Steroidal compounds, pharmaceutical compositions thereof and uses thereof

Abstract

The application discloses a kind of steroidal compounds, its pharmaceutical composition and application, specifically disclose as shown in compound or its pharmaceutically acceptable salt of formula I-0.The compound of the application has SREBP pathway inhibitory activity, can be used for preventing and / or treating obesity, hyperlipidemia, fatty liver, diabetes, atherosclerosis, cardiovascular and cerebrovascular diseases, liver cancer, skin damage and other diseases.

Description

[0001] This application claims priority to Chinese Patent Application No. 2025101236077, filed on January 26, 2025; Chinese Patent Application No. 2025118292286, filed on December 5, 2025; and Chinese Patent Application No. 2026100729743, filed on January 19, 2026. The full text of the above-mentioned 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 then transported to the Golgi apparatus via SREBP cleavage-activating protein (SCAP). After further cleavage by two proteases (Site-1 protease (S1P) and Site-2 protease (S2P)), their N-terminal active domain is released, allowing them to enter the nucleus and function as transcription factors. They bind 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 nuclear 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 in 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. Existing studies have shown that abnormal activation of SREBPs has been found in fatty liver 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 occurrence of fatty liver and hyperlipidemia. Furthermore, recent studies have shown that endoplasmic reticulum stress-induced aberrant activation of the SREBP 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] This invention provides a compound as shown in Formula I-0 or a pharmaceutically acceptable salt thereof:

[0010] in, R 3a For H or -(CH2) m -OH; m is 1, 2 or 3; R 4a It is H or OH; R 7a and R 7b Each is independently a halogen or H; R 19 It is H or CH3; R 21 for ; L 1It is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, or -(CH2)6-; wherein one of the -CH2- portions of -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, and -(CH2)6- is optionally -Y 1 -replace; L 2 It is a single bond, -CH2-, -(CH2)2-, or -(CH2)3-; wherein one of the -CH2- portions of -CH2-, -(CH2)2-, and -(CH2)3- is optionally -Y 2 -replace; L 3 It is a single bond, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, or -(CH2)6-, wherein one of the -CH2- portions of -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, and -(CH2)6- is optionally -Y 3 -replace; X is -O-, -S-, or -NR-; R is H or C 1-6 alkyl; Y 1 -O-, -S-, -CHR Y1 -or -NR-; R Y1 Halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups or -OH; Y 2 For -CHR Y2 -; R Y2 Halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups or -OH; Y 3 -O-, -S-, -CHR Y3 -、-NR- or -NR-C(O)-NR-; R Y3 C 1-6 Alkyl, -OH or with one or more R 1 Replacement C 1-6 alkyl; R 21a For H or C 1-6 alkyl; R 21b C 1-6 Alkyl, with one or more R1 Replacement C 1-6 Alkyl group, "a 5-10 membered heteroaryl group selected from one, two, or three heteroatoms selected from N, O, and S, with one, two, three, or four heteroatoms", and surrounded by one or more R... b1 The substituted "heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, three, or four, belonging to a 5-10 member heteroaryl group", C 6-10 aryl or aryl with one or more R 1d Replacement C 6-10 Aryl; R A -C(O)NR 2a R 2b -CR 2c R 2d R 2e -S(O)2R 2f -OH, -N(R) 3b )-S(O)2R 3c -NR 3d R 3e -S(O)2-N(R) 3d R 3e -NR 5a C(O)NR 5b R 5c -COOR 5d "The heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, three, or four, belonging to a 5-10 member heteroaryl group" or is composed of one or more R... 1a The substituted "5-10-membered heteroaryl group selected from one, two, or three of N, O, and S, with one, two, three, or four heteroatoms" or "3-10-membered heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" or "substituted by one or more R 1b 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" or C3- 10 cycloalkyl, with one or more R 1c Replacement C3- 10 cycloalkyl, C 6-10 aryl or aryl with one or more R 1d Replacement C 6-10 Aryl; R 2a For H or C 1-6 alkyl; R 2b For H, C 1-6 Alkyl, with one or more R 1 Replacement C1-6 Alkyl, C3- 10 cycloalkyl, with one or more R 1c Replacement C3- 10 Cycloalkyl, "a 3-10 membered heterocycloalkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms", or consisting of one or more R... 1b 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. R 2c For H, C 1-6 Alkyl, with one or more R 1 Replacement C 1-6 Alkyl, halogen, C 1-6 Alkyl group, by one or more R 2 Replacement C 1-6 Alkoxy, C3-C 10 cycloalkyl or with one or more R 1c Replacement C3- 10 cycloalkyl; R 2d For H, C 1-6 Alkyl, with one or more R 1 Replacement C 1-6 Alkyl, halogen, C3- 10 cycloalkyl, with one or more R 1c Replacement C3- 10 Cycloalkyl, "a 3-10 membered heterocycloalkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms", or consisting of one or more R... 1b 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. Or, R 2c R 2d Together with the C atoms they are attached to, they form C3- 10 cycloalkyl; R 2e C 1-6 Alkyl group, by one or more R 1 Replacement C 1-6 Alkyl, with one or more R 2 Replacement C 1-6 Alkyl group, halogen, -OH, "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 surrounded by one or more R 1bThe 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. R 2f For H, C 1-6 Alkyl or with one or more R 1 Replacement C 1-6 alkyl; R 3b For H or C 1-6 alkyl; R 3c For H, C 1-6 Alkyl or with one or more R 1 Replacement C 1-6 alkyl; R 3d For H or C 1-6 alkyl; R 3e For H, C 1-6 Alkyl, with one or more R 1 Replacement C 1-6 Alkyl group, "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 formed by one or more R... 1b 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" or C3- 10 cycloalkyl, or by one or more R 1c Replacement C3- 10 cycloalkyl; Each R 5a R 5b and R 5c Each independently represents H and C. 1-6 Alkyl or with one or more R 1 Replacement C 1-6 alkyl; R 5d For H or C 1-6 alkyl; Each R 1 and R 2 Each is independently a halogen, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups; Each R b1 R 1a R 1b R 1c and R 1d Each independently constitutes a halogen, C 1-6Alkoxy, -OH, C 1-6 Alkyl, with one or more R 1 Replacement C 1-6 Alkyl, C 1-6 Halogenated alkoxy or -COOR 5d ; The labeled carbon atoms are 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.

[0011] 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:

[0012] in, R 7a and R 7b Each is an independent halogen.

[0013] In certain preferred embodiments of the present invention, certain groups in the compounds represented by formulas I-0, I or pharmaceutically acceptable salts thereof 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").

[0014] In some implementation schemes, R 19 For H.

[0015] In some implementation schemes, R 19 It is CH3.

[0016] In some implementation schemes, R 7a and R 7b Each is an independent halogen.

[0017] In some implementation schemes, R 3a For H or H is preferred.

[0018] In some implementations, L 1 It is -(CH2)2- or -(CH2)3-; wherein one of the -CH2- portions of the -(CH2)3- is optionally -Y 1 - Alternative. Better, L 1 It is -(CH2)3-, wherein one of the -CH2- portions of the -(CH2)3- is optionally -Y 1 -replace, -Y 1 - is -O-.

[0019] In some implementations, L 1 It is -(CH2)3-, wherein one of the -CH2- portions of the -(CH2)3- is optionally -Y 1 -replace, -Y 1 -for-CHR Y1 -

[0020] In some implementations, L 1 It is -(CH2)3-.

[0021] In some implementation schemes, Y 1 -O- or -CHR Y1 -

[0022] In some implementation schemes, R Y1 It is -OH.

[0023] In some implementations, L 2 It is a single bond or -CH2-, wherein the -CH2- is optionally replaced by -Y 2 -replace.

[0024] In some implementation schemes, R Y2 C 1-6 alkyl.

[0025] In some implementation schemes, R Y2 C 1-6 Halogenated alkyl groups.

[0026] In some implementations, L 2 It is a single key.

[0027] In some implementations, L 2 -CH2-, wherein the -CH2- is optionally -Y 2 -replace.

[0028] In some implementations, L 2 It is -CH2-.

[0029] In some implementations, L 3 It is a single bond, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, or -(CH2)5-; wherein one of the -CH2- portions of -(CH2)3-, -(CH2)4-, and -(CH2)5- is optionally -Y 3 - Instead; preferably a single bond, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4- or -(CH2)5-; wherein one of the -CH2- portions of -(CH2)4- and -(CH2)5- is optionally replaced by -Y 3-replace.

[0030] In some implementations, L 3 It is -CH2-, -(CH2)2-, or -(CH2)5-; wherein one of the -CH2- portions of the -(CH2)5- is optionally -Y 3 - Replace; for example, -CH2-.

[0031] In some implementation schemes, Y 3 It is -O-.

[0032] In some implementations, X is -O- or -NR-.

[0033] In some implementations, X is -O- or -S-.

[0034] In some implementations, R is H.

[0035] In some implementations, X is -O-.

[0036] In some implementation schemes, R 21a For H.

[0037] In some implementation schemes, R 21a C 1-6 alkyl.

[0038] In some implementation schemes, R 21b C 1-6 Alkyl, with one or more R 1 Replacement C 1-6 Alkyl or with one or more R b1 The substituted heteroatom is selected from one, two, or three of N, O, and S, and is a 5-10 membered heteroaryl group with one, two, three, or four heteroatoms; preferably C. 1-6 Alkyl or with one or more R b1 The substituted heteroatom is selected from one, two, or three of N, O, and S, and is a 5-10 membered heteroaryl group with one, two, three, or four heteroatoms; preferably C. 1-6 Alkyl, or with one or more R 1 Replacement C 1-6 alkyl.

[0039] In some implementation schemes, R 21b C 1-6 alkyl.

[0040] In some implementation schemes, R A -C(O)NR 2a R 2b -CR 2c R 2d R 2e-S(O)2R 2f -OH, -N(R) 3b )-S(O)2R 3c -NR 3d R 3e -S(O)2-N(R) 3d R 3e -NR 5a C(O)NR 5b R 5c -COOR 5d "The heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, three, or four, belonging to a 5-10 member heteroaryl group" or is composed of one or more R... 1a The substituted "5-10-membered heteroaryl group selected from one, two, or three of N, O, and S, with one, two, three, or four heteroatoms" or "3-10-membered heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" or "substituted by one or more R 1b The substituted "heteroatom selected from one, two, or three of N, O, and S, and a 3-10 membered heterocyclic alkyl group having one, two, or three heteroatoms" or being replaced by one or more R 1c Replacement C3- 10 cycloalkyl; Preferably, R A -C(O)NR 2a R 2b -CR 2c R 2d R 2e -S(O)2R 2f -OH, -N(R) 3b )-S(O)2R 3c -NR 3d R 3e -S(O)2-N(R) 3d R 3e -NR 5a C(O)NR 5b R 5c "The heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, three, or four, belonging to a 5-10 member heteroaryl group" or is composed of one or more R... 1a The substituted "5-10-membered heteroaryl group selected from one, two, or three of N, O, and S, with one, two, three, or four heteroatoms" or "3-10-membered heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" or "substituted by one or more R 1bThe substituted "heteroatom selected from one, two, or three of N, O, and S, and a 3-10 membered heterocyclic alkyl group having one, two, or three heteroatoms" or being replaced by one or more R 1c Replacement C3- 10 Cycloalkyl.

[0041] In some implementation schemes, R A -C(O)NR 2a R 2b -CR 2c R 2d R 2e -OH, "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 surrounded by one or more R 1c Replacement C3- 10 cycloalkyl; for example -CR 2c R 2d R 2e .

[0042] In some implementation schemes, R 2a For H.

[0043] In some implementation schemes, R 2a C 1-6 alkyl.

[0044] In some implementation schemes, R 2b For H, C 1-6 Alkyl, with one or more R 1 Replacement C 1-6 Alkyl, with one or more R 1c Replacement C3-C 10 Cycloalkyl or "a 3-10 membered heterocycloalkyl group selected from one, two or three of N, O and S, with one, two or three heteroatoms"; preferably H.

[0045] In some implementation schemes, R 2b C 1-6 alkyl.

[0046] In some implementation schemes, R 2c For H or C 1-6 Alkyl group. In some embodiments, R 2c C 1-6 alkyl.

[0047] In some implementation schemes, R 2d C 1-6 Alkyl, with one or more R 1 Replacement C 1-6 Alkyl, halogen, C3- 10Cycloalkyl or "a 3-10 membered heterocycloalkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms"; preferably C. 1-6 Alkyl, C3- 10 cycloalkyl or with one or more R 1 Replacement C 1-6 alkyl.

[0048] In some implementation schemes, R 2d C 1-6 Alkyl, or with one or more R 1 Replacement C 1-6 Alkyl; for example, C 1-6 alkyl.

[0049] In some implementation schemes, R 2d For H.

[0050] In some implementation schemes, R 2e C 1-6 Alkyl group, by one or more R 1 Replacement C 1-6 Alkyl, with one or more R 2 Replacement C 1-6 Alkyl, halogen, or -OH; preferably -OH or surrounded by one or more R 1 Replacement C 1-6 alkyl.

[0051] In some implementation schemes, R 2e It is OH.

[0052] In some implementation schemes, R 2f C 1-6 alkyl.

[0053] In some implementation schemes, R 3b For H.

[0054] In some implementation schemes, R 3c C 1-6 Alkyl or with one or more R 1 Replacement C 1-6 Alkyl; preferably C 1-6 alkyl.

[0055] In some implementation schemes, R 3d For H.

[0056] In some implementation schemes, R 3e For H, C 1-6 Alkyl, with one or more R 1 Replacement C 1-6Alkyl or "a 3-10 membered heterocyclic alkyl group selected from one, two or three of N, O and S, with one, two or three heteroatoms"; preferably H.

[0057] In some implementations, each R 5a R 5b and R 5c Each is independently of H or is controlled by one or more R. 1 Replacement C 1-6 Alkyl group; preferably H.

[0058] In some implementation schemes, R 5d For H.

[0059] In some implementations, each R 1 and R 2 Each can be a halogen or -OH independently.

[0060] In some implementations, each R 1 and R 2 Each is an independent halogen.

[0061] In some implementations, each R b1 R 1a R 1b and R 1c Each independently constitutes a halogen, C 1-6 Alkyl group, -OH group, or grouped by one or more R groups 1 Replacement C 1-6 Alkyl; preferably halogen or C 1-6 Alkyl group.

[0062] In some implementations, each R b1 R 1a R 1b and R 1c Each is an independent C substituted by one or more OH groups. 1-6 alkyl.

[0063] In some implementations, each R 1 R 2 R 1a R 1b R 1c and R 2e Each is independently -OH.

[0064] In some embodiments, the halogen is independently F, Cl, Br, or I, for example, F.

[0065] In some implementations, the C 1-6 Alkyl groups and the substituted C 1-6 C in alkyl 1-6The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl, ethyl, isopropyl, or tert-butyl.

[0066] In some implementations, the C 1-6 alkoxy groups and the substituted C 1-6 C in alkoxy 1-6 Alkoxy groups are independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy; for example, methoxy or ethoxy.

[0067] In some implementations, the C 1-6 The alkyl halide is independently -CF3, -CHF2, -CH2F, -CH2CF3 or -CH2CHF2; for example -CF3 or -CHF2.

[0068] In some implementations, the C 1-6 The haloalkoxy group is independently -OCF3, -OCHF2, -OCH2F, -OCH2CF3 or -OCH2CHF2.

[0069] In some embodiments, the phrase "5-10 membered heteroaryl groups selected from one, two, or three of N, O, and S, with one, two, three, or four heteroatoms" and the phrase "5-10 membered heteroaryl groups selected from one, two, or three of N, O, and S, with one, two, three, or four heteroatoms" in the substituted phrase "5-10 membered heteroaryl groups selected from one, two, or three of N, O, and S, with one, two, three, or four heteroatoms" are independently defined as "5- or 6 membered heteroaryl groups selected from N, with one, two, or three heteroatoms." For example... , , or .

[0070] In some embodiments, the substituted "5- to 10-membered heteroaryl group selected from one, two, or three of N, O, and S, with one, two, three, or four heteroatoms" is independently the substituted "5- or 6-membered heteroaryl group selected from N, with one, two, or three heteroatoms," for example... , , or For example... or .

[0071] 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 O and S, 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, oxetane (e.g., ...). , ) or 2-oxaspiro[3.3]heptane (e.g. () Preferably, it is a 3-6 membered monocyclic heterocyclic alkyl group with one heteroatom selected from O.

[0072] 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 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). (); preferably, “the heteroatom is selected from N, and the number of heteroatoms is 1 in a 3-6 member monocyclic heterocyclic alkyl group”.

[0073] In some embodiments, the C3-C 10 The cycloalkyl group is independently a C3-C6 monocyclic or C5-C6 monocyclic ring. 10 Bicycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentane or spiro[3.3]heptane (e.g. ); preferably C3-C6 monocyclic alkyl.

[0074] In some implementations, the C 6-10 aryl and the substituted C 6-10 C in aryl 6-10 The aryl group can be phenyl or naphthyl independently.

[0075] In some implementations... The labeled carbon atom has an S configuration.

[0076] In some implementations, when the carbon atom marked with # is a chiral carbon atom, it is in the R configuration.

[0077] In some implementation schemes, R 7a and R 7b Each is independently represented by F.

[0078] In some implementations... for , or .

[0079] In some implementations... for .

[0080] In some implementations... for .

[0081] In some implementations... for or .

[0082] In some implementations, L 1 -(CH2)2-, -(CH2)3-, , , or Preferably -(CH2)3- or Preferably, L 1 for , or ; where a' end and or Connected. In some implementations, L 1 for ;For example .

[0083] In some implementations, L 2 It is a single bond, -CH2- or -CH(CH3); preferably a single bond or -CH2-.

[0084] In some implementations, L 2 For -CH(CF3).

[0085] In some implementations, L 3 For single bonds, -CH2-, -(CH2)2-, -(CH2)3-, , , or Preferably, L 3 for , or ; where b' is connected to X.

[0086] In some implementation schemes, R 21 In for , , , , , , , or , where the a end and L 3 Connection; preferably , , , or More preferably or .

[0087] In some implementation schemes, R 21 In for , or Among them, the a end and the L end 3 connect.

[0088] In some implementation schemes, R A -C(O)NR 2a R 2b for , , , , or Preferred .

[0089] In some implementation schemes, R A -CR 2c R 2d R 2e for , , , , , , , , , , , , , , , , , , , , , or Preferred , , , , , or .

[0090] In some implementation schemes, R A -CR 2c R 2d R 2e for -CH2F , or .

[0091] In some implementation schemes, R A Medium, -S(O)2R 2f for .

[0092] In some implementation schemes, R A In, -N(R) 3b )-S(O)2R 3c for or Preferred .

[0093] In some implementation schemes, R A In the middle, -NR 3d R 3e -NH2, , , or The preferred option is -NH2.

[0094] In some implementation schemes, R A In, -S(O)2-N(R) 3d R 3e )for .

[0095] In some implementation schemes, R A In the middle, -NR 5a C(O)NR 5b R 5c for or Preferred .

[0096] In some implementation schemes, R AIn this context, "a 5- to 10-membered heteroaryl group selected from one, two, or three of N, O, and S, with one, two, three, or four heteroatoms" is defined as... or Preferred .

[0097] In some implementation schemes, R A In this context, "a 3-10 membered heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" is defined as... , or Preferred .

[0098] In some implementation schemes, R A In this context, the substituted "heteroatom selected from one, two, or three of N, O, and S, and a 3-10 membered heterocyclic alkyl group having one, two, or three heteroatoms" is... .

[0099] In some implementation schemes, R A In this context, the substituted "heteroatom selected from one, two, or three of N, O, and S, and a 3-10 membered heterocyclic alkyl group having one, two, or three heteroatoms" is... or .

[0100] In some implementation schemes, R A In, C3- is replaced 10 cycloalkyl is , , , or .

[0101] In some implementation schemes, R A In, C3- is replaced 10 cycloalkyl is .

[0102] In some implementation schemes, R A In, C3- is replaced 10 cycloalkyl is .

[0103] In some implementation schemes, R 21 for , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0104] In some implementation schemes, R 21 for , , , , , , , , , , , , , , , , , , , or .

[0105] In some embodiments, the compound shown in Formula I is a compound shown in Formula I-1: #, L 3 and R A The definition is as described in any one of the present invention.

[0106] In some implementations, in formula I-1, L3 It is -CH2-, -(CH2)2-, -(CH2)3- or -(CH2)5-; wherein one of the -CH2- portions of the -(CH2)5- is optionally replaced by -O-.

[0107] In some implementations, in formula I-1, R A -OH, -CR 2c R 2d OH, -NH2, or -C(O)NH2.

[0108] In some implementations, in formula I-1, R 2c For H or C 1-6 alkyl.

[0109] In some implementations, in formula I-1, R 2d C 1-6 Alkyl or -C 1-4 Alkylene-OH.

[0110] In some implementations, in formula I-1, R 2d For C3- 10 Cycloalkyl.

[0111] In some embodiments, the compound shown in Formula I is a compound shown in Formula I-2: L 3 and R A The definition is as described in any one of the present invention.

[0112] In some implementations, in formula I-2, L 3 It is a single bond, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4- or -(CH2)5-; wherein one of the -CH2- portions of -(CH2)4- and -(CH2)5- is optionally replaced by -O-.

[0113] In some implementations, in formula I-2, R A -NH-S(O)2R 3c -CR 2c R 2d R 2e -C(O)NH2, "5-10 membered heteroaryl groups selected from one, two, or three of N, O, and S, with one, two, three, or four heteroatoms", -OH, -S(O)2R 2f , by one or more R 1aThe substituted "5-10-membered heteroaryl group selected from one, two, or three of N, O, and S, with one, two, three, or four heteroatoms" or "3-10-membered heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" or "substituted by one or more R 1c Replacement C3- 10 Cycloalkyl or -NHC(O)NH2.

[0114] In some implementations, in formula I-2, R 2c For H or C 1-6 alkyl.

[0115] In some implementations, in formula I-2, R 2d C 1-6 Alkyl, C3- 10 cycloalkyl or C 1-6 Halogenated alkyl groups.

[0116] In some implementations, in formula I-2, R 2e -OH or -C 1-4 Alkylene-OH.

[0117] In some implementations, in formula I-2, R 2f C 1-6 alkyl.

[0118] In some implementations, in formula I-2, R 3c C 1-6 alkyl.

[0119] In some embodiments, the compound shown in Formula I is a compound shown in Formulas I-3: #, &, R b1 L 3 and R A The definition is as described in any one of the present invention; n is 1, 2, or 3; Ring A is "a 5-10 membered heteroaryl group selected from one, two or three of N, O and S, with one, two, three or four heteroatoms".

[0120] In some implementations, in formula I-3, R b1 Independently halogen or C 1-6 Alkyl group.

[0121] In some implementations, in formula I-3, L 3 It is -CH2- or -(CH2)2-.

[0122] In some implementations, in formula I-3, R A For -CR 2c R 2d OH, -OH or -C(O)NH2;

[0123] In some implementations, in formula I-3, R 2c C 1-6 alkyl.

[0124] In some implementations, in formula I-3, R 2d C 1-6 alkyl.

[0125] In some implementations, the -C 1-4 Alkylene is independently -CH2-, -CH2CH2-, -CH(CH3)-, -CH2CH2CH2-, -C(CH3)2-, -CH2CH(CH3)-, -CH2CH2CH2CH2-, -CH(CH3)CH(CH3)- or -CH2CH(CH3)CH2-; for example -CH2- or -C(CH3)2-.

[0126] In some embodiments, the compound shown in Formula I is a compound shown in Formulas I-4: R 21a R 21b L 2 L 3 X and R A The definition is as described in any one of the present invention.

[0127] In some implementations, in formula I-4, R 21a For H or C 1-6 alkyl.

[0128] In some implementations, in formula I-4, R 21b C 1-6 Alkyl or with one or more R 1 Replacement C 1-6 alkyl.

[0129] In some implementations, in formula I-4, R 1 It is a halogen.

[0130] In some implementations, in formula I-4, L 2 It is a single bond or -CH2-; wherein the -CH2- is optionally replaced by -Y 2 -replace.

[0131] In some implementations, in formula I-4, RY2 C 1-6 alkyl.

[0132] In some implementations, in formula I-4, L 3 It is -(CH2)2-.

[0133] In some implementations, in formula I-4, R A It is -OH.

[0134] In some implementations, X in Equation I-4 is -O- or -S-.

[0135] In some embodiments, the compound is a compound as shown in Formulas I-5: R 21a R 21b L 2 L 3 X and R A The definition is as described in any one of the present invention.

[0136] In some implementations, in formula I-5, R 21a C 1-6 alkyl.

[0137] In some implementations, in formula I-5, R 21b C 1-6 alkyl.

[0138] In some implementations, in formula I-5, L 2 It is a single bond or -CH2-.

[0139] In some implementations, in formula I-5, L 3 It is -CH2- or -(CH2)2-.

[0140] In some implementations, in formula I-5, R A For -CR 2c R 2d OH or -OH.

[0141] In some implementations, in formula I-5, R 2c C 1-6 alkyl.

[0142] In some implementations, in formula I-5, R 2d C 1-6 alkyl.

[0143] In some implementations, X in Equation I-5 is -O- or -S-.

[0144] The present invention also provides any of the following compounds or pharmaceutically acceptable salts thereof: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , or .

[0145] The present invention also provides any of the following compounds or pharmaceutically acceptable salts thereof: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0146] The present invention also provides a compound as shown in Formula II or III:

[0147] in, and R 21 The definition is as described in any one of the present invention; R 6a It is a hydroxyl protecting group.

[0148] In some implementations, R 6a for .

[0149] In some embodiments, the compound represented by formula II or III has any of the following structures: , , , , , , , , , , , , , , , , , , , , , , or .

[0150] The present invention also provides a pharmaceutical composition comprising the compound as described above or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient.

[0151] 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: (1) Prepare a drug 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; preferably hyperlipidemia or fatty liver; (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 damage; preferably hyperlipidemia or fatty liver; (3) Preparation of SREBP pathway inhibitors.

[0152] 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.

[0153] Definitions and Explanations

[0154] 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.

[0155] In chemical structures, wedge-shaped solid lines are used ( ) and wedge-shaped dashed key ( ) represents the absolute configuration of a solid center, using a straight solid line key ( ) and straight dashed key ( () indicates the relative configuration of the solid center. Key " "No configuration is specified, meaning that if configurational isomerism exists in the chemical structure, the bond..." "can be " "or" , or both contain " "and" "Two configurations (e.g., " "and" The ratio is 1:1. When the carbon-carbon double bond does not specify its specific configuration, it can be either E or Z configuration. Stereoisomers can be synthesized using chiral starting materials, prepared by chiral resolution, or resolved using conventional techniques such as, but not limited to, high-performance liquid chromatography (HPLC) using chiral columns.

[0156] 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.

[0157] In this document, the term "substitution" or "substituent" refers to the replacement of a hydrogen atom in a group by a specified group. Substitution can occur at any position unless the substitution position is specified, but it is only permitted if a stable or chemically viable chemical is formed. Examples are given below: [The text abruptly ends here, likely due to an incomplete sentence or missing information.] 1c Replacement C3-C 10 Cycloalkyl means C3-C 10 The hydrogen atom on the cycloalkyl group is affected by one or more R 1c Replaced when there are multiple R 1c At that time, each R 1c Same or different.

[0158] When any variable (e.g., R) 21aWhen a compound appears more than once in its composition or structure, its definition is independent in each case.

[0159] In this document, the term "alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group. C1-6 alkyl means alkyl with 1-6 carbon atoms.

[0160] In this document, the term "alkylene" refers to a saturated straight-chain or branched divalent hydrocarbon group. C1-4 alkylene refers to alkylene having 1-4 carbon atoms, specifically methylene, ethylene (e.g., -CH2CH2-, -CH(CH3)-), propylene (e.g., -CH2CH2CH2-, -C(CH3)2-, -CH2CH(CH3)-), and butylene (e.g., -CH2CH2CH2CH2-, -CH(CH3)CH(CH3)-, -CH2CH(CH3)CH2-).

[0161] 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.

[0162] In this document, the term "alkoxy" refers to -O-alkyl, where alkyl is defined as previously stated.

[0163] 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.

[0164] In this document, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic cyclic hydrocarbon group (e.g., fused, spirocyclic, or bridged). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, and... or C 3-10 Specifically, cycloalkyl groups can be C3, C4, C5, C6, C7, C8, C9 ... 10 Cycloalkyl. C 3-6 The cycloalkyl group can specifically be a C3, C4, C5, or C6 cycloalkyl group. In some embodiments, the cycloalkyl group is a monocyclic ring. In some embodiments, the cycloalkyl group is a polycyclic ring (e.g., fused ring, spiro ring, or bridged ring).

[0165] In this document, the term "heterocyclic alkyl" refers to a saturated monocyclic or polycyclic (e.g., fused, spirocyclic, or bridged) cyclic group formed by a carbon atom and at least one heteroatom, wherein the heteroatom is independently selected from N, O, and S. Heterocyclic alkyl groups can be linked to other structures via carbon atoms and heteroatoms on the ring. Examples of heterocyclic alkyl groups include, but are not limited to, those shown below. or The 3-10 membered heterocyclic alkyl group can specifically be a 3, 4, 5, 6, 7, 8, 9, or 10 membered heterocyclic alkyl group. The 3-6 membered heterocyclic alkyl group can specifically be a 3, 4, 5, or 6 membered heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is monocyclic. In some embodiments, the heterocyclic alkyl group is polycyclic (e.g., fused, spirocyclic, or bridged).

[0166] In this article, the term "C" 6-10 "Aryl" refers to phenyl or naphthyl.

[0167] In this document, the term "heteroaryl" refers to an aromatic monocyclic group consisting of a carbon atom and at least one heteroatom, wherein the heteroatom is independently selected from N, O, and S. Specifically, 5-10-membered heteroaryls can be 5, 6, 7, 8, 9, or 10-membered heteroaryls, for example, 5-6-membered heteroaryls. Specific examples of heteroaryls include, but are not limited to, those mentioned above. , , or .

[0168] In this document, the term "subject" includes any animal, preferably a mammal, and more preferably a human.

[0169] 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.

[0170] 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.

[0171] The reagents and raw materials used in this invention are all commercially available.

[0172] 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. Attached Figure Description

[0173] Figure 1 This is the full two-dimensional NMR spectrum of compound I-5. Detailed Implementation

[0174] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0175] Preparation Example 1

[0176] Synthesis of intermediate 98-0 7,7-difluoro-25-methyl-3β-{[(2-methylprop-2-yl)diphenylsilyl]oxy}-5α-cholesterol

[0177] Step 1: Dissolve II-11 (2 g, 3.1 mmol) in dichloromethane (40 mL), add Desmartin oxidant (2 g, 4.7 mmol) 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 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 98-0-0 (1.5 g, yield: 68%). 1 H NMR (400 MHz, CDCl3) d 9.75 (t, J = 1.8 Hz, 1H), 7.66 (m,4H), 7.38 (m, 6H), 3.59 (tt, J = 10.3, 5.1 Hz, 1H), 2.39 (m, 2H), 1.82 (m,4H), 1.59 (ddd, J = 22.4, 15.0, 6.3 Hz, 6H), 1.44 (m, 5H), 1.29 (m, 5H), 1.06(m, 11H), 0.89 (dd, J = 7.8, 4.9 Hz, 4H), 0.82 (s, 4H), 0.64 (s, 3H).

[0178] Step 2: Dissolve 98-0-0 (5 g, 2.5 mmol) in tetrahydrofuran (20 mL), add methyl (triphenyl-λ5-methylphosphine) acetate (2 g, 4.7 mmol) at room temperature, and heat to 90°C. oAfter stirring at C for 16 hours, the reaction was monitored by TLC (petroleum ether: ethyl acetate = 20:1) to confirm completion. The mixture was diluted with 200 mL of water at room temperature, extracted with ethyl acetate (200 mL × 2), and the organic phase was washed with saturated brine (50 mL). The organic phase was then evaporated to dryness to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to give 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 98-0-1 (1.5 g, yield: 77%). 1 H NMR (400 MHz, CDCl3) d 7.59 (dd, J =6.1, 1.6 Hz, 4H), 7.32 (m, 6H), 6.88 (d, J = 15.6 Hz, 1H), 5.73 (d, J = 15.6Hz, 1H), 3.64 (d, J = 7.2 Hz, 3H), 3.52 (tt, J = 10.4, 5.1 Hz, 1H), 2.17 (qd,J = 10.6, 5.3 Hz, 1H), 1.98 (s, 1H), 1.86 (d, J = 12.7 Hz, 1H), 1.74 (d, J =7.1 Hz, 2H), 1.57 (dd, J = 10.7, 3.7 Hz, 3H), 1.40 (m, 7H), 1.19 (dt, J =15.9, 14.3 Hz, 5H), 0.99 (m, 12H), 0.82 (m, 5H), 0.75 (s, 3H), 0.69 (d, J =3.8 Hz, 1H), 0.57 (s, 3H).

[0179] Step 3: Dissolve 98-0-1 (1.5 g, 2.2 mmol) in tetrahydrofuran (10 mL) and methanol (5 mL), add nickel chloride (0.3 g, 2.6 mmol) at room temperature, then slowly add sodium borohydride (0.1 g, 2.6 mmol), stir at room temperature for 1 hour, and monitor the reaction for completeness by TLC (petroleum ether: ethyl acetate = 20:1). 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 = 20:1) to give 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 98-0-2 (1.2 g, yield: 72%). 1 H NMR (400 MHz, CDCl3) d 7.66 (m, 4H), 7.38 (m, 6H), 3.66 (s, 3H), 3.58 (dt, J = 15.6, 5.2 Hz, 1H), 2.29 (m, 2H), 1.93 (dd, J = 9.4, 3.3 Hz, 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 = 6.5 Hz, 4H), 0.82 (s,3H), 0.76 (dd, J = 13.3, 9.4 Hz, 1H), 0.63 (s, 3H).

[0180] Step 4: Dissolve 98-O-2 (1.5 g, 2.2 mmol, 1 eq) in tetrahydrofuran (50 mL) and cool to -78°C. o After step C, add diisopropylaminolithium (6.5 mL, 13 mmol) dropwise, maintain the temperature and stir for 30 minutes, then slowly add iodomethane (2.5 g, 17 mmol). oAfter stirring at C for 30 min, the reaction was monitored by TLC (petroleum ether: ethyl acetate = 20:1) to ensure complete reaction. The reaction was quenched at room temperature with 200 mL of saturated ammonium chloride aqueous solution, extracted with ethyl acetate (200 mL × 2), and the organic phase was washed with saturated brine (50 mL). The organic phase was then evaporated to dryness to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to give 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 98-0-3 (200 mg, yield: 11%). 1 H NMR (400 MHz, cdcl3) d 7.67 (m, 4H), 7.39 (m,6H), 3.65 (s, 3H), 3.59 (m, 1H), 1.92 (s, 1H), 1.80 (d, J = 7.1 Hz, 2H), 1.65(m, 3H), 1.53 (m, 3H), 1.41 (m, 4H), 1.27 (ddd, J = 18.7, 13.9, 9.5 Hz, 8H), 1.16 (s, 6H), 1.06 (d, J = 11.3 Hz, 14H), 0.87 (d, J = 6.5 Hz, 4H), 0.83 (s,3H), 0.77 (s, 1H), 0.64 (s, 3H).

[0181] Step 5: Dissolve 98-0-3 (500 mg, 0.7 mmol) in tetrahydrofuran (10 mL), and slowly add lithium aluminum hydride (52 mg, 0.14 mmol) at room temperature. Maintain the temperature and stir for 30 minutes. Monitor the reaction for completeness by TLC (petroleum ether: ethyl acetate = 5:1). Quench 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 = 10:1) to obtain 7,7-difluoro-25-methyl-3β-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}-5α-cholesterol-26-ol 98-0 (420 mg, yield: 79%). 1 H NMR (400 MHz, CDCl3) d7.66 (d, J = 6.7 Hz, 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 = 18.7 Hz, 15H), 0.86 (dd, J = 20.2, 10.3 Hz, 14H), 0.77 (s, 1H), 0.64 (s, 3H).

[0182] Preparation Example 2

[0183] Preparation of compound 88-1

[0184] Compound II (650 mg, 0.96 mmol), silver trifluoromethanesulfonate (TfOAg) (737.83 mg, 2.87 mmol), and 2,6-di-tert-butylpyridine (915.61 mg, 4.79 mmol) were dissolved in a reaction flask containing 15 mL of dichloromethane at room temperature, followed by the addition of ethyl 3-bromopropionate (519.85 mg, 2.87 mmol). The reaction mixture was stirred at room temperature for 18 h. TLC (petroleum ether:ethyl acetate = 10:1) showed the formation of a new spot and the presence of remaining starting material. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by rapid column chromatography (ethyl acetate / petroleum ether = 1-10%) to obtain methyl 3-{[(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-methylhept-2-yl]oxy}propionate 88-1 (200 mg, yield: 24.1%) as a colorless viscous oil. 1H NMR (400 MHz, CDCl3) δ 7.67 - 7.65 (m, 4H), 7.42 - 7.34 (m, 6H), 3.67 (s, 3H), 3.58 (t, J =6.7 Hz, 3H), 2.52 (t, J = 6.6 Hz, 2H), 1.93 (d, J = 12.7 Hz, 1H), 1.82 - 1.73(m, 2H), 1.65 - 1.55 (m, 7H), 1.48 - 1.27 (m, 14H), 1.12 (s, 6H), 1.07 - 0.97(m, 13H), 0.89 (d, J = 6.5 Hz, 3H), 0.82 (s, 3H), 0.63 (s, 3H). 19 F NMR (376MHz, CDCl3) δ -88.82, -89.45, -110.86, -111.49.

[0185] Example 1

[0186] Synthesis of Intermediate I (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]-2-methylhept-2-ol

[0187] Step 1: Add 6α-hydroxy-3α-hydroxy-5β-cholan-24-acid I-0 (150.00 g, 382.088 mmol, 1.0... eq Dissolve the compound in MeOH (methanol) (500 mL), and slowly add sulfuric acid (50 mL, 938.105 mmol, 2.5 eq) to the reaction system. Place the reaction system at 75°C. oStirred at C for 2 hours. After the reaction was complete, monitored by TLC (dichloromethane: methanol = 10:1). Cooled to room temperature, 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), dried over anhydrous sodium sulfate, concentrated and dried to obtain crude methyl 6α-hydroxy-3α-hydroxycholan-24-oate I-1 (150 g, yield 86.90%). The crude product was directly added to the next reaction step.

[0188] Step 2: I-1 (150.0 g, 368.9 mmol, 1.0 g) eq Dissolved in pyridine (500 mL), p-toluenesulfonyl chloride (422 g, 2213 mmol, 6 eq) was added at room temperature and stirred overnight at room temperature. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1). After the reaction was 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-oxylidene-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%).

[0189] Step 3: Dissolve I-2 (100 g, 139.8 mmol, 1.0 eq) in water (40 mL) and N,N-dimethylformamide (400 mL), add sodium acetate (120 g, 139.8 mmol, 10 eq), and heat the system to 110 °C. o C, reflux for 4 hours. Monitor the reaction by TLC (petroleum ether: ethyl acetate = 5:1). After the reaction is complete, cool to room temperature. Pour the reaction solution into 1000 mL of 5% hydrochloric acid solution with crushed ice, filter, and dilute the solid with 100 mL of water. 2) After washing and 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.

[0190] Step 4: I-3 (100 g, 184.2 mmol, 1.0 g) eq The solution was dissolved in 500 mL of 4% potassium hydroxide-methanol solution, 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, 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 (400 MHz, CDCl3) δ 5.37 – 5.33 (m, 1H), 3.66 (s, 3H), 2.34 (dt, J = 13.0, 4.0 Hz, 1H), 2.30 – 2.23 (m, 2H), 2.24 – 2.18 (m, 2H),2.05 –1.93 (m, 3H), 1.82 (tdd, J = 10.1, 8.1, 4.9 Hz, 5H), 1.53 – 1.40 (m,7H), 1.36 – 1.25 (m, 3H), 1.01 (s, 3H), 0.92 (t, J = 5.1 Hz, 5H), 0.68 (s, 4H).

[0191] Step 5: Dissolve reactant I-4 (30 g, 77.2 mmol, 1.0 eq) in chloroform (180 mL), add selenium dioxide (21 g, 189.40 mmol, 2.5 eq) and NMM (25.4 mL, 231.60 mmol, 3.0 eq), and incubate the reaction at 75°C. o Stir at C for 18 h. After the reaction was essentially complete, monitored by TLC (petroleum ether: ethyl acetate = 5:1), the reaction was stopped. 200 mL of water was added to the reaction system, and ethyl acetate (100 mL) was used as the solvent. 3) Extraction, combine organic phases with water (100 mL) 2) Wash with saturated brine, dry with anhydrous sodium sulfate, and collect the organic phase to concentrate and 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, yield 50.3%). 1H NMR (400 MHz, CDCl3) δ 5.71 – 5.63 (m,1H), 4.14 (d, J = 3.2 Hz, 1H), 3.66 (s, 3H), 3.56 (d, J = 11.5 Hz, 1H), 2.34(dd, J = 10.2, 5.2 Hz,1H), 2.27 – 2.17 (m, 1H), 2.07 (s, 1H), 2.00 (d, J =12.5 Hz, 1H), 1.89 (s, 1H), 1.88 – 1.78 (m, 3H), 1.65 – 1.51 (m, 4H), 1.46 –1.39 (m, 3H), 1.36– 1.25 (m, 2H), 1.18 (s, 3H), 1.15 – 1.05 (m, 4H), 1.03 –0.96 (m, 1H), 0.92 (d, J = 6.5 Hz, 4H), 0.68 (s, 3H). The configuration of compound I-5 was confirmed by two-dimensional spectral characterization, see details below. Figure 1 .

[0192] Step 6: Dissolve reactant I-5 (22.5 g, 55.6 mmol, 1.0 eq) in acetone (300 mL), add p-toluenesulfonic acid (6.70 g, 38.9 mmol, 0.7 eq) and 4A molecular sieve (5 g), and stir the reaction system at room temperature for 2 hours. Monitor the reaction progress using a TLC plate (petroleum ether: ethyl acetate = 5:1). After the reaction is complete, add 100 mL of water to the reaction system, and use ethyl acetate (100 mL) as the solvent. 3) Extraction, collect the organic phase with 100 mL of water. 2) Wash with saturated brine, dry with anhydrous sodium sulfate, and collect the organic phase for concentration 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, yield 69%). 1H NMR (400MHz, CDCl3) δ 5.82 – 5.79 (m, 1H), 4.41 (d, J = 5.8 Hz, 1H), 3.66 (s, 3H), 2.35 (td, J = 10.2, 5.1 Hz, 1H), 2.23 (td, J = 9.6, 4.9Hz, 1H), 2.12 (dd, J =12.6, 4.5 Hz, 1H), 2.00 (dt, J = 12.4, 3.3 Hz, 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, 21.7 Hz, 2H), 1.16 (s, 4H), 1.14 – 0.98 (m, 4H), 0.93 (d, J = 6.4 Hz,4H), 0.69 (d, J = 4.6 Hz, 3H).

[0193] Step 7: Add reactant I-6 (19 g, 44.9 mmol, 1.0 μL) to the solution. eq Dissolve in acetone (200 mL), add N-hydroxyphthalimide (2.79 g, 17.0 mmol, 0.4 mmol). eq ), tert-butyl hydroperoxide (20.5 mL, 213.6 mmol, 5.0 mmol / L) eq ), cobalt acetate (1.5 g, 8.5 mmol, 0.2 eq The reaction system is at 35 oThe mixture was stirred at 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 (400 MHz, CDCl3) δ 5.93 (s, 1H), 4.52 (d, J =6.4 Hz, 1H), 4.33 (d, J = 5.8 Hz, 1H), 3.66 (d, J = 4.0 Hz, 3H), 2.36 (ddd, J= 15.3, 10.0,5.2 Hz, 3H), 2.26 – 2.17 (m, 1H), 2.07 – 1.88 (m, 3H), 1.81(ddd, J = 9.6, 8.0, 3.1 Hz, 3H), 1.64 – 1.60 (m, 2H), 1.57 – 1.54 (m, 3H),1.45 (dd, J =12.7, 9.9 Hz, 2H), 1.37 (s, 4H), 1.34 (d, J = 4.8 Hz, 5H), 1.20– 1.07 (m, 3H), 0.93 (d, J = 6.4 Hz, 4H), 0.71 (s, 3H).

[0194] Step 8: Add reactant I-7 (10.5 g, 23.9 mmol, 1.0 mmol) to the solution. eqThe palladium on carbon (4.0 g, 37.5 mmol, 40 wt%) was dissolved in a mixed solution of methanol (300 mL) and ethyl acetate (100 mL). The mixture was then purged with hydrogen three times, and the reaction mixture was stirred at 35 °C for 2 hours. The reaction progress was monitored by TLC (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-oxonyl-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, yield 44.8%). 1 H NMR (400 MHz, CDCl3) δ 4.06 –3.95 (m, 2H), 3.66 (d, J = 2.9 Hz, 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= 5.8 Hz, 2H), 1.43 (ddd, J = 18.2, 12.4, 8.5 Hz, 2H), 1.34 – 1.27 (m, 4H),1.13 – 0.98 (m, 2H), 0.92(d, J = 6.4 (Hz, 2H), 0.66 (s, 1H).

[0195] Step 9: Dissolve reactant I-8 (6.2 g, 13.5 mmol, 1 eq) in diethylaminosulfur trifluoride (10 mL), and incubate the resulting mixture at 80°C. oStir in C for 1 h. Monitor the consumption of starting materials by TLC plate (petroleum ether:ethyl acetate = 10:1). Cool the reaction solution to room temperature, add dichloromethane (50 mL) to dilute the reaction system, and slowly quench the reaction system dropwise in ice water. Extract with dichloromethane (50 mL × 3), collect the organic phase, dry with anhydrous sodium sulfate, and evaporate the organic phase under vacuum to obtain the crude product. Dissolve the crude product in ethyl acetate and perform column chromatography (petroleum ether:ethyl acetate = 30:1 to 20:1 to 15:1) to obtain white solid I-9 (purity ~88%). Dissolve I-9 in dichloromethane (200 mL), add m-chloroperoxybenzoic acid m-CPBA (579 mg, 3.37 mmol), and stir for 1 hour. After hours, saturated sodium sulfite was added for quenching, followed by washing with saturated brine, drying with anhydrous sodium sulfate, and concentration 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, 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]valerate methyl ester I-9 (4.4 g, yield 54%). 1 H NMR (400 MHz, CDCl3) δ 4.13 – 3.98 (m, 2H), 3.66 (s, 3H), 2.29 (ddd, J = 16.0, 9.9, 5.8 Hz, 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, 5.5 Hz, 2H),1.34 – 1.28 (m, 3H), 1.14 (dd, J = 12.9, 4.3 Hz, 1H), 1.08 (d, J = 5.8 Hz,2H), 0.92 (d, J = 6.4 Hz, 2H), 0.70 – 0.63 (m, 2H).

[0196] Step 10: Compound I-9 (4.35 g, 9.0 mmol, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (50 mL). Lithium aluminum hydride (2.05 g, 27 mmol, 3.0 eq) was added under ice bath conditions, and the mixture was stirred for 30 minutes after returning to room temperature. 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. Water (50 mL) was added to the reaction system, and 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 (400 MHz, CDCl3) δ 4.02 (dq, J =8.4, 5.2 Hz, 2H), 3.62 (td, J = 6.7, 2.2 Hz, 2H), 2.07 – 1.96 (m, 1H), 1.94(dd, J = 5.3, 2.9 Hz, 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, 5.4 Hz, 3H), 1.34 – 1.28 (m, 2H), 1.27 – 1.09(m,2H), 1.07(s,2H), 0.98 (dd, J = 12.1, 3.8 Hz, 1H), 0.94 (d, J = 6.5 Hz, 2H), 0.89 (dd, J = 13.6, 3.2 Hz, 0H), 0.72 – 0.63 (m, 2H).

[0197] Step 11: Dissolve iodine (25.1 g, 98.9 mmol, 5.0 eq) in dichloromethane (100 mL), then add imidazole (13.5 g, 198 mmol, 10.0 eq). Under ice bath conditions, add a dichloromethane solution of triphenylphosphine (26.0 g, 98.9 mmol, 5.0 eq) dropwise to the system. Return to room temperature and stir for 2 hours until the reaction system turns pale yellow. Under ice bath conditions, add a dichloromethane solution of I-10 (9 g, 19.8 mmol, 1.0 eq) dropwise and stir the system at room temperature for 12 hours. Monitor the consumption of starting materials using a TLC plate (petroleum ether: ethyl acetate = 5:1). Add water (200 mL) to the reaction system to stop the reaction. Wash the system with water (100 mL x 3), extract the aqueous phase with dichloromethane (100 mL x 3), combine the organic phases, concentrate, and dry the crude product. The crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 100:0 to 90:10) to give 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-cyclopentazo[1',2':7,8]phenanthro[1,2-d][1,3]dioxanecyclopentazoI-11 (8.25 g, 72% yield). 1 HNMR (400 MHz, CDCl3) δ 4.13 – 3.93 (m, 2H), 3.25 – 3.03 (m, 2H), 2.11 (d, J =50.8 Hz, 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 = 6.9 Hz, 2H), 1.44 (dd, J = 10.7, 6.1 Hz, 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 =6.6 Hz, 2H), 0.67 (d, J = 12.1 Hz, 1H).

[0198] 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 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]dioxane-8-yl]hexanonitrile I-12 (5.25 g, yield: 77%). 1 H NMR (400 MHz, CDCl3) δ 4.02 (dq, J = 8.4,5.2 Hz, 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 =5.7 Hz, 2H), 1.34 – 1.28 (m, 2H), 1.19 – 1.10 (m, 1H), 1.07 (d, J = 4.8 Hz,2H), 1.01 – 0.87(m, 3H), 0.68 (d, J = 5.0 Hz, 2H).

[0199] Step 13: I-12 (600 mg, 1.294 mmol) was suspended in methanol (30 mL) in a 250 mL round-bottom flask at room temperature. 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 (400 MHz, 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).

[0200] Step 14: Dissolve I-13 (1.2 g, 2.63 mmol) in tetrahydrofuran (30 mL), and add methyl magnesium bromide solution (5.3 mL, 13.14 mmol) dropwise at room temperature. Stir the mixture at room temperature for 1 hour. Monitor the reaction by TLC (petroleum ether / ethyl acetate = 1 / 1) until the reaction is complete. Add 30 mL of saturated ammonium chloride aqueous solution to the reaction mixture, extract with ethyl acetate (30 mL × 3), dry the organic phase with anhydrous sodium sulfate, and evaporate 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, purity: 75%, yield: 62.5%) as a white solid.

[0201] Step 15: Similar to the synthesis of intermediate I in step 6, replace I-5 with I-14 and purify 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]dioxane-8-yl]-2-methylhept-2-ol I (850 mg, yield: 66.4%) as a white solid. 1 H NMR (400MHz, CDCl3) δ 4.07 – 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), 1.17 – 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 (377 MHz, CDCl3) δ -88.99, -89.62, -111.36, -111.99.

[0202] Example 2

[0203] Preparation of Intermediate II (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-methylhept-2-ol

[0204] 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 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.

[0205] Step 2: Dissolve II-5 (40 g, 92.89 mmol) in acetone (400 mL), add tert-butyl hydroperoxide (111.47 mL, 557.32 mmol), cobalt acetate (3 g, 18.58 mmol), and N-hydroxybenzodicarboximide (6 g, 37.16 mmol), and heat to 35°C under nitrogen protection. o The reaction was carried out for 18 hours, and the reaction was monitored by TLC to ensure the reaction was complete. The reaction solution was quenched with water (200 mL), extracted with ethyl acetate (300 mL x 3), and the combined organic phases were dried with anhydrous sodium sulfate. The crude product was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate = 1:0-4:1) to obtain methyl 3β-acetoxy-7-oxomylcholene-6(5)-en-24-oic acid ester II-6 (16 g, yield 35%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 5.70 (d, J = 1.6 Hz, 1H), 4.71 (m, 1H), 3.66 (s, 3H), 2.45 (m, 4H), 2.22 (ddd, J = 19.3, 9.4, 6.5 Hz, 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 = 6.4 Hz, 3H), 0.68 (s, 3H).

[0206] 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. o The reaction was carried out at C for 4 hours, and the reaction was monitored by TLC to ensure that the reaction was complete. The reaction solution was filtered through diatomaceous earth and concentrated under reduced pressure to obtain a crude product. The crude product was then separated and purified by column chromatography (petroleum ether: ethyl acetate = 1:0-4:1) to obtain the product methyl 3β-acetoxy-7-oxylidene-24-acid II-7 (2.6 g, yield 58.2%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 4.67 (m, 1H), 3.66 (s, 3H), 2.34(m, 3H), 2.21 (m, 2H), 2.03 (m, 4H), 1.94 (m, 3H), 1.78 (m, 2H), 1.66 (m,1H), 1.43-1.05 m, 10H), 1.08 (m, 7H), 0.92 (d, J = 6.4 Hz, 3H), 0.65 (s, 3H).

[0207] Step 4: Similar to step 8 of intermediate I, replace I-7 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%), a white solid. 1 H NMR (400 MHz, CDCl3) δ 4.69 (m,1H), 3.66 (s, 3H), 2.35 (td, J = 10.1, 5.0 Hz, 1H), 2.22 (td, J = 9.5, 4.9Hz, 1H), 2.03 (d, J = 2.1 Hz, 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 = 5.4 Hz, 3H), 0.83 (m, 3H), 0.67 (m,3H). 19 F NMR (376MHz, CDCl3) δ = -89.09, -89.72, -110.84, -111.47.

[0208] 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 mixture was monitored by TLC to ensure complete reaction of the starting material. 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-cyclopentano[1,2-a]phenanthrene-1-yl]valerate methyl ester II-9 (4.5 g, 89% yield) as a white solid.

[0209] Step 6: In a 100 mL round-bottom flask at room temperature, dissolve II-9 (4 g, 9.37 mmol) in dichloromethane (50 mL), add imidazole (1.28 g, 18.75 mmol) and tert-butyldiphenylchlorosilane TBDPSCl (3.66 mL, 14.07 mmol) at room temperature, then stir at room temperature for 4 hours. 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), 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%).

[0210] Step 7: Similar to intermediate I, in step 10, replacing I-9 with II-10 yields 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.

[0211] Step 8: Similar to intermediate I, step 11 is synthesized by replacing I-10 with II-11 to obtain 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, 80% yield). 1 H NMR (400 MHz, CDCl3) δ 7.66 (m, 4H), 7.36 (m, 16H), 3.58 (dq, J =15.3, 5.1 Hz, 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 = 4.2 Hz, 3H), 0.64 (s, 3H).

[0212] Step 9: Similar to intermediate I, step 12 is synthesized by replacing 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 (400 MHz, CDCl3) δ 3.63(m, 1H), 2.31 (td, J = 7.0, 3.4 Hz, 2H), 1.97 (dt, J = 12.8, 3.3 Hz, 1H), 1.86 (m, 3H), 1.72 (m, 5H), 1.58 (m, 4H), 1.44 (td, J =12.0, 4.3 Hz, 3H), 1.19 (m, 10H), 0.94 (d, J = 6.6 Hz, 3H), 0.85 (s, 3H), 0.67 (s, 3H).

[0213] Step 10: Similar to intermediate I, step 13 is synthesized by replacing 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-144 (0.89 g, yield 65%).

[0214] Step 11: Similar to the synthesis of intermediate II in step 6, at room temperature, replacing II-9 with II-14 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 (3.0 g, yield: 84.6%). 1 HNMR (400MHz, CDCl3) d 7.66 (m, 4H), 7.38 (m, 6H), 3.66 (s, 3H),3.58 (dt, J = 15.7, 5.2 Hz,1H), 2.26 (dt, J = 15.4, 7.6 Hz, 2H), 1.93 (m,1H),1.80 (d, J = 7.6 Hz, 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 = 12.1 Hz, 3H).

[0215] Example 3

[0216] Preparation of compound 3 (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(10R)-3,3,6,6-tetramethyl-2,5-dioxaundecan-10-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0217] Step 1: At room temperature, compound I (200 mg, 0.40 mmol, 1 eq) was dissolved in dichloromethane (5 mL), and rhodium acetate (23 mg, 0.081 mmol, 0.2 eq) and ethyl azide (520 mg, 4.0 mmol, 10 eq) were added with stirring. After 12 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 water at room temperature, extract with ethyl acetate (100 mL × 2), wash the organic phase with saturated brine (50 mL), dry to anhydrous sodium sulfate, and purify by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) 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]dioxane-8-yl]-2-methylhept-2-yl]oxy}ethyl acetate 3-A0 (120 mg, yield: 51.5%). 1 H NMR (400MHz, CDCl3) d 4.20 (q, J = 7.2 Hz, 2H), 4.07 – 3.95 (m, 4H), 2.19 – 2.03 (m,1H), 2.01 – 1.80 (m, 5H), 1.73 – 1.58 (m, 3H), 1.55 – 1.48 (m, J = 10.6 Hz,7H), 1.46 – 1.34 (m, 7H), 1.31 – 1.25 (m, 8H), 1.18 (s, 6H), 1.16 – 1.09 (m,J = 10.6, 6.4 Hz, 2H), 1.07 (s, 3H), 1.04 – 0.94 (m, J = 19.7, 10.8 Hz, 2H), 0.92 (d, J = 6.5 Hz, 3H), 0.66 (d, J = 11.9 Hz, 3H).

[0218] Step 2: At room temperature, 3-A0 (40 mg, 0.069 mmol, 1 eq) was dissolved in tetrahydrofuran (2 mL), and methyl magnesium bromide (3.0 M tetrahydrofuran solution) (0.1 mL, 0.34 mmol, 5 eq) was added with stirring. After 0.5 hours at room temperature, the reaction was monitored by TLC (petroleum ether:ethyl acetate = 3:1) to ensure complete reaction. The mixture was diluted with 100 mL of water at room temperature, extracted with ethyl acetate (100 mL × 2), and the organic phase was treated with saturated brine (50 mL). Washed with anhydrous sodium sulfate (mL), the crude product 1-{[(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-yl]oxy}-2-methylprop-2-ol 3-A1 was directly added to the next step.

[0219] Step 3: Dissolve compound 3-A1 (40 mg, 0.07 mmol) in N,N-dimethylformamide (2.5 mL), purge with nitrogen, add sodium hydride (31 mg, 1.29 mmol) at room temperature, stir the mixture at room temperature for 30 minutes, then add methyl iodide (31 mg, 0.22 mmol), stir the mixture at room temperature for 3 hours. Monitor the reaction for completeness by TLC (petroleum ether / ethyl acetate = 5 / 1). Add ethyl acetate (30 mL) to the reaction mixture, wash with water (10 mL × 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 = 0-5%) to give a white solid (3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-8-[(10R)-3,3,6,6-tetramethyl-2,5-dioxaundecan-10-yl]-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]dioxacyclopentamin 3-1 (23 mg, yield: 47.7%). 1HNMR(400MHz, CDCl3) δ 4.08 – 3.96 (m, 2H), 3.25 (s, 3H), 3.17 (s, 2H), 2.10 (ddd,J = 23.5, 13.9, 6.9Hz, 1H), 1.96 (ddd,J = 7.9, 7.3, 3.1Hz, 2H),1.91 – 1.76 (m, 4H), 1.73 – 1.67 (m, 1H), 1.64 – 1.59(m, 2H), 1.51 (s, 3H),1.46 – 1.32 (m, 9H), 1.30 (s, 3H), 1.29 – 1.18 (m, 4H), 1.16 (s, 6H), 1.12(s, 6H), 1.07 (s, 3H), 1.04 – 0.93 (m, 3H), 0.91 (d,J = 6.5Hz, 3H), 0.68 (s,3H). 19 F NMR (377 MHz, CDCl3) δ -88.99, -89.62, -111.37, -111.99.

[0220] Step 4: Dissolve 3-1 (20 mg, 0.03 mmol) in tetrahydrofuran (3 mL), and add hydrochloric acid (1 mL) at room temperature. Stir the mixture at room temperature for 1 hour. Monitor the reaction for completeness by TLC (petroleum ether / ethyl acetate = 1 / 1). Add water (10 mL) to the reaction mixture, extract with ethyl acetate (10 mL × 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 = 0-50%) to give a white solid (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(10R)-3,3,6,6-tetramethyl-2,5-dioxaundecan-10-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 3 (10 mg, 0.02 mmol, yield: 54.5%). 1H NMR (400MHz, CDCl3) δ 3.74 (s, 1H), 3.64 – 3.57 (m, 1H), 3.25 (s, 3H), 3.17 (s, 2H), 2.29– 2.12 (m, 1H), 1.99 (dd,J = 10.4, 7.2Hz, 1H), 1.88 – 1.65 (m, 10H), 1.48 –1.28 (m, 11H), 1.16 (s, 6H), 1.12(s, 6H), 1.06 (s, 3H), 1.04 – 0.94 (m, 3H), 0.91 (d,J = 6.5Hz, 3H), 0.67 (s, 3H). 19 F NMR (377 MHz, CDCl3) δ -88.63, -89.25, -110.63, -111.26. LC-MS: [MH] - = 541.50.

[0221] Example 4

[0222] Preparation of compound 4 (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(2-fluoro-2-methylpropyl)oxy]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0223] Step 1: Dissolve compound 3-A1 (50 mg, 0.09 mmol) in 99.9% dichloromethane (3 mL), and add diethylaminosulfur trifluoride (21 mg, 0.13 mmol) dropwise at -78°C. Stir the mixture at -78°C for 1 hour. Monitor the reaction for completeness by TLC (petroleum ether / ethyl acetate = 5 / 1). Carefully add saturated sodium bicarbonate aqueous solution (10 mL) to the reaction mixture, extract with ethyl acetate (10 mL × 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 = 0-10%) to give a white solid (3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-8-[(2R)-6-[(2-fluoro-2-methylpropyl)oxy]-6-methylhept-2-yl]-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecylhydro-3aH-cyclopenta[1',2':7,8]phenanthro[1,2-d][1,3]dioxanecyclopentamin 4-1 (30 mg, 0.05 mmol, yield: 50.8%). 1 HNMR(400MHz, CDCl3)δ 4.11 – 3.95 (m, 2H), 3.28 (d,J = 16.7Hz, 2H), 2.19 – 2.02 (m, 1H), 2.01 –1.92 (m, 2H), 1.84 (ddd,J = 25.3, 16.6, 6.9Hz, 4H), 1.73 – 1.67 (m, 1H), 1.61(d,J = 13.8Hz,2H), 1.54 (s, 4H), 1.51 (s, 3H), 1.38 (s, 6H), 1.32 (s, 3H), 1.30 (s, 3H), 1.29 – 1.16 (m, 6H), 1.14 (s, 6H), 1.07 (s, 3H), 0.98 (dd,J =22.6, 11.8Hz, 3H), 0.91 (d,J = 6.5Hz, 3H), 0.68 (s, 3H). 19 F NMR (377 MHz, CDCl3 δ -88.99, -89.62, -111.36, -111.99, -145.45

[0224] Step 2: Similar to Step 4 of Example 3, replacing 3-1 with 4-1 yields a white solid (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(2-fluoro-2-methylpropyl)oxy]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol (9 mg, 0.02 mmol, yield: 48.5%). 1 H NMR 1HNMR(400MHz, CDCl3) δ 3.74 (s, 1H), 3.64 – 3.57 (m, 1H), 3.28(d,J = 16.7Hz, 2H), 2.19 (ddd,J = 18.4, 14.0, 6.8Hz, 1H), 1.98 (d,J = 12.4Hz,1H), 1.89 – 1.64 (m, 9H), 1.48 – 1.39 (m, 5H), 1.38 (s,3H), 1.35 (s, 2H), 1.32 (s, 3H), 1.29 – 1.17 (m, 3H), 1.14 (s, 6H), 1.12 – 1.07 (m, 2H), 1.06(s, 3H), 0.99 (dd,J = 15.6, 5.6Hz, 3H), 0.91 (d,J = 6.5Hz, 3H), 0.67 (s, 3H). 19 F NMR (377 MHz, CDCl3) δ -88.63, -89.26, -110.63, -111.25, -145.45. LC-MS:[MH] - = 529.50.

[0225] Example 5

[0226] Preparation of Compound 5 (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(2R)-6-methyl-6-{[2-(methyldioxane-λ6-thio)ethyl]oxy}hept-2-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0227] Step 1: Compound I (30 mg, 0.06 mmol) was dissolved in tetrahydrofuran (3 mL), and nitrogen gas was introduced. Sodium hydride (35 mg, 0.86 mmol) was added at room temperature, and the mixture was stirred at room temperature for 20 minutes. Then, methyl vinyl sulfone (0.1 mL, 1.14 mmol) was added, and the mixture was stirred overnight at room temperature. TLC (petroleum ether / ethyl acetate = 5 / 1) monitoring of the reaction solution revealed the formation of a new spot with increased polarity, indicating that the starting material had not completely reacted. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 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 = 0-25%) to give (3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-8-[(2R)-6-methyl-6-{[2-(methyldioxane-λ6-thio)ethyl]oxy}hept-2-yl]-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]dioxanecyclopentazone 5-1 (15 mg, yield: 35%) as a white solid. 1 HNMR(400MHz, CDCl3) δ4.02 (dt,J = 8.3, 5.1Hz, 2H), 3.81 – 3.73 (m, 2H), 3.17 (t,J = 5.3Hz, 2H), 3.01 (s, 3H), 2.20 – 2.03 (m, 1H), 1.97 (dd,J = 17.9, 8.6Hz, 2H), 1.90 – 1.76(m, 4H), 1.73 – 1.66(m, 1H), 1.61 (d,J = 13.7Hz, 2H), 1.53 (d,J = 6.0Hz, 2H), 1.51 (s, 3H), 1.48 – 1.33 (m, 8H), 1.30 (s, 3H), 1.26 (d,J = 6.9Hz, 2H), 1.17(s, 6H), 1.14 – 1.09 (m, 2H), 1.07 (s, 3H), 1.02 (dd,J = 21.6, 11.1Hz, 2H), 0.91 (d,J = 6.5Hz, 3H), 0.68 (s, 3H). 19 F NMR (377 MHz, CDCl3) δ -88.99, -89.62, -111.36, -111.98.

[0228] Step 2: Similar to Step 4 of Example 3, replacing 3-1 with 5-1 yields a white solid purified from (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(2R)-6-methyl-6-{[2-(methyldioxane-λ6-thio)ethyl]oxy}hept-2-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 5 (4 mg, 0.01 mmol, purity: 100%, yield: 28.57%). 1 H NMR (400MHz, CDCl3) δ 3.77 (t,2H), 3.74 (s, 1H), 3.64 – 3.56 (m, 1H), 3.17 (t, 2H), 3.01 (s, 3H), 2.29 –2.12 (m, 1H), 1.98 (d, J = 12.2 Hz, 1H), 1.88 – 1.78 (m, 4H), 1.75 (s, 7H), 1.39 (d, J = 15.0 Hz, 10H), 1.17 (s, 6H), 1.06 (s, 3H), 0.99 (dd, J = 19.3,9.6 Hz, 3H), 0.91 (d, J = 6.5 Hz, 3H), 0.67 (s, 3H). 19 F NMR (377 MHz, CDCl3)δ -88.63, -89.26, -110.62, -111.25. LC-MS: [MH] - = 561.55.

[0229] Example 6

[0230] Preparation of Compound 6 (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(2-hydroxyethyl)oxy]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0231] Step 1: At room temperature, 3-A0 (40 mg, 0.07 mmol, 1 eq) was dissolved in tetrahydrofuran (5 mL), and lithium aluminum hydride (5.2 mg, 0.14 mmol, 2 eq) was added with stirring. After 0.5 hours at room temperature, the reaction was monitored by TLC (petroleum ether: ethyl acetate = 3:1) 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 rotary evaporate to obtain crude 2-{[(6R)-6-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecylhydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxane-8-yl]-2-methylhept-2-yl]oxy}eth-1-ol 6-1, which was used directly in the next step.

[0232] Step 2: Similar to Step 4 of Example 3, replacing 3-1 with 6-1 yields a white solid (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(2-hydroxyethyl)oxy]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 6 (25 mg, yield: 70.4%). 1 H NMR (400MHz, CDCl3) d 3.74 (s, 1H), 3.71 – 3.65 (m, 2H), 3.60 (dd, J = 7.2, 4.2 Hz,1H), 3.47 – 3.40 (m, 2H), 2.29 – 2.12 (m, 1H), 2.01 – 1.96(m, 1H), 1.89 – 1.78(m, 8H), 1.74 – 1.66 (m, 2H), 1.52 – 1.37 (m, 6H), 1.35 – 1.23 (m, 4H), 1.16(s, 6H), 1.10 (dd, J = 9.8, 7.4 Hz, 2H), 1.06 (s,3H),0.99 (dd, J = 15.4, 5.0Hz, 2H), 0.92 (d, J = 6.5 Hz, 3H), 0.65 (d, J = 12.3 Hz, 3H). 19F NMR (376MHz, CDCl3) d -88.62, -89.25, -110.62, -111.24. LC-MS: [MH] - =499.45.

[0233] Example 7

[0234] Preparation of Compound 7 (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(2-hydroxy-2-methylpropyl)oxy]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0235] Similar to step 4 of Example 3, replacing 3-1 with 3-A1 yields a white solid (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(2-hydroxy-2-methylpropyl)oxy]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 7 (16 mg, yield: 44.3%). 1 H NMR (400 MHz, CDCl3) d 3.74 (s, 1H), 3.63 – 3.57 (m, 1H), 3.12 (s, 2H), 2.19 (dd,J = 21.6,13.4 Hz, 1H), 2.00 – 1.96 (m, 1H), 1.89 – 1.79 (m, 6H),1.70 (ddd, J= 16.6, 10.3, 4.7 Hz, 4H),1.51 – 1.42 (m, 3H), 1.38 – 1.20 (m, 8H), 1.19 (s,6H), 1.14 (s, 6H), 1.09 (d, J = 4.8 Hz, 1H),1.06 (s, 3H), 0.99 (dd,J = 14.9,5.6 Hz, 2H), 0.91 (d, J = 6.5 Hz, 3H), 0.67 (s, 3H). 19 F NMR (376 MHz, CDCl3) d-88.63, -89.26, -110.62, -111.25. LC-MS: [MH] - =527.45.

[0236] Example 8

[0237] Preparation of compound 82 {[(6R)-6-[(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]-2-methylheptyl-2-yl]oxy}acetic acid

[0238] Step 1: 3-A0 (40 mg, 0.069 mmol, 1 eq) was dissolved in methanol (2 mL) and water (1 mL) at room temperature, and lithium hydroxide (16 mg, 0.69 mmol, 10 eq) was added with stirring. After 0.5 hours at room temperature, the reaction was monitored by TLC (petroleum ether: ethyl acetate = 3:1) to ensure completion. 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 rotary evaporate to obtain crude 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]-2-methylhept-2-yl]oxy}acetic acid 82-1, which is directly added to the next step.

[0239] Step 2: Similar to Step 4 of Example 3, replace 3-1 with 82-1 to obtain a white solid {[(6R)-6[(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]-2-methylhept-2-yl]oxy}acetic acid 82 (25 mg, yield: 72.2%). 1 H NMR (400MHz, MeOD) d3.96 (s, 2H), 3.63 (s, 1H), 3.51 – 3.45 (m, 1H), 2.28 – 2.09 (m,1H), 2.04 – 1.98 (m, 1H), 1.89 – 1.69 (m, 6H), 1.62 –1.47 (m, 3H), 1.45 – 1.33(m, 8H), 1.29(s,3H), 1.18 (s, 6H), 1.12 (dd, J = 11.3, 7.7 Hz, 2H), 1.07 (s,3H), 1.03 – 0.99 (m, 1H), 0.95(d,J= 6.5 Hz,3H), 0.89 (d, J = 7.2 Hz, 1H), 0.70 (s, 3H). 19 F NMR (376 MHz, CDCl3) δ -88.99, -89.62, -111.36, -111.99. LC-MS: [MH] - =513.50

[0240] Example 9

[0241] Preparation of Compound 8 2-{[(6R)-6-[(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]-2-methylhept-2-yl]oxy}-N,N-dimethylacetamide

[0242] Compound 82 (50 mg, 0.10 mmol, 1 eq) was dissolved in N,N-dimethylformamide DMF (2 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (74 mg, 0.19 mmol, 2 eq), diisopropylethylamine (37 mg, 0.29 mmol, 3 eq), and dimethylamine hydrochloride (16 mg, 0.19 mmol, 2 eq) were added at room temperature. After stirring at this temperature for 1 h, the reaction was monitored for safety by TLC (dichloromethane:methanol = 10:1). Quenching was performed at room temperature with 100 mL of 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. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give a white solid 2-{[(6R)-6-[(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]-2-methylhept-2-yl]oxy}-N,N-dimethylacetamide 8 (36.27 mg, yield: 68.9%). 1 H NMR (400 MHz, CDCl3) d 3.77 (s, 2H), 3.48 (s, 1H), 3.34 (dd, J =10.4, 3.4 Hz, 1H), 2.78 (s,6H), 2.02 (m, 1H), 1.83 (s, 5H), 1.70 (d, J = 6.6Hz,3H), 1.58 (d, J = 14.1 Hz, 2H), 1.39 (dd, J =15.9, 9.1 Hz, 3H), 1.29 (d, J= 9.7 Hz, 6H), 1.16 (d, J = 4.1 Hz, 2H), 1.10 (s, 6H), 1.03 (m, 2H),0.99(s,3H), 0.93 (m, 2H), 0.85 (d, J = 6.0 Hz, 3H), 0.62 (s, 3H). 19 F NMR (377 MHz, CDCl3) d -88.62, -89.25, -110.62, -111.24. LC-MS: [M+Na] + =564.60.

[0243] Example 10

[0244] Synthesis of intermediate 62-1

[0245] At room temperature, compound 3-aminocyclobut-1-ol 62-0 (100 mg, 1.148 mmol) was dissolved in dichloromethane (5 mL), and imidazole (156.29 mg, 2.296 mmol) and tert-butyldimethylchlorosilane (346.01 mg, 2.296 mmol) were added at room temperature under nitrogen protection. The reaction was carried out at room temperature for 2 hours, and the reaction was monitored by TLC until the starting material was completely reacted. The reaction solution was quenched with water (10 mL), extracted with dichloromethane (10 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 = 1:0-10:1) to obtain the product 3-{[dimethyl(2-methylpropyl-2-yl)methsilyl]oxy}cyclobut-1-amine 62-1 (100 mg, 0.497 mmol, 43.26%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 3.01 – 2.90 (m, 1H), 2.69 – 2.61 (m, 2H), 2.24(t, J = 6.0 Hz, 1H), 1.86 – 1.59 (m, 2H), 0.87 (s, 9H), 0.03 (s, 6H).

[0246] Similar to Example 9, by replacing dimethylamine hydrochloride with other amines, the following examples can be synthesized respectively.

[0247] Example 15

[0248] Preparation of compound 9 (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-1-[(2R)-6-[(2,2-difluoroethyl)oxy]-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0249] Step 1: At room temperature, compound II (200 mg, 0.3 mmol, 1 eq) was dissolved in dichloromethane (15 mL), and rhodium acetate (16.5 mg, 0.06 mmol, 0.2 eq) and ethyl azide (380 mg, 3 mmol, 10 eq) were added with stirring. After 12 hours at room temperature, the reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1), and 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 = 10:1) to give 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]-2-methylheptyl-2-yl]oxy}ethyl acetate 9-2 (100 mg, yield: 44.2%). The crude product was directly added to the next step.

[0250] Step 2: At room temperature, 9-2 (100 mg, 0.13 mmol, 1 eq) was dissolved in tetrahydrofuran (5 mL), and lithium aluminum hydride (10 mg, 0.26 mmol, 2 eq) was added with stirring. After 12 hours at room temperature, the reaction was monitored by TLC (petroleum ether: ethyl acetate = 3:1). The starting material disappeared and all the solution was converted to the new spot. The solution 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 = 1:1). 5:1), yielded a white solid 2-{[(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-methylhept-2-yl]oxy}eth-1-ol 9-3 (40 mg, yield: 40.2%). 1 H NMR (400 MHz, CDCl3) d7.64 – 7.52 (m, 4H), 7.40 – 7.26 (m, 6H), 3.65 – 3.56 (m, 2H), 3.52(s, 1H), 3.42 – 3.26 (m, 2H), 1.86 (d, J = 12.8 Hz, 1H), 1.78 – 1.69 (m, 2H),1.66 – 1.53 (m, 4H), 1.52 – 1.35 (m, 7H), 1.33 – 1.23 (m, 6H), 1.22 – 1.14(m, 5H), 1.09 (d, J = 10.9 Hz, 7H), 1.02 – 0.94 (m, 11H), 0.82 (d, J = 6.5Hz, 3H), 0.75 (s, 3H), 0.56 (s, 3H).

[0251] Step 3: Dissolve 9-3 (150 mg, 0.21 mmol, 1 eq) in dichloromethane (5 mL), and add Desmartin oxidant (176 mg, 0.42 mmol, 2 eq) at room temperature. After stirring at the maintained temperature for 1 h, the reaction was monitored by TLC (petroleum ether: ethyl acetate = 5:1). The starting material disappeared and was completely converted to a new spot. The reaction was quenched by adding 100 mL of aqueous solution at room temperature, extracted with ethyl acetate (100 mL × 2), and the organic phase was washed with saturated brine (50 mL). The organic phase was evaporated to dryness to obtain crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) by rotary evaporation to obtain 2-{[(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-methylheptyl-2-yl]oxy}acetaldehyde 9-4 (100 mg, yield: 67%). 1 H NMR (400 MHz, CDCl3) d9.72 (s, 1H), 7.66 (m, 4H), 7.38 (m, 6H), 3.95 (t, J =13.1 Hz, 2H), 3.59 (dq, J = 15.6, 5.1 Hz, 1H), 1.92 (s, 1H), 1.80 (d, J = 6.8Hz, 2H), 1.63 (m, 3H), 1.49 (m, 7H), 1.29 (ddd, J = 28.6, 14.0, 9.2 Hz, 10H), 1.17 (s, 6H), 1.07 (m, 12H), 0.89 (d, J = 6.5 Hz, 4H), 0.82 (s, 4H), 0.64 (s, 3H).

[0252] Step 4: Dissolve 9-4 (50 mg, 0.07 mmol, 1 eq) in dichloromethane (2 mL), 0 o Diethylaminosulfur trifluoride (DAST) (22 mg, 0.14 mmol, 2 eq) was added at temperature C. The mixture was stirred at this temperature for 10 min, and the reaction was monitored by TLC (petroleum ether: ethyl acetate = 10:1) 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), 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 {[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-1-[(2R)-6-[(2,2-difluoroethyl)oxy]-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-yl]oxy}(2-methylpropyl-2-yl)diphenylsilane 9-5 (25 mg, yield: 48.5%). 1 H NMR (400MHz, CDCl3) d7.59 (d, J = 6.8 Hz, 4H), 7.31 (m, 6H), 5.71 (s, 1H), 3.47 (m,3H), 1.86 (d, J = 12.7 Hz, 1H), 1.73 (d, J = 6.9 Hz, 2H), 1.52 (dd, J = 30.2,10.2 Hz, 6H), 1.34 (d, J = 8.3 Hz, 4H), 1.22 (dd, J = 20.7, 11.2 Hz, 9H),1.08 (s, 6H), 0.97 (s, 11H), 0.79 (m, 10H), 0.56 (s, 3H). 19 F NMR (376 MHz,CDCl3) d -88.79, -89.42, -110.82, -111.45, -124.70.

[0253] Step 5: Dissolve 9-5 (25 mg, 0.03 mmol, 1 eq) in tetrahydrofuran (0.5 mL), and add tetrabutylammonium fluoride (TBAF) (1M tetrahydrofuran solution) (0.3 mL, 0.34 mmol, 10 eq) at room temperature. After stirring at this temperature for 3 h, monitor the reaction for completeness by TLC (petroleum ether:ethyl acetate = 1:1). Quenching was performed at room temperature with 100 mL of 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 = 1:1) to give a white solid (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-1-[(2R)-6-[(2,2-difluoroethyl)oxy]-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 9 (12 mg, 71% yield). 1H NMR (400 MHz, CDCl3) δ 5.80 (s,1H), 3.63 (s, 1H), 3.53 (td, J = 13.9, 4.2 Hz, 2H), 1.97 (s,1H), 1.83 (d, J =8.0 Hz, 3H), 1.73 (m, 3H), 1.59(m, 2H), 1.43 (m, 5H), 1.34 (dd, J = 15.0,8.6Hz,6H), 1.25 (t, J = 5.4 Hz, 2H), 1.16 (s, 7H), 1.04 (m, 5H), 0.92 (d, J =6.5 Hz, 3H), 0.85 (s, 3H), 0.67 (s, 3H). 19F NMR (377 MHz, CDCl3) δ -88.96, -89.59, -110.84, -111.47, -124.74.

[0254] Example 16

[0255] Preparation of compound 10 N-(2-{[(6R)-6-[(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-methylhept-2-yl]oxy}ethyl)methanesulfonamide

[0256] Step 1: In a 100 mL round-bottom flask at room temperature, compound 9-3 (165 mg, 0.23 mmol) and phthalimide (128 mg, 0.87 mmol) were dissolved in tetrahydrofuran (5 mL). Triphenylphosphine (359 mg, 1.37 mmol) and diisopropyl azodicarbonate (300 mg, 1.48 mmol) were added to the flask at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1). After the reaction was completed, water (30 mL) was added to the reaction solution to quench the dichloromethane (20 mL × 3) extraction, the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, the organic phase was concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1). The solution was then rotary evaporated to give a white solid 2-(2-{[(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-methylheptyl-2-yl]oxy}ethyl)isoindole-1,3-dione 10-1 (170 mg, yield: 78.7%). 1 H NMR (400 MHz, CDCl3) δ = 7.84 (dd, J=5.4,3.1, 2H), 7.70 (dd, J=5.5, 3.0, 2H), 7.68 – 7.64 (m, 4H), 7.42 (dtd, J=4.8,3.3, 1.5, 2H), 7.39 – 7.34 (m, 4H), 3.84 (t, J=6.1, 2H), 3.64 – 3.57 (m, 1H), 3.55 (t, J=6.1, 2H), 1.95 – 1.88 (m, 1H), 1.80 – 1.72 (m, 2H), 1.67 – 1.60(m, 3H), 1.56 – 1.42 (m, 6H), 1.41 – 1.26 (m, 6H), 1.24 – 1.12 (m, 5H), 1.06 (s, 6H), 1.04 (s, 9H), 1.02 – 0.85 (m, 5H), 0.82 (s, 3H), 0.80 (d, J=6.4,3H), 0.61 (s, 3H). 19 F NMR (376 MHz, CDCl3) δ = -88.82, -89.45, -110.82, -111.45.

[0257] Step 2: In a 50 mL round-bottom flask at room temperature, 10⁻¹ (130 mg, 0.15 mmol) was dissolved in ethanol (3 mL), and hydrazine hydrate (3 mL) was added to the solution at room temperature. The reaction mixture was stirred at 80 °C for 2 hours. The reaction was monitored by TLC (ethyl acetate: petroleum ether = 5:1). After the reaction was completed, water (40 mL) was added to quench the reaction, dichloromethane (20 mL × 3) was used for extraction, the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, the organic phase was concentrated, and purified by silica gel column chromatography (dichloromethane: methanol = 20:1) to give a white solid 2-{[(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-methylheptyl-2-yl]oxy}eth-1-amine 10-2 (82 mg, yield: 66.8%). 1 H NMR (400 MHz, CDCl3) δ = 7.68 – 7.64 (m, 4H), 7.44 – 7.39 (m, 2H), 7.39 – 7.34 (m, 4H), 3.61 – 3.56 (m, 1H), 3.42 (t, J =5.2, 2H), 2.92 (t, J =5.1, 2H), 1.96 – 1.91(m, 1H), 1.87 – 1.69 (m, 3H), 1.69 – 1.51 (m, 6H), 1.50 – 1.19 (m, 18H), 1.14(s, 6H), 1.04 (s, 9H), 0.89 (d, J =6.5, 3H), 0.82 (s, 3H), 0.63 (s, 3H). 19 FNMR (376 MHz, CDCl3) δ = -88.81, -89.44, -110.84, -111.47.

[0258] Step 3: In a 50 mL round-bottom flask at room temperature, dissolve 10⁻² (40 mg, 0.055 mmol) in dichloromethane (3 mL), add triethylamine (17 mg, 0.17 mmol) at room temperature, and then add methanesulfonyl chloride (9 mg, 0.083 mmol) dropwise at 0 °C. Remove the ice bath. Stir at room temperature for 3 hours. Monitor the reaction by TLC (petroleum ether: ethyl acetate = 4:1). After the reaction was completed, water (20 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (10 mL × 3). The mixture was dried over anhydrous sodium sulfate, the organic phase was concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to give a white solid N-(2-{[(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-methylheptyl-2-yl]oxy}ethyl)methanesulfonamide 10-3 (36 mg, yield: 73.1%). 1 H NMR (400 MHz, CDCl3) δ = 7.68 – 7.63 (m, 4H),7.45 – 7.39 (m, 2H), 7.36 (ddd, J=5.6, 5.1, 1.5, 4H), 3.62 – 3.56 (m, 1H),3.45 (t, J=4.9, 2H), 3.25 (dd, J=9.9, 5.1, 2H), 2.97 (s, 3H), 1.97 – 1.91 (m,1H), 1.80 (ddd, J=12.8, 7.6, 3.1, 2H), 1.68 – 1.54 (m, 7H), 1.50 – 1.18 (m,18H), 1.13 (s, 6H), 1.04 (s, 9H), 0.90 (d, J=6.5, 3H), 0.82 (s, 3H), 0.64 (s, 3H). 19 F NMR (376 MHz, CDCl3) δ = -88.81, -89.44, -110.85, -111.47.

[0259] Step 4: Similar to Step 5 of Example 9, replace 9-5 with 10-3 to obtain a white solid N-(2-{[(6R)-6-[(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-methylhept-2-yl]oxy}ethyl)methanesulfonamide 10 (15 mg, yield: 33.9%). 1 HNMR(400MHz, CDCl3) δ = 4.63 (s, 1H), 3.63 (td,J=10.5, 5.2, 1H), 3.46 (t,J=4.9, 2H), 3.27 (dd,J=9.5, 5.0, 2H), 2.98 (s, 3H), 2.02 – 1.96 (m,1H), 1.85 –1.69 (m, 6H), 1.67 – 1.53 (m, 6H), 1.49 – 1.41 (m, 4H), 1.38 – 1.31 (m, 6H),1.14 (s, 6H), 1.11 – 0.97 (m, 5H), 0.92 (d,J=6.5, 3H), 0.85 (s, 3H), 0.67 (s, 3H). 19 F NMR (376MHz, CDCl3) δ = -88.95, -89.57, -110.83, -111.46. LC-MS: [MH] - =560.5

[0260] Example 17

[0261] Preparation of compound 13 (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(2-hydroxy-2-methylpropyl)oxy]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0262] Step 1: Similar to Step 2 of Example 3, replacing 3-A0 with 9-2 yields the white solid 1-{[(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-methylhept-2-yl]oxy}-2-methylprop-2-ol 13-1. 1 H NMR (400 MHz, CDCl3) δ 7.66 (m, 4H), 7.39 (m, 6H), 3.58 (dd, J = 10.1,5.2 Hz, 1H), 3.11 (s, 2H), 1.94 (d, J = 12.6 Hz, 1H), 1.77 (m, 4H), 1.60 (dd, J = 27.8, 11.9 Hz, 6H), 1.44 (dd, J = 19.0, 13.3 Hz, 5H), 1.35 (dd, J = 13.8,8.2 Hz, 5H), 1.26 (m, 3H), 1.18 (s, 7H), 1.13 (s, 6H), 1.04 (s, 11H), 0.89(d, J = 6.5 Hz, 4H), 0.82 (s, 3H), 0.64 (s, 3H).

[0263] Step 2: Similar to Step 5 of Example 15, replace 9-5 with 13-1 to obtain a white solid (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(2-hydroxy-2-methylpropyl)oxy]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 13 (15 mg, yield: 87.9%). 1 H NMR (400MHz, CDCl3) d3.62 (dt, J = 15.8, 5.4 Hz, 1H), 3.12 (s, 2H), 2.01 – 1.96 (m,1H), 1.84 (d, J = 7.6 Hz, 4H), 1.78 – 1.70 (m, 4H), 1.63 –1.54 (m, 3H), 1.46 –1.36 (m, 7H), 1.28 (dd, J =11.4,5.4 Hz, 5H), 1.19 (s, 6H), 1.14 (s, 6H), 1.08– 0.97 (m, 4H), 0.92 (d, J = 6.5 Hz, 3H), 0.85 (s,3H), 0.67 (s,3H). 19 F NMR (376 MHz, CDCl3) d -88.96, -89.59, -110.84, -111.47.

[0264] Example 18

[0265] Preparation of compound 15 (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-1-[(2R)-6-[(2-aminoethyl)oxy]-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0266] Step 1: Compound 6-1 (60 mg, 0.11 mmol, 1 eq) was dissolved in tetrahydrofuran (4 mL). Phthalimide (62 mg, 0.42 mmol, 3 eq), triphenylphosphine (175 mg, 0.67 mmol, 6 eq), and diisopropyl azodicarbonate (146 mg, 0.72 mmol, 6.5 eq) were added at room temperature with stirring. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 3:1) to ensure complete reaction. The reaction was quenched with 100 mL of water at room temperature, extracted with ethyl acetate (100 mL × 2), and the organic phase was treated with saturated brine (50 mL). Washed (mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give a white solid 2-(2-{[(6R)-6-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecylhydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxacyclopentanthro-8-yl]-2-methylhept-2-yl]oxy}ethyl)isoindole-1,3-dione 15-1 (50 mg, yield: 67.3%). 1 H NMR (400 MHz, CDCl3) d 7.76 (dd,J = 5.5, 3.1Hz, 2H), 7.71 (m, 2H), 4.02 (dd,J = 13.9, 7.4Hz, 2H), 3.85 (t,J =6.1Hz, 2H), 3.56 (t,J = 6.1Hz, 2H), 2.14 (m, 1H), 1.96 (d,J = 12.7Hz, 2H), 1.82 (dd,J = 10.3, 6.8Hz, 3H), 1.65 (m, 3H), 1.48 (m, 5H), 1.31 (m, 13H), 1.07 (s, 10H), 0.91 (m,4H), 0.83 (d,J = 6.4Hz, 3H), 0.65 (s, 3H).

[0267] Step 2: 15-1 (50 mg, 0.07 mmol, 1 eq) was added to ethanol (2 mL), followed by 0.1 mL of hydrazine hydrate (60% aqueous solution), and the mixture was heated to reflux. After stirring for 30 minutes, the reaction was monitored by TLC (dichloromethane:methanol = 10:1) to confirm completion. The reaction was quenched at room temperature by adding 100 mL of saturated ammonium chloride aqueous solution, 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 (dichloromethane:methanol = 10:1) to give a white solid 2-{[(6R)-6 [(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecylhydro-3aH-cyclopentano[1',2':1,2]phenanthro[7,8-d][1,3]dioxacyclopentano-8-yl]-2-methylhept-2-yl]oxy}eth-1-amine 15-2 (36 mg, yield: 88.6%), crude product proceeded directly to the next step.

[0268] Step 3: Similar to Step 4 of Example 3, replace 3-1 with 15-2 to obtain a white solid (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-1-[(2R)-6-[(2-aminoethyl)oxy]-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 15 (35 mg, yield: 94.5%). 1 H NMR (400MHz, MeOD) d 3.63 (s, 1H), 3.56 (m, 2H), 3.47 (m, 1H), 3.05 (m, 2H), 2.17 (m,1H), 2.02 (d, J = 12.6 Hz, 1H), 1.76 (dd, J = 26.2, 14.2Hz, 6H), 1.49 (s, 3H), 1.39 (m, 9H), 1.19 (s, 7H), 1.08 (m, 7H), 0.96 (d, J = 6.5 Hz, 4H), 0.70 (s, 3H). 19 F NMR (376 MHz, CDCl3) d -81.90, -82.52, -103.90, -104.52. LC-MS:[M+H] + = 500.5.

[0269] Example 19

[0270] Preparation of compound 16 (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-1-[(2R)-6-[(2,2-difluoroethyl)oxy]-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0271] Step 1: Compound 6-1 (60 mg, 0.11 mmol, 1 eq) was dissolved in dichloromethane (4 mL), and Dysmartin oxidant (94 mg, 0.22 mmol, 2 eq) was added at room temperature. After stirring at this temperature for 1 hour, the reaction was monitored by TLC (petroleum ether:ethyl acetate = 3:1). The reaction was quenched with 100 mL of water at room temperature, extracted with ethyl acetate (100 mL × 2), and the organic phase was quenched with saturated brine (50 mL). Washed (mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give a white solid 2-{[(6R)-6-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecylhydro-3aH-cyclopenta[1',2':1,2]phenanthrene[7,8-d][1,3]dioxacyclopentaman-8-yl]-2-methylhept-2-yl]oxy}acetaldehyde 16-1 (45 mg, yield: 75.3%). 1 H NMR (400 MHz, CDCl3) d9.73 (s, 1H), 4.00 (m, 4H), 2.13 (ddd, J = 24.1, 14.8, 3.3 Hz, 1H), 1.97 (dd, J = 18.3, 8.9 Hz, 2H), 1.83 (dd,J = 21.7, 14.6 Hz, 4H), 1.69 (m, 2H), 1.52 (m, 10H), 1.40 (m, 6H), 1.29 (d, J= 5.9 Hz, 4H), 1.17 (d, J = 8.5 Hz, 6H), 1.07 (s, 4H), 0.99 (dd, J = 15.4,6.6 Hz, 2H), 0.92 (d, J = 6.5 (Hz, 3H), 0.68 (s, 3H).

[0272] Step 2: Add 16-1 (40 mg, 0.07 mmol, 1 eq) to dichloromethane (2 mL) and cool to -78°C. o After step C, diethylaminosulfur trifluoride (DAST) (24 mg, 0.15 mmol) was added. The mixture was stirred at the same temperature for 30 minutes, and the reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 5:1). The reaction was quenched at room temperature with 100 mL of saturated ammonium chloride aqueous solution, extracted with ethyl acetate (100 mL × 2), and the organic phase was treated with saturated brine (50 mL). Washed (mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give a white solid (3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-8-[(2R)-6-[(2,2-difluoroethyl)oxy]-6-methylhept-2-yl]-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-cyclopentazo[1',2':7,8]phenanthro[1,2-d][1,3]dioxanecyclopentazo16-2 (25 m, yield: 60.1%). 1 H NMR (400 MHz, CDCl3) d 5.80 (m, 1H), 4.02 (d, J = 15.0 Hz, 2H), 3.53 (td, J = 13.9, 4.2 Hz, 2H), 2.11 (m,1H), 1.99 (d, J= 12.7 Hz, 2H), 1.84 (m, 4H), 1.63 (m, 4H), 1.48 (m, 5H), 1.30(m, 12H), 1.17 (d, J = 8.0 Hz, 7H), 1.07 (s, 4H), 0.92 (d, J = 6.4 Hz, 5H), 0.68 (s, 3H). 19 F NMR (376 MHz, CDCl3) d -88.99, -89.62, -111.36, -111.98, -124.74.

[0273] Step 3: Similar to Step 4 of Example 3, replace 3-1 with 16-2 to obtain a white solid (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-1-[(2R)-6-[(2,2-difluoroethyl)oxy]-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 16 (20 mg, yield: 53.9%). 1 H NMR (400 MHz, MeOD) d 1.36 (d, J= 7.9 Hz, 5H), 1.28 (s, 3H), 1.16 (s, 6H), 1.11 (d, J = 4.8 Hz, 2H), 1.06 (s,4H), 0.99 (d, J = 10.4 Hz, 2H), 0.92 (d, J = 6.5 Hz, 4H),0.67 (s, 3H). 19 F NMR (376 MHz, CDCl3) d -88.63, -89.26, -110.63, -111.25, -124.74. LC-MS: [MH] + =519.4

[0274] Example 20

[0275] Preparation of compound 80 {[(6R)-6-[(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-methylheptyl-2-yl]oxy}acetic acid

[0276] Step 1: Compound 9-2 (400 mg, 0.52 mmol, 1 eq) was dissolved in methanol (4 mL) and water (2 mL), and lithium hydroxide (127 mg, 5.2 mmol, 10 eq) was added at room temperature. After stirring at the temperature for 1 hour, the reaction was monitored for completion by TLC (petroleum ether: ethyl acetate = 1:1). 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) and dried over anhydrous sodium sulfate. The crude 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]-2-methylheptyl-2-yl]oxy}acetic acid 80-1 (380 mg) was directly added to the next step.

[0277] Step 2: Crude product 80-1 was dissolved in tetrabutylammonium fluoride (1 N tetrahydrofuran solution) (3 mL) and stirred at room temperature for 2 hours. After the reaction was complete, it was monitored by TLC (petroleum ether: ethyl acetate = 1:1). The reaction solution was then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain a white solid {[(6R)-6-[(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-methylheptyl-2-yl]oxy}acetic acid 80 (240 mg, yield: 92.0%). 1 H NMR (400 MHz, MeOD) d3.97 (s, 2H), 3.53(s, 1H), 2.02 (d, J = 12.7 Hz, 1H), 1.76 (ddd, J= 14.7, 12.2, 8.2 Hz, 6H), 1.55 (d, J = 15.0 Hz, 3H), 1.42 (m, 9H), 1.28 (m, 4H), 1.18 (s, 6H), 1.07(m,5H), 0.95 (d, J = 6.5 Hz, 3H), 0.87 (s, 3H), 0.71 (s, 3H). 19 F NMR (376 MHz, MeOD) d -89.91, -90.54, -112.25, -112.88. LC-MS: [MH] + =497.50.

[0278] Example 21

[0279] Preparation of compound 19 2-{[(6R)-6-[(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-methylhept-2-yl]oxy}acetamide

[0280] Compound 80 (40 mg, 0.08 mmol, 1 eq) was dissolved in N,N-dimethylformamide DMF (2 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (92 mg, 0.24 mmol, 3 eq), diisopropylethylamine (62 mg, 0.48 mmol, 6 eq), and ammonium chloride (21 mg, 0.40 mmol, 5 eq) were added at room temperature. After stirring at this temperature for 1 hour, the reaction was monitored by TLC (dichloromethane:methanol = 10:1) until complete. Quenching was performed at room temperature with 100 mL of 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. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give a white solid 2-{[(6R)-6-[(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-methylhept-2-yl]oxy}acetamide 19 (28 mg, yield: 70%). 1 H NMR (400 MHz, CDCl3) d 6.64 (s, 1H), 5.53 (s, 1H), 3.86 (s, 2H), 3.63 (t, J = 5.0 Hz, 1H), 1.98 (dd, J = 9.5, 3.3 Hz, 1H), 1.84 (dd, J = 9.2, 5.8Hz, 3H), 0.67 (s, 3H). 19 F NMR (377 MHz, CDCl3) d -88.96, -89.60, -110.85, -111.48. LC-MS: [MH] + =496.50.

[0281] Similar to Example 21, replacing ammonium chloride with other amines can synthesize the following examples respectively.

[0282] Example 27

[0283] Preparation of compound 26 (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(2-hydroxypropyl)oxy]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0284] Step 1: Compound 9-3 (150 mg, 0.21 mmol, 1 eq) was dissolved in dichloromethane (5 mL), and Desmartin oxidant (176 mg, 0.42 mmol, 2 eq) was added at room temperature. After stirring at this temperature for 1 hour, the reaction was monitored for completion by TLC (petroleum ether: ethyl acetate = 5:1). Quenching was performed at room temperature with 100 mL of 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 crude product. Purification was achieved by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain 2-{[(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-methylheptyl-2-yl]oxy}acetaldehyde 26-1 (100 mg, yield: 67%). 1 H NMR (400 MHz, CDCl3) d 9.72 (s, 1H), 7.66 (m, 4H), 7.38 (m, 6H), 3.95 (t, J = 13.1 Hz, 2H), 3.59 (dq, J = 15.6, 5.1 Hz, 1H), 1.92 (s, 1H), 1.80 (d, J = 6.8 Hz, 2H), 1.63 (m,3H), 1.49 (m, 7H), 1.29 (ddd, J = 28.6, 14.0, 9.2 Hz, 10H), 1.17 (s, 6H), 1.07 (m, 12H), 0.89 (d, J = 6.5 Hz, 4H), 0.82 (s, 4H), 0.64 (s, 3H).

[0285] Step 2: Dissolve 26-1 (70 mg, 0.10 mmol, 1 eq) in tetrahydrofuran (3 mL), and add methyl magnesium bromide (3M tetrahydrofuran solution) (0.2 mL, 0.49 mmol, 5 eq) at room temperature. After stirring at this temperature for 1 hour, monitor the reaction for completion by TLC (petroleum ether:ethyl acetate = 5:1). Quenching was performed at room temperature with 100 mL of 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 crude product. Purification was achieved by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain 1-{[(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-methylheptyl-2-yl]oxy}prop-2-ol 26-2 (60 mg, yield: 75.5%). 1 H NMR (400MHz, CDCl3) d 7.66 (dd, J = 5.4, 1.4 Hz, 4H), 7.39 (m, 6H), 3.86 (m, 1H), 3.58 (dd, J = 10.4, 5.0 Hz, 1H), 3.30 (d, J = 8.8 Hz, 1H), 3.08 (s, 1H), 1.94(d, J = 12.9 Hz, 1H), 1.80 (d, J = 7.0 Hz, 2H), 1.60 (s, 14H), 1.45 (m, 4H), 1.36 (d, J = 10.0 Hz, 5H), 1.13 (d, J = 4.7 Hz, 8H), 1.04 (s, 10H), 0.89 (d,J = 6.5 Hz, 4H), 0.82 (s, 3H), 0.75 (d, J = 13.5 Hz, 1H), 0.64 (s, 3H).

[0286] Step 3: Similar to Step 5 of Example 15, replace 9-5 with 26-2 to obtain a white solid (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(2-hydroxypropyl)oxy]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol (11 mg, purity: 100.0%, yield: 65.0%). 1HNMR (400 MHz, CDCl3) d 3.86 (m, 1H), 3.63 (m, 1H), 3.23 (m, 2H), 1.99 (dd, J= 9.5, 3.3 Hz,1H), 1.83 (d, J = 8.1 Hz, 3H), 1.70 (m, 9H), 1.42 (m, 8H), 1.27(m, 3H), 1.14 (d, J = 5.7 Hz, 9H), 1.09 (d, J = 9.1 Hz, 1H), 1.01 (m, 3H), 0.92 (d, J = 6.5 Hz, 3H), 0.85 (s, 3H), 0.67 (s, 3H). 19 F NMR (377 MHz, CDCl3) d -88.96, -89.59, -110.84, -111.47.

[0287] Similar to steps 3 and 4 of Example 27, replacing methyl magnesium bromide with other reagents can synthesize the following examples.

[0288] Example 33

[0289] Preparation of compound 27 (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(2R)-6-methyl-6-{[2-(1,2,3-triazacyclopentanyl-2-yl)ethyl]oxy}hept-2-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0290] Step 1: Compound 9-3 (20 mg, 0.03 mmol, 1 eq) was dissolved in tetrahydrofuran (2 mL), and 2H-1,2,3-triazacyclopentane (7 mg, 0.10 mmol, 3 eq), triphenylphosphine (43 mg, 0.17 mmol, 6 eq), and diisopropyl azodicarbonate (DIAD) (36 mg, 0.18 mmol, 6 eq) were added at room temperature. The mixture was stirred at this temperature for 1 hour, and the reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 5:1). Quenching was performed at room temperature with 100 mL of 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. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain 2-(2-{[(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-methylheptyl-2-yl]oxy}ethyl)-2H-1,2,3-triazacyclopentafenyl 27-1 (15 mg, yield: 70%). 1 H NMR (400 MHz, CDCl3) d 7.59 (dd, J = 5.6, 1.4 Hz, 4H), 7.51 (s,2H), 7.32 (m, 6H), 4.48 (t, J = 6.1 Hz, 2H), 3.73 (t, J = 6.1 Hz, 2H), 3.53(m, 1H), 1.86 (d, J = 12.7 Hz, 1H), 1.72 (m, 2H), 1.54 (t, J = 12.7 Hz, 7H), 1.37 (m, 4H), 1.21 (ddd, J = 24.7, 16.3, 8.8 Hz, 11H), 0.97 (t, J = 6.9 Hz,17H), 0.78 (m, 7H), 0.56 (s, 3H).

[0291] Step 2: Similar to Step 5 of Example 15, replace 9-5 with 27-1 to obtain a white solid (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(2R)-6-methyl-6-{[2-(1,2,3-triazacyclopentanyl-2-yl)ethyl]oxy}hept-2-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 27 (12 mg, yield: 69.4%). 1 H NMR (400 MHz, CDCl3) d 7.59 (s, 2H), 4.56 (t, J = 6.1 Hz, 2H), 3.81 (t, J = 6.1 Hz, 2H), 3.63 (m, 1H), 1.98 (d, J = 13.0 Hz, 1H), 1.83 (m, 3H), 1.72 (m, 3H), 1.61 (m, 6H), 1.45 (d, J = 13.0Hz, 3H), 1.30 (dd, J = 17.6, 7.0Hz, 7H), 1.12 (d, J = 3.9 Hz, 2H), 1.06 (s, 6H), 1.00 (dd, J =12.6, 2.9 Hz, 3H), 0.87 (m, 6H), 0.66 (s, 3H). 19 F NMR (377 MHz, CDCl3) d -88.95, -89.58, -110.84, -111.47.

[0292] Example 34

[0293] Preparation of compound 28 (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(10R)-2,6,6-trimethyl-2-aza-5-oxaundecane-10-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0294] Step 1: Compound 26-1 (20 mg, 0.08 mmol, 1 eq) was dissolved in 1,2-dichloroethane (1 mL), and dimethylamine (2 M in THF) (0.1 mL, 0.08 mmol, 3 eq) was added at room temperature. After stirring at this temperature for 30 minutes, sodium cyanoborohydride (5 mg, 0.08 mmol, 3 eq) was added. The reaction was monitored by TLC (dichloromethane:methanol = 10:1) after 30 minutes to ensure safety. Quenching was performed at room temperature with 100 mL of 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 (ethyl acetate: petroleum ether = 1:1) to give (10R)-10-[(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]-2,6,6-trimethyl-2-aza-5-oxaundecanane 28-1 (10 mg, yield: 70%). LC-MS: [M+H] + =750.1.

[0295] Step 2: Similar to Step 5 of Example 15, replace 9-5 with 28-1 to obtain the white solid product (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(10R)-2,6,6-trimethyl-2-aza-5-oxaundecan-10-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 28 (7 mg, yield: 51.8%). 1 H NMR (400 MHz, CDCl3) d 3.81 (s, 2H), 3.63 (m, 1H), 3.17 (s, 2H), 2.84 (s, 6H), 1.98 (d, J =12.8 Hz, 1H), 1.76 (m, 7H), 1.43 (m, 7H), 1.27 (d, J= 12.2 Hz,7H), 1.18 (s, 6H), 1.07 (dd, J =34.2, 11.7 Hz, 6H), 0.91 (d, J = 6.5 Hz, 3H), 0.85 (s, 3H), 0.67 (s, 3H). 19 F NMR (377 MHz, CDCl3) d-88.95, -89.58, -110.84, -111.47. LC-MS: [M+H] + =512.60.

[0296] Example 35

[0297] Preparation of compound 32 (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-1-[(2R)-6-[(2-aminoethyl)oxy]-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0298] Similar to step 5 of Example 15, 9-5 was replaced with 10-2 to obtain a white solid (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-1-[(2R)-6-[(2-aminoethyl)oxy]-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 32 (22 mg, yield: 88.5%). 1 HNMR(400MHz, MeOD) δ =3.55 – 3.48 (m, 3H), 2.98 (t,J=5.1, 2H), 2.04 – 2.00 (m, 1H), 1.92 – 1.69 (m,8H), 1.68 – 1.49 (m, 5H), 1.40 – 1.30(m, 8H), 1.18 (s, 6H), 1.15 – 0.98 (m,6H), 0.96 (d,J=6.4, 3H), 0.87 (s, 3H), 0.70 (s, 3H). 19 F NMR (376MHz, MeOD) δ =-89.92, -90.55, -112.26, -112.89. LC-MS: [[M+H] + =484.6.

[0299] Example 36

[0300] Preparation of compound 33 (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-1-[(10R)-6,6-dimethyl-2-aza-5-oxaundecane-10-yl]-4,4-difluoro-9a,11a-dimethylhexadecane-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0301] Step 1: Similar to Example 34. Step 1, replacing dimethylamine with a methylamine tetrahydrofuran solution yields (10R)-10-[(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]-6,6-dimethyl-2-aza-5-oxaundecane 33-1 (10 mg, yield: 50.0%). LC-MS: [M+H] + =736.5.

[0302] Step 2: Similar to Step 5 of Example 15, replace 9-5 with 33-1 to obtain a white solid (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-1-[(10R)-6,6-dimethyl-2-aza-5-oxaundecan-10-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 33 (7 mg, purity: 100.0%, yield: 51.8%). 1 HNMR (400 MHz, CDCl3) d 3.64 (dt, J = 20.9, 5.4 Hz, 3H), 3.10 (t, J = 4.9 Hz,2H), 2.74 (s,3H), 1.98 (d, J = 12.7 Hz, 1H), 1.77 (m, 6H), 1.59 (dd,J = 19.6,9.9 Hz, 3H), 1.44 (dd, J = 15.2, 5.7 Hz,4H), 1.31 (m, 9H), 1.18 (s, 6H), 1.09(s, 2H), 1.02 (m, 3H), 0.91 (d, J = 6.4 Hz, 3H), 0.85 (s,3H), 0.67(s,3H). 19 FNMR (377 MHz, CDCl3) d -88.92, -89.55, -110.78, -111.41. LC-MS: [M+H] + =498.70.

[0303] Example 37

[0304] Preparation of compound 41 (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(2-hydroxypropyl)oxy]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0305] Step 1: Under nitrogen protection, compound 16-1 (50 mg, 0.09 mmol) was dissolved in tetrahydrofuran (5 mL), and methylmagnesium bromide (0.12 mL, 0.35 mmol) 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, at which point the reaction was stopped. Water (10 mL) was added to the reaction system, 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 1-{[(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]phenanthrene[7,8-d][1,3]dioxacyclopentan-8-yl]-2-methylhept-2-yl]oxy}prop-2-ol 41-1 (45 mg, yield 83.0%). 1 HNMR (400MHz, CDCl3) δ 4.02 (d,J= 15.1Hz, 2H), 3.86 (d,J = 6.0Hz, 1H), 3.30 (dd,J = 8.8, 1.6Hz, 1H), 3.08 (t,J = 8.5Hz,1H), 1.97 (t,J = 12.8Hz, 3H), 1.88 – 1.60 (m, 10H), 1.51 (s, 3H), 1.47 – 1.33 (m, 7H), 1.31 – 1.25 (m, 5H), 1.19 – 1.11 (m, 11H), 1.07 (s, 4H), 0.90 (t,J = 9.2Hz, 4H), 0.68 (s, 3H). 19F NMR (376MHz, CDCl3) δ -88.99, -89.62, -111.35, -111.97.

[0306] Step 2: Similar to Step 4 of Example 3, replace 3-1 with 41-1 to obtain the white solid product (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(2-hydroxypropyl)oxy]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 41 (30 mg, 71.9%). 1 H NMR (400MHz, CDCl3) δ 3.91 – 3.82 (m, 1H), 3.74 (s, 1H), 3.60 (d, J = 11.2 Hz, 1H), 3.30 (dd, J = 8.8, 1.7 Hz, 1H), 3.08 (t, J = 8.5 Hz, 1H), 2.32 – 2.11 (m,1H), 1.98 (s, 5H), 1.89 – 1.62 (m, 8H), 1.46 – 1.27 (m, 11H), 1.14 (d, J =5.5 Hz, 9H), 1.08 – 1.03 (m, 4H), 0.92 (d, J = 6.5 Hz, 3H), 0.67 (s, 3H). 19 FNMR (376 MHz, CDCl3) δ -88.62, -89.24, -110.60, -111.23. LC-MS: [M+Na] + =537.4.

[0307] Example 38

[0308] Preparation of compound 42 (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(2R)-6-methyl-6-{[2-(oxetanebut-3-ylamino)ethyl]oxy}hept-2-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0309] Step 1: Similar to Step 1 of Example 34, replacing dimethylamine with oxetine-3-amine yields (2-{[(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-methylheptyl-2-yl]oxy}ethyl)(oxetine-3-yl)amine 42-1 (40 mg, yield: 74%). LC-MS: [M+H] + =777.53.

[0310] Step 2: Similar to Step 5 of Example 15, replace 9-5 with 42-1 to obtain a white solid (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(2R)-6-methyl-6-{[2-(oxacyclobut-3-ylamino)ethyl]oxy}hept-2-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 42 (18 mg, purity: 99.49%, yield: 74%). 1 H NMR (400 MHz, MeOD) d 4.79 (t, J = 6.8 Hz, 2H), 4.48(t, J = 6.3 Hz, 2H), 3.99 (t, J = 6.5Hz, 1H), 3.53 (s, 1H), 3.41 (t, J = 5.4Hz, 2H), 2.66(t, J = 5.4 Hz, 2H), 2.02 (d, J = 12.9 Hz, 1H), 1.86 (m, 1H), 1.74 (m, 5H), 1.57 (s, 2H), 1.42 (dd, J = 14.9, 9.2 Hz, 8H), 1.30 (m, 6H), 1.14 (d, J= 11.9Hz, 8H), 1.05 (m, 3H), 0.96 (d, J = 6.5 Hz, 3H), 0.87 (s, 3H), 0.71 (s, 3H). 19 F NMR (376 MHz, MeOD) d -89.91, -90.54, -112.24, -112.87.LC-MS: [M+H] + =540.60.

[0311] Example 39

[0312] Preparation of compound 43 3-{[(6R)-6-[(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-methylhept-2-yl]oxy}propionamide

[0313] Compound 14 (30 mg, 0.06 mmol, 1 eq) was dissolved in methanol (1 mL). o Lithium hydroxide (4 mg, 0.18 mmol, 3 eq) was added at temperature C, followed by slow dropwise addition of hydrogen peroxide (85%) (6 mg, 0.18 mmol, 3 eq). The reaction was maintained at this temperature and stirred for 30 minutes. The reaction was then monitored for completeness by TLC (dichloromethane:methanol = 10:1). Dilute with 100 mL of aqueous solution at room temperature, extract with ethyl acetate (100 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 (dichloromethane:methanol = 10:1) to obtain 3-{[(6R)-6-[(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-methylheptyl-2-yl]oxy}propionamide 43 (19 mg, purity: 96.54%, yield: 61%). 1 H NMR (400 MHz, DMSO) d 7.23 (s, 1H), 6.75 (s, 1H), 4.54 (d, J = 4.8 Hz, 1H), 3.43 (t, J =6.6Hz, 2H), 3.36 (d, J = 6.2 Hz, 1H), 2.18 (t, J =6.5 Hz, 2H), 1.93 (d, J =13.0 Hz, 1H), 1.66 (m,7H),1.47 (m, 2H), 1.27 (dd, J = 22.6, 11.0 Hz, 12H),1.15 (m, 2H), 1.06 (s, 7H), 0.98 (m, 2H),0.89(d, J = 6.4 Hz, 4H), 0.79 (s, 3H), 0.64 (s, 3H). 19F NMR (376 MHz, DMSO) δ -87.39, -88.02, -109.13, -109.76.LC-MS: [M+Na] + =534.60.

[0314] Example 40

[0315] Preparation of compound 44 (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(3-hydroxypropyl)oxy]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0316] Step 1: Dissolve compound 14 (42 mg, 0.083 mmol, 1 eq) in dichloromethane (5 mL) at -78°C. o DIBAL-H (1 M tetrahydrofuran solution) (0.16 mL, 0.16 mmol, 2 eq) was added at C. After stirring at this temperature for 30 minutes, the reaction was monitored for completeness by TLC (petroleum ether: ethyl acetate = 1:1). The reaction was quenched by adding 100 mL of aqueous solution at room temperature, extracted with ethyl acetate (100 mL × 2), and the organic phase was washed with saturated brine (50 mL). The organic phase was evaporated to dryness to obtain crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain 3-{[(6R)-6-[(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-methylheptyl-2-yl]oxy}propionaldehyde 44-1 (25 mg, yield: 36%), which was directly used for the next step.

[0317] Step 2: Dissolve 44-1 (25 mg, 0.05 mmol, 1 eq) in tetrahydrofuran (1 mL), add lithium aluminum hydride (6 mg, 0.15 mmol, 3 eq) at room temperature, and stir for 30 minutes while maintaining the temperature. Monitor the reaction by TLC (petroleum ether:ethyl acetate = 1:1). The starting material disappears and is completely converted to a new spot. Quench the reaction by adding 100 mL of aqueous solution at room temperature, extract with ethyl acetate (100 mL × 2), and irrigate the organic phase with saturated brine (50 mL). Washed with mL, the organic phase was evaporated to dryness to obtain crude product, which was then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(3-hydroxypropyl)oxy]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 44-2 (15 mg, purity: 60.0%).

[0318] Step 3: Dissolve 44-2 (15 mg, 0.03 mmol, 1 eq) in dichloromethane (2 mL), and add triethylamine (18 mg, 0.2 mmol, 6 eq), 4-dimethylaminopyridine (DMAP) (4 mg, 0.03 mmol, 1 eq) and benzoyl chloride (16 mg, 0.1 mmol, 3 eq) at room temperature. After stirring at the maintained temperature for 1 hour, the reaction was monitored by TLC (petroleum ether: ethyl acetate = 5:1). The starting material disappeared and was completely converted to a new spot. The reaction was quenched by adding 100 mL of aqueous solution at room temperature, extracted with ethyl acetate (100 mL × 2), and the organic phase was washed with saturated brine (50 mL). The organic phase was evaporated to dryness to obtain crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain (11R)-11-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-7-(benzyloxy)-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-7,7-dimethyl-1-phenyl-2,6-dioxadodecane 44-3 (10 mg, yield: 48%). 1 H NMR (400 MHz, CDCl3) d7.97 (dd, J =7.1, 5.3 Hz, 4H), 7.48 (m, 2H), 7.36 (td, J = 7.7, 3.4 Hz, 4H), 4.88 (m, 1H), 4.35 (t, J = 6.3 Hz, 2H), 3.40 (t, J = 6.1 Hz, 2H), 1.92 (m, 4H), 1.73 (dd, J= 10.2, 5.8 Hz, 4H), 1.55 (m, 6H), 1.28 (m, 10H), 1.06 (m, 9H), 0.93 (m, 2H), 0.83 (d, J = 6.6 Hz, 6H), 0.78 (d, J = 5.9 Hz, 1H), 0.59 (s, 3H).

[0319] Step 4: Dissolve 44-3 (10 mg, 0.02 mmol, 1 eq) in methanol (2 mL), add lithium hydroxide (4 mg, 0.2 mmol, 10 eq) at room temperature, and stir for 1 hour while maintaining the temperature. Monitor the reaction by TLC (petroleum ether: ethyl acetate = 1:1). The starting material disappears and is completely converted to the new spot. Dilute with 100 mL of aqueous solution at room temperature, extract with ethyl acetate (100 mL × 2), and saturate the organic phase with 50 mL of saturated brine. Washed with (mL), the organic phase was evaporated to dryness to obtain crude product, which was then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(3-hydroxypropyl)oxy]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 44 (6m, yield: 82%). 1 H NMR (400 MHz, CDCl3) d3.77 (m, 2H), 3.62 (dd, J = 10.5, 5.5Hz, 1H), 3.55 (t, J = 5.5 Hz,2H), 1.99 (d, J = 12.9 Hz, 1H), 1.81 (m, 8H),1.65(ddd, J = 44.5, 23.3, 10.4 Hz, 5H), 1.43 (m,5H), 1.29 (dd, J = 18.4, 13.2Hz, 8H), 1.16 (s, 6H), 1.10 (m, 2H), 1.01 (m, 3H), 0.92 (d, J = 6.5Hz, 3H), 0.85 (s, 3H), 0.67 (s, 3H). 19 F NMR (376 MHz, CDCl3) d -88.95, -89.58, -110.83, -111.46. LC-MS: [M+Na] + =521.2.

[0320] Example 41

[0321] Preparation of compound 45 2-{[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(2-hydroxyethyl)oxy]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-yl]oxy} ethanol-1-ol

[0322] Step 1: Similar to Step 5 of Example 15, replace 9-5 with II to obtain a white solid (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 45-0.

[0323] Step 2: Compound 45-0 (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 diazonate (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 stopped after complete TLC (petroleum ether: ethyl acetate = 5:1). The reaction was quenched with H₂O (5 mL), extracted with dichloromethane (30 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 purified by rapid chromatography (petroleum ether: ethyl acetate = 100-0: 100-0). 90:10) yielded 45-1 (45 mg, 37.44% yield) of the product {[(6R)-6-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-7-[(2-ethoxy-2-oxoylethyl)oxy]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2-methylhept-2-yl]oxy} ethyl acetate.

[0324] Step 3: 0 o At temperature C, starting material 45-1 (100 mg, 0.163 mmol, 1 eq) was dissolved in tetrahydrofuran (5 mL), and lithium aluminum hydride (9.29 mg, 0.245 mmol, 1.5 eq) was added. The reaction mixture was then subjected to a nitrogen atmosphere. o The reaction was carried out at C for 0.5 h. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 5:1) until complete, at which point the reaction was stopped. The reaction was quenched by adding water (5 mL). The organic phase was extracted with ethyl acetate (10 mL × 3), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give 45 (30 mg, yield: 60%) of white solid 2-{[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(2-hydroxyethyl)oxy]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-yl]oxy} ethanol-1-ol. 1 H NMR (400 MHz, CDCl3) d3.74 –3.66 (m, 4H), 3.61 – 3.54 (m, 2H), 3.46 – 3.40 (m, 2H), 3.29 (s, 1H), 2.02 –1.96 (m, 1H), 1.93 – 1.84 (m, 2H),1.81 – 1.67 (m, 8H), 1.66 – 1.52 (m, 2H), 1.48 – 1.40 (m, 4H), 1.31 (dd, J = 22.9, 12.3 Hz, 7H), 1.16 (s, 6H), 1.13 –0.98 (m, 4H), 0.92 (d,J = 6.5Hz, 3H), 0.84 (s, 3H), 0.67 (s, 3H). 19 F NMR (377MHz, CDCl3) d -88.95, -89.57, -110.84, -111.47. LC-MS: [MH] - =527.35

[0325] Example 42

[0326] Preparation of compound 47 (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(2-hydroxyethyl)oxy]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0327] Similar to step 5 of Example 15, 9-5 was replaced with 9-3 to obtain a white solid (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(2-hydroxyethyl)oxy]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 47 (20 mg yield: 74.6%). 1H NMR (400 MHz, CDCl3)δ3.70 – 3.66 (m, 2H), 3.63 (t, J = 5.0 Hz, 1H), 3.46 – 3.40 (m, 2H), 1.99 (d,J = 12.7 Hz, 1H), 1.87 – 1.78 (m, 3H), 1.72 (ddd, J = 11.7, 9.4, 6.0 Hz, 3H),1.65 – 1.54 (m, 5H), 1.49 – 1.26 (m, 12H), 1.16 (s, 6H), 1.13 – 1.10 (m, 1H),1.03 (dd, J = 19.3, 11.5 Hz, 3H), 0.92 (d, J = 6.5 Hz, 3H), 0.85 (s, 3H), 0.67 (s, 3H) 19 F NMR (376 MHz, CDCl3) d -88.96, -89.59, -110.84, -111.47.

[0328] Example 43

[0329] Preparation of compound 51 (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-1-[(10R)-6,6-dimethyl-2-aza-5-oxaundecane-10-yl]-4,4-difluoro-9a,11a-dimethylhexadecane-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0330] Step 1: Compound 16-1 (80 mg, 0.15 mmol) was dissolved in dichloroethane (5 mL) at room temperature, and methylamine (18.45 mg, 0.30 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 hours. Sodium borohydride acetate (62.64 mg, 0.30 mmol) was then added to the system, and the reaction was continued at room temperature for 2 hours. The reaction was monitored by TLC (dichloromethane:methanol = 10:1) until complete, at which point the reaction was stopped. 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 purified by rapid chromatography (dichloromethane: methanol = 15:1) to give a white solid product (10R)-10-[(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]dioxacyclopentanthro-8-yl]-6,6-dimethyl-2-aza-5-oxaundecane 51-1 (46 mg, 55.9%). 1 H NMR (400 MHz, CDCl3) δ 4.02 (d, J = 15.1 Hz, 2H), 3.62 (t, J =5.0 Hz, 2H), 3.00 (t, J = 5.1 Hz, 2H), 2.67 (s, 3H), 2.19 –2.04 (m, 1H), 1.97(t, J = 13.6 Hz, 2H), 1.83 (d, J = 7.2 Hz, 4H), 1.71 – 1.56 (m, 3H), 1.51 (s,5H), 1.46 – 1.32 (m, 8H), 1.30 (s,4H), 1.25 (s, 2H), 1.18 (s, 7H), 1.07 (s, 4H), 0.90 (t, J = 8.5 Hz, 4H), 0.68 (s, 3H). 19 F NMR (376MHz, CDCl3) δ -88.98,-89.61, -111.34, -111.97

[0331] Step 2: Similar to Step 4 of Example 3, replace 3-1 with 51-1 to obtain a white solid. The white solid product (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-1-[(10R)-6,6-dimethyl-2-aza-5-oxaundecan-10-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 51 (25 mg, 60.9%) is obtained. 1 H NMR (400 MHz, MeOD) δ 3.63 (s, 1H), 3.60 – 3.55 (m, 2H), 3.48 (dd, J = 7.6, 4.2 Hz, 1H), 3.09 – 3.04 (m, 2H), 2.65 (s, 3H), 2.17 (dt, J = 13.7, 11.5 Hz, 1H), 2.02 (d, J = 12.8 Hz, 1H), 1.75 (dd, J = 26.2, 14.3 Hz, 6H),1.60 – 1.49 (m, 2H), 1.36 (ddd, J = 27.4, 20.7, 9.6 Hz, 12H), 1.19 (s, 6H), 1.12 – 1.03 (m, 6H), 0.96 (d, J = 6.5 Hz, 4H), 0.70 (s, 3H). 19 F NMR (376 MHz, MeOD) δ -89.33, -89.96, -111.86, -112.52. LC-MS: [M+H] + = 514.65.

[0332] Example 44

[0333] Preparation of compound 52 (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(2R)-6-methyl-6-{[2-(oxetanebut-3-ylamino)ethyl]oxy}hept-2-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0334] Similar to Example 43, the methylamine in step 1 was replaced with oxetine-3-amine, yielding a white solid product (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(2R)-6-methyl-6-{[2-(oxetine-3-ylamino)ethyl]oxy}hept-2-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 52 (15 mg, 40.12%). 1 H NMR (400 MHz, CDCl3) δ 4.82 (t, J = 6.9 Hz, 2H), 4.51 (t, J = 6.3Hz, 2H), 4.07 – 3.98 (m, 1H), 3.74 (s, 1H), 3.64 – 3.56 (m,1H), 3.41 (t, J =5.1 Hz, 2H), 2.73 (t, J = 5.1 Hz, 2H), 2.31 – 2.06 (m, 4H), 1.98 (d, J = 12.6Hz, 1H), 1.86 – 1.64 (m, 8H), 1.38 (dd, J = 31.7, 17.7 Hz, 10H), 1.25 (s, 2H), 1.15 (s, 6H), 1.06 (s, 3H), 0.92 (d, J = 6.4 Hz, 4H), 0.67 (s, 3H). 19 F NMR (376 MHz, CDCl3) δ -88.61, -89.24, -110.61, -111.23. LC-MS [M+H] + =556.6.

[0335] Example 45

[0336] Preparation of compound 53 (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(2R)-6-methyl-6-{[2-(methyldioxane-λ6-thio)ethyl]oxy}hept-2-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0337] Step 1: Add compound II (120 mg, 0.18 mmol) to a reaction flask containing tetrahydrofuran (5 mL), then... o Sodium hydride (85 mg, 3.53 mmol) was added at C, and the reaction was carried out at room temperature (25 °C). o Stirring for 0.5 h under C) conditions, then adding methyldioxane (vinyl)-λ6-thione (375 mg, 3.53 mmol). The reaction was monitored by TLC until complete. Water (20 mL) was added for dilution, followed by dichloromethane (20 mL × 3). Extraction was performed three times, followed by washing with sodium chloride, drying to anhydrous sodium sulfate, and then evaporating the reaction solution under reduced pressure (using a water pump, 45°C). o C) The product was purified by column chromatography (petroleum ether: ethyl acetate = 80:20) to obtain {[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(2R)-6-methyl-6-{[2-(methyldioxane-λ6-thio)ethyl]oxy}hept-2-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-yl]oxy}(2-methylpropyl-2-yl)diphenylsilane 53-1 (35 mg, 22.7%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.66(d, J = 7.6 Hz, 4H), 7.38 (m, 6H), 3.76 (t, J = 5.2 Hz, 2H), 3.59 (d, J = 5.1Hz, 1H), 3.16 (t, J = 5.0 Hz, 2H), 3.00 (s, 3H), 1.93 (d, J = 13.2 Hz, 1H), 1.77 (m, 6H), 1.63 (d, J = 9.9 Hz, 4H), 1.46 (m, 4H), 1.25 (s, 8H).

[0338] Step 2: Similar to Step 5 of Example 15, replace 9-5 with 53-1 to obtain a white solid (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(2R)-6-methyl-6-{[2-(methyldioxane-λ6-thio)ethyl]oxy}hept-2-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 53 (16 mg, 0.03 mmol, 76.2%). 1H NMR (400 MHz, CDCl3) δ 3.77 (m, 2H), 3.62 (dd, J = 10.3, 5.6 Hz,1H), 3.17 (t, J = 5.3 Hz, 2H), 3.01 (s, 3H), 1.99 (m, 1H), 1.83 (d, J = 7.3Hz, 3H), 1.73 (m, 2H), 1.55 (s, 7H), 1.44 (m, 3H), 1.35 (m, 7H), 1.17 (s,7H), 1.02 (dd, J = 24.2, 13.4 Hz, 4H), 0.92 (d, J = 6.5 Hz, 3H), 0.85 (s,3H), 0.67 (s, 3H). 19 F NMR (376 MHz, CDCl3) δ -88.96, -89.59, -110.84, -111.47. LC-MS: [M+Na] + = 569.60.

[0339] Example 46

[0340] Compound 55 (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(10R)-3,3,6,6-tetramethyl-2,5-dioxaundecane-10-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol Preparation

[0341] Step 1: Similar to Step 3 of Example 3, replace compound 3-A1 with compound 13-1 to obtain a white solid {[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(10R)-3,3,6,6-tetramethyl-2,5-dioxaundecan-10-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-yl]oxy}(2-methylpropyl-2-yl)diphenylsilane 55-1 (50 mg, yield: 63.24%).

[0342] Step 2: Similar to Step 5 of Example 15, replace 9-5 with 55-1 to obtain a white solid (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(10R)-3,3,6,6-tetramethyl-2,5-dioxaundecan-10-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 55 (30 mg, 69%). 1 HNMR(400MHz, CDCl3) δ 3.62 (dd,J = 10.4, 5.5Hz, 1H), 3.26 (s, 3H), 3.17 (s, 2H), 1.99 (d,J= 12.8Hz, 1H), 1.90 – 1.68 (m, 6H), 1.67-1.58 (m, 2H), 1.53 (s, 3H), 1.48 –1.23 (m, 11H), 1.14 (d,J=13.7Hz, 13H), 1.08 – 0.96 (m, 4H), 0.91 (d,J =6.5Hz, 3H), 0.85 (s, 3H), 0.67 (s, 3H).

[0343] Example 47

[0344] Compound 56 (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(2-fluoro-2-methylpropyl)oxy]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol Preparation

[0345] Step 1: Similar to Step 1 of Example 4, compound 3-A1 was transformed into compound 13-1 to obtain a white solid {[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(2-fluoro-2-methylpropyl)oxy]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-yl]oxy}(2-methylpropyl-2-yl)diphenylsilane 56-1 (40 mg, 51.29%).

[0346] Step 2: Similar to Step 5 of Example 15, replace 9-5 with 56-1 to obtain a white solid (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(2-fluoro-2-methylpropyl)oxy]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol (8 mg, 0.015 mmol, 27.80%). 1 HNMR(400 MHz, CDCl3) δ 3.67 – 3.59 (m, 1H), 3.28 (d, J = 16.8 Hz, 2H), 1.99 (d, J= 12.7 Hz, 1H), 1.88 – 1.70 (m, 6H), 1.62-1.58 (m, 2H), 1.54 (s, 3H), 1.43-1.41 (m, 4H), 1.38-1.28 (m, 12H), 1.22 – 1.08 (m, 9H), 1.03-0.98 (m, 3H), 0.92 (d, J = 6.5 Hz, 3H), 0.85 (s, 3H), 0.67 (s, 3H). 19 F NMR (376 MHz, CDCl3)δ -88.96, -89.59, -110.84, -111.47.-145.46.

[0347] Example 48

[0348] Preparation of compound 57 (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(11R)-1-hydroxy-7,7-dimethyl-3,6-dioxadodecane-11-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0349] Step 1: Compound 9-3 (60 mg, 0.1 mmol, 1 eq) and rhodium dimer acetate (4 mg, 0.01 mmol, 0.1 eq) were dissolved in dichloromethane (1 mL), and ethyl diazonate (95 mg, 0.8 mmol, 10 eq) was slowly added dropwise at room temperature. After stirring at this temperature for 6 h, the reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 5:1). Dilute with 100 mL of aqueous solution at room temperature, extract with ethyl acetate (100 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 = 5:1) to obtain ethyl acetate [(2-{[(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-methylheptyl-2-yl]oxy}ethyl)oxy] 57-1 (45 mg, yield: 67%).

[0350] Step 2: Dissolve 57-1 (30 mg, 0.04 mmol, 1 eq) in tetrahydrofuran (2 mL), and slowly add lithium aluminum hydride (3 mg, 0.07 mmol, 2 eq) at room temperature. After stirring for 1 hour, monitor the reaction for completeness by TLC (petroleum ether: ethyl acetate = 1:1). Quenching was performed at room temperature with 100 mL of aqueous solution, followed by extraction with ethyl acetate (100 mL × 2). The organic phase was washed with saturated brine (50 mL) and evaporated to dryness to obtain crude product 2-[(2-{[(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-methylheptyl-2-yl]oxy}ethyl)oxy]eth-1-ol 57-2, which was directly added to the next step.

[0351] Step 3: Crude product 57-2 was dissolved in 1 mL of tetrabutylfluorinated TBAF (1M tetrahydrofuran), stirred at room temperature for 3 hours, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(11R)-1-hydroxy-7,7-dimethyl-3,6-dioxadodecane-11-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 57 (15 mg, two-step yield: 68%).1 H NMR (400 MHz, CDCl3) d 3.67 (ddt, J = 18.3, 13.6, 6.9 Hz, 7H), 3.49 (m, 2H), 1.98 (d, J=12.9Hz, 1H), 1.82 (s, 7H), 1.71 (dd, J = 14.8, 10.8 Hz, 2H), 1.58 (m, 2H),1.36 (m, 11H),1.17(s,6H), 1.11 (dd, J = 12.0, 6.4 Hz, 2H), 1.01 (t, J = 11.2Hz, 3H), 0.92 (d, J = 6.5 Hz, 3H),0.85(s, 3H), 0.67 (s, 3H) 19 F NMR (376 MHz, CDCl3) d -88.95, -89.58, -110.84, -111.47. LC-MS: [M+Na] + =551.65, tR= 5.802min.

[0352] Example 49

[0353] Preparation of compound 58 (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(11R)-1-hydroxy-4,4,7,7-tetramethyl-3,6-dioxadodecane-11-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0354] Step 1: Similar to Step 1 of Example 48, replace 9-3 with compound 13-1 to obtain [(1-{[(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-methylheptyl-2-yl]oxy}-2-methylpropyl-2-yl)oxy]ethyl acetate 58-1 (25 mg, yield: 54%).

[0355] Step 2: Dissolve 58-1 (25 mg, 0.03 mmol, 1 eq) in tetrahydrofuran (2 mL), and slowly add lithium aluminum hydride (3 mg, 0.09 mmol, 3 eq) at room temperature. After stirring for 1 h, monitor the reaction for completeness by TLC (petroleum ether: ethyl acetate = 1:1). Quenching was performed at room temperature with 100 mL of aqueous solution, followed by extraction with ethyl acetate (100 mL × 2). The organic phase was washed with saturated brine (50 mL) and evaporated to dryness to obtain crude product 2-[(1-{[(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-methylheptyl-2-yl]oxy}-2-methylprop-2-yl)oxy]eth-1-ol 58-2, which was directly added to the next step.

[0356] Step 3: Similar to Step 5 of Example 15, replace 9-5 with crude product 58-2 to obtain a white solid (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(11R)-1-hydroxy-4,4,7,7-tetramethyl-3,6-dioxadodecane-11-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 58 (15 mg, yield: 86%). 1 H NMR (400 MHz, CDCl3) d 3.63 (t, J = 10.7 Hz, 3H), 3.53 (m, 2H), 3.20 (s,2H), 1.98 (d, J =12.4 Hz, 1H), 1.84 (m, 6H), 1.74 (m, 3H), 1.56 (d, J= 17.6Hz, 2H), 1.36 (m, 11H), 1.16 (d, J =19.0 Hz, 14H), 1.01 (t, J = 12.0 Hz, 3H), 0.91 (d, J = 6.3 Hz, 3H), 0.85 (s, 3H), 0.67 (s, 3H). 19 F NMR (376 MHz, CDCl3) d -88.95, -89.58, -110.84, -111.47. LC-MS: [M+Na] + =579.6.

[0357] Example 50

[0358] Preparation of compound 64 (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(3-hydroxy-3-methylbut-2-yl)oxy]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0359] Step 1: Compound II (200 mg, 0.29 mmol) was added to a reaction flask containing dichloromethane (2 mL), followed by the sequential addition of rhodium dimer acetate (147 mg, 0.06 mmol) and ethyl 2-diazopropionate (28 mg, 0.22 mmol). The reaction was carried out at room temperature (25 °C). o C) Stir for 48 hours. 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, and evaporate the reaction solution to dryness under reduced pressure (water pump, 45). o C) Ethyl 2-{[(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-methylheptyl-2-yl]oxy}butyrate 64-1 (135 mg, 52.9%) was obtained as a white solid by column chromatography (petroleum ether:ethyl acetate = 80:20). 1 H NMR (400 MHz, CDCl3) δ 7.66 (m, 4H), 7.38 (m, 6H), 4.17 (dt, J = 7.2, 6.2 Hz, 2H), 4.08 (t, J = 6.9 Hz, 1H), 3.58 (s,1H), 1.94 (m, 1H), 1.78 (d, J = 11.0 Hz, 2H), 1.46 (m, 5H), 1.32 (d, J = 6.8Hz, 7H), 1.26 (d, J = 6.6 Hz, 13H), 1.13 (d, J = 5.0 Hz, 6H), 1.07 (s, 3H),1.04 (s, 10H), 0.89 (d, J = 6.4 Hz, 5H), 0.82 (s, 3H), 0.63 (s, 3H).

[0360] Step 2: Add 64-1 (135 mg, 0.17 mmol) to a reaction flask containing tetrahydrofuran (3 mL), and heat at 0°C. o Methylmagnesium bromide (207 mg, 1.73 mmol) was added at C, and the reaction was carried out at room temperature (25 °C). o C) Stir for 3 hours. 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, and evaporate the reaction solution to dryness under reduced pressure (water pump, 45). o C) The product was purified by column chromatography (petroleum ether:ethyl acetate = 90:10) to obtain 3-{[(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-methylhept-2-yl]oxy}-2-methylbut-2-ol 64-2 (110 mg, 66.4%) as a white solid. 1 H NMR(400 MHz, CDCl3) δ 7.66 (m, 4H), 7.39 (m, 6H), 3.59 (s, 1H), 3.44 (q, J = 6.3Hz, 1H), 1.94 (d, J = 12.3 Hz, 1H), 1.59 (m, 11H), 1.37 (m, 14H), 1.15 (d, J= 7.3 Hz, 8H), 1.09 (m, 6H), 1.04 (s, 11H), 0.89 (d, J = 6.5 Hz, 4H), 0.82(s, 3H), 0.64 (s, 3H).

[0361] Step 3: Similar to Step 5 of Example 15, replace 9-5 with 64-2 to obtain a white solid (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(3-hydroxy-3-methylbut-2-yl)oxy]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 64 (8 mg, 0.02 mmol, 58.1%). 1H NMR (400 MHz, CDCl3) δ 3.63 (s, 1H), 3.45 (q, J = 6.1 Hz, 1H), 1.99 (d, J= 13.1 Hz, 1H), 1.83 (s, 3H), 1.73 (d, J = 14.0 Hz, 3H), 1.59 (s, 6H), 1.33(m, 14H), 1.16 (d, J = 8.2 Hz, 9H), 1.09 (m, 7H), 0.92 (d, J = 6.5 Hz, 3H), 0.85 (s, 3H), 0.67 (s, 3H). 19 F NMR (376 MHz, CDCl3) δ -88.96, -89.59, -110.84, -111.47.

[0362] Example 51

[0363] Preparation of compound 65 (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(11R)-1-hydroxy-4,4,7,7-tetramethyl-3,6-dioxadodecane-11-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0364] Step 1: Add 3-A1 (130 mg, 0.23 mmol) to a reaction flask containing dichloromethane (5 mL), then add rhodium dimeracetate (20 mg, 0.01 mmol), followed by slow dropwise addition of ethyl diazonate (261 mg, 2.29 mmol). The reaction is carried out at room temperature (25 °C). oC) Stir for 0.5 hours. TLC monitoring showed that the reaction of the raw materials was complete. Dilute with water (20 mL), then add dichloromethane (20 mL). Extracted three times with 3 mL of the solution, then 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 65-1 mL of ethyl acetate [(1-{[(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]-2-methylhept-2-yl]oxy}-2-methylpropyl-2-yl)oxy]ethyl acetate. (100 mg, yield 40.1%) is a white solid. 1 H NMR (400 MHz, CDCl3) δ 4.18 (d, J = 6.3 Hz, 6H), 4.00 (s,2H), 1.83 (s, 3H), 1.56 (s, 7H), 1.40 (d, J = 11.2 Hz, 5H), 1.31 (s, 6H),1.29 (s, 10H), 1.28 (s, 5H), 1.20 (d, J = 8.4 Hz, 5H), 1.09 (d, J = 11.9 Hz, 9H), 0.91 (d, J = 6.4 Hz, 3H), 0.68 (s, 3H).

[0365] Step 2: Add 65-1 (200 mg, 0.31 mmol) to a reaction flask containing tetrahydrofuran (3 mL), then slowly add lithium aluminum hydride (58 mg, 1.53 mmol) in portions. The reaction is carried out at room temperature (25°C). o C) Stir for 1 hour. 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, and evaporate the reaction solution to dryness under reduced pressure (water pump, 45). oC) The white solid [(1-{[(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-cyclopentano[1',2':1,2]phenanthro[7,8-d][1,3]dioxacyclopentanthro-8-yl]-2-methylhept-2-yl]oxy}-2-methylpropyl-2-yl)oxy]ethyl acetate 65-2 (40 mg, yield 19.2%) was obtained by column chromatography (petroleum ether:ethyl acetate = 80:20). 1 H NMR (400MHz, CDCl3) δ 4.00 (s, 2H), 3.65 (m, 2H), 3.53 (m, 2H), 3.20 (s, 2H), 1.95(d, J = 12.2 Hz, 1H), 1.82 (s, 3H), 1.65 (s, 11H), 1.51 (s, 4H), 1.28 (m,10H), 1.18 (s, 7H), 1.14 (s, 7H), 1.07 (s, 3H), 0.91 (d, J = 6.4 Hz, 4H), 0.68 (s, 3H).

[0366] Step 3: Similar to Step 4 of Example 3, replace 3-1 with 65-2 to obtain a white solid (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(11R)-1-hydroxy-4,4,7,7-tetramethyl-3,6-dioxadodecane-11-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 65- (37 mg). 1 H NMR(400 MHz, CDCl3) δ 3.74 (s, 1H), 3.65 (m, 2H), 3.60 (m, 1H), 3.53 (m, 2H), 3.20 (s, 2H), 1.83 (d, J = 8.3 Hz, 4H), 1.30 (m, 15H), 1.18 (s, 7H), 1.14 (s,9H), 1.06 (s, 5H), 0.91 (d, J = 6.5 Hz, 4H), 0.67 (s, 3H). 19F NMR (376 MHz, CDCl3) δ -88.63, -89.25, -110.63, -111.25 LC-MS (ESI) [M+Na] + = 595.70.

[0367] Example 52

[0368] Preparation of compound 66 (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(11R)-1-hydroxy-7,7-dimethyl-3,6-dioxadodecane-11-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0369] Step 1: Similar to Step 1 of Example 51, replace compound 3-A1 with 6-1 to obtain a white solid [(2-{[(6R)-6-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecylhydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxacyclopentanthro-8-yl]-2-methylhept-2-yl]oxy}ethyl)oxy]ethyl acetate 66-1 (110 mg, yield 66.4%). 1 H NMR (400 MHz, CDCl3) δ 4.20 (d, J = 6.9 Hz, 2H), 4.17 (s, 2H), 4.00 (s, 2H), 3.68 (t, J = 5.2 Hz, 2H), 3.52 (t, J = 5.1 Hz, 2H), 1.95 (d, J= 13.5 Hz, 1H), 1.82 (s, 3H), 1.70 (d, J = 13.2 Hz, 1H), 1.53 (d, J = 15.2Hz, 12H), 1.28 (dt, J = 9.9, 6.4 Hz, 15H), 1.15 (s, 7H), 1.07 (s, 4H), 0.91(d, J = 6.4 (Hz, 4H), 0.68 (s, 3H).

[0370] Step 2: Similar to Step 2 of Example 51, replace compound 65-1 with 66-1 to obtain the white solid 2-[(2-{[(6R)-6-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecylhydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxacyclopentanthro-8-yl]-2-methylhept-2-yl]oxy}ethyl)oxy]eth-1-ol 66-2 (55 mg, yield 47.2%). 1 H NMR (400 MHz, CDCl3) δ 4.00 (s, 2H), 3.72 (m, 2H), 3.65 (dt, J = 8.5, 4.1 Hz, 4H), 3.49 (m, 2H), 1.98 (d, J = 13.1 Hz, 1H), 1.82(s, 3H), 1.59 (s, 7H), 1.51 (s, 4H), 1.35 (d, J = 16.9 Hz, 7H), 1.28 (m, 7H), 1.17 (s, 7H), 1.07 (s, 4H), 0.92 (d, J = 6.3 Hz, 4H), 0.68 (s, 3H).

[0371] Step 3: Similar to Step 4 of Example 3, replace 3-1 with 66-2 to obtain a white solid (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(11R)-1-hydroxy-7,7-dimethyl-3,6-dioxadodecane-11-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 66 (37 mg, 72.2%). 1 H NMR (400 MHz, CDCl3) δ 3.68 (m, 8H), 3.49 (m, 2H), 2.00 (m, 1H), 1.83(d, J = 7.3 Hz, 4H), 1.39 (m, 9H), 1.25 (s, 8H), 1.17 (s, 7H), 1.06 (s, 3H), 1.02 (d, J = 9.8 Hz, 2H), 0.92 (d, J = 6.6 Hz, 4H), 0.67 (s, 3H). 19F NMR (376MHz, CDCl3) δ -88.62, -89.25, -110.62, -111.25.

[0372] Example 53

[0373] Preparation of compound 67 (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(3-hydroxy-3-methylbutyl)oxy]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0374] Step 1: Dissolve compound 14 (100 mg, 0.2 mmol, 1 eq) in 10% sodium hydroxide aqueous solution (5 mL) and ethanol (5 mL), and heat to 85°C. o After overnight incubation at C, the reaction was monitored for completeness by TLC (petroleum ether: ethyl acetate = 1:1). The pH was adjusted to acidic by adding 3 N hydrochloric acid at room temperature, 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 = 1:1) to obtain 67-1 (60 mg, yield: 66%) of 3-{[(6R)-6-[(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-methylheptyl-2-yl]oxy}propionic acid. 1 HNMR (400 MHz, CDCl3) d 3.63 (m, 3H), 2.61 (t, J = 6.1 Hz, 2H), 1.99 (d, J =12.7 Hz, 1H), 1.77 (ddd, J = 16.3, 12.3, 8.1 Hz, 4H), 1.58 (m,3H), 1.34 (m,15H), 1.18 (d, J = 9.5 Hz, 6H), 1.04 (m, 4H), 0.89 (m, 7H), 0.67 (s, 3H).

[0375] Step 2: Dissolve 67-1 (60 mg, 0.1 mmol, 1 eq) in methanol (1 mL), and add thionyl chloride (55 mg, 0.5 mmol, 4 eq) at room temperature. After stirring at the same temperature for 15 minutes, monitor the reaction for completeness by TLC (petroleum ether: ethyl acetate = 1:1). Quenching was performed at room temperature with 100 mL of 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 crude product. Purification was achieved by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain methyl 3-{[(6R)-6-[(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-methylheptyl-2-yl]oxy}propionate 67-2 (45 mg, yield: 66%). 1 H NMR (400 MHz, CDCl3) d 3.62 (m, 6H), 2.53 (t, J = 6.6 Hz, 2H), 1.99 (d,J = 12.7 Hz, 1H), 1.75 (m, 4H), 1.59 (m, 3H), 1.37 (dd, J = 15.2, 9.4 Hz,6H), 1.25 (s, 9H), 1.13 (s, 7H), 1.01 (dd, J = 16.4, 8.2 Hz, 3H), 0.88 (m,7H), 0.67 (s, 3H).

[0376] Step 3: Dissolve 67-2 (15 mg, 0.03 mmol, 1 eq) in tetrahydrofuran (2 mL), and add methyl magnesium bromide (3 M tetrahydrofuran solution) (0.1 mL, 0.3 mmol, 10 eq) at room temperature. After stirring at the maintained temperature for 1 h, the reaction was monitored by TLC (petroleum ether: ethyl acetate = 5:1). The starting material disappeared and was completely converted to a new spot. The reaction was quenched by adding 100 mL of aqueous solution at room temperature, extracted with ethyl acetate (100 mL × 2), and the organic phase was washed with saturated brine (50 mL). The organic phase was evaporated to dryness to obtain crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give a white solid (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(3-hydroxy-3-methylbutyl)oxy]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 66 (10 mg, yield: 60%). 1H NMR (400 MHz, CDCl3) d 3.62 (m, 3H), 2.00 (s, 1H), 1.84 (m, 3H), 1.72 (m, 4H), 1.60 (dd, J= 29.2,15.1 Hz, 3H), 1.43 (m, 5H), 1.30 (m, 9H), 1.23 (s, 6H), 1.17 (s, 6H), 1.06 (m,5H), 0.91(d, J = 6.5 Hz, 3H), 0.85 (s, 3H), 0.66 (s, 3H). 19 F NMR (376 MHz, CDCl3) d -89.01, -89.64, -110.74, -111.37. LC-MS: [M+Na] + =545.6.

[0377] Example 54

[0378] Preparation of compound 68 2-{[(6R)-6-[(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-methylhept-2-yl]oxy}prop-1,3-diol

[0379] Step 1: Dissolve ethyl 3-ethoxy-3-oxomylidene propionate (1 g, 6 mmol, 1 eq) in acetonitrile (20 mL), add 4-acetamidobenzenesulfonyl azide (9 g, 37 mmol, 6 eq) at room temperature, and cool to 0°C. o C. 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (5.7 g, 37 mmol, 6 eq) was slowly added dropwise. After restoring to room temperature overnight, the reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 10:1). The organic phase was collected after filtration and 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 give ethyl 2-diazo-3-ethoxy-3-oxonylpropionate 68-0-1 (1 g, yield: 86%). 1 H NMR (400 MHz, CDCl3) d 4.31 (q, J = 7.1 Hz, 4H), 1.32 (t, J = 7.1 Hz, 6H).

[0380] Step 2: Similar to Step 1 of Example 50, replacing ethyl 2-diazo-3-ethoxy-3-oxylidene propionate 68-0-1 yields ethyl 3-ethoxy-2-{[(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-methylheptyl-2-yl]oxy}-3-oxylidene propionate 68-1 (30 mg, yield: 24%). 1 HNMR (400 MHz, CDCl3) d 7.59 (dd, J = 5.6, 1.4 Hz, 4H), 7.32 (m, 6H), 4.51 (s,1H), 4.17 (m, 4H), 3.51 (m, 1H), 1.86 (d, J = 12.7 Hz, 1H), 1.72 (d, J = 6.9Hz, 2H), 1.56 (d, J = 6.0 Hz, 4H), 1.40 (m, 7H), 1.28 (m, 4H), 1.20 (m, 10H), 1.11 (s, 6H), 0.97 (m, 12H), 0.89 (d, J = 6.6 Hz, 1H), 0.81 (d, J = 6.5 Hz, 4H), 0.75 (s, 3H), 0.69 (d, J = 3.6 Hz, 1H), 0.56 (s, 3H).

[0381] Step 3: Dissolve 68-1 (25 mg, 0.03 mmol, 1 eq) in tetrahydrofuran (2 mL), add lithium aluminum hydride (4 mg, 0.1 mmol, 3 eq) at room temperature, maintain the temperature and stir for 1 h, and monitor the reaction for completeness by TLC (petroleum ether: ethyl acetate = 1:1). Quenching was performed at room temperature with 100 mL of 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 crude product. Purification was achieved by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain 2-{[(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-methylheptyl-2-yl]oxy}prop-1,3-diol 68-2 (10 mg, yield: 44%).

[0382] Step 4: Similar to Step 5 of Example 15, replace 9-5 with 68-2 to obtain a white solid 2-{[(6R)-6-[(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-methylheptane-2-yl]oxy}prop-1,3-diol 68 (6 mg, yield: 85%). 1 H NMR (400MHz, CDCl3) d 3.66 (m, 6H), 2.00 (s, 1H), 1.82 (s, 5H), 1.60 (d, J = 13.7 Hz, 6H), 1.42 (dd, J = 17.8, 10.5 Hz, 6H), 1.31 (d, J =19.3 Hz, 5H), 1.19 (s, 6H), 1.10 (m, 2H), 1.01 (m, 3H), 0.92 (d, J = 6.5 Hz, 3H), 0.85 (s, 3H), 0.67 (s, 3H). 19 F NMR (376 MHz, CDCl3) d -88.97, -89.59, -110.84, -111.47. LC-MS: [MH] + =513.45.

[0383] Example 55

[0384] Preparation of compound 69 (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-1-[(2R)-6-[(2,3-dihydroxy-2-methylpropyl)oxy]-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0385] Step 1: At room temperature, dissolve starting material 41-1 (280 mg, 0.50 mmol) in dichloromethane (5 mL), and slowly add Dysmartin oxidant (535.1 mg, 1.25 mmol). The reaction mixture is reacted at room temperature under a nitrogen atmosphere for 1.5 hours. The reaction is stopped after complete TLC (petroleum ether: ethyl acetate = 3:1). The reaction is quenched with saturated sodium thiosulfate solution (10 mL), and extracted with dichloromethane (10 mL × 3). The organic phases are combined and washed with saturated brine (10 mL × 3). The organic phase is 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 = 90:10) to give product 1-{[(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]dioxacyclopentanthro-8-yl]-2-methylhept-2-yl]oxy}prop-2-one 69-1 (180 mg, 0.32 mmol, 64.5%). 1 HNMR(400MHz, CDCl3)δ 4.06 – 3.96 (m, 2H), 3.90 (s, 2H), 2.18 (d,J = 5.7Hz, 3H), 2.00 (s, 1H), 1.95 (d,J = 14.1 Hz, 1H), 1.88 – 1.73 (m, 3H), 1.71 – 1.55 (m, 4H), 1.51 (s,4H), 1.45 – 1.23 (m, 12H), 1.15 (d,J = 17.6Hz, 8H), 1.11 – 0.99 (m, 6H), 0.92(d,J = 6.5Hz, 5H), 0.68 (s, 3H).

[0386] Step 2: Trimethyl sulfoxide (239.9 mg, 1.08 mmol) was dissolved in tetrahydrofuran (5 mL) at room temperature, followed by the dropwise addition of potassium tert-butoxide (1.08 mL, 1.08 mmol) to the suspension. The reaction mixture was stirred under nitrogen protection for 0.5 hours. Then, 69-1 (120 mg, 0.21 mmol) was dissolved in a small amount of tetrahydrofuran and added dropwise to the above reaction mixture using a syringe. The reaction was continued at room temperature with stirring for 8 hours. The reaction was monitored for completeness by TLC (petroleum ether:ethyl acetate = 3:1). Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (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 (3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-8-[(2R)-6-methyl-6-{[(2-methyloxacycloprop-2-yl)methyl]oxy}hept-2-yl]-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]dioxacyclopentamin 69-2 (85 mg, 69.1%). 1 H NMR (400 MHz, CDCl3) δ 4.00 (s, 2H), 3.33 (dd, J = 25.9, 10.0 Hz, 2H), 2.75 (d, J = 5.0 Hz, 1H), 2.62 (d, J = 4.9 Hz,1H), 2.19 (s, 1H), 1.97(t, J = 12.8 Hz, 3H), 1.67 (dd, J = 21.1, 13.5 Hz, 4H), 1.51 (s, 5H), 1.46 –1.38 (m, 5H), 1.33 – 1.21(m, 13H), 1.17 – 1.08 (m, 11H), 0.92 (d, J = 6.4 Hz, 4H), 0.68 (s, 4H).

[0387] Step 3: Dissolve 69-2 (30 mg, 0.05 mmol) in dioxane (3 mL) at room temperature, then add 1 mL of 6 N sodium hydroxide aqueous solution dropwise to the reaction solution. The reaction solution is heated to 100°C. o The reaction mixture was stirred at C for 18 hours. The reaction was monitored for completeness by TLC (petroleum ether:ethyl acetate = 3:1). Water (10 mL) was added to the reaction mixture, 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 = 50:50) to give a white solid product 3-{[(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]dioxacyclopentanthro-8-yl]-2-methylhept-2-yl]oxy}-2-methylprop-1,2-diol 69-3 (17 mg, 54.9%). 1 HNMR(400MHz, CDCl3) δ 4.02 (d,J =15.4Hz, 2H), 3.65 (d,J = 11.1Hz, 1H), 3.44 (d,J = 11.1Hz, 1H), 3.38 (d,J =8.6Hz, 1H), 3.29 (d,J = 8.7Hz, 1H), 2.03 (ddd,J = 37.0, 30.8, 22.5Hz, 4H), 1.81 (t,J = 16.6Hz, 5H), 1.66 (dd,J = 34.6,13.6Hz, 3H), 1.51 (s, 3H), 1.31(t,J = 22.4Hz, 12H), 1.18 – 1.07 (m, 14H), 0.98 – 0.85 (m, 6H), 0.68 (s, 3H).

[0388] Step 4: Similar to Step 4 of Example 3, replace 3-1 with 69-3 to obtain a white solid (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-1-[(2R)-6-[(2,3-dihydroxy-2-methylpropyl)oxy]-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 69 (5 mg, 30.3%). 1 HNMR (400 MHz, CDCl3) δ 3.74 (s, 1H), 3.62 (dd, J = 18.4, 11.2 Hz, 2H), 3.43(d, J = 11.0 Hz, 1H), 3.38 (d, J = 8.8 Hz, 1H), 3.29 (d, J = 8.7Hz, 1H), 2.25(s, 1H), 1.98 (d, J = 12.6 Hz, 4H), 1.87 – 1.67 (m, 9H), 1.49 – 1.40 (m, 4H), 1.26 (s, 6H), 1.15 (s, 6H), 1.12 (s, 3H), 1.06 (s, 4H), 0.92 (d, J = 6.4 Hz, 4H), 0.67 (s, 3H). 19 F NMR (376 MHz, CDCl3) δ -88.63, -89.25, -110.61, -111.24.LC-MS: [MH] - =543.5.

[0389] Example 56

[0390] Compound 73 Preparation of (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-7-hydroxy-6-[(2-hydroxyethyl)oxy]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0391] Step 1: Compound 26-2 (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 carried out at room temperature (25°C). o C) Stir for 2 hours, monitoring completeness by TLC. Dilute with water (20 mL), then add dichloromethane (20 mL × 3), extract three times, wash with sodium chloride, dry to anhydrous sodium sulfate, and evaporate the reaction solution to dryness under reduced pressure (water pump, 45°C). o C) The product was purified 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]hepta-2-one 73-0-1 (100 mg, yield: 75.23%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.70 – 7.62 (m, 4H), 7.44 – 7.33 (m, 6H), 3.63 – 3.53 (m, 1H), 2.37(d, J = 8.1 Hz, 1H), 2.12 (s, 3H), 2.05 (s, 2H), 1.93 (d, J = 13.1 Hz, 1H), 1.80 (d, J = 7.4 Hz, 2H), 1.68 – 1.59 (m, 4H), 1.53 (s, 10H), 1.44 (d, J =8.4 Hz, 3H), 1.26 (dd, J = 8.4, 5.9 Hz, 4H), 1.04 (s, 10H), 0.90 (d, J = 6.5Hz, 3H), 0.82 (s, 3H), 0.63 (s, 3H).

[0392] Step 2: Add trimethyl sulfoxide (93.36 mg, 0.42 mmol, 3.5 eq) to a reaction flask containing tetrahydrofuran (2 mL), and heat at 0°C. o Sodium hydride (10.14 mg, 0.42 mmol, 3.5 eq) was added at C, and the mixture was stirred at room temperature for 30 min. Then, 73-O-1 (80 mg, 0.12 mmol, 1.0 eq) was added. The reaction was carried out at 40 °C. oC) After stirring for 16 hours, the reaction of the raw materials was confirmed to be complete by TLC monitoring. Water (20 mL) was added for dilution, followed by dichloromethane (20 mL × 3), and the mixture was extracted three times. The solution was then washed with sodium chloride, dried over anhydrous sodium sulfate, and the reaction mixture was evaporated to dryness under reduced pressure. The solution was purified by column chromatography (petroleum ether: ethyl acetate = 95:5) to obtain [(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 73-0 (35 mg, 38.56%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.66(m, 4H), 7.39 (ddd, J = 14.2, 7.7, 4.4 Hz, 6H), 3.58 (dd, J = 10.2, 5.5 Hz,1H), 2.57 (t, J = 7.2 Hz, 1H), 1.93 (d, J = 13.0 Hz, 1H), 1.79 (d, J = 10.7Hz, 2H), 1.63 (dd, J = 11.2, 4.7 Hz, 3H), 1.54 (s, 10H), 1.45 (m, 9H), 1.28(m, 6H), 1.04 (s, 10H), 0.90 (d, J = 6.5 Hz, 3H), 0.82 (s, 3H), 0.63 (s, 3H).

[0393] Step 3: Add 73-0 (70 mg, 0.10 mmol) to a reaction flask containing dioxane (2 mL) and water (0.5 mL), then add tetrabutylammonium hydrogen sulfate (7 mg, 0.02 mmol). React at 100 °C. o The mixture was stirred at C for 18 hours, and TLC monitoring confirmed that the reaction of the starting material was complete. 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 = 0:20) 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]-2-methylhept-1,2-diol 73-1 (32 mg, 40.2%) as a white solid.1 H NMR (400 MHz, CDCl3) δ 7.66 (d, J =3.8 Hz, 4H), 7.38 (m, 6H), 3.58 (s, 1H), 3.43 (dd, J = 23.7, 10.7 Hz, 2H), 2.05 (s, 1H), 1.93 (d, J = 12.9 Hz, 1H), 1.80 (d, J = 7.2 Hz, 2H), 1.63 (s,10H), 1.39 (d, J = 8.0 Hz, 6H), 1.26 (dd, J = 8.5, 5.8 Hz, 5H), 1.17 (s, 3H), 1.04 (s, 11H), 0.90 (d, J = 6.4 Hz, 4H), 0.82 (s, 3H), 0.62 (d, J = 12.2 Hz, 3H).

[0394] Step 4: Add 73-1 (35 mg, 0.08 mmol) to a reaction flask containing dichloromethane (2 mL), then add tert-butyldimethylchlorosilane (46 mg, 0.31 mmol) and imidazole (26 mg, 0.38 mmol). React at room temperature (25 °C). o C) Stir for 0.5 hours. TLC monitoring showed that the reaction of the raw materials was complete. Add water (20 mL) to dilute, then add dichloromethane (20 mL × 3), extract three times, wash with sodium chloride, dry with anhydrous sodium sulfate, and vortex the reaction solution under reduced pressure. 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-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2-methylhept-1,2-diol 73-2 (31 mg, 45.5%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 3.6 Hz, 4H), 7.38 (m, 6H), 3.58 (s, 1H), 3.41 (d, J = 9.2 Hz, 1H), 3.35 (d, J = 9.5 Hz, 1H), 1.93 (d, J = 12.1 Hz, 1H), 1.64 (s, 4H), 1.39 (d, J = 45.6 Hz, 10H), 1.27 (d,J = 13.1 Hz, 8H), 1.10 (s, 3H), 1.04 (s, 11H), 0.91 (d, J = 5.5 Hz, 15H),0.82 (s, 3H), 0.63 (s, 3H), 0.06 (s, 6H).

[0395] Step 5: Add 73-2 (30 mg, 0.04 mmol) to a reaction flask containing dichloromethane (1 mL), followed by the addition of rhodium dimeracetate (21 mg, 0.01 mmol) and ethyl diazonate (9.30 mg, 0.08 mmol). The reaction is carried out at room temperature (25°C). o C) Stirring for 0.5 hours, TLC monitoring showed that the reaction of the raw materials was complete. 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 subjected to vacuum vortexing and purified by column chromatography (petroleum ether: ethyl acetate = 80:20) to obtain ethyl acetate {[(10R)-10-[(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]-2,2,3,3,6-pentamethyl-4-oxa-3-silazane-6-yl]oxy}73-3 (15 mg, 40.7%) as a white solid.

[0396] Step 6: Add 73-3 (15 mg, 0.02 mmol) to a reaction flask containing tetrahydrofuran (2 mL), then add lithium aluminum hydride (1 mL, 1.00 mmol). React at room temperature (25°C). oC) Stir for 0.5 hours, and TLC monitoring showed that the reaction of the raw 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, and vortex the reaction solution under reduced pressure. Purify by column chromatography (petroleum ether: ethyl acetate = 90:10) to obtain 2-{[(10R)-10-[(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]-2,2,3,3,6-pentamethyl-4-oxa-3-silazane-1-yl]oxy}eth-1-ol 73-4 (5 mg, 28.0%) as a white solid. 1 H NMR (400MHz, CDCl3) δ 7.65 (s, 4H), 7.39 (dd, J = 16.3, 6.6 Hz, 6H), 3.65 (s, 2H), 3.59 (m, 1H), 3.48 (d, J = 11.8 Hz, 4H), 1.33 (s, 9H), 1.27 (d, J = 12.8 Hz,16H), 1.04 (s, 12H), 0.89 (s, 15H), 0.82 (s, 3H), 0.63 (s, 3H), 0.05 (s, 6H).

[0397] Step 6: Similar to step 5 of Example 15, replace 9-5 with 73-4 to obtain a pale yellow solid (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-7-hydroxy-6-[(2-hydroxyethyl)oxy]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol (2.9 mg, 93.03%). 1 H NMR (400MHz, CDCl3) δ 3.74 (m, 2H), 3.64 (d, J = 8.6 Hz, 1H), 3.48 (m, 4H), 1.98 (d,J = 12.6 Hz, 1H), 1.82 (s, 3H), 1.36 (m, 8H), 1.27 (d, J = 12.4 Hz, 14H), 1.16 (s, 4H), 0.92 (d, J = 6.6 Hz, 3H), 0.85 (s, 4H), 0.65 (d, J = 11.8 Hz, 3H). 19F NMR (376 MHz, CDCl3) δ -88.96, -89.59, -110.85, -111.47. LC-MS: [M+Na] + = 523.60.

[0398] Example 57

[0399] Preparation of compound 78 3-{[(6R)-6-[(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-methylhept-2-yl]oxy}prop-1,2-diol

[0400] Step 1: At room temperature, dissolve the compound trimethyl sulfoxide (613.2 mg, 2.77 mmol) in tetrahydrofuran (5 mL). o Sodium hydroxide (66.66 mg, 2.77 mmol) was added at C, and the mixture was stirred at room temperature for 1 hour under nitrogen protection. Compound 26-1 (200 mg, 0.277 mmol) was then added at room temperature, and the mixture was stirred at room temperature for 4 hours under nitrogen protection. The reaction of the starting material was monitored by TLC to ensure complete reaction. The reaction solution was quenched with water (10 mL), extracted with ethyl acetate (10 mL x 3), and 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 = 1:0-6:1) to obtain the product {[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(2R)-6-methyl-6-[(oxacycloprop-2-ylmethyl)oxy]hept-2-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-yl]oxy}(2-methylprop-2-yl)diphenylsilane 78-1 (30 mg, 14.71%) as a colorless oil. 1H NMR (400 MHz, CDCl3)δ 7.69 – 7.62 (m, 4H), 7.41 – 7.35 (m, 6H), 3.65 – 3.54 (m, 1H), 3.51 – 3.34(m, 2H), 3.09 (dt, J = 7.9, 3.9 Hz, 1H), 2.79 (t, J = 4.6 Hz, 1H), 2.60 (dd,J = 5.0, 2.6 Hz, 1H), 1.94 (d, J = 12.7 Hz, 1H), 1.80 (d, J = 6.8 Hz, 2H), 1.67 – 1.53 (m, 6H), 1.43 (t, J = 7.1 Hz, 4H), 1.39 – 1.31 (m, 5H), 1.25 (t,J = 14.6 Hz, 5H), 1.14 (s, 6H), 1.07 (s, 4H), 1.04 (s, 9H), 0.90 (d, J = 6.5Hz, 4H), 0.82 (s, 3H), 0.63 (s, 3H).

[0401] Step 2: At room temperature, dissolve 78-1 (20 mg, 0.027 mmol) in dioxane (0.5 mL) in a sealed tube, add sodium hydroxide (0.227 mL, 1.360 mmol) at room temperature, and heat to 105°C under nitrogen protection. o Stirred at C for 24 hours, the reaction mixture was monitored by TLC to indicate that the reaction was essentially complete. After cooling to room temperature, the reaction solution was quenched with saturated ammonium chloride solution (5 mL), extracted with ethyl acetate (10 mL x 3), and the organic phase was 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 3-{[(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-methylheptyl-2-yl]oxy}prop-1,2-diol 78-2 (10 mg, 48.80%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.71 – 7.61 (m, 4H), 7.45 –7.33 (m, 6H), 3.81 – 3.56 (m, 4H), 3.44 (ddd, J = 14.7, 9.1, 4.8 Hz, 2H), 1.94 (d, J = 12.8 Hz, 1H), 1.80 (d, J = 6.9 Hz, 3H), 1.60 (dd, J = 29.7, 10.1Hz, 8H), 1.50 – 1.42 (m, 4H), 1.40 – 1.31 (m, 6H), 1.29 – 1.22 (m, 5H), 1.15(s, 6H), 1.04(s, 9H), 0.89 (d, J = 6.5 Hz, 4H), 0.82 (s, 3H), 0.64 (s, 3H).

[0402] Step 3: At room temperature, similar to Step 5 of Example 15, but with 9-5 replaced by 78-2, to obtain the white solid product 3-{[(6R)-6-[(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-methylhept-2-yl]oxy}prop-1,2-diol (2 mg, 29.26%). 1 HNMR (400 MHz, CDCl3) δ 3.79 (d, J = 4.6 Hz, 1H), 3.73 – 3.64 (m, 2H), 3.45 (ddd, J = 14.7, 9.1, 4.9 Hz, 2H), 1.99 (d, J = 13.0 Hz, 2H), 1.83 (d, J = 7.4Hz, 3H), 1.76 – 1.69 (m, 3H), 1.60 (d, J = 13.5 Hz, 3H), 1.45 (dd, J = 11.2,4.3 Hz, 3H), 1.37 (s, 3H), 1.33 (s, 3H), 1.29 (s, 3H), 1.25 (s, 6H), 1.16 (s,5H), 1.01 (d, J = 3.1 Hz, 1H), 0.92 (d, J = 6.5 Hz, 3H), 0.85 (s, 3H), 0.67(s, 3H). 19F NMR (376 MHz, CDCl3) δ -88.95, -89.58, -110.82, -111.45.

[0403] Example 58

[0404] Preparation of compound 79 N-(2-{[(6R)-6-[(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]-2-methylhept-2-yl]oxy}ethyl)methanesulfonamide

[0405] Step 1: In a 50 mL round-bottom flask at room temperature, compound 15-2 (100 mg, 0.185 mmol) was dissolved in dichloromethane (3 mL). Methylsulfonyl chloride (63.66 mg, 0.556 mmol) and triethylamine (0.077 mL, 0.556 mmol) were added at 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC (ethyl acetate / petroleum ether = 1:3) to ensure complete reaction. After the reaction was complete, the reaction was quenched with water (10 mL), extracted with dichloromethane (10 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain a colorless oily product N-(2-{[(6R)-6-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecylhydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxane-8-yl]-2-methylhept-2-yl]oxy}ethyl)methanesulfonamide 79-1 (100 mg, 78.63%). 1H NMR (400 MHz, CDCl3) δ4.61 (s, 1H), 4.00 (s, 2H), 3.52 (d, J = 14.1 Hz, 3H), 3.46 (t, J = 4.9 Hz, 2H), 3.26 (t, J = 4.7 Hz, 2H), 2.98 (s, 3H), 1.97 (s, 2H), 1.83 (d, J = 6.8Hz, 4H), 1.61 (d, J = 13.3 Hz, 3H), 1.48 (d, J = 25.0 Hz, 6H), 1.38 – 1.28(m, 9H), 1.17 – 1.07 (m, 13H), 0.92 (d, J = 6.4 Hz, 4H), 0.68 (s, 3H).

[0406] Step 2: Similar to Step 4 of Example 3, replace 3-1 with 79-1 to obtain a white solid N-(2-{[(6R)-6-[(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]-2-methylhept-2-yl]oxy}ethyl)methanesulfonamide (50 mg, 0.082 mmol, 63.49%). 1 HNMR(400MHz, CDCl3) δ 4.64 (s, 1H), 3.74 (s, 1H), 3.67 – 3.57 (m,1H), 3.46 (t,J = 4.9Hz, 2H), 3.26 (d,J = 4.0Hz, 2H), 2.99 (d,J = 7.5Hz, 3H),2.36 – 2.12(m, 1H), 1.98 (d,J = 12.7Hz, 1H), 1.89 – 1.68 (m, 9H), 1.48 – 1.26(m, 10H), 1.18 – 1.00 (m, 13H), 0.98 – 0.88 (m, 4H), 0.66 (d,J = 7.5Hz, 3H). LC-MS: [MH] + =576.4.

[0407] Example 59

[0408] Preparation of compound 81 2-{[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-5-[(2-hydroxyethyl)oxy]-5-methylhex-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-yl]oxy} ethanol-1-ol

[0409] Step 1: Similar to Step 5 of Example 15, replace 9-5 with II-10 to obtain (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 81-0-1.

[0410] Step 2: Compound 81-0-1 (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. The reaction system was stirred at room temperature for 2 hours. The reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 3:1). Ethyl acetate (10 mL) was added to the reaction system, 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 81-0 (400 mg, yield 45%). 1 HNMR (400 MHz, CDCl3) δ3.63 (m, 0H), 1.98 (dt, J = 12.7, 3.3 Hz, 1H), 1.77 (m, 2H), 1.58 (m, 1H),1.44 (m, 3H), 1.30 (m, 2H), 1.20 (d, J = 1.7 Hz, 2H), 1.12 (m, 1H), 1.00 (m, 1H), 0.93 (t, J = 5.5 Hz, 1H), 0.83 (d, J = 10.6 Hz, 1H), 0.66 (d, J = 11.7Hz, 3H). 19F NMR (376 MHz, CDCl3) δ -88.97, -89.58, -110.82, -111.44.

[0411] Step 3: Similar to Step 1 of Example 41, replace 45-0 with 81-0 to obtain the product {[(5R)-5-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-7-[(2-ethoxy-2-oxoylideneethyl)oxy]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2-methylhexyl-2-yl]oxy}ethyl acetate 81-1 (65 mg, yield 46.39%).

[0412] Step 4: Similar to Step 2 of Example 41, replace 45-1 with 81-1 to obtain product 2-{[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-5-[(2-hydroxyethyl)oxy]-5-methylhex-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-yl]oxy}eth-1-ol 81 (40 mg, yield 69.05%). 1 HNMR (400 MHz, CDCl3) δ 3.74 – 3.66 (m, 4H), 3.60 – 3.55 (m, 2H), 3.45 – 3.40(m, 2H), 3.35 – 3.23 (m, 1H), 2.01 – 1.89 (m, 2H), 1.77 – 1.68 (m, 7H), 1.55 (ddd, J = 15.7, 10.6, 5.7 Hz, 2H), 1.49 – 1.37 (m, 5H), 1.35 – 1.23 (m, 5H), 1.12 (dd, J = 17.5, 6.3 Hz, 8H), 1.08 – 0.98 (m, 2H), 0.92 (d, J = 6.5 Hz,3H), 0.84 (s, 3H), 0.67 (s, 3H). 19 F NMR (376 MHz, CDCl3) δ -88.95, -89.58, -110.85, -111.48.

[0413] Example 60

[0414] Preparation of Compound 17 (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-(6-fluoro-2-methoxypyridin-3-yl)-6-[(2-hydroxy-2-methylpropyl)oxy]hex-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0415] Step 1: Dissolve I-12 (2.0 g, 4.3 mmol) in anhydrous dichloromethane (100 mL), add diisobutylaluminum hydride (8.6 mL, 1 mol / L, 2.0 eq), and react the solution at -70°C. o Stir in C for 2 hours. Monitor the reaction completion by TLC plate (petroleum ether: ethyl acetate = 5:1). Quench the reaction with water (50 mL), extract the aqueous phase with ethyl acetate (50 mL x 3), collect the organic phase, combine the organic phases, wash with saturated brine (40 mL), filter and concentrate to obtain 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]dioxane-8-yl]hexanal 17-0 (1.34 g, yield: 60%). 1H NMR (400 MHz, CDCl3) δ 9.76 (t, J = 1.7 Hz, 1H), 4.01 (dt, J = 8.4, 6.2 Hz, 2H), 2.40 (ddd, J = 12.8, 7.2, 1.8 Hz, 2H), 2.17 (s, 1H), 2.08 –1.92 (m, 3H), 1.84 (ddd, J = 17.9, 9.8, 4.6 Hz, 4H), 1.77– 1.65 (m, 3H), 1.64 – 1.57 (m, 2H), 1.55 (d, J = 10.6 Hz, 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 = 6.5 Hz, 4H), 0.68 (s, 3H).

[0416] Step 2: Dissolve 2,6-difluoropyridine (437 mg, 3.80 mmol) in tetrahydrofuran (10 mL), evacuate, and purge with nitrogen. After cooling to -78°C, add n-butyllithium and 2.5M hexane solution (1.4 mL, 3.45 mmol) dropwise, stirring for 30 minutes. Then, add a tetrahydrofuran solution of compound 17-0 (320 mg, 0.69 mmol) to the reaction flask. Stir the mixture at -78°C for 1 hour. Monitor the reaction for completeness by TLC (petroleum ether / ethyl acetate = 5 / 1). At low temperature, add saturated ammonium chloride aqueous solution (20 mL), extract with ethyl acetate (20 mL × 3), wash the organic phase with saturated brine (20 mL), and dry. Reduce the concentration by rotary evaporation. The product was purified by rapid chromatography (petroleum ether / ethyl acetate = 0-35%) to give (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecylhydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxacyclopentaman-8-yl]-1-(2,6-difluoropyridin-3-yl)hex-1-ol 17-1 (290 mg, yield: 61.8%) as a white solid. 1H NMR (400MHz, CDCl3) δ 8.02 (d,J = 8.0Hz, 1H), 6.85(dd,J = 8.1, 2.7Hz, 1H), 4.96 (d,J = 7.1Hz, 1H), 4.07 – 3.94 (m, 2H), 2.17(s, 1H), 1.99 (ddd,J = 22.7, 16.9, 5.2Hz, 3H), 1.87 – 1.79 (m,4H), 1.75 –1.66 (m, 4H), 1.61 (d,J = 13.9Hz, 3H), 1.50 (s, 3H), 1.47 – 1.32 (m, 6H),1.30 (s, 3H), 1.20 – 1.09 (m, 3H), 1.07 (s, 3H), 0.95 (dd,J = 17.2, 7.6Hz,2H), 0.90 (dd,J = 6.4, 2.5Hz, 3H), 0.66 (d,J = 11.8Hz, 3H). 19 F NMR (376 MHz, CDCl3) δ -70.66, -70.69, -70.73, -70.77, -72.95, -72.98, -89.00, -89.63, -109.55, -110.64, -111.37, -112.00.

[0417] Step 3: Dissolve 17-1 (210 mg, 0.36 mmol) in diethyl ether (7 mL), and add sodium methoxide (19.50 mg, 0.36 mmol) sequentially at room temperature. Stir the mixture at room temperature for 30 minutes, and monitor the reaction for completion by TLC (petroleum ether / ethyl acetate = 5 / 1). Quench the reaction mixture with an aqueous sodium sulfite solution (10 mL), extract with ethyl acetate (10 mL × 3), and dry the organic phase with anhydrous sodium sulfate. The crude product was purified by rapid chromatography (petroleum ether / ethyl acetate = 0-35%) to give (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecylhydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxacyclopentanthro-8-yl]-1-(6-fluoro-2-methoxypyridin-3-yl)hex-1-ol 17-2 (120 mg, yield: 47.6%) as a white solid. 1H NMR (400MHz, CDCl3) δ 7.70 (td, J = 8.0, 4.1 Hz, 1H), 6.48 (dd, J = 7.9, 2.7 Hz, 1H), 4.83 (dd, J = 7.8, 5.2 Hz, 1H), 4.01 (q, J =4.7 Hz, 2H), 3.96 (s, 3H), 2.17 – 2.02 (m, 1H), 1.94 (dd, J = 9.6, 4.6 Hz,2H), 1.86 – 1.79 (m, 5H), 1.73 – 1.58 (m, 10H), 1.51 (s, 3H), 1.46 – 1.33 (m,6H), 1.30 (s, 3H), 1.13 (dd, J = 14.4, 5.2 Hz, 2H), 1.07 (s, 3H), 0.96 (dd, J= 12.0, 8.7 Hz, 0H), 0.90 (dd, J = 6.4, 3.2 Hz, 3H), 0.67 (s, 3H). 19 F NMR (377 MHz, CDCl3) δ -73.27, -73.36, -89.00, -89.62, -111.36, -111.99.

[0418] Step 4: Dissolve 17-2 (120 mg, 0.20 mmol) in toluene (1 mL), add tert-butyl bromoacetate (87 mg, 0.45 mmol), tetrabutylammonium hydrogen sulfate (TBA) (15 mg, 0.05 mmol), and add 50% sodium hydroxide aqueous solution (1 mL, 0.20 mmol) dropwise at room temperature. Stir the mixture overnight at room temperature. Monitor the reaction for completeness by TLC (petroleum ether / ethyl acetate = 5 / 1). Add water (10 mL) to the reaction mixture, extract with ethyl acetate (10 mL × 3), wash with saturated sodium chloride aqueous solution (15 mL), dry the organic phase with anhydrous sodium sulfate, and evaporate to dryness. The crude product was purified by rapid chromatography (petroleum ether / ethyl acetate = 0-25%) 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 17-3 (115 mg, 0.14 mmol, yield: 68.3%) as a white solid. 1H NMR(400MHz, CDCl3) δ 7.76(s, 1H), 6.50 (dd, J = 8.0, 2.6 Hz, 1H), 4.70 (s, 1H), 4.05 – 3.98 (m, 2H), 3.92 (s, 3H), 3.80 (ddd, J = 43.3, 16.2, 1.2 Hz, 2H), 2.18 – 2.03 (m, 1H), 1.96 (s, 2H), 1.82 (d, J = 6.7 Hz, 5H), 1.73 – 1.57 (m, 5H), 1.54 (d, J = 7.8Hz, 4H), 1.50 (s, 3H), 1.48 (s, 2H), 1.45 (s, 9H), 1.43 – 1.31 (m, 5H), 1.30 (s, 3H), 1.10 (s, 2H), 1.07 (s, 3H), 0.90 – 0.86 (m, 3H), 0.66 (s, 3H).

[0419] Step 5: Dissolve 17-3 (75 mg, 0.11 mmol) in tetrahydrofuran (5 mL), and add methyl magnesium bromide solution (0.4 mL, 1.10 mmol) dropwise at 0 °C. Stir the mixture at room temperature for 1 hour. Monitor the reaction by TLC (petroleum ether / ethyl acetate = 5 / 1) until the reaction is complete. Add water (10 mL) to the reaction mixture, extract with ethyl acetate (10 mL × 2), dry the organic phase with anhydrous sodium sulfate, and evaporate to dryness. The crude product was purified by rapid chromatography (petroleum ether / ethyl acetate = 0-35%) to give 1-{[(5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecylhydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxacyclopentanthro-8-yl]-1-(6-fluoro-2-methoxypyridin-3-yl)hexyl]oxy}-2-methylprop-2-ol 17-4 (55 mg yield: 66.3%) as a white solid. 1H NMR (400MHz, CDCl3) δ 7.67 (t,J= 8.0Hz, 1H), 6.49 (dd,J = 7.9, 2.6Hz, 1H), 4.58 (s, 1H), 4.00 (d,J = 3.3Hz,2H), 3.93 (s, 4H), 3.19 – 3.06 (m, 2H), 2.16 (d,J = 9.2Hz, 1H), 1.96 (dd,J =12.3,9.5Hz, 2H), 1.83 (d,J = 4.2Hz, 5H), 1.65 (ddd,J = 17.5, 14.5, 3.8Hz,11H), 1.50 (s, 3H), 1.40 (dd,J = 32.7, 8.8Hz, 6H), 1.30 (s, 3H), 1.20 (d,J =8.9Hz, 6H), 1.07 (s, 3H), 0.90 – 0.87 (m, 3H), 0.67 (d,J= 2.7Hz, 3H). 19 F NMR (376 MHz, CDCl3) δ -73.19, -73.26, -88.99, -89.62, -111.36, -111.99.

[0420] Step 6: Similar to Step 4 of Example 3, replace 3-1 with 17-4 to obtain (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-(6-fluoro-2-methoxypyridin-3-yl)-6-[(2-hydroxy-2-methylpropyl)oxy]hex-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 17 (40 mg, yield: 75.74%) as a white solid. 1H NMR (400MHz, CDCl3) δ 7.67 (t, J = 8.1 Hz, 1H), 6.49(dd, J = 7.9, 2.7 Hz, 1H), 4.58 (dd, J = 7.3, 3.8 Hz, 1H), 3.93 (s, 3H), 3.74(s, 1H), 3.60 (dt, J = 11.2, 4.1 Hz, 1H), 3.12 (ddd, J = 10.6, 8.8, 2.6 Hz, 2H), 2.29 – 2.10 (m, 1H), 2.01 – 1.95 (m, 1H), 1.83 (dd, J = 20.4, 14.0 Hz,4H), 1.67 (td, J = 16.1, 5.6 Hz, 10H), 1.48 – 1.31 (m, 8H), 1.20 (d, J = 8.2Hz, 6H), 1.12 (d, J = 14.1 Hz, 2H), 1.06 (s, 3H), 0.89 (dd, J = 6.4, 4.4 Hz,3H), 0.66 (d, J = 2.8 Hz, 3H). 19 F NMR (377MHz, CDCl3) δ -73.21, -73.28, -88.64, -89.27, -110.63, -111.26.

[0421] Example 61

[0422] Compound 18 (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-(6-fluoro-2-methoxypyridin-3-yl)-6-[(2-hydroxyethyl)oxy]hex-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0423] Step 1: Compound 17-3 (30 mg, 0.04 mmol) was dissolved in tetrahydrofuran (5 mL), and lithium aluminum hydride (powder) (16 mg, 0.42 mmol) was slowly added at 0 °C. The mixture was stirred for another 20 minutes. The reaction was monitored by TLC (petroleum ether / ethyl acetate = 1 / 1) to ensure complete reaction. Add decahydrate and sodium sulfate solid to the reaction solution to quench the reaction, filter, collect the filtrate, and evaporate to dryness to obtain crude 2-{[(5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecylhydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxacyclopentanthro-8-yl]-1-(6-fluoro-2-methoxypyridin-3-yl)hexyl]oxy} ethylene-1-ol 18-1 (20 mg) as a white solid, which is directly added to the next step.

[0424] Step 2A: Similar to Step 4 of Example 3, replace 3-1 with 18-1, and purify to obtain (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-(6-fluoro-2-methoxypyridin-3-yl)-6-[(2-hydroxyethyl)oxy]hex-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 18 (11 mg, 0.02 mmol, purity: 97.3%, yield: 57.10%) as a white solid.

[0425] Compound 18: 1H NMR (400MHz, CDCl3) δ 7.70 (t, J = 8.1 Hz, 1H), 6.49 (dd,J = 8.0, 2.5 Hz, 1H), 4.63 – 4.55 (m, 1H), 3.92 (s, J = 6.8 Hz, 3H), 3.72(dd, J = 9.9, 5.6 Hz, 3H), 3.63 – 3.56 (m, 1H), 3.42 (d, J = 5.0 Hz, 2H), 2.28 – 2.12 (m, 1H), 1.97 (d, J = 12.6 Hz, 1H), 1.88 – 1.78 (m, 4H), 1.68 (s,10H), 1.45 – 1.29 (m, 8H), 1.10 (s, 2H), 1.06 (s, 3H), 0.91 – 0.86 (m, 3H), 0.66 (d, J = 1.9 Hz, 3H). 19 F NMR (377 MHz, CDCl3) δ -73.04, -73.13, -88.64, -89.26, -110.63, -111.26. LC-MS: [MH] - = 596.40.

[0426] Example 62

[0427] Preparation of compound 54 2-{[(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]-1-(6-fluoro-2-methoxypyridin-3-yl)hexyl]oxy}acetamide

[0428] Step 1: Compound 17-3 (65 mg, 0.09 mmol) was added to a reaction flask containing tetrahydrofuran (1.0 mL), water (0.5 mL), and methanol (0.5 mL), followed by lithium hydroxide (22 mg, 0.92 mmol). The reaction was carried out at 25°C. oThe mixture was stirred at C for 0.5 h, and TLC monitoring confirmed that the reaction of the raw materials was complete. Water (20 mL) was added for dilution, followed by the addition of dichloromethane (20 mL). Extracted three times (mL×3), then washed with sodium chloride, dried over anhydrous sodium sulfate, and the reaction solution was evaporated to dryness under reduced pressure. The solution was then purified by column chromatography (petroleum ether:ethyl acetate = 80:20) to obtain {[(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]-1-(6-fluoro-2-methoxypyridin-3-yl)hexyl]oxy}acetic acid 54-1 (40 (mg, 60.2%) is a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.68 (t, J = 8.1 Hz, 1H), 6.53 (dd, J = 8.0, 2.6 Hz, 1H), 4.72 (s,1H), 4.00 (s, 2H), 3.97 (s, 2H), 3.95 (s, 3H), 2.05 (s, 1H), 1.95 (s, 5H), 1.82 (s, 10H), 1.61 (d, J = 13.3 Hz, 3H), 1.29 (d, J = 8.0 Hz, 5H), 1.25 (m,4H), 1.07 (s, 5H), 0.88 (t, J = 6.2 Hz, 5H), 0.67 (s, 3H).

[0429] Step 2: Add 54-1 (40 mg, 0.06 mmol) to a reaction flask containing N,N-dimethylformamide (DMF) (2 mL), followed by ammonium chloride (7 mg, 0.12 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (47 mg, 0.12 mmol), and N,N-diisopropylethylamine (0.04 mL, 0.25 mmol). The reaction was carried out at room temperature (25 °C). oC) Stirring for 0.5 h, TLC monitoring showed that the reaction of the raw materials was complete. Dilute with water (20 mL), then add dichloromethane (20 mL). Extracted three times (mL×3), then washed with sodium chloride, dried over anhydrous sodium sulfate, and the reaction solution was evaporated to dryness under reduced pressure. The solution was then purified by column chromatography (petroleum ether:ethyl acetate = 70:30) to obtain 2-{[(5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecylhydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxacyclopentanthro-8-yl]-1-(6-fluoro-2-methoxypyridin-3-yl)hexyl]oxy}acetamide 54-2 (25 mg, 56.33%) is a colorless oily substance. 1 H NMR (400 MHz, CDCl3) δ 7.65 (t, J = 7.9 Hz, 1H), 6.58 (s, 1H), 6.51 (m,1H), 5.50 (s, 1H), 4.65 (s, 1H), 4.00 (s, 2H), 3.94 (s, 3H), 3.83 (s, 2H),2.05 (s, 2H), 1.82 (s, 5H), 1.68 (s, 7H), 1.51 (s, 5H), 1.30 (s, 5H), 1.25(m, 4H), 1.07 (s, 5H), 0.89 (m, 5H), 0.67 (s, 3H).

[0430] Step 3: Similar to Step 4 of Example 3, replace 3-1 with 54-2 to obtain 2-{[(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]-1-(6-fluoro-2-methoxypyridin-3-yl)hexyl]oxy}acetamide (16 mg, 0.025 mmol, 65.47%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.65 (t, J = 8.0 Hz, 1H), 6.58(s, 1H), 6.51 (dd, J = 8.0, 2.6 Hz, 1H), 5.52 (s, 1H), 4.65 (s, 1H), 3.94 (s,4H), 3.83 (s, 2H), 3.74 (s, 1H), 3.60 (m, 1H), 1.97 (d, J = 10.9 Hz, 1H), 1.82 (s, 4H), 1.71 (s, 10H), 1.36 (dd, J = 19.7, 7.9 Hz, 8H), 1.25 (s, 3H),1.06 (s, 4H), 0.88 (m, 4H), 0.66 (d, J = 1.7 Hz, 3H). 19 F NMR (376 MHz, CDCl3)δ -71.80, -71.89, -88.64, -89.26, -110.63, -111.26. LC-MS: [M+Na] + = 633.65.

[0431] Example 63

[0432] Synthesis of compound 83 (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(2R)-6-methyl-6-[(oxepylbut-2-ylmethyl)oxy]hept-2-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0433] Step 1: At room temperature, dissolve trimethyl sulfoxide (155 mg, 0.71 mmol) in tert-butanol (5 mL), slowly add potassium tert-butoxide solution (1 M tetrahydrofuran solution, 0.7 mL, 0.70 mmol), and stir for 10 min. Then add a tetrahydrofuran solution of compound 26-1 (80 mg, 0.11 mmol) (2 mL). The mixture is then heated at 60°C. oThe mixture was stirred in an oil bath for 16 hours. The reaction was monitored for completeness by TLC (petroleum ether:ethyl acetate = 10:1). The reaction solution 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, 0–10% ethyl acetate / petroleum ether, 20 mL / min) yielded a white solid {[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(2R)-6-methyl-6-[(oxacyclobut-2-ylmethyl)oxy]hept-2-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-yl]oxy}(2-methylpropyl-2-yl)diphenylsilane 81-1 (30 mg, yield 34.3%).

[0434] 1 H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 6.3 Hz, 4H), 7.37 – 7.27 (m,6H), 4.84 – 4.72 (m, 1H), 4.62 – 4.40 (m, 2H), 3.52 (dd, J = 15.3, 9.6 Hz,1H), 3.45 – 3.35 (m, 2H), 2.68 – 2.51 (m, 1H), 2.49 – 2.35 (m, 1H), 1.86 (d, J = 12.1 Hz, 1H), 1.80 – 1.63 (m, 5H), 1.49 (d, J = 13.5 Hz, 5H), 1.42 – 1.21(m, 14H), 1.15 (s, 2H), 1.09 (s, 6H), 0.97 (s, 9H), 0.82 (d, J = 6.4 Hz, 3H), 0.75 (s, 3H), 0.71 – 0.65 (m, 1H), 0.56 (s, 4H).

[0435] Step 2: Similar to Step 5 of Example 15, replace 9-5 with 81-1 to obtain a white solid (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(2R)-6-methyl-6-[(oxacyclobut-2-ylmethyl)oxy]hept-2-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol (19 mg, yield 68.4%). 1 H NMR (400 MHz, CDCl3) δ 4.87 (dd, J = 15.4, 8.3 Hz, 1H), 4.65 (dd, J = 15.0, 6.5 Hz, 1H), 4.56 (dt, J = 9.0, 6.0 Hz, 1H), 3.70 – 3.57 (m, 1H), 3.54 – 3.43 (m, 2H), 2.72 – 2.58 (m, 1H), 2.56 – 2.42 (m, 1H), 1.98 (d, J = 12.7 Hz, 1H), 1.87 –1.68 (m, 6H), 1.62 (dd, J = 16.3, 12.0 Hz, 2H), 1.49 – 1.21 (m, 14H), 1.16(d, J = 4.2 Hz, 6H), 1.13 – 0.97 (m, 5H), 0.92 (d, J = 6.5 Hz, 3H), 0.85 (s, 3H), 0.67 (s, 3H). 19 F NMR (376 MHz, CDCl3) δ -88.96, -89.59, -110.85, -111.48.LC-MS: [M+Na] + =533.55.

[0436] Example 64

[0437] Preparation of compound 85 (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(3-hydroxypropyl)oxy]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0438] Step 1: Dissolve compound 25 (90 mg, 0.2 mmol, 1 eq) in 10% sodium hydroxide aqueous solution (5 mL) and ethanol (5 mL), and heat to 85°C. o After overnight incubation at C, the reaction was monitored by TLC (petroleum ether:ethyl acetate = 1:1). The starting material disappeared, and all the reaction was converted to the new phase. The pH was adjusted to acidic by adding 3 N hydrochloric acid at room temperature, followed by extraction with ethyl acetate (100 mL × 2). The organic phase was then extracted with saturated brine (50 mL). Washed (mL), the organic phase was evaporated to dryness to obtain crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain 3-{[(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]dioxacyclopentanthro-8-yl]-2-methylhept-2-yl]oxy}propionic acid 85-1 (40 mg, yield: 43%). The crude product was directly used for the next step.

[0439] Step 2: Compound 85-1 (45 mg, 0.1 mmol, 1 eq) was dissolved in methanol (1 mL), and thionyl chloride (40 mg, 0.3 mmol, 4 eq) was added at room temperature. After stirring for 15 minutes while maintaining the temperature, the reaction was monitored by TLC (petroleum ether:ethyl acetate = 1:1). The starting material disappeared and was completely converted to the new spot. The reaction was quenched by adding 100 mL of aqueous solution at room temperature, and extracted with ethyl acetate (100 mL × 2). The organic phase was treated with saturated brine (50 mL). The product was washed with the organic phase (mL), dried by rotary evaporation to obtain a crude product, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give methyl 3-{[(6R)-6-[(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]-2-methylheptane-2-yl]oxy}propionate 85-2 (40 mg, yield: 93%). 1 H NMR (400 MHz, CDCl3) d3.73 (s, 1H), 3.68 (s, 3H), 3.59 (t, J = 6.6 Hz, 3H), 2.53 (t, J = 6.6 Hz, 2H), 2.19 (dd, J= 27.8, 6.5 Hz, 3H), 1.98 (d, J = 12.7 Hz, 1H), 1.77 (tdd, J = 19.1, 16.0,7.7 Hz, 7H), 1.39 (m, 12H), 1.13 (s, 7H), 1.06 (s, 3H), 1.00 (dd, J = 9.4,6.5 Hz, 2H), 0.91 (d, J = 6.4 Hz, 3H), 0.66 (d, J = 7.5 Hz, 3H).

[0440] Step 3: Compound 85-2 (45 mg, 0.1 mmol, 1 eq) was dissolved in tetrahydrofuran (2 mL), and lithium aluminum hydride (10 mg, 0.3 mmol, 3 eq) was added at room temperature. After stirring for 1 h, the reaction was monitored by TLC (petroleum ether: ethyl acetate = 5:1). The starting material disappeared and was completely converted to a new spot. The reaction was quenched by adding 100 mL of aqueous solution at room temperature, and extracted with ethyl acetate (100 mL × 2). The organic phase was treated with saturated brine (50 mL). Washed with (mL), the organic phase was evaporated to dryness to obtain crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(3-hydroxypropyl)oxy]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 85 (28 mg, yield: 65%). 1 H NMR (400 MHz, CDCl3) d 3.77 (dd, J = 12.1, 6.8Hz, 3H), 3.59 (m, 3H), 2.19 (m, 1H), 1.98(d, J = 12.8 Hz, 1H), 1.80 (m, 10H), 1.69 (dd, J =13.2, 7.6 Hz, 2H), 1.41 (m, 9H), 1.27 (m, 2H), 1.16(s, 6H), 1.06(s, 3H), 1.00 (m, 2H), 0.92 (d, J = 6.5 Hz, 4H), 0.66 (d, J = 7.5 Hz, 3H). 19FNMR (376 MHz, CDCl3) d -88.63, -89.25, -110.61, -111.24. LC-MS: [MH] + =513.55.

[0441] Example 65

[0442] Preparation of compound 86 (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(12R)-2-hydroxy-2,8,8-trimethyl-4,7-dioxatridecane-12-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0443] Step 1: Add compound 57-1 (90 mg, 0.11 mmol) to a reaction flask containing tetrahydrofuran (2 mL), then... o Magnesium methyl bromide (133 mg, 1.11 mmol) was added at C, and the reaction was carried out at room temperature (25 °C). o C) Stirring for 1 minute, TLC monitoring showed that the reaction of the raw materials was complete 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 evaporated to dryness under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate = 85:15) to obtain 1-[(2-{[(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-methylheptyl-2-yl]oxy}ethyl)oxy]-2-methylprop-2-ol 86-1 (52 mg, yield 52.9%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 6.8 Hz, 4H), 7.39 (dd, J =15.1, 6.8 Hz, 6H), 3.69 (s, 2H), 3.58 (s, 1H), 3.47 (s, 2H), 3.35 (s, 2H), 1.93 (d, J = 11.8 Hz, 1H), 1.79 (s, 2H), 1.42 (dd, J = 33.8, 17.1 Hz, 11H), 1.27 (d, J = 10.8 Hz, 10H), 1.17 (d, J = 11.3 Hz, 12H), 1.04 (s, 12H), 0.89(d, J = 6.5 Hz, 4H), 0.82 (s, 3H), 0.63 (s, 3H).

[0444] Step 2: Similar to Step 5 of Example 15, replace 9-5 with 86-1 to obtain a white solid (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(12R)-2-hydroxy-2,8,8-trimethyl-4,7-dioxatridecane-12-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol (27 mg, 0.05 mmol, 76.3%). 1 HNMR (400 MHz, CDCl3) δ 3.70 (m, 2H), 3.63 (d, J = 5.0 Hz, 1H), 3.48 (t, J =4.9 Hz, 2H), 3.35 (s, 2H), 1.98 (d, J = 12.2 Hz, 1H), 1.69 (s, 0.85 (s, 3H), 0.66 (s, 3H). 19 F NMR (376MHz, CDCl3) δ -88.96, -89.59, -110.84, -111.47. LC-MS (ESI) [M+Na] + = 579.65.

[0445] Example 66

[0446] Preparation of compound 89 (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(3-hydroxy-3-methylbutyl)oxy]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0447] Step 1: At room temperature, compound I (50 mg, 0.1 mmol), silver trifluoromethanesulfonate (TfOAg) (129 mg, 0.5 mmol), and 2,6-di-tert-butylpyridine (115 mg, 0.6 mmol) were dissolved in a reaction flask containing 1 mL of dichloromethane, followed by the addition of ethyl 3-bromopropionate (84.05 mg, 0.5 mmol). The reaction mixture was stirred at room temperature for 12 hours. TLC (petroleum ether:ethyl acetate = 5:1) showed that the starting material disappeared. The crude product was purified by rapid column chromatography (ethyl acetate / petroleum ether = 4:1) to obtain methyl 3-{[(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]dioxacyclopentanthro-8-yl]-2-methylhept-2-yl]oxy}propionate 89-1 (10 mg, yield: 15%). 1 H NMR (400 MHz, CDCl3) d3.95 (d, J = 3.5 Hz, 2H), 3.61 (s, 3H), 3.53 (t, J = 6.6 Hz, 2H), 2.46 (t, J = 6.6 Hz, 2H), 2.04 (m,1H), 1.90 (m, 1H), 1.77 (m, 5H), 1.64 (m, 1H), 1.55 (d, J = 14.0 Hz, 2H), 1.44 (s, 4H), 1.32 (m, 8H), 1.20 (m, 6H), 1.10 (d, J = 4.3 Hz, 1H), 1.07 (s, 6H), 1.02 (s, 3H), 0.89 (dd, J = 21.2, 15.0 Hz, 6H), 0.62 (s, 3H).

[0448] Step 2: Compound 89-1 (35 mg, 0.06 mmol, 1 eq) was dissolved in tetrahydrofuran (1 mL), and methyl magnesium bromide (3 tetrahydrofuran solution) (0.2 mL, 0.6 mmol, 10 eq) was added at room temperature. The mixture was stirred for 30 minutes and the reaction was monitored by TLC (petroleum ether: ethyl acetate = 1:1) 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) and evaporated to dryness to obtain crude product 4-{[(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]dioxanecyclopentanthro-8-yl]-2-methylhept-2-yl]oxy}-2-methylbut-2-ol 89-2(30 mg (yield: 77%), proceed directly to the next step.

[0449] Step 3: Similar to Step 4 of Example 3, replace 3-1 with 89-2 to obtain a white solid (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(3-hydroxy-3-methylbutyl)oxy]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol (25 mg, yield: 76.70%). 1 H NMR (400 MHz, CDCl3) d 3.74 (s, 1H), 3.60 (m, 3H), 2.20 (m, 1H), 1.96 (s, 1H), 1.83 (dd, J=14.4, 7.6 Hz, 4H), 1.70 (dt, J = 11.5, 5.5 Hz, 6H), 1.42 (m, 9H), 1.24 (d, J = 8.2 Hz, 9H), 1.15 (d, J = 12.1 Hz, 8H), 1.06 (s, 3H), 1.00 (m, 2H), 0.91 (d, J = 6.5 Hz, 3H), 0.66 (s, 3H). 19 F NMR (376 MHz, CDCl3) d -88.63, -89.25, -110.62, -111.25. LC-MS: [M+Na] + =565.65.

[0450] Example 67

[0451] Preparation of compound 90 (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(2R)-6-methyl-6-[(4,4,4-trifluoro-3-hydroxybutyl)oxy]hept-2-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0452] Step 1: Similar to Step 1 of Example 27, replace 9-3 with 88-2 to obtain 3-{[(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-methylhept-2-yl]oxy}propionaldehyde 90-1 (67 mg, 0.082 mmol, yield: 54.9%) as a colorless viscous oil. 1H NMR (400 MHz, CDCl3) δ 9.77 (t, J = 1.8Hz, 1H), 7.67 - 7.64 (m, 4H), 7.42 - 7.34 (m, 6H), 3.66 (t, J = 6.1 Hz, 2H), 3.63 - 3.55 (m, 1H), 2.58 (td, J = 6.1, 2.0 Hz, 2H), 1.95 - 1.91 (m, 1H), 1.85 - 1.75 (m, 2H), 1.69 - 1.59 (m, 6H), 1.40 - 1.26 (m, 16H), 1.14 (s, 6H),1.04 (s, 9H), 0.89 (d, J = 6.5 Hz, 6H), 0.82 (s, 3H), 0.64 (s, 3H).

[0453] Step 2: At room temperature, compound 90-1 (40 mg, 0.054 mmol) was dissolved in anhydrous tetrahydrofuran (1 mL), and trifluoromethyltrimethylsilyl (38.69 mg, 0.27 mmol) and tetrabutylammonium fluoride (71.14 mg, 0.27 mmol) were added. The reaction mixture was stirred at room temperature for 1 h. TLC (petroleum ether:ethyl acetate = 3:1) showed that a new spot was formed and the starting material was completely consumed. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by rapid column chromatography (ethyl acetate / petroleum ether = 1-30%) to give (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(2R)-6-methyl-6-[(4,4,4-trifluoro-3-hydroxybutyl)oxy]hept-2-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 90 (22.55 mg, yield: 73.1%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 4.18 - 4.10 (m, 1H), 3.74 - 3.69 (m, 1H), 3.67 - 3.54 (m, 2H), 2.02- 1.89 (m, 3H), 1.87 - 1.79 (m, 3H), 1.78 - 1.70 (m, 3H), 1.62 - 1.54 (m,3H), 1.49 - 1.24 (m, 14H), 1.17 (s, 6H), 1.14 - 1.10 (m, 1H), 1.05 - 0.98 (m,3H), 0.92 (d, J = 6.5 Hz, 3H), 0.85 (s, 3H), 0.67 (s, 3H). 19 F NMR (376 MHz, CDCl3) δ -79.73, -88.96, -89.59, -110.86, -111.49. LC-MS: [MH] - = 565.55.

[0454] Example 68

[0455] Preparation of compound 93 (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(12R)-2-hydroxy-8,8-dimethyl-4,7-dioxatridecane-12-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0456] Step 1: Add 57-2 (100 mg, 0.13 mmol) to a reaction flask containing dichloromethane (2 mL), and heat at 0°C. o Add Desmond-Martin oxidant (83 mg, 0.20 mmol) at C, and react at room temperature (25°C). oC) Stir for 2 h, and monitor the reaction until complete by TLC. Dilute with water (20 mL), then add dichloromethane (20 mL × 3), extract three times, wash with sodium chloride, dry with anhydrous sodium sulfate, and vortex the reaction solution under reduced pressure. Separate and purify by column chromatography (petroleum ether: ethyl acetate = 90:10) to obtain 2-[(2-{[(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-methylheptyl-2-yl]oxy}ethyl)oxy]acetaldehyde 93-1 (43 mg, 38.8%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ9.74 (s, 1H), 7.66 (dd, J = 6.0, 1.9 Hz, 4H), 7.40 (m, 6H), 4.16 (s, 2H), 3.68 (m, 2H), 3.59 (dd, J = 10.5, 5.4 Hz, 1H), 3.51 (dd, J = 10.1, 5.6 Hz, 2H), 1.93 (d, J = 12.5 Hz, 1H), 1.80 (d, J = 7.4 Hz, 2H), 1.63 (m, 4H), 1.45(s, 2H), 1.36 (dd, J = 21.1, 9.0 Hz, 8H), 1.25 (t, J = 12.2 Hz, 6H), 1.15 (d,J = 9.8 Hz, 7H), 1.05 (d, J = 10.7 Hz, 12H), 0.89 (d, J = 6.4 Hz, 4H), 0.82(s, 3H), 0.63 (s, 3H).

[0457] Step 2: Similar to steps 2-3 of Example 27, replace compound 26-1 with 93-1 to obtain (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(12R)-2-hydroxy-8,8-dimethyl-4,7-dioxatridecane-12-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol (9 mg, yield 61.5%) as a yellow oil.

[0458] Compound 93-2: 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 6.4 Hz, 4H), 7.38 (d, J = 7.0 Hz, 6H), 3.92 (s, 1H), 3.62 (m, 3H), 3.50 (s, 1H), 3.46 (m, 2H),1.94 (d, J = 13.1 Hz, 1H), 1.81 (s, 2H), 1.59 (m, 7H), 1.38 (s, 10H), 1.27(s, 8H), 1.14 (s, 7H), 1.05 (s, 11H), 0.91 (d, J = 6.2 Hz, 4H), 0.82 (s, 3H), 0.65 (s, 3H).

[0459] Compound 93: 1 H NMR (400 MHz, CDCl3) δ 3.96 (d, J = 6.4 Hz, 1H), 3.65 (m,3H), 3.55 (dd, J = 10.4, 2.8 Hz, 1H), 3.47 (t, J = 4.9 Hz, 2H), 3.25 (m, 1H),2.00 (s, 1H), 1.82 (s, 3H), 1.42 (d, J = 11.1 Hz, 6H), 1.27 (d, J = 12.2 Hz, 14H), 1.16 (s, 7H), 1.12 (d, J = 6.4 Hz, 5H), 0.92 (d, J = 6.5 Hz, 4H), 0.85(s, 3H), 0.67 (s, 3H). 19 F NMR (376 MHz, CDCl3) δ -88.96, -89.59, -110.84, -111.47. LC-MS: [M+Na] + = 565.65.

[0460] Example 69

[0461] Preparation of compound 95, 1-amino-N-(2-{[(6R)-6-[(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-methylhept-2-yl]oxy}ethyl)methaneamide

[0462] Step 1: At room temperature, compound 10⁻² (15 mg, 0.021 mmol) was dissolved in tetrahydrofuran (1 mL), followed by the addition of acetic acid (0.2 mL) and water (0.5 mL), then potassium cyanate (17 mg, 0.21 mmol), and the mixture was stirred at room temperature for 5 hours. The reaction was monitored for completeness by TLC (dichloromethane:methanol = 10:1). The reaction mixture was slowly added to 10 mL of water, extracted with ethyl acetate (15 mL x 2), and the combined organic phases were washed with saturated sodium bicarbonate solution (20 mL) and saturated brine solution (20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Separation by column chromatography (4 g, 0–40% ethyl acetate / petroleum ether, 20 mL / min) yielded a white solid 1-amino-N-(2-{[(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-methylheptyl-2-yl]oxy}ethyl)methaneamide 95-1 (14 mg, 88.1% yield). 1 H NMR(400 MHz, CDCl3) δ 7.71 – 7.60 (m, 4H), 7.47 – 7.31 (m, 6H), 3.62 – 3.55 (m,1H), 3.52 (s, 2H), 3.40 (s, 2H), 1.93 (d, J = 12.8 Hz, 1H), 1.79 (d, J = 6.8Hz, 2H), 1.68 – 1.57 (m, 4H), 1.50 – 1.23 (m, 19H), 1.17 (s, 6H), 1.10 – 1.06(m, 1H), 1.03 (s, 9H), 0.89 (d, J = 6.3 Hz, 3H), 0.82 (s, 3H), 0.78 – 0.72(m, 1H), 0.63 (s, 3H).

[0463] Step 2: Similar to Step 5 of Example 15, replace 9-5 with 10-3 to obtain a white solid 1-amino-N-(2-{[(6R)-6-[(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-methylhept-2-yl]oxy}ethyl)methaneamide (5.4 mg, yield 56.0%). 1 H NMR (400 MHz, CDCl3) δ 5.49 (d, J = 225.0 Hz, 2H), 3.68 – 3.58 (m,1H), 3.45 (t, J = 4.6 Hz, 2H), 3.34 (t, J = 4.6 Hz, 2H), 1.99 (d, J = 12.6Hz, 1H), 1.88 – 1.68 (m, 7H), 1.66 – 1.57 (m, 2H), 1.51 – 1.29 (m, 12H), 1.16(s, 6H), 1.15 – 0.96 (m, 6H), 0.92 (d, J = 6.5 Hz, 3H), 0.85 (s, 3H), 0.67(s, 3H). 19 F NMR (377 MHz, CDCl3) δ -88.95, -89.57, -110.83, -111.46. LC-MS: [M+Na] + =549.55.

[0464] Example 70

[0465] Preparation of Compound 96: 2-hydroxy-N-(2-{[(6R)-6-[(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-methylhept-2-yl]oxy}ethyl)ethanesulfonamide

[0466] Step 1: At room temperature, compound 57-2 (50 mg, 0.069 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (105 mg, 1.04 mmol) was added. The mixture was then cooled to 0°C in an ice bath. oC. Slowly add a solution of (chlorodioxymethylene-λ6-thio)methyl acetate (36 mg, 0.21 mmol) in 0.5 mL of dichloromethane. After 10 min, raise the temperature to room temperature and stir for 4 hours. Monitor the reaction for completeness using a TLC plate (dichloromethane:methanol = 10:1). Dilute the reaction solution with 20 mL of dichloromethane, wash successively with 20 mL of water and 20 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Separation by column chromatography (4 g, 0–10% ethyl acetate / petroleum ether, 20 mL / min) yielded a white solid {[(2-{[(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-methylheptyl-2-yl]oxy}ethyl)amino]dioxane-λ6-thio}methyl acetate 96-1 (35 mg, yield 56.0%). 1 H NMR (400 MHz, CDCl3) δ 7.70 – 7.63 (m,4H), 7.45 – 7.32 (m, 6H), 5.11 (s, 1H), 4.06 (s, 2H), 3.80 (s, 3H), 3.64 –3.54 (m, 1H), 3.45 (t, J = 4.9 Hz, 2H), 3.34 – 3.26 (m, 2H), 1.94 (d, J =12.6 Hz, 1H), 1.80 (d, J = 7.2 Hz, 2H), 1.70 – 1.56 (m, 4H), 1.35 (ddt, J =17.1, 14.3, 10.1 Hz, 18H), 1.13 (s, 6H), 1.08 (dd, J = 9.4, 4.7 Hz, 1H), 1.04(s, 9H), 1.02 – 0.98 (m, 1H), 0.90 (d, J = 6.5 Hz, 3H), 0.82 (s, 3H), 0.75(dd, J = 21.3, 8.2 Hz, 1H), 0.64 (s, 3H).

[0467] Step 2: At room temperature, dissolve 96-1 (25 mg, 0.029 mmol) in tetrahydrofuran (2 mL), cool to 0 °C in an ice bath, and then slowly add sodium borohydride (22 mg, 0.58 mmol). The mixture should be 70 mL in volume. o The reaction was heated in an oil bath for 1 hour. The reaction was monitored for completeness by TLC plate (petroleum ether: ethyl acetate = 3:1). The reaction solution was quenched by adding saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (15 mL x 2), the organic phases were combined and 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, 0–30% ethyl acetate / petroleum ether, 20 mL / min) yielded a white solid 2-hydroxy-N-(2-{[(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-methylheptyl-2-yl]oxy}ethyl)ethanesulfonamide 96-2 (20 mg yield 82.7%). 1 H NMR (400MHz, CDCl3) δ 7.68 – 7.64 (m, 4H), 7.44 – 7.34 (m, 6H), 4.67 (s, 1H), 4.08 –4.02 (m, 2H), 3.59 (s, 1H), 3.45 (s, 2H), 3.32 – 3.23 (m, 4H), 1.94 (d, J =13.0 Hz, 1H), 1.79 (s, 2H), 1.64 (d, J = 6.0 Hz, 5H), 1.52 – 1.27 (m, 17H), 1.14 (s, 6H), 1.06 (s, 1H), 1.04 (s, 9H), 1.02 – 0.98 (m, 1H), 0.90 (d, J =6.5 Hz, 3H), 0.82 (s, 3H), 0.75 (d, J = 9.3 Hz, 1H), 0.64 (s, 3H).

[0468] Step 3: Similar to Step 5 of Example 15, replace 9-5 with 10-3 to obtain a white solid 2-hydroxy-N-(2-{[(6R)-6-[(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-methylhept-2-yl]oxy}ethyl)ethanesulfonamide (9 mg, yield 63.1%). 1 H NMR (400 MHz, CDCl3) δ 4.69 (s, 1H), 4.08 – 4.03 (m, 2H), 3.68 –3.57 (m, 1H), 3.46 (t, J = 4.9 Hz, 2H), 3.32 – 3.25 (m, 4H), 1.99 (d, J =12.9 Hz, 1H), 1.87 – 1.69 (m, 7H), 1.60 (dd, J = 23.9, 10.3 Hz, 4H), 1.50 –1.34 (m, 10H), 1.15 (s, 6H), 1.13 – 0.96 (m, 6H), 0.92 (d, J = 6.5 Hz, 3H), 0.85 (s, 3H), 0.67 (s, 3H). 19 F NMR (376 MHz, CDCl3) δ -88.94, -89.57, -110.83, -111.46. LC-MS: [M+Na] + =614.60.

[0469] Example 98

[0470] Synthesis of Compound 98 (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-7-[(2-hydroxy-2-methylpropyl)oxy]-6,6-dimethylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-

[0471] Step 1: Dissolve 98-0 (200 mg, 0.3 mmol) in dichloromethane (3 mL), add rhodium dimer acetate (12 mg, 0.03 mmol) at room temperature, and then slowly add ethyl diazonate (300 mg, 3 mmol). Maintain the temperature and stir for 5 minutes. Monitor the reaction for completeness by TLC (petroleum ether: ethyl acetate = 10:1). 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), and evaporate the organic phase to dryness to obtain crude product. Purify by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain ethyl acetate {[(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-dimethylheptyl]oxy}98-1 (160 mg, yield: 64%).

[0472] Step 2: Dissolve 98-1 (90 mg, 0.1 mmol) in tetrahydrofuran (3 mL), add 3M methyl magnesium bromide (0.4 mL, 1.2 mmol) at room temperature, stir for 1 hour while maintaining the temperature, and monitor the reaction for completeness by TLC (petroleum ether: ethyl acetate = 5:1). 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 = 4:1) to give a white solid 1-{[(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]-2,2-dimethylheptyl]oxy}-2-methylprop-2-ol 98-2 (70 mg, yield: 71.3%).

[0473] Step 3: Similar to the synthesis of compound 9, replace 9-5 with 98-2 to obtain a white solid (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-7-[(2-hydroxy-2-methylpropyl)oxy]-6,6-dimethylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 98 (40 mg, yield: 66%). 1 H NMR (400 MHz, CDCl3) d3.63 (t, J = 4.9 Hz, 1H), 3.22 (s, 2H), 3.14 (s, 2H), 1.98 (d, J = 12.7Hz, 1H), 1.77 (m, 9H), 1.53 (m, 5H), 1.32 (m,6H), 1.20 (s, 6H), 1.07 (ddd, J = 37.1, 16.7, 7.9Hz, 7H), 0.89 (dd, J = 18.3, 10.2 Hz, 12H), 0.66 (s, 3H). 19 F NMR (376 MHz, CDCl3) d -88.96, -89.59, -110.85, -111.48. LC-MS: [MH] + =525.70.

[0474] Example 99

[0475] Synthesis of compound 99 (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-7-[(2-hydroxyethyl)oxy]-6,6-dimethylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0476] Step 1: Dissolve 98-1 (90 mg, 0.1 mmol) in tetrahydrofuran (3 mL), add lithium aluminum hydride (11 mg, 0.3 mmol) at room temperature, and stir for 1 h while maintaining the temperature. Monitor the reaction for completeness by TLC (petroleum ether: ethyl acetate = 5:1). Quenching with 100 mL of water at room temperature, extraction with ethyl acetate (100 mL × 2), washing the organic phase with saturated brine (50 mL), drying to anhydrous sodium sulfate, and purification by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) yielded a white solid 2-{[(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-dimethylheptyl]oxy}eth-1-ol 99-1 (80 mg, yield: 93.9%).

[0477] Step 2: Similar to the synthesis of compound 9, replace 9-5 with 99-1 to obtain (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-7-[(2-hydroxyethyl)oxy]-6,6-dimethylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 99 (40 mg, yield: 66%). 1 H NMR (400 MHz, CDCl3) d 3.72 (m, 2H), 3.63 (m, 1H), 3.52 (m, 2H), 3.14 (s, 2H), 1.99 (d, J = 12.6Hz, 1H), 1.83 (d, J = 7.5 Hz, 3H), 1.71 (m,4H), 1.59 (m, 2H), 1.45 (m, 3H), 1.31 (dt, J = 27.8, 13.6 Hz, 8H), 1.08 (ddd, J = 37.6, 19.8, 10.9 Hz, 7H), 0.89 (m, 12H), 0.67 (s, 3H). 19 F NMR (376 MHz, CDCl3) d -88.96, -89.59, -110.85, -111.47. LC-MS: [MH] + =497.80.

[0478] Example 100

[0479] Synthesis of compound 100 (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-1-[(2R)-6-[(3-ethyl-3-hydroxypentyl)oxy]-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0480] Step 1: At room temperature, intermediate II (650 mg, 0.96 mmol), silver trifluoroacetate (TfOAg) (737.83 mg, 2.87 mmol), and 2,6-di-tert-butylpyridine (915.61 mg, 4.79 mmol) were dissolved in a reaction flask containing 15 mL of dichloromethane, followed by the addition of ethyl 3-bromopropionate (519.85 mg, 2.87 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction was monitored for completeness by TLC (petroleum ether:ethyl acetate = 10:1). The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by rapid column chromatography (ethyl acetate / petroleum ether = 1-10%) to obtain methyl 3-{[(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-methylheptyl-2-yl]oxy}propionate 100-0 (200 mg, yield: 24.1%) as a colorless viscous oil.

[0481] Step 2: Similar to the synthesis of compound 98-2, replacing methyl magnesium bromide with ethyl magnesium bromide yields the crude product 3-ethyl-1-{[(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-methylhept-2-yl]oxy}pentan-3-ol 100-1 (50 mg).

[0482] Step 3: Similar to the synthesis of compound 9, replace 9-5 with 100-1 to obtain (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-1-[(2R)-6-[(3-ethyl-3-hydroxypentyl)oxy]-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 100 (18.98 mg) as a white solid. 1 H NMR (400 MHz, CDCl3) d3.68 – 3.58 (m, 1H), 3.56 (t, J = 5.8 Hz, 2H), 2.01 – 1.96 (m, 1H), 1.87 – 1.79 (m, 3H), 1.77 – 1.74 (m, 2H), 1.69 (t, J = 5.8 Hz, 3H), 1.63 –1.56 (m, 2H), 1.56 – 1.45 (m, 6H), 1.44 – 1.43 (m, 1H), 1.41 – 1.39 (m, 2H), 1.37 – 1.32 (m, 5H), 1.29 – 1.22 (m, 3H), 1.16 (s, 7H), 1.13 – 1.08 (m, 2H), 1.07 – 0.95 (m, 4H), 0.92 (d, J = 6.5 Hz, 3H), 0.88 – 0.82 (m, 10H), 0.66 (s, 3H). 19 F NMR (376 MHz, CDCl3) d -88.96, -89.58, -110.85, -111.48.

[0483] Example 101

[0484] Compound 101 Synthesis of (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-1-[(2R)-6-[(2-cyclobutyl-2-hydroxyethyl)oxy]-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0485] Step 2: Similar to the synthesis of compound 26-2, methyl magnesium bromide was replaced with cyclobutyl magnesium bromide to obtain the product 1-cyclobutyl-2-{[(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-methylheptyl-2-yl]oxy}eth-1-ol 101-1 (45 mg, 52.2%) 1H NMR (400 MHz, CDCl3) δ 7.68 – 7.65 (m,4H), 7.39 (ddd,J = 15.5, 7.4, 1.7 Hz, 6H), 3.63 – 3.54 (m, 2H), 3.27 (s, 1H), 3.09– 2.98 (m, 1H), 2.36 (dd,J = 15.2, 7.7Hz, 1H), 2.01 – 1.92 (m, 3H), 1.83– 1.77 (m, 4H), 1.68 – 1.56 (m, 7H), 1.44 (dd,J = 21.2,12.5Hz, 6H), 1.37 –1.23 (m, 11H), 1.12 (s, 6H), 1.04 (s, 11H), 0.89 (d,J = 6.6Hz, 4H), 0.82 (s,3H), 0.64 (s,3H).

[0486] Step 3: Similar to the synthesis of compound 9, replace 9-5 with 101-1 to obtain product (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-1-[(2R)-6-[(2-cyclobutyl-2-hydroxyethyl)oxy]-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 101 (15 mg, 48.08%). 1H NMR (400 MHz, CDCl3) δ 3.62 (dd, J = 10.5, 6.4 Hz, 2H), 3.30 – 3.26 (m, 1H), 3.08 – 3.01(m, 1H), 2.37 (dd, J = 15.0, 7.8 Hz, 1H), 1.95 (ddd, J = 11.9, 10.4, 7.5 Hz,4H), 1.87 – 1.74 (m, 7H), 1.68 – 1.51 (m, 8H), 1.44 (dd, J = 14.2, 7.7 Hz,5H), 1.36 – 1.27 (m, 6H), 1.13 (s, 6H), 1.05 – 0.97 (m, 4H), 0.92 (d, J = 6.5Hz, 3H), 0.85 (s, 3H), 0.67 (s, 3H).19F NMR (376 MHz, CDCl3) δ -88.96, -89.59, -110.85, -111.48. LC-MS [MH] - =537.4.

[0487] Example 102

[0488] Synthesis of Compound 102 2-[(2-{[(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-methylheptyl-2-yl]oxy}ethyl)oxy]acetamide

[0489] Step 1: Compound 57-1 (90 mg, 0.11 mmol) was added to a reaction flask containing tetrahydrofuran (1 mL), methanol (1 mL), and water (0.5 mL), followed by lithium hydroxide (14 mg, 0.57 mmol). The reaction was carried out at room temperature (25 °C). o C) Stir for 0.5 hours, and monitor the reaction for completeness by TLC (petroleum ether: ethyl acetate = 4:1). 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). oC) The product was purified by column chromatography (petroleum ether: ethyl acetate = 80:20) to obtain [(2-{[(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-methylheptyl-2-yl]oxy}ethyl)oxy]acetic acid 102-1 (90 mg, 81.4%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 5.4 Hz,4H), 7.39 (dd, J = 14.6, 6.5 Hz, 6H), 4.13 (s, 2H), 3.74 (s, 2H), 3.58 (m,1H), 3.52 (s, 2H), 1.92 (s, 1H), 1.78 (s, 1H), 1.64 (s, 3H), 1.33 (s, 4H), 1.25 (s, 12H), 1.21 (s, 8H), 1.04 (s, 11H), 0.89 (d, J = 6.9 Hz, 5H), 0.82(s, 4H), 0.64(s, 3H).

[0490] Step 2: Add 102-1 (80 mg, 0.10 mmol) to a reaction flask containing N,N-dimethylformamide (2 mL), then add ammonium chloride (11 mg, 0.205 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (78 mg, 0.21 mmol), and N,N-diisopropylethylamine (0.07 mL, 0.41 mmol). The reaction is carried out at room temperature (25 °C). o C) Stir for 0.5 hours, and monitor the reaction by TLC (dichloromethane:methanol = 20:1). 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). oC) The 2-[(2-{[(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-methylheptyl-2-yl]oxy}ethyl)oxy]acetamide 102-2 (60 mg, 67.6%) was obtained as a colorless oil by column chromatography (dichloromethane:methanol = 90:10). 1 H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 5.5Hz, 4H), 7.38 (m, 6H), 4.01 (s, 2H), 3.59 (s, 1H), 3.48 (m, 2H), 2.04 (s,1H), 1.93 (d, J = 12.5 Hz, 1H), 1.71 (s, 6H), 1.45 (s, 4H), 1.35 (s, 5H), 1.26 (dd, J = 8.3, 6.1 Hz, 8H), 1.16 (s, 7H), 1.04 (s, 12H), 0.89 (d, J = 6.5Hz, 4H), 0.82 (s, 3H), 0.64 (s, 3H).

[0491] Step 4: Similar to the synthesis of compound 9, replace 9-5 with 102-2 to obtain 2-[(2-{[(6R)-6-[(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-methylhept-2-yl]oxy}ethyl)oxy]acetamide 102 (37 mg, 84.6%) as a white solid. 1HNMR (400 MHz, CDCl3) δ 7.54 (d, J = 16.0 Hz, 1H), 5.57 (s, 1H), 4.01 (s, 2H), 3.67 (dd, J = 5.4, 3.4 Hz, 2H), 3.62 (dd, J = 10.3, 5.5 Hz, 1H), 3.50 (dd, J= 5.3, 3.4 Hz, 2H), 1.98 (m, 1H), 1.83 (d, J = 8.0 Hz, 3H), 1.73 (m, 8H), 1.60 (d, J = 13.7 Hz, 3H), 1.43 (dd, J = 12.1, 6.7 Hz, 3H), 1.34 (dd, J =16.4, 8.2 Hz, 6H), 1.17 (s, 7H), 1.02 (d, J = 10.5 Hz, 3H), 0.92 (d, J = 6.5Hz, 3H), 0.85 (s, 3H), 0.67 (s, 3H). 19 F NMR (377 MHz, CDCl3) δ -88.95, -89.58,-110.83, -111.46.LC-MS (ESI) [MH] + = 541.39.

[0492] Example 103

[0493] Synthesis of compound 103 (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-1-[(2R)-6-[(2-ethyl-2-hydroxybutyl)oxy]-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0494] Step 1: Similar to the synthesis of compound 13-1, replacing methyl magnesium bromide with ethyl magnesium bromide yields 3-({[(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-methylhept-2-yl]oxy}methyl)pentan-3-ol 103-0 (50 mg, 44.2%), a white solid. 1H NMR (400 MHz, CDCl3) δ 7.66 (m, 4H), 7.39 (dd, J = 14.6, 6.7 Hz, 6H), 3.59 (s, 1H), 3.13 (s, 2H), 1.94 (d, J =12.6 Hz, 1H), 1.79 (s, 2H), 1.62 (m, 7H), 1.49 (m, 8H), 1.35 (m, 5H), 1.27(d, J = 10.4 Hz, 5H), 1.12 (s, 6H), 1.04 (s, 11H), 0.88 (m, 6H), 0.85 (s,3H), 0.83 (d, J = 4.2 Hz, 5H), 0.64 (s, 3H).

[0495] Step 2: Similar to the synthesis of compound 9, replace 9-5 with 103-0 to obtain (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-1-[(2R)-6-[(2-ethyl-2-hydroxybutyl)oxy]-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 103 (25 mg, 0.05 mmol, 72.1%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 3.63 (m, 1H), 3.14 (s, 2H), 1.99 (d, J = 12.5 Hz,1H), 1.83 (d, J = 7.5 Hz, 3H), 1.74 (m, 4H), 1.48 (ddd, J = 14.1, 9.3,3.9 Hz,8H), 1.34 (m, 7H), 1.25 (s, 5H), 1.13 (s, 7H), 1.01 (d, J = 3.8 Hz, 3H), 0.91(d, J = 6.6 Hz, 3H), 0.86 (dd, J = 9.9, 5.1 Hz, 9H), 0.67 (s, 3H). 19 F NMR (377MHz, CDCl3) δ -88.96, -89.59, -110.85, -111.48.

[0496] Example 104

[0497] Synthesis of Compound 104: 1-[(2-hydroxyethyl)amino]-N-(2-{[(6R)-6-[(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-methylhept-2-yl]oxy}ethyl)methaneamide

[0498] Step 1: At room temperature, dissolve compound 2-{[dimethyl(2-methylprop-2-yl)methsilyl]oxy}eth-1-amine 104-0 (500 mg, 2.85 mmol) in dichloromethane (8 mL), add triethylamine (866 mg, 8.55 mmol), and cool to 0°C in an ice bath. o C. Slowly add a 2 mL solution of dichloromethane (575 mg, 2.85 mmol) of 4-nitrophenyl chloromethane. After 10 min, raise the temperature to room temperature and stir for 4 hours. Dilute the reaction solution with 20 mL of dichloromethane, wash successively with 20 mL of water and 20 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Separate by column chromatography (12 g, 0–20% ethyl acetate / petroleum ether, 30 mL / min) to obtain a white solid [(4,4,5,5-tetramethyl-3-oxa-4-silazhex-1-yl)amino]4-nitrophenyl methane ester 104-1 (240 mg, yield 23.5%). 1 H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 9.1 Hz, 2H), 7.32 (d, J = 9.1 Hz, 2H), 5.45 (s, 1H), 3.76 (t, J = 5.1 Hz, 2H), 3.41 (dd, J = 10.6, 5.5 Hz, 2H), 0.93 (s, 9H), 0.10 (s, 6H).

[0499] Step 2: At room temperature, dissolve 10⁻² (40 mg, 0.055 mmol) in dichloromethane (3 mL), add triethylamine (56 mg, 0.55 mmol), and cool to 0°C in an ice bath. oAt C, slowly add 10⁴⁻¹ (37 mg, 0.11 mmol) of dichloromethane (0.5 mL) solution dropwise. After 10 min, raise the temperature to room temperature and stir for 3 hours. Dilute the reaction solution with dichloromethane (20 mL), wash successively with water (20 mL) and saturated saline (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Separation by column chromatography (4 g, 0–40% ethyl acetate / petroleum ether, 30 mL / min) yielded a white solid N-(2-{[(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-methylheptyl-2-yl]oxy}ethyl)-1-[(4,4,5,5-tetramethyl-3-oxa-4-silazhex-1-yl)amino]methaneamide 104-2 (40 mg, yield 78.2%). 1 H NMR (400 MHz, CDCl3) δ 7.66 (dd, J = 9.8, 4.4 Hz, 4H), 7.46 – 7.32 (m, 6H), 3.81– 3.66 (m, 2H), 3.50 (dt, J = 47.5, 17.7 Hz, 7H), 1.93 (d, J = 11.8 Hz, 2H), 1.80 (dd, J = 26.2, 14.8 Hz, 6H), 1.66 (d, J = 10.0 Hz, 8H), 1.56 – 1.51 (m,4H), 1.48 – 1.43 (m, 4H), 1.37 – 1.32 (m, 4H), 1.19 (s, 6H), 1.04 (s, 9H), 0.90 (s, 12H), 0.82 (s, 3H), 0.64 (s, 3H), 0.08 (d, J = 8.9 Hz, 6H).

[0500] Step 5: Similar to the synthesis of compound 9, replace 9-5 with 104-2 to obtain a white solid 1-[(2-hydroxyethyl)amino]-N-(2-{[(6R)-6-[(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-methylhept-2-yl]oxy}ethyl)methaneamide 104 (17 mg, yield 68.8%). 1 H NMR (400 MHz, CDCl3) δ 3.80 – 3.70 (m, 2H), 3.63 (s, 1H), 3.47 (t, J = 4.6 Hz, 2H), 3.37 (dd, J = 10.6, 5.9 Hz, 4H), 1.99 (d, J = 12.7Hz, 1H), 1.88 – 1.61 (m, 8H), 1.37 (ddd, J = 33.0, 24.9, 11.1 Hz, 13H), 1.18(s, 6H), 1.08 (ddd, J = 30.4, 10.9, 3.7 Hz, 6H), 0.92 (d, J = 6.5 Hz, 3H), 0.85 (s, 3H), 0.67 (s, 3H). 19 F NMR (377 MHz, CDCl3) δ -88.94, -89.57, -110.83, -111.46.LC-MS: [M+Na] + =593.65.

[0501] Example 105

[0502] Synthesis of compound 105 (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-1-[(2R)-6-[(2-ethyl-2-hydroxybutyl)oxy]-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0503] Step 1 is similar to the synthesis of compound 3-A1. Methyl magnesium bromide is replaced with ethyl magnesium bromide to obtain a white solid 3-({[(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]phenanthrene[7,8-d][1,3]dioxane-8-yl]-2-methylhept-2-yl]oxy}methyl)pentan-3-ol 105-1 (50 mg, 21.97%). 1 H NMR (400 MHz, CDCl3) δ 4.07 – 3.94 (m, 2H), 3.14 (s, 2H), 2.05 – 1.96 (m, 2H), 1.87 – 1.62 (m, 10H), 1.54 – 1.47 (m, 8H), 1.36 – 1.26 (m,10H), 1.18 – 1.04 (m, 12H), 0.95 – 0.85 (m, 12H), 0.68 (s, 3H).

[0504] Step 2: Similar to the synthesis of compound 3, replace 3-1 with 105-1 to obtain a white solid (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-1-[(2R)-6-[(2-ethyl-2-hydroxybutyl)oxy]-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 105 (25 mg, 52.5%). 1 HNMR(400MHz, CDCl3) δ 3.74 (s, 1H), 3.63-3.58 (m, 1H), 3.14 (s, 2H), 2.30 – 1.95 (m, 2H), 1.88 – 1.69 (m, 10H), 1.52 – 1.44 (m, 5H), 1.38-1.28 (m, 8H), 1.15-1.04 (d,J = 27.1Hz, 12H), 0.98-0.91 (m, 5H), 0.86 (t,J = 7.5Hz, 6H), 0.67 (s,3H).

[0505] Example 106

[0506] Synthesis of compound 106 (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(12R)-2-hydroxy-2,8,8-trimethyl-4,7-dioxatridecane-12-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0507] Step 1 is similar to the synthesis of compound 3-A1, but 3-A0 is replaced with compound 66-1 to obtain the crude product 1-[(2-{[(6R)-6-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecylhydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxacyclopentanthro-8-yl]-2-methylhept-2-yl]oxy}ethyl)oxy]-2-methylprop-2-ol 106-1 (100 mg) as a white solid.

[0508] Step 2: Similar to the synthesis of compound 3, replacing 3-1 with 106-1 yields (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(12R)-2-hydroxy-2,8,8-trimethyl-4,7-dioxatridecane-12-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 106 (46.85 mg, yield: 50.1%) as a white solid. 1 H NMR (400 MHz, CDCl3) d3.77 – 3.72 (m, 1H), 3.72 – 3.66 (m, 2H), 3.64 –3.57 (m, 1H), 3.52 – 3.45 (m, 2H), 3.35 (s, 2H), 2.06 – 1.96 (m, 6H), 1.86 –1.78 (m, 8H), 1.77 – 1.66 (m, 3H), 1.47 – 1.39 (m, 4H), 1.38 – 1.33 (m, 4H), 1.30 – 1.24 (m, 3H), 1.19 (s, 6H), 1.16 (s, 6H), 1.14 – 1.08 (m, 2H), 1.06(s, 3H), 1.04 – 0.94 (m, 3H), 0.91 (d, J = 6.5 Hz, 3H), 0.65 (d, J = 7.7 Hz, 3H). 19 F NMR (377 MHz, CDCl3) d -88.62, -89.25, -110.62, -111.24. LCMS (ESI)[MH] + =571.55.

[0509] Example 107

[0510] Synthesis of compound 107 (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(2-hydroxyethyl)amino]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0511] Step 1: At room temperature, dissolve II (250 mg, 0.37 mmol) in anhydrous toluene (5 mL). Under nitrogen protection, add a toluene solution (0.5 mL) of azidotrimethylsilane (127 mg, 1.10 mmol), followed by the slow addition of a toluene solution (0.5 mL) of boron trifluoride diethyl ether (157 mg, 1.10 mmol). Incubate the mixture at 30°C. oThe mixture was stirred in an oil bath for 16 hours. The reaction was monitored for completeness by TLC (petroleum ether: ethyl acetate = 3:1). 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, 0–5% ethyl acetate / petroleum ether, 20 mL / min) yielded {[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-1-[(2R)-6-azido-6-methylhept-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-yl]oxy}(2-methylpropyl-2-yl)diphenylsilane 107-0 (230 mg, yield 84.3%). 1 H NMR (400 MHz, CDCl3) δ 7.70 – 7.61 (m, 4H), 7.46 –7.31 (m, 6H), 3.58 (d, J = 5.2 Hz, 1H), 1.94 (d, J = 12.5 Hz, 1H), 1.79 (s,2H), 1.69 – 1.57 (m, 4H), 1.53 – 1.25 (m, 15H), 1.24 (s, 6H), 1.20 (s, 2H), 1.07 (d, J = 16.0 Hz, 2H), 1.04 (s, 9H), 1.02 – 0.98 (m, 1H), 0.90 (d, J =6.5 Hz, 3H), 0.82 (s, 3H), 0.75 (d, J = 13.7 Hz, 1H), 0.64 (s, 3H).

[0512] Step 2: At room temperature, 107-0 (230 mg, 0.33 mmol) was dissolved in methanol (5 mL) and ethyl acetate (8 mL), and Pd / C (100 mg, 10%) was added. The mixture was purged three times with hydrogen balloons and then stirred at room temperature for 1 hour. The reaction was monitored for completeness by TLC plate (petroleum ether: ethyl acetate = 30:1). 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 give 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]-2-methylhept-2-amine 107-1 (200 mg, yield 90.3%). 1 H NMR (400 MHz, CDCl3) δ 8.31 (s, 2H), 7.66 (d, J = 7.7 Hz, 4H), 7.48– 7.30 (m, 6H), 3.65 – 3.50 (m, 1H), 1.91 (d, J = 9.6 Hz, 1H), 1.83 – 1.42(m, 19H), 1.38 (s, 6H), 1.33 – 1.28 (m, 3H), 1.21 – 1.15 (m, 2H), 1.04 (s,9H), 1.03 – 0.98 (m, 2H), 0.89 (d, J = 6.3 Hz, 3H), 0.81 (s, 3H), 0.74 (dd, J = 18.5, 7.2 Hz, 1H), 0.61 (s, 3H).

[0513] Step 3: At room temperature, 107-1 (180 mg, 0.27 mmol) was dissolved in dichloromethane (3 mL), and tetraphenylporphyrin iron (20 mg, 0.028 mmol) was added. Under nitrogen protection, ethyl diazonium acetate (31 mg, 0.27 mmol) was slowly added dropwise, generating a large number of bubbles. The mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 3:1). Water (20 mL) was added to the reaction solution, and the solution was concentrated to remove dichloromethane. The solution was extracted with ethyl acetate (20 mL x 2), and the combined organic phases were washed with saturated brine (30 mL). The solution was 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 a light brown 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]-2-methylhept-2-yl]amino}ethyl acetate 107-2 (120 mg, yield 56.2%). 1 H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 6.9 Hz, 4H), 7.47 – 7.31 (m, 6H), 6.24 (s,1H), 4.35 – 4.29 (m, 2H), 3.59 (s, 1H), 3.43 (s, 2H), 1.93 (d, J = 13.0 Hz,1H), 1.78 (s, 2H), 1.60 (dd, J = 29.7, 10.1 Hz, 7H), 1.48 – 1.32 (m, 20H), 1.25 (s, 6H), 1.04 (s, 9H), 0.89 (d, J = 6.3 Hz, 3H), 0.82 (s, 3H), 0.77 (s,1H), 0.63 (s, 3H).

[0514] Step 4: At room temperature, dissolve 107-2 (45 mg, 0.059 mmol) in tetrahydrofuran (2 mL) and ethanol (1 mL), then add sodium borohydride (25 mg, 0.66 mmol). The mixture is then heated at 45°C. oThe mixture was stirred in a heated pan for 16 hours. The reaction was monitored for completeness using a TLC plate (petroleum ether: ethyl acetate = 3:1). The reaction solution was quenched with saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (15 mL x 2), and 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. Separation by column chromatography (4 g, 0–30% ethyl acetate / petroleum ether, 20 mL / min) yielded a white solid 2-{[(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-methylhept-2-yl]amino} ethanol 107-3 (40 mg, 90.0%). 1 H NMR (400 MHz, CDCl3) δ 8.86(s, 1H), 7.66 (dd, J = 8.8, 3.3 Hz, 4H), 7.39 (dt, J = 14.5, 8.8 Hz, 6H), 4.03 – 3.95 (m, 2H), 3.60 (dd, J = 16.9, 10.5 Hz, 1H), 3.11 – 3.00 (m, 2H), 1.92 (d, J = 9.1 Hz, 1H), 1.83 – 1.68 (m, 7H), 1.57 – 1.47 (m, 6H), 1.44 (s, 6H), 1.42 – 1.16 (m, 13H), 1.04 (s, 9H), 0.90 (d, J = 6.4 Hz, 3H), 0.82 (s,3H), 0.76 (dd, J = 15.5, 8.9 Hz, 1H), 0.63 (s, 3H).

[0515] Step 5: Similar to the synthesis of compound 9, replace 9-5 with 107-3 to obtain a white solid (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(2-hydroxyethyl)amino]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 107 (16 mg, yield 57.8%). 1H NMR (400 MHz, MeOD) δ 3.81 – 3.74 (m, 2H), 3.57 – 3.48 (m, 1H), 3.09 – 3.01 (m, 2H), 2.03(d, J = 12.4 Hz, 1H), 1.92 – 1.68 (m, 7H), 1.67 – 1.36 (m, 13H), 1.33 (s, 6H), 1.29 – 1.21 (m, 3H), 1.14 (t, J = 10.6 Hz, 3H), 1.06 – 1.01 (m, 1H), 0.98 (d, J = 6.5 Hz, 3H), 0.87 (s, 3H), 0.72 (s, 3H). 19 F NMR (376 MHz, MeOD) δ-89.93, -90.56, -112.29, -112.92. LC-MS: [M+H] + =484.55.

[0516] Example 108

[0517] Synthesis of Compound 108: 1-[(2-hydroxyethyl)amino]-N-[(6R)-6-[(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-methylhept-2-yl]methaneamide

[0518] Step 1: At room temperature, dissolve 107-1 (35 mg, 0.052 mmol) in dichloromethane (2 mL), add triethylamine (52 mg, 0.52 mmol), and cool to 0°C in an ice bath. oC. Slowly add a solution of [(4,4,5,5-tetramethyl-3-oxa-4-silazhex-1-yl)amino]methane-4-nitrophenyl ester (35 mg, 0.10 mmol) in 0.5 mL of dichloromethane. After 10 min, raise the temperature to room temperature and stir for 3 hours. Monitor the reaction for completeness using a TLC plate (dichloromethane:methanol = 10:1). Dilute the reaction solution with 20 mL of dichloromethane, wash successively with 20 mL of water and 20 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Separation by column chromatography (4 g, 0–50% ethyl acetate / petroleum ether, 20 mL / min) yielded a white solid N-[(6R)-6-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-7-{[(2-methylpropyl-2-yl)diphenylsilyl]oxy}hexadecyl-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-2-methylhept-2-yl]-1-[(4,4,5,5-tetramethyl-3-oxa-4-silazhex-1-yl)amino]methaneyl108-0 (40 mg, 83.7%). 1 H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 7.0 Hz, 4H), 7.46 – 7.32 (m,6H), 3.82 – 3.71 (m, 3H), 3.65 – 3.52 (m, 1H), 3.44 – 3.32 (m, 3H), 1.93 (d, J = 9.9 Hz, 1H), 1.79 (dd, J = 18.8, 12.4 Hz, 2H), 1.52 (ddd, J = 35.4, 34.5,18.1 Hz, 16H), 1.34 (s, 6H), 1.21 (ddd, J = 48.5, 24.8, 13.6 Hz, 8H), 1.04(s, 9H), 0.93 (s, 9H), 0.89 (d, J = 6.4 Hz, 3H), 0.82 (s, 3H), 0.78 – 0.70 (m, 1H), 0.63 (s, 3H), 0.09 (d, J = 13.2 Hz, 6H).

[0519] Step 2: Similar to the synthesis of compound 9, replace 9-5 with 108-0 to obtain a white solid 1-[(2-hydroxyethyl)amino]-N-[(6R)-6-[(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-methylhept-2-yl]methaneamide 108 (14 mg, yield 58.4%). 1 H NMR (400 MHz, MeOD) δ 3.52 (dt, J = 13.9, 6.5 Hz, 3H), 3.17 (t, J =5.6 Hz, 2H), 2.02 (d, J = 12.7 Hz, 1H), 1.70 (ddd, J = 53.2, 38.1, 13.2 Hz,11H), 1.38 (ddd, J = 35.5, 18.9, 11.0 Hz, 11H), 1.24 (s, 6H), 1.17 – 1.00 (m,5H), 0.95 (d, J = 6.5 Hz, 3H), 0.87 (s, 3H), 0.70 (s, 3H). 19 F NMR (376 MHz, CDCl3) -89.92, -90.56, -112.28, -112.91. LC-MS: [MH] - =525.50.

[0520] Example 109

[0521] Synthesis of compound 109 (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(2-hydroxybutyl)oxy]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0522] Step 1: Similar to the synthesis of compound 41-1, replace methyl magnesium bromide with ethyl magnesium bromide to obtain a white solid 1-{[(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]-2-methylhept-2-yl]oxy}but-2-ol 109-1 (40 mg, 72%). 1 H NMR (400 MHz, CDCl3) δ 4.09 – 3.96 (m, 2H), 3.62 (dd, J = 14.6, 6.4Hz, 1H), 3.40 – 3.31 (m, 1H), 3.13 (t, J = 8.4 Hz, 1H), 2.20 – 1.93 (m, 3H), 1.88 – 1.58 (m, 11H), 1.52 – 1.30 (m, 16H), 1.18 – 1.07 (m, 11H), 0.95 (dt, J= 15.1, 7.1 Hz, 8H), 0.67 (d, J = 8.0 Hz, 3H).

[0523] Step 2: Similar to the synthesis of compound 3, replace 3-1 with 109-1 to obtain a white solid (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(2-hydroxybutyl)oxy]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 109 (25.4 mg, 54%). 1 H NMR (400 MHz, CDCl3) δ 3.74 (s, 1H), 3.65 – 3.56 (m, 2H), 3.36-3.33 (m, 1H), 3.13 (t, J =8.4 Hz, 1H), 2.36 – 2.11 (m, 1H), 1.95 – 1.70 (m, 11H), 1.49 – 1.27 (m, 13H), 1.16 – 1.06 (m, 11H), 1.00 – 0.90 (m, 7H), 0.66 (d, J = 7.7 Hz, 3H).LC-MS:[MH]+=527.50.

[0524] Example 110

[0525] Synthesis of compound 110 25-[(2-cyclopropyl-2-hydroxyethyl)oxy]-7,7-difluoro-5α-cholesterol-3β,4β-diol

[0526] Step 1: Similar to the synthesis of compound 41-1, replace methyl magnesium bromide with cyclopropyl magnesium bromide to obtain a white solid 1-cyclopropyl-2-{[(6R)-6-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-11,11-difluoro-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecylhydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxacyclopentaman-8-yl]-2-methylhept-2-yl]oxy} ethylene-1-ol 110-0 (50 mg, 52.17%). 1 H NMR (400 MHz, CDCl3) δ 4.01 (dt, J = 8.3, 6.1 Hz, 2H), 3.79(ddd, J = 44.5, 32.4, 18.4 Hz, 2H), 3.48 – 3.41 (m, 1H), 3.28 (t, J = 8.5 Hz, 1H), 2.98 (td, J = 8.3, 3.0 Hz, 1H), 2.00 – 1.83 (m, 6H), 1.66 – 1.49 (m,10H), 1.41 – 1.27 (m, 10H), 1.17 – 1.06 (m, 12H), 0.89 (dd, J = 19.7, 5.2 Hz, 5H), 0.67 (d, J = 8.0 Hz, 3H), 0.56 – 0.35 (m, 3H), 0.20 (dd, J = 9.5, 4.5Hz, 1H).

[0527] Step 2: Similar to the synthesis of compound 3, replace 3-1 with 110-0 to obtain the white solid 25-[(2-cyclopropyl-2-hydroxyethyl)oxy]-7,7-difluoro-5α-cholest-3β,4β-diol 110 (26 mg, 50.96%). 1 H NMR (400 MHz, CDCl3) δ 3.74 (s, 1H), 3.64 – 3.56 (m, 1H), 3.47-3.42 (m, 1H), 3.28 (t, J =8.6 Hz, 1H), 2.98 (td, J = 8.4, 3.0 Hz, 1H), 2.36 – 2.12 (m, 1H), 1.93 – 1.68(m, 11H), 1.48 – 1.27 (m, 11H), 1.17 – 1.05 (m, 11H), 0.96 – 0.83 (m, 5H),0.66 (d, J = 7.7 Hz, 3H), 0.57 – 0.36 (m, 3H), 0.20 (td, J = 9.3, 4.8 Hz,1H). LC-MS: [MH]+=539.5.

[0528] Example 111

[0529] Synthesis of Compound 111: 7,7-Difluoro-24-{2,2,2-trifluoro-1-[(2-hydroxy-2-methylpropyl)oxy]ethyl}-5α-cholan-3β-ol

[0530] Step 1: Dissolve II-15 (2.5 g, 1.0 eq) in tetrahydrofuran (20 mL), add lithium aluminum hydride (0.42 g, 11.05 mmol, 3 eq), and stir the reaction mixture at room temperature for 1 hour. Monitor the reaction for completion using a TLC plate (petroleum ether:ethyl acetate = 5:1). Add water (10 mL) to the reaction mixture, and extract the aqueous layer with ethyl acetate (3 × 25 mL). Combine the ethyl acetate layers and wash with saturated brine (3 × 10 mL). Dry the ethyl acetate layer with anhydrous sodium sulfate, filter, and concentrate 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 111-0 (1.7 g, yield 72%). 1 HNMR(400MHz, CDCl3) δ 7.70 – 7.62 (m, 4H), 7.45 – 7.33 (m, 6H), 3.63 (s, 3H), 1.93 (d,J = 12.7Hz, 1H), 1.81 (d,J = 9.4Hz,2H), 1.68 – 1.60 (m, 3H), 1.54 (s,7H), 1.38 (ddd,J = 23.8, 18.6, 8.6Hz, 8H), 1.25 (d,J = 7.1Hz, 5H), 0.90 (d,J= 6.5Hz, 4H), 0.82 (s,4H), 0.63 (s, 3H)

[0531] In step 2, 111-0 (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 completeness 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 111-1 (1.4 g, yield 87%). 1H NMR (400 MHz, CDCl3) δ 9.75 (t, J = 1.7 Hz, 1H), 7.69 – 7.63 (m,4H), 7.44 – 7.34 (m, 6H), 3.59 (td, J = 10.5, 5.3 Hz, 1H), 2.38(d, J = 6.4Hz, 2H), 1.55 (s, 6H), 1.04 (s, 10H), 0.92 (d, J = 6.5 Hz, 3H), 0.82 (s, 3H), 0.62 (d, J = 12.3 Hz, 3H).

[0532] Step 3: Dissolve 111-1 (150 mg, 1.0 eq) in tetrahydrofuran (10 mL). After complete dissolution, add cesium fluoride (11 mg, 0.08 mmol, 0.3 eq) and (trifluoromethyl)trimethylsilane (109.5 mg, 0.77 mmol, 3.3 eq) to the reaction system in sequence. After the addition is complete, stir at room temperature for 2 hours. The reaction was monitored 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. 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), extracted with ethyl acetate (10 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (90:10 to 75:25) to give (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]-1,1,1-trifluoroheptane-2-ol 111-2 (150mg, yield 81.24%). 1H NMR (400 MHz, CDCl3) δ 7.66 (dd, J = 5.9, 2.1 Hz, 4H), 7.37 (m, 7H), 3.89 (s, 1H), 3.59 (m, 1H), 1.93 (d, J = 13.0 Hz, 2H), 1.80 (s,2H), 1.53 (s, 25H), 1.26 (d,J = 2.3 Hz, 7H), 1.04 (s, 11H), 0.88 (m, 10H), 0.64 (s, 3H).

[0533] Step 4: Dissolve 111-2 (200 mg, 0.278 mmol) and rhodium dimer acetate (11.01 mg, 0.004 mmol) in dichloromethane (5 mL), and add ethyl azide (359 mg, 2.78 mmol) dropwise with stirring at 0 °C. After restoring to room temperature and stirring for 48 hours, monitor the reaction for completeness by TLC (petroleum ether: ethyl acetate = 10:1). Quenching with 10 mL of aqueous solution, extraction with ethyl acetate (10 mL × 2), washing the organic phase with saturated brine (50 mL), drying to anhydrous sodium sulfate, and purification by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) yielded 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]-1,1,1-trifluoroheptane-2-yl]oxy}ethyl acetate 111-3 (50 mg, 20.1%).

[0534] Step 5: Dissolve 111-3 (60 mg, 0.075 mmol) in tetrahydrofuran (2 mL). After complete dissolution, add 3M methylmagnesium bromide (0.124 mL, 0.37 mmol) to the reaction system. After the addition is complete, stir at room temperature for 2 hours. Monitor the reaction for completeness by TLC (petroleum ether: ethyl acetate = 10:1). Extraction was performed under ice bath conditions with saturated ammonium chloride solution (5 mL). The reaction solution was washed with water (10 mL x 3), extracted with ethyl acetate (10 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate. Purification was carried out by silica gel column chromatography (90:10 to 75:25) to give 1-{[(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-trifluoroheptane-2-yl]oxy}-2-methylprop-2-ol 111-4 (50 mg, yield 76.33%). 1HNMR (400 MHz, CDCl3) δ 7.66 (m, 4H), 7.38 (m, 6H), 3.60 (t, J= 8.9 Hz, 3H), 3.36 (d, J = 8.6 Hz, 1H), 1.91 (s, 1H), 1.80 (s, 2H), 1.58 (m,10H), 1.42 (m,8H), 1.27 (d, J = 11.9 Hz, 3H), 1.22 (d, J = 4.4 Hz, 6H), 1.06(m, 12H), 0.90 (d, J = 6.5 Hz, 1H), 0.82 (s, 3H), 0.77 (m, 3H), 0.64 (s, 3H).

[0535] Step 6: Similar to the synthesis of compound 9, replace 9-5 with 111-4 to obtain the white solid 7,7-difluoro-24-{2,2,2-trifluoro-1-[(2-hydroxy-2-methylpropyl)oxy]ethyl}-5α-cholan-3β-ol 111 (29.08 mg, yield 80.64%). 1 HNMR (400 MHz, CDCl3) δ 3.62 (d, J = 6.2 Hz, 3H), 3.39 (s, 1H), 1.98 (d, J =12.7 Hz, 1H), 1.83 (s, 3H), 1.70 (m, 6H), 1.42 (m, 12H), 1.23 (d, J = 4.3 Hz, 6H), 1.01 (d, J = 3.5 Hz, 6H), 0.92 (d, J = 6.4 Hz, 3H), 0.85 (s, 3H), 0.67 (s, 3H). 19 FNMR (376 MHz, CDCl3) δ -76.55, -80.03, -89.11, -89.68, -110.80, -111.49.

[0536] Example 113

[0537] Synthesis of compound 113 (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(2R)-6-methyl-6-{[2-(1,2,3-triazacyclopentanyl-1-yl)ethyl]oxy}hept-2-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0538] Step 1: At room temperature, the reactants iodine (105.30 mg, 0.42 mmol), triphenylphosphine (108.82 mg, 0.42 mmol), and imidazole (56.49 mg, 0.83 mmol) were dissolved sequentially in dichloromethane (3 mL). 101-0-1 (60 mg, 0.083 mmol) was added dropwise with stirring at 0°C. After returning to room temperature and stirring for 60 minutes, the reaction was monitored for completeness by TLC (petroleum ether:ethyl acetate = 1:1). Quenching with 100 mL of aqueous solution, extraction with ethyl acetate (100 mL × 2), washing the organic phase with saturated brine (50 mL), drying with anhydrous sodium sulfate, and purification by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) yielded a white solid {[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(2-iodoethyl)oxy]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-yl]oxy}(2-methylpropyl-2-yl)diphenylsilane 113-0 (45 mg, yield: 65.1%). 1 H NMR (400 MHz, CDCl3) d 7.61 – 7.54 (m, 4H), 7.34 – 7.27 (m, 6H), 3.57 – 3.44 (m, 3H), 3.10 (t, J = 7.0 Hz, 2H), 1.86 (d, J = 12.8 Hz, 1H), 1.73 (d, J = 6.8 Hz, 2H), 1.59 – 1.50 (m, 4H), 1.39 – 1.32 (m, 5H), 1.28 – 1.20 (m, 8H), 1.07 (s, 6H), 0.97 (s, 10H), 0.84 –0.79 (m, 9H), 0.75 (d, J= 4.5 Hz, 3H), 0.69 (d, J = 3.7 (Hz, 1H), 0.56 (s, 3H).

[0539] Step 2: At room temperature, triazole (10.78 mg, 0.16 mmol) was added to a reaction flask containing N,N-dimethylformamide (3 mL). After cooling to 0°C, sodium hydride (4.12 mg, 0.17 mmol) was added, and nitrogen gas was purged. The mixture was then brought to room temperature and stirred for 45 minutes. Tetrabutylammonium bromide (5.03 mg, 0.02 mmol) dissolved in dichloromethane was added dropwise, followed by 113-O (130 mg, 0.16 mmol) dissolved in dichloromethane. The mixture was stirred for 1.5 hours, and the reaction was monitored for completeness by TLC (petroleum ether:ethyl acetate = 5:1). 50 mL of ethyl acetate and 50 mL of water were added to the reaction mixture. After separation, the aqueous phase was analyzed by ethyl acetate (30 mL)... 3) Extraction: The combined organic phases were washed with 50 mL of water, dried over anhydrous sodium sulfate, filtered, and then evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:0-5:1) to obtain the desired product 3-(2-{[(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-methylheptyl-2-yl]oxy}ethyl)-3H-1,2,3-triazacyclopentacyclopentane 113-1 (67 mg, yield: 51.9%) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ 7.76 (d, J = 4.4 Hz, 2H), 7.69 – 7.61 (m, 4H), 7.45 – 7.33 (m,6H), 4.55 (t, J = 4.9 Hz, 2H), 3.69 (t, J = 4.8 Hz, 2H), 3.59 (dt, J = 10.4,5.3 Hz, 1H), 2.63 (s, 2H), 1.93 (d, J = 12.7 Hz, 1H), 1.81 – 1.43 (m, 11H), 1.40 – 1.25 (m, 11H), 1.05 (d, J = 4.6 Hz, 17H), 0.86 (d, J = 6.5 Hz, 3H), 0.82 (s, 3H), 0.64 (s, 3H).

[0540] Step 3: Similar to the synthesis of compound 9, replace 9-5 with 113-1 to obtain (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(2R)-6-methyl-6-{[2-(1,2,3-triazacyclopentanyl-1-yl)ethyl]oxy}hept-2-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 113 (21.77 mg, yield: 46.9%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.69 (s, 1H), 4.53 (t, J =5.0 Hz, 2H), 3.69 (t, J = 5.0 Hz, 2H), 3.66 – 3.58 (m, 1H), 2.02 – 1.95 (m,2H), 1.87 – 1.80 (m, 3H), 1.78 – 1.69 (m, 3H), 1.66 – 1.52 (m, 3H), 1.48 –1.40 (m, 3H), 1.37 – 1.25 (m, 9H), 1.16 – 1.08 (m, 2H), 1.06 (s, 6H), 1.03 –0.96 (m, 3H), 0.89 (d, J = 6.5 Hz, 3H), 0.85 (s, 3H), 0.67 (s, 3H). 19 F NMR (377 MHz, CDCl3) δ -88.94, -89.57, -110.83, -111.46. LC-MS: [M+Na] + =558.6

[0541] Example 115

[0542] Synthesis of Compound 115 2-{[(6R)-6-[(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-methylhept-2-yl]oxy}ethane-1-sulfonamide

[0543] Step 1: Add 113-0 (2.5 g, 3.00 mmol) to a reaction flask containing tetrahydrofuran (30 mL), then add tetrabutylammonium fluoride trihydrate (4.73 g, 15.01 mmol). The reaction is carried out at room temperature (25°C).o C) Stir for 18 hours, and monitor the reaction until complete by TLC (petroleum ether:ethyl acetate = 4). 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). o C) The product was purified by column chromatography (petroleum ether:ethyl acetate = 80:20) to give a white solid: (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(2-iodoethyl)oxy]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 115-0 (0.25 g, 0.38 mmol, 12.6%). 1 H NMR (400 MHz, CDCl3) δ 3.63 (m, 1H), 3.57 (m, 2H), 3.19 (m, 2H), 1.99 (m, 1H), 1.84 (d, J =7.4 Hz, 3H), 1.73 (m, 3H), 1.58 (d, J = 3.0 Hz, 2H), 1.50 (s, 3H), 1.38 (m,11H), 1.25 (t, J = 5.5 Hz, 2H), 1.16 (d, J = 4.0 Hz, 6H), 1.02 (m, 3H), 0.93(d, J = 6.5 Hz, 3H), 0.85 (s, 3H), 0.67 (s, 3H).

[0544] Step 2: Add 115-O (270 mg, 0.45 mmol) to a reaction flask containing N,N-dimethylformamide (5 mL), then add potassium [(1-thionylethyl)oxy] (77.78 mg, 0.68 mmol), and react at 70 °C. o The mixture was stirred at C for 8 hours, and the reaction was monitored by TLC (petroleum ether:ethyl acetate = 3:1) until complete. After cooling to room temperature, it was diluted with water (20 mL), then dichloromethane (20 mL × 3) was added, and the mixture was extracted three times. The extract was then washed with sodium chloride, dried over anhydrous sodium sulfate, and the reaction solution was evaporated to dryness under reduced pressure (water pump, 45°C). oC) The ethanethioic acid-S-(2-{[(6R)-6-[(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-methylheptyl-2-yl]oxy}ethyl) ester 115-1 (180 mg 65.7%) was purified by column chromatography (petroleum ether:ethyl acetate = 3:1). 1 H NMR (400MHz, CDCl3) δ 3.63 (t, J = 5.1 Hz, 1H), 3.44 (t, J = 6.4 Hz, 2H), 3.04 (t, J= 6.4 Hz, 2H), 2.33 (s, 3H), 1.99 (d, J = 12.7 Hz, 1H), 1.84 (d, J = 7.8 Hz, 3H), 1.71 (s, 1H), 1.58 (dd, J = 16.8, 13.5 Hz, 8H), 1.37 (m, 9H), 1.26 (d, J= 2.5 Hz, 3H), 1.13 (s, 6H), 1.02 (m, 3H), 0.93 (d, J = 6.5 Hz, 3H), 0.85 (s,3H), 0.67 (s, 3H).

[0545] Step 3: Add 115-1 (180 mg, 0.33 mmol) to a reaction flask containing dichloromethane (5 mL), followed by the addition of imidazole (67.73 mg, 0.99 mmol) and tert-butyldiphenylchlorosilane (0.1 mL, 0.39 mmol). The reaction is carried out at room temperature (25°C). o C) Stirring for 0.5 minutes, the reaction was monitored by TLC (petroleum ether: ethyl acetate = 20:1) to confirm completion. 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 (using a water pump, 45°C). o C) The ethanethioic acid-S-(2-{[(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-methylheptyl-2-yl]oxy}ethyl) ester 115-2 (220 mg, 76.4%) was obtained as a white solid by column chromatography (petroleum ether:ethyl acetate = 95:5). 1H NMR (400 MHz, CDCl3) δ7.66 (m, 4H), 7.38 (m, 6H), 3.59 (m, 1H), 3.43 (t, J = 6.4 Hz, 2H), 3.03 (t,J = 6.4 Hz, 2H), 2.32 (s, 3H), 1.94 (d, J = 12.7 Hz, 1H), 1.79 (s, 2H), 1.63(m, 3H), 1.57 (m, 6H), 1.46 (m, 3H), 1.36 (m, 6H), 1.25 (m, 6H), 1.12 (s,6H), 1.04 (s, 10H), 0.90 (d, J = 6.5 Hz, 3H), 0.82 (s, 3H), 0.64 (s, 3H).

[0546] Step 4: Add N-chlorosuccinimide (54.70 mg, 0.410 mmol) to a reaction flask containing acetonitrile (5 mL), and heat at 0°C. o Dilute hydrochloric acid (0.01 mL) and 115-2 (80 mg, 0.10 mmol) were added at C, and the reaction was carried out at room temperature (25 °C). o C) Stir for 0.5 hours, and monitor the reaction by TLC (petroleum ether:ethyl acetate = 4:1). 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). o C) 2-{[(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-methylheptyl-2-yl]oxy}ethane-1-sulfonyl chloride 115-3 (70 mg, 80%).

[0547] Step 5: Add 115-3 (70 mg, 0.09 mmol) to a reaction flask containing ammonia (0.5 mL) and tetrahydrofuran (0.5 mL), and react at room temperature (25 °C). o C) Stir for 0.5 hours, and monitor the reaction for completeness by TLC (petroleum ether: ethyl acetate = 4:1). 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). oC) The product was purified by column chromatography (petroleum ether: ethyl acetate = 70:30) to obtain 2-{[(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-methylheptyl-2-yl]oxy}ethane-1-sulfonamide 115-4 (60 mg, 79.1%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 6.8 Hz, 4H), 7.39 (dd, J = 14.7, 6.1 Hz, 6H), 4.77 (s,2H), 3.81 (t, J = 5.4 Hz, 2H), 3.59 (s, 1H), 0.89 (d, J = 6.4 Hz, 5H), 0.82 (s, 3H), 0.64 (s, 3H).

[0548] Step 6 is similar to the synthesis of compound 9, replacing 9-5 with 115-4 to obtain 2-{[(6R)-6-[(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-methylhept-2-yl]oxy}ethane-1-sulfonamide 115 (32 mg, 76.5%). 1H NMR (400 MHz, CDCl3) δ 4.78 (s, 2H), 3.82 (t, J = 5.4 Hz, 2H), 3.63 (m, 1H), 3.31 (t, J =5.4 Hz, 2H), 1.98 (d, J = 12.7 Hz, 1H), 1.83 (m, 3H), 1.74 (m, 3H), 1.60 (m,2H), 1.54 (s, 7H), 1.34 (m, 7H), 1.19 (s, 6H), 1.11 (dd, J = 16.4, 7.0 Hz,2H), 1.01 (dd, J = 12.7, 9.4 Hz, 3H), 0.92 (d, J = 6.5 Hz, 3H), 0.85 (s, 3H), 0.67 (s, 3H). 19 F NMR (376 MHz, CDCl3) δ -88.96, -89.59, -110.84, -111.47.LC-MS(ESI) [MH] + = 546.50.

[0549] Example 116

[0550] Synthesis of compound 116 (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(2-hydroxy-2-methylpropyl)amino]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0551] Step 1: At room temperature, 107-2 (40 mg, 0.052 mmol) was dissolved in tetrahydrofuran (3 mL), cooled in an ice bath, and methylmagnesium bromide (3 M, 0.2 mL, 0.60 mmol) was slowly added dropwise. The mixture was then heated to room temperature and stirred for 1 hour. The reaction was confirmed to be complete by TLC (petroleum ether:ethyl acetate = 3:1, phosphomolybdic acid plate). The reaction was quenched with ammonium chloride 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, 0–10% methanol / dichloromethane, 20 mL / min) yielded a white solid 1-{[(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-methylhept-2-yl]amino}-2-methylprop-2-ol 116-0 (35 mg, yield 89.1%). 1 H NMR (400 MHz, CDCl3) δ 7.65 (dd, J = 9.7,4.3 Hz, 4H), 7.45 – 7.32 (m, 6H), 3.65 – 3.52 (m, 1H), 3.04 – 2.85 (m, 2H), 1.92 (d, J = 13.3 Hz, 1H), 1.83 – 1.74 (m, 4H), 1.66 (dd, J = 19.9, 10.7 Hz,11H), 1.47 (dd, J = 11.6, 4.2 Hz, 12H), 1.41 – 1.34 (m, 5H), 1.26 (d, J = 2.4Hz, 6H), 1.04 (s, 9H), 0.91 – 0.87 (m, 3H), 0.82 (s, 3H), 0.75 (dd, J = 19.0,9.1 Hz, 1H), 0.63 (s, 3H).

[0552] Step 2: Similar to the synthesis of compound 9, replace 9-5 with 116-0 to obtain a white solid (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-[(2-hydroxy-2-methylpropyl)amino]-6-methylhept-2-yl]-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 116 (12 mg, 100% purity (ELSD), 44.0% yield). 1 H NMR (400 MHz, MeOD) δ 3.52 (m, 1H), 2.83 (s, 2H), 2.03 (d, J = 13.0Hz, 1H), 1.90 – 1.70 (m, 6H), 1.69 – 1.52 (m, 5H), 1.51 – 1.31 (m, 11H), 1.29(d, J = 3.3 Hz, 12H), 1.24 – 1.08 (m, 4H), 1.03 (d, J = 5.0 Hz, 1H), 0.98 (d, J = 6.5 Hz, 3H), 0.87 (s, 3H), 0.71 (s, 3H). 19 F NMR (376 MHz, MeOD) δ -89.93,-90.56, -112.28, -112.91.LC-MS: [M+H] + =512.65.

[0553] Example 117

[0554] Synthesis of compound 117 (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(2R)-6-methyl-6-[(3,3,3-trifluoro-2-hydroxypropyl)oxy]hept-2-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0555] Step 1: At room temperature, 16-1 (60 mg, 0.11 mmol) was dissolved in tetrahydrofuran (3 mL). Under nitrogen protection, a tetrahydrofuran solution of (trifluoromethyl)trimethylsilane (80 mg, 0.56 mmol) (0.2 mL) was added, followed by a tetrahydrofuran solution of tetrabutylammonium fluoride (1 M, 0.5 mL). The mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 5:1). Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine (20 mL x 2), 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 1,1,1-trifluoro-3-{[(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]phenanthrene[7,8-d][1,3]dioxacyclopentaman-8-yl]-2-methylhept-2-yl]oxy}prop-2-ol 117-0 (20 mg, yield 29.5%). 1 H NMR (400MHz, CDCl3) δ 4.11 – 3.98 (m, 1H), 3.74 (s, 1H), 3.65 – 3.48 (m, 3H), 2.28 –2.13 (m, 1H), 1.98 (d, J = 12.8 Hz, 1H), 1.78 (ddd, J = 31.0, 24.1,17.1 Hz,9H), 1.49 – 1.32 (m, 11H), 1.17 (s, 6H), 1.15 – 1.09 (m, 2H), 1.06 (s, 3H),0.99 (dd, J = 16.7, 6.6 Hz, 2H), 0.91 (d, J = 6.5 Hz, 3H), 0.67 (s, 3H). 19 FNMR (377 MHz, CDCl3) δ -77.51, -88.99, -89.62, -111.36, -111.99.

[0556] Step 2: Similar to the synthesis of compound 3, replace 3-1 with 117-0 to obtain a white solid (1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(2R)-6-methyl-6-[(3,3,3-trifluoro-2-hydroxypropyl)oxy]hept-2-yl]hexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol 117 (4 mg, yield 21.3%). 1 HNMR (400 MHz, CDCl3) δ 4.05 (s, 1H), 3.74 (s, 1H), 3.66 – 3.47 (m, 3H), 2.20(d, J = 34.7 Hz, 1H), 1.98 (d, J = 12.8 Hz, 1H), 1.75 (s, 9H), 1.36 (dd, J =19.2, 8.6 Hz, 11H), 1.17 (s, 6H), 1.11 (d, J = 8.9 Hz, 2H), 1.06 (s, 3H), 1.02 – 0.95 (m, 2H), 0.91 (d, J = 6.5 Hz, 3H), 0.67 (s, 3H). 19 F NMR (377 MHz, CDCl3) δ -77.50, -88.64, -89.26, -110.63, -111.25.LC-MS: [MH] - = 567.85.

[0557] Example 118

[0558] Synthesis of compound 118 (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-1-[(11R)-4-ethyl-1-hydroxy-7,7-dimethyl-3,6-dioxadodecane-11-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0559] Step 1 is similar to the synthesis of compound 26-2, but methyl magnesium bromide is replaced with ethyl magnesium bromide to obtain product 1-{[(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-methylhept-2-yl]oxy}but-2-ol 118-0 (200 mg, 64%), which is a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.70 – 7.62(m, 4H), 7.45 – 7.34 (m, 6H), 3.67 – 3.52 (m, 2H), 3.40 – 3.28 (m, 1H), 3.12(t, J = 8.4 Hz, 1H), 1.93 (d, J = 12.9 Hz, 1H), 1.84 – 1.75 (m, 2H), 1.66 –1.61 (m, 3H), 1.54 (d, J = 7.8 Hz, 3H), 1.50 – 1.42 (m, 6H), 1.40 – 1.31 (m,6H), 1.26 (dd, J = 8.4, 5.8 Hz, 5H), 1.14 (s, 6H), 1.04 (s, 9H), 0.96 (t, J =7.4 Hz, 4H), 0.91 – 0.85 (m, 7H), 0.82 (s, 3H), 0.64 (s, 3H).

[0560] Step 2: At room temperature, 118-0 (300 mg, 0.399 mmol) was dissolved in dichloromethane (10 mL), and rhodium dimer acetate (29.93 mg, 0.012 mmol) and ethyl diazonate (455.26 mg, 3.990 mmol) were added. The reaction was carried out at room temperature for 3 hours under nitrogen protection, and the reaction was monitored by TLC (petroleum ether: ethyl acetate = 4:1) to ensure complete reaction. The reaction solution was quenched with water (10 mL), extracted with dichloromethane (20 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 column chromatography (petroleum ether: ethyl acetate = 1:0-4:1) to obtain the product [(1-{[(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-methylheptyl-2-yl]oxy}but-2-yl)oxy]ethyl acetate 118-1 (200 mg, 59.81%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.69 – 7.63 (m,4H), 7.45 – 7.34 (m, 6H), 4.24 – 4.16 (m, 4H), 3.59 (tt, J = 10.3, 5.2 Hz,1H), 3.39 (d, J = 5.7 Hz, 3H), 1.93 (d, J = 12.7 Hz, 1H), 1.80 (dd, J = 14.5,7.2 Hz, 2H), 1.68 – 1.51 (m, 9H), 1.46 (s, 4H), 1.32 (s, 12H), 1.26 (d, J =7.1 Hz, 4H), 1.11 (s, 6H), 1.04 (s, 9H), 0.97 (t, J = 7.4 Hz, 3H), 0.89 (d, J= 6.5 Hz, 4H), 0.82 (s, 3H), 0.64 (s, 3H).

[0561] Step 3: At room temperature, dissolve 118-1 (200 mg, 0.239 mmol) in tetrahydrofuran (4 mL) under nitrogen protection. oLithium aluminum hydride (1M, 0.358 mL, 0.358 mmol) was added dropwise at C, and the mixture was allowed to react at room temperature for 1 hour. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 4:1) to ensure complete reaction. The reaction solution was quenched with sodium sulfate decahydrate solid, extracted with water (5 mL) and dichloromethane (10 mL x 3), the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude product, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-4:1) to obtain product 2-[(1-{[(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-methylheptyl-2-yl]oxy}but-2-yl)oxy]eth-1-ol 118-2 (130 mg, 68.44%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.66 (dd, J =5.6, 1.4 Hz, 4H), 7.47 – 7.30 (m, 6H), 3.86 – 3.55 (m, 5H), 3.43 (dd, J =11.5, 5.6 Hz, 1H), 3.31 (d, J = 1.29 – 1.20 (m, 5H), 1.16 (s, 6H), 1.10 – 0.99 (m, 12H), 0.95 (t, J= 7.4 Hz, 4H), 0.91 – 0.84 (m, 5H), 0.83 (d, J = 5.5 Hz, 3H), 0.63 (s, 3H).

[0562] Step 4: Similar to the synthesis of compound 9, replace 9-5 with 118-2 to obtain the product (1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-1-[(11R)-4-ethyl-1-hydroxy-7,7-dimethyl-3,6-dioxadodecane-11-yl]-4,4-difluoro-9a,11a-dimethylhexadecylhydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 118 (25.36 mg, 80.48%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 3.84 – 3.78 (m, 1H), 3.75 – 3.69 (m, 1H), 3.63(ddd, J = 16.2, 8.9, 4.7 Hz, 3H), 3.44 (dd, J = 11.7, 5.7 Hz, 1H), 3.32 (d, J= 5.0 Hz, 2H), 1.98 (d, J = 12.9 Hz, 2H), 1.82 (d, J= 4.0 Hz, 3H), 1.74 (ddd,J = 16.6, 9.6, 5.4 Hz, 4H), 1.64 – 1.56 (m, 3H), 1.50 – 1.42 (m, 6H), 1.39 – 1.26 (m, 9H), 1.17 (s, 6H), 1.02 (d, J = 13.5 Hz, 3H), 0.98 – 0.91 (m, 6H), 0.85 (s, 3H), 0.67 (s, 3H). 19 F NMR (376 MHz, CDCl3) δ -88.95, -89.58, -110.85, -111.48.

[0563] Example 119

[0564] Synthesis of compound 119 (20S)-7,7-difluoro-20-(7-hydroxy-4,4-dimethyl-2,5-dioxahept-1-yl)-5α-pregn-3β-ol

[0565] Step 1: Similar to the synthesis of compound II-5, replace I-4 with stigmasterol 119-0 to obtain white solid acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R,3E,5S)-5-ethyl-6-methylhept-3-en-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecanoyl-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 119-1 (5.30 g, yield 86.58%). 1H NMR (400 MHz, CDCl3) δ 5.37 (d, J = 4.8 Hz, 1H), 5.09 (ddd, J = 56.1, 15.2, 8.6 Hz, 2H), 4.61 (ddd, J = 15.9, 9.0, 4.2 Hz, 1H), 2.32 (d, J = 7.3 Hz, 2H), 2.03 (s, 3H), 2.01 – 1.92 (m, 2H), 1.87 (dd, J =8.9, 6.6 Hz, 2H), 1.73 – 1.40 (m, 12H), 1.30 – 1.07 (m, 6H), 1.02 (t, J = 3.3Hz, 6H), 0.87 – 0.79 (m, 9H), 0.70 (s, 3H).

[0566] Step 2: Weigh 119-1 (10.0 g, 22 mmol, 1 eq) and dissolve it in tetrahydrofuran (100 mL) and water (10.0 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) monitoring showed some remaining starting material and the formation of an intermediate (vicinal diol). Then, sodium periodate (18.80 g, 88 mmol, 4 eq) was added to the reaction solution at 0°C. Stirring for 1 hour at room temperature was performed, and the reaction was again monitored by TLC (petroleum ether:ethyl acetate = 3:1). Finally, 50 mL of water and 50 mL of ethyl acetate were added. 3. After extraction, drying, and concentration, the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 60:1) to obtain acetic acid-(1R, 3aS, 3bS, 7S, 9aR, 9bS, 11aR)-1-[(2R,3E, 5S)-5-ethyl-6-methylhept-3-en-2-yl]-9a, 11a-dimethyl-2, 3, 3a, 3b, 4, 6, 7, 8, 9, 9a, 9b, 10, 11, 11a-tetradecano-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester (3.3 g, purity 60%). (1.9 g, yield 21.20%) 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-tetradecanoyl-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 119-2. 1 H NMR (400 MHz, CDCl3) δ 9.50 (d, J = 3.3 Hz, 1H), 5.31 (d, J = 5.1 Hz, 1H), 4.54 (dd, J = 6.4, 4.2 Hz, 1H), 2.34 – 2.23 (m,3H), 1.96 (s, 3H), 1.89 (dt, J = 6.6, 3.6 Hz, 2H), 1.83 – 1.72 (m, 3H), 1.66– 1.09 (m, 14H), 1.06 (d, J = 6.8 Hz, 3H), 0.96 (s, 3H), 0.66 (s, 3H).

[0567] Step 3: Dissolve 119-2 (20 g, 53.68 mmol) in methanol (50 mL) and 99.9% dichloromethane (10 mL), and slowly add sodium borohydride (3.05 g, 80.53 mmol) at room temperature. Stir the mixture at room temperature for 1 hour, and monitor the reaction for completion by TLC (petroleum ether / ethyl acetate = 5:1). Quench the reaction by slowly adding saturated ammonium chloride aqueous solution (50 mL) at room temperature, concentrate the solution at low temperature, and then extract with ethyl acetate (50 mL × 3). Dry the organic phase with anhydrous sodium sulfate and evaporate to dryness. Purify the crude product by rapid chromatography (petroleum ether / ethyl acetate = 0-20%) to obtain 119-3 (13 g, yield: 54.95%) as a white solid. 1H NMR (400MHz, CDCl3) δ 5.37 (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 – 1.93 (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).

[0568] Step 4: Dissolve 119-3 (6 g, 16.019 mmol) in 99.9% dichloromethane (10 mL), and add 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). Stir the mixture at room temperature for 3 hours. Add water (50 mL × 3) to the reaction mixture, shake and allow to stand for phase separation. Extract the organic phase once more with dichloromethane (50 mL), combine the organic phases, wash with saturated brine (50 mL), dry with anhydrous sodium sulfate, and evaporate to dryness. Purify the solid by rapid chromatography (petroleum ether / ethyl acetate = 0-10%) to obtain 119-4 (6 g, yield: 65.13%) as a white solid. 1H NMR (400MHz, CDCl3) δ 5.37 (d,J =4.9Hz, 1H), 4.65 – 4.55 (m, 1H), 3.58 (dd,J = 9.6, 3.4Hz, 1H), 3.24 (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).

[0569] Step 5: Dissolve 119-4 (2 g, 4.091 mmol) in acetone (50 mL), add 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), and stir overnight at room temperature. Monitor the reaction for completeness by TLC (petroleum ether / ethyl acetate = 5:1). Add sodium sulfite solution (30 mL) to the reaction mixture, shake and allow to stand for phase separation, extract with dichloromethane (30 mL × 3), combine the organic phases, wash with saturated brine (30 mL), dry with anhydrous sodium sulfate, and evaporate to dryness. Purify the crude product by rapid chromatography (petroleum ether / ethyl acetate = 0-15%) to obtain 119-5 (0.97 g, yield: 40.08%) as a white solid.

[0570] Step 6: Dissolve 119-5 (970 mg, 1.929 mmol) in ethyl acetate (20 mL), add 10% palladium on carbon (485 mg, 0.456 mmol), and replace the system with hydrogen gas. Stir the mixture at 40 °C for 2 hours. Monitor the reaction mixture by TLC (petroleum ether / ethyl acetate = 10 / 1). After the reactants have reacted completely, filter through diatomaceous earth to remove the palladium on carbon, and evaporate the filtrate to dryness. Purify the crude product by rapid chromatography (petroleum ether / ethyl acetate = 0-15%) to obtain 119-6 (790 mg, yield: 68.95%) as a white solid.

[0571] Step 7: Place 119-6 (690 mg, 1.367 mmol) in a single-necked flask and add tetrabutylammonium fluoride (357.38 mg, 1.367 mmol). Stir the mixture at room temperature for 1 hour, and monitor the reaction for completion by TLC (petroleum ether / ethyl acetate = 3:1). Dilute the reaction mixture with ethyl acetate (30 mL), wash with water (15 mL × 2), dry the organic phase with anhydrous sodium sulfate, and evaporate to dryness. The crude product was purified by rapid chromatography (petroleum ether / ethyl acetate = 0-50%) to give acetic acid-(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-1-[(2S)-1-hydroxypropyl-2-yl]-9a,11a-dimethyl-4-oxoylidenehexadecyl-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester 119-7 (420 mg, yield: 66.88%) as a white solid. 1 H NMR (400MHz, CDCl3)δ 4.67 (dd,J = 11.1, 5.2Hz, 1H), 3.65 (dd,J = 10.5, 3.3Hz, 1H), 3.36 (dd,J =10.5, 7.1Hz, 1H), 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).

[0572] Step 8: Dissolve 119-7 (300 mg, 0.768 mmol) in 99.9% dichloromethane (2 mL), add 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). Stir the mixture overnight at room temperature. Monitor the reaction for completeness by TLC (petroleum ether / ethyl acetate = 3:1). Add water (15 mL) to the reaction mixture, extract with ethyl acetate (15 mL × 3), wash with saturated sodium chloride aqueous solution (15 mL), dry the organic phase to anhydrous sodium sulfate, and evaporate 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 119-8 (115 mg, yield: 25.21%) as a white solid. 1 H NMR (400MHz, CDCl3) δ 4.68(td,J = 10.8, 5.0Hz, 1H), 3.92 (s, 2H), 3.47 (d,J = 3.2Hz, 1H), 3.21 (d,J =8.2Hz, 1H), 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).

[0573] Step 9: Dissolve 119-8 (200 mg, 0.396 mmol) in diethylaminotrifluoride (3 mL) and stir at 50 °C for 3 hours....

Claims

1. A compound of formula I-0 or a pharmaceutically acceptable salt thereof: ； in, R 3a For H or -(CH2) m -OH; m is 1, 2 or 3; R 4a It is H or OH; R 7a and R 7b Each is independently a halogen or H; R 19 It is H or CH3; R 21 for ; L 1 It is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, or -(CH2)6-; wherein one of the -CH2- portions of -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, and -(CH2)6- is optionally -Y 1 -replace; L 2 It is a single bond, -CH2-, -(CH2)2-, or -(CH2)3-; wherein one of the -CH2- portions of -CH2-, -(CH2)2-, and -(CH2)3- is optionally -Y 2 -replace; L 3 It is a single bond, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, or -(CH2)6-, wherein one of the -CH2- portions of -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, and -(CH2)6- is optionally -Y 3 -replace; X is -O-, -S-, or -NR-; R is H or C 1-6 alkyl; Y 1 -O-, -S-, -CHR Y1 -or -NR-; R Y1 Halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups or -OH; Y 2 For -CHR Y2 -; R Y2 Halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups or -OH; Y 3 -O-, -S-, -CHR Y3 -、-NR- or -NR-C(O)-NR-; R Y3 C 1-6 Alkyl, -OH or with one or more R 1 Replacement C 1-6 alkyl; R 21a For H or C 1-6 alkyl; R 21b C 1-6 Alkyl, with one or more R 1 Replacement C 1-6 Alkyl group, "a 5-10 membered heteroaryl group selected from one, two, or three heteroatoms selected from N, O, and S, with one, two, three, or four heteroatoms", and surrounded by one or more R... b1 The substituted heteroatom is selected from one, two, or three of N, O, and S, and is a 5-10 membered heteroaryl group with one, two, three, or four heteroatoms. 6-10 aryl or aryl with one or more R 1d Replacement C 6-10 Aryl; R A -C(O)NR 2a R 2b -CR 2c R 2d R 2e -S(O)2R 2f -OH, -N(R) 3b )-S(O)2R 3c -NR 3d R 3e -S(O)2-N(R) 3d R 3e -NR 5a C(O)NR 5b R 5c -COOR 5d "A 5-10 membered heteroaryl group selected from one, two, or three of N, O, and S, with one, two, three, or four heteroatoms" or containing one or more R... 1a The substituted "5-10-membered heteroaryl group selected from one, two, or three of N, O, and S, with one, two, three, or four heteroatoms" or "3-10-membered heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" or "substituted by one or more R 1b 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" or C3- 10 cycloalkyl, with one or more R 1c Replacement C3- 10 cycloalkyl, C 6-10 aryl or aryl with one or more R 1d Replacement C 6-10 Aryl; R 2a For H or C 1-6 alkyl; R 2b For H, C 1-6 Alkyl, with one or more R 1 Replacement C 1-6 Alkyl, C3- 10 cycloalkyl, with one or more R 1c Replacement C3- 10 Cycloalkyl, "a 3-10 membered heterocycloalkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms", or consisting of one or more R... 1b 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. R 2c For H, C 1-6 Alkyl, with one or more R 1 Replacement C 1-6 Alkyl, halogen, C 1-6 Alkyl group, by one or more R 2 Replacement C 1-6 Alkoxy, C3-C 10 cycloalkyl or with one or more R 1c Replacement C3- 10 cycloalkyl; R 2d For H, C 1-6 Alkyl, with one or more R 1 Replacement C 1-6 Alkyl, halogen, C3- 10 cycloalkyl, with one or more R 1c Replacement C3- 10 Cycloalkyl, "a 3-10 membered heterocycloalkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms", or consisting of one or more R... 1b 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. Or, R 2c R 2d Together with the C atoms they are attached to, they form C3- 10 cycloalkyl; R 2e C 1-6 Alkyl group, by one or more R 1 Replacement C 1-6 Alkyl, with one or more R 2 Replacement C 1-6 Alkyl group, halogen, -OH, "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 surrounded by one or more R 1b 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. R 2f For H, C 1-6 Alkyl or with one or more R 1 Replacement C 1-6 alkyl; R 3b For H or C 1-6 alkyl; R 3c For H, C 1-6 Alkyl or with one or more R 1 Replacement C 1-6 alkyl; R 3d For H or C 1-6 alkyl; R 3e For H, C 1-6 Alkyl, with one or more R 1 Replacement C 1-6 Alkyl group, "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 surrounded by one or more R... 1b 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" or C3- 10 cycloalkyl, or by one or more R 1c Replacement C3- 10 cycloalkyl; Each R 5a R 5b and R 5c Each independently represents H and C. 1-6 Alkyl or with one or more R 1 Replacement C 1-6 alkyl; R 5d For H or C 1-6 alkyl; Each R 1 and R 2 Each is independently a halogen, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups; Each R b1 R 1a R 1b R 1c and R 1d Each independently constitutes a halogen, C 1-6 Alkoxy, -OH, C 1-6 Alkyl, with one or more R 1 Replacement C 1-6 Alkyl, C 1-6 Halogenated alkoxy or -COOR 5d ; The labeled carbon atoms are 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.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, It is a compound as shown in Formula I or a pharmaceutically acceptable salt thereof: ； in, R 7a and R 7b Each is an independent halogen.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) R 3a For H or ; (2) L 1 It is -(CH2)2- or -(CH2)3-; wherein one of the -CH2- portions of the -(CH2)3- is optionally -Y 1 - Alternative; better, L 1 It is -(CH2)3-, wherein one of the -CH2- portions of the -(CH2)3- is optionally -Y 1 -replace, -Y 1 -for -O- or -CHR Y1 -; (3) Y 1 -O- or -CHR Y1 -; (4) R Y1 It is -OH; (5) L 2 It is a single bond or -CH2-, wherein the -CH2- is optionally replaced by -Y 2 - Alternative; better, L 2 -CH2-, wherein the -CH2- is optionally -Y 2 - Replace; for example, -CH2-; (6) R Y2 C 1-6 alkyl; (7) L 3 It is a single bond, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, or -(CH2)5-; wherein one of the -CH2- portions of -(CH2)3-, -(CH2)4-, and -(CH2)5- is optionally -Y 3 - instead; for example -CH2-, -(CH2)2- or -(CH2)5-; wherein one of the -CH2- portions of the -(CH2)5- is optionally replaced by -Y 3 - to replace; for example, -CH2-; (8) Y 3 -O-; (9) X is -O- or -NR-; (10) R is H; (11) R 21b C 1-6 Alkyl, with one or more R 1 Replacement C 1-6 Alkyl or with one or more R b1 The substituted heteroatom is selected from one, two, or three of N, O, and S, and is a 5-10 membered heteroaryl group with one, two, three, or four heteroatoms; preferably C. 1-6 Alkyl, or with one or more R 1 Replacement C 1-6 Alkyl; for example, C 1-6 alkyl; (12) R A -C(O)NR 2a R 2b -CR 2c R 2d R 2e -S(O)2R 2f -OH, -N(R) 3b )-S(O)2R 3c -NR 3d R 3e -S(O)2-N(R) 3d R 3e -NR 5a C(O)NR 5b R 5c -COOR 5d "A 5-10 membered heteroaryl group selected from one, two, or three of N, O, and S, with one, two, three, or four heteroatoms" or containing one or more R... 1a The substituted "5-10-membered heteroaryl group selected from one, two, or three of N, O, and S, with one, two, three, or four heteroatoms" or "3-10-membered heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" or "substituted by one or more R 1b The substituted heteroatom is a 3-10 membered heterocyclic alkyl group selected from one, two, or three of N, O, and S, and has one, two, or three heteroatoms, or is replaced by one or more R... 1c Replacement C3- 10 Cycloalkyl; for example -C(O)NR 2a R 2b -CR 2c R 2d R 2e -OH, "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 surrounded by one or more R 1c Replacement C3- 10 cycloalkyl; for example -CR 2c R 2d R 2e ; (13) R 2a For H; (14) R 2b For H, C 1-6 Alkyl, with one or more R 1 Replacement C 1-6 Alkyl, with one or more R 1c Replacement C3-C 10 Cycloalkyl or "a 3-10 membered heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms"; for example, C 1-6 alkyl; (15) R 2c For H or C 1-6 Alkyl; for example, C 1-6 alkyl; (16) R 2d C 1-6 Alkyl, with one or more R 1 Replacement C 1-6 Alkyl, halogen, C3- 10 Cycloalkyl or "a 3-10 membered heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms"; for example, C 1-6 Alkyl, or with one or more R 1 Replacement C 1-6 Alkyl; for example, C 1-6 alkyl; (17) R 2e C 1-6 Alkyl group, by one or more R 1 Replacement C 1-6 Alkyl, with one or more R 2 Replacement C 1-6 Alkyl groups, halogens, or -OH; for example, OH. (18)R 2f C 1-6 alkyl; (19) R 3b For H; (20)R 3c C 1-6 Alkyl or with one or more R 1 Replacement C 1-6 alkyl; (21) R 3d For H; (22)R 3e For H, C 1-6 Alkyl, with one or more R 1 Replacement C 1-6 Alkyl or "a 3- to 10-membered heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms"; (23) Each R 5a R 5b and R 5c Each is independently of H or is controlled by one or more R. 1 Replacement C 1-6 alkyl; (24) R 5d For H; (25) Each R 1 and R 2 Each can be a halogen or -OH group independently; for example, halogens. (26) Each R b1 R 1a R 1b and R 1c Each independently constitutes a halogen, C 1-6 Alkyl groups, -OH groups are affected by one or more R groups. 1 Replacement C 1-6 Alkyl groups; for example, C substituted with one or more OH groups. 1-6 Alkyl; and, (27) R 21a For H.

4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) R 3a For H; (2) L 1 It is -(CH2)3-; (3) L 2 It is a single bond; (4) L 3 It is a single bond, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, or -(CH2)5-; wherein one of the -CH2- portions of -(CH2)4- and -(CH2)5- is optionally -Y 3 -replace; (5) X is -O- or -S-; preferably, X is -O-; (6) R 21b C 1-6 Alkyl or with one or more R b1 The substituted heteroatom is selected from one, two, or three of N, O, and S, and is a 5-10 membered heteroaryl group with one, two, three, or four heteroatoms. (7) R A -C(O)NR 2a R 2b -CR 2c R 2d R 2e -S(O)2R 2f -OH, -N(R) 3b )-S(O)2R 3c -NR 3d R 3e -S(O)2-N(R) 3d R 3e -NR 5a C(O)NR 5b R 5c "A 5-10 membered heteroaryl group selected from one, two, or three of N, O, and S, with one, two, three, or four heteroatoms" or containing one or more R... 1a The substituted "5-10-membered heteroaryl group selected from one, two, or three of N, O, and S, with one, two, three, or four heteroatoms" or "3-10-membered heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" or "substituted by one or more R 1b The substituted heteroatom is a 3-10 membered heterocyclic alkyl group selected from one, two, or three of N, O, and S, and has one, two, or three heteroatoms, or is replaced by one or more R... 1c Replacement C3- 10 cycloalkyl; (8) R 2b For H; (9) R 2d C 1-6 Alkyl, C3- 10 cycloalkyl or with one or more R 1 Replacement C 1-6 alkyl; (10) R 2e It is -OH or is affected by one or more R 1 Replacement C 1-6 alkyl; (11) R 3c C 1-6 alkyl; (12) R 3e For H; (13) Each R 5a R 5b and R 5c Each is independently represented by H; (14) Each R b1 R 1a R 1b and R 1c Each is independently a halogen or C 1-6 Alkoxy; (15) R 21a C 1-6 Alkyl; and, (16) R 2a C 1-6 alkyl.

5. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) Each R 1 R 2 R 1a R 1b R 1c and R 2e Each is independently -OH; (2) R Y2 C 1-6 Halogenated alkyl groups; and, (3) R 2d For H.

6. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) The halogen is independently F, Cl, Br or I, for example F; (2) The C 1-6 Alkyl groups and the substituted C 1-6 C in alkyl 1-6 The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl, ethyl, isopropyl, or tert-butyl; (3) The C 1-6 alkoxy groups and the substituted C 1-6 C in alkoxy 1-6 The alkoxy group can be independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy; for example, methoxy or ethoxy. (4) The C 1-6 The alkyl halide is independently -CF3, -CHF2, -CH2F, -CH2CF3 or -CH2CHF2; for example -CF3 or -CHF2; (5) The C 1-6 The haloalkoxy group is independently -OCF3, -OCHF2, -OCH2F, -OCH2CF3 or -OCH2CHF2; (6) The phrase "5-10 membered heteroaryl groups selected from 1, 2, or 3 of N, O, and S, with 1, 2, 3, or 4 heteroatoms" and the phrase "5-10 membered heteroaryl groups selected from 1, 2, or 3 of N, O, and S, with 1, 2, 3, or 4 heteroatoms" in the substituted phrase "5-10 membered heteroaryl groups selected from 1, 2, or 3 of N, O, and S, with 1, 2, 3, or 4 heteroatoms" are independently defined as "5- or 6 membered heteroaryl groups selected from N, with 1, 2, or 3 heteroatoms". For example... , , or ; (7) The substituted "5- to 10-membered heteroaryl group selected from one, two, or three of N, O, and S, with one, two, three, or four heteroatoms" is independently the substituted "5- or 6-membered heteroaryl group selected from N, with one, two, or three heteroatoms," for example... , , or For example... or ; (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 3-10-membered heterocyclic alkyl” 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 3-10-membered heterocyclic alkyl” is independently “the heteroatom is selected from one, two or three of N, O and S, and the number of heteroatoms is one, two or three 3-10-membered heterocyclic alkyl”, for example, oxacyclobutane or 2-oxaspiro[3.3]heptane; preferably, “the heteroatom is selected from O, and the number of heteroatoms is one 3-6-membered monocyclic or 7-10-membered bicyclic heterocyclic alkyl”. Preferably, the phrase "a heteroatom selected from one, two, or three of N, O, and S, and a 3-10 membered heterocyclic alkyl group having one, two, or three heteroatoms" and "the substituted heteroatom selected from one, two, or three of N, O, and S, and a 3-10 membered heterocyclic alkyl group having one, two, or three heteroatoms" is independently defined as "a heteroatom selected from one or two of N, and a 3-6 membered monocyclic or 7-10 membered bicyclic heterocyclic alkyl group having one or two heteroatoms," for example, azacyclobutane; more preferably, "a heteroatom selected from N, and a 3-6 membered monocyclic or bicyclic heterocyclic alkyl group having one heteroatom." (9) The C3-C 10 The cycloalkyl group is independently a C3-C6 monocyclic or C5-C6 monocyclic ring. 10 Bicycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentane or spiro[3.3]heptane; preferably C3-C6 monocycloalkyl groups; and, (10) The C 6-10 aryl and the substituted C 6-10 C in aryl 6-10 The aryl group can be phenyl or naphthyl independently.

7. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) The labeled carbon atom has an S configuration; (2) When the carbon atom marked with # is a chiral carbon atom, it is in the R configuration; (3) R 7a and R 7b Each is independently F; (4) L 1 -(CH2)2-, -(CH2)3-, , , , or Preferably -(CH2)3- or ; (5) L 2 It can be -CH(CF3), a single bond, -CH2- or -CH(CH3); for example, a single bond, -CH2- or -CH(CH3); preferably a single bond or -CH2; (6) L 3 For single bonds, -CH2-, -(CH2)2-, -(CH2)3-, , , or ; (7) R 21 In for , , , , , , , , , or , where the a end and L 3 Connection; preferably , , , or More preferably or ; (8) R A -C(O)NR 2a R 2b for , , , , or Preferred ; (9) R A -CR 2c R 2d R 2e for , , , , , , , , , , , , , , , , , , , , , , , -CH2F , or Preferred , , , , , or ; (10) R A Medium, -S(O)2R 2f for ; (11) R A In, -N(R) 3b )-S(O)2R 3c for or Preferred ; (12) R A In the middle, -NR 3d R 3e -NH2, , , or Preferred NH2; (13) R A In, -S(O)2-N(R) 3d R 3e )for ; (14) R A In the middle, -NR 5a C(O)NR 5b R 5c for or Preferred ; (15) R A In the text, "a 5- to 10-membered heteroaryl group selected from one, two, or three of N, O, and S, with one, two, three, or four heteroatoms" is defined as... or Preferred ; (16) R A In the text, "a 3-10 membered heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" is... , or Preferred ; (17) R A In this context, the substituted "heteroatom selected from one, two, or three of N, O, and S, and a 3-10 membered heterocyclic alkyl group having one, two, or three heteroatoms" is... , or ;and, (18)R A In, C3- is replaced 10 cycloalkyl is , , , , , or .

8. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or two of the following conditions: (1) for , , or ;and, (2) R 21 for , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

9. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that: It meets one or two of the following conditions: (1) The compound is a compound as shown in formula I-1, I-2 or I-3: ； #, &, R b1 L 3 and R A The definition is as described in any one of claims 1 to 8; n is 1, 2, or 3; Ring A is "a 5-10 membered heteroaryl group selected from one, two, or three of N, O, and S, with one, two, three, or four heteroatoms"; and, (2) The compounds mentioned are those shown in formulas I-4 and I-5: or ; R 21a R 21b L 2 L 3 X and R A The definition is as described in any one of claims 1 to 8; Preferably, it satisfies one or more of the following conditions: (1) In equation I-1, L 3 It is -CH2-, -(CH2)2-, -(CH2)3- or -(CH2)5-; wherein one of the -CH2- portions of the -(CH2)5- is optionally replaced by -O-; (2) In equation I-1, R A -OH, -CR 2c R 2d OH, -NH2, or -C(O)NH2; (3) In equation I-1, R 2c For H or C 1-6 alkyl; (4) In equation I-1, R 2d For C3- 10 cycloalkyl, C 1-6 Alkyl or -C 1-4 alkylene-OH; for example, C 1-6 Alkyl or -C 1-4 alkylene-OH; (5) In equation I-2, L 3 It is a single bond, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4- or -(CH2)5-; wherein one of the -CH2- portions of -(CH2)4- and -(CH2)5- is optionally replaced by -O-; (6) In equation I-2, R A -NH-S(O)2R 3c -CR 2c R 2d R 2e -C(O)NH2, "5-10 membered heteroaryl groups selected from one, two, or three of N, O, and S, with one, two, three, or four heteroatoms", -OH, -S(O)2R 2f , by one or more R 1a The substituted "5-10-membered heteroaryl group selected from one, two, or three of N, O, and S, with one, two, three, or four heteroatoms" or "3-10-membered heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" or "substituted by one or more R 1c Replacement C3- 10 cycloalkyl groups or -NHC(O)NH2; (7) In equation I-2, R 2c For H or C 1-6 alkyl; (8) In equation I-2, R 2d C 1-6 Alkyl, C3- 10 cycloalkyl or C 1-6 Halogenated alkyl groups; (9) In Equation I-2, R 2e -OH or -C 1-4 alkylene-OH; In equation (10) I-2, R 2f C 1-6 alkyl; In equation (11) I-2, R 3c C 1-6 alkyl; (12) In Equation I-3, R b1 Independently halogen or C 1-6 Alkoxy; In equation (13) I-3, L 3 It is -CH2- or -(CH2)2-; In equation (14) I-3, R A For -CR 2c R 2d OH, -OH, or -C(O)NH2; In equation (15) I-3, R 2c C 1-6 alkyl; In equation (16) I-3, R 2d C 1-6 alkyl; In equation (17) I-4, R 21a For H or C 1-6 alkyl; In equation (18) I-4, R 21b C 1-6 Alkyl or with one or more R 1 Replacement C 1-6 alkyl; In equation (19) I-4, R 1 It is a halogen; In equation (20) I-4, L 2 It is a single bond or -CH2-; wherein the -CH2- is optionally replaced by -Y 2 -replace; In equation (21) I-4, R Y2 C 1-6 alkyl; In equation (22) I-4, L 3 It is -(CH2)2-; In equation (23) I-4, R A It is -OH; (24) In equation I-4, X is -O- or -S-; In equation (25) I-5, R 21a C 1-6 alkyl; In equation (26) I-5, R 21b C 1-6 alkyl; In equation (27) I-5, L 2 It is a single bond or -CH2-; In equation (28) I-5, L 3 It is -CH2- or -(CH2)2-; In equation (29) I-5, R A For -CR 2c R 2d OH or -OH; In equation (30) I-5, R 2c C 1-6 alkyl; In equation (31) I-5, R 2d C 1-6 Alkyl; and, (32) In formula I-5, X is -O- or -S-.

10. A compound or a pharmaceutically acceptable salt thereof, as shown in any of the following: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

11. A compound as shown in Formula II or III: ； in, and R 21 The definition is as described in any one of claims 1 to 8; R 6a It is a hydroxyl protecting group; preferably ; Preferably, it is any of the following structures: , , , , , , , , , , , , , , , , , , , , , , or .

12. A pharmaceutical composition comprising a compound as claimed in any one of claims 1-10 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient.

13. Use of the compound of any one of claims 1-10 or a pharmaceutically acceptable salt thereof, or of the pharmaceutical composition of claim 12, wherein the use is selected from: (1) Prepare a drug 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; preferably hyperlipidemia or fatty liver; (2) Preparation of a medicament 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; preferably hyperlipidemia or fatty liver; and, (3) Preparation of SREBP pathway inhibitors.

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