by inhibiting the SREBP pathway is an effective strategy to prevent and / or treat metabolic disorders including fatty liver. SUMMARY

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

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

[0010]

[0011] wherein,

[0012] each is independently a single bond or a double bond;

[0013] R 4a is H; R 4b is H or OH; or, R 4a and R 4b together with the carbon atom to which they are attached form

[0014] when the bond between the 7th carbon atom and the 8th carbon atom is a single bond, R 7a and R 7b are independently H or halogen; R 8a is H;

[0015] when the bond between the 7th carbon atom and the 8th carbon atom is a double bond, R 7a is absent, R7b is halogen; R 8a is absent;

[0016] R 22 is

[0017] n1, n2, n3, n4 and n5 are independently 2, 3, 4 or 5;

[0018] m1, m2, m3 and m4 are independently 0, 1, 2, 3, 4 or 5;

[0019] Ring A, Ring B, Ring C and Ring D are independently C6-C 10 is a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S, or C3-C6cycloalkyl;

[0020] R 1 is C1-C6alkoxy, or NR 1a R 1b ;

[0021] R 2 and R 3 are independently H or C1-C6alkyl;

[0022] R A , R B , R C and R D are independently halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy or C1-C6haloalkoxy;

[0023] Ring E is C3-C6cycloalkyl;

[0024] m5 is 0, 1, 2 or 3;

[0025] R E are independently OH, NR e1 R e2 , COOH, C1-C6alkyl, oxo (=0) or

[0026] R 1a , R 1b , R e1 and R e2 are independently H or C1-C6alkyl;

[0027] the carbon atom marked with “*” represents the R configuration, the S configuration or a mixture of both when being a chiral carbon atom;

[0028] The carbon atom with "#" indicates R configuration, S configuration or a mixture of both when it is a chiral carbon atom;

[0029] The carbon atom with "&" indicates R configuration, S configuration or a mixture of both when it is a chiral carbon atom;

[0030] The compound of Formula I is not the following compound:

[0031]

[0032]

[0033] and isomers thereof.

[0034] In some preferred embodiments of the present application, certain groups in the compound of Formula I or a pharmaceutically acceptable salt thereof are defined as follows, and the groups not mentioned are as described in any of the embodiments of the present application (simply "in some embodiments"), R 7a and R 7b , the halogen is independently F, Cl, Br or I; preferably F.

[0035] 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.

[0036] In some embodiments, in ring A, ring B, ring C and ring D, the "5-10 membered heteroaryl having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3" is independently "5-6 membered heteroaryl having 1 or 2 heteroatoms selected from N, O and S" or "9-10 membered heteroaryl having 1 or 2 heteroatoms selected from O", preferably pyridyl (e.g. ), pyrazinyl (e.g. ), pyrimidinyl (e.g. ), triazinyl (e.g. ), thiazolyl (e.g. ), oxazolyl (e.g. )

[0037] In some embodiments, in ring A, ring B, ring C and ring D, the C3-C6 cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or bicyclo[1.1.1]pentanyl (e.g. ), preferably

[0038] In some embodiments, R 1In this context, the C1-C6 alkoxy groups are independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, preferably methoxy.

[0039] In some implementation schemes, R 2 and R 3 In this context, the C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; preferably methyl.

[0040] In some implementation schemes, R A R B R C and R D In this context, the halogen is independently F, Cl, Br, or I; preferably F or Cl, for example, F.

[0041] In some implementation schemes, R A R B R C and R D In this context, the C1-C6 alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0042] In some implementation schemes, R A R B R C and R D In this context, the C1-C6 haloalkyl group is independently CHF2, CH2F, or CF3.

[0043] In some implementation schemes, R A R B R C and R D In this context, the C1-C6 alkoxy groups are independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, preferably methoxy or ethoxy.

[0044] In some implementation schemes, R A R B R C and R D In this context, the C1-C6 haloalkoxy groups are independently -OCHF2, -OCH2F, or -OCF3; preferably -OCF3.

[0045] 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.

[0046] In some embodiments, R E , the C1-C6alkyl is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, for example methyl.

[0047] In some embodiments, R 1a , R 1b , R e1 , and R e2 , the C1-C6alkyl is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, for example methyl.

[0048] In some embodiments, n1 is 3.

[0049] In some embodiments, n2 is 3.

[0050] In some embodiments, n3 is 2.

[0051] In some embodiments, n4 is 2.

[0052] In some embodiments, n5 is 2.

[0053] In some embodiments, m1 is 0, 1, 2, or 3.

[0054] In some embodiments, m2 is 0, 1, 2, or 3, for example 2.

[0055] In some embodiments, m3 is 1.

[0056] In some embodiments, m4 is 1.

[0057] In some embodiments, m5 is 1 or 2.

[0058] In some embodiments, R A is independently halogen, C1-C6alkoxy, or C1-C6haloalkoxy.

[0059] In some embodiments, ring A is phenyl, pyridyl, (e.g. ), pyrazinyl (e.g. ), pyrimidinyl (e.g. ), triazinyl (e.g. ), thiazolyl (e.g. ), oxazolyl (e.g. ),

[0060] In some embodiments, R B is independently halogen, C1-C6alkoxy, or C1-C6haloalkoxy; for example halogen or C1-C6alkoxy.

[0061] In some embodiments, ring B is phenyl.

[0062] In some embodiments, R 1 is methoxy, or NH2.

[0063] In some embodiments, R C and R D are independently halogen.

[0064] In some embodiments, ring C is phenyl.

[0065] In some embodiments, ring D is phenyl.

[0066] In some embodiments, ring E is cyclopropyl or cyclobutyl.

[0067] In some embodiments, R 1a and R 1b are independently H.

[0068] In some embodiments, R e1 and R e2 are independently C1-C6 alkyl (e.g., methyl).

[0069] In some embodiments, the carbon atom with an “*” denotes an S configuration when a chiral carbon atom.

[0070] In some embodiments, the carbon atom with an “#” denotes an R configuration when a chiral carbon atom.

[0071] In some embodiments, wherein R 4b is H or OH, R 7a and R 7b are independently H or halogen (e.g., F); preferably, R 4b is OH, R 7a and R 7b are independently halogen (e.g., F).

[0072] In some embodiments,

[0073] In some embodiments,

[0074] In some embodiments, wherein m 1A is 0, 1, 2, 3, or 4; m1B independently 0, 1, 2, or 3; m 1C independently 0, 1, or 2.

[0075] In some embodiments, wherein m 2A is 0, 1, 2, 3, or 4.

[0076] In some embodiments,

[0077]

[0078] In some embodiments,

[0079] In some embodiments, independently

[0080] In some embodiments,

[0081] In some embodiments, R 22 is

[0082]

[0083]

[0084] In some embodiments, the compound of Formula I is any one of the following compounds:

[0085]

[0086]

[0087] wherein the carbon atom with “&” represents R configuration, S configuration, or a mixture of the two when it is a chiral carbon atom;

[0088] Ring A, Ring B, R A , R B , m1, and m2 are defined as in any of the aspects of the application.

[0089] In some embodiments, the compound of Formula I is any one of the following compounds:

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110] The present application also provides a pharmaceutical composition comprising a compound according to any one of the present application or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical adjuvant.

[0111] The present application also provides use of a compound according to any one of the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to any one of the present application 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.

[0112] The present application also provides use of a compound of any one of the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described above in the manufacture of a medicament for inhibiting SREBP pathway.

[0113] The present application also provides a method for inhibiting SREBP pathway, which comprises administering to a subject an effective amount of a compound as described above or a pharmaceutically acceptable salt thereof.

[0114] The present application also provides a method for preventing and / or treating a disease, which comprises administering to a subject an effective amount of a compound of any one of the present application or a pharmaceutically acceptable salt thereof, wherein the disease is obesity, hyperlipidemia, fatty liver, diabetes, atherosclerosis, cardiovascular and cerebrovascular diseases, liver cancer or skin damage.

[0115] Definitions and Descriptions

[0116] Unless otherwise indicated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be construed as undefined or unclear unless specifically defined. When a trade name appears herein, it is intended to refer to the corresponding product or active ingredient thereof.

[0117] In the present text, the term "substituted" or "substituent" means that a hydrogen atom in a group is replaced by a designated group. When the position of substitution is not specified, substitution can occur at any position, but only to the extent that a stable or chemically feasible compound results. Illustrations are as follows: The structure indicates that a hydrogen atom on ring A is replaced by m1 R A substituted, when there are multiple R A , each R A is the same or different.

[0118] When any variable (e.g., R A ) occurs more than one time in a compound or substituent, its definition on each occurrence is independent of its definition at every other occurrence.

[0119] In the present text, the term "alkyl" means a saturated straight-chain or branched-chain monovalent hydrocarbon radical. C1-C6 alkyl means an alkyl group having 1 to 6 carbon atoms. In some embodiments, C1-C6 alkyl can be C1-C4 alkyl. C1-C4 alkyl includes methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl.

[0120] In the present text, the term "haloalkyl" means a group in which one or more of the hydrogen atoms in an alkyl group, as previously defined, is replaced by a halogen. Examples of haloalkyl groups include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, and the like.

[0121] In the present text, the term "alkoxy" refers to -O-alkyl, wherein alkyl is defined as before. C1-C4alkoxy refers to -O-(C1-C4alkyl), wherein C1-C4alkyl is defined as before, i.e. C1-C4alkoxy can in particular be methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy or t-butoxy.

[0122] In the present text, the term "cycloalkyl" refers to saturated monocyclic or polycyclic (e.g. fused, spiro or bridged) cyclic hydrocarbon groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C3-C6cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are defined as before. C3-C6cycloalkyl can in particular be cyclopropyl, cyclobutyl or cyclopentyl. 3-6 Cycloalkyl can in particular be C3, C4, C5, C6cycloalkyl. In some embodiments, cycloalkyl is monocyclic. In some embodiments, cycloalkyl is polycyclic (e.g. fused, spiro or bridged).

[0123] In the present text, the term "C 6-10 Aryl refers to phenyl or naphthyl.

[0124] In the present text, the term "heteroaryl" refers to aromatic monocyclic or fused ring groups formed from carbon atoms and at least one heteroatom, wherein the heteroatom is independently selected from 1, 2 or 3 of N, O and S. 5-10 membered heteroaryl can in particular be 5, 6, 7, 8, 9 or 10 membered heteroaryl, e.g. 5-6 membered heteroaryl or 8-10 membered fused heteroaryl. 5-6 membered heteroaryl is monocyclic, specific examples include, but are not limited to, pyrrole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, pyridine, pyrimidine, pyrazine. Examples of 8-10 membered fused heteroaryl include, but are not limited to, benzopyrrole, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzoisothiazole, benzopyrazole, benzoimidazole, benzopyridine, benzopyrimidine, benzopyrazine, thiazolothiazole, pyridopyridine, pyridopyrazine, pyridopyrimidine,

[0125] In the present text, the chemical formulae indicate the position of attachment. When contained in a cyclic group and no ring atom to which it is attached is indicated, it can be attached to any ring atom, but only to those which form a stable or chemically feasible compound.

[0126] ​In this document, the term "pharmaceutically acceptable salt" refers to a salt formed from a suitable nontoxic organic acid, inorganic acid, organic base, or inorganic base with a compound, which retains the biological activity of the compound. The organic acid can be any of the conventionally salt-forming organic acids in the art. The inorganic acid can be any of the conventionally salt-forming inorganic acids in the art. The organic base can be any of the conventionally salt-forming organic bases in the art. The inorganic base can be any of the conventionally salt-forming inorganic bases in the art.

[0127] In chemical structures, wedge-shaped solid lines are used. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key Represents the relative configuration of the solid center. (Key "") "No configuration is specified, meaning that if configurational isomerism exists in the chemical structure, the bond..." "can be " "or" , or both contain " "and" "Two configurations (e.g., " "and" The ratio is 1:1. When the carbon-carbon double bond does not specify its specific configuration, it can be either E or Z configuration. 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 chiral columns.

[0128] In this document, the term "subject" includes any animal, preferably a mammal, and more preferably a human.

[0129] In this document, the term "effective amount" refers to a sufficient amount of a drug or pharmaceutical agent that is non-toxic but achieves the desired effect. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. The appropriate effective amount in a case can be determined by a person skilled in the art based on routine testing.

[0130] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0131] The reagents and raw materials used in this invention are all commercially available.

[0132] The positive and progressive effects of this invention are as follows: This 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 Implementation

[0133] The application is further illustrated by the following examples without thereby limiting the application to the examples described. The experimental procedures in the following examples, where no specific conditions are indicated, were carried out according to standard methods and conditions, or as selected according to the manufacturer's instructions.

[0134] Preparation of key intermediates

[0135] Examples I & II

[0136] 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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]hexanal I

[0137] 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[l',2':7,8]phenanthro[l,2-d][l,3]dioxol-8-yl]hexanal II

[0138]

[0139]

[0140] Step 1: (22E,24S)-Stigmasta-6(5),22(23)-dien-3β-ol I-1 (5.00 g, 12.11 mmol, 1.0 eq) was dissolved in dichloromethane (50 mL), the reaction system was placed in an ice water bath, cooled to about 5°C, and 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) were added to the reaction system in turn, and the reaction system was stirred at room temperature for 2 hours. After the reaction was completed by TLC (petroleum ether: ethyl acetate = 10:1), it was quenched with methanol (20 mL), and the reaction liquid was washed with saturated sodium bicarbonate (~ 50 mL) and water (~ 50 mL) once, dried over anhydrous sodium sulfate, concentrated, and when the concentrated liquid was about to dry, methanol (~ 20 mL) was added, stirred in an ice bath for 30 minutes, filtered, and the filter cake was washed with a small amount of methanol. The filter cake was dried to obtain 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]phenanthren-7-yl ester I-2 (5.30 g, purity 90.0%, yield 86.58%). 1 H NMR (400 MHz, CDCl3) δ 5.37 (d, J = 4.8 Hz, 1H), 5.09 (ddd, J = 56.1, 15.2, 8.6 Hz, 2H), 4.61 (ddd, J = 15.9, 9.0, 4.2 Hz, 1H), 2.32 (d, J = 7.3 Hz, 2H), 2.03 (s, 3H), 2.01 - 1.92 (m, 2H), 1.87 (dd, J = 8.9, 6.6 Hz, 2H), 1.73 - 1.40 (m, 12H), 1.30 - 1.07 (m, 6H), 1.02 (t, J = 3.3 Hz, 6H), 0.87 - 0.79 (m, 9H), 0.70 (s, 3H).

[0141] Step 2: (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,4,6,7,8,09,9a,9b,10,11,11a-tetradecahydro-1H- cyclopenta[1,2-i]phenanthren-7-yl acetate I-2 (10.0 g, 22 mmol, 1 eq) was dissolved in tetrahydrofuran (200 mL) and water (20.0 mL), pyridine (4.5 mL, 55 mmol, 2.5 eq), N-methylmorpholine oxide (10.30 g, 88 mmol, 4 eq), potassium osmate (0.81 g, 2.2 mmol, 0.1 eq) were added at room temperature, stirred at room temperature overnight, TLC (petroleum ether: ethyl acetate = 3:1) monitoring, there was some starting material left, and an intermediate (ortho-diol generated), then sodium periodate (18.80 g, 88 mmol, 4 eq) was added to the reaction solution at 0 °C, stirred at room temperature for 1 h, TLC (petroleum ether: ethyl acetate = 3:1) detection, there was some starting material left, and the intermediate was converted to the product. Then 50 mL of water was added, and 50 mL of ethyl acetate was extracted three times, dried, concentrated, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 60:1) to give (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]phenanthren- 7-yl acetate I-3 (3.3 g, 60% purity, 19.8% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 9.50 (d, J = 3.3 Hz, 1H), 5.31 (d, J = 5.1 Hz, 1H), 4.54 (dd, J = 6.4, 4.2 Hz, 1H), 2.34 - 2.23 (m, 3H), 1.96 (s, 3H), 1.89 (dt, J = 6.6, 3.6 Hz, 2H), 1.83 - 1.72 (m, 3H), 1.66 - 1.09 (m, 14H), 1.06 (d, J = 6.8 Hz, 3H), 0.96 (s, 3H), 0.66 (s, 3H).

[0142] Third step: (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 an ice-acetone bath, sodium bis(trimethylsilyl)amide (80.526 mL, 1 mol / L, 2.5 eq) was added, after stirring for 30 minutes in an ice-acetone bath, (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]phenanthren-7-yl acetate I-3 (12.0 g, 13.4 mmol, 1.0 eq) dissolved in anhydrous tetrahydrofuran (50 mL) was added to the reaction solution, the system was allowed to return to room temperature and stirred for 30 minutes. TLC (petroleum ether: ethyl acetate = 10:1) was used to monitor the completion of the reaction. 100 mL of saturated sodium bicarbonate solution was slowly added to the reaction system, extracted with ethyl acetate (100 mL x 3), the organic phase was collected and washed with water (100 mL x 2), saturated brine, dried over anhydrous sodium sulfate, and concentrated to give yellow solid (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]phenanthren-7-yl acetate I-4 (8 g, purity 90.0%, yield 65.0%), which was directly used in the next step.

[0143] Step 4: Acetic acid-(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]phenanthren-7-yl ester I-4 (8 g, 1.0 eq) was dissolved in tetrahydrofuran (100 mL), dilute hydrochloric acid (5 mol / L, 50 mL) was added slowly, the reaction mixture was stirred at room temperature for 30 minutes. TLC (petroleum ether: ethyl acetate = 10:1) was used to monitor the reaction. After the reaction was completed, 80 mL of water was added to the reaction, the reaction liquid was extracted with ethyl acetate (50 mL x 3), washed with saturated brine (20 mL x 3), dried with anhydrous sulfuric acid, and the organic phase was 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 white solid acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-1- formylprop-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester I-5 (6.3 g, purity 90%, yield 48.63%). 1 H NMR (400 MHz, CDCl3) δ 9.76 (dd, J = 3.3, 1.3 Hz, 1H), 5.37 (d, J = 4.9 Hz, 1H), 4.65 - 4.55 (m, 1H), 2.46 (dd, J = 15.6, 2.8 Hz, 1H), 2.32 (d, J = 7.0 Hz, 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, 7.1 Hz, 6H), 1.03 (dd, J = 7.5, 3.5 Hz, 6H), 0.73 (d, J = 5.3 Hz, 3H).

[0144] Step 5: (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]phenanthren-7- yl Acetate I-5 (10.00 g, 25.87 mmol, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (150 mL), (triphenyl-λ5-phosphoranylidene)acetic acid methyl ester (51.89 g, 155.21 mmol, 6.0 eq) was added, and the reaction system was stirred at 90 °C for 18 h. The reaction was monitored by NMR until the starting material was consumed. 100 mL of water was added to the reaction system, extracted with ethyl acetate (100 mL x 3), the organic phase was collected and washed with water (100 mL x 2), saturated brine, dried over anhydrous sodium sulfate, and the organic phase was 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 white solid (2E,5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-Acetyloxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthren-1-yl]hex-2-enoic acid methyl ester I-6 (9.0 g, purity 90%, yield 71.1%). 1 H NMR (400 MHz, CDC13) δ 6.95 (ddd, J = 15.4, 8.7, 6.4 Hz, 1H), 6.26 (d, J = 11.6 Hz, 1H), 5.82 (d, J = 15.5 Hz, 1H), 5.37 (d, J = 4.9 Hz, 1H), 4.60 (tdd, J = 10.9, 6.6, 4.2 Hz, 1H), 3.72 (d, J = 10.2 Hz, 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 = 6.7 Hz, 3H), 0.72 - 0.68 (m, 3H).

[0145] Step 6: The reactant (2E,5R)-methyl 5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetyloxy- 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 mixed solvent of tetrahydrofuran (100 mL) and methanol (50 mL), nickel chloride (2.93 g, 22.59 mmol, 1.0 eq) was added, and sodium borohydride (1.28 g, 33.89 mmol) was slowly added. The reaction system was stirred at room temperature for 1 h. NMR monitoring showed that the raw material was consumed. 100 mL of water was added to the reaction system, extracted with ethyl acetate (100 mL x 3), the organic phase was collected and washed with water (100 mL x 2), saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 60:1 to 30:1) to obtain white solid methyl (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetyloxy-9a,11a-dimethyl- 2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1- yl]hexanoate I-7 (9 g, purity 90%, yield 80.6%). 1 H NMR (400 MHz, CDCl3) δ 5.37 (d, J = 4.9 Hz, 1H), 4.66 - 4.54 (m, 1H), 3.67 (s, 3H), 2.29 (ddd, J = 15.9, 11.9, 6.6 Hz, 4H), 2.03 (s, 3H), 2.02 - 1.93 (m, 2H), 1.82 (ddd, J = 13.0, 10.8, 8.3 Hz, 3H), 1.62 - 1.38 (m, 11H), 1.19 (dddd, J = 32.6, 25.0, 13.7, 6.9 Hz, 9H), 1.01 (d, J = 5.8 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H), 0.87 (tdd, J = 10.2, 4.8, 2.0 Hz, 4H), 0.67 (s, 3H).

[0146] Seventh step: (5R)-methyl 5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetyloxy- 9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H- cyclopenta[1,2-a]phenanthren-1-yl]hexanoate I-7 (2.5 g, 5.62 mmol) was dissolved in chloroform (80 mL) at room temperature, 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 was completed, it was quenched with water (100 mL) and extracted with dichloromethane (80 mL x 3). The organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain (5R)-methyl 5-[(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-7-acetyloxy-6-hydroxy-9a,11a-dimethyl- 2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1- yl]hexanoate I-8 (1.4 g, purity: 90%, yield: 48.65%) as a white solid. 1 H NMR (400 MHz, 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).

[0147] Eighth step: The reactant (5R)-methyl 5-[(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-7-acetyloxy-6-hydroxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoate I-8 (5 g, 11.5 mmol, 1.0 eq) was dissolved in methanol (150 mL), potassium carbonate (6.37 g, 46 mmol, 4.0 eq) was added, the reaction system was stirred at room temperature for 30 min. TLC (petroleum ether: ethyl acetate = 5:1) was used to monitor the reaction. When the starting material was consumed, the reaction was stopped. Water (100 mL) was added to the reaction system, the aqueous layer was extracted with ethyl acetate (3 x 50 mL). The ethyl acetate layers were combined and washed with saturated brine (3 x 50 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated to give crude (5R)-methyl 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]hexanoate I-9, which was used directly in the next step.

[0148] Ninth step: The reactant (5R)-methyl 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]hexanoate I-9 (5 g, 1 eq) was dissolved in acetone (150 mL), p-toluenesulfonic acid (1.59 g, 8.4 mmol, 0.7 eq) and 4A molecular sieves were added, and the reaction system was stirred at room temperature for 1 h. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 10:1). After the raw material was consumed, the reaction was stopped by quenching with saturated sodium sulfite. 100 mL of water was added to the reaction system, extracted with ethyl acetate (50 mL x 3), the organic phase was collected, dried with anhydrous sodium sulfate, and the organic phase was rotary evaporated under vacuum 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 (5R)-methyl 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]hexanoate I-10 (3.8 g, purity 90%, yield 62%) as a white solid.1H NMR (400 MHz, CDCl3) δ 5.80 (d, J = 2.9 Hz, 1H), 4.41 (d, J = 5.8 Hz, 1H), 4.10 (dd, J = 13.5, 6.5 Hz, 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 = 6.5 Hz, 3H), 0.69 (s, 3H).

[0149] Step 10: Compound (5R)-methyl 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]hexanoate I-10 (3.8 g, 8.2 mmol, 1.0 eq) was dissolved in acetone (50 mL), 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, and the resulting mixture was stirred at 25 °C under N2for 18 h. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 10:1). When the starting material was consumed, the reaction was quenched with saturated sodium sulfite solution, water (10 mL) was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 87:13) to give (5R)-methyl 5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-11-oxo-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]dioxol-8-yl]hexanoate I-11 (2.5 g, 95% purity, 60% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 5.85 (s, 1H), 4.45 (d, J = 6.4 Hz, 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, 2.3 Hz, 5H), 1.50 (s, 3H), 1.40 (ddd, J = 16.5, 9.3, 3.9 Hz, 4H), 1.30 (s, 3H), 1.26 (s, 4H), 1.12 - 0.97 (m, 4H), 0.87 (d, J = 6.6 Hz, 3H), 0.66 - 0.59 (m, 3H).

[0150] Step 11: Compound (5R)-5-[(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-7-acetyloxy-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), then palladium on carbon (1.2 g, 11 mmol, 2.2 eq) was added and the reaction system was replaced with hydrogen atmosphere, the reaction system was stirred at room temperature for 1 h. TLC (petroleum ether: ethyl acetate = 5:1) was used to monitor the reaction, and the starting material was consumed. The reaction system was filtered, the organic phase was collected and concentrated to give a 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- oxo-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecahydro-3aH- cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]hexanoic acid methyl ester I-12 (1.7 g, purity 95%, yield 67%) as a white solid.1H NMR (400 MHz, CDCl3) δ 4.00-3.87 (m, 2H), 3.60 (s, 3H), 2.75-2.66 (m, 1H), 2.36 (t, J = 11.3 Hz, 1H), 2.25-2.09 (m, 4H), 1.85 (dddd, J = 28.9, 13.2, 6.5, 3.1 Hz, 3H), 1.62 (dddd, J = 20.4, 14.3, 6.7, 3.3 Hz, 4H), 1.46 (s, 3H), 1.43-1.26 (m, 5H), 1.23 (s, 6H), 0.98 (ddt, J = 14.4, 11.7, 7.4 Hz, 5H), 0.86 (d, J = 6.6 Hz, 3H), 0.59 (s, 3H).

[0151] In step 12, compound (5R)-methyl 5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)- 2,2,5a,7a-tetramethyl-11-oxysulfonyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]hexanoate I-12 (1.7 g, 3.6 mmol) was dissolved in diethylamine trifluoride (10 mL), and the resulting mixture was stirred at 80 °C for 1 h. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 10:1). The reaction was cooled to room temperature, diluted with dichloromethane (50 mL), and quenched by careful addition of ice water. The organic phase was collected, and the aqueous layer was extracted with dichloromethane (3 x 30 mL). The combined organic phases were washed with saturated brine (40 mL), filtered, and concentrated to give a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 93:7) to give a mixture of (5R)-methyl 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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]hexanoate I-13 and (5R)-methyl 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[l',2':7,8]phenanthro[l,2- d][l,3]dioxol-8-yl]hexanoate II-1 (1.4 g, 95% purity of I-13, yield: 74% calculated as I-13).

[0152] Compound I-3: 1 H NMR (400 MHz, CDC13) δ 4.02 (d, J = 15.0 Hz, 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, 7.0 Hz, 1H), 1.07 (s, 1H), 0.93 (d, J = 6.3 Hz, 2H), 0.68 (s, 3H).

[0153] Step 13 A mixture of 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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]hexanoic acid methyl ester I-13 and (5R)-5-[(3aS,5aR,5bR,7aR,8R,10aR,12aR,12bR)-l l-fluoro-2,2,5a,7a- tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,12,12a,12b-tetradecahydro-3aH- cyclopenta[l',2':7,8]phenanthro[l,2-d][l,3]dioxol-8-yl]hexanoic acid methyl ester II-1 (1.3 g, 2.6 mmol, 1.0 eq) was dissolved in tetrahydrofuran (50 mL), lithium aluminum hydride (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 by TLC (petroleum ether: ethyl acetate = 10: 1). The reaction was quenched with sodium sulfate decahydrate, filtered and concentrated to give white solid (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-l l,l l-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]hexan-l-ol I-14 and (5R)-5-[(3aS,5aR,5bR,7aR,8R,10aR,12aR,12bR)-l l-fluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,12,12a,12b-tetradecahydro-3aH- cyclopenta[l',2':7,8]phenanthro[l,2-d][l,3]dioxol-8-yl]hexanoic acid methyl ester II-2 crude (0.9 g, 96% purity, yield: 92% calculated for I-14), which was directly used in the next step.

[0154] Fourteenth step: A mixture of 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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]hexan-1-ol I-14 and (5R)-5-[(3aS,5aR,5bR,7aR,8R,10aR,12aR,12bR)-l l-fluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,12,12a,12b-tetradecahydro-3aH- cyclopenta[l',2':7,8]phenanthro[l,2-d][l,3]dioxol-8-yl]hexanoic acid methyl ester II-2 (1.3 g, 1.0 eq) was dissolved in dichloromethane (50 mL), Dess-Martin reagent (2.3 g, 5.5 mmol, 2 eq) was added, the resulting mixture was stirred at 25 °C under N2for 1 h. TLC (petroleum ether: ethyl acetate = 10: 1) was used to monitor the reaction completion. Saturated sodium bicarbonate (10 mL) was added to the reaction mixture, the organic phase was extracted with saturated sodium sulfite (3 x 30 mL), the concentrated organic phase was collected. Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 92: 8) gave a mixture of (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-l l,l l-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]hexanal I and (5R)-5-[(3aS,5aR,5bR,7aR,8R,10aR,12aR,12bR)-l l-fluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,12,12a,12b-tetradecahydro-3aH- cyclopenta[l',2':7,8]phenanthro[l,2-d][l,3]dioxol-8-yl]hexanal II as a white solid (0.95 g, 90% purity. Yield 66% was calculated based on compound I).

[0155] Compound I: 1H NMR (400 MHz, CDC13) δ 9.70 (t, J = 1.7 Hz, 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, 4.7 Hz, 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 = 9.1 Hz, 1H), 1.08 - 1.02 (m, 1H), 1.00 (s, 1H), 0.87 (d, J = 6.5 Hz, 2H), 0.83 - 0.77 (m, 1H), 0.60 (d, J = 12.0 Hz, 2H).

[0156] Example III

[0157] 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[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]hexanal (III)

[0158]

[0159] 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[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]hexanoic acid methyl ester I-10 (1 g, 2.18 mmol, 1.0 eq) was dissolved in tetrahydrofuran (50 mL), after nitrogen replacement, lithium aluminum hydride (0.12 g, 3.270 mmol, 1.5 eq) was added, stirred at 25 °C for 1 h. TLC plate (petroleum ether: ethyl acetate = 5: 1) was used to monitor the reaction progress, the starting material was consumed. Quenched with sodium sulfate decahydrate, filtered, the filtrate was concentrated to get the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 80:20) to get (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[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]hexan-l-ol III-1 (1000 mg, 2.09 mmol, purity: 90%, yield: 96%) as a white solid. 1 H NMR (400 MHz, CDCL 3 ) δ 5.80 (d, J = 2.6 Hz, 1H), 4.41 (d, J = 5.8 Hz, 1H), 4.09 (m, 1H), 3.64 (t, J = 6.5 Hz, 2H), 2.08 (m, 2H), 1.84 (tt, J = 18.5, 7.8 Hz, 2H), 1.67 (m, 8H), 1.41 (td, J = 12.7, 6.2 Hz, 4H), 1.35 (s, 3H), 1.24 (m, 2H), 1.17 (s, 4H), 1.08 (m, 5H), 0.93 (d, J = 6.5 Hz, 4H), 0.69 (d, J = 4.6 Hz, 3H).

[0160] 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[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]hexan-1-ol III-1 (1 g, 1.0 eq) was dissolved in dichloromethane (50 mL), Dess-Martin Oxidizing reagent (1.18 g, 2.79 mmol, 1.2 eq) was added, stirred at 25 °C for 1 h. TLC (petroleum ether: ethyl acetate = 5:1) was used to monitor the reaction progress, the starting material was consumed. Quenched with saturated sodium sulfite, water (10 mL) was added to the reaction system, the aqueous layer was extracted with dichloromethane (3 x 50 mL). The organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, concentrated to give 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[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]hexanal III (750 mg, 1.58 mmol, purity: 90%, yield: 68%) as a white solid. 1 H NMR (400 MHz, CDCL3) δ 9.76 (s, 1H), 5.80 (d, J = 2.7 Hz, 1H), 4.41 (d, J = 5.8 Hz, 1H), 4.10 (dd, J = 13.6, 6.3 Hz, 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, 4.2 Hz, 3H), 1.35 (s, 3H), 1.17 (s, 3H), 1.10 (m, 4H), 0.92 (dd, J = 18.2, 5.8 Hz, 4H), 0.71 (d, J = 12.1 Hz, 3H).

[0161] Example IV

[0162] 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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]hexanal (IV)

[0163]

[0164] First step: Compound (5R)-5-[(lR,3aS,3bS,6R,7S,9aR,9bS,l laR)-7-acetyloxy-6- hydroxy-9a,l la-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,l l,l la-tetradecahydro-lH- cyclopenta[l,2-a]phenanthren-l-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, 25 °C for 3 h. The reaction progress was monitored by TLC (petroleum ether: ethyl acetate = 3: 1), and the starting material was consumed. Filtration, the filtrate was concentrated to give the crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 80:20) to give (5R)-5-[(lR,3aS,3bS,5aR,6R,7S,9aR,9bS,l laR)-7-acetyloxy-6-hydroxy-9a,l la- dimethylhexadecahydro-lH-cyclopenta[l,2-a]phenanthren-l-yl]hexanoic acid methyl ester IV-1 (100 mg, 59.74%) as a white solid. 1 H NMR (400 MHz, CDC13) δ 4.72 (m, 1H), 3.83 (s, 1H), 3.66 (s, 3H), 2.27 (dd, J = 16.4, 8.7 Hz, 2H), 2.10 (d, J = 8.1 Hz, 3H), 1.79 (dddd, J = 37.0, 16.1, 10.1, 3.7 Hz, 8H), 1.29 (m, 8H), 0.99 (m, 14H), 0.62 (d, J = 14.3 Hz, 4H).

[0165] Second step: (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6-hydroxy-1-[(2R)-6-methoxy-6- oxohexan-2-yl]-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl acetate IV-1 (300 mg, 0.65 mol, 1.0 eq.) was dissolved in anhydrous methanol (5 mL), potassium carbonate (897 mg, 6.5 mmol) was added, then stirred at 25 °C for 16 hours, TLC (petroleum ether: ethyl acetate = 2:1) was used to monitor the reaction, after the reaction was completed. The reaction was filtered and concentrated, the obtained crude product was purified by column chromatography (petroleum ether: ethyl acetate = 0-50%) to give (5R)-methyl 5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6,7-dihydroxy-9a,11a-dimethylhexadecahydro-1H- cyclopenta[1,2-i]phenanthren-1-yl]hexanoate IV-2 (210 mg, 0.5 mmol, 76.9%) as a white solid.1H NMR (399 MHz, Chloroform-d) δ 3.71 (d, J = 3.1 Hz, 1H), 3.65 (s, 3H), 3.53 (dt, J = 11.3, 4.4 Hz, 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 = 6.5 Hz, 4H), 0.62 (s, 3H), 0.57 (td, J = 11.4, 4.2 Hz, 1H).

[0166] Third step: Methyl (5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6,7-dihydroxy- 9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoate IV-2 (250 mg, 0.59 mmol) was dissolved in acetone (20 mL), 4A molecular sieves (250 mg) were added, and p-toluenesulfonic acid (203 mg, 1.18 mmol) was added, followed by stirring at room temperature, and monitoring by TLC (petroleum ether: ethyl acetate = 2:1). After the reaction was completed, the insoluble matter was removed by filtration, and the filtrate was concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 0~30%) to obtain methyl (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b- hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]hexanoate IV-3 (220 mg, 0.48 mmol, 81.3%) as a white solid. 1 H NMR (399 MHz, Chloroform-d) δ 3.97 (dt, J = 8.8, 5.7 Hz, 2H), 3.65 (s, 3H), 2.25 (ddd, J = 10.5, 8.5, 6.7 Hz, 2H), 1.97 - 1.90 (m, 1H), 1.76 (td, J = 11.5, 6.6 Hz, 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, 5.6 Hz, 3H), 1.08 (td, J = 10.7, 9.2, 3.7 Hz, 3H), 1.02 (s, 3H), 0.98 - 0.93 (m, 1H), 0.90 (d, J = 6.4 Hz, 3H), 0.86 - 0.80 (m, 2H), 0.64 (s, 3H), 0.61 - 0.54 (m, 1H).

[0167] Fourth step: Weigh (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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]hexanoic acid methyl ester IV-3 (180 mg, 0.39 mmol) dissolved in diethyl ether (20 mL), dry ice-acetone cooling to -78 °C, then diisobutylaluminum hydride (1 M, 1.17 mL) was added dropwise, after the addition was completed, it was stirred to room temperature. TLC (petroleum ether: ethyl acetate = 3:1) was monitored. After the reaction was completed, saturated aqueous ammonium chloride solution was added to quench, extracted with ethyl acetate, the organic phase was separated, dried, 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-hexadecahydro-3aH- cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]hexan-l-ol IV-4 (120 mg, 0.28 mmol, 71.8%) white solid. 1 H NMR (399 MHz, Chloroform-d) δ 3.98 (d, J = 7.6 Hz, 2H), 3.62 (t, J = 6.6 Hz, 2H), 1.94 (d, J = 12.3 Hz, 1H), 1.76 (d, J = 10.5 Hz, 3H), 1.65 (t, J = 13.8 Hz, 3H), 1.54 (d, J = 9.8 Hz, 4H), 1.49 (s, 4H), 1.48 - 1.34 (m, 7H), 1.29 (s, 3H), 1.25 (d, J = 11.2 Hz, 6H), 1.13 - 1.05 (m, 3H), 1.02 (s, 3H), 1.00 (d, J = 6.1 Hz, 1H), 0.89 (d, J = 6.2 Hz, 4H), 0.84 (s, 1H), 0.64 (s, 3H), 0.63 - 0.54 (m, 1H).

[0168] Fifth step: Weigh (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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]hexan- 1-ol IV-4 (100 mg, 0.23 mmol) was dissolved in dichloromethane (10 mL), and Dess-Martin Oxidizer (195 mg, 0.46 mmol) was added at room temperature, and then continued to stir at room temperature, TLC (petroleum ether: ethyl acetate = 3: 1) was used to monitor the reaction. After the reaction was completed, saturated aqueous sodium bicarbonate solution was added and extracted with ethyl acetate, the organic phase was separated, dried, 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-hexadecahydro-3aH- cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]hexanal IV (53 mg, 0.12 mmol, 52.2%) as a white solid. 1 H NMR (399 MHz, Chloroform-d) δ 9.74 (t, J = 1.8 Hz, 1H), 3.97 (dt, J = 8.9, 5.7 Hz, 2H), 2.37 (tdd, J = 8.1, 6.8, 1.9 Hz, 2H), 1.94 (d, J = 12.5 Hz, 1H), 1.76 (td, J = 10.3, 5.3 Hz, 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, 3.8 Hz, 5H), 1.08 (dd, J = 11.8, 7.5 Hz, 3H), 1.02 (s, 3H), 0.91 (d, J = 6.5 Hz, 3H), 0.89 - 0.83 (m, 2H), 0.64 (s, 3H), 0.58 (d, J = 2.5 Hz, 1H).

[0169] Examples VI and V

[0170] Intermediate VI (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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenalene-8-yl]pentanal and

[0171] Preparation of Intermediate V (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[l',2':7,8]phenalene-l,2-dl[l,3]dioxol-8-yl]pentanal

[0172]

[0173]

[0174] In the first step, 6a-hydroxy-3a-hydroxy-5b-cholan-24-oic acid VI-1 (15 g, 38.2 mmol, 1.0 eq) was dissolved in MeOH (200 mL), and sulfuric acid (5 mL, 93.8 mmol, 2.5 eq) was slowly added to the reaction system, which was stirred at 75 °C for 2 hours. After monitoring the reaction completion by TLC (dichloromethane:methanol = 10:1), the reaction was cooled to room temperature, and the reaction solution was slowly added to saturated sodium bicarbonate (~ 200 mL), which was washed with saturated sodium bicarbonate solution (~ 100 mL) and water (~ 100 mL) once each, dried over anhydrous sodium sulfate, concentrated and dried to obtain crude 6a-hydroxy-3a-hydroxycholan-24-oic acid methyl ester VI-2 (15 g, yield 86.90%), which was directly used in the next step.

[0175] Second step 6a-hydroxy-3a-hydroxy-5b-cholan-24-oic acid methyl ester VI-2 (15.0 g, 36.9 mmol, 1.0 eq) was dissolved in pyridine (50 mL), p-toluenesulfonyl chloride (42.2 g, 221.3 mmol, 6 eq) was added at room temperature, stirred at room temperature overnight, TLC (petroleum ether: ethyl acetate = 5:1) was used to monitor the reaction. After the reaction was completed, the reaction liquid was poured into 5% hydrochloric acid solution (100 mL) added with crushed ice, after the solid was precipitated, suction filtration, water washing, drying to obtain the crude product 4-methylbenzenesulfonic acid-(1R,3aS,3bS,5aR,5S,7R,9aR,9bS,11aR)-1-[(2R)-5-methoxy-5-oxovanyl]-9a,11a-dimethyl-7-{[(4-methylphenyl)dioxo-λ6-sulfenyl]oxy}hexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-5-yl ester VI-3 (20 g, yield 70.20%).

[0176] Third step 4-methylbenzenesulfonic acid-(1R,3aS,3bS,5aR,5S,7R,9aR,9bS,11aR)-1-[(2R)-5-methoxy-5-oxovanyl]-9a,11a-dimethyl-7-{[(4-methylphenyl)dioxo-λ6-sulfenyl]oxy}hexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-5-yl ester VI-3 (10 g, 69.9 mmol, 1.0 eq) was dissolved in water (20 mL) and N,N-dimethylformamide (200 mL), the system was heated to 110 °C, refluxed for 4 hours. TLC (petroleum ether: ethyl acetate = 5:1) was used to monitor the reaction. After the reaction was completed, it was cooled to room temperature, and a white solid was precipitated. The reaction liquid was poured into 5% hydrochloric acid solution (500 mL) added with crushed ice, washed with water (50 mL x 2), dried to obtain the intermediate, which was then dissolved in 4% KOH methanol solution (250 mL), and the reaction mixture was stirred at room temperature for 3 hours. TLC (petroleum ether: ethyl acetate = 5:1) was used to monitor the reaction. After the reaction was completed, 5% hydrochloric acid was used to adjust the pH to neutral, the reaction liquid was extracted with ethyl acetate (100 mL x 3), washed with saturated brine (100 mL x 3), dried with anhydrous sulfuric acid, and the organic phase was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30:1 to 10:1 to 5:1) to obtain white solid 3β-hydroxycholan-5(6)-ene-24-oic acid methyl ester VI-4 (30 g, yield 75.6%).

[0177] Compound VI-4: 1H NMR (400 MHz, CDC13) δ 5.37 - 5.33 (m, 1H), 3.66 (s, 3H), 2.34 (dt, J = 13.0, 4.0 Hz, 1H), 2.30 - 2.23 (m, 2H), 2.24 - 2.18 (m, 2H), 2.05 - 1.93 (m, 3H), 1.82 (tdd, J = 10.1, 8.1, 4.9 Hz, 5H), 1.53 - 1.40 (m, 7H), 1.36 - 1.25 (m, 3H), 1.01 (s, 3H), 0.92 (t, J = 5.1 Hz, 5H), 0.68 (s, 4H).

[0178] Fourth Step The reactant 3β-hydroxycholan-5(6)-ene-24-oic acid methyl ester VI-4 (15 g, 38.5 mmol, 1.0 eq) was dissolved in chloroform (90 mL), selenium dioxide (10.5 g, 89.7 mmol, 2.5 eq), NMM (12.7 mL, 115.8 mmol, 3.0 eq) were added, the reaction system was stirred at 75 °C for 18 h. The reaction progress was detected by TLC plate (petroleum ether: ethyl acetate = 5:1), when most of the starting material was consumed, the product spot was denser than the starting material spot, the reaction was stopped. 100 mL of water was added to the reaction system, extracted with ethyl acetate (50 mL x 3), the combined organic phase was washed with water (50 mL x 2), saturated brine, dried over anhydrous sodium sulfate, and the organic phase was collected and concentrated to give the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1 to 6:1 to 3:1) to give 4β-hydroxy-3β-hydroxycholan-5(6)-ene-24-oic acid methyl ester VI-5 (10 g, purity 70%, yield 50.3%) as a white solid.

[0179] Compound VI-5: 1 H NMR (400 MHz, CDC13) δ 5.71 - 5.63 (m, 1H), 4.14 (d, J = 3.2 Hz, 1H), 3.66 (s, 3H), 3.56 (d, J = 11.5 Hz, 1H), 2.34 (dd, J = 10.2, 5.2 Hz, 1H), 2.27 - 2.17 (m, 1H), 2.07 (s, 1H), 2.00 (d, J = 12.5 Hz, 1H), 1.89 (s, 1H), 1.88 - 1.78 (m, 3H), 1.65 - 1.51 (m, 4H), 1.46 - 1.39 (m, 3H), 1.36 - 1.25 (m, 2H), 1.18 (s, 3H), 1.15 - 1.05 (m, 4H), 1.03 - 0.96 (m, 1H), 0.92 (d, J = 6.5 Hz, 4H), 0.68 (s, 3H).

[0180] Referring to Examples I & II, replacing I-9 with VI-5 gives (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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]pentanal VI and (4R)-4-[(3aS,5aR,5bR,7aR,8R,10aR,12aR,12bR)-l l-fluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,12,12a,12b-tetradecahydro-3aH- cyclopenta[l',2':7,8]phenanthro[l,2-d][l,3]dioxol-8-yl]pentanal V (2.5 g, 90% pure. Yield 56% calculated on compound VI).

[0181] Compound VI: 1 H NMR (400 MHz, CDC13) δ 9.77 (t, J = 1.9 Hz, 1H), 4.01 (dt, J = 8.4, 6.2 Hz, 2H), 2.50 - 2.30 (m, 2H), 2.18 - 2.02 (m, 1H), 1.96 (ddd, J = 8.1, 7.3, 3.0 Hz, 2H), 1.88 - 1.76 (m, 4H), 1.72 - 1.66 (m, 1H), 1.65 - 1.58 (m, 2H), 1.56 (d, J = 9.3 Hz, 2H), 1.51 (s, 3H), 1.48 - 1.41 (m, 2H), 1.39 - 1.25 (m, 7H), 1.18 - 1.05 (m, 5H), 0.99 (dd, J = 11.9, 3.8 Hz, 1H), 0.95 - 0.89 (m, 4H), 0.67 (d, J = 12.1 Hz, 3H).

[0182] Examples 1 & 2

[0183] 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-dimethylhexadecahydro-1H- cyclopenta[l,2-a]phenanthrene-6,7-diol

[0184] 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.

[0185]

[0186] 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. A mixture of 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-hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthrol[7,8-d][1,3]dioxol-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,6,7,7a,8,9,10,10a,12,12a,12b-tetradecahydro-3aH-cyclopenta[1',2':7,8]phenanthrol[1,2-d][1,3]dioxol-8-yl]hexanal II (70 mg, 0.15 mmol, 1.0 eq) were dissolved in tetrahydrofuran (2 mL) and added to the above reaction solution. The reaction system was stirred at -78 °C for 30 min. After the reaction was completed, TLC (petroleum ether: ethyl acetate = 5:1) was used to monitor the reaction. 10 mL of water was added to the reaction system, and ethyl acetate (100 mL x 3) was used to extract the mixture. The combined organic phase was washed with saturated sodium chloride (10 mL), dried over sodium sulfate, and concentrated to obtain a crude product.The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 90:10) to give a mixture of 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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthrol[7,8-d][l,3]dioxol-8-yl]-l-{2-[(trifluoromethyl)oxy]phenyl}hexan-l-ol 1-1 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[l',2':7,8]phenanthrol[l,2-d][l,3]dioxol-8-yl]-l-{2-[(trifluoromethyl)oxy]phenyl}hexan-l-ol 2-1 (70 mg, purity 95%, yield 70% of compound 1-1 calculated).

[0187] Compound 1-1: 1 H NMR (400 MHz, CDC13) δ 7.54 - 7.49 (m, 1H), 7.24 (dt, J = 6.2, 4.0 Hz, 2H), 7.15 (dd, J = 4.7, 2.9 Hz, 1H), 5.03 - 4.96 (m, 1H), 3.94 (dt, J = 8.3, 6.2 Hz, 2H), 2.09 - 1.85 (m, 3H), 1.78 - 1.51 (m, 12H), 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, 6.5 Hz, 1H), 1.00 (s, 3H), 0.97 - 0.86 (m, 2H), 0.83 (dd, J = 6.4, 3.9 Hz, 3H), 0.59 (t, J = 5.9 Hz, 3H).

[0188] Step 2: A mixture 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- hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]-1-{2-[(trifluoro- methyl)oxy]phenyl}hexan-1-ol 1-1 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]dioxol-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), diluted 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) was used to monitor the completion of the reaction. Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 x 10 mL). The ethyl acetate layers were combined and washed with saturated brine (3 x 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 separated by chiral resolution SFC (instrument: Waters Acquity UPC; 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-{2-[(trifluoromethyl)oxy]phenyl}hexan-2-yl]-9a,11a-dimethylhexadecahydro-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, 96% purity, 5% yield, retention time t R = 1.109 min).

[0189] Compound 1: 1 H NMR (400 MHz, CDC13) δ 7.55 - 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 = 12.7 Hz, 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, 3.9 Hz, 3H), 0.59 (s, 3H). 19 F NMR (377 MHz, CDC13) δ -56.80, -56.81, -88.64, -89.27, -110.64, -111.27.

[0190] Compound 2: 1 H NMR (400 MHz, CDC13) δ 7.52 (d, J = 7.4 Hz, 1H), 7.28 - 7.21 (m, 2H), 7.15 (d, J = 7.4 Hz, 1H), 4.99 (dd, J = 11.4, 5.4 Hz, 1H), 3.78 (s, 1H), 3.52 (d, J = 12.0 Hz, 1H), 2.57 (d, J = 12.0 Hz, 1H), 1.95 (d, J = 12.6 Hz, 1H), 1.83 - 1.50 (m, 16H), 1.41 - 1.17 (m, 11H), 1.06 - 0.99 (m, 3H), 0.97 (s, 3H), 0.84 (dd, J = 6.4, 4.1 Hz, 3H), 0.56 (s, 3H). 19 F NMR (377 MHz, CDC13) δ -56.79, -56.81, -109.80. LC-MS: [M-H20] + = 551.80.

[0191] Examples 3 & 4

[0192] 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-dimethylhexadecahydro-1H- cyclopenta[1,2-a]phenanthrene-6,7-diol

[0193] 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

[0194]

[0195] First Step: Compound 1 -bromo-2-fluorobenzene (195.96 mg, 1.12 mmol, 1.2 eq) was dissolved in tetrahydrofuran (30 mL), cooled to -78 °C with a dry ice bath under nitrogen protection, then n-butyllithium 2.5 M n-hexane solution (89.67 mg, 1.400 mmol, 1.5 eq) was added, and stirred for 30 min, 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]dioxol-8-yl]hexanal III (400 mg, 0.933 mmol, 1.0 eq) was added, and then naturally warmed to room temperature. The reaction progress was monitored by TLC (petroleum ether: ethyl acetate = 5:1), after the reaction was completed, quenched with saturated ammonium chloride, and the aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated brine (15 mL). The ethyl acetate layer was dried over Na2SO4, filtered, and concentrated to give a 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]dioxol-8-yl]-1-(2- fluorophenyl)hexan-1-ol 3-1 (400 mg, purity: 80%, yield: 65%) as a white solid.1 H NMR (400 MHz, CDC13) δ 7.46 (t, J = 7.4 Hz, 1H), 7.23 (s, 1H), 7.15 (s, 1H), 7.02 (m, 1H), 5.80 (s, 1H), 5.00 (dd, J = 12.0, 7.0 Hz, 1H), 4.41 (d, J = 5.8 Hz, 1H), 4.10 (dd, J = 13.9, 6.1 Hz, 1H), 2.06 (dd, J = 44.2, 10.2 Hz, 3H), 1.65 (dd, J = 30.7, 25.0 Hz, 9H), 1.41 (d, J = 9.7 Hz, 4H), 1.35 (s, 3H), 1.25 (s, 3H), 1.16 (s, 3H), 1.10 (m, 6H), 0.90 (dd, J = 6.4, 4.0 Hz, 3H), 0.68 (m, 3H).

[0196] 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[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]-l-(2-fluorophenyl)hexan- 1-ol 3-1 (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. TLC (petroleum ether: ethyl acetate = 5: 1) was used to monitor the reaction progress, the starting material was consumed, quenched with methanol, water (10 mL) was added to the reaction system, the aqueous layer was extracted with dichloromethane (3 x 20 mL). The combined organic phases were washed with saturated brine (50 mL), dried over Na2S04, filtered and concentrated to give the crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 95: 5) to give 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[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]-l-(2-fluorophenyl)hexyl ester 3-2 (400 mg, purity: 90%, yield: 83%) as a white solid. 1H NMR (400 MHz, CDC13) δ 7.34 (t, J = 7.4 Hz, 1H), 7.24 (d, J = 7.2 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 7.03 (m, 1H), 6.01 (m, 1H), 5.80 (d, J = 2.8 Hz, 1H), 4.41 (d, J = 5.8 Hz, 1H), 4.10 (dd, J = 13.6, 6.3 Hz, 1H), 2.08 (d, J = 2.4 Hz, 3H), 1.61 (m, 8H), 1.43 (s, 4H), 1.34 (d, J = 6.2 Hz, 5H), 1.26 (s, 3H), 1.16 (s, 5H), 1.02 (m, 9H), 0.86 (m, 7H), 0.67 (m, 4H).

[0197] Step 3: 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[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]-l-(2-fluorophenyl) hexyl ester 3-2 (120 mg, 0.21 mmol, 1.0 eq) was dissolved in acetone (5 mL), N-hydroxyphthalimide (6.92 mg, 0.042 mmol, 0.2 eq), tert-butyl hydroperoxide (0.170 mL, 0.848 mmol, 4.0 eq) and cobalt(II) acetate anhydrous (1.88 mg, 0.011 mmol, 0.05 eq) were added, the resulting mixture was stirred at 25 °C for 18 h. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 10: 1). The reaction was quenched with saturated sodium sulfite, water (10 mL) was added to the reaction, the aqueous layer was extracted with ethyl acetate (3 x 15 mL). The combined ethyl acetate layers were washed with saturated brine (15 mL), dried over Na2S04, filtered and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 80:20), to give acetic acid-(5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl- 11-oxo-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetradecahydro-3aH- cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]-l-(2-fluorophenyl) hexyl ester 3-3 (60 mg, purity: 90%, yield: 44%). 1H NMR (400 MHz, CDC13) δ 7.34 (t, J = 7.3 Hz, 1H), 7.23 (m, 1H), 7.12 (t, J = 7.5 Hz, 1H), 7.03 (m, 1H), 6.02 (d, J = 5.0 Hz, 1H), 5.92 (s, 1H), 4.52 (d, J = 6.4 Hz, 1H), 4.32 (d, J = 5.6 Hz, 1H), 2.34 (d, J = 10.6 Hz, 2H), 2.08 (s, 3H), 2.02 (m, 1H), 1.82 (dd, J = 20.1, 10.2 Hz, 4H), 1.57 (t, J = 12.4 Hz, 13H), 1.34 (m, 17H), 1.07 (m, 5H), 0.87 (dd, J = 11.7, 6.8 Hz, 4H), 0.80 (d, J = 5.9 Hz, 1H), 0.69 (d, J = 3.5 Hz, 3H)

[0198] Fourth Step: Compound Acetic acid-(5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)- 2,2,5a,7a-tetramethyl-11-oxo-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b- tetradecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]-l- (2-fluorophenyl)hexyl ester 3-3 (60 mg, 0.10 mmol) was dissolved in methanol (5 mL), palladium on carbon (11 mg, 0.103 mmol) was added, after hydrogen gas was replaced for 3 times, the resulting mixture was stirred in hydrogen gas, 25 °C for 1 h. TLC (petroleum ether: ethyl acetate = 3: 1) was used to monitor the reaction progress, the starting material was consumed. Filtration, concentration to get the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 80:20), to get white solid acetic acid-(5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-2,2,5a,7a- tetramethyl-11-oxo-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]-l- (2-fluorophenyl)hexyl ester 3-4 (40 mg, purity: 90%, yield: 60%). 1HNMR (400 MHz, CDC13) δ 7.34 (s, 1H), 7.23 (s, 1H), 7.12 (s, 1H), 7.03 (s, 1H), 6.01 (dd, J = 10.9, 6.4 Hz, 1H), 3.98 (d, J = 3.4 Hz, 2H), 2.77 (s, 1H), 2.42 (s, 1H), 2.19 (dd, J = 12.7, 2.7 Hz, 2H), 2.08 (s, 3H), 1.74 (m, 9H), 1.53 (s, 3H), 1.38 (dd, J = 11.7, 7.8 Hz, 4H), 1.28 (d, J = 17.1 Hz, 10H), 0.95 (ddd, J = 10.8, 9.5, 6.5 Hz, 10H), 0.64 (d, J = 3.2 Hz, 3H).

[0199] Fifth Step: Compound Acetic acid-(5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)- 2,2,5a,7a-tetramethyl-11-oxymethylen-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]-l-(2- fluorophenyl)hexyl ester 3-4 (250 mg, 0.43 mmol) was dissolved in diethylamine trifluoride (5 mL) and the resulting mixture was stirred at 80 °C for 1 h. The reaction progress was monitored by TLC (petroleum ether: ethyl acetate = 10: 1) and the starting material was consumed. The reaction was diluted with dichloromethane (20 mL) and quenched with ice water carefully. The organic phase was collected and the aqueous phase was extracted with dichloromethane (3 x 10 mL). The combined organic phase was washed with saturated brine (15 mL), filtered and concentrated to give a crude product. The crude product was loaded on silica gel and eluted with petroleum ether: ethyl acetate = 93: 7 to give a mixture of 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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]-l-(2- fluorophenyl)hexyl ester 3-5 and Acetic acid-(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[l',2':7,8]phenanthro[l,2-d][l,3]dioxol-8-yl]-l-(2-fluorophenyl)hexyl ester 4-1 (210 mg, purity: 90%, yield: 72.85% calculated for 3-5).

[0200] Compound 3-5 1H NMR: (400 MHz, CDC13) δ 7.34 (t, J = 7.4 Hz, 1H), 7.24 (d, J = 6.6 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 7.06 - 7.00 (m, 1H), 6.05 - 5.98 (m, 1H), 4.07 - 3.98 (m, 2H), 2.08 (d, J = 1.3 Hz, 3H), 1.98 - 1.68 (m, 9H), 1.63 - 1.57 (m, 2H), 1.50 (s, 3H), 1.39 (dd, J = 10.5, 5.0 Hz, 4H), 1.30 (s, 3H), 1.07 (s, 3H), 1.05 - 0.90 (m, 4H), 0.87 (dd, J = 6.3, 4.7 Hz, 4H), 0.64 (dd, J = 11.7, 3.6 Hz, 3H).

[0201] Step 6: A mixture of 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- hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]-1-(2- fluorophenyl)hexyl ester 3-5 and acetic acid-(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]dioxol-8-yl]-1-(2-fluorophenyl)hexyl ester 4-1 (210 mg, 0.34 mmol, 1.0 eq) was dissolved in tetrahydrofuran (10 mL), diluted hydrochloric acid (1 mL, 3 mol / L) was added, and the reaction system was stirred at room temperature for 1 h. TLC plate (petroleum ether: ethyl acetate = 5:1) was used to monitor the progress of the reaction. Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 x 25 mL). The EA layers were combined and washed with saturated brine (3 x 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 mixture of acetic acid-(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-fluorophenyl)hexyl ester 3-6 and acetic acid-(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-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren- 1-yl]-1-(2-fluorophenyl)hexyl ester 4-2 (200 mg, 95% purity, 96.9% yield calculated for 3-6).

[0202] 3-6: 1H NMR (400 MHz, CDC13) δ 7.34 (t, J = 7.4 Hz, 1H), 7.23 (s, 1H), 7.12 (t, J = 7.5 Hz, 1H), 7.07 - 6.98 (m, 1H), 6.01 (dd, J = 11.2, 6.4 Hz, 1H), 3.85 (s, 0H), 3.74 (s, 1H), 3.64 - 3.55 (m, 1H), 2.09 (s, 3H), 1.96 (d, J = 12.7 Hz, 1H), 1.88 - 1.67 (m, 9H), 1.49 - 1.29 (m, 8H), 1.09 (d, J = 4.6 Hz, 1H), 1.05 (s, 3H), 1.03 - 0.94 (m, 2H), 0.89 - 0.84 (m, 3H), 0.63 (dd, J = 12.0, 3.6 Hz, 3H).

[0203] Step 7: A mixture of compound Acetic acid-(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-fluorophenyl)hexyl ester 3-6 and Acetic acid-(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-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 mixture solvent of tetrahydrofuran (2 mL) and methanol (2 mL), potassium carbonate (122 mg, 0.89 mmol, 10 eq) was added, the resulting mixture was stirred at 25 °C for 1 h. TLC (petroleum ether: ethyl acetate = 1:1) was used to monitor the reaction. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 71:29) to give a white mixture, then chiral separation to give white solid (Instrument: Waters Acquity; UPC column: REGIS CHIRAL (S, S)-Whelk O1 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 give 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-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 3 (25.6 mg, purity: 95.02%, yield: 52.56%, retention time t R = 1.205 min) 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 = 1.666 min).

[0204] Compound 3: 1H NMR (400 MHz, CDC13) 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 C NMR (101 MHz, CDC13) 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 F NMR (377 MHz, CDC13) δ -88.63, -89.26, -110.63, -111.25, -119.75, -119.78.

[0205] Compound 4: 1 H NMR (400 MHz, CDC13) 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 F NMR (377 MHz, CDC13) δ -109.79, -119.75, -119.78.

[0206] Example 5

[0207] Preparation of compound 5 24-[hydroxy(3-methoxyphenyl)methyl]-5α-cholestane-3β,4β-diol

[0208]

[0209] First step 5R-1-(3-methoxyphenyl)-5-((3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)- 2,2,5a,7a-tetramethylhexadecahydro-4H-cyclopenta[7,8]phenalene[1,2-d][1,3]dioxol-8- yl)hexan-1-ol 5-1 (30 mg, 0.056 mmol, 48.0%) was obtained as a white solid from the reaction of 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-hexadecahydro-3aH- cyclopenta[1 ',2':1,2]phenalene-8-yl]hexanal III (50 mg, 0.12 mmol) and 3- methoxyphenylboronic acid (20 mg, 0.15 mmol) in the presence of Pd(PPh3)4 (10 mg, 0.008 mmol) and potassium carbonate (40 mg, 0.3 mmol) in dry tetrahydrofuran (5 mL) at room temperature for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. The residue 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-tetramethylhexadecahydro-4H-cyclopenta[7,8]phenalene[1,2-d][1,3]dioxol-8- yl)hexan-1-ol 5-1 (30 mg, 0.056 mmol, 48.0%) as a white solid.

[0210] Second step Weigh (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-hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]hexanal 5-1 (30 mg, 0.056 mmol) into anhydrous methanol (10 mL), add 2M hydrochloric acid (3 mL) at room temperature, continue to stir at room temperature after adding, TLC (petroleum ether: ethyl acetate = 3:1) monitor the reaction is complete. Add water and ethyl acetate extraction, separation of organic phase, dry, concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 0-50%) to get 24-[hydroxy(3-methoxyphenyl)methyl]-5α-cholestane-3β,4β-diol 5 (15 mg, 0.030 mmol, 54.1%) white solid.

[0211] Compound 5: 1 H NMR (399 MHz, Chloroform-d) δ 6.91 (d, J = 7.1 Hz, 2H), 4.63 (q, J = 6.3 Hz, 1H), 3.81 (s, 3H), 3.73 (s, 1H), 3.55 (dd, J = 11.5, 5.0 Hz, 1H), 1.93 (d, J = 12.5 Hz, 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 = 8.6 Hz, 1H), 1.06 - 1.02 (m, 3H), 1.00 (s, 3H), 0.97 - 0.91 (m, 2H), 0.86 (dd, J = 6.5, 4.7 Hz, 3H), 0.62 (d, J = 2.7 Hz, 3H). 13 C NMR (100 MHz, Chloroform-d) δ 159.69, 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, 48.77, 42.57, 39.85, 39.52, 39.48, 36.82, 35.67, 35.44, 35.36, 32.36, 28.24, 25.96, 25.83, 24.18, 22.46, 22.37, 20.55, 18.58, 18.56, 14.66, 12.05. LC-MS: [M+H]+ = 498.37.

[0212] The synthesis of Examples 6, 7, 8, 20, 28 and 104 was accomplished using the synthetic method of Reference Example 5

[0213] Structural spectral analysis of compounds 6, 7, 8, 20, 28 and 104

[0214]

[0215]

[0216] Example 11

[0217] 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-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthren-6-one.

[0218]

[0219]

[0220] The first step, compound 1-bromo-2-fluorobenzene (195.96 mg, 1.12 mmol, 1.2 eq) was dissolved in tetrahydrofuran (30 mL), and cooled to -78 °C under nitrogen protection. Then n-butyllithium 2.5 M in hexane (89.67 mg, 1.400 mmol, 1.5 eq) was added, and stirred for 30 min. After that, (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]phenanthrol[7,8-d][1,3]dioxol-8-yl]hexanal III (400 mg, 0.933 mmol, 1.0 eq) was added, and the reaction mixture was allowed to warm to room temperature. The reaction progress was monitored by TLC (petroleum ether: ethyl acetate = 5:1). After the reaction was completed, the reaction mixture was quenched with saturated ammonium chloride. The aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated brine (15 mL). The ethyl acetate layer was dried over Na2SO4, filtered, and concentrated to give a 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]phenanthrol[7,8-d][1,3]dioxol-8-yl]-1-(2-fluorophenyl)hexan-1-ol 11-1 (400 mg, purity: 80%, yield: 65%) as a white solid. 1 H NMR (400 MHz, CDCL3) δ 7.46 (t, J = 7.4 Hz, 1H), 7.23 (s, 1H), 7.15 (s, 1H), 7.02 (m, 1H), 5.80 (s, 1H), 5.00 (dd, J = 12.0, 7.0 Hz, 1H), 4.41 (d, J = 5.8 Hz, 1H), 4.10 (dd, J = 13.9, 6.1 Hz, 1H), 2.06 (dd, J = 44.2, 10.2 Hz, 3H), 1.65 (dd, J = 30.7, 25.0 Hz, 9H), 1.41 (d, J = 9.7 Hz, 4H), 1.35 (s, 3H), 1.25 (s, 3H), 1.16 (s, 3H), 1.10 (m, 6H), 0.90 (dd, J = 6.4, 4.0 Hz, 3H), 0.68 (m, 3H).

[0221] In 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[l',2':l,2]phenalene-8-yl]-l-(2- fluorophenyl)hexan-l-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, and 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 consumption of the starting material, the reaction was quenched with methanol, water (10 mL) was added to the reaction mixture, and the aqueous layer was extracted with dichloromethane (3 x 20 mL). The combined organic phases were 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 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[l',2':l,2]phenalene-8-yl]-l-(2-fluorophenyl)hexyl ester 11-2 (400 mg, purity: 90%, yield: 83%) as a white solid. 1 H NMR (400 MHz, CDCL3) δ 7.34 (t, J = 7.4 Hz, 1H), 7.24 (d, J = 7.2 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 7.03 (m, 1H), 6.01 (m, 1H), 5.80 (d, J = 2.8 Hz, 1H), 4.41 (d, J = 5.8 Hz, 1H), 4.10 (dd, J = 13.6, 6.3 Hz, 1H), 2.08 (d, J = 2.4 Hz, 3H), 1.61 (m, 8H), 1.43 (s, 4H), 1.34 (d, J = 6.2 Hz, 5H), 1.26 (s, 3H), 1.16 (s, 5H), 1.02 (m, 9H), 0.86 (m, 7H), 0.67 (m, 4H).

[0222] The third step involves adding 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-tetradecanohydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxacyclopenta-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 hrs. The reaction progress and reactant 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 and washed with saturated brine (15 mL), dried over Na₂SO₄, filtered, and concentrated to obtain the crude product. Crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 80:20) to obtain acetic acid-(5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-11-oxonyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetradecanoyl-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxacyclopenta-8-yl]-1-(2-fluorophenyl)hexyl ester 11-3 (60 mg, purity: 90%, yield: 44%). 1H NMR (400 MHz, CDC13) δ 7.34 (t, J = 7.3 Hz, 1H), 7.23 (m, 1H), 7.12 (t, J = 7.5 Hz, 1H), 7.03 (m, 1H), 6.02 (d, J = 5.0 Hz, 1H), 5.92 (s, 1H), 4.52 (d, J = 6.4 Hz, 1H), 4.32 (d, J = 5.6 Hz, 1H), 2.34 (d, J = 10.6 Hz, 2H), 2.08 (s, 3H), 2.02 (m, 1H), 1.82 (dd, J = 20.1, 10.2 Hz, 4H), 1.57 (t, J = 12.4 Hz, 13H), 1.34 (m, 17H), 1.07 (m, 5H), 0.87 (dd, J = 11.7, 6.8 Hz, 4H), 0.80 (d, J = 5.9 Hz, 1H), 0.69 (d, J = 3.5 Hz, 3H)

[0223] In the fourth step, compound acetic acid-(5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)- 2,2,5a,7a-tetramethyl-11-oxo-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetradecahydro- 3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]-l-(2-fluorophenyl)hexyl ester 11-3 (60 mg, 0.10 mmol) was dissolved in methanol (5 mL), palladium on carbon (11 mg, 0.103 mmol) was added, and the resulting mixture was stirred under H2at 25 °C for 1 h. The reaction progress was monitored by TLC (petroleum ether: ethyl acetate = 3: 1), and the starting material was consumed. Filtration and concentration gave a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 80:20) to give acetic acid-(5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-2,2,5a,7a-tetramethyl-11-oxo- 4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]-l-(2-fluorophenyl)hexyl ester 11-4 (40 mg, 0.062 mmol, purity: 90%, yield: 60%) as a white solid. 1HNMR (400 MHz, CDC13) δ 7.34 (s, 1H), 7.23 (s, 1H), 7.12 (s, 1H), 7.03 (s, 1H), 6.01 (dd, J = 10.9, 6.4 Hz, 1H), 3.98 (d, J = 3.4 Hz, 2H), 2.77 (s, 1H), 2.42 (s, 1H), 2.19 (dd, J = 12.7, 2.7 Hz, 2H), 2.08 (s, 3H), 1.74 (m, 9H), 1.53 (s, 3H), 1.38 (dd, J = 11.7, 7.8 Hz, 4H), 1.28 (d, J = 17.1 Hz, 10H), 0.95 (ddd, J = 10.8, 9.5, 6.5 Hz, 10H), 0.64 (d, J = 3.2 Hz, 3H).

[0224] In the fifth step, compound Acetic acid-(5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)- 2,2,5a,7a-tetramethyl-11-oxo-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]-l-(2- fluorophenyl)hexyl ester 11-4 (250 mg, 0.43 mmol) was dissolved in diethylamine trifluoride (5 mL) and the resulting mixture was stirred at 80 °C for 1 h. The reaction progress was monitored by TLC (petroleum ether: ethyl acetate = 10: 1) and the starting material was consumed. The reaction was cooled to room temperature, diluted with dichloromethane (20 mL) and quenched by careful addition of ice water. The organic phase was collected, the aqueous phase was extracted with dichloromethane (3 x 10 mL), the combined organic phase was washed with saturated brine (15 mL), filtered and concentrated to give the crude product. The crude product was loaded onto silica gel and eluted with petroleum ether: ethyl acetate = 93:7 to give 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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]-l-(2- fluorophenyl)hexyl ester 11-5 (210 mg, purity: 90%, yield: 72.85%) as a colorless transparent solid. 1H NMR (400 MHz, CDC13) δ 7.34 (t, J = 7.4 Hz, 1H), 7.24 (d, J = 6.6 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 7.06 - 7.00 (m, 1H), 6.05 - 5.98 (m, 1H), 4.07 - 3.98 (m, 2H), 2.08 (d, J = 1.3 Hz, 3H), 1.98 - 1.68 (m, 9H), 1.63 - 1.57 (m, 2H), 1.50 (s, 3H), 1.39 (dd, J = 10.5, 5.0 Hz, 4H), 1.30 (s, 3H), 1.07 (s, 3H), 1.05 - 0.90 (m, 4H), 0.87 (dd, J = 6.3, 4.7 Hz, 4H), 0.64 (dd, J = 11.7, 3.6 Hz, 3H).

[0225] In the sixth step, (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-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 turn, and the reaction system was stirred at room temperature for 1 hour. After the reaction was completed, TLC (petroleum ether: ethyl acetate = 10:1) was used to monitor the reaction, and methanol (20 mL) was used to extract the reaction solution. The reaction solution was washed with water (40 mL x 2), saturated sodium bicarbonate (40 mL x 2), and dichloromethane (40 mL x 2). The organic phase was collected and vacuum dried to obtain a crude product. The crude product was separated and purified by flash chromatography (petroleum ether: ethyl acetate = 80:20) to obtain white solid (5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-7-acetyloxy-4,4-difluoro-6-hydroxy-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-1-(2-fluorophenyl)hexyl acetate 11-6 (90 mg, purity 95%, yield 61%). 1H NMR (400 MHz, CDC13) δ 7.34 (t, J = 7.4 Hz, 1H), 7.24 (d, J = 5.8 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 7.02 (dd, J = 15.2, 6.7 Hz, 1H), 6.05 - 5.97 (m, 1H), 4.73 (dd, J = 9.2, 6.0 Hz, 1H), 3.88 (d, J = 39.4 Hz, 1H), 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 = 8.7 Hz, 3H), 0.87 (dd, J = 6.4, 4.1 Hz, 3H), 0.63 (dd, J = 12.2, 3.5 Hz, 3H).

[0226] In the seventh step, compound acetic acid-(5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-7-acetyloxy-4,4-difluoro-6-hydroxy-9a,11a-dimethylhexadecahydro-1H- cyclopenta[1,2-a]phenanthren-1-yl]-1-(2-fluorophenyl)hexyl ester 11-6 (80 mg, 0.132 mmol) was dissolved in dichloromethane (10 mL), Dess-Martin oxidizing reagent (67 mg, 0.158 mmol), stirred at room temperature for 1 h, TLC (petroleum ether: ethyl acetate = 3:1) was used to monitor the reaction. Water (10 mL) was added to the reaction system, the water layer was extracted with ethyl acetate (3 x 25 mL). The ethyl acetate layers were combined and washed with saturated brine (3 x 10 mL). The ethyl acetate layer was dried over Na2S04, filtered and concentrated to give the crude product. The reaction was completed, the reaction liquid was filtered, the filtrate was washed with water, the organic phase was dried, concentrated, and the crude product was purified by flash column chromatography (petroleum ether: ethyl acetate = 84:16) to give acetic acid-(5R)-5-[(1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-7-acetyloxy-4,4-difluoro-9a,11a-dimethyl-6- oxohexadecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-1-(2-fluorophenyl)hexyl ester 11-7 (85 mg, purity 95%, yield 90%) as a white solid. 1H NMR (400 MHz, CDC13) δ 7.34 (t, J = 7.4 Hz, 1H), 7.25 (s, 1H), 7.12 (t, J = 7.5 Hz, 1H), 7.07 - 7.00 (m, 1H), 6.05 - 5.99 (m, 1H), 5.18 (dd, J = 12.2, 7.4 Hz, 1H), 2.53 (t, J = 10.2 Hz, 1H), 2.09 (s, 3H), 2.05 (s, 4H), 1.99 - 1.56 (m, 11H), 1.38 (ddd, J = 26.0, 14.1, 6.7 Hz, 6H), 1.22 - 0.99 (m, 4H), 0.89 - 0.85 (m, 3H), 0.77 (d, J = 10.9 Hz, 3H), 0.63 (dd, J = 15.2, 3.6 Hz, 3H).

[0227] In the eighth step, compound acetic acid-(5R)-5-[(1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-7-acetyloxy-4,4-difluoro-9a,11a-dimethyl-6-oxohexadecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-1-(2-fluorophenyl)hexyl ester 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 aqueous lithium hydroxide solution (0.5 mL, 3 mol / L) was added, and the resulting mixture was stirred at 25 °C for 1 h. TLC (petroleum ether: ethyl acetate = 1:1) was used to monitor the progress of the reaction, and the consumption of the starting material was observed. The reaction solution was diluted with ethyl acetate (20 mL) and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 76:24). Further SFC separation (instrument: Waters Acquity UPC C; chromatographic column: REGIS CHIRAL (S, S)-Whelk O1 4.6*150mm, 3.5um; mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 50 / 50; flow rate: 1.5 milliliter / minute; column temperature: 37 degrees; retention time t R = 2.417 min) to obtain 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-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthren-6-one 11 (6.04 mg, purity: 95.12%, yield: 8.34%).

[0228] Compound 11: 1H NMR (400 MHz, CDC13) δ 7.46 (t, J = 7.5 Hz, 1H), 7.23 (d, J = 5.9 Hz, 1H), 7.15 (t, J = 7.2 Hz, 1H), 7.05 - 6.98 (m, 1H), 5.04 - 4.96 (m, 1H), 4.14 (dd, J = 11.2, 8.1 Hz, 1H), 2.46 (ddd, J = 16.8, 12.7, 8.3 Hz, 2H), 2.18 - 2.07 (m, 1H), 1.77 - 1.50 (m, 11H), 1.27 (dddd, J = 55.4, 28.2, 14.6, 6.8 Hz, 12H), 0.90 (dd, J = 6.4, 4.0 Hz, 3H), 0.76 (s, 3H), 0.66 (d, J = 2.0 Hz, 3H). 19 F NMR (377 MHz, CDC13) δ -90.21, -90.85, -111.50, -112.14, -119.77, -119.80.

[0229] Examples 15A & 15B

[0230] Preparation of compounds 15A & 15B 2-Fluoro-N-[(3R)-3-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6,7-dihydroxy-5a,9a,11a-trimethylhexadecahydro-1H- cyclopenta[1,2-a]phenanthren-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-trimethylhexadecahydro-1H- cyclopenta[1,2-a]phenanthren-1 -yl]butyl]-N-methylbenzamide

[0231]

[0232]

[0233] A solution of (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]phenanthren-7-yl acetate I-5 (300 mg, 0.776 mmol) in tetrahydrofuran (5 mL) was prepared. Zinc chloride (105.76 mg, 0.776 mmol) was added, followed by the addition of methylamine in tetrahydrofuran (1.552 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, followed by the addition of sodium cyanoborohydride (48.77 mg, 0.776 mmol). 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 the mixture was extracted with ethyl acetate. The organic phase was separated and dried. The solvent was removed under reduced pressure, and the residue was 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]phenanthren-7-yl acetate 15-1 (220 mg, 0.438 mmol, 56.47%) as a white solid. 1 H NMR (399 MHz, Chloroform-d) δ 5.35 (d, J = 5.0 Hz, 1H), 4.59 (d, J = 13.0 Hz, 1H), 2.95 (d, J = 36.8 Hz, 2H), 2.69 (s, 2H), 2.30 (d, J = 7.3 Hz, 2H), 2.01 (s, 3H), 1.96 (d, J = 13.5 Hz, 2H), 1.88 - 1.81 (m, 3H), 1.56 (d, J = 10.6 Hz, 3H), 1.50 (d, J = 16.6 Hz, 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 = 6.0 Hz, 3H), 0.94 - 0.84 (m, 1H), 0.68 (s, 3H).

[0234] Second step, (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]phenanthren-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, o-fluorobenzoyl chloride (47.37 mg, 0.299 mmol) was added with stirring, and the reaction was continued to stir at room temperature. TLC (petroleum ether: ethyl acetate = 10:1) was used to monitor the reaction. After the reaction was completed, 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 ~ 5:1) to obtain (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]phenanthren-7-yl acetate 15-2 (40 mg, 0.061 mmol, 40.90%) as a white solid. 1 H NMR (399 MHz, Chloroform-d) δ 7.32 (dt, J = 15.8, 6.9 Hz, 2H), 7.17 (t, J = 7.5 Hz, 1H), 7.07 (q, J = 8.8 Hz, 1H), 5.36 (d, J = 5.7 Hz, 1H), 4.58 (d, J = 6.0 Hz, 1H), 3.20 - 3.09 (m, 1H), 3.07 (s, 2H), 2.86 (d, J = 1.5 Hz, 1H), 2.30 (t, J = 5.8 Hz, 2H), 2.01 (d, J = 1.9 Hz, 4H), 1.97 - 1.87 (m, 2H), 1.83 (t, J = 9.9 Hz, 2H), 1.51 - 1.36 (m, 5H), 1.34 - 1.25 (m, 2H), 1.14 (ddd, J = 33.9, 16.5, 6.5 Hz, 5H), 1.01 (dd, J = 14.9, 8.0 Hz, 6H), 0.96 - 0.83 (m, 2H), 0.69 (s, 1H), 0.63 (d, J = 5.9 Hz, 2H), 0.59 (s, 2H).

[0235] In the third step, (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]phenanthren-7-yl acetate 15-2 (232 mg, 0.443 mmol) was dissolved in chloroform (10 mL), and selenium dioxide (245.76 mg, 2.215 mmol) and NMM (268.84 mg, 2.658 mmol) were added sequentially with stirring at room temperature, followed by stirring at 75°C, and the reaction was monitored by TLC (petroleum ether: ethyl acetate = 3:1). After the reaction was completed, it was cooled to room temperature, filtered to obtain a filtrate, and then water and dichloromethane were added and extracted, and 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]phenanthren-7-yl acetate 15-3 (136 mg, 0.202 mmol, 45.51%) as a white solid. 1 H NMR (399 MHz, Chloroform-d) δ 7.32 (dt, J = 15.9, 7.0 Hz, 2H), 7.17 (t, J = 7.5 Hz, 1H), 7.07 (q, J = 8.7 Hz, 1H), 5.69 (d, J = 5.6 Hz, 1H), 4.69 (d, J = 11.4 Hz, 1H), 4.22 (d, J = 4.2 Hz, 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 = 12.1 Hz, 3H), 1.65 (d, J = 9.2 Hz, 3H), 1.49 - 1.38 (m, 3H), 1.30 (s, 3H), 1.19 (d, J = 9.7 Hz, 3H), 1.11 (dd, J = 23.4, 9.3 Hz, 3H), 1.03 (d, J = 6.6 Hz, 2H), 0.98 - 0.80 (m, 3H), 0.69 (s, 1H), 0.64 (d, J = 5.9 Hz, 1H), 0.59 (s, 1H).

[0236] Fourth step: (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]phenanthren-7-yl acetate 15-3 (136 mg, 0.252 mmol) was dissolved in acetic acid (3 mL), after addition of platinum dioxide (85.83 mg, 0.378 mmol) under hydrogen replacement, followed by heating to 60 °C with stirring, TLC (petroleum ether: ethyl acetate = 5:1) was used to monitor the reaction. After the reaction was completed, the platinum dioxide was removed by filtration, most of the acetic acid was removed by concentration, followed by the addition of saturated aqueous sodium bicarbonate solution and ethyl acetate extraction, the organic phase was separated, dried, concentrated to give the crude (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]phenanthren-7-yl acetate 15-4 (130 mg), which was directly used in the next step.

[0237] Fifth step (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]phenanthren-7-yl acetate 15-4 (130 mg, 0.234 mmol) was dissolved in a mixture of methanol (1 mL) and tetrahydrofuran (2 mL) and aqueous lithium hydroxide (2.339 mL) was added and stirring was continued at room temperature. TLC (petroleum ether: ethyl acetate = 2:1) was used to monitor the reaction. After the reaction was completed, water was added and the mixture was extracted with ethyl acetate. The organic phase was separated, dried, concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 20:1 to 1:1) to give 2-fluoro-N-[(3R)-3-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6,7-dihydroxy-5a,9a,11a- trimethylhexadecahydro-1H-cyclopenta[1,2-i]phenanthren-1-yl]butyl]-N- methylbenzamide 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- trimethylhexadecahydro-1H-cyclopenta[1,2-i]phenanthren-1-yl]butyl]-N- methylbenzamide 15B (18 mg, 0.035 mmol, 14.82%)

[0238] 15A: 1 H NMR (399 MHz, Chloroform-d) δ 7.33 (d, J = 22.2 Hz, 2H), 7.18 (t, J = 7.6 Hz, 1H), 7.08 (q, J = 8.3 Hz, 1H), 4.01 (s, 1H), 3.88 (t, J = 11.1 Hz, 1H), 3.67 (s, 1H), 3.44 (s, 1H), 3.17 (d, J = 14.2 Hz, 1H), 3.08 (s, 2H), 2.87 (s, 1H), 1.99 (s, 6H), 1.81 (d, J = 39.6 Hz, 2H), 1.64 (s, 3H), 1.47 (s, 2H), 1.41 (d, J = 9.7 Hz, 2H), 1.29 (d, J = 9.4 Hz, 2H), 1.18 (d, J = 15.9 Hz, 3H), 1.05 (s, 2H), 1.01 (d, J = 6.7 Hz, 3H), 0.96 (d, J = 9.2 Hz, 3H), 0.66 (s, 1H), 0.62 (d, J = 5.9 Hz, 1H), 0.56 (s, 2H). 19F NMR (376 MHz, Chloroform-d) δ -115.20. LC-MS: [M+H] + = 500.35.

[0239] 15B: 1 H NMR (399 MHz, Chloroform-d) δ 7.39 - 7.28 (m, 2H), 7.18 (d, J = 7.7 Hz, 1H), 7.07 (q, J = 8.4 Hz, 1H), 3.74 (s, 1H), 3.56 (s, 1H), 3.44 (s, 1H), 3.16 (d, J = 13.0 Hz, 1H), 3.07 (s, 2H), 2.86 (s, 1H), 2.46 (s, 4H), 1.95 (d, J = 13.2 Hz, 1H), 1.73 (d, J = 12.6 Hz, 5H), 1.48 (s, 1H), 1.33 (s, 3H), 1.10 (dd, J = 22.5, 10.9 Hz, 5H), 0.98 (d, J = 9.3 Hz, 6H), 0.87 (d, J = 6.3 Hz, 3H), 0.65 (s, 1H), 0.61 (d, J = 5.6 Hz, 2H), 0.55 (s, 2H). 19 F NMR (376 MHz, Chloroform-d) δ -115.13 (d, J = 49.4 Hz). 13 C NMR (100 MHz, Chloroform-d) δ 110.00, 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.

[0240] Example 21

[0241] 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.

[0242]

[0243] Step 1: Reagent 2-bromo-1,3-difluorobenzene (270 mg, 1.40 mmol, 3.0 eq) was dissolved in tetrahydrofuran (5 mL), nitrogen protection, dry ice bath cooling to -78 °C, then n-butyllithium, 2.5 M n-hexane solution (0.67 mL, 1.680 mmol, 3.6 eq) was added, and the reaction was carried out 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-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]hexanal III (200 mg, 0.467 mmol, 1.0 eq) tetrahydrofuran solution (10 mL) was added, TLC (petroleum ether: ethyl acetate = 5:1) was used to monitor the reaction, and the raw material was basically disappeared. The reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by flash column chromatography (petroleum ether: ethyl acetate = 80:20). White solid (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetradecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]-1-(2,6-difluorophenyl)hexan-1-ol 21-1 (180 mg, purity: 90%, yield: 63.97%). 1 H NMR (400 MHz, DMSO-d6) δ 7.21 (s, 1H), 6.87 (t, J = 8.2 Hz, 2H), 5.80 (d, J = 2.7 Hz, 1H), 5.03 (s, 1H), 4.40 (d, J = 5.8 Hz, 1H), 4.10 (d, J = 7.4 Hz, 1H), 2.12 (m, 1H), 2.00 (d, J = 13.4 Hz, 2H), 1.69 (m, 10H), 1.39 (m, 8H), 1.08 (m, 10H), 0.90 (dd, J = 14.8, 8.6 Hz, 5H), 0.68 (d, J = 3.9 Hz, 3H).

[0244] 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[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]-l-(2,6-difluorophenyl)hexan- 1-ol 21-1 (180 mg, 0.332 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), 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 resulting reaction was stirred at 25 °C for 1 h. The reaction progress was monitored by TLC plate (petroleum ether: ethyl acetate = 5: 1), the starting material was consumed, quenched with methanol, washed with saturated sodium bicarbonate, washed with saturated brine (15 mL), dried over Na2S04, filtered and concentrated to give the crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 90: 10) to give 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[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]-l-(2,6-difluorophenyl)hexyl ester 21-2 (150 mg, purity: 90%, yield: 69.61%) as a white solid. 1 H NMR (400 MHz, CDC13) δ 7.23 (m, 1H), 6.86 (t, J = 8.0 Hz, 2H), 6.05 (t, J = 7.5 Hz, 1H), 5.80 (d, J = 2.6 Hz, 1H), 4.40 (d, J = 5.8 Hz, 1H), 4.10 (dd, J = 13.7, 6.2 Hz, 1H), 2.11 (dd, J = 12.6, 4.2 Hz, 1H), 2.06 (s, 3H), 2.01 (m, 2H), 1.77 (m, 3H), 1.61 (m, 6H), 1.41 (d, J = 12.5 Hz, 4H), 1.30 (m, 6H), 1.06 (m, 11H), 0.87 (m, 5H), 0.67 (d, J = 4.0 Hz, 3H).

[0245] Step 3: 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[l',2':l,2]phenal ene[7,8-d][l,3]dioxol-8-yl]- 1-(2,6-difluorophenyl)hexyl ester 21-2 (150 mg, 0.257 mmol, 1.0 eq) was dissolved in acetone (5 mL), N-hydroxyphthalimide (8.37 mg, 0.051 mmol, 0.2 eq), tert-butyl hydroperoxide (0.205 mL, 1.026 mmol, 4.0 eq) and cobalt(II) acetate, anhydrous (2.27 mg, 0.013 mmol, 0.05 eq) were added, the resulting mixture was stirred at 25 °C under N2for 18 hrs. The reaction progress was monitored by TLC plate (petroleum ether: ethyl acetate = 10: 1), the starting material was consumed completely, quenched with saturated sodium sulfite, water (10 mL) was added to the reaction mixture, the aqueous layer was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with saturated brine (15 mL), dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 80:20) to give white solid acetic acid-(5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl- 11-oxo-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetradecahydro-3aH- cyclopenta[l',2':l,2]phenal ene[7,8-d][l,3]dioxol-8-yl]-l-(2,6-difluorophenyl)hexyl ester 21-3 (90 mg, purity: 90%. yield: 52.74%). 1 H NMR (400 MHz, CDC13) δ 7.23 (s, 1H), 6.86 (t, J = 8.2 Hz, 2H), 6.04 (t, J = 7.4 Hz, 1H), 5.92 (s, 1H), 4.52 (d, J = 6.4 Hz, 1H), 4.33 (d, J = 5.6 Hz, 1H), 2.34 (d, J = 10.5 Hz, 2H), 2.06 (s, 3H), 1.82 (m, 3H), 1.63 (dd, J = 15.0, 9.3 Hz, 3H), 1.56 (d, J = 5.4 Hz, 8H), 1.37 (s, 4H), 1.28 (m, 9H), 1.07 (m, 4H), 0.87 (dd, J = 12.8, 6.4 Hz, 4H), 0.69 (d, J = 3.9 Hz, 3H).

[0246] Fourth step: Compound Acetic acid-(5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-11-oxo-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]dioxol-8-yl]-1-(2-fluorophenyl)hexyl ester 21-3 (90 mg, 0.150 mmol) was dissolved in methanol (5 mL), palladium on carbon (10.99 mg) was added, and the resulting mixture was stirred under H2at 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 get the crude. The crude was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 80:20), and acetic acid-(5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-2,2,5a,7a-tetramethyl-11-oxo-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]-1-(2,6-difluorophenyl)hexyl ester 21-4 (50 mg, 0.067 mmol, purity: 80%, yield: 44.30%) was obtained. 1 H NMR (400 MHz, CDCl3) δ 7.34 (s, 1H), 7.23 (s, 1H), 7.12 (s, 1H), 7.03 (s, 1H), 6.01 (dd, J = 10.9, 6.4 Hz, 1H), 3.98 (d, J = 3.4 Hz, 2H), 2.77 (s, 1H), 2.42 (s, 1H), 2.19 (dd, J = 12.7, 2.7 Hz, 2H), 2.08 (s, 3H), 1.74 (m, 9H), 1.53 (s, 3H), 1.38 (dd, J = 11.7, 7.8 Hz, 4H), 1.28 (d, J = 17.1 Hz, 10H), 0.95 (ddd, J = 10.8, 9.5, 6.5 Hz, 10H), 0.64 (d, J = 3.2 Hz, 3H).

[0247] Fifth step: Compound Acetic acid-(5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)- 2,2,5a,7a-tetramethyl-11-oxo-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]-l-(2,6- difluorophenyl)hexyl ester 21-4 (800 mg, 1.332 mmol) was dissolved in DAST (30 mL), the resulting mixture was stirred at 80 °C under N2for 3 h. The reaction progress was monitored by TLC plate (petroleum ether: ethyl acetate = 5: 1), the starting material was consumed. The reaction was cooled down to room temperature, and was added to ice water mixture carefully, the water layer was extracted with ethyl acetate (3 x 100 mL). The combined ethyl acetate layer was washed with saturated brine (100 mL). The organic phase was dried over Na2SO4, filtered and concentrated to get the crude, the crude was monitored by TLC plate (petroleum ether: ethyl acetate = 1: 1). The crude was added to silica gel and was columned with petroleum ether: ethyl acetate = 1: 1 to get colorless transparent solid acetic acid-(5R)-l-(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[l',2':7,8]phenanthro[l,2-d][l,3]dioxol-8-yl]hexyl ester 21-5 (600 mg, purity: 10%).

[0248] Step 6: Compound Acetic acid-(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]phenanthrol[1,2-d][1,3]dioxol-8-yl]hexyl ester 21-5 (600 mg, 10% content) was dissolved in tetrahydrofuran (30 mL), 3 mol / L hydrochloric acid solution (5 mL) was added, and the resulting mixture was stirred at 25 °C for 1 h. The reaction was monitored by TLC plate (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, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product 4 (petroleum ether: ethyl acetate = 1:1) was concentrated to give acetic acid-(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-(2,6-difluorophenyl)hexyl ester 21-6 (420 mg, purity: 10%).

[0249] 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, 10% content) was dissolved in a mixture solvent of methanol (10 mL) and tetrahydrofuran (10 mL), lithium hydroxide solution (3 mL) was added, the resulting mixture was stirred at 25 °C for 1 h. The reaction was monitored by TLC plate (petroleum ether: ethyl acetate = 1:1), the starting material was consumed. Water (5 mL) was added to the reaction system, the water layer was extracted with ethyl acetate (3 x 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 give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give the crude product, which was further separated by chiral resolution SFC (Instrument: Waters Acquity UPC C; 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 degree; Retention time t R = 1.738 min) to give white solid 24-[(2,6-difluorophenyl)(hydroxy)methyl]-7-fluoro-5a- cholan-3b,4b-diol 21 (30 mg, 0.055 mmol, 7.57%). 1 H NMR (400 MHz, CDCl3) d 7.20 (m, 1H), 6.88 (m, 2H), 5.03 (m, 1H), 3.85 (s, 1H), 3.59 (dt, J = 11.8, 4.1 Hz, 1H), 2.66 (t, J = 12.6 Hz, 1H), 2.01 (m, 2H), 1.83 (ddd, J = 33.4, 31.9, 12.6 Hz, 13H), 1.61 (m, 2H), 1.46 (m, 3H), 1.37 (m, 3H), 1.09 (dd, J = 12.7, 4.5 Hz, 3H), 1.04 (s, 3H), 0.90 (t, J = 6.0 Hz, 3H), 0.62 (d, J = 3.8 Hz, 3H). 13C NMR (101 MHz, CDC13) δ 151.96, 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 (377 MHz, CDC13) δ -89.26, -109.78, -115.39, -115.45. LC-MS: [M+H-H20] + = 503.7.

[0250] Example 22

[0251] Preparation of compound 22 24-[Methoxy(2-methoxyphenyl)methyl]-5α-cholestane-3β,4β-diol

[0252]

[0253] The first step, compound (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-hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]hexanal III (58 mg, 0.058 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 mL), the reaction system was cooled to 0 °C, then (2-methoxyphenyl)lithium (1.22 mL, 0.29 mmol, 5 eq) was added slowly, the reaction system was stirred at room temperature for 1 h. TLC (petroleum ether: ethyl acetate = 5:1) was used to monitor the reaction completion. 20 mL water was added to the reaction system, extracted with ethyl acetate (50 mL x 3), the combined organic phase was washed with water (30 mL), the combined organic phase was dried and concentrated to get the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 88:12 to 85:15) to get white solid (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-hexadeca- hydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]-1-(2-methoxyphenyl)hexan-1-ol 22-1 (7 mg, purity 90%, yield 20.14%). 1H NMR (400 MHz, CDC13) δ 7.32 - 7.27 (m, 1H), 7.25 - 7.21 (m, 1H), 6.95 (t, J = 7.5 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 4.85 (dt, J = 9.9, 5.8 Hz, 1H), 4.02 - 3.94 (m, 2H), 3.85 (s, 3H), 1.95 (d, J = 12.7 Hz, 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, 9.7 Hz, 2H), 1.04 (s, 2H), 0.89 (d, J = 4.0 Hz, 1H), 0.83 (dd, J = 16.6, 9.1 Hz, 1H), 0.65 (d, J = 2.7 Hz, 1H), 0.58 (d, J = 8.2 Hz, 1H).

[0254] 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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-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), and 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. Then iodomethane (39.51 mg, 0.278 mmol, 3.0 eq) was 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). After the raw material was consumed, the reaction was stopped. Water (10 mL) was added to the reaction system, and the water layer was extracted with ethyl acetate (3 x 25 mL). The EA layers were combined and washed with saturated brine (3 x 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 = 94: 6) to obtain a white solid (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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol 22-2 (20 mg, purity 95%, yield 88.89%). 1H NMR (400 MHz, CDC13) δ 7.34 (d, J = 7.5 Hz, 1H), 7.24 - 7.20 (m, 1H), 6.98 (t, J = 7.7 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 4.59 (dd, J = 11.1, 5.1 Hz, 1H), 4.05 - 3.91 (m, 2H), 3.82 (s, 3H), 3.22 (d, J = 1.6 Hz, 3H), 1.95 (d, J = 12.2 Hz, 1H), 1.76 (dd, J = 15.0, 5.6 Hz, 3H), 1.66 (dd, J = 20.4, 8.4 Hz, 4H), 1.51 (s, 3H), 1.41 (ddd, J = 29.3, 15.8, 6.4 Hz, 6H), 1.30 (s, 3H), 1.28 - 1.18 (m, 3H), 1.08 (d, J = 9.2 Hz, 2H), 1.04 (s, 3H), 1.01 - 0.96 (m, 2H), 0.88 (dd, J = 6.4, 3.6 Hz, 3H), 0.64 (t, J = 2.5 Hz, 3H), 0.62 - 0.55 (m, 1H).

[0255] The third step is to dissolve 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-hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-22-2 (45 mg, 0.072 mmol, 1.0 eq) in tetrahydrofuran (5 mL), add dilute hydrochloric acid (0.5 mL, 3 mol / L), and stir the reaction system at room temperature for 40 min. TLC (petroleum ether: ethyl acetate = 2:1) is used to monitor the reaction. When the raw material is consumed, the reaction is stopped. Add water (10 mL) to the reaction system, and extract the water layer with ethyl acetate (3 x 25 mL). Combine the EA layers and wash with saturated brine (3 x 10 mL). Dry the ethyl acetate layer with anhydrous sodium sulfate, filter and concentrate to obtain the crude product. Purify the crude product by column chromatography (petroleum ether: ethyl acetate = 73:27) to obtain white solid 24-[methoxy(2-methoxyphenyl)methyl]-5α-cholestane-3β,4β-diol 22 (21.37 mg, purity 91.20%, yield 52.53%). 1H NMR (400 MHz, CDC13) δ 7.34 (d, J = 7.6 Hz, 1H), 7.25 - 7.19 (m, 1H), 6.98 (t, J = 7.8 Hz, 1H), 6.86 (d, J = 8.1 Hz, 1H), 4.59 (dd, J = 11.1, 5.1 Hz, 1H), 3.82 (s, 3H), 3.73 (s, 1H), 3.55 (d, J = 11.2 Hz, 1H), 3.22 (d, J = 1.5 Hz, 3H), 1.95 (d, J = 12.0 Hz, 1H), 1.74 (dt, J = 15.2, 14.2 Hz, 6H), 1.54 (dd, J = 16.6, 7.5 Hz, 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, 3.6 Hz, 3H), 0.63 (d, J = 1.1 Hz, 3H), 0.57 (dd, J = 16.8, 5.9 Hz, 1H). 13 C NMR (101 MHz, CDC13) δ 157.13, 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.

[0256] Examples 35 & 36

[0257] 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-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0258] 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-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol.

[0259]

[0260] First Step: Dissolve the starting 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-butyllithium (1.8 mL, 0.45 mmol, 3.0 eq), and keep the temperature stirring for 30 min. Dissolve the mixture of 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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]hexanal I and (5R)-5-[(3aS,5aR,5bR,7aR,8R,10aR,12bR)-l l-fluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,12,12a,12b-tetradecahydro-3aH- cyclopenta[l',2':7,8]phenanthro[l,2-d][l,3]dioxol-8-yl]hexanal II (70 mg, 0.15 mmol, 1.0 eq) in tetrahydrofuran (2 mL) to the above reaction solution, and stir the reaction system at -78 °C for 30 min. Monitor the completion of the reaction by TLC plate (petroleum ether: ethyl acetate = 5: 1). Add 10 mL of water to the reaction system, extract with ethyl acetate (100 mL x 3), wash the combined organic phase with saturated sodium chloride (10 mL), dry the combined organic phase, and concentrate to obtain colorless oil of 35-1 and 36-1 crude product (70 mg), which is then directly used in the next step.

[0261] Step 2: 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- hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]-1-(4-fluoro-2- methoxyphenyl)hexan-1-ol 35-1 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]dioxol-8-yl]-1-(4-fluoro-2-methoxyphenyl) hexan-1-ol 36-1 (70 mg, 0.11 mmol, 1.0 eq) were dissolved in tetrahydrofuran (3 mL), diluted 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) was used to monitor the reaction. When the raw material was consumed, the reaction was stopped. Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 x 10 mL). The EA layers were combined and washed with saturated brine (3 x 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 resolution SFC (instrument: Waters Acquity UPC C; 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-dimethylhexadecahydro-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, 99% purity, 7% yield, retention time t R = 2.015 min).

[0262] Compound 35: 1 H NMR (400 MHz, CDC13) δ 7.19 - 7.16 (m, 1H), 6.62 - 6.50 (m, 2H), 4.81 - 4.74 (m, 1H), 3.75 (d, J = 13.2 Hz, 3H), 3.67 (s, 1H), 3.56 - 3.49 (m, 1H), 2.22 - 2.05 (m, 1H), 1.90 (d, J = 12.9 Hz, 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, 4.1 Hz, 3H), 0.59 (d, J = 1.7 Hz, 3H). 19 F NMR (376 MHz, CDC13) δ -88.63, -89.25, -110.63, -111.25, -113.00, -113.06.

[0263] Compound 36: 1 H NMR (400 MHz, CDC13) δ 7.17 (d, J = 4.3 Hz, 1H), 6.64 - 6.47 (m, 2H), 4.82 - 4.74 (m, 1H), 3.78 (s, 1H), 3.77 (d, J = 5.9 Hz, 3H), 3.56 - 3.49 (m, 1H), 2.59 (s, 1H), 1.96 (d, J = 11.9 Hz, 1H), 1.90 - 1.73 (m, 6H), 1.68 - 1.51 (m, 11H), 1.42 - 1.16 (m, 10H), 1.06 - 0.99 (m, 3H), 0.97 (s, 3H), 0.84 (dd, J = 6.5, 3.3 Hz, 3H), 0.56 (d, J = 1.9 Hz, 3H). 19 F NMR (376 MHz, CDC13) δ -109.80, -113.00, -113.06.

[0264] Examples 37 & 38

[0265] Preparation of 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-dimethylhexadecahydro-1H- cyclopenta[1,2-a]phenanthrene-6,7-diol and 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.

[0266]

[0267] Step 1: Compound 1-bromo-2-methoxybenzene (1309.01 mg, 6.999 mmol. 3.0 eq) was dissolved in tetrahydrofuran (50 mL) under nitrogen protection, cooled to -78 °C, and n-butyllithium, 2.5 M n-hexane solution (3.359 mL, 8.398 mmol, 3.6 eq) was added. The reaction was incubated for 1 h, 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]phenalene-8-yl]hexanal III (1000 mg, 2.333 mmol, 1.0 eq) in tetrahydrofuran (10 mL) was added. The reaction was incubated for 1 h. TLC (petroleum ether: ethyl acetate = 5:1) was used to monitor the progress of the reaction, and the starting material was consumed. The reaction was quenched with saturated ammonium chloride, and the aqueous layer was extracted with ethyl acetate (3 x 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]phenalene-8-yl]-1-(2-methoxyphenyl)hexan-1-ol 37-1 (750 mg, purity: 90%, yield: 53.90%) as a white solid. 1H NMR (400 MHz, CDC13) δ 7.30 (ddd, J = 7.4, 3.9, 1.6 Hz, 1H), 7.23 (m, 1H), 6.95 (t, J = 7.4 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 5.74 (dd, J = 49.3, 2.9 Hz, 1H), 4.85 (d, J = 7.3 Hz, 1H), 4.40 (d, J = 5.8 Hz, 1H), 4.14 (d, J = 3.6 Hz, 0H), 3.85 (s, 3H), 3.56 (dd, J = 7.3, 3.8 Hz, 1H), 2.05 (m, 3H), 1.71 (m, 10H), 1.42 (d, J = 8.4 Hz, 4H), 1.17 (d, J = 6.5 Hz, 4H), 1.06 (ddd, J = 25.8, 14.6, 5.0 Hz, 6H), 0.90 (dt, J = 7.5, 3.7 Hz, 4H), 0.68 (dd, J = 4.6, 2.7 Hz, 3H).

[0268] 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[l’,2’:l,2]phenanthrol[7,8-d][l,3]dioxol-8-yl]-l-(2-methoxyphenyl)hexan- 1-ol 37-1 (750 mg, 1.397 mmol, 1.0 eq) was dissolved in dichloromethane (50 mL), 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 at 25 °C under N2for 3 h. TLC (petroleum ether: ethyl acetate = 5: 1) was used to monitor the reaction progress, the starting material was consumed completely, the reaction was quenched with methanol, water (10 mL) was added to the reaction system, the aqueous layer was extracted with dichloromethane (3 x 15 mL). The combined organic phase was washed with saturated brine (5 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was added to silica gel and eluted with petroleum ether: ethyl acetate = 10: 1 to give white solid 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[l’,2’:l,2]phenanthrol[7,8-d][l,3]dioxol-8-yl]-l-(2-methoxyphenyl)hexyl ester 37-2 (750 mg, purity: 90%, yield: 83.46%). 1H NMR (400 MHz, CDC13) δ 7.30 (d, J = 7.6 Hz, 1H), 7.22 (dd, J = 5.5, 4.0 Hz, 1H), 6.94 (t, J = 7.5 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 6.16 (m, 1H), 5.80 (d, J = 2.7 Hz, 1H), 4.40 (d, J = 5.8 Hz, 1H), 4.11 (m, 1H), 3.84 (d, J = 6.8 Hz, 3H), 3.55 (d, J = 12.1 Hz, 0H), 2.09 (t, J = 3.8 Hz, 3H), 2.00 (d, J = 12.6 Hz, 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 = 3.5 Hz, 3H).

[0269] Step 3: 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[l',2':l,2]phenal eno[7,8-d][l,3]dioxol-8-yl]- 1-(2-methoxyphenyl)hexyl ester 37-2 (750 mg, 1.296 mmol, 1.0 eq) was dissolved in acetone (30 mL), 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, and the resulting mixture was stirred at 25 °C under N2for 18 h. The reaction was monitored by TLC plate (petroleum ether: ethyl acetate = 5: 1). Diluted with ethyl acetate, quenched with saturated sodium sulfite, the aqueous layer was extracted with ethyl acetate (3 x 10 mL). The combined ethyl acetate layers were washed with saturated brine (15 mL). The ethyl acetate layer was dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 80:20) to give acetic acid-(5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl- 11-oxo-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetradecahydro-3aH- cyclopenta[l',2':l,2]phenal eno[7,8-d][l,3]dioxol-8-yl]-l-(2-methoxyphenyl)hexyl ester 37-3 (340 mg, purity: 90%, yield: 39.84%) as a white solid. 1H NMR (400 MHz, CDC13) δ 7.30 (d, J = 7.5 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 6.94 (t, J = 7.5 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 6.16 (s, 1H), 5.92 (s, 1H), 4.52 (d, J = 6.4 Hz, 1H), 4.33 (d, J = 5.7 Hz, 1H), 3.84 (s, 3H), 2.35 (d, J = 10.3 Hz, 2H), 2.08 (d, J = 1.8 Hz, 3H), 2.05 (s, 1H), 1.80 (m, 4H), 1.63 (dd, J = 16.1, 10.4 Hz, 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, 9.0 Hz, 4H), 0.88 (dt, J = 7.8, 3.9 Hz, 3H), 0.69 (d, J = 1.7 Hz, 3H).

[0270] Fourth Step: Compound Acetic acid-(5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)- 2,2,5a,7a-tetramethyl-11-oxo-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b- tetradecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]-l- (2-methoxyphenyl)hexyl ester 37-3 (340 mg, 0.574 mmol) was dissolved in methanol (20 mL), palladium on carbon (100 mg, 0.940 mmol) was added, and the resulting mixture was stirred in H2, 25 °C for 1 h. TLC (petroleum ether: ethyl acetate = 5: 1) was used to monitor the reaction progress. Filtration and concentration gave the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 80:20) to give white solid acetic acid-(5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-2,2,5a,7a- tetramethyl-11-oxo-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]-l- (2-methoxyphenyl)hexyl ester 37-4 (250 mg, purity: 90%, yield: 65.95%). 1H NMR (400 MHz, CDC13) δ 7.29 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 8.2 Hz, 1H), 6.94 (t, J = 7.5 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 6.16 (t, J = 6.3 Hz, 1H), 3.99 (dt, J = 8.4, 7.3 Hz, 2H), 3.84 (d, J = 6.9 Hz, 3H), 2.77 (t, J = 13.5 Hz, 1H), 2.42 (t, J = 11.2 Hz, 1H), 2.21 (d, J = 2.7 Hz, 1H), 2.08 (d, J = 0.9 Hz, 3H), 1.97 (d, J = 12.5 Hz, 1H), 1.87 (m, 2H), 1.74 (m, 3H), 1.63 (d, J = 14.5 Hz, 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 = 1.5 Hz, 3H).

[0271] Step 5: Compound Acetic acid-(5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)- 2,2,5a,7a-tetramethyl-11-oxymethylene-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]-l-(2- methoxyphenyl)hexyl ester 37-4 (180 mg, 0.303 mmol) was dissolved in DAST (5 mL, 0.333 mmol) and the resulting mixture was stirred at 80 °C under N2for 3 h. The reaction progress was monitored by TLC (petroleum ether: ethyl acetate = 5: 1), and the starting material was consumed. The reaction mixture was cooled to room temperature, diluted with dichloromethane, and added carefully to an ice-water mixture. The aqueous layer was extracted with dichloromethane (3 x 25 mL). The combined dichloromethane was washed with saturated brine (15 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to give a mixture of 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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]-l-(2- methoxyphenyl)hexyl ester 37-5 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-cyclopenta[l,2-d][l,3]dioxol-8-yl)-l-(2-methoxyphenyl)hexyl acetate 38-1 (150 mg, purity: 80%, yield: 64.29%), which was used in the next step without further purification.

[0272] Step 6: A mixture of compound 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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]-l-(2- methoxyphenyl)hexyl ester 37-5 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-cyclopenta[7,8]phenanthro[l,2-d][l,3]dioxol-8-yl)-l-(2-methoxyphenyl)hexyl acetate 38-1 mixture (120 mg, 0.202 mmol) was dissolved in tetrahydrofuran (20 mL), diluted with dilute hydrochloric acid (0.067 mL), and 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 mixture was diluted with ethyl acetate, and the aqueous layer was extracted with ethyl acetate (3 x 25 mL). The combined ethyl acetate layers were washed with saturated brine (15 mL). The ethyl acetate layer was dried over anhydrous Na2SO4, filtered, and concentrated to give a mixture of crude 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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]-l-(2- methoxyphenyl)hexyl ester 37-6 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-cyclopenta[7,8]phenanthro[l,2-d][l,3]dioxol-8-yl)-l-(2-methoxyphenyl)hexyl acetate 38-2 mixture (80 mg, 37-6 purity: 80%), which was used in the next step without further purification.

[0273] Step 7: A mixture of compound 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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]-l-(2- methoxyphenyl)hexyl ester 37-6 and (5R)-5-((3S,4R,5R,9R,10R,13R,14R,17R)-7-fluoro-3,4- dihydroxy-10,13-dimethyl-2,3,4,5,6,9,10,l l,12,13,14,15,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-17-yl)-l-(2-methoxyphenyl)hexyl acetate 38-2 (80 mg, 0.139 mmol) was dissolved in a mixture solvent of methanol (1 mL) and tetrahydrofuran (1 mL), the resulting mixture was stirred at 25 °C for 3 h. TLC plate (petroleum ether: ethyl acetate = 1: 1) was used to monitor the reaction. The reaction was cooled down to room temperature, and was added to ice water mixture carefully, the water layer was extracted with ethyl acetate (3 x 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 a crude product. The crude product was added to silica gel and was columned with petroleum ether: ethyl acetate, to give a white solid, the solid was further separated by chiral separation (instrument: Waters Acquity UPC C; 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 give (lR,3aS,3bS,5aR,6R,7S,9aR,9bS,l laR)-4,4-difluoro-l-[(2R)-6-hydroxy-6-(2- methoxyphenyl)hexan-2-yl]-9a,l la-dimethylhexadecahydro-lH-cyclopenta[l,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-1 / - / -cyclopenta[a]phenanthrene-3,4-diol 38 (8.67 mg, 0.016 mmol, purity: 93.98%, yield: 11.34%, retention time t R = 1.748 min).

[0274] Compound 37: 1 H NMR (400 MHz, CDCb) d 7.32 - 7.28 (m, 1H), 7.25 - 7.21 (m, 1H), 7.00 - 6.93 (m, 1H), 6.88 (dd, J = 8.1, 3.7 Hz, 1H), 4.85 (dt, J = 9.7, 5.9 Hz, 1H), 3.86 (s, 3H), 3.74 (s, 1H), 3.64 - 3.57 (m, 1H), 2.35 - 1.94 (m, 4H), 1.88 - 1.78 (m, 5H), 1.40 (ddd, J = 18.9, 11.1, 7.2 Hz, 8H), 1.27 (t, J = 14.2 Hz, 4H), 1.16 - 1.07 (m, 3H), 1.06 (s, 3H), 1.02 - 0.93 (m, 2H), 0.90 (dd, J = 6.4, 4.1 Hz, 3H), 0.65 (d, J = 2.3 Hz, 3H). 13 C NMR (101 MHz, CDCb) d 161.17, 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 (377 MHz, CDCb) d -88.63, -89.25, -110.62, -111.25.

[0275] Compound 38: 1H NMR (400 MHz, CDC13) δ 7.30 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 7.9 Hz, 1H), 6.96 (t, J = 7.5 Hz, 1H), 6.88 (d, J = 8.1 Hz, 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, 3.5 Hz, 3H), 0.62 (d, J = 2.5 Hz, 3H). 19 F NMR (377 MHz, CDC13) δ -119.83.

[0276] Examples 39 & 40

[0277] 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-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene- 6,7-diol 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

[0278]

[0279] Step 1: Dissolve the starting 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-butyllithium (1.8 mL, 0.45 mmol, 3.0 eq), and keep the temperature stirring for 30 min. Dissolve the mixture of 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-hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-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,6,7,7a,8,9,10,10a,12,12a,12b-tetradecahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxol-8-yl]hexanal II (70 mg, 0.15 mmol, 1.0 eq) in tetrahydrofuran (2 mL) to the above reaction solution, and stir the reaction system at -78 °C for 30 min. Monitor the progress of the reaction by TLC (petroleum ether: ethyl acetate = 5:1), and the starting material is consumed. Add 10 mL of water to the reaction system, extract with ethyl acetate (100 mL x 3), wash the combined organic phase with saturated sodium chloride (10 mL), dry the combined organic phase, and concentrate to give a colorless oil mixture 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-hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]-1-(3-methoxyphenyl)hexan-1-ol 39-1 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]dioxol-8-yl]-1-(3-methoxyphenyl)hexan-1-ol 40-1 (70 mg), which is then directly used in the next step.

[0280] Step 2: 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- hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]-1-(3- methoxyphenyl)hexan-1-ol 39-1 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]dioxol-8-yl]-1-(3-methoxyphenyl)hexan-1- ol 40-1 crude (70 mg, 0.11 mmol, 1.0 eq) were dissolved in tetrahydrofuran (3 mL), diluted hydrochloric acid (1 mL, 3 mol / L) was added, and the reaction system was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC plate (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 x 10 mL). The EA layers were combined and washed with saturated brine (3 x 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 resolution SFC (instrument: Waters Acquity UPC C; 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 milliliters / minute; column temperature: 37 degrees) to give (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-(3- methoxyphenyl)hexan-2-yl]-9a,11a-dimethylhexadecahydro-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, 100% purity, 6% yield, retention time t R = 3.272 min).

[0281] Compound 39: 1 H NMR (400 MHz, CDC13) δ 7.25 (s, 1H), 6.93 (d, J = 6.9 Hz, 2H), 6.82 (dd, J = 8.6, 2.0 Hz, 1H), 4.65 (dd, J = 13.1, 6.0 Hz, 1H), 3.83 (s, 3H), 3.75 (s, 1H), 3.64 - 3.57 (m, 1H), 1.97 (d, J = 12.8 Hz, 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 = 2.3 Hz, 3H). 19 F NMR (376 MHz, CDC13) δ -88.64, -89.26, -110.63, -111.26. Compound 40: 1 H NMR (400 MHz, CDC13) δ 7.25 (s, 0H), 6.95 - 6.90 (m, 2H), 6.82 (dd, J = 8.7, 2.0 Hz, 1H), 4.66 (dd, J = 13.3, 6.3 Hz, 1H), 3.86 (s, 1H), 3.83 (s, 3H), 3.63 - 3.56 (m, 1H), 2.66 (t, J = 13.5 Hz, 1H), 1.78 (dddd, J = 45.2, 31.3, 23.5, 11.4 Hz, 17H), 1.49 - 1.42 (m, 4H), 1.28 (d, J = 11.9 Hz, 5H), 1.05 (s, 3H), 0.91 (dd, J = 6.4, 4.2 Hz, 3H), 0.63 (d, J = 2.4 Hz, 3H). 19 F NMR (376 MHz, CDC13) δ -109.78.

[0282] Example 43

[0283] Preparation of compound 43, 24-(hydroxy{2-[(trifluoromethyl)oxy]phenyl}methyl)-5α-cholan-3β-ol

[0284]

[0285]

[0286] The first step involves reacting acetic acid-(1R,3aS,7S,9aR,11aR)-1-[(2R)-6-methoxy-6-oxoylide-2-yl]-9a,11a-dimethyl-2,3,3a,3b,

[0287] 4,6,7,8,9,9a,9b,10,11,11a-tetradecano-1H-cyclopentano[1,2-i]phenanthrene-7-yl ester 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 lithium hydroxide aqueous solution (5 mL, 5 mmol) was added. The reaction was carried out at room temperature, and the reaction was monitored by TLC (petroleum ether: ethyl acetate = 10:1) until complete. The organic solvent was removed by concentration. The remaining crude product was extracted with water and ethyl acetate. The organic phase was separated, dried, and concentrated to obtain (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-tetradecanoic acid 43-1 (800 mg, 2.06 g / L).

[0288] (91.6% mmol) White solid. 1 H NMR (399MHz, Chloroform-d) δ5.33 (s, 1H), 3.49 (d, J = 12.8Hz, 1H),

[0289] 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).

[0290] 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]phenanthren-1-yl]hexanoic acid 43-1 (300 mg, 0.77 mmol) was dissolved in tetrahydrofuran (5 mL), after adding 2-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (354 mg, 0.93 mmol), N,N- diisopropylethylamine (300 mg, 2.32 mmol), it was stirred at room temperature for 30 minutes, then after adding hydroxylamine hydrochloride (150.2 mg, 1.54 mmol), it was stirred at room temperature overnight. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 5:1). It was extracted with ethyl acetate and water, 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]phenanthren-1-yl]-N-methoxy-N-methylhexanamide 43-2 (100 mg, 30%). 1 H NMR (399 MHz, Chloroform-d) δ 5.33 (d, J = 5.1 Hz, 1H), 3.66 (s, 3H), 3.49 (dq, J = 10.9, 5.6, 4.9 Hz, 1H), 3.16 (s, 3H), 2.35 (q, J = 7.6 Hz, 2H), 2.29 - 2.15 (m, 2H), 2.01 - 1.90 (m, 2H), 1.88 - 1.76 (m, 3H), 1.46 (d, J = 8.3 Hz, 5H), 1.43 - 1.36 (m, 3H), 1.21 (ddd, J = 26.0, 13.5, 5.9 Hz, 2H), 1.15 - 1.01 (m, 5H), 0.98 (s, 4H), 0.96 - 0.85 (m, 5H), 0.65 (s, 3H).

[0291] Third step, dissolve (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-hydroxy-9a,11a- dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2- a]phenanthren-1-yl]-N-methoxy-N-methylhexanamide 43-2 (200 mg, 0.51 mmol) in methanol (5 mL), add Pd / C (20 mg, 10%), replace H2, continue stirring at room temperature overnight, TLC (petroleum ether: ethyl acetate = 5:1) monitor the reaction complete. Add ethyl acetate and water extraction, organic phase separation, anhydrous sodium sulfate drying, concentrated, column chromatography (petroleum ether: ethyl acetate = 0~20%) purification get (5R)-5-[(1R,3aS,3bR,5aS,7S,9aS,9bS,11aR)-7-hydroxy-9a,11a- dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-N-methoxy-N- methylhexanamide 43-3 (100 mg, 0.25 mmol, 50%). 1 H NMR (399 MHz, Chloroform-d) δ 3.66 (s, 3H), 3.57 (s, 1H), 3.16 (s, 3H), 2.35 (d, J = 7.7 Hz, 2H), 1.92 (s, 1H), 1.71 (dt, J = 37.0, 17.5 Hz, 5H), 1.49 (d, J = 30.3 Hz, 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).

[0292] Fourth step, dissolve (5R)-5-[(1R,3aS,3bR,5aS,7S,9aS,9bS,11aR)-7-hydroxy-9a,11a- dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-N-methoxy-N- methylhexanamide 43-3 (100 mg, 0.25 mmol) in THF (10 mL), cooling to -50 °C, add DIBAL-H (0.5 mL, 5.0 eq), rise to room temperature reaction 2 h. TLC (petroleum ether: ethyl acetate = 5:1) monitor the reaction complete. Add ethyl acetate and water extraction, organic phase separation, anhydrous sodium sulfate drying, concentrated, column chromatography (petroleum ether: ethyl acetate = 0~20%) purification get (5R)-5-[(1R,3aS,3bR,5aS,7S,9aS,9bS,11aR)-7-hydroxy-9a,11a- dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanal 43-4 (60 mg, 0.16 mmol, 64%). 1H NMR (399 MHz, Chloroform-d) δ 9.74 (s, 1H), 3.57 (s, 1H), 2.37 (d, J = 6.9 Hz, 1H), 1.96 - 1.62 (m, 5H), 1.55 (s, 11H), 1.45 - 1.21 (m, 14H), 1.07 (q, J = 8.5, 6.5 Hz, 5H), 1.00 - 0.84 (m, 7H), 0.78 (s, 3H), 0.63 (s, 3H), 0.60 (s, 1H).

[0293] To a solution of (5R)-5-[(1R,3aS,3bR,5aS,7S,9aS,9bS,11aR)-7-hydroxy-9a,11a- dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanal 43-4 (60 mg, 0.16 mmol) in THF (10 mL) was added n-BuLi (1.6 M, 1.15 mmol) dropwise at -78 °C. The mixture was stirred at -78 °C for 1 h. Then, 2-bromo-5-fluorophenylboronic acid (30 mg, 0.16 mmol) and Pd(PPh3)4(10 mg) were added. The mixture was stirred at room temperature for 16 h. The reaction was quenched with saturated NH4CI solution. The mixture was extracted with EtOAc. The organic phase was separated and concentrated. The residue was purified by column chromatography (petroleum ether: EtOAc = 5:1) to give 24-(hydroxy{2-fluorophenyl}methyl)-5α- cholan-3β-ol 43-5 (9 mg, 0.016 mmol, 10%) as a white solid. 1 H NMR (399 MHz, Chloroform-d) δ 7.57 (dt, J = 6.7, 2.3 Hz, 1H), 7.29 (td, J = 6.8, 6.2, 3.9 Hz, 2H), 7.22 - 7.17 (m, 1H), 5.04 (d, J = 6.8 Hz, 1H), 1.93 (d, J = 12.5 Hz, 1H), 1.77 (d, J = 11.6 Hz, 2H), 1.73 - 1.60 (m, 4H), 1.52 (s, 3H), 1.43 (d, J = 3.2 Hz, 1H), 1.39 (d, J = 18.7 Hz, 4H), 1.29 (dd, J = 18.1, 6.2 Hz, 4H), 1.24 (d, J = 3.9 Hz, 3H), 1.11 (s, 1H), 1.08 - 1.03 (m, 3H), 1.02 - 0.93 (m, 3H), 0.87 (dd, J = 6.5, 4.0 Hz, 3H), 0.78 (s, 3H), 0.62 (d, J = 1.5 Hz, 3H). 13C NMR (100 MHz, Chloroform-d) δ 128.44, 128.42, 127.40, 127.00, 119.93, 71.37, 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 (376 MHz, Chloroform-d) δ -56.84 (dd, J = 4.0, 1.8 Hz). LC-MS: [M-OH] + = 436.4. Examples 44 & 45

[0294] 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-dimethylhexadecahydro-1H- cyclopenta[1,2-a]phenanthrene-6,7-diol

[0295]

[0296] Step 1: Dissolve the starting 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-butyllithium (1.8 mL, 0.45 mmol, 3.0 eq), and keep the temperature stirring for 30 min. Dissolve the mixture of 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- hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-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,6,7,7a,8,9,10,10a,12,12a,12b-tetradecahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxol-8-yl]hexanal II (70 mg, 0.15 mmol, 1.0 eq) in tetrahydrofuran (2 mL) to the above reaction solution, and stir the reaction system at -78 °C for 30 min. Monitor the progress of the reaction by TLC (petroleum ether: ethyl acetate = 5:1, molybdenum phosphate baking plate), and the starting material is consumed. Add 10 mL of water to the reaction system, extract with ethyl acetate (100 mL x 3), wash the combined organic phase with saturated sodium chloride (10 mL), dry the combined organic phase, and concentrate to obtain colorless oil 44-1 and 45-1 crude product (70 mg), which is then directly used in the next step.Step 2: 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- hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]-1-(3- fluorophenyl)hexan-1-ol 44-1 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]dioxol-8-yl]-1-(3-fluorophenyl)hexan-1-ol 45-1 crude (70 mg, 0.11 mmol, 1.0 eq) were 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 progress of the reaction was detected by TLC plate (petroleum ether: ethyl acetate = 5:1, molybdenum acid baking plate), and the reaction was stopped when the raw material was consumed. Water (10 mL) was added to the reaction system, and the water layer was extracted with ethyl acetate (3 x 10 mL). The EA layer was combined and washed with saturated brine (3 x 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 resolution SFC (instrument: Waters Acquity UPC C; 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 give (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-(3-fluorophenyl)-6- hydroxyhexan-2-yl]-9a,11a-dimethylhexadecahydro-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, 91.52% purity, 5% yield; retention time t R = 1.730 min).

[0297] Compound 44: 1 H NMR (400 MHz, CDC13) δ 7.23 (dd, J = 13.8, 7.9 Hz, 1H), 7.02 (dd, J = 12.2, 9.2 Hz, 2H), 6.89 (t, J = 8.4 Hz, 1H), 4.60 (dd, J = 12.9, 5.9 Hz, 1H), 3.67 (s, 1H), 3.53 (dt, J = 11.3, 4.1 Hz, 1H), 2.22 - 2.02 (m, 1H), 1.90 (d, J = 12.8 Hz, 1H), 1.80 - 1.55 (m, 13H), 1.43 - 1.14 (m, 10H), 1.04 (dd, J = 14.1, 5.4 Hz, 2H), 0.99 (s, 3H), 0.93 - 0.86 (m, 2H), 0.84 - 0.80 (m, 3H), 0.58 (d, J = 1.7 Hz, 3H). 19 F NMR (377 MHz, CDC13) δ -88.64, -89.26, -110.63, -111.26, -113.02.

[0298] Compound 45: 1 H NMR (400 MHz, CDC13) δ 7.27 - 7.20 (m, 1H), 7.02 (dd, J = 12.1, 9.3 Hz, 2H), 6.89 (t, J = 8.4 Hz, 1H), 4.61 (dd, J = 12.9, 5.9 Hz, 1H), 3.78 (s, 1H), 3.52 (dt, J = 11.7, 4.0 Hz, 1H), 2.58 (dd, J = 16.6, 8.1 Hz, 1H), 1.95 (d, J = 12.5 Hz, 1H), 1.67 (dddd, J = 32.2, 23.7, 10.5, 6.3 Hz, 17H), 1.42 - 1.16 (m, 13H), 1.05 - 0.99 (m, 4H), 0.97 (s, 3H), 0.83 (dt, J = 6.7, 3.4 Hz, 3H), 0.57 (dd, J = 14.6, 4.4 Hz, 3H). 19F NMR (377 MHz, CDC13) δ -109.76, -113.02. LC-MS: [M+H-H20] + = 485.65.

[0299] Examples 46 & 48

[0300] 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-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 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 Preparation of Compound 48.

[0301]

[0302]

[0303] First step: Dissolve the starting 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-butyllithium (1.8 mL, 0.45 mmol, 3.0 eq), and keep the temperature stirring for 30 min. Dissolve the mixture of 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- hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-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,6,7,7a,8,9,10,10a,12,12a,12b-tetradecahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxol-8-yl]hexanal II (70 mg, 0.15 mmol, 1.0 eq) in tetrahydrofuran (2 mL) to the above reaction solution, and stir the reaction system at -78 °C for 30 min. Monitor the progress of the reaction by TLC plate (petroleum ether: ethyl acetate = 5:1), and the starting material is consumed. Add 10 mL of water to the reaction system, extract with ethyl acetate (100 mL x 3), wash the combined organic phase with saturated sodium chloride (10 mL), dry the combined organic phase, and concentrate to obtain colorless oil 46-1 and 48-1 crude (70 mg), which is directly used in the next step.

[0304] Step 2: The 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- hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]-1-(3-fluoro-2- methoxyphenyl)hexan-1-ol 46-1 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]dioxol-8-yl]-1-(3-fluoro-2-methoxyphenyl) hexan-1-ol 48-1 (70 mg, 0.11 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL), diluted 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) was used to monitor the progress of the reaction, and 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 x 10 mL). The ethyl acetate layers were combined and washed with saturated brine (3 x 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 resolution SFC (instrument: Waters Acquity UPC C; 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 give (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-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7- diol 46 (38.58 mg, purity 100%, yield 53%, retention time t R= 1.341 min) 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-dimethylhexadecahydro-1H-cyclopenta[1,2- a]phenanthrene-6,7-diol 48 (3.464 mg, purity 95.32%, yield 5%, retention time t R = 1.879 min).

[0305] Compound 46: 1 H NMR (400 MHz, CDC13) δ 7.04 (dd, J = 6.5, 3.2 Hz, 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 = 16.5 Hz, 1H), 1.95 (d, J = 15.1 Hz, 1H), 1.83 - 1.64 (m, 10H), 1.32 (ddd, J = 59.4, 28.0, 19.9 Hz, 12H), 1.10 - 1.00 (m, 4H), 0.98 (s, 3H), 0.85 (dd, J = 6.5, 3.3 Hz, 3H), 0.82 (d, J = 8.3 Hz, 2H), 0.56 (t, J = 4.6 Hz, 3H). 19 F NMR (376 MHz, Chloroform-d) δ -88.63, -89.26, -110.63, -111.26, -130.48, -130.51.

[0306] Compound 48: 1 H NMR (400 MHz, CDC13) δ 7.07 - 6.99 (m, 1H), 6.97 - 6.88 (m, 2H), 4.84 (dt, J = 13.2, 5.9 Hz, 1H), 3.90 (d, J = 1.6 Hz, 3H), 3.67 (s, 1H), 3.53 (dt, J = 11.3, 4.0 Hz, 1H), 2.23 - 2.04 (m, 1H), 1.90 (d, J = 12.8 Hz, 1H), 1.68 (dddd, J = 19.3, 16.3, 8.7, 3.9 Hz, 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, 3.8 Hz, 3H), 0.59 (d, J = 2.4 Hz, 3H). 19F NMR (376 MHz, Chloroform-d) δ -109.78, 130.48. LC-MS: [M+H-H20] + = 515.70.

[0307] Example 47

[0308] Preparation of Compound 47 (3S,4R,5R,8S,9S,10R,13R,14S,17R,20R)-N-(2- fluorophenyl)-3,4-dihydroxy-N-methyl-5a-cholan-24-amide

[0309]

[0310]

[0311] 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]phenanthren-7-yl acetate I-3 (2 g, 5.368 mmol) was dissolved in tetrahydrofuran (30 mL), (methoxycarbonylmethylidene)triphenylphosphonium bromide (5.38 g, 16.105 mmol) was added at room temperature, then heated to 90 °C with stirring, TLC (petroleum ether: ethyl acetate = 10:1) was used to monitor the reaction, after the reaction was completed, it was cooled to room temperature, water and ethyl acetate were added for extraction, the organic phase was separated and dried, concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 20:1 ~ 5:1) to obtain (1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R,3E)-5-methoxy-5-oxovinyl]-9a,11a- dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H- cyclopenta[1,2-i]phenanthren-7-yl acetate 47-1 (1.4 g, 54.76%) white solid. 1H NMR (399 MHz, Chloroform-d) δ 6.82 (dd, J = 15.6, 9.0 Hz, 1H), 5.72 (d, J = 15.6 Hz, 1H), 5.35 (d, J = 5.1 Hz, 1H), 4.64 - 4.52 (m, 1H), 3.70 (s, 3H), 2.30 (d, J = 7.8 Hz, 2H), 2.25 (d, J = 6.8 Hz, 1H), 2.01 (s, 3H), 1.97 (d, J = 9.8 Hz, 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, 3.8 Hz, 3H), 1.18 - 1.09 (m, 2H), 1.07 (d, J = 6.7 Hz, 3H), 1.00 (s, 3H), 0.98 - 0.90 (m, 2H), 0.88 - 0.78 (m, 1H), 0.69 (s, 3H).

[0312] The second step, (1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R,3E)-5-methoxy-5- oxovinyl] -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, 3.266 mmol) was dissolved in a mixed solvent of THF (5 mL) and MeOH (3 mL), and then nickel chloride (0.42 g, 3.266 mmol) and sodium borohydride (0.19 g, 4.900 mmol) were sequentially added, followed by stirring at room temperature. TLC (petroleum ether: ethyl acetate = 10:1) was used for monitoring. After the reaction was completed, water was added, and extraction was performed with ethyl acetate. The organic phase was separated, dried, concentrated, and then purified by column chromatography (petroleum ether: ethyl acetate = 30:1 ~ 10:1) to obtain (1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-5-methoxy-5-oxovinyl]-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, 66.47%) as a white solid. 1HNMR (399 MHz, Chloroform-d) δ 5.35 (d, J = 5.2 Hz, 1H), 4.58 (d, J = 9.8 Hz, 1H), 3.64 (s, 3H), 2.30 (d, J = 7.6 Hz, 2H), 2.21 (td, J = 9.8, 5.0 Hz, 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 = 10.5 Hz, 3H), 1.18 - 1.02 (m, 5H), 0.99 (s, 3H), 0.90 (d, J = 6.4 Hz, 3H), 0.66 (s, 3H).

[0313] The third step, (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]phenanthren-7-yl acetate 47-2 (1.1 g, 2.554 mmol) was dissolved in chloroform (10 mL), selenium dioxide (1.42 g, 12.772 mmol) and NMM (1.55 g, 15.326 mmol) were added in turn, then raised to 75 °C, stirred. TLC (petroleum ether: ethyl acetate = 5:1) monitoring, after the reaction was completed, the insoluble solid was removed by filtration with diatomite, the filtrate was added with water and dichloromethane extraction, the organic phase was separated, dried, concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 30:1~2:1) to obtain (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]phenanthren-7-yl acetate 47-3 (630 mg, 1.270 mmol, 49.70%) white solid. 1H NMR (400 MHz, Chloroform-d) δ 5.73 - 5.63 (m, 1H), 4.70 (dt, J = 12.2, 3.9 Hz, 1H), 4.23 (d, J = 3.2 Hz, 1H), 3.67 (d, J = 22.0 Hz, 3H), 2.40 - 2.14 (m, 2H), 2.09 (s, 4H), 2.05 - 1.97 (m, 2H), 1.85 (d, J = 11.8 Hz, 3H), 1.65 (d, J = 10.5 Hz, 1H), 1.54 - 1.52 (m, 1H), 1.47 - 1.37 (m, 3H), 1.34 - 1.21 (m, 4H), 1.20 (d, J = 2.5 Hz, 3H), 1.13 (d, J = 15.9 Hz, 2H), 1.09 - 1.04 (m, 2H), 0.99 (t, J = 7.2 Hz, 1H), 0.90 (d, J = 6.3 Hz, 3H), 0.67 (d, J = 15.0 Hz, 3H).

[0314] Fourth step (1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-6-hydroxy-1-[(2R)-5-methoxy-5- oxovanyl]-9a,11a-dimethyltetradecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl acetate 47-3 (30 mg, 0.067 mmol) was dissolved in acetic acid (3 mL), after addition of platinum dioxide (15.25 mg, 0.067 mmol), hydrogen replacement, followed by stirring at 40 °C. TLC (petroleum ether: ethyl acetate = 3:1) monitoring, after the reaction was completed, the catalyst was removed by filtration, then most of the acetic acid was removed by concentration, 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 ~ 2:1) to give (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6-hydroxy-1-[(2R)-5-methoxy-5-oxovanyl]-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl acetate 47-4 (8 mg, 0.016 mmol, 23.89%) white solid. 1H NMR (399 MHz, Chloroform-d) δ 4.70 (dd, J = 11.8, 4.1 Hz, 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), 1.32 (dd, J = 24.6, 13.3 Hz, 7H), 1.08 (q, J = 9.9, 8.1 Hz, 4H), 1.03 (s, 3H), 0.97 (d, J = 18.7 Hz, 1H), 0.89 (d, J = 6.4 Hz, 3H), 0.80 (d, J = 6.5 Hz, 1H), 0.63 (s, 3H), 0.58 (d, J = 10.0 Hz, 1H).

[0315] The fifth step, (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6-hydroxy-1-[(2R)-5-methoxy-5- oxovanyl]-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl acetate 47-4 (100 mg, 0.223 mmol) was dissolved in a mixed solvent of tetrahydrofuran (3 mL) and methanol (2 mL), and lithium hydroxide (0.669 mL, 0.669 mmol) was added at room temperature, followed by stirring at room temperature. After the reaction was completed, 1 N hydrochloric acid was added to adjust the pH to 3-4, followed by the addition of water and extraction with ethyl acetate. The organic phase was separated, dried, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 5:1 ~ 0:1) to obtain 3β-hydroxy-4β-hydroxy-5α-cholan-24-oic acid 47-5 (70 mg, 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 = 12.5 Hz, 2H), 1.40 (d, J = 10.3 Hz, 3H), 1.32 (d, J = 3.8 Hz, 3H), 1.16 - 1.03 (m, 4H), 1.01 (s, 4H), 0.97 (d, J = 3.8 Hz, 1H), 0.92 (d, J = 6.6 Hz, 3H), 0.89 - 0.82 (m, 1H), 0.67 (s, 3H), 0.62 (d, J = 12.6 Hz, 1H).

[0316] In the sixth step, 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, and then acetic anhydride (0.034 mL, 0.367 mmol) was added with stirring at room temperature. After the reaction was completed, water was added, and extraction was performed with ethyl acetate. The organic phase was separated, dried, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 20: 1 ~ 3: 1) to obtain 4β-acetyloxy-3β-acetyloxy-5α-cholan-24-oic acid 47-6 (81 mg, 83.39%) as a white solid. 1 H NMR (399 MHz, Chloroform-d) δ 5.18 (s, 1H), 4.77 (d, J = 12.1 Hz, 1H), 2.44 - 2.35 (m, 1H), 2.25 (q, J = 9.7, 8.5 Hz, 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, 14.6 Hz, 4H), 0.99 (s, 3H), 0.91 (d, J = 6.4 Hz, 3H), 0.63 (s, 3H).

[0317] Step 7 To a solution of 4β-acetyloxy-3β-acetyloxy-5α-cholan-24-oic acid 47-6 (50 mg, 0.105 mmol) in dichloromethane (5 mL) was added SOCl2(0.015 mL, 0.210 mmol) dropwise at room temperature, followed by stirring at 40 °C for 2 h, monitoring by TLC (petroleum ether: ethyl acetate = 3: 1). After the reaction was completed, the solvent was removed by concentration, followed by dilution with dichloromethane, cooling in an ice bath, addition of diisopropylethylamine (0.017 mL, 0.105 mmol), and then dropwise addition of (2-fluorophenyl)(methyl)amine (13.14 mg, 0.105 mmol). After the dropwise addition was completed, the temperature was gradually increased to 40 °C, and the mixture was stirred overnight. Monitoring by TLC (petroleum ether: ethyl acetate = 3: 1) was performed, and after the reaction was completed, the mixture was cooled to room temperature, water was added, and extraction was performed with ethyl acetate. The organic phase was separated, dried, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 30: 1 to 2: 1) to obtain (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6-acetyloxy-1-[(2R)-5-[(2-fluorophenyl)(methyl)amino]-5-oxovanyl]-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate 47-7 (20 mg, 29.39%) as a white solid.

[0318] Step 8 To a solution of (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6-acetyloxy-1-[(2R)-5-[(2-fluorophenyl)(methyl)amino]-5-oxovanyl]-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate 47-7 (60 mg, 0.103 mmol) in a mixture of tetrahydrofuran (2 mL) and methanol (1 mL) was added potassium carbonate (28.41 mg, 0.206 mmol) at room temperature, followed by stirring. Monitoring by TLC (petroleum ether: ethyl acetate = 3: 1) was performed, and after the reaction was completed, water was added, extraction was performed with ethyl acetate, the organic phase was separated, dried, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 20: 1 to 1: 1) to obtain (3S,4R,5R,8S,9S,10R,13R,14S,17R,20R)-N-(2-fluorophenyl)-3,4-dihydroxy-N-methyl-5α-cholanamide 47 (40 mg, 0.076 mmol, 74.10%) as a white solid. 1H NMR (399 MHz, Chloroform-d) δ 7.33 (d, J = 6.8 Hz, 1H), 7.18 (q, J = 9.8, 9.4 Hz, 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 = 12.6 Hz, 1H), 1.71 - 1.58 (m, 6H), 1.50 (d, J = 9.4 Hz, 1H), 1.35 (d, J = 13.9 Hz, 3H), 1.28 (s, 1H), 1.21 (s, 3H), 1.06 - 0.99 (m, 3H), 0.98 (s, 3H), 0.97 - 0.82 (m, 5H), 0.67 (d, J = 5.6 Hz, 3H), 0.57 (s, 3H), 0.52 (s, 1H). 19 F NMR (376 MHz, Chloroform-d) δ -121.32. LCMS: [M+H] + = 500.45.

[0319] Example 49 & 105

[0320] 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-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol and

[0321] 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.

[0322]

[0323] First Step: Dissolve the starting 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-butyllithium (1.8 mL, 0.45 mmol, 3.0 eq), and keep the temperature stirring for 30 min. Dissolve the mixture 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- hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-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,6,7,7a,8,9,10,10a,12,12a,12b-tetradecahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxol-8-yl]hexanal II (70 mg, 0.15 mmol, 1.0 eq) in tetrahydrofuran (2 mL) to the above reaction solution, and stir the reaction system at -78 °C for 30 min. Monitor the progress of the reaction by TLC (petroleum ether: ethyl acetate = 5:1), and the starting material is consumed. Add 10 mL of water to the reaction system, extract with ethyl acetate (100 mL x 3), wash the combined organic phase with saturated sodium chloride (10 mL), dry the combined organic phase, and concentrate to obtain colorless oil 49-1 and 105-1 crude (70 mg), which is directly used in the next step.

[0324] Step 2: A mixture 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- hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]-1-(6-fluoro-2- methoxyphenyl)hexan-1-ol 49-1 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]dioxol-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), diluted hydrochloric acid (1 mL, 3 mol / L) was added, and the reaction system was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC plate (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 x 10 mL). The EA layers were combined and washed with saturated brine (3 x 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 resolution SFC (instrument: Waters Acquity UPC C; 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 give (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-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7- diol 49 (44.57 mg, purity 100%, yield 68.30%, retention time t R= 1.876 min) 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, 93.67% purity, 6.42% yield, retention time t R = 2.785 min).

[0325] Compound 49: 1 H NMR (400 MHz, CDCl3) δ 7.18 (td, J = 8.3, 6.6 Hz, 1H), 6.74 - 6.67 (m, 2H), 5.01 (t, J = 6.1 Hz, 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), 1.06 (s, 3H), 1.03 - 0.94 (m, 2H), 0.90 (dd, J = 6.4, 4.5 Hz, 3H), 0.66 (d, J = 4.6 Hz, 3H). 19 F NMR (377 MHz, CDCl3) δ -88.62, -89.25, -110.62, -111.24, -117.19, -117.26.

[0326] Compound 105: 1 H NMR (100 MHz, CDCl3) δ 7.17 (dd, J = 14.9, 8.3 Hz, 1H), 6.69 (dt, J = 8.6, 4.5 Hz, 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, 8.6 Hz, 1H), 2.19 (s, 1H), 2.02 (t, J = 6.0 Hz, 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 = 5.0 Hz, 3H). 19 F NMR (376 MHz, CDCl3) δ -109.83, -117.20, -117.28.

[0327] Examples 50 & 51

[0328] 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-dimethylhexadecahydro-1H- cyclopenta[1,2-a]phenanthrene-6,7-diol and 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.

[0329]

[0330]

[0331] First step: Dissolve the starting 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-butyllithium (1.8 mL, 0.45 mmol, 3.0 eq), and keep the temperature stirring for 30 min. Dissolve the mixture of 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- hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-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,6,7,7a,8,9,10,10a,12,12a,12b-tetradecahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxol-8-yl]hexanal II (70 mg, 0.15 mmol, 1.0 eq) in tetrahydrofuran (2 mL) to the above reaction solution, and stir the reaction system at -78 °C for 30 min. Monitor the progress of the reaction by TLC (petroleum ether: ethyl acetate = 5:1, molybdenum phosphate baking plate), and the starting material is consumed. Add 10 mL of water to the reaction system, extract with ethyl acetate (100 mL x 3), wash the combined organic phase with saturated sodium chloride (10 mL), dry the combined organic phase, and concentrate to obtain 50-1 and 51-1 crude products (70 mg) as colorless oil, which are then directly used in the next step.Step 2: 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- hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]-1-(4- methoxyphenyl)hexan-1-ol 50-1 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]dioxol-8-yl]-1-(4-methoxyphenyl)hexan-1- ol 51-1 crude (70 mg, 0.11 mmol, 1.0 eq) were dissolved in tetrahydrofuran (3 mL), diluted 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) was used to monitor the progress of the reaction, and the reaction was stopped after the raw material was consumed. Water (10 mL) was added to the reaction system, and the water layer was extracted with ethyl acetate (3 x 10 mL). The EA layers were combined and washed with saturated brine (3 x 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 resolution SFC (instrument: Waters Acquity UPC C; 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 give (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-(4- methoxyphenyl)hexan-2-yl]-9a,11a-dimethylhexadecahydro-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 = 3.557 min).

[0332] Compound 50: 1 H NMR (400 MHz, CDC13) δ 7.21 (s, 2H), 6.81 (d, J = 8.6 Hz, 2H), 4.54 (dd, J = 12.2, 5.9 Hz, 1H), 3.74 (s, 3H), 3.67 (s, 1H), 3.53 (dd, J = 7.1, 4.2 Hz, 1H), 2.22 - 1.99 (m, 2H), 1.89 (d, J = 12.6 Hz, 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 = 6.3 Hz, 3H), 0.58 (d, J = 2.5 Hz, 3H). 19 F NMR (376 MHz, CDC13) δ -88.64, -89.26, -110.63, -111.26.

[0333] Compound 51. 1 H NMR (400 MHz, CDC13) δ 7.28 (d, J = 3.3 Hz, 2H), 6.88 (t, J = 6.0 Hz, 2H), 4.62 (dd, J = 12.8, 6.0 Hz, 1H), 3.86 (d, J = 9.2 Hz, 1H), 3.81 (s, 3H), 3.63 - 3.55 (m, 1H), 2.66 (t, J = 12.4 Hz, 1H), 1.86 (ddt, J = 46.3, 23.4, 12.1 Hz, 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 = 2.7 Hz, 3H). 19 F NMR (376 MHz, CDC13) δ -109.79. LC-MS: [M+H-H20] + = 497.60

[0334] Example 54

[0335] 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-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol.

[0336]

[0337] The starting material 3-bromopyridine (169 mg, 1.07 mmol, 5 eq) was dissolved in anhydrous tetrahydrofuran (3 mL), the system was cooled to -78 °C, and n-butyllithium (0.34 mL, 0.86 mmol, 4 eq) was added, and the temperature was 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-hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]hexanal I (100 mg, 0.214 mmol, 1.0 eq) was dissolved in tetrahydrofuran (2 mL) and added to the above reaction solution, and the reaction system was stirred at -78 °C for 30 min. The progress of the reaction was monitored by TLC (petroleum ether: ethyl acetate = 5:1), and the starting material was consumed. 10 mL of water was added to the reaction system, extracted with ethyl acetate (100 mL x 3), the organic phase was combined and washed with saturated sodium chloride (10 mL), the combined organic phase was dried, concentrated to obtain white solid 54-1, dissolved in anhydrous tetrahydrofuran (3 mL), slowly added 3M hydrochloric acid aqueous solution (1 ml), TLC (petroleum ether: ethyl acetate = 1:1) was used to monitor the completion of the reaction. 10 mL of water was added to the reaction system, extracted with ethyl acetate (100 mL x 3), the organic phase was combined and washed with saturated sodium chloride (10 mL), the combined organic phase was dried, concentrated to obtain 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-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 54 (36.95 mg, purity 99.63%, yield 34%).

[0338] Compound 54: 1H NMR (400 MHz, CDC13) δ 8.55 (dd, J = 18.2, 3.1 Hz, 2H), 7.71 (d, J = 7.9 Hz, 1H), 7.29 (dd, J = 7.8, 4.9 Hz, 1H), 4.73 (d, J = 6.5 Hz, 1H), 3.74 (s, 1H), 3.60 (d, J = 10.9 Hz, 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, 4.4 Hz, 2H), 1.06 (s, 3H), 1.02 - 0.92 (m, 2H), 0.89 (t, J = 6.0 Hz, 3H), 0.65 (d, J = 2.2 Hz, 3H). 19 F NMR (376 MHz, CDC13) δ -88.63, -89.26, -110.62, -111.25.

[0339] Example 62

[0340] 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-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol.

[0341]

[0342] First Step: Dissolve the starting 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-butyllithium (1.28 mL, 0.32 mmol, 3.0 eq), and keep the temperature 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-hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthrol[7,8-d][1,3]dioxol-8-yl]hexanal I (50 mg, 0.1 mmol, 1.0 eq) dissolved in tetrahydrofuran (2 mL) is added to the above reaction solution, and the reaction system is stirred at -78 °C for 30 min. Monitor the reaction completion by TLC plate (petroleum ether: ethyl acetate = 5:1). Add 10 mL of water to the reaction system, extract with ethyl acetate (100 mL x 3), wash the combined organic phase with saturated sodium chloride (10 mL), dry the combined organic phase, and concentrate to obtain colorless oil (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-hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthrol[7,8-d][1,3]dioxol-8-yl]-1-{2-fluoro-4-[(trifluoromethyl)oxy]phenyl}hexan-1-ol 62-1 crude (50 mg), which is directly used in the next step.

[0343] Second step: 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- hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-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), 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) was used to monitor the completion of the reaction. Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 x 10 mL). The EA layers were combined and washed with saturated brine (3 x 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 chiral resolution 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-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7- diol 62 (19.80 mg, purity 95.76%, yield 50.53%).

[0344] Compound 62: 1 H NMR (400 MHz, CDCl3) δ 7.23 (dd, J = 13.8, 7.9 Hz, 1H), 7.02 (dd, J = 12.2, 9.2 Hz, 2H), 6.89 (t, J = 8.4 Hz, 1H), 4.60 (dd, J = 12.9, 5.9 Hz, 1H), 3.67 (s, 1H), 3.53 (dt, J = 11.3, 4.1 Hz, 1H), 2.22 - 2.02 (m, 1H), 1.90 (d, J = 12.8 Hz, 1H), 1.80 - 1.55 (m, 13H), 1.43 - 1.14 (m, 10H), 1.04 (dd, J = 14.1, 5.4 Hz, 2H), 0.99 (s, 3H), 0.93 - 0.86 (m, 2H), 0.84 - 0.80 (m, 3H), 0.58 (d, J = 1.7 Hz, 3H). 19F NMR (376 MHz, cdcl3) δ -58.06, -58.07, -58.09, -88.65, -89.28, -110.65, -111.27, -115.89, -115.92.

[0345] Examples 63 & 64

[0346] 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-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 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 Preparation of Compound 64.

[0347]

[0348]

[0349] Step 1: Dissolve the starting 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-butyllithium (1.28 mL, 0.32 mmol, 3.0 eq), and keep the temperature stirring for 30 min. Dissolve the mixture of 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- hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-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,6,7,7a,8,9,10,10a,12,12a,12b-tetradecahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxol-8-yl]hexanal II (50 mg, 0.1 mmol, 1.0 eq) in tetrahydrofuran (2 mL) to the above reaction solution, and stir the reaction system at -78 °C for 30 min. Monitor the reaction completion by TLC (petroleum ether: ethyl acetate = 5:1). Add 10 mL of water to the reaction system, extract with ethyl acetate (100 mL x 3), wash the combined organic phase with saturated sodium chloride (10 mL), dry the combined organic phase, and concentrate to obtain colorless oil 63-1 and 64-1 crude (70 mg), which is then directly used in the next step.

[0350] Step 2: The 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- hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]-1-(2-fluoro-3- methoxyphenyl)hexan-1-ol 63-1 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]dioxol-8-yl]-1-(4-methoxyphenyl)hexan-1- ol 64-1 (50 mg, 0.1 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL), diluted 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) was used to monitor the progress of the reaction, and 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 x 10 mL). The ethyl acetate layers were combined and washed with saturated brine (3 x 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 resolution SFC (instrument: Waters Acquity UPC C; 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 give (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-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7- diol 63 (29.11 mg, purity 99.70%, yield 77.81%, retention time t R= 1.966 min) 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, 98.77% purity, 5.70% yield, retention time t R = 2.943 min).

[0351] Compound 63: 1 H NMR (400 MHz, CDC13) δ 7.05 (dt, J = 13.5, 7.9 Hz, 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, 4.0 Hz, 1H), 2.29 - 2.11 (m, 1H), 1.97 (d, J = 13.2 Hz, 1H), 1.89 - 1.63 (m, 13H), 1.39 (ddd, J = 29.8, 17.0, 8.6 Hz, 8H), 1.11 (dd, J = 14.4, 5.4 Hz, 2H), 1.05 (s, 3H), 1.02 - 0.93 (m, 2H), 0.89 (dd, J = 6.4, 4.2 Hz, 3H), 0.65 (d, J = 2.3 Hz, 3H). 19 F NMR (377 MHz, CDC13) δ -88.64, -89.27, -110.63, -111.26, -142.59, -142.62.

[0352] Compound 64: 1 H NMR (400 MHz, CDC13) δ 7.14 - 7.04 (m, 2H), 6.95 - 6.89 (m, 1H), 5.06 (dd, J = 12.2, 5.6 Hz, 1H), 3.93 (s, 3H), 3.89 (s, 1H), 3.67 - 3.59 (m, 1H), 2.68 (d, J = 13.8 Hz, 1H), 2.06 (d, J = 13.5 Hz, 1H), 2.00 - 1.75 (m, 10H), 1.64 (d, J = 12.3 Hz, 4H), 1.52 - 1.44 (m, 5H), 1.14 (dd, J = 18.2, 5.5 Hz, 4H), 1.08 (s, 3H), 0.96 - 0.92 (m, 3H), 0.89 (dd, J = 9.0, 5.2 Hz, 2H), 0.66 (d, J = 2.5 Hz, 3H). 19F NMR (377 MHz, CDC13) δ -109.79, -142.59, -142.62.

[0353] Examples 67 & 68

[0354] 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-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 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

[0355]

[0356]

[0357] Step 1: Dissolve the starting 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-butyllithium (1.28 mL, 0.32 mmol, 3.0 eq), and keep the temperature stirring for 30 min. Dissolve the mixture of 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- hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-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,6,7,7a,8,9,10,10a,12,12a,12b-tetradecahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxol-8-yl]hexanal II (50 mg, 0.1 mmol, 1.0 eq) in tetrahydrofuran (2 mL) to the above reaction solution, and stir the reaction system at -78 °C for 30 min. Monitor the reaction completion by TLC (petroleum ether: ethyl acetate = 5:1). Add 10 mL of water to the reaction system, extract with ethyl acetate (100 mL x 3), wash the combined organic phase with saturated sodium chloride (10 mL), dry the combined organic phase, and concentrate to obtain colorless oil 67-1 and 68-1 crude (70 mg), which is then directly used in the next step.

[0358] Step 2: 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- hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]-1-(2-fluoro-4- methoxyphenyl)hexan-1-ol 67-1 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]dioxol-8-yl]-1-(2-fluoro-4-methoxyphenyl) hexan-1-ol 68-1 crude (50 mg, 0.1 mmol, 1.0 eq) were dissolved in tetrahydrofuran (3 mL), diluted 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) was used to monitor the completion of the reaction. Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 x 10 mL). The EA layers were combined and washed with saturated brine (3 x 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 resolution SFC (instrument: Waters Acquity UPC C; 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-(2-fluoro-4-methoxyphenyl)-6- hydroxyhexan-2-yl]-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7- diol 67 (16 mg, purity 100%, yield 29.77%, retention time t R= 1.135 min) 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, 98.44% purity, 2.57% yield, retention time t R = 1.497 min).

[0359] Compound 67: 1 H NMR (400 MHz, CDC13) δ 7.33 (td, J = 8.6, 1.7 Hz, 1H), 6.70 (dd, J = 8.6, 2.4 Hz, 1H), 6.58 (dd, J = 12.3, 2.5 Hz, 1H), 4.92 (m, 1H), 3.79 (s, 3H), 3.74 (s, 1H), 3.60 (m, 1H), 2.19 (m, 1H), 1.97 (d, J = 12.8 Hz, 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, 4.5 Hz, 3H), 0.65 (d, J = 2.0 Hz, 3H). 19 F NMR (377 MHz, CDC13) δ -88.64, -89.26, -110.63, -111.25, -117.79, -117.83. LC-MS: [M+1-H20] + = 535.80.

[0360] Compound 68: 1H NMR (400 MHz, CDC13) δ 7.33 (td, J = 8.6, 2.0 Hz, 1H), 6.70 (dd, J = 8.5, 2.4 Hz, 1H), 6.58 (dd, J = 12.3, 2.5 Hz, 1H), 4.92 (dd, J = 13.1, 6.1 Hz, 1H), 3.85 (s, 1H), 3.79 (s, 3H), 3.59 (m, 1H), 2.66 (s, 1H), 2.02 (d, J = 10.7 Hz, 1H), 1.92 (s, 1H), 1.86 (s, 2H), 1.81 (s, 2H), 1.74 (d, J = 9.5 Hz, 3H), 1.61 (d, J = 11.8 Hz, 4H), 1.45 (dd, J = 12.6, 5.6 Hz, 4H), 1.26 (s, 6H), 1.08 (d, J = 4.5 Hz, 2H), 1.04 (s, 3H), 0.90 (dd, J = 6.4, 4.3 Hz, 4H), 0.62 (d, J = 2.2 Hz, 3H). 19 F NMR (377 MHz, CDC13) δ -109.79, -117.80, -117.83. LC-MS: [M+H-H20]+= 515.70.

[0361] Example 69

[0362] 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-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol.

[0363]

[0364] First Step: 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-butyllithium (1.28 mL, 0.32 mmol, 3.0 eq), and keep the temperature 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- hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]hexanal I (50 mg, 0.1 mmol, 1.0 eq) dissolved in tetrahydrofuran (2 mL) is added to the above reaction solution, and the reaction system is stirred at -78 °C for 30 min. TLC (petroleum ether: ethyl acetate = 5:1) is used to monitor the completion of the reaction. Add 10 mL of water to the reaction system, extract with ethyl acetate (100 mL x 3), wash the combined organic phase with saturated sodium chloride (10 mL), dry the combined organic phase, and concentrate to obtain colorless oil (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- hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]-1-(2,4,6- trifluorophenyl)hexan-1-ol 69-1 crude (50 mg) is directly used in the next step.

[0365] 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- hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-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), 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) was used to monitor the completion of the reaction. Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 x 10 mL). The ethyl acetate layers were combined and washed with saturated brine (3 x 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 resolution SFC (instrument: Waters Acquity UPC C; 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-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene- 6,7-diol 69 (13.91 mg, purity 98.75%, yield 24.77%, retention time t R = 1.107 min).

[0366] Compound 69: 1 H NMR (400 MHz, CDC13) δ 6.65 (m, 2H), 4.98 (t, J = 6.9 Hz, 1H), 3.74 (s, 1H), 3.60 (dt, J = 11.3, 4.2 Hz, 1H), 2.22 (m, 1H), 2.02 (m, 4H), 1.83 (m, 5H), 1.68 (ddd, J = 13.6, 10.8, 5.5 Hz, 3H), 1.35 (m, 9H), 1.11 (m, 2H), 1.06 (s, 3H), 0.98 (dd, J = 16.3, 5.7 Hz, 2H), 0.89 (t, J = 6.0 Hz, 3H), 0.65 (d, J = 2.9 Hz, 3H).19 F NMR (377 MHz, CDC13) δ -88.64, -89.27, -109.16, -110.64, -111.26, -112.09, -112.16.

[0367] Examples 70 & 71

[0368] Preparation of 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-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol and 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-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol.

[0369]

[0370]

[0371] Step 1: Dissolve the starting 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-butyllithium (0.13 mL, 0.32 mmol, 3.0 eq), and keep the temperature 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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]hexanal I (50 mg, 0.11 mmol, 1.0 eq) dissolved in tetrahydrofuran (2 mL) was added to the above reaction, and the reaction system was stirred at -78 °C for 30 min. TLC (petroleum ether: ethyl acetate = 5: 1) was used to monitor the completion of the reaction. Add 10 mL of water to the reaction system, extract with ethyl acetate (10 mL x 3), wash the combined organic phase with saturated sodium chloride (20 mL), dry the combined organic phase, and concentrate to give (5R)-5-((3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)- 11,11-difluoro-2,2,5a,7a-tetramethylhexahydro-4H-cyclopenta[7,8]phenanthro[l,2-d][l,3]dioxol-8-yl)-l-(2,3-dimethoxyphenyl)hexan-l-ol crude, which was purified by column chromatography (petroleum ether: ethyl acetate = 90: 10) to give (5R)-5-((3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)- 11,11-difluoro-2,2,5a,7a-tetramethylhexahydro-4H-cyclopenta[7,8]phenanthro[l,2-d][l,3]dioxol-8-yl)-l-(2,3-dimethoxyphenyl)hexan-l-ol 70-1 (32 mg, yield 49%) as a white solid.

[0372] Second step: 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]phenanthro[1,2- d][1,3]dioxol-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 progress of the reaction was detected by TLC plate (petroleum ether: ethyl acetate = 5:1, molybdenum phosphate baking plate), 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 x 10 mL). The ethyl acetate layers were combined and washed with saturated brine (3 x 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 UPC C; column: Daicel CHIRALPAK OZ3, 3*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 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 = 2.840 min).

[0373] Compound 70: 1 H NMR (400 MHz, CDC13) δ 7.05 (t, J = 7.9 Hz, 1H), 6.94 (d, J = 6.6 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 4.91 (dd, J = 8.1, 5.0 Hz, 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 (377 MHz, CDC13) δ -88.94 (d, J = 235.7 Hz, IF), -110.94 (d, J = 236.0 Hz, IF).

[0374] Compound 71: 1 H NMR (400 MHz, CDC13) δ 7.05 (t, J = 7.9 Hz, IH), 6.94 (dd, J = 7.8, 1.4 Hz, IH), 6.84 (dd, J = 8.1, 1.4 Hz, IH), 4.90 (t, J = 6.6 Hz, IH), 3.88 (s, 3H), 3.87 (s, 3H), 3.76 - 3.71 (m, IH), 3.63 - 3.55 (m, IH), 2.40 - 2.23 (m, IH), 2.22 - 2.01 (m, 2H), 2.00 - 1.93 (m, IH), 1.88 - 1.78 (m, 4H), 1.77 - 1.65 (m, 5H), 1.61 - 1.50 (m, 2H), 1.50 - 1.33 (m, 6H), 1.32 - 1.24 (m, 3H), 1.23 - 1.16 (m, IH), 1.14 - 1.03 (m, 6H), 1.01 - 0.93 (m, IH), 0.89 (d, J = 6.5 Hz, 3H), 0.65 (s, 3H). 19 F NMR (377 MHz, CDC13) δ -88.95 (d, J = 236.5 Hz, IF), -110.94 (d, J = 236.0 Hz, IF).

[0375] Examples 72 & 73

[0376] 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-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0377] 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]phenanthrene-7-ol

[0378]

[0379]

[0380] The first step, (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetyloxy-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), to the solution was added cobalt acetate (80 mg, 0.45 mmol, 0.2 eq), N-hydroxyl phthalimide (0.15 g, 0.90 mmol, 0.4 eq), tert-butyl hydroperoxide (1.01 g, 11.25 mmol, 5 eq), stirred at room temperature for 20 hours. After the reaction was completed, 30 mL of water was added, extracted with ethyl acetate (30 mL*3), the obtained organic phase was dried with anhydrous sodium sulfate and rotary evaporated to obtain the crude product, the crude product was purified by silica gel column (petroleum ether / ethyl acetate = 10 / 1) to obtain (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetyloxy-9a,11a-dimethyl-4-oxo-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 72-1 (0.6 g, 1.31 mmol, yield: 58%). 1 H NMR (400 MHz, CDC13) δ 5.70 (d, J = 1.5 Hz, 1H), 4.80 - 4.64 (m, 1H), 3.67 (s, 3H), 2.48 (dddd, J = 15.6, 12.1, 9.1, 2.4 Hz, 3H), 2.25 (ddd, J = 22.3, 12.9, 5.3 Hz, 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, 4.3 Hz, 2H), 1.28 (ddd, J = 10.9, 10.5, 5.9 Hz, 3H), 1.21 (s, 3H), 1.18 - 1.05 (m, 3H), 0.94 (d, J = 6.5 Hz, 3H), 0.68 (s, 3H).

[0381] In the second step, compound (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetyloxy- 9a,11a-dimethyl-4-oxo-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 72-1 (0.6 g, 1.31 mmol, 1 eq) was dissolved in ethyl acetate (15 mL), then palladium on carbon (10%) (120 mg) was added to it, after stirring at room temperature for 12 hours, it was filtered and the organic solvent was evaporated to obtain the product (5R)-5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-7-acetyloxy-9a,11a-dimethyl-4-oxo- hexadecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester 72-2 (450 mg, 0.977 mmol, yield: 75%) as an oily compound. 1 H NMR (400 MHz, cdcl3) δ 5.36 - 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, 3.5 Hz, 1H), 2.35 - 2.26 (m, 2H), 2.22 - 2.10 (m, 6H), 2.09 - 1.99 (m, 3H), 1.86 (d, J = 12.4 Hz, 1H), 1.76 (s, 1H), 1.73 (s, 1H), 1.73 (s, 3H), 1.70 (s, 1H), 1.69 (d, J = 3.3 Hz, 1H), 1.67 - 1.56 (m, 1H), 1.56 (d, J = 6.5 Hz, 3H), 1.28 (s, 3H).

[0382] 1.60 (m, 1H), 1.56 (d, J = 6.5 Hz, 3H), 1.28 (s, 3H).

[0383] In the third step, compound (5R)-5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-7-acetyloxy- 9a,11a-dimethyl-4-oxoheptadecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester 72-2 (150 mg, 0.326 mmol, 1.0 eq), 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 extracted with ethyl acetate (50 mL), the organic phase was washed with saturated brine twice, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was then purified by silica gel separation (petroleum ether: ethyl acetate = 1:1) to give a mixture of (5R)-5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-7-acetyloxy-4,4-difluoro-9a,11a-dimethylheptadecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester 72-3 and (5R)-5-[(1R,3aR,5aR,7S,9aS,9bR,11aR)-7-acetyloxy-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]hexanoic acid methyl ester 73-1 (70 mg, 0.145 mmol, calculated from 72-3: 45% yield) as a white solid.

[0384] Compound 72-3: 1 H NMR (400 MHz, CDCl3) δ 4.75 - 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, 3.7 Hz, 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, 9.4 Hz, 5H), 0.94 (t, J = 5.4 Hz, 3H), 0.85 (d, J = 11.0 Hz, 3H), 0.71 - 0.62 (m, 3H).

[0385] In the fourth step, a mixture of (5R)-5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-7-acetoxy- 4,4-difluoro-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester 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]hexanoic acid methyl ester 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 added slowly, the reaction system was stirred at room temperature for 5 hours. TLC (petroleum ether: ethyl acetate = 2:1) was used to monitor the completion of the reaction. Water (10 mL) was added to the reaction system, the water layer was extracted with ethyl acetate (3 x 25 mL). The ethyl acetate layers were combined and washed with saturated brine (3 x 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 = 5:1) to give a mixture of (5R)-5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-4,4-difluoro-7-hydroxy-9a,11a- dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthren-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,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2- a]phenanthren-1-yl]hexanoic acid methyl ester 73-2 white solid mixture (100 mg, purity 95%, yield 91% calculated for 72-4), the crude product was directly used in the next step reaction.

[0386] A mixture of (5R)-5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-4,4-difluoro-7- hydroxy-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthren-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,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H- cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester 73-2 (1.1 g, 2.496 mmol, 1.0 eq) was dissolved in dimethylformamide (10 mL), chloro(2-methylpropan-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 was stirred at 40 °C for 12 h. The reaction progress was monitored by TLC (petroleum ether: ethyl acetate = 5:1). Water (10 mL) was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (3 x 25 mL). The combined ethyl acetate layers were washed with saturated brine (3 x 10 mL). The organic phase 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 = 10:1) to give a mixture of (5R)-5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2- methylpropan-2-yl)diphenylsilyl]oxy}hexadecahydro-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-{[(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]hexanoic acid methyl ester 73-3 as a white solid (1.65 g, 95% purity, 92% yield calculated for 72-5).

[0387] Compound 72-5: 1H NMR (400 MHz, CDC13) δ 7.63 - 7.56 (m, 4H), 7.36 - 7.26 (m, 6H), 3.55 (d, J = 27.4 Hz, 4H), 2.25 - 2.12 (m, 2H), 1.85 (d, J = 12.7 Hz, 1H), 1.74 (dd, J = 13.6, 6.1 Hz, 2H), 1.65 - 1.49 (m, 6H), 1.45 - 1.34 (m, 5H), 1.30 (dd, J = 15.2, 11.1 Hz, 4H), 1.23 - 1.13 (m, 5H), 1.04 - 1.00 (m, 2H), 0.97 (s, 9H), 0.84 (t, J = 5.6 Hz, 3H), 0.76 - 0.71 (m, 3H), 0.69 (d, J = 3.3 Hz, 1H), 0.55 (d, J = 12.1 Hz, 3H).

[0388] In the sixth step, a mixture of white solid (5R)-methyl 5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)- 4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropan-2-yl)diphenylsilyl]oxy}hexadecahydro- 1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoate 72-5 and (5R)-methyl 5-[(1R,3aR,5aR,7S,9aS,9bR,11aR)-4-fluoro-9a,11a-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]phenanthren-1-yl]hexanoate 73-3 (2.5 g, 3.682 mmol, 1.0 eq) was dissolved in tetrahydrofuran (20 mL), lithium aluminum hydride (0.42 g, 11.05 mmol, 3 eq) was added, and 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 x 25 mL). The combined ethyl acetate layers were washed with saturated brine (3 x 10 mL). The organic phase 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 = 10:1) to give a mixture of white solid (5R)-5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropan-2- yl)diphenylsilyl]oxy}hexadecahydro-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-{[(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 (1.7 g, 95% purity, 72% yield calculated for 72-6).

[0389] Compound 72-6: 1HNMR (400 MHz, CDC13) δ 7.70 - 7.62 (m, 4H), 7.45 - 7.33 (m, 6H), 3.63 (s, 3H), 1.93 (d, J = 12.7 Hz, 1H), 1.81 (d, J = 9.4 Hz, 2H), 1.68 - 1.60 (m, 3H), 1.54 (s, 7H), 1.38 (ddd, J = 23.8, 18.6, 8.6 Hz, 8H), 1.25 (d, J = 7.1 Hz, 5H), 0.90 (d, J = 6.5 Hz, 4H), 0.82 (s, 4H), 0.63 (s, 3H)

[0390] In the seventh step, a mixture of white solid (5R)-5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)- 4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropan-2-yl)diphenylsilyl]oxy}hexadeca- 1H- cyclopenta[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-{[(2-methylpropan-2-yl)diphenylsilyl]oxy}-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[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. The reaction was monitored to completion by TLC (petroleum ether: ethyl acetate = 10:1). Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 x 25 mL). The ethyl acetate layers were combined and washed with saturated sodium sulfite (3 x 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 = 10:1) to obtain a mixture of white solid (5R)-5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropan-2-yl)diphenylsilyl]oxy}hexadeca-1H-cyclopenta[a]phenanthren-1-yl]hexanal 72-7 and (5R)-5-[(1R,3aR,5aR,7S,9aS,9bR,11aR)-4-fluoro-9a,11a-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[a]phenanthren-1-yl]hexanal 73-5 (1.4 g, 95% purity, 87% yield calculated for 72-7).

[0391] Compound 72-7: 1H NMR (400 MHz, CDC13) δ 9.75 (t, J = 1.7 Hz, 1H), 7.69 - 7.63 (m, 4H), 7.44 - 7.34 (m, 6H), 3.59 (td, J = 10.5, 5.3 Hz, 1H), 2.38 (d, J = 6.4 Hz, 2H), 1.55 (s, 6H), 1.04 (s, 10H), 0.92 (d, J = 6.5 Hz, 3H), 0.82 (s, 3H), 0.62 (d, J = 12.3 Hz, 3H).

[0392] In the eighth step, the starting material 1-bromo-2-methoxybenzene (173 mg, 0.9 mmol, 4 eq) was dissolved in anhydrous tetrahydrofuran (3 mL), the system was cooled to -78 °C, and n-butyllithium (1.8 mL, 0.28 mmol, 3 eq) was added, and the temperature was stirred for 30 min. A mixture of (5R)-5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropan-2-yl)diphenylsilyl]oxy}hexadeca-hydro-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-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]phenanthren-1-yl]hexanal 73-5 (150 mg, 0.23 mmol, 1.0 eq) were dissolved in tetrahydrofuran (2 mL) and added to the above reaction solution, and the reaction system was stirred at -78 °C for 30 min. The reaction was monitored to 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 x 3), the combined organic phase was washed with saturated sodium chloride (10 mL), the combined organic phase was dried and concentrated to give a white solid of crude (5R)-5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropan-2-yl)diphenylsilyl]oxy}hexadeca-hydro-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-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), which was directly used in the next step.

[0393] In the ninth step, a mixture of white solid (5R)-5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropan-2-yl)diphenylsilyl]oxy}hexadecahydro-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-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), tetrabutylammonium fluoride (1 mL, 1 mol / L) was added, and the reaction system was stirred at 40 h for 12 h. TLC (petroleum ether: ethyl acetate = 5:1) was used to monitor the completion of the reaction. Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 x 10 mL). The ethyl acetate layers were combined and washed with saturated brine (3 x 10 mL). Anhydrous sodium sulfate was used for drying, filtration and concentration 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 resolution SFC (instrument: Waters Acquity UPC C; 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-hydroxy-6-(2-methoxyphenyl)hexan-2-yl]-9a,11a-dimethylhexadecahydro-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 = 2.241 min).

[0394] 72: 1H NMR (400 MHz, CDC13) δ 7.32 - 7.27 (m, 1H), 7.26 - 7.21 (m, 1H), 7.00 - 6.84 (m, 2H), 4.85 (dt, J = 9.1, 5.9 Hz, 1H), 3.85 (s, 3H), 3.68 - 3.58 (m, 1H), 1.98 (d, J = 11.4 Hz, 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, 3.8 Hz, 3H), 0.84 (s, 3H), 0.65 (d, J = 2.3 Hz, 3H). 19 F NMR (377 MHz, CDC13) δ -88.96, -89.59, -110.85, -111.48.

[0395] 73: 1 H NMR (400 MHz, CDC13) δ 7.31 - 7.28 (m, 1H), 7.24 (s, 1H), 6.92 (dd, J = 32.7, 7.8 Hz, 2H), 4.85 (dd, J = 14.9, 8.1 Hz, 1H), 3.86 (s, 3H), 3.68 - 3.54 (m, 1H), 2.02 (d, J = 11.5 Hz, 3H), 1.81 (ddd, J = 17.2, 12.6, 8.5 Hz, 6H), 1.64 (s, 2H), 1.54 (d, J = 3.1 Hz, 4H), 1.44 (dd, J = 13.3, 4.6 Hz, 3H), 1.34 - 1.28 (m, 5H), 1.13 - 1.02 (m, 4H), 0.91 (dd, J = 6.5, 3.6 Hz, 3H), 0.80 (d, J = 10.7 Hz, 3H), 0.71 - 0.60 (m, 3H). 19 F NMR (376 MHz, CDC13) δ -106.98, -110.64.

[0396] Examples 74 & 75

[0397] Preparation of compound 74 (1R,3aS,3bR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-(2-fluorophenyl)-6-hydroxyhexyl-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol. Preparation of compound 75 (1R,3aR,7S,9aS,9bR,11aR)-4-fluoro-1-[(2R)-6-(2-fluorophenyl)-6-hydroxyhexyl-2-yl]-9a,11a-dimethyl-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol.

[0398]

[0399] Referring to Examples 72 & 73, the 1-bromo-2-methoxybenzene in step 8 was replaced with 1-bromo-2-fluorobenzene, and separated by chiral resolution SFC (instrument: Waters Acquity UPCC; 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°C) to obtain (1R,3aS,3bR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-(2-fluorophenyl)-6-hydroxyhexyl-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 74 (35 mg, purity 100%, yield 56%, retention time t) R =1.167 min) and (1R,3aR,7S,9aS,9bR,11aR)-4-fluoro-1-[(2R)-6-(2-fluorophenyl)-6-hydroxyhexyl-2-yl]-9a,11a-dimethyl-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecanohydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 75 (5 mg, purity 100%, yield 8%), retention time t R =1.410min).

[0400] Compound 74: 1H NMR (400 MHz, CDC13) δ 7.32 - 7.27 (m, 1H), 7.26 - 7.21 (m, 1H), 7.00 - 6.84 (m, 2H), 4.85 (dt, J = 9.1, 5.9 Hz, 1H), 3.85 (s, 3H), 3.68 - 3.58 (m, 1H), 1.98 (d, J = 11.4 Hz, 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, 3.8 Hz, 3H), 0.84 (s, 3H), 0.65 (d, J = 2.3 Hz, 3H). 19 F NMR (376 MHz, CDC13) δ -88.98, -89.60, -110.85, -111.48, -119.75, -119.78.

[0401] Compound 75: 1 H NMR (400 MHz, CDC13) δ 7.31 - 7.28 (m, 1H), 7.24 (s, 1H), 6.92 (dd, J = 32.7, 7.8 Hz, 2H), 4.85 (dd, J = 14.9, 8.1 Hz, 1H), 3.86 (s, 3H), 3.68 - 3.54 (m, 1H), 2.02 (d, J = 11.5 Hz, 3H), 1.81 (ddd, J = 17.2, 12.6, 8.5 Hz, 6H), 1.64 (s, 2H), 1.54 (d, J = 3.1 Hz, 4H), 1.44 (dd, J = 13.3, 4.6 Hz, 3H), 1.34 - 1.28 (m, 5H), 1.13 - 1.02 (m, 4H), 0.91 (dd, J = 6.5, 3.6 Hz, 3H), 0.80 (d, J = 10.7 Hz, 3H), 0.71 - 0.60 (m, 3H). 19 F NMR (376 MHz, CDC13) δ 110.61, 105.12, 105.11.

[0402] Example 76

[0403] 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.

[0404]

[0405] Step 1 : Dissolve the starting material 4-bromo-pyridine (118.50 mg, 0.75 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL), cool the system to -78 °C, add n-butyllithium (2.5 mL, 0.45 mmol, 3.0 eq), and keep the temperature stirring for 30 min. Dissolve compound (5R)-5-((3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)- 11,11-difluoro-2,2,5a,7a-tetramethylhexahydro-4H-cyclopenta[7,8]phenanthro[1,2- d][1,3]dioxol-8-yl)hexanal I (100 mg, 0.21 mmol, 1.0 eq) in tetrahydrofuran (2 mL) and add to the above reaction solution, and stir the reaction system at -78 °C for 30 min. Monitor the reaction completion by TLC (petroleum ether: ethyl acetate = 5:1). Add 10 mL of water to the reaction system, extract with ethyl acetate (100 mL x 3), wash the combined organic phase with saturated sodium chloride (10 mL), dry the combined organic phase, and concentrate to obtain the crude product. Purify the crude product by silica gel column chromatography (petroleum ether: ethyl acetate = 90:10) to obtain white solid (5R)-5-((3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)- 11,11-difluoro-2,2,5a,7a-tetramethylhexahydro-4H-cyclopenta[7,8]phenanthro[1,2- d][1,3]dioxol-8-yl)-1-(pyridin-4-yl)hexan-1-ol 76-1 (24 mg, purity 90%, yield 18.8%).

[0406] 1 H NMR (400 MHz, CDC13) δ 8.59 (s, 2H), 7.39 (s, 2H), 4.75 (s, 1H), 4.02 (d, J = 15.0 Hz, 1H), 2.20 (dd, J = 22.6, 14.8 Hz, 1H), 2.09 - 1.93 (m, 3H), 1.82 (d, J = 7.0 Hz, 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, 3.8 Hz, 2H), 0.65 (d, J = 11.8 Hz, 2H).

[0407] Second step: 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]phenanthrene[l,2- d][l,3]dioxol-8-yl)-l-(pyridin-4-yl)hexan-l-ol 76-1 (24 mg, 0.044 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 to 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 x 10 mL). The ethyl acetate layer was combined and washed with saturated brine (3 x 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 UPC C; 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 give (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-l-[(2R)-6-hydroxy-6-(pyridin-4-yl)hexan-2-yl]-9a,11a-dimethylhexadecahydro-lH-cyclopenta[l,2-a]phenanthrene-6,7-diol 76 (3.04 mg, purity 100%, yield 13.7%, retention time t R = 1.965 min). Compound 76: 1 H NMR (400 MHz, CDC13) δ 8.56 (d, J = 5.9 Hz, 2H), 7.28 (s, 2H), 4.68 (t, J = 6.4 Hz, 1H), 3.73 (s, 1H), 3.64 - 3.55 (m, 1H), 2.23 - 2.14 (m, 1H), 1.96 (d, J = 12.7 Hz, 1H), 1.82 - 1.65 (m, 10H), 1.46 - 1.23 (m, 10H), 1.09 (d, J = 6.4 Hz, 2H), 1.05 (d, J = 5.2 Hz, 3H), 1.01 - 0.92 (m, 2H), 0.88 (d, J = 6.5 Hz, 3H), 0.65 (s, 3H). 19 F NMR (377 MHz, CDC13) δ -88.62, -89.25, -109.77, -110.65, -111.24.

[0408] Example 77

[0409] Preparation of compound 77 (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-1-[(2R)-6-(2,2- difluorobenzo[d][1,3]dioxol-4-yl)-6-hydroxyhexan-2-yl]-4,4-difluoro-9a,11a- dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol.

[0410]

[0411] First step: Dissolve the starting material 4-bromo-2,2-difluorobenzo[d][1,3]dioxole (177.8 mg, 0.75 mmol, 3.5 eq) in anhydrous tetrahydrofuran (4 mL), cool the system to -78 °C, add n-butyllithium (0.26 mL, 0.64 mmol, 3.0 eq), and keep the temperature stirring for 30 min. Dissolve 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-hexadecahydro-3aH-cyclopenta[1’,2’:1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]hexanal I (100 mg, 0.21 mmol, 1.0 eq) in tetrahydrofuran (2 mL) and add to the above reaction solution, and stir the reaction system at -78 °C for 30 min. Monitor the reaction completion by TLC plate (petroleum ether: ethyl acetate = 5:1, molybdenum phosphate baking plate). Add 20 mL of water to the reaction system, extract with ethyl acetate (20 mL x 2), wash the combined organic phase with saturated sodium chloride (30 mL), dry the combined organic phase, and concentrate to obtain the crude product. Purify the crude product 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]phenanthro[1,2-d][1,3]dioxol-8-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)hexan-1-ol 77-1 (80 mg, yield 60%) as a white solid.

[0412] Second step: 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]phenanthrene[l,2- d][l,3]dioxol-8-yl)-l-(2,2-difluorobenzo[d][l,3]dioxol-4-yl)hexan-l-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. TLC plate (petroleum ether: ethyl acetate = 5: 1) was used to monitor the reaction. Water (10 mL) was added to the reaction system, and the water layer was extracted with ethyl acetate (3 x 10 mL). The combined ethyl acetate layer was washed with saturated brine (3 x 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 = 80:20) to give a white solid, which was then separated by chiral resolution (instrument: Waters Acquity UPC C; 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 give (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-1-[(2R)-6-(2,2-difluorobenzo[d][l,3]dioxol-4-yl)-6-hydroxyhexan-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecahydro-lH-cyclopenta[l,2-a]phenanthrene-6,7-diol 77 (28.80 mg, purity 97%, yield 38%, retention time t R = 0.921 min). 1H NMR (400 MHz, CDC13) δ 7.13 (dd, J = 8.0, 1.8 Hz, 1H), 7.07 (t, J = 7.9 Hz, 1H), 6.97 (d, J = 7.3 Hz, 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 = 1.9 Hz, 3H). 19 F NMR (376 MHz, CDC13) δ -49.75 (qd, J = 97.3, 9.6 Hz, 2F), -88.95 (d, J = 235.8 Hz, IF), -110.94 (d, J = 235.9 Hz, IF).

[0413] Example 80

[0414] 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-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol.

[0415]

[0416] Step 1: Dissolve the starting 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-butyllithium (0.26 mL, 0.64 mmol, 3.0 eq), and keep the temperature 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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenalene-8-yl]hexanal I (100 mg, 0.214 mmol, 1.0 eq) dissolved in tetrahydrofuran (2 mL) is added to the above reaction, and the reaction system is stirred at -78 °C for 30 min. TLC plate (petroleum ether: ethyl acetate = 5: 1) monitors the completion of the reaction. Add 10 mL water to the reaction system, extract with ethyl acetate (100 mL x 3), wash the combined organic phase with saturated sodium chloride (10 mL), dry the combined organic phase, and concentrate 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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenalene-8-yl]-l-(2-fluoropyridin-3-yl)hexan-l-ol 80-1 (50 mg) as a colorless oil, which is directly used in the next step. LC-MS: [M+H-H2O] += 594.3. Second step: 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- hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-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), diluted 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) was used to monitor the completion of the reaction. Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 x 10 mL). The ethyl acetate layers were combined and washed with saturated brine (3 x 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 resolution (instrument: Waters Acquity UPC C; 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 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-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7- diol 80 (4.06 mg, purity 100%, yield 8.07%, retention time t R = 1.683 min).

[0417] Compound 80: 1 H NMR (400 MHz, CDC13) δ 8.12 (d, J = 4.5 Hz, 1H), 7.92 (t, J = 8.5 Hz, 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 = 12.9 Hz, 4H), 1.82 (d, J = 7.2 Hz, 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, 2.3 Hz, 3H), 0.66 (s, 3H).19 F NMR (377 MHz, CDC13) δ -72.48, -76.69, -88.63, -89.26, -110.61, -111.22. LC-MS: [M+H] + = 524.35.

[0418] Examples 81 & 83

[0419] Preparation of 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-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol and 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.

[0420]

[0421]

[0422] Step 1: Dissolve the starting 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-butyllithium (0.26 mL, 0.64 mmol, 3.0 eq), and keep the temperature stirring for 30 min. Dissolve the mixture of 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- hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-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,6,7,7a,8,9,10,10a,12,12a,12b-tetradecahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxol-8-yl]hexanal II (100 mg, 0.214 mmol, 1.0 eq) in tetrahydrofuran (2 mL) to the above reaction solution, and stir the reaction system at -78 °C for 30 min. Monitor the reaction completion by TLC plate (petroleum ether: ethyl acetate = 5: 1). Add 10 mL water to the reaction system, extract with ethyl acetate (100 mL x 3), wash the combined organic phase with saturated sodium chloride (10 mL), dry the combined organic phase, and concentrate to obtain a colorless oil 81-1 and 83-1 crude mixture (80 mg), which is directly used in the next step. LC-MS: ([M+H-H2O] = 594.3. +

[0423] ​Step 2: The crude (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- hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-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-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]dioxol-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), diluted hydrochloric acid (1 mL, 3 mol / L) was added, and the reaction system was stirred at room temperature for 1 h. TLC plate (petroleum ether: ethyl acetate = 5:1) was used to monitor the completion of the reaction. Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 x 10 mL). The ethyl acetate layers were combined and washed with saturated brine (3 x 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 subjected to chiral resolution (instrument: Waters Acquity UPC C; column: Daicel CHIRALPAK IB 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 give (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-dimethylhexadecahydro-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-methoxy-pyridin-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 83 (1.98 mg, 89.13% purity, 2.75% yield, retention time t R = 1.986 min).

[0424] Compound 81: 1H NMR (400 MHz, CDC13) δ 8.08 (m, 1H), 7.62 (t, J = 5.2 Hz, 1H), 6.91 (dd, J = 7.2, 5.1 Hz, 1H), 4.79 (dt, J = 13.4, 6.7 Hz, 1H), 4.01 (s, 3H), 3.74 (s, 1H), 3.60 (m, 1H), 2.16 (m, 2H), 1.97 (d, J = 13.2 Hz, 1H), 1.82 (m, 4H), 1.70 (m, 4H), 1.36 (m, 11H), 1.10 (s, 2H), 1.06 (s, 3H), 0.98 (m, 2H), 0.90 (dd, J = 6.5, 3.3 Hz, 3H), 0.66 (d, J = 1.8 Hz, 3H). 19 F NMR (377 MHz, CDC13) δ -88.63, -89.26, -110.63, -111.26. LC-MS: [M+H] + = 536.35.

[0425] Compound 83: 1H NMR (400 MHz, CDC13) 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, 13.4 Hz, 6H), 1.77 (s, 3H), 1.61 (d, J = 9.5 Hz, 3H), 1.44 (m, 7H), 1.25 (s, 3H), 1.10 (m, 3H), 1.05 (s, 3H), 0.92 (dd, J = 6.5, 2.8 Hz, 3H), 0.63 (d, J = 1.5 Hz, 3H). 19 F NMR (377 MHz, CDC13) δ -109.77. LC-MS: [M+H]+ = 516.35.

[0426] Example 82 & 87

[0427] Compound 87 (1R,3aS,3bR,7S,9aS,9bS,11aR)-1-[(2R)-6-(2,6-difluorophenyl)-6- hydroxyhexan-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecahydro-1H- cyclopenta[1,2-a]phenanthrene-7-ol was prepared from 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

[0428]

[0429] Referring to Examples 74 & 75, the 1-bromo-2-methoxybenzene of Step 8 was replaced with 2-bromo-1,3-difluorobenzene and separated by chiral resolution SFC (Instrument: Waters Acquity UPC C; Column: Daicel CHIRALPAK IB 4.6*250mm, 5um; Mobile Phase: A / B: CO2 / MeOH (0.1% DEA) = 60 / 40; Flow Rate: 1.5 mL / min; Column Temperature: 37 degrees) to give (1R,3aS,3bR,7S,9aS,9bS,11aR)-1-[(2R)-6-(2,6-difluorophenyl)-6- hydroxyhexan-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecahydro-1H- cyclopenta[1,2-a]phenanthrene-7-ol 87 (35 mg, 100% purity, 56% yield, 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, 100% purity, 8% yield, retention time t R = 1.646 min).

[0430] 87: 1H NMR (400 MHz, CDC13) δ 7.25 - 7.16 (m, 1H), 6.87 (t, J = 8.3 Hz, 2H), 5.03 (t, J = 7.2 Hz, 1H), 3.69 - 3.53 (m, 1H), 2.03 - 1.92 (m, 2H), 1.86 - 1.70 (m, 7H), 1.64 - 1.49 (m, 4H), 1.47 - 1.25 (m, 10H), 1.07 (ddd, J = 27.8, 15.1, 11.4 Hz, 5H), 0.89 (t, J = 6.0 Hz, 3H), 0.84 (s, 3H), 0.65 (d, J = 3.7 Hz, 3H). 19 F NMR (376 MHz, CDC13) δ -88.97, -89.60, -110.85, -111.48, -115.39, -115.46.

[0431] 82: 1 H NMR (400 MHz, CDC13) δ 7.21 (t, J = 7.4 Hz, 1H), 6.87 (t, J = 8.2 Hz, 2H), 5.03 (s, 1H), 3.63 (d, J = 26.3 Hz, 1H), 2.01 (dd, J = 11.2, 8.9 Hz, 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, 5.9 Hz, 2H), 1.38 (d, J = 5.0 Hz, 2H), 1.30 (dd, J = 11.6, 5.1 Hz, 4H), 1.13 (d, J = 12.9 Hz, 1H), 1.08 (d, J = 10.0 Hz, 2H), 1.02 (d, J = 11.9 Hz, 1H), 0.92 - 0.84 (m, 5H), 0.80 (d, J = 11.0 Hz, 3H), 0.66 (dd, J = 28.8, 3.7 Hz, 3H). 19 F NMR (376 MHz, CDC13) δ -110.61, -115.39, -115.46.

[0432] Examples 84 & 88

[0433] Preparation of 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-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol and 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.

[0434]

[0435] First step: Dissolve starting 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-butyllithium (1.8 mL, 0.45 mmol, 3.0 eq), and keep the temperature stirring for 30 min. Dissolve a mixture of 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-hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-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,6,7,7a,8,9,10,10a,12,12a,12b-tetradecahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxol-8-yl]hexanal II (70 mg, 0.15 mmol, 1.0 eq) in tetrahydrofuran (2 mL) to the above reaction solution, and stir the reaction system at -78 °C for 30 min. Monitor the reaction completion by TLC plate (petroleum ether: ethyl acetate = 5:1). Add 10 mL water to the reaction system, extract with ethyl acetate (100 mL x 3), wash the combined organic phase with saturated sodium chloride (10 mL), dry the combined organic phase, and concentrate to obtain a colorless oil of a mixture of 84-1 and 88-1 crude (70 mg), which is then directly used in the next step.

[0436] Step 2: The 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- hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]-1-{3-[(trifluoro- methyl)oxy]phenyl}hexan-1-ol 84-1 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]dioxol-8-yl]-1-(3-[(trifluoromethyl)oxy]phenyl) hexan-1-ol 88-1 (70 mg, 0.11 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL), diluted 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) was used to monitor the completion of the reaction. Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 x 10 mL). The ethyl acetate layers were combined and washed with saturated brine (3 x 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 resolution SFC (instrument: Waters Acquity UPC C; 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-hydroxy-6-{3-[(trifluoromethyl)oxy]phenyl}hexan-2-yl]-9a,11a-dimethylhexadecahydro-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, 97.97% purity, 4.96% yield, retention time t R = 0.927 min).

[0437] Compound 84: 1 H NMR (400 MHz, CDC13) δ 7.37 (t, J = 7.9 Hz, 1H), 7.28 (s, 1H), 7.22 (s, 1H), 7.12 (d, J = 8.0 Hz, 1H), 4.74 - 4.65 (m, 1H), 3.74 (s, 1H), 3.60 (dt, J = 11.0, 4.0 Hz, 1H), 2.29 - 2.07 (m, 1H), 1.97 (d, J = 12.9 Hz, 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, 5.1 Hz, 2H), 1.06 (s, 3H), 1.02 - 0.92 (m, 2H), 0.89 (t, J = 5.9 Hz, 3H), 0.65 (s, 3H). 19 F NMR (377 MHz, CDC13) δ -57.72, -88.64, -89.27, -110.64, -111.26.

[0438] Compound 88: 1H NMR (400 MHz, CDC13) δ 7.37 (t, J = 7.9 Hz, 1H), 7.28 (s, 1H), 7.22 (s, 1H), 7.12 (d, J = 7.9 Hz, 1H), 4.74 - 4.67 (m, 1H), 3.85 (s, 1H), 3.63 - 3.56 (m, 1H), 2.65 (t, J = 14.8 Hz, 1H), 2.02 (d, J = 14.1 Hz, 2H), 1.90 - 1.66 (m, 11H), 1.61 (d, J = 12.8 Hz, 4H), 1.45 (dd, J = 15.3, 7.8 Hz, 4H), 1.35 - 1.22 (m, 7H), 1.09 (dd, J = 12.2, 4.5 Hz, 3H), 1.04 (s, 3H), 0.90 (dd, J = 6.4, 4.4 Hz, 3H), 0.62 (d, J = 1.3 Hz, 3H). LC-MS: [M+1-H20] + = 551.30. 19 F NMR (376 MHz, CDC13) δ -57.72, -109.77.

[0439] Examples 89 & 90

[0440] Compound 89 (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-(1,3- thiaazacyclopentan-2-yl)hexan-2-yl]-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2- a]phenanthrene-6,7-diol and

[0441] Preparation of Compound 90 (1R,3aR,5aR,6R,7S,9aR,9bR,11aR)-4-fluoro-1-[(2R)-6-hydroxy-6-(1,3- thiaazacyclopentan-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.

[0442]

[0443] First step: Dissolve starting material 1,3-thiazolidine (44.7 mg, 0.5 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL), cool the system to -78 °C, add n-butyllithium (1.8 mL, 0.45 mmol, 3.0 eq), and keep the temperature stirring for 30 min. Dissolve the mixture 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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]hexanal I and (5R)-5-[(3aS,5aR,5bR,7aR,8R,10aR,12bR)-l l-fluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,12,12a,12b-tetradecahydro-3aH- cyclopenta[l',2':7,8]phenanthro[l,2-d][l,3]dioxol-8-yl]hexanal II (70 mg, 0.15 mmol, 1.0 eq) in tetrahydrofuran (2 mL) to the above reaction solution, and stir the reaction system at -78 °C for 30 min. Monitor the reaction completion by TLC plate (petroleum ether: ethyl acetate = 5: 1). Add 10 mL water to the reaction system, extract with ethyl acetate (100 mL x 3), wash the combined organic phase with saturated sodium chloride (10 mL), dry the combined organic phase, and concentrate to obtain colorless oil 89-1 and 90-1 crude (70 mg), which is then directly used in the next step.

[0444] Step 2: 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- hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]-1-(1,3- thiazinan-2-yl)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-tetradecahydro- 3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxol-8-yl]-1-(3-[(1,3-thiazinan-2-yl)hexan- 1-ol 90-1 crude (70 mg, 0.1 mmol, 1.0 eq) were dissolved in tetrahydrofuran (3 mL), diluted 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) was used to monitor the completion of the reaction. Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 x 10 mL). The EA layers were combined and washed with saturated brine (3 x 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 resolution SFC (instrument: Waters Acquity UPC; 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- thiazinan-2-yl)hexan-2-yl]-9a,11a-dimethylhexadecahydro-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- thiaazolidin-2-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 90 (2.09 mg, 98.75% purity, 4.63% yield, retention time t R = 1.618 min).

[0445] Compound 89: 1 H NMR (400 MHz, DMSO) δ 7.72 - 7.69 (m, 1H), 7.58 (dd, J = 3.2, 1.8 Hz, 1H), 6.05 (dd, J = 5.2, 1.2 Hz, 1H), 4.78 (dt, J = 8.0, 3.9 Hz, 1H), 4.40 (d, J = 6.0 Hz, 1H), 4.24 (d, J = 3.4 Hz, 1H), 3.49 (d, J = 2.4 Hz, 1H), 3.35 (d, J = 6.6 Hz, 1H), 2.17 - 1.97 (m, 1H), 1.91 (d, J = 12.5 Hz, 1H), 1.85 - 1.54 (m, 8H), 1.43 (d, J = 9.9 Hz, 3H), 1.37 - 1.15 (m, 9H), 1.05 (t, J = 10.5 Hz, 3H), 0.98 (s, 3H), 0.87 (d, J = 6.4 Hz, 3H), 0.62 (s, 3H). LC-MS: [M+1] + = 512.37. 19 F NMR (377 MHz, DMSO) δ -86.66, -87.28, -108.65, -109.27. Compound 90: 1H NMR (400 MHz, DMSO) δ 7.70 (d, J = 3.2 Hz, 1H), 7.58 (dd, J = 3.2, 1.7 Hz, 1H), 6.06 (d, J = 5.2 Hz, 1H), 4.77 (dt, J = 8.2, 4.8 Hz, 1H), 4.41 (d, J = 6.0 Hz, 1H), 4.24 (d, J = 3.4 Hz, 1H), 3.59 (d, J = 2.8 Hz, 1H), 3.29 (d, J = 4.2 Hz, 1H), 2.03 - 1.93 (m, 2H), 1.84 - 1.56 (m, 10H), 1.47 - 1.27 (m, 8H), 1.25 (d, J = 9.6 Hz, 4H), 1.07 (ddd, J = 35.6, 21.8, 13.4 Hz, 4H), 0.95 (s, 3H), 0.88 (d, J = 6.5 Hz, 3H), 0.57 (s, 3H). LC-MS: [M+1] + = 492.25. 19 F NMR (377 MHz, CDC13) δ -103.90.

[0446] Examples 91 & 92

[0447] 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-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol and

[0448] 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-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol.

[0449]

[0450]

[0451] Step 1: Dissolve the starting material 2-bromopyridine (118.50 mg, 0.750 mmol) in anhydrous tetrahydrofuran (5 mL), cool the system to -78 °C, add n-butyllithium (0.257 mL, 0.643 mmol), and keep the temperature 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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenalene-8-yl]hexanal I (100 mg, 0.214 mmol) dissolved in tetrahydrofuran (5 mL) is added to the above reaction, and the reaction system is stirred at -78 °C for 30 min. TLC plate (petroleum ether: ethyl acetate = 5: 1) monitors the completion of the reaction. Add 10 mL water to the reaction system, extract with ethyl acetate (100 mL x 3), wash the combined organic phase with saturated sodium chloride (10 mL), dry the combined organic phase, and concentrate 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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenalene-8-yl]-l-(pyridin-2-yl)hexan-l-ol 91-1 (70 mg, 0.103 mmol, 47.88%) as a colorless oil.

[0452] Second step: 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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]-l- (pyridin-2-yl)hexan-l-ol 91-1 (70 mg, 0.11 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL), diluted 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 plate (petroleum ether: ethyl acetate = 5:1). Water (10 mL) was added to the reaction system, and the water layer was extracted with ethyl acetate (3 x 10 mL). The EA layers were combined and washed with saturated brine (3 x 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 subjected to chiral resolution (instrument: Waters Acquity UPC C; 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 give 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 = 1.986 min).

[0453] Compound 91:1H NMR (400 MHz, CDC13) δ 8.55 (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, 3.3 Hz, 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, 8.8 Hz, 1H), 1.34 - 1.24 (m, 2H), 1.15 - 1.08 (m, 1H), 1.06 (s, 3H), 1.01 - 0.93 (m, 1H), 0.89 (t, J = 5.2 Hz, 3H), 0.65 (s, 3H). 19 FNMR (376 MHz, CDC13) δ -88.63, -89.26, -110.62, -111.25.

[0454] Compound 92: 1 H NMR (400 MHz, CDC13) δ 8.55 (d, J = 4.8 Hz, 1H), 7.70 (td, J = 7.7, 1.5 Hz, 1H), 7.22 (dd, J = 7.2, 5.2 Hz, 1H), 4.74 (dd, J = 7.7, 4.2 Hz, 1H), 3.74 (s, 1H), 3.59 (m, 1H), 2.21 (ddd, J = 28.4, 13.8, 7.1 Hz, 1H), 1.97 (d, J = 12.7 Hz, 1H), 1.80 (dd, J = 16.2, 6.4 Hz, 4H), 1.70 (m, 6H), 1.33 (ddd, J = 20.1, 16.0, 6.8 Hz, 11H), 1.11 (d, J = 5.4 Hz, 2H), 1.05 (s, 3H), 0.97 (m, 2H), 0.90 (d, J = 6.4 Hz, 3H), 0.63 (d, J = 11.0 Hz, 3H). 19 F NMR (376 MHz, CDC13) δ -88.58, -89.21, -110.56, -111.19.

[0455] Example 93

[0456] 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-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0457]

[0458] First step: (5R)-5-((3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-11,11-difluoro-2,2,5a

[0459] Methyl (5R)-5-((3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-11,11-difluoro-2,2,5a

[0460] The reaction progress was detected by TLC plate (petroleum ether: ethyl acetate = 10: 1, molybdenum phosphorus acid baking plate), and the reaction was stopped when the raw material was consumed. Water (30 mL) was added to the reaction system, and the water layer was extracted with ethyl acetate (3 x 20 mL). The EA layer was combined and washed with saturated brine (50 mL). The ethyl acetate layer was dried with anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 80:20) to obtain white solid methyl (5R)-5-((3S,4R,8S,9S,10R,13R,14S,17R)-7,7-difluoro-3,4-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)hexanoate 93-1 (330 mg, purity 90%, yield 73.42%). Compound 93-1: 1 H NMR (400 MHz, CDC13) δ 3.74 (s, 1H), 3.67 (s, 3H), 3.64 - 3.56 (m, 1H), 2.31 - 2.23 (m, 2H), 1.97 (d, J = 12.7 Hz, 1H), 1.89 - 1.77 (m, 5H), 1.75 - 1.66 (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 = 3.0 Hz, 2H), 0.93 (d, J = 6.5 Hz, 3H), 0.66 (s,

[0461] 3H). 19F NMR (377 MHz, CDC13) δ -88.96 (d, J = 235.9 Hz, IF), -110.94 (d, J = 236.0 Hz, IF).

[0462] The second step, compound (5R)-methyl 5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-6,7-dihydroxy-9a,11a-dimethylhexadeca-hydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoate 93-1 (300 mg, 0.66 mmol, 1.0 eq) was dissolved in tetrahydrofuran (15 mL), isopropyl titanate (938 mg, 3.30 mmol, 5.0 eq) was added under nitrogen protection, ethyl magnesium bromide (1 M in THF, 6.6 mL, 6.60 mmol, 10 eq) was added dropwise slowly, keeping the temperature at 18-20 °C. Then stirred at room temperature for 1 hour. TLC (petroleum ether: ethyl acetate = 2:1) was used to monitor the reaction. Ammonium chloride solution was used to quench, and ethyl acetate (30 mL) and water (20 mL) were added, diatomite was used to filter, the water phase was extracted with ethyl acetate (20 mL), the organic phase was combined and 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 obtain white solid (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-5-(hydroxycyclopropyl)pentan-2-yl]-9a,11a-dimethylhexadeca-hydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 93-2 (185 mg, purity: 90%, yield: 61.67%) 1 H NMR (400 MHz, CDC13) δ 3.74 (s, 1H), 3.65 - 3.56 (m, 1H), 2.27 - 2.11 (m, 1H), 1.98 (d, J = 12.9 Hz, 1H), 1.91 - 1.78 (m, 5H), 1.77 - 1.65 (m, 4H), 1.54 (dd, J = 13.4, 9.8 Hz, 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 = 6.5 Hz, 3H), 0.91 - 0.82 (m, 2H), 0.73 (t, J = 5.5 Hz, 2H), 0.67 (s, 3H), 0.47 - 0.41 (m, 2H).

[0463] Third step ((1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-5- (hydroxycyclopropyl)pentan-2-yl]-9a,11a-dimethylhexadecahydro-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), triethylamine (41 mg, 1.23 mmol, 3 eq), 4-dimethylaminopyridine (40 mg, 0.33 mmol, 0.8 eq) and benzoyl chloride (58 mg, 0.62 mmol, 1.5 eq) were added at room temperature, followed by stirring at room temperature for 4 hours, TLC (petroleum ether: ethyl acetate = 1:1) was used to monitor the reaction, after the reaction was completed, ice water (20 mL) was used for quenching, ethyl acetate (20 mL x 2) was used for extraction, the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, the organic phase was concentrated, purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) and SFC resolution (instrument: Waters Acquity UPC C column: Daicel CHIRALPAK IH_3, 3.0*150mm, 3um; mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 70 / 30; flow rate: 2.0 milliliter / minute; column temperature: 37 degrees) to obtain benzonic acid-(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-6-hydroxy-1-[(2R)-5- (hydroxycyclopropyl)pentan-2-yl]-9a,11a-dimethylhexadecahydro-1H- cyclopenta[1,2-i]phenanthrene-7-yl ester 93-3 (75 mg, purity: 95%, yield: 32.75%, retention time t R = 1.171 min). 1 H NMR (400 MHz, CDC13) δ 8.04 (d, J = 7.5 Hz, 2H), 7.58 (t, J = 7.6 Hz, 1H), 7.46 (t, J = 7.8 Hz, 2H), 4.99 (d, J = 11.2 Hz, 1H), 3.98 (s, 1H), 2.25 (d, J = 35.4 Hz, 1H), 2.02 (dd, J = 17.0, 8.7 Hz, 2H), 1.83 (d, J = 10.0 Hz, 7H), 1.55 (s, 6H), 1.49 - 1.32 (m, 8H), 1.14 (s, 3H), 1.09 - 0.98 (m, 2H), 0.95 (d, J = 6.5 Hz, 3H), 0.74 (t, J = 5.5 Hz, 2H), 0.68 (s, 3H), 0.50 - 0.37 (m, 2H). 19F NMR (376 MHz, CDC13) δ -89.03 (d, J = 236.3 Hz, IF), -110.80 (d, J = 236.4 Hz, IF).

[0464] Fourth step, (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-6-hydroxy-1-[(2R)-5- (hydroxycyclopropyl)pentan-2-yl]-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2- a]phenanthren-7-yl benzoate 93-3 (20 mg, 0.036 mmol, 1.0 eq) was dissolved in tetrahydrofuran (1 mL) and methanol (1 mL), potassium carbonate (25 mg, 0.18 mmol, 5.0 eq) and water (0.5 mL) were added at room temperature, then stirred at room temperature for 4 hours, TLC (petroleum ether: ethyl acetate = 4:1) was used to monitor the reaction, after the reaction was completed, diluted with water (10 mL), extracted with ethyl acetate (10 mL x 2), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, the organic phase was concentrated, purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1), to obtain white solid ((1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-5- (hydroxycyclopropyl)pentan-2-yl]-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2- a]phenanthrene-6,7-diol 93 (2.79 mg, purity: 100%, yield: 17.01%). 1 H NMR (400 MHz, CDC13) δ 3.76 - 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 = 5.4 Hz, 2H), 0.67 (s, 3H), 0.44 (t, J = 5.4 Hz, 2H). 19 F NMR (377 MHz, CDC13) δ -88.95 (d, J = 235.7 Hz, IF), -110.94 (d, J = 235.7 Hz, IF).

[0465] Examples 95 & 96

[0466] Compound 95 (4R)-4-[(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]-N-(2- fluorophenyl)-N-methylpentanamide and

[0467] 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]phenanthren-1-yl]-N-(2-fluorophenyl)-N-methylpentanamide

[0468]

[0469]

[0470] In the first step, the reactant (4R)-4-((3S,8S,9S,10R,13R,14S,17R)-3-acetyloxy-4- hydroxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H- cyclopenta[a]phenanthren-17-yl)methyl 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), and 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 x 80 mL). The ethyl acetate layers were combined and washed with saturated brine (3 x 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]phenanthren-17-yl)methyl pentanoate 95-1 (4.0 g, 9.89 mmol, 80% purity, 78.5% yield) as a white solid. 1H NMR (400 MHz, CDC13) δ 5.68 (d, J = 3.7 Hz, 1H), 4.14 (d, J = 3.3 Hz, 1H), 3.66 (s, 3H), 3.56 (d, J = 11.5 Hz, 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, 4.8 Hz, 3H), 1.30 (dd, J = 19.1, 9.5 Hz, 3H), 1.18 (s, 3H), 1.09 (d, J = 9.3 Hz, 4H), 0.92 (d, J = 6.4 Hz, 4H), 0.68 (s, 3H).

[0471] The second step, the reactant (4R)-methyl 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]phenanthren-17-yl)valerate 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, the reaction system was stirred at room temperature for 1 h. TLC (petroleum ether: ethyl acetate = 10:1) was used to monitor the progress of the reaction. The reaction was stopped by quenching with saturated sodium sulfite. 20 mL of water was added to the reaction system, extracted with ethyl acetate (25 mL x 3), the organic phase was collected, dried with anhydrous sodium sulfate, and the organic phase was rotary evaporated under vacuum to obtain the crude product. The crude product was dissolved in ethyl acetate and purified by column chromatography (petroleum ether: ethyl acetate = 95:5) to obtain (R)-methyl 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- tetradecahydro-4H-cyclopenta[7,8]phenalene[1,2-d][1,3]dioxol-8-yl)valerate 95-2 (3.5 g, 7.87 mmol, purity 90%, yield 72.6%) as a white solid. 1H NMR (400 MHz, CDC13) δ 5.80 (d, J = 2.7 Hz, 1H), 4.41 (d, J = 5.8 Hz, 1H), 4.15 (s, 1H), 3.66 (s, 3H), 2.43 - 2.10 (m, 3H), 1.99 (s, 1H), 1.67 - 1.58 (m, 4H), 1.53 (s, 3H), 1.35 (s, 3H), 1.26 (t, J = 7.1 Hz, 13H), 1.16 (s, 3H), 0.93 (d, J = 6.4 Hz, 3H), 0.69 (s, 3H).

[0472] The third step, compound (R)-methyl 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-tetradecahydro- 4H-cyclopenta[7,8]phenalene[l,2-d][l,3]dioxol-8-yl)pentanoate 95-2 (3.4 g, 7.61 mmol, 1.0 eq) was dissolved in acetone (50 mL), N-hydroxyphthalimide (0.99 g, 6.12 mmol, 0.8 eq), tert-butyl hydroperoxide (11 mL, 61.88 mmol, 8.0 eq) and cobalt(II) acetate, anhydrous (0.27 g, 1.52 mmol, 0.2 eq) were added, the resulting mixture was stirred at 25 °C under N2for 36 h. TLC plate (petroleum ether: ethyl acetate = 10: 1) was used to monitor the reaction progress, the starting material was consumed completely, quenched with saturated sodium sulfite, water (10 mL) was added to the reaction system, the aqueous layer was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 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-tetradecahydro-4H- cyclopenta[7,8]phenalene[l,2-d][l,3]dioxol-8-yl)pentanoate 95-3 (0.9 g, 1.96 mmol, 90% purity, 23.2% yield) as a white solid. 1H NMR (400 MHz, CDC13) δ 5.93 (s, 1H), 4.53 (d, J = 6.4 Hz, 1H), 4.33 (dd, J = 11.3, 5.5 Hz, 1H), 3.67 (d, J = 5.3 Hz, 3H), 2.36 (ddd, J = 15.3, 10.0, 5.1 Hz, 3H), 2.28 - 2.18 (m, 1H), 1.88 (dddd, J = 16.7, 10.3, 9.6, 3.8 Hz, 5H), 1.59 - 1.55 (m, 4H), 1.50 - 1.42 (m, 2H), 1.33 (s, 5H), 1.18 - 1.06 (m, 2H), 0.94 (t, J = 7.6 Hz, 3H), 0.72 (d, J = 10.0 Hz, 3H).

[0473] The fourth step, 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- tetradecahydro-4H-cyclopenta[7,8]phenanthro[1,2-d][1,3]dioxol-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), then palladium on carbon (1.2 g, 11 mmol, 2.2 eq) was added and the reaction system was replaced with a hydrogen atmosphere, the reaction system was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC plate (petroleum ether: ethyl acetate = 5:1), the starting material was consumed. The reaction system was filtered, the organic phase was collected and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 90:10) to give white solid (4R)-methyl 4-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-2,2,5a,7a-tetramethyl-11- oxo-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecahydro-3aH- cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]pentanoate 95-4 (1.7 g, 95% purity, 67% yield).

[0474] 1H NMR (400 MHz, CDC13) δ 4.07 - 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, 3.6 Hz, 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).

[0475] In the fifth step, (4R)-4-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)- 2,2,5a,7a-tetramethyl-11-oxysulfonyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]pentanoic acid methyl ester 95-4 (400 mg, 0.87 mmol) was dissolved in diethylamine sulfide (5 mL), and the resulting mixture was stirred at 80 °C for 1 h. The reaction progress was monitored by TLC (petroleum ether: ethyl acetate = 10: 1), and the starting material was consumed completely with a small polar spot generated. The reaction mixture was reduced to room temperature, diluted with dichloromethane (50 mL), and quenched by dropwise addition of ice water. The organic phase was collected, and the aqueous phase was extracted with dichloromethane (3 x 30 mL). The combined organic phase was washed with saturated brine (40 mL), filtered, and concentrated to give a crude product. The crude product was added to silica gel and eluted with petroleum ether: ethyl acetate = 93:7 to give a mixture of (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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-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[l',2':7,8]phenanthro[l,2-d][l,3]dioxol-8-yl]pentanoic acid methyl ester 96-1 (300 mg, 0.62 mmol, 90% purity, 64.3% yield calculated for 95-5).

[0476] Compound 95-5: 1H NMR (400 MHz, CDC13) δ 4.15 - 3.95 (m, 2H), 3.66 (s, 3H), 2.29 (dddd, J = 21.8, 15.6, 9.8, 5.8 Hz, 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, 5.9 Hz, 3H), 1.34 - 1.25 (m, 8H), 1.14 - 1.05 (m, 4H), 0.93 (t, J = 5.8 Hz, 3H), 0.66 (d, J = 12.0 Hz, 3H).

[0477] A mixture of methyl (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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]valerate 95-5 and methyl (4R)-4-[(3aS,5aR,5bR,7aR,8R,10aR,12aR,12bR)-l l-fluoro-2,2,5a,7a- tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,12,12a,12b-tetradecahydro-3aH- cyclopenta[l',2':7,8]phenanthro[l,2-d][l,3]dioxol-8-yl]valerate 96-1 (100 mg, 0.21 mmol) was dissolved in tetrahydrofuran (1 mL) solvent, 1 mol / L lithium hydroxide solution (0.5 mL) was added, and the resulting mixture was stirred at 25 °C for 16 h. The reaction progress was monitored by TLC (petroleum ether: ethyl acetate = 1:1), and the starting material was consumed. The reaction solution was diluted with ethyl acetate (20 mL) and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 60:40) to give a mixture of (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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]valerate 95-6 and (4R)-4-[(3aS,5aR,5bR,7aR,8R,10aR,12aR,12bR)-l l-fluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,12,12a,12b-tetradecahydro-3aH- cyclopenta[l',2':7,8]phenanthro[l,2-d][l,3]dioxol-8-yl]valerate 96-2 (65 mg, 0.14 mmol, purity: 90%, yield 59.4% calculated for 95-6) as a white solid.

[0478] Compound 95-6: 1H NMR (400 MHz, CDC13) δ 9.25 (s, 1H), 4.02 (s, 2H), 2.34 (ddd, J = 25.4, 17.2, 9.7 Hz, 2H), 1.99 (s, 2H), 1.96 - 1.57 (m, 8H), 1.51 (s, 3H), 1.40 (dd, J = 34.3, 11.9 Hz, 6H), 1.30 (s, 3H), 1.26 (s, 3H), 1.08 (t, J = 16.2 Hz, 4H), 0.90 (dd, J = 28.7, 9.1 Hz, 5H), 0.69 (s, 3H).

[0479] Step 7 A mixture of (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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenalene-8-yl]pentanoic acid 95-6 and (4R)-4- [(3aS,5aR,5bR,7aR,8R,10aR,12aR,12bR)-l l-fluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,12,12a,12b-tetradecahydro-3aH-cyclopenta[l',2':7,8]phenalene-l,2- d][l,3]dioxol-8-yl]pentanoic acid 96-2 (50 mg, 0.11 mmol, 1.0 eq) was dissolved in DMF (3 mL), HATU (2-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate) (50 mg, 0.13 mmol, 1.2 eq) and N,N-diisopropyl ethylamine (28 mg, 0.22 mmol, 2.0 eq) were added successively, stirred at room temperature for about 15 minutes, then o-fluoroaniline (12 mg, 0.11 mmol, 1.0 eq) was added, stirred at room temperature for 2 hours, the reaction was monitored by TLC (petroleum ether: ethyl acetate = 5: 1). After the reaction was completed, the reaction solution was diluted with water, extracted with ethyl acetate, the organic phase was washed with saturated brine twice, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 60:40) to give a mixture of (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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenalene-8-yl]-N-(2-fluorophenyl)pentanamide 95-7 and (4R)-4-[(3aS,5aR,5bR,7aR,8R,10aR,12aR,12bR)-l l-fluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,12,12a,12b-tetradecahydro-3aH-cyclopenta[l',2':7,8]phenalene-l,2- d][l,3]dioxol-8-yl]-N-(2-fluorophenyl)pentanamide 96-3 (30 mg, 0.053 mmol, purity: 90%, yield: 48.2% calculated based on 95-7).LC-MS: [M+H]+. + = 562.3

[0480] In the eighth step, a mixture of (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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]-N-(2- fluorophenyl)pentanamide 95-7 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[l',2':7,8]phenanthro[l,2-d][l,3]dioxol-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 a nitrogen atmosphere. After the reaction system was cooled to 0 °C, sodium hydride (60%, paraffin) (2.26 mg, 0.056 mmol, 1.3 eq) was slowly added, and then the reaction was stirred at room temperature for 30 min. Iodomethane (8.00 mg, 0.056 mmol, 1.3 eq) was added, and the reaction system was stirred at room temperature for 2 h. The reaction was monitored to completion by TLC (petroleum ether: ethyl acetate = 5: 1), and the reaction was stopped. The system was diluted with water (10 mL), extracted with EA (ethyl acetate) (20 mL x 3), and the combined organic phase was washed with saturated brine (10 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product.The crude product was purified by flash chromatography (petroleum ether: ethyl acetate = 90:10 to 80:20) to give a mixture of (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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthrol[7,8-d][l,3]dioxol-8-yl]-N-(2- fluorophenyl)-N-methylpentanamide 95-8 and (4R)-4-[(3aS,5aR,5bR,7aR,8R,10aR,12aR, 12bR)-l l-fluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,12,12a,12b-tetradecahydro- 3aH-cyclopenta[l',2':7,8]phenanthrol[l,2-d][l,3]dioxol-8-yl]-N-(2-fluorophenyl)-N- methylpentanamide 96-4 (25 mg, 90% purity, 90.3% yield of 95-8 calculated). LC-MS: [M+H]. + = 576.4

[0481] In the eighth step, a mixture of (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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]-N-(2- fluorophenyl)-N-methylpentanamide 95-8 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[l',2':7,8]phenanthro[l,2-d][l,3]dioxol-8-yl]-N-(2-fluorophenyl)-N- methylpentanamide 96-4 (25 mg, 0.043 mmol, 1.0 eq) was dissolved in tetrahydrofuran (1 mL), diluted hydrochloric acid (1 mL, 3 mol / L) was added, and the reaction system was stirred at room temperature for 1 h. The progress of 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 x 10 mL). The EA layers were combined and washed with saturated brine (3 x 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 obtain a white solid, which was then subjected to chiral resolution (instrument: Waters Acquity UPC C; column: REGIS CHIRAL (S, S)-WHEAT O1 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 (4R)-4-[(lR,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-6,7-dihydroxy-9a,11a- dimethylhexadecahydro-lH-cyclopenta[l,2-a]phenanthren-l-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]phenanthren-1-yl]-N-(2-fluorophenyl)-N-methylpentanamide 96 (0.68 mg, 97% purity, 3% yield, retention time t R = 3.328 min).

[0482] Compound 95: 1 H NMR (400 MHz, CDC13) δ 7.35 (dd, J = 13.9, 6.3 Hz, 1H), 7.26 - 7.14 (m, 3H), 3.73 (s, 1H), 3.58 (dd, J = 11.4, 3.6 Hz, 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 = 5.5 Hz, 3H), 0.60 (s, 3H). 19 F NMR (377 MHz, CDC13) δ -89.00 (d, J = 235.7 Hz, 1F), -110.96 (d, J = 236.0 Hz, 1F), -121.27 (d, J = 11.7 Hz, 1F).

[0483] Compound 96: 1 H NMR (400 MHz, CDC13) δ 7.36 (s, 1H), 7.20 (d, J = 7.4 Hz, 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 = 13.2 Hz, 2H), 1.02 (s, 3H), 0.88 (s, 4H), 0.73 (d, J = 5.7 Hz, 3H), 0.57 (s, 3H). 19 F NMR (377 MHz, CDC13) δ -109.72 (s, 1F), -121.29 (s, 1F).

[0484] Example 97

[0485] 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-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-6-one

[0486]

[0487]

[0488] 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-hexadeca-hydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]-1-{2-[(trifluoromethyl)oxy]phenyl}hexan-1-ol 1-1 (220 mg, 0.35 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), the reaction system was placed in an ice water bath, cooled to about 5°C, and 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 sequentially added to the reaction system, and the reaction system was stirred at room temperature for 1 hour. After monitoring the reaction to completion by TLC (petroleum ether: ethyl acetate = 10:1), the reaction solution was washed with water (10 mL x 2), saturated sodium bicarbonate (10 mL x 2), and dichloromethane (10 mL x 2), and the organic phase was collected and vacuum dried to obtain a crude product. The crude product was separated and purified by flash chromatography (petroleum ether: ethyl acetate = 92:8) to obtain white solid acetic acid-(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-hexadeca-hydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]-1-{2-[(trifluoromethyl)oxy]phenyl}hexyl ester 97-1 (190 mg, purity 95%, yield 72%). 1HNMR (400 MHz, CDC13) δ 7.43 (d, J = 7.7 Hz, 1H), 7.34 - 7.27 (m, 2H), 7.23 (s, 1H), 6.08 - 6.00 (m, 1H), 4.05 - 3.98 (m, 2H), 2.13 (dd, J = 15.2, 5.1 Hz, 1H), 1.96 (dd, J = 12.6, 3.5 Hz, 2H), 1.87 - 1.55 (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, 3.9 Hz, 2H), 1.07 (s, 4H), 1.04 - 0.90 (m, 4H), 0.87 (dd, J = 6.3, 4.3 Hz, 3H), 0.69 - 0.63 (m, 3H). 19 F NMR (376 MHz, CDC13) δ -56.48, -89.01, -89.64, -111.37, -112.00.

[0489] The second step, the reactant acetic acid-(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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]-l-{2- [(trifluoromethyl)oxy]phenyl}hexyl ester 97-1 (190 mg, 0.28 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 mL), dilute hydrochloric acid (1.5 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) was used to detect the progress of the reaction, and the consumption of the raw material was stopped. Water (10 mL) was added to the reaction system, and the water layer was extracted with ethyl acetate (3 x 10 mL). The combined ethyl acetate layer was washed with saturated brine (3 x 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 acetic acid-(5R)-5-[(lR,3aS,3bS,5aR,6R,7S,9aR,9bS,llaR)-4,4-difluoro-6,7-dihydroxy- 9a,lla-dimethylhexadecahydro-lH-cyclopenta[l,2-a]phenanthren-l-yl]-l-{2-[(trifluoromethyl)oxy]phenyl}hexyl ester 97-2 (180 mg, purity 99%, yield 90%) as a white solid. 1H NMR (400 MHz, CDC13) δ 7.43 (d, J = 7.3 Hz, 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, 4.0 Hz, 1H), 2.08 (s, 3H), 2.05 (s, 2H), 1.96 (d, J = 12.8 Hz, 1H), 1.89 - 1.55 (m, 13H), 1.49 - 1.29 (m, 9H), 1.16 - 1.08 (m, 2H), 1.05 (s, 4H), 0.95 (ddd, J = 12.4, 11.2, 2.5 Hz, 3H), 0.87 (dd, J = 6.3, 4.5 Hz, 3H), 0.67 - 0.61 (m, 3H).

[0490] The third step, (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 (180 mg, 0.28 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), the reaction system was placed in an ice water bath, and 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 turn, and the reaction system was stirred at room temperature for 1 hour. After monitoring the completion of the reaction by TLC (petroleum ether: ethyl acetate = 10:1), the reaction solution was washed with water (10 mL x 2), saturated sodium bicarbonate (10 mL x 2), and dichloromethane (10 mL x 2), and the organic phase was collected and removed under vacuum to obtain a crude product. The crude product was separated and purified by flash chromatography (petroleum ether: ethyl acetate = 80:20) to obtain white solid (5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-7-acetyloxy-4,4-difluoro-6-hydroxy-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-1-{2-[(trifluoromethyl)oxy]phenyl}hexyl acetate 97-3 (150 mg, purity 95%, yield 74%). 1H NMR (400 MHz, CDC13) δ 7.43 (d, J = 7.7 Hz, 1H), 7.34 - 7.27 (m, 2H), 7.23 (s, 1H), 6.08 - 6.00 (m, 1H), 4.05 - 3.98 (m, 2H), 2.13 (dd, J = 15.2, 5.1 Hz, 1H), 1.96 (dd, J = 12.6, 3.5 Hz, 2H), 1.87 - 1.55 (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, 3.9 Hz, 2H), 1.07 (s, 4H), 1.04 - 0.90 (m, 4H), 0.87 (dd, J = 6.3, 4.3 Hz, 3H), 0.69 - 0.63 (m, 3H).

[0491] In the fourth step, compound Acetic acid-(5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-7-acetyloxy-4,4-difluoro-6-hydroxy-9a,11a-dimethylhexadecahydro-1H- cyclopenta[1,2-a]phenanthren-1-yl]-1-{2-[(trifluoromethyl)oxy]phenyl}hexyl ester 97-3 (140 mg, 0.2 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), Dess-Martin reagent (176 g, 0.4 mmol, 2 eq) was added, the resulting mixture was stirred at 25 °C under N2for 1 h. TLC (petroleum ether: ethyl acetate = 10:1) was used to monitor the reaction progress, and the starting material was almost consumed. Saturated sodium bicarbonate (10 mL) was added to the reaction system, and the organic phase was extracted with saturated sodium sulfite (3 x 10 mL). The concentrated organic phase was collected. Purification was performed by silica gel column chromatography (petroleum ether: ethyl acetate = 92:8) to obtain white solid acetic acid-(5R)-5-[(1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-7-acetyloxy-4,4-difluoro-9a,11a-dimethyl-6- oxymethylene hexadecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-1-{2-[(trifluoromethyl)oxy]phenyl}hexyl ester 97-4 (150 mg, purity 90%. yield 96%). 1HNMR (400 MHz, CDC13) δ 7.43 (d, J = 7.0 Hz, 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, 7.4 Hz, 1H), 2.53 (t, J = 10.6 Hz, 1H), 2.29 - 2.23 (m, 1H), 2.16 (d, J = 2.8 Hz, 3H), 2.08 (s, 3H), 2.03 - 1.78 (m, 8H), 1.60 (dd, J = 23.4, 10.1 Hz, 5H), 1.45 - 1.00 (m, 14H), 0.88 (dd, J = 6.4, 3.8 Hz, 3H), 0.79 (s, 3H), 0.66 - 0.60 (m, 3H).

[0492] The fifth step, the reactant acetic acid-(5R)-5-[(1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-7-acetyloxy-4,4-difluoro-9a,11a-dimethyl-6-oxohexadecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-1-{2-[(trifluoromethyl)oxy]phenyl}hexyl ester 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, the reaction system was stirred at room temperature for 30 min. TLC (petroleum ether: ethyl acetate = 5:1) was used to monitor the progress of the reaction, the starting material was consumed, and the reaction was stopped. Water (10 mL) was added to the reaction system, the aqueous layer was extracted with ethyl acetate (3 x 10 mL). The combined ethyl acetate layer was washed with saturated brine (3 x 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 resolution (instrument: Waters Acquity UPC C; column: Daicel CHIRALPAK IC_3, 3.0*150mm, 3um; mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 60 / 40; flow rate: 1.5 milliliter / minute; column temperature: 37 degrees) to give (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-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-6-one 97 (3.74 mg, purity 99.64%, yield 8.52%, retention time t R = 1.876 min). 1H NMR (400 MHz, CDC13) δ 7.62 - 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, 8.3 Hz, 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, 3.8 Hz, 3H), 0.76 (s, 3H), 0.66 (s, 3H). 19 FNMR (377 MHz, CDC13) δ -56.78, -56.79, -56.81, -90.21, -90.85, -111.50, -112.14.

[0493] Example 98

[0494] 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-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol.

[0495]

[0496] First Step: 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-butyllithium (0.18 mL, 0.45 mmol, 3.0 eq), and keep the temperature 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- hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]hexanal I (70 mg, 0.15 mmol, 1.0 eq) dissolved in tetrahydrofuran (2 mL) is added to the above reaction solution, and the reaction system is stirred at -78 °C for 30 min. Monitor the reaction completion by TLC plate (petroleum ether: ethyl acetate = 5:1). Add 10 mL water to the reaction system, extract with ethyl acetate (100 mL x 3), wash the combined organic phase with saturated sodium chloride (10 mL), dry the combined organic phase, and concentrate to obtain colorless oil (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- hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]-1-(4,6-difluoro- 2-methoxyphenyl)hexan-1-ol 98-1 crude product (70 mg), which is directly used in the next step.

[0497] Second step: 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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]-l-(4,6-difluoro- 2-methoxyphenyl)hexan-l-ol (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. TLC (petroleum ether: ethyl acetate = 5: 1) was used to monitor the completion of the reaction. Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 x 10 mL). The ethyl acetate layers were combined and washed with saturated brine (3 x 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 subjected to chiral resolution (instrument: Waters Acquity UPC C; 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 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-dimethylhexadecahydro-lH-cyclopenta[l,2-a]phenanthrene- 6,7-diol 98 (21.58 mg, purity 100%, yield 32.99%, retention time t R = 1.486 min).

[0498] Compound 98: 1H NMR (400 MHz, CDC13) δ 6.44 (dd, J = 9.6, 8.0 Hz, 2H), 4.98 - 4.92 (m, 1H), 3.82 (d, J = 33.4 Hz, 3H), 3.74 (s, 1H), 3.60 (dt, J = 11.3, 4.1 Hz, 1H), 2.30 - 2.11 (m, 2H), 1.97 (d, J = 12.6 Hz, 2H), 1.83 - 1.77 (m, 3H), 1.69 (ddd, J = 20.3, 13.9, 9.8 Hz, 5H), 1.46 - 1.24 (m, 10H), 1.11 (dd, J = 12.7, 4.3 Hz, 2H), 1.06 (s, 4H), 1.02 - 0.91 (m, 2H), 0.90 - 0.85 (m, 3H), 0.65 (d, J = 3.7 Hz, 3H). 19 F NMR (377 MHz, CDC13) 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.

[0499] Example 99

[0500] Preparation of Compound 99 (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-(1,3-oxazol-2-yl)hexan-2-yl]-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol.

[0501]

[0502]

[0503] Step 1: Dissolve starting material 1,3-oxazolidine (51.8 mg, 0.75 mmol, 3.5 eq) in anhydrous tetrahydrofuran (3 mL), cool the system to -78 °C, add n-butyllithium (0.25 mL, 0.64 mmol, 3.0 eq), and keep the temperature stirring for 30 min. Dissolve 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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenalene[7,8-d][l,3]dioxol-8-yl]hexanal I (100 mg, 0.21 mmol, 1.0 eq) in tetrahydrofuran (2 mL) and add to the above reaction, keep the reaction system stirring at -78 °C for 30 min. Monitor the reaction completion by TLC plate (petroleum ether: ethyl acetate = 5: 1). Add 10 mL water to the reaction system, extract with ethyl acetate (100 mL x 3), wash the combined organic phase with saturated sodium chloride (10 mL), dry the combined organic phase, concentrate 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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenalene[7,8-d][l,3]dioxol-8-yl]-l-(l,3-oxazolidin- 2-yl)hexan-l-ol 99-1 crude (70 mg) as colorless oil, which is directly used for next step.

[0504] Second step: 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- hexadecahydro-3aH-cyclopenta[l',2':l,2]phenanthro[7,8-d][l,3]dioxol-8-yl]-l-(l,3- oxazolidin-2-yl)hexan-l-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) was used to monitor the completion of the reaction. Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 x 10 mL). The ethyl acetate layers were combined and washed with saturated brine (3 x 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 subjected to chiral resolution (instrument: Waters Acquity UPC C; column: Daicel CHIRALPAK IC_3, 3.0*150mm, 3um; mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 60 / 40; flow rate: 1.5 milliliter / minute; column temperature: 37 degrees) to give (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-l-[(2R)-6-hydroxy-6-(l,3- oxazolidin-2-yl)hexan-2-yl]-9a,11a-dimethylhexadecahydro-lH-cyclopenta[l,2-a]phenanthrene- 6,7-diol 99 (8.64 mg, purity 94.39%, yield 22.04%, retention time t R = 1.684 min). 1H NMR (400 MHz, DMSO) δ 8.25 (s, 1H), 7.85 (d, J = 2.6 Hz, 1H), 5.11 (dd, J = 5.2, 1.2 Hz, 1H), 4.46 (s, 1H), 4.40 (d, J = 6.0 Hz, 1H), 4.24 (d, J = 3.4 Hz, 1H), 3.49 (d, J = 2.2 Hz, 1H), 3.36 (s, 1H), 2.19 - 1.86 (m, 3H), 1.65 (ddd, J = 31.6, 22.1, 14.8 Hz, 9H), 1.43 (d, J = 9.8 Hz, 3H), 1.35 - 1.22 (m, 8H), 1.05 (t, J = 10.9 Hz, 3H), 0.98 (s, 3H), 0.87 (d, J = 5.8 Hz, 3H), 0.62 (s, 3H). 19 F NMR (377 MHz, DMSO) δ -86.66, -87.28, -108.65, -109.27. LC-MS: [M+1] + = 496.3.

[0505] Examples 100 & 101

[0506] Preparation of 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-dimethylhexadecahydro-1H- cyclopenta[l,2-a]phenanthrene-6,7-diol and 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[l,2-a]phenanthrene-6,7-diol.

[0507]

[0508] Step 1: Dissolve the starting 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-butyllithium (0.128 mL, 0.3 mmol, 3.0 eq), and keep the temperature stirring for 30 min. Dissolve the mixture of 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-hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-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,6,7,7a,8,9,10,10a,12,12a,12b-tetradecahydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxol-8-yl]hexanal II (50 mg, 0.1 mmol, 1.0 eq) in tetrahydrofuran (2 mL) to the above reaction solution, and stir the reaction system at -78 °C for 30 min. Detect the progress of the reaction by TLC plate (petroleum ether: ethyl acetate = 5:1, molybdenum pyrophosphate baking plate), and the starting material is consumed. Add 10 mL of water to the reaction system, extract with ethyl acetate (100 mL x 3), wash the combined organic phase with saturated sodium chloride (10 mL), dry the combined organic phase, and concentrate to obtain colorless oil (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-hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-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]dioxol-8-yl]-1-(4-fluorophenyl)hexan-1-ol 101-1 crude (70 mg), which is directly used in the next step.

[0509] Step 2: 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- hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-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]dioxol-8-yl]-1-(4-fluorophenyl)hexan-1-ol 101-1 crude (70 mg, 0.09 mmol, 1.0 eq) were 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. TLC (petroleum ether: ethyl acetate = 5:1) was used to detect the progress of the reaction, 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 x 10 mL). The ethyl acetate layers were combined and washed with saturated brine (3 x 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 resolution SFC (instrument: Waters Acquity UPC C; chromatographic c...

Claims

1. A compound of Formula I or a pharmaceutically acceptable salt thereof: in, for When there is a single bond between carbon atom 7 and carbon atom 8, R 7a and R 7b Independently H or halogen; When there is a double bond between carbon atom 7 and carbon atom 8, R 7b It is a halogen; 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 is C6-C 10 aryl, "a 5-10 membered heteroaryl group selected from one, two, or three heteroatoms from N, O, and S, with one, two, or three heteroatoms", C3-C6 cycloalkyl, or Ring B is C6-C 10 aryl, "a 5-6 membered heteroaryl group selected from one or two of N, O and S, with one or two heteroatoms" or triazine; Rings C and D are independently C6-C 10 Aryl; R 1 C1-C6 alkoxy, or NR 1a R 1b ; R 2 and R 3 Independently H or C1-C6 alkyl; R A R B R C and R D It is independently a halogen, a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, or a C1-C6 haloalkoxy; Ring E is a C3-C6 cycloalkyl group; m5 can be 0, 1, 2, or 3; R E Independent of OH and NR e1 R e2 COOH, C1-C6 alkyl, oxo group (=O) or R 1a R 1b R e1 and R e2 Independently H or C1-C6 alkyl; A carbon atom with an "&" indicates that when it is a chiral carbon atom, it is in the R configuration, S configuration, or a mixture of both. The compound shown in Formula I is not one of the following compounds or their isomers:

2. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, One or more of the following conditions must be met: (1)R 7a and R 7b In this context, the halogen is independently F, Cl, Br, or I; (2) Among rings A, B, C, and D, C6-C 10 The aryl group can be phenyl or naphthyl independently; (3) In ring A, the phrase "the heteroatom is selected from one, two or three of N, O and S, and the number of heteroatoms is one, two or three, of a 5-10 membered heteroaryl" is "the heteroatom is selected from one or two of N, O and S, and the number of heteroatoms is one or two, of a 5-6 membered heteroaryl" or "the heteroatom is selected from O, and the number of heteroatoms is one or two, of a 9-10 membered heteroaryl"; (4) In ring A, the C3-C6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or bicyclo[1.1.1]pentyl; (5)R 1 In this context, the C1-C6 alkoxy groups are independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy. (6)R 2 and R 3 In this context, the C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; (7)R A R B R C and R D In this context, the halogen is independently F, Cl, Br, or I; (8)R A R B R C and R D In this context, the C1-C6 alkyl group 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 In this context, the C1-C6 haloalkyl group is independently CHF2, CH2F, or CF3; (10)R A R B R C and R D In this context, the C1-C6 alkoxy groups are independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy. (11)R A R B R C and R D In this context, the C1-C6 haloalkoxy groups are independently -OCHF2, -OCH2F, or -OCF3; (12) In ring E, the C3-C6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or bicyclo[1.1.1]pentyl; (13)R E In this context, the C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; and (14)R 1a R 1b R e1 and R e2 In this context, the C1-C6 alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

3. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, One or more of the following conditions must be met: (1)R 7a and R 7b In this context, the halogen is independently F; (2) Among rings A, B, C, and D, C6-C 10 The aryl group is independently a phenyl group; (3) In ring A, the "5-10 membered heteroaryl group selected from 1, 2 or 3 of N, O and S, and having 1, 2 or 3 heteroatoms" is pyridyl, pyrazinyl, pyrimidinyl, triazinyl, thiazolyl or oxazolyl; (4) In ring B, the "5-6 membered heteroaryl group selected from one or two of N, O and S, and having one or two heteroatoms" is pyridyl, pyrazinyl, pyrimidinyl, thiazolyl or oxazolyl; (5) In ring A, the C3-C6 cycloalkyl group is (6)R 1 In this context, the C1-C6 alkoxy groups are independently methoxy groups; (7)R 2 and R 3 In this context, the C1-C6 alkyl group is independently methyl; (8)R A R B R C and R D In this context, the halogen is independently either F or Cl; (9)R A R B R C and R D In this context, the C1-C6 alkoxy groups are independently methoxy or ethoxy; (10)R A R B R C and R D In this context, the C1-C6 haloalkoxy groups are independently -OCF3; (11) In ring E, the C3-C6 cycloalkyl group is cyclopropyl or cyclobutyl; (12)R E In this context, the C1-C6 alkyl group is independently methyl; and (13)R 1a R 1b R e1 and R e2 In this context, the C1-C6 alkyl group is independently methyl.

4. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, One or more of the following conditions must be met: (1) In ring A, the pyridinyl group is (2) In ring A, the pyrazinyl group is (3) In ring A, the pyrimidine group is (4) In ring A, the triazine group is (5) In ring A, the thiazolyl group is (6) In ring A, the oxazolyl group is (7) In ring B, the pyridinyl group is (8) In ring B, the pyrazinyl group is (9) In ring B, the pyrimidine group is (10) In ring B, the triazine group is (11) In ring B, the thiazolyl group is (12) In ring B, the oxazolyl group is and (13)R A R B R C and R D In this context, the halogen is independently F.

5. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, One or more of the following conditions must be 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; (8) m3 is 1; (9) m4 is 1; (10) m5 is 1 or 2; (11)R A It is independently a halogen, a C1-C6 alkoxy, or a C1-C6 haloalkoxy; (12) Ring A is phenyl, pyridyl, pyrazinyl, pyrimidinyl, triazinyl, thiazolyl, oxazolyl, (13)R B It is independently a halogen, a C1-C6 alkoxy, or a C1-C6 haloalkoxy; (14) Ring B is phenyl; (15)R 1 For methoxy, Or NH2; (16)R 1a and R 1b H is independent; (17)R C and R D Halogens are independent of each other; (18) Ring C is phenyl; (19) Ring D is phenyl; (20) Ring E is cyclopropyl or cyclobutyl; and (21)R e1 and R e2 It is independently a C1-C6 alkyl group.

6. The compound of formula I as claimed in claim 5, or a pharmaceutically acceptable salt thereof, characterized in that, One or more of the following conditions must be met: (1) m2 is 2; (2) Ring A is a phenyl group. (3)R B Independently halogenated or C1-C6 alkoxy; and (4)R e1 and R e2 It is methyl on its own.

7. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, One or more of the following conditions must be met: (1)R 7a and R 7b Halogens are independent of each other; (2) for Where, m 1A It can be 0, 1, 2, 3, or 4; m 1B Independently 0, 1, 2, or 3; m 1C Independently 0, 1, or 2; and (3) for Where, m 2A It can be 0, 1, 2, 3, or 4.

8. The compound of formula I as claimed in claim 7, or a pharmaceutically acceptable salt thereof, characterized in that, R 7a and R 7b Independently, it is F.

9. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, One or more of the following conditions must be met: (1) for (2) for (3) for (4) Independently (5) for 10. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R 22 for 11. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by Formula I is a compound represented by Formula I-1, I-2, I-3, I-5, I-6, I-7, I-8, I-9 or I-10: Among them, the carbon atom with "&" indicates that when it is a chiral carbon atom, it has the R configuration, S configuration, or a mixture of both; ring A, ring B, R A R B The definitions of m1 and m2 are as described in any one of claims 1-10.

12. Any of the following compounds or their pharmaceutically acceptable salts:

13. A pharmaceutical composition comprising the compound of any one of claims 1-12 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient.

14. The use of a compound of any one of claims 1-12 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 13 in the preparation of a medicament for inhibiting the SREBP pathway, the medicament being used to prevent and / or treat a disease, wherein the disease is obesity, fatty liver, diabetes, cardiovascular disease, liver cancer, or skin lesions.

15. The use of a compound of any one of claims 1-12 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 13 in the preparation of a medicament for inhibiting the SREBP pathway, the medicament being used to prevent and / or treat a disease, wherein the disease is hyperlipidemia or atherosclerosis.

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