Steroid compound, pharmaceutical composition thereof, and use thereof

Abstract

Disclosed in the present invention are a steroid compound, a pharmaceutical composition thereof, and use thereof. Specifically, disclosed is a compound represented by formula I-0 or a pharmaceutically acceptable salt thereof. The compound of the present invention has SREBP pathway inhibitory activity, and can be used for preventing and / or treating diseases such as obesity, hyperlipidemia, fatty liver, diabetes, atherosclerosis, cardiovascular and cerebrovascular diseases, liver cancer, and skin damage.

Description

Steroids, their pharmaceutical compositions and applications

[0001] This application claims priority to Chinese Patent Application No. 2025101234048, filed on January 26, 2025; Chinese Patent Application No. 2025118294987, filed on December 5, 2025; and Chinese Patent Application No. 2026100735640, filed on January 19, 2026. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention relates to a steroidal compound, pharmaceutical compositions thereof, and applications. Background Technology

[0003] With changing lifestyles, including increased consumption of high-calorie foods and sugary drinks, and lack of exercise and physical activity, metabolic diseases such as hyperlipidemia, obesity, type 2 diabetes, and fatty liver have become increasingly serious health problems worldwide. Fatty liver has become a significant cause of chronic liver disease, with a prevalence of 10%–30% of adults experiencing simple hepatic lipid accumulation, of which 10%–20% are steatohepatitis, which has a 25% incidence of cirrhosis and liver cancer within 10 years. However, the pathophysiological mechanisms of fatty liver are not yet fully understood, and effective and specific treatments are still lacking in clinical practice. It is known that the accumulation of lipids such as cholesterol and triglycerides in the blood and liver is a major cause of hyperlipidemia, which in turn is a significant contributing factor to atherosclerosis, stroke, and fatty liver disease. Therefore, developing novel drugs targeting lipid metabolism regulatory pathways, with a focus on reducing lipids, is increasingly becoming an important direction in the development of new drugs for metabolic diseases.

[0004] Lipid synthesis pathways in mammalian cells are known to be crucial for regulating lipid homeostasis. A key factor regulating cholesterol and fatty acid synthesis is the sterol-regulatory element-binding protein (SREBP), a class of transcription factor proteins. The precursors of this protein are first synthesized in the endoplasmic reticulum (ER). These precursors are transported to the Golgi apparatus via SREBP cleavage-activating protein (SCAP), and then cleaved by two proteases (Site-1 protease (S1P) and Site-2 protease (S2P)). This releases the N-terminal active domain, allowing the protein to enter the nucleus and act as a transcription factor. It binds to the SREBP response element (SRE) in the promoter region of target genes, initiating the expression of downstream genes. The cleavage and maturation of SREBP proteins are strictly regulated by intracellular sterol levels (such as cholesterol and 25-hydroxycholesterol). When cells accumulate sufficient cholesterol in the endoplasmic reticulum, cholesterol binds to SCAP and alters the conformation of SCAP, causing the SCAP-SREBP complex to bind to the protein Insig (an insulin-induced gene), thereby blocking the transport of SREBP to the Golgi apparatus and subsequent SREBP activation. Conversely, an increase in the intranuclear active form of SREBP promotes cellular lipid synthesis. Besides cholesterol, 25-hydroxylcholesterol (25-HC) is another potent endogenous inhibitor of the SREBP pathway. Unlike cholesterol binding to SCAP, 25-HC directly binds to Insig and induces the binding of SCAP to Insig.

[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, and diabetes, as well as cardiovascular and cerebrovascular diseases, skin lesions, and liver cancer.

[0006] Hyperlipidemia's pathogenesis primarily involves increased lipid synthesis or abnormal lipid transport caused by factors such as diet or gene mutations, leading to excessive accumulation of lipids like cholesterol and fatty acids in the blood. Currently, statins and fibrates are the main lipid-lowering drugs used clinically. Statins, in particular, work by inhibiting cellular cholesterol synthesis while simultaneously promoting reverse cholesterol transport in the blood. This indicates that targeting key factors in cellular lipid synthesis is an important means of effectively reducing lipid levels.

[0007] Currently, there are no approved treatments for fatty liver disease, making it crucial to identify therapeutic targets and develop new, effective therapies. The pathogenesis of fatty liver disease involves multiple risk factors, such as the accumulation of triglycerides in the form of lipid droplets, which may trigger steatosis; and abnormally increased cholesterol and fatty acids in cells, which can cause endoplasmic reticulum stress and mitochondrial dysfunction, leading to cell death, inflammation, and fibrosis. Free cholesterol accumulation has been reported as a key driver of the transformation from simple steatosis to invasive steatohepatitis. Furthermore, establishing a mouse model of fatty liver disease has shown that a simple cholesterol-free, high-fat diet, even after prolonged feeding, only induces steatosis, while adding 1-2% cholesterol to the diet is necessary to induce inflammation and fibrosis. Therefore, lowering cholesterol may be a novel treatment strategy for fatty liver disease. Previous studies have shown that abnormal activation of SREBPs has been found in both patients and mouse models of fatty liver disease; the deletion or knockout of liver-specific Scap in mice can eliminate the activation of all SREBPs, thereby preventing the development of fatty liver and hyperlipidemia. Furthermore, recent studies have shown that endoplasmic reticulum stress-induced aberrant SREBP activation promotes adipogenesis and fatty liver. Therefore, this evidence suggests that reducing hepatic triglyceride and cholesterol levels by inhibiting the SREBP pathway is an effective strategy for preventing and / or treating metabolic disorders, including fatty liver. Summary of the Invention

[0008] The technical problem to be solved by the present invention is to provide new compounds with inhibitory activity against the SREBP pathway.

[0009] The present invention also provides a compound as shown in Formula I-0 or a pharmaceutically acceptable salt thereof:

[0010] in,

[0011] It can be a single bond or a double bond.

[0012] R 3a It is H or -(CH2)n-OH; n is 1, 2 or 3;

[0013] R 4a For H; R 4b It is H, OH or C1-C6 alkoxy; or, R 4a and R 4b Together with the carbon atoms they are connected to form

[0014] When there is a single bond between carbon atom 7 and carbon atom 8, R 7a and R 7b Independently halogenated; or R 7a and R 7bTogether with the carbon atoms they are connected to form Among them, the a-end is connected to carbon number 8; R 8a For H;

[0015] When there is a double bond between carbon atom 7 and carbon atom 8, R 7a It does not exist, R 7b It is a halogen; R 8a It does not exist;

[0016] R 19 It is H or CH3;

[0017] R 21 -L 1 -C(R 21b (R) 21c -OH, -L 2 -C(R 21d (R) 21e )-OH、 -L 1 -C(R 21d (R) 21e )-R 22 -L 1 -C(R 21f (R) 21g )-CR a (OH)-R 21h -L 3 -YR 21i ,

[0018] L 1 For -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, or -(CH2)6-, L 1 One of -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5- and -(CH2)6- described herein, is optionally replaced by -X. 1 -replace;

[0019] L 2 For -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, or -(CH2)6-, L 2 One of the -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, and -(CH2)6- mentioned above, is -X 2 -replace;

[0020] X1 and X 2 Independently -O-, -S-, -NH-, -N(C 1-6 Alkyl group, -CH=CH-, -CR a (OH)- or -CR 1a R 1b -;

[0021] R 1a H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0022] R 1b Halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0023] L 3 For -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, or -(CH2)6-, L 3 One of the -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, and -(CH2)6- mentioned above, is -X 3 -replace;

[0024] X 3 -O-, -CR a (OH)-, -S-, -NH- or -N(C 1-6 alkyl)-;

[0025] Y is -O-, -S-, or -CR a (OH)-;

[0026] R 21a For H or C 1-6 alkyl;

[0027] Ring A is a C3-C6 cycloalkyl group, surrounded by one or more R groups. 3 Substituted C3-C6 cycloalkyl, "a 3-6 membered heterocycloalkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms", or substituted with one or more R 4 The substituted heteroatom is "a 3-6 membered heterocyclic alkyl group selected from one, two or three of N, O and S, and having one, two or three heteroatoms";

[0028] n1 is 1, 2, 3 or 4;

[0029] Ring B is a C3-C6 cycloalkyl group, surrounded by one or more R groups. 3Substituted C3-C6 cycloalkyl, "a 3-6 membered heterocycloalkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms", or substituted with one or more R 4 The substituted heteroatom is "a 3-6 membered heterocyclic alkyl group selected from one, two or three of N, O and S, and having one, two or three heteroatoms";

[0030] Ring C is formed by one or more R 3-1 Substituted C3-C6 cycloalkyl, "a 3-6 membered heterocycloalkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms", or substituted with one or more R 4 The substituted heteroatom is "a 3-6 membered heterocyclic alkyl group selected from one, two or three of N, O and S, and having one, two or three heteroatoms";

[0031] R 3 and R 4 Independently OH, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C substituted with one or more OH groups 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups or C groups substituted with one or more OH groups 1-6 Alkoxy;

[0032] R 3-1 Independently, C substituted by one or more OH groups 1-6 Alkoxy; R 21b For H or C 1-6 alkyl;

[0033] R 21c C 2-6 Alkyl or with one or more R 6 Replacement C 1-6 alkyl;

[0034] Or, R 21b and R 21c Together with the carbon atoms connecting them, they form "a 3-6 membered heterocyclic alkyl group consisting of one, two, or three heteroatoms selected from N, O, and S, with one, two, or three heteroatoms" or is bounded by one or more R 4 The substituted heteroatom is "a 3-6 membered heterocyclic alkyl group selected from one, two or three of N, O and S, and having one, two or three heteroatoms";

[0035] R 6 Independent of halogen, C 1-6 Haloalkyl, C 1-6 Alkyl group, by one or more R 6-1 Replacement C1-6 alkoxy or OH;

[0036] R 6-1 It can be a halogen or OH on its own;

[0037] R 21d For H or C 1-6 alkyl;

[0038] R 21e C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0039] R 22 For NR a R b Or by one or more R 22-1 Replacement C 1-6 alkyl;

[0040] R 22-1 Independently OH;

[0041] R 21f and R 21g Independently for C 1-6 alkyl;

[0042] R 21h C 1-6 Alkyl or with one or more R 7 Replacement C 1-6 alkyl;

[0043] R 7 Independently OH, halogen, C 3-6 cycloalkyl or with one or more R 7-1 Replacement C 3-6 cycloalkyl;

[0044] R 7-1 It can be a halogen or OH on its own;

[0045] R 21i For one or more R 8 Replacement C 1-6 alkyl;

[0046] R 8 Independently OH, halogen, C 3-6 cycloalkyl or with one or more R 8-1 Replacement C 3-6 cycloalkyl;

[0047] R 8-1 It can be a halogen or OH on its own;

[0048] R a and R b Independently H or C1-6 alkyl;

[0049] Ring D is "a 3-10 membered heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms", or is surrounded by one or more R... 4 The substituted heteroatom is selected from one, two, or three of N, O, and S, and is a 3-10 membered heterocyclic alkyl group with one, two, or three heteroatoms.

[0050] n2 is 0, 1, 2, 3 or 4;

[0051] Ring E is a C3-C6 cycloalkyl group, or a C3-C6 cycloalkyl group substituted with one or more OH groups;

[0052] The carbon atom marked with * is in the R configuration, S configuration, or a mixture of both; the carbon atom marked with ** is in the R configuration, S configuration, or a mixture of both; when the carbon atom marked with # is a chiral carbon atom, it is in the R configuration, S configuration, or a mixture of both; when the carbon atom marked with & is a chiral carbon atom, it is in the R configuration, S configuration, or a mixture of both.

[0053] When R 21b For H, R 21c C substituted by one or more halogens 1-6 When alkyl, R 4b For H;

[0054] When R 21a When H is present and ring A is a C3-C6 cycloalkyl group, R 4b For H.

[0055] In this invention, the compound of formula I-0 or its pharmaceutically acceptable salt is the compound of formula I or its pharmaceutically acceptable salt:

[0056] in,

[0057] R 21 -L 1 -C(R 21b (R) 21c -OH, -L 2 -C(R 21d (R) 21e )-OH、 -L 1 -C(R 21d (R) 21e )-R 22 -L 1 -C(R 21f (R) 21g )-CR a(OH)-R 21h or -L 3 -YR 21i ;

[0058] The ring C is "a 3-6 membered heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" or is surrounded by one or more R... 4 The substituted heteroatom is selected from one, two or three of N, O and S, and is a 3-6 membered heterocyclic alkyl group with one, two or three heteroatoms.

[0059] In certain preferred embodiments of the present invention, certain groups in the compounds represented by formulas I-0, I or their pharmaceutically acceptable salts are defined as follows, and groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in some embodiments"), where n is 2.

[0060] In some implementations, R 4b For H.

[0061] In some implementations, R 4b It is OH.

[0062] In some implementations, when there is a single bond between carbon atom 7 and carbon atom 8, R 7a and R 7b Halogens are independent of each other; R 8a For H;

[0063] When there is a double bond between carbon atom 7 and carbon atom 8, R 7a It does not exist, R 7b It is a halogen; R 8a It does not exist.

[0064] In some implementations, when there is a single bond between carbon atom 7 and carbon atom 8, R 7a and R 7b Independently F; R 8a For H; when there is a double bond between carbon atoms 7 and 8, for R 7a It does not exist, R 7b For F; R 8a It does not exist.

[0065] In some implementations, R 19 For H.

[0066] In some implementations, R 19 It is CH3.

[0067] In some implementations, R 21 -L 1 -C(R 21b (R) 21c)-OH.

[0068] In some implementations, L 1 For -(CH2)2- or -(CH2)3-, L 1 The -CH2- in the -(CH2)2- or -(CH2)3- mentioned above is optionally replaced by -X 1 - Alternative. Better, L 1 It is -(CH2)3-.

[0069] In some implementations, L 1 For -(CH2)4- or -(CH2)5-, L 1 The -CH2- in either -(CH2)4- or -(CH2)5- is optionally replaced by -X 1 - Alternative. Better, X 1 -for-CR 1a R 1b -

[0070] In some implementations, L 1 For -(CH2)3-, L 1 In the -(CH2)3- described above, one of the -CH2- groups is -X 1 - Alternative. Better, X 1 -for -O- or -CR a (OH)-.

[0071] In some implementations, L 2 For -(CH2)2- or -(CH2)3-, L 2 The -CH2- in the -(CH2)2- or -(CH2)3- mentioned above is optionally replaced by -X 1 -replace.

[0072] In some implementations, L 2 For -(CH2)2- or -(CH2)3-, L 2 One of the -CH2- or -(CH2)3- in the above-described -(CH2)2- or -(CH2)3- is -X 2 -replace.

[0073] In some implementations, X 1 and X 2 Independently -O-, -NH-, -N(C 1-6 alkyl)-, -CR a (OH)- or -CR 1a R 1b -; better, X 1 and X 2 Independently for -O-, -CR a (OH)- or -CR 1a R 1b -

[0074] In some implementations, X 2 For -CR 1a R 1b -, R 1a H or halogen; R 1b It is a halogen.

[0075] In some implementations, R 1a Halogen or C 1-6 alkyl.

[0076] In some implementations, R 1b Halogen or C 1-6 alkyl.

[0077] In some implementations, L 3 For -(CH2)3- or -(CH2)5-, L 3 One of the -CH2- and -(CH2)5- mentioned above is -X 3 -replace.

[0078] In some implementations, X 3 -O- or -CR a (OH)-.

[0079] In some embodiments, ring A is a C3-C6 cycloalkyl group, surrounded by one or more R groups. 3 The substituted C3-C6 cycloalkyl or "a 3-6 membered heterocycloalkyl whose heteroatoms are selected from one, two or three of N, O and S, and whose heteroatoms number one, two or three".

[0080] In some implementations, R 21a H is a cyclic A, which is a 3-6 membered heterocyclic alkyl group selected from 1, 2 or 3 of N, O and S, with 1, 2 or 3 heteroatoms.

[0081] In some implementations, n1 is 1.

[0082] In some embodiments, ring B is "a 3-6 membered heterocyclic alkyl group selected from one, two or three of N, O and S, with one, two or three heteroatoms".

[0083] In some embodiments, the ring C is "a 3-6 membered heterocyclic alkyl group selected from one, two or three of N, O and S, and having one, two or three heteroatoms".

[0084] In some implementations, ring C is surrounded by one or more R3-1 Substituted C3-C6 cycloalkyl groups.

[0085] In some implementations, ring C is surrounded by one or more R 4 The substituted "heteroatom is selected from one, two, or three of N, O, and S, and is a 3-6 membered heterocyclic alkyl group with one, two, or three heteroatoms"; R 4 It is OH on its own.

[0086] In some implementations, R 3 and R 4 Independent of OH and C 1-6 Alkyl, halogen, or C substituted with one or more OH groups 1-6 Alkyl group.

[0087] In some implementations, R 3 and R 4 Independently, C substituted by one or more OH groups 1-6 alkyl.

[0088] In some implementations, R 21b For H or C 1-6 alkyl;

[0089] R 21c C 2-6 Alkyl or with one or more R 6 Replacement C 1-6 alkyl;

[0090] Or, R 21b and R 21c Together with the carbon atoms that connect them, they form "3-6 membered heterocyclic alkyl groups selected from one, two or three of N, O and S, with one, two or three heteroatoms".

[0091] In some implementations, R 21b For H or C 1-6 Alkyl, R 21c C 2-6 Alkyl or with one or more R 6 Replacement C 1-6 Alkyl; R 6 Halogens are independent of each other.

[0092] In some implementations, R 21b For H; R 21c For one or more R 6 Replacement C 1-6 Alkyl; R 6 Halogens are independent of each other.

[0093] In some implementations, R 21b C1-6 Alkyl; R 21c C 2-6 alkyl.

[0094] In some implementations, R 21b C 1-6 Alkyl; R 21c For one or more R 6 Replacement C 1-6 Alkyl; R 6 It can be a halogen or OH on its own.

[0095] In some implementations, R 21d C 1-6 Alkyl; R 21e C 1-6 alkyl.

[0096] In some implementations, R 21d C 1-6 Alkyl; R 21e C 1-6 Alkyl; R 22 For one or more R 22-1 Replacement C 1-6 alkyl.

[0097] In some implementations, R 6 Independent of halogen, C 1-6 Alkyl group, by one or more R 6-1 Replacement C 1-6 Alkyl groups or OH groups.

[0098] In some implementations, R 6-1 It is OH on its own.

[0099] In some implementations, R 7 Independently OH or by one or more R 7-1 Replacement C 3-6 Cycloalkyl.

[0100] In some implementations, R a For H, R 21h C 1-6 Alkyl or with one or more R 7 Replacement C 1-6 Alkyl; R 7 It can be OH or halogen on its own.

[0101] In some implementations, R 7 Halogens are independent of each other.

[0102] In some implementations, R 7-1 It is OH on its own.

[0103] In some implementations, R 8 It is OH on its own.

[0104] In some implementations, R a and R b H stands for H independently.

[0105] In some implementations, ring D is bounded by one or more R 4 The substituted heteroatom is selected from one, two, or three of N, O, and S, and is a 3-10 membered heterocyclic alkyl group having one, two, or three heteroatoms; preferably, R 4 It is OH on its own.

[0106] In some implementations, n2 is 1 or 2; for example, 1.

[0107] In some embodiments, ring E is a C3-C6 cycloalkyl group substituted with one or more OH groups.

[0108] In some embodiments, the C1-C6 alkoxy group and the substituted C1-C6 alkoxy group are independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy; for example, methoxy.

[0109] In some embodiments, the halogen is independently F, Cl, Br, or I; for example, F.

[0110] In some embodiments, the C1-C6 alkyl group and the C1-C6 alkyl group in the substituted C1-C6 alkyl group are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; for example, methyl, ethyl, isopropyl, or

[0111] In some embodiments, the C2-C6 alkyl group is independently ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; for example, ethyl, isopropyl, or

[0112] In some implementations, the C 1-6 The alkyl halide is independently -CF3, -CHF2, -CH2F, -CH2CF3 or -CH2CHF2; for example -CF3 or -CHF2.

[0113] In some implementations, the C 1-6 The haloalkoxy group is independently -OCF3, -OCHF2, -OCH2F, -OCH2CF3 or -OCH2CHF2.

[0114] In some embodiments, the C3-C6 cycloalkyl group and the substituted C3-C6 cycloalkyl group are independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, for example, cyclopropyl or cyclohexyl.

[0115] In some embodiments, the phrase "a 3-6 membered heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" and the phrase "a 3-6 membered heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" in the substituted phrase "a 3-6 membered heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" are independently defined as "a 4-, 5-, or 6-membered heterocyclic alkyl group selected from O, with one heteroatom," for example...

[0116] In some embodiments, 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 in a 3-10 membered heterocyclic alkyl group" and "the substituted heteroatom is selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three in a 3-10 membered heterocyclic alkyl group" is independently defined as "the heteroatom is selected from one or two of N and O, and the number of heteroatoms is one or two in a 3-6 membered monocyclic or 7-10 membered bicyclic heterocyclic alkyl group," for example, aziridine (e.g., aziridine). ) or 2-azaspiro[3.3]heptane (e.g. ).

[0117] In some implementations, R 3a For H or

[0118] In some implementations, R 4a For H; R 4b It is H, OH or methoxy; or, R 4a and R 4b Together with the carbon atoms they are connected to form

[0119] In some implementations, when there is a single bond between carbon atom 7 and carbon atom 8, R 7a and R 7b For F; or R 7a and R 7b Together with the carbon atoms they are connected to form Among them, the a-end is connected to carbon number 8; R 8a For H;

[0120] When there is a double bond between carbon atom 7 and carbon atom 8, R 7a It does not exist, R 7b For F; R 8a It does not exist.

[0121] In some implementations, the carbon atom marked with * has an S configuration.

[0122] In some implementations, the carbon atom marked with ** has an S configuration.

[0123] In some implementations... for

[0124] In some implementations, L 1 -(CH2)2-, -(CH2)3-,

[0125] Among them, the B end and Connected.

[0126] In some implementations, L 2 for Among them, the B end and Connected.

[0127] In some implementations, L 3 for Among them, the B end and Connected.

[0128] In some implementations, R 21 for

[0129] In some embodiments, the compound represented by Formula I is a compound represented by Formula I-1 or I-2:

[0130] Among them, R 21b and R 21c The definition is as described in any embodiment of this invention.

[0131] Better, R 21c C 2-6 Alkyl groups or C atoms substituted with one or more halogens 1-6 alkyl.

[0132] In some embodiments, the compound, for R 21 -L 1 -C(R 21f (R) 21g )-CR a (OH)-R 21h The carbon atoms marked with 、;** have an S configuration.

[0133] In some implementations, L 1 It is -(CH2)3-.

[0134] In some implementation schemes, R a For H.

[0135] In some implementation schemes, R 21h C substituted by one or more OH groups 1-6 alkyl.

[0136] The present invention also provides any of the following compounds or pharmaceutically acceptable salts thereof:

[0137] The present invention also provides any of the following compounds or pharmaceutically acceptable salts thereof:

[0138] The present invention provides a pharmaceutical composition comprising a compound as described in any one of the present invention or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient.

[0139] This invention also provides uses of the compounds as described in any one of these inventions, or pharmaceutically acceptable salts thereof, and the pharmaceutical compositions thereof, wherein the uses are selected from:

[0140] (1) Prepare a medicine for the prevention and / or treatment of a disease, wherein the disease is obesity, hyperlipidemia, fatty liver, diabetes, atherosclerosis, cardiovascular and cerebrovascular diseases, liver cancer or skin lesions;

[0141] (2) Prepare a drug for the prevention and / or treatment of diseases related to the SREBP pathway; preferably, the diseases related to the SREBP pathway are obesity, hyperlipidemia, fatty liver, diabetes, atherosclerosis, cardiovascular and cerebrovascular diseases, liver cancer or skin lesions;

[0142] (3) Preparation of SREBP pathway inhibitors.

[0143] The present invention also provides a method for preventing and / or treating a disease, comprising administering to a subject an effective amount of a compound as described in any one of the present invention or a pharmaceutically acceptable salt thereof, wherein the disease is obesity, hyperlipidemia, fatty liver, diabetes, atherosclerosis, cardiovascular disease, liver cancer, or skin lesions.

[0144] Definitions and Explanations

[0145] In this article, the chemical structural formula Indicates the connection position. When Contained in cyclic groups and not specified When the ring atoms are connected, It can be attached to any ring atom, but it is only allowed to form a stable or chemically viable chemical compound.

[0146] 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) The configuration is not specified, meaning that if configurational isomerism exists in the chemical structure, the bond... It can be Or simultaneously include Two configurations (e.g.) The ratio is 1:1. When the specific configuration of the carbon-carbon double bond is not specified, 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.

[0147] 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.

[0148] In this document, the term "substitution" or "substituent" means that a hydrogen atom in a group is replaced by a specified group. When the substitution position is not specified, substitution can occur at any position, but it is only permitted if a stable or chemically viable chemical is formed.

[0149] When any variable (e.g., R) aWhen a compound appears more than once in its composition or structure, its definition is independent in each case.

[0150] The term "one or more" refers to one, two, or three.

[0151] In this document, the term "alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group. For example, C1-C6 alkyl refers to a straight-chain or branched alkyl group having 1-6 carbon atoms.

[0152] In this document, the term "haloalkyl" refers to a group formed by replacing one or more hydrogen atoms in an alkyl group with a halogen, wherein the definition of alkyl is as described above.

[0153] In this document, the term "alkoxy" refers to -O-alkyl, where alkyl is defined as previously stated.

[0154] In this document, the term "haloalkoxy" refers to a group formed by replacing one or more hydrogen atoms in an alkoxy group with a halogen, wherein the definition of an alkoxy group is as described above.

[0155] In this document, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., fused, spiro, or bridged) cyclic hydrocarbon group.

[0156] In this document, the term "heterocyclic alkyl" refers to a cyclic, saturated monovalent group having a specified number of ring atoms (e.g., 3-6), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatoms (e.g., one, two, or three of N, O, and S), which is monocyclic or polycyclic (e.g., fused, spirocyclic, or bridged).

[0157] In this document, the term "subject" includes any animal, preferably a mammal, and more preferably a human.

[0158] 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.

[0159] 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.

[0160] The reagents and raw materials used in this invention are all commercially available.

[0161] 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

[0162] Synthesis of 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-hexadecylhydro-3aH-cyclopentano[1',2':1,2]phenanthro[7,8-d][1,3]dioxacyclopentanthro-8-yl]hexanal

[0163] In step 1, 150.00 g (382.088 mmol, 1.0 eq) of 6α-hydroxy-3α-hydroxy-5β-cholan-24-acid I-0 was dissolved in 500 mL of MeOH (methanol). Sulfuric acid (50 mL, 938.105 mmol, 2.5 eq) was slowly added to the reaction system, and the system was stirred at 75 °C for 2 hours. After the reaction was complete, it was monitored by TLC (dichloromethane:methanol = 10:1). The mixture was then cooled to room temperature, and the reaction solution was slowly added to saturated sodium bicarbonate (~500 mL). The reaction system was washed once with saturated sodium bicarbonate solution (~500 mL) and once with water (~500 mL). The solution was dried over anhydrous sodium sulfate, concentrated, and dried to obtain crude methyl 6α-hydroxy-3α-hydroxycholan-24-acid I-1 (150 g, yield 86.90%).

[0164] Step 2: I-1 (150.0 g, 368.9 mmol, 1.0 eq) was dissolved in pyridine (500 mL), and p-toluenesulfonyl chloride (422 g, 2213 mmol, 6 eq) was added at room temperature. The mixture was stirred overnight at room temperature. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 5:1) until complete. The reaction solution was poured into a 5% hydrochloric acid solution (1000 mL) containing crushed ice. After the solid precipitated, it was filtered, washed with water, and dried to obtain crude 4-methylbenzenesulfonic acid-(1R,3aS,3bS,5S,7R,9aR,9bS,11aR)-1-[(2R)-5-methoxy-5-oxylidenepent-2-yl]-9a,11a-dimethyl-7-{[(4-methylphenyl)dioxylidene-λ6-thio]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-5-yl ester I-2 (200 g, yield 70.20%).

[0165] In step 3, I-2 (100 g, 139.8 mmol, 1.0 eq) was dissolved in water (40 mL) and N,N-dimethylformamide (400 mL), and sodium acetate (120 g, 139.8 mmol, 10 eq) was added. The system was heated to 110 °C and refluxed for 4 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1). After the reaction was complete, it was cooled to room temperature. The reaction solution was poured into a 5% hydrochloric acid solution (1000 mL) containing crushed ice, filtered, and the solid was washed with water (100 mL * 2). After drying, crude 4-methylbenzenesulfonic acid-(1R,3aS,3bS,7R,9aR,9bS,11aR)-1-[(2R)-5-methoxy-5-oxoylidenepent-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecanoyl-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester I-3 (60 g, yield 80.0%) was directly added to the next reaction step.

[0166] Step 4: I-3 (100 g, 184.2 mmol, 1.0 eq) was dissolved in 4% potassium hydroxide-methanol solution (500 mL), and the reaction mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 5:1). After the reaction was complete, the pH was adjusted to neutral with 5% hydrochloric acid, and the reaction solution was extracted with ethyl acetate (200 mL × 3), washed with saturated brine (200 mL × 3), dried over anhydrous sulfuric acid, and the organic phase was collected and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30:1 to 10:1 to 5:1) to give a white solid methyl 3β-hydroxycholan-5(6)-ene-24-oic acid I-4 (60 g, yield 75.6%). 1 H NMR (400MHz, CDCl3) δ5.37–5.33(m,1H),3.66(s,3H),2.34(dt,J=13.0,4.0Hz,1H),2.30–2.23(m,2H),2.24–2.18(m,2H),2.05–1.9 3(m,3H),1.82(tdd,J=10.1,8.1,4.9Hz,5H),1.53–1.40(m,7H),1.36–1.25(m,3H),1.01(s,3H),0.92(t,J=5.1Hz,5H),0.68(s,4H).

[0167] In step 5, reactant I-4 (30 g, 77.2 mmol, 1.0 eq) was dissolved in chloroform (180 mL), and selenium dioxide (21 g, 189.40 mmol, 2.5 eq) and NMM (25.4 mL, 231.60 mmol, 3.0 eq) were added. The reaction system was stirred at 75 °C for 18 h. After the reaction was basically complete as monitored by TLC plate (petroleum ether: ethyl acetate = 5:1), the reaction was stopped. 200 mL of water was added to the reaction system, and the mixture was extracted with ethyl acetate (100 mL * 3). The combined organic phases were washed with water (100 mL * 2), washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was collected and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1 to 6:1 to 3:1) to obtain a white solid methyl 4β-hydroxy-3β-hydroxycholan-5(6)-ene-24-oic acid I-5 (20 g, purity 70%, yield 50.3%). 1 H NMR (400MHz, CDCl3) δ5.71–5.63(m,1H),4.14(d,J=3.2Hz,1H),3.66(s,3H),3.56(d,J=11. 5Hz,1H),2.34(dd,J=10.2,5.2Hz,1H),2.27–2.17(m,1H),2.07(s,1H),2.00(d,J=12.5Hz, 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,2 H),1.18(s,3H),1.15–1.05(m,4H),1.03–0.96(m,1H),0.92(d,J=6.5Hz,4H),0.68(s,3H).

[0168] In step 6, reactant I-5 (22.5 g, 55.6 mmol, 1.0 eq) was dissolved in acetone (300 mL), and p-toluenesulfonic acid (6.70 g, 38.9 mmol, 0.7 eq) and 4A molecular sieve (5 g) were added. The reaction system was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC plate (petroleum ether: ethyl acetate = 5:1). After the reaction was completed, 100 mL of water was added to the reaction system, and the mixture was extracted with ethyl acetate (100 mL * 3). The organic phase was collected, washed with water (100 mL * 2), washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was collected and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 5:1) to give a white solid (4R)-4-[(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-tetradecanoic acid methyl ester I-6 (19 g, purity 90%, yield 69%). 1 H NMR (400MHz, CDCl3) δ5.82–5.79(m,1H),4.41(d,J=5.8Hz,1H),3.66(s,3H),2.35(td,J=10.2,5.1Hz,1H) ,2.23(td,J=9.6,4.9Hz,1H),2.12(dd,J=12.6,4.5Hz,1H),2.00(dt,J=12.4,3.3Hz,1H),1.95–1.77(m,2H ),1.76–1.69(m,1H),1.63(ddd,J=10.5,6.8,4.3Hz,4H),1.53(s,5H),1.49–1.37(m,2H),1.35(s,3H),1. 28(dd,J=25.3,21.7Hz,2H),1.16(s,4H),1.14–0.98(m,4H),0.93(d,J=6.4Hz,4H),0.69(d,J=4.6Hz,3H).

[0169] In step 7, reactant I-6 (19 g, 44.9 mmol, 1.0 eq) was dissolved in acetone (200 mL), and N-hydroxyphthalimide (2.79 g, 17.0 mmol, 0.4 eq), tert-butyl hydroperoxide (20.5 mL, 213.6 mmol, 5.0 eq), and cobalt acetate (1.5 g, 8.5 mmol, 0.2 eq) were added. The reaction mixture was stirred at 35 °C for 24 hours. The reaction was stopped when complete as monitored by TLC (petroleum ether:ethyl acetate = 5:1). Water (100 mL) was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (150 mL x 3). The ethyl acetate layers were combined and washed with saturated brine (50 mL x 3). The ethyl acetate layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 10:1 to 8:1) to give a white solid (4R)-4-[(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-tetradecanoic acid-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxacyclopentanthro-8-yl]valerate methyl ester I-7 (10.5 g, yield 42.8%). 1 H NMR (400MHz, CDCl3) δ5.93(s,1H),4.52(d,J=6.4Hz,1H),4.33(d,J=5.8Hz,1H),3.66(d,J=4 .0Hz,3H),2.36(ddd,J=15.3,10.0,5.2Hz,3H),2.26–2.17(m,1H),2.07–1.88(m,3H),1.81(d dd,J=9.6,8.0,3.1Hz,3H),1.64–1.60(m,2H),1.57–1.54(m,3H),1.45(dd,J=12.7,9.9Hz,2H ),1.37(s,4H),1.34(d,J=4.8Hz,5H),1.20–1.07(m,3H),0.93(d,J=6.4Hz,4H),0.71(s,3H).

[0170] In step 8, reactant I-7 (10.5 g, 23.9 mmol, 1.0 eq) was dissolved in a mixed solution of methanol (300 mL) and ethyl acetate (100 mL), and palladium on carbon (4.0 g, 37.5 mmol, 40 wt%) was added. The mixture was purged with hydrogen three times, and the reaction system was stirred at 35 °C for 2 hours. The reaction progress was monitored by TLC plate (petroleum ether:ethyl acetate = 5:1). The palladium on carbon was filtered through diatomaceous earth, and the diatomaceous earth was washed with ethyl acetate (50 mL x 3). The organic phases were combined and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1 to 10:1 to 6:1) to give a white solid (4R)-4-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-2,2,5a,7a-tetramethyl-11-oxomethylene-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecylhydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxacyclopentanthro-8-yl]valerate methyl ester I-8 (6.2 g, purity 80%, yield 44.8%). 1 H NMR (400MHz, CDCl3) δ4.06–3.95(m,2H),3.66(d,J=2.9Hz,3H),2.82–2.73(m,1H),2.46–2.31(m,1H),2.29–2.15(m,2H),1.88–1.75(m,1H),1.70– 1.59(m,2H),1.54(d,J=5.8Hz,2H),1.43(ddd,J=18.2,12.4,8.5Hz,2H), 1.34–1.27(m,4H),1.13–0.98(m,2H),0.92(d,J=6.4Hz,2H),0.66(s,1H).

[0171] In step 9, reactant I-8 (6.2 g, 13.5 mmol, 1 eq) was dissolved in diethylaminosulfur trifluoride (10 mL), and the resulting mixture was stirred at 80 °C for 1 h. The consumption of the reactants was monitored by TLC (petroleum ether: ethyl acetate = 10:1). The reaction mixture was cooled to room temperature, and dichloromethane (50 mL) was added to dilute the reaction system. The reaction system was then slowly quenched dropwise in ice water. Extraction was performed using dichloromethane (50 mL × 3), and the organic phase was collected and dried over anhydrous sodium sulfate. The organic phase was then evaporated under vacuum to obtain the crude product. The crude product was dissolved in ethyl acetate and subjected to column chromatography (petroleum ether: ethyl acetate = 30:1 to 20:1 to 15:1) to give a white solid I-9 (purity ~88%). I-9 was dissolved in dichloromethane (200 mL), and m-chloroperoxybenzoic acid (MCPBA) (579 mg, 3.37 mmol) was added. After stirring for 1 h, saturated sodium sulfite was added to quench the reaction, followed by washing with saturated brine, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography (petroleum ether:ethyl acetate = 1:0-4:1) to obtain the product as a white solid (4R)-4-[(3aS,5aR,5bS,7aR,8R, 10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecylhydro-3aH-cyclopentano[1',2':1,2]phenanthro[7,8-d][1,3]dioxane-8-yl]valerate methyl ester I-9 (4.4 g, yield 54%). 1 H NMR (400MHz, CDCl3) δ4.13–3.98 (m, 2H), 3.66 (s, 3H), 2.29 (ddd, J = 16.0, 9.9 ,5.8Hz,1H),2.12–2.03(m,0H),1.96–1.75(m,4H),1.74–1.57(m,2H),1.51(s ,2H),1.41(ddd,J=16.1,8.0,5.5Hz,2H),1.34–1.28(m,3H),1.14(dd,J=12.9 ,4.3Hz,1H),1.08(d,J=5.8Hz,2H),0.92(d,J=6.4Hz,2H),0.70–0.63(m,2H).

[0172] In step 10, compound I-9 (4.35 g, 9.0 mmol, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (50 mL), and lithium aluminum hydride (2.05 g, 27 mmol, 3.0 eq) was added under ice bath conditions. The mixture was then stirred at room temperature for 30 minutes. The consumption of the starting material was monitored by TLC (petroleum ether: ethyl acetate = 2:1). The reaction mixture was completely quenched with sodium sulfate decahydrate, and water (50 mL) was added to the reaction system. The aqueous layer was extracted with ethyl acetate (50 × 3 mL). The organic layers were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30:1 to 20:1 to 10:1 to 5:1) to give a white solid (4R)-4-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecylhydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxane-8-yl]pentan-1-ol I-10 (3.6 g, yield 82%). 1 H NMR (400MHz, CDCl3) δ4.02 (dq, J=8.4, 5.2Hz, 2H), 3.62 (td, J=6.7, 2.2Hz, 2H), 2.07–1.96 ( m,1H),1.94(dd,J=5.3,2.9Hz,1H),1.91–1.79(m,2H),1.69–1.57(m,2H),1.51(s,2H),1.42 (ddd,J=17.1,8.1,5.4Hz,3H),1.34–1.28(m,2H),1.27–1.09(m,2H),1.07(s,2H),0.98(dd, J=12.1,3.8Hz,1H),0.94(d,J=6.5Hz,2H),0.89(dd,J=13.6,3.2Hz,0H),0.72–0.63(m,2H).

[0173] Step 11: Iodine (25.1 g, 98.9 mmol, 5.0 eq) was dissolved in dichloromethane (100 mL), then imidazole (13.5 g, 198 mmol, 10.0 eq) was added. Under ice bath conditions, a dichloromethane solution of triphenylphosphine (26.0 g, 98.9 mmol, 5.0 eq) was added dropwise. The mixture was brought to room temperature and stirred for 2 hours until the reaction mixture turned pale yellow. I-10 (9 g, 19.8 mmol, 1.0 eq) was added dropwise under ice bath conditions, and the reaction mixture was stirred at room temperature for 12 hours. The consumption of the starting material was monitored by TLC (petroleum ether: ethyl acetate = 5:1). Water (200 mL) was added to the reaction mixture to stop the reaction. The mixture was washed with water (100 mL x 3), and the aqueous phase was extracted with dichloromethane (100 mL x 3). The organic phases were combined, concentrated, and dried to obtain the crude product. The crude product was then subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 100: 0.0). (90:10) A white solid (3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-8-[(2R)-5-iodopentan-2-yl]-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecylhydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxanecyclopentaman I-11 (8.25 g, 72% yield) was obtained. 1 H NMR (400MHz, CDCl3) δ4.13–3.93(m,2H),3.25–3.03(m,2H),2.11(d,J=50.8Hz, 1H),2.02–1.79(m,3H),1.78–1.66(m,1H),1.65–1.57(m,1H),1.54(s,1H),1.50 (d,J=6.9Hz,2H),1.44(dd,J=10.7,6.1Hz,2H),1.33–1.23(m,3H),1.19–1.10( m,1H),1.07(s,1H),1.04(s,1H),0.93(d,J=6.6Hz,2H),0.67(d,J=12.1Hz,1H).

[0174] In step 12, compound I-11 (7.5 g, 13.3 mmol) was dissolved in acetonitrile (100 mL), and tetrabutylammonium fluoride trihydrate (11.1 g, 39.9 mmol, 3.0 eq) and trimethylcyanosilane (5.4 mL, 39.9 mmol, 3.0 eq) were added. The resulting mixture was stirred overnight at room temperature. The consumption of the reactants was monitored by TLC (petroleum ether: ethyl acetate = 10:1). The reaction was quenched with water (50 mL), washed with water (50 mL x 3), and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phase was collected, combined, washed with saturated brine (40 mL), filtered, and concentrated to obtain the crude product. The crude product was added to silica gel and filtered through a column in a petroleum ether:ethyl acetate ratio of 10:1 to obtain a white solid (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecylhydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxane-8-yl]hexanonitrile I-12 (5.25 g, yield: 77%). 1 H NMR(400MHz, CDCl3)δ4.02(dq,J=8.4,5.2Hz,2H),2.36–2.23(m,1H),2.19–2.01(m,1H),2.00–1.92(m,1H),1.91–1.79(m,2H),1.77–1.62(m,2H) ,1.59–1.53(m,2H),1.50(d,J=5.7Hz,2H),1.34–1.28(m,2H),1.19–1.10 (m,1H),1.07(d,J=4.8Hz,2H),1.01–0.87(m,3H),0.68(d,J=5.0Hz,2H).

[0175] Step 13: At room temperature, I-12 (600 mg, 1.294 mmol) was suspended in methanol (30 mL) in a 250 mL round-bottom flask. Concentrated sulfuric acid (10 mL) was added at room temperature, and the mixture was stirred at 80 °C for 12 hours. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 2:1). After the reaction was complete, 100 mL of saturated sodium bicarbonate aqueous solution was added to quench the reaction, followed by extraction with 60 mL × 3 ethyl acetate solutions. The organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give a white solid (5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-6,7-dihydroxy-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoate methyl ester I-13 (450 mg, yield: 72.35%). 1 HNMR (400MHz, CDCl3) δ = 3.74 (s, 1H), 3.67 (s, 3H), 3.63–3.57 (m, 1H), 2.28 (dd, J = 8.9, 6.8, 2H), 2.23–2.11 (m, 1H), 1.97(dt,J=12.7,3.4,1H),1.90–1.63(m,12H),1.53–1.22(m,10H),1.06(s,3H),0.93(d,J=6.5,3H),0.66(s,3H).

[0176] In step 14, I-13 (1.2 g, 2.63 mmol) was dissolved in tetrahydrofuran (30 mL), and methyl magnesium bromide solution (5.3 mL, 13.14 mmol) was added dropwise at room temperature. The mixture was stirred at room temperature for 1 hour. TLC (petroleum ether / ethyl acetate = 1 / 1) was used to monitor the reaction until the reactants were completely reacted. Saturated ammonium chloride aqueous solution (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to obtain crude product (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol I-14 (1 g, yield: 62.5%) as a white solid.

[0177] Step 15 is similar to the synthesis of intermediate I. Step 6 involves replacing I-5 with I-14 and purifying to obtain (6R)-6-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecylhydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxacyclopentaman-8-yl]-2-methylhept-2-ol I-15 (850 mg, yield: 66.4%) as a white solid. 1 H NMR (400MHz, CDCl3) δ4.07–3.96(m,2H),2.05(s,1H),2.02–1.91(m,2H),1.91–1.75(m, 4H),1.73–1.66(m,1H),1.66–1.58(m,2H),1.51(s,3H),1.47(s,4H),1.40(ddd,J=22.5 ,12.6,6.5Hz,6H),1.30(s,3H),1.26(dd,J=8.9,5.5Hz,2H),1.22(d,J=5.5Hz,6H),1.1 7–1.09(m,2H),1.07(s,3H),0.97(d,J=3.3Hz,2H),0.93(d,J=6.6Hz,3H),0.68(s,3H). 19 F NMR(377MHz, CDCl3)δ-88.99,-89.62,-111.36,-111.99.

[0178] In step 15, I-12 (2.0 g, 4.3 mmol) was dissolved in anhydrous dichloromethane (100 mL), and diisobutylaluminum hydride (8.6 mL, 1 mol / L, 2.0 eq) was added. The reaction mixture was stirred at -70 °C for 2 hours. The reaction was monitored for completeness by TLC (petroleum ether: ethyl acetate = 5:1). The reaction was quenched with water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phase was collected, combined, washed with saturated brine (40 mL), filtered, and concentrated to obtain the crude product. The crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 95:5) to give a white solid (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecylhydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxacyclopentaman-8-yl]hexanal I (1.34 g, yield: 60%). 1 H NMR(400MHz, CDCl3) δ9.76(t,J=1.7Hz,1H),4.01(dt,J=8.4,6.2Hz,2H),2.40(ddd,J =12.8,7.2,1.8Hz,2H),2.17(s,1H),2.08–1.92(m,3H),1.84(ddd,J=17.9,9.8,4.6H z,4H),1.77–1.65(m,3H),1.64–1.57(m,2H),1.55(d,J=10.6Hz,2H),1.51(s,4H),1. 46–1.34(m,5H),1.33–1.25(m,5H),1.07(s,4H),0.94(d,J=6.5Hz,4H),0.68(s,3H).

[0179] Preparation of Intermediate II (5R)-5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanal II

[0180] In step 1, compound I-4 (7 g, 17.39 mmol) was dissolved in dichloromethane (100 mL), and acetic anhydride (3.3 mL, 34.78 mmol), triethylamine (12.1 mL, 86.94 mmol), and 4-dimethylaminopyridine DMAP (420 mg, 3.48 mmol) were added at room temperature. The reaction was carried out at room temperature for 2 hours under nitrogen protection, and the reaction was monitored by TLC to ensure the reaction was complete. The reaction solution was quenched with water (100 mL), extracted with dichloromethane (200 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-4:1) to obtain methyl 3β-acetoxy-7-oxomylcholene-6(5)-en-24-olate II-5 (7 g, yield 81%) as a white solid.

[0181] In step 2, II-5 (40 g, 92.89 mmol) was dissolved in acetone (400 mL), and tert-butyl hydroperoxide (111.47 mL, 557.32 mmol), cobalt acetate (3 g, 18.58 mmol) and N-hydroxybenzoic acid diimide (6 g, 37.16 mmol) were added. The mixture was heated to 35 °C under nitrogen protection and reacted for 18 hours. The reaction was monitored by TLC to ensure the reaction was complete. The reaction solution was quenched with water (200 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:0-4:1) to obtain the product methyl 3β-acetoxy-7-oxylidene-6(5)-ene-24-olate II-6 (16 g, yield 35%) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ5.70(d,J=1.6Hz,1H),4.71(m,1H),3.66(s,3H),2.45(m,4H),2.22(ddd,J=19.3,9.4,6.5Hz,2H),2.05(s,3H ),1.97(m,3H),1.82(m,1H),1.68(m,1H),1.57(m,3H),1.33(m,7H),1.21(s,3H),1.13(m,2H),0.93(d,J=6.4Hz,3H),0.68(s,3H).

[0182] In step 3, compound II-6 (4 g, 9.00 mmol) was dissolved in ethyl acetate (40 mL) and methanol (20 mL), and palladium on carbon (1.91 g, 17.99 mmol) was added. The mixture was heated to 40 °C under hydrogen protection and reacted for 4 hours. The reaction was monitored by TLC to ensure the starting material was completely reacted. The reaction solution was filtered through diatomaceous earth and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:0-4:1) to obtain methyl 3β-acetoxy-7-oxomylcholine-24-olate II-7 (2.6 g, yield 58.2%) as a white solid. 1 H NMR (400MHz, CDCl3) δ4.67(m,1H),3.66(s,3H),2.34(m,3H),2.21(m,2H),2.03(m,4H),1.94(m,3 H),1.78(m,2H),1.66(m,1H),1.43-1.05m,10H),1.08(m,7H),0.92(d,J=6.4Hz,3H),0.65(s,3H).

[0183] Step 4 is similar to step 9 of intermediate I, but I-8 is replaced with II-7 to obtain product (4R)-4-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-7-acetoxy-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]valerate methyl ester II-8 (3 g, yield 64%), which is a white solid. 1 H NMR (400MHz, CDCl3) δ4.69(m,1H),3.66(s,3H),2.35(td,J=10.1,5.0Hz,1H),2.22(td,J=9.5,4.9Hz,1H),2.03(d,J=2.1H z,3H),1.96(m,1H),1.80(m,6H),1.65(m,2H),1.43(m,11H),1.09(m,4H),0.93(t,J=5.4Hz,3H),0.83(m,3H),0.67(m,3H). 19 F NMR (376MHz, CDCl3) δ = -89.09, -89.72, -110.84, -111.47.

[0184] In step 5, compound II-8 (5 g, 10.67 mmol) was dissolved in methanol (50 mL) and tetrahydrofuran (50 mL). Under nitrogen protection, potassium carbonate (7.37 g, 53.35 mmol) was added at room temperature, and the reaction was carried out at room temperature for 1 hour. The reaction was monitored by TLC to ensure the starting material was completely reacted. The reaction solution was quenched with water (100 mL), extracted with ethyl acetate (100 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product (4R)-4-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-7-hydroxy-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]valerate methyl ester II-9 (4.5 g, yield 89%) as a white solid.

[0185] In step 6, at room temperature, dissolve II-9 (4 g, 9.37 mmol) in dichloromethane (50 mL) in a 100 mL round-bottom flask. Add imidazole (1.28 g, 18.75 mmol) and tert-butyldiphenylchlorosilane TBDPSCl (3.66 mL, 14.07 mmol) at room temperature. Stir for 4 hours at room temperature and monitor the reaction by TLC (petroleum ether: ethyl acetate = 5:1). After the reaction was completed, the mixture was quenched with water (10 mL), extracted with ethyl acetate (100 mL × 3), washed with saturated brine (100 mL) on the organic phase, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give a white solid (4R)-4-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]valerate methyl ester II-10 (6.6 g, yield 94%).

[0186] Step 7 is similar to the synthesis of intermediate I. Step 10 replaces I-9 with II-10 to obtain the oily product (4R)-4-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylprop-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentan-1-ol II-11 (850 mg, yield 89%). The crude product is directly fed into the next step.

[0187] Step 8 is similar to the synthesis of intermediate I. Step 11, by replacing I-10 with II-11, yields the white solid {[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-5-iodopentan-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-yl]oxy}(2-methylpropyl-2-yl)diphenylsilane II-12 (938 mg, yield 80%). 1 H NMR (400MHz, CDCl3) δ7.66 (m, 4H), 7.36 (m, 16H), 3.58 (dq, J = 15.3, 5.1Hz, 1H), 3.14 (m, 2H), 1.70(m,17H),1.31(m,10H),1.04(s,10H),0.90(m,9H),0.83(d,J=4.2Hz,3H),0.64(s,3H).

[0188] Step 9 is similar to the synthesis of intermediate I. Step 12 replaces I-11 with II-12 to obtain the product (5R)-5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-4,4-difluoro-7-hydroxy-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanonitrile II-13 (0.28 g, yield 88%). 1 H NMR (400MHz, CDCl3) δ3.63(m,1H),2.31(td,J=7.0,3.4Hz,2H),1.97(dt,J=12.8,3.3Hz,1H),1.86(m,3H),1.72( m,5H),1.58(m,4H),1.44(td,J=12.0,4.3Hz,3H),1.19(m,10H),0.94(d,J=6.6Hz,3H),0.85(s,3H),0.67(s,3H).

[0189] Step 10 is similar to the synthesis of intermediate I. Step 13 replaces I-12 with II-13 to obtain the product (5R)-5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-4,4-difluoro-7-hydroxy-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoate methyl ester II-14 (0.89 g, yield 65%).

[0190] Step 11 is similar to the synthesis of intermediate II in step 6. Replacing II-9 with II-14 at room temperature yields a white solid (5R)-5-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylprop-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoate methyl ester II-15 (3.0 g, yield: 84.6%). 1 HNMR (400MHz, CDCl3) δ7.66(m,4H),7.38(m,6H),3.66(s,3H),3.58(dt,J=15.7,5.2Hz,1H),2.26(dt,J=15.4,7.6Hz,2H),1.93(m,1 H),1.80(d,J=7.6Hz,2H),1.65(m,4H),1.46(m,10H),1.25(m,4H),1.06(m,12H),0.90(m,4H),0.79(m,4H),0.62(d,J=12.1Hz,3H).

[0191] In step 12, II-15 (2.5 g, 3.682 mmol, 1.0 eq) was dissolved in tetrahydrofuran (20 mL), and lithium aluminum hydride (0.42 g, 11.05 mmol, 3 eq) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction was monitored for completeness 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 × 25 mL). The ethyl acetate layers were combined and washed with saturated brine (3 × 10 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to give a white solid (5R)-5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylprop-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hex-1-ol II-16 (1.7 g, yield 72%). 1HNMR (400MHz, CDCl3) δ7.70–7.62(m,4H),7.45–7.33(m,6H),3.63(s,3H),1.93(d,J=12.7Hz,1H),1.81(d,J=9.4Hz,2H),1.68–1.6 0(m,3H),1.54(s,7H),1.38(ddd,J=23.8,18.6,8.6Hz,8H),1.25(d,J=7.1Hz,5H),0.90(d,J=6.5Hz,4H),0.82(s,4H),0.63(s,3H)

[0192] In step 13, II-16 (1.6 g, 2.46 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), and Dysmartin oxidant (2.08 g, 4.92 mmol, 2.0 eq) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 10:). Water (10 mL) was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (3 × 25 mL). The ethyl acetate layers were combined and washed with saturated sodium sulfite (3 × 10 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to give a white solid (5R)-5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanal II (1.4 g, yield 87%). 1 H NMR(400MHz, CDCl3) δ9.75(t,J=1.7Hz,1H),7.69–7.63(m,4H),7.44–7.34(m,6H),3.59(td,J=10.5,5.3Hz,1H) ,2.38(d,J=6.4Hz,2H),1.55(s,6H),1.04(s,10H),0.92(d,J=6.5Hz,3H),0.82(s,3H),0.62(d,J=12.3Hz,3H).

[0193] Example 1 & 43

[0194] Compound 1 or 43(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-1-[(2R,6R)-6-cyclopropyl-6-hydroxyhex-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0195] Preparation of compounds 43 or 1(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-1-[(2R,6S)-6-cyclopropyl-6-hydroxyhex-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol]

[0196] In step 1, compound II (120 mg, 0.185 mmol, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (10 mL) under nitrogen protection and cooled to 0 °C in an ice bath. Then, 0.555 mL of cyclopropylmagnesium bromide (dissolved in 1 M tetrahydrofuran) was added at di7, and the reaction was maintained at this temperature for 1 hour. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 5:1) to indicate completion. The reaction solution was quenched with saturated ammonium chloride (1 mL), and ethyl acetate (10 mL x 3) Extraction: The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 80:20) to give a white solid (6R)-6-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecylhydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxacyclopentaman-8-yl]-1,1,1-trifluorohept-2-ol 1-1 (100 mg, yield 74.35%). 1 H NMR (400MHz, CDCl3) δ7.66(m,4H),7.38(m,6H),3.59(m,1H),2.84(m,1H),1.93(d,J=12.5Hz,1H),1.80(m,2H),1. 42(m,27H),1.04(s,10H),0.88(m,6H),0.82(s,3H),0.64(s,3H),0.50(m,2H),0.23(ddd,J=12.9,9.0,4.5Hz,2H).

[0197] In step 2, compound 1-1 (100 mg, 0.145 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL) under nitrogen protection, and dilute hydrochloric acid (1 mL) was added. The reaction was carried out at 50°C for 1 hour. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 5:1) until completion. The reaction solution was quenched with saturated sodium chloride (10 mL), extracted with ethyl acetate (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 80:20) to give a white solid (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-1-[(2R)-6-cyclopropyl-6-hydroxyhexyl-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 1-2 (44.6 mg, yield 62.64%). 1 H NMR (400MHz, CDCl3) δ3.62(m,1H),2.85(m,1H),1.98(m,1H),1.77(m,6H),1.53(s,5H),1.25(s,11H),1.06(dtd,J=27.2, 13.2, 3.9Hz, 5H), 0.93 (d, J = 6.5Hz, 3H), 0.88 (dd, J = 8.7, 4.1Hz, 1H), 0.85 (s, 3H), 0.67 (s, 3H), 0.51 (m, 2H), 0.24 (m, 2H). 19 F NMR (377MHz, CDCl3) δ-88.97,-89.59,-110.85,-111.49.

[0198] In step 3, compounds 1-2 (46 mg, 0.098 mmol, 1.0 eq) were dissolved in dichloromethane (5 mL), and benzoyl chloride (0.057 mL, 0.491 mmol, 5.0 eq), triethylamine (0.136 mL, 0.982 mmol, 10.0 eq), and 4-dimethylaminopyridine (DMAP) (11.99 mg, 0.098 mmol, 1.0 eq) were added sequentially. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction was monitored for completeness by TLC (petroleum ether: ethyl acetate = 3:1). Dichloromethane (10 mL) was added to the reaction mixture, and the mixture was washed with saturated ammonium chloride (25 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-7-(benzyloxy)-1-[(2R)-6-(benzyloxy)-6-cyclopropylhex-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6-ol 1-3 (60 mg, yield 84.78%).1 H NMR (400MHz, CDCl3) δ8.04(m,4H),7.54(m,2H),7.44(d,J=7.5Hz,4H),4.94(m,1H),4.55(s,1H),1.99(s,2H),1.69(ddd,J=40.1 ,16.5,8.9Hz,13H),1.32(m,7H),1.11(m,6H),0.90(m,7H),0.66(s,3H),0.59(m,1H),0.49(dd,J=14.4,6.9Hz,2H),0.34(s,1H).

[0199] In step 4, compounds 1-3 (60 mg, 0.083 mmol) were chirally separated (separation conditions: instrument: SFC Acquity UPCC; column: Daicel CHIRALPAK IG-3, 3 mm * 150 mm, 3 μm; mobile phase: CO2 / MeOH (0.1% DEA) = 50 / 50; flow rate: 2.0 ml / min; wavelength: UV 214 & 254 nm; column temperature: 37 °C) to obtain compounds 43-1 (25 mg, yield 44%, retention time 4.446 min) and compounds 1-4 (25 mg, yield 44%, retention time 5.506 min).

[0200] In step 5A, compound 43-1 (25 mg, 0.04 mmol, 1.0 eq) was dissolved in tetrahydrofuran (1 mL) and methanol (1 mL). Lithium hydroxide (13 mg, 0.40 mmol, 10.0 eq) and water (0.5 mL) were added at room temperature, followed by stirring at 50 °C for 2 hours. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 2:1) to ensure complete reaction. The mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give compound 43 (8.7 mg, 0.010 mmol, purity 95%, yield 30%) as a white solid. 1H NMR (400MHz, CDCl3) δ3.67–3.57(m,1H),2.90–2.81(m,1H),1.99(d,J=12.8Hz,1H),1.89–1.79(m,3H),1.74(d,J=3.8Hz,3H),1.45–1.32(m,8H ),1.27(d,J=12.0Hz,8H),1.14–0.99(m,5H),0.93(d,J=6.6Hz,3H),0.85(s,3H),0.67(s,3H),0.56–0.45(m,2H),0.24(dd,J=9.0,4.1Hz,2H). 19 F NMR (376MHz, CDCl3) δ-88.96,-89.59,-110.85,-111.48.

[0201] Step 5B is similar to Step 5A of Example 1, except that compound 43-1 is replaced with 1-4 to obtain white solid compound 1 (5.9 mg, 0.012 mmol, yield 27%). 1 H NMR (400MHz, CDCl3) δ3.63(m,1H),2.85(m,1H),1.99(m,1H),1.74(s,6H),1.56(m,5H),1.35(m,12H),1.05(d d,J=37.8,6.5Hz,5H),0.92(t,J=5.0Hz,3H),0.83(d,J=10.6Hz,3H),0.67(s,3H),0.51(m,2H),0.24(m,2H). 19 F NMR (376MHz, CDCl3) δ-88.92,-89.63,-110.90,-111.52.

[0202] Example 2

[0203] Preparation of compound 2, 20-[(3-hydroxy-3-methylbutyl)oxy]-5α-pregn-3β-ol

[0204] In step 1, 3β-hydroxypregn-5(6)-en-20-one 2-1 (60 g, 189.58 mmol, 1.0 eq) was added to a reaction flask containing dichloromethane (10 mL), followed by triethylamine (158.11 mL, 1137.48 mmol, 6.0 eq), 4-dimethylaminopyridine (DMAP (6.95 g, 56.87 mmol, 0.3 eq), and acetic anhydride (53.42 mL, 568.74 mmol, 3.0 eq). The reaction was stirred at room temperature (25 °C) for 1 h. TLC monitoring showed that the starting material reaction was complete. Water (2... Dilute with 0 mL, add dichloromethane (20 mL × 3), extract three times, wash with sodium chloride, dry with anhydrous sodium sulfate, evaporate the reaction solution to dryness under reduced pressure, and purify by column chromatography (petroleum ether: ethyl acetate = 80:20) to obtain acetic acid-(1S,3aS,3bS,7S,9aR,9bS,11aS)-1-acetyl-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecanoic-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 2-2 (60 g, 79.45%) as a white solid. 1 H NMR (400MHz, CDCl3) δ5.44–5.32(m,1H),4.61(tdd,J=10.6,6.4,4.2Hz,1H),2.53(dd,J=11.3,6.5Hz,1H),2.32(dd,J=8.2,4.0Hz,2H),2.23–2.10 (m,4H),2.08–1.95(m,5H),1.88(dt,J=9.5,4.4Hz,2H),1.71–1.56(m,5H ),1.54–1.42(m,3H),1.27–1.12(m,3H),1.05–0.97(m,4H),0.63(s,3H).

[0205] In step 2, 2-2 (2.5 g, 6.97 mmol, 1.0 eq) was added to a reaction flask containing methanol (30 mL). Sodium borohydride (0.45 g, 11.85 mmol, 1.5 eq) was added at 0 °C. The reaction was stirred at room temperature (25 °C) for 1 hour. TLC monitoring showed that the starting material had reacted completely and a new spot appeared. Water (20 mL) was added for dilution, followed by ethyl acetate (20 mL × 3). Extraction was performed three times, followed by washing with sodium chloride and drying with anhydrous sodium sulfate. The reaction solution was evaporated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate = 80:20) to obtain acetic acid-(1S,3aS,3bS,7S,9aR,9bS,11aS)-1-(1-hydroxyethyl)-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecanoic-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 2-3 (2.6 g, 93.08%) as a white solid. 1 H NMR(400MHz, CDCl3)δ5.37(d,J=5.1Hz,1H),4.65–4.53(m,1H),3.80–3.67(m,1H),2.37 –2.27(m,2H),2.07(dd,J=9.6,6.0Hz,1H),2.04(d,J=5.3Hz,3H),1.90–1.81(m,2H),1.7 3–1.54(m,4H),1.50(ddd,J=15.9,8.5,3.7Hz,3H),1.38–1.26(m,3H),1.21(dd,J=23.6 ,11.0Hz,2H),1.14(d,J=6.1Hz,4H),1.09–1.02(m,4H),1.00–0.92(m,1H),0.77(s,3H).

[0206] In step 3, 2-3 (600 mg, 1.66 mmol, 1.0 eq) was added to a reaction flask containing dichloromethane (2 mL), followed by the addition of methyl propionate (280 mg, 3.33 mmol, 2.0 eq) and N-methylmorpholine (337 mg, 3.33 mmol, 2.0 eq). The reaction was stirred at room temperature (25 °C) for 5 days, and a new spot was observed by TLC monitoring. Dilute with water (20 mL), then add dichloromethane (20 mL × 3), extract three times, wash with sodium chloride, dry with anhydrous sodium sulfate, evaporate the reaction solution to dryness under reduced pressure, and purify by column chromatography (petroleum ether: ethyl acetate = 80:20) to obtain (2E)-3-{[(1S)-1-[(1S,3aS,3bS,7S,9aR,9bS,11aS)-7-acetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecanohydro-1H-cyclopenta[1, Methyl 2-a]phenanthrene-1-yl]ethyl]oxy]prop-2-enoate 2-4 (120 mg, 0.135 mmol, 8.11%) is a white solid, and acetic acid-(1S,3aS,3bS,7S,9aR,9bS,11aS)-1-[(1S)-1-hydroxyethyl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecanoyl-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 2-4 (480 mg, 64.00%) is a white solid. 1 H NMR (400MHz, CDCl3) δ7.53 (d, J = 12.4Hz, 1H), 5.38 (d, J = 4.7Hz, 1H), 5.22 (dd, J=12.4,8.3Hz,1H),4.60(m,1H),3.96(m,1H),3.69(s,3H),2.32(d,J=6.6Hz,2 H),2.04(d,J=5.2Hz,3H),1.86(d,J=9.9Hz,3H),1.56(s,3H),1.54(s,7H),1. 29(d,J=6.2Hz,3H),1.19(m,4H),1.01(d,J=3.7Hz,4H),0.67(d,J=3.3Hz,3H).

[0207] In step 4, 2-4 (90 mg, 0.20 mmol, 1.0 eq) was added to a reaction flask containing ethyl acetate (1.5 mL) and methanol (0.5 mL), and then palladium on carbon (21.54 mg, 0.20 mmol, 1.0 eq) was added. The reaction was stirred at 25 °C for 18 hours, and the reaction was monitored by TLC until it was complete. Dilute with water (20 mL), then add ethyl acetate (20 mL × 3), extract three times, wash with sodium chloride, dry with anhydrous sodium sulfate, evaporate the reaction solution under reduced pressure (water pump, 45 °C), and separate and purify by column chromatography (petroleum ether: ethyl acetate = 65:35) to obtain methyl 3-{[(1S)-1-[(1S,3aS,3bR,7S,9aS,9bS,11aS)-7-acetoxy-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]ethyl]oxy}propionate 2-5 (90 mg, 0.18 mmol, 89.2%) as a white solid. 1 H NMR (400MHz, CDCl3) δ4.68(m,1H),3.80(dt,J=9.2,6.0Hz,1H),3.68(d,J=4.0Hz,3H),3.53(dt,J =9.2,6.7Hz,1H),3.24(dd,J=8.4,6.1Hz,1H),2.53(td,J=6.1,2.6Hz,2H),2.03(d,J=11.4Hz,3H) ,1.82(dd,J=8.3,4.3Hz,2H),1.72(d,J=13.3Hz,1H),1.62(m,3H),1.49(m,6H),1.34(m,3H),1.2 6(td,J=7.4,4.0Hz,3H),1.14(d,J=6.1Hz,3H),1.03(m,5H),0.81(s,3H),0.63(d,J=13.3Hz,3H).

[0208] In step 5, 2-5 (90 mg, 0.05 mmol, 1.0 eq) was added to a reaction flask containing tetrahydrofuran (2 mL), and methyl magnesium bromide (5.32 mg, 0.05 mmol, 1.5 eq) was added at 0 °C. The reaction was stirred at room temperature (25 °C) for 1 h, and TLC monitoring showed that the starting material had reacted completely. Dilute with water (20 mL), then add dichloromethane (20 mL × 3), extract three times, wash with sodium chloride, dry with anhydrous sodium sulfate, and evaporate the reaction solution under reduced pressure. The solution is then purified by column chromatography (petroleum ether: ethyl acetate = 80:20) to obtain (1S,3aS,3bR,5aR,7S,9aS,9bS,11aS)-4,4-difluoro-1-[(1S)-1-[(3-hydroxy-3-methylbutyl)oxy]ethyl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 2 (74 mg, 0.17 mmol) as a white solid. 1 H NMR (400MHz, CDCl3) δ3.83(m,1H),3.59(m,1H),3.48(m,1H),3.24(dd,J=8.4,6 .0Hz,1H),1.82(dd,J=16.2,12.8Hz,4H),1.72(m,3H),1.64(dd,J=14.9,12.0Hz ,4H),1.53(dd,J=18.5,15.5Hz,4H),1.37(m,4H),1.23(d,J=2.6Hz,6H),1.16( t,J=7.8Hz,3H),1.10(m,3H),0.99(d,J=13.0Hz,2H),0.80(s,3H),0.65(m,4H).

[0209] Examples 3 & 4

[0210] Compound 3 or 4(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2S)-1-{[(2S)-3,3,3-trifluoro-2-hydroxypropyl]oxy}propyl-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0211] Preparation of compounds 4 or 3(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2S)-1-{[(2R)-3,3,3-trifluoro-2-hydroxypropyl]oxy}propyl-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0212] Step 1: Dissolve (22E,24S)-stigmaster-6(5),22(23)-dien-3β-ol 3-0-1 (5.00 g, 12.11 mmol, 1.0 eq) in dichloromethane (50 mL), place the reaction system in an ice-water bath and cool to about 5 °C, then add acetic anhydride (3.4 mL, 36.35 mmol, 3.0 eq), 4-dimethylaminopyridine (300 mg, 2.42 mmol, 0.2 eq) and triethylamine (8 mL, 60.57 mmol, 5.0 eq) to the reaction system in sequence, and stir the reaction system at room temperature for 2 hours. After the reaction was complete as monitored by TLC (petroleum ether:ethyl acetate = 10:1), it was quenched with methanol (20 mL). The reaction solution was washed once each with saturated sodium bicarbonate (~50 mL) and water (~50 mL), dried over anhydrous sodium sulfate, and concentrated. When the solution was almost dry, methanol (~20 mL) was added, and the mixture was stirred in an ice bath for 30 minutes. The mixture was then filtered, and the filter cake was washed with a small amount of methanol. The filter cake was dried to give a white solid acetic acid-(1R,3aS,3) (bS,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-tetradecanohydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 3-0-2 (5.30 g, yield 86.58%). 1 H NMR (400MHz, CDCl3) δ5.37(d,J=4.8Hz,1H),5.09(ddd,J=56.1,15.2,8.6Hz,2H),4.61(ddd,J=15.9,9.0,4.2Hz,1H),2.32(d,J=7.3Hz,2H),2.03(s ,3H),2.01–1.92(m,2H),1.87(dd,J=8.9,6.6Hz,2H),1.73–1.40(m,12H), 1.30–1.07(m,6H),1.02(t,J=3.3Hz,6H),0.87–0.79(m,9H),0.70(s,3H).

[0213] Step 2: Weigh 3-O-2 (10.0 g, 22 mmol, 1 eq) and dissolve it in tetrahydrofuran (200 mL) and water (20.0 mL). Add pyridine (4.5 mL, 55 mmol, 2.5 eq), N-methylmorpholine oxide (10.30 g, 88 mmol, 4 eq), and potassium osmium tetroxide (0.81 g, 2.2 mmol, 0.1 eq) at room temperature. Stir overnight at room temperature. TLC (petroleum ether: ethyl acetate = 3:1) showed that some raw material remained and an intermediate (vicinal diol) was formed. Then, sodium periodate (18.80 g, 88 mmol, 4 eq) was added to the reaction solution at 0 °C and stirred at room temperature for 1 hour. TLC (petroleum ether: ethyl acetate = 3:1) showed that some raw material remained and the intermediate was converted into the product. Subsequently, 50 mL of water and 50 mL of ethyl acetate were added for extraction, dried, and concentrated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 60:1) to obtain a white solid acetic acid-(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-tetradecanoic-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 3-O-3 (1.9 g, yield 21.20%). 1 H NMR (400MHz, CDCl3) δ9.50(d,J=3.3Hz,1H),5.31(d,J=5.1Hz,1H),4.54(dd,J=6.4,4.2Hz,1H),2.34–2.23(m,3H),1.96(s ,3H),1.89(dt,J=6.6,3.6Hz,2H),1.83–1.72(m,3H),1.66–1.09(m,14H),1.06(d,J=6.8Hz,3H),0.96(s,3H),0.66(s,3H).

[0214] In step 3, 3-O-3 (20 g, 53.68 mmol) was dissolved in methanol (50 mL) and dichloromethane (99.9% (10 mL)). Sodium borohydride (3.05 g, 80.53 mmol) was slowly added at room temperature. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by TLC (petroleum ether / ethyl acetate = 5 / 1) until the reactants had reacted completely. The reaction was quenched by slow dropwise addition of saturated ammonium chloride aqueous solution (50 mL) at room temperature. The solution was concentrated at low temperature and then extracted with ethyl acetate (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by rapid chromatography (petroleum ether / ethyl acetate = 0-20%) to give acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aS)-1-[(2S)-1-hydroxypropyl-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecanoyl-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 3-0-4 (13 g, yield: 54.95%) as a white solid. 1 H NMR(400MHz, CDCl3) δ5.37(d,J=4.9Hz,1H),4.67–4.52(m,1H),3.64(dd,J=10.5,3. 2Hz,1H),3.37(dd,J=10.5,6.9Hz,1H),2.32(d,J=7.0Hz,2H),2.03(s,3H),2.02–1.9 3(m,2H),1.85(dd,J=12.0,6.9Hz,3H),1.62–1.53(m,4H),1.48–1.38(m,4H),1.24– 1.09(m,5H),1.05(d,J=6.6Hz,3H),1.02(s,3H),0.96(d,J=6.5Hz,1H),0.70(s,3H).

[0215] In step 4, 3-O-4 (6 g, 16.019 mmol) was dissolved in 99.9% dichloromethane (10 mL), and imidazole (3.27 g, 48.056 mmol), 4-dimethylaminopyridine (DMAP) (130.47 mg, 1.068 mmol), and tert-butyldimethylchlorosilane (6.04 g, 40.047 mmol) were added. The mixture was stirred at room temperature for 3 hours. Water (50 mL × 3) was added to the reaction solution, the mixture was shaken and allowed to stand to separate into layers. The organic phase was extracted once again with dichloromethane (50 mL), the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and evaporated to dryness. The solid was purified by rapid chromatography (petroleum ether / ethyl acetate = 0-10%) to give acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aS)-9a,11a-dimethyl-1-[(6S)-2,2,3,3-tetramethyl-4-oxa-3-silazepen-6-yl]-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecanohydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl 3-0-5 (6 g, yield: 65.13%) as a white solid. 1 H NMR(400MHz, CDCl3) δ5.37(d,J=4.9Hz,1H),4.65–4.55(m,1H),3.58(dd,J=9.6,3.4Hz,1H),3.2 4(dd,J=9.6,7.6Hz,1H),2.32(d,J=7.1Hz,2H),2.03(s,3H),1.99(s,2H),1.86(d,J=10.8Hz,2H ),1.77(ddd,J=13.0,9.4,6.0Hz,1H),1.64–1.39(m,9H),1.28(dd,J=17.0,6.9Hz,1H),1.20–1. 07(m,4H),1.02(s,3H),0.99(d,J=6.5Hz,3H),0.88(d,J=6.9Hz,9H),0.69(s,3H),0.03(s,6H).

[0216] In step 5, 3-O-5 (2 g, 4.091 mmol) was dissolved in acetone (50 mL), and N-hydroxyphthalimide (0.27 g, 1.637 mmol), tert-butyl hydroperoxide (1.84 g, 20.457 mmol), and cobalt(II) acetate, anhydrous (0.14 g, 0.818 mmol) were added. The mixture was stirred overnight at room temperature. Complete reaction was monitored by TLC (petroleum ether / ethyl acetate = 5 / 1). Sodium sulfite solution (30 mL) was added to the reaction mixture, which was shaken and allowed to stand for separation. The mixture was extracted with dichloromethane (30 mL × 3), and the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and then evaporated to dryness. The crude product was purified by rapid chromatography (petroleum ether / ethyl acetate = 0-15%) to give acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-9a,11a-dimethyl-4-oxonyl-1-[(6S)-2,2,3,3-tetramethyl-4-oxa-3-silazepen-6-yl]-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecanohydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 3-0-6 (0.97 g, yield: 40.08%) as a white solid. 1 H NMR(400MHz, CDCl3) δ5.68(d,J=1.5Hz,1H),4.75–4.62(m,1H),3.55(d,J=3.3Hz,1H),3.27–3.1 9(m,1H),2.56–2.37(m,3H),2.20(s,1H),2.03(s,3H),1.99–1.92(m,2H),1.86–1.79(m,1H),1.6 7(dd,J=17.4,5.8Hz,1H),1.52(t,J=10.1Hz,4H),1.33–1.20(m,5H),1.18(s,3H),1.12(dd,J=11 .9,7.3Hz,2H),0.97(d,J=6.5Hz,3H),0.85(d,J=5.0Hz,9H),0.67(s,3H),0.00(d,J=0.9Hz,6H).

[0217] In step 6, 3-O-6 (970 mg, 1.929 mmol) was dissolved in ethyl acetate (20 mL), and 10% palladium on carbon (485 mg, 0.456 mmol) was added to replace the system with hydrogen gas. The mixture was stirred at 40 °C for 2 hours, and the reaction was monitored for completeness by TLC (petroleum ether / ethyl acetate = 10 / 1). The reaction solution was filtered through diatomaceous earth to remove the palladium on carbon, and the filtrate was evaporated to dryness. The crude product was purified by rapid chromatography (petroleum ether / ethyl acetate = 0-15%) to give acetic acid-(1R,3aS,3bR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-4-oxonyl-1-[(6S)-2,2,3,3-tetramethyl-4-oxa-3-silazepen-6-yl]hexadecylhydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 3-O-7 (790 mg, yield: 68.95%) as a white solid. 1 H NMR (400MHz, CDCl3) δ4.65 (tt, J=9.9, 4.9Hz, 1H), 3.55 (dd, J=9.6, 3.3Hz, 1H), 3.23 (dd, J=9.6 ,7.4Hz,1H),2.31(t,J=11.8Hz,2H),2.25–2.13(m,1H),2.05–1.92(m,5H),1.89–1.73(m,3H),1 .67–1.60(m,1H),1.59–1.36(m,8H),1.28–1.20(m,1H),1.13(dd,J=19.3,10.4Hz,2H),1.08(s, 3H),1.07–0.99(m,2H),0.96(d,J=6.5Hz,3H),0.87(d,J=4.9Hz,9H),0.64(s,3H),0.02(s,6H).

[0218] Step 7: 3-O-7 (690 mg, 1.367 mmol) was placed in a single-necked flask, and tetrabutylammonium fluoride (357.38 mg, 1.367 mmol) was added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored for safety by TLC (petroleum ether / ethyl acetate = 3 / 1). The reaction mixture was diluted with ethyl acetate (30 mL), washed with water (15 mL × 2), and the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by rapid chromatography (petroleum ether / ethyl acetate = 0-50%) to give acetate-(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-1-[(2S)-1-hydroxypropyl-2-yl]-9a,11a-dimethyl-4-oxylidene hexadecylhydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 3-O (420 mg, yield: 66.88%) as a white solid. 1H NMR(400MHz, CDCl3) δ4.67(dd,J=11.1,5.2Hz,1H),3.65(dd,J=10.5,3.3Hz,1H),3.36(dd,J=10.5,7.1Hz,1 H),2.33(dd,J=18.2,7.1Hz,2H),2.24(dd,J=10.0,2.7Hz,1H),2.06–1.96(m,5H),1.88(ddd,J=12.4,6.4,3. 1Hz,2H),1.78(dd,J=10.1,6.5Hz,1H),1.69–1.63(m,1H),1.62–1.48(m,5H),1.46(s,3H),1.44–1.38(m,1H) ),1.34–1.25(m,1H),1.22–1.12(m,2H),1.10(s,3H),1.05(d,J=6.6Hz,3H),1.01–0.94(m,1H),0.68(s,3H).

[0219] In step 8, 3-0 (300 mg, 0.768 mmol) was dissolved in 99.9% dichloromethane (2 mL), and tetrabutylammonium bromide (247.63 mg, 0.768 mmol), 40% sodium hydroxide aqueous solution (2 mL, 0.768 mmol), and bromoacetic acid-2-methylpropyl-2-yl ester (2996.62 mg, 15.363 mmol) were added. The mixture was stirred overnight at room temperature. TLC (petroleum ether / ethyl acetate = 3 / 1) monitoring of the reaction solution revealed the formation of new spots with decreasing polarity. Water (15 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL × 3), washed with saturated sodium chloride aqueous solution (15 mL), dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was purified by rapid chromatography (petroleum ether / ethyl acetate = 0-25%) to obtain {[(2S)-2-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-4-oxoylidenehexadecyl-1H-cyclopenta[1,2-a]phenanthrene-1-yl]propyl]oxy}acetate-2-methylpropyl-2-yl ester 3-1 (115 mg, yield: 25.21%) as a white solid. 1H NMR (400MHz, CDCl3) δ4.68(td,J=10.8,5.0Hz,1H),3.92(s,2H),3.47(d,J=3.2Hz,1H),3.21(d,J=8.2Hz,1 H),2.33(t,J=12.2Hz,2H),2.28–2.17(m,1H),2.06–1.96(m,5H),1.88(d,J=9.4Hz,2H),1.79(d,J=13.9Hz, 1H),1.71–1.64(m,2H),1.60(s,2H),1.55(s,3H),1.48(s,9H),1.42(dd,J=11.5,4.3Hz,2H),1.32–1.24(m ,2H),1.16(dd,J=17.3,7.6Hz,2H),1.09(s,3H),1.07(d,J=6.6Hz,3H),0.97(d,J=6.3Hz,1H),0.67(s,3H).

[0220] Step 9: Dissolve 3-1 (200 mg, 0.396 mmol) in diethylaminotrifluoride (3 mL) and stir at 50 °C for 3 hours. Monitor the reaction solution by TLC (petroleum ether / ethyl acetate = 5 / 1). When a new point with decreasing polarity is observed, stop heating and allow the reaction solution to cool to room temperature. Dilute the reaction solution with dichloromethane, and then slowly quench the solution by adding it dropwise to a saturated sodium bicarbonate aqueous solution (50 mL). Extract the organic phase with ethyl acetate (20 mL × 3), wash with saturated brine (20 mL), dry with anhydrous sodium sulfate, and evaporate to dryness. The crude product was purified by rapid chromatography (petroleum ether / ethyl acetate = 0-15%) to obtain {[(2S)-2-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-7-acetoxy-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]propyl]oxy}acetate-2-methylpropyl-2-yl ester 3-2 (150 mg, yield: 61.09%) as a white solid. 1H NMR (400MHz, CDCl3) δ4.75–4.64(m,1H),3.93(s,2H),3.55(ddd,J=58.3,8.6,3.6Hz,1H) ,3.22(s,1H),2.03(d,J=2.2Hz,3H),2.01(s,1H),1.83(d,J=13.1Hz,4H),1.77–1.72(m,2 H),1.65(dd,J=11.0,3.7Hz,2H),1.60–1.51(m,5H),1.48(s,9H),1.34(dd,J=9.9,6.8Hz ,5H),1.20(s,2H),1.07(d,J=6.6Hz,4H),0.85(d,J=10.8Hz,3H),0.67(d,J=12.2Hz,3H). 19 F NMR (377MHz, CDCl3) δ-89.10,-89.73,-110.83,-111.46.

[0221] Step 10: Dissolve 3-2 (600 mg, 1.14 mmol) in potassium carbonate (1574 mg, 11.39 mmol). Stir the mixture at room temperature for 1 hour. Monitor the reaction mixture by TLC (petroleum ether / ethyl acetate = 1 / 1), and the starting material will disappear. Filter, evaporate to dryness, dissolve in water (10 mL), acidify with hydrochloric acid (1 N), extract with ethyl acetate (10 mL × 3), dry the organic phase with anhydrous sodium sulfate, evaporate to dryness, and purify by rapid chromatography (dichloromethane / methanol = 0-10%) to obtain {[(2S)-2-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-7-hydroxy-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]propyl]oxy}acetic acid 3-3 (400 mg, yield: 69.65%) as a white solid. 1HNMR (400MHz, DMSO) δ12.46 (s, 1H), 4.52 (d, J = 4.5Hz, 1H), 3.95 (t, J = 3.1Hz, 2H), 3.38 (dd, J = 8.8, 3.1Hz,2H),3.18(dd,J=8.6,7.3Hz,1H),1.91(t,J=6.1Hz,1H),1.78(dd,J=18.1,9.8Hz,2H),1.66 (dd,J=11.5,6.9Hz,4H),1.61–1.50(m,3H),1.45(d,J=12.4Hz,1H),1.39–1.22(m,7H),1.20–1.07 (m,3H),0.99(d,J=6.5Hz,2H),0.96–0.87(m,2H),0.76(d,J=20.6Hz,3H),0.63(d,J=19.6Hz,3H). 19 F NMR(376MHz, DMSO)δ-87.42,-88.04,-109.16,-109.78.

[0222] Step 11: Dissolve 3-3 (400 mg, 0.90 mmol) in N,N-dimethylformamide >99.9% (6 mL), add imidazole (123 mg, 1.81 mmol), 4-dimethylaminopyridine (DMAP) (55 mg, 0.45 mmol), and tert-butyldiphenylchlorosilane / TBDPSCL (497 mg, 1.81 mmol). Stir the mixture at room temperature for 2 hours. Monitor the reaction mixture by TLC (petroleum ether / ethyl acetate = 1 / 1). Dilute the reaction mixture with ethyl acetate (30 mL), wash with water (10 mL × 3), phase with an aqueous camera, extract with ethyl acetate (10 mL × 2), dry with anhydrous sodium sulfate, and evaporate to dryness. The solid was purified by rapid chromatography (petroleum ether / ethyl acetate = 0-50%) to obtain {[(2S)-2-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]propyl]oxy}acetic acid 3-4 (200 mg, yield: 28.20%) as a white solid. 1HNMR (400MHz, CDCl3) δ7.68 (dd, J=7.9, 1.3Hz, 4H), 7.44–7.35 (m, 6H), 4.16 ( s,2H),3.62(s,1H),3.54–3.47(m,1H),3.25(d,J=7.8Hz,1H),1.96(s,1H),1. 81(d,J=6.7Hz,7H),1.73–1.54(m,8H),1.43(t,J=12.0Hz,3H),1.33(d,J=3. 3Hz, 3H), 1.12 (s, 9H), 1.06 (d, J = 6.5Hz, 3H), 0.84 (s, 3H), 0.68–0.63 (m, 3H).

[0223] In step 12, dissolve 3-4 (400 mg, 0.60 mmol) in tetrahydrofuran (10 mL), and slowly add lithium aluminum hydride (34 mg, 0.90 mmol) at room temperature for 10 minutes. Monitor the reaction by TLC (petroleum ether: ethyl acetate = 3:1). The starting material spot disappears, and a small polar spot appears. Quench the reaction with sodium sulfate decahydrate, filter, and concentrate the filtrate to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 60:40) to give a white solid 2-{[(2S)-2-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]propyl]oxy}ethanol-1-ol 3-5 (300 mg, yield 61.3%). 1 H NMR (400MHz, CDCl3) δ7.66(ddd,J=6.4,3.3,2.0Hz,4H),7.45–7.34(m,6H),3.71(t,J=4.6Hz,2H),3.64–3.40(m,4H),3.25–3.11(m,1H),1.94(d,J= 12.7Hz,1H),1.78(d,J=6.6Hz,2H),1.59–1.09(m,15H),1.06(d,J=12.1H z,10H),1.01(d,J=6.6Hz,2H),0.98–0.70(m,8H),0.64(d,J=12.5Hz,3H).

[0224] Step 13: Dissolve 3-5 (350 mg, 0.54 mmol) in dichloromethane (5 mL), and add Desmartin oxidant (341 mg, 0.80 mmol) dropwise with stirring at 0 °C. Return to room temperature and stir. After stirring at room temperature for 1 hour, monitor the reaction by TLC (petroleum ether: ethyl acetate = 5:1). The starting material disappears, and the reaction completely transforms into a new phase. Quench with sodium thiosulfate aqueous solution (10 mL), extract with ethyl acetate (10 mL × 2), wash the organic phase with saturated brine (10 mL), and then with anhydrous sulfuric acid. Sodium was dried, the crude product was concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 80:20) to give a white solid 2-{[(2S)-2-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]propyl]oxy}acetaldehyde 3-6 (150 mg, yield 30.1%). 1 H NMR (400MHz, CDCl3) δ9.73(s,1H),7.66(m,4H),7.38(m,6H),4.01(m,2H),3.58( s,1H),3.47(dd,J=8.9,3.2Hz,1H),3.25(d,J=7.6Hz,1H),1.94(d,J=12.7Hz,1H ),1.80(m,2H),1.63(m,3H),1.38(m,13H),1.07(m,13H),0.97(d,J=6.6Hz,1H), 0.87(dd,J=10.3,2.8Hz,1H),0.82(s,3H),0.77(s,1H),0.65(d,J=12.6Hz,3H).

[0225] In step 14, 3-6 (100 mg, 0.15 mmol) was dissolved in tetrahydrofuran (3 mL). After complete dissolution, (trifluoromethyl)trimethylsilane (76 mg, 0.54 mmol) and cesium fluoride (12 mg, 0.08 mmol) were added sequentially to the reaction system, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1) to ensure complete reaction. Tetrabutylammonium fluoride (2 mL, 1 mol / L, 10.0 eq) was added, and the mixture was stirred at room temperature for 1 hour. A large polarity point was observed by TLC (petroleum ether:ethyl acetate = 2:1). Extraction was performed under ice bath conditions with saturated ammonium chloride solution (10 mL). The reaction solution was washed with water (10 mL x 3) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 80:20) to give 1,1,1-trifluoro-3-{[(2S)-2-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylprop-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]propyl]oxy}prop-2-ol 3-7 (50 mg, 40.63%). 1 H NMR(400MHz, CDCl3)δ7.66(m,4H),7.39(m,6H),4.09(s,1H),3.60(m,3H),3 .45(dd,J=9.0,3.3Hz,1H),3.22(m,1H),2.80(s,1H),1.93(d,J=13.0Hz,1H) ,1.78(m,2H),1.64(d,J=7.3Hz,4H),1.25(s,10H),1.07(s,1H),1.04(s,9H) ,1.00(d,J=6.6Hz,3H),0.88(m,2H),0.82(s,3H),0.77(m,1H),0.66(s,3H).

[0226] Step 15: Chiral separation of 3-7 (50 mg, 0.06 mmol) (Instrument information: Waters Acquity UPCC column: Daicel CHIRALPAK AS_3, 3*150 mm, 3 μm; Flowability: A / B: CO2 / MeOH (0.1% DEA) = 90 / 10; Flow rate: 2.0 ml / min; Column temperature: 37 °C) yielded 3-8 (10 mg, 200% yield, retention time 3.317 min) and 4-1 (30 mg, 60%, retention time 3.658 min).

[0227] In step 16A, compounds 3-8 (10 mg, 0.01 mmol) were dissolved in tetrahydrofuran (2 mL), and tetrabutylammonium fluoride (0.5 mL, 0.50 mmol) was added. The reaction mixture was stirred at 60°C for 3 h. The reaction was monitored for completeness by TLC (petroleum ether: ethyl acetate = 3:1). Ethyl acetate (10 mL) was added to the reaction mixture, and the mixture was washed with saturated ammonium chloride (5 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 50:50) to give compound 3 (2.5 mg, yield 35.6%) as a white solid. 1 H NMR (400MHz, CDCl3) δ4.09(m,1H),3.62(d,J=3.8Hz,2H),3.54(m,1H),3.33(m,1H),2.99(s,1H),1.83(s,3H),1.77(m,2H),1.70 (s,3H),1.44(d,J=7.9Hz,6H),1.33(s,2H),1.28(s,2H),1.00(d,J=5.5Hz,4H),0.94(d,J=6.7Hz,3H),0.85(s,3H),0.68(s,3H). 19 F NMR(377MHz, CDCl3)δ-77.62,-77.66,-89.12,-89.79,-110.83,-111.51.LC-MS: [MH] - =481.40

[0228] Step 16B is similar to step 16A of Example 3, except that 3-8 is replaced with 4-1 to obtain compound 4 (27.56 mg, yield 96.0%). 1 H NMR (400MHz, CDCl3) δ4.02(d,J=4.8Hz,1H),3.55(d,J=5.0Hz,3H),3.40(dd,J=9.0,3.3Hz,1H),3.17(m,1H),1.92(dd,J=9.7,6.2Hz ,1H),1.65(m,8H),1.36(s,3H),1.26(s,3H),1.20(d,J=12.0Hz,4H),1.09(m,2H),0.96(d,J=6.6Hz,4H),0.78(s,3H),0.62(s,3H). 19 F NMR(376MHz, CDCl3)δ-77.68,-77.73,-88.99,-89.65,-110.90,-111.47.LC-MS: [MH] - =481.45

[0229] Example 5

[0230] Preparation of compound 5(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-7-methoxy-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0231] Step 1 is similar to Example 1. Replacing cyclopropyl magnesium bromide with methyl magnesium bromide yields (6R)-6-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hept-2-ol 5-1 (130 mg, 76.12%), which is a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.67–7.64(m,4H),7.42–7.34(m,6H),3.78(dd,J=11.9,5.8Hz,1H ),3.63–3.55(m,1H),2.05(s,1H),1.93(d,J=12.8Hz,1H),1.81(dd,J=16.3,7.4Hz,2H) ,1.66–1.60(m,3H),1.51(s,10H),1.44(d,J=10.2Hz,3H),1.38(dd,J=11.8,6.8Hz,5H) ,1.18(d,J=6.1Hz,3H),1.04(s,11H),0.90(d,J=6.5Hz,4H),0.82(s,3H),0.63(s,3H).

[0232] In step 2, 5-1 (120 mg, 0.18 mmol, 1.0 eq) was added to a reaction flask containing 1 mL of dichloromethane, followed by the addition of Desmartin oxidant (114.80 mg, 0.27 mmol, 1.5 eq). The reaction was stirred at room temperature (25 °C) for 2 h, and the reaction was monitored by TLC until complete. The mixture was diluted with 20 mL of water, and then 3 times of dichloromethane (20 mL each) was added. The mixture was extracted three times, washed with sodium chloride, dried over anhydrous sodium sulfate, and the reaction solution was evaporated to dryness under reduced pressure. (6R)-6-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hepta-2-one 5-2 (100 mg, 75.23%) was obtained by column chromatography (petroleum ether:ethyl acetate = 80:20) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.70–7.62(m,4H),7.44–7.33(m,6H),3.63–3.53(m,1H),2 .37(d,J=8.1Hz,1H),2.12(s,3H),2.05(s,2H),1.93(d,J=13.1Hz,1H),1.80(d,J =7.4Hz,2H),1.68–1.59(m,4H),1.53(s,10H),1.44(d,J=8.4Hz,3H),1.26(dd,J =8.4,5.9Hz,4H),1.04(s,10H),0.90(d,J=6.5Hz,3H),0.82(s,3H),0.63(s,3H).

[0233] In step 3, trimethyl sulfoxide (93.36 mg, 0.42 mmol, 3.5 eq) was added to a reaction flask containing tetrahydrofuran (2 mL). Sodium hydride (10.14 mg, 0.42 mmol, 3.5 eq) was added at 0 °C, and the mixture was stirred at room temperature for 30 min. Then, 5-2 (80 mg, 0.12 mmol, 1.0 eq) was added, and the reaction was stirred at 40 °C for 16 h. The reaction was monitored by TLC until complete. The mixture was diluted with water (20 mL), and then dichloromethane (20 mL × 3) was added. The mixture was extracted three times, washed with sodium chloride, dried over anhydrous sodium sulfate, and the reaction solution was evaporated to dryness under reduced pressure. [(3aR,3R,5aS,7R,9aR,9bS)-9,9-difluoro-3a,6,6-trimethyl-3-[(2R)-5-(2-methyloxacycloprop-2-yl)pent-2-yl]dodecylhydro-1H-cyclopenta[1,2-a]naphth-7-yl]-5,5-dimethyl-4,4-diphenyl-3-oxa-4-silazhexane 5-3 (35 mg, yield 38.56%) was purified by column chromatography (petroleum ether:ethyl acetate = 95:5) as a white solid. 1 H NMR (400MHz, CDCl3) δ7.66(m,4H),7.39(ddd,J=14.2,7.7,4.4Hz,6H),3.58(dd,J=10.2,5.5Hz,1H),2.57(t,J=7.2Hz,1H),1.93(d,J=13.0Hz,1H),1.79 (d,J=10.7Hz,2H),1.63(dd,J=11.2,4.7Hz,3H),1.54(s,10H),1.45(m,9H), 1.28(m,6H),1.04(s,10H),0.90(d,J=6.5Hz,3H),0.82(s,3H),0.63(s,3H).

[0234] In step 4, 5-3 (35 mg, 0.05 mmol, 1.0 eq) was added to a reaction flask containing methanol (2 mL), followed by sodium hydroxide (20.68 mg, 0.51 mmol, 1.0 eq). The reaction was stirred at 60 °C for 5 h, and TLC monitoring showed that the reaction of the starting materials was complete. Dilute with water (20 mL), then add dichloromethane (20 mL × 3), extract three times, wash with sodium chloride, dry with anhydrous sodium sulfate, evaporate the reaction solution under reduced pressure (water pump, 45 °C), and separate and purify by column chromatography (petroleum ether: ethyl acetate = 80:20) to obtain (6R)-6-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1-methoxy-2-methylhept-2-ol 5-4 (24 mg, 58.92%) as a white solid. 1 H NMR (400MHz, CDCl3) δ7.66 (ddd, J=6.4, 3.4, 2.0Hz, 4H), 7.39 (ddd, J=14.3, 7.7, 4.4Hz,6H),3.59(s,1H),3.38(s,3H),3.23(m,2H),1.92(s,1H),1.79(s,2H),1. 63(d,J=6.1Hz,4H),1.42(m,12H),1.26(dd,J=13.3,3.6Hz,6H),1.14(d,J=0.9H z,3H),1.04(s,10H),0.90(d,J=6.5Hz,4H),0.80(d,J=12.1Hz,4H),0.62(m,3H).

[0235] Step 5 is similar to step 16A of Example 3. Replacing 3-8 with 5-4 yields (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-7-methoxy-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 5 (10 mg, yield 75.30%), a white solid. 1H NMR (400MHz, CDCl3) δ3.62(dd,J=10.4,5.4Hz,1H),3.39(s,3H),3.22(dd,J=21.0,9.1Hz,2H),1.98(d,J=12.5Hz,1H),1.83(d,J =9.3Hz,3H),1.73(m,3H),1.58(s,8H),1.36(m,12H),1.15(s,3H),1.00(s,1H),0.92(d,J=6.5Hz,3H),0.85(s,3H),0.66(s,3H). 19 F NMR (376MHz, CDCl3) δ-88.97,-89.59,-110.86,-111.49.

[0236] Example 6 & 21

[0237] Compound 6 or 21(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R,4S)-4-fluoro-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0238] Preparation of compound 21 or 6(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R,4R)-4-fluoro-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0239] Step 1: (Methoxymethyl)triphenylphosphine 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 ethyl acetate bath on dry ice. Sodium di(trimethylsilyl)aminocyanate (80.526 mL, 1 mol / L, 2.5 eq) was added. The mixture was stirred in an ethyl acetate bath on dry ice for 30 minutes. Then, 3-O-3 (12.0 g, 13.4 mmol, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (50 mL) and added to the reaction solution. The system was brought back to room temperature and stirred for 30 minutes. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 10:1) to ensure complete reaction. 100 mL of saturated sodium bicarbonate solution was slowly added to the reaction system. The mixture was extracted with ethyl acetate (100 mL × 3). The organic phase was collected, washed with water (100 mL × 2), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a yellow solid 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-tetradecanoyl-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 6-0-1 (8 g, yield 65.0%). The crude product was directly added to the next reaction step.

[0240] Step 2: Dissolve 6-O-1 (8 g, 1.0 eq) in tetrahydrofuran (100 mL), and slowly add dilute hydrochloric acid (5 mol / L, 50 mL). Stir the reaction mixture at room temperature for 30 minutes. Monitor the reaction by TLC (petroleum ether: ethyl acetate = 10:1). After the reaction is complete, add 80 mL of water to the reaction mixture. Extract the reaction solution with ethyl acetate (50 mL × 3), wash with saturated brine (20 mL × 3), dry with anhydrous sulfuric acid, collect the organic phase, and concentrate 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 give a white solid acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-1-formylpropyl-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecanoyl-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 6-0 (6.3 g, yield 48.63%). 1H NMR (400MHz, CDCl3) δ9.76 (dd, J=3.3, 1.3Hz, 1H), 5.37 (d, J=4.9Hz, 1H), 4.65–4.5 5(m,1H),2.46(dd,J=15.6,2.8Hz,1H),2.32(d,J=7.0Hz,2H),2.22–2.14(m,1H),2 .03(s,3H),2.03–1.93(m,2H),1.89–1.78(m,3H),1.66–1.40(m,9H),1.17(dddd,J =16.5,14.2,10.9,7.1Hz,6H),1.03(dd,J=7.5,3.5Hz,6H),0.73(d,J=5.3Hz,3H).

[0241] Step 3: At room temperature, zinc powder (135 mg, 2.07 mmol, 1.0 eq) was dissolved in tetrahydrofuran (2 mL), and trimethylchlorosilane (5.6 mg, 0.052 mmol, 0.2 eq) was added with stirring. The mixture was heated to 45 degrees Celsius and stirred for 20 minutes. Ethyl bromofuran (173 mg, 1.03 mmol, 4.0 eq) was then added. The mixture was stirred at room temperature for 40 minutes and then cooled to room temperature. 6-0 (100 mg, 0.26 mmol, 1 eq) was dissolved in 1 mL of tetrahydrofuran and added dropwise to the above solution. After stirring at room temperature for half an hour, the reaction was monitored by TLC (petroleum ether: ethyl acetate = 5:1) to ensure complete reaction. Dilute with 100 mL of water at room temperature, extract with ethyl acetate (100 mL × 2), wash the organic phase with saturated brine (50 mL), dry with anhydrous sodium sulfate, and purify by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to give a white solid (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecanoic acid ethyl ester 6-1 (70 mg, yield: 57.1%). 1 H NMR (400MHz, CDCl3) δ5.37(d,J=4.5Hz,1H),4.65–4.54(m,1H),4.22–4.07(m,3H),2.58–2.24(m,4H),2.05–1.92(m,5H),1.84( t,J=11.0Hz,3H),1.79–1.34(m,9H),1.28(td,J=7.1,2.7Hz,4H),1.18–1.10(m,2H),1.08–0.86(m,10H),0.69(t,J=8.6Hz,3H).

[0242] In step 4, at room temperature, 6-1 (70 mg, 0.15 mmol, 1.0 eq) was dissolved in dichloromethane (3 mL), and diethylaminotrifluoride DAST (47 mg, 0.30 mmol, 2.0 eq) was added with stirring. After 10 minutes at room temperature, the reaction was monitored by TLC (petroleum ether: ethyl acetate = 10:1) to ensure complete reaction. Dilute with 100 mL of water at room temperature, extract with ethyl acetate (100 mL × 2), wash the organic phase with saturated brine (50 mL), dry with anhydrous sodium sulfate, and purify by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to give a white solid (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecanoic acid ethyl ester 6-2 (50 mg, yield: 71.1%). 1 H NMR (400MHz, CDCl3) δ5.42–4.96(m,2H),4.65–4.57(m,1H),4.22–4.12(m,2H),2.59(dd,J=29.4,13.5Hz,1H),2.32(d,J=7.2Hz,2H),2. 06–1.95(m,5H),1.86(d,J=10.8Hz,3H),1.69–1.42(m,9H),1.35–1.16(m,7H),1.14–1.07(m,2H),1.04–0.92(m,8H),0.72–0.65(m,3H).

[0243] In step 5, at room temperature, 6-2 (79 mg, 0.88 mmol, 6.0 eq), N-hydroxyphthalimide (5 mg, 0.029 mmol, 0.2 eq) and cobalt acetate (2.6 mg, 0.015 mmol, 0.1 eq) were added and the reaction was monitored by TLC (petroleum ether: ethyl acetate = 5:1) after 12 hours at room temperature until the reaction was complete. Dilute with 100 mL of water at room temperature, extract with ethyl acetate (100 mL × 2), wash the organic phase with saturated brine (50 mL), dry with anhydrous sodium sulfate, and purify by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to give a white solid (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-4-oxoylide-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecanoic acid-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-3-fluorohexanoate ethyl 6-3 (40 mg, yield: 55.5%). 1H NMR(400MHz, CDCl3)δ5.70(d,J=1.1Hz,1H),5.20–4.89(m,1H),4.76–4.67(m,1H),4.23–4.12(m,2H),2.65–2.43(m,4H),2.27–2.20(m,1H),2 .05(s,3H),2.02–1.96(m,2H),1.90–1.43(m,9H),1.33–1.16(m,13H), 1.03(t,J=6.1Hz,2H),0.96–0.86(m,1H),0.72(dd,J=16.4,4.9Hz,3H).

[0244] In step 6, at room temperature, 6-3 (160 mg, 0.33 mmol, 1.0 eq) was dissolved in methanol (3 mL), and palladium on carbon (10% Pd, containing 40-60% water) (40 mg) was added with stirring. After 2 hours at room temperature, the reaction was monitored by TLC (petroleum ether: ethyl acetate = 5:1) to ensure complete reaction. The mixture was diluted with 100 mL of water at room temperature, extracted with ethyl acetate (100 mL × 2), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give a white solid (5R)-5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-4-oxoylidenehexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-3-fluorohexanoate ethyl 6-4 (110 mg, yield: 68.5%). 1 H NMR (400MHz, CDCl3) δ5.15–4.90(m,1H),4.73–4.61(m,1H),4.21–4.14(m,J=13.6,6.4Hz,2H),2.70–2.42(m,2H),2.37–2.14(m,3H),2. 02(s,3H),1.95–1.76(m,4H),1.71–1.24(m,18H),1.21–1.14(m,2H),1.10(s,3H),1.05–0.98(m,J=12.5,6.4Hz,3H),0.73–0.63(m,3H).

[0245] Step 7 is similar to Step 3. Step 9, replacing 3-1 with 6-4, yields a white solid (5R)-5-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-7-acetoxy-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-3-fluorohexanoate ethyl 6-5 (65 mg, yield: 62.2%). 1H NMR (400MHz, CDCl3) δ5.22–4.79(m,1H),4.74–4.64(m,1H),4.17(dd,J=9.7,4.1Hz,2H ),2.78–2.39(m,2H),2.03(d,J=2.0Hz,3H),1.93–1.79(m,4H),1.76–1.65(m,4H),1.5 4(dddd,J=38.2,25.1,8.9,5.6Hz,7H),1.41–1.30(m,3H),1.27–1.05(m,8H),1.02(t, J=6.0Hz,3H),0.90(d,J=19.6Hz,1H),0.87–0.80(m,3H),0.67(dd,J=12.3,7.8Hz,3H).

[0246] In step 8, at room temperature, 6-5 (65 mg, 0.13 mmol, 1.0 eq) was dissolved in tetrahydrofuran (2 mL), and methyl magnesium bromide (3.0 M tetrahydrofuran solution) (0.4 mL, 1.3 mmol, 10.0 eq) was added with stirring. After 3 hours at room temperature, the reaction was monitored by TLC (petroleum ether: ethyl acetate = 1:1) to ensure complete reaction. Dilute with 100 mL of water at room temperature, extract with ethyl acetate (100 mL × 2), wash the organic phase with saturated brine (50 mL), dry with anhydrous sodium sulfate, and purify by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give a white solid (1R,3aS,3bR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-4-fluoro-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 6-6 (40 mg, yield: 69.1%). 1 H NMR (400MHz, CDCl3) δ5.07–4.79(m,1H),3.66–3.59(m,1H),2.00(dd,J=11.9,8.7Hz,1H),1.84(d,J=10.4Hz,4H),1.72(dd,J=11.3,7.7Hz,4H) ,1.58–1.55(m,4H),1.45(d,J=10.9Hz,4H),1.34–1.25(m,10H),1.21– 1.08(m,3H),1.00(d,J=6.4Hz,5H),0.85(s,3H),0.69(d,J=6.4Hz,3H).

[0247] In step 8, at room temperature, 6-6 (60 mg, 0.13 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL), and benzoyl chloride (55 mg, 0.39 mmol, 3.0 eq), triethylamine (46 mg, 0.46 mmol, 3.0 eq) and 4-dimethylaminopyridine DMAP (8 mg, 0.066 mmol, 0.5 eq) were added. After 3 hours at room temperature, the reaction was monitored for safety by TLC (petroleum ether: ethyl acetate = 5:1). Dilute with 100 mL of water at room temperature, extract with ethyl acetate (100 mL × 2), wash the organic phase with saturated brine (50 mL), dry with anhydrous sodium sulfate, and purify by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to give a white solid (6R)-6-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-7-(benzyloxy)-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-4-fluoro-2-methylhept-2-ol 6-7 (50 mg, yield: 69.7%). 1 H NMR (400MHz, CDCl3) δ8.07–8.00(m,2H),7.55(t,J=7.4Hz,1H),7.47(dd,J=13.6,6. 0Hz,2H),4.96(d,J=5.0Hz,2H),2.04–1.97(m,2H),1.84(ddd,J=16.9,12.8,8.0Hz,6 H),1.75–1.72(m,1H),1.69–1.50(m,8H),1.47–1.37(m,2H),1.33–1.25(m,10H),1. 21–1.07(m,4H),1.01(d,J=6.4Hz,2H),0.91(d,J=5.0Hz,3H),0.69(t,J=9.2Hz,3H).

[0248] Step 9: 6-7 (50 mg, 0.089 mmol, 1.0 eq) was passed through an SFC (instrument: Waters Acquity UPCC, column: Daicel CHIRALPAK OJ_3, 3*150 mm, 3 μm, mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 70 / 30, flow rate: 2.0 mL / min, column temperature: 37 °C) to obtain white solid 6-8 (20 mg, yield: 40.0%, retention time: 1.404 min) and crude white solid 21-1 (impure, retention time: 1.509 min). Crude white solid 21-1 was again passed through an SFC (instrument: Waters Acquity UPCC, column: Daicel CHIRALPAK). IC_3, 3.0*150mm, 3um, mobile phase: A / B:CO2 / MeOH (0.1% DEA)=60 / 40, flow rate: 1.5ml / min, column temperature: 37 degrees) was used to separate 21-1 (10mg, retention time: 1.433min).

[0249] Compounds 6-8: 1 H NMR (400MHz, CDCl3) δ8.03(d,J=7.2Hz,2H),7.55(t,J=7.4Hz,1H),7.43(t,J=7.7 Hz,2H),5.04–4.77(m,2H),2.00(dd,J=9.5,3.1Hz,2H),1.94–1.74(m,7H),1.71–1 .53(m,8H),1.46(ddd,J=23.5,12.0,4.5Hz,3H),1.35–1.25(m,9H),1.12(ddd,J= 15.0,12.2,6.1Hz,3H),1.01(d,J=6.3Hz,3H),0.91(d,J=7.1Hz,3H),0.69(s,3H).

[0250] Compound 21-1: 1 H NMR (400MHz, CDCl3) δ8.03(d,J=7.6Hz,2H),7.55(t,J=7.3Hz,1H),7.43(t,J=7.6Hz,2H),5.14–4.79(m,2H),2.04(dt,J=26.2,9.1Hz,3H),1 .89–1.76(m,7H),1.67–1.49(m,8H),1.30(d,J=11.6Hz,9H),1.18–1.0 7(m,4H),1.01(d,J=6.4Hz,3H),0.95–0.86(m,4H),0.76–0.64(m,3H).

[0251] Step 10A is similar to Step 5A of Example 1, where compound 43-1 is replaced with 6-8 to obtain compound 6 (6.15m, yield: 37.7%). 1 H NMR(400MHz, CDCl3)δ4.92(dd,J=50.4,8.1Hz,1H),3.69–3.57(m,1H),1.99(d,J=12.7H z,1H),1.85(dd,J=15.2,10.2Hz,3H),1.78–1.70(m,3H),1.65–1.56(m,J=12.4Hz,8H), 1.52–1.43(m,4H),1.41–1.34(m,J=11.5,4.2Hz,2H),1.32–1.27(m,7H),1.25–1.12(m, J=17.9,6.4Hz,3H),1.08–1.03(m,1H),1.00(d,J=6.3Hz,3H),0.85(s,3H),0.68(s,3H). 19 F NMR (376MHz, CDCl3) δ-88.99,-89.62,-110.84,-111.47,-175.56.

[0252] Step 10B is similar to Step 5A of Example 1, except that compound 43-1 is replaced with 21-1 to obtain compound 21 (4.31 mg, yield: 26.4%). 1 H NMR(400MHz, CDCl3) δ4.96(dt,J=20.1,9.8Hz,1H),3.68–3.57(m,1H),2.00(dd,J=16.6,7.2Hz,1H),1.84(dd,J=12.5,4.6Hz,4H),1.79–1.69 (m,4H),1.54(s,3H),1.46(dd,J=19.4,7.8Hz,4H),1.28(dd,J=11.8,9.0Hz,10H),1.00(d,J=6.5Hz,8H),0.85(s,4H),0.69(d,J=8.8Hz,3H). 19 F NMR(376MHz, CDCl3)δ-88.99,-89.62,-110.88,-111.50,-180.98.

[0253] Example 7

[0254] Preparation of compound 7(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-5-hydroxy-6-(oxacyclobut-3-yl)hex-2-yl]-9a,11a-dimethylhexadecyl-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0255] Step 1: In a 50 mL round-bottom flask at room temperature, dissolve II-9 (250 mg, 0.59 mmol) in tetrahydrofuran (10 mL). Purify the flask three times with a nitrogen balloon. Slowly add 1 M diisobutylaluminum hydride in n-hexane (1.2 mL, 1.2 mmol) dropwise to the reaction solution at -70 °C. Stir the reaction solution at -70 °C for 2 hours. Monitor the reaction by TLC (ethyl acetate / petroleum ether = 3:1). After the reaction was completed, saturated ammonium chloride aqueous solution (30 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give a white solid (5R)-5-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-7-hydroxy-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanal 7-0 (150 mg, yield: 56.1%). 1 H NMR(400MHz, CDCl3)δ=9.77(t,J=1.8,1H),3.65–3.59(m,1H),2.45(dddd,J=15.1,9.6,5.4,1.7,1H),2.40–2.31(m,1H),2.01–1.94(m,1H),1.90 –1.69(m,8H),1.65–1.53(m,4H),1.46–1.32(m,7H),1.18–1.09(m,2H),1 .02(dt,J=13.8,6.8,2H),0.93(d,J=6.5,3H),0.85(s,3H),0.67(s,3H).

[0256] In step 2, at room temperature, 3-(bromomethyl)oxetane (571 mg, 3.76 mmol) was dissolved in tetrahydrofuran (8 mL) in a 50 mL round-bottom flask. A 2.5 M solution of n-butyllithium tetrahydrofuran (1.4 mL, 3.5 mmol) was added at -70 °C, followed by stirring for 0.5 hours. Then, a 7-O (150 mg, 0.38 mmol) solution of tetrahydrofuran (1.5 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC (petroleum ether / ethyl acetate = 2:1). After the reaction was completed, water (40 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give a white solid (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-5-hydroxy-6-(oxacyclobut-3-yl)hex-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 7 (31 mg, yield: 15.7%). 1 H NMR(400MHz, CDCl3)δ=3.77(ddd,J=22.1,14.6,7.8,3H),3.66–3.56(m,3H),2.48(dd,J=12.9,6.7,1H),2.17–2.08(m,1H),2.01–1.95(m,1H), 1.87–1.68(m,7H),1.66–1.45(m,10H),1.42–1.36(m,3H),1.15–1.07(m ,3H),1.06–0.95(m,3H),0.93(d,J=6.4,3H),0.84(s,3H),0.67(s,3H). 19 F NMR(376MHz, CDCl3)δ-88.96,-88.59,-110.84,-111.47LC-MS:[M+Na] + :491.3.

[0257] Example 10, 48 & 67

[0258] Preparation of compound 10 3-[(4R)-4-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-4,4-difluoro-7-hydroxy-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentyl]oxetane-3-ol

[0259] Compound 48 contains 3-[(4R)-4-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-4,4-difluoro-7-hydroxy-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pent-1-ynyl]oxetanebut-3-ol and

[0260] Preparation of compound 67 3-[(4R)-4-[(1R,3aR,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-tetradecanohydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentan-1-ynyl]oxetanebut-3-ol

[0261] Step 1 is similar to Step 5A of Example 1, except that compound 43-1 is replaced with 6-0 to obtain (3R)-3-[(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-tetradecano-1H-cyclopenta[1,2-a]phenanthrene-1-yl]butanal 10-1, which is then directly added to the next step.

[0262] In step 2, 10⁻¹ (3 g, 8.71 mmol) was added to a reaction flask containing methanol (30 mL) and dichloromethane (10 mL). Sodium borohydride (19 mg, 0.49 mmol) was slowly added at 0 °C. The reaction was stirred at room temperature (25 °C) for 1 h. TLC monitoring showed that the starting material had reacted completely and a new spot appeared. Water (20 mL) was added for dilution, followed by dichloromethane (20 mL × 3). The mixture was extracted three times, washed with sodium chloride, and dried over anhydrous sodium sulfate. The reaction solution was then vortexed under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate = 80:20) to obtain (20R)-21-(hydroxymethyl)-20-methylpregn-6(5)-en-3β-ol 10⁻² (1.3 g, yield 38.8%) as a white solid. 1H NMR (400MHz, CDCl3) δ5.35 (d, J = 5.4Hz, 1H), 3.69 (m, 2H), 3.52 (m, 1H), 2.27 (m,2H),2.00(m,2H),1.85(dt,J=8.4,3.6Hz,3H),1.73(ddd,J=10.9,8.0,4 .1Hz,1H),1.52(dd,J=11.5,5.4Hz,4H),1.43(m,8H),1.28(m,2H),1.13(dd d,J=19.8,8.9,5.4Hz,3H),1.01(s,3H),0.96(d,J=6.6Hz,3H),0.70(s,3H).

[0263] In step 3, 10⁻² (1.20 g, 3.46 mmol) was added to a reaction flask containing 15 mL of dichloromethane, followed by triethylamine (2.4 mL, 17.31 mmol), 4-dimethylaminopyridine (0.08 g, 0.69 mmol), and acetic anhydride (1 mL, 10.39 mmol). The reaction was stirred at room temperature (25 °C) for 2 h, and TLC monitoring showed that the starting materials had completely reacted. Dilute with water (20 mL), then add dichloromethane (20 mL × 3), extract three times, wash with sodium chloride, dry with anhydrous sodium sulfate, and evaporate the reaction solution to dryness under reduced pressure (water pump, 45 °C). Purify by column chromatography (petroleum ether:ethyl acetate = 80:20) to obtain 10⁻³ (1.30 g, yield 78.5%) of acetic acid-(3R)-3-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecanoic-1H-cyclopenta[1,2-a]phenanthrene-1-yl]butyl ester as a white solid. 1 H NMR (400MHz, CDCl3) δ5.38(d,J=4.4Hz,1H),4.60(m,1H),4.09(m,2H),2.32(d,J=6.9Hz,2H),2.04(d,J=4.2Hz,8H),1.86(d,J=1 0.1Hz, 4H), 1.52 (dd, J = 26.7, 14.3Hz, 8H), 1.32 (m, 2H), 1.15 (d, J = 10.3Hz, 4H), 1.02 (s, 3H), 0.97 (d, J = 6.5Hz, 4H), 0.69 (s, 3H).

[0264] Step 4 is similar to Example 6. Step 5, replacing 6-2 with 10-3, yields acetic acid-(3R)-3-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-4-oxoylide-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecanohydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]butyl ester 10-4 (480 mg, yield 32.2%), a white solid. 1 H NMR (400MHz, CDCl3) δ5.71(d,J=1.5Hz,1H),4.72(m,1H),4.10(m,2H),2.50(m,3H),2.24(t,J=11.1Hz,1H),2.05(d,J=3.7Hz ,6H),1.97(m,3H),1.78(m,2H),1.54(dd,J=15.7,8.0Hz,7H),1.31(m,5H),1.21(s,3H),0.97(d,J=6.6Hz,3H),0.69(s,3H).

[0265] Step 5 is similar to Step 6 of Example 6. Replacing 6-3 with 10-4 yields acetic acid-(3R)-3-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-4-oxoylidenehexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]butyl ester 10-5 (420 mg, 89.6%), which is a white solid. 1 H NMR (400MHz, CDCl3) δ4.67(m,1H),4.09(ddt,J=25.9,18.3,5.4Hz,2H),2.33(dd,J=18.1,7.6Hz,2H),2.22(m,1H),2.04(m,7H),1.94(ddd,J=18.9,14. 2,9.8Hz,3H),1.79(m,2H),1.65(d,J=5.3Hz,1H),1.52(d,J=6.8Hz,8H),1. 26(dd,J=8.6,5.8Hz,2H),1.10(m,7H),0.96(d,J=6.6Hz,3H),0.66(s,3H).

[0266] In step 6, 10⁻⁵ (380 mg, 0.85 mmol) was added to a reaction flask containing diethylaminotrifluoride DAST (2 mL). The reaction was stirred at room temperature (80 °C) for 2 h. TLC monitoring showed that the starting material had reacted completely and a new spot appeared. Saturated sodium bicarbonate aqueous solution (20 mL) was added dropwise at 0 °C, followed by dichloromethane (20 mL × 3). The mixture was extracted three times, washed with sodium chloride, and dried over anhydrous sodium sulfate. The reaction solution was evaporated to dryness under reduced pressure (water pump, 45 °C). The mixture was then purified by column chromatography (petroleum ether: ethyl acetate = 95: 5) to obtain a mixture of 10⁻⁶ and 67⁻¹⁻⁰ (290 mg) as a white solid.

[0267] Compound 10-6: 1 H NMR (400MHz, CDCl3) δ4.10(m,2H),2.04(dd,J=8.1,3.0Hz,6H),1.79(m,6H),1.65(m,2H),1.53(s,8H),1.31(ddd,J= 20.6,10.4,3.6Hz,6H),1.13(d,J=9.4Hz,3H),0.96(d,J=6.5Hz,3H),0.85(d,J=10.7Hz,3H),0.66(d,J=12.1Hz,3H).

[0268] Step 7 is similar to Step 5A of Example 1, where compound 43-1 is replaced with a mixture of 10-6 and 67-1-0 to obtain a mixture of 10-7 and 67-1-1 (150 mg, 63.3%) as a white solid.

[0269] Compound 10-7: 1 H NMR (400MHz, CDCl3) δ3.71 (m, 1H), 3.63 (m, 2H), 1.99 (d, J = 12.6Hz, 1H), 1.90 ( d,J=9.1Hz,1H),1.84(d,J=16.2Hz,2H),1.74(ddd,J=10.8,8.8,4.1Hz,4H),1 .59(dd,J=20.1,10.3Hz,3H),1.48(s,7H),1.31(m,4H),1.14(dd,J=11.5,7.8 Hz, 2H), 0.96 (t, J = 5.4Hz, 3H), 0.83 (d, J = 10.6Hz, 3H), 0.67 (d, J = 11.9Hz, 3H).

[0270] In step 8, 10-7 and 67-1-1 (180 mg, 0.47 mmol) were added to a reaction flask containing dichloromethane (4 mL) and tetrahydrofuran (1 mL). Dys-Martin oxidant (198 mg, 0.47 mmol) was added at 0 °C, and the reaction was stirred at 0 °C for 1 h. TLC monitoring confirmed the reaction was complete. The mixture was diluted with saturated sodium thiosulfate aqueous solution (20 mL), and then dichloromethane (20 mL × 3) was added. Extraction was performed three times, followed by washing with sodium chloride and drying with anhydrous sodium sulfate. The reaction solution was evaporated to dryness under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 85:15) to obtain a mixture of 10-8 and 67-1-2 (110 mg, yield 55.3%) as a colorless oil.

[0271] Compound 10-8: 1 H NMR (400MHz, CDCl3) δ9.76(m,1H),3.63(s,1H),2.48(d,J=16.2Hz,1H),2.18(ddd,J=16.0,9.4,3.3Hz,1H),2.00(m,3H),1.85(s,4H) ,1.75(m,3H),1.35(m,9H),1.25(m,2H),1.17(d,J=8.6Hz,1H),1.02(d,J=6.5Hz,3H),0.84(d,J=10.5Hz,3H),0.71(d,J=12.7Hz,3H).

[0272] In step 9, a mixture of 10⁻⁸ and 67⁻¹⁻² (90 mg, 0.24 mmol) and dimethyl (1-diazo-2-oxomylidenepropyl)phosphonate (73 mg, 0.38 mmol) were added to a reaction flask containing methanol (2 mL) and dichloromethane (0.5 mL), followed by potassium carbonate (97 mg, 0.71 mmol). The reaction was stirred at room temperature (25 °C) for 3 hours. TLC monitoring showed that the starting material had reacted completely and a new spot appeared. Water (20 mL) was added for dilution, followed by dichloromethane (20 mL × 3). The mixture was extracted three times, washed with sodium chloride, and dried over anhydrous sodium sulfate. The reaction solution was then evaporated to dryness under reduced pressure. Column chromatography (petroleum ether:ethyl acetate = 85:15) was used to separate and purify the mixture of 10⁻⁹ and 67⁻¹⁻² (80 mg, yield 80.8%) as a white solid.

[0273] Compound 10-9: 1H NMR (400MHz, CDCl3) δ3.61(m,1H),2.24(dd,J=11.3,8.3Hz,1H),2.06(d,J=10.1Hz,3H),1.94(dd,J=6.1,3.5Hz,1H),1.85(m,3H),1.75 (m,3H),1.59(s,3H),1.29(dt,J=14.3,9.3Hz,9H),1.09(d,J=6.5Hz,3H),1.01(s,2H),0.84(d,J=10.7Hz,3H),0.67(d,J=12.2Hz,3H).

[0274] In step 10, a mixture of 10-9 and 67-1-3 (90 mg, 0.24 mmol) was dissolved in a reaction flask containing tetrahydrofuran (10 mL). Butyllithium (76 mg, 1.19 mmol) was added at -78 °C, and the mixture was stirred for 30 min. Then, oxetane-3-one (171 mg, 2.38 mmol) was added, and the mixture was stirred for another 30 min. TLC monitoring showed that the basic reaction of the starting materials was complete. Water (20 mL) was added for dilution, followed by the addition of ethyl acetate (20 mL × 3). The mixture was extracted three times, washed with sodium chloride, and dried over anhydrous sodium sulfate. The reaction solution was evaporated to dryness under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 80:20) to obtain a mixture of 10-10 and 67-1-4 (80 mg, yield 52.3%) as a white oil.

[0275] Compound 10-10: 1 H NMR (400MHz, CDCl3) δ4.80(d,J=6.5Hz,2H),4.70(d,J=6.5Hz,2H),3.62(dt,J=15.5,5.4Hz,1H),2.32(dd,J=16.7,3.5Hz,1H),2.08(m,2H),1.97( m,1H),1.85(m,3H),1.72(ddd,J=15.7,12.7,5.0Hz,5H),1.61(m,6H),1. 33(s,4H),1.26(s,2H),1.08(d,J=6.6Hz,3H),0.85(s,3H),0.69(s,3H).

[0276] In step 11, a mixture of 10-10 and 67-1-4 (80 mg, 0.18 mmol) was added to a reaction flask containing 4 mL of dichloromethane. Triethylamine (0.1 mL, 0.53 mmol), 4-dimethylaminopyridine (DMAP) (43.38 mg, 0.355 mmol), and benzoyl chloride (0.031 mL, 0.27 mmol) were then added. The reaction was stirred at 40 °C for 2 h. TLC monitoring showed that the reactants had completely reacted and new spots appeared. Water (20 mL) was added for dilution, followed by 3 applications of dichloromethane (20 mL × 3). The mixture was extracted three times, washed with sodium chloride, and dried over anhydrous sodium sulfate. The reaction solution was evaporated to dryness under reduced pressure (water pump, 45 °C). The solution was then purified by column chromatography (petroleum ether:ethyl acetate = 80:20) to obtain a mixture of 10-11 and 67-1 (70 mg, 0.098 mmol, 54.9%) as a white solid.

[0277] Compounds 10-11: 1 H NMR (400MHz, CDCl3) δ8.05(dd,J=16.6,7.2Hz,4H),7.58(d,J=21.5Hz,2H),7.46(dd,J=15.8,7.9Hz,4H),4.96(t,J=5.1Hz,5H),2.28(d,J=3. 4Hz,1H),2.12(m,1H),2.05(s,1H),1.79(m,5H),1.53(s,11H),1.27(dd,J=12.1,4.9Hz,4H),1.06(d,J=6.5Hz,4H),0.90(s,3H),0.66(s,3H).

[0278] Step 12: The mixture of 10-11 and 67-1 (75 mg, 0.11 mmol) was resolved by chiral resolution (instrument: Waters Acquity UPCC, column: Daicel CHIRALPAK IH-3, 3.0*150 mm, 3 μm, mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 70 / 30, flow rate: 1.5 ml / min, column temperature: 37 degrees, retention time: P1: 1.150 min, P2: 1.455 min) to obtain benzoic acid-3-[(4R)-4-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-7-(phenylcarbonyloxy)-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pent-1-ynyl) Oxycyclobutane-3-yl ester 10-11 (56 mg, 67.2%, retention time: 1.15 min) and benzoic acid-3-[(4R)-4-[(1R,3aR,7S,9aS,9bR,11aR)-7-(phenylcarbonyloxy)-4-fluoro-9a,11a-dimethyl-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecanohydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pent-1-ynyl]oxycyclobutane-3-yl ester 67-1 (7 mg, 8.7%, retention time: 1.455 min).

[0279] Compounds 10-11: 1 H NMR(400MHz, CDCl3) δ8.05(m,4H),7.57(dd,J=21.6,7.4Hz,2H),7.45(dt,J=15.5,7.7Hz,4H),4.9 6(t,J=5.1Hz,5H),2.30(dd,J=16.7,3.5Hz,1H),2.11(dd,J=16.9,7.4Hz,1H),1.92(d,J=12.5Hz,1 H),1.80(dd,J=15.3,6.0Hz,4H),1.67(dd,J=16.5,12.3Hz,2H),1.58(d,J=11.0Hz,7H),1.32(d,J =13.2Hz,2H),1.26(t,J=7.1Hz,3H),1.21(m,2H),1.06(d,J=6.6Hz,4H),0.90(s,3H),0.66(s,3H).

[0280] Compound 67-1: 1H NMR (400MHz, CDCl3) δ8.05(dd,J=13.7,7.1Hz,4H),7.57(m,2H),7.45(dt,J=15.2,7.7Hz,4H),4.96(s,5H),2.30(d,J=3.5Hz,1H),2.12(m,1 H),1.97(d,J=10.1Hz,4H),1.87(s,3H),1.58(s,8H),1.27(d,J=11.6Hz,4H),1.18(s,2H),1.07(d,J=6.5Hz,4H),0.87(s,3H),0.63(s,3H).

[0281] Step 12A is similar to Step 5A of Example 5, where compound 43-1 is replaced with 10-11 to obtain 3-[(4R)-4-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-4,4-difluoro-7-hydroxy-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pent-1-ynyl]oxetanebut-3-ol 48 (32 mg, 0.071 mmol, 85.1%) as a white solid. 1 H NMR (400MHz, CDCl3) δ4.80 (d, J = 6.5Hz, 2H), 4.70 (m, 2H), 3.63 (s, 1H), 2.32 (dd, J=16.7,3.5Hz,1H),2.08(dd,J=16.7,7.9Hz,1H),1.97(d,J=12.6Hz,1H),1.86(d ,J=7.5Hz,3H),1.73(d,J=13.3Hz,3H),1.62(d,J=5.1Hz,4H),1.46(d,J=10.7Hz ,3H),1.31(m,6H),1.08(d,J=6.6Hz,3H),1.02(s,2H),0.85(s,3H),0.69(s,3H). 19 F NMR (377MHz, CDCl3) δ-89.01,-89.64,-110.81,-111.44.

[0282] Step 12B is similar to Step 5A of Example 5, except that compound 43-1 is replaced with 67-1 to obtain 3-[(4R)-4-[(1R,3aR,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-tetradecanohydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentan-1-ynyl]oxetanebut-3-ol 67 (3 mg, 0.007 mmol, 44.5%) as a white solid. 1H NMR (400MHz, CDCl3) δ4.81(d,J=6.5Hz,2H),4.70(d,J=6.5Hz,2H),3.60(td,J=11.1,5.5Hz,1H),2.34(dd,J=16.7,3.5Hz,1H),2.03( d,J=15.0Hz,3H),1.91(m,4H),1.80(m,7H),1.43(s,2H),1.33(s,3H),1.28(s,3H),1.09(d,J=6.6Hz,3H),0.82(s,3H),0.66(s,3H). 19 F NMR (377MHz, CDCl3) δ-110.37.

[0283] In step 13, 48 (25 mg, 0.055 mmol) was added to a reaction flask containing ethyl acetate (1 mL) and methanol (0.5 mL), followed by palladium on carbon (5.90 mg, 0.055 mmol). The reaction was stirred at 25 °C for 2 h. TLC monitoring showed that the reaction of the starting material was complete and a new spot appeared. The mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure (water pump, 45 °C). The filtrate was purified by column chromatography (petroleum ether: ethyl acetate = 65:35) to obtain 10 (20 mg, 77.8%) of 3-[(4R)-4-[(1R,3aS,3bR,7S,9aS,9bS,11aR)-4,4-difluoro-7-hydroxy-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentyl]oxetane-3-ol as a white solid. 1 H NMR (400MHz, CDCl3) δ4.57(d,J=6.8Hz,2H),4.51(d,J=6.8Hz,2H),3.62(dd,J=10.6,5.6Hz,1H),1.98(dd,J=9.4,3.5Hz,1H),1.83(dd,J=11.5,6.6 Hz,4H),1.75(m,5H),1.44(m,5H),1.33(s,2H),1.28(s,2H),1.25(s,5H) ,1.05(d,J=37.3Hz,4H),0.93(d,J=6.5Hz,3H),0.85(s,3H),0.67(s,3H). 19 F NMR (377MHz, CDCl3) δ-88.97,-89.60,-110.86,-111.48.

[0284] Example 11

[0285] Preparation of compound 11(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-7-(oxacyclobut-3-yl)hept-2-yl]-9a,11a-dimethylhexadecyl-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0286] In a 50 mL round-bottom flask at room temperature, 3-(bromomethyl)oxetane (368 mg, 0.24 mmol) was dissolved in tetrahydrofuran (5 mL). A 2.5 M solution of n-butyllithium in tetrahydrofuran (0.9 mL, 2.25 mmol) was added at -70 °C, and the mixture was stirred for 0.5 h. Subsequently, a solution of (5R)-5-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-7-hydroxy-9a,11a-dimethylhexadecylhydro-1H-cyclopentano[1,2-a]phenanthrene-1-yl]hexanal 11-1 (100 mg, 0.24 mmol) in tetrahydrofuran (1 mL) was added to the reaction mixture, and the mixture was stirred at -70 °C for 2 h. The reaction was monitored for completeness by TLC (petroleum ether / ethyl acetate = 2:1). After the reaction was completed, water (40 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give a white solid (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-7-(oxacyclobut-3-yl)hept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 11 (40 mL, yield: 27.2%). 1 H NMR (400MHz, CDCl3) δ = 3.84–3.69 (m, 3H), 3.66–3.57 (m, 3H), 2.48 (dt, J = 13.6, 7.0, 1H), 2.17–2.09 (m, 1H), 2.00–1. 95(m,1H),1.89–1.67(m,8H),1.57–1.34(m,12H),1.20–0.96(m,8H),0.91(d,J=6.4,3H),0.84(s,3H),0.66(s,3H). 19 F NMR(376MHz, CDCl3)δ-89.96,-88.59,-110.85,-111.48.LC-MS:[MH]-=481.20

[0287] Example 12

[0288] Preparation of compound 12(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6,7-dimethyloctyl-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0289] Step 1 is similar to Example 1. In Step 1, cyclopropyl magnesium bromide is replaced with isopropyl magnesium chloride to obtain a white solid (7R)-7-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2-methyloctyl-3-ol 12-1 (80 mg, yield: 74.9%). 1 HNMR (400MHz, CDCl3) δ7.68–7.64(m,4H),7.44–7.34(m,6H),3.58(dt,J=9.9,4.7Hz ,1H),3.42–3.25(m,1H),1.93(dd,J=9.6,3.2Hz,1H),1.78(dd,J=20.8,14.8Hz,2H), 1.68–1.58(m,6H),1.52–1.32(m,10H),1.26–1.21(m,7H),1.08(d,J=2.5Hz,2H),1. 04(s,10H),0.90(ddd,J=11.3,6.3,3.8Hz,9H),0.82(s,3H),0.62(d,J=12.1Hz,3H).

[0290] In step 2, at room temperature, 12-1 (100 mg, 0.12 mmol, 1 eq) was dissolved in dichloromethane (5 mL), and Dysmartin oxidant (122 mg, 0.29 mmol, 2 eq) was added with stirring. After 2 hours at room temperature, the reaction was monitored by TLC (petroleum ether: ethyl acetate = 5:1) to ensure complete reaction. Dilute with 100 mL of saturated sodium sulfite at room temperature, extract with ethyl acetate (100 mL × 2), wash the organic phase with saturated brine (50 mL), dry with anhydrous sodium sulfate, and purify by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give a white solid (7R)-7-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2-methyloct-3-one 12-2 (70 mg, yield: 70.2%). 1H NMR (400MHz, CDCl3) δ7.72–7.58(m,4H),7.51–7.29(m,6H),3.66–3.48(m,1H),2. 58(s,1H),2.47–2.28(m,2H),1.93(dt,J=12.9,3.4Hz,1H),1.80(ddd,J=18.1,9. 7,6.1Hz,2H),1.70–1.58(m,6H),1.44(d,J=8.7Hz,6H),1.40–1.26(m,9H),1.24( s,5H),1.08(d,J=6.9Hz,6H),1.03–0.85(m,9H),0.84–0.81(m,3H),0.63(s,3H).

[0291] Step 3 is similar to Step 1 of Example 1, except that cyclopropyl magnesium bromide is replaced with methyl magnesium bromide to obtain crude product 12-3. 12-3 is then separated by SFC (instrument: Waters Acquity UPCC, column: Daicel CHIRALPAK IB). 4.6*250mm, 5um, mobile phase: CO2 / IPA (0.1% DEA) = 70 / 30, flow rate: 2.0ml / min, column temperature: 37℃) yielded (7R)-7-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2,3-dimethyloct-3-ol 12-3 (60mg, yield: 80.7%, retention time: 1.165min). 1 H NMR(400MHz, CDCl3)δ7.66(d,J=7.9Hz,4H),7.43–7.34(m,6H),3.64–3.54(m,1H),1.94(d,J=12.8Hz,1H),1.80(s,2H),1.71–1.60(m,5H),1 .52–1.38(m,12H),1.24(dd,J=25.1,10.3Hz,6H),1.06(d,J=13.8Hz,13H),0.93–0.86(m,10H),0.82(s,3H),0.78–0.71(m,1H),0.64(s,3H).

[0292] Step 4 is similar to step 16A of Example 3. Replacing 3-8 with 12-3 yields a white solid (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6,7-dimethyloctyl-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 12 (40 mg, yield: 92.8%). 1 H NMR(400MHz, CDCl3) δ3.62(dd,J=10.5,5.5Hz,1H),2.04–1.92(m,1H),1.89–1.68(m,7H),1.62–1.54(m,2H),1.50–1.33(m,13H ),1.30–1.21(m,3H),1.15(dd,J=9.2,4.0Hz,1H),1.08(s,3H),1.06–0.96(m,3H),0.94–0.88(m,8H),0.85(s,3H),0.67(s,3H). 19 F NMR (376MHz, CDCl3) δ-88.96,-89.59,-110.84,-111.47.

[0293] Example 13

[0294] Compound 13(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-5-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol and

[0295] In step 11 of the first similar embodiment 3, replacing 3-8 with II-13 yields (5R)-5-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanonitrile 13-1, which can be directly added to the next step.

[0296] In step 2, 13-1 (100 mg, 0.16 mmol, 1 eq) was dissolved in tetrahydrofuran (4 mL), cooled to -78 °C, and then diisopropylaminolithium LDA (1 M n-hexane solution) (0.5 mL, 0.46 mmol, 3 eq) was added. The mixture was stirred for 30 min while maintaining the temperature, and then iodomethane (66 mg, 0.46 mmol, 3 eq) was added. The mixture was stirred for 30 min while maintaining the temperature, and the reaction was monitored by TLC (petroleum ether: ethyl acetate = 5:1) to ensure complete reaction. Quenching was performed at room temperature with 100 mL of saturated ammonium chloride aqueous solution, followed by extraction with ethyl acetate (100 mL × 2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to give a white solid (5R)-5-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2-methylhexanonitrile 13-2 (50 mg, yield: 48.9%) and crude product 19-1. Crude product 19-1 was purified by SFC (instrument: Waters Acquity UPCC, column: Daicel CHIRALPAK IB). 4.6*250mm, 5um, mobile phase: A / B:CO2 / MeOH (0.1% DEA)=70 / 30, flow rate: 2.5ml / min, column temperature: 37℃) was resolved to obtain (5R)-5-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylprop-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2,2-dimethylhexanonitrile 19-1 (10mg, yield: 9.6%, retention time: 0.935min).

[0297] Compound 13-2: 1 HNMR(400MHz, CDCl3)δ7.55(ddd,J=6.3,3.2,1.9Hz,4H),7.32–7.23(m,6H),3.48(s,1H),2.52–2.29(m,1H),1.74(dd,J=25.5,13.9Hz,3H),1.54– 1.45(m,5H),1.36–1.30(m,4H),1.18(dd,J=13.5,6.7Hz,11H),0.99–0.9 1(m,11H),0.84–0.76(m,6H),0.73–0.67(m,4H),0.54(d,J=10.5Hz,3H).

[0298] In step 3, compound 13-2 (140 mg, 0.21 mmol, 1 eq) was added to dichloromethane (4 mL), cooled to -78 °C, and then diisobutylaluminum hydride DABAL-H (1 M n-hexane solution) was added. The mixture was stirred for 30 minutes while maintaining the temperature, and the reaction was monitored by TLC (petroleum ether: ethyl acetate = 5:1) to ensure complete reaction. Quenching was performed at room temperature with 100 mL of saturated ammonium chloride aqueous solution, followed by extraction with ethyl acetate (100 mL × 2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to give a white solid (5R)-5-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2-methylhexanal 13-3 (70 mL, yield: 49.7%). 1 H NMR (400MHz, CDCl3) δ9.60–9.44(m,1H),7.58(d,J=6.3Hz,4H),7.32(dt,J=13. 9,6.1Hz,6H),3.57–3.46(m,1H),2.19(s,1H),1.85(d,J=12.5Hz,1H),1.73(d,J =7.4Hz,3H),1.56(d,J=6.6Hz,4H),1.44–1.35(m,5H),1.25(d,J=7.2Hz,3H),1 .20(d,J=12.0Hz,6H),0.98(d,J=8.1Hz,12H),0.85–0.74(m,10H),0.56(s,3H).

[0299] Step 4 is similar to Step 1 of Example 1, where cyclopropyl magnesium bromide is replaced with methyl magnesium bromide to obtain a white solid (6R)-6-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-3-methylhept-2-ol 13-4 (25 mg, yield: 48.8%). 1H NMR (400MHz, CDCl3) δ7.75–7.59(m,4H),7.50–7.31(m,6H),3.59(s,2H),1.96 –1.90(m,1H),1.86–1.77(m,2H),1.68–1.53(m,8H),1.45(dd,J=17.9,9.6Hz,5 H),1.38–1.25(m,9H),1.12(dd,J=14.2,6.2Hz,4H),1.04(s,9H),0.88(ddd,J =11.1,6.0,3.7Hz,6H),0.83(d,J=4.3Hz,3H),0.79–0.74(m,1H),0.63(s,3H).

[0300] Step 5 is similar to Step 16A of Example 3, except that 3-8 is replaced with 13-4 to obtain a white solid (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-5-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 13 (10 mg yield: 77.1%). 1 H NMR (400MHz, CDCl3) δ3.79–3.54(m,2H),1.98(dd,J=12.7,3.0Hz,1H),1.88–1.69(m,6H),1.64–1.56(m,2H),1.47(d,J=13.4Hz,7H ),1.38–1.28(m,6H),1.17–1.10(m,5H),1.05–0.95(m,3H),0.92(dd,J=6.5,3.8Hz,3H),0.89–0.81(m,6H),0.65(d,J=11.7Hz,3H). 19 F NMR (376MHz, CDCl3) δ-88.96,-89.59,-110.85,-111.48.

[0301] Examples 14, 15 & 24

[0302] Compound 14(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-1-[(2R)-7,7-difluoro-6-hydroxy-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol,

[0303] Compound 15 or 24(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-1-[(2R,6S)-7,7-difluoro-6-hydroxy-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0304] Preparation of compounds 24 or 15(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-1-[(2R,6R)-7,7-difluoro-6-hydroxy-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0305] Step 1: At room temperature, dissolve II (200 mg, 0.30 mmol) and cesium fluoride (23.41 mg, 0.15 mmol) in N,N-dimethylformamide solution (5 mL). Under nitrogen protection, add (difluoromethyl)trimethylsilane (191.39 mg, 1.54 mmol). Stir the reaction mixture at room temperature for 3 hours. Monitor the reaction for completeness by TLC (petroleum ether:ethyl acetate = 5:1). Add tetrabutylammonium fluoride solution (1.54 mL, 1.54 mmol) to the system and continue stirring for 30 minutes. Monitor the reaction progress again by TLC (petroleum ether:ethyl acetate = 5:1). When a large polar point is formed, stop the reaction. Quench the reaction with water (10 mL), extract with ethyl acetate (10 mL × 3), collect the organic phase, dry with anhydrous sodium sulfate, and evaporate the organic phase under vacuum to obtain the crude product. The crude product was separated and purified by rapid chromatography (petroleum ether: ethyl acetate = 85:15) to give the product (6R)-6-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1,1-difluorohept-2-ol 14-1 (150 mg, 0.21 mmol, 69.43%). 1HNMR (400MHz, CDCl3) δ7.68–7.64(m,4H),7.41–7.35(m,6H),5.60(d,J=4.2Hz,1H),3.80–3.67(m,1H),3.64–3.53(m,1H),1.95–1.90(m,1H),1 .81(d,J=7.6Hz,2H),1.66–1.57(m,9H),1.46–1.36(m,7H),1.27(d,J=1 2.3Hz,6H),1.04(s,11H),0.93–0.88(m,4H),0.82(s,3H),0.64(s,3H). 19 F NMR(376MHz, CDCl3)δ-88.83,-89.46,-110.87,-111.49,-129.71,-129.76,-129.80

[0306] Step 2 is similar to Example 12. In Step 2, compound 12-1 is replaced with 14-1 to obtain product (6R)-6-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1,1-difluoroheptane-2-one 14-2 (185 mg, 92.77%). 1 HNMR(400MHz, CDCl3)δ7.71–7.62(m,4H),7.45–7.30(m,6H),5.66(t,J=54.1Hz,1H),3.65– 3.52(m,1H),2.61(d,J=6.7Hz,2H),1.93(dt,J=12.7,3.3Hz,1H),1.80(d,J=7.5Hz,1H),1. 66(ddd,J=14.4,11.2,5.0Hz,4H),1.58–1.48(m,5H),1.42–1.32(m,4H),1.30–1.19(m,8H) ,1.10–1.00(m,12H),0.92(t,J=5.6Hz,3H),0.81(d,J=12.2Hz,3H),0.62(d,J=12.3Hz,3H). 19 F NMR(376MHz, CDCl3)δ-88.84,-89.47,-110.86,-111.49,-126.93

[0307] Step 3 is similar to Step 1 of Example 1, where cyclopropyl magnesium bromide is replaced with methyl magnesium bromide to obtain a white solid product (6R)-6-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1,1-difluoro-2-methylhept-2-ol 14-3 (80 mg, 74.29%). 1 HNMR (400MHz, CDCl3) δ7.66 (ddd, J=6.3, 3.4, 2.0Hz, 4H), 7.38 (tdd, J=8.1, 6.1, 1.9Hz,6H),5.53(s,1H),3.67–3.52(m,1H),1.92(s,1H),1.80(d,J=7.4Hz,2H), 1.61(dt,J=28.5,9.0Hz,8H),1.51–1.36(m,8H),1.29–1.17(m,9H),1.06(d,J=1 2.1Hz,12H),0.94–0.87(m,4H),0.81(d,J=12.1Hz,3H),0.62(d,J=12.2Hz,3H). 19 F NMR(376MHz, CDCl3)δ-88.83,-89.46,-110.87,-111.50,-131.04,-131.12,-131.77,-131.86,-132.92,-133.02,-133.66,-133.76

[0308] In step 4, compound 14-3 (100 mg, 0.14 mmol) was purified by SFC (resolution method: instrument: Waters Acquity UPCC; column: Daicel CHIRALPAK IF_3, 3.0*150 mm, 3 μm; flow rate: A / B: CO2 / MeOH (0.1% DEA) = 50 / 50; flow rate: 1.5 ml / min; column temperature: 37 degrees) to obtain 24-1 (30 mg, 30.00%, Rt = 1.155 min) and 15-1 (30 mg, 30.00%, Rt = 1.663 min).

[0309] Compound 24-1: 1HNMR (400MHz, CDCl3) δ7.70–7.62(m,4H),7.45–7.33(m,6H),5.53(t,J=56.7Hz,1H),3.59(td,J=10.5,5.2Hz,1H),1.97–1.90(m,1H),1.79(s,1H) ,1.69–1.59(m,5H),1.55–1.33(m,12H),1.27–1.18(m,7H),1.06(d,J=13 .7Hz,12H),0.90(t,J=6.5Hz,4H),0.82(s,3H),0.77(s,1H),0.64(s,3H). 19 FNMR(377MHz, CDCl3)δ-88.84,-89.47,-110.87,-111.50,-131.13,-131.87,-132.93,-133.67

[0310] Compound 15-1: 1 HNMR (400MHz, CDCl3) δ7.70–7.62(m,4H),7.45–7.33(m,6H),5.53(s,1H),3.63–3.52(m,1H),1.93(d,J=12.7Hz,1H),1.86–1.77(m,2H),1.6 3(d,J=10.8Hz,5H),1.51–1.37(m,9H),1.30–1.20(m,9H),1.06(d,J=14.2Hz,13H),0.94–0.86(m,4H),0.82(s,3H),0.62(d,J=12.3Hz,3H). 19 F NMR (377MHz, CDCl3) δ-88.83,-89.46,-110.87,-111.50,-131.01,-131.77,-133.03,-133.77.

[0311] Step 5A, similar to Step 16A of Example 3, replaces 3-8 with 14-3 to obtain (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-1-[(2R)-7,7-difluoro-6-hydroxy-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 14 (5 mg, yield 71.26%). 1H NMR (400MHz, CDCl3) δ5.54(s,1H),3.71–3.54(m,1H),2.04–1.94(m,1H),1.83(d,J=7.8Hz,3H),1.78–1.61(m,4H),1.53–1.36( m,9H),1.36–1.22(m,9H),1.17–1.05(m,3H),0.97(dd,J=30.5,5.2Hz,5H),0.83(d,J=10.4Hz,3H),0.65(d,J=12.0Hz,3H).19F NMR(376MHz, CDCl3)δ-88.96,-89.59,-110.86,-111.49,-131.02,-131.11,-131.76,-131.85,-132.91,-133.01,-133.75.LC-MS: [MH] - =475.35

[0312] Step 5B is similar to Step 16A of Example 3, except that 3-8 is replaced with 24-1 to obtain white solid compound 24 (13 mg, yield 68.27%). 1 H NMR(400MHz, CDCl3)δ5.47(t,J=56.7Hz,1H),3.61–3.50(m,1H),1.92(dt,J=12.7,3.3Hz,1H),1.85–1.73(m,3H),1.71–1.62(m,3H),1.60–1.50 (m,3H),1.39(ddd,J=11.1,9.8,6.7Hz,5H),1.32–1.21(m,6H),1.16(s, 5H),1.10–0.92(m,5H),0.86(d,J=6.5Hz,3H),0.78(s,3H),0.60(s,3H). 19 F NMR (377MHz, CDCl3)δ-88.97,-89.60,-110.85,-111.48,-131.11,-131.87,-132.91,-133.65.LC-MS: [MH] - =475.55

[0313] Step 5c is similar to step 16A of Example 3, except that 3-8 is replaced with 15-1 to obtain compound 15 (12 mg, purity 99.55%, yield 63.02%). 1H NMR (400MHz, CDCl3) δ5.54(t,J=56.7Hz,1H),3.62(dd,J=10.5,5.5Hz,1H),1.98(dt ,J=12.6,3.3Hz,1H),1.85(dd,J=9.4,5.8Hz,3H),1.78–1.63(m,4H),1.55(dd,J=8. 9,5.3Hz,4H),1.50–1.41(m,5H),1.38–1.29(m,4H),1.26(dd,J=12.2,6.4Hz,6H),1 .17–0.97(m,4H),0.99–0.91(m,3H),0.83(d,J=10.6Hz,3H),0.65(d,J=11.9Hz,3H). 19 F NMR(377MHz, CDCl3)δ-88.97,-89.60,-110.85,-111.48,-131.02,-131.78,-133.01,-133.78.LC-MS: [MH] - =475.45

[0314] Examples 16 & 17

[0315] Compound 16 or 17(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(2R,6S)-7,7,7-trifluoro-6-hydroxy-6-methylhept-2-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0316] Preparation of compounds 17 or 16(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(2R,6R)-7,7,7-trifluoro-6-hydroxy-6-methylhept-2-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0317] Step 1 is similar to Example 1. In Step 1, cyclopropyl magnesium bromide is replaced with methyl magnesium bromide to obtain (6R)-6-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hepta-2-ol 16-1 (132 mg, 0.17 mmol, yield: 66.4%), which is a white solid. 1HNMR(400MHz, CDCl3)δ7.68–7.63(m,4H),7.42–7.33(m,6H),3.78(d,J=5.9Hz ,1H),3.58(ddd,J=15.1,10.3,4.8Hz,1H),1.93(d,J=12.8Hz,1H),1.86–1.72 (m,3H),1.68–1.50(m,7H),1.45(s,7H),1.40–1.23(m,10H),1.18(d,J=6.2Hz ,3H),1.04(s,9H),0.90(d,J=6.5Hz,3H),0.82(s,3H),0.62(d,J=12.1Hz,3H). 19 F NMR(377MHz, CDCl3)δ-88.83,-89.46,-110.87,-111.49

[0318] Step 2 is similar to Example 12. In Step 2, compound 12-1 is replaced with 16-1 to obtain (6R)-6-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hepta-2-one 16-2 (100 mg, yield: 60.9%) as a white solid. 1 HNMR (400MHz, CDCl3) δ7.69–7.60(m,4H),7.45–7.32(m,6H),3.59(td,J=10.5,5. 4Hz,1H),2.37(dd,J=14.9,7.1Hz,2H),2.12(s,3H),1.92(d,J=12.7Hz,1H),1.80 (d,J=7.1Hz,3H),1.68–1.57(m,5H),1.54(s,3H),1.51–1.30(m,10H),1.28–1.19 (m,4H),1.04(s,9H),0.91(t,J=5.6Hz,3H),0.82(s,3H),0.62(d,J=12.3Hz,3H). 19 F NMR (377MHz, CDCl3) δ-88.84,-89.47,-110.86,-111.49.

[0319] In step 3, 16-2 (140 mg, 0.21 mmol) was dissolved in tetrahydrofuran (5 mL), and cesium fluoride (3.2 mg, 0.021 mmol) and (trifluoromethyl)trimethylsilane (150 mg, 1.06 mmol) were added. The mixture was stirred for 30 minutes, and the reaction was monitored by TLC (petroleum ether / ethyl acetate = 5 / 1) until complete. Then, tetrabutylammonium fluoride (TBAF) (1 mL, 1.000 mmol) was added, and the mixture was stirred for another 30 minutes. The small polarity points disappeared when the reaction mixture was monitored by TLC (petroleum ether / ethyl acetate = 5 / 1). Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3), dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was purified by rapid chromatography (petroleum ether / ethyl acetate = 0-15%) to give (6R)-6-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylprop-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1,1,1-trifluoro-2-methylhept-2-ol 16-3 (110 mg, yield: 60.4%) as a white solid. 1 HNMR (400MHz, CDCl3) δ7.69–7.63(m,4H),7.45–7.33(m,6H),3.67–3.52(m,1H),1.93(d,J=12.9Hz,1H),1.66(ddd,J=38.1,23.8,7.6Hz,9H),1.55 –1.37(m,10H),1.31(d,J=24.7Hz,7H),1.14(d,J=58.0Hz,4H),1.04(s,9 H), 0.91 (d, J = 6.4Hz, 3H), 0.81 (d, J = 12.1Hz, 3H), 0.62 (d, J = 12.3Hz, 3H). 19 F NMR(376MHz, CDCl3)δ-83.04,-83.13,-88.84,-89.47,-110.87,-111.50.

[0320] In step 4, compound 16-3 (110 mg, 0.16 mmol) was resolved by SFC (instrument: Waters Acquity UPCC; column model: Daicel CHIRALPAK IG_3, 3.0*150 mm, 3 μm; mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 90 / 10; flow rate: 2.0 ml / min; column temperature: 37 degrees) to obtain 16-4 (40 mg, 32.00%, retention time 2.582 min) as a white solid and 17-1 (40 mg, 32.0%, retention time 3.657 min) as a white solid.

[0321] Step 5A is similar to Step 16A of Example 3, except that 3-8 is replaced with 16-4 to obtain white solid compound 16 (23 mg, 0.046 mmol, purity: 85%, yield: 83.9%). 1 HNMR (400MHz, CDCl3) δ3.70–3.57(m,1H),1.99(dd,J=9.4,3.4Hz,1H),1.84(d,J=8.2Hz,3H),1.75–1.69(m,2H),1.59(dd,J=17.7,7.6Hz ,10H),1.47–1.39(m,4H),1.34(s,3H),1.28(dd,J=12.0,5.2Hz,3H),1.16–0.97(m,5H),0.94(d,J=6.5Hz,3H),0.85(s,3H),0.67(s,3H). 19 F NMR(376MHz, CDCl3)δ-83.11,-88.97,-89.61,-110.86,-111.49.

[0322] Step 5B is similar to Step 16A of Example 3, except that 3-8 is replaced with 17-1 to obtain white solid compound 17 (23 mg, 0.046 mmol, purity: 85%, yield: 85.0%). 1 HNMR(400MHz, CDCl3)δ3.63(d,J=5.0Hz,1H),1.99(dd,J=9.4,3.4Hz,1H),1.88–1.80(m,3H),1.71(ddd,J=16.2,9.7,3.9Hz,4H),1.63–1.5 2(m,7H),1.43(dd,J=15.6,9.2Hz,5H),1.35(s,3H),1.32–1.24(m,3H),1.16–0.97(m,5H),0.94(d,J=6.5Hz,3H),0.84(s,3H),0.66(s,3H). 19F NMR(376MHz, CDCl3)δ-83.02,-88.97,-89.60,-110.86,-111.49.

[0323] Example 18

[0324] Preparation of compound 18(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2S)-1-[(2-hydroxy-2-methylpropyl)oxy]propyl-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0325] Step 1: Dissolve 10⁻³ (3.30 g, 7.92 mmol) in chloroform (35 mL), and add N-methylmorpholine (2.40 g, 23.76 mmol) and selenium dioxide (2.40 g, 21.60 mmol). Stir the mixture at 75 °C for 24 hours. Monitor the reaction by TLC (petroleum ether / ethyl acetate = 5 / 1) until complete. Add saturated sodium bicarbonate aqueous solution (10 mL) to the reaction mixture, extract with dichloromethane (10 mL x 3), dry the organic phase with anhydrous sodium sulfate, and evaporate to dryness. The crude product was purified by rapid chromatography (petroleum ether / ethyl acetate = 0-20%) to give acetic acid-(2S)-2-[(1R,3aS,3bS,6R,7S,9aR,9bS,11aS)-7-acetoxy-6-hydroxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecanohydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]propyl ester 18-1 (1.9 g, yield: 47.1%) as a white solid. 1 HNMR 1HNMR (400MHz, CDCl3) δ5.75–5.65(m,1H),4.78–4.67(m,1H),4.25(d,J=2.5Hz,1H),4.07(dd,J=1 0.7,3.4Hz,1H),3.78(dd,J=10.7,7.5Hz,1H),2.10(s,3H),2.10–2.07(m,1H),2.05(s,3H),2.04– 1.98(m,1H),1.90–1.79(m,2H),1.74–1.53(m,7H),1.51–1.43(m,2H),1.39–1.29(m,1H),1.22(s, 3H),1.21–1.05(m,4H),1.02(d,J=6.6Hz,3H),0.95(dd,J=16.4,5.9Hz,1H),0.70(d,J=4.9Hz,3H).

[0326] Step 2 is similar to Example 10. Step 3 replaces 10-2 with 18-1 to obtain acetic acid-(2S)-2-[(1R,3aS,3bS,6R,7S,9aR,9bS,11aS)-6,7-diacetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecanoyl-1H-cyclopenta[1,2-a]phenanthrene-1-yl]propyl ester 18-2 (1.8 g, 3.22 mmol, purity: 85%, yield: 73.39%) as a white solid. 1 HNMR (400MHz, CDCl3) δ5.81(d,J=3.0Hz,1H),5.50(d,J=2.6Hz,1H),4.74(dt,J=12.3,3.9Hz,1H),4.07(dd,J=10.7,3 .3Hz,1H),3.78(dd,J=10.7,7.5Hz,1H),2.13–2.08(m,1H),2.06(d,J=5.1Hz,6H),2.01(s,3H),1.98(d,J=2.9Hz,1H) ,1.92–1.87(m,1H),1.85–1.78(m,1H),1.75–1.58(m,4H),1.56–1.45(m,5H),1.32(dd,J=17.0,6.8Hz,1H),1.20(dd, J=18.7,8.2Hz,3H),1.13(s,3H),1.11–1.04(m,1H),1.02(d,J=6.6Hz,3H),0.93(dd,J=10.7,6.0Hz,1H),0.70(s,3H).

[0327] Step 3 is similar to Step 5 of Example 6, except that 6-2 is replaced with 18-2 to obtain white solid acetic acid-(2S)-2-[(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-7-acetoxy-6-hydroxy-9a,11a-dimethyl-4-oxoylide-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecanohydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]propyl ester 18-3 (500 mg, yield 38.75%). 1H NMR (400MHz, CDCl3) δ5.93 (s, 1H), 5.61 (d, J = 2.3Hz, 1H), 4.80 (dt, J = 7.8, 4.2Hz, 1H),4.09(m,1H),3.79(dd,J=10.7,7.4Hz,1H),2.40(dd,J=7.9,3.9Hz,1H),2.30 (t,J=11.1Hz,1H),2.05(m,13H),1.80(m,4H),1.58(m,3H),1.37(dd,J=10.9,7.2 Hz, 2H), 1.33 (s, 4H), 1.22 (ddd, J = 29.5, 17.0, 8.4Hz, 4H), 1.03 (t, J = 6.1Hz, 3H).

[0328] Step 4 is similar to Step 6 of Example 6, except that 6-3 is replaced with 18-3 to obtain white solid acetic acid-(2S)-2-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6,7-diacetoxy-9a,11a-dimethyl-4-oxoylidenehexadecyl-1H-cyclopenta[1,2-a]phenanthrene-1-yl]propyl ester 18-4 (200 mg, yield 44.80%). 1 H NMR(400MHz,)δ6.63(s,1H),6.52(d,J=3.7Hz,1H),6.30(dd,J=3.2,1.0Hz,1H),6.2 1(dd,J=3.2,2.2Hz,1H),5.81(dt,J=6.8,3.7Hz,2H),5.71(d,J=1.4Hz,3H),5.70(m ,4H),5.68(m,5H),5.65(m,3H),5.60(ddd,J=4.2,3.4,0.9Hz,3H),5.54(d,J=1.9Hz ,6H),5.45(m,6H),5.38(d,J=2.0Hz,3H),5.35(dd,J=2.6,1.5Hz,1H),5.28(s,3H).

[0329] Step 5 is similar to Step 9 of Example 3, except that 3-1 is replaced with 18-4 to obtain the product acetic acid-(2S)-2-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6,7-diacetoxy-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]propyl ester 18-5 (300 mg, yield 64.60%), which is a white solid. 1H NMR (400MHz, CDCl3) δ5.21 (s, 1H), 4.80 (m, 1H), 4.09 (m, 1H), 3.78 (dd, J = 10.7, 7.4Hz, 1H), 2.11 (d, J = 9.3Hz, 3H), 2.04(m,3H),1.98(d,J=2.0Hz,3H),1.85(m,6H),1.70(m,4H),1.50(m,3H),1.23(m,7H),1.03(m,6H),0.66(m,3H).

[0330] Step 6 is similar to Step 5A of Example 1, except that compound 43-1 is replaced with 18-5 to obtain a white solid (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2S)-1-hydroxypropyl-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 18-6 (150 mg, yield 59.68%). 1 H NMR (400MHz, CDCl3) δ3.74(s,1H),3.62(ddd,J=14.8,11.0,3.3Hz,2H),3.37(dd,J=10.5,6.9Hz,1H),2.20(dd,J=28.0,6.9Hz,1H),1.98(d,J=1 2.4Hz,1H),1.77(ddd,J=28.7,15.8,5.7Hz,7H),1.31(d,J=19.4Hz,6H),1.25(s,2H),1.06(m,6H),0.97(dd,J=31.9,18.9Hz,3H),0.69(s,3H).

[0331] In step 7, compound 18-6 (150 mg, 0.39 mmol) was dissolved in acetone (5 mL), a small amount of 4A molecular sieve was added, and the reaction was carried out at room temperature for 1 hour. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 1:1). The TLC showed that the reactants had basically reacted completely. The reaction solution was quenched with saturated sodium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 80:20) to give a white solid (2S)-2-[(3aS,5a R,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-hexadecylhydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxane-8-yl]prop-1-ol 18-7 (110 mg, yield 59.80%).

[0332] Step 8 is similar to Example 3. In Step 8, 3-0 is replaced with 18-7 to obtain {[(2S)-2-[(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-hexadecylhydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxane-8-yl]propyl]oxy}acetate-2-methylpropyl-2-yl ester 18-8 (60 mg, yield 35.50%), which is a white solid.

[0333] Step 9 is similar to Step 1 of Example 1. Cyclopropyl magnesium bromide is replaced with methyl magnesium bromide to obtain a crude white solid 1-{[(2S)-2-[(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-hexadecylhydro-3aH-cyclopenta[1',2':1,2]phenanthrene[7,8-d][1,3]dioxacyclopenta-8-yl]propyl]oxy}-2-methylprop-2-ol 18-9 (40 mg, yield 65.03%).

[0334] In step 10, compound 18-9 (40 mg, 0.08 mmol) was dissolved in tetrahydrofuran (5 mL), and dilute hydrochloric acid (0.5 mL, 1.50 mmol) was added at room temperature. The reaction was carried out for 2 hours, and the reaction was monitored by TLC (petroleum ether: ethyl acetate = 3:1) until completion. The reaction solution was quenched with saturated sodium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 80:20) to give a white solid (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2S)-1-[(2-hydroxy-2-methylpropyl)oxy]propyl-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 18 (33 mg, 0.07 mmol, yield 86.01%). 1 H NMR (400MHz, DMSO) δ4.39(d,J=6.0Hz,1H),4.23(d,J=4.0Hz,2H),3.49(d,J=2.5Hz,1H),3.35(d,J=3.5Hz,2H),3.13(d,J=8.9Hz,2H),3.02(d,J=8.9Hz ,1H),2.05(m,2H),1.63(m,8H),1.43(dd,J=9.1,3.2Hz,2H),1.27(m,5H),1 .13(m,1H),1.06(s,6H),0.98(m,6H),0.88(t,J=10.1Hz,2H),0.64(s,3H). 19 F NMR(376MHz, DMSO)δ-86.68,-87.30,-108.56,-109.26.

[0335] Example 20

[0336] Preparation of compound 20(8R)-8-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-7-hydroxy-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2,4-dimethylnon-2,4-diol

[0337] Step 1: At room temperature, II-15 (100 mg, 0.15 mmol, 1.0 eq) was dissolved in methanol (2 mL), and lithium hydroxide (35 mg, 1.4 mmol, 10 eq) was added with stirring. After 5 hours at room temperature, the reaction was completed by TLC (petroleum ether: ethyl acetate = 2:1). The pH was adjusted to acidic by adding 3N hydrochloric acid aqueous solution at room temperature, and ethyl acetate (100 mL × 2) was added for extraction. The organic phase was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate to give a white solid (5R)-5-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoate methyl 20-0 (90 mg, yield: 83%).

[0338] In step 2, at room temperature, magnesium chloride (122 mg, 0.6 mmol, 2 eq), potassium monoethyl malonate (102 mg, 0.6 mmol, 2 eq), and tetrahydrofuran (5 mL) were added sequentially to a 50 mL three-necked flask. Under nitrogen protection, the mixture was heated in a 65 °C oil bath for 3 hours and then cooled to room temperature. In another 50 mL three-necked flask, 20-O (200 mg, 0.3 mmol, 1 eq), carbonyl diimidazole (CDI) (73 mg, 0.5 mmol, 1.5 eq), and tetrahydrofuran (5.0 mL) were added sequentially. The mixture was stirred at room temperature for 30 min, and then heated and stirred in a 40 °C oil bath for 30 min. The above solution was cooled to room temperature and slowly added dropwise to the first reaction solution. The mixture was stirred at room temperature for 16 h. The reaction was monitored for completion by TLC (petroleum ether: ethyl acetate = 2:1). Add 20 mL of water, extract with ethyl acetate (20 mL x 2), filter to recover the suspended solids (raw material), combine the organic phases and wash with saturated brine (20 mL), dry with anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Separate by column chromatography (4 g, 0-30% ethyl acetate / petroleum ether, 20 mL / min) and prepare a white solid (7R)-7-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-3-oxylidene octanoate ethyl ester 20-1 (150 mg, yield: 68%). 1H NMR (400MHz, CDCl3) δ7.66 (m, 4H), 7.38 (m, 6H), 4.19 (q, J = 7.1Hz, 2H), 3.59 ( dq,J=15.5,5.1Hz,1H),3.41(s,2H),2.48(m,2H),1.92(dd,J=9.6,3.2Hz,1H) ,1.79(d,J=7.2Hz,2H),1.62(m,6H),1.42(m,9H),1.24(dd,J=10.6,5.1Hz,6H ),1.06(d,J=12.1Hz,12H),0.89(m,4H),0.79(m,4H),0.61(d,J=12.3Hz,3H).

[0339] In step 3, at room temperature, 20-1 (150 mg, 0.2 mmol, 1.0 eq) was dissolved in methanol (2 mL), and sodium borohydride (20 mg, 0.5 mmol, 2.5 eq) was added with stirring. After 10 min at room temperature, the reaction was monitored by TLC (petroleum ether: ethyl acetate = 5:1) to ensure complete reaction. Quenching was performed at room temperature with 100 mL of saturated sodium sulfite aqueous solution, followed by extraction with ethyl acetate (100 mL × 2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give a white solid (7R)-7-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-3-hydroxyoctanoic acid ethyl ester 20-2 (110 mg, yield: 73%). 1 H NMR (400MHz, CDCl3) δ7.70–7.58(m,4H),7.44–7.33(m,6H),4.17(q,J=7.1Hz,2H),4.02–3.93( m,1H),3.59(td,J=10.4,5.2Hz,1H),2.44(ddd,J=10.8,6.0,1.8Hz,2H),1.93(d,J=12.8Hz,1H ),1.79(s,2H),1.68–1.56(m,6H),1.50–1.40(m,6H),1.38–1.31(m,4H),1.26(ddd,J=20.1,11 .4,7.5Hz,9H),1.04(s,11H),0.89(d,J=6.5Hz,3H),0.83–0.76(m,4H),0.62(d,J=12.1Hz,3H).

[0340] In step 4, at room temperature, 20-2 (50 mg, 0.06 mmol, 1.0 eq) was dissolved in tetrahydrofuran (2 mL), and methyl magnesium bromide (3 N in THF) (0.2 mL, 0.6 mmol, 10 eq) was added with stirring. After one hour at room temperature, the reaction was monitored by TLC (petroleum ether: ethyl acetate = 5:1) to ensure complete reaction. Quenching was performed at room temperature with 100 mL of saturated sodium sulfite aqueous solution, followed by extraction with ethyl acetate (100 mL × 2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give a white solid (8R)-8-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2-methylnonan-2,4-diol 20-3 (40 mg, yield: 80%). 1 H NMR (400MHz, CDCl3) δ7.66(d,J=6.5Hz,4H),7.44–7.34(m,6H),3.99(s,1H),3.59(s,1H),1.93(d,J=12.7Hz,1H),1.74(s,10H),1.63(dd,J=16.8,7. 7Hz, 4H), 1.44 (dd, J=22.8, 13.7Hz, 9H), 1.27 (t, J=5.7Hz, 8H), 1.06 (d, J= 14.8Hz,11H),0.90(d,J=6.2Hz,4H),0.79(d,J=21.2Hz,4H),0.63(s,3H).

[0341] In step 5, at room temperature, 20-3 (40 mg, 0.056 mmol, 1.0 eq) was dissolved in tetrahydrofuran (2 mL), and Desmartin oxidant (59 mg, 0.14 mmol, 2.5 eq) was added with stirring. After one hour at room temperature, the reaction was monitored by TLC (petroleum ether: ethyl acetate = 5:1) to ensure complete reaction. Quenching was performed at room temperature with 100 mL of saturated sodium sulfite aqueous solution, followed by extraction with ethyl acetate (100 mL × 2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give a white solid (8R)-8-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2-hydroxy-2-methylnon-4-one 20-4 (30 mg, yield: 75.2%). 1H NMR (400MHz, CDCl3) δ7.62–7.57(m,4H),7.37–7.27(m,6H),3.51(dt,J=15.5,5.2Hz ,1H),2.51(s,2H),2.35–2.21(m,2H),1.88–1.82(m,1H),1.72(d,J=7.7Hz,2H),1.55 (dd,J=18.3,12.0Hz,6H),1.43–1.35(m,4H),1.33–1.24(m,4H),1.20–1.16(m,10H), 0.99(d,J=13.2Hz,12H),0.83(t,J=6.9Hz,4H),0.72(d,J=21.1Hz,4H),0.56(s,3H).

[0342] In step 6, at room temperature, 20-4 (30 mg, 0.03 mmol, 1.0 eq) was dissolved in tetrahydrofuran (1 mL), and methyl magnesium bromide (3.0 M IN THF) (0.14 mL, 0.42 mmol, 10.0 eq) was added with stirring. After 3 hours at room temperature, the reaction was monitored by TLC (petroleum ether: ethyl acetate = 1:1) to ensure complete reaction. Dilute with 100 mL of water at room temperature, extract with ethyl acetate (100 mL × 2), wash the organic phase with saturated brine (50 mL), dry with anhydrous sodium sulfate, and purify by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give a white solid (8R)-8-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2,4-dimethylnonan-2,4-diol 20-5 (15 mg, yield: 49.0%). 1 H NMR (400MHz, CDCl3) δ7.66(dd,J=5.9,1.9Hz,4H),7.44–7.33(m,6H),3.59(s,1H),1.93(d,J=12.2Hz,1H),1.77(d,J=14.7Hz,3 H),1.69–1.59(m,7H),1.47(d,J=13.5Hz,5H),1.38–1.19(m,18H),1.04(s,12H),0.92–0.86(m,4H),0.82(s,4H),0.64(s,3H).

[0343] Step 7 is similar to Step 5A of Example 1. Compound 43-1 is replaced with 20-5 to obtain a white solid (8R)-8-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-7-hydroxy-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2,4-dimethylnonan-2,4-diol 20 (8 mg). 1 H NMR (400MHz, CDCl3) δ3.72–3.54(m,1H),1.99(d,J=12.9Hz,1H),1.83(d,J=17.0Hz,10H),1.74–1.54(m,6H),1.45–1.36( m,7H),1.32(s,6H),1.29–1.24(m,3H),1.13(s,3H),1.08–0.97(m,3H),0.93(d,J=6.5Hz,3H),0.85(s,3H),0.67(s,3H). 19 F NMR(376MHz, CDCl3)δ-88.96,-89.59,-110.85,-111.48.LC-MS:[MH]-=497.60

[0344] Examples 22 & 23

[0345] Compound 22 or 23 (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-1-[(2R,6S)-6-cyclohexyl-6-hydroxyhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecyl-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0346] Compound 23 or 22 (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-1-[(2R,6R)-6-cyclohexyl-6-hydroxyhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecyl-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0347] Steps 1-2 are similar to those in Example 16. In Steps 1-2, methyl magnesium bromide is replaced with cyclohexane magnesium bromide to obtain (5R)-1-cyclohexyl-5-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylprop-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hex-1-one 22-2 (100 mg, yield: 71.03%) as a white solid.

[0348] Compound 22-1: 1 H NMR (400MHz, CDCl3) δ7.66 (ddd, J=6.4, 3.4, 2.0Hz, 4H), 7.38 (ddd, J=14.4, 7.7, 4 .4Hz,6H),3.65–3.54(m,1H),3.34(s,1H),1.93(d,J=12.7Hz,1H),1.78(d,J=8.8 Hz,5H),1.68–1.56(m,5H),1.50(s,9H),1.46–1.20(m,15H),1.18–1.07(m,4H),1 .04(s,9H),0.90(d,J=6.5Hz,3H),0.80(d,J=12.1Hz,3H),0.62(d,J=12.0Hz,3H).

[0349] Compound 22-2: 1 H NMR (400MHz, CDCl3) δ7.66 (dd, J=5.9, 2.1Hz, 4H), 7.38 (ddd, J=14.2, 7.7, 4.4Hz, 6H ),3.71–3.46(m,1H),2.37(dd,J=13.2,7.0Hz,3H),1.92(d,J=12.8Hz,1H),1.79(t,J =11.4Hz,6H),1.69–1.57(m,6H),1.54(s,6H),1.30(tdd,J=23.2,17.8,9.8Hz,17H) ,1.04(s,9H),0.90(d,J=6.4Hz,3H),0.80(d,J=12.1Hz,3H),0.61(d,J=12.3Hz,3H).

[0350] Step 3 is similar to Step 1 of Example 1, using methyl magnesium bromide to obtain (6R)-2-cyclohexyl-6-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylprop-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hepta-2-ol 22-3 (85 mg, yield: 70.7%) as a white solid. 1H NMR (400MHz, CDCl3) δ7.71–7.61 (m, 4H), 7.38 (tdd, J = 8.2, 6.1, 2.0Hz, 6H), 3.67 –3.51(m,1H),1.94(d,J=12.7Hz,1H),1.79(d,J=11.5Hz,6H),1.72–1.53(m,9H) ,1.47(s,8H),1.41–1.29(m,9H),1.16(dd,J=19.3,12.3Hz,5H),1.08(s,4H),1. 04(s,9H),0.90(d,J=6.5Hz,3H),0.81(d,J=12.2Hz,3H),0.62(d,J=12.2Hz,3H). 19 F NMR (377MHz, CDCl3) δ-88.83,-89.46,-110.86,-111.49.

[0351] Step 4: 22-3 (85 mg) was separated by SFC (instrument: Waters Acquity UPCC; column model: Daicel CHIRALPAK IG_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 22-4 (26 mg, retention time: 2.756 min) as a white solid and 23-1 (33 mg, 3.706 min) as a white solid.

[0352] 22-3: 1 H NMR (400MHz, CDCl3) δ7.66 (ddd, J=8.0, 2.6, 1.5Hz, 4H), 7.46–7.32 (m, 6H), 3.64 –3.54(m,1H),1.94(d,J=12.7Hz,1H),1.80(d,J=10.6Hz,5H),1.63(dd,J=23.1,1 7.1Hz,7H),1.50(s,8H),1.43–1.28(m,10H),1.18(dd,J=16.1,7.1Hz,4H),1.08( s,4H),1.02(d,J=17.5Hz,12H),0.90(d,J=6.5Hz,3H),0.82(s,3H),0.64(s,3H). 19 F NMR (376MHz, CDCl3) δ-88.82,-89.45,-110.86,-111.49.

[0353] 23-1: 1H NMR (400MHz, CDCl3) δ7.66 (dd, J=5.8, 2.0Hz, 4H), 7.47–7.32 (m, 6H), 3.64– 3.54(m,1H),1.94(d,J=12.9Hz,1H),1.79(d,J=5.6Hz,5H),1.65(t,J=10.0H z,7H),1.42(s,15H),1.23(ddd,J=31.5,19.9,9.3Hz,11H),1.08(s,3H),1. 04(s,9H),0.90(d,J=6.4Hz,3H),0.81(d,J=12.0Hz,3H),0.69–0.59(m,3H). 19 F NMR (376MHz, CDCl3) δ-88.83,-89.46,-107.36,-110.66,-110.86,-111.49.

[0354] Step 5A is similar to step 16A of Example 3. Replacing 3-8 with 22-3 yields 22 (9 mg, yield: 50.9%), which is a white solid. 1 H NMR(400MHz, CDCl3)δ3.70–3.56(m,1H),1.99(d,J=12.8Hz,1H),1.84–1.69(m,9H),1.66–1.57(m,3H),1.50(s,7H),1 .41–1.31(m,7H),1.29–1.13(m,7H),1.09(s,3H),1.07–0.96(m,5H),0.93(d,J=6.5Hz,3H),0.85(s,3H),0.67(s,3H). 19 F NMR (377MHz, CDCl3) δ-88.96,-89.59,-110.85,-111.48.

[0355] Step 5B is similar to step 16A of Example 3, but replacing 3-8 with 23-1 yields 23 (7 mg, yield: 55.4%), which is a white solid. 1 H NMR(400MHz, CDCl3) δ3.70–3.56(m,1H),1.99(d,J=12.7Hz,1H),1.84–1.56(m,12H),1.47(s,7H),1.42–1.31 (m,7H),1.29–1.12(m,7H),1.09(s,3H),1.07–0.96(m,5H),0.93(d,J=6.5Hz,3H),0.85(s,3H),0.67(s,3H). 19F NMR(376MHz, CDCl3)δ-88.96,-89.59,-110.85,-111.48

[0356] Examples 25, 26 & 27

[0357] Compound 25(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-(3,4,5,6-tetrahydro-2H-pyran-4-yl)hept-2-yl]-9a,11a-dimethylhexadecyl-1H-cyclopenta[1,2-a]phenanthrene-7-ol,

[0358] Compound 26 or 27 (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R,6S)-6-hydroxy-6-(3,4,5,6-tetrahydro-2H-pyran-4-yl)hept-2-yl]-9a,11a-dimethylhexadecyl-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0359] Preparation of compounds 27 or 26 (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R,6R)-6-hydroxy-6-(3,4,5,6-tetrahydro-2H-pyran-4-yl)hept-2-yl]-9a,11a-dimethylhexadecyl-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0360] Step 1: At room temperature, pour the treated magnesium shavings (177 mg, 7.27 mmol) into a three-necked flask (50 mL), add iodine (80 mg, 0.32 mmol), add tetrahydrofuran (1 mL), replace with N2 three times, and stir slowly for 20 min. The system changes from a dark brown to a pale yellow turbid liquid. Then add 1 / 3 of the tetrahydrofuran solution (9 mL) of 4-bromotetrahydropyran (1.00 g, 6.06 mmol). Stir slowly in a 50°C oil bath for 10 min until the solution becomes clear. Then add the remaining 2 / 3 of the raw material dropwise. Continue stirring at 50°C for 1 hour. The remaining magnesium shavings are cooled to room temperature to form (3,4,5,6-tetrahydro-2H-pyran-4-yl)magnesium 25-0 (0.6 M tetrahydrofuran solution) and used directly in the next step.

[0361] Steps 2-4 are similar to steps 1-3 of Examples 22 & 23. Replacing magnesium cyclohexane bromide with (3,4,5,6-tetrahydro-2H-pyran-4-yl)magnesium 25-0 yields a white solid (6R)-6-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylprop-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2-(3,4,5,6-tetrahydro-2H-pyran-4-yl)hepta-2-ol 25-3 (56 mg).

[0362] 25-1: 1 H NMR(400MHz, CDCl3)δ7.65(dd,J=4.7,3.1Hz,4H),7.45–7.33(m,6H),4.00(t,J=10.5Hz,2H), 3.65–3.53(m,1H),3.37(t,J=11.4Hz,3H),1.93(d,J=12.1Hz,1H),1.87–1.76(m,2H),1.66(dd ,J=28.3,13.4Hz,6H),1.50–1.19(m,21H),1.11–1.07(m,1H),1.04(s,9H),1.02–0.98(m,1H) ,0.90(d,J=6.4Hz,3H),0.86(d,J=6.5Hz,1H),0.81(d,J=12.2Hz,3H),0.62(d,J=12.0Hz,3H). 19 F NMR (376MHz, CDCl3) δ-88.83,-89.46,-110.86,-111.49.

[0363] 25-2: 1 H NMR (400MHz, CDCl3) δ7.70–7.63(m,4H),7.45–7.33(m,6H),3.99(dd,J=8.9,5.3Hz,2H ),3.63–3.52(m,1H),3.41(td,J=11.3,3.1Hz,2H),2.59–2.46(m,1H),2.38(dt,J=17.0 ,8.3Hz,2H),1.93(d,J=12.6Hz,1H),1.84–1.59(m,12H),1.52–1.18(m,16H),1.07(s,1 H),1.04(s,9H),0.91(d,J=6.5Hz,3H),0.80(d,J=12.4Hz,3H),0.61(d,J=12.4Hz,3H). 19F NMR (377MHz, CDCl3) δ-88.83,-89.46,-110.86,-111.49.

[0364] 25-3: 1 H NMR (400MHz, CDCl3) δ7.66 (d, J=7.6Hz, 4H), 7.39 (dd, J=15.1, 6.0Hz, 6H), 4.05–3.99 (m, 2H),3.64–3.54(m,1H),3.35(d,J=10.1Hz,2H),1.94(d,J=12.9Hz,1H),1.78(dd,J=23.2 ,10.3Hz,2H),1.64(dd,J=13.8,8.4Hz,6H),1.48–1.22(m,22H),1.11(s,3H),1.04(s,9H ),0.90(d,J=6.5Hz,3H),0.88–0.84(m,1H),0.82(s,3H),0.80–0.72(m,1H),0.64(s,3H). 19 F NMR (376MHz, CDCl3) δ-88.83,-89.46,-110.86,-111.49.

[0365] In step 4, compound 25-3 (70 mg, 0.093 mmol) was chirally resolved by SFC (instrument: Waters Acquity UPCC, column: Daicel CHIRALPAK IC_3, 3.0*150 mm, 3 μm, mobile phase: CO2 / MeOH (0.1% DEA) = 70 / 30, flow rate: 1.5 mL / min, column temperature: 37 °C) to obtain 26-1 (28 mg, yield 40.0%, retention time: 2.067 min) and 27-1 (26 mg, yield 37.1%, retention time: 2.600 min), both white solids.

[0366] 26-1: 1H NMR(400MHz, CDCl3)δ7.66(dd,J=6.0,1.9Hz,4H),7.46–7.32(m,6H),4.07–3.97(m,2H),3.65– 3.52(m,1H),3.36(t,J=11.1Hz,2H),1.94(d,J=11.9Hz,1H),1.79(t,J=17.6Hz,2H),1.72–1.6 0(m,6H),1.41(ddd,J=38.1,26.3,11.0Hz,18H),1.25–1.14(m,4H),1.11(s,3H),1.04(s,9H), 0.90(d,J=6.5Hz,3H),0.87(d,J=8.8Hz,1H),0.82(s,3H),0.75(d,J=13.1Hz,1H),0.64(s,3H). 19 F NMR (376MHz, CDCl3) δ-88.83,-89.46,-110.87,-111.50.

[0367] 27-1: 1 H NMR (400MHz, CDCl3) δ7.66 (d, J=7.0Hz, 4H), 7.46–7.32 (m, 6H), 4.07–3.97 (m, 2H), 3. 66–3.53(m,1H),3.36(t,J=11.3Hz,2H),1.94(d,J=12.4Hz,1H),1.88–1.72(m,2H),1 .63(dd,J=29.4,16.1Hz,6H),1.50–1.15(m,22H),1.10(s,3H),1.04(s,9H),0.90(d, J=6.5Hz,3H),0.87(d,J=5.9Hz,1H),0.82(s,3H),0.76(t,J=9.5Hz,1H),0.64(s,3H). 19 F NMR (376MHz, CDCl3) δ-88.83,-89.46,-110.86,-111.49.

[0368] Step 5A is similar to Step 16A of Example 3, except that 3-8 is replaced with 25-3 to obtain a white solid (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-(3,4,5,6-tetrahydro-2H-pyran-4-yl)hept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 25 (8 mg, yield 46.5%). 1H NMR (400MHz, CDCl3) δ4.04(dt,J=10.6,5.2Hz,2H),3.68–3.57(m,1H),3.37(t,J=10.9Hz,2H),2.03–1.94(m,1H),1.89–1.69(m,6H) ,1.67–1.52(m,7H),1.47–1.15(m,16H),1.12(s,3H),1.02(dt,J=12.9,8.7Hz,3H),0.93(d,J=6.5Hz,3H),0.85(s,3H),0.67(s,3H). 19 F NMR (377MHz, CDCl3) δ-88.96,-89.59,-110.85,-111.48.

[0369] Step 5B is similar to Step 16A of Example 3, except that 3-8 is replaced with 26-1 to obtain white solid 26 (11 mg, yield 57.6%). 1 H NMR (400MHz, CDCl3) δ4.09–3.99(m,2H),3.68–3.58(m,1H),3.37(t,J=11.5Hz ,2H),1.99(d,J=12.6Hz,1H),1.77(ddd,J=20.5,18.2,5.9Hz,6H),1.60(dd,J= 29.2,12.3Hz,6H),1.43(ddd,J=21.4,14.4,5.9Hz,10H),1.35–1.14(m,7H),1. 12(s,3H),1.07–0.97(m,3H),0.93(d,J=6.5Hz,3H),0.85(s,3H),0.67(s,3H). 19 F NMR (377MHz, CDCl3) δ-88.96,-89.59,-110.85,-111.48.

[0370] Step 5C is similar to step 16A of Example 3, except that 3-8 is replaced with 27-1 to obtain white solid 27 (12 mg, yield 67.7%). 1 H NMR (400MHz, CDCl3) δ4.09–3.98(m,2H),3.68–3.58(m,1H),3.37(t,J=10.7Hz,2H),2.03–1.95(m,1H),1.89–1.69(m,6H) ,1.67–1.54(m,6H),1.49–1.14(m,17H),1.12(s,3H),1.08–0.96(m,3H),0.93(d,J=6.5Hz,3H),0.85(s,3H),0.67(s,3H).19 F NMR (377MHz, CDCl3) δ-88.96,-89.59,-110.84,-111.47.

[0371] Examples 28, 29 & 30

[0372] Compound 28(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-1-[(2R)-7,7-difluoro-6-hydroxy-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol,

[0373] Compounds 29 or 30 (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-1-[(2R,6R)-7,7-difluoro-6-hydroxy-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0374] Preparation of compounds 30 or 29 (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-1-[(2R,6S)-7,7-difluoro-6-hydroxy-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0375] Steps 1-3 are similar to those in Example 14. Changing compound II to I yields the white solid product (6R)-6-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecylhydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxane-8-yl]-1,1-difluoro-2-methylhept-2-ol 28-3 (130 mg).

[0376] Compound 28-1: 1HNMR (400 MHz, CDCl3) δ 5.61 (ddd, J = 56.2, 55.2, 3.2 Hz, 1H), 4.06–3.94 (m, 2H), 3.74 (dd, J = 10.5, 3.8 Hz, 1H), 2.21–2.06 (m, 1H), 1.96 (ddd, J = 9.0, 8.0, 3.1 Hz, 2H), 1.90–1.80 (m, 4H), 1.75–1.60 (m, 6H), 1.48–1.37 (m, 5H), 1.34–1.24 (m, 7H), 1.17–1.04 (m, 7H), 1.01–0.85 (m, 6H), 0.68 (s, 3H). 19 F NMR (376 MHz, CDCl3) δ -88.97, -89.61, -111.36, -111.99, -129.70, -129.72, -129.74, -129.77.

[0377] Compound 28-2: 1 HNMR (400 MHz, CDCl3) δ 5.67 (t, J = 54.1 Hz, 1H), 4.02 (dt, J = 8.2, 5.1 Hz, 2H), 2.63 (dd, J = 13.2, 6.5 Hz, 2H), 2.21–2.06 (m, 1H), 1.99 (ddd, J = 19.2, 8.8, 3.2 Hz, 2H), 1.90–1.76 (m, 4H), 1.76–1.60 (m, 4H), 1.51 (s, 4H), 1.46–1.34 (m, 4H), 1.33–1.24 (m, 5H), 1.16–1.02 (m, 6H), 1.00–0.87 (m, 5H), 0.68 (s, 3H). 19 F NMR (376 MHz, CDCl3) δ -89.00, -89.63, -111.36, -111.99, -126.92.

[0378] Compound 28-3: 1 HNMR (400 MHz, CDCl3) δ 5.73–5.37 (m, 1H), 4.06–3.97 (m, 2H), 2.19–2.09 (m, 1H), 2.04–1.93 (m, 2H), 1.84 (d, J = 8.6 Hz, 3H), 1.68–1.60 (m, 5H), 1.51 (s, 6H), 1.45–1.35 (m, 5H), 1.32–1.24 (m, 9H), 1.08 (d, J = 6.7 Hz, 5H), 0.94 (t, J = 7.9 Hz, 5H), 0.68 (s, 3H). 19F NMR (376MHz, CDCl3) δ-88.99,-89.62,-111.36,-111.99,-131.01,-131.10,-131.75,-131.85,-132.91,-133.02,-133.65,-133.74.

[0379] In step 4, under nitrogen protection, 28-3 (180 mg, 0.34 mmol) was dissolved in THF (10 mL), and 2N dilute HCl (3 mL) solution was added to the system. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 3:1) until complete, and then the reaction was stopped. The reaction was quenched with ice water (10 mL), and the aqueous layer was extracted with ethyl acetate (15 mL x 3). The ethyl acetate layers were combined and washed with saturated brine (10 mL x 3). The ethyl acetate layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by rapid chromatography (petroleum ether: ethyl acetate = 80:20) to give a white solid product (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-1-[(2R)-7,7-difluoro-6-hydroxy-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 28 (130 mg, yield 74.2%). 1 HNMR (400MHz, CDCl3) δ5.54(t,J=56.7Hz,1H),3.74(s,1H),3.68–3.54(m,1H),2.33–2.09(m,1H),1.98(d,J=12.7Hz,1H),1.77 (ddd,J=14.5,12.9,4.8Hz,6H),1.55–1.35(m,9H),1.33–1.21(m,7H),1.17–1.01(m,7H),0.95(t,J=11.2Hz,4H),0.67(s,3H). 19 F NMR(376MHz, CDCl3)δ-88.63,-89.26,-110.63,-111.26,-131.01,-131.76,-133.02,-133.77.LC-MS: [MH] - =491.45,

[0380] In step 5, compound 28 (100 mg, 0.203 mmol) was dissolved in anhydrous DCM (10 mL) at room temperature, and triethylamine (0.085 mL, 0.609 mmol), 4-dimethylaminopyridine (DMAP) (37.20 mg, 0.305 mmol), and benzoyl chloride (0.047 mL, 0.406 mmol) were added. The reaction was carried out under nitrogen protection at room temperature for 18 hours. The reaction was monitored for completeness by TLC (petroleum ether:ethyl acetate = 5:1, phosphomolybdic acid plate). The reaction was quenched with water (10 mL), extracted with dichloromethane (10 mL × 3), and the organic phase was collected, dried over anhydrous sodium sulfate, and then evaporated under vacuum to obtain the crude product. The crude product was purified by rapid chromatography (petroleum ether: ethyl acetate = 82:18) to give benzoic acid-(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6-(phenylcarbonyloxy)-1-[(2R)-7,7-difluoro-6-hydroxy-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 28-5 (50 mg, 0.071 mmol, 35.14%). 1 HNMR(400MHz, CDCl3)δ8.04(d,J=8.1Hz,4H),7.81(d,J=7.3Hz,2H),7.64–7.56(m,2H),7.52–7.43(m, 5H),7.29(d,J=7.9Hz,2H),5.57(dd,J=77.1,36.2Hz,3H),5.20–5.11(m,1H),4.99(dd,J=8.4,3.3Hz,1 H),3.98(s,1H),2.32–2.06(m,3H),2.02–1.91(m,6H),1.88–1.76(m,9H),1.65–1.51(m,16H),1.44–1. 33(m,8H),1.32–1.21(m,17H),1.20–1.03(m,12H),0.94(dd,J=6.3,2.1Hz,6H),0.68(d,J=3.0Hz,6H). 19 F NMR(376MHz, CDCl3)δ-88.71,-88.98,-89.34,-89.62,-110.22,-110.49,-110.85,-111.12,-131.09,-131.83,-132.90,-133.66

[0381] Step 6: Crude product 28-5 (60 mg) was separated by SFC (Separation conditions: 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 Temp: 37 degrees) to obtain 29-1 (20 mg, retention time: 3.210 min) and 30-1 (25 mg, retention time: 3.758 min).

[0382] Compound 29-1: 1 H NMR (400MHz, CDCl3) δ8.04(d,J=7.2Hz,2H),7.81(d,J=7.2Hz,2H),7.61(t,J=7.4Hz,1H) ,7.47(dd,J=15.4,7.7Hz,3H),7.29(d,J=7.8Hz,2H),5.57(dd,J=77.6,35.8Hz,2H),5.19 –5.11(m,1H),2.14–2.01(m,2H),1.98–1.80(m,6H),1.51(dd,J=22.9,13.8Hz,5H),1.43 –1.32(m,4H),1.30–1.20(m,12H),1.17–1.07(m,3H),0.95(d,J=6.5Hz,3H),0.67(s,3H). 19 F NMR (376MHz, CDCl3) δ-88.99,-89.62,-110.22,-110.85,-131.09,-131.85,-132.93,-133.63,-293.51.

[0383] Compound 30-1: 1 H NMR (400MHz, CDCl3) δ8.07–8.02(m,2H),7.81(d,J=7.2Hz,2H),7.60(d,J=7.5 Hz,1H),7.47(dd,J=15.3,7.7Hz,3H),7.29(d,J=7.9Hz,2H),5.69–5.39(m,2H ),5.19–5.12(m,1H),2.00(ddd,J=40.6,15.8,7.5Hz,8H),1.55–1.37(m,8H), 1.26(t,J=8.4Hz,12H),1.19–1.05(m,4H),0.95(d,J=6.5Hz,3H),0.67(s,3H).19 F NMR (376MHz, CDCl3) δ-88.99,-89.62,-110.23,-110.86,-131.01,-131.75,-133.01,-133.75.

[0384] Step 6A is similar to step 4 of Example 28, except that 28-3 is replaced with 29-1 to obtain white solid compound 29 (8 mg, 0.02 mmol, 56.9%). 1 H NMR (400MHz, MeOD) δ5.54(t,J=56.6Hz,1H),3.63(s,1H),3.48(dt,J=11.6,3.9Hz,1H),2.24–2.12(m,1H),2.01(s,1H),1.87–1. 68(m,6H),1.61–1.53(m,2H),1.40(s,6H),1.29(d,J=3.9Hz,9H),1.16(s,3H),1.07(s,3H),0.96(d,J=6.5Hz,4H),0.70(s,3H). 19 F NMR(376MHz,MeOD)δ-89.33,-89.96,-111.86,-112.49,-132.50,-133.24,-133.80,-134.55.LC-MS: [MH] - =491.4

[0385] Step 6B is similar to Step 3 of Example 28, except that 28-3 is replaced with 30-1 to obtain white solid compound 30 (7.5 mg, 0.015 mmol, 35.5%). 1 H NMR (400MHz, CDCl3) δ5.54(t,J=56.7Hz,1H),3.74(s,1H),3.65–3.54(m,1H),2.32–2.13(m,1H),1.98(dd,J=9.5, 3.3Hz,1H),1.88–1.66(m,12H),1.48–1.25(m,12H),1.15–1.03(m,6H),0.95(dd,J=15.0,7.1Hz,3H),0.67(s,3H). 19 F NMR (376MHz, CDCl3) δ-88.62,-89.23,-110.63,-111.26,-131.01,-131.75,-133.01,-133.75.LC-MS: [MH) - =491.50

[0386] Example 31

[0387] Preparation of compound 31(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-(4-hydroxycyclohexyl)hept-2-yl]-9a,11a-dimethylhexadecyl-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0388] Step 1: At room temperature, 3.00 g (18.96 mmol) of 1,4-dioxaspiro[4.5]dec-8-ol 31-O-1 was dissolved in dichloromethane (50 mL), and triphenylphosphine (7.46 g, 28.45 mmol) was added. The mixture was cooled in an ice bath, and a dichloromethane solution (20 mL) of carbon tetrabromide (9.43 g, 28.45 mmol) was slowly added dropwise. The mixture was brought to room temperature and stirred for 16 hours. The reaction was monitored for completeness by TLC (petroleum ether: ethyl acetate = 5:1). Water (40 mL) was added, and the mixture was extracted with dichloromethane (50 mL x 2). The combined organic phases were washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Separation by column chromatography (40 g, 0-5% ethyl acetate / petroleum ether, 40 mL / min) yielded a light brown oily substance, 8-bromo-1,4-dioxane[4.5]decane 31-0-2 (3.4 g, 14.61 mmol, yield 77.0%). 1 H NMR (400MHz, CDCl3) δ4.39–4.25(m,1H),4.02–3.87(m,4H),2.22–2.02(m,4H),1.92(ddd,J=12.6,8.6,4.4Hz,2H),1.62(ddd,J=12.8,7.9,4.6Hz,2H).

[0389] In step 2, at room temperature, the treated magnesium shavings (132 mg, 5.43 mmol) were poured into a three-necked flask (50 mL), iodine (57 mg, 0.23 mmol) was added, followed by tetrahydrofuran (1 mL). After three N2 purgings, the mixture was stirred at low speed for 5 min. Then, 1 / 3 of a tetrahydrofuran solution of 8-bromo-1,4-dioxaspiro[4.5]decane (1.00 g, 4.52 mmol) was added (7 mL). While stirring, the mixture was heated with a hot gun until the system changed from a dark brown to a light brown clear liquid. The remaining 2 / 3 of the raw material was then added dropwise. The mixture was stirred at 65 °C for 1 hour, and the remaining magnesium shavings were collected. The system was cooled to room temperature to obtain bromo(1,4-dioxaspiro[4.5]dec-8-yl)magnesium 31-0 (0.5 M tetrahydrofuran), which was used directly in the next step.

[0390] Steps 3-5 are similar to those in Example 22. Steps 1-3 are performed by replacing magnesium cyclohexane bromide with (1,4-dioxaspiro[4.5]dec-8-yl)magnesium bromo(1,4-dioxaspiro[4.5]dec-8-yl)31-0 to obtain a white solid (6R)-6-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylprop-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2-(1,4-dioxaspiro[4.5]dec-8-yl)hepta-2-ol 31-3 (42 mg).

[0391] Compound 31-1: 1 H NMR (400MHz, CDCl3) δ7.69–7.63(m,4H),7.45–7.33(m,6H),3.94(s,4H),3. 60–3.53(m,1H),3.40(s,1H),1.99–1.89(m,2H),1.86–1.67(m,9H),1.57–1 .30(m,19H),1.23(d,J=13.3Hz,3H),1.18–1.06(m,3H),1.04(s,9H),0.90( d,J=6.6Hz,3H),0.82(s,3H),0.78(d,J=9.0Hz,1H),0.62(d,J=12.4Hz,3H). 19 F NMR (377MHz, CDCl3) δ-88.83,-89.46,-110.86,-111.49.

[0392] Compound 31-2: 1 H NMR (400MHz, CDCl3) δ7.66 (ddd, J=6.3, 3.4, 2.0Hz, 4H), 7.44–7.33 (m, 6H), 3.93 (s, 4H), 3.63– 3.54(m,1H),2.37(ddd,J=25.4,19.1,14.4Hz,3H),2.00–1.75(m,8H),1.66(dd,J=23.4,9.2Hz ,8H),1.49(dd,J=17.2,11.2Hz,4H),1.40–1.15(m,11H),1.04(s,9H),0.96–0.92(m,1H),0.90 (d,J=6.5Hz,3H),0.86(dd,J=6.6,3.1Hz,2H),0.80(d,J=12.2Hz,3H),0.61(d,J=12.3Hz,3H). 19 F NMR (376MHz, CDCl3) δ-88.83,-89.46,-110.86,-111.49.

[0393] Compound 31-3: 1 H NMR (400MHz, CDCl3) δ7.68–7.63(m,4H),7.44–7.34(m,6H),3.94(s,4H),3.64–3.53(m ,1H),1.94(d,J=12.3Hz,1H),1.85–1.75(m,5H),1.68(dd,J=24.9,8.0Hz,6H),1.50(d d,J=25.9,12.1Hz,8H),1.42–1.28(m,12H),1.20(d,J=10.8Hz,2H),1.11(s,3H),1.04 (s,9H),0.90(d,J=6.5Hz,3H),0.86(dd,J=6.6,3.1Hz,3H),0.82(s,3H),0.64(s,3H).

[0394] In step 6, reactant 31-3 (20 mg, 0.025 mmol) was dissolved in tetrahydrofuran (2 mL) and water (0.5 mL), and p-toluenesulfonic acid (20 mg, 0.12 mmol) was added. The reaction mixture was stirred in an oil bath at 60 °C for 2 hours. The reaction was monitored for completeness by TLC (petroleum ether: ethyl acetate = 3:1). A saturated sodium bicarbonate solution (10 mL) was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (2 × 10 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was then separated by column chromatography (4 g, 0–30% ethyl acetate / petroleum ether, 20 mL / min) to obtain a white solid 4-[(6R)-6-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2-hydroxyhept-2-yl]cyclohexane-1-one 31-4 (16 mg, yield 80.4%). 1H NMR (400MHz, CDCl3) δ7.66 (dd, J=5.9, 2.0Hz, 4H), 7.47–7.32 (m, 6H), 3.64–3.54 (m, 1H), 2.47–2.25(m,4H),2.21–2.12(m,1H),1.94(d,J=12.9Hz,1H),1.85–1.68(m,10H),1.67– 1.48(m,10H),1.35(dd,J=23.4,7.5Hz,6H),1.15(s,3H),1.12–1.07(m,2H),1.04(s,9H) ,0.91(d,J=6.5Hz,3H),0.88–0.83(m,2H),0.82(s,3H),0.80–0.73(m,1H),0.64(s,3H). 19 F NMR (376MHz, CDCl3) δ-88.83,-89.46,-110.86,-111.49.

[0395] In step 7, at room temperature, 31-4 (16 mg, 0.021 mmol) was dissolved in methanol (1 mL), cooled to 0°C in an ice bath, and then NaBH4 (16 mg, 0.42 mmol) was added in portions. The mixture was stirred at room temperature for 30 minutes. The reaction was monitored for completeness by TLC (petroleum ether: ethyl acetate = 2:1). The reaction solution was quenched with saturated ammonium chloride solution (10 mL), 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL x 2). The organic phases were combined and washed with saturated brine (20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated by column chromatography (4 g, 0-40% ethyl acetate / petroleum ether, 20 mL / min) to obtain a white solid 4-[(6R)-6-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2-hydroxyhept-2-yl]cyclohexyl-1-ol 31-5 (10 mg, yield 59.2%). 1H NMR (400MHz, CDCl3) δ7.68–7.64(m,4H),7.43–7.34(m,6H),3.67–3.49(m,2H),2.31( dd,J=19.9,12.5Hz,1H),1.94(d,J=13.0Hz,2H),1.88–1.69(m,6H),1.50(dd,J=24.0 ,12.5Hz,8H),1.35(dd,J=26.3,11.9Hz,10H),1.24–1.16(m,6H),1.09(s,3H),1.04( s,9H),0.90(dd,J=11.4,5.1Hz,6H),0.82(s,3H),0.75(t,J=7.9Hz,1H),0.64(s,3H). 19 F NMR(376MHz, CDCl3)δ-88.83,-89.45,-110.86,-111.49.

[0396] In step 16A of Example 3 of Example 8, steps 3-8 were replaced with 31-5 to obtain a white solid (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-(4-hydroxycyclohexyl)hept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 31 (3 mg, yield 42.3%). 1 H NMR (400MHz, CDCl3) δ5.25(s,1H),3.71–3.49(m,2H),2.09–1.95(m,3H),1.91–1.63(m,10H),1.32(dddd,J=47.6,42 .6,29.4,16.1Hz,21H),1.10(s,3H),1.03(dd,J=23.0,11.2Hz,3H),0.93(d,J=6.4Hz,3H),0.85(s,3H),0.67(s,3H). 19 F NMR (376MHz, CDCl3) δ-88.96,-89.59,-110.84,-111.47.

[0397] Example 32

[0398] Preparation of compound 32(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-1-[(2R)-5,5-difluoro-6-hydroxy-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0399] In step 1, Zn (0.61 g, 9.312 mmol) was dissolved in THF (15 mL), and then stirred under reflux for 1 hour under nitrogen protection. A mixture of 6-O (1.2 g, 3.104 mmol) and BrCF2CO2Et (1.89 g, 9.312 mmol) was dissolved in tetrahydrofuran (3 mL), and then added dropwise to the above zinc solution. The reaction was carried out under reflux for 0.5 hours, and the reaction of the starting materials was monitored by TLC (petroleum ether: ethyl acetate = 5:1) to ensure complete reaction. The reaction solution was poured into water and extracted with ethyl acetate (20 mL x 2). The organic phases were combined and concentrated. The crude product was purified by rapid chromatography (petroleum ether: ethyl acetate = 95:5 to 80:20) to give a white solid (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecanoic acid ethyl ester 32-1 (700 mg, yield: 39.74%). 1 H NMR(400MHz, CDCl3)δ5.37(d,J=4.5Hz,1H),4.68–4.52(m,1H),4.47–4.28(m,2H),4 .12(d,J=7.0Hz,1H),2.32(d,J=7.1Hz,2H),2.08–1.94(m,5H),1.86(d,J=9.6Hz,3H ),1.69(d,J=13.0Hz,2H),1.60(td,J=16.9,6.6Hz,4H),1.47(dd,J=15.7,11.6Hz,3 H),1.37(t,J=7.1Hz,3H),1.29–1.09(m,6H),1.07–0.94(m,8H),0.75–0.67(m,3H).

[0400] In step 2, 32-1 (300 mg, 0.587 mmol) was dissolved in dichloromethane (10 mL), and then di(imidazol-1-yl)methylthione (314.08 mg, 1.762 mmol) and 4-dimethylaminopyridine DMAP (14.35 mg, 0.117 mmol) were added sequentially. The reaction was carried out under reflux for 12 hours and monitored by TLC (petroleum ether: ethyl acetate = 3:1) until complete. The reaction solution was poured into water and extracted with ethyl acetate (20 mL x 2). The organic phases were combined and concentrated. The crude product was purified by rapid chromatography (petroleum ether: ethyl acetate = 95:5 to 60:40) to obtain a colorless oily liquid (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecanoic acid ethyl ester 32-2 (250 mg, 61.69%). 1 H NMR (400MHz, CDCl3) δ8.47(d,J=9.6Hz,1H),7.67(d,J=11.0Hz,1H),7.14(d,J=6.8Hz,1 H),6.32–6.12(m,1H),5.37(d,J=4.8Hz,1H),5.30(s,2H),4.68–4.54(m,1H),4.32(q,J =7.2Hz,2H),2.32(d,J=6.8Hz,2H),2.11(s,1H),2.06–1.93(m,5H),1.85(d,J=10.4Hz, 3H),1.73–1.39(m,9H),1.35–1.24(m,5H),1.22–0.94(m,13H),0.68(t,J=18.8Hz,3H).

[0401] In step 3, 32-2 (200 mg, 0.322 mmol) was dissolved in toluene (5 mL), and benzoic acid peroxyanhydride (15.61 mg, 0.064 mmol) and triethylsilane (299.69 mg, 2.577 mmol) were added sequentially. The reaction was carried out under reflux for 18 hours, and the reaction was monitored by TLC (petroleum ether: ethyl acetate = 8:). The reaction solution was poured into water and extracted with ethyl acetate (20 mL x 2). The organic phases were combined and concentrated. The crude product was purified by rapid chromatography (petroleum ether: ethyl acetate = 95:5) to obtain ethyl (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecanoic acid-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2,2-difluorohexanoate ethyl ester 32-3 (90 mg, yield 50.83%).

[0402] In step 4, 32-3 (1.7 g, 3.43 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL) at room temperature. Under nitrogen protection, the mixture was cooled to 0 °C, and methyl magnesium bromide (3 M in 2-methyltetrahydrofuran, 11.5 mL, 34.4 mmol) was added dropwise. The mixture was then stirred at room temperature for 2 hours, and the reaction was monitored by TLC (petroleum ether: ethyl acetate = 2:1) to ensure complete reaction. The system was cooled to 0 °C, quenched with saturated ammonium chloride aqueous solution (100 mL), extracted with ethyl acetate (100 mL × 2), washed with saturated brine (50 mL) of organic phase, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to give a white solid 24,24-difluorocholest-6(5)-ene-3β,25-diol 32-4 (195 mg, yield: 49%). 1 H NMR(400MHz, CDCl3)δ5.35(d,J=5.2Hz,1H),3.53(m,1H),2.28(m,2H),1.99(m,3H),1.85(m,3H),1 .68(m,7H),1.49(m,5H),1.29(m,8H),1.12(m,3H),1.01(s,3H),0.94(d,J=6.6Hz,3H),0.69(s,3H)

[0403] In step 5, 24,24-difluorocholest-6(5)-ene-3β,25-diol 32-4 (400 mg, 0.91 mmol, 1.0 eq) was dissolved in tetrahydrofuran (10 mL) at room temperature. Triethylamine (180 mg, 1.82 mmol, 2 eq), 4-dimethylaminopyridine (10 mg, 0.09 mmol, 0.1 eq), and benzoyl chloride (190 mg, 1.37 mmol, 1.5 eq) were added at room temperature. The mixture was then stirred at room temperature for 1 hour. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 1:1). After the reaction was complete, the solution was quenched with water (100 mL) and ethyl acetate (10 mL) was added. Extracted with 0 mL × 2), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, the organic phase was concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give a white solid benzoic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-5,5-difluoro-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecanoic-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 32-5 (380 mg, yield: 76%).

[0404] In step 6, 32-5 (400 mg, 0.737 mmol, 1.0 eq) was dissolved in tetrahydrofuran (10 mL) at room temperature. Triethylamine (3.0 mL, 22.1 mmol, 30 eq), 4-dimethylaminopyridine (90.4 mg, 0.737 mmol, 1.0 eq), and acetic anhydride (11.1 mL, 21.0 mmol, 15 eq) were added at room temperature. The mixture was then stirred at 80 °C for 24 hours. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 1:1) to ensure safety. Quenching with ice water (50 mL), extraction with ethyl acetate (30 mL × 2), washing the organic phase with saturated brine (50 mL), drying with anhydrous sodium sulfate, concentrating the organic phase, and purifying by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to give a white solid acetic acid-(6R)-6-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-(phenylcarbonyloxy)-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecanoyl-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-3,3-difluoro-2-methylhept-2-yl ester 32-6 (320 mg, yield: 74.2%). 1H NMR (400MHz, CDCl3) δ8.04(m,2H),7.54(dt,J=2.6,1.6Hz,1H),7.43(dd,J=10.5,4.7Hz,2H) ,5.42(d,J=3.8Hz,1H),4.86(dd,J=7.9,3.6Hz,1H),2.47(d,J=7.7Hz,2H),2.39(s,1H),2.0 3(s,3H),1.92(m,5H),1.70(ddd,J=18.9,16.3,8.2Hz,5H),1.60(s,6H),1.49(m,5H),1.28( m,4H),1.15(m,2H),1.07(s,3H),1.02(m,1H),0.95(t,J=5.9Hz,3H),0.72(d,J=3.8Hz,3H).

[0405] Step 7 is similar to Step 5 of Example 6, except that 6-2 is replaced with 32-6. The product is a white solid (acetic acid-(6R)-6-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-(benzyloxy)-9a,11a-dimethyl-4-oxoylide-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecanoyl-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-3,3-difluoro-2-methylheptane-2-yl ester 32-7 (300 mg, yield: 41.8%). 1 H NMR (400MHz, CDCl3) δ8.04(m,2H),7.56(m,1H),7.45(t,J=7.7Hz,2H),5.76(d,J= 1.5Hz,1H),4.98(s,1H),2.66(m,2H),2.45(d,J=4.2Hz,1H),2.41(s,1H),2.27(s, 1H),2.14(d,J=13.0Hz,1H),2.04(d,J=4.1Hz,4H),1.87(ddd,J=49.8,25.5,9.0Hz ,5H),1.57(m,10H),1.33(m,8H),1.15(m,2H),0.97(d,J=6.5Hz,3H),0.72(s,3H).

[0406] In step 8, at room temperature, 32-7 (300 mg, 0.553 mmol, 1.0 eq) was dissolved in ethyl acetate (10 mL), and 100 mg of 10% Pd on carbon (containing 40-60% water) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction was monitored by TLC (ethyl acetate / petroleum ether = 1:4). After the reaction was completed, the reaction solution was diluted with ethyl acetate (100 mL), filtered through diatomaceous earth, the organic phase was concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give a white solid acetic acid-(6R)-6-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-7-(phenylcarbonyloxy)-9a,11a-dimethyl-4-oxoylidenehexadecyl-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-3,3-difluoro-2-methylhept-2-yl ester 32-8 (150 mg, yield: 50.0%). 1 H NMR (400MHz, CDCl3) δ8.03(m,2H),7.55(t,J=7.4Hz,1H),7.43(t,J=7.6Hz,2H),4.94(m,1H),2.38(t,J=11.4Hz,2H),2.24(m,1H),2.06(m,6H),1 .94(m,2H),1.84(dd,J=17.9,7.2Hz,2H),1.70(m,5H),1.60(s,6H),1.4 9(m,3H),1.28(m,4H),1.14(m,5H),0.96(m,4H),0.70(d,J=13.2Hz,3H).

[0407] Step 9 is similar to Example 3. In Step 9, 3-1 is replaced with 32-8 to obtain crude product 32-9. Crude product 32-9 is obtained by SFC (instrument: Waters Acquity UPCC, column: Daicel CHIRALPAK IB 4.6*250mm, 5um, mobile phase: A / B:CO2 / MeOH (0.1% DEA)=60 / 40, flow rate: 1.5ml / min, column temperature: 37 degrees) to obtain acetic acid-(6R)-6-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-7-(phenylcarbonyloxy)-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-3,3-difluoro-2-methylhept-2-yl ester 32-99 (200mg, retention time: 1.192min). 1H NMR (400MHz, CDCl3) δ8.03(dd,J=5.3,3.2Hz,2H),7.55(dd,J=10.5,4.3Hz,1H),7.43(t,J=7.6Hz,2H),4.96(m,1H),2.04(s,3H),2.01(m,2H),1.90 (dd,J=14.8,5.7Hz,2H),1.80(dt,J=16.3,7.9Hz,5H),1.68(m,3H),1.60 (s,6H),1.49(m,5H),1.32(m,4H),1.15(m,4H),0.93(m,6H),0.70(m,3H).

[0408] Step 10 is similar to Step 5A of Example 1, where compound 43-1 is replaced with 32-9 to obtain a white solid (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-1-[(2R)-5,5-difluoro-6-hydroxy-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 32 (120 mg, yield: 72.0%). 1 H NMR (400MHz, CDCl3) δ3.63(m,1H),1.98(ddd,J=11.8,7.1,3.7Hz,2H),1.84(m,3H),1.72(m,6H),1.57(dd,J=13.8,2.8Hz,2H),1.45 (dt,J=14.9,7.7Hz,4H),1.31(m,11H),1.14(m,2H),1.01(td,J=13.0,3.4Hz,2H),0.94(d,J=6.6Hz,3H),0.85(s,3H),0.68(s,3H). 19 F NMR(377MHz, CDCl3)δ-88.98,-89.61,-110.85,-111.48,-115.19,-115.84,-116.09,-116.74.LC-MS:[MH] - =475.35

[0409] Examples 40, 33 & 34

[0410] Compound 40(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(2R)-7,7,7-trifluoro-6-hydroxy-6-methylhept-2-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol,

[0411] Compound 33 or 34 (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(2R,6R)-7,7,7-trifluoro-6-hydroxy-6-methylhept-2-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0412] Preparation of compounds 34 or 33 (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(2R,6S)-7,7,7-trifluoro-6-hydroxy-6-methylhept-2-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0413] Steps 1-3 are similar to steps 1-3 of Example 28, except that (difluoromethyl)trimethylsilane is replaced with (trifluoromethyl)trimethylsilane to obtain a white solid (6R)-6-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecylhydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxacyclopenta-8-yl]-1,1,1-trifluoro-2-methylhept-2-ol 40-3 (150 mg, yield 87.38%).

[0414] Compound 40-1: 1 H NMR(400MHz, CDCl3) δ4.01(dt,J=8.4,6.1Hz,2H),3.90(s,1H),1.96(ddd,J=8.1,7.5,3.1Hz,4H),1.8 5(m,4H),1.63(m,7H),1.51(s,3H),1.40(m,4H),1.29(m,6H),1.12(m,6H),0.94(m,6H),0.68(s,3H).

[0415] Compound 40-2: 1 H NMR (400MHz, CDCl3) δ4.01 (dd, J=5.4, 2.9Hz, 2H), 2.67 (m, 2H), 1.90 (m, 8H), 1.62 (m ,4H),1.51(s,2H),1.42(m,3H),1.29(m,8H),1.12(m,4H),0.89(m,6H),0.68(s,3H).

[0416] In step 4, 40-3 (20 mg, 0.040 mmol, 1.0 eq) was dissolved in tetrahydrofuran (1 mL), and dilute hydrochloric acid (0.5 mL) was added. The reaction system was stirred at room temperature for 1.5 h. The reaction was monitored for completeness by TLC (petroleum ether: ethyl acetate = 3:1). Ethyl acetate (10 mL) was added to the reaction system, and the mixture was extracted with water (25 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 86:14 to 84:16) to give a white solid (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(2R)-7,7,7-trifluoro-6-hydroxy-6-methylhept-2-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 40 (8.87 mg, yield 23.28%). 1 H NMR (400MHz, CDCl3) δ3.74(s,1H),3.60(m,1H),2.21(m,1H),1.98(m,1H),1.83(m,4H),1.65(m,7H),1.44(m,6H),1.35(s,3H ),1.28(dt,J=21.8,8.9Hz,4H),1.12(dd,J=12.9,9.1Hz,2H),1.06(s,3H),1.00(m,1H),0.93(d,J=6.5Hz,3H),0.67(s,3H). 19 F NMR(376MHz, CDCl3)δ-83.02,-83.11,-88.69,-89.33,-110.66,-111.25.

[0417] In step 5, compound 40 (150 mg, 0.294 mmol, 1.0 eq) was dissolved in 99.9% dichloromethane (5 mL), and benzoyl chloride (0.068 mL, 0.588 mmol, 2.0 eq), triethylamine (0.122 mL, 0.881 mmol, 3.0 eq), and 4-dimethylaminopyridine (DMAP) (35.89 mg, 0.294 mmol, 1.0 eq) were added sequentially. The reaction mixture was stirred at room temperature for 1.5 h. The reaction was monitored for completeness by TLC (petroleum ether: ethyl acetate = 3:1). Dichloromethane (10 mL) was added to the reaction mixture, and the mixture was washed with saturated ammonium chloride (25 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 80:20) to give a white solid (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-7-(benzyloxy)-4,4-difluoro-9a,11a-dimethyl-1-[(2R)-7,7,7-trifluoro-6-hydroxy-6-methylhept-2-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6-ol 40-5 (150 mg, yield 80.75%). 1 H NMR (400MHz, CDCl3) δ8.03 (m, 2H), 7.58 (t, J = 7.5Hz, 1H), 7.46 (s, 2H), 4.99 (m ,1H),3.98(s,1H),2.23(dd,J=33.0,16.1Hz,1H),2.03(dd,J=27.6,14.6Hz,2H ),1.84(s,6H),1.61(m,2H),1.42(dd,J=24.8,12.7Hz,5H),1.35(s,4H),1.25( s,4H),1.14(s,3H),1.01(d,J=9.6Hz,2H),0.94(d,J=6.4Hz,3H),0.68(s,3H).

[0418] In step 6, compound 40-5 (100 mg, 0.166 mmol, 1.0 eq) was chirally resolved (resolution conditions: Instrument: Acquity UPCC; Column: Daicel CHIRALCEL OJ-3 4.6 mm * 150 mm, 3 μm; Mobile phase: CO2 / EtOH (0.1% DEA) = 85 / 15; Flow rate: 2.0 mL / min; Wavelength: UV 214 & 254 nm; Column temperature: 37 °C) to obtain 33-1 (30 mg, retention time = 3.666 min) and 34-1 (32 mg, retention time = 4.105 min).

[0419] In step 7A, 33-1 (30 mg, 0.047 mmol) was dissolved in tetrahydrofuran (1 mL), methanol (1 mL), and water (0.5 mL) at room temperature. Lithium hydroxide (13 mg, 0.47 mmol, 10.0 eq) and water (0.5 mL) were added at room temperature, followed by stirring at 35 °C for 2 hours. The reaction was monitored for completion by TLC (petroleum ether: ethyl acetate = 2:1). The solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give a white solid 33 (18.06 mg, yield: 66.67%). 1 H NMR (400MHz, CDCl3) δ3.74(s,1H),3.60(m,1H),2.21(dd,J=34.9,4.5Hz,1H),1.99(m,1H),1.82(m,3H),1.73(m,6H),1.47(m ,7H),1.35(s,3H),1.28(dd,J=13.1,8.7Hz,3H),1.12(m,3H),1.06(s,3H),1.00(m,2H),0.94(d,J=6.5Hz,3H),0.67(s,3H). 19 F NMR(377MHz, CDCl3)δ-83.01,-88.63,-89.26,-110.63,-111.25.LC-MS:[MH] - =509.65,

[0420] Step 7B is similar to Example 33. Step 7A replaces 33-1 with 34-1 to obtain white solid 34 (12.35 mg, yield: 66.67%). 1 H NMR(400MHz, CDCl3)δ3.74(s,1H),3.61(dd,J=9.6,6.2Hz,1H),2.29–2.12(m,1H),2 .01–1.95(m,1H),1.83(dd,J=19.8,12.5Hz,4H),1.71(dd,J=14.0,10.6Hz,3H),1.6 5–1.59(m,6H),1.41(dd,J=19.6,9.6Hz,5H),1.34(s,3H),1.29–1.24(m,2H),1.13– 1.09(m,2H),1.06(s,3H),1.01(d,J=3.7Hz,2H),0.93(d,J=6.5Hz,3H),0.67(s,3H). 19F NMR(376MHz, CDCl3)δ-83.12,-88.65,-89.27,-110.64,-111.26.LC-MS:[MH] - =509.7,

[0421] Examples 35 & 36

[0422] Compound 35 or 36 (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R,6R)-6-hydroxy-6,7-dimethyloctyl-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0423] Preparation of compounds 36 or 35(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R,6S)-6-hydroxy-6,7-dimethyloctyl-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0424] In step 1, compound 12 (100 mg, 0.20 mmol) was dissolved in anhydrous dichloromethane (10 mL) at room temperature, and triethylamine (0.09 mL, 0.64 mmol), 4-dimethylaminopyridine (DMAP) (13.03 mg, 0.107 mmol), and benzoyl chloride (0.05 mL, 0.40 mmol) were added. The reaction was then carried out under nitrogen protection at room temperature for 18 hours. The reaction was monitored for completeness by TLC (petroleum ether: ethyl acetate = 5:1). The reaction was quenched by adding protective sodium bicarbonate solution (10 mL), and extracted with dichloromethane (10 mL × 3). The organic phase was collected, dried over anhydrous sodium sulfate, and then evaporated under vacuum to obtain the crude product. The crude product was purified by rapid chromatography (petroleum ether:ethyl acetate = 82:18) to give benzoic acid-(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6,7-dimethyloctyl-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 35-1 (100 mg, yield 78%). 1HNMR(400MHz, CDCl3)δ8.06–7.98(m,2H),7.55(t,J=7.4Hz,1H),7.43(t,J=7.6Hz,2H),5.04–4.89(m,1H),2.05–1.96(m,3H),1.85(ddd,J= 14.0,11.2,4.3Hz,4H),1.76–1.61(m,4H),1.58–1.41(m,6H),1.37–1 .23(m,6H),1.22–0.99(m,9H),0.97–0.87(m,12H),0.72–0.62(m,3H). 19 F NMR (376MHz, CDCl3) δ-89.03,-89.66,-110.79,-111.42.

[0425] Step 2: Compound 35-1 (130 mg, 0.23 mmol) was purified by SFC (resolution method: instrument: Waters Acquity UPCC; column: Daicel CHIRALPAK AD_3, 3*150 mm, 3 μm; mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 50 / 50; flow rate: 2.0 ml / min; column temperature: 37 degrees) to obtain white solid compound 35-2 (50 mg, retention time = 3.008 min) and white solid compound 36-1 (55 mg, retention time = 3.512 min).

[0426] Step 3A is similar to Step 5A of Example 1, except that compound 43-1 is replaced with 35-2 to obtain white solid compound 35 (23 mg, yield 56.2%). 1 H NMR (400MHz, CDCl3) δ3.68–3.58(m,1H),2.03–1.96(m,1H),1.84(td,J=8.6, 4.8Hz,3H),1.78–1.66(m,5H),1.59(dd,J=10.5,6.6Hz,4H),1.44(dd,J=16.3 ,6.5Hz,6H),1.34(dd,J=15.0,10.4Hz,10H),1.08(s,3H),1.01(dd,J=13.8, 10.5Hz, 3H), 0.91 (dd, J=8.8, 3.9Hz, 6H), 0.85 (d, J=6.3Hz, 3H), 0.67 (s, 3H). 19 F NMR (376MHz, CDCl3) δ-88.96,-89.58,-110.84,-111.47.

[0427] Step 3B is similar to Step 5A of Example 1, except that compound 43-1 is replaced with 36-1 to obtain white solid compound 36 (13 mg, yield 33.5%). 1 H NMR (400MHz, CDCl3) δ3.63(s,1H),2.02–1.96(m,1H),1.84(d,J=7.0Hz,2H),1.80–1.65(m,5H),1.63–1.51(m,7H),1.42(d dd,J=23.7,14.4,5.7Hz,7H),1.34–1.19(m,6H),1.09(s,4H),0.91(ddd,J=25.1,14.2,8.6Hz,12H),0.65(d,J=11.6Hz,3H) 19 F NMR (376MHz, CDCl3) δ-88.96,-89.59,-110.85,-111.48.

[0428] Example 39

[0429] Preparation of compound 39(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(2R)-7,7,7-trifluoro-6-hydroxyhept-2-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0430] Step 1: Compound II (150 mg, 0.23 mmol, 1.0 eq) was dissolved in tetrahydrofuran (10 mL). After complete dissolution, cesium fluoride CsF (11 mg, 0.08 mmol, 0.3 eq) and (trifluoromethyl)trimethylsilane (109.5 mg, 0.77 mmol, 3.3 eq) were added sequentially to the reaction system. After the addition was complete, the mixture was stirred at room temperature for 2 hours. After the appearance of a small polarity point was detected by TLC (petroleum ether:ethyl acetate = 10:1), tetrabutylammonium fluoride (2.3 mL, 1 mol / L, 10.0 eq) was added, and the mixture was stirred at room temperature for 1 hour. The appearance of a large polarity point was detected by TLC (petroleum ether:ethyl acetate = 2:1), and the mixture was quenched with saturated ammonium chloride solution (10 mL) under ice bath conditions. The reaction solution was washed with water (10 mL x 3), extracted with ethyl acetate (10 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and subjected to silica gel column chromatography (90:10). 75:25) Purification yielded (6R)-6-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylprop-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1,1,1-trifluorohept-2-ol 39-1 (150 mg, 90% purity). 1 H NMR (400MHz, CDCl3) δ7.66(dd,J=5.9,2.1Hz,4H),7.37(m,7H),3.89(s,1H),3.59(m,1H),1.93(d,J=13 .0Hz,2H),1.80(s,2H),1.53(s,25H),1.26(d,J=2.3Hz,7H),1.04(s,11H),0.88(m,10H),0.64(s,3H).

[0431] Step 2 is similar to Step 16A of Example 3, except that 3-8 is replaced with 39-1 to obtain a white solid (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(2R)-7,7,7-trifluoro-6-hydroxyhept-2-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 39 (69.4 mg, yield 69.04%). 1H NMR (400MHz, CDCl3) δ3.90(dd,J=7.9,5.2Hz,1H),3.63(m,1H),1.98(m,1H),1.84(m,3H),1.73(m,4H),1.61(m,6H),1.44(ddd,J=23 .1,12.7,8.4Hz,6H),1.28(ddd,J=14.3,11.5,6.6Hz,4H),1.06(m,4H),0.94(t,J=5.5Hz,3H),0.85(s,3H),0.66(d,J=11.8Hz,3H). 19 F NMR(377MHz, CDCl3)δ-80.11,-88.93,-89.52,-110.88,-111.46.

[0432] Example 44

[0433] Preparation of compound 44(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-5-hydroxy-5-methylhex-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0434] In step 1, compound II-9 (800 mg, 1.875 mmol, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (5 mL). Under nitrogen protection, methyl magnesium bromide and 3M diethyl ether solution (1.875 mL, 3.0 eq) were added, and the reaction mixture was stirred at room temperature for 2 h. The reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 3:1). Ethyl acetate (10 mL) was added to the reaction mixture, and the mixture was washed with saturated ammonium chloride (25 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 80:20) to give a white solid (4R)-4-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-7-hydroxy-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]valerate methyl ester 44-1 (400 mg, 0.844 mmol, yield 45%). 1HNMR(400MHz, CDCl3)δ3.63(m,0H),1.98(dt,J=12.7,3.3Hz,1H),1.77(m,2H),1.58(m,1H),1.44(m,3H),1.30(m,2H), 1.20(d,J=1.7Hz,2H),1.12(m,1H),1.00(m,1H),0.93(t,J=5.5Hz,1H),0.83(d,J=10.6Hz,1H),0.66(d,J=11.7Hz,3H).

[0435] In step 2, compound 44-1 (300 mg, 0.703 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL), and benzoyl chloride (0.122 mL, 1.055 mmol, 1.5 eq), triethylamine (0.195 mL, 1.406 mmol, 2.0 eq), and 4-dimethylaminopyridine DMAP (8.59 mg, 0.070 mmol, 0.1 eq) were added sequentially. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored for completeness by TLC (petroleum ether: ethyl acetate = 3:1). Dichloromethane (10 mL) was added to the reaction mixture, and the mixture was washed with saturated ammonium chloride (25 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 80:20) and chiral purification (instrument: SFC 150, column: REGIS(S,S)-Whelk O1, 250mm, 30mm ID, 10μm, mobile phase: CO2 / MeOH [0.2% NH3 (7M Solution in MeOH)] = 65 / 35, flow rate: 120g / min, absorption: UV 214nm, column temperature: 35℃) to obtain (5R)-5-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-7-(benzyloxy)-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2-methylhex-2-ol 44-2 (300mg, 0.522mmol, yield 74.30%). 1H NMR (400MHz, CDCl3) δ8.03(dd,J=5.3,3.2Hz,2H),7.54(d,J=7.4Hz,1H),7.43(t,J=7.6Hz,2H),4.96(dd,J=13.5,8.7Hz,1H),2.00(m,3H),1.84(ddd,J=1 6.7,11.6,4.2Hz,5H),1.58(ddd,J=20.7,19.8,10.0Hz,6H),1.32(m,4H),1. 20(d,J=1.9Hz,7H),1.13(m,4H),0.94(dd,J=11.0,4.5Hz,5H),0.69(m,3H).

[0436] Step 3 is similar to Step 5A of Example 1, except that compound 43-1 is replaced with 44-2 to obtain a white solid (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-5-hydroxy-5-methylhex-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 44 (23.96 mg, yield 28.93%). 1 HNMR (400MHz, CDCl3) δ3.63 (m, 1H), 1.98 (dt, J = 12.7, 3.2Hz, 1H), 1.80 (m, 6H), 1.43 (m, 14H), 1. 20(d,J=1.8Hz,6H),1.13(m,3H),1.00(m,2H),0.93(d,J=6.5Hz,3H),0.85(s,3H),0.67(s,3H). 19 F NMR (376MHz, CDCl3) δ-88.97,-89.58,-110.82,-111.44.

[0437] Example 45

[0438] Preparation of compound 45, 24,24-dimethyl-5α-cholan-3β,4β,24-triol

[0439] In step 1, compound I-5 (80 mg, 0.198 mmol) was dissolved in ethyl acetate (5 mL), and platinum dioxide (44.90 mg, 0.198 mmol) and acetic acid (0.3 mL) were added. The mixture was stirred at room temperature for 5 hours, and the reaction was monitored for completeness by TLC (petroleum ether / ethyl acetate = 1 / 1). The platinum dioxide was removed by diatomaceous earth filtration, the filtrate was evaporated to dryness, and the crude product was purified by rapid chromatography (petroleum ether / ethyl acetate = 0-20%) to give methyl 4β-hydroxy-3β-hydroxy-5α-cholene-24-oate 45-1 (20 mg, yield: 19.90%) as a white solid. 1 HNMR(400MHz, CDCl3)δ3.74(s,1H),3.66(s,3H),3.57(s,1H),2.34(td,J=10.2,5.0 Hz,1H),2.25–2.17(m,1H),1.94(dd,J=9.2,3.2Hz,1H),1.84–1.72(m,6H),1.58(dd ,J=20.2,8.7Hz,2H),1.43–1.25(m,8H),1.07(dd,J=16.5,6.6Hz,4H),1.02(s,3H), 0.96(dd,J=11.8,4.5Hz,2H),0.91(d,J=6.4Hz,3H),0.65(s,3H),0.62–0.55(m,1H)

[0440] In step 2, compound 45-1 (60 mg, 0.148 mmol) was dissolved in tetrahydrofuran (5 mL), and methylmagnesium bromide (in diethyl ether) (0.492 mL, 1.476 mmol) was added dropwise at 0 °C. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored for completion by TLC (petroleum ether / ethyl acetate = 1 / 1). The reaction mixture was quenched with saturated ammonium chloride aqueous solution (10 mL), extracted with ethyl acetate (20 mL × 2), and the organic phase was washed once again with saturated ammonium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was purified by rapid chromatography (petroleum ether / ethyl acetate = 0-50%) to give 24,24-dimethyl-5α-cholan-3β,4β,24-triol 45 (17 mg, yield: 28%) as a white solid. 1HNMR(400MHz,DMSO)δ4.29(d,J=6.0Hz,1H),4.00(s,1H),3.90(d,J=3.0Hz,1H),3.47(d, J=2.2Hz,1H),3.31–3.25(m,J=4.5Hz,1H),1.89(d,J=12.1Hz,1H),1.82–1.75(m,1H),1.7 0–1.48(m,6H),1.41–1.29(m,6H),1.26–1.13(m,6H),1.08(d,J=9.0Hz,3H),1.03(d,J=2 .6Hz,6H),0.94(s,5H),0.86(d,J=6.5Hz,3H),0.61(s,3H),0.58–0.51(m,1H).LC-MS[MH] - =405.35.

[0441] Examples 46 & 47

[0442] Compound 46(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-1-[(2R)-6,8-dihydroxyoct-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0443] Preparation of compound 47(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(2R)-5-(oxacyclobut-2-yl)pentan-2-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0444] Step 1: At room temperature, trimethyl sulfoxide (169.72 mg, 0.771 mmol) was dissolved in tert-butanol (2 mL), and potassium tert-butoxide solution (0.771 mL of 1 M tetrahydrofuran solution) was slowly added dropwise while stirring for 10 min. The temperature was then raised to 60 °C, and the mixture was stirred for 10 min. A solution of starting material I (60 mg, 0.129 mmol) in tert-butanol (2 mL) and tetrahydrofuran (1 mL) was added. The mixture was stirred in an oil bath at 60 °C for 16 hours. The reaction was monitored for completeness by TLC (petroleum ether: ethyl acetate = 5:1). The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Separation by column chromatography (4 g, 0–10% ethyl acetate c / petroleum ether, 20 mL / min) yielded the product (3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-8-[(2R)-5-(oxacyclobut-2-yl)pentan-2-yl]-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecylhydro-3aH-cyclopentazo[1',2':7,8]phenanthro[1,2-d][1,3]dioxacyclopentazo 47-1 (20 mg, 0.036 mmol, 28.30%), a white solid. 1 HNMR (400MHz, CDCl3) δ4.85–4.77(m,1H),4.66(dd,J=14.0,8.1Hz,1H),4.50(dd ,J=9.2,5.9Hz,1H),4.00(s,2H),2.62(s,1H),2.32(s,1H),1.98(d,J=12.3Hz,3H ),1.73(d,J=79.1Hz,11H),1.51(s,3H),1.39(s,5H),1.30(s,3H),1.11(s,4H), 1.07(s,3H),1.04(s,2H),0.91(d,J=6.4Hz,3H),0.89–0.79(m,1H),0.67(s,3H).

[0445] In step 2, 47-1 (25 mg, 0.051 mmol) was dissolved in tetrahydrofuran (1 mL) and water (0.5 mL), and p-toluenesulfonic acid (8.70 mg, 0.051 mmol) was added. The reaction system was stirred in an oil bath at 40 °C for 5 hours. The reaction was monitored for completeness by TLC (petroleum ether: ethyl acetate = 5:1). Sodium bicarbonate solution (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (2 × 10 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Separation by column chromatography (4 g, 0–25% ethyl acetate / petroleum ether, 20 mL / min) yielded a white solid (1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(2R)-5-(oxacyclobut-2-yl)pentan-2-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-di Alcohol 47 (10.37 mg, yield 44.68%) and (1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-1-[(2R)-6,8-dihydroxyoct-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 46 (2.45 mg, yield 10.05%).

[0446] Compound 47: 1 H NMR (400MHz, CDCl3) δ4.90–4.74(m,1H),4.72–4.60(m,1H),4.56–4.43(m,1H),3.74(s,1 H),3.60(d,J=11.0Hz,1H),2.64(s,1H),2.38–2.11(m,2H),1.97(d,J=12.7Hz,1H),1.83( d,J=7.0Hz,5H),1.73(d,J=13.8Hz,4H),1.46(s,2H),1.39(d,J=14.0Hz,6H),1.31–1.20 (m,3H),1.10(s,2H),1.06(s,3H),1.03–0.94(m,2H),0.91(d,J=6.4Hz,3H),0.66(s,3H). 19 F NMR(376MHz, CDCl3)δ-88.94(d,J=235.9Hz,1F),-110.94(d,J=236.0Hz,1F).LC-MS:[MH] - =453.35.

[0447] Compound 46: 1H NMR (400MHz, CDCl3) δ3.88 (ddd, J=11.8, 9.4, 4.8Hz, 3H), 3.74 (s, 1H), 3.60 (d, J=11.3H z,1H),2.18(dd,J=35.0,13.9Hz,1H),1.98(d,J=12.5Hz,1H),1.90–1.78(m,4H),1.75(s ,5H),1.47(s,4H),1.39(d,J=12.0Hz,5H),1.34–1.27(m,3H),1.24–1.18(m,1H),1.12(d ,J=9.4Hz,2H),1.06(s,3H),0.99(d,J=13.7Hz,2H),0.92(d,J=6.5Hz,3H),0.66(s,3H). 19 F NMR (376MHz, CDCl3) δ-88.94 (d, J=235.9Hz, 1F), -110.94 (d, J=235.8Hz, 1F). LC-MS: [MH] - =471.40.

[0448] Example 49

[0449] Preparation of compound 49(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-1,2,3,3a,3b,5,5a,6,7,8,9,9a,9b,10,11,11a-hexadecylhydrospiro[cyclopenta[1,2-a]phenanthrene-4,2'-oxetane]-7-ol

[0450] Step 1: Dissolve reactant 6-0 (10.00 g, 25.87 mmol, 1.0 eq) in anhydrous tetrahydrofuran (150 mL), add methyl (triphenyl-λ5-methylphosphine)acetate (51.89 g, 155.21 mmol, 6.0 eq), and stir the reaction system at 90 °C for 18 h. Monitor the depletion of the reactants using NMR spectroscopy. Add 100 mL of water to the reaction system, extract with ethyl acetate (100 mL × 3), collect the organic phase, wash with water (100 mL × 2), wash with saturated brine, dry with anhydrous sodium sulfate, collect the organic phase, and concentrate to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 60:1 to 30:1) to give a white solid (2E,5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecanoic acid methyl ester 49-0-1 (9.0 g, yield 71.1%). 1 H NMR (400MHz, CDCl3) δ6.95 (ddd, J=15.4, 8.7, 6.4Hz, 1H), 6.26 (d, J=11.6Hz, 0H), 5.82 ( d,J=15.5Hz,1H),5.37(d,J=4.9Hz,1H),4.60(tdd,J=10.9,6.6,4.2Hz,1H),3.72(d,J=1 0.2Hz,3H),2.35–2.24(m,3H),2.03(s,3H),2.01–1.91(m,3H),1.90–1.78(m,3H),1.68 –1.40(m,8H),1.31–1.07(m,5H),1.02(s,3H),0.95(d,J=6.7Hz,3H),0.72–0.68(m,3H).

[0451] Step 2: Dissolve reactant 49-0-1 (10 g, 22.59 mmol, 1.0 eq) in a mixed solvent of tetrahydrofuran (100 mL) and methanol (50 mL), add nickel chloride (2.93 g, 22.59 mmol, 1.0 eq), and slowly add sodium borohydride (1.28 g, 33.89 mmol). Stir the reaction system at room temperature for 1 h. NMR monitoring indicates complete consumption of the reactants. Add 100 mL of water to the reaction system, extract with ethyl acetate (100 mL × 3), collect the organic phase, wash with water (100 mL × 2), wash with saturated brine, dry with anhydrous sodium sulfate, collect the organic phase, and concentrate to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 60:1 to 30:1) to give a white solid (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecanoic acid methyl ester 49-0-2 (9 g, yield 80.6%). 1 H NMR(400MHz, CDCl3)δ5.37(d,J=4.9Hz,1H),4.66–4.54(m,1H),3.67(s,3H),2.29(dd d,J=15.9,11.9,6.6Hz,4H),2.03(s,3H),2.02–1.93(m,2H),1.82(ddd,J=13.0,10.8, 8.3Hz,3H),1.62–1.38(m,11H),1.19(dddd,J=32.6,25.0,13.7,6.9Hz,9H),1.01(d, J=5.8Hz,3H),0.93(d,J=6.6Hz,3H),0.87(tdd,J=10.2,4.8,2.0Hz,4H),0.67(s,3H).

[0452] Step 3 is similar to Step 5A of Example 1. Compound 43-1 is replaced with 49-0-2 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 methyl ester 49-0, which is then directly introduced to the next step.

[0453] Step 4 is similar to Step 11 of Example 3, except that 3-3 is replaced with 49-0 to obtain a white solid product (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-9a,11a-dimethyl-7-({[(2-methylprop-2-yl)oxy]diphenylsilyl}oxy)-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecanoic acid methyl ester 49-1 (650 mg, 81.4%). 1 HNMR(400MHz, CDCl3)δ7.67(ddd,J=8.0,2.4,1.6Hz,4H),7.45–7.31(m,6H),5.12(d,J=5.0Hz,1H ),3.65(s,3H),3.53(s,1H),2.27(ddd,J=15.3,11.4,9.9Hz,3H),2.13(ddd,J=13.3,4.7,1.8Hz,1 H),1.99–1.85(m,2H),1.82–1.66(m,3H),1.57–1.33(m,9H),1.26(dd,J=12.5,5.3Hz,3H),1.09–1 .00(m,12H),0.98(s,3H),0.91(d,J=6.6Hz,3H),0.85(ddd,J=14.0,8.8,4.2Hz,3H),0.64(s,3H).

[0454] Step 5 is similar to Step 2 of Example 45, where 45-1 is replaced with 49-1 to obtain the white solid product 3β-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cholest-6(5)-en-25-ol 49-2 (450 mg, 69.5%). 1 H NMR (400MHz, CDCl3) δ7.69–7.65(m,4H),7.42–7.33(m,6H),5.12(d,J=5.0Hz,1 H),3.53(s,1H),2.33(t,J=12.1Hz,1H),2.12(ddd,J=36.3,16.2,13.4Hz,1H),1 .95(s,3H),1.67(d,J=3.4Hz,3H),1.55(d,J=9.3Hz,2H),1.46–1.32(m,11H),1. 20(s,7H),1.11–1.01(m,14H),0.98(s,3H),0.91(d,J=6.5Hz,3H),0.65(s,3H).

[0455] Step 6 is similar to Step 5 of Example 6, except that 6-2 is replaced with 49-2 to obtain a white solid product 25-hydroxy-3β-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}cholest-6(5)-en-7-one 49-3 (150 mg, 46.8%). 1 H NMR(400MHz, CDCl3)δ7.66(dt,J=8.0,1.3Hz,4H),7.43–7.35(m,6H),5.45(d,J=1.6Hz,1H) ,3.66–3.55(m,1H),2.46(s,1H),2.41–2.29(m,2H),2.17(dd,J=12.4,10.6Hz,1H),1.98(dd ,J=9.4,3.3Hz,1H),1.90–1.67(m,5H),1.55–1.47(m,3H),1.42–1.33(m,6H),1.26(dd,J=6 .6, 4.3Hz, 3H), 1.20 (s, 6H), 1.16 (s, 3H), 1.06 (s, 11H), 0.91 (d, J = 6.6Hz, 4H), 0.65 (s, 3H).

[0456] Step 7 is similar to Step 16A of Example 3, except that 3-8 is replaced with 49-3, a white solid product 3β,25-dihydroxycholest-6(5)-en-7-one 49-4 (80 mg, 86.4%). 1 H NMR(400MHz, CDCl3)δ5.69(d,J=1.5Hz,1H),3.75-3.68(m,1H),2.57–2.47(m ,1H),2.40(dd,J=18.2,6.9Hz,2H),2.24(t,J=11.3Hz,1H),2.08–2.01(m,1H) ,1.98–1.86(m,3H),1.63–1.54(m,3H),1.47–1.24(m,10H),1.21(d,J=5.7Hz, 10H), 1.10 (ddd, J=19.3, 9.4, 5.7Hz, 3H), 0.94 (d, J=6.5Hz, 3H), 0.68 (s, 3H).

[0457] In step 8, the reactant 3β,25-dihydroxycholest-6(5)-en-7-one 49-4 (80 mg, 0.19 mmol) was dissolved in a mixture of methanol (3 mL) and ethyl acetate (1 mL), and Pd / C (37 mg, 0.19 mmol) was added. The mixture was purged with hydrogen three times, and the reaction system was stirred at room temperature for 3 hours. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 3:1) until complete, at which point the reaction was stopped. The diatomaceous earth was filtered through palladium on carbon, and the diatomaceous earth was washed with ethyl acetate (10 mL x 3). The organic phases were combined and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15:1) to give the white solid product 3β,25-dihydroxy-5α-cholest-7-one 49-5 (70 mg, 87.1%). 1 H NMR (400MHz, CDCl3) δ3.61(s,1H),2.41–2.31(m,2H),2.21(s,1H),2.08–1.96(m,2H),1.93–1.82(m,2H),1.77( d,J=13.3Hz,1H),1.60–1.35(m,14H),1.26–1.20(m,9H),1.14–1.06(m,6H),0.92(d,J=6.5Hz,3H),0.65(s,3H).

[0458] In step 9, trimethyl sulfoxide (133 mg, 0.60 mmol) and potassium tert-butoxide (67 mg, 0.60 mmol) were dissolved in tert-butanol (5 mL) at room temperature. The reaction mixture was stirred at 60 °C for 1 hour under nitrogen protection, and then 49-5 (50 mg, 0.12 mmol) was added, and the reaction was continued for 18 hours. The reaction was monitored by TLC plate (petroleum ether: ethyl acetate = 3:1) until complete, and the reaction was stopped. The reaction was quenched with water (15 mL), extracted with ethyl acetate (10 mL × 3), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate and then evaporated under vacuum to obtain the crude product. The crude product was purified by rapid chromatography (petroleum ether: ethyl acetate = 20:1 to 65:35) to give a white solid product (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-1,2,3,3a,3b,5,5a,6,7,8,9,9a,9b,10,11,11a-hexadecylhydrospiro[cyclopenta[1,2-a]phenanthrene-4,2'-oxetane]-7-ol 49 (17 mg, yield 31.8%). 1H NMR (400MHz, CDCl3) δ4.53(d,J=8.4Hz,1H),4.41(d,J=9.3Hz,1H),3.62(s,1H),2.85(dd,J =18.0,9.3Hz,1H),2.25–2.16(m,1H),2.01(dd,J=17.7,13.5Hz,2H),1.93(d,J=10.7Hz,3H) ,1.80(d,J=10.9Hz,2H),1.69(dd,J=11.5,7.9Hz,3H),1.50–1.44(m,5H),1.42–1.37(m,6H) ,1.30–1.25(m,6H),1.22(d,J=3.1Hz,6H),0.95(d,J=6.6Hz,4H),0.78(s,3H),0.69(s,3H).

[0459] Example 50

[0460] Preparation of compound 50(1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-6-methoxy-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0461] Step 1: In a 50 mL round-bottom flask at room temperature, I-13 (100 mg, 0.22 mmol) was dissolved in 3 mL of dichloromethane. Triethylamine (66 mg, 0.66 mmol), 4-dimethylaminopyridine (5 mg, 0.04 mmol), and acetic anhydride (22 mg, 0.22 mmol) were added at room temperature. The mixture was then stirred at room temperature for 0.5 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 2:1). After the reaction was complete, the solution was quenched with 30 mL of water and 20 mL of ethyl acetate. ×3) Extraction, washing the organic phase with saturated brine (30 mL), drying with anhydrous sodium sulfate, concentrating the organic phase, and purifying by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give a white solid (5R)-5-[(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-7-acetoxy-4,4-difluoro-6-hydroxy-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoate methyl 50-1 (90 mg, yield: 78.3%). 1HNMR (400MHz, CDCl3) δ4.75–4.69(m,1H),3.83(s,1H),3.67(s,3H),2.28(dt,J=12.2,6.0Hz,2H),2.23–2.11( m,1H),2.09(s,3H),2.01–1.62(m,12H),1.55–1.17(m,11H),1.09(s,3H),0.93(d,J=6.5Hz,3H),0.66(s,3H). 19 F NMR (376MHz, CDCl3) δ = -89.05, -110.86.

[0462] Step 2: In a 50 mL round-bottom flask at room temperature, dissolve 50-1 (40 mg, 0.080 mmol) in 3 mL of 1,2-dichloroethane. Add 4A molecular sieve (40 mg), 1,8-bis(dimethylamino)naphthalene (86 mg, 0.40 mmol), and trimethyloxonium tetrafluoroboric acid (59 mg, 0.40 mmol) at 0 °C. Stir at 70 °C for 12 hours. Monitor the reaction by TLC (petroleum ether:ethyl acetate = 5:1). After the reaction is complete, quench with water (20 mL) and ethyl acetate (10 mL)... Extracted by L×3), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, the organic phase was concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give a white solid (5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-7-acetoxy-4,4-difluoro-6-methoxy-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoate methyl 50-2 (18 mg, yield: 39.5%). 1 H NMR(400MHz, CDCl3)δ=3.66(s,4H),3.33(s,3H),3.19–3.12(m,1H),2.30–2.24(m,2H),2.09(s,3H),2.00–1.95(m,1H),1 .91–1.79(m,5H),1.65–1.45(m,7H),1.43–1.32(m,6H),1.16–1.05(m,5H),1.02(s,3H),0.93(d,J=6.5,3H),0.65(s,3H). 19 F NMR (376MHz, CDCl3) δ = -89.11, -110.66.

[0463] Step 3 is similar to Example 45. Step 2 is to replace 45-1 with 50-2 to obtain a white solid (1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-6-methoxy-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 50 (7 mg, yield: 36.5%). 1 H NMR (400MHz, CDCl3) δ = 3.88 (t, J = 2.5, 1H), 3.39 (s, 3H), 3.16–3.10 (m, 1H), 2.25 (dddd, J = 28.2, 18.5, 14.0, 6.2, 2H), 2.01–1.95 (m, 1H), 1.91–1.79(m,4H),1.78–1.62(m,6H),1.49–1.39(m,6H),1.39–1.29(m,7H),1.21(s,6H),1.07(s,3H),0.93(d,J=6.5,3H),0.67(s,3H). 19 F NMR (376MHz, CDCl3) δ = -89.04 (dd, J = 236.4, 43.7, 1F), -110.87 (dd, J = 236.5, 163.9, 1F).

[0464] Example 51

[0465] Preparation of compound 51(1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-1,2,3,3a,3b,4,5,5a,7,8,9,9a,9b,10,11,11a-hexadecylhydrospiro[cyclopenta[1,2-a]phenanthrene-6,1'-cyclopropane]-7-ol

[0466] Step 1: In a 100 mL round-bottom flask, methyltriphenylphosphine bromide (360 mg, 1.00 mmol) was suspended in tetrahydrofuran (5 mL) at room temperature. A 1 mol / L potassium tert-butoxide tetrahydrofuran solution (1 mL, 1.00 mmol) was added dropwise at 0 °C. After stirring the mixture at room temperature for 2 hours, a tetrahydrofuran solution of compound 56-2 (100 mg, 0.20 mmol) (1 mL) was added dropwise to the reaction mixture at 0 °C. The mixture was stirred at room temperature for 4 hours. The reaction was monitored for completeness by TLC (petroleum ether: ethyl acetate = 4:1). Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The extracted organic solution was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to give a white solid (1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-6-methyl-6-methyl-hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 51-1 (30 mg, yield: 29.6%). 1 H NMR (400MHz, CDCl3) δ = 5.13 (s, 1H), 4.60 (s, 1H), 4.01 (dd, J = 11.4, 5.3, 1H), 2.05–1.95 (m, 4H), 1.91–1.74 (m,5H),1.49–1.27(m,12H),1.21(s,6H),1.20–1.02(m,5H),0.93(d,J=6.5,3H),0.72(s,3H),0.67(s,3H). 19 F NMR (376MHz, CDCl3) δ = -89.16, -111.36.

[0467] In step 2, 51-1 (30 mg, 0.066 mmol) was dissolved in toluene (1.5 mL) in a 50 mL round-bottom flask at room temperature. Diiodomethane (177 mg, 0.66 mmol) and diethylzinc tetrahydrofuran solution (0.33 mL, 0.66 mmol) were added at 0 °C. The mixture was then stirred at room temperature for 16 hours. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 2:1) to ensure complete reaction. Quenching with water (15 mL), extraction with ethyl acetate (10 mL × 3), washing the organic phase with saturated brine (10 mL), drying with anhydrous sodium sulfate, and purification by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give a white solid (1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-1,2,3,3a,3b,4,5,5a,7,8,9,9a,9b,10,11,11a-hexadecylhydrospiro[cyclopenta[1,2-a]phenanthrene-6,1'-cyclopropane]-7-ol 51 (8 mg, yield: 24.7%). 1 H NMR (400MHz, CDCl3) δ = 3.70 (dd, J = 11.5, 4.2, 1H), 2.01–1.96 (m, 1H), 1.89–1.78 (m, 5H), 1.73–1.52 (m, 5H), 1.43–1.26 (m, 10H), 1.2 1(s,6H),1.16–1.03(m,5H),0.93(d,J=6.5,3H),0.91(s,3H),0.72–0.67(m,1H),0.66(s,3H),0.44–0.39(m,1H),0.31–0.25(m,2H). 19 F NMR (376MHz, CDCl3) δ = -88.17, -110.68.LC-MS: [M+Na] + =489.3.

[0468] Examples 52 & 64

[0469] Compounds 52 or 64 (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R,6S)-6-hydroxy-6-(4-hydroxycyclohexyl)hept-2-yl]-9a,11a-dimethylhexadecyl-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0470] Preparation of compounds 64 or 52(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R,6R)-6-hydroxy-6-(4-hydroxycyclohexyl)hept-2-yl]-9a,11a-dimethylhexadecyl-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0471] Step 1: At room temperature, 1,4-dioxaspiro[4.5]dec-8-ol 52-O-1 (3.00 g, 18.96 mmol) was dissolved in dichloromethane (50 mL), and triphenylphosphine (7.46 g, 28.45 mmol) was added. The mixture was cooled in an ice bath, and a dichloromethane solution of carbon tetrabromide (9.43 g, 28.45 mmol) was slowly added dropwise (20 mL). The mixture was brought to room temperature and stirred for 16 hours. The reaction was monitored for completeness by TLC (petroleum ether: ethyl acetate = 5:1). Water (40 mL) was added, and the mixture was extracted with dichloromethane (50 mL x 2). The combined organic phases were washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Separation by column chromatography (40 g, 0-5% ethyl acetate / petroleum ether, 40 mL / min) yielded a light brown oily substance, 8-bromo-1,4-dioxane[4.5]decane 52-0-2 (3.4 g, 14.61 mmol, yield 77.0%). 1 H NMR (400MHz, CDCl3) δ4.39–4.25(m,1H),4.02–3.87(m,4H),2.22–2.02(m,4H),1.92(ddd,J=12.6,8.6,4.4Hz,2H),1.62(ddd,J=12.8,7.9,4.6Hz,2H)

[0472] In step 2, at room temperature, the treated magnesium shavings (132 mg, 5.43 mmol) were poured into a three-necked flask (50 mL), iodine (57 mg, 0.23 mmol) was added, followed by tetrahydrofuran (1 mL). After three N2 purgings, the mixture was stirred at low speed for 5 min. Then, 1 / 3 of a tetrahydrofuran solution (7 mL) of 8-bromo-1,4-dioxaspiro[4.5]decane 52-0-2 (1.00 g, 4.52 mmol) was added. While stirring, the mixture was heated with a hot gun until the system changed from a dark brown to a light brown clear liquid. The remaining 2 / 3 of the raw material was then added dropwise. The mixture was stirred at 65 °C for 1 hour, and the remaining magnesium shavings were collected. The system was cooled to room temperature to obtain bromo(1,4-dioxaspiro[4.5]dec-8-yl)magnesium (0.5 M tetrahydrofuran solution) 52-0, which was used directly in the next step.

[0473] Steps 3-5 are similar to steps 1-3 of Example 22. Cyclohexane magnesium bromide is replaced with (1,4-dioxaspiro[4.5]dec-8-yl)magnesium (0.5M tetrahydrofuran solution) 52-0 to obtain a white solid (6R)-6-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylprop-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2-(1,4-dioxaspiro[4.5]dec-8-yl)hepta-2-ol 52-3 (42 mg).

[0474] Compound 52-1: 1 H NMR (400MHz, CDCl3) δ7.69–7.63(m,4H),7.45–7.33(m,6H),3.94(s,4H),3. 60–3.53(m,1H),3.40(s,1H),1.99–1.89(m,2H),1.86–1.67(m,9H),1.57–1 .30(m,19H),1.23(d,J=13.3Hz,3H),1.18–1.06(m,3H),1.04(s,9H),0.90( d,J=6.6Hz,3H),0.82(s,3H),0.78(d,J=9.0Hz,1H),0.62(d,J=12.4Hz,3H). 19 F NMR (377MHz, CDCl3) δ-88.83,-89.46,-110.86,-111.49.

[0475] Compound 52-2: 1 H NMR (400MHz, CDCl3) δ7.66 (ddd, J=6.3, 3.4, 2.0Hz, 4H), 7.44–7.33 (m, 6H), 3.93 (s, 4H), 3.63– 3.54(m,1H),2.37(ddd,J=25.4,19.1,14.4Hz,3H),2.00–1.75(m,8H),1.66(dd,J=23.4,9.2Hz ,8H),1.49(dd,J=17.2,11.2Hz,4H),1.40–1.15(m,11H),1.04(s,9H),0.96–0.92(m,1H),0.90 (d,J=6.5Hz,3H),0.86(dd,J=6.6,3.1Hz,2H),0.80(d,J=12.2Hz,3H),0.61(d,J=12.3Hz,3H). 19F NMR (376MHz, CDCl3) δ-88.83,-89.46,-110.86,-111.49.

[0476] Compound 52-3: 1 H NMR (400MHz, CDCl3) δ7.68–7.63(m,4H),7.44–7.34(m,6H),3.94(s,4H),3.64–3.53(m ,1H),1.94(d,J=12.3Hz,1H),1.85–1.75(m,5H),1.68(dd,J=24.9,8.0Hz,6H),1.50(d d,J=25.9,12.1Hz,8H),1.42–1.28(m,12H),1.20(d,J=10.8Hz,2H),1.11(s,3H),1.04 (s,9H),0.90(d,J=6.5Hz,3H),0.86(dd,J=6.6,3.1Hz,3H),0.82(s,3H),0.64(s,3H).

[0477] In step 6, compound 52-3 (220 mg, 0.27 mmol) was chirally resolved by SFC (instrument: Waters Acquity UPCC, column: Daicel CHIRALPAK IC_3, 3.0*150 mm, 3 μm, mobile phase: CO2 / MeOH (0.1% DEA) = 50 / 50, flow rate: 1.5 mL / min, column temperature: 37 °C) to obtain 52-4 (90 mg, retention time: 1.423 min) and 64-1 (80 mg, yield 36.4%, retention time: 3.016 min), both white solids.

[0478] Compound 52-4: 1 H NMR(400MHz, CDCl3) δ7.66(d,J=6.9Hz,4H),7.48–7.30(m,6H),3.94(s,4H),3.65–3.53(m,1H),1.93(d,J=12.9Hz,1H),1.86–1.4 9(m,18H),1.48–1.26(m,17H),1.11(s,3H),1.04(s,9H),0.90(d,J=6.4Hz,3H),0.82(s,3H),0.76(t,J=10.0Hz,1H),0.63(s,3H).

[0479] Compound 64-1: 1H NMR (400MHz, CDCl3) δ7.66 (d, J=5.3Hz, 4H), 7.39 (dd, J=14.7, 6.6Hz, 6H), 3.9 4(s,4H),3.57(d,J=9.6Hz,1H),1.97–1.90(m,1H),1.85–1.59(m,10H),1.38(d d,J=29.6,18.6Hz,17H),1.27–1.15(m,7H),1.11(s,3H),1.04(s,9H),1.01–0. 96(m,1H),0.90(d,J=6.6Hz,3H),0.82(s,3H),0.79–0.72(m,1H),0.63(s,3H).

[0480] In step 7A, reactant 52-4 (70 mg, 0.087 mmol) was dissolved in tetrahydrofuran (1 mL), and tetrabutylammonium fluoride solution (2 mL, 1 mol / L) was added. The reaction system was stirred at 40 °C for 1 hour. The reaction was monitored for completeness by TLC (petroleum ether: ethyl acetate = 2:1). Water (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated by column chromatography (4 g, 0–30% ethyl acetate / petroleum ether, 20 mL / min) to give a white solid 52-5 (45 mg, yield 86.8%).

[0481] In step 8A, reactant 52-5 (45 mg, 0.079 mmol) was dissolved in tetrahydrofuran (3 mL) and water (1 mL), and p-toluenesulfonic acid (20 mg, 0.12 mmol) was added. The reaction mixture was stirred in an oil bath at 70 °C for 2 hours. The reaction was monitored for completeness by TLC (petroleum ether: ethyl acetate = 2:1). A saturated sodium bicarbonate solution (20 mL) was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude white solid 52-6 (40 mg, yield 91.6%).

[0482] In step 9A, 52-6 (40 mg, 0.077 mmol) was dissolved in methanol (4 mL) at room temperature and cooled to 0°C in an ice bath. Then, NaBH4 (30 mg, 0.79 mmol) was added in portions. The mixture was stirred at room temperature for 1 hour. The reaction was monitored for completeness by TLC (petroleum ether: ethyl acetate = 1:1). The reaction solution was quenched with saturated ammonium chloride solution (10 mL), 10 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated to obtain crude product, and separated by column chromatography (4 g, 0–60% ethyl acetate / petroleum ether, 20 mL / min) to obtain white solid 52 (24 mg, yield 56.2%). 1 H NMR (400MHz, CDCl3) δ3.70–3.50(m,2H),2.11–1.94(m,3H),1.91–1.50(m,13H),1.44–1.12 (m,18H),1.10(s,3H),1.07–0.97(m,3H),0.93(d,J=6.5Hz,3H),0.85(s,3H),0.67(s,3H). 19 F NMR (377MHz, CDCl3) δ-88.96,-89.59,-110.84,-111.47.

[0483] Steps 7B-9B are similar to those in Example 52. Steps 7A-9A are similar to those in Example 52, except that 52-4 is replaced with 64-1 to obtain white solid 64 (23 mg, yield 48.7%). 1 H NMR(400MHz, CDCl3) δ3.59(dtd,J=14.9,10.8,5.5Hz,2H),2.01(dd,J=20.0,9.9Hz,3H),1.89–1.53(m,12 H),1.43–1.12(m,18H),1.10(s,3H),1.09–0.96(m,4H),0.93(d,J=6.5Hz,3H),0.85(s,3H),0.67(s,3H). 19 F NMR (376MHz, CDCl3) δ-88.96,-89.59,-110.84,-111.47.

[0484] Example 63

[0485] Preparation of compound 63(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-1-[(2R)-6-amino-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0486] Step 1: At room temperature, compound I-14 (200 mg, 0.44 mmol) was dissolved in dichloromethane (8 mL), and 4-dimethylaminopyridine (DMAP) (54 mg, 0.44 mmol) and triethylamine (355 mg, 3.50 mmol) were added. The mixture was cooled to 0°C in an ice bath, and a solution of acetic anhydride (201 mg, 1.97 mmol) in dichloromethane (1 mL) was slowly added dropwise. After 10 min, the mixture was brought to room temperature and stirred for 4 hours. The reaction solution was diluted with dichloromethane (20 mL), washed successively with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Separation by column chromatography (4 g, 0–10% ethyl acetate / petroleum ether, 20 mL / min) yielded a white solid acetic acid-(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-7-acetoxy-4,4-difluoro-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-i]phenanthrene-6-yl ester 63-1 (150 mg, yield 60.2%). 1 H NMR(400MHz, CDCl3)δ5.21(s,1H),4.80(dt,J=8.1,4.5Hz,1H),2.10(s,3H),1.98(s,3H),1.94–1.62(m,9H),1.51–1.25(m, 13H),1.21(s,6H),1.13(dd,J=15.6,11.6Hz,3H),1.05(s,3H),1.00(d,J=12.3Hz,1H),0.93(d,J=6.5Hz,3H),0.66(s,3H).

[0487] In step 2, at room temperature, 63-1 (150 mg, 0.28 mmol) was dissolved in anhydrous toluene (2 mL). Under nitrogen protection, a toluene solution of azidotrimethylsilane (48 mg, 0.42 mmol) (0.5 mL) was added, followed by the slow dropwise addition of a toluene solution of boron trifluoride diethyl ether (59 mg, 0.42 mmol) (0.5 mL). The mixture was stirred at room temperature for 16 hours. The reaction was monitored for completion by TLC (petroleum ether: ethyl acetate = 5:1). The reaction was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Separation by column chromatography (4 g, 0–20% ethyl acetate / petroleum ether, 20 mL / min) yielded acetic acid-(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6-acetoxy-1-[(2R)-6-azido-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 63-2 (120 mg, yield 68.8%). 1 H NMR(400MHz, CDCl3)δ5.21(s,1H),4.80(d,J=12.5Hz,1H),2.10(s,3H),1.98(s,3H),1.96–1.71(m,9H),1.67–1.63(m, 1H),1.52–1.26(m,10H),1.25(s,4H),1.22–1.08(m,4H),1.05(s,3H),1.01(s,2H),0.93(d,J=5.7Hz,3H),0.66(s,3H).

[0488] In step 3, at room temperature, 63-2 (120 mg, 0.21 mmol) was dissolved in methanol (5 mL), and Pd / C (80 mg, 10%) was added. The mixture was purged three times with hydrogen balloons and stirred at room temperature for 3 hours. The reaction was monitored for completeness by TLC (petroleum ether: ethyl acetate = 5:1). The reaction solution was filtered through diatomaceous earth, concentrated, and dried to obtain a crude product, which was then separated by column chromatography (4 g, 0–10% methanol / dichloromethane, 20 mL / min) to obtain compound acetic acid-(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6-acetoxy-1-[(2R)-6-amino-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 63-3 (40 mg, yield 34.9%). 1H NMR (400MHz, CDCl3) δ5.21(s,1H),4.85–4.75(m,1H),2.10(s,3H),1.97(s,3H),1.92–1.61(m,10H),1.44(ddd,J=25.9,2 4.1,12.1Hz,8H),1.29(d,J=5.8Hz,6H),1.25–1.08(m,6H),1.05(s,3H),1.00(s,2H),0.93(d,J=6.4Hz,3H),0.65(s,3H).

[0489] In step 4, at room temperature, 63-3 (40 mg, 0.074 mmol) was dissolved in methanol (2 mL) and tetrahydrofuran (2 mL), and then lithium hydroxide solution (2 M, 0.5 mL, 1.00 mmol) was added in one step. The mixture was stirred at room temperature for 1 hour. The reaction was monitored for completeness by TLC (dichloromethane:methanol = 10:1). The reaction solution was concentrated, 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Separation by column chromatography (4 g, 0–10% methanol / dichloromethane, 20 mL / min) yielded (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-1-[(2R)-6-amino-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 63 (19 mg, purity: 53.8%). 1 H NMR (400MHz, DMSO) δ4.33(d,J=59.8Hz,2H),3.49(s,1H),3.34(s,1H),2.10(dd,J=51.8,12.6Hz,1H),1.92(d,J=12.6Hz,1H),1.81–1.52(m ,6H),1.23(tdd,J=42.0,33.6,9.2Hz,16H),0.99(d,J=6.6Hz,9H),0.94(d,J=7.6Hz,1H),0.90(d,J=6.3Hz,3H),0.87(s,1H),0.63(s,3H). 19 F NMR(376MHz,DMSO)δ-86.65,-87.27,-108.66,-109.28.LC-MS:[M+H] + =456.50

[0490] Example 61

[0491] Preparation of compound 61(6R)-6-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-7-[(2-hydroxyethyl)oxy]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2-methylhept-2-ol

[0492] Step 1, similar to Example 45. Step 2, replace 45-1 with II-14 to obtain (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 61-1

[0493] In step 2, 61-1 (100 mg, 0.227 mmol, 1 eq) was dissolved in dichloromethane (5 mL), followed by the sequential addition of rhodium acetate (6.56 mg, 0.023 mmol, 0.1 eq) and ethyl diazonium acetate (133.72 mg, 1.172 mmol, 5 eq). The reaction mixture was reacted at room temperature under a nitrogen atmosphere for 3 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1) to ensure complete reaction. The reaction was quenched with H2O (5 mL), and extracted with dichloromethane (30 mL × 3). The organic phase was collected. The product was dried over anhydrous sodium sulfate, and the organic phase was evaporated under vacuum to obtain the crude product. The crude product was purified by rapid chromatography (petroleum ether:ethyl acetate = 100-0:90:10) to give product P1{[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-yl]oxy}ethyl acetate 61-2 (65 mg, yield 46.39%).

[0494] In steps 3-4, starting material 61-2 (35 mg, 0.068 mmol, 1 eq) was dissolved in tetrahydrofuran (5 mL) at 0 °C, and lithium aluminum hydride (7.77 mg, 0.205 mmol, 3 eq) was added. The reaction mixture was reacted at 0 °C for 0.5 h under a nitrogen atmosphere. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 5:1) until complete, and the reaction was stopped. The reaction was quenched with water (5 mL), extracted with ethyl acetate (10 mL × 3), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate and then evaporated under vacuum to obtain crude product 61-3. Crude product 61-3 was dissolved in dichloromethane (3 mL), and triethylamine (14 mg, 0.14 mmol, 2.0 eq), 4-dimethylaminopyridine (3 mg, 0.014 mmol, 0.2 eq), and benzoyl chloride (20 mg, 0.14 mmol, 2 eq) were added at room temperature. The mixture was then stirred at room temperature for 3 hours, and the reaction was monitored by TLC (petroleum ether: ethyl acetate = 1:1) to ensure complete reaction. The reaction was quenched with water (10 mL), extracted with ethyl acetate (10 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated. The organic phase was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) and chiral resolution (instrument: Waters Acquity UPCC, column: Daicel CHIRALPAK). OD_3, 3*150mm, 3um, Mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 80 / 20, Flow rate: 2.0ml / min, Column temperature: 37 degrees (6R)-6-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-7-{[2-(benzyloxy)ethyl]oxy}-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2-methylhept-2-ol 61-4 (30mg, Yield: 77%, Retention time: 2.221min). 1 H NMR (400MHz, CDCl3) δ8.11–8.04(m,3H),7.60–7.54(m,2H),7.48–7.42(m,2H),4.51–4. 40(m,2H),3.85–3.78(m,2H),3.38–3.29(m,1H),2.00–1.96(m,1H),1.92-1.79(m,4H), 1.76–1.66(m,4H),1.59–1.52(m,2H),1.41(ddd,J=23.1,10.4,6.5Hz,9H),1.31–1.21( m,10H),1.18–0.97(m,6H),0.93(d,J=6.5Hz,3H),0.86–0.78(m,3H),0.73–0.61(m,3H).

[0495] In step 5, at room temperature, 61-4 (50 mg, 0.103 mmol, 1.0 eq) was dissolved in tetrahydrofuran (1 mL) and methanol (1 mL). Lithium hydroxide monohydrate (25 mg, 1.03 mmol, 10.0 eq) and water (0.5 mL) were added. The mixture was then stirred at 40 °C for 30 min. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 1:1). After the reaction was complete, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 2). The organic phase was saturated. Wash with brine (100 mL), dry with anhydrous sodium sulfate, concentrate the organic phase, and purify by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give a white solid (6R)-6-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-7-[(2-hydroxyethyl)oxy]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2-methylhept-2-ol 61 (30 mg, yield: 60%). 1 H NMR (400MHz, CDCl3) δ3.71(dd,J=5.5,3.7Hz,2H),3.62–3.55(m,2H),3.29(s,1H),1.99(d,J=12.8Hz,1H),1.89(s,1H),1.85–1.66(m,6H),1.61(d, J=4.5Hz,1H),1.54(s,1H),1.48–1.36(m,8H),1.33–1.23(m,5H),1.21(s ,6H),1.16–0.97(m,5H),0.93(d,J=6.5Hz,3H),0.84(s,3H),0.67(s,3H). 19 F NMR(377MHz, CDCl3)δ-88.95,-89.58,-110.86,-111.48.LC-MS:[MH] - =483.80

[0496] Examples 8, 9, 65, 73

[0497] Compounds 8 or 9 (1S,3aS,3bR,5aR,7S,9aS,9bS,11aS)-4,4-difluoro-1-[(1R)-1-[(3-hydroxy-3-methylbutyl)oxy]ethyl]-9a,11a-dimethylhexadecylhydro-1H-cyclopentano[1,2-a]phenanthrene-7-ol or (1S,3aS,3bR,5aR,7S,9aS,9bS,11aS)-4,4-difluoro-1-[(1S)-1-[(3-hydroxy-3-methylbutyl)oxy]ethyl]-9a,11a-dimethylhexadecylhydro-1H-cyclopentano[1,2-a]phenanthrene-7-ol

[0498] Compound 73 or 65 (1S,3aR,5aR,7S,9aS,9bR,11aS)-4-fluoro-1-[(1R)-1-[(3-hydroxy-3-methylbutyl)oxy]ethyl]-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 Preparation of 7-ols or (1S,3aR,5aR,7S,9aS,9bR,11aS)-4-fluoro-1-[(1S)-1-[(3-hydroxy-3-methylbutyl)oxy]ethyl]-9a,11a-dimethyl-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecanohydro-1H-cyclopentano[1,2-a]phenanthrene-7-ol

[0499] In step 1, 2-4 (900 mg, 2.02 mmol) was added to a reaction flask containing acetone (15 mL), followed by N-hydroxyphthalimide (132 mg, 0.81 mmol), cobalt acetate (72 mg, 0.41 mmol), and tert-butyl hydroperoxide (912 mg, 10.12 mmol). The reaction was stirred at 35 °C for 48 hours. TLC monitoring showed that the starting material had reacted completely and a new spot appeared. Water (20 mL) was added for dilution, followed by dichloromethane (20 mL × 3). The mixture was extracted three times, washed with sodium chloride, and dried over anhydrous sodium sulfate. The reaction solution was evaporated to dryness under reduced pressure (water pump, 45 °C). The solution was then purified by column chromatography (petroleum ether: ethyl acetate = 93:7) to obtain 8-1 (380 mg, 36.6%) as a white solid and 9-1 (160 mg, 15.5%) as a white solid.

[0500] Compound 8-1: 1 H NMR (400MHz, CDCl3) δ7.53(d,J=12.4Hz,1H),5.71(d,J=1.6Hz,1H),5.23(d,J =12.4Hz,1H),4.72(m,1H),3.99(dd,J=10.2,6.1Hz,1H),3.70(s,3H),2.50(d d,J=14.7,12.9Hz,3H),2.24(t,J=11.2Hz,1H),2.05(d,J=2.9Hz,5H),1.96(d d,J=8.5,5.1Hz,3H),1.55(s,7H),1.22(dd,J=11.0,4.9Hz,8H),0.67(s,3H).

[0501] Compound 9-1: 1H NMR (400MHz, CDCl3) δ7.52(d,J=12.4Hz,1H),5.72(d,J=1.6Hz,1H),5.23(dd,J=12.4,5.4Hz,1H),4.71(dd,J=10.5,5.8Hz,1H),4.00(m,1H),3. 69(d,J=2.9Hz,3H),2.51(m,3H),2.25(s,1H),2.05(d,J=3.2Hz,3H),1. 94(m,4H),1.54(s,8H),1.28(m,4H),1.21(d,J=4.3Hz,4H),0.67(s,3H).

[0502] In step 2, 8-1 (380 mg, 0.83 mmol) was added to a reaction flask containing methanol (1 mL) and ethyl acetate (1 mL), followed by palladium on carbon (150 mg, 1.41 mmol). The reaction was stirred at 25 °C for 5 h and monitored by TLC until complete. Water (20 mL) was added for dilution, followed by the addition of ethyl acetate (20 mL × 3). The mixture was extracted three times, washed with sodium chloride, and dried over anhydrous sodium sulfate. The reaction solution was then evaporated to dryness under reduced pressure (using a water pump at 45 °C). The solution was purified by column chromatography (petroleum ether:ethyl acetate = 90:10) to obtain 8-2 (250 mg, 0.49 mmol, 58.7%) as a white solid. 1 H NMR (400MHz, CDCl3) δ4.67 (s, 1H), 3.80 (dt, J = 9.1, 5.8Hz, 1H), 3.67 (s, 3H), 3.52 (m, 1H), 3.3 0(dd,J=10.0,5.9Hz,1H),2.54(m,2H),2.33(m,2H),2.23(dd,J=9.9,2.6Hz,1H),2.05(s,1H) ,2.02(s,3H),1.89(d,J=13.1Hz,1H),1.79(m,1H),1.68(m,2H),1.55(d,J=18.4Hz,6H),1.45 (ddd,J=18.1,10.9,6.0Hz,4H),1.26(m,1H),1.10(t,J=6.2Hz,6H),1.07(s,2H),0.65(s,3H).

[0503] In step 3, 8-2 (190 mg, 0.41 mmol) was added to a reaction flask containing diethylaminotrifluoride DAST (4 mL). The reaction was stirred at room temperature (80 °C) for 2 h. TLC monitoring showed that the starting material had reacted completely and a new spot appeared. Saturated sodium bicarbonate aqueous solution (20 mL) was added dropwise at 0 °C, followed by dichloromethane (20 mL × 3). The mixture was extracted three times, washed with sodium chloride, and dried over anhydrous sodium sulfate. The reaction solution was evaporated to dryness under reduced pressure (water pump, 45 °C). The mixture was then purified by column chromatography (petroleum ether: ethyl acetate = 80:20) to obtain a mixture of 8-3 and 73-1 (190 mg) as a white solid.

[0504] Compound 8-3: 1 H NMR (400MHz, CDCl3) δ4.69 (m, 1H), 3.81 (dt, J = 9.1, 5.8Hz, 1H), 3.67 (s, 3H), 3. 52(m,1H),3.31(dd,J=10.0,5.9Hz,1H),2.55(m,2H),2.03(m,4H),1.84(s,2H) ,1.73(dd,J=13.2,9.7Hz,3H),1.68(d,J=6.0Hz,2H),1.54(s,8H),1.27(dd,J= 12.1,4.9Hz,2H),1.09(m,6H),0.85(d,J=10.2Hz,3H),0.65(d,J=15.5Hz,3H).

[0505] In step 4, the mixture of 8-3 and 73-1 (180 mg, 0.37 mmol) was added to a reaction flask containing tetrahydrofuran (2 mL). Methylmagnesium bromide (1.24 mL, 3.71 mmol) was added at 0 °C. The reaction was stirred at room temperature (25 °C) for 1 h. TLC monitoring showed that the starting material had reacted completely and a new spot appeared. The mixture was diluted with ammonium chloride aqueous solution (20 mL), followed by dichloromethane (20 mL × 3). Extraction was performed three times, followed by washing with sodium chloride and drying with anhydrous sodium sulfate. The reaction solution was then evaporated to dryness under reduced pressure (water pump, 45 °C). The mixture of 8-4 and 73-2 (130 mg, 71.2%) was purified by column chromatography (petroleum ether:ethyl acetate = 70:30) to obtain a white solid.

[0506] Compound 8-4: 1H NMR (400MHz, CDCl3) δ3.86 (d, J=4.0Hz, 1H), 3.62 (s, 1H), 3.45 (m, 1H), 3.28 (dd, J=10 .0,5.9Hz,1H),2.11(m,1H),1.86(m,4H),1.71(m,4H),1.60(dd,J=8.4,4.1Hz,4H),1. 44(dd,J=13.6,8.5Hz,4H),1.31(dt,J=6.4,5.3Hz,3H),1.23(d,J=5.7Hz,6H),1.12( d,J=5.9Hz,4H),1.01(d,J=9.6Hz,2H),0.83(d,J=9.4Hz,3H),0.67(d,J=14.7Hz,3H).

[0507] In step 5, a mixture of 8-4 and 73-2 (100 mg, 0.23 mmol) was added to a reaction flask containing 2 mL of dichloromethane. Then, benzoyl chloride (48 mg, 0.34 mmol), triethylamine (69 mg, 0.68 mmol), and 4-dimethylaminopyridine (2.76 mg, 0.023 mmol) were added. The reaction was stirred at room temperature (25 °C) for 1 hour. TLC monitoring showed that half of the reactants had reacted and a new spot appeared. The temperature was then increased to 40 °C. The mixture was stirred at ℃ for 2 hours. After the reaction was complete as monitored by TLC, water (20 mL) was added for dilution, followed by the addition of ethyl acetate (20 mL × 3). The mixture was extracted three times, washed with sodium chloride, and dried over anhydrous sodium sulfate. The reaction solution was evaporated to dryness under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 90:10) to obtain a mixture of 8-5 and 73-3 (120 mg, 0.203 mmol, 89.7%) as a white solid. The crude product was further purified by chiral resolution (instrument: Waters). Acquity UPCC, 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: 1.5ml / min, column temperature: 37 degrees Celsius. Separation yielded 8-5 (110mg, 67.8%, retention time 2.975min) and 73-3 (13mg, 8.3%, retention time: 3.332min).

[0508] Compound 8-5: 1H NMR (400MHz, CDCl3) δ8.03(m,2H),7.54(d,J=7.4Hz,1H),7.43(t,J=7.6Hz,2H),4.95(m,1H ),3.86(td,J=9.5,4.1Hz,1H),3.45(dt,J=9.5,4.9Hz,1H),3.29(dd,J=10.0,6.0Hz,1H),2. 13(d,J=12.9Hz,1H),2.00(d,J=15.6Hz,1H),1.79(m,3H),1.65(m,10H),1.46(m,6H),1.23( d,J=5.8Hz,6H),1.14(dd,J=8.3,5.1Hz,5H),0.90(d,J=9.8Hz,3H),0.68(d,J=14.3Hz,3H).

[0509] In step 6A, 8-5 (110 mg, 0.20 mmol) was added to a reaction flask containing tetrahydrofuran (2 mL), water (1 mL), and methanol (1 mL), followed by lithium hydroxide (4.82 mg, 0.20 mmol). The reaction was stirred at 40 °C for 2 hours. TLC monitoring showed that the starting material had reacted completely and a new spot appeared. Water (20 mL) was added for dilution, followed by dichloromethane (20 mL × 3). The mixture was extracted three times, washed with sodium chloride, and dried over anhydrous sodium sulfate. The reaction solution was evaporated to dryness under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate = 80:20) to obtain 8 (85 mg, 95.5%) as a white solid.

[0510] 1 H NMR (400MHz, CDCl3) δ3.86 (td, J=9.5, 4.0Hz, 1H), 3.62 (m, 1H), 3.45 (dt, J=9.5, 4.8Hz, 1H), 3.28(dd,J=10.0,5.9Hz,1H),2.11(d,J=12.9Hz,1H),1.85(m,3H),1.71(dd,J=13.7,4.2Hz, 4H),1.61(ddd,J=10.2,7.5,3.4Hz,5H),1.43(m,4H),1.31(dd,J=15.6,3.7Hz,3H),1.23(d, J=5.8Hz, 6H), 1.12 (d, J=5.9Hz, 4H), 1.00 (dd, J=18.7, 8.6Hz, 2H), 0.84 (s, 3H), 0.69 (s, 3H). 19 F NMR (377MHz, CDCl3) δ-89.07,-89.70,-110.75,-111.37.

[0511] Step 6B is similar to Step 6A of Example 8, except that 8-5 is replaced with 73-3 to obtain compound 73 (10 mg, 95.9%) as a white solid. 1 H NMR (400MHz, CDCl3) δ3.85 (td, J=9.5, 4.1Hz, 1H), 3.60 (m, 1H), 3.46 (dt, J= 9.5,4.8Hz,1H),3.26(dd,J=10.0,5.9Hz,1H),2.16(m,1H),1.88(m,3H),1. 80(m,4H),1.62(m,5H),1.43(m,2H),1.33(d,J=4.1Hz,2H),1.29(d,J=3.9H z,2H),1.24(m,8H),1.13(dd,J=5.9,3.5Hz,4H),0.82(s,3H),0.65(s,3H). 19 F NMR (377MHz, CDCl3) δ -110.77.

[0512] Step 2b is similar to step 2 of Example 8, except that 8-1 is replaced with 9-1 to obtain white solid 9-2 (100 mg, 8.7%). 1 H NMR(400MHz, CDCl3) δ4.68(d,J=5.2Hz,1H),3.80(dt,J=9.2,6.0Hz,1H),3.68( d,J=2.9Hz,3H),3.53(m,1H),3.27(m,1H),2.53(td,J=6.0,3.4Hz,2H),2.33(t ,J=12.1Hz,2H),2.04(m,5H),1.85(m,4H),1.60(s,3H),1.42(m,6H),1.27(dd, J=12.1,5.0Hz,3H),1.15(d,J=6.1Hz,3H),1.09(s,4H),0.63(d,J=12.7Hz,3H).

[0513] Step 3b is similar to Step 3 of Example 8, except that 8-2 is replaced with 9-2 to obtain a white solid mixture of 8-3 and 65-1 (290 mg, 0.56 mmol, 65.5%).

[0514] Compound 9-2: 1H NMR (400MHz, CDCl3) δ4.10(m,2H),2.04(dd,J=8.1,3.0Hz,6H),1.79(m,6H),1.65(m,2H),1.53(s,8H),1.31(ddd,J= 20.6,10.4,3.6Hz,6H),1.13(d,J=9.4Hz,3H),0.96(d,J=6.5Hz,3H),0.85(d,J=10.7Hz,3H),0.66(d,J=12.1Hz,3H).

[0515] Step 4b is similar to Step 4 of Example 8, where the mixture of white solids 8-3 and 73-1 is replaced with a mixture of white solids 9-3 and 65-1, and the mixture of white solids 9-4 and 65-2 (130 mg, 71.2%) is a white solid.

[0516] Compound 9-3: 1 H NMR (400MHz, CDCl3) δ3.86 (d, J=4.0Hz, 1H), 3.62 (s, 1H), 3.45 (m, 1H), 3.28 (dd, J=10 .0,5.9Hz,1H),2.11(m,1H),1.86(m,4H),1.71(m,4H),1.60(dd,J=8.4,4.1Hz,4H),1. 44(dd,J=13.6,8.5Hz,4H),1.31(dt,J=6.4,5.3Hz,3H),1.23(d,J=5.7Hz,6H),1.12( d,J=5.9Hz,4H),1.01(d,J=9.6Hz,2H),0.83(d,J=9.4Hz,3H),0.67(d,J=14.7Hz,3H).

[0517] Step 5b is similar to Step 5 of Example 8, where the mixture of white solids 8-4 and 73-2 is replaced with a mixture of 9-4 and 65-2 to obtain a crude mixture of white solids 9-5 and 65-3 (50 mg, 0.091 mmol). Chiral resolution (instrument: Waters Acquity UPCC, column: REGIS CHIRAL(S,S)-WhelK O1 4.6*150 mm, 3.5 μm, mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 40 / 60, flow rate: 1.5 ml / min, column temperature: 37 degrees) yielded white solid 9-5 (110 mg, 67.8%, retention time: 2.598 min) and white solid 65-3 (5 mg, yield 9.6%, retention time: 2.871 min).

[0518] Compound 65-3: ¹H NMR (400 MHz, CDCl₃) δ 8.03 (d, J = 7.3 Hz, 2H), 7.54 (d, J = 7.3 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 4.95 (s, 1H), 3.83 (t, J = 7.6 Hz, 1H), 3.49 (m, 1H), 3.27 (m, 1H), 1.99 (s, 1H), 1.87 (d, J = 12.7 Hz, 2H), 1.80 (d ,J=13.0Hz,3H),1.73(s,3H),1.55(s,13H),1.23(s,5H),1.19(d,J=6.1Hz,3H),1.13(d,J=6.0Hz,2H),0.91(s,3H),0.67(s,3H). Step 6B is similar to Example 8. Step 6C is similar to Example 8. Step 6A replaces 8-5 with 9-5 to obtain compound 9 (20mg,63.5%) as a white solid. 1 H NMR (400MHz, CDCl3) δ3.83 (dt, J=9.4, 5.5Hz, 1H), 3.62 (td, J=11.1, 5.6Hz, 1H), 3.48 (dt,J=9.2,5.7Hz,1H),3.26(dq,J=12.3,6.1Hz,1H),1.85(m,3H),1.73(t,J=5.7Hz, 4H),1.60(ddd,J=10.8,10.2,6.1Hz,5H),1.44(m,6H),1.32(dd,J=21.6,7.1Hz,4H), 1.23(s,6H),1.18(d,J=6.1Hz,2H),1.02(s,2H),0.84(s,3H),0.67(d,J=11.5Hz,3H). 19 F NMR (377MHz, CDCl3) δ-89.17,-89.80,-110.83,-111.46.

[0519] Step 6D is similar to step 6A of Example 8, except that 8-5 is replaced with 65-3 to obtain compound 65 (1.8 mg, 42.5%) as a white solid. 1 H NMR (400MHz, CDCl3) δ3.85(s,1H),3.60(s,1H),3.48(s,1H),3.26(s,1H),2.02(m,1H),1.92(s,4H),1.80(s,3H),1.73 (m,3H),1.33(s,3H),1.28(s,3H),1.25(s,6H),1.24(d,J=3.4Hz,5H),1.19(d,J=6.0Hz,3H),0.82(s,3H),0.62(s,3H).19 F NMR (377MHz, CDCl3) δ-110.16.

[0520] Example 70

[0521] Preparation of compound 70(1R,3aR,5aR,7S,9aR,9bR,11aR)-4-fluoro-1-[(2S)-1-[(2-hydroxy-2-methylpropyl)oxy]propyl-2-yl]-5a,9a,11a-trimethyl-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecanohydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0522] Step 1: Dissolve 3-1 (200 mg, 0.396 mmol) in diethylaminosulfur trifluoride (3 mL) and stir at 50 °C for 3 hours. Monitor the reaction by TLC (petroleum ether / ethyl acetate = 5 / 1). After the reaction solution cools to room temperature, dilute with dichloromethane, then slowly quench the solution by adding it dropwise to a saturated sodium bicarbonate aqueous solution (50 mL). Extract the organic phase with ethyl acetate (20 mL × 3), wash with saturated brine (20 mL), dry with anhydrous sodium sulfate, and evaporate to dryness. The crude product was purified by rapid chromatography (petroleum ether / ethyl acetate = 0-15%) to obtain {[(2S)-2-[(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-tetradecanoyl-1H-cyclopenta[1,2-a]phenanthrene-1-yl]propyl]oxy}acetate-2-methylpropyl-2-yl ester 70-1 (150 mg, purity: 15%) as a white solid. The crude product was directly added to the next step.

[0523] Step 2 is similar to Example 45. In Step 2, 45-1 is replaced with 70-1 to obtain (1R,3aR,7S,9aS,9bR,11aR)-4-fluoro-1-[(2S)-1-[(2-hydroxy-2-methylpropyl)oxy]propyl-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 70-2 (90 mg, purity: 15%, yield: 57.12%), which is a white solid.

[0524] Step 3: 70-2 (80 mg, 15% purity) was dissolved in 99.9% dichloromethane (10 mL). Triethylamine (0.100 mL, 0.723 mmol), benzoyl chloride (0.034 mL, 0.289 mmol), and 4-dimethylaminopyridine (DMAP) (11.04 mg, 0.090 mmol) were added at room temperature. The mixture was stirred at 30 °C for 1 hour. The reaction was monitored by TLC (petroleum ether / ethyl acetate = 3 / 1). Water (15 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (15 mL × 3), washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was subjected to SFC (instrument: Waters Acquity UPCC; column type: Daicel CHIRALPAK IB). 4.6*250mm, 5um; Mobile phase: A / B:CO2 / MeOH (0.1% DEA)=70 / 30; Flow rate: 2.0ml / min; Column temperature: 37 degrees;) Benzoic acid-(1R,3aR,5aR,7S,9aS,9bR,11aR)-4-fluoro-1-[(2S)-1-[(2-hydroxy-2-methylpropyl)oxy]propyl-2-yl]-9a,11a-dimethyl-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecanoic-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 70-3 (12mg, purity: 95%, yield: 11.96%, retention time: 1.552min) was obtained as a white solid. 1 H NMR (400MHz, CDCl3) δ8.04(d,J=7.3Hz,2H),7.55(t,J=7.4Hz,1H),7.43(t,J=7. 6Hz,2H),5.00–4.90(m,1H),3.45(dd,J=9.1,3.3Hz,1H),3.21(dt,J=20.3,8.7H z,3H),2.08–1.87(m,7H),1.80(d,J=9.4Hz,1H),1.73–1.53(m,10H),1.39–1.26 (m,3H),1.21(d,J=1.1Hz,6H),1.06(d,J=6.6Hz,3H),0.89(s,3H),0.67(s,3H). 19 FNMR (376MHz, CDCl3) δ -110.39

[0525] In step 4, 70-3 (12 mg, 0.022 mmol) was dissolved in tetrahydrofuran (0.5 mL) and methanol (1 mL), and water (0.5 mL) and lithium hydroxide monohydrate (20 mg, 0.476 mmol) were added. The mixture was stirred at 40 °C for 30 minutes. The reaction was monitored by TLC (petroleum ether / ethyl acetate = 3 / 1) to ensure complete reaction. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was purified by rapid chromatography (petroleum ether / ethyl acetate = 0-50%) to give (1R,3aR,5aR,7S,9aR,9bR,11aR)-4-fluoro-1-[(2S)-1-[(2-hydroxy-2-methylpropyl)oxy]propyl-2-yl]-5a,9a,11a-trimethyl-2,3,3a,5,5a,6,7,8,9,9a,9b,10,11,11a-tetradecanohydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 70 (4 mg, yield: 41.28%) as a white solid. 1 H NMR (400MHz, CDCl3) δ3.66–3.54 (m, 1H), 3.44 (dd, J = 9.1, 3.3Hz, 1H), 3.29–3. 12(m,3H),2.06–1.96(m,2H),1.93–1.87(m,2H),1.84–1.76(m,4H),1.66(dd,J =8.8,5.3Hz,4H),1.58–1.51(m,2H),1.48–1.38(m,2H),1.36–1.27(m,3H),1. 20(s,6H),1.18–1.10(m,2H),1.05(d,J=6.6Hz,3H),0.82(s,3H),0.66(s,3H). 19 F NMR (376MHz, CDCl3) δ-110.39.

[0526] Examples 60 & 62

[0527] Compound 60(20S)-21-[(2-hydroxy-2-methylpropyl)(methyl)amino]-20-methyl-5α-pregn-3β-ol and

[0528] Preparation of compound 62(20S)-21-[(2-hydroxy-2-methylpropyl)amino]-20-methyl-5α-pregn-3β-ol

[0529] Step 1: 3-O-3 (3g, 8.05mmol), glycine ethyl ester hydrochloride (2.24g, 16.105mmol), and dichloroethane (DCE) (20mL) were added, followed by N,N-diisopropylethylamine (3.12g, 24.16mmol) and sodium triacetoxyborohydride (3.41g, 16.10mmol). The mixture was stirred at room temperature for 5 hours, quenched with water, dried over anhydrous sodium sulfate, and the solvent was evaporated before column chromatography (developing solvent). System: 0-50% ethyl acetate / petroleum ether) to obtain {[(2S)-2-[(1R,3aS,3bS,7S,9aR,9bS,11aS)-7-acetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecano-1H-cyclopenta[1,2-a]phenanthrene-1-yl]propyl]amino} ethyl acetate 60-0 (2g, 43.2%) 1 H NMR (400MHz, CDCl3) δ5.37 (d, J=5.2Hz, 1H), 4.59 (dd, J=9.8, 4.8Hz, 1H), 4.19 (q, J= 7.1Hz,2H),3.38(d,J=7.1Hz,2H),2.60(dd,J=11.3,3.1Hz,1H),2.31(d,J=7.0Hz,2 H),2.03(d,J=5.7Hz,4H),1.88(d,J=12.9Hz,6H),1.58–1.43(m,6H),1.27(d,J=7.5 Hz,7H),1.19–1.12(m,3H),1.03(d,J=12.3Hz,7H),0.90–0.81(m,4H),0.69(s,2H).

[0530] In step 2, 60-0 (320 mg, 0.69 mmol) was added to a reaction flask containing methanol (3 mL) and ethyl acetate (3 mL), followed by palladium on carbon 10% (20 mg, 0.44 mmol). The reaction was stirred at 40 °C for 2 h. TLC monitoring showed that the starting material had reacted completely and a new spot appeared. Water (20 mL) was added for dilution, and the mixture was filtered to obtain a filtrate. The filtrate was then evaporated to dryness under reduced pressure to obtain ethyl acetate {[(2S)-2-[(1R,3aS,3bR,5aS,7S,9aS,9bS,11aS)-7-acetoxy-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]propyl]amino}60-1 (300 mg), which was directly added to the next step. LC-MS: [M+H] + =462.30.

[0531] Step 3: Add 60-1 (90 mg, 0.19 mmol) to a reaction flask containing 1,2-dichloroethane (1 mL), then add paraformaldehyde (150 mg, 0.59 mmol). Stir at room temperature for 30 min, then add sodium borohydride acetate (205 mg, 0.98 mmol). Stir the reaction at room temperature (25 °C) for 18 h. LCMS monitoring showed that the starting material reaction was complete and a new spot appeared. Dilute with water (20 mL), then add dichloromethane (20 mL). ×3), extract three times, wash with sodium chloride, dry with anhydrous sodium sulfate, and evaporate the reaction solution under reduced pressure (water pump, 45℃) to obtain crude acetic acid-(1R,3aS,3bR,5aS,7S,9aS,9bS,11aS)-1-[(2S)-1-[(2-hydroxy-2-methylpropyl)(methyl)amino]propyl-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 60-2 (50 mg), proceed to the next step. LC-MS: [M+H] + =476.50.tR=1.306min.

[0532] In step 4, 60-2 (50 mg, 0.11 mmol) was added to a reaction flask containing tetrahydrofuran (2 mL), and methyl magnesium bromide (63 mg, 0.53 mmol) was added at 0 °C. The reaction was stirred at 0 °C for 0.5 h, and the reaction was monitored by TLC until it was complete. Dilute with water (20 mL), then add dichloromethane (20 mL × 3), extract three times, wash with sodium chloride, dry with anhydrous sodium sulfate, and evaporate the reaction solution to dryness under reduced pressure (water pump, 45 °C). Purify by column chromatography (petroleum ether:ethyl acetate = 90:10) to obtain crude product 60 (10 mg). The crude product is then processed using preparative chromatography (instrument: Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150 x 19 mm, mobile phase: A / B:CO2 / MeOH (0.1% DEA) = 60 / 40, flow rate: 20 mL / min, wavelength: 214 nm, gradient). Method: 0-13 min, acetonitrile: 27-95%, water (0.1% FA): 5-73,) resolution yielded (20S)-21-[(2-hydroxy-2-methylpropyl)(methyl)amino]-20-methyl-5α-pregn-3β-ol 60 (6 mg, 0.014 mmol, 29.40%) as a white solid. 1H NMR (400MHz, DMSO) δ4.40(s,1H),3.67(s,1H),3.10(m,1H),2.24(d,J=11.3Hz,1H),2.19(s,3H),2.09(d,J=13.3Hz,1H),1.96(m,2H),1.77 (s,1H),1.59(d,J=13.2Hz,3H),1.43(m,4H),1.24(s,7H),1.06(s,6H),0.97(d,J=6.3Hz,3H),0.74(s,3H),0.64(s,3H).LC-MS(ESI)[M+H] + =420.30.tR=6.408min.

[0533] Step 5 is similar to Example 60. Step 3, 60-2, is replaced with 60-1 to obtain (20S)-21-[(2-hydroxy-2-methylpropyl)amino]-20-methyl-5α-pregn-3β-ol 62 (10 mg, 22.08%), which is a white solid. 1 H NMR(400MHz, CDCl3) δ6.01(t,J=6.3Hz,1H),5.17(dt,J=14.9,7.2Hz,4H),5.06( t,J=6.6Hz,1H),3.74(s,1H),3.60(dt,J=11.3,4.1Hz,1H),2.19(m,2H),1.95(m ,3H),1.81(dd,J=15.3,6.7Hz,4H),1.69(m,5H),1.42(m,7H),1.27(d,J=12.0Hz ,3H),1.12(m,2H),1.06(s,3H),0.92(d,J=6.5Hz,3H),0.66(s,3H).LC-MS: [M+H] + =406.30.

[0534] Examples 54, 55

[0535] Compound 54 or 55 (1R,2'R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxyhept-2-yl]-9a,11a-dimethyl-1,2,3,3a,3b,4,5,5a,7,8,9,9a,9b,10,11,11a-hexadecylhydrospiro[cyclopenta[1,2-a]phenanthrene-6,2'-oxetane]-7-ol

[0536] Compound 55 or 54 (1R,2'S,3aS,3bS,5aR,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxyhept-2-yl]-9a,11a-dimethyl-1,2,3,3a,3b,4,5,5a,7,8,9,9a,9b,10,11,11a-hexadecylhydrospiro[cyclopenta[1,2-a]phenanthrene-6,2'-oxetane]-7-ol

[0537] Step 1 is similar to implementation 1. Step 1 replaces cyclopropyl magnesium bromide with methyl magnesium bromide to obtain the white solid product (6R)-6-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecylhydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxane-8-yl]hepta-2-ol 54-1 (450 mg, 87.0%). 1 H NMR (400MHz, CDCl3) δ4.01 (dt, J=8.3, 6.2Hz, 2H), 3.79 (dd, J=11.7, 5.6Hz, 1H), 2. 20–2.06(m,1H),1.98(dt,J=12.8,3.2Hz,2H),1.94–1.81(m,4H),1.79–1.66(m,2H) ,1.62(dd,J=18.4,8.5Hz,2H),1.51(s,5H),1.43–1.37(m,4H),1.34–1.21(m,7H), 1.19(dd,J=6.2,0.5Hz,3H),1.16–0.99(m,7H),0.93(t,J=5.7Hz,4H),0.68(s,3H). 19 F NMR(376MHz, CDCl3)δ-88.99,-89.62,-111.36,-111.99.

[0538] In step 2, 54-1 (450 mg, 0.93 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature, and dilute hydrochloric acid (3 mL) was added. The mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC (petroleum ether: ethyl acetate = 1:1), and the reactants were consumed. Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (10 × 3 mL). The organic layers were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1 to 1:1) to give a white solid product (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxyhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 54-2 (400 mg, 96.9%). 1 HNMR(400MHz, CDCl3)δ3.79(d,J=6.0Hz,1H),3.74(s,1H),3.60(d,J=11.4Hz, 1H),2.20(dtd,J=23.0,13.7,6.7Hz,1H),1.98(d,J=12.8Hz,1H),1.83(ddd,J= 18.9,12.7,5.5Hz,4H),1.74–1.54(m,7H),1.48–1.26(m,11H),1.19(dd,J=6.2 ,0.6Hz,3H),1.08–1.03(m,5H),0.93(t,J=5.6Hz,3H),0.65(d,J=12.2Hz,3H). 19 F NMR(376MHz, CDCl3)δ-75.66,-88.63,-89.26,-110.63,-111.25.

[0539] In step 3, 54-2 (300 mg, 0.68 mmol) was dissolved in dichloromethane (15 mL) at room temperature. Under nitrogen protection, 4-dimethylaminopyridine (8 mg, 0.068 mmol), triethylamine (0.5 mL, 3.39 mmol), and benzoyl chloride (0.2 mL, 2.03 mmol) were added to the system. The reaction mixture was stirred at room temperature for 18 h. The reaction was monitored for completion by TLC (petroleum ether: ethyl acetate = 1:1). Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with dichloromethane (15 mL x 3). The organic layers were combined and washed with saturated brine (10 mL x 3). The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by rapid chromatography (petroleum ether: ethyl acetate = 10:1) to obtain benzoic acid-(6R)-6-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-7-(phenylcarbonyloxy)-4,4-difluoro-6-hydroxy-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hept-2-yl ester 54-3 (280 mg, 63.3%). 1 H NMR(400MHz, CDCl3)δ8.09–8.00(m,4H),7.63–7.51(m,2H),7.45(dt,J=12.8,6.4Hz,4H),5 .15(d,J=6.2Hz,1H),4.99(dd,J=8.1,3.4Hz,1H),3.98(s,1H),2.34–2.13(m,1H),2.13–1. 91(m,3H),1.82(d,J=10.1Hz,5H),1.64(d,J=5.7Hz,3H),1.55–1.39(m,6H),1.34(d,J=6.2 Hz, 5H), 1.25 (s, 3H), 1.12 (d, J = 9.9Hz, 5H), 0.90 (t, J = 6.1Hz, 4H), 0.65 (d, J = 11.8Hz, 3H). 19 F NMR(376MHz, CDCl3)δ-88.72,-89.34,-110.48,-111.11.

[0540] In step 4, the starting material 54-3 (300 mg, 0.46 mmol) was dissolved in dichloromethane (5 mL), and Desmartin oxidant (489 mg, 1.15 mmol) was slowly added. The reaction mixture was reacted at room temperature under a nitrogen atmosphere for 2 h. After the reaction was complete, the reaction was stopped by TLC (petroleum ether: ethyl acetate = 3:1). The reaction was quenched by adding saturated Na2S2O4 solution (10 mL), and extracted with dichloromethane (10 mL × 3). The organic phases were combined and washed with saturated brine (10 mL × 3). The organic phase was collected, dried over anhydrous sodium sulfate, and evaporated under vacuum to obtain the crude product. The crude product was separated and purified by rapid chromatography (petroleum ether: ethyl acetate = 85:15) to obtain benzoic acid-(6R)-6-[(1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-7-(phenylcarbonyloxy)-4,4-difluoro-9a,11a-dimethyl-6-oxoylidenehexadecyl-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hept-2-yl ester 54-4 (280 mg, 89.1%). 1 HNMR (400MHz, CDCl3) δ8.13–8.01(m,4H),7.56(q,J=7.6Hz,2H),7.44(td,J=7.7,1.5Hz,4H),5.43(dd,J =12.1,7.3Hz,1H),5.16(dd,J=12.4,6.2Hz,1H),2.62(d,J=12.2Hz,1H),2.48–2.36(m,1H),2.11(dt,J=1 2.4,9.1Hz,2H),2.03(dt,J=9.4,4.1Hz,3H),1.86(td,J=13.4,6.3Hz,2H),1.73–1.53(m,5H),1.49–1.20 (m,13H),1.11(td,J=16.8,8.7Hz,2H),0.91(d,J=6.5Hz,3H),0.83(d,J=11.2Hz,3H),0.72–0.62(m,3H). 19 F NMR(376MHz, CDCl3)δ-90.27,-90.90,-111.41,-112.05.

[0541] In step 5, under nitrogen protection, trimethyl sulfoxide (681 mg, 3.08 mmol) and potassium tert-butoxide (346 mg, 3.08 mmol) were dissolved in tert-butanol (15 mL). The reaction mixture was stirred at 65 °C for 1 hour under nitrogen protection, and then 54-4 (200 mg, 0.30 mmol) was added, and the reaction was continued for 24 hours. The reaction was monitored for completeness by TLC (petroleum ether: ethyl acetate = 1:1). The reaction was quenched with water (15 mL), and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was collected, dried over anhydrous sodium sulfate, and then evaporated under vacuum to give the crude product (1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxyhept-2-yl]-9a,11a-dimethyl-1,2,3,3a,3b,4,5,5a,7,8,9,9a,9b,10,11,11a-hexadecylhydrospiro[cyclopenta[1,2-a]phenanthrene-6,2'-oxetane]-7-ol 54-5 (100 mg, 66.7%). The crude product was used directly in the next step. 1 H NMR(400MHz, CDCl3)δ4.01(q,J=8.1Hz,1H),3.94–3.83(m,1H),3.79(dd,J=11.9,5.9Hz,1H),3.10(t, J=9.6Hz,1H),2.17(dd,J=10.9,5.9Hz,1H),2.03–1.93(m,3H),1.85(ddd,J=20.1,10.8,6.0Hz,4H),1 .72(ddd,J=18.0,11.1,4.5Hz,2H),1.49(ddd,J=16.1,11.4,3.9Hz,5H),1.40(dd,J=11.9,5.6Hz,7H) ,1.19(d,J=6.2Hz,4H),1.14–1.02(m,5H),0.92(d,J=6.5Hz,4H),0.87(s,2H),0.67(d,J=1.6Hz,3H). 19 F NMR (376MHz, CDCl3) δ-88.24,-88.58,-88.87,-89.21,-109.80,-110.11,-110.43,-110.74.

[0542] In step 6, 54-5 (100 mg, 0.21 mmol) was dissolved in anhydrous dichloromethane (5 mL) at room temperature, and triethylamine (0.2 mL, 1.05 mmol), 4-dimethylaminopyridine (3 mg, 0.021 mmol), and benzoyl chloride (0.05 mL, 0.43 mmol) were added. The reaction was then carried out under nitrogen protection at room temperature for 18 hours. The reaction was monitored for completeness by TLC (petroleum ether: ethyl acetate = 3:1). The reaction was quenched with water (10 mL), extracted with dichloromethane (10 mL × 3), and the organic phase was collected, dried over anhydrous sodium sulfate, and then evaporated under vacuum to obtain the crude product. The crude product was separated and purified by rapid chromatography (petroleum ether: ethyl acetate = 82:18) to obtain benzoic acid-(6R)-6-[(1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-4,4-difluoro-7-hydroxy-9a,11a-dimethyl-1,2,3,3a,3b,4,5,5a,7,8,9,9a,9b,10,11,11a-hexadecylhydrospiro[cyclopenta[1,2-a]phenanthrene-6,2'-oxetane]-1-yl]hept-2-yl ester 54-6 (100 mg, yield 80.9%). 1 H NMR (400MHz, CDCl3) δ8.07–8.01(m,2H),7.54(dd,J=10.5,4.3Hz,1H),7.44(t,J=7.6Hz,2H),5. 15(d,J=6.2Hz,1H),4.00(t,J=8.4Hz,1H),3.95–3.82(m,1H),3.11(d,J=11.5Hz,1H),1.98(ddd ,J=11.7,7.9,3.8Hz,3H),1.90–1.81(m,3H),1.75–1.64(m,4H),1.53–1.39(m,6H),1.36(dd,J= 16.8,10.2Hz,6H),1.25(q,J=7.5Hz,7H),1.14–1.04(m,4H),0.90(d,J=6.5Hz,4H),0.65(s,3H). 19 F NMR (377MHz, CDCl3) δ-88.25,-88.59,-88.88,-89.22,-109.80,-110.11,-110.42,-110.74.

[0543] In step 7, compound 54-6 (120 mg, 0.21 mmol) was resolved by SFC (Separation method: Instrument: Waters Acquity UPCC; Column: Daicel CHIRALPAK AS_3, 3*150 mm, 3 μm; Mobile Phase: A / B: CO2 / MeOH (0.1% DEA) = 60 / 40; Flow rate: 1.5 ml / min; Column Temp: 37 degrees) to obtain 54-7 (60 mg, yield 50.00%, retention time: 1.818 min) and 55-1 (30 mg, yield 25.00%, retention time: 2.378 min).

[0544] Compound 54-7: 1 H NMR (400MHz, CDCl3) δ8.07–8.02(m,2H),7.55(t,J=7.4Hz,1H),7.44(t,J=7.6Hz,2H),5.15(dd,J=12.4,6. 3Hz,1H),4.01(q,J=8.1Hz,1H),3.86(td,J=9.9,3.4Hz,1H),3.11(d,J=11.4Hz,1H),2.21–2.11(m,1H),2. 04–1.93(m,4H),1.90–1.80(m,3H),1.76–1.60(m,6H),1.57–1.43(m,6H),1.35(dd,J=11.1,4.8Hz,5H),1. 23(dd,J=21.5,8.8Hz,3H),1.11(dd,J=18.6,6.7Hz,3H),0.89(d,J=6.5Hz,3H),0.86(s,3H),0.65(s,3H). 19 F NMR (377MHz, CDCl3) δ-88.59,-89.22,-110.11,-110.74.

[0545] Compound 55-1: 1H NMR (400MHz, CDCl3) δ8.01–7.94(m,2H),7.51–7.44(m,1H),7.37(dd,J=10.5,4.7Hz,2 H),5.08(d,J=6.2Hz,1H),3.93(t,J=8.4Hz,1H),3.87–3.79(m,1H),3.08–2.97(m,1H) ,2.23–2.01(m,1H),1.97–1.85(m,2H),1.82–1.67(m,7H),1.55–1.47(m,4H),1.38–1. 22(m,10H),1.23–1.13(m,2H),1.07–0.92(m,8H),0.83(d,J=6.4Hz,3H),0.59(s,3H). 19 F NMR (377MHz, CDCl3) δ-88.25,-88.88,-109.80,-110.43.

[0546] In step 8a, 54-7 (60 mg, 0.10 mmol) was dissolved in a mixed solvent of tetrahydrofuran (3 mL), water (1 mL), and methanol (1 mL) at room temperature, and lithium hydroxide (42 mg, 1.0 mmol) was added. The reaction was then carried out under nitrogen protection at room temperature for 18 hours. The reaction progress was monitored by TLC (petroleum ether: ethyl acetate = 10:1), and the reaction was stopped when the starting material was consumed. The reaction was quenched with water (10 mL), extracted with ethyl acetate (10 mL × 3), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate and then evaporated under vacuum to obtain the crude product. The crude product was purified by rapid chromatography (petroleum ether: ethyl acetate = 85:15) to give a white solid compound 54 (25 mg, yield 43.9%). 1 H NMR (400MHz, CDCl3) δ4.01(q,J=8.1Hz,1H),3.86(td,J=10.1,3.5Hz,1H),3.79(dd,J=11.9,5.8Hz,1H),3 .12(d,J=11.5Hz,1H),2.16(ddd,J=13.6,8.7,4.2Hz,1H),1.99(ddd,J=11.5,7.7,5.2Hz,4H),1.92–1.81 (m,3H),1.80–1.67(m,2H),1.58–1.53(m,3H),1.52–1.44(m,4H),1.41–1.31(m,6H),1.27(d,J=12.1Hz,2 H),1.21–1.17(m,4H),1.13(d,J=9.0Hz,2H),0.92(d,J=6.5Hz,3H),0.87(s,3H),0.65(d,J=10.4Hz,3H).19 F NMR (376MHz, CDCl3) δ-88.58,-89.21,-110.11,-110.74.

[0547] Step 8 is similar to Step 6A of Example 54, except that 54-7 is replaced with 55-1 to obtain white solid compound 55 (15 mg, purity 98.99%, yield 59.8%). 1 H NMR(400MHz, CDCl3)δ4.01(q,J=8.0Hz,1H),3.95–3.87(m,1H),3.83–3.76(m, 1H),3.10(dd,J=8.6,7.1Hz,1H),2.19(dd,J=34.6,4.6Hz,1H),2.04–1.88(m,3 H),1.85–1.74(m,6H),1.60(s,3H),1.47–1.38(m,6H),1.36–1.24(m,6H),1.19 (dd,J=6.2,0.6Hz,3H),1.11–1.02(m,6H),0.92(d,J=6.5Hz,3H),0.67(s,3H). 19 F NMR(377MHz, CDCl3)δ-88.24,-88.87,-109.80,-110.44.

[0548] Example 56

[0549] Preparation of compound 56(1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-1,2,3,3a,3b,4,5,5a,7,8,9,9a,9b,10,11,11a-hexadecylhydrospiro[cyclopenta[1,2-a]phenanthrene-6,2'-oxetane]-7-ol

[0550] Step 1: I-14 (500 mg, 1.09 mmol) was dissolved in dichloromethane (10 mL) at room temperature. Under nitrogen protection, 4-dimethylaminopyridine (27 mg, 0.22 mmol), triethylamine (330 mg, 3.27 mmol), and acetic anhydride (167 mg, 1.64 mmol) were added to the system. The reaction mixture was stirred at room temperature for 30 minutes. The reaction was monitored for completion by TLC (petroleum ether: ethyl acetate = 1:1). Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with dichloromethane (15 mL x 3). The organic layers were combined and washed with saturated brine (10 mL x 3). The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by rapid chromatography (petroleum ether: ethyl acetate = 1:1) to obtain the product acetic acid-(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-6-hydroxy-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 56-1 (400 mg, 73.6%). 1 H NMR (400MHz, CDCl3) δ4.73 (dd, J = 7.7, 4.5Hz, 1H), 3.83 (s, 1H), 2.31–2.13 (m, 1H), 2.09 (s, 3H), 2.03–1.93 (m, 1H), 1.92–1. 80(m,4H),1.77–1.69(m,2H),1.59–1.31(m,12H),1.27–1.17(m,8H),1.15–1.01(m,7H),0.93(t,J=5.5Hz,3H),0.67(s,3H). 19 F NMR (376MHz, CDCl3) δ-88.72,-89.34,-110.54,-111.16.

[0551] In step 2, starting material 56-1 (400 mg, 0.80 mmol) was dissolved in dichloromethane (20 mL), and Dys-Martin oxidant (680 mg, 1.60 mmol) was slowly added. The reaction mixture was reacted at room temperature for 2 h under nitrogen protection. The reaction was stopped after complete TLC (petroleum ether: ethyl acetate = 5:1). The reaction was quenched with saturated sodium thiosulfate solution (10 mL), and extracted with dichloromethane (10 mL x 3). The organic phases were combined and washed with saturated brine (10 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, and evaporated under vacuum to obtain the crude product. The crude product was separated and purified by rapid chromatography (petroleum ether: ethyl acetate = 85:15) to give product acetic acid-(1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-6-oxoylidenehexadecyl-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 56-2 (300 mg, 75.4%). 1 H NMR (400MHz, CDCl3) δ5.18(dd,J=12.2,7.3Hz,1H),2.54(d,J=12.4Hz,1H),2.27(d,J =6.8Hz,1H),2.16(d,J=2.7Hz,3H),2.02(ddd,J=28.3,18.6,8.9Hz,4H),1.91–1.78(m ,3H),1.58(dd,J=15.5,11.4Hz,4H),1.39(ddd,J=18.7,16.7,5.2Hz,8H),1.27–1.15( m,9H),1.15–1.03(m,2H),0.93(d,J=6.5Hz,3H),0.78(d,J=10.7Hz,3H),0.67(s,3H). 19 F NMR(376MHz, CDCl3)δ-90.29,-90.93,-111.47,-112.11.

[0552] In step 3, trimethyl sulfoxide (445 mg, 2.0 mmol) and potassium tert-butoxide (226 mg, 2.0 mmol) were dissolved in tert-butanol (15 mL). The reaction mixture was stirred at 60 °C for 1 hour under nitrogen protection, and then 56-2 (200 mg, 0.40 mmol) was added, and the reaction was continued for 2 days. The reaction progress was monitored by TLC (petroleum ether: ethyl acetate = 3:1). Once the reactants had reacted completely, the reaction was stopped. The reaction was quenched with water (15 mL), and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was collected, dried over anhydrous sodium sulfate, and then evaporated under vacuum to obtain the crude product. The crude product was purified by rapid chromatography (petroleum ether: ethyl acetate = 80:20) to give the product (1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-9a,11a-dimethyl-1,2,3,3a,3b,4,5,5a,7,8,9,9a,9b,10,11,11a-hexadecylhydrospiro[cyclopenta[1,2-a]phenanthrene-6,2'-oxetane]-7-ol 56 (70 mg, purity 98.02%, yield 35.3%). 1 H NMR (400MHz, CDCl3) δ4.01 (d, J = 8.7Hz, 1H), 3.94–3.84 (m, 1H), 3.12 (d, J = 11. 3Hz,1H),2.27–2.09(m,1H),1.99(d,J=13.4Hz,3H),1.85(ddd,J=19.9,11.1,6 .0Hz,4H),1.76(s,1H),1.53(s,3H),1.46–1.28(m,9H),1.23(d,J=10.0Hz,8H) ,1.18–0.98(m,6H),0.93(d,J=6.5Hz,3H),0.87(s,2H),0.67(d,J=1.8Hz,3H). 19 F NMR (376MHz, CDCl3)δ-88.24,-88.58,-88.87,-89.21,-109.80,-110.12,-110.43,-110.75.LC-MS: [MH) - =481.60

[0553] Example 57

[0554] Preparation of compound 57(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-1-[(2R)-6,7-dihydroxyhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0555] Step 1: At room temperature, trimethylsulfur iodide (131.15 mg, 0.643 mmol) was dissolved in tetrahydrofuran (4 mL), cooled to 0°C in an ice bath, and potassium tert-butoxide solution (1 M in THF, 0.643 mL) was slowly added dropwise while stirring at room temperature for 30 min. Then, a tetrahydrofuran solution of compound I (100 mg, 0.214 mmol) (2 mL) was added dropwise. The mixture was stirred at room temperature for 2 hours. The reaction was monitored for completeness by TLC (petroleum ether: ethyl acetate = 5:1). The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Separation by column chromatography (4 g, 0–20% ethyl acetate / petroleum ether, 20 mL / min) yielded the product (3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-8-[(2R)-5-(oxacycloprop-2-yl)pentan-2-yl]-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecylhydro-3aH-cyclopentazo[1',2':7,8]phenanthro[1,2-d][1,3]dioxacyclopentazo 57-1 (80 mg, 69.90%), a white solid. 1 H NMR (400MHz, CDCl3) δ4.08–3.96 (m, 2H), 2.90 (s, 1H), 2.75 (t, J = 4.4Hz, 1H), 2. 51–2.43(m,1H),2.22–1.87(m,4H),1.87–1.55(m,9H),1.51(s,3H),1.41(dd,J= 24.5,18.9Hz,7H),1.30(s,3H),1.25(s,1H),1.12(s,2H),1.07(s,3H),1.05–0. 95(m,2H),0.93(d,J=6.5Hz,3H),0.87(d,J=7.8Hz,1H),0.66(d,J=12.0Hz,3H).

[0556] In step 2, at room temperature, 57-1 (60 mg, 0.125 mmol) was dissolved in dioxane (2 mL) and water (2 mL), followed by the addition of tetrabutylammonium hydrogen sulfate (12.71 mg, 0.037 mmol). The mixture was heated in an oil bath at 100 °C for 16 hours. The reaction was monitored for completeness by TLC (petroleum ether: ethyl acetate = 5:1). The reaction mixture was added to 20 mL of water, extracted with ethyl acetate (20 mL x 2), and the organic phases were combined and washed with saturated brine (30 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Separation by column chromatography (4 g, 0–60% ethyl acetate / petroleum ether, 20 mL / min) yielded a white solid (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-1-[(2R)-6,7-dihydroxyhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 57 (32.68 mg, yield: 57.09%). 1 H NMR (400MHz, CDCl3) δ3.84–3.51 (m, 4H), 3.44 (dd, J = 10.9, 7.6Hz, 1H), 2.29–2 .11(m,1H),1.98(d,J=13.3Hz,1H),1.90–1.78(m,4H),1.73(dd,J=13.5,4.4H z,5H),1.47–1.36(m,7H),1.32(dd,J=12.0,4.7Hz,3H),1.22(s,1H),1.14–1. 08(m,2H),1.06(s,3H),1.04–0.95(m,2H),0.92(d,J=6.5Hz,3H),0.66(s,3H). 19 FNMR(377MHz, CDCl3)δ-88.95(d,J=235.8Hz,1F),-110.94(d,J=235.9Hz,1F).LC-MS:[MH] - =457.45.

[0557] Example 58

[0558] Preparation of compound 5(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-5-hydroxy-5-methylhex-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0559] Step 1: I-9 (100 mg, 0.207 mmol, 1.0 eq) was added to a reaction flask containing tetrahydrofuran (1 mL). Methylmagnesium bromide (0.691 mL, 2.072 mmol, 10.0 eq) was added at 0 °C. The reaction was stirred at 0 °C for 0.5 hours. TLC monitoring showed that the starting material had reacted completely and a new spot appeared. Water (20 mL) was added for dilution, followed by dichloromethane (20 mL × 3). Extraction was performed three times, followed by washing with sodium chloride and drying with anhydrous sodium sulfate. The reaction solution was then evaporated to dryness under reduced pressure (water pump, 45 °C) and separated by column chromatography (petroleum ether: ethyl acetate = 90:10). Purification yielded (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-hexadecylhydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxacyclopenta-8-yl]-2-methylhex-2-ol 58-1 (70 mg, 0.131 mmol, 62.99%) as a white solid. 1 H NMR(400MHz, CDCl3)δ4.02(dt,J=8.4,6.2Hz,2H),2.18–2.05(m,1H),2.03–1.93(m,2H),1.91–1.78(m,4H),1.76–1.57(m,4H),1.54(s,3 H),1.47–1.34(m,5H),1.30(q,J=5.9Hz,6H),1.19(t,J=6.9Hz,7H),1.16–1.09(m,3H),1.07(s,3H),0.93(d,J=6.6Hz,4H),0.68(s,3H).

[0560] In step 2, 58-1 (75 mg, 0.155 mmol, 1.0 eq) was added to a reaction flask containing tetrahydrofuran (1 mL) and water (0.5 mL), followed by p-toluenesulfonic acid (14.78 mg, 0.078 mmol, 0.5 eq). The reaction was stirred at 80 °C for 0.5 h and was found to be complete by TLC monitoring. Dilute with water (20 mL), then add dichloromethane (20 mL × 3), extract three times, wash with sodium chloride, dry with anhydrous sodium sulfate, and evaporate the reaction solution to dryness under reduced pressure (water pump, 45 °C). Purify by column chromatography (petroleum ether: ethyl acetate = 80:20) to obtain crude (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-5-hydroxy-5-methylhexyl-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 58 (50 mg, yield 65.44%) as a white solid.

[0561] In step 3, crude compound 58 (50 mg, 0.113 mmol, 1.0 eq) was added to a reaction flask containing 2 mL of dichloromethane, followed by benzoyl chloride (0.020 mL, 0.169 mmol, 1.5 eq), triethylamine (0.047 mL, 0.339 mmol, 3.0 eq), and 4-dimethylaminopyridine (11.04 mg, 0.090 mmol, 0.8 eq). The reaction was stirred at room temperature (25 °C) for 0.5 h. TLC monitoring showed that the starting material had reacted completely and a new spot appeared. Water (20 mL) was added for dilution, followed by the addition of 20 mL of dichloromethane. Extracted three times with 3 mL of the solution, then washed with sodium chloride and dried over anhydrous sodium sulfate. The reaction solution was then evaporated under reduced pressure (water pump, 45℃) and purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain benzoic acid-(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-6-hydroxy-1-[(2R)-5-hydroxy-5-methylhex-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 58-2 (50 mg, 0.08 mmol, 92.33%) as a white solid. 1H NMR (400MHz, CDCl3) δ8.08–8.00(m,2H),7.58(t,J=7.4Hz,1H),7.46(t,J=7.7Hz,2H),5.06–4.95(m,1H),3.98(s,1H),2.26(ddd,J=25.4,13.7,6.9Hz ,1H),2.13–1.97(m,2H),1.90–1.80(m,5H),1.54(s,10H),1.39–1.29(m,4 H),1.20(d,J=1.9Hz,6H),1.14(s,5H),0.94(d,J=6.5Hz,3H),0.68(s,3H).

[0562] Step 4 is similar to Step 5A of Example 1, except that compound 43-1 is replaced with 58-2 to obtain a white solid (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-5-hydroxy-5-methylhex-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 58 (24 mg, 0.054 mmol, 98.59%). 1 H NMR(400MHz,MeOD)δ3.63(s,1H),3.51–3.46(m,1H),2.27–1.94(m,2H),1.93–1.82(m,2H),1.81–1.68(m,4H),1.59(d,J=11.8Hz,1H),1.50(d d,J=19.5,11.5Hz,3H),1.37(dd,J=36.5,22.6Hz,7H),1.13(dd,J=16.5,6.9Hz,9H),1.07(s,3H),0.98(dd,J=21.7,9.3Hz,5H),0.70(s,3H). 19 F NMR(376MHz,MeOD)δ-89.34,-89.97,-111.87,-112.50.LCMS(ESI)[MH] - =441.40.

[0563] Example 74

[0564] Preparation of compound 74, 7,7-difluoro-26-(2-hydroxy-2-methylpropyl)-25-methyl-5α-cholesterol-3β,26-diol

[0565] Step 1: Dissolve II-11 (2g, 3.1mmol, 1eq) in dichloromethane (40mL), add Desmartin oxidant (2g, 4.7mmol, 1.5eq) at room temperature, maintain the temperature and stir for 30 minutes, and monitor the reaction for completeness by TLC (petroleum ether: ethyl acetate = 10:1). Quenching was performed at room temperature with 100 mL of saturated sodium sulfite aqueous solution, followed by extraction with ethyl acetate (100 mL × 2). The organic phase was washed with saturated brine (50 mL), and the organic phase was evaporated to dryness to obtain a crude product. Purification was achieved by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain (4R)-4-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentanal 74-1 (1.5 g, yield: 68%). 1 H NMR (400MHz, CDCl3) δ9.75(t,J=1.8Hz,1H),7.66(m,4H),7.38(m,6H),3.59(tt,J=10.3,5.1Hz,1H),2.39(m,2H),1.82(m,4H),1. 59(ddd,J=22.4,15.0,6.3Hz,6H),1.44(m,5H),1.29(m,5H),1.06(m,11H),0.89(dd,J=7.8,4.9Hz,4H),0.82(s,4H),0.64(s,3H).

[0566] In step 2, compound 74-1 (1.5 g, 2.4 mmol, 1 eq) was dissolved in tetrahydrofuran (20 mL), and methyl (triphenyl-λ5-methylphosphine) acetate (2 g, 4.7 mmol, 6 eq) was added at room temperature. The mixture was heated to 90 °C and stirred for 16 hours. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 20:1) to ensure complete reaction. Dilute with 200 mL of water at room temperature, extract with ethyl acetate (200 mL × 2), wash the organic phase with saturated brine (50 mL), and evaporate the organic phase to dryness to obtain crude product. Purify by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain methyl (2E,6R)-6-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hept-2-enoate 74-2 (1.5 g, yield: 77%). 1H NMR (400MHz, CDCl3) δ7.59(dd,J=6.1,1.6Hz,4H),7.32(m,6H),6.88(d,J=15.6Hz,1H),5.73(d,J=15 .6Hz,1H),3.64(d,J=7.2Hz,3H),3.52(tt,J=10.4,5.1Hz,1H),2.17(qd,J=10.6,5.3Hz,1H),1.98(s, 1H),1.86(d,J=12.7Hz,1H),1.74(d,J=7.1Hz,2H),1.57(dd,J=10.7,3.7Hz,3H),1.40(m,7H),1.19( dt,J=15.9,14.3Hz,5H),0.99(m,12H),0.82(m,5H),0.75(s,3H),0.69(d,J=3.8Hz,1H),0.57(s,3H).

[0567] In step 3, compound 74-2 (1.5 g, 2.2 mmol, 1 eq) was dissolved in tetrahydrofuran (10 mL) and methanol (5 mL), and nickel chloride (0.3 g, 2.6 mmol, 1.2 eq) was added at room temperature, followed by the slow addition of sodium borohydride (0.1 g, 2.6 mmol, 1.2 eq). After stirring at room temperature for 1 hour, the reaction was monitored by TLC (petroleum ether: ethyl acetate = 20:1) to ensure complete reaction. Quenching was performed at room temperature with 200 mL of water, followed by extraction with ethyl acetate (200 mL × 2). The organic phase was washed with saturated brine (50 mL), and the organic phase was evaporated to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain methyl (6R)-6-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]heptanoate 74-3 (1.2 g, yield: 72%). 1 H NMR (400MHz, CDCl3) δ7.66(m,4H),7.38(m,6H),3.66(s,3H),3.58(dt,J=15.6,5.2Hz,1H),2.29(m,2H),1.93(dd,J=9.4,3.3Hz,1H),1.79( s,2H),1.58(m,8H),1.39(m,9H),1.21(m,3H),1.05(m,12H),0.88(d,J=6.5Hz,4H),0.82(s,3H),0.76(dd,J=13.3,9.4Hz,1H),0.63(s,3H).

[0568] In step 4, compound 74-3 (1.5 g, 2.2 mmol, 1 eq) was dissolved in tetrahydrofuran (10 mL), cooled to -78 °C, and then diisopropylaminolithium (2 mol / L tetrahydrofuran solution) (6.5 mL, 13 mmol, 6 eq) was added dropwise. The mixture was stirred at the same temperature for 30 minutes, and then iodomethane (2.5 g, 17 mmol, 8 eq) was slowly added dropwise. The mixture was stirred at -78 °C for 30 minutes, and the reaction was monitored by TLC (petroleum ether: ethyl acetate = 20:1) to ensure complete reaction. Quenching was performed at room temperature with 200 mL of saturated ammonium chloride aqueous solution, followed by extraction with ethyl acetate (200 mL × 2). The organic phase was washed with saturated brine (50 mL), and the organic phase was evaporated to dryness to obtain crude product. Purification was achieved by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain methyl (6R)-6-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2,2-dimethylheptanoate 74-4 (200 mg, yield: 11%). 1 H NMR(400MHz,cdcl3)δ7.67(m,4H),7.39(m,6H),3.65(s,3H),3.59(m,1H),1.92(s,1H),1.80(d,J=7.1Hz,2H),1.65(m,3H),1.53(m,3H),1.41(m ,4H),1.27(ddd,J=18.7,13.9,9.5Hz,8H),1.16(s,6H),1.06(d,J=11.3 Hz,14H),0.87(d,J=6.5Hz,4H),0.83(s,3H),0.77(s,1H),0.64(s,3H).

[0569] Step 5: Dissolve 74-4 (500 mg, 0.7 mmol, 1 eq) in tetrahydrofuran (10 mL), and slowly add lithium aluminum hydride (52 mg, 0.14 mmol, 2 eq) at room temperature. After stirring for 30 minutes while maintaining the temperature, monitor the reaction for completeness by TLC (petroleum ether: ethyl acetate = 5:1). Quenching was performed at room temperature with 200 mL of water, followed by extraction with ethyl acetate (200 mL × 2). The organic phase was washed with saturated brine (50 mL), and the organic phase was evaporated to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain (6R)-6-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2,2-dimethylhept-1-ol 74-5 (420 mg, yield: 79%). 1 H NMR (400MHz, CDCl3) δ7.66(d,J=6.7Hz,4H),7.38(m,6H),3.59(s,1H),3.31(s,2H),1.90(m,1H),1.59(m ,6H),1.29(m,12H),1.06(d,J=18.7Hz,15H),0.86(dd,J=20.2,10.3Hz,14H),0.77(s,1H),0.64(s,3H).

[0570] Step 6, similar to Step 1 of Example 74, replaces II-11 with 74-5 to obtain (6R)-6-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2,2-dimethylheptanal 74-6 (150 mg yield: 67%). 1 H NMR (400MHz, CDCl3) δ9.44(s,1H),7.66(d,J=5.5...

Claims

A compound of Formula I-0 or a pharmaceutically acceptable salt thereof: in, It can be a single bond or a double bond. R 3a H or -(CH2)n-OH; n is 1, 2 or 3; R 4a is H; R 4b is H, OH or C1-C6 alkoxy; or, R 4a and R 4b together with the carbon atom to which they are attached form a R 7a and R 7b are independently halogen; or R 7a and R 7b together with the carbon atom to which they are attached form a wherein a is attached to the 8-carbon; R 8a is H; R 7a is absent, R 7b is halogen; R 8a is absent; R 19 is H or CH3; R 21 -L 1 -C(R 21b )(R 21c )-OH、-L 2 -C(R 21d )(R 21e )-OH、 -L 1 -C(R 21d )(R 21e )-R 22 、-L 1 -C(R 21f )(R 21g )-CR a (OH)-R 21h 、-L 3 -Y-R 21i 、 L 1 For -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, or -(CH2)6-, L 1 One of -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5- and -(CH2)6- described herein, is optionally replaced by -X. 1 -replace; L 2 is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, or -(CH2)6-, L 2 one -CH2- in said -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, and -(CH2)6- is replaced by -X 2 -; X 1 and X 2 independently -O-, -S-, -NH-, -N(C 1-6 alkyl)-, -CH=CH-, -CR a (OH)- or -CR 1a R 1b -; R 1a is H, halogen, C 1-6 alkyl or C 1-6 haloalkyl; R 1b halogen, C 1-6 alkyl or C 1-6 haloalkyl; L 3 is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5- or -(CH2)6-, L 3 one -CH2- in -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5- and -(CH2)6- is replaced by -X 3 -; X 3 is -O-, -CR a (OH)-, -S-, -NH- or -N(C 1-6 alkyl)-; Y is -0-, -S- or -CR a (OH)-; R 21a is H or C 1-6 alkyl; Ring A is a C3-C6 cycloalkyl group, surrounded by one or more R groups. 3 The substituted C3-C6 cycloalkyl group, "a 3-6 membered heterocycloalkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms", or substituted with one or more R 4 The substituted heteroatom is selected from one, two, or three of N, O, and S, and is a 3-6 membered heterocyclic alkyl group with one, two, or three heteroatoms. n1 is 1, 2, 3 or 4; Ring B is a C3-C6 cycloalkyl group, surrounded by one or more R groups. 3 The substituted C3-C6 cycloalkyl group, "a 3-6 membered heterocycloalkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms", or substituted with one or more R 4 The substituted heteroatom is selected from one, two, or three of N, O, and S, and is a 3-6 membered heterocyclic alkyl group with one, two, or three heteroatoms. Ring C is formed by one or more R 3-1 The substituted C3-C6 cycloalkyl group, "a 3-6 membered heterocycloalkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms", or substituted with one or more R 4 The substituted heteroatom is selected from one, two, or three of N, O, and S, and is a 3-6 membered heterocyclic alkyl group with one, two, or three heteroatoms. R 3 and R 4 Independent of OH and C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C substituted with one or more OH groups 1-6 Alkyl, C 1- 6-alkoxy, C 1-6 Halogenated alkoxy or C substituted with one or more OH groups 1-6 Alkoxy; R 3-1 independently C1-6alkyl substituted with one or more OH; 1-6 C1-6alkoxy; R 21b is H or C 1-6 alkyl; R 21c is C 2-6 alkyl or C 6 substituted C 1-6 alkyl; Or, R 21b and R 21c Together with the carbon atoms connecting them, they form "a 3-6 membered heterocyclic alkyl group consisting of one, two, or three heteroatoms selected from N, O, and S, with one, two, or three heteroatoms" or is bounded by one or more R 4 The substituted heteroatom is selected from one, two, or three of N, O, and S, and is a 3-6 membered heterocyclic alkyl group with one, two, or three heteroatoms. R 6 Independent of halogen, C 1-6 Haloalkyl, C 1-6 Alkyl group, by one or more R 6-1 Replacement C 1-6 alkoxy or OH; R 6-1 independently halogen or OH; R 21d is H or C 1-6 alkyl; R 21e is C 1-6 alkyl or C 1-6 haloalkyl; R 22 NR a R b or C 22-1 alkyl substituted by one or more R 1-6 alkyl; R 22-1 independently OH; R 21f and R 21g independently C 1-6 alkyl; R 21h is C 1-6 alkyl or C 7 substituted C 1-6 alkyl; R 7 independently OH, halogen, C 3-6 cycloalkyl or substituted C 7-1 substituted C 3-6 cycloalkyl; R 7-1 independently halogen or OH; R 21i substituted by one or more R 8 substituted by one or more R 1-6 alkyl; R 8 independently OH, halogen, C 3-6 cycloalkyl or substituted C 8-1 substituted C 3-6 cycloalkyl; R 8-1 independently halogen or OH; R a and R b are independently H or C 1-6 alkyl; Ring D is "a 3-10 membered heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms", or is surrounded by one or more R... 4 The substituted heteroatom is selected from one, two, or three of N, O, and S, and is a 3-10 membered heterocyclic alkyl group with one, two, or three heteroatoms. n2 is 0, 1, 2, 3 or 4; Ring E is a C3-C6 cycloalkyl group, or a C3-C6 cycloalkyl group substituted with one or more OH groups; The carbon atom marked with * is in the R configuration, S configuration, or a mixture of both; the carbon atom marked with ** is in the R configuration, S configuration, or a mixture of both; when the carbon atom marked with # is a chiral carbon atom, it is in the R configuration, S configuration, or a mixture of both; when the carbon atom marked with & is a chiral carbon atom, it is in the R configuration, S configuration, or a mixture of both. when R 21b is H, R 21c is C 1-6 alkyl substituted by one or more halogen; and R 4b is H. when R is H, ring A is C3-C6cycloalkyl, R 21a is H, and R 4b is H. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein which is a compound of Formula I: in, R 21 -L 1 -C(R 21b )(R 21c )-OH、-L 2 -C(R 21d )(R 21e )-OH、 -L 1 -C(R 21d )(R 21e )-R 22 、-L 1 -C(R 21f )(R 21g )-CR a (OH)-R 21h or -L 3 -Y-R 21i ; The ring C is "a 3-6 membered heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" or is surrounded by one or more R... 4 The substituted heteroatom is selected from one, two, or three of N, O, and S, and is a 3-6 membered heterocyclic alkyl group with one, two, or three heteroatoms. The compound or pharmaceutically acceptable salt thereof of claim 1 or 2, wherein It meets one or more of the following conditions: (1) n is 2; (2) When there is a single bond between carbon atom 7 and carbon atom 8, R 7a and R 7b Halogens are independent of each other; R 8a For example, R. 7a and R 7b Independently for F, R 8a For H; When there is a double bond between carbon atom 7 and carbon atom 8, R 7a It does not exist, R 7b It is a halogen; R 8a It does not exist; for example, R 7a It does not exist, R 7b For F; R 8a It does not exist; (3)L 1 For -(CH2)2-, -(CH2)3-, -(CH2)4- or -(CH2)5-, L 1 The -CH2- of -(CH2)2-, -(CH2)3-, -(CH2)4-, or -(CH2)5- mentioned above is optionally replaced by -X. 1 -replace; (4) L 2 is -(CH2)2- or -(CH2)3-, L 2 one -CH2- in said -(CH2)2- or -(CH2)3- is optionally replaced by -X 1 -; (5) X 1 and X 2 independently -O-, -NH-, -N(C 1-6 alkyl)-, -CR a (OH)- or -CR 1a R 1b -; (6) R 1a halogen or C 1-6 alkyl; (7) R 1b halogen or C 1-6 alkyl; (8) L 3 is -(CH2)3- or -(CH2)5-, L 3 one -CH2- in said -(CH2)3- and -(CH2)5- is replaced by -X 3 -; (9) X 3 is -O- or -CR a (OH)-; (10) Ring A is a C3-C6 cycloalkyl group, and is surrounded by one or more R 3 The substituted C3-C6 cycloalkyl group or "a 3-6 membered heterocycloalkyl group selected from one, two or three of N, O and S, with one, two or three heteroatoms"; (11) n1 is 1; (12) Ring B is "a 3-6 membered heterocyclic alkyl group selected from 1, 2 or 3 of N, O and S, with 1, 2 or 3 heteroatoms"; (13) Ring C is "3-6 membered heterocycloalkyl, wherein the heteroatoms are selected from 1, 2, or 3 N, O, and S, and the number of heteroatoms is 1, 2, or 3" or is substituted with one or more R 3-1 substituted C3-C6cycloalkyl; (14) R 3 and R 4 independently OH, C 1-6 alkyl, halogen, C 1-6 alkoxy or C 1-6 alkyl substituted by one or more OH; (15) R 21b is H or C 1-6 alkyl; R 21c C 2-6 Alkyl or with one or more R 6 Replacement C 1-6 Alkyl; for example, R 21b C 1-6 Alkyl; R 21c For one or more R 6 Replacement C 1-6 Alkyl; R 6 It can be a halogen or OH on its own; or R 21b and R 21c and the carbon atoms connecting them form together a "3-6 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S, the number of heteroatoms being 1, 2 or 3"; (16) R 6 independently halogen, C 1-6 alkoxy, substituted C 6-1 alkyl, or OH; and 1-6 alkoxy or OH; (17) R 6-1 independently OH; (18) R 7 independently OH, substituted C 7-1 substituted C 3-6 cycloalkyl or halogen; (19) R 7-1 independently OH; (20) R 8 independently OH; (21) R a and R b are independently H; (22) R 4b is H; (23) R 21a is H, and ring A is "3-6 membered heterocycloalkyl having 1, 2, or 3 heteroatoms selected from N, O, and S, the number of heteroatoms being 1, 2, or 3"; (24) Ring C is bounded by one or more R 4 The substituted "heteroatom is selected from one, two, or three of N, O, and S, and is a 3-6 membered heterocyclic alkyl group with one, two, or three heteroatoms"; R 4 Independently OH; and, (25) R 21d is C 1-6 alkyl; R 21e is C 1-6 alkyl. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein It meets one or more of the following conditions: (1) R 21 -L 1 -C(R 21b )(R 21c )-OH; (2) L 1 is -(CH2)3-; preferably, L 1 one -CH2- in said -(CH2)3- is replaced by -X 1 X 1 is -O- or -CR a (OH)-; (3) X 1 and X 2 independently -O-, -CR a (OH)- or -CR 1a R 1b -; for example -CR 1a R 1b - or -O-; (4)R 21b For H or C 1-6 Alkyl, R 21c C 2-6 Alkyl or with one or more R 6 Replacement C 1-6 Alkyl; R 6 Independently halogenated; preferably, R 21b For H; R 21c For one or more R 6 Replacement C 1-6 Alkyl; R 6 Independently halogenated; preferably, R 21b C 1-6 Alkyl; R 21c C 2-6 Alkyl; for example, R 21b C 1-6 Alkyl; R 21c C 2-6 alkyl; (5) Ring D is formed by one or more R 4 The substituted heteroatom is selected from one, two, or three of N, O, and S, and is a 3-10 membered heterocyclic alkyl group having one, two, or three heteroatoms; preferably, R 4 Independently OH; (6) n2 is 1 or 2; for example, 1; (7) Ring E is a C3-C6 cycloalkyl group substituted with one or more OH groups; (8) R 4b is OH; (9)L 2 For -(CH2)2- or -(CH2)3-, L 2 One of the -CH2- or -(CH2)3- in the description is -X 2 - Instead of; preferably, X 2 For -CR 1a R 1b -, R 1a H or halogen; R 1b It is a halogen; (10) R 21d is C 1-6 alkyl; R 21e is C 1-6 alkyl; R 22 is C 22-1 substituted with one or more R 1-6 alkyl; and, (11) R a is H, R 21h is C 1-6 alkyl or C 7 substituted by one or more R 1-6 alkyl; R 7 is independently OH or halogen. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein It meets one or more of the following conditions: (1) The C1-C6 alkoxy group and the substituted C1-C6 alkoxy group are independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy. (2) The halogen is independently F, Cl, Br or I; (3) The C1-C6 alkyl group and the substituted C1-C6 alkyl group are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (4) the C 2-6 alkyl is independently ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl; (5) the C 1-6 haloalkyl is independently -CF3, -CHF2, -CH2F, -CH2CF3, or -CH2CHF2; (6) the C 1-6 haloalkoxy is independently -OCF3, -OCHF2, -OCH2F, -OCH2CF3, or -OCH2CHF2; (7) The C3-C6 cycloalkyl group and the substituted C3-C6 cycloalkyl group are independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; and, (8) 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 3-10 member heterocyclic alkyl group” and “the substituted 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 3-10 member heterocyclic alkyl group” are independently defined as “the heteroatom is selected from one or two of N and O, and the number of heteroatoms is one or two, of a 3-6 member monocyclic or 7-10 member bicyclic heterocyclic alkyl group”. The compound or pharmaceutically acceptable salt thereof of claim 1 or 2, wherein It meets one or more of the following conditions: (1) The C1-C6 alkoxy group and the substituted C1-C6 alkoxy group are independently methoxy groups; (2) The halogen is independently F; (3) the C1-C6alkyl and the substituted C1-C6alkyl independently are methyl, ethyl, isopropyl or (4) the C 2-6 alkyl is independently ethyl, isopropyl or (5) the C 1-6 haloalkyl is independently -CF3or -CHF2; (6) The C3-C6 cycloalkyl group and the substituted C3-C6 cycloalkyl group are independently cyclopropyl or cyclohexyl; and, (7) The phrase "a 3-6 membered heterocyclic alkyl group selected from 1, 2, or 3 of N, O, and S, with 1, 2, or 3 heteroatoms" and the phrase "a 3-6 membered heterocyclic alkyl group selected from 1, 2, or 3 of N, O, and S, with 1, 2, or 3 heteroatoms" in the substituted phrase "a 3-6 membered heterocyclic alkyl group selected from 1, 2, or 3 of N, O, and S, with 1, 2, or 3 heteroatoms" are independently defined as... The compound or pharmaceutically acceptable salt thereof of claim 1 or 2, wherein It meets one or more of the following conditions: (1) R 3a is H or (2) R 4a is H; R 4b is H, OH or methoxy; or, R 4a and R 4b together with the carbon atom to which they are attached form a (3) when the bond between the 7thand 8thcarbon atoms is a single bond, R 7a and R 7b are F; or R 7a and R 7b together with the carbon atom to which they are attached form wherein a is attached to the 8-carbon; R 8a is H; R is absent, F, Cl, CH3, CF3, or CN; R 7a is absent, F, Cl, CH3, CF3, or CN; R 7b is F; R 8a is absent; (4) The carbon atom marked with * has an S configuration; (5) The carbon atom marked with ** has an S configuration; (6) L 1 -(CH2)2-, -(CH2)3-, wherein b end is connected to Connected; (7) L 2 To wherein b end is connected to Connected; and (8) L 3 To wherein b end is connected to Connected. The compound or pharmaceutically acceptable salt thereof of claim 1 or 2, wherein It meets one or more of the following conditions: (1) For and, (2) R 21 To The compound or pharmaceutically acceptable salt thereof of claim 1 or 2, wherein The compound is a compound as shown in Formula I-1 or I-2: wherein R 21b and R 21c are as defined in any one of claims 1 to 8. or, in the compounds described above, For R 21 R 1 -C(R 21f )(R 21g )-CR a (OH)-R 21h ; the carbon atom marked with an asterisk is in the S configuration; wherein R 21f , R 21g , R a and R 21h are as defined in any one of claims 1 to 8; Better, R 21c C 2-6 Alkyl groups or C atoms substituted with one or more halogens 1-6 alkyl; Preferably, L 1 is -(CH2)3-; Preferably, R a is H; Better, R 21h C substituted by one or more OH groups 1-6 alkyl. a compound as shown by either of the following or a pharmaceutically acceptable salt thereof: A pharmaceutical composition comprising a compound as described in any one of claims 1-10 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient. Use of the compound of any one of claims 1-10 or a pharmaceutically acceptable salt thereof, or of the pharmaceutical composition of claim 11, wherein the use is selected from: (1) Prepare a medicine for the prevention and / or treatment of a disease, wherein the disease is obesity, hyperlipidemia, fatty liver, diabetes, atherosclerosis, cardiovascular and cerebrovascular diseases, liver cancer or skin lesions; (2) Prepare a drug for the prevention and / or treatment of diseases related to the SREBP pathway; preferably, the diseases related to the SREBP pathway are obesity, hyperlipidemia, fatty liver, diabetes, atherosclerosis, cardiovascular and cerebrovascular diseases, liver cancer or skin lesions; (3) Preparation of SREBP pathway inhibitors.

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