Steroid compounds, their preparation methods and applications

Abstract

The present invention discloses a steroid compound, its preparation method, and application. The steroid compound may have a structure as shown in Formula I. The compound of the present invention has SREBP pathway inhibitory activity 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. #imgabs0#

Description

Technical Field

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

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

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

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

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

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

[0007] The technical problem to be solved by the present invention is to provide a new compound having inhibitory activity on the SREBP pathway.

[0008] The present invention provides a compound represented by formula I or a pharmaceutically acceptable salt thereof:

[0009]

[0010] Among them, R 21 -L 1 -C(O)R A 、-L 1 -S(O)2R A 、-L 1 -R B 、 -L 2 -R C or -L 3 -R D ;

[0011] Each L 1 and L 2is independently a single bond, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5- or -(CH2)6-, wherein one of the -CH2- moieties of -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5- and -(CH2)6- is optionally replaced by -X-;

[0012] L 3 is -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5- or -(CH2)6-, wherein one of the -CH2- moieties in -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5- and -(CH2)6- is replaced by -Y-;

[0013] Each X is independently -CHR 5a -、-CR 5a R 5b -、C 3-6 Cycloalkyl, C 3-6 Oxycycloalkyl, C 3-6 Azacycloalkyl or -Y-;

[0014] Each R 5a and R 5b Each independently is F or fluoro C 1-4 alkyl;

[0015] Each Y is independently -O-, -NH-, -N(C 1-4 alkyl)-, -CH=CH-, or -CHR g -;

[0016] R g -C 1-4 Alkylene-OH;

[0017] Each R A are independently -NR 21a R 21b ;

[0018] R B -N(R 21a )-C(O)R 21b or -N(R 21a )-S(O)2R 21b ;

[0019] R D -OH, -CH2OH, R C , -CH(CH3)-OH or -C(CH3)2-OH;

[0020] Each R C are independently -C(R 21c )(R 21d )-OH、-C(R 21c )(R 21d )-CN、CN、-C(O)R E 、NH2、C 1-4 Alkoxy, 3-6 membered heterocycloalkyl or 5-10 membered heteroaryl; the 5-10 membered heteroaryl is unsubstituted or substituted by p R c replace;

[0021] R E C 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl; wherein the C 1-4 Alkoxy, C 3-6 The cycloalkyl and 3-6 membered heterocycloalkyl groups are independently unsubstituted or substituted with m R a replace;

[0022] Each R 21a Independently H, C 1-6 Alkyl or 3-6 membered heterocycloalkyl, wherein the C 1-6 The alkyl group and the 3-6 membered heterocycloalkyl group are independently unsubstituted or substituted with m R a replace;

[0023] Each R 21b Independently H, C 1-6 Alkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are independently unsubstituted or substituted with q R b replace;

[0024] Alternatively, in-NR 21a R 21b In, R 21a and R 21b and the nitrogen atoms connecting them together form a 3-10 membered heterocycloalkyl group, wherein the 3-10 membered heterocycloalkyl group is unsubstituted or substituted by p R c replace;

[0025] Each of m, p and q is independently 1, 2, 3, 4 or 5;

[0026] Each R a 、R b and R cEach independently is F, Cl, OH, COOH, CN, NO2, C 1-4 Alkyl, fluorinated C 1-4 Alkyl, C 1-4 Alkoxy,

[0027] R 21c H, F, C 1-4 Alkyl, fluorinated C 1-4 Alkyl, C 2-4 Alkenyl or C 3-6 Cycloalkyl;

[0028] R 21d F, C 2-4 Alkyl, fluorinated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or -L 4 -R 21e wherein the phenyl group and the 5-6 membered heteroaryl group are independently unsubstituted or replaced by j R d replace;

[0029] Or, R 21c and R 21d and the carbon atoms that connect them together to form C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl;

[0030] L 4 is methylene or ethylene;

[0031] R 21e OH, CN, C 1-4 Alkoxy, phenyl or 5-6 membered heteroaryl, wherein the phenyl and 5-6 membered heteroaryl are independently unsubstituted or substituted by j R d replace;

[0032] Each j is independently 1, 2, 3 or 4;

[0033] Each r is independently 0, 1, 2, 3 or 4;

[0034] Each R d and R f independently F, Cl, OH, CN, NO2, C 1-4 Alkyl, fluorinated C 1-4 Alkyl, fluorinated C 1-4 Alkoxy or C 1-4 alkoxy;

[0035] The number of heteroatoms in the heterocycloalkyl and heteroaryl groups is independently 1, 2, 3 or 4, and each heteroatom is independently N, O or S;

[0036] The compound shown in formula I is not:

[0037] The carbon atoms marked with * in Formula I are in S configuration, R configuration or a mixture of the two.

[0038] In certain preferred embodiments of the present invention, certain groups in the compound of formula I or a pharmaceutically acceptable salt thereof are defined as follows, and the unmentioned groups are the same as those described in any embodiment of the present invention (referred to as "in some embodiments" or "in some preferred embodiments").

[0039] In some embodiments, in the compound of formula I as described in any of the previous schemes, wherein R 21 -L 1 -C(O)R A 、-L 1 -S(O)2R A 、-L 1 -R B 、 -L 2 -R C or -L 3 -R D ;

[0040] Each L 1 and L 2 is independently a single bond, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5- or -(CH2)6-, wherein one of the -CH2- moieties of -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5- and -(CH2)6- is optionally replaced by -X-;

[0041] L 3 is -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5- or -(CH2)6-, wherein one of the -CH2- moieties in -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5- and -(CH2)6- is replaced by -Y-;

[0042] Each X is independently -CHR 5a -、-CR 5a R 5b -or-Y-;

[0043] Each R 5a and R 5b Each independently is F, C 1-4 Alkyl or fluorinated C1-4 alkyl;

[0044] Each Y is independently -O-, -NH-, -N(C 1-4 alkyl)-, -CH=CH-, or -CHR g -;

[0045] R g -C 1-4 Alkylene-OH;

[0046] Each R A are independently -NR 21a R 21b ;

[0047] R B -N(R 21a )-C(O)R 21b ;

[0048] R D -OH, -CH2OH, R C , -CH(CH3)-OH or -C(CH3)2-OH;

[0049] Each R C are independently -C(R 21c )(R 21d )-OH、CN、-C(O)R E 、NH2、C 1-4 Alkoxy, 3-6 membered heterocycloalkyl or 5-10 membered heteroaryl; the 5-10 membered heteroaryl is unsubstituted or substituted by p R c replace;

[0050] R E C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl; wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl and 3-6 membered heterocycloalkyl groups are independently unsubstituted or substituted with m R a replace;

[0051] Each R 21a Independently H, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 3-6The cycloalkyl and 3-6 membered heterocycloalkyl groups are independently unsubstituted or substituted with m R a replace;

[0052] Each R 21b Independently H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are independently unsubstituted or substituted with q R b replace;

[0053] Alternatively, in-NR 21a R 21b In, R 21a and R 21b and the nitrogen atoms connecting them together form a 3-10 membered heterocycloalkyl group, wherein the 3-10 membered heterocycloalkyl group is unsubstituted or substituted by p R c replace;

[0054] Each of m, p and q is independently 1, 2, 3, 4 or 5;

[0055] Each R a 、R b and R c Each independently is F, Cl, OH, COOH, CN, NO2, C 1-4 Alkyl, fluorinated C 1-4 Alkyl, C 1-4 Alkoxy,

[0056] R 21c H, F, C 1-4 Alkyl, fluorinated C 1-4 Alkyl, C 2-4 Alkenyl or C 3-6 Cycloalkyl;

[0057] R 21d F, C 2-4 Alkyl, fluorinated C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or -L 4 -R 21e wherein the phenyl group and the 5-6 membered heteroaryl group are independently unsubstituted or replaced by j R d replace;

[0058] Or, R 21c and R21d and the carbon atoms that connect them together to form C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl;

[0059] L 4 C 1-4 alkylene;

[0060] R 21e OH, CN, C 1-4 Alkoxy, phenyl or 5-6 membered heteroaryl, wherein the phenyl and 5-6 membered heteroaryl are independently unsubstituted or substituted by j R d replace;

[0061] Each j is independently 1, 2, 3 or 4;

[0062] Each r is independently 0, 1, 2, 3 or 4;

[0063] Each R d and R f independently F, Cl, OH, CN, NO2, C 1-4 Alkyl, fluorinated C 1-4 Alkyl or C 1-4 alkoxy;

[0064] The number of heteroatoms in the heterocycloalkyl and heteroaryl groups is independently 1, 2, 3 or 4, and each heteroatom is independently N, O or S;

[0065] The carbon atoms marked with * in Formula I are in S configuration, R configuration or a mixture of the two.

[0066] In some embodiments, in the compound of formula I as described in any of the previous schemes, wherein R 21 -L 1 -C(O)R A 、-L 1 -S(O)2R A 、-L 1 -R B 、 -L 2 -R C or -L 3 -R D ;

[0067] Each L 1 and L 2is independently a single bond, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5- or -(CH2)6-, wherein one of the -CH2- moieties of -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5- and -(CH2)6- is optionally replaced by -X-;

[0068] L 3 is -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5- or -(CH2)6-, wherein one of the -CH2- moieties in -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5- and -(CH2)6- is replaced by -Y-;

[0069] Each X is independently -CHR 5a -、-CR 5a R 5b -or-Y-;

[0070] Each R 5a and R 5b Each independently is F, C 1-4 Alkyl or fluorinated C 1-4 alkyl;

[0071] Each Y is independently -O-, -NH-, -N(C 1-4 alkyl)-, -CH=CH-, or -CHR g -;

[0072] R g -C 1-4 Alkylene-OH;

[0073] Each R A are independently -NR 21a R 21b ;

[0074] R B -N(R 21a )-C(O)R 21b or -N(R 21a )-S(O)2R 21b ;

[0075] R D -OH, -CH2OH, R C , -CH(CH3)-OH or -C(CH3)2-OH;

[0076] Each R Care independently -C(R 21c )(R 21d )-OH、CN、-C(O)R E 、NH2、C 1-4 Alkoxy, 3-6 membered heterocycloalkyl or 5-10 membered heteroaryl; the 5-10 membered heteroaryl is unsubstituted or substituted by p R c replace;

[0077] R E C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl; wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl and 3-6 membered heterocycloalkyl groups are independently unsubstituted or substituted with m R a replace;

[0078] Each R 21a Independently H, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl and 3-6 membered heterocycloalkyl groups are independently unsubstituted or substituted with m R a replace;

[0079] Each R 21b Independently H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are independently unsubstituted or substituted with q R b replace;

[0080] Alternatively, in-NR 21a R 21b In, R 21a and R 21b and the nitrogen atoms connecting them together form a 3-10 membered heterocycloalkyl group, wherein the 3-10 membered heterocycloalkyl group is unsubstituted or substituted by p R c replace;

[0081] Each of m, p and q is independently 1, 2, 3, 4 or 5;

[0082] Each Ra 、R b and R c Each independently is F, Cl, OH, COOH, CN, NO2, C 1-4 Alkyl, fluorinated C 1-4 Alkyl, C 1-4 Alkoxy,

[0083] R 21c H, F, C 1-4 Alkyl, fluorinated C 1-4 Alkyl, C 2-4 Alkenyl or C 3-6 Cycloalkyl;

[0084] R 21d F, C 2-4 Alkyl, fluorinated C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or -L 4 -R 21e wherein the phenyl group and the 5-6 membered heteroaryl group are independently unsubstituted or replaced by j R d replace;

[0085] Or, R 21c and R 21d and the carbon atoms that connect them together to form C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl;

[0086] L 4 C 1-4 alkylene;

[0087] R 21e OH, CN, C 1-4 Alkoxy, phenyl or 5-6 membered heteroaryl, wherein the phenyl and 5-6 membered heteroaryl are independently unsubstituted or substituted by j R d replace;

[0088] Each j is independently 1, 2, 3 or 4;

[0089] Each r is independently 0, 1, 2, 3 or 4;

[0090] Each R d and R f independently F, Cl, OH, CN, NO2, C 1-4 Alkyl, fluorinated C 1-4 Alkyl or C 1-4 alkoxy;

[0091] The number of heteroatoms in the heterocycloalkyl and heteroaryl groups is independently 1, 2, 3 or 4, and each heteroatom is independently N, O or S;

[0092] The carbon atoms marked with * in Formula I are in S configuration, R configuration or a mixture of the two.

[0093] In some embodiments, in the compound of formula I as described in any of the previous schemes, wherein R 21 -L 1 -C(O)R A 、-L 1 -R B 、-L 2 -R C or -L 3 -R D .

[0094] In some embodiments, in the compound of formula I as described in any of the previous embodiments, L 1 It is a single bond, -CH2-, -(CH2)2- or -(CH2)3-.

[0095] In some embodiments, in the compound of formula I as described in any of the previous embodiments, each R 21a are independently H or C 1-6 Alkyl, wherein the C 1-6 The alkyl group is unsubstituted or substituted with m R a Replace; each R 21b Independently H, C 1-6 Alkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are independently unsubstituted or substituted with q R b Substitute; or, in -NR 21a R 21b In, R 21a and R 21b and the nitrogen atoms connecting them together form a 3-10 membered heterocycloalkyl group, wherein the 3-10 membered heterocycloalkyl group is unsubstituted or substituted by p R c replace.

[0096] In some embodiments, in the compound of formula I as described in any of the preceding embodiments, each m, p and q is independently 1 or 2.

[0097] In some embodiments, in the compound of formula I as described in any of the previous embodiments, L 2is -CH2-, -(CH2)2-, -(CH2)3- or -(CH2)4-; wherein one of the -CH2- moieties in said -CH2-, -(CH2)2-, -(CH2)3- and -(CH2)4- is optionally replaced by -X-; each X is independently -CHR 5a -, each R 5a and R 5b Each independently is F; preferably, L 2 It is -(CH2)3-.

[0098] In some embodiments, in the compound of formula I as described in any of the previous embodiments, each R C are independently -C(R 21c )(R 21d )-OH、CN、-C(O)R E 、NH2、C 1-4 Alkoxy, 3-6 membered heterocycloalkyl or 5-10 membered heteroaryl; the 5-10 membered heteroaryl is unsubstituted or substituted by p R c replace.

[0099] In some embodiments, in the compound of formula I as described in any of the previous embodiments, R 21c H or C 1-4 Alkyl; R 21d F, C 2-4 Alkyl, fluorinated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or -L 4 -R 21e wherein the phenyl group and the 5-6 membered heteroaryl group are independently unsubstituted or replaced by j R d Replace; or, R 21c and R 21d and the carbon atoms that connect them together to form C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl.

[0100] In some embodiments, R d are independently F, Cl, OH, CN, C 1-4 Alkyl, fluorinated C 1-4 Alkyl, fluorinated C 1-4 Alkoxy or C 1-4 Alkoxy.

[0101] In some embodiments, in the compound of formula I as described in any of the previous embodiments, R E C 1-4 Alkyl or C 3-6 Cycloalkyl.

[0102] In some embodiments, in the compound of formula I as described in any of the previous embodiments, R D It is -OH, -CH2OH or -C(CH3)2-OH.

[0103] In some embodiments, in the compound of formula I as described in any of the preceding embodiments, each j is independently 1 or 2.

[0104] In some embodiments, in the compound of formula I as described in any of the preceding embodiments, each r is independently 0.

[0105] In some embodiments, in the compound of formula I as described above, each X is independently -CHR 5a -or-CR 5a R 5b -, for example -CHR 5a -.

[0106] In some embodiments, in the compound of formula I as described in any of the previous embodiments, L 1 For a single bond.

[0107] In some embodiments, in the compound of formula I as described in any of the previous embodiments, L 1 -(CH2)2- or -CH2-CHR 5a -.

[0108] In some embodiments, in the compound of formula I as described in any of the previous embodiments, each R 5a and R 5b Each is independently F, methyl, ethyl or trifluoromethyl.

[0109] In some embodiments, in the compound of formula I as described in any of the previous embodiments, L 1 It is -(CH2)3-.

[0110] In some embodiments, in the compound of formula I as described in any of the previous embodiments, L 1 It is -(CH2)4-.

[0111] In some embodiments, in the compound of formula I as described in any of the previous embodiments, L 1 It is -(CH2)5-.

[0112] In some embodiments, in the compound of formula I as described in any of the previous embodiments, L 1 It is -(CH2)6-.

[0113] In some embodiments, in the compound of formula I as described in any of the previous embodiments, R 21 -L1 -C(O)R A .

[0114] In some embodiments, in the compound of formula I as described in any of the previous embodiments, R 21 -L 1 -S(O)2R A .

[0115] In some embodiments, in the compound of formula I as described in any of the previous embodiments, R 21 -L 1 -R B .

[0116] In some embodiments, in the compound of formula I as described in any of the previous embodiments, each R 21a Independently H, C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein the C 1-6 Alkyl and C 3-6 The cycloalkyl groups are independently unsubstituted or substituted with m R a replace.

[0117] In some embodiments, in the compound of formula I as described in any of the preceding embodiments, m is 1, 2 or 3.

[0118] In some embodiments, in the compound of formula I as described in any of the previous embodiments, each R a are independently F, OH, CN or methoxy.

[0119] In some embodiments, in the compound of formula I as described in any of the previous embodiments, each R 21a Independently H, C 1-4 Alkyl, -C 1-4 Alkylene-OH, -C 1-4 Alkylene-OC 1-4 Alkyl, fluorinated C 1-4 Alkyl or cyclopropyl.

[0120] In some embodiments, in the compound of formula I as described in any of the previous embodiments, each R 21a are independently H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, cyclopropyl or trifluoromethyl.

[0121] In some embodiments, in the compound of formula I as described in any of the previous embodiments, each R 21b Independently H, C 1-6 Alkyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C1-6 Alkyl, C 6-10 Aryl and 5-10 membered heteroaryl are independently unsubstituted or substituted with q R b replace.

[0122] In some embodiments, in the compound of formula I as described in any of the previous embodiments, each R 21b are independently H, -C 1-4 Alkylene-OH, -C 1-4 Alkylene-OC 1-4 Alkyl, fluorinated C 1-4 R is alkyl, tetrahydromorpholinyl, phenyl, pyridyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrimidinyl or benzopyrazolyl, wherein the phenyl, pyridyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrimidinyl and benzopyrazolyl are independently unsubstituted or replaced by q R b replace.

[0123] In some embodiments, in the compound of formula I as described in any of the previous embodiments, each R 21b are independently H, -C 1-4 Alkylene-OH, -C 1-4 Alkylene-OC 1-4 Alkyl, fluorinated C 1-4 Alkyl, tetrahydromorpholinyl, phenyl,

[0124] wherein the phenyl group, are independently unsubstituted or substituted by q R b replace.

[0125] In some embodiments, in the compound of formula I as described in any of the preceding schemes, q is 1, 2 or 3.

[0126] In some embodiments, in the compound of formula I as described in any of the previous embodiments, each R b are independently F, Cl, OH, COOH, CN, NO2, methyl, trifluoromethyl, methoxy,

[0127] In some embodiments, in the compound of formula I as described in any of the previous embodiments, each R 21b are independently H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, phenyl,

[0128]

[0129] In some embodiments, in the compound of formula I as described in any of the previous embodiments, each R 21b Independently

[0130] In some embodiments, in the compound of formula I as described in any of the previous embodiments, 21a R 21b In, R 21a and R 21b and the nitrogen atoms that connect them together to form wherein is unsubstituted or replaced by p R c replace.

[0131] In some embodiments, in the compound of formula I as described in any of the preceding embodiments, p is 1, 2 or 3.

[0132] In some embodiments, in the compound of formula I as described in any of the previous embodiments, each R c Each independently is F, OH, CN, C 1-4 Alkyl or fluorinated C 1-4 alkyl.

[0133] In some embodiments, in the compound of formula I as described in any of the previous embodiments, each R c Each is independently F, OH, CN, methyl or trifluoromethyl.

[0134] In some embodiments, in the compound of formula I as described in any of the previous embodiments, 21a R 21b In, R 21a and R 21b and the nitrogen atoms that connect them together to form

[0135] In some embodiments, in the compound of formula I as described in any of the previous embodiments, each R A are independently -NH2,

[0136]

[0137]

[0138] In some preferred embodiments, in the compound of formula I as described in any of the above schemes, each R A Independently

[0139]

[0140]

[0141] In some preferred embodiments, in the compound of formula I as described in any of the above schemes, each R A Independently

[0142] In some preferred embodiments, in the compound of formula I as described in any of the above schemes, -L 1 -C(O)R A for

[0143] In some embodiments, in the compound of formula I as described in any of the previous embodiments, R B for

[0144] In some preferred embodiments, in the compound of formula I as described in any of the above schemes, R B for

[0145] In some embodiments, in the compound of formula I as described in any of the previous embodiments, -L 1 -R B for

[0146] In some embodiments, in the compound of formula I as described in any of the previous embodiments, R 21 -L 2 -R C .

[0147] In some embodiments, in the compound of formula I as described in any of the previous embodiments, L 2 For a single bond.

[0148] In some embodiments, in the compound of formula I as described in any of the previous embodiments, L 2 It is -CH2-.

[0149] In some embodiments, in the compound of formula I as described in any of the previous embodiments, L 2 It is -(CH2)2-.

[0150] In some embodiments, in the compound of formula I as described in any of the previous embodiments, L 2 It is -(CH2)3-.

[0151] In some embodiments, in the compound of formula I as described in any of the previous embodiments, L 2 It is -(CH2)4-.

[0152] In some embodiments, in the compound of formula I as described in any of the previous embodiments, L 2 It is -(CH2)5-.

[0153] In some embodiments, in the compound of formula I as described in any of the previous embodiments, L 2 It is -(CH2)6-.

[0154] In some embodiments, in the compound of formula I as described in any of the previous embodiments, each R C are independently -C(R 21c )(R 21d )-OH.

[0155] In some embodiments, in the compound of formula I as described in any of the previous schemes, when R C -C(R 21c )(R 21d )-OH, R 21c H, R 21d C 2-4 Alkyl, fluorinated C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl, fluorophenyl, 5-6 membered heteroaryl or -L 4 -R 21e .

[0156] In some embodiments, in the compound of formula I as described in any of the previous schemes, when R C -C(R 21c )(R 21d )-OH, R 21c H, R 21d C 2-4 Alkyl, fluorinated C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or -L 4 -R 21e , wherein the phenyl group is optionally replaced by 1 or 2 R d Replace, each R d are independently F, OH, CN or C 1-4 Alkoxy.

[0157] In some embodiments, in the compound of formula I as described in any of the previous embodiments, L 4 It is methylene or ethylene.

[0158] In some embodiments, in the compound of formula I as described in any of the previous embodiments, R21e OH, CN, C 1-4 Alkoxy, phenyl or

[0159] In some embodiments, in the compound of formula I as described in any of the previous embodiments, R C -C(R 21c )(R 21d )-OH is

[0160] In some embodiments, in the compound of formula I as described in any of the previous schemes, when R C -C(R 21c )(R 21d )-OH, R 21c F, R 21d C 2-4 Alkyl (eg, ethyl).

[0161] In some embodiments, in the compound of formula I as described in any of the previous embodiments, R C -C(R 21c )(R 21d )-OH is

[0162] In some embodiments, in the compound of formula I as described in any of the previous schemes, when R C -C(R 21c )(R 21d )-OH, R 21c is CH3 or trifluoromethyl, R 21d C 2-4 alkyl (eg ethyl) or trifluoromethyl.

[0163] In some embodiments, in the compound of formula I as described in any of the previous embodiments, R C -C(R 21c )(R 21d )-OH is

[0164] In some embodiments, in the compound of formula I as described in any of the previous schemes, when R C -C(R 21c )(R 21d )-OH, R 21c C 2-4 Alkyl, C 2-4 Alkenyl (e.g. ) or C 3-6 Cycloalkyl (e.g. cyclopropyl), R 21d C2-4 Alkyl, C 2-4 Alkenyl (e.g. ) or C 3-6 Cycloalkyl (eg, cyclopropyl).

[0165] In some embodiments, in the compound of formula I as described in any of the previous schemes, when R C -C(R 21c )(R 21d )-OH, R 21c For ethyl, n-propyl, isopropyl, or cyclopropyl, R 21d For ethyl, n-propyl, isopropyl, or cyclopropyl.

[0166] In some embodiments, in the compound of formula I as described in any of the previous embodiments, R C -C(R 21c )(R 21d )-OH is

[0167]

[0168] In some embodiments, in the compound of formula I as described in any of the previous schemes, when R C -C(R 21c )(R 21d )-OH, R 21c and R 21d and the carbon atoms that connect them together to form C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl (e.g. ).

[0169] In some embodiments, in the compound of formula I as described in any of the previous schemes, when R C -C(R 21c )(R 21d )-OH, R 21c and R 21d and the carbon atoms connecting them together form cyclopropyl, cyclobutyl or

[0170] In some embodiments, in the compound of formula I as described in any of the previous embodiments, R C -C(R 21c )(R 21d )-OH is

[0171]

[0172] In some preferred embodiments, in the compound of formula I as described in any of the above schemes, R C-C(R 21c )(R 21d )-OH is

[0173]

[0174] In some preferred embodiments, in the compound of formula I as described in any of the above schemes, R C -C(R 21c )(R 21d )-OH is

[0175]

[0176] In some embodiments, in the compound of formula I as described in any of the previous schemes, R C For CN.

[0177] In some embodiments, in the compound of formula I as described in any of the previous embodiments, R C -C(O)R E .

[0178] In some embodiments, in the compound of formula I as described in any of the previous embodiments, R E C 1-4 Alkyl or C 3-6 Cycloalkyl.

[0179] In some embodiments, in the compound of formula I as described in any of the previous embodiments, R E is methyl, ethyl or cyclohexyl.

[0180] In some embodiments, in the compound of formula I as described in any of the previous embodiments, R C is NH2.

[0181] In some embodiments, in the compound of formula I as described in any of the previous embodiments, R C C 1-4 Alkoxy groups, such as methoxy groups.

[0182] In some embodiments, in the compound of formula I as described in any of the previous embodiments, R C for For example

[0183] In some embodiments, in the compound of formula I as described in any of the previous schemes, R C for For example

[0184] In some embodiments, in the compound of formula I as described in any of the previous embodiments, RC for For example

[0185] In some embodiments, in the compound of formula I as described in any of the previous embodiments, R C is a 5-10 membered heteroaryl group, wherein the 5-10 membered heteroaryl group is unsubstituted or substituted by p R c replace.

[0186] In some embodiments, in the compound of formula I as described in any of the previous embodiments, R C The 5-10 membered heteroaryl group in the definition is

[0187] In some embodiments, in the compound of formula I as described in any of the previous embodiments, R C for

[0188] In some embodiments, in the compound of formula I as described in any of the previous embodiments, R C It is a 3-6 membered heterocycloalkyl group.

[0189] In some embodiments, in the compound of formula I as described in any of the previous embodiments, R C The 3-6 membered heterocycloalkyl group in the definition is

[0190] In some preferred embodiments, in the compound of formula I as described in any of the above schemes, -L 2 -R C for

[0191]

[0192] In some preferred embodiments, in the compound of formula I as described in any of the above schemes, -L 2 -R C for

[0193] In some embodiments, in the compound of formula I as described in any of the previous embodiments, R 21 -L 3 -R D .

[0194] In some embodiments, in the compound of formula I as described in any of the previous embodiments, L 3 for

[0195]

[0196] The b-end of the above structure is connected to R D connect.

[0197] In some embodiments, in the compound of formula I as described in any of the previous embodiments, R D -OH, -CH2OH, -CH(CH3)-OH or -C(CH3)2-OH.

[0198] In some embodiments, in the compound of formula I as described in any of the previous embodiments, R 21 -L in 3 -R D for

[0199] In some preferred embodiments, in the compound of formula I as described in any of the above schemes, R 21 -L in 3 -R D for

[0200]

[0201] In some preferred embodiments, in the compound of formula I as described in any of the above schemes, R 21 -L in 3 -R D for In some embodiments, in the compound of formula I as described in any of the previous embodiments, R 21 for In some embodiments, in the compound of formula I as described in any of the previous embodiments, R 21 for In some embodiments, in the compound of formula I as described in any of the previous embodiments, R 21 for In some embodiments, in the compound of formula I as described in any of the previous embodiments, R 21 for In some embodiments, in the compound of formula I as described in any of the previous embodiments, R 21 for In some embodiments, in the compound of formula I as described in any of the previous embodiments, R 21 for

[0202]

[0203]

[0204] In some embodiments, in the compound represented by Formula I as described in any of the preceding schemes, the carbon atom marked with * in Formula I is in S configuration.

[0205] In some embodiments, in the compound represented by Formula I as described in any of the preceding schemes, the carbon atom marked with * in Formula I is in R configuration.

[0206] In some embodiments, in the compound represented by Formula I as described in any of the previous schemes, the carbon atom marked with * in Formula I is a mixture of S configuration and R configuration, for example, S configuration: R configuration = 1:1.

[0207] In some embodiments, the compound represented by Formula I is a compound represented by Formula I-1 or I-2:

[0208]

[0209] Among them, R 21 The definition of is as described in any one of the present invention.

[0210] In some embodiments, the compound represented by Formula I is any of the following compounds:

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225] The compounds of the present invention can be prepared from known starting materials (e.g., lanosterol) via various conventional reaction methods in the art (e.g., hydroxyl protection, double bond ozone oxidation, Wittig reaction, hydrolysis, amide condensation, Grignard reagent addition reaction, reduction reaction, nucleophilic substitution reaction, and epoxidation reaction). Exemplary preparation methods are described in the preparation examples of this application.

[0226] For example, the preparation method of compound 37 and its analogues can be obtained by using lanosterol as the starting material, and then undergoing hydroxyl protection, double bond ozone oxidation, Wittig reaction, hydrolysis, and condensation to obtain compound 37 and its analogues; the reaction scheme is shown below:

[0227]

[0228] For example, the preparation method of compound 101 and its analogues can be carried out by using lanosterol as the starting material, and then undergoing hydroxyl protection, double bond ozone oxidation, Wittig reaction, hydrolysis, and Grignard reagent addition reaction to obtain compound 101 and its analogues; the reaction scheme is shown below:

[0229]

[0230] For example, the preparation method of compound 80 and its analogues can be obtained by using lanosterol as a raw material, and performing hydroxyl protection, double bond ozonation, reduction, two-step substitution, and addition reaction to obtain compound 80 and its analogues; the reaction scheme is shown below:

[0231]

[0232] For example, the preparation method of compound 125 and its analogues can be carried out by using lanosterol as a raw material, and finally obtaining compound 125 and its analogues through hydroxyl protection, double bond ozone oxidation, Wittig reaction, hydrolysis, epoxidation, and hydrolysis. The reaction scheme is shown below:

[0233]

[0234] For example, the preparation method of compound 193 and its analogs can be carried out by using lanosterol as the starting material, and undergoing hydroxyl protection, double bond ozone oxidation, double bond shift, double bond ozone oxidation, reductive amination, condensation, and hydrolysis to obtain compound 193. The reaction scheme of the preparation method is as follows:

[0235]

[0236] For example, the preparation method of compound 199 and its analogs uses (22E,24S)-stigmaster-6(5),22(23)-diene-3β-ol as the starting material, and undergoes hydroxyl protection, double bond ozone oxidation, Wittig reaction, hydrolysis, Wittig reaction, double bond reduction, addition of an organolithium reagent, and epoxidation to obtain product 199. The reaction scheme of the preparation method is as follows:

[0237]

[0238] 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.

[0239] The present invention also provides a use of the above-mentioned compound or a pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition in the preparation of a medicament for preventing and / or treating a disease, wherein the disease is obesity, hyperlipidemia, fatty liver, diabetes, atherosclerosis, cardiovascular and cerebrovascular diseases, liver cancer or skin damage.

[0240] The present invention also provides a use of the above-mentioned compound or a pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition in the preparation of a drug for inhibiting the SREBP pathway.

[0241] The present invention also provides a method for inhibiting the SREBP pathway, comprising administering an effective amount of the compound as described above or a pharmaceutically acceptable salt thereof to a subject.

[0242] The present invention also provides a method for preventing and / or treating a disease, comprising administering an effective amount of the compound as described above or a pharmaceutically acceptable salt thereof to a subject, wherein the disease is obesity, hyperlipidemia, fatty liver, diabetes, atherosclerosis, cardiovascular and cerebrovascular diseases, liver cancer, or skin damage.

[0243] Definition and Description

[0244] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0245] As used herein, the term "substituted" or "substituent" refers to the replacement of a hydrogen atom in a group with a specified group. When the position of substitution is not specified, substitution can be made at any position, but only if a stable or chemically feasible compound is formed. Examples are as follows: The structure shows that the hydrogen atoms on the benzene ring are replaced by q R 8When there are multiple R 8 When each R 8 Same or different.

[0246] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0247] When the linking group listed herein does not specify its connection direction, the connection direction can be arbitrary, including connection from left to right or from right to left. For example, in the following example, if the linking group L in -ALB is -CD-, when the connection direction of L is not specified, -ALB includes -ACDB and -ADCB.

[0248] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0249] As used herein, the term "alkyl" refers to a saturated, linear or branched, monovalent hydrocarbon group. A C1-C6 alkyl group represents an alkyl group having 1 to 6 carbon atoms. In some embodiments, the C1-C6 alkyl group may be a C1-C4 alkyl group. C1-C4 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0250] As used herein, the term "alkenyl" refers to a linear or branched monovalent hydrocarbon group containing at least one carbon-carbon double bond. When an alkenyl group contains both saturated and unsaturated carbon atoms, it can be connected to other structures via either a saturated carbon atom or an unsaturated carbon atom. C2-C4 alkenyl refers to an alkenyl group having 2, 3, or 4 carbon atoms. Specific examples of alkenyl groups include, but are not limited to, vinyl and allyl.

[0251] As used herein, the term "alkylene" refers to a saturated, linear or branched divalent hydrocarbon group. C1-C4 alkylene refers to an alkylene group having 1 to 4 carbon atoms, specifically methylene, ethylene (e.g., -CH2CH2-, -CH(CH3)-), propylene (e.g., -CH2CH2CH2-, -C(CH3)2-, -CH2CH(CH3)-), butylene (e.g., -CH2CH2CH2CH2-, -CH(CH3)CH(CH3)-, -CH2CH(CH3)CH2-).

[0252] As used herein, the term "fluoroalkyl" refers to a group in which one or more hydrogen atoms in an alkyl group are replaced by fluorine, wherein the definition of alkyl is as described above. Examples of fluoroalkyl groups include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, and pentafluoroethyl.

[0253] As used herein, the term "alkoxy" refers to an -O-alkyl group, where alkyl is as defined above. A C1-C4 alkoxy group refers to an -O-(C1-C4 alkyl group), where C1-C4 alkyl is as defined above, i.e., the C1-C4 alkoxy group can specifically be a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, or a tert-butoxy group.

[0254] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., fused, spiro, or bridged) cyclic hydrocarbon group. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 3-10 The cycloalkyl group can be C3, C4, C5, C6, C7, C8, C9, C 10 Cycloalkyl. C 3-6 The cycloalkyl group may specifically be a C3, C4, C5, or C6 cycloalkyl group. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is polycyclic (e.g., a fused ring, a spiro ring, or a bridged ring).

[0255] As used herein, the term "heterocycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., cyclic, spirocyclic, or bridged) cyclic group formed by carbon atoms and at least one heteroatom, wherein the heteroatoms are independently selected from N, O, and S. Heterocycloalkyl can be connected to other structures through the carbon atoms and heteroatoms on the ring. Examples of heterocycloalkyl include, but are not limited to Tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl. 3-10 membered heterocycloalkyl groups may specifically be 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl groups. 3-6 membered heterocycloalkyl groups may specifically be 3-, 4-, 5-, or 6-membered heterocycloalkyl groups. In some embodiments, the heterocycloalkyl group is monocyclic. In some embodiments, the heterocycloalkyl group is polycyclic (e.g., fused ring, spirocyclic ring, or bridged ring).

[0256] In this article, the term “C 6-10 "Aryl" means phenyl or naphthyl.

[0257] As used herein, the term "heteroaryl" refers to an aromatic monocyclic or fused ring group formed by carbon atoms and at least one heteroatom, wherein the heteroatoms are independently selected from N, O, and S. A 5-10 membered heteroaryl group can specifically be a 5, 6, 7, 8, 9, or 10 membered heteroaryl group, such as a 5-6 membered heteroaryl group or an 8-10 membered fused heteroaryl group. A 5-6 membered heteroaryl group is a monocyclic group, and specific examples include but are not limited to pyrrole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, pyridine, pyrimidine, and pyrazine. Examples of 8-10 membered fused heteroaryls include but are not limited to benzopyrrole, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzopyrazole, benzimidazole, benzopyridine, benzopyrimidine, benzopyrazine, thiazolothiazole, pyridopyridine, pyridopyrazine, and pyridopyrimidine.

[0258] In this article, the chemical structure Indicates the connection location. Contained in a cyclic group and not specified When the ring atoms are connected, Attachment to any ring atom is permitted, but only if it results in a stable or chemically feasible compound. For example, include etc. structures.

[0259] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed with a compound using a suitable non-toxic organic acid, inorganic acid, organic base, or inorganic base that retains the biological activity of the compound. The organic acid may be any conventional organic acid capable of forming a salt, preferably one or more of methanesulfonic acid, p-toluenesulfonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, malic acid, lactic acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid, oxalic acid, succinic acid, benzoic acid, isethionic acid, naphthalenesulfonic acid, and salicylic acid. The inorganic acid may be any conventional inorganic acid capable of forming a salt, preferably one or more of hydrochloric acid, sulfuric acid, and phosphoric acid. The organic base may be any conventional organic base capable of forming a salt, preferably one or more of pyridines, imidazoles, pyrazines, indoles, purines, tertiary amines, and anilines. The tertiary amine organic base is preferably triethylamine and / or N,N-diisopropylethylamine. The aniline organic base is preferably N,N-dimethylaniline. The pyridine organic base is preferably one or more of pyridine, picoline, 4-dimethylaminopyridine and 2-methyl-5-ethylpyridine. The inorganic base can be any conventional inorganic base capable of forming a salt in the art, preferably one or more of alkali metal hydrides, alkali metal hydroxides, alkali metal alkoxides, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, potassium bicarbonate and sodium bicarbonate. The alkali metal hydride is preferably sodium hydride and / or potassium hydride. The alkali metal hydroxide is preferably one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide. The alkali metal alkoxide is preferably one or more of sodium methoxide, sodium ethoxide, potassium tert-butoxide and sodium tert-butoxide.

[0260] In chemical structures, the absolute configuration of a stereocenter is represented by a wedge-shaped solid bond and a wedge-shaped dashed bond, and the relative configuration of a stereocenter is represented by a straight solid bond and a straight dashed bond. The bond " / " does not specify the configuration, that is, if there is a configurational isomerism in the chemical structure, the bond " / " can be or or include both and Two configurations (e.g. and The ratio is 1:1). When the specific configuration of a carbon-carbon double bond is not specified, it may be E or Z. Stereoisomers can be synthesized using chiral starting materials, prepared by chiral resolution, or resolved using conventional techniques such as, but not limited to, high performance liquid chromatography (HPLC) using a chiral column.

[0261] As used herein, the term "subject" includes any animal, preferably a mammal, and more preferably a human.

[0262] As used herein, the term "effective amount" refers to a non-toxic amount of a drug or pharmaceutical agent sufficient to achieve the desired effect. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0263] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0264] The reagents and raw materials used in the present invention are commercially available.

[0265] The positive progress of the present invention is that the present invention provides a new class of compounds that have inhibitory activity on the SREBP pathway and can be used to prevent and / or treat diseases such as obesity, hyperlipidemia, fatty liver, diabetes, atherosclerosis, cardiovascular and cerebrovascular diseases, liver cancer, and skin damage. BRIEF DESCRIPTION OF THE DRAWINGS

[0266] Figure 1 25-Hydroxylanosterol inhibits the weight gain induced by AMLN diet in mice.

[0267] Figure 2 The effect of 25-hydroxylanosterol on the food intake of mice.

[0268] Figure 3 25-Hydroxylanosterol reduces the total cholesterol content in the blood of mice.

[0269] Figure 4 25-Hydroxylanosterol reduces the total triglyceride content in the blood of mice.

[0270] Figure 5 25-Hydroxylanosterol reduces the total cholesterol content in mouse liver.

[0271] Figure 6 25-Hydroxylanosterol reduces the total triglyceride content in mouse liver.

[0272] Figure 7 25-Hydroxylanosterol reduces the blood aspartate aminotransferase (AST) level in mice.

[0273] Figure 8 25-Hydroxylanosterol reduces the blood alanine aminotransferase (ALT) level in mice.

[0274] Figure 9 HE staining results of mouse liver sections: C57BL / 6J CD group.

[0275] Figure 10 HE staining results of mouse liver sections: Ldlr - / -CD set.

[0276] Figure 11 HE staining results of mouse liver sections: Ldlr - / - AMLN group.

[0277] Figure 12 HE staining results of mouse liver sections: Ldlr - / - AMLN+25-HL group.

[0278] Figure 13 The results of HE staining of liver sections and quantitative statistical results of NAFLD activity scores of the four groups of mice are shown.

[0279] Figure 14 Oil Red O staining results of mouse liver sections: C57BL / 6J CD group.

[0280] Figure 15 Oil red O staining results for mouse liver sections: Ldlr - / - CD set.

[0281] Figure 16 Oil red O staining results for mouse liver sections: Ldlr - / - AMLN group.

[0282] Figure 17 Oil red O staining results for mouse liver sections: Ldlr - / - AMLN+25-HL group.

[0283] Figure 18 Quantitative results of Oil Red O staining of liver sections of mice in four groups.

[0284] Figure 19 The results of Sirius red staining of mouse liver sections: C57BL / 6J CD group.

[0285] Figure 20 Sirius red staining results for mouse liver sections: Ldlr - / - CD set.

[0286] Figure 21 Sirius red staining results for mouse liver sections: Ldlr - / - AMLN group.

[0287] Figure 22 Sirius red staining results for mouse liver sections: Ldlr - / - AMLN+25-HL group.

[0288] Figure 23 The quantitative results of Sirius red staining of liver sections of four groups of mice.

[0289] Figure 24The results of F4 / 80 immunostaining of mouse liver sections and polarized light imaging indicating cholesterol crystals: C57BL / 6J CD group.

[0290] Figure 25 The results of F4 / 80 immunostaining of mouse liver sections and polarized light imaging indicating cholesterol crystals: Ldlr - / - CD set.

[0291] Figure 26 The results of F4 / 80 immunostaining of mouse liver sections and polarized light imaging indicating cholesterol crystals: Ldlr - / - AMLN group.

[0292] Figure 27 The results of F4 / 80 immunostaining of mouse liver sections and polarized light imaging indicating cholesterol crystals: Ldlr - / - AMLN+25-HL group.

[0293] Figure 28 The quantitative results of F4 / 80 immunostaining of liver sections of mice in four groups.

[0294] Figure 29 Polarized light imaging of liver sections from four groups of mice indicates quantitative imaging results of cholesterol crystals.

[0295] Figure 30 Sudan IV staining results of mouse aortic tree: C57BL / 6J CD group.

[0296] Figure 31 Sudan IV staining results for the mouse aortic tree: Ldlr - / - CD set.

[0297] Figure 32 Sudan IV staining results for the mouse aortic tree: Ldlr - / - AMLN group.

[0298] Figure 33 Sudan IV staining results for the mouse aortic tree: Ldlr - / - AMLN+25-HL group.

[0299] Figure 34 Quantitative results of Sudan IV staining of the aortic tree of four groups of mice.

[0300] Figure 35 25-Hydroxylanosterol reduces the expression of lipid-generating related genes (Hmgcs, Hmgcr, SCD1, FASN) in liver organoids.

[0301] Figure 3625-Hydroxylanosterol reduces the expression of fibrosis-related genes (Col1a1, αSMA) in liver organoids.

[0302] Figure 37 Brightfield imaging results of mouse liver organoids: vehicle control group.

[0303] Figure 38 Bright field imaging results of mouse liver organoids: obeticholic acid 1μM group.

[0304] Figure 39 Bright field imaging results of mouse liver organoids: obeticholic acid 3μM group.

[0305] Figure 40 Bright field imaging results of mouse liver organoids: 25-HL 1μM group.

[0306] Figure 41 Bright field imaging results of mouse liver organoids: 25-HL 3μM group.

[0307] Figure 42 Nile red staining results of mouse liver organoids: vehicle control group.

[0308] Figure 43 Nile red staining results of mouse liver organoids: obeticholic acid 1μM group.

[0309] Figure 44 Nile red staining results of mouse liver organoids: obeticholic acid 3μM group.

[0310] Figure 45 Nile red staining results of mouse liver organoids: 25-HL 1μM group.

[0311] Figure 46 Nile red staining results of mouse liver organoids: 25-HL 3μM group.

[0312] Figure 47 Quantitative results of Nile red staining of 5 groups of mouse liver organoids.

[0313] Figure 48 Immunofluorescence staining results of fibrosis marker protein αSMA in mouse liver organoids: vehicle control group.

[0314] Figure 49 The results of immunofluorescence staining of the fibrosis marker protein αSMA in mouse liver organoids: obeticholic acid 1μM group.

[0315] Figure 50 The results of immunofluorescence staining of the fibrosis marker protein αSMA in mouse liver organoids: obeticholic acid 3μM group.

[0316] Figure 51 The results of immunofluorescence staining of fibrosis marker protein αSMA in mouse liver organoids: 25-HL 1μM group.

[0317] Figure 52 The results of immunofluorescence staining of fibrosis marker protein αSMA in mouse liver organoids: 25-HL 3μM group.

[0318] Figure 53 The quantitative results of immunofluorescence staining of fibrosis marker protein αSMA in 5 groups of mouse liver organoids. DETAILED DESCRIPTION

[0319] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0320] In the following examples, 25-hydroxylanosterol (25-HL) refers to the compound of Example 68.

[0321] Biological Test Examples

[0322] Animals: Adult male C57BL / 6J mice were purchased from Shanghai Slake Company. Low-density lipoprotein receptor gene knockout mice (Ldlr - / - Mice (T001464) were purchased from Jiangsu Jicui Pharmaceutical Biotechnology Co., Ltd. Mice were maintained under pathogen-free conditions with a 12-hour light / dark cycle and free access to water and feed. The gavage medium consisted of 0.5% Tween-80, 0.5% methylcellulose, and 0.9% sodium chloride. AMLN feed (AMLN, Dyets) contained 40% (kcal) fat (80% of which was trans fat), 22% (wt) fructose, and 2% (wt) cholesterol.

[0323] Reagents: Mevalonic acid (41288), paraformaldehyde (P6148), Tween-80 (P8074), methylcellulose (V900506), Oil Red O (O0625), and the nuclear stain DAPI were purchased from Sigma-Aldrich. Lovastatin (purity ≥98.5%, HPLC) was purchased from Shanghai Yaogu Company. Dulbecco's modified eagle medium (DMEM) for cell culture was purchased from Thermo Scientific, and fetal bovine serum (S1580) was purchased from Biowest. Lipoprotein-depleted serum (LPDS) was prepared in our laboratory by ultracentrifugation. Obeticholic acid (OCA, CAS registration number 459789-99-2, purity 98% (HPLC). Total cholesterol and total triglyceride assay kits were purchased from Shanghai Kehua Bioengineering Co., Ltd. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) assay kits were purchased from Lai Er Bio-tech. Hematoxylin-eosin staining kits (6765001, 6766010) were purchased from Thermo Scientific. Sirius red staining kit (ab150681) was purchased from Abcam. Sudan Red IV (A610914) was purchased from Sangon Biotech (Shanghai) Co., Ltd. Nile red (HY-D0718) was purchased from MCE.

[0324] Antibodies: The antibodies used for immunofluorescence staining analysis are as follows: anti-alpha smooth muscle actin (αSMA, ab7817, 1:500) antibody was purchased from Abcam; the secondary antibody fluorescein (FITC)-conjugated goat anti-mouse IgG (H+L) (115-095-003) was purchased from Jackson Immunoresearch. The primary antibody anti-F4 / 80 (14-4801-85, Invitrogen, 1:100) and the secondary fluorescent antibody Alexa Fluor Plus 488-conjugated goat anti-rat IgG (A-11006, 1:500) were purchased from Invitrogen.

[0325] Biological Test Example 1: Cell Culture

[0326] The human hepatocellular carcinoma cell line Huh-7 / SRE-Luc was grown in a medium containing DMEM, 10% fetal bovine serum, 100 units / ml penicillin, 100 μg / ml streptomycin and 200 μg / ml G418.

[0327] Biological test example 2: SREBP luciferase reporter gene system

[0328] The Huh-7 / SRE-Luc cell line is a human hepatocellular carcinoma cell line, Huh-7, that stably expresses the LDLR promotor-luciferase and green fluorescent protein (GFP). The LDLR promotor region contains a sterol-regulatory element (SRE), which effectively and sensitively responds to regulation by the transcription factor SREBP. The GFP signal serves as an internal control, indicating changes in cell number. Therefore, this cell line can be used to screen for active small molecules that regulate the SREBP signaling pathway. In our work, we used this cell line to screen for inhibitors that effectively inhibit the SREBP signaling pathway. Cells were incubated in sterol-deficient medium (5% delipidated serum, 2 μM lovastatin, 10 μM mevalonic acid) and treated with the corresponding concentrations of compounds for 16 hours. After the compound treatment, the cells were lysed with lysis buffer (E397A, Promega), and after adding luciferase substrate (E1500, Promega), the activity of SRE-driven luciferase was measured by BioTek Synergy HTX microplate reader (including but not limited to this type of instrument). The fluorescence intensity of green fluorescent protein (EGFP) was also measured by the above-mentioned BioTek microplate reader (including but not limited to this type of instrument) and used as an internal reference. The ratio of SRE-driven luciferase activity divided by the fluorescence intensity of green fluorescent protein was used as an indicator of SREBP pathway activity. The test data of each test compound was analyzed by prism software to obtain the IC value of the compound. 50 parameter.

[0329] Biological test example 3: Real-time fluorescence quantitative PCR

[0330] Liver or liver organoid samples were homogenized in TRI Reagent (T9424, Sigma), and total RNA was extracted according to the manufacturer's protocol. Equal amounts of RNA template were used to synthesize cDNA using oligo dT primers and MLV reverse transcriptase (Promega). Gene quantitative data were collected using a Bio-Rad CFX96 real-time PCR system, and relative mRNA levels were quantified using the relative CT method. The primer sequences used are shown in the table below:

[0331]

[0332]

[0333] Biological Test Example 4 Measurement of Serum and Liver Metabolic Parameters

[0334] After drug treatment, the mice were starved for 4 hours after the feed was removed and the mice were killed, and blood and liver were collected. After the blood coagulated, it was centrifuged at 4°C 1500g for 10 minutes, and the supernatant was serum. The lipids in the liver were extracted by the chloroform / methanol method, first homogenized and broken with a homogenizer Precelly 24, centrifuged at 4°C 16000g for 10 minutes, and the organic phase was transferred to a new tube, blown dry with nitrogen, and then dissolved with ethanol. The total cholesterol and triglyceride levels in the blood and liver were measured by cholesterol and triglyceride kits (Shanghai Kehua Bioengineering Co., Ltd.), respectively. ALT (LE-M0477, Lai Er Bio-tech) and AST (LE-M0568, Lai Er Bio-tech) in the serum were measured using the analysis system of Sysmex Medical Electronics (Shanghai) Co., Ltd. according to the manuals of the corresponding manufacturers.

[0335] Biological Test Example 5: Analysis of Liver Tissue Sections

[0336] Hematoxylin-eosin staining: The excised livers were fixed with 4% paraformaldehyde overnight at 4°C, embedded in paraffin, and sectioned at 7 μm using a paraffin microtome (Leica RM2235). After dewaxing and rehydration, sections were stained using a hematoxylin-eosin staining kit (6765001, 6766010, Thermo Scientific). Images were captured using an Olympus VS 120 slide microscope and quantified using ImageJ software. Oil Red O staining: The livers were embedded in OCT embedding medium (Leica), sectioned at 7 μm using a cryostat (Leica CM1950), and stained with Oil Red O (O0625, Sigma). Images were captured using an Olympus VS 120 slide microscope and quantified using ImageJ software. Sirius Red collagen staining: Paraffin sections of the livers were dewaxed and rehydrated, then stained using a Sirius Red staining kit (ab150681, Abcam) according to the manufacturer's instructions. Immunofluorescence staining: Livers were embedded in OCT embedding medium (Leica) and cut into 7 μm thick sections using a cryostat (Leica CM1950). Cryosections were stained with an anti-F4 / 80 rat monoclonal antibody (14-4801-85, Invitrogen, 1:100), an Alexa Fluor 488-conjugated goat anti-rat IgG secondary antibody (A-11006, Invitrogen, 1:500), and DAPI (Sigma)30 for nuclei staining. After staining and mounting, images were taken using a spinning disk confocal microscope (Nikon CSU-W1 SoRa) and quantitatively analyzed using ImageJ software. Polarized light imaging of cholesterol crystals: Cryosections stained with F4 / F80 and DAPI were photographed using a spinning disk confocal microscope (Nikon CSU-W1 SoRa) equipped with a polarizing filter, and quantified using ImageJ software.

[0337] Biological Test Example 6 Isolation of Mouse Arterial Tree and Sudan IV Staining of Atherosclerotic Plaques

[0338] After the mouse dosing experiment, the aorta was isolated and fixed in 4% PFA. Perivascular adipose tissue was removed using ophthalmic forceps under a stereomicroscope and then stained with Sudan IV. Atherosclerotic plaques were cleaned with 70% ethanol. After staining, the aortic tree was imaged using a ZEISS Axio Zoom.V16 stereomicroscope. Atherosclerotic lesions were quantified using ImageJ software.

[0339] Biological Test Example 7 Preparation and Culture of Mouse Liver Organoids

[0340] C57BL / 6N mice were fed a fatty liver-inducing diet (TrophicDiet, TP2630052A, containing 10.2% kcal protein, 37.3% kcal carbohydrates, and 52.6% kcal fat) and fructose-containing drinking water (23.1 g fructose and 18.9 g glucose dissolved in 1 L of water and then filter-sterilized) for 16 weeks at 12 weeks of age to establish a fatty liver model. To generate fatty liver organoids, liver tissue from fatty liver mice was minced and digested in digestion buffer at 37°C for 30-60 minutes. The digestion buffer consisted of DMEM / F-12 (Cytiva, SH30023.01) and 2.5 mg / mL collagenase D (Roche, COLLD-RO) and 0.1 mg / mL DNaseI (Sigma-Aldrich, DN25). Isolated single hepatocytes were filtered through a 70 μm filter and washed once. Cells were harvested by centrifugation and resuspended in culture medium mixed with basement membrane extract (BME) (R&D Systems, 3533-010-02) at a 1:3 ratio. The culture medium consisted of AdDMEM / F12, 10 mM Hepes, 1x Glutamax, 1% pen / strep, 1x B27, 1x N2, NAC (1 mM), NIC (10 mM), gastrin (10 nM), EGF (50 ng / mL), FGF10 (100 ng / mL), A83-01 (5 μM), Rki (10 μM), 10% RSPO1-conditioned medium, 30% Wnt3a-conditioned medium, and 5% Noggin-conditioned medium. Prior to dosing, organoids were trypsinized (Gibco, Cat# 25200072) and resuspended. After 24 hours, the organoids were fed with culture medium containing various concentrations of OCA or 25-HL, with DMSO as a blank control. Fatty liver organoids were divided into five groups (1‰ DMSO, 1μM OCA, 3μM OCA, 1μM 25-HL, and 3μM 25-HL) and treated with drugs for 72 h.

[0341] Biological Test Example 8 Histochemical Staining of Mouse Liver Organoids

[0342] Immunocytochemistry: Organoids were fixed in immunostaining fixative (Beyotime Biotechnology, P0098) at 4°C overnight. They were then washed in PBS and treated with PBS containing 0.5% Triton X-100 for 20 minutes at room temperature. The organoids were then treated with PBS blocking solution containing 10% goat serum for 1 hour at room temperature and incubated with the primary antibody (Anti-alpha smooth muscle Actin, ab7817, Abcam, 1:500 dilution) at 4°C overnight. The next day, the organoids were washed and incubated with the secondary antibody fluorescein (FITC)-conjugated goat anti-mouse IgG (H+L) (Jackson Immunoresearch, 115-095-003). The nuclei were stained with fluorescent shield. TM Counterstained with DAPI (Sigma-Aldrich, F6057).

[0343] To visualize lipid droplets, organoids were fixed with 4% paraformaldehyde (PFA) for 1 hour and stained with 250 nmol / L Nile Red (MCE, HY-D0718) for 3 minutes at room temperature. Organoids were rinsed twice with PBS before imaging. The stained organoids were observed using a Dragonfly high-speed confocal microscope (Andor, Dragonfly 200).

[0344] Biological Test Example 9 Inhibitory Effects of the Compounds of the Present Invention on SREBP Pathway

[0345] The inhibitory effect of the compounds of the present invention on the SREBP pathway was tested by the method of biological test Example 2. The concentration gradient of each compound was designed to be 0.01, 0.03, 0.1, 0.3, 1.0, 3.0, and 10 μM, and the control was the solvent DMSO. IC of some compounds 50 The values are shown in Table 1.

[0346] Table 1: Activity data of some compounds in the examples

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370] Biological Test Example 10 25-Hydroxylanosterol Reduces Blood Lipid Levels, Alleviates Fatty Liver and Liver Damage

[0371] Elevated blood lipid levels and hepatic lipid accumulation are known to be high-risk factors for fatty liver disease. The present invention further analyzed whether 25-hydroxylanosterol can alleviate the typical symptoms of diet-induced fatty liver in mice: lipid accumulation, liver damage, inflammation and fibrosis.

[0372] Purchase 8-week-old male C57BL / 6J mice and male Ldlr - / - Mice (T001464, Jiangsu Jicui Pharmaceutical Biotechnology Co., Ltd.) were divided into groups and fed with different feeds and given different drug treatments. The mice were randomly divided into 4 groups, with 8-9 mice in each group: Group 1 was C57BL / 6J wild-type mice fed with a basic diet (chow diet, CD) and a vehicle control group. The other 3 groups were Ldlr - / -Knockout mice were placed in a basal diet (CD) vehicle control group, an AMLN diet (20% fat, 22% fructose, and 2% cholesterol) vehicle control group, and an AMLN diet supplemented with 25-hydroxylanosterol (30 mg / kg / day). The mice were gavaged once daily, and changes in food intake and body weight were recorded. After 8 weeks, blood and liver samples were collected for analysis of blood lipids, hepatic lipids, and liver damage phenotypes.

[0373] The results are as follows Figure 1-8 As shown, Figure 1 The statistical results of weekly weighing of mice in each group are shown in Table 2. Figure 2 is the cumulative statistics of food intake of mice in each group. Figure 3 25-Hydroxylanosterol reduces the total cholesterol content in the blood of mice. Figure 4 25-Hydroxylanosterol reduces the total triglyceride content in the blood of mice. Figure 5 25-Hydroxylanosterol reduces the total cholesterol content in mouse liver. Figure 6 25-Hydroxylanosterol reduces the total triglyceride content in mouse liver. Figure 7 25-Hydroxylanosterol reduces the level of aspartate aminotransferase (AST) in the blood of mice. Figure 8 25-Hydroxylanosterol reduces the blood alanine aminotransferase (ALT) level in mice.

[0374] Figure 1 and Figure 2 In the table, P values were calculated using two-way ANOVA (Dunnett's multiple comparisons test); * indicates P < 0.05; ns indicates no statistically significant difference. Figure 3-Figure 8 Data are presented as mean ± standard deviation. P values were analyzed by one-way ANOVA. * indicates P < 0.05, ** indicates P < 0.01, and *** indicates P < 0.001.

[0375] The results showed that after 8 weeks of continuous administration, Ldlr - / - The weight gain of mice in the 25-hydroxylanosterol group, which was fed with AMLN diet and administered simultaneously, was significantly lower than that in the AMLN diet vehicle control group. This indicates that 25-hydroxylanosterol has a good inhibitory effect on the weight gain induced by the AMLN diet. The pathological characteristics of fatty liver disease mainly include fatty degeneration of the liver, liver damage, inflammatory infiltration and fibrosis. After 8 weeks of administration to the four groups of mice, we first detected the changes in the levels of lipids such as total cholesterol and total triglycerides in the mice's blood, as well as the changes in the levels of total cholesterol and total triglycerides in the liver. Figure 3-4As shown in the following table: Compared with the control group, 25-hydroxylanosterol significantly reduced the levels of total cholesterol and total triglycerides in serum. Figure 5-6 The results show that 25-hydroxylanosterol significantly reduced the levels of total cholesterol and total triglycerides in the liver of mice. This indicates that 25-hydroxylanosterol has a good effect in lowering blood lipids and liver fat. Figure 7-8 As can be seen from the results, serum levels of liver damage markers, aspartate aminotransferase (AST) and alanine aminotransferase (ALT), were significantly reduced by 25-hydroxylanosterol, indicating that 25-hydroxylanosterol has a good effect in improving liver damage.

[0376] Biological Test Example 11 25-Hydroxylanosterol Alleviates Fatty Liver and Atherosclerosis

[0377] Furthermore, we performed multiple staining or immunohistochemical procedures on the liver tissue sections of each group of mice to analyze the phenotypic changes of liver lipid accumulation and fatty liver. Figure 9-29 As shown, Figure 9-13 HE staining results of mouse liver sections and quantitative results of NAFLD activity score: 25-hydroxylanosterol reduced liver steatosis and significantly lowered NAFLD activity score; Figure 14-18 Oil red O staining and quantification of mouse liver sections showed that 25-hydroxylanosterol reduced lipid droplets in the liver; Figure 19-23 Sirius red staining and quantitative analysis of mouse liver sections showed that 25-hydroxylanosterol reduced fibrosis in the liver; Figure 24-29 F4 / 80 immunostaining and quantification results of mouse liver sections, as well as polarized light imaging and quantification results indicating cholesterol crystallization: 25-hydroxylanosterol reduces the aggregation of Kupffer cells and the formation of cholesterol crystals in the liver.

[0378] Figure 9-29 Quantitative analysis was performed using Image J software, and data are presented as mean ± standard deviation. P values were analyzed using one-way ANOVA. * indicates P < 0.05, ** indicates P < 0.01, and *** indicates P < 0.001.

[0379] The results are as follows Figure 9-13 Hematoxylin-eosin staining shows: male Ldlr - / - After 8 weeks of feeding mice with AMLN diet, the livers showed obvious macrovesicular lipid droplets and vesicular degenerated hepatocytes. Compared with the control group, 25-hydroxylanosterol significantly reduced these phenotypes. Figure 14-18 Oil red O staining of liver tissue sections showed that compared with the control group, 25-hydroxylanosterol significantly reduced the accumulation of neutral lipid droplets in the liver, including cholesterol and fatty acids. Figure 1-8The results of the present invention is consistent with the results of the present invention on reducing liver lipid content in the liver, indicating that 25-hydroxylanosterol effectively improves the liver lipid accumulation phenotype induced by AMLN diet. In addition, the present invention further analyzes the changes in the inflammatory and fibrotic phenotypes associated with fatty liver in the liver. Figure 24-29 Immunofluorescence staining results showed that the vehicle control Ldlr - / - In AMLN-fed mice, F4 / 80-specific staining showed that Kupffer cells aggregated and formed a crown-like structure around cholesterol crystals ( Figures 24-27 Enlarged image). 25-hydroxylanosterol significantly reduced the crown-shaped structures formed by Kupffer cells, indicating that 25-hydroxylanosterol can significantly reduce inflammatory infiltration of the liver. Polarized light imaging of cholesterol crystals in liver sections showed that in vehicle-controlled mice, the crown-shaped structures formed by Kupffer cells contained a large number of cholesterol crystals. Compared with simple fatty degeneration, these cholesterol crystals and the crown-shaped structures formed by Kupffer cells are hallmark features of fatty liver. Macrophages are attracted to cholesterol crystals and try to clear these residual lipid droplets, which is similar to the phenomenon described in atherosclerosis. More importantly, 25-hydroxylanosterol significantly reduced the number of crown-shaped structures and cholesterol crystals ( Figure 24-29 ).at the same time, Figure 19-23 Sirius red staining revealed that 25-hydroxylanosterol significantly reduced the fibrotic phenotype of collagen fibrillation in mouse liver tissue sections. These results suggest that 25-hydroxylanosterol alleviates hepatic fat accumulation and the symptoms of fatty liver, and could be used to prevent and / or treat conditions such as hyperlipidemia and fatty liver.

[0380] AMLN-fed Ldlr - / - The mouse is also a common model of atherosclerosis, so we can study fatty liver and atherosclerosis simultaneously. - / - Mice were fed an AMLN diet and given the drug by gavage once daily for 8 weeks. After sacrifice, the aortas were isolated and fixed with 4% paraformaldehyde. Perivascular adipose tissue was removed under a stereomicroscope, stained with Sudan IV, and rinsed with 70% ethanol. The aortic tree was imaged using a stereomicroscope (Zeiss Axio Zoom V16, Germany). Atherosclerotic plaques were quantitatively analyzed using ImageJ software.

[0381] The results are as follows Figures 30-34 As shown, Figures 30-34 Sudan IV staining and quantification of mouse aortic tree: 25-hydroxylanosterol reduces atherosclerotic plaque formation.

[0382] The results showed that after 8 weeks of continuous administration, the aortic tree of each group of mice was isolated and the aorta was stained with Sudan IV lipid-specific staining. Figures 30-34 As shown, 25-hydroxylanosterol significantly reduced the formation and number of atherosclerotic plaques compared with the control group. 25-hydroxylanosterol has a slowing effect on the formation of atherosclerosis.

[0383] Figure 1-8 to Figure 9-34 These data indicate that 25-hydroxylanosterol reduces elevated blood lipid levels, reduces liver fat accumulation, cholesterol crystallization, liver cell damage, inflammatory infiltration, and fibrosis, and reduces the formation and number of atherosclerotic plaques. This suggests that 25-hydroxylanosterol has a beneficial effect on hyperlipidemia, fatty liver, and atherosclerosis.

[0384] Biological Test Example 12 Using in vitro liver organoids to demonstrate the inhibitory effect of 25-hydroxylanosterol on lipid formation and fibrosis in fatty liver

[0385] To distinguish whether the inhibitory effects of 25-hydroxylanosterol are directly due to effects on the liver or systemic effects, we used 3D liver organoids as an in vitro model of fatty liver disease to analyze the effects of 25-hydroxylanosterol on lipid production and expression of fibrotic markers in liver organoids. We fed C57BL / 6N mice at 12 weeks of age a fatty liver-inducing diet (TrophicDiet, TP2630052A, containing 10.2% kcal protein, 37.3% kcal carbohydrates, and 52.6% kcal fat) and fructose-containing drinking water (23.1g fructose and 18.9g glucose dissolved in 1L of filter-sterilized water) for 16 weeks to establish a fatty liver model. Liver organoids were isolated from the livers of these mice and cultured in vitro. The organoids were also treated in vitro with obeticholic acid (OCA), a farnesoid X receptor (FXR) agonist that has demonstrated promising anti-fatty liver effects in Phase III clinical trials. This drug served as a control in this example. The organoids were grouped and treated with the same concentration gradient of OCA and 25-hydroxylanosterol for three days. RNA was collected from the organoids and analyzed using real-time quantitative PCR to analyze the expression of genes involved in lipid synthesis (Hmgcs, Hmgcr, SCD1, FASN) and fibrosis markers (αSMA, Col1α1).

[0386] The results are as follows Figure 35-53 As shown, Figure 35 25-Hydroxylanosterol reduced the expression of lipid-forming genes (Hmgcs, Hmgcr, SCD1, FASN) in liver organoids, and the effect was better than that of the control drug obeticholic acid at the same concentration; Figure 3625-Hydroxylanosterol reduced the expression of fibrosis-related genes (Col1a1, αSMA) in liver organoids, and the effect was better than the control drug obeticholic acid at the same concentration; Figure 37-53 These are the bright field imaging results, Nile red staining and quantitative results, and immunofluorescence staining and quantitative results of the fibrosis marker protein αSMA of liver organoids: 25-hydroxylanosterol reduces lipid accumulation in liver organoids and also reduces the expression of the fibrosis marker protein αSMA in liver organoids.

[0387] Figure 35 , Figure 36 Data are presented as mean ± standard deviation. P values were analyzed using one-way ANOVA. ns indicates no statistically significant difference, * indicates P < 0.05, ** indicates P < 0.01, and *** indicates P < 0.001. Figure 47 and Figure 53 Quantitative analysis was performed using Image J software. Data are presented as mean ± standard deviation. P values were analyzed using one-way ANOVA. * indicates P < 0.05, ** indicates P < 0.01, and *** indicates P < 0.001.

[0388] The results showed that compared with obeticholic acid, which failed to inhibit the expression of lipid synthesis genes, 25-hydroxylanosterol could significantly inhibit the expression of lipid synthesis-related genes ( Figure 35 ) and fibrosis-related genes ( Figure 36 ) expression levels. At the same time, Nile red staining experiments were used to detect the accumulation of neutral lipids in organoids, such as Figure 37-53 The results showed that 25-hydroxylanosterol and OCA reduced lipid accumulation in organoids, and staining data of the fibrosis marker protein αSMA showed that the expression of the fibrosis protein αSMA was significantly reduced. Figure 35-53 The results suggest that 25-hydroxylanosterol directly reduces hepatic lipid accumulation and fibrosis by inhibiting lipogenesis and fibrosis gene expression, while OCA may indirectly inhibit hepatic lipid accumulation by promoting lipid oxidation. These data demonstrate that 25-hydroxylanosterol directly targets the hepatic lipid synthesis pathway and regulates fibrosis genes.

[0389] Effect Example 13: Liver microsome metabolic stability experiment

[0390] PBS solution (100 mM), MgCl2 solution (100 mM) and NADPH solution (20 mM) were prepared respectively, and then the compound and testosterone (positive control) stock solutions were prepared with dimethyl sulfoxide (DMSO), diluted to 100 μM with methanol for sample incubation, and stored at -10 to -30°C. 12.5 μL of rat liver microsomes (purchased from XenoTech, catalog number R1000, lot number 1310030, 20 mg / ml), 432.5 μL of 100 mM PBS solution, 25 μL of 20 mM NADPH solution, and 25 μL of 100 mM MgCl₂ solution were added to a 96-well plate, mixed, and preincubated at 37°C for 5 minutes. The reaction was initiated by adding 5 μL of substrate (test compound) solution. At each time point (0, 5, 15, 30, 45, and 60 minutes (0 and 60 minutes for the negative control group), 50 μL of the incubation sample was placed in the stop plate with 100 μL of ice-cold stop solution, vortexed for 1 minute to inactivate the sample, and stored at -60 to -90°C until further analysis. Samples of the test compound and the control testosterone were analyzed using LC-MS / MS. Chromatographic peaks were integrated, calculated, and processed using Analyst software. The test compound and the reference compound testosterone were both analyzed using a semi-quantitative method and calculated based on the peak area ratio.

[0391] Table 2: Rat liver microsome stability results of some compounds in the examples

[0392] Example ID <![CDATA[Metabolic half-life (t 1 / 2 )(minutes)]]> 68 8.36 98 14.9 180 25.98 90 18.15

[0393] Compared with the control compound 68, the metabolic stability of the compound of the present invention in rat liver microsomes is significantly improved, which is significantly better than compound 68.

[0394] Preparation of key intermediates

[0395] Intermediate II Preparation of (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-formylbutyl-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate

[0396]

[0397]

[0398] Step 1: (1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-pentamethyl-1-[(2R)-6-methylhept-5-en-2-yl]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol (10.00 g, 23.4 mmol, 1.0 eq) was dissolved in DCM (250 mL). After complete dissolution, acetic anhydride (6.7 mL, 71.0 mmol, 3.0 eq), DMAP (0.57 g, 4.7 mmol, 0.2 eq) and TEA (16.3 mL, 117.2 mmol, 5.0 eq) were added to the reaction system in sequence. After the addition was complete, the mixture was stirred at room temperature for 2 hours. After the reaction was completed as monitored by TLC (PE:EtOAc=5:1, phosphomolybdic acid baking plate), the mixture was quenched with methanol (10 mL), and the reaction solution was washed once with saturated sodium bicarbonate (~100 mL) and water (~100 mL), dried over anhydrous sodium sulfate, and concentrated. When the concentration was almost dry, methanol (~100 mL) was added, and the mixture was stirred in an ice bath for 30 minutes. The mixture was filtered, and the filter cake was rinsed with a small amount of methanol. The filter cake was dried to obtain a white solid acetic acid (1R, 3aR, 5 aR,7S,9aS,11aR)-3a,6,6,9a,11a-pentamethyl-1-[(2R)-6-methylhept-5-en-2-yl]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl ester (I) (9.00 g, 17.3 mmol, purity 90.0%, yield 82.54%). 1 H NMR (400MHz, CDCl3): δ4.50 (dd, J=11.5, 4.5Hz, 1H), 2.69 (s, 1H), 2.09-1.87 (m, 8H), 1.77-1 .24(m,26H),1.15(d,J=11.4Hz,3H),1.00(s,3H),0.93-0.85(m,12H),0.69(d,J=2.7Hz,3H). 13 CNMR (400MHz, CDCl3): δ203.21,171.00,134.37,134.32,99.99,80.90,77.34,77.02,76.71,50.50,50.30,49.82,44.54,41.14,37.81,36. 90,36.08,36.03,35.27,30.95,30.78,28.24,28.15,27.91,26.38,2 4.23,24.17,21.33,20.98,19.19,18.46,18.40,18.11,16.53,15.78.

[0399] Step 2: (1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-pentamethyl-1-[(2R)-6-methylhept-5-en-2-yl]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate (I) (15.00 g, 32.0 mmol, 1.0 eq) was dissolved in DCM (dichloromethane) (300 mL), replaced with nitrogen, and the system was cooled to 0°C in an ice bath. Ozone was introduced and aerated for 10 min. The reaction was monitored by TLC (PE:EtOAc=5:1, phosphomolybdic acid hotplate). The product spot was significantly more concentrated than the starting material spot. Aeration was stopped, the system was replaced with nitrogen, and then directly concentrated to dryness. The crude product was separated and purified by flash chromatography (PE:EtOAc=95:5 to 90:10, phosphomolybdic acid hotplate) to give (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-formylbutyl-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate (II) (6.50 g, 13.2 mmol, purity 95.5%, yield 41.3%) as a white solid. 1 H NMR (400MHz, CDCl3): δ9.77 (t, J=1.9Hz, 1H), 4.50 (dd, J=11.6, 4.5Hz, 1H), 2.51 -2.30 (m, 2H), 2.09 -1.88(m,8H),1.86-1.24(m,17H),1.23-1.12(m,2H),0.99(d,J=11.2Hz,3H),0.93-0.84(m,12H).

[0400] Preparation of Intermediate VI (5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoic acid

[0401]

[0402] The first step: (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-formylbutyl-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate (II) (1.50 g, 3.4 mmol, 1.0 eq) was dissolved in dichloromethane (50 mL). Triethylamine (1.41 mL, 10.2 mmol, 3.0 eq) and tert-butyldimethylsilyl trifluoromethanesulfonate (1.30 g, 5.1 mmol, 1.5 eq) were added sequentially at 0°C. The reaction solution was stirred at 0 ° C for 2 hours. TLC (PE: DCM = 3: 1, phosphomolybdic acid baking plate) showed that the raw material spot disappeared. The reaction solution was concentrated to dryness, and n-hexane (50 mL) was added and stirred for 10 minutes. The mixture was filtered, and the filtrate was dried. DCM (50 mL) was added and the reaction solution was cooled to -78 ° C. Ozone was introduced and bubbled for 10 minutes. TLC (PE: DCM = 3: 1) monitored the disappearance of the raw material spot. PPh3 (0.89 g, 3.4 mmol, 1.0 eq) was added and stirred for 30 minutes. The reaction solution was directly concentrated and column chromatography Purification (PE:EtoAc=90:10) gave (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-1-formylpropan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate (III) (300 mg, 0.560 mmol, 16.52%) as a white solid. 1 H NMR (400MHz, CDCl3) δ9.76 (dd, J=3.3, 1.1Hz, 1H), 4.50 (dd, J=11.6, 4.5Hz, 1H), 2.47 (dd, J=16.4, 2.5Hz, 1H), 2.17(m,1H),2.04(m,7H),1.92(m,1H),1.43(m,18H),0.99(dd,J=9.3,2.8Hz,5H),0.90(m,12H),0.74(s,2H).

[0403] Step 2: (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-1-formylpropan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (III) (300 mg, 0.700 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), and ethyl (triphenylphosphine) acetate (243.81 mg, 0.700 mmol, 1.0 eq) was added. The reaction solution was stirred at room temperature for 2 hours. The reaction was completed as monitored by TLC (PE:DCM=3:1, phosphomolybdic acid hotplate). The reaction solution was directly concentrated and purified by silica gel column chromatography (PE:EtOAc=95:5) to give (2E,5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-acetyloxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hex-2-enoic acid ethyl ester (IV) (250 mg, 0.401 mmol, 57.30%) as a white solid. 1 H NMR (400MHz, CDCl3) δ6.96(m,1H),5.81(d,J=15.5Hz,1H),4.50(dd,J=11.5,4.5Hz,1H),4.19(q,J=7.1Hz,2H),1. 99(m,8H),1.63(m,12H),1.31(m,6H),1.17(m,3H),1.00(s,3H),0.92(t,J=5.3Hz,4H),0.87(m,10H),0.69(m,3H). 13 C NMR (101MHz, CDCl3) δ171.01,148.45,134.35,122.47,80.90,77.33,77.21,77.01,76.69,60.12,50.50,50.24,49.86,44.60,39.33,37.8 1,36.91,36.38,35.26,30.80,28.22,27.91,26.92,26.38,24.25,24 .17,21.33,20.96,19.19,18.96,18.11,16.53,15.78,14.29,-0.01.

[0404] Step 3: Ethyl (2E,5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hex-2-enoate (IV) (250 mg, 0.55 mmol, 1.0 eq) was dissolved in methanol (10 mL), and palladium (palladium on carbon) (30 mg, 0.282 mmol) was added. The mixture was stirred for 3 hours under a hydrogen atmosphere. TLC (PE:EtOAc= After the reaction was complete, the palladium-carbon was filtered off with celite, and the filtrate was concentrated to dryness and purified by silica gel column chromatography (PE:EtOAc=80:20, phosphomolybdic acid hotplate) to give (5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid ethyl ester (V) (200 mg, 0.392 mmol, 71.68%) as a white solid. 1 H NMR (400MHz, CDCl3) δ4.50(dd,J=11.5,4.5Hz,1H),4.13(q,J=7.1Hz,2H),2.26(dd,J=15.5,8.6Hz,2H),2.04(m, 8H),1.68(m,7H),1.50-1.37(m,9H),1.26(t,J=7.1Hz,3H),1.15(m,3H),1.00(s,3H),0.90(m,12H),0.68(s,3H). 13 C NMR (101MHz, CDCl3) δ173.95,171.03,80.95,77.33,77.22,77.02,76.70,60.16,50.52,50.26,49.82,44.49,37.82,36.91,36.21,35 .69,35.28,34.82,30.96,30.80,28.16,27.92,26.39,24.25,24.18,21.85,21.34,21.00,19.19,18.61,18.13,16.54,15.75,14.28,

[0405] Step 4: Ethyl (5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-acetyloxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoate (V) (200 mg, 0.40 mmol) was dissolved in ethanol (2 mL). Sodium hydroxide solution (2 mL, 4 mol / L) was added. The reaction mixture was heated to reflux and stirred overnight. The reaction was monitored by TLC (PE:EtOAc = 5:1, phosphomolybdic acid hotplate). After the reaction was complete, the reaction solution was cooled to room temperature, adjusted to pH 1 with 1N hydrochloric acid, extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EtOAc=90:10 to 50:50) to give (5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid (VI) (150 mg, 0.331 mmol, 82.84%) as a white solid. 1 H NMR (400MHz, CDCl3) δ3.24(dd,J=11.6,4.5Hz,1H),2.33(m,2H),2.04(d,J=8.2Hz,4H),1.91(dd,J=13.4,7.5Hz,1H),1.7 0(m,6H),1.50(m,7H),1.19(m,7H),0.99(d,J=7.8Hz,5H),0.91(t,J=5.9Hz,3H),0.87(s,3H),0.81(s,3H),0.69(s,3H).

[0406] Preparation of Intermediate VII (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-acetyloxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]pentanoic acid

[0407]

[0408]

[0409] (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-formylbutyl-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate (II) (3.00 g, 6.78 mmol, 1.0 eq.) was dissolved in acetone (50.0 mL) (not clear, turbid). After replacing with nitrogen three times, the temperature was lowered to 0°C and Jones reagent (7.8 mL, 2.0 M, 2.0 eq.) was slowly added dropwise. The reaction was continued for 5 minutes and monitored by TLC (PE:EA=5:1, phosphomolybdic acid colorimetry, Rf1=0.72, Rf2=0.34). After the reaction was complete, 15.0 mL of isopropanol was added dropwise at low temperature to quench the reaction. The mixture was stirred for 30 minutes, concentrated, and then dissolved in 50.0 mL of dichloromethane. The mixture was washed once with 30.0 mL of 1.5N NaHSO₃ and 30.0 mL of H₂O, dried, and concentrated to give a crude white solid (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-acetyloxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]pentanoic acid (VII) (3.00 g, 4.56 mmol, 67.56%). 1 H NMR (400MHz, Chloroform-d) δ4.48(dd,J=11.6,4.6Hz,1H),2.40(ddd,J=15.4,9.9,5.0Hz,2H),2.25(ddd,J=15.9,9.5,6.4Hz,1H),2.08–1.92(m,7H),1.8 4–1.56(m,8H),1.45(td,J=13.6,12.0,7.2Hz,3H),1.31(dt,J=11.8,4.3Hz,2 H),1.23–1.07(m,3H),0.98(s,3H),0.88(q,J=4.7,3.8Hz,12H),0.67(s,3H). 13 C NMR(100MHz,Chloroform-d)δ179.93,171.11,134.35,134.23,80.94,50.44,50.18,49.78,44.49,37.77,36.86,35.98, 35.22,31.14,30.99,30.92,30.74,28.04,27.88,26.33,24.20,24.13,21.32,20.95,19.17,18.24,18.08,16.51,15.75.

[0410] Preparation of Intermediate VIII (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentanoic acid

[0411]

[0412] Weigh (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-acetyloxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentanoic acid (500 mg, 1.09 mmol, 1.0 eq.), add tetrahydrofuran (20.0 mL), methanol (20.0 mL), and 1 M lithium hydroxide aqueous solution (20.0 mL), and stir at room temperature overnight with plate monitoring. After the reaction, tetrahydrofuran and methanol were removed by concentration. Water (30.0 mL) was then added to the concentrate, followed by extraction with ethyl acetate (30.0 mL x 3). The organic phases were combined, dried, and concentrated to give (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]pentanoic acid (VIII) (350 mg, 77.1%). 1 HNMR(400MHz,DMSO-d6)δ11.99(s,1H),4.35(d,J=5.1Hz,1H),3.07–2.96(m,1H),2.18(dddd,J=22.7,15.9,9.3,6 .2Hz,2H),2.04–1.84(m,5H),1.73–1.06(m,16H),0.92(ddd,J=30.4,18.0,4.7Hz,12H),0.70(s,3H),0.65(s,3H).

[0413] Preparation of Intermediate IX (3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-acetoxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]butanoic acid

[0414]

[0415] Compound (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-formylbutyl-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate (III) (2.30 g, 5.2 mmol) , 1.0 eq) was dissolved in t-BuOH (tert-butyl alcohol) (60 mL). 2-Methyl-2-butene (2.19 g, 31.2 mmol, 6.0 eq) and an aqueous solution (15 mL) of sodium dihydrogen phosphate (2.1 g, 15.6 mmol, 3.0 eq) and sodium chlorite (1.41 g, 15.6 mmol, 3.5 eq) were added under ice-cooling. The reaction mixture was stirred at room temperature for 2 hr. TLC (PE:EtOAc = 5:1, phosphomolybdic acid as a colorimetric reagent) indicated the reaction was complete. The reaction mixture was concentrated, extracted with EtOAc (50 mL), and washed with saturated sodium bicarbonate (50 mL x 2). The organic layer was dried over anhydrous sodium sulfate, and the crude product was filtered through a column using PE:EtOAc = 3:1 to give (3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-acetoxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]butanoic acid (IX) (1.6 g, purity 90%, yield 60.42%) as a solid. 1 H NMR (400MHz, CDCl3) δ4.50(dd,J=11.6,4.5Hz,1H),2.40(dd,J=10.2,5.2Hz,1H),2.29(dd,J=9.5,6.5Hz,1H),2.11–1.87(m,8H),1.83(dd,J= 10.0,3.5Hz,1H),1.77–1.54(m,7H),1.53–1.44(m,2H),1.43–1.22(m, 4H),1.22–1.10(m,2H),1.00(s,3H),0.97–0.81(m,12H),0.69(s,3H).

[0416] Preparation Example

[0417] Example 1

[0418] Preparation of compound 1(5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanamide

[0419]

[0420]

[0421] (5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid VI (50 mg, 0.116 mmol, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (5 mL), and DCC (dicyclohexylcarbodiimide) (72 mg, 0.35 mmol, 3.0 eq) and N-hydroxysuccinimide (40 mg, 0.35 mmol, 3.0 eq) were added in sequence, and the reaction was stirred overnight. The system produced a solid, which was removed by filtration. The filtrate was dried and the residue was dissolved in DMF (3 mL). Ammonia water (25%) (0.05 mL, 1.298 mmol, 11 eq) was added. The reaction was heated to 50 ° C. and stirred overnight. The reaction was monitored by TLC (PE: EtOAc = 1: 1, phosphomolybdic acid baking plate). After the reaction was complete, the reaction solution was diluted with water (30 mL), and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE :EtOAc=50:50) to give a white solid (5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanamide (1) (30 mg, 0.052 mmol, 45.10%). 1H NMR (400MHz, CDCl3) δ5.31 (d, J = 44.1Hz, 2H), 3.23 (dd, J = 11.5, 4.5Hz, 1H), 2.30-2.10 (m 2H),2.09-1.96(m,4H),1.95-1.85(m,1H),1.75-1.65(m,5H),1.60-1.38(m,10H),1.35-1.27(m,1H),1.24 -1.05(m,4H),1.01(dd,J=16.9,5.1Hz,6H),0.93(d,J=6.5Hz,2H),0.87(s,3H),0.81(s,3H),0.69(s,3H). 13 C NMR (101MHz, CDCl3) δ175.45,134.54,79.00,77.34,77.22,77.02,76.70,50.42,38.90,36.27,35.79,35.60,3 0.98,30.83,29.71,28.21,27.97,27.86,26.51,24.27,21.00,19.15,18.65,18.26,15.75,15.42.LC-MS:[M+H] + =530.10

[0422] Example 2

[0423] Preparation of Compound 2(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N-propylpentanamide

[0424]

[0425]

[0426] In the first step, (4R)-4-[(1R,3aR,5aR,9aS,11aR)-7-acetyloxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]pentanoic acid VII (100 mg, 0.22 mmol) was dissolved in DMF (N,N-dimethylformamide) (5.0 mL), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (99.47 mg, 0.26 mmol) and diisopropylethylamine (0.04 mL, 0.26 mmol) were added. After stirring at room temperature for 0.5 h, propylamine (29.06 mg, The reaction was continued at room temperature for 4 h and monitored by TLC (PE:EtOAc=3:1, phosphomolybdic acid color development, Rf1=0.52, Rf2=0.62). After the reaction was completed, the reaction solution was washed with water and EtOAc, and the organic phase was washed once with brine, combined, dried and concentrated to obtain a yellow solid (1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-pentamethyl-1-[(2R)-5-oxyylidene-5-(propylamino)pentan-2-yl]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (2-1) (100 mg, 0.167 mmol, 83.33%), which was used directly in the next step.

[0427] In the second step, (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N-propylpentanamide (100 mg, 0.167 mmol) was dissolved in tetrahydrofuran (2.0 mL) and methanol (2.0 mL), and 1 M aqueous lithium hydroxide solution (2.0 mL, 2.00 mmol) was added, and the mixture was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated and sent for preparative separation to obtain a white solid (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N-propylpentanamide (2) (37.63 mg, 0.08 mmol, 40.43%). 1H NMR(399MHz, CDCl3)δ5.57(1H,s)3.19(3H,d,J=3.5),2.24(1H,s)2.00(6H,s),1.80(3H,s),1.80(3H,s),1.67(4H,m),1.47 (5H,m),1.34(3H,d,J=23.5),1.18(3H,dd,J=27.9,10.4),0.96(7H,t,J=8.2),0.85(3H,s)0.78(3H,d,J=23.5)0.66(3H,s). 13 C NMR (101MHz, CDCl3) δ173.73,134.38,78.94,77.32,77.00,76.69,50.36,50.28,49.79,44.50,41.35,38.86,36.99,36.20,35.55,3 4.04,32.22,30.97,30.79,28.19,27.94,27.80,26.46,24.24,22.93,20.96,19.12,18.48,18.21,15.77,15.40,11.42.LC-MS:[M+H] + =458.60

[0428] Example 3

[0429] Preparation of compound 3(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetrahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-N-(3,4,5,6-tetrahydro-2H-pyran-4-yl)pentanamide

[0430]

[0431] Referring to Example 2, the amine in the first step was replaced with tetrahydropyran-4-amine to finally obtain (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetrahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N-(3,4,5,6-tetrahydro-2H-pyran-4-yl)pentanamide (3). 1HNMR (399MHz, CDCl3) δ5.30 (s, 1H), 3.93 (d, J = 11.5Hz, 2H), 3.45 (t, J = 11.4Hz, 2H), 3.21(d,J=11.2Hz,1H),2.22(s,1H),2.00(s,5H),1.87(d,J=12.9Hz,3H),1.81–1.5 9(m,6H),1.58(s,2H),1.42(d,J=9.8Hz,5H),1.31(s,2H),1.27–1.11(m,3H),0.9 8(t,J=10.3Hz,6H),0.89(d,J=5.3Hz,3H),0.85(s,3H),0.79(s,3H),0.67(s,3H). 13 C NMR (101MHz, CDCl3) δ172.86,134.38,134.28,78.95,77.31,76.99,76.67,66.78,50.35,50.25,49.78,45.51,44.50,38.86,36.98,36.1 3,35.55,33.94,33.22,32.02,30.96,30.77,28.15,27.93,27.79,26.45,24.21,20.95,19.12,18.41,18.21,15.74,15.39.LC-MS:[M+H] + =500.60.

[0432] Example 4

[0433] Preparation of compound 4(4R)–4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-N-(2-methylphenyl)pentanamide

[0434]

[0435] Referring to Example 2, the amine in the first step was replaced with 2-methylaniline to finally obtain (4R)–4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N-(2-methylphenyl)pentanamide (4). 1H NMR.(399MHz, CDCl3)δ7.80(s,1H),7.17(s,2H),7.05(s,1H),6.89(m,1H),3.22(d,J=11.1Hz,1H),2.47(m,1H),2.29(s,1H),2.25(s,3H),2.01( s,5H),1.71(s,4H),1.49(s,3H),1.41(s,2H),1.22(d,J=12.0Hz,4H),1. 05(s,1H),0.97(d,J=7.8Hz,9H),0.87(s,3H),0.79(s,3H),0.69(s,3H). 13 CNMR(101MHz,CDCl3)δ171.72,135.65,134.38,134.29,130.41,126.79,12 5.09,123.16,78.97,77.31,76.99,76.67,50.35,49.80,44.53,38.87,37. 00,36.16,35.55,34.75,32.07,30.98,30.79,28.15,27.94,27.80,26.46, 24.23,20.96,19.13,18.43,18.21,17.80,15.78,15.40,1.00.LC-MS:[M+H] + =506.65

[0436] Example 5

[0437] Preparation of Compound 5(4R)-N-(2-fluorophenyl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentanamide

[0438]

[0439] Referring to Example 2, the amine in the first step was replaced with 2-fluoroaniline to obtain (4R)-N-(2-fluorophenyl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]pentanamide (5). 1H NMR (399MHz, CDCl3) δ8.31 (s, 1H), 7.30 (s, 1H), 7.08 (m, 3H), 3.22 (dd, J = 11.5, 4.4H z,1H),2.47(s,1H),2.29(s,1H),2.02(s,4H),1.91(m,1H),1.68(dd,J=27.2,10.4Hz ,5H),1.47(t,J=20.3Hz,6H),1.20(dd,J=20.5,10.9Hz,3H),1.03(d,J=12.4Hz,1H), 0.97(d,J=7.6Hz,6H),0.94(d,J=4.9Hz,3H),0.87(s,3H),0.79(s,3H),0.68(s,3H). 13 C NMR(101MHz,Chloroform-d)δ134.29,124.59,121.66,78.97,77.18,50.36,50.28,49.80,44.53,38.86,36.99,36.12,35. 55,34.90,31.72,30.97,30.79,28.12,27.93,27.80,26.46,24.22,20.96,19.12,18.42,18.21,15.76,15.39.LC-MS:[M+H] + =510.40

[0440] Example 6

[0441] Preparation of compound 6(4R)-N-(2-chlorophenyl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentanamide

[0442]

[0443] Referring to Example 2, the amine in the first step was replaced with 2-chloroaniline to obtain (4R)-N-(2-chlorophenyl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]pentanamide (6). 1H NMR (399MHz, CDCl3) δ8.36 (s, 1H), 7.59 (s, 1H), 7.34 (d, J = 8.0Hz, 1H), 7.01 (t, J = 7 .9Hz,1H),3.22(dd,J=11.6,4.5Hz,1H),2.49(s,1H),2.37–2.27(m,1H),2.01(s,6 H),1.69(t,J=16.6Hz,6H),1.41(s,2H),1.27–1.07(m,4H),1.03(d,J=12.1Hz,1H) ,0.98(s,3H),0.95(d,J=8.3Hz,6H),0.89–0.86(m,3H),0.79(s,3H),0.69(s,3H). 13 C NMR(101MHz,Chloroform-d)δ134.62,128.90,127.73,124.40,121.53,78.95,77.19,50.36,50.28,49.80,44.54,38.87,37.00 ,36.10,35.55,31.77,30.97,30.79,28.13,27.94,27.81,26.46,24.24,20.97,19.13,18.43,18.22,15.78,15.40.LC-MS:[M+1] + =526.40.

[0444] Example 7 Preparation of Compound 7(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N-(2-hydroxyethyl)pentanamide

[0445]

[0446] Referring to Example 2, the amine in the first step was replaced with 2-{[dimethyl(2-methylprop-2-yl)silyl]oxy}ethan-1-amine to obtain (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-N-(2-hydroxyethyl)pentanamide (7). 1H NMR(399MHz, CDCl3)δ5.94(s,1H),3.73(s,2H),3.43(s,2H),3.35–3.11(m,1H),2. 30(s,1H),2.11(s,1H),2.01(s,5H),1.74–1.62(m,5H),1.55(s,2H),1.45(d,J=8.0 Hz,2H),1.33(s,2H),1.21(d,J=24.4Hz,4H),1.03(d,J=11.2Hz,1H),0.97(d,J=8.3 Hz, 6H), 0.90 (d, J = 6.0Hz, 3H), 0.86 (s, 3H), 0.79 (s, 3H), 0.67 (s, 3H). LC-MS: [M+H] + =460.50

[0447] Example 8

[0448] Preparation of Compound 8(2S)-2-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N-(2-hydroxyethyl)propionamide

[0449]

[0450]

[0451] In the first step, (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-acetyloxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]pentanoic acid (VII) (3.00 g, 6.54 mmol, 1.0 eq.) was dissolved in benzene (40.00 mL). Pyridine (20.00 mL) and Cu(OAc)2 (copper acetate, 0.47 g, 2.62 mmol, 0.4 eq.) were added, and the argon atmosphere was replaced three times. The temperature was raised to 90°C, and Pb(OAc)4 (lead tetraacetate, 8.98 g, 20.28 mmol, 3.1 eq.) was added in batches. After reflux for 12 h, the mixture was naturally cooled to room temperature and monitored by TLC (PE:EtOAc=2:1, phosphomolybdic acid colorimetry, Rf1=0.42, Rf2=0.89). After the reaction was complete, the reaction solution was concentrated to remove benzene, dissolved in 200.0 mL of dichloromethane, and washed sequentially with 100.0 mL of 5% HCl (severe emulsification, filtered through celite), 100.0 mL of saturated NaHCO3, and 100.0 mL of saturated brine. The product was dried, concentrated, and subjected to column chromatography with PE-PE:EtOAc = 30:1 (product) to afford (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-but-3-en-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate (8-1) (1.50 g, 2.91 mmol, 44.46%) as a white solid. 1 HNMR(399MHz, CDCl3)δ5.71–5.59(m,1H),4.95–4.76(m,2H),4.48(dd,J=11.5,4.7Hz,1H),2.08–1.98(m,7H),1.79–1.59(m,7H),1 .59–1.42(m,4H),1.28(dtd,J=19.3,8.8,5.2Hz,3H),1.18–1.09(m,2H),0.99(d,J=5.9Hz,5H),0.86(d,J=1.5Hz,9H),0.70(s,3H). 13C NMR (100MHz, Chloroform-d) δ170.99,145.50,134.44,134.17,111.52,80.89,50.46,49.83,49.74,44.45,41.82,37. 77,36.88,35.23,30.90,30.81,28.22,27.88,26.35,24.23,24.14,21.31,20.96,20.05,19.16,18.08,16.51,15.97.

[0452] In the second step, (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-but-3-en-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetrahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate (8-1) (1.50 g, 3.64 mmol, 1.0 eq.) was dissolved in dichloromethane (30.0 mL), replaced with nitrogen three times, and cooled to 0°C. Ozone was slowly introduced. After 10 minutes, the reaction was complete under TLC monitoring (PE:EtOAc=10:1, phosphomolybdic acid color development, Rf1=0.84, Rf2=0.51); then N2 was introduced to drive out the ozone, and PPh3 (2.86 g, 10.90 mmol, 3.0 eq) was added. The temperature was raised to room temperature and the reaction was allowed to react for 30 minutes under TLC monitoring (PE:EtOAc=10:1, phosphomolybdic acid color development, Rf1=0.85, Rf2=0.49). The reaction solution was concentrated and column chromatography (PE- The resulting product was purified by PE:EtOAc = 20:1) and concentrated to give (1R,3aR,5aR,7S,9aS,11aR)-1-[(1S)-1-formylethyl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthren-7-yl acetate (8-2) (800 mg, 1.54 mmol, 42.46%). 1 H NMR(399MHz,Chloroform-d)δ9.55(d,J=3.3Hz,1H),4.47(dd,J=11.6,4.5Hz,1H),2.35(dqd,J=10.1,6.8,3.2Hz,1H),2.08–1.99(m,7H),1.9 3–1.81(m,2H),1.71–1.60(m,6H),1.53–1.33(m,3H),1.32–1.17(m,3H ),1.12–1.05(m,3H),0.98(s,3H),0.87(d,J=9.5Hz,9H),0.72(s,3H).13 C NMR(101MHz,Chloroform-d)δ205.34,170.99,134.28,80.80,77.17,50.40,50.15,49.27,45.54,45.14,37.77,36.90,3 5.21,31.13,30.77,27.88,26.95,26.38,24.17,24.13,24.11,21.32,20.90,19.18,19.16,18.04,16.51,16.25,13.46.

[0453] Step 3: (1R,3aR,5aR,7S,9aS,11aR)-1-[(1S)-1-formylethyl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl ester (8-2) (100 mg, 0.24 mmol, 1.0 eq.) was dissolved in water (1.0 mL) and tert-butanol (5.0 mL). The combined solution (not clearly soluble, turbid) was replaced with nitrogen three times, then cooled to 0°C, and 2-methyl-2-butene (168 mg, 2.40 mmol, 10.0 eq.), sodium chlorite (65 mg, 0.72 mmol, 3.0 eq.), and sodium dihydrogen phosphate (158 mg, 1.31 mmol, 5.5 eq.) were added respectively. After reacting at room temperature for 30 minutes, the mixture was monitored by TLC (PE:EtOAc=3:1, phosphomolybdic acid color development, Rf1=0.8, Rf2=0.4). After the reaction was completed, the mixture was concentrated and dissolved in 10.0 ml of ethyl acetate, and then 10.0 ml of water was added. After the organic phase was separated, the aqueous phase was extracted twice with 5.0 ml of ethyl acetate respectively. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 123 mg of a crude white solid, which was finally purified by column chromatography (PE:EtOAc=10:1~5:1~3:1) to give (2S)-2-[(1R,3aR,5aR,7S,9aS,11aR)-7-acetoxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]propanoic acid (8-3) (73 mg, 0.17 mmol, 64.68%) as a white solid. 1HNMR(399MHz, CDCl3)δ4.48(dd,J=11.6,4.5Hz,1H),2.41(dd,J=15.3,8.5Hz,1H),2.08–2.00(m,7H),2.00–1.92(m,2H),1.71(d,J=13.7Hz,2H) ,1.68–1.59(m,2H),1.56(d,J=9.7Hz,3H),1.35–1.27(m,3H),1.25–1.1 0(m,2H),0.96(d,J=16.0Hz,3H),0.94–0.76(m,12H),0.76–0.63(m,3H).

[0454] Step 4: (2S)-2-[(1R,3aR,5aR,7S,9aS,11aR)-7-acetoxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]propanoic acid (8-3) (130 mg, 0.30 mmol, 1.0 eq.) was dissolved in DMF (N, N-dimethylformamide) (4.0 mL), HATU (N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl) urea hexafluorophosphate) (137.74 mg, 0.36 mmol, 1.2 eq.), diisopropylethylamine (46.82 mg, 0.36 mmol, 1.2 eq.) were added, and stirred at room temperature for 30 minutes, followed by the addition of 2-{[dimethyl(2-methylprop-2-yl)methyl Silyl]oxy}eth-1-amine (68.82 mg, 0.39 mmol, 1.3 eq.), then continued to stir at room temperature for 2 hours, monitored by TLC (PE:EtOAc=3:1, phosphomolybdic acid color development, Rf1=0.5, Rf2=0.6), after the reaction was completed, 20.0 mL of water was added, and then extracted with 30 mL*3 of ethyl acetate. The organic phases were combined, dried, and concentrated to obtain acetic acid-(1R,3aR,5aR,7S,9aS,1 1aR)-3a,6,6,9a,11a-pentamethyl-1-[(9S)-2,2,3,3-tetramethyl-8-oxo-7-aza-4-oxa-3-siladec-9-yl]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester (8-4) (200 mg). The crude yellow oil was directly used in the next reaction.

[0455] Step 5: Weigh acetic acid-(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-pentamethyl-1-[(9S)-2,2,3,3-tetramethyl-8-oxoylide-7-aza-4-oxa-3-siladecan-9-yl]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetrahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester (8-4) (200 mg, 0.34 mmol, 1.0 eq.), add tetrahydrofuran (10.0 mL), methanol (10.0 mL), 1 M lithium hydroxide aqueous solution (5.0 mL), and stir at room temperature overnight. Monitor by TLC (PE:EtOAc=3: 1, phosphomolybdic acid color development, Rf1 = 0.6, Rf2 = 0.2). After the reaction, tetrahydrofuran and methanol were concentrated, and water (30.0 mL) was added to the concentrate, and then extracted with ethyl acetate (20 mL * 3). The organic phases were combined, dried, concentrated, and purified by preparative HPLC to obtain (2S)-2-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N-(2-hydroxyethyl)propionamide (8) (5.8 mg, 0.012 mmol, 4.54%). 1 HNMR(399MHz, CDCl3)δ3.60(s,1H),3.38–3.12(m,3H),2.11(d,J=6.5Hz,1H),1.97(s,5H),1.80(s,2H),1.70–1.40(m,7H),1.19( dd,J=27.0,14.9Hz,3H),1.15–1.05(m,3H),0.99(d,J=11.9Hz,1H),0.93(d,J=5.3Hz,6H),0.86(s,3H),0.75(s,3H),0.65(s,3H).

[0456] LC-MS[M+1] + =432.35

[0457] Example 9

[0458] Preparation of Compound 9(4R)-N-(2,6-dimethylphenyl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentanamide

[0459]

[0460] Referring to Example 2, the amine in the first step was replaced with 2,6-dimethylaniline to obtain (4R)-N-(2,6-dimethylphenyl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]pentanamide (9). 1 H NMR (399MHz, CDCl3) δ7.06 (d, J=3.7Hz, 2H), 6.66 (s, 1H), 3.22 (dd, J=11.5, 4.7 Hz,1H),2.49(s,1H),2.32(s,1H),2.25(s,1H),2.21(s,5H),2.01(s,7H),1.72( s,2H),1.57(d,J=12.5Hz,3H),1.51(s,3H),1.40(s,2H),1.28–1.09(m,5H),1. 03(d,J=12.1Hz,1H),1.01–0.95(m,9H),0.88(s,3H),0.79(s,3H),0.69(s,3H). 13 C NMR (101MHz, CDCl3) δ135.46,128.19,127.36,78.97,77.20,76.95,50.40,50.36,38.87,36.22,35.55,34.04,32.4 1,31.00,30.93,30.79,28.16,27.94,27.80,26.46,24.25,20.97,19.13,18.56,18.21,15.80,15.41.LC-MS:[M+H] + =520.50

[0461] Example 10

[0462] Preparation of Compound 10 (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetrahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-N-[2-(propan-2-yl)phenyl]pentanamide

[0463]

[0464] Referring to Example 2, the amine in the first step was replaced with 2-isopropylaniline to obtain (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-N-[2-(prop-2-yl)phenyl]pentanamide (10). 1 H NMR (399MHz, CDCl3) δ7.63(s,1H),7.18(s,2H),6.97(s,1H),3.22(dd,J=11.5,4.5H z,1H),3.00(s,1H),2.47(s,1H),2.31(s,1H),2.06–1.92(m,8H),1.67(d,J=16.4Hz ,5H),1.57(d,J=12.6Hz,2H),1.50(s,3H),1.41(s,3H),1.24(s,3H),1.22(s,3H),1 .03(d,J=12.4Hz,2H),0.97(d,J=7.3Hz,9H),0.87(s,3H),0.79(s,3H),0.69(s,3H). 13 C NMR(101MHz,Chloroform-d)δ134.38,133.90,126.38,126.08,125.55,125.00,78.98,77.19,50.35,38.86,36.99,36.16,35.55,34.66 ,32.08,30.98,30.91,30.78,28.14,28.02,27.93,27.78,26.45,24.23,23.03,20.95,19.12,18.41,18.21,15.76,15.39.LC-MS:[M+H] + =534.50

[0465] Example 11

[0466] Preparation of Compound 11(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N-(2-methoxyethyl)pentanamide

[0467]

[0468] Referring to Example 2, the amine in the first step was replaced with 2-methoxyethylamine to obtain compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-N-(2-methoxyethyl)pentanamide (11). 1 H NMR(399MHz, CDCl3)δ5.76(s,1H),3.43(s,3H),3.34(s,3H),3.20(s,1H),2.25(s ,0.5H),2.06(s,0.5H),2.01(s,5H),1.69(dd,J=20.7,12.6Hz,6H),1.56(s,1H), 1.44(d,J=9.0Hz,4H),1.22(dd,J=30.2,17.4Hz,6H),1.03(d,J=12.1Hz,1H),0.9 7(d,J=8.4Hz,6H),0.89(d,J=5.9Hz,3H),0.85(s,3H),0.79(s,3H),0.67(s,3H). 13 C NMR (100MHz, CDCl3) δ173.51,134.38,134.34,78.93,77.29,76.97,76.65,71.29,58.72,50.36,50.27,49.78,44.49,39.07,38.86,36.9 9,36.14,35.55,33.78,31.97,30.96,30.78,28.10,27.93,27.81,26.46,24.21,20.95,19.11,18.38,18.21,15.73,15.38.LC-MS:[M+H] + =474.40

[0469] Example 12

[0470] Preparation of Compound 12 (4R)-N-(3-cyanophenyl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]pentanamide

[0471]

[0472] Referring to Example 2, the amine in the first step was replaced with 3-cyanoaniline to finally obtain compound (4R)-N-(3-cyanophenyl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]pentanamide (12). 1 H NMR (400MHz, CDCl3) δ7.85 (s, 1H), 7.65 (d, J = 7.8Hz, 1H), 7.40–7.26 (m, 2H), 3.17 (dd,J=11.5,4.5Hz,1H),2.39(ddd,J=15.0,10.2,4.9Hz,1H),2.26–2.18(m,1H),2 .01–1.82(m,6H),1.67–1.35(m,13H),1.17(ddd,J=22.0,12.4,6.0Hz,3H),0.90(d d,J=16.2,6.7Hz,8H),0.81(d,J=5.2Hz,3H),0.74(s,3H),0.61(d,J=19.3Hz,3H). 13 C NMR (101MHz, CDCl3) δ138.78,134.47,134.31,129.87,113.08,78.99,77.33,77.22,77.01,76.70,50.40,50.31,49.85,44.57,38.90, 37.04,36.16,35.59,31.67,31.02,30.81,28.19,27.97,27.84,26.49,24.25,20.99,19.16,18.47,18.24,15.81,15.42.LC-MS:[M+H] + =517.4

[0473] Example 13

[0474] Preparation of Compound 13 (4R)-N-(3-fluorophenyl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentanamide

[0475]

[0476] Referring to Example 12, the amine in the first step was replaced with 3-fluoroaniline to obtain the compound (4R)-N-(3-fluorophenyl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]pentanamide (13). 1 H NMR (400MHz, CDCl3) δ7.43 (d, J=10.8Hz, 1H), 7.09 (dd, J=27.5, 16.0Hz, 2H), 6.73 (t, J= 7.4Hz, 1H), 3.17 (dd, J=11.5, 4.5Hz, 1H), 2.37 (ddd, J=15.0, 10.3, 4.9Hz, 1H), 2.24–2. 14(m,1H),1.99–1.84(m,5H),1.70–1.52(m,6H),1.47–1.29(m,8H),1.15(dd,J=21.6,1 1.6Hz,2H),1.00–0.86(m,9H),0.83–0.79(m,3H),0.74(s,3H),0.60(d,J=19.3Hz,3H). 13 C NMR (101MHz, CDCl3) δ134.45,134.33,78.99,77.33,77.22,77.01,76.69,50.40,50.32,49.84,44.57,38.90,37.03,36.1 7,35.59,31.75,31.02,30.81,28.18,27.97,27.85,26.49,24.25,20.99,19.15,18.47,18.25,15.80,15.42.LC-MS:[M+H] + =510.4

[0477] Example 14

[0478] Preparation of Compound 14 (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N-(pyridin-2-yl)pentanamide

[0479]

[0480] Referring to Example 2, the amine in the first step was replaced with 2-aminopyridine to obtain the compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-N-(pyridin-2-yl)pentanamide (14). 1 H NMR (399MHz, CDCl3) δ8.23 (dd, J=14.5, 6.8Hz, 2H), 7.73 (t, J=7.8Hz, 1H), 7.07–7.02 (m, 1H), 3.22(dd,J=11.6,4.4Hz,1H),2.53–2.42(m,1H),2.32(dd,J=15.0,8.9Hz,1H),1.96–1.86(m, 2H),1.72–1.63(m,10H),1.52(dd,J=35.3,9.9Hz,8H),1.23–1.13(m,3H),1.03(d,J=12.4Hz, 1H),0.98(s,3H),0.96(s,3H),0.93(d,J=4.8Hz,3H),0.86(s,3H),0.79(s,3H),0.68(s,3H). 13 C NMR(101MHz,Chloroform-d)δ172.31,151.30,147.24,138.72,134.38,134.27,119.60,114.03,78.95,77.20,50.34,50.25,49.79,44.51,38.8 7,36.99,36.15,35.55,34.95,31.68,30.95,30.79,28.15,27.94,27.8 1,26.46,24.22,20.96,19.14,18.43,18.22,15.77,15.41.LC-MS:[M+H] + =493.65

[0481] Example 15

[0482] Preparation of Compound 15 (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N-(pyridin-3-yl)pentanamide

[0483]

[0484] Referring to Example 2, the amine in the first step was replaced with pyridin-3-amine to obtain compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-N-(pyridin-3-yl)pentanamide (15). 1 H NMR (399MHz, CDCl3) δ8.25(dd,J=48.5,40.7Hz,3H),7.23(d,J=13.2Hz,1H),3.31(s,1H),2.37(d,J=10.6Hz,1H),2.21(s,1H),1.89(m,6H),1.60( dd,J=38.4,14.0Hz,6H),1.40(dd,J=25.4,17.7Hz,3H),1.14(m,4H),0.9 6(d,J=12.6Hz,1H),0.90(m,9H),0.80(s,3H),0.73(s,3H),0.62(s,3H). 13 CNMR (101MHz, CDCl3) δ173.53,143.74,140.22,134.34,134.21,127.50,123.86,78.7 3,77.36,77.04,76.72,50.31,50.24,49.72,49.54,49.33,49.11,48.90,48.68,48.4 7,44.44,38.75,36.90,36.16,35.52,34.20,31.73,30.91,30.71,29.59,28.02,27.7 9,27.42,26.38,24.09,20.88,19.01,18.25,18.14,15.65,15.31,0.88.LC-MS:[M+H] + =493.60.

[0485] Example 16

[0486] Preparation of Compound 16 (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N-(pyridin-4-yl)pentanamide

[0487]

[0488] Referring to Example 2, the amine in the first step was replaced with pyridin-4-amine to obtain the compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-N-(pyridin-4-yl)pentanamide (16). 1 HNMR (399MHz, CDCl3) δ8.32 (d, J=6.0Hz, 2H), 7.48 (d, J=6.2Hz, 2H), 3.15 (dd, J= 11.4,4.8Hz,1H),2.38(m,1H),2.24(m,1H),1.90(m,6H),1.57(m,6H),1.40(dd, J=32.1,23.5Hz,4H),1.15(dd,J=22.5,10.3Hz,4H),0.98(d,J=11.6Hz,1H),0.9 2(d,J=5.0Hz,6H),0.88(d,J=5.6Hz,3H),0.81(s,3H),0.74(s,3H),0.63(s,3H). 13 CNMR(101MHz,CDCl3)δ149.80,134.35,134.21,113.56,78.77,77.35,77.0 4,76.72,50.31,50.27,49.74,49.68,49.47,49.26,49.04,48.83,44.46,38 .78,36.92,36.14,35.52,34.49,31.52,30.92,30.72,28.05,27.82,27.47, 26.40,24.11,20.90,19.05,18.28,18.16,15.68,15.34,0.92.LC-MS:[M+H] + =493.55.

[0489] Example 17

[0490] Preparation of Compound 17 (4R)-N-(4-cyanophenyl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]pentanamide

[0491]

[0492] Referring to Example 12, the amine in the first step was replaced with 4-cyanoaniline to obtain the compound (4R)-N-(4-cyanophenyl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]pentanamide (17). 1 H NMR (400MHz, CDCl3) δ7.59(d,J=8.8Hz,2H),7.53(d,J=8.7Hz,2H),7.30(s,1H),3.17(dd ,J=11.5,4.4Hz,1H),2.40(ddd,J=15.0,10.3,4.9Hz,1H),2.28–2.18(m,1H),2.01–1.83 (m,6H),1.60(dd,J=22.2,9.3Hz,8H),1.44–1.30(m,4H),1.15(dd,J=21.3,11.5Hz,3H), 0.90(dd,J=17.2,6.9Hz,8H),0.81(d,J=4.3Hz,3H),0.74(s,3H),0.60(d,J=19.4Hz,3H). 13 C NMR (101MHz, CDCl3) δ141.99,134.48,134.29,133.31,119.39,118.83,78.99,77.33,77.22,77.02,76.70,50.39,50.30,49.84,44.57,38.90, 37.03,36.14,35.59,34.93,31.60,31.02,30.81,28.19,27.97,27.84, 26.49,24.25,20.98,19.16,18.48,18.24,15.80,15.42.LC-MS:[M-17] + =499.

[0493] Example 18

[0494] Preparation of Compound 18 (4R)-N-(2,6-difluorophenyl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentanamide

[0495]

[0496] Referring to Example 12, the amine in the second step was replaced with 2,6-difluoroaniline to obtain the compound (4R)-N-(2,6-difluorophenyl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]pentanamide (18). 1 H NMR (400MHz, CDCl3) δ7.24–7.15(m,1H),6.95(t,J=8.1Hz,2H),6.70(s,1H),3.24(dd,J=11.5 ,4.5Hz,1H),2.49(d,J=12.1Hz,1H),2.40–2.30(m,1H),2.07–1.93(m,6H),1.82(s,2H),1.77– 1.58(m,8H),1.50(t,J=10.9Hz,3H),1.41(d,J=7.2Hz,2H),1.23–1.14(m,2H),1.05(dd,J=12 .6,1.9Hz,1H),1.00(s,3H),0.98(s,3H),0.96(s,3H),0.88(s,3H),0.81(s,3H),0.70(s,3H). 13 C NMR (101MHz, CDCl3) δ134.4,111.579.00,77.34,77.02,76.71,50.39,50.35,49.84,44.56,38.90,37.03, 36.08,35.59,31.00,30.83,28.15,27.97,27.84,26.49,24.25,21.00,19.16,18.41,18.25,15.77,15.43.

[0497] Example 19

[0498] Preparation of Compound 19 (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetrahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-N-[3-(trifluoromethyl)phenyl]pentanamide

[0499]

[0500] Referring to Example 12, the amine in the second step was replaced with 3-trifluoromethylaniline to obtain compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-N-[3-(trifluoromethyl)phenyl]pentanamide (19). 1 H NMR (400MHz, CDCl3) δ7.81 (s, 1H), 7.73 (d, J = 8.1Hz, 1H), 7.43 (t, J = 7.9Hz, 1H), 7.3 5(d,J=7.7Hz,1H),7.24(s,1H),3.24(dd,J=11.5,4.5Hz,1H),2.45(td,J=10.0,4.9H z,1H),2.33–2.24(m,1H),2.07–1.87(m,6H),1.62(dddd,J=34.6,25.4,14.3,7.8Hz ,12H),1.31–1.14(m,3H),1.04–0.91(m,9H),0.88(s,3H),0.81(s,3H),0.70(s,3H). 13 C NMR (101MHz, CDCl3) δ134.46,134.32,129.55,78.99,77.33,77.01,76.70,50.40,50.32,49.84,44.57,38.90,37.03,36.1 6,35.59,31.72,31.02,30.81,28.18,27.97,27.85,26.49,24.25,20.99,19.15,18.48,18.25,15.80,15.42.LC-MS:[M+H] + =560.45

[0501] Example 20

[0502] Preparation of Compound 20 (4R)-N-(2-cyanophenyl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]pentanamide

[0503]

[0504] Referring to Example 12, the amine in the second step was replaced with 2-cyanoaniline to obtain the compound (4R)-N-(2-cyanophenyl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]pentanamide (20). 1 H NMR(400MHz, CDCl3)δ8.43(d,J=8.6Hz,1H),7.66–7.48(m,2H),7.16(t,J=7.6Hz,1H),3 .24(dd,J=11.5,4.4Hz,1H),2.53(ddd,J=14.8,10.1,4.6Hz,1H),2.39–2.26(m,1H),2.1 1–1.87(m,6H),1.60(dddd,J=21.5,17.4,12.4,4.6Hz,13H),1.32–1.14(m,3H),1.07–0 .94(m,9H),0.88(d,J=5.0Hz,3H),0.83(d,J=12.7Hz,3H),0.69(dd,J=12.1,7.4Hz,3H). 13 C NMR (101MHz, CDCl3) δ172.08,140.60,134.46,134.32,134.24,133.45,132.16,123.9 5,121.62,121.15,116.44,78.99,77.33,77.22,77.02,76.70,50.41,50.34,50.27,4 9.84,44.59,38.90,37.03,36.10,35.59,34.91,31.58,31.00,30.82,28.15,27.97,2 7.85,26.50,24.27,21.00,19.15,18.46,18.25,15.80,15.42.LC-MS:[M+H]+=517.40

[0505] Example 21

[0506] Preparation of Compound 21 (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N-phenylpentanamide

[0507]

[0508] Referring to Example 2, the amine in the first step was replaced with aniline to obtain compound 4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-N-phenylpentanamide (21). 1 H NMR(399MHz, CDCl3) δ7.49(d,J=7.9Hz,2H),7.32–7.26(m,2H),7.18(s,1H),7.08(d,J=7.4Hz,1H),3 .22(dd,J=11.7,4.4Hz,1H),2.40(dt,J=10.1,4.3Hz,1H),2.30–2.19(m,1H),1.90(dd,J=17.1,9.5Hz ,2H),1.75–1.55(m,10H),1.53–1.29(m,7H),1.20(tt,J=12.5,6.8Hz,2H),1.03(dd,J=12.6,2.2Hz, 1H),0.97(dd,J=8.2,1.8Hz,6H),0.95–0.90(m,3H),0.86(s,3H),0.79(d,J=1.8Hz,3H),0.68(s,3H). 13 C NMR(101MHz,Chloroform-d)δ171.75,144.87,134.33,128.96,124.12,119.71,78.96,50.35,50.29,49.79,38.87,36.99,36.16 ,35.55,34.86,31.84,30.97,30.79,28.15,27.94,27.80,26.46,24.24,20.96,19.13,18.46,18.22,15.77,15.41.LC-MS:[M+H] + =492.55

[0509] Example 22

[0510] Preparation of Compound 22 (4R)-N-(4-fluorophenyl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentanamide

[0511]

[0512] Referring to Example 2, the amine in the first step was replaced with p-fluoroaniline to obtain the compound (4R)-N-(4-fluorophenyl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]pentanamide (22). 1 H NMR (399MHz, CDCl3) δ7.44(s,2H),7.06(s,1H),6.99(t,J=8.6Hz,2H),3.20(s,1H),2.41(s,1H),2.23(s,1H),2.01(s,5H),1.69(m,4H) ,1.36(s,4H),1.21(m,6H),1.03(d,J=11.4Hz,1H),0.97(d,J=7.9Hz,6H),0.93(d,J=5.2Hz,3H),0.86(s,3H),0.79(s,3H),0.68(s,3H). 13 C NMR (101MHz, CDCl3) δ171.85,134.41,134.29,133.88,121.59,121.52,1 15.71,115.48,78.95,77.30,76.98,76.67,50.28,49.79,44.52,38.86,3 6.99,36.16,35.55,34.70,31.81,30.97,30.77,28.15,27.93,27.80,26 .45,24.21,20.95,19.12,18.44,18.20,15.76,15.38,0.99.LC-MS:[M+H] + =510.60

[0513] Example 23

[0514] Preparation of Compound 23 2-{[(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-1-oxypentylene]amino}benzoic acid

[0515]

[0516] Referring to Example 12, the amine in the second step was replaced with methyl 2-aminobenzoate to obtain the compound 2-{[(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-1-oxopentanyl]amino}benzoic acid (23). 1 H NMR (400MHz, DMSO) δ11.52(s,1H),8.48(d,J=8.3Hz,1H),7.97(d,J=7.7Hz,1H),7.53( t,J=7.5Hz,1H),7.10(t,J=7.6Hz,1H),4.34(s,1H),3.03–2.97(m,1H),2.32–2.23(m, 1H),2.07–1.88(m,5H),1.85–1.75(m,1H),1.74–1.59(m,4H),1.53–1.29(m,8H),1.23 (s,3H),1.19–1.08(m,2H),0.91(d,J=6.2Hz,8H),0.84(s,3H),0.68(d,J=17.2Hz,6H). 13 CNMR(101MHz,DMSO)δ182.46,172.15,142.13,139.93,134.79,134.00,131.56,122.74,113.41,77.23,50.51,50.19,49.86,44.52,39.00,3 7.02,35.98,35.67,35.25,34.28,31.92,30.97,30.87,28.73,28.58, 28.04,26.46,24.50,20.98,19.47,18.72,16.31,16.05.LC-MS:[M+H] + =536.35.

[0517] Example 24

[0518] Preparation of Compound 24 (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-N-{2-[(1-oxyylideneprop-2-enyl)amino]phenyl}pentanamide

[0519]

[0520] In the first step, o-phenylenediamine (1 g, 9.25 mmol, 1.0 eq.) was dissolved in dichloromethane (15.0 mL), and triethylamine (2.6 mL, 18.5 mmol, 2.0 eq.) was added. After nitrogen replacement, the mixture was cooled in an ice bath, and acryloyl chloride (0.84 g, 9.25 mmol, 1.0 eq.) was added dropwise. The reaction was continued at 0°C for one hour and monitored by TLC (PE:EA=10:1, phosphomolybdic acid color development, Rf1=0.3, Rf2=0.4). After the reaction was completed, 10 mL of water was added to quench the reaction, and the mixture was extracted with 20 mL*3 of dichloromethane. The organic phase was dried, concentrated, and purified by column chromatography (PE:EA=50:1 to 10:1) to obtain N-(2-aminophenyl)prop-2-enamide (24-1) (120 mg, 0.66 mmol) as a white solid. 1 HNMR (399MHz, CDCl3) δ7.48(s,1H),7.21(d,J=7.9Hz,1H),7.05(t,J=7.6Hz,1H),6.78(d,J =7.5Hz,2H),6.39(d,J=16.8Hz,1H),6.27(dd,J=16.8,10.1Hz,1H),5.74(d,J=10.0Hz,1H).

[0521] In the second step, (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentanoic acid (VIII) (50 mg, 0.19 mmol, 1.0 eq.) was dissolved in N,N'-dimethylformamide (2.0 mL), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (54.76 mg, 0.144 mmol, 1.2 eq.) was added at room temperature, diisopropylethylamine (24-1) (0.03 mL, 0.18 mmol, 1.5 eq.) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. The mixture was stirred for 1 minute, and then N-(2-aminophenyl)prop-2-enamide (25 mg, 0.12 mmol) was added. The mixture was stirred at room temperature and monitored by TLC (PE:EA=3:1). After the reaction was completed, 8 mL of water was added for dilution, and then the mixture was extracted with 10 mL*3 of dichloromethane. The organic phases were combined, dried, concentrated, and purified by preparative HPLC to give (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-N-{2-[(1-oxyylideneprop-2-enyl)amino]phenyl}pentanamide (24) (12 mg, 0.02 mmol, 17.47%). 1 H NMR (399MHz, CDCl3) δ8.55(s,1H),8.25(s,1H),7.38(d,J=6.8Hz,1H),7.24(s,1H),7.14(d,J=3.5Hz,2H),6.39(d,J=17 .1Hz,1H),6.21(dd,J=17.1,10.1Hz,1H),5.76(d,J=10.1Hz,1H),3.22(dd,J=11.3,4.2Hz,1H),2.37(s,1H),2.30–2.10 (m,1H),2.02(s,5H),1.71(dd,J=31.4,14.8Hz,7H),1.47(d,J=7.5Hz,3H),1.38(d,J=21.9Hz,3H),1.20(dd,J=20.9,10 .7Hz,3H),1.03(d,J=12.6Hz,1H),0.99(t,J=10.6Hz,6H),0.93(d,J=5.4Hz,3H),0.87(s,3H),0.79(s,3H),0.68(s,3H). 13CNMR(100MHz,CDCl3)δ173.51,164.49,134.42,134.24,130.90,130.44,130.36,12 7.85,126.19,125.50,125.39,78.96,77.30,76.98,76.66,50.35,50.28,49.80,44 .52,38.86,36.99,36.19,35.54,34.20,31.93,30.97,30.91,30.78,28.16,27.93, 27.79,26.46,24.22,20.96,19.12,18.40,18.21,15.78,15.39,0.99.LC-MS:[M+H] + =561.60

[0522] Example 25

[0523] Preparation of Compound 25 Prop-2-enoic acid-2-{[(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-1-oxopentanyl]amino}phenyl ester

[0524]

[0525]

[0526] In the first step, 2-aminophenol (1 g, 9.16 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (20.0 mL), and di-tert-butyl dicarbonate (4.2 g, 18.33 mmol, 2.0 eq.) was added at room temperature. The mixture was stirred at room temperature for 16 hours and monitored by TLC (PE:EA=10:1, phosphomolybdic acid color development, Rf1=0.3, Rf2=0.5). After the reaction was completed, the mixture was concentrated and column chromatography (PE:EA=30:1~20:1) was performed to obtain 2-methylprop-2-yl[(2-hydroxyphenyl)amino]methane ester (25-1) (800 mg, 3.44 mmol) as a white solid.

[0527] Step 2: 2-Methylprop-2-yl[(2-hydroxyphenyl)amino]methane ester (800 mg, 3.82 mmol, 1.0 eq.) was weighed and dissolved in dichloromethane (15.0 mL). Triethylamine (1.063 mL, 7.65 mmol) was added, the atmosphere was replaced with nitrogen, the temperature was lowered to 0°C, and acryloyl chloride (346.04 mg, 3.823 mmol) was added dropwise. The mixture was then stirred at room temperature overnight and monitored by TLC (PE:EA=10:1). After the reaction was completed, 15 mL of water was added to quench the reaction. The mixture was then extracted with 10 mL of dichloromethane*3 times. The organic phases were combined, dried, concentrated, and purified by column chromatography (PE:EA=30:1~20:1~15:1) to obtain 2-({[(2-methylprop-2-yl)oxy]carbonyl}amino)phenyl prop-2-enoate (25-2) (600 mg, 2.05 mmol, 53.65%). 1 HNMR(399MHz, CDCl3)δ8.04(d,J=8.1Hz,1H),7.22–7.15(m,1H),7.11(dd,J=8.2,1.5Hz,1H),7.08–7.00(m,1H),6.65(d d,J=17.3,1.3Hz,1H),6.47(s,1H),6.37(dd,J=17.3,10.5Hz,1H),6.07(dd,J=10.4,1.2Hz,1H),1.49(d,J=2.2Hz,9H).

[0528] Step 3: 2-({[(2-methylpropan-2-yl)oxy]carbonyl}amino)phenyl prop-2-enoate (25-2) (300 mg, 2.05 mmol, 1.0 eq.) was dissolved in dichloromethane (1.0 mL), replaced with nitrogen, and cooled to 0°C. Trifluoroacetic acid (2 mL, 0.76 mmol) was added dropwise, followed by stirring at room temperature and monitoring by TLC (PE:EA = 10:1). After the reaction, the dichloromethane was removed by concentration at 25°C, the mixture was diluted with 5 mL of water, and the pH was adjusted to 7-8 with saturated sodium bicarbonate aqueous solution. The mixture was then extracted with 10 mL of ethyl acetate (3 times). The organic phases were combined, dried, concentrated, and purified by preparative TLC (PE:EA = 3:1) to give 2-aminophenyl prop-2-enoate trifluoroacetate (25-3) (30 mg, 0.16 mmol, 14.52%). LCMS: 164.20

[0529] In the fourth step, referring to Example 24, the amine was replaced with 2-aminophenyl prop-2-enoate trifluoroacetate to obtain the compound 2-{[(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-1-oxopentanyl]amino}phenyl prop-2-enoate (25). 1 H NMR (399MHz, CDCl3) δ8.23 (s, 1H), 7.24 (s, 2H), 7.13 (s, 2H), 6.40 (d, J = 16.8Hz, 1H), 6.2 0(dd,J=16.7,9.9Hz,1H),5.77(d,J=10.0Hz,1H),3.26–3.18(m,1H),2.66(s,1H),2.59– 2.47(m,1H),2.01(s,6H),1.76–1.61(m,6H),1.49(s,5H),1.37(s,1H),1.26–1.16(m,3H ),1.03(d,J=13.2Hz,1H),0.98(d,J=6.5Hz,9H),0.88(s,3H),0.79(s,3H),0.69(s,3H). 13 C NMR (100MHz, CDCl3) δ171.90,134.46,134.21,129.48,126.41,78.93,77.29,76.97,76.66,50.35,50.25,49.81,44.56,38.86,37.00,36. 13,35.54,31.56,31.38,30.98,30.90,30.76,28.16,27.93,27.79,26.46,24.21,20.95,19.13,18.32,18.20,15.79,15.39.LC-MS:[M+H] + =562.60

[0530] Example 26

[0531] Preparation of Compound 26 (4R)-N-(3-fluoropyridin-4-yl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentanamide

[0532]

[0533] Referring to Example 2, the amine in the first step was replaced with 3-fluoro-4-aminopyridine to obtain the compound (4R)-N-(3-fluoropyridin-4-yl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]pentanamide (26). 1 H NMR(399MHz, CDCl3)δ8.47–8.22(m,3H),7.53(s,1H),3.21(d,J=7.8Hz,1H), 2.50(s,1H),2.34(s,1H),2.01(s,4H),1.96–1.85(m,2H),1.66(d,J=15.3Hz ,4H),1.61–1.52(m,2H),1.49(s,2H),1.36(s,2H),1.28–1.16(m,4H),1.03( d,J=12.3Hz,1H),0.99–0.91(m,9H),0.86(s,3H),0.79(s,3H),0.68(s,3H). 13 C NMR (101MHz, CDCl3) δ172.23,146.86,136.91,136.70,134.43,134.23,1 14.45,78.91,77.30,77.19,76.99,76.67,50.35,50.22,49.80,44.53,38 .86,36.99,36.05,35.55,34.88,31.33,30.97,30.77,28.13,27.94,27. 79,26.45,24.23,20.95,19.13,18.42,18.21,15.76,15.39.LC-MS:[M+H] + =511.60

[0534] Example 27

[0535] Preparation of Compound 27 (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N-(2-methylpyrazol-3-yl)pentanamide

[0536]

[0537] Referring to Example 2, the amine in the first step was replaced with 1-methyl-5-aminopyrazole to obtain the compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-N-(2-methylpyrazol-3-yl)pentanamide (27). 1 HNMR(400MHz, Methanol-d4)δ7.38(s,1H),6.20(d,J=1.7Hz,1H),3.69(s,3H),3.18–3.10(m,1H),2.55–2.29(m,2H),2.06(s,5H),1.90(s,1H),1.83 –1.58(m,8H),1.58–1.47(m,3H),1.39(s,2H),1.31–1.15(m,3H),1.04(d, J=12.5Hz,1H),1.01–0.95(m,9H),0.91(s,3H),0.79(s,3H),0.75(s,3H). 13 C NMR(101MHz,DMSO)δ172.02,137.71,136.90,134.74,133.95,99.11,77.20 ,50.48,50.20,49.83,44.48,40.54,40.33,40.12,39.91,39.70,39.50,39. 29,38.97,36.98,36.02,35.93,35.64,32.79,31.80,30.96,30.83,28.54,2 8.01,26.45,24.48,20.96,19.43,18.72,18.33,16.27,16.01.LC-MS:[M+H] + =496.35

[0538] Example 28

[0539] Preparation of Compound 28 (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N-(isoxazol-3-yl)pentanamide

[0540]

[0541] Referring to Example 2, the amine in the first step was replaced with isoxazol-3-amine to obtain compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-N-(isoxazol-3-yl)pentanamide (28). 1 H NMR (400MHz, CDCl3) δ8.38(d,J=30.0Hz,1H),7.22(s,1H),3.24(dd,J=11.5,4.4Hz,1H),2.55–2.25(m,2H),2.07–1.99(s,3H),1.95–1.89(s,1H) ,1.76–1.58(s,10H),1.55–1.45(m,3H),1.30–1.17(s,4H),0.99(d,J=8 .3Hz, 6H), 0.95 (d, J = 4.8Hz, 3H), 0.88 (s, 3H), 0.81 (s, 3H), 0.70 (s, 3H). 13 CNMR(101MHz, CDCl3)δ184.86,146.42,137.97,134.46,134.29,124.83,78.99,50.38,50.24,49.83,44.56,38.90,37.03,36.1 2,35.58,34.33,31.47,30.99,30.81,28.17,27.97,27.84,26.49,24.25,20.99,19.16,18.43,18.25,15.80,15.43.LC-MS[M+H] + =546.40

[0542] Example 29

[0543] Preparation of Compound 29 (5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1-(1,4-oxazacyclohexan-4-yl)hexan-1-one

[0544]

[0545] (5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid (VI) (75 mg, 0.174 mmol, 1.0 eq) was dissolved in DMF (3 ml) L), HATU (2-(7-azobenzotriazole)-N,N,N\',N\'-tetramethyluronium hexafluorophosphate) (66 mg, 0.174 mmol) and DIPEA (N,N-diisopropylethylamine) (0.03 mL, 0.17 mmol, 1.0 eq) were added, and the mixture was stirred for 30 minutes. Morpholine (0.011 mL, 0.174 mmol, 1.0 eq) was added and stirred at room temperature for 2 hours. After the reaction was completed as monitored by TLC (PE:EtOAc=1:1, phosphomolybdic acid hotplate), the reaction solution was diluted with ethyl acetate (20 mL), washed twice with water, and the organic phases were combined, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PA:EA=80:20 to 50:50) to give (5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-1-(1,4-oxazacyclohexan-4-yl)hexan-1-one (29) (25 mg, 0.048 mmol, 27.29%) as a white solid. 1 H NMR (400MHz, DMSO) δ4.31 (d, J=5.1Hz, 1H), 3.52 (dd, J=10.9, 4.9Hz, 4H), 3.4 2(d,J=4.5Hz,4H),2.05-2.30(m,2H),2.05-1.95(m,4H),1.86(m,1H),1.61(m ,6H),1.54-1.22(m,9H),1.13(m,2H),1.03(m,1H),0.98-0.94(m,1H),0.91(d ,J=7.5Hz,5H),0.88(d,J=6.3Hz,3H),0.84(s,3H),0.70(s,3H),0.66(s,3H). 13C NMR (101MHz, DMSO) δ171.33,134.82,134.02,77.24,66.64,50.53,50.35,49.86,44.48,41.84,39.01,37.03,36.2 2,32.93,31.02,30.85,28.58,28.16,28.05,26.48,24.51,20.98,19.47,18.98,18.36,16.30,16.05.LC-MS:[M+H] + =500

[0546] Example 30

[0547] Preparation of Compound 30 (4R)-1-(hexahydropyridin-1-yl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentan-1-one

[0548]

[0549] Referring to Example 2, the amine in the second step was replaced with piperidine to obtain the compound (4R)-1-(hexahydropyridin-1-yl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]pentan-1-one (30). 1 H NMR (399MHz, CDCl3) δ3.52(s,1H),3.37(s,1H),3.20(s,1H),2.35(d,J=11.3Hz,1H),2.21(m,5H),2.01(s,4H),1.67(m,6H),1.48(d, J=8.7Hz,5H),1.25(m,9H),1.03(d,J=13.1Hz,1H),0.97(d,J=Hz,6H),0.91(d,J=6.1Hz,3H),0.86(s,3H),0.79(s,3H),0.67(s,3H). 13CNMR (101MHz, CDCl3) δ171.97,134.33,78.96,77.30,76.98,76.66,50.35,49.79,46.74,44.50,42.58,38.86,36.99,36.47,35.55,31. 87,30.95,30.81,28.16,27.93,27.81,26.57,26.46,25.55,24.58,24.22,20.96,19.12,18.51,18.22,15.75,15.40,1.00.LC-MS:[M+H] + =484.55

[0550] Example 31

[0551] Preparation of Compound 31 (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetrahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1-(1,4-oxazacyclohexan-4-yl)pentan-1-one

[0552]

[0553] Referring to Example 2, the amine in the second step was replaced with morpholine to obtain the compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-1-(1,4-oxazacyclohexan-4-yl)pentan-1-one (31). 1 H NMR (400MHz, CDCl3) δ3.69–3.58(m,6H),3.46(d,J=5.1Hz,2H),3.22(dd,J=11.5 ,4.4Hz,1H),2.43–2.32(m,1H),2.25–2.16(m,1H),2.01(s,4H),1.67(d,J=12.8 Hz,5H),1.51–1.39(m,5H),1.33(d,J=11.5Hz,2H),1.23(d,J=12.8Hz,3H),0.98 (d,J=8.3Hz,6H),0.91(d,J=5.9Hz,3H),0.86(s,4H),0.80(s,3H),0.68(s,3H). 13CNMR(100MHz,Chloroform-d)δ172.32,78.94,66.93,66.66,50.35,50.31,49.79,46.06,44.50,41.85,38.86,36.36,35.5 5,31.61,30.94,30.79,30.38,28.18,27.93,27.80,26.45,24.22,20.95,19.12,18.51,18.21,15.75,15.39.LC-MS:[M+H] + =486.50

[0554] Example 32

[0555] Preparation of Compound 32 (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetrahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1-(tetrahydro-1H-pyrrol-1-yl)pentan-1-one

[0556]

[0557] Referring to Example 2, the amine in the second step was replaced with tetrahydropyrrole to obtain the compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetrahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1-(tetrahydro-1H-pyrrol-1-yl)pentan-1-one (32). 1 H NMR (399MHz, CDCl3) δ3.44 (s, 4H), 3.22 (dd, J = 11.4, 4.4Hz, 1H), 2.36 (s, 1H), 2.20 ( s,1H),2.01(s,4H),1.90(s,3H),1.73(s,1H),1.66(d,J=13.5Hz,5H),1.56(d,J=17. 0Hz,2H),1.47(s,4H),1.35(s,2H),1.20(d,J=26.1Hz,3H),1.03(d,J=12.5Hz,1H), 0.97(d,J=8.1Hz,6H),0.91(d,J=5.6Hz,3H),0.86(s,3H),0.79(s,3H),0.67(s,3H). 13C NMR (101MHz, CDCl3) δ134.37,78.96,77.19,50.36,50.30,44.52,38.87,36.99,36.43,35.56,31.45,30 .96,30.81,28.16,27.94,27.81,26.46,24.24,20.97,19.13,18.51,18.22,15.76,15.40.LC-MS:[M+H] + =470.50

[0558] Example 33

[0559] Preparation of Compound 33 (4R)-1-(azetidin-1-yl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentan-1-one

[0560]

[0561] Referring to Example 2, the amine in the second step was replaced with azetidine to obtain the compound (4R)-1-(azetidin-1-yl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentan-1-one (33). 1 H NMR (399MHz, CDCl3) δ4.08 (s, 4H), 3.22 (dd, J = 11.5, 4.5Hz, 1H), 2.26 (s, 2H ),2.13(s,1H),2.00(s,6H),1.73(s,1H),1.70–1.61(m,5H),1.58(s,2H),1 .32(d,J=69.1Hz,7H),1.22–1.11(m,2H),1.03(d,J=12.8Hz,1H),0.97(d,J =8.3Hz,6H),0.89(d,J=5.9Hz,3H),0.85(s,3H),0.79(s,3H),0.67(s,3H). 13C NMR (101MHz, CDCl3) δ134.31,78.96,77.18,50.35,50.25,49.78,38.86,36.99,36.31,35.55,30 .96,30.78,28.13,27.93,27.80,26.45,24.23,20.95,19.12,18.21,15.75,15.39.LC-MS:[M+H] + =456.50

[0562] Example 34

[0563] Preparation of Compound 34 (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1-(piperazin-1-yl)pentan-1-one

[0564]

[0565] Referring to Example 2, the amine in the second step was replaced with piperazine to obtain the compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1-(piperazin-1-yl)pentan-1-one (34). 1 H NMR (399MHz, CDCl3) δ3.56(t,J=5.1Hz,2H),3.41(t,J=5.0Hz,2H),3.20(dd,J=11.5,4.5Hz,1H),2.82(dt, J=13.6,5.1Hz,4H),2.42–2.29(m,1H),2.21(dd,J=10.4,5.4Hz,1H),1.97(dt,J=25.9,9.4Hz,5H),1.83–1 .72(m,1H),1.61–1.53(m,2H),1.46(dt,J=15.0,8.1Hz,3H),1.37–1.28(m,2H),1.23–1.10(m,2H),1.02(d d,J=12.5,2.2Hz,1H),0.96(d,J=7.9Hz,6H),0.90(d,J=6.0Hz,3H),0.85(s,3H),0.78(s,3H),0.67(s,3H). 13C NMR (101MHz, CDCl3) δ78.93,76.92,50.35,50.32,49.79,46.87,46.39,45.87,44.50,42.58,38.86,36.99,36.41,35.55 ,31.74,30.95,30.80,30.58,28.18,27.94,27.80,26.46,24.22,20.96,19.12,18.52,18.22,15.75,15.40.LC-MS:[M+H] + =485.50

[0566] Example 35

[0567] Preparation of Compound 35 (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N,N-dipropylpentanamide

[0568]

[0569] Referring to Example 2, the amine in the second step was replaced with dipropylamine to obtain the compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N,N-dipropylpentanamide (35). 1 H NMR (399MHz, CDCl3) δ3.30–3.11(m,5H),2.40–2.29(m,1H),2.25–2.14(m,1H),2.00(s,5H),1.72(dd,J=27.7,18.5Hz,7H),1.52(ddd,J=27.0,17 .8,10.5Hz,9H),1.30–1.12(m,3H),1.02(d,J=12.6Hz,1H),0.97(d,J=7 .8Hz,6H),0.90(d,J=5.9Hz,6H),0.85(s,6H),0.79(s,3H),0.67(s,3H). 13C NMR (100MHz, CDCl3) δ173.38,134.34,78.92,77.29,76.98,76.66,50.36,49.78,47.57,44.49,38.85,36.99,36.33,35.56,3 2.01,30.97,30.80,30.25,28.14,27.93,27.81,26.45,24.19,20.96,19.11,18.52,18.21,15.74,15.38,11.29.LC-MS:[M+H] + =500.65

[0570] Example 36

[0571] Preparation of Compound 36 (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1-(4-methylpiperazin-1-yl)pentan-1-one

[0572]

[0573] (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1-(piperazin-1-yl)pentan-1-one (34) (100 mg, 0.206 mmol) and formaldehyde (24.75 mg, 0.825 mmol) were dissolved in tetrahydrofuran (5.0 ml). The mixture was stirred at room temperature for 0.5 h, and then sodium cyanoborohydride (64.81 mg, 1.031 mmol) was added and the reaction was allowed to proceed at room temperature overnight. After the reaction was completed, the reaction solution was washed with water and EtOAc, and the organic phase was washed once with brine, combined, dried, concentrated, and sent for preparative separation to obtain a white solid (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1-(4-methylpiperazin-1-yl)pentan-1-one (36) (5.3 mg, 0.01 mmol, 3.80%). 1H NMR(399MHz,Chloroform-d)δ4.75(s,1H),3.96(s,2H),3.24(dd,J=11.5,4.5Hz,1 H),2.84(s,3H),2.74(s,2H),2.38(s,2H),1.76–1.64(m,7H),1.57(d,J=14.7Hz,2H ),1.44(dt,J=17.4,8.4Hz,4H),1.36–1.17(m,7H),1.05(s,1H),1.02(s,1H),0.98 (s,3H),0.96(s,3H),0.90(d,J=5.8Hz,3H),0.86(s,3H),0.79(s,3H),0.67(s,3H). 13 C NMR(100MHz,Chloroform-d)δ79.02,50.34,49.80,38.85,36.25,35.53,30.95,30.76,30.24 ,28.20,27.92,27.74,26.45,24.21,20.94,19.12,18.51,18.20,15.76,15.39.LC-MS:[M+H] + =499.50

[0574] Example 37

[0575] Preparation of Compound 37 (5R)-1-(hexahydropyridin-1-yl)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexan-1-one

[0576]

[0577] In the first step, (methoxymethyl)triphenylphosphonium chloride (7.5 g, 23 mmol, 2.0 eq.) was dissolved in tetrahydrofuran (50.0 mL). Under nitrogen protection, the mixture was cooled to 0°C in an ice bath. Then, sodium bis(trimethylsilyl)amide (10.0 mL, 23 mmol, 2.0 eq.) was added dropwise. After the addition was complete, stirring was continued in an ice bath for 30 minutes. Acetic acid (3aR, 7S, 9aS, 11 aR)-1-[(2R)-4-formylbutyl-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester (II) (5.0 g, 11.6 mol, 1.0 eq.) was dissolved in tetrahydrofuran (30.0 mL) and heated at 0 ℃ was added dropwise to the above reaction solution. After the addition was complete, the temperature was slowly raised to room temperature and stirring was continued at room temperature for 2.0 hours. TLC monitoring (PE:EA=10:1, phosphomolybdic acid color development, Rf1=0.6, Rf2=0.8) was performed. After the reaction was completed, 30.0 mL of saturated aqueous ammonium chloride solution was added, and the mixture was extracted with 70 mL*3 of ethyl acetate. The organic phases were combined, dried, and concentrated to obtain 11 g of white solid crude product of (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R,5E)-6-methoxyhex-5-en-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (37-1), which was directly used in the next reaction.

[0578] Step 2: Weigh 3.5 g, 4.46 mmol, 1.0 eq., of (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R,5E)-6-methoxyhex-5-en-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (37-1), add tetrahydrofuran (60.0 mL) and 5 M aqueous hydrochloric acid solution (9.0 mL), stir at 50° C. for 2 h, monitor by TLC (PE:EA=10:1, phosphomolybdic acid color development, Rf1=0.7, Rf2=0.6), and react. After completion, tetrahydrofuran was removed by concentration, and then saturated aqueous sodium bicarbonate solution (100.0 mL) was added to the concentrate, followed by extraction with ethyl acetate (50.0 mL*3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE:EA=50:1-20:1) to give (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-formylpentan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (37-2) (930 mg, 1.934 mmol, 43.36%). 1 H NMR(399MHz, CDCl3) δ9.75(s,1H),4.48(dd,J=11.5,4.4Hz,1H),2.38(dd,J=13.6,6.8Hz,2H ),2.03(s,4H),1.98(s,2H),1.89(dt,J=17.1,9.3Hz,1H),1.77–1.56(m,8H),1.49(dd,J=14. 5,9.2Hz,3H),1.34(ddd,J=27.1,24.4,13.2Hz,5H),1.15(dd,J=17.5,11.1Hz,2H),1.04(dd ,J=12.3,7.3Hz,1H),0.98(s,3H),0.90(d,J=6.2Hz,3H),0.86(d,J=4.6Hz,9H),0.67(s,3H).

[0579] Step 3: Acetic acid-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-formylpentan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester (37-2) (830 mg, 1.82 mmol, 1.0 eq.) was weighed, water (14.0 mL) and tert-butanol (90 mL) were added, and 2-methyl-2-butene (2.5 g, 36.35 mmol, 20.0 eq.), sodium dihydrogen phosphate (2.4 g, 20.0 mmol, 10.0 eq.), sodium chlorite (493 mg, 5.4 mmol) were added in sequence at room temperature. , 3.0 eq.), stirred at room temperature for 2 hours, monitored by TLC (PE:EA=3:1, phosphomolybdic acid color development, Rf1=0.8, Rf2=0.4). After the reaction, the tert-butanol was removed by concentration, and water (10.0 mL) was added to the concentrate, followed by extraction with ethyl acetate (10.0 mL*3). The organic phases were combined, dried, and concentrated to give (5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-acetoxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid (37-3) (1.05 g, 1.77 mmol, 97.78%). 1 H NMR (399MHz, CDCl3) δ4.48(dd,J=11.6,4.5Hz,1H),2.42–2.22(m,2H),2.03(s,4H),1.98(s,2H),1.94–1.85(m,1H),1.76–1.63(m,8H),1.51(dd,J =20.7,7.5Hz,4H),1.41(s,2H),1.32–1.24(m,3H),1.13(d,J=14.2Hz,3H ),0.98(s,3H),0.90(d,J=6.3Hz,3H),0.86(d,J=4.8Hz,9H),0.67(s,3H).

[0580] In the fourth step, (5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-acetoxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid (37-3) (120 mg, 0.27 mmol, 1.0 eq.) was dissolved in DMF (N,N-dimethylformamide) (5.0 mL), and HATU (N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate) (123.13 mg, 0.32 mmol, 1.2 eq.) and diisopropylethylamine (41.85 mg, 0.32 mmol, 1.2 eq.) were added. The mixture was stirred at room temperature for 30 minutes, and then piperidine (25.28 mg, 0.30 mmol, 1.3 eq.) was added at room temperature. The mixture was stirred for 2 hours and monitored by TLC (PE:EA=3:1, phosphomolybdic acid color development, Rf1=0.5, Rf2=0.6). After the reaction was completed, 15.0 mL of water was added, and the mixture was extracted with 10 mL*3 of ethyl acetate. The organic phases were combined, dried, and concentrated to obtain acetic acid-(1R,3aR,5aR,7S, 9aS,11aR)-1-[(2R)-6-(hexahydropyridin-1-yl)-6-oxylidenehexan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester (37-4) 260 mg of the crude yellow oil was directly used in the next reaction.

[0581] Step 5: Weigh (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-(hexahydropyridin-1-yl)-6-oxylidenehexan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (37-4) (260 mg, 0.25 mmol, 1.0 eq.), add tetrahydrofuran (6.0 mL), methanol (6.0 mL), 1 M lithium hydroxide aqueous solution (3.5 mL), and stir at room temperature overnight. Monitor by TLC (PE:EA=3:1, phosphomolybdic acid color development, Rf1= 0.6, Rf2=0.5). After the reaction, tetrahydrofuran and methanol were removed by concentration. Water (15.0 mL) was then added to the concentrate, and the mixture was extracted with ethyl acetate (15.0 mL*3). The organic phases were combined, dried, concentrated, and purified by preparative HPLC to give (5R)-1-(hexahydropyridin-1-yl)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexan-1-one (37) (4.11 mg, 0.01 mmol, 3.7%).

[0582] 1 H NMR (399MHz, CDCl3) δ3.53(s,2H),3.37(s,2H),3.21(d,J=7.3Hz,1H),2.26(s,2H),1.94(d,J=46.1Hz,6H),1.70(s,1H),1.54(s,9H),1.3 9(s,4H),1.32–1.12(m,7H),1.03(d,J=12.3Hz,2H),0.97(d,J=7.8Hz,6H),0.90(d,J=5.7Hz,3H),0.85(s,3H),0.79(s,3H),0.67(s,3H). 13 C NMR(101MHz,dmso)δ166.89,129.58,74.22,72.55,72.24,71.92,45.02,42.00,39.70,34 .11,32.24,29.21,26.12,23.18,21.25,19.99,17.45,16.14,13.49,10.17.LC-MS:[M+H] + =498.70

[0583] Example 38

[0584] Preparation of Compound 38 (3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetrahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1-(1,4-oxazacyclohexan-4-yl)butan-1-one

[0585]

[0586] In the first step, compound (3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-acetoxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]butanoic acid III (60 mg, 0.14 mmol, 1.0 eq) was dissolved in DMF (N,N-dimethylformamide) (2 mL). HATU (61.57 mg, 0.16 mmol, 1.2 eq) and N,N-diisopropylethylamine (26.16 g, 0.20 mmol, 1.5 eq) were added in sequence and stirred at room temperature for half an hour. After monitoring the disappearance of the starting material, morpholin (87.12 g, 0.14 mmol, 1.3 eq) was added and allowed to react for 3 hours. The reaction was then completed as monitored by TLC (PE:EtOAc = 5:1, phosphomolybdic acid hotplate). The mixture was diluted with water, extracted with ethyl acetate, and the solvent was concentrated to afford (1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-pentamethyl-1-[(2R)-4-(1,4-oxazepan-4-yl)-4-oxobutan-2-yl]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate IX (60 mg, 0.10 mmol, 80% purity, 77.90% yield). The crude product was directly used in the next step.

[0587] Step 2: Compound (1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-pentamethyl-1-[(2R)-4-(1,4-oxazepan-4-yl)-4-oxobutan-2-yl]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (IX) was dissolved in EtOH (ethanol) (4 mL), and sodium hydroxide aqueous solution (4 mol / L, 0.5 mL) was added and reacted at room temperature for 16 hours. The reaction was complete as monitored by TLC (PE:EtOAc=5:1, phosphomolybdic acid hotplate). The reaction solution was concentrated to remove ethanol, diluted with water, and extracted twice with ethyl acetate (20 mL). The organic phases were combined, washed twice with brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EtOAc=50:10). The product was (3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-1-(1,4-oxazacyclohexan-4-yl)butan-1-one (38) (44.99 mg, purity 92.43%, yield 88.2%). 1 HNMR (400MHz, CDCl3) δ3.61–3.59(m,4H),3.50(s,4H),3.16(dd,J=11.6,4.5Hz,1H),2.32(d,J=12.2Hz,1H),2.05–1.79(m, 7H),1.70–1.47(m,10H),1.31–1.07(m,4H),0.91(dd,J=9.9,6.8Hz,8H),0.81(s,3H),0.74(s,3H),0.65(d,J=18.9Hz,3H). 13 C NMR (101MHz, CDCl3) δ171.70,134.57,134.17,78.97,77.33,77.22,77.01,76.70,50.95,50.41,49.91,44.72,39.81,3 8.90,37.04,35.59,34.50,30.92,30.82,28.32,27.97,27.85,26.49,24.23,20.98,19.63,19.15,18.24,15.85,15.42

[0588] Example 39

[0589] Preparation of Compound 39 (3R)-1-(hexahydropyridin-1-yl)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]butan-1-one

[0590]

[0591] Referring to Example 38, the amine in the first step was replaced with hexahydropyridine to obtain the compound (3R)-1-(hexahydropyridin-1-yl)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]butan-1-one (39). 1 H NMR (400MHz, CDCl3) δ3.42(s,4H),3.16(dd,J=11.5,4.5Hz,1H),2.33(d,J=13.8Hz,1H),2.06–1.81(m,7H),1.69–1.44(m,14H),1.31(dd,J =21.5,11.2Hz,2H),1.14(dd,J=22.0,12.0Hz,3H),0.94(ddd,J=20.1,12.3,3.9Hz,9H),0.81(s,3H),0.74(s,3H),0.65(d,J=18.7Hz,3H). 13 C NMR (101MHz, CDCl3) δ171.40,134.53,134.23,78.99,77.33,77.22,77.01,76.70,51.05,50.41,49.89,44.72,38.90,3 7.04,35.59,34.58,30.92,30.84,28.25,27.97,27.85,26.49,24.61,24.25,20.99,19.56,19.15,18.24,15.86,15.42.

[0592] Example 40

[0593] Preparation of Compound 40 (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N,N-dimethylpentanamide

[0594]

[0595] Referring to Example 12, the amine was replaced with dimethylamine to obtain the compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N,N-dimethylpentanamide (40). 1 H NMR (400MHz, CDCl3) δ3.17 (dd, J=11.5, 4.5Hz, 1H), 2.92 (s, 6H), 2.35 (ddd, J=15.9, 11.1,5.1Hz,1H),2.23–2.14(m,1H),1.98–1.89(m,5H),1.81–1.71(m,3H),1.66–1. 57(m,4H),1.55–1.35(m,5H),1.20(dddd,J=15.7,11.3,5.9,2.8Hz,4H),0.92(d,J= 8.3Hz, 6H), 0.86 (d, J = 6.0Hz, 3H), 0.81 (s, 3H), 0.74 (s, 3H), 0.60 (d, J = 19.3Hz, 3H). 13 C NMR(101MHz)δ134.41,134.38,78.98,77.34,77.23,77.02,76.70,50.40,49.83,44.54,38.90,37.03,36.41,35.59,3 1.58,31.00,30.84,30.49,28.18,27.97,27.85,26.49,24.25,21.00,19.15,18.52,18.25,15.78,15.42.LC-MS:[M+H] + =444.35

[0596] Example 41 Preparation of Compound 41 (4R)-N,N-diethyl-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentanamide

[0597]

[0598] Referring to Example 12, the amine was replaced with diethylamine to obtain compound (4R)-N,N-diethyl-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]pentanamide (41). 1 H NMR (400MHz, CDCl3) δ3.28 (s, 4H), 3.17 (dd, J=11.5, 4.5Hz, 1H), 2.33 (ddd, J=1 5.7,11.0,5.0Hz,1H),2.22–2.13(m,1H),2.01–1.84(m,7H),1.80–1.58(m,6H), 1.41(dddd,J=25.1,21.0,10.4,5.2Hz,6H),1.20–1.04(m,8H),0.92(d,J=8.3H z, 6H), 0.86 (d, J = 6.0Hz, 3H), 0.81 (s, 3H), 0.74 (s, 3H), 0.60 (d, J = 19.3Hz, 3H). 13 C NMR (101MHz, CDCl3) δ134.41,78.98,77.34,77.23,77.02,76.71,50.43,50.40,49.83,44.54,38.90,37.03,36.45,35.59 ,32.02,31.00,30.84,30.19,28.20,27.97,27.85,26.49,24.24,21.00,19.15,18.55,18.25,15.78,15.42.LC-MS:[M+H] + =472.45

[0599] Example 42

[0600] Preparation of Compound 42 (4R)-1-(4-fluorohexahydropyridin-1-yl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentan-1-one

[0601]

[0602] Referring to Example 12, the amine was replaced with 4-fluoropiperidine to obtain the compound (4R)-1-(4-fluorohexahydropyridin-1-yl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]pentan-1-one (42). 1 H NMR (400MHz, CDCl3) δ4.93–4.86(m,1H),4.81–4.74(m,1H),3.55(s,2H),3.51(s,2H),3.20 (dd,J=11.5,4.5Hz,1H),2.45–2.32(m,1H),2.27–2.16(m,1H),2.04–1.91(m,4H),1.89–1.7 1(m,5H),1.71–1.53(m,10H),1.45(ddd,J=17.7,13.6,5.9Hz,3H),1.33–1.12(m,4H),1.05– 0.93(m,6H),0.90(d,J=6.0Hz,3H),0.86–0.81(m,3H),0.78(s,3H),0.64(d,J=19.4Hz,3H). 13 CNMR (101MHz, CDCl3) δ134.35,78.98,77.33,77.01,76.70,50.40,49.84,44.55,38.90,37.03,36.46,3 5.59,31.00,30.83,28.22,27.96,27.85,26.49,24.27,20.99,19.15,18.25,15.79,15.42.LC-MS:[M+H] + =502.45

[0603] Example 43

[0604] Preparation of Compound 43 (4R)-1-(4-fluorohexahydropyridin-1-yl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentan-1-one

[0605]

[0606] Referring to Example 12, the amine was replaced with 4,4-difluoropiperidine to obtain the compound (4R)-1-(4-fluorohexahydropyridin-1-yl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]pentan-1-one (43). 1 H NMR (400MHz, CDCl3) δ3.58 (s, 4H), 3.17 (dd, J = 11.5, 4.5Hz, 1H), 2.41–2.30 (m, 1 H),2.25–2.14(m,1H),1.93(ddd,J=20.6,11.9,7.5Hz,7H),1.69–1.50(m,11H), 1.41(dt,J=12.9,8.0Hz,3H),1.28–1.08(m,4H),0.94(dd,J=17.3,4.9Hz,6H),0 .86(d,J=6.0Hz,3H),0.82(d,J=5.1Hz,3H),0.74(s,3H),0.60(d,J=19.4Hz,3H). 13 C NMR (101MHz, CDCl3) δ172.17,134.46,134.33,78.98,77.33,77.01,76.70,50.40,50.37,49.84,44.56,38.90,37.03,36.41,3 5.59,31.74,30.99,30.82,30.54,28.21,27.96,27.84,26.49,24.24,20.99,19.15,18.54,18.24,15.78,15.42.LC-MS:[M+H] + =520.50

[0607] Example 44

[0608] Preparation of Compound 44 (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1-[4-(trifluoromethyl)hexahydropyridin-1-yl]pentan-1-one

[0609]

[0610] Referring to Example 2, the amine was replaced with 4-trifluoromethylpiperidine to obtain the compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1-[4-(trifluoromethyl)hexahydropyridin-1-yl]pentan-1-one (44). 1 HNMR(400MHz, CDCl3) δ4.73(d,J=14.3Hz,1H),3.94(d,J=12.8Hz,1H),3.22(d,J=7.0Hz,1H) ,3.00(t,J=13.0Hz,1H),2.48(d,J=12.2Hz,1H),2.38(s,1H),2.23(d,J=5.0Hz,2H),2.01(s, 4H),1.92(d,J=14.6Hz,3H),1.69(m,6H),1.48(d,J=8.2Hz,5H),1.21(m,7H),1.03(d,J=12.6 Hz,1H),0.97(d,J=7.8Hz,6H),0.91(d,J=5.9Hz,3H),0.86(s,3H),0.79(s,3H),0.68(s,3H). 13 CNMR (100MHz, CDCl3) δ172.05,134.30,109.99,78.93,77.30,76.98,76.66,50.31,49.80,44.49,40.42,38.85,36.98,3 6.38,35.54,31.69,30.95,30.80,30.63,28.18,27.93,27.79,26.45,24.21,20.95,19.12,18.51,18.21,15.74,15.39. 19 FNMR(376MHz, CDCl3)δ-73.89,-73.92.LC-MS:[M+H] + =552.50

[0611] Example 45

[0612] Preparation of Compound 45 (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1-(4-methylhexahydropyridin-1-yl)pentan-1-one

[0613]

[0614] Referring to Example 2, the amine was replaced with 4-methylpiperidine to obtain the compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1-(4-methylhexahydropyridin-1-yl)pentan-1-one (45). 1 H NMR(399MHz, CDCl3) δ4.54(d,J=12.7Hz,1H),3.78(d,J=12.9Hz,1H),3.21(dd,J=11.4,4 .2Hz,1H),2.96(t,J=12.3Hz,1H),2.50(t,J=12.4Hz,1H),2.36(t,J=10.4Hz,1H),2.19(m ,1H),1.97(d,J=26.1Hz,5H),1.68(dt,J=27.2,14.0Hz,12H),1.32(m,7H),1.03(m,3H),0 .96(d,J=7.9Hz,6H),0.91(dd,J=9.1,6.3Hz,6H),0.85(s,3H),0.78(s,3H),0.67(s,3H). 13 CNMR (100MHz, CDCl3) δ171.95,134.37,98.57,78.92,77.30,76.98,76.66,50.36,49.78,46.02,44.50,41.95,38.85,36.99,36.44,35.56,34. 74,33.79,31.86,31.10,30.96,30.80,28.15,27.93,27.80,26.45,24. 21,21.71,20.96,19.11,18.50,18.21,15.74,15.38,0.98.LC-MS:[M+H]+ =498.65

[0615] Example 46

[0616] Preparation of Compound 46 (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1-(2-azaspiro[3.3]hept-2-yl)pentan-1-one

[0617]

[0618] Referring to Example 2, the amine was replaced with 2-azaspiro[3.3]heptane to obtain the compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1-(2-azaspiro[3.3]hept-2-yl)pentan-1-one (46). 1 HNMR (399MHz, CDCl3) δ4.02 (s, 2H), 3.91 (s, 2H), 3.66 (s, 0.16H), 3.21 (dd, J = 11.5, 4.4Hz, 1H), 2.14 (t, J = 7.2Hz, 4H), 2.07 (m, 1H), 1.96 (m, 5H) ),1.84(m,2H),1.68(m,6H),1.47(m,5H),1.26(m,3H),1.17(m,2H),1.0 2(m,1H),0.96(d,J=8.4Hz,6H),0.87(m,6H),0.79(s,3H),0.66(s,3H). 13 CNMR(101MHz,CDCl3)δ173.72,134.34,134.32,78.93,77.31,77.00,76.6 8,62.44,60.01,50.35,50.25,49.77,44.47,38.86,37.45,36.98,36.26, 35.55,33.08,31.20,30.95,30.79,29.67,28.64,28.09,27.93,27.80,26 .45,24.21,20.95,19.12,18.44,18.21,16.03,15.74,15.40LC-MS:[M+H] + =496.65

[0619] Example 47

[0620] Preparation of Compound 47 (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N,N-bis(2-methylpropyl)pentanamide

[0621]

[0622] Referring to Example 2, the amine was replaced with diisobutylamine to obtain the compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-N,N-bis(2-methylpropyl)pentanamide (47). 1 H NMR (399MHz, CDCl3) δ3.21(d,J=8.8Hz,1H),3.16(d,J=7.3Hz,2H),3.06(d,J =7.4Hz,2H),2.35(m,1H),2.22(m,1H),1.93(m,7H),1.85(s,1H),1.68(m,6H) ,1.48(m,3H),1.21(dt,J=21.2,20.7Hz,6H),1.03(d,J=12.7Hz,1H),0.97(d ,J=7.8Hz,6H),0.90(d,J=6.7Hz,9H),0.85(m,9H),0.79(s,3H),0.67(s,3H). 13 C NMR (101MHz, CDCl3) δ173.98,134.34,78.95,77.31,76.99,76.67,55.63,53.07,50.35,49.78,44.48,38.86,36.98,36.29,35.55,32.09,30. 96,30.80,30.57,28.14,27.98,27.93,27.80,26.50,26.45,24.20,20. 96,20.18,20.11,19.12,18.53,18.22,15.74,15.40,1.00.LC-MS:[M+H + =528.70

[0623] Example 48

[0624] Compound 48 Preparation of 1-[(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-1-oxopentanyl]hexahydropyridine-4-carbonitrile

[0625]

[0626] Referring to Example 12, the amine was replaced with 4-cyanopiperidine to obtain the compound 1-[(4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-1-oxopentanyl]hexahydropyridine-4-carbonitrile (48). 1 H NMR(400MHz, CDCl3) δ3.73(d,J=35.0Hz,2H),3.50(d,J=34.4Hz,2H),3.23(dd, J=11.5,4.4Hz,1H),2.88(dt,J=11.6,3.8Hz,1H),2.44–2.33(m,1H),2.28–2.1 8(m,1H),2.07–1.85(m,8H),1.75–1.58(m,8H),1.53–1.15(m,8H),1.02(dd,J= 23.5,9.5Hz,7H),0.93(d,J=6.0Hz,3H),0.88(s,3H),0.81(s,3H),0.69(s,3H). 13 C NMR (101MHz, CDCl3) δ172.09,134.45,134.32,120.75,78.96,77.35,77.03,76.71,50.40,50.37,49.83,44.55,38.90,37.03,36.41, 35.59,31.70,30.99,30.82,30.57,28.22,27.97,27.84,26.49,26.41,24.25,20.99,19.15,18.54,18.25,15.79,15.42.LC-MS:[M+H] + =509.45.

[0627] Example 49

[0628] Preparation of Compound 49 (4R)-N-(2-fluorophenyl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N-methylpentanamide

[0629]

[0630] Referring to Example 2, the amine was replaced with (2-fluorophenyl)(methyl)amine to obtain the compound ((4R)-N-(2-fluorophenyl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-N-methylpentanamide (49). 1 H NMR (399MHz, CDCl3) δ7.32(s,1H),7.18(dd,J=18.6,11.2Hz,3H),3.21(d,J=8.6Hz,4 H),2.09(s,1H),1.95(s,4H),1.79(s,1H),1.72–1.60(m,6H),1.50(d,J=26.5Hz,6H), 1.33(d,J=8.5Hz,1H),1.21(d,J=13.4Hz,3H),1.18–1.09(m,1H),1.02(d,J=12.8Hz,1 H),0.96(d,J=13.8Hz,6H),0.79(d,J=5.8Hz,6H),0.66(d,J=5.3Hz,3H),0.60(s,3H). 13 CNMR(101MHz, CDCl3)δ173.99,145.24,134.29,129.71,125.01,117.01,116.81,78.95,77.31,77.20,76.99,76.68,50.33,49.73,4 4.38,38.85,36.96,36.45,36.06,35.53,30.86,30.76,27.93,27.79,26.43,24.14,20.92,19.11,18.20,15.67,15.39.LC-MS:[M+H] + =524.40

[0631] Example 50

[0632] Preparation of Compound 50 (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetrahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N,N-di(propan-2-yl)pentanamide

[0633]

[0634] Referring to Example 2, the amine was replaced with diisopropylamine to obtain the compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-N,N-di(propan-2-yl)pentanamide (50). 1 H NMR (399MHz, CDCl3) δ3.94 (s, 1H), 3.45 (s, 1H), 3.22 (dd, J = 11.2, 4.2Hz, 1H), 2.31 (d, J =10.1Hz,1H),2.15(s,1H),2.01(s,4H),1.69(dd,J=20.1,12.6Hz,7H),1.49(m,7H),1. 35(d,J=6.7Hz,5H),1.25(d,J=11.5Hz,4H),1.18(d,J=6.6Hz,6H),1.03(d,J=13.0Hz,1 H),0.97(d,J=8.3Hz,6H),0.91(d,J=6.1Hz,3H),0.85(s,3H),0.79(s,3H),0.67(s,3H). 13 C NMR (100MHz, CDCl3) δ172.41,134.34,78.96,77.30,77.18,76.99,76.67,75.96,50.37,49.78,48.36,45.53,44.49,38.86,36.98,36.42,3 5.55,32.72,31.92,30.95,30.81,28.20,27.93,27.80,26.45,24.21,21.05,20.70,19.12,18.57,18.22,15.74,15.39,1.00.LC-MS:[M+H] + =500.70

[0635] Example 51

[0636] Preparation of Compound 51 (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N-(2-hydroxyethyl)-N-propylpentanamide

[0637]

[0638] Referring to Example 2, the amine was replaced with 2-(propylamino)ethan-1-ol to obtain the compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-N-(2-hydroxyethyl)-N-propylpentanamide (51). 1 H NMR (399MHz, CDCl3) δ8.32(d,J=6.0Hz,2H),7.48(d,J=6.2Hz,2H),3.15(dd,J=1 1.4,4.8Hz,1H),2.38(m,1H),2.24(m,1H),1.90(m,6H),1.57(m,6H),1.40(dd,J =32.1,23.5Hz,4H),1.15(dd,J=22.5,10.3Hz,4H),0.98(d,J=11.6Hz,1H),0.92 (d,J=5.0Hz,6H),0.88(d,J=5.6Hz,3H),0.81(s,3H),0.74(s,3H),0.63(s,3H). 13 C NMR (101MHz, CDCl3) δ149.80,134.35,134.21,113.56,78.77,77.35,77.04 ,76.72,50.31,50.27,49.74,49.68,49.47,49.26,49.04,48.83,44.46,38. 78,36.92,36.14,35.52,34.49,31.52,30.92,30.72,28.05,27.82,27.47, 26.40,24.11,20.90,19.05,18.28,18.16,15.68,15.34,0.92.LC-MS:[M+H] + =502.60

[0639] Example 52

[0640] Preparation of Compound 52 (4R)-N-(2-fluorophenyl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-N-(2-hydroxyethyl)pentanamide

[0641]

[0642] Referring to Example 12, the amine was replaced with (2-fluorophenyl)(4,4,5,5-tetramethyl-3-oxa-4-silanhexan-1-yl)amine to obtain the compound (4R)-N-(2-fluorophenyl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-N-(2-hydroxyethyl)pentanamide (52). 1 H NMR (400MHz, CDCl3) δ7.44–7.34(m,1H),7.33–7.27(m,1H),7.25–7.16(m,2H),4.05–3 .94(m,1H),3.85–3.64(m,3H),3.23(dd,J=11.5,4.4Hz,1H),2.18–2.09(m,1H),1.93– 2.05(m,5H),1.80–1.64(m,11H),1.30–1.20(m,4H),1.18–1.10(m,1H),1.06–1.02(m, 1H), 0.98 (d, J = 14.3Hz, 6H), 0.81 (d, J = 6.2Hz, 6H), 0.69 (d, J = 4.7Hz, 3H), 0.62 (s, 3H). 13 C NMR (101MHz, CDCl3) δ176.20,134.35,134.32,130.36,130.30,125.23,12 5.19,117.10,116.90,78.96,61.96,52.76,50.35,50.21,50.16,49.76,4 4.42,38.87,36.99,35.55,31.70,31.64,31.24,31.10,30.89,30.76,27. 95,27.81,26.45,24.15,20.94,19.13,18.22,15.69,15.41.LC-MS:[M+H] +=554.00

[0643] Example 53

[0644] Preparation of Compound 53 (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N-methyl-N-phenylpentanamide

[0645]

[0646] Referring to Example 2, the amine was replaced with N-methylaniline to obtain the compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-N-methyl-N-phenylpentanamide (53). 1 HNMR(400MHz, CDCl3)δ7.43(t,J=7.5Hz,2H),7.35(t,J=7.3Hz,1H),7.19(d,J=7 .6Hz,2H),3.27(s,3H),3.23(dd,J=11.5,4.4Hz,1H),2.06–1.88(m,8H),1.86–1 .74(m,2H),1.72–1.48(m,7H),1.34–1.10(m,6H),1.03(dd,J=12.6,1.8Hz,1H), 0.99(s,3H),0.96(s,3H),0.81(d,J=5.0Hz,6H),0.72–0.64(m,3H),0.62(s,3H). 13 C NMR (101MHz, CDCl3) δ173.92,144.29,134.34,129.70,127.35,78.96,77.33,77.22,77.01,76.69,50.36,50.21,49.76,44.41,38.87, 36.98,36.16,35.56,31.29,30.89,30.78,28.03,27.95,27.82,26.45,24.17,20.94,19.12,18.22,15.70,15.70,15.41.LC-MS:[M+H] + =507.4

[0647] Example 54

[0648] Compound 54 Preparation of 2-fluoro-N-[(3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]butyl]-N-methylbenzamide

[0649]

[0650] In the first step, (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-1-formylpropan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate (III) (50 mg, 0.12 mmol) was dissolved in methanol (5.0 mL), and a methanol solution of methylamine (0.1 mL, 3.2 mmol, 27 eq.) was added. The mixture was stirred at room temperature for 30 minutes, and then palladium carbon (1.25 mg, 0.012 mmol) was added at room temperature. The mixture was replaced with hydrogen, and then stirred at room temperature for 2 hours. The mixture was monitored by TLC (PE:EA=10:1, phosphomolybdic acid color development, Rf1=0.8, Rf2=0.6). After the reaction was completed, palladium carbon was removed by filtration, and the filtrate was concentrated to obtain 90 mg of white solid acetate-(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-pentamethyl-1-[(2R)-4-(methylamino)butan-2-yl]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester (54-1). The crude product was directly used in the next reaction.

[0651] Step 2: Acetic acid-(1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-pentamethyl-1-[(2R)-4-(methylamino)butan-2-yl]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester (54-1) (90 mg, 0.142 mmol, 1.0 eq.) was weighed, dichloromethane (5.0 mL) and triethylamine (0.02 mL, 0.142 mmol) were added, and o-fluorobenzoyl chloride (22.51 mg, 0.142 mmol) was added under ice bath. The mixture was stirred at room temperature overnight and monitored by LC-MS. After the reaction was complete, the dichloromethane was removed by concentration. Saturated aqueous sodium bicarbonate (10.0 mL) was then added to the concentrate, followed by extraction with ethyl acetate (10.0 mL*3). The organic phases were combined, dried, concentrated, and purified by preparative TLC to give (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-{[(2-fluorophenyl)carbonyl](methyl)amino}butan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (54-2) (80 mg, 0.134 mmol, 94.61%). 1 H NMR(399MHz, CDCl3)δ7.37–7.29(m,2H),7.15(dd,J=21.3,13.9Hz,1H),7.08(t,J=8.7Hz,1H),4.55–4.39 (m,1H),3.78–3.68(m,0.3H),3.47–3.35(m,0.4H),3.15(d,J=7.2Hz,1H),3.07(s,2H),2.86(s,1H),2.03 (s,5H),1.98–1.91(m,2H),1.68(d,J=19.3Hz,6H),1.54(d,J=19.5Hz,4H),1.40–1.24(m,4H),1.13(d,J= 10.3Hz,3H),1.01–0.92(m,5H),0.86(d,J=3.5Hz,7H),0.79(s,2H),0.70–0.67(m,1H),0.66–0.54(m,3H).

[0652] Step 3: Acetic acid-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-{[(2-fluorophenyl)carbonyl](methyl)amino}butyl-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester (54-2) (80 mg, 0.141 mmol) was dissolved in a mixed solvent of tetrahydrofuran (3.0 mL) and methanol (3.0 mL). 1 M aqueous lithium hydroxide solution (1.5 mL) was added under stirring at room temperature, followed by stirring at room temperature and monitoring by LCMS. After the reaction, the reaction solvent was removed by concentration, and then 10 mL of water was added, followed by extraction with ethyl acetate (10.0 mL*3). The organic phases were combined, dried, concentrated, and purified by preparative HPLC to obtain 2-fluoro-N-[(3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]butyl]-N-methylbenzamide (54) (15.41 mg, 0.029 mmol, 20.24%) as a white solid. 1 HNMR (400MHz, CDCl3) δ7.42–7.28(m,2H),7.17(t,J=7.4Hz,1H),7.07(q,J=8.6Hz,1H),3.24–3.15(m ,1H),3.07(s,1.8H),2.82(d,J=35.9Hz,1.4H),1.98(d,J=20.3Hz,5H),1.69(dd,J=24.3,14.3Hz,8H ),1.54(d,J=7.8Hz,3H),1.42–1.29(m,2H),1.26–1.12(m,4H),1.07–1.02(m,1H),0.98(dd,J=7.1,4 .1Hz,6H),0.95(s,2H),0.88(s,1.3H),0.79(d,J=3.7Hz,5H),0.71(s,1.3H),0.61(d,J=8.4Hz,3H). 13CNMR(101MHz, CDCl3)δ166.74,166.38,144.85,134.42,134.28,134.14,130.85,130.78,128.89,128.65,124.53,124.40,1 15.87,115.75,115.66,115.53,78.95,78.91,77.31,76.99,76.67,50.40,50.37,50.34,49.94,49.82,49.76,48.61,45.09, 44.56,44.42,38.85,36.97,36.14,35.53,34.38,34.34,34.01,33.08,32.72,30.96,30.82,30.70,28.27,28.05,27.93,27 .82,27.78,26.47,26.43,24.23,24.12,20.97,20.89,19.11,18.78,18.47,18.22,18.19,15.68,15.58,15.39.LC-MS:[M+H] + =524.35.

[0653] Example 55

[0654] Preparation of Compound 55 (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N-methyl-N-(1,3-thiazolylcyclopentan-2-yl)pentanamide

[0655]

[0656] Referring to Example 2, the amine was replaced with N-methyl-2-thiazolamine to obtain compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-N-methyl-N-(1,3-thiazolyl)pentanamide (55). 1H NMR(399MHz, CDCl3)δ7.48(d,J=3.5Hz,1H),6.96(d,J=3.3Hz,1H),3.72(s,3H), 3.21(dd,J=11.5,4.4Hz,1H),2.67(dd,J=10.7,5.8Hz,1H),2.57–2.47(m,1H),2 .07–1.90(m,6H),1.75–1.62(m,6H),1.62–1.34(m,6H),1.25–1.17(m,2H),1.03 (d,J=11.8Hz,1H),0.96(t,J=7.5Hz,9H),0.86(s,3H),0.79(s,3H),0.69(s,3H). 13 CNMR(101MHz, CDCl3)δ172.80,160.29,136.58,134.40,134.26,114.77,78.91,77.31,76.99,76.67,50.33,49.80,44.53,38.86,36.99,36 .14,35.54,34.89,32.08,30.96,30.88,30.79,28.16,27.93,27.80,26.45,24.21,20.95,19.12,18.54,18.21,15.77,15.40.LC-MS:[M+H] + =513.60.

[0657] Example 56

[0658] Preparation of Compound 56 (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N-methyl-N-(2-methylpyrazol-3-yl)pentanamide

[0659]

[0660]

[0661] Step 1: Weigh (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-acetoxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]pentanoic acid (VII) (100 mg, 0.218 mmol) and dissolve it in dichloromethane (10.0 mL). Add N,N'-dimethylformamide (1d), replace N2, and place in an ice bath. Dissolve oxalyl chloride (36.89 mg, 0.291 mmol) in dichloromethane (3.0 mL) and slowly add dropwise to the reaction system. Stir under ice-bath for half an hour and monitor by TLC (petroleum ether:ethyl acetate = 10:1). Upon completion of the reaction, spin dry the mixture and dilute with dichloromethane (10.0 mL). Slowly add dropwise to a solution of 1-methyl-5-aminopyrazole (10.59 mg, 0.109 mmol) and 4-dimethylaminopyridine (106.54 mg, 0.872 mmol) in DCM under ice-bath. After complete addition, react in an ice-bath for 0.5 h before warming to room temperature. Completion of the reaction is monitored by TLC (PE:EtOAc = 3:1), and product is confirmed by LCMS. The product was purified by column chromatography (PE:EtOAc=30:1-20:1-15:1) to give (1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-pentamethyl-1-[(2R)-5-[(2-methylpyrazol-3-yl)amino]-5-oxopentan-2-yl]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (56-1) (60 mg, 0.11 mmol, 46.06%). 1 H NMR(400MHz, Methanol-d4)δ7.38(s,1H),6.20(d,J=1.7Hz,1H),3.69(s,3H),3.18–3.10(m,1H),2.55–2.29(m,2H),2.06(s,5H),1.90(s,1H),1.83 –1.58(m,8H),1.58–1.47(m,3H),1.39(s,2H),1.31–1.15(m,3H),1.04(d, J=12.5Hz,1H),1.01–0.95(m,9H),0.91(s,3H),0.79(s,3H),0.75(s,3H).

[0662] Step 2: (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N-(2-methylpyrazol-3-yl)pentanamide (56-1) (10 mg, 0.019 mmol) was dissolved in N,N'-dimethylformamide (1.0 mL), potassium carbonate (7.71 mg, 0.056 mmol) was added, and then iodomethane (15.83 mg, 0.112 mmol) was added at room temperature. TLC (PE:EtOAc=1:1) was performed. ) was monitored. After the reaction was complete and the product was confirmed by LCMS, 5.0 mL of water and 3.0 mL of ethyl acetate were added. The organic phases were separated, combined, dried, and concentrated. The crude product was purified by preparative TLC (PE:EtOAc = 1:1) to give (1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-pentamethyl-1-[(2R)-5-[methyl(2-methylpyrazol-3-yl)amino]-5-oxopentan-2-yl]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (56-2) (6.0 mg, 0.01 mmol, 48.64%). 1 H NMR (400MHz, Methanol-d4) δ7.50(d,J=2.0Hz,1H),6.27(s,1H),4.43(t,J=8.3Hz,1H),3.70(s,3H),3.15(s,3H),2.03(d,J=14.7Hz,8H),1.8 2–1.50(m,13H),1.39(t,J=8.8Hz,6H),1.17(dd,J=24.7,12.2Hz,4H),1.02(s,3H),0.87(d,J=2.4Hz,9H),0.76(d,J=5.9Hz,4H),0.68(s,3H).

[0663] Step 3: (1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-pentamethyl-1-[(2R)-5-[methyl(2-methylpyrazol-3-yl)amino]-5-oxopentan-2-yl]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (56-2) (114 mg, 0.21 mmol) was dissolved in tetrahydrofuran (5.0 mL), methanol (3.00 mL) was added, and finally a solution of lithium hydroxide (8.91 mg, 0.372 mmol) in water (1 M, 2.0 mL) was added. After the addition was complete, the mixture was stirred at room temperature for 18 h. The reaction was monitored by TLC (EA) and the reaction was completed. Preparative HPLC was used to obtain (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N-methyl-N-(2-methylpyrazol-3-yl)pentanamide (56) (19.32 mg, 0.038 mmol, 18.41%). 1 H NMR (399MHz, Methanol-d4) δ7.49 (s, 1H), 6.26 (d, J = 2.0Hz, 1H), 3.69 (s, 3H), 3 .14(s,4H),2.06(d,J=30.0Hz,7H),1.84(s,1H),1.72(d,J=13.5Hz,5H),1.60(s ,6H),1.34(dt,J=32.2,11.1Hz,4H),1.16(d,J=10.2Hz,1H),1.02(d,J=13.4Hz, 2H),0.96(s,3H),0.85(s,3H),0.78(s,3H),0.75(d,J=5.9Hz,3H),0.67(s,3H). 13 C NMR(101MHz,CD3OD)δ175.21,140.83,138.54,134.56,134.15,78.19,50 .50,49.57,48.20,47.98,47.84,47.77,47.61,47.56,47.49,47.35,47. 13,46.92,44.23,38.52,36.76,35.52,33.95,31.43,30.77,27.17,27.0 4,26.20,23.14,20.59,18.17,17.98,17.37,14.84,14.71.LC-MS:[M+H] + =510.40

[0664] Example 57

[0665] Preparation of compound 57 N-ethyl-2-fluoro-N-[(3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]butyl]benzamide

[0666]

[0667] In the first step, (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-1-formylpropan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate III (100 mg, 0.233 mmol), tetraethyl titanate (106.42 mg, 0.467 mmol), and ethylamine (45.09 mg, 0.7 mmol) were dissolved in tetrahydrofuran (10.0 mL), and then the temperature was raised to 80°C with stirring. TLC (DCM:MeOH=20 After completion of the reaction, the mixture was cooled to room temperature and diluted with 15 mL of water. 3 mL of ethyl acetate was then added for extraction. The organic phases were combined, dried, and concentrated to obtain a crude product, which was then purified by column chromatography (dichloromethane:methanol=100:1-30:1) to obtain (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-(ethylamino)butan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (57-1) (65 mg, 0.13 mmol, 54.79%).

[0668] Step 2: (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-(ethylamino)butan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (57-1) (50 mg, 0.11 mmol) was dissolved in dichloromethane (5.0 mL), replaced with nitrogen, cooled in an ice bath, and diisopropylethylamine (19.4 mg, 0.15 mmol) was added, followed by dropwise addition of o-fluorobenzoyl chloride (19.0 mg, 0.12 mmol). After the addition was complete, the temperature was gradually raised to room temperature with stirring. TLC (PE The reaction was monitored for completion by adding 10 mL of saturated aqueous sodium bicarbonate solution, followed by 3 mL of ethyl acetate. The organic phase was separated, dried, and concentrated. The resulting crude product was analyzed by preparative TLC (developing solvent: PE:EtOAc = 1:1) to give (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-{ethyl[(2-fluorophenyl)carbonyl]amino}butan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (57-2) (39.6 mg, 0.07 mmol, 62.18%). 1 H NMR (399MHz, Chloroform-d) δ7.31 (dt, J=14.4, 7.1Hz, 2H), 7.16 (t, J=7.5Hz, 1H), 7. 07(t,J=8.9Hz,1H),4.53–4.43(m,1H),3.55(s,2H),3.18(q,J=7.6Hz,2H),2.03(d,J =2.1Hz,8H),1.68(q,J=18.6,14.1Hz,6H),1.53(d,J=17.7Hz,7H),1.42–1.21(m,6H) ,1.20–0.91(m,11H),0.91–0.82(m,8H),0.79(s,2H),0.70(s,1H),0.63–0.55(m,3H).

[0669] Step 3: (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-{ethyl[(2-fluorophenyl)carbonyl]amino}butyl-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (57-2) (39.6 mg, 0.07 mmol, 1.0 eq.) was added to tetrahydrofuran (4.0 mL), methanol (4.0 mL), and 1 M lithium hydroxide aqueous solution (2.5 mL). The mixture was stirred at room temperature overnight and monitored by LCMS. The reaction was complete. The reaction mixture was concentrated to remove tetrahydrofuran and methanol, and water (10.0 mL) was added to the concentrate, followed by extraction with ethyl acetate (8.0 mL*3). The organic phases were combined, dried, concentrated, and purified by preparative HPLC to give N-ethyl-2-fluoro-N-[(3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]butyl]benzamide (57) (11.90 mg, 0.022 mmol, 31.6%). 1 H NMR (400MHz, CD3OD) δ7.45 (s, 1H), 7.36–7.22 (m, 2H), 7.19 (t, J = 8.7Hz, 1H), 3.54 ( s,2H),3.17(ddd,J=22.8,15.0,7.2Hz,3H),2.09–1.97(m,4H),1.73(ddd,J=30.2,1 7.9,10.2Hz,5H),1.63–1.49(m,5H),1.40–1.31(m,1H),1.29–1.09(m,6H),1.00(dd d,J=34.8,17.9,11.4Hz,12H),0.78(dd,J=13.9,7.6Hz,6H),0.64(d,J=5.3Hz,3H). 13C NMR (400MHz, CD3OD) δ167.16,134.56,134.08,131.10,131.08,131.04,128.12,127.83,124.47,115.61,11 5.57,115.40,115.36,78.17,50.48,50.33,49.74,49.64,49.54,48.19,47.98,47.76,47.55,47.34,47.12 ,46.91,44.35,44.20,38.51,36.74,35.49,34.59,34.47,34.10,33.37,30.86,30.69,30.35,27.88,27.57 ,27.16,27.02,26.17,23.22,23.12,20.55,18.16,17.95,17.61,14.86,14.70,12.62,11.62.LC-MS:[M+H] + =538.45

[0670] Example 58

[0671] Preparation of Compound 58 (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1-(4-hydroxyhexahydropyridin-1-yl)pentan-1-one

[0672]

[0673] Referring to Example 2, the amine was replaced with 4-hydroxy-piperidine to obtain the compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-1-(4-hydroxyhexahydropyridin-1-yl)pentan-1-one (58). 1H NMR(400MHz,DMSO)δ4.71(d,J=4.1Hz,1H),4.32(d,J=5.0Hz,1H),3.89(s, 1H),3.71–3.62(m,2H),3.14–3.07(m,1H),3.03–2.87(m,2H),2.37–2.10( m,4H),2.03–1.85(m,5H),1.75–1.57(m,8H),1.49–1.40(m,4H),1.27–1.2 1(m,3H),1.18–1.10(m,3H),0.93–0.83(m,12H),0.70(s,3H),0.66(s,3H). 13 C NMR (101MHz, CDCl3) δ182.82,134.40,78.77,78.71,62.50,44.47,43.17,42.49,38.78,36.93,36.43,35.54,33.60,32.82,31.8 4,30.90,30.75,28.10,27.81,27.44,26.41,25.37,24.13,20.91,19.04,18.72,18.39,18.17,17.70,15.67,15.33.LC-MS[M+H] + =500.00

[0674] Example 59

[0675] Preparation of Compound 59 (4R)-N-ethyl-N-(2-fluorophenyl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentanamide

[0676]

[0677]

[0678] Step 1: Weigh (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-acetoxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentanoic acid VII (200 mg, 0.44 mmol, 1.0 eq.) and o-fluoroaniline (72.68 mg, 0.65 mmol), dissolve in dichloromethane (4 mL), add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (331.59 mg, 0.872 mmol) and diisopropylethylamine (0.288 mL, 1.744 mmol). The reaction mixture was stirred at room temperature overnight and monitored by TLC (PE:EA=10:1). After the reaction was completed, water (30.0 mL) was added and the mixture was extracted with ethyl acetate (30.0 mL*3). The organic phases were combined, dried, and concentrated. The crude product was purified by column chromatography (PE:EA=50:1-30:1) to obtain (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-[(2-fluorophenyl)amino]-5-oxopentan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (59-1) (85 mg, 0.15 mmol, 33.50%) as a pale yellow solid.

[0679] In the second step, (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-[(2-fluorophenyl)amino]-5-oxopentan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (59-1) (80 mg, 0.15 mmol, 1.0 eq.) was dissolved in DMF (N,N-dimethylformamide) (8.0 mL). After nitrogen replacement, the mixture was cooled in an ice bath. Then, sodium hydride (34.8 mg, 1.45 mmol) was weighed and added to the reaction system. The mixture was stirred for half an hour, and then ethyl bromide (0.011 mL, 0.145 mmol) was added. The mixture was heated to room temperature. The mixture was stirred at room temperature for 2 hours and monitored by TLC (PE:EA=10:1, phosphomolybdic acid color development, Rf1=0.57, Rf2=0.7). After the reaction, 10.0 mL of saturated aqueous ammonium chloride solution was added, followed by extraction with 10 mL*3 of ethyl acetate. The organic phases were combined, dried, and concentrated by preparative TLC to give (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-[ethyl(2-fluorophenyl)amino]-5-oxopentan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (59-2) (50 mg, 0.078 mmol, 53.53%) as a white solid. 1 H NMR (399MHz, CDCl3) δ7.33(s,1H),7.18(d,J=7.6Hz,3H),4.47(dd,J=11.0,4.5Hz,1H),3.70(dd,J=14.2,7.2Hz,2H),1.98(d,J=34.5Hz,8H),1 .64(d,J=8.4Hz,5H),1.54–1.46(m,2H),1.23(s,6H),1.07(t,J=7.3Hz ,3H),0.96(s,3H),0.85(s,6H),0.79(s,3H),0.66(s,3H),0.60(s,3H).

[0680] Step 3: (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-[ethyl(2-fluorophenyl)amino]-5-oxopentan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (59-2) (50 mg, 0.086 mmol) was dissolved in tetrahydrofuran (3 mL), methanol (3 mL) was added, and 1 M lithium hydroxide aqueous solution (3.62 mg, 0.086 mmol) was added under stirring at room temperature. , then continued to stir at room temperature for 16 hours. After the reaction was completed, 5 mL of water was added for dilution, and then 5 mL*3 of ethyl acetate was added for extraction, dried, and concentrated. The crude product was subjected to preparative HPLC to obtain a white solid (4R)-N-ethyl-N-(2-fluorophenyl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]pentanamide (59) (25 mg, 0.048 mmol, 60%). 1 H NMR(399MHz, CDCl3)δ7.33(s,1H),7.21–7.13(m,3H),3.78–3.63(m,2H),3.25–3.16(m,1H),2.06–1.87(m,6H),1.69–1.45(m,9H),1. 33–1.15(m,7H),1.07(t,J=7.1Hz,3H),0.98(d,J=9.2Hz,4H),0.93(s,3H),0.78(d,J=5.2Hz,6H),0.65(d,J=4.5Hz,3H),0.60(s,3H). 13C NMR (100MHz, CDCl3) δ173.38,159.75,159.67,157.26,157.18,134.31,130.67,130.61,130.15,1 30.01,129.72,129.64,124.87,116.89,116.68,78.93,77.31,76.99,76.68,50.33,50.21,50.17, 49.72,44.38,43.51,38.85,36.96,36.06,36.03,35.53,31.74,31.67,31.29,31.14,30.86,30.75 ,27.95,27.93,27.79,26.43,24.14,20.92,19.10,18.21,15.66,15.39,12.91,1.00.LC-MS:[M+H] + =538.65.

[0681] Example 60

[0682] Preparation of Compound 60 (4R)-N-(2-fluorophenyl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-N-(2-hydroxy-2-methylpropyl)pentanamide

[0683]

[0684] In the first step, the starting materials, 2-bromoethan-1-ol (6 mL, 88.02 mmol, 1.1 eq) and 2,2-dimethyloxirane (100 mg, 1.387 mmol, 1.0 eq), were dissolved in diethyl ether (10 mL). Lithium perchlorate (147.54 mg, 1.387 mmol, 10 eq) was added, and the reaction system was replaced with a nitrogen atmosphere. Stirring was carried out at room temperature for 18 hours. TLC (PE:EtOAc = 10:1, phosphomolybdic acid hotplate) indicated that the reaction was complete, and the reaction was stopped. Water (20 mL) was added to the reaction system, and the mixture was extracted with DCM (dichloromethane) (3 x 25 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by flash chromatography (PE:EtOAc = 94:6 to 92:) to afford 1-[(2-fluorophenyl)amino]-2-methylpropan-2-ol (60-1) as a brown oil (40 mg, 95% purity, 14.95% yield). 1H NMR (400 MHz, CDCl3) δ 7.02–6.94 (m, 2H), 6.82–6.76 (m, 1H), 6.68–6.61 (m, 1H), 3.14 (s, 2H), 1.32 (s, 6H).

[0685] The second and third steps were carried out according to Example 2, except that the amine in the first step was replaced with 60-1, to obtain the compound (4R)-N-(2-fluorophenyl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-N-(2-hydroxy-2-methylpropyl)pentanamide (60). 1 H NMR (400MHz, CDCl3) δ7.39–7.28(m,2H),7.24–7.16(m,2H),3.91(dd,J=14.4,7.8Hz,1H),3.54 (dd,J=14.4,9.5Hz,1H),3.23(dd,J=11.5,4.4Hz,1H),2.35(s,2H),2.20–2.09(m,1H),2.06–1. 93(m,5H),1.89–1.24(m,15H),1.22(d,J=1.8Hz,3H),1.20(s,3H),1.16–1.09(m,1H),1.03(d,J =11.0Hz,1H),0.99(s,3H),0.96(s,3H),0.81(d,J=6.0Hz,6H),0.72–0.64(m,3H),0.62(s,3H). 13CNMR (101MHz, CDCl3) δ176.90,134.40,130.08,129.97,129.77,129.69,125. 04,117.15,116.95,78.97,71.78,50.41,50.25,50.21,49.79,48.24,44.46, 38.89,37.02,36.03,35.59,31.71,31.66,31.14,30.98,30.94,30.77,27.95 ,27.85,27.70,26.47,24.15,20.95,19.12,18.24,15.70,15.39.LC-MS[M+H] + =582.5

[0686] Example 61

[0687] Synthesis of Compound 61 (4R)-N-(3-fluoropyridin-4-yl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N-methylpentanamide

[0688]

[0689] The first step was carried out by referring to Example 2, except that the amine was replaced with 3-fluoro-4-amino-pyridine to obtain the compound (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-[(3-fluoropyridin-4-yl)amino]-5-oxopentan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetrahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (61-1) (300 mg).

[0690] In the second step, the acetic acid (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-[(3-fluoropyridin-4-yl)amino]-5-oxopentan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl)- The ester (61-1) (300 mg, 0.54 mmol, 1.0 eq.) was dissolved in N,N'-dimethylformamide (7.0 mL), replaced with nitrogen, and cooled in an ice bath. Then, sodium hydride (65.13 mL, 1.63 mmol) was added. Then, iodomethane (80.89 mg, 0.57 mmol) was dissolved in N,N'-dimethylformamide (3.0 mL) and added to the above reaction system. The reaction system was then warmed to room temperature and stirred. TLC (DCM:MeOH = 20:1) was used for monitoring. After the reaction was completed, water (10.0 mL) was added and the mixture was extracted with ethyl acetate (8.0 mL*3). The organic phases were combined, dried, and the concentrated crude product was purified by column chromatography (DCM:MeOH = 100:1 to 30:1) to obtain acetic acid (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)- 5-[(3-Fluoropyridin-4-yl)(methyl)amino]-5-oxopentan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester (61-2) (120 mg, 0.20 mmol, 37.06%) was obtained as a white solid. 1 H NMR (399MHz, CDCl3) δ8.57(s,1H),8.46(d,J=4.5Hz,1H),7.22(d,J=5.1Hz,1H),4.47 (d,J=7.8Hz,1H),3.25(s,3H),2.22(s,2H),2.03(s,3H),1.96(s,3H),1.79(s,3H),1. 67(d,J=8.9Hz,3H),1.62(s,3H),1.53(s,2H),1.37(d,J=9.1Hz,2H),1.28(s,3H),1.1 3(t,J=13.0Hz,2H),0.97(s,3H),0.85(s,6H),0.81(s,3H),0.74(s,3H),0.62(s,3H).

[0691] Step 3: (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-[(3-fluoropyridin-4-yl)(methyl)amino]-5-oxopentan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (61-2) (70 mg, 0.12 mmol) was dissolved in tetrahydrofuran (5.0 mL) and methanol (5.0 mL). 1 M aqueous lithium hydroxide solution (2.0 mL) was added under stirring at room temperature, and then stirring was continued at room temperature for 3 hours. TLC (DCM:MeOH=20:1) was used. The reaction mixture was monitored (hydrolysis of the acetyl group and the amide bond occurred simultaneously). After the reaction was completed, 10 mL of water was added for dilution, followed by extraction with 10 mL of ethyl acetate (3 times). The mixture was dried and concentrated, and the crude product was purified by preparative TLC (DCM:MeOH=20:1) to obtain (4R)-N-(3-fluoropyridin-4-yl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N-methylpentanamide (61) (6.0 mg, 0.011 mmol, 8.8%) as a white solid. 1 H NMR(399MHz, CDCl3)δ8.58(s,1H),8.47(s,1H),7.21(s,2H),3.26(s,3H),3.20(m,1H),2.22(s,2H),1.99(s,5H),1.79(s,3H),1.66 (d,J=14.9Hz,4H),1.50(m,4H),1.28(s,4H),1.17(s,2H),0.96(d,J=11.9Hz,6H),0.80(d,J=13.2Hz,6H),0.74(s,3H),0.63(s,3H). 13 C NMR (101MHz, CDCl3) δ173.09,145.45,145.42,134.34,134.25,78.92,77.31,77.00,76.68,50.32,50.25,49.75,44.43,38.85,36. 96,36.06,35.53,31.59,30.94,30.88,30.74,28.03,27.93,27.79,26.43,24.16,20.92,19.11,18.27,18.20,15.69,15.40,1.00.

[0692] LC-MS[M+1] + =525.4

[0693] Example 62

[0694] Preparation of Compound 62 (4R)-N-(2-fluorophenyl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-N-(propan-2-yl)pentanamide

[0695]

[0696] Weigh out (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-[(2-fluorophenyl)amino]-5-oxopentan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (61-1) (100 m g, 0.181 mmol) was dissolved in N,N'-dimethylformamide (3 mL). After nitrogen replacement three times, the ice bath was cooled to 0°C, and sodium hydride (21.75 mg, 0.544 mmol) was added. The mixture was stirred at 0°C for 30 minutes. Isopropyl iodide (61.61 mg, 0.36 mmol) was dissolved in N,N'-dimethylformamide (2 mL) and added to the reaction system. The mixture was warmed to room temperature after the addition. After stirring at room temperature for 1 hour, TLC (PE:EA=5:1) showed that a large amount of starting material remained. The mixture was then heated to 80°C and stirred for 1 hour. TLC (PE:EA=5:1) showed that the reaction was complete. The mixture was then cooled to room temperature, diluted with 10 mL of water, and extracted with 10 mL*3 of ethyl acetate. The mixture was dried and concentrated. The crude product was purified by preparative TLC (DCM:EA=50:1) to obtain (4R)-N-(2-fluorophenyl)-4- [(1R,3aR,5aR,7S,9aS,11aR)-7-Hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-N-(propan-2-yl)pentanamide (62) (30 mg, 0.052 mmol, 28.5%) was obtained as a white solid. 1H NMR(399MHz, CDCl3)δ7.36(s,1H),7.15(m,3H),4.99(s,1H),3.21(m,1H),1.97(d ,J=17.9Hz,5H),1.81(m,2H),1.73(d,J=18.5Hz,2H),1.65(d,J=14.8Hz,4H),1.5 6(m,3H),1.50(s,3H),1.31(dd,J=16.1,7.7Hz,2H),1.19(m,3H),1.09(d,J=6.7H z,3H),0.97(s,6H),0.94(s,3H),0.78(s,6H),0.64(d,J=5.5Hz,3H),0.60(s,3H). 13 C NMR (100MHz, CDCl3) δ173.17,134.32,134.29,132.23,130.03,130.03,124.49,124.45,116 .76,116.55,78.93,77.30,76.98,76.66,50.34,50.25,50.20,49.73,46.54,44.38,38.85, 36.96,36.07,36.02,35.54,31.94,31.76,31.68,31.65,30.87,30.76,27.98,27.93,27.80 ,26.43,24.13,21.46,21.41,20.92,19.75,19.10,18.24,18.21,15.66,15.38.LC-MS:[M+H] + =552.4

[0697] Example 63

[0698] Preparation of Compound 63 (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N-methyl-N-(1,3,4-thiadiazacyclopentan-2-yl)pentanamide

[0699]

[0700] In the first step, 1(4R)-4-[(1R,3aR,5aR,9aS,11aR)-7-acetyloxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]pentanoic acid (100 mg, 0.22 mmol, 1.0 eq.) was dissolved in dichloromethane (5.0 mL) and N, N'-dimethylformamide (1 drop), nitrogen replacement, ice bath cooling to 0 ℃, dropwise addition of oxalyl chloride (166.67 mg, 1.3 mmol) in dichloromethane (2.0 mL), continued stirring in ice bath for 30 minutes after completion of the dropwise addition, TLC (PE: EA = 3: 1) monitored the reaction completion, concentrated to remove dichloromethane, then added dichloromethane (3.0 mL) to dilute, and added dropwise to 1,3,4-thiadiazacyclopentane-2-amine (48 mg, 0.4 7mmol) and diisopropylethylamine (133.3mg, 1.03mmol) in dichloromethane (5.0mL) were added dropwise, and the mixture was stirred for 30 minutes under ice bath, then heated to room temperature and stirred for 2 hours, monitored by TLC (PE:EA=1:1, phosphomolybdic acid color development, Rf1=0.8, Rf2=0.4). After the reaction was completed, the mixture was concentrated and column chromatography (PE:EA=100:1~5:1) was performed to obtain the acid-(1R,3aR,5aR,7 S,9aS,11aR)-3a,6,6,9a,11a-pentamethyl-1-[(2R)-5-oxo-5-(1,3,4-thiadiazacyclopentan-2-ylamino)pentan-2-yl]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester (63-1) (50 mg, 0.083 mmol, 45%) was obtained as a white solid. LC-MS: [M+H] + =542.50

[0701] Step 2: Weigh out 20 mg of (1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-pentamethyl-1-[(2R)-5-oxo-5-(1,3,4-thiadiazacyclopentan-2-ylamino)pentan-2-yl]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester (63-1) in tetrahydrofuran (2.0 mL) and add methanol (2.0 mL). Then, add lithium hydroxide (0.04 mL, 0.04 mmol) at room temperature and stir at room temperature for 16 hours. Monitor by TLC (PE After the reaction, 5 mL of water was added to quench the reaction, followed by extraction with 5 mL of ethyl acetate. The organic phases were combined, dried, concentrated, and purified by column chromatography (PE:EA=100:1-2:1) to obtain (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-N-(1,3,4-thiadiazacyclopentan-2-yl)pentanamide (63-2) ((10 mg, 0.02 mmol, 48.79%)). LC-MS: [M+H] + =500.50

[0702] Step 3: (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N-(1,3,4-thiadiazacyclopentan-2-yl)pentanamide (63-2) (10 mg, 0.02 mmol, 1.0 eq.) was dissolved in N,N'-dimethylformamide (3.0 mL), and the atmosphere was replaced with nitrogen. Potassium carbonate (2.77 mg, 0.02 mmol) and methyl iodide (2.84 mmol, 0.02 mmol) were added, and the mixture was heated to 60°C with stirring. The mixture was stirred for 2 hours and monitored by TLC (PE:EA=1:1). After the reaction was completed, 5 mL of water was added for dilution, followed by extraction with 5 mL*3 of ethyl acetate. The organic phases were combined, dried, concentrated, and purified by preparative TLC (PE:EA=1:1) to give (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N-methyl-N-(1,3,4-thiadiazacyclopentan-2-yl)pentanamide (63) (3 mg, 0.005 mmol, 23.34%). 1 HNMR (399MHz, CDCl3) δ8.83 (s, 1H), 3.83 (s, 3H), 3.23 (s, 1H), 2.65 (d, J = 59.7Hz, 2H), 2.01 (s, 6H), 1.61 (dd, J =47.5,22.0Hz,11H),1.22(s,3H),1.05(s,1H),0.98(d,J=7.3Hz,9H),0.87(s,3H),0.79(s,3H),0.69(s,3H). 13 CNMR(101MHz, CDCl3)δ172.82,160.34,145.43,134.43,134.21,78.92,77.31,77.00,76.68,50.33,49.80,44.54,38.86,36.99,36 .11,35.53,35.40,31.66,30.94,30.78,28.18,27.93,27.79,26.45,24.21,20.95,19.13,18.53,18.20,15.77,15.40.LC-MS[M+1] + =514.45.

[0703] Example 64

[0704] Preparation of Compound 64 (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N-methyl-N-(1-methylimidazol-2-yl)pentanamide

[0705]

[0706] In the first step, the starting material (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-acetoxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]pentanoic acid VII (100 mg, 0.22 mmol, 1.0 eq) was dissolved in DCM (dichloromethane) (5 mL). Oxalyl chloride (138 mg, 1.09 mmol, 5 eq) was added dropwise. The reaction mixture was stirred at 25°C under nitrogen for 1 hr. The solvent and unreacted oxalyl chloride were removed by concentration to obtain the crude product. The crude product was dissolved in DCM (5 mL), and 1-methylimidazol-2-amine (63.52 mg, 0.65 mmol, 1.2 eq) was added. The reaction system was replaced with a nitrogen atmosphere and stirred at room temperature for 18 hours. The reaction was monitored by TLC (DCM:MeOH = 20:1, phosphomolybdic acid hotplate). Water (20 mL) was added to the reaction system, and the mixture was extracted with DCM (dichloromethane) (3 x 25 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by flash chromatography (DCM:MeOH=96:4 to 94:6) to give (1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-pentamethyl-1-[(2R)-5-[(1-methylimidazol-2-yl)amino]-5-oxopentan-2-yl]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (64-1) (92 mg, purity 85%, yield 66.70%) as an orange solid. 1H NMR (400MHz, CDCl3) δ6.81 (s, 1H), 6.73 (s, 1H), 4.50 (dd, J = 11.5, 4.5Hz, 1H), 3 .59(s,3H),2.59–2.33(m,2H),2.05(s,3H),2.03–1.84(m,5H),1.77–1.62(m,6H ),1.62–1.44(m,4H),1.43–1.25(m,4H),1.23–1.11(dd,J=16.6,11.7Hz,2H),1 .00(s,3H),0.93(d,J=4.8Hz,3H),0.87(d,J=4.4Hz,9H),0.69(d,J=4.6Hz,3H).

[0707] In the second step, the starting material (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-acetoxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]pentanoic acid (64-1) (200 mg, 0.372 mmol, 1.0 eq) was dissolved in DMF (20 mL), and the reaction system was replaced with a nitrogen atmosphere. After cooling the reaction system to 0°C, sodium hydride (60%, paraffin) (11.60 mg, 0.483 mmol, 1.3 eq) was slowly added. The reaction was then stirred at room temperature for 30 minutes. Methyl iodide (68.62 mg, 0.483 mmol, 1.3 eq) was then added and the reaction system was stirred at room temperature for 2 hours. The reaction was stopped after completion of the reaction as monitored by TLC (DCM:MeOH = 20:1, phosphomolybdic acid hotplate). Water (20 mL) was added to dilute the system, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by flash chromatography (PE:EtOAC=40:60 to 30:70) to give (1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-pentamethyl-1-[(2R)-5-[methyl(1-methylimidazol-2-yl)amino]-5-oxopentan-2-yl]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (64-2) (130 mg, purity 90%, yield 57.01%) as an orange solid. 1HNMR(400MHz, CDCl3)δ7.01(s,1H),6.90(s,1H),4.49(dd,J=11.5,4.4Hz,1H),3.53(s,3H),3.19(s,2H),2.05(s,3H),1.98(s,4H),1.85(d ,J=32.9Hz,3H),1.76–1.61(m,6H),1.61–1.46(m,4H),1.43–1.10(m, 8H),0.99(s,3H),0.88(s,7H),0.83(s,3H),0.75(s,3H),0.64(s,3H).

[0708] In the third step, the raw material acetic acid-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-(isoxazol-3-ylamino)-5-oxopentan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester (150 mg, 0.27 mmol, 1 eq) was dissolved in THF (tetrahydrofuran) (1 mL) and MeOH (methanol) (1 mL), and 1N lithium hydroxide (0.6 mL) was added dropwise, and the reaction mixture was stirred at 50 ° C for 2 hrs. The reaction was completed by monitoring with TLC (DCM:MeOH=20:1, phosphomolybdic acid hotplate). The reaction solution was cooled to room temperature and acidified to pH=3-4 using 1N HCl. After ethanol was concentrated, the mixture was extracted with EA (ethyl acetate) (20 mL×3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated and purified by flash chromatography (DCM:MeOH=95:5 to 94:6) to give a yellow solid (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N-methyl-N-(1-methylimidazol-2-yl)pentanamide (64) (138.26 mg, purity 98.03%, yield 97.81%). 1HNMR (400MHz, DMSO) δ7.44(s,1H),7.18(s,1H),3.58(s,3H),3.07(s,3H),3.00(dd,J=9.8,5.5Hz,1H),1.98(s,5H ),1.84(s,2H),1.73-1.40(m,10H),1.23(s,4H),1.12(s,3H),0.90(s,7H),0.81(s,3H),0.70(s,4H),0.61(s,2H).

[0709] 13 CNMR(101MHz,DMSO)δ181.72,138.05,134.81,133.99,132.82,77.21,50.53,49.85,44.50,39.00,37.02,35.84,35.69,34.88,34 .85,30.95,30.86,28.60,28.04,27.94,26.48,24.47,21.82,20.97,19.47,19.34,18.93,18.63,18.36,16.31,16.06.LCMS[M+H] + =510.40

[0710] Example 65

[0711] Preparation of Compound 65 (4R)-N-(2-fluorophenyl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-N-(methoxymethyl)pentanamide

[0712]

[0713] Referring to Example 64, the amine in the first step was replaced with bromomethoxymethyl ether to obtain compound (4R)-N-(2-fluorophenyl)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-N-(methoxymethyl)pentanamide (65). 1H NMR (400MHz, CDCl3) δ7.40-7.32(m,1H),7.28-7.31(m,1H),7.20(dd,J=15.6,7.7Hz,2H),5.25(dd,J=1 0.1,5.2Hz,1H),4.89-4.81(m,1H),3.43(s,3H),3.23(dd,J=11.5,4.3Hz,1H),2.21-2.08(m,1H),2.07 -1.91(m,5H),1.90–1.77(m,2H),1.75-1.61(m,4H),1.51(dd,J=27.4,12.9Hz,3H),1.37–1.10(m,7H), 1.04(d,J=11.1Hz,1H),0.98(d,J=13.9Hz,6H),0.87–0.77(m,6H),0.69(d,J=5.6Hz,3H),0.62(s,3H). 13 C NMR (101MHz, CDCl3) δ174.74,158.68,134.38,134.35,130.76,130.66,130.13,130.04,78.98,78.56,56.60,50.33,50.30,49.78, 44.38,41.13,38.89,37.01,35.58,30.92,30.79,28.01,27.96,27.84,26.47,24.17,20.96,19.14,18.24,15.71,15.42.LCMS[M+H] + =554.5

[0714] Example 66

[0715] Preparation of compound 66 (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]-N-methyl-N-(1,3-thiazolyl-5-yl)pentanamide

[0716]

[0717] Referring to Example 63, the amine in the first step was replaced with 1,3-thiazol-5-amine to obtain compound (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-N-methyl-N-(1,3-thiazolyl-5-yl)pentanamide (66). 1 HNMR(400MHz,DMSO)δ8.59(s,1H),7.69(s,1H),6.87(s,1H),6.65(s,1H),4.32(d,J=5.1Hz,1H),3.50(s,2H),2.03 –1.85(m,6H),1.64(d,J=13.1Hz,4H),1.54–1.42(m,5H),1.23(s,10H),0.96–0.82(m,10H),0.69(d,J=12.6Hz,4H). 13 CNMR(101MHz,CDCl3)δ1.81,190.70,157.30,152.65,135.56,135.46,127.84,127 .44,100.11,100.01,72.49,72.39,72.29,26.60,24.55,18.57,9.12.LC-MS:[M+1] + =513.55

[0718] Example 68

[0719] Preparation of Compound 68 (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-3a, 6, 6, 9a, 11a-pentamethyl-2, 3, 3a, 4, 5, 5a, 6, 7, 8, 9, 9a, 10, 11, 11a-tetrahydro-1H-cyclopenta[1, 2-a]phenanthrene-7-ol

[0720]

[0721]

[0722] In the first step, lanosterol (3.00 g, 7.03 mmol, 1.0 eq) was dissolved in THF (tetrahydrofuran) (273 mL). Water (68 mL) was added, followed by NBS (0.73 g, 4.08 mmol, 0.58 eq) at room temperature. The mixture was stirred at 25°C for 2 hours. TLC (n-hexane:EtOAc = 5:1, phosphomolybdic acid) indicated the reaction was complete. The mixture was extracted three times with dichloromethane, dried over sodium sulfate, and evaporated to dryness. The mixture was purified by column chromatography (PE:EtOAc=50:1 to 5:1) and concentrated to give (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-bromo-6-hydroxy-6-methylhept-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol (68-1) (1.3 g, purity 90%, yield 35.3%). 1 H NMR (400MHz, CDCl3) δ3.98(dd,J=21.0,12.3Hz,1H),3.27–3.19(m,1H),2.14(d,J=6.0Hz,1H),2.00(d,J=11.7Hz,5H),1.84–1.61(m,6H),1.58(s,9 H),1.33(t,J=10.8Hz,9H),1.27–1.12(m,3H),1.04(d,J=12.2Hz,1H),0.9 9(d,J=7.9Hz,7H),0.94–0.84(m,7H),0.80(s,3H),0.69(d,J=2.2Hz,3H).

[0723] In the second step, (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-bromo-6-hydroxy-6-methylhept-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol (68-1) (900 mg, 1.72 mmol, 1.0 eq) was dissolved in THF (tetrahydrofuran) (90 mL) and LAH (433 mg, 12.40 mmol, 7.2 eq) was added. After the addition was complete, the temperature was raised to 70°C and refluxed, and the mixture was stirred for 2 hrs. After the reaction was completed, TLC (n-hexane:EtOAc=5:1, phosphomolybdic acid) was used to detect the reaction. The reaction system was poured into ice water (10 mL) to quench the reaction, and extracted with DCM (dichloromethane) (30 mL x 3). The mixture was dried over anhydrous sodium sulfate and dried in a rotary evaporation cycle to obtain (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-7-ol (68) (0.4 g, purity 90%, yield 48.7%). 1 H NMR (400MHz, CDCl3) δ3.23(d,J=8.8Hz,1H),2.02(s,4H),1.92(d,J=8.4Hz,1H),1.69(d,J=24.3Hz,7H),1.58(d,J=11.1Hz,2H),1 .52–1.33(m,8H),1.30(s,2H),1.18(d,J=25.9Hz,8H),1.01(dd,J=22.8,9.8Hz,8H),0.93–0.84(m,6H),0.80(s,3H),0.68(s,3H). 13 C NMR (101MHz, CDCl3) δ134.38,78.97,77.33,77.01,76.69,71.13,50.49,50.38,49.79,44.46,44.39,38.87,37.00,36.72,36 .45,35.57,30.97,30.82,29.31,29.18,28.23,27.95,27.82,26.48,24.26,21.10,20.99,19.13,18.67,18.24,15.74,15.41

[0724] Example 72

[0725] Preparation of Compound 72 (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(2R)-5-hydroxy-5-methylhexan-2-yl]-3a, 6, 6, 9a, 11a-pentamethyl-2, 3, 3a, 4, 5, 5a, 6, 7, 8, 9, 9a, 10, 11, 11a-tetrahydro-1H-cyclopenta[1, 2-a]phenanthren-7-ol

[0726]

[0727] In the first step, the starting material (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-acetyloxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]pentanoic acid (VII) (250 mg, 0.55 mmol, 1 eq) was dissolved in methanol (0.22 mL) and dichloromethane (10 mL). 4-Dimethylaminopyridine (67 mg, 0.55 mmol, 1 eq) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (209 mg, 1.09 mmol, 2 eq) were then added. The reaction mixture was stirred at room temperature for 2 hrs. The reaction was confirmed to be complete by TLC (PE / DCM = 2:1). The reaction solution was poured into water and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was separated and purified by flash chromatography (PE / DCM = 5:1) to give (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-acetyloxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]pentanoic acid methyl ester (72-1) (180 mg, yield 62%) as a white solid. 1 H NMR (400MHz, CD3Cl): δ4.48(dd,J=11.4,4.7Hz,1H),3.65(s,3H),2.36(ddd,J=15.3,10.2,5.2Hz,1H),2.22(ddd,J =15.7,9.6,6.4Hz,1H),1.98(m,8H),1.64(m,11H),1.26(m,6H),0.99(s,3H),0.87(t,J=7.4Hz,11H),0.67(s,3H). 13C NMR (100MHz, CD3Cl): δ174.76,171.01,134.29,80.89,77.32,77.00,76.69,51.48,50.45,50.17,49.78,49.19,44.47,37.77,3 6.86,36.03,35.83,35.23,31.33,30.83,27.97,26.34,25.48,24.17,22.77,21.33,20.95,19.17,18.18,16.92,16.52,15.68.

[0728] In the second step, the starting material, methyl (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-acetyloxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]pentanoate (72-1) (100 mg, 0.21 mmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (10 mL). 1.0 mol / L methylmagnesium bromide (2.1 mL, 2.1 mmol, 10 eq) was added dropwise under ice-cooling. The reaction mixture was stirred under ice-cooling for 2 hours and then at room temperature for 1 hour. TLC (PE / EtOAc = 4:1) confirmed the reaction was complete. The reaction mixture was poured into saturated ammonium chloride water and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was separated and purified by flash chromatography (PE / EtOAc = 5:1) to give (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-hydroxy-5-methylhexan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate (72-2) (60 mg, 53% yield) as a white solid. 1 H NMR (400MHz, CD3Cl): δ4.46 (dd, J=11.4, 4.6Hz, 1H), 2.05 (d, J=4.9Hz, 1H), 2.02 (s, 3H), 1.96 (m, 3H) ,1.58(m,14H),1.30(m,5H),1.17(d,J=1.8Hz,6H),0.97(s,3H),0.85(d,J=6.9Hz,12H),0.66(s,3H). 13CNMR (100MHz, CD3Cl): δ171.03,134.40,134.19,80.91,71.17,50.44,50.13,49.76,44.41,40.31,37.76,36.85,36. 58,35.22,30.84,30.43,29.35,28.98,27.99,27.78,26.34,24.19,21.33,20.96,19.16,18.74,18.09,16.52,15.74.

[0729] Step 3: Dissolve the starting material (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-hydroxy-5-methylhexan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate (72-2) (60 mg, 0.13 mmol, 1 eq) in methanol (20 mL). Add potassium hydroxide (712 mg, 13 mmol, 100 eq) and water (2 mL). The reaction mixture was heated to 80°C and stirred for 18 hours. TLC (PE / EtOAc = 3:1) confirmed the reaction was complete. The reaction solution was poured into ice water and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was separated and purified by flash chromatography (PE / EtOAc = 3:1) to give (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(2R)-5-hydroxy-5-methylhexan-2-yl]-3a, 6, 6, 9a, 11a-pentamethyl-2, 3, 3a, 4, 5, 5a, 6, 7, 8, 9, 9a, 10, 11, 11a-tetrahydro-1H-cyclopenta[1, 2-a] phenanthren-7-ol (72-3) (60 mg, purity 99%, yield 34%) as a white solid. 1 H NMR (400MHz, CD3Cl): δ3.22(s,1H),2.02(s,3H),1.92(m,1H),1.66(s,5H),1.56(s,10H),1.32(s,3H ),1.19(s,6H),1.04(d,J=11.2Hz,2H),0.98(d,J=5.4Hz,6H),0.89(m,6H),0.80(s,3H),0.68(s,3H). 13C NMR (100MHz, CD3Cl): δ134.36,78.97,71.20,50.37,50.14,44.44,40.31,38.87,36.99,36.57,3 5.56,30.87,30.45,29.35,29.01,27.95,26.48,24.25,20.98,19.12,18.74,18.23,15.74,15.41

[0730] Example 73

[0731] Preparation of Compound 73 (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(2R)-4-[(2-hydroxyethyl)amino]butan-2-yl]-3a, 6, 6, 9a, 11a-pentamethyl-2, 3, 3a, 4, 5, 5a, 6, 7, 8, 9, 9a, 10, 11, 11a-tetradecahydro-1H-cyclopenta[1, 2-a]phenanthren-7-ol

[0732]

[0733] In the first step, the raw material (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-1-formylpropyl-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate (III) (300 mg, 0.70 mmol, 1.0 eq) and ethanolamine (214 mg, 3.5 mmol, 5 eq) were dissolved in dichloromethane (50 mL) and stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (132 mg, 3.5 mmol, 5 eq) was added and stirred for 18 hrs. After the reaction was completed, TLC (PE:EtOAc=3:1) was used to detect the reaction. The reaction system was quenched with water (50 mL) and extracted with DCM (dichloromethane) (50 mL x 2). The combined organic phase was washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was separated and purified by flash chromatography (PE:EtOAc=3:1) to give (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-[(2-hydroxyethyl)amino]butan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate (73-1) (120 mg, yield 32%) as a white solid. 1H NMR (400MHz, CDCl3): δ4.47(dd,J=11.5,4.3Hz,1H),3.92(d,J=21.0Hz,2H),2.92(s,2H),2.02(d,J=10.5Hz,7H),1.65(m, 8H),1.46(s,4H),1.27(dd,J=21.3,8.4Hz,4H),1.14(s,2H),0.97(s,3H),0.90(s,3H),0.85(d,J=6.7Hz,9H),0.65(s,3H). 13 C NMR (100MHz, CDCl3): δ171.05,134.25,80.87,50.43,49.89,49.65,46.52,45.86,44.51,37.76,36.86,3 5.20,34.57,31.96,30.90,30.69,27.84,26.31,24.13,21.32,20.92,19.16,18.42,18.07,16.50,15.60.

[0734] In the second step, the starting material (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-[(2-hydroxyethyl)amino]butan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate (73-1) (120 mg, 0.25 mmol, 1 eq) was dissolved in methanol (20 mL) and water (5 mL), followed by the addition of potassium hydroxide (1.42 g, 25.3 mmol, 100 eq). The reaction mixture was heated to 80°C in an oil bath and stirred at this temperature for 6 hrs. The reaction was complete as determined by LCMS. The reaction mixture was poured into ice water and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was separated and purified by Prep-HPLC (0.01% FA in water, MeCN) to give (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-[(2-hydroxyethyl)amino]butan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-7-ol (73) (70 mg, purity 100%, yield 64%) as a white solid. 1H NMR (400MHz, CD3OD-d4): δ3.74(m,2H),3.13(m,1H),3.03(m,2H),2.89(m,1H),2.05(m,4H),1.96(s,1H),1.74(m,6H),1.57(m,6H), 1.41(m,2H),1.23(dd,J=19.1,8.9Hz,2H),1.03(d,J=10.7Hz,1H),1.00(s,3H),0.97(m,6H),0.91(m,3H),0.78(m,3H),0.75(m,3H). 13 C NMR (100MHz, CD3OD-d4): δ134.68,134.09,78.20,56.90,50.52,50.26,49.65,49.42,45.62,44.37,38.52,36.78,35.52 ,34.55,32.54,30.84,30.43,27.72,27.10,27.04,26.21,23.16,20.60,18.07,17.97,17.65,14.84,14.68.LC-MS:[M+H] + =432.50.

[0735] Example 74

[0736] Preparation of Compound 74 (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-[(2-hydroxyethyl)(methyl)amino]butan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0737]

[0738] The starting material (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(2R)-4-[(2-hydroxyethyl)amino]butan-2-yl]-3a, 6, 6, 9a, 11a-pentamethyl-2, 3, 3a, 4, 5, 5a, 6, 7, 8, 9, 9a, 10, 11, 11a-tetrahydro-1H-cyclopenta[1, 2-a] phenanthren-7-ol (73) (50 mg, 0.12 mmol, 1 eq) was dissolved in dichloromethane (10 mL), and then 37% formaldehyde solution (1 mL) and sodium triacetoxyborohydride (43.8 mg, 1.16 mmol, 10 eq) were added. The mixture was stirred at room temperature for 18 hrs. The reaction was completed by LCMS. The reaction solution was introduced into a saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (50 mL x 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was separated and purified by preparative HPLC (0.01% FA in water, MeCN) to give (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-[(2-hydroxyethyl)(methyl)amino]butan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-7-ol (74) (40 mg, purity 98%, yield 75%) as a white solid. 1 HNMR (400MHz, CD3OD-d4): δ3.72(t,J=5.8Hz,2H),3.13(m,1H),2.76(m,4H),2.51(s,3H),2.05(s,4H),1.98(m,1H),1.72(m,6H),1.56(m,6H),1.3 5(dd,J=21.8,9.5Hz,2H),1.20(dd,J=19.6,10.1Hz,2H),1.03(m,1H),0. 99(s,3H),0.95(d,J=8.0Hz,6H),0.90(s,3H),0.79(s,3H),0.74(s,3H). 13 C NMR (100MHz, CD3OD-d4): δ134.60,134.05,78.19,58.03,57.11,54.97,50.51,50.31,49.64,44.33,40.56,38.53,36.78,35 .52,34.93,31.38,30.84,30.45,27.78,27.18,27.04,26.22,23.19,20.62,18.19,17.99,17.88,14.85,14.72.LC-MS:[M+H]+ =446.50

[0739] Example 75

[0740] Preparation of Compound 75 (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-7-hydroxy-7-methyloctan-2-yl]3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0741]

[0742] In the first step, (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-formylbutyl-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate (II) (500 mg, 1.1 mmol) was dissolved in tetrahydrofuran (30 mL), ventilated three times with N2, and cooled to 0°C. Potassium tert-butoxide (253 mg, 2.3 mmol) was added as a solid, and stirred at 0°C for 30 min. Compound R1 (500 mg, 1.1 mmol) was dissolved in THF (5 ml) and added dropwise to the above reaction system. The mixture was naturally warmed to room temperature and stirred for 2 h. TLC (PE:EtOAc = 10:1) revealed no residual starting material. The mixture was cooled to zero degrees Celsius and 1M HCl (2 mL) was added. The mixture was separated and extracted twice with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, spin-dried, and filtered through a column to obtain (2E,6R)-6-[(1R,3aR,5aR,7S,9aS,11aR)-7-acetyloxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hept-2-enoic acid methyl ester (75-1) (430 mg, 0.86 mmol, 76.65%) as a white solid. 1H NMR (399MHz, CDCl3) δ7.03–6.85(m,1H),5.80(d,J=15.6Hz,1H),4.48(dd,J=1 1.7,4.5Hz,1H),3.77–3.62(m,3H),2.25(s,1H),2.12–1.92(m,8H),1.89(d,J= 21.3Hz,1H),1.57–1.39(m,4H)1.57–1.39(m,5H),1.36–1.21(m,3H),1.15(dd ,J=19.7,10.5Hz,3H),0.98(s,3H),0.87(dd,J=14.6,4.9Hz,12H),0.66(s,3H)

[0743] In the second step, (2E,6R)-6-[(1R,3aR,5aR,7S,9aS,11aR)-7-acetyloxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hept-2-enoic acid methyl ester (75-1) (380 mg, 0.762 mmol) was dissolved in ethyl acetate (380 mL), and Pd / C (palladium carbon) (38 mg, 0.762 mmol) was added. The mixture was purged with hydrogen three times and stirred at room temperature for 30 min. TLC (PE: EtOAc= The mixture was stirred for 10 min at 4 ℃ for 2 h. After 10 min, the mixture was stirred for 10 min. The reaction mixture was stirred for 10 min. The mixture was stirred for 10 min. After 10 min, the mixture was stirred for 10 min. The ... 1 H NMR (400MHz, CDCl3) δ4.49(dd,J=11.5,4.6Hz,1H),3.66(d,J=1.1Hz,3H),2.30(t,J=8.0Hz,2H),2.11–1.94(m,7H ),1.94–1.82(m,1H),1.82–1.46(m,8H),1.46–1.09(m,8H),0.99(s,3H),0.87(q,J=2.7,2.2Hz,12H),0.67(s,3H). 13C NMR (101MHz, CDCl3) δ134.42,134.20,51.46,50.38,49.77,44.43,37.78,36.86,36.25,35.77,35.24,34.18,30.9 2,30.78,28.18,27.90,26.35,25.90,25.39,24.23,24.15,21.35,20.97,19.17,18.62,18.10,16.52,15.73,1.02.

[0744] In the third step, (6R)-6-[(1R,3aR,5aR,7S,9aS,11aR)-7-acetyloxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]heptanoic acid methyl ester (75-2) (100 mg, 0.170 mmol) was added. ) was dissolved in tetrahydrofuran (5 mL), purged with N2, and cooled to zero degrees Celsius. Methylmagnesium bromide (1 M, 2 mL) was added dropwise. TLC indicated no residual starting material. Ammonium chloride was added to quench the reaction, and the mixture was dried over anhydrous sodium sulfate. The reaction mixture was spin-dried, and tetrahydrofuran (5 mL) was added. The mixture was treated with 30% potassium hydroxide (5 mL) and methanol (5 mL). The mixture was heated at 100 degrees Celsius overnight. TLC was performed using PE:EtOAc = 5:1. The mixture was washed three times with EtOAc and dried over sodium sulfate. The mixture was passed through a column using PE:EtOAc = (100:1 to 20:1). The resulting product was (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-7-hydroxy-7-methyloctan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol (75-3) (10 mg, 0.017 mmol, 8.72%) as a white solid. 1 H NMR(400MHz,Chloroform-d)δ3.22(dd,J=11.6,4.4Hz,1H),2.01(s,5H),1.78–1.64(m,4H),1.59–1.41(m,9H),1. 41–1.30(m,4H),1.30–1.13(m,10H),1.01(dd,J=24.3,10.1Hz,7H),0.91–0.83(m,6H),0.80(s,3H),0.68(s,3H). 13C NMR(101MHz, CDCl3)134.36,78.97,71.07,50.41,50.38,49.78,44.43,44.05,38.87,36.99,36.39,36.22,35.56,30 .96,30.82,29.25,29.19,28.21,27.94,27.82,26.87,26.48,24.83,24.25,20.98,19.12,18.71,18.24,15.73,15.40

[0745] Examples 76 and 77

[0746] Preparation of Compound 76 (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(2R)-6-ethyl-6-hydroxyoctan-2-yl]-3a, 6, 6, 9a, 11a-pentamethyl-2, 3, 3a, 4, 5, 5a, 6, 7, 8, 9, 9a, 10, 11, 11a-tetradecahydro-1H-cyclopenta[1, 2-a]phenanthren-7-ol

[0747]

[0748] Preparation of Compound 77 (1R, 3aR, 5aR, 7R, 9aS, 11aR)-1-[(2R)-6-ethyl-6-hydroxyoctan-2-yl]-3a, 6, 6, 9a, 11a-pentamethyl-2, 3, 3a, 4, 5, 5a, 6, 7, 8, 9, 9a, 10, 11, 11a-tetradecahydro-1H-cyclopenta[1, 2-a]phenanthren-7-ol

[0749]

[0750] Step 1: (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-formylbutyl-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate (II) (5.00 g, 11.3 mmol, 1.0 eq) was dissolved in a mixed solvent of THF (100 mL) and H2O (20 mL), and NaBH4 (0.64 g, 16.9 mmol, 1.5 eq) was added to the reaction system. After the reaction was completed as monitored by TLC (PE:EtOAc=5:1, phosphomolybdic acid hotplate), water (~100 mL) was added to the system for dilution, and the mixture was extracted twice with ethyl acetate (100 mL). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EtOAc=90:10) to give (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-hydroxypentan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate (76-1) (3.4 g, 6.9 mmol, purity 90.5%, yield 60.9%) as a white solid. 1 H NMR (400MHz, CDCl3) δ4.50 (dd, J=11.6, 4.5Hz, 1H), 3.66–3.59 (m, 2H), 2.09–1.97 (m, 6H), 1.96–1.87 (m, 1H), 1.77–1.52 (m, 8H) ),1.51–1.38(m,8H),1.37-1.25(m,3H),1.21–1.12(m,2H),1.10-1.02(m,1H),1.00(s,3H),0.94–0.84(m,10H),0.69(s,3H). 13 C NMR (101MHz, CDCl3) δ171.02,134.46,134.28,80.94,77.33,77.22,77.02,76.70,63.63,50.51,50.37,49.82,44.49,37.81,36.9 1,36.24,35.28,32.11,30.97,30.80,29.62,28.20,27.92,26.39,24.24,24.18,21.34,21.00,19.19,18.68,18.13,16.54,15.77.

[0751] Step 2: (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-hydroxypentan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate (76-1) (3.00 g, 6.7 mmol, 1.0 eq) was dissolved in DCM (dichloromethane) (50 mL), and imidazole (0.83 g, 12.1 mmol, 1.8 eq), triphenylphosphine (2.30 g, 8.8 mmol, 1.3 eq) and iodine (2.23 g, 8.8 mmol, 1.3 eq) were added in sequence, and the mixture was stirred at room temperature for 2 hours. The reaction was completed as monitored by TLC (PE:EtOAc=5:1, phosphomolybdic acid hotplate). The system was directly spin-dried and purified by silica gel column chromatography (PE:EtOAc=95:5) to give (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-iodopentan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate (76-2) (3.5 g, 5.7 mmol, purity 95.1%, yield 84.2%) as a white solid. 1 H NMR (400MHz, CDCl3) δ4.50 (dd, J=11.6, 4.5Hz, 1H), 3.19-3.13 (m, 2H), 2.05-1.90 (m, 9H), 1.70-1.59 (m, 8H ),1.59-1.39(m,4H),1.35-1.30(m,2H),1.20-1.13(m,3H),1.00(s,3H),0.95-0.75(m,12H),0.69(s,3H). 13 CNMR(101MHz, CDCl3)δ170.98,134.38,134.24,80.88,77.32,77.00,76.68,50.47,50.26,49.79,44.48,37.78,37.12,36.87, 35.75,35.24,30.92,30.78,30.58,28.19,27.90,26.36,24.23,24.15,21.33,20.96,19.17,18.73,18.10,16.52,15.74,7.94.

[0752] Step 3: (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-iodopent-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate (76-2) (3.50 g, 6.31 mmol, 1.0 eq) was dissolved in DMF (50 mL), potassium cyanide (4.78 g, 73.4 mmol, 11.6 eq) was added, and the system was heated to 100 °C. The reaction was completed as monitored by TLC (PE:EtOAc=5:1, phosphomolybdic acid hotplate). The reaction solution was cooled to room temperature, poured into water, and extracted twice with ethyl acetate (100 mL). The organic phases were combined, washed twice with brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EtOAc=90:10) to give (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-cyanopentan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate (76-3) (2.50 g, 5.0 mmol, purity 91.5%, yield 78.6%) as a white solid. 1 H NMR (400MHz, CDCl3) δ4.50 (dd, J=11.5, 4.5Hz, 1H), 2.35-2.29 (m, 2H), 2.08-1.85 (m, 10H ),1.69-1.30(m,14H),1.29-1.15(m,6H),0.99(s,3H),0.95-0.85(m,12H),0.69(s,3H). 13 CNMR(101MHz,CDCl3)δ171.01,162.56,134.37,134.29,119.89,80.90,77.38,7 7.26,77.06,76.74,50.48,50.30,50.22,49.80,44.51,37.79,36.89,36.50,35. 89,35.29,35.25,31.44,30.95,30.75,28.16,27.90,26.36,24.74,24.21,24.15,22.41,21.31,20.96,19.18,18.74,18.51,18.09,17.54,16.62,16.52,15.74.

[0753] Step 4: (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-cyanopentan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate (76-3) (1.00 g, 2.2 mmol, 1.0 eq) was dissolved in methanolic hydrogen chloride solution (30 mL, 4 mol / L) and the reaction was heated to reflux. The disappearance of the raw material spot was monitored by TLC (PE:EtOAc=5:1, phosphomolybdic acid hotplate), the reaction solution was concentrated, the residue was dissolved with ethyl acetate, the organic phase was washed with saturated sodium bicarbonate (50 mL x 3) and saturated brine (50 mL x 3) in sequence, the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE:EtOAc=90:10 to 80:20) was purified to give (5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-acetyloxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester (76-4) (650 mg, 1.2 mmol, purity 95.5%, yield 54.5%) as a white solid. 1 H NMR (400MHz, CDCl3) δ3.67(s,3H),3.26-3.21(m,1H),2.30-2.25(m,2H),2.15-1.85(m,5H),1.80-1.65(m, 8H),1.50-1.36(m,6H),1.35-1.01(m,7H),1.00-0.95(m,6H),0.94-0.85(m,7H),0.81(s,3H),0.66(s,3H).

[0754] Step 5: Methyl (5R)-5-[(1R,3aR,5aR,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoate (76-4) (80 mg, 0.16 mmol) was dissolved in dry tetrahydrofuran (5 mL). Ethylmagnesium chloride (1 MOL / L) (1.64 mL, 1.64 mmol, 10.0 eq) was slowly added dropwise at -10 °C under nitrogen protection. After the addition was complete, the system was automatically heated to room temperature and reacted for 1 hour. After the reaction was complete as monitored by TLC (PE:EtOAc=5:1, phosphomolybdic acid hotplate), saturated ammonium chloride solution was added to the reaction system under an ice-water bath until no bubbles were generated. The mixture was extracted with ethyl acetate (~10 mL x 3). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (PE:EtOAc=80:20) to obtain a white solid. The solid was further separated by SFC (Column: Daicel CHIRALCEL IA-H, 250 mm×30 mm ID, 10 μm; Mobile phase: CO2 / MeOH [0.2% NH3 (7 M Solution in MeOH)] = 75 / 25; Flow rate: 80 g / min; Wave length: UV 214nm; Temperature: 35℃) to give (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-ethyl-6-hydroxyoctan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol (76, first peak) (12.05 mg, 0.025 mmol, purity 95.8%, yield 22.0%) and compound (1R,3aR,5aR,7R,9aS,11aR)-1-[(2R)-6-ethyl-6-hydroxyoctan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol (77, second peak) (5.09 mg, 0.011 mmol, purity 96.19%, yield 9.3%).

[0755] Compound 76: 1H NMR (400MHz, CDCl3) δ3.24(dd,J=11.6,4.5Hz,1H),2.02(m,5H),1.91(dd,J=13.4,7.5Hz,1H),1.69(m,6H),1.56(m,13H),1. 45(d,J=7.4Hz,4H),1.33(m,11H),1.18(m,3H),1.05(m,1H),0.99(d,J=7.7Hz,6H),0.87(m,12H),0.81(s,3H),0.69(s,3H). 13 C NMR (101MHz, CDCl3) δ134.41,79.00,77.33,77.22,77.02,76.70,74.71,50.51,50.42,49.82,44.50,38.90,38.72,37.03,36.89,36.4 5,35.60,31.12,31.03,31.00,30.85,28.23,27.97,27.86,26.51,24.27,21.01,20.12,19.15,18.72,18.26,15.77,15.42,7.83,7.79

[0756] Compound 77: 1 H NMR (400MHz, CDCl3): δ5.21(m,1H),3.25(dd,J=10.9,4.8Hz,1H),1.95(m,4H),1.80(dt,J=13.3,3. 4Hz, 1H), 1.61 (m, 7H), 1.46 (m, 7H), 1.30 (m, 13H), 0.98 (d, J = 8.2Hz, 6H), 0.87 (m, 12H), 0.64 (s, 3H).

[0757] Examples 78 and 79

[0758] Preparation of Compound 78 (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(2R)-6-hydroxy-6-propylnonan-2-yl]-3a, 6, 6, 9a, 11a-pentamethyl-2, 3, 3a, 4, 5, 5a, 6, 7, 8, 9, 9a, 10, 11, 11a-tetradecahydro-1H-cyclopenta[1, 2-a]phenanthren-7-ol

[0759]

[0760] Preparation of Compound 79 (1R, 3aR, 5aR, 7R, 9aS, 11aR)-1-[(2R)-6-hydroxy-6-propylnonan-2-yl]-3a, 6, 6, 9a, 11a-pentamethyl-2, 3, 3a, 4, 5, 5a, 6, 7, 8, 9, 9a, 10, 11, 11a-tetradecahydro-1H-cyclopenta[1, 2-a]phenanthren-7-ol

[0761]

[0762] Referring to Example 76, the Grignard reagent in the fifth step was replaced with propylmagnesium chloride, and finally prepared by SFC (Column: Daicel CHIRALCEL IA-H, 250 mm × 30 mm ID, 10 μm; Mobile phase: CO2 / MeOH [0.2% NH3 (7MSolution in MeOH)] = 80 / 20; Flow rate: 70 g / min; Wave length: UV 214 nm; Temperature: 35°C) to obtain compound (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(2R)-6-hydroxy-6-propylnonan-2-yl]-3a, 6, 6, 9a, 11a-pentamethyl-2, 3, 3a, 4, 5, 5a, 6, 7, 8, 9, 9a, 10, 11, 11a-tetradecahydro-1H-cyclopenta[1, 2-a] phenanthren-7-ol (78, first peak) and compound (1R,3aR,5aR,7R,9aS,11aR)-1-[(2R)-6-hydroxy-6-propylnonan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol (79, second peak)

[0763] Compound 78: 1 H NMR (400MHz, CDCl3): δ3.24(dd,J=11.5,4.5Hz,1H),2.10–1.96(M,4H),1.95–1.85(m,1H),1.75–1.65(m,5H),1.64–1.53(m,3H),1.50–1.40(m,8H) ),1.35–1.25(m,8H),1.24–1.13(m,3H),1.08-1.02(dd,J=12.7,2.0Hz,1 H),0.99(d,J=7.6Hz,6H),0.94–0.86(m,12H),0.81(s,3H),0.69(s,3H). 13C NMR (101MHz, CDCl3) δ134.43,134.41,79.00,77.33,77.22,77.02,76.70,74.56,50.55,50.42,49.82,44.50,41.81,41.68,39.81,38.90,37.0 3,36.87,36.46,35.60,31.01,30.85,28.25,27.97,27.87,26.51,24.2 6,21.01,20.23,19.15,18.71,18.27,16.80,16.76,15.77,15.42,14.76

[0764] Compound 79: 1 H NMR (400MHz, CDCl3) δ5.24–5.18(m,1H),3.25(dd,J=10.9,4.8Hz,1H),2.04–1.87(m,4H),1.84-1.76(m,1H),1.70–1.54(m,5H),1.48 -1.45(m,2H),1.44–1.10(m,21H),0.99(s,3H),0.97(s,3H),0.95–0.85(m,14H),0.64(s,3H).

[0765] Examples 80 and 81

[0766] Preparation of Compound 80 (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(2R)-6-hydroxy-6-(prop-2-enyl)non-8-en-2-yl]-3a, 6, 6, 9a, 11a-pentamethyl-2, 3, 3a, 4, 5, 5a, 6, 7, 8, 9, 9a, 10, 11, 11a-tetradecahydro-1H-cyclopenta[1, 2-a]phenanthren-7-ol

[0767]

[0768] Preparation of Compound 81 (1R, 3aR, 5aR, 7R, 9aS, 11aR)-1-[(2R)-6-hydroxy-6-(prop-2-enyl)non-8-en-2-yl]-3a, 6, 6, 9a, 11a-pentamethyl-2, 3, 3a, 4, 5, 5a, 6, 7, 8, 9, 9a, 10, 11, 11a-tetradecahydro-1H-cyclopenta[1, 2-a]phenanthren-7-ol

[0769]

[0770] Referring to Example 76, the Grignard reagent in the fifth step was replaced with allylmagnesium chloride, and finally the reaction was carried out by SFC (Column: Daicel CHIRALCEL IA-H, 250 mm × 30 mm ID, 10 μm; Mobile phase: CO 2 / MeOH [0.2% NH 3 (7MS solution in MeOH)] = 80 / 20; Flow rate: 70 g / min; Wave length: UV 214nm; Temperature: 35℃) to prepare the compound (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-hydroxy-6-(prop-2-enyl)non-8-en-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol (80, first peak) and compound (1R,3aR,5aR,7R,9aS,11aR)-1-[(2R)-6-hydroxy-6-(prop-2-enyl)non-8-en-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol (81, second peak).

[0771] Compound 80: 1 H NMR (400MHz, CDCl3) δ5.91-5.80(m,2H),5.17–5.08(m,4H),3.24(dd,J=11.6,4.5Hz,1H),2.30–2.16(m,4H),2.10–1.98(m,4H),1.96–1.84(m,1H ),1.78–1.55(m,7H),1.52–1.14(m,13H),1.08-1.02(m,2H),0.99(d,J=7 .7Hz, 6H), 0.90 (d, J = 6.3Hz, 3H), 0.88 (s, 3H), 0.81 (s, 3H), 0.69 (s, 3H). 13C NMR (101MHz, CDCl3): δ133.61,78.19,76.52,76.40,76.20,75.88,70.09,49.85,49.61,49.01,43.70,42.23,38.09,36.22,36.1 6,35.72,34.79,30.21,30.05,27.45,27.16,27.05,25.70,23.46,20.20,19.86,18.34,17.88,17.70,17.45,14.97,14.61,3.63

[0772] Compound 81: 1 H NMR (400MHz, CDCl3) δ5.91–5.79(m,2H),5.21(m,1H),5.23–5.19(m,4H),3.25(dd,J=10.9,4.7Hz,1H),2.30–2.15(m,4H),2.05–1.90( m,4H),1.84–1.76(m,1H),1.67–1.60(m,3H),1.50–1.35(m,8H),1.30–1.10(m,8H),1.00–0.96(m,6H),0.92–0.84(m,9H),0.64(s,3H).

[0773] Examples 82 and 83

[0774] Preparation of Compound 82 (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6,6-dicyclopropyl-6-hydroxyhexan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0775]

[0776] Preparation of Compound 83 (1R,3aR,5aR,7R,9aS,11aR)-1-[(2R)-6,6-dicyclopropyl-6-hydroxyhexan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0777]

[0778] Referring to Example 76, the Grignard reagent in the fifth step was replaced with cyclopropylmagnesium chloride, and finally the reaction was carried out by SFC (Column: Daicel CHIRALCEL IA-H, 250 mm × 30 mm ID, 10 μm; Mobile phase: CO 2 / MeOH [0.2% NH 3 (7MS solution in MeOH)] = 80 / 20; Flow rate: 70 g / min; Wave length: UV 214nm; Temperature: 35℃) to prepare the compound (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6,6-dicyclopropyl-6-hydroxyhexan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol (82, first peak) and compound (1R,3aR,5aR,7R,9aS,11aR)-1-[(2R)-6,6-dicyclopropyl-6-hydroxyhexan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol (83, second peak).

[0779] Compound 82: 1 H NMR (400MHz, CDCl3) δ3.24 (dd, J=11.5, 4.5Hz, 1H), 2.08–1.97 (m, 4H), 1.96–1.87 (m, 1H), 1.77–1.64 (m, 5H), 1.63–1.30 (m, 13H), 1.29 -1.14(m,3H),1.08–1.03(m,1H),0.99(d,J=7.3Hz,6H),0.94–0.90(m,3H),0.88(s,3H),0.84–0.80(m,4H),0.69(s,3H),0.50 -0.20(m,8H). 13C NMR (101MHz, CDCl3) δ133.61,78.19,76.52,76.40,76.20,75.88,70.09,49.85,49.61,49.01,43.70,42.23,38.09,36.22,36.1 6,35.72,34.79,30.21,30.05,27.45,27.16,27.05,25.70,23.46,20.20,19.86,18.34,17.88,17.70,17.45,14.97,14.61,3.63

[0780] Compound 83: 1 H NMR (400MHz, CDCl3) δ5.23–5.19(m,1H),5.12-5.09(s,1H),3.25(dd,J=10.9,4.8Hz,1H),2.26–2.12(m,1H),2.08–1.88(m,5H),1.84–1.54(m ,8H),1.52-1.04(m,13H),1.04–0.95(m,6H),0.94–0.85(m,9H),0.76– 0.68(m,2H),0.67–0.56(m,5H),0.52-0.34(m,2H),0.32–0.26(m,1H).

[0781] Example 84

[0782] Preparation of Compound 84 (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(2R)-4-[(3-hydroxycyclobutyl)amino]butan-2-yl]-3a, 6, 6, 9a, 11a-pentamethyl-2, 3, 3a, 4, 5, 5a, 6, 7, 8, 9, 9a, 10, 11, 11a-tetradecahydro-1H-cyclopenta[1, 2-a]phenanthren-7-ol

[0783]

[0784] In the first step, the starting material, (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-1-formylpropan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate (III) (200 mg, 0.47 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL). 3-Aminocyclobutan-1-ol (81 mg, 0.93 mmol, 2.0 eq) was added. The reaction mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (177 mg, 4.7 mmol, 10 eq) was then added and stirred overnight. TLC (PE:DCM = 3:1) indicated the reaction was complete. The reaction system was quenched with water (50 mL) and extracted with DCM (dichloromethane) (50 mL x 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-[(3-hydroxycyclobutyl)amino]butan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate (84-1) (200 mg, 68% yield) as a white solid. LC-MS: [M+H] + =500.55.

[0785] In the second step, the starting material (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-[(3-hydroxycyclobutyl)amino]butan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate (84-1) (200 mg, 0.40 mmol, 1 eq) was dissolved in methanol (50 mL) and water (5 mL), followed by the addition of potassium hydroxide (673 mg, 12.0 mmol, 300 eq). The reaction mixture was heated to 80°C in an oil bath and stirred at this temperature for 16 hr. The reaction was complete after LCMS analysis. The reaction solution was poured into ice water and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated and purified by Prep-HPLC (0.01% FA in water, MeCN) to obtain a white solid (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-[(3-hydroxycyclobutyl)amino]butan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-7-ol (84) (20 mg, purity 100%, yield 10%). 1 HNMR (400MHz, CD3OD-d4): δ4.45(s,0.5H),4.05(m,0.5H),3.82(s,0.5H),3.23(m,0.5H),3.13 (m,1H),2.91(d,J=9.1Hz,1H),2.82(s,1H),2.68(d,J=6.8Hz,1H),2.43(dd,J=13.3,6.7Hz,1H) ,2.31(d,J=8.4Hz,1H),2.05(s,4H),1.98(s,1H),1.66(m,12H),1.38(s,2H),1.21(d,J=11.2Hz ,1H),1.03(d,J=12.7Hz,1H),0.99(s,3H),0.96(s,6H),0.90(s,3H),0.78(s,3H),0.75(s,3H). 13C NMR (100MHz, CD3OD-d4): δ134.66,134.06,78.17,62.68,59.12,50.49,50.2 5,49.65,49.09,44.37,43.63,43.43,38.53,36.87,36.85,36.78,35.51,35 .22,35.16,34.48,34.46,32.38,32.33,30.81,30.43,29.26,27.73,27.18, 27.03,26.21,23.18,20.60,18.20,17.98,17.56,14.87,14.73.LC-MS:[M+H] + =458.55.

[0786] Example 85

[0787] Preparation of Compound 85 (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(2R)-4-[3-(hydroxymethyl)azetidin-1-yl]butan-2-yl]-3a, 6, 6, 9a, 11a-pentamethyl-2, 3, 3a, 4, 5, 5a, 6, 7, 8, 9, 9a, 10, 11, 11a-tetrahydro-1H-cyclopenta[1, 2-a]phenanthren-7-ol

[0788]

[0789] Referring to Example 84, the amine in the first step was replaced with azetidin-3-ylmethanol to finally obtain the compound (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-[3-(hydroxymethyl)azetidin-1-yl]butan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol (85). 1 HNMR (400MHz, CD3OD-d4): δ4.05(t,J=9.5Hz,2H),3.87(m,2H),3.62(d,J=4.3 Hz,2H),3.15(dt,J=16.5,8.4Hz,2H),3.02(td,J=11.7,5.5Hz,1H),2.93(s,1H ),2.05(s,4H),1.97(d,J=13.9Hz,1H),1.64(m,12H),1.22(m,3H),1.03(d,J= 12.5Hz,1H),0.99(s,3H),0.96(s,6H),0.90(s,3H),0.78(s,3H),0.74(s,3H).13 C NMR (100MHz, CD3OD-d4): δ134.66,134.07,78.18,59.83(s,2H),55.33,55.24,53.07,50.50,50.09,49.63,44.36,38.52,36.77,35 .51,34.29,31.15,30.80,30.51,30.43,27.67,27.17,27.03,26.20,23.16,20.60,18.18,17.9,17.70,14.83,14.71.LC-MS:[M+H] + =458.55.

[0790] Example 86

[0791] Preparation of Compound 86 (1R,3aR,5aR,7S,9aS,11aR)-1-[(2S)-1-[(2-hydroxyethyl)amino]propan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-ol

[0792]

[0793]

[0794] In the first step, (4R)-4-[(1R,3aR,5aR,7S,9aS,11aR)-7-acetyloxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]pentanoic acid (VII) (3 g, 6.541 mmol, 1.0 eq) was dissolved in benzene (40 mL) and added. Pyridine (20 mL), Cu(OAc)2 (copper acetate, 0.473 g, 2.616 mmol, 0.4 eq), argon was replaced three times; the temperature was raised to 90°C, and Pb(OAc)4 (lead tetraacetate, 8.98 g, 20.276 mmol, 3.1 eq) was added in batches. After reflux for 12 h, the temperature was naturally cooled to room temperature and monitored by TLC (PE:EtOAc=2:1, phosphomolybdic acid color development, Rf1=0.42, Rf2=0.89). After the reaction, the reaction solution was concentrated to remove benzene, dissolved in 200 ml of dichloromethane, and washed sequentially with 100 ml of 5% HCl (severe emulsification, filtered through celite), 100 ml of saturated NaHCO₃, and 100 ml of saturated brine. The solution was dried, concentrated, and subjected to column chromatography (PE-PE:EtOAc=30:1) to obtain (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-but-3-en-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate (86-1) (1.5 g, 2.908 mmol, 44.46%) as a white solid. 1 H NMR (399MHz, CDCl3) δ5.71–5.59(m,1H),4.95–4.76(m,2H),4.48(dd,J=11.5,4.7Hz,1H),2.08–1.98(m,7H),1.79–1.59(m,7H),1. 59–1.42(m,4H),1.28(dtd,J=19.3,8.8,5.2Hz,3H),1.18–1.09(m,2H),0.99(d,J=5.9Hz,5H),0.86(d,J=1.5Hz,9H),0.70(s,3H). 13CNMR(100MHz,Chloroform-d)δ170.99,145.50,134.44,134.17,111.52,80.89,50.46,49.83,49.74,44.45,41.82,37 .77,36.88,35.23,30.90,30.81,28.22,27.88,26.35,24.23,24.14,21.31,20.96,20.05,19.16,18.08,16.51,15.97.

[0795] Step 2. Dissolve (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-but-3-en-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate (86-1) (1.5 g, 3.635 mmol, 1.0 eq) in dichloromethane (30 mL), replace nitrogen three times, and cool to 0°C. Ozone was slowly introduced, and after 10 minutes, TLC monitoring (PE:EtOAc=10:1, phosphomolybdic acid color development, Rf1=0.84, Rf2=0.51); after the reaction was complete, N2 was introduced to drive out the ozone, PPh3 (2.86 g, 10.905 mmol, 3.0 eq) was added, and the temperature was raised to room temperature for reaction for 30 minutes, and TLC monitoring (PE:EtOAc=10:1, phosphomolybdic acid color development, Rf1=0.85, Rf2=0.49) was performed. The reaction solution was concentrated and column chromatography (PE- PE:EtOAc = 20:1), and concentrated to give (1R,3aR,5aR,7S,9aS,11aR)-1-[(1S)-1-formylethyl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate (86-2) (800 mg, 1.544 mmol, 42.46%). 1 H NMR(399MHz, CDCl3)δ9.55(d,J=3.3Hz,1H),4.47(dd,J=11.6,4.5Hz,1H),2.35(dqd,J=10.1,6.8,3.2Hz,1H),2.08–1.99(m,7H),1.93–1 .81(m,2H),1.71–1.60(m,6H),1.53–1.33(m,3H),1.32–1.17(m,3H),1.12–1.05(m,3H),0.98(s,3H),0.87(d,J=9.5Hz,9H),0.72(s,3H).13 C NMR (101MHz, CDCl3) δ205.34, 170.99, 134.28 (d, J = 34.8Hz), 80.80, 77.17, 50.40, 50.15, 49.27, 45.54, 45.14, 37.77, 36.9 0,35.21,31.13,30.77,27.88,26.95,26.38,24.17,24.13,24.11,21.32,20.90,19.18,19.16,18.04,16.51,16.25,13.46.

[0796] In the third step, (1R,3aR,5aR,7S,9aS,11aR)-1-[(1S)-1-formylethyl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate (86-2) (200 mg, 0.482 mm ol, 1.0 eq) was dissolved in dichloromethane (20 mL), and ethanolamine (58.92 mg, 0.965 mmol, 2.0 eq) and sodium triacetoxyborohydride (1022.31 mg, 4.824 mmol, 10.0 eq) were added. The reaction was allowed to react at room temperature overnight, monitored by TLC (PE:EtOAc = 10:1, phosphomolybdic acid colorimetry, Rf1 = 0.51, Rf2 = 0.33). After the reaction was complete, 20 mL of water and 20 mL of dichloromethane were added, and the layers were separated. The aqueous phase was extracted with dichloromethane (20 mL x 2), dried, concentrated, and then purified by column chromatography (PE-DCM:MeOH = 10:1, 0.1% triethylamine). A crude product of (1R,3aR,5aR,7S,9aS,11aR)-1-[(2S)-1-[(2-hydroxyethyl)amino]propan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate (86-3) (300 mg, 0.457 mmol, 94.71%) was obtained as a pale yellow solid. LC-MS: [M+H] + =460.30

[0797] Step 4: (1R,3aR,5aR,7S,9aS,11aR)-1-[(2S)-1-[(2-hydroxyethyl)amino]propan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate (86-3) (300 mg, 0.653 mmol) was dissolved in methanol (10 mL), 30% KOH (10 mL) was added, the temperature was raised to 100 ° C, and the reaction was monitored by LCMS overnight (CL210736-022-1). After the reaction, the reaction mixture was concentrated to remove methanol, 20 ml of dichloromethane was added, the aqueous phase was separated, extracted with 20 ml of dichloromethane, and concentrated to obtain a pale yellow solid (1R,3aR,5aR,7S,9aS,11aR)-1-[(2S)-1-[(2-hydroxyethyl)amino]propan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthren-7-ol (86) (8 mg, 0.018 mmol, 2.79%). 1 HNMR(400MHz,Methanol-d4)δ8.45(s,1H),5.40(s,1H),3.71(t,J=5.3Hz,2H ),3.14–2.90(m,4H),1.99(s,5H),1.74(d,J=11.1Hz,2H),1.64(dt,J=15.9,6 .4Hz,4H),1.57–1.40(m,4H),1.25(s,2H),1.21–1.06(m,3H),0.99(dd,J=11 .2, 4.3Hz, 4H), 0.92 (s, 4H), 0.89 (s, 3H), 0.83 (s, 3H), 0.71 (d, J = 1.5Hz, 3H). 13 CNMR(101MHz,Methanol-d4)δ134.80,133.96,78.19,56.22,53.09,50.51,49.58,44.67,38.57,36.82,35.52,34.8 3,30.78,30.50,29.30,27.36,27.21,27.06,26.24,23.17,20.62,18.24,18.00,16.01,14.92,14.76.LC-MS: [M+H] + =418.30

[0798] Example 87

[0799] Preparation of Compound 87 1-[(2S)-2-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]propyl]azetidin-3-ol

[0800]

[0801] Referring to Example 86, the amine in the third step was replaced with azetidin-3-ol to finally obtain compound 1-[(2S)-2-[(1R,3aR,5aR,7S,9aS,11aR)-7-hydroxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]propyl]azetidin-3-ol (87). 1 H NMR (400MHz, Methanol-d4) δ8.43 (s, 1H), 4.49 (p, J = 6.2Hz, 1H), 4.20 (q, J = 10.0Hz, 2H) ,3.71(dd,J=9.9,6.3Hz,2H),3.05(dd,J=10.6,5.5Hz,2H),2.80(dd,J=12.6,10.2Hz,1H ),2.03–1.93(m,4H),1.76–1.59(m,6H),1.57–1.41(m,4H),1.32(dddd,J=13.4,10.9,8. 1, 2.1Hz, 1H), 1.25–1.05 (m, 3H), 0.96–0.87 (m, 9H), 0.82 (s, 3H), 0.70 (d, J = 6.2Hz, 6H). 13 CNMR(101MHz,Methanol-d4)δ134.81,133.94,78.19,63.82,62.47,59.77,50.50,49.59,44.68,38.56,36.81,35.51,34.32,34.32, 30.79,30.51,27.59,27.39,27.20,27.05,27.05,26.24,26.24,23.15,20.61,18.23,18.11,18.00,15.99,15.99,14.81.LCMS:[M+H] + =430.35

[0802] Example 88

[0803] Preparation of Compound 88 (1R,3aR,5aR,7S,9aS,11aR)-1-[(2S)-1-[(3-hydroxycyclobutyl)amino]propan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0804]

[0805] Referring to Example 86, the amine in the third step was replaced with 3-aminocyclobutanol to obtain the compound (1R,3aR,5aR,7S,9aS,11aR)-1-[(2S)-1-[(3-hydroxycyclobutyl)amino]propan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-7-ol (88). 1 H NMR(400MHz, Methanol-d4)δ8.44(s,1H),3.06(dd,J=9.9,6.6Hz,1H),2.79(d,J=12.4Hz,1H),2.65–2 .48(m,2H),2.36(q,J=6.7Hz,1H),2.22(t,J=10.3Hz,1H),1.98(d,J=7.3Hz,4H),1.91(d,J=10.2Hz,1H ),1.75–1.58(m,6H),1.50(dd,J=21.0,10.8Hz,4H),1.29(q,J=11.2Hz,1H),1.15(ddd,J=23.4,14.8,1 0.7Hz,2H),1.05–0.96(m,4H),0.91(dd,J=13.8,1.7Hz,6H),0.83(s,3H),0.70(dd,J=4.3,1.7Hz,6H). 13 C NMR(101MHz,Methanol-d4)δ136.81,133.94,78.19,49.58,48.23,48.02,47.81,46.95,44.64,3 8.56,36.81,35.52,35.22,30.49,27.42,27.20,27.05,23.14,20.61,18.22,17.99.LC-MS:[M+H] + =444.35

[0806] Example 89

[0807] Preparation of Compound 89 (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(2S)-1-[3-(hydroxymethyl)azetidin-1-yl]propan-2-yl]-3a, 6, 6, 9a, 11a-pentamethyl-2, 3, 3a, 4, 5, 5a, 6, 7, 8, 9, 9a, 10, 11, 11a-tetrahydro-1H-cyclopenta[1, 2-a]phenanthren-7-ol

[0808]

[0809] Referring to Example 86, the amine in the third step was replaced with azetidin-3-ylmethanol to obtain the compound (1R,3aR,5aR,7S,9aS,11aR)-1-[(2S)-1-[3-(hydroxymethyl)azetidin-1-yl]propan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-7-ol (89). 1 H NMR(400MHz, Methanol-d4)δ8.56(s,1H),4.23–4.16(m,1H),3.99(t,J=8.8Hz,2H),3.27(dd,J=12.7, 3.0Hz,4H),3.03(ddp,J=12.6,8.6,4.2Hz,1H),2.89(dd,J=12.6,10.4Hz,1H),2.22–2.04(m,4H),2.0 3–1.92(m,1H),1.91–1.70(m,6H),1.65(tt,J=7.4,4.1Hz,2H),1.58(q,J=9.0Hz,2H),1.45(dddd,J=1 3.2,10.7,8.1,2.0Hz,1H),1.34–1.17(m,2H),1.12–0.99(m,9H),0.95(s,3H),0.82(d,J=5.2Hz,6H). 13 C NMR (101MHz, Methanol-d4) δ134.82,133.92,78.19,61.10,59.51,50.05,44.69,38.56,36.81,35.51,33.8 4,30.79,30.50,27.57,27.20,27.05,26.24,23.15,20.61,18.23,18.00,15.89,14.87,14.76.LCMS:[M+H] + =444.35

[0810] Example 90

[0811] Preparation of Compound 90 (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(2R)-5-(hydroxycyclopropyl)pentan-2-yl]-3a, 6, 6, 9a, 11a-pentamethyl-2, 3, 3a, 4, 5, 5a, 6, 7, 8, 9, 9a, 10, 11, 11a-tetradecahydro-1H-cyclopenta[1, 2-a]phenanthren-7-ol

[0812]

[0813] In the first step, (5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-acetyloxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoic acid methyl ester (V) (100 mg, 0.170 mmol) was dissolved in THF (5 mL), and tetraisopropyl titanate (150 mg, 0.103 mmol) was added at room temperature. The mixture was purged with nitrogen three times, and ethylmagnesium bromide (1 mL) was added dropwise at room temperature. The mixture was stirred overnight. TLC (PE:EtOAc = 10:1) showed a lot of starting material. The product was quenched with saturated brine at low temperature, diluted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, spin-dried, and passed through a column (PE:EtOAc = 100% to 50%). The product was concentrated to give (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-(hydroxycyclopropyl)pentan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate (90-1) (3 mg, 0.005 mmol, 4.82%) as a white solid. 1 HNMR(399MHz, CDCl3)δ4.48(dd,J=11.5,4.6Hz,1H),2.03(d,J=2.0Hz,8H),1.94–1.83(m,1H),1.76–1.57(m,10H),1.46(s,3H),1 .15(s,9H),0.98(s,3H),0.90(d,J=6.4Hz,3H),0.86(d,J=2.6Hz,9H),0.71(d,J=1.8Hz,2H),0.67(s,3H),0.42(d,J=2.0Hz,2H). 13C NMR (100MHz, CDCl3) δ170.99,134.43,134.21,80.91,77.30,76.99,76.67, 55.86,50.46,50.38,49.77,44.44,38.80,37.76,36.86,36.45,36.20,36.1 5,35.23,30.93,30.77,28.17,27.93,27.87,27.80,26.34,24.23,24.13,22.62,21.29,20.96,19.14,19.10,18.65,18.09,16.49,15.73,13.55,13.44.

[0814] The second step: Compound (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-(hydroxycyclopropyl)pentan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate (90-1) (60 mg, 0.062 mmol) was dissolved in THF (3 mL) and MeOH (3 mL), and 1 M LiOH (3 mL) was added at room temperature, and the mixture was stirred at room temperature for 5 h. After the reaction of the raw material was completed by TLC (PE: EtOAc = 10:1), the solvent was dried, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated by column chromatography (PE: EtOAc = 100% to 50%) to give (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(2R)-5-(hydroxycyclopropyl)pentan-2-yl]-3a, 6, 6, 9a, 11a-pentamethyl-2, 3, 3a, 4, 5, 5a, 6, 7, 8, 9, 9a, 10, 11, 11a-tetrahydro-1H-cyclopenta[1, 2-a]phenanthren-7-ol (90) (10 mg, 0.021 mmol, 17.34%) and 1H NMR (399MHz, CDCl3) δ3.21 (dd, J=11.4, 4.5Hz, 1H), 2.02 (d, J=7.0Hz, 4H), 1.88 (d, J=7.5Hz ,1H),1.73–1.64(m,4H),1.50–1.35(m,6H),1.32(d,J=7.5Hz,2H),1.25(d,J=11.8Hz,4H),1 .17(dd,J=22.2,11.6Hz,2H),1.03(d,J=11.2Hz,2H),0.98(s,3H),0.96(s,3H),0.90(d,J=6 .3Hz,3H),0.86(s,3H),0.79(s,3H),0.71(t,J=5.4Hz,2H),0.67(s,3H),0.47–0.38(m,2H). 13 C NMR (100MHz, CDCl3) δ134.36,134.34,78.96,77.30,76.98,76.66,55.94,50.36,49.77,44.44,38.85,38.80,36.98,36.44,36.20,35.55 ,31.40,30.95,30.80,30.15,29.67,28.18,27.93,27.81,26.46,24.25,22.59,20.97,19.11,18.66,18.22,15.72,15.39,13.59,13.46.

[0815] Example 91

[0816] Preparation of Compound 91 (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(2R)-6-hydroxy-7-methyl-6-(propan-2-yl)octan-2-yl]-3a, 6, 6, 9a, 11a-pentamethyl-2, 3, 3a, 4, 5, 5a, 6, 7, 8, 9, 9a, 10, 11, 11a-tetrahydro-1H-cyclopenta[1, 2-a]phenanthren-7-ol

[0817]

[0818] Referring to Example 76, the Grignard reagent in the fifth step was replaced with isopropylmagnesium chloride, and finally the compound (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-hydroxy-7-methyl-6-(propyl-2-yl)octan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol (91) was prepared by SFC.1 H NMR (400MHz, CDCl3) δ3.24(dd,J=11.5,4.5Hz,1H),2.03(m,4H),1.91(m,3H),1.64(m,9H),1.29(m,1 2H),1.05(dd,J=12.6,2.0Hz,1H),1.00(s,3H),0.98(s,3H),0.92(m,17H),0.81(s,3H),0.69(s,3H).

[0819] LC-MS[M-17] + =483

[0820] Example 92

[0821] Preparation of Compound 92 (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(2R)-5-hydroxypentan-2-yl]-3a, 6, 6, 9a, 11a-pentamethyl-2, 3, 3a, 4, 5, 5a, 6, 7, 8, 9, 9a, 10, 11, 11a-tetradecahydro-1H-cyclopenta[1, 2-a]phenanthren-7-ol

[0822]

[0823]

[0824] Ethyl (5R)-5-[(1R,3aR,5aR,7S,9aS,11aR)-7-acetyloxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoate (V) (50 mg, 0.10 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) under nitrogen protection. Lithium aluminum tetrahydride (5.69 mg, 0.150 mmol) was added under ice-bath, and the mixture was naturally warmed to room temperature and stirred for 1 hour. TLC (PE:EtOAc) indicated the reaction mixture had a 1:1 % yield. The reaction was monitored by ethanol (5:1, phosphomolybdic acid baking plate). After completion of the reaction, the product was quenched with sodium sulfate decahydrate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (PE:EtOAc=80:20) to give (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-hydroxypentan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-7-ol (92) (25 mg, 0.056 mmol, 56.59%) as a white solid. 1H NMR (400MHz, CDCl3) δ3.65(t,J=6.5Hz,2H),3.23(dd,J=11.6,4.5Hz,1H),2.01(m,2.10-1.95,4H),1.91(m,1.95-1.85,1H),1.70(m,1.77-1.64 5H),1.53(m,1.63-1.42,7H),1.26(m,1.40-1.14,6H),1.06(dd,J=10.1,7.9Hz,2H), 0.99(d,J=7.7Hz,6H),0.91(d,J=6.6Hz,3H),0.88(s,3H),0.81(s,3H),0.70(s,3H). 13 C NMR (101MHz, CDCl3) δ134.43,134.40,79.00,77.33,77.21,77.01,76.69,63.17,50.42,50.40,49.82,44.49,38.90,37.03,36.39,3 6.00,35.60,33.31,31.00,30.84,28.22,27.97,27.87,26.51,24.27,22.47,21.01,19.15,18.67,18.26,15.75,15.42.LC-MS[M-17] + =399

[0825] Example 93

[0826] Preparation of Compound 93 (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(2S)-1-[(2-hydroxy-2-methylpropyl)amino]propan-2-yl]-3a, 6, 6, 9a, 11a-pentamethyl-2, 3, 3a, 4, 5, 5a, 6, 7, 8, 9, 9a, 10, 11, 11a-tetradecahydro-1H-cyclopenta[1, 2-a]phenanthren-7-ol

[0827]

[0828] Referring to Example 86, the amine in the third step was replaced with 1-amino-2-methylpropanol to obtain the compound (1R,3aR,5aR,7S,9aS,11aR)-1-[(2S)-1-[(2-hydroxy-2-methylpropyl)amino]propan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-7-ol (93). 1HNMR (399MHz, Methanol-d4) δ8.52(s,1H),3.13(t,J=8.2Hz,1H),2.94(d,J=12.2Hz,1H),2.85(d,J=12.8Hz,1H),2.66(t,J=11.6Hz,1H),2. 07(s,4H),1.74(d,J=13.2Hz,4H),1.63–1.47(m,4H),1.27(s,8H),1.06(d,J=6.6Hz,3H),0.98(d,J=14.2Hz,6H),0.91(s,3H),0.79(s,6H). 13 C NMR (100MHz, Methanol-d4) δ134.77,133.92,78.15,67.42,57.72,54.48,50.47,49.52,48.46,48.20,47.98,47.77,47.56,47.34,47.13,46.9 2,44.67,38.53,36.78,35.49,34.24,30.77,30.48,27.37,27.17,27.0 2,26.22,23.13,20.59,18.20,17.97,15.87,14.94,14.72.LCMS:[M+H] + =446.50

[0829] Example 94

[0830] Preparation of Compound 94 (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(2R)-7-hydroxy-6,6-dimethylhept-2-yl]-3a, 6, 6, 9a, 11a-pentamethyl-2, 3, 3a, 4, 5, 5a, 6, 7, 8, 9, 9a, 10, 11, 11a-tetradecahydro-1H-cyclopenta[1, 2-a]phenanthrene-7-ol

[0831]

[0832] In the first step, ethyl isobutyrate (63 mg, 0.361 mmol) was dissolved in tetrahydrofuran (1 ml), cooled to -70 ° C, lithium diisopropylamide (0.902 mL, 1.803 mmol) was added dropwise, and the temperature was kept at -70 ° C and stirred for 10 minutes. The compound acetic acid (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(2R)-5-iodopentan-2-yl]-3a, 6,6,9a,11a-Pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl ester (76-2) (100 mg, 0.180 mmol) was dissolved in tetrahydrofuran (1 ml) and added dropwise to the above system at -70°C. The mixture was stirred at this temperature for 30 minutes and then allowed to warm to room temperature for two hours. The reaction was monitored by TLC (PE:EtOAc = 10:1). The temperature was lowered to zero degrees, and two drops of saturated aqueous ammonium chloride solution were added to quench the reaction. The mixture was then passed through a column (PE:EtOAc = 100% to 10%) to obtain compound (6R)-6-[(1R,3aR,5aR,7S,9aS,11aR)-7-acetyloxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-2,2-dimethylheptanoic acid methyl ester (94-1) (10 mg, 0.015 mmol, 8.39%). 1 H NMR (400MHz, CDCl3) δ3.31(s,1H),3.23(d,J=6.8Hz,2H),1.99(s,9H),1.88(m,1H),1.69(dd,J=19.2,14.4Hz,4H),1.47(m,3H),1.32 (s,3H),1.24(s,8H),1.13(m,3H),1.04(d,J=11.2Hz,1H),0.98(d,J=7.1Hz,6H),0.87(d,J=12.2Hz,12H),0.80(s,3H),0.67(s,3H).

[0833] In the second step, lithium aluminum tetrahydride (26 mg, 0.183 mmol) was added to tetrahydrofuran, protected by nitrogen, and cooled to zero degrees. Compound (6R)-6-[(1R,3aR,5aR,7S,9aS,11aR)-7-acetyloxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetrahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-2,2-dimethylheptanoic acid methyl ester (94-1) (20 mg, 0.038 mmol) was dissolved in tetrahydrofuran and added dropwise to the above system. The temperature was raised to room temperature and stirred for two hours. The reaction was monitored by TLC (PE:EtOAc=10:1), quenched with saturated aqueous ammonium chloride at low temperature, passed through a column (PE:EtOAc=80:20), and concentrated to give (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-7-hydroxy-6,6-dimethylhept-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol 94 (10 mg, 95%) as a white solid. 1 H NMR (400MHz, CDCl3) δ3.30(s,2H),3.22(dd,J=11.3,3.8Hz,1H),1.92(m,5H),1.69(dd,J=17.3,13.0Hz,6H),1.52(m,2H),1.33(s,4H), 1.24(t,J=10.1Hz,5H),1.13(m,2H),1.03(d,J=12.9Hz,1H),0.98(d,J=7.2Hz,6H),0.87(d,J=11.9Hz,12H),0.80(s,3H),0.67(s,3H). 13 C NMR (101MHz, CDCl3) δ134.36,78.97,77.31,76.99,76.67,72.11,50.58,50.37,49.78,44.45,39.10,38.86,37.14,36.99,36.47,35 .56,35.09,30.97,30.81,28.22,27.94,27.82,26.47,24.25,23.83,20.98,20.60,19.12,18.69,18.23,15.74,15.41.LC-MS:[M+H] + =441.55

[0834] Example 95

[0835] Preparation of Compound 95 (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(2R)-4-(3-hydroxycyclobutyl)butan-2-yl]-3a, 6, 6, 9a, 11a-pentamethyl-2, 3, 3a, 4, 5, 5a, 6, 7, 8, 9, 9a, 10, 11, 11a-tetradecahydro-1H-cyclopenta[1, 2-a]phenanthren-7-ol

[0836]

[0837] The first step compound, methyltriphenyl iodide (189 mg, 0.47 mmol, 1.0 eq), was dissolved in anhydrous toluene (3 mL). n-Butyl lithium (0.37 mL, 0.93 mmol, 2.0 eq) was added at 0°C and stirred for 30 minutes to obtain a light yellow solution. Epichlorohydrin (43.17 mg, 0.47 mmol, 1.0 eq) was added and stirred for 30 minutes. After that, n-Butyl lithium (0.37 mL, 0.93 mmol, 2.0 eq) was added and stirred for another 30 minutes. The system was then cooled to -40°C. (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-1-formylpropan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (III) (200 mg, 0.47 mmol, 1.0 eq) was dissolved in anhydrous toluene (3 mL) and slowly added to the reaction mixture. After stirring for 1 hour, the mixture was allowed to warm to room temperature. The reaction was monitored by TLC (PE:EtOAc = 5:1, phosphomolybdic acid hotplate) and was complete. The reaction solution was quenched with saturated ammonium chloride solution (~10 mL), extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated by silica gel column chromatography (PE:EtOAc=90:10) to give (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-(3-hydroxycyclobutylidene)butan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (95-1) (20 mg, 0.03 mmol, 7.1%) as a white solid.

[0838] Step 2: (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-(3-hydroxycyclobutylidene)butan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (95-1) (40 mg, 0.08 mmol) was dissolved in methanol (5 mL), palladium carbon (10 mg, 10%) was added, and the gas was replaced by hydrogen balloon three times and stirred for 5 hours. The palladium carbon was removed by filtration on celite. The residue was concentrated to dryness and purified by silica gel column chromatography (PE:EtOAc=80:20, phosphomolybdic acid hotplate) to give a brown solid ((1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-(3-hydroxycyclobutyl)butan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (95-2) (30 mg, 0.056 mmol, 67.22%). The crude product was directly used in the next step.

[0839] Step 3: (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-(3-hydroxycyclobutyl)butan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (95-2) (30 mg, 0.06 mmol) was dissolved in ethanol (1 mL), 4N sodium hydroxide solution (0.5 mL) was added, and the mixture was heated to 50°C and stirred for 5 hours. The reaction was monitored by TLC (PE:EtOAc=5:1, phosphomolybdic acid hotplate). After the reaction was complete, the reaction solution was diluted with water, the pH was adjusted to 4-5 with dilute hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EtOAc=80:20) to give (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-(3-hydroxycyclobutyl)butan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-7-ol (95) (6 mg, 0.012 mmol, 20.15%) as a white solid. 1H NMR (400MHz, CDCl3) δ4.43–4.34(m,0H),4.09(s,1H),3.24(dd,J=11.5,4.5Hz,1H),2.45( dd,J=7.2,3.9Hz,1H),2.02(dd,J=6.4,2.6Hz,6H),1.89(dd,J=22.3,8.8Hz,1H),1.76–1.5 9 (m, 7H), 1.49–1.40 (m, 4H), 1.36–1.24 (m, 9H), 1.21 (dd, J = 17.8, 7.8 Hz, 2H), 1.05 (dd, J = 12.6, 1.9 Hz, 1H), 0.99 (d, J = 8.0 Hz, 6H), 0.91–0.85 (m, 6H), 0.81 (s, 3H), 0.68 (s, 3H). Example 96

[0840] Preparation of Compound 96 (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(2R)-4-[(2-hydroxyethyl)oxy]butan-2-yl]-3a, 6, 6, 9a, 11a-pentamethyl-2, 3, 3a, 4, 5, 5a, 6, 7, 8, 9, 9a, 10, 11, 11a-tetradecahydro-1H-cyclopenta[1, 2-a]phenanthren-7-ol

[0841]

[0842]

[0843] In the first step, (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-formylbutyl-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate III (300.0 mg, 0.724 mmol) was dissolved in dichloromethane (10 mL) and isopropanol (10 mL). Sodium borohydride (30.0 mg 0.80 mmol) was added at room temperature and stirred at room temperature for 1 h. The mixture was detected by spot plate (PE:EtOAc=10:1). When the raw material was completely reacted, saturated aqueous ammonium chloride solution was added at low temperature, and the mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, spin-dried, and passed through a column. The mixture was stirred for 2 h (PE:EtOAc=50:1 to 5:1) to give (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-hydroxybutan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (96-1) (200 mg, 0.405 mmol, 59.73%) as a white solid. 1 HNMR.(399MHz,CDCl3)δ4.47(1H,dd,J11.5,4.5),3.66(2H,ddt,J 17.7,10.4,5.5),1.96(9H,m),1.68(6H,m),1.52(6H,m),1.25(4H,m),0.98(3H,s),0.91(3H,t,J 5.9),0.85(9H,s),0.68(3H,d,J 6.4).

[0844] In the second step, the compound (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-hydroxybutan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (96-1) (50.0 mg, 0.023 mmol) was dissolved in dichloromethane (2 mL), and tetrabutylammonium bromide (43.5) was added at room temperature. 2mg, 0.135mmol), 2-methylpropane-2-yl bromoacetate (262.42mg, 1.345mmol), 40% sodium hydroxide aqueous solution (2mL, 0.022mmol) was added at room temperature, and the reaction was allowed to proceed overnight at room temperature. TLC (PE:EA=10:1) showed that there was no residual starting material on the plate. The liquid was separated, and dichloromethane was added and extracted twice. The organic phase was washed with water, dried over anhydrous sodium sulfate, and dried by column PE:EA (100%-20%) to obtain an off-white solid [(3R)-3-[(1R,3a R,5aR,7S,9aS,11aR)-7-acetyloxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]butyl]oxy}-2-methylprop-2-yl acetate (96-2) (40 mg, 0.068 mmol, 78.12%) 1 HNMR.(399MHz, CDCl3) δ4.48(1H,dd,J=11.5,4.6),3.92(2H,d,J=1.5),3.52(2H,t,J=7.2),2.02(8H,d,J=9.6),1.67(7H,m),1. 47(16H,d,J=9.7),1.32(4H,m),1.15(2H,dd,J=17.7,9.8),0.98(4H,s),0.91(1H,d,J=6.0),0.86(10H,d,J=2.2),0.67(3H,s).

[0845] Step 3: Dissolve lithium aluminum tetrahydride (32.0 mg, 0.184 mmol) in tetrahydrofuran (1.0 mL) under nitrogen and cool to zero degrees Celsius. Dissolve [(3R)-3-[(1R,3aR,5aR,7S,9aS,11aR)-7-acetyloxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]butyl]oxy}acetate (40 mg, 0.073 mmol) in tetrahydrofuran (1.0 mL) and add dropwise to the above system. After the addition is complete, warm the temperature to room temperature and react for 3 hours. After the reaction of the starting materials, the temperature was lowered to 0°C and a few drops of ammonium chloride were added to quench the reaction. The mixture was filtered through celite, dried by rotary evaporation, and passed through a column with PE:EA (100%-20%) to obtain the compound (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-[(2-hydroxyethyl)oxy]butan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-7-ol (96) (15.27 mg, 0.026 mmol, 35.89%). 1 HNMR. (400MHz, CDCl3) δ3.71 (2H, t, J = 4.6), 3.51 (4H, m), 3.22 (1H, dd, J = 1 1.5,4.5),1.95(5H,m),1.75(4H,m),1.51(5H,m),1.23(6H,m),1.05(1H,d,J=2.0 ),0.98(6H,d,J=7.5),0.91(3H,d,J=5.7),0.87(3H,s),0.80(3H,s),0.68(3H,s). 13 CNMR(101MHz, CDCl3)δ134.39,134.29,78.95,77.31,76.99,76.67,71.69,69.54,61.86,50.68,50.36,49.80,44.50,38.8 6,36.99,35.88,35.55,33.85,30.97,30.78,28.26,27.94,27.81,26.46,24.22,20.96,19.12,18.93,18.22,15.69,15.40. LC-MS:[M-17] + =415.55

[0846] Example 97

[0847] Preparation of Compound 97 (1R, 3aR, 5aR, 7S, 9aS, 11aR)-1-[(2R)-5-[(2-hydroxyethyl)oxy]pentan-2-yl]-3a, 6, 6, 9a, 11a-pentamethyl-2, 3, 3a, 4, 5, 5a, 6, 7, 8, 9, 9a, 10, 11, 11a-tetradecahydro-1H-cyclopenta[1, 2-a]phenanthren-7-ol

[0848]

[0849] In the first step, (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-formylbutyl-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate (II) (5 g, 11.29 mmol) was dissolved in dichloromethane (100 mL) and isopropanol (100 mL), and sodium borohydride (27 mg) was added at room temperature. The reaction mixture was added with 4% paraformaldehyde (0.76 mmol), stirred at room temperature for 1 h, and detected by spot plate detection (PE:EtOAc=10:1). After the reaction of the starting material was complete, saturated aqueous ammonium chloride solution was added at low temperature, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, spin-dried, and passed through a column (PE:EtOAc=50:1 to 5:1) to obtain (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-hydroxypentan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate (97-1) (3.6 g, 7.286 mmol, 64.50%) as a white solid. 1 H NMR(400MHz,Chloroform-d)δ4.49(dd,J=11.6,4.5Hz,1H),3.73–3.51(m,2H),2.02(s,7H),1.68(dddd,J=19.7,15.9,7.8,2.7Hz,7H) ,1.52–1.35(m,6H),1.30(td,J=13.0,4.0Hz,2H),1.25–1.11(m,2H),1.09–1.02(m,1H),0.99(s,3H),0.93–0.82(m,12H),0.68(s,3H).

[0850] In the second step, the compound (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-hydroxypentan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate (97-1) (3.6 g, 8.095 mmol) was dissolved in dichloromethane (100 mL), and triphenylphosphine (3.18 g, 12.143 mmol) and imidazole (0.83 g, 12.143 mmol) were added. Under nitrogen protection, the temperature was lowered to zero degrees and iodine (7.18 g, 16.19 mmol) was added. The mixture was stirred at room temperature for 3 hours. TLC (PE:EtOAc = 10:1) was performed. The raw materials reacted completely, the temperature was lowered to zero degrees, quenched by adding a saturated sodium bisulfite solution, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, dried with acetonitrile, slurried, filtered, and dried to give a white solid compound (1R, 3aR, 5aR, 7S, 9aS, 11aR) -1- [(2R) -5-iodopentan-2-yl] -3a, 6, 6, 9a, 11a-pentamethyl-2, 3, 3a, 4, 5, 5a, 6, 7, 8, 9, 9a, 10, 11, 11a-tetrahydro-1H-cyclopenta [2, 1-i] phenanthren-7-yl acetate (97-2) (3.8 g, 6.167 mmol, 76.17%). 1 H NMR (399MHz, CDCl3) δ4.48 (dd, J=11.6, 4.5Hz, 1H), 3.25–3.0 5(m,2H),2.03(s,7H),1.90(s,2H),1.76–1.65(m,5H),1.57(d,J=9.9Hz,4H),1.52–1.39(m,4H) ,1.31(dd,J=12.8,3.8Hz,2H),1.20–1.08(m,3H),0.98(s,3H),0.91–0.83(m,12H),0.67(s,3H)

[0851] Step 3: Dissolve (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-iodopentan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (97-2) (50.0 mg, 0.046 mmol) in tetrahydrofuran (2 mL), and add sodium hydroxide (36.1 mg, 0.90 mmol). Heat to reflux and stir for 3 h. TLC (PE:EtOAc=10:1) was performed. The starting material was reacted completely, cooled to room temperature, poured into ice water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, spin-dried, passed through a column, and PE:EtOAc (100%-20%) to obtain a white solid compound (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-[(2-hydroxyethyl)oxy]pentan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-7-ol (97) (9.01 mg, 0.018 mmol, 20.16%). 1H(399MHz, CDCl3)δ3.75–3.69(2H,m),3.55–3.49(2H,m),3.43(2H,t,J=6.2H z),3.21(1H,dd,J=11.4,4.5Hz),2.01(4H,s),1.93–1.87(1H,m),1.67(9H,dd ,J=21.1,13.2Hz),1.49–1.39(4H,m),1.32–1.14(4H,m),1.05(1H,s),0.97(6 H,d,J=7.3Hz),0.89(3H,d,J=6.2Hz),0.85(3H,s),0.79(3H,s),0.67(3H,s). 13 C NMR (100MHz, CDCl3) δ134.33,78.95,77.28,76.97,76.65,71.89,71.62,61.85,50.37,50.30,49.78,44.45,38.85,36.99,36.20 ,35.55,32.36,30.95,30.79,28.15,27.92,27.81,26.46,26.37,24.21,20.96,19.10,18.63,18.22,15.72,15.38.LC-MS:[M-17] + =429.55

[0852] Example 98

[0853] Preparation of Compound 98 (1R, 3aR, 5aR, 7S, 9aS, 11aR)-3a, 6, 6, 9a, 11a-pentamethyl-1-[(2R)-7, 7, 7-trifluoro-6-hydroxyhept-2-yl]-2, 3, 3a, 4, 5, 5a, 6, 7, 8, 9, 9a, 10, 11, 11a-tetrahydro-1H-cyclopenta[1, 2-a]phenanthrene-7-ol

[0854]

[0855] Step 1: (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R,4E)-5-methoxypent-4-en-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (37-1) (700 mg, 1.49 mmol, 1.0 eq) was dissolved in a mixed solvent of dilute hydrochloric acid (5 mol / L, 20 mL) and THF (20 mL). The reaction solution was heated to 50°C and stirred for 2 hours. The reaction was monitored by TLC (PE:EtOAc=10:1, phosphomolybdic acid hotplate). After the reaction was complete, the reaction solution was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sulfuric acid, and purified by silica gel column chromatography (PE:EtOAc = 95:5 to 85:15) to give (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-formylpentan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (37-2) (500 mg, 1.09 mmol, purity 80%, yield 58.5%) as a white solid. 1 H NMR (400MHz, CDCl3) δ9.77(t,J=1.7Hz,1H),4.50(dd,J=11.6,4.5Hz,1H),2.40(td,J=7.9,1.7Hz,2H),2.12–1.97(m,7H),1.96– 1.85(m,1H),1.78–1.63(m,7H),1.59–1.24(m,9H),1.21–1.06(m,3H),1.00(s,3H),0.90(dd,J=17.5,5.5Hz,12H),0.69(s,3H). 13C NMR (101MHz, CDCl3) δ202.99,171.02,134.43,134.30,129.64,115.29,80.93,77.33,77.02,76.70,50.51,50.24,49.82,44.50,44.35,37. 81,36.90,36.31,35.74,35.27,30.96,30.79,28.19,27.92,26.38,2 4.24,24.18,21.33,20.99,19.19,18.96,18.57,18.12,16.53,15.75.

[0856] Step 2: (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-formylpentan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (37-2) (500 mg, 1.10 mmol, 1.0 eq) and cesium fluoride (83 mg, 0.55 mmol, 0.5 eq) were dissolved in anhydrous tetrahydrofuran (10 mL), and (trifluoromethyl)trimethylsilane (1.56 g, 10.95 mmol.5.0 eq) was added. The mixture was stirred at room temperature for 1 h. TBAF (5.0 mL, 5.0 mmol) was added to the reaction solution and stirred for 1 h. The reaction was monitored by TLC (PE:EtOAc=5:1, phosphomolybdic acid hotplate). After the reaction was complete, the reaction solution was diluted with ethyl acetate, washed with saturated NaHCO3 solution, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EtOAc=80:20) to give (1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-pentamethyl-1-[(2R)-7,7,7-trifluoro-6-hydroxyhept-2-yl]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (98-2) (190 mg, 0.33 mmol, 29.65%) as a white solid. 1H NMR(400MHz, CDCl3)δ4.50(dd,J=11.6,4.5Hz,1H),3.97–3.87(m,1H),2.08–1.86(m,8H),1.77–1.34(m,16H),1.33–1.25(m, 2H),1.22–1.12(m,2H),1.09(d,J=12.8Hz,1H),1.00(s,3H),0.98–0.82(m,12H),0.69(s,3H).19F(376MHz,CDCl3)δ-80.02.

[0857] Step 3: (1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-pentamethyl-1-[(2R)-7,7,7-trifluoro-6-hydroxyhept-2-yl]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetrahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (98-2) (190 mg, 0.36 mmol) was dissolved in a mixed solution of ethanol (1 mL) and sodium hydroxide solution (1 mL, 4 mol / L), the reaction solution was heated to 50°C and stirred for 2 hours, and TLC (PE:EtOAc=5:1 phosphomolybdic acid baking plate) was performed. After the reaction was completed, the reaction solution was concentrated to remove ethanol, ethyl acetate was added, and the mixture was washed with saturated ammonium chloride and saturated brine, respectively. The organic phase was dried over anhydrous sodium sulfate and purified by silica gel column chromatography (PE:EtOAc=90:10 to The reaction mixture was stirred at 4 ℃ for 1 hr (70:30) to give (1R,3aR,5aR,7S,9aS,11aR)-3a,6,6,9a,11a-pentamethyl-1-[(2R)-7,7,7-trifluoro-6-hydroxyhept-2-yl]-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol (98) (100 mg, 0.19 mmol, 53.8%) as a white solid. 1 HNMR(400MHz, CDCl3)δ3.96-3.86(m,1H),3.24(dd,J=11.5,4.5Hz,1H),2.11–1.98(m,4H),1.97-1.85(m,1H),1.76–1.43(m,15H) ,1.35–1.15(m,5H),1.08-1.03(m,1H),0.99(d,J=7.4Hz,6H),0.91(d,J=6.2Hz,3H),0.88(s,3H),0.83–0.78(m,3H),0.69(s,3H). 13C NMR (101MHz, CDCl3) δ134.39,134.30,78.96,77.29,76.97,76.65,50.36,50.31,49.78,44.45,38.85,36.98,36.33,36.23,35 .86,35.65,35.54,30.95,30.78,28.19,27.92,27.80,26.46,24.22,21.79,21.62,20.96,19.11,18.59,18.21,15.71,15.38.

[0858] Example 99

[0859] Preparation of Compound 99 (1R, 3aR, 5aR, 7S, 9aS, 11aR) -1-[(2R)-6-cyclopropyl-6-hydroxyhexan-2-yl]-3a, 6, 6, 9a, 11a-pentamethyl-2, 3, 3a, 4, 5, 5a, 6, 7, 8, 9, 9a, 10, 11, 11a-tetrahydro-1H-cyclopenta[1, 2-a]phenanthren-7-ol

[0860]

[0861] Step 1: (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-formylpentan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (37-2) (100 mg, 0.22 mmol, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (5 mL). Cyclopropylmagnesium chloride (2.2 mL, 2.19 mmol, 10 eq) was added under nitrogen protection at 0°. TLC (PE:EtOAc=5:1, phosphorus) showed the following results: The reaction was monitored by HPLC (molybdate hotplate). After completion, the reaction was quenched with ammonium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EtOAc=90:10) to give (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-cyclopropyl-6-hydroxyhexan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (99-1) (80 mg, 0.16 mmol, yield 73.0%) as a white solid. 1H NMR (400MHz, CDCl3) δ4.50 (dd, J=11.5, 4.5Hz, 1H), 3.82 (ddt, J=28.3, 21.7, 7.3Hz, 1H), 2.86(d,J=5.2Hz,1H),2.08–1.97(m,7H),1.96–1.86(m,2H),1.77–1.62(m,7H),1.61–1. 46(m,8H),1.40–1.24(m,5H),1.21–1.12(m,2H),1.08–1.02(m,1H),1.00(s,3H),0.90(d ,J=6.4Hz,3H),0.88(d,J=4.2Hz,9H),0.69(s,3H),0.58–0.45(m,2H),0.31–0.18(m,2H).

[0862] Step 2: (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-cyclopropyl-6-hydroxyhexan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate 99-1 (80 mg, 0.16 mmol) was dissolved in ethanol (2 mL). Sodium hydroxide solution (2 mL, 4 mol / L) was added. The reaction mixture was heated to 50°C and stirred for 4 hours. The reaction was monitored by TLC (PE:EtOAc = 5:1, phosphomolybdic acid hotplate). After the reaction was complete, the reaction solution was cooled to room temperature and adjusted to pH 5 with 1N hydrochloric acid. The product was extracted with ethyl acetate three times. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EtOAc=90:10 to 50:50) to give (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-cyclopropyl-6-hydroxyhexan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-7-ol (99) (50 mg, 0.11 mmol, purity 96%, yield 68.8%) as a white solid. 1H NMR (400MHz, CDCl3) δ3.17 (dd, J=11.6, 4.5Hz, 1H), 2.79 (dd, J=12.9, 7.6Hz, 1H ),1.97(d,J=8.0Hz,4H),1.89–1.79(m,1H),1.73–1.45(m,10H),1.41–1.05(m, 9H),0.98(dd,J=12.6,1.7Hz,2H),0.92(d,J=7.8Hz,6H),0.83(d,J=6.3Hz,3H) ,0.81(s,3H),0.74(s,3H),0.62(s,3H),0.51-0.38(m,2H),0.23–0.11(m,2H). 13 C NMR (101MHz, CDCl3) δ134.42,78.99,50.50,50.46,50.42,49.82,44.49,38.82,37.80,37.57,37.03,36.50,36.40,36.25,35.60 ,30.99,30.85,28.25,28.18,27.96,27.86,26.51,24.27,22.58,22.47,21.01,19.14,18.69,18.26,18.08,18.05,15.75,15.41

[0863] Example 100

[0864] Preparation of Compound 100 (1R,3aR,5aR,7S,9aS,11aR)-1-[(2S)-1-[(2-hydroxyethyl)oxy]propan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthrene-7-ol

[0865]

[0866]

[0867] In the first step, (1R,3aR,5aR,7S,9aS,11aR)-1-[(1S)-1-formylethyl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[2,1-i]phenanthrene-7-yl acetate (86-2) (800 mg, 1.81 mmol, 1.0 eq.) was dissolved in dichloromethane (20 mL) and isopropanol (20 mL), and sodium borohydride (30.0 mg) was added at room temperature. The reaction mixture was stirred at room temperature for 1 h, and the reaction mixture was detected by spot plate detection (PE:EtOAc=10:1). After the reaction was completed, a saturated aqueous ammonium chloride solution was added at low temperature, and the mixture was extracted three times with dichloromethane. The mixture was dried over anhydrous sodium sulfate, spin-dried, and passed through a column (PE:EtOAc=50:1 to 5:1) to obtain (1R,3aR,5aR,7S,9aS,11aR)-1-[(2S)-1-hydroxypropan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (100-1) (600 mg, 1.08 mmol, 74.72%) as a white solid. 1 H NMR(399MHz, CDCl3) δ4.48(dd,J=11.7,4.6Hz,1H),3.64(d,J=10.6Hz,1H),3.33(d,J=10.2Hz,1H),2.03(s ,7H),1.88(m,1H),1.67(m,8H),1.31(d,J=13.4Hz,3H),1.18(m,4H),1.00(m,6H),0.86(s,9H),0.70(s,3H)

[0868] Step 2: (1R,3aR,5aR,7S,9aS,11aR)-1-[(2S)-1-hydroxypropan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,4,5,5a,6,7,8,9,9a,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl acetate (100-1) (100 mg, 0.24 mmol, 1.0 eq.) was dissolved in dichloromethane (2.0 mL). Tetrabutylammonium bromide (80 mg,...

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof: in, R 21 -L 1 -C(O)R A 、-L 1 -R B or -L 2 -R C ; Each L 1 and L 2 are independently -CH2-, -(CH2)2-, -(CH2)3- or -(CH2)4-, wherein one of the -CH2- moieties of -CH2-, -(CH2)2-, -(CH2)3- and -(CH2)4- is optionally replaced by -X-; Each -X- is independently Each R A are independently -NR 21a R 21b ; R B is -N(R 21a )-C(O)R 21b or -N(R 21a )-S(O)2R 21b ; Each R C are independently -C(R 21c )(R 21d )-OH, Each R 21a are independently H or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently unsubstituted or substituted with m R a Replace; each R 21b Independently C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 6-10 Aryl and 5-10 membered heteroaryl are independently unsubstituted or substituted with q R b Substitute; or, in -NR 21a R 21b In, R 21a and R 21b and the nitrogen atoms connecting them together form a 3-10 membered heterocycloalkyl group, wherein the 3-10 membered heterocycloalkyl group is unsubstituted or substituted by p R c replace; Each of m, p and q is independently 1, 2, 3, 4 or 5; Each R a are independently OH, C 1-4 Alkyl or C 1-4 alkoxy; Each R b independently F, Cl, OH, COOH, CN, NO2, C 1-4 Alkyl, fluorinated C 1-4 Alkyl, C 1-4 Alkoxy or Each R c are independently F, Cl, C 1-4 Alkyl or fluorinated C 1-4 alkyl; R 21c and R 21d The definition is as follows: a)R 21c H, R 21d is phenyl, 5-6 membered heteroaryl or -L 4 -R 21e , wherein the phenyl group is optionally replaced by 1 or 2 R d Replace, each R d are independently F, OH, CN or C 1-4 alkoxy; b)R 21c and R 21d and the carbon atoms connecting them together form a 3-6 membered heterocycloalkyl group; L 4 is methylene or ethylene; R 21e is a 5-6 membered heteroaryl group; Each r is independently 0; Each R f independently F, Cl, OH, CN, NO2, C 1-4 Alkyl, fluorinated C 1-4 Alkyl, fluorinated C 1-4 Alkoxy or C 1-4 alkoxy; The number of heteroatoms in the heterocycloalkyl and heteroaryl groups is independently 1, 2 or 3, and each heteroatom is independently N, O or S; The carbon atoms marked with * in Formula I are in S configuration, R configuration or a mixture of the two.

2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein: in, R 21 -L 1 -C(O)R A 、-L 1 -R B or -L 2 -R C ; Each L 1 and L 2 are independently -CH2-, -(CH2)2-, -(CH2)3- or -(CH2)4-, wherein one of the -CH2- moieties of -CH2-, -(CH2)2-, -(CH2)3- and -(CH2)4- is optionally replaced by -X-; Each -X- is independently Each R A are independently -NR 21a R 21b ; R B -N(R 21a )-C(O)R 21b ; Each R C are independently -C(R 21c )(R 21d )-OH, Each R 21a are independently H or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently unsubstituted or substituted with m R a Replace; each R 21b Independently C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 6-10 Aryl and 5-10 membered heteroaryl are independently unsubstituted or substituted with q R b Substitute; or, in -NR 21a R 21b In, R 21a and R 21b and the nitrogen atoms connecting them together form a 3-10 membered heterocycloalkyl group, wherein the 3-10 membered heterocycloalkyl group is unsubstituted or substituted by p R c replace; Each of m, p and q is independently 1, 2, 3, 4 or 5; Each R a are independently OH, C 1-4 Alkyl or C 1-4 alkoxy; Each R b independently F, Cl, OH, COOH, CN, NO2, C 1-4 Alkyl, fluorinated C 1-4 Alkyl, C 1-4 Alkoxy or Each R c are independently F, Cl, C 1-4 Alkyl or fluorinated C 1-4 alkyl; R 21c and R 21d The definition is as follows: a)R 21c H, R 21d is phenyl, 5-6 membered heteroaryl or -L 4 -R 21e , wherein the phenyl group is optionally replaced by 1 or 2 R d Replace, each R d are independently F, OH, CN or C 1-4 alkoxy; b)R 21c and R 21d and the carbon atoms connecting them together form a 3-6 membered heterocycloalkyl group; L 4 is methylene or ethylene; R 21e is a 5-6 membered heteroaryl group; Each r is independently 0; Each R f independently F, Cl, OH, CN, NO2, C 1-4 Alkyl, fluorinated C 1-4 Alkyl or C 1-4 alkoxy; The number of heteroatoms in the heterocycloalkyl and heteroaryl groups is independently 1, 2 or 3, and each heteroatom is independently N, O or S; The carbon atoms marked with * in Formula I are in S configuration, R configuration or a mixture of the two.

3. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein: in, R 21 -L 1 -C(O)R A 、-L 1 -R B or -L 2 -R C ; Each L 1 and L 2 are independently -CH2-, -(CH2)2-, -(CH2)3- or -(CH2)4-, wherein one of the -CH2- moieties of -CH2-, -(CH2)2-, -(CH2)3- and -(CH2)4- is optionally replaced by -X-; Each -X- is independently Each R A are independently -NR 21a R 21b ; R B is -N(R 21a )-C(O)R 21b or -N(R 21a )-S(O)2R 21b ; Each R C are independently -C(R 21c )(R 21d )-OH, Each R 21a are independently H or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently unsubstituted or substituted with m R a Replace; each R 21b Independently C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 6-10 Aryl and 5-10 membered heteroaryl are independently unsubstituted or substituted with q R b Substitute; or, in -NR 21a R 21b In, R 21a and R 21b and the nitrogen atoms connecting them together form a 3-10 membered heterocycloalkyl group, wherein the 3-10 membered heterocycloalkyl group is unsubstituted or substituted by p R c replace; Each of m, p and q is independently 1, 2, 3, 4 or 5; Each R a are independently OH, C 1-4 Alkyl or C 1-4 alkoxy; Each R b independently F, Cl, OH, COOH, CN, NO2, C 1-4 Alkyl, fluorinated C 1-4 Alkyl, C 1-4 Alkoxy or Each R c are independently F, Cl, C 1-4 Alkyl or fluorinated C 1-4 alkyl; R 21c and R 21d The definition is as follows: a)R 21c H, R 21d is phenyl, 5-6 membered heteroaryl or -L 4 -R 21e , wherein the phenyl group is optionally replaced by 1 or 2 R d Replace, each R d are independently F, OH, CN or C 1-4 alkoxy; b)R 21c and R 21d and the carbon atoms connecting them together form a 3-6 membered heterocycloalkyl group; L 4 is methylene or ethylene; R 21e is a 5-6 membered heteroaryl group; Each r is independently 0; Each R f independently F, Cl, OH, CN, NO2, C 1-4 Alkyl, fluorinated C 1-4 Alkyl or C 1-4 alkoxy; The number of heteroatoms in the heterocycloalkyl and heteroaryl groups is independently 1, 2 or 3, and each heteroatom is independently N, O or S; The carbon atoms marked with * in Formula I are in S configuration, R configuration or a mixture of the two.

4. The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein: It meets one or more of the following conditions: (1)L 1 is -CH2-, -(CH2)2- or -(CH2)3-; (2) each of m, p and q is independently 1 or 2; (3)L 2 It is -(CH2)3-.

5. The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein: It meets one or more of the following conditions: (1)L 1 is defined as follows in either group: a)L 1 is -(CH2)2-; b)L 1 is -(CH2)3-; and c)L 1 is -(CH2)4-; (2) Each R 21a are independently H or C 1-6 Alkyl, wherein the C 1-6 The alkyl groups are independently unsubstituted or substituted with m R a Replace; each R 21b Independently C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 6-10 Aryl and 5-10 membered heteroaryl are independently unsubstituted or substituted with q R b Substitute; or, in -NR 21a R 21b In, R 21a and R 21b and the nitrogen atoms that connect them together to form wherein is unsubstituted or replaced by p R c replace; (3) m is 1, 2 or 3; (4) Each R a are independently OH or methoxy; (5)q is 1, 2, or 3; (6) Each R b are independently F, Cl, OH, COOH, CN, NO2, methyl, trifluoromethyl, methoxy or (7) p is 1, 2 or 3; (8) Each R c Each independently is F, C 1-4 Alkyl or fluorinated C 1-4 alkyl; (9)L 2 is defined as follows in either group: a)L 2 is -CH2-; b)L 2 is -(CH2)2-; c)L 2 is -(CH2)3-; and d)L 2 is -(CH2)4-; (10)R C is defined as follows in either group: a) Each R C are independently -C(R 21c )(R 21d )-OH; b)R C for c)R C for and d)R C for (11) When R C -C(R 21c )(R 21d )-OH, R 21c and R 21d is defined as follows in either group: a)R 21c H, R 21d is phenyl, fluorophenyl, 5-6 membered heteroaryl or -L 4 -R 21e ; b)R 21c and R 21d and the carbon atoms connecting them together form a 3-6 membered heterocycloalkyl group; and (12)R 21e for 6. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 5, wherein: In-NR 21a R 21b In, R 21a and R 21b and the nitrogen atoms that connect them together to form 7. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 5, wherein: Each R c Each is independently F, methyl or trifluoromethyl.

8. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 5, wherein: When R C -C(R 21c )(R 21d )-OH, R C -C(R 21c )(R 21d )-OH is Or, R 21c and R 21d and the carbon atoms that connect them together to form 9. The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein: It meets one or more of the following conditions: (1) Each R 21a Independently H, C 1-4 Alkyl, -C 1-4 Alkylene -OH or -C 1-4 Alkylene-OC 1-4 alkyl; (2) Each R 21b R is independently phenyl, pyridyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrimidinyl or benzopyrazolyl, wherein the phenyl, pyridyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrimidinyl and benzopyrazolyl are independently unsubstituted or replaced by q R b Replacement; and (3)R C -C(R 21c )(R 21d )-OH is 10. The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein: It meets one or more of the following conditions: (1) Each R 21a are independently H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, (2) Each R 21b are independently phenyl, wherein the phenyl group, are independently unsubstituted or replaced by q R b replace; (3)R C -C(R 21c )(R 21d )-OH is 11. The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein: It meets one or more of the following conditions: (1) Each R 21b are independently phenyl, (2)R C -C(R 21c )(R 21d )-OH is 12. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 9, wherein: Each R 21b Independently 13. The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein: It meets one or more of the following conditions: (1) Each R A Independently (2)R B for 14. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 13, wherein: It meets one or more of the following conditions: (1) Each R A Independently (2)R B for 15. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 13, wherein: Each R A Independently 16. The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein: It meets one or more of the following conditions: (1)-L 1 -C(O)R A for (2)-L 1 -R B for (3)-L 2 -R C for 17. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 16, wherein: -L 2 -R C for 18. The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein: The compound represented by formula I is a compound represented by formula I-1 or I-2 below: Among them, R 21 The definition as described in any one of claims 1 to 17.

19. Any of the following compounds or pharmaceutically acceptable salts thereof:

20. A pharmaceutical composition comprising the compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, and at least one pharmaceutical excipient.

21. Use of the compound of formula I according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 20, in the preparation of a medicament for inhibiting the SREBP pathway.

Images