Steroid compounds, their preparation and use

Abstract

The present invention discloses a steroid compound, its preparation method and use. The steroid compound may have a structure represented by formula XXI or the like. The compound of the present invention has an inhibitory activity against the SREBP pathway and can be used to prevent and / or treat diseases such as obesity, hyperlipidemia, fatty liver, diabetes, atherosclerosis, cardiovascular disease, cerebrovascular disease, liver cancer, and skin damage. [Formula 1] JPEG2025504580000419.jpg45169

Description

Detailed Description of the Invention

[0001] This application claims priority to Chinese Patent Application No. 2022101071901, filed on January 28, 2021, and Chinese Patent Application No. 2022108692823, filed on July 22, 2022. This application cites the above Chinese patent applications in their entirety.

[0002] [Technical field] The present invention relates to steroidal compounds, their preparation and use. [Background technology] Due to lifestyle changes such as increased intake 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, in particular, is a significant cause of chronic liver disease in affluent regions such as Europe, the United States, and China. The prevalence of simple hepatic lipid accumulation in the general adult population is 10%-30%, of which 10%-20% is steatohepatitis, and the incidence of cirrhosis and liver cancer within 10 years reaches 25%. However, the pathophysiological mechanisms of fatty liver disease have not yet been fully elucidated, and effective, specific therapeutic agents are still lacking in clinical practice. The accumulation of lipids, such as cholesterol and triglycerides, in the blood and liver is known to be the primary cause of hyperlipidemia, which is an important pathogenic factor in atherosclerosis, stroke, and fatty liver disease. Therefore, the development of novel drugs targeting lipid metabolism regulatory pathways aimed at reducing lipids is becoming an increasingly important direction in drug research and development for metabolic diseases.

[0003] The lipid synthesis pathway in mammalian cells is known to be an important factor in regulating the lipid metabolic balance. The key factor regulating cholesterol and fatty acid synthesis is the sterol-regulatory element binding protein (SREBP), a type of transcription factor protein. The precursor of this type of protein is first synthesized in the endoplasmic reticulum (ER), and the precursor is then activated by the SREBP cleavage-activating protein (SCAP). SREBP is transported to the Golgi apparatus via the SCAP complex (SCAP-SREBP) and then enzymatically cleaved by two proteases (Site-1 protease (S1P) and Site-2 protease (S2P)), releasing its N-terminal active domain. It then enters the nucleus and functions as a transcription factor, binding to the SREBP response element (SRE) in the promoter region of target genes to initiate downstream gene expression. The splicing and maturation of SREBP proteins are tightly regulated by the levels of intracellular sterols (e.g., cholesterol and 25-hydroxycholesterol). When cells accumulate sufficient cholesterol in the endoplasmic reticulum, cholesterol binds to SCAP, changing its conformation and triggering the SCAP-SREBP complex-binding protein Insig (insulin-induced gene), thereby inhibiting SREBP transport to the Golgi apparatus and subsequent SREBP activation. Conversely, increased active SREBP in the nucleus promotes cellular lipid synthesis. In addition to cholesterol, 25-hydroxycholesterol (25-HC) is also a potent endogenous inhibitor of the SREBP pathway. Unlike cholesterol-bound SCAP, 25-HC binds directly to Insig and induces the association of SCAP with Insig.

[0004] Previous studies have shown that inhibition of the SREBP pathway is an effective strategy and method for the prevention and / or treatment of metabolic diseases such as obesity, hyperlipidemia, fatty liver, atherosclerosis, and diabetes, as well as diseases such as cardiovascular and cerebrovascular diseases, skin damage, and liver cancer.

[0005] The pathogenesis of hyperlipidemia is mainly due to increased lipid synthesis or abnormal lipid transport caused by factors such as diet or genetic mutations, resulting in excessive accumulation of lipids such as cholesterol and fatty acids in the blood. Currently, statins and fibrates are the main lipid-regulating drugs used in clinical practice. The mechanism of action of statins is achieved by inhibiting the intracellular cholesterol synthesis pathway while simultaneously promoting reverse cholesterol transport in the blood. Targeting key factors in the cellular lipid synthesis pathway has been shown to be an important means of effectively lowering lipid levels.

[0006] To date, there are no approved therapeutic drugs for fatty liver disease, making it extremely important to identify therapeutic targets and develop new, effective treatments. Various risk factors are known to be involved in the pathogenesis of fatty liver disease. For example, the accumulation of triglycerides in the form of lipid droplets leads to steatosis, and abnormal increases in intracellular cholesterol and fatty acids can cause endoplasmic reticulum stress and mitochondrial dysfunction, which can lead to cell death, inflammation, and fibrosis. Among these, the accumulation of free cholesterol has been reported as a major factor in the transition from simple steatosis to progressive steatohepatitis. Second, we established a mouse model of fatty liver disease and found that long-term feeding of a simple cholesterol-free high-fat diet only induces steatosis, whereas adding 1–2% cholesterol to the diet is a necessary condition for achieving inflammation and fibrosis. Therefore, cholesterol reduction may be a new therapeutic strategy for fatty liver disease. Studies have shown that abnormal activation of SREBPs is observed in patients with fatty liver and in mouse models of fatty liver. Deletion or knockout of liver-specific Scap in mice eliminates activation of all SREBPs, thereby preventing the development of fatty liver and hyperlipidemia. Furthermore, recent studies have shown that abnormal activation of SREBPs induced by endoplasmic reticulum stress promotes lipogenesis and fatty liver. Therefore, these evidences suggest that lowering hepatic triglyceride and cholesterol levels by inhibiting the SREBP pathway may be an effective strategy for preventing and / or treating metabolic disorders, including fatty liver.

[0007] [Summary of the Invention] The technical problem to be solved by the present invention is to provide novel compounds that have inhibitory activity against the SREBP pathway.

[0008] The present invention further provides a compound of formula XXI or a pharmaceutically acceptable salt thereof.

[0009] [ka]

[0010] However, R 3d is H or R 3c and R 3c is —S(O)OH, —C(O)—CHCHCOOH, —C(O)—CHCOOH, —C(O)—CHOH, —C(O)—COOH, —CHCHOH or —CHCOOH, R 4a is H, F, CH3, CF3 or OH, R 4b is H, F, NH2, OH or CF3, R 4a and R 4b together with the carbon atoms connected to them

[0011] [ka] Forming

[0012] R 7a is H, F, NH2, CH3 or CF3, R 7b is F or OH, Or, R 7a and R 7b together with the carbon atoms connected to them

[0013] [ka] Forming

[0014] R 8a is H or F, R 14a is H, R 22 teeth,

[0015] [ka] or R 21 and

[0016] R 21 -L 1 -C(O)R A , -L 1 -S(O)2R A , -L 1 -R B ,

[0017] [ka] , -L 2 -R C or -L 3 -R D and

[0018] Each L 1 and L 2 is independently a single bond, —CH—, —(CH)—, —(CH)—, —(CH)—, —(CH)—, —(CH)—, or —(CH)—, wherein one CH— moiety in said —CH—, —(CH)—, —(CH)—, —(CH)—, and —(CH)— is optionally replaced by —X—; L 3 is —(CH)—, —(CH)—, —(CH)—, —(CH)—, or —(CH)—, wherein one CH— moiety in —(CH)—, —(CH)—, —(CH)—, —(CH)—, or —(CH)— is replaced by —Y—; Each X is independently -CHR 5a -, -CR 5a R 5b - or -Y-, Each R 5a and R 5b are independently F, C 1-4 Alkyl or Fluoro C 1-4 is alkyl, Each Y is independently —O—, —NH—, —N(C 1-4 alkyl)-,

[0019] [ka] , -CH=CH-,

[0020] [ka] or -CHR g - and

[0021] R g -C 1-4 alkylene-OH, Each R A independently -NR 21a R 21b and R B is -N(R 21a )-C(O)R 21b or -N(R 21a )-S(O)2R 21b and R D -OH, -CHOH, R C , —CH(CH3)—OH or —C(CH3)2—OH; Each R C are independently -C(R 21c )(R 21d )-OH, CN, -C(O)R E , NH2, C 1-4 Alkoxy,

[0022] [ka] , 3- to 6-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is unsubstituted or has p R c is replaced by

[0023] R E is C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or 3-6 and wherein said C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl and 3- to 6-membered heterocycloalkyl are independently unsubstituted or substituted with m Ra is replaced by Each R 21a are independently H, C 1-6 Alkyl, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl and 3- to 6-membered heterocycloalkyl are independently unsubstituted or substituted with m R a is replaced by Each R 21b are independently H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are independently unsubstituted or q R b is replaced by Or, -NR 21a R 21b In R 21a and R 21b together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocycloalkyl, wherein said 3- to 10-membered heterocycloalkyl is unsubstituted or has p R c is replaced by each m, p, and q is independently 1, 2, 3, 4, or 5; Each R a , R b and R c are independently F, Cl, OH, COOH, CN, NO2, and C 1-4 Alkyl, Fluoro C 1-4 Alkyl, C 1-4 Alkoxy,

[0024] [ka] and

[0025] R 21c are H, F, and C1-4 Alkyl, Fluoro C 1-4 Alkyl, C 2-4 Alkenyl or C 3-6 is cycloalkyl, R 21d is F, C 2-4 Alkyl, Fluoro C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl or -L 4 -R 21e wherein the phenyl and 5- to 6-membered heteroaryl are independently unsubstituted or substituted with j R d is replaced by Or, R 21c and R 21d C together with the carbon atoms connected to them 3-6 forming a cycloalkyl or a 3- to 6-membered heterocycloalkyl; L 4 is C 1-4 is alkylene, R 21e OH, CN, C 1-4 alkoxy, phenyl, or 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl are independently unsubstituted or d is replaced by each j is independently 1, 2, 3, or 4; each r is independently 0, 1, 2, 3, or 4; Each R d and R f are independently F, Cl, OH, CN, NO2, C 1-4 Alkyl, Fluoro C 1-4 Alkyl, C 1-4 Alkoxy or Fluoro C 1-4 is an alkoxy, The number of heteroatoms in the heterocycloalkyl and heteroaryl is independently 1, 2, 3, or 4, and each heteroatom is independently N, O, or S. In Formula XXI, the carbon atom labeled with * is in the R configuration, the S configuration, or a mixture of the two; if the carbon atom labeled with # is a chiral carbon atom, it is in the R configuration, the S configuration, or a mixture of the two; if the carbon atom labeled with A is a chiral carbon atom, it is in the R configuration, the S configuration, or a mixture of the two; and if the carbon atom labeled with B is a chiral carbon atom, it is in the R configuration, the S configuration, or a mixture of the two.

[0026] In some preferred embodiments of the present invention, specific groups in the compound represented by formula XXI, XVI, XIX, XXIII, XXIV, or XXVI or a pharmaceutically acceptable salt thereof are as defined below, and groups not mentioned are as described in any embodiment of the present invention (hereinafter abbreviated as "in some embodiments" or "in some preferred embodiments").

[0027] In some embodiments, in the compound of formula XXI, R 3d is H or R 3c and R 3c is —S(O)OH, —C(O)—CHCOOH, —C(O)—CHOH, —C(O)—COOH, —CHCHOH or —CHCOOH, R 4a is H, F, CH3, CF3 or OH, R 4b is H, F, OH, CHOH, CN, COOH, CF or cyclopropyl, Or, R 4a and R 4b together with the carbon atoms connected to them

[0028] [ka] Forming

[0029] R 7ais H, F, CH3 or CF3, and R 7b is F or OH, or R 7a and R 7b together with the carbon atoms connected to them

[0030] [ka] Forming

[0031] R 8a is H or F, R 14a is H, R 22 teeth,

[0032] [ka] or R 21 and

[0033] R 21 -L 1 -C(O)R A , -L 1 -S(O)2R A , -L 1 -R B ,

[0034] [ka] , -L 2 -R C or -L 3 -R D and

[0035] Each L 1 and L 2 is independently a single bond, —CH—, —(CH)—, —(CH)—, —(CH)—, —(CH)—, —(CH)—, or —(CH)—, wherein one CH— moiety in said —CH—, —(CH)—, —(CH)—, —(CH)—, and —(CH)— is optionally replaced by —X—; L 3is —(CH)—, —(CH)—, —(CH)—, —(CH)—, or —(CH)—, wherein one CH— moiety in —(CH)—, —(CH)—, —(CH)—, —(CH)—, or —(CH)— is replaced by —Y—; Each X is independently -CHR 5a -, -CR 5a R 5b - or -Y-, Each R 5a and R 5b are independently F, C 1-4 Alkyl or Fluoro C 1-4 is alkyl, Each Y is independently —O—, —NH—, —N(C 1-4 alkyl)-,

[0036] [ka] , -CH=CH-,

[0037] [ka] or -CHR g - and

[0038] R g -C 1-4 alkylene-OH, Each R A independently -NR 21a R 21b and R B is -N(R 21a )-C(O)R 21b or -N(R 21a )-S(O)2R 21b and R D -OH, -CHOH, R C , —CH(CH3)—OH or —C(CH3)2—OH; Each R C are independently -C(R 21c )(R 21d)-OH, CN, -C(O)R E , NH2, C 1-4 Alkoxy,

[0039] [ka] , 3- to 6-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is unsubstituted or has p R c is replaced by

[0040] R E is C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl and 3- to 6-membered heterocycloalkyl are independently unsubstituted or substituted with m R a is replaced by Each R 21a are independently H, C 1-6 Alkyl, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl and 3- to 6-membered heterocycloalkyl are independently unsubstituted or substituted with m R a is replaced by Each R 21b are independently H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are independently unsubstituted or q R b is replaced by Or, -NR 21a R 21b In R 21a and R21b together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocycloalkyl, wherein said 3- to 10-membered heterocycloalkyl is unsubstituted or has p R c is replaced by each m, p, and q is independently 1, 2, 3, 4, or 5; Each R a , R b and R c are independently F, Cl, OH, COOH, CN, NO2, and C 1-4 Alkyl, Fluoro C 1-4 Alkyl, C 1-4 Alkoxy,

[0041] [ka] and

[0042] R 21c are H, F, and C 1-4 Alkyl, Fluoro C 1-4 Alkyl, C 2-4 Alkenyl or C 3-6 is cycloalkyl, R 21d is F, C 2-4 Alkyl, Fluoro C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl or -L 4 -R 21e wherein the phenyl and 5- to 6-membered heteroaryl are independently unsubstituted or substituted with j R d is replaced by Or, R 21c and R 21d C together with the carbon atoms connected to them 3-6 forming a cycloalkyl or a 3- to 6-membered heterocycloalkyl; L 4 is C 1-4 is alkylene, R 21e OH, CN, C 1-4alkoxy, phenyl, or 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl are independently unsubstituted or R d is replaced by each j is independently 1, 2, 3, or 4; each r is independently 0, 1, 2, 3, or 4; Each R d and R f are independently F, Cl, OH, CN, NO2, C 1-4 Alkyl, Fluoro C 1-4 Alkyl or C 1-4 is an alkoxy, the number of heteroatoms in said heterocycloalkyl and heteroaryl is independently 1, 2, 3, or 4, and each heteroatom is independently N, O, or S; In formula XXI, the carbon atom labeled * is in the R configuration, the S configuration, or a mixture of the two; if the carbon atom labeled # is a chiral carbon atom, it is in the R configuration, the S configuration, or a mixture of the two; if the carbon atom labeled A is a chiral carbon atom, it is in the R configuration, the S configuration, or a mixture of the two; and if the carbon atom labeled B is a chiral carbon atom, it is in the R configuration, the S configuration, or a mixture of the two.

[0043] In some embodiments, in the compound of formula XXI, R 3d is H. In some embodiments, in the compound of formula XXI, R 4a is H and R 4b is H or OH, or R 4a and R 4b together with the carbon atoms connected to them

[0044] [ka] Form.

[0045] In some embodiments, in the compound of formula XXI, R 4ais H and R 4b is H. In some embodiments, in the compound of formula XXI, R 4a is H and R 4b is OH.

[0046] In some embodiments, in the compound of formula XXI, R 4a and R 4b together with the carbon atoms connected to them

[0047] [ka] Form.

[0048] In some embodiments, in the compound of formula XXI, R 7a is H and R 7b is F. In some embodiments, in the compound of formula XXI, R 7a is F and R 7b is F.

[0049] In some embodiments, in the compound of formula XXI, R 7a is H and R 7b is OH. In some embodiments, in the compound of formula XXI, R 7a and R 7b together with the carbon atoms connected to them

[0050] [ka] Form.

[0051] In some embodiments, in the compound of formula XXI, R 7a and R 7b together with the carbon atoms connected to them

[0052] [ka] Form.

[0053] In some embodiments, in the compound of formula XXI, R 7a is H and R 7b is NH2. In some embodiments, in the compound of formula XXI, R 8a is H.

[0054] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R 22 teeth,

[0055] [ka] is.

[0056] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R 22 is R 21 is. In some embodiments, in compounds of Formula XXI according to any one of the preceding embodiments, each X is independently —CHR 5a -or-CR 5a R 5b -, for example, -CHR 5a -It is.

[0057] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, L 1 is a single bond. In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, L 1 is -(CH2)2- or -CH2-CHR 5a -It is.

[0058] In some embodiments, in the compound of Formula XXI described in any one of the preceding embodiments, each R 5a and R 5b are each independently F, methyl, ethyl, or trifluoromethyl.

[0059] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, L 1 is -(CH2)3-. In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, L 1 is -(CH2)4-.

[0060] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, L 1 is -(CH2)5-. In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, L 1 is -(CH2)6-.

[0061] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R 21 -L 1 -C(O)R A is. In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R 21 -L 1 -S(O)2R A is.

[0062] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R 21 -L 1 -R B is. In some embodiments, in the compound of Formula XXI described in any one of the preceding embodiments, each R 21a are independently H, C1-6 Alkyl or C 3-6 cycloalkyl, wherein said C 1-6 Alkyl and C 3-6 Cycloalkyl is independently unsubstituted or has m R a is replaced by

[0063] In some embodiments, in the compound of Formula XXI described in any one of the preceding embodiments, m is 1, 2, or 3. In some embodiments, in the compound of Formula XXI described in any one of the preceding embodiments, each R a are independently F, OH, CN or methoxy.

[0064] In some embodiments, in the compound of Formula XXI described in any one of the preceding embodiments, each R 21a are independently H, C 1-4 Alkyl, -C 1-4 Alkylene -OH, -C 1-4 Alkylene-OC 1-4 Alkyl, Fluoro C 1-4 It is alkyl or cyclopropyl.

[0065] In some embodiments, in the compound of Formula XXI described in any one of the preceding embodiments, each R 21a are independently H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,

[0066] [ka] , cyclopropyl or trifluoromethyl.

[0067] In some embodiments, in the compound of Formula XXI described in any one of the preceding embodiments, each R 21b are independently H, C 1-6 Alkyl, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein 1-6Alkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are independently unsubstituted or q R b is replaced by

[0068] In some embodiments, in the compound of Formula XXI described in any one of the preceding embodiments, each R 21b are independently H, -C 1-4 Alkylene -OH, -C 1-4 Alkylene-OC 1-4 Alkyl, Fluoro C 1-4 alkyl, tetrahydromorpholinyl, phenyl, pyridyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrimidinyl, or benzopyrazolyl, wherein said phenyl, pyridyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrimidinyl, and benzopyrazolyl are independently unsubstituted or q R b is replaced by

[0069] In some embodiments, in the compound of Formula XXI described in any one of the preceding embodiments, each R 21b are independently H, -C 1-4 Alkylene -OH, -C 1-4 Alkylene-OC 1-4 Alkyl, Fluoro C 1-4 alkyl, tetrahydromorpholinyl, phenyl,

[0070] [ka] wherein said phenyl,

[0071] [ka] are independently unsubstituted or q R b is replaced by

[0072] In some embodiments, in the compound of Formula XXI according to any one of the preceding embodiments, q is 1, 2, or 3. In some embodiments, in the compound of Formula XXI described in any one of the preceding embodiments, each R b are independently F, Cl, OH, COOH, CN, NO2, methyl, trifluoromethyl, methoxy,

[0073] [ka] is.

[0074] In some embodiments, in the compound of Formula XXI described in any one of the preceding embodiments, each R 21b are independently H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, phenyl,

[0075] [ka] is.

[0076] In some embodiments, in the compound of Formula XXI described in any one of the preceding embodiments, each R 21b independently

[0077] [ka] is.

[0078] In some embodiments, the compound of formula XXI according to any one of the preceding embodiments is Among the compounds, -NR 21a R 21b In R 21a and R 21b together with the nitrogen atoms connected to them

[0079] [ka] wherein said

[0080] [ka] is unsubstituted or p R c is replaced by

[0081] In some embodiments, in the compound of Formula XXI according to any one of the preceding embodiments, p is 1, 2, or 3. In some embodiments, in the compound of Formula XXI described in any one of the preceding embodiments, each R c are independently F, OH, CN, and C 1-4 Alkyl or Fluoro C 1-4 It is alkyl.

[0082] In some embodiments, in the compound of Formula XXI described in any one of the preceding embodiments, each R c are each independently F, OH, CN, methyl or trifluoromethyl. In some embodiments, in the compound of Formula XXI according to any one of the preceding embodiments, —NR 21a R 21b In R 21a and R 21b together with the nitrogen atoms connected to them

[0083] [ka] Form.

[0084] In some embodiments, in the compound of Formula XXI described in any one of the preceding embodiments, each R A are independently -NH2,

[0085] [ka] JPEG2025504580000034.jpg42170.

[0086] In some preferred embodiments, in the compound of formula XXI described in any one of the preceding embodiments, each R A independently

[0087] [ka] is.

[0088] In some preferred embodiments, in the compound of formula XXI described in any one of the preceding embodiments, each R A independently

[0089] [ka] is.

[0090] In some preferred embodiments, in the compound of formula XXI described in any one of the above embodiments, -L 1 -C(O)R A teeth,

[0091] [ka] is.

[0092] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R B teeth,

[0093] [ka] is.

[0094] In some preferred embodiments, in the compound of formula XXI described in any one of the above embodiments, R B teeth,

[0095] [ka] is.

[0096] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R 21 -L 2 -R C is. In some embodiments, the compound of formula XXI according to any one of the preceding embodiments is Among the compounds, L 2 is a single bond.

[0097] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, L 2 is -CH2-. In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, L 2 is -(CH2)2-.

[0098] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, L 2 is -(CH2)3-. In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, L 2 is -(CH2)4-.

[0099] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, L 2 is -(CH2)5-. In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, L 2 is -(CH2)6-.

[0100] In some embodiments, in the compound of Formula XXI described in any one of the preceding embodiments, each R C are independently -C(R 21c )(R 21d )-OH. In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R C But -C(R 21c )(R 21d )-OH, R 21c is H and R 21d is phenyl, or R 21c and R 21d C together with the carbon atoms connected to them 3-6 Forms a cycloalkyl (e.g., cyclopropyl), where phenyl optionally has one or two R d and each R d are independently F or C 1-4 It is an alkoxy.

[0101] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R C -C(R 21c )(R 21d )-OH is

[0102] [ka] is.

[0103] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R C But -C(R 21c )(R 21d )-OH, R 21c is H and R 21d is C 2-4 Alkyl, Fluoro C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl, fluorophenyl, 5- to 6-membered heteroaryl or -L 4 -R 21eis.

[0104] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R C But -C(R 21c )(R 21d )-OH, R 21c is H and R 21d is C 2-4 Alkyl, Fluoro C 1-4 Alkyl, C 3-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl or -L 4 -R 21e wherein the phenyl optionally contains one or two R d and each R d are independently F, OH, CN or C 1-4 It is an alkoxy.

[0105] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, L 4 is methylene or ethylene. In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R 21e OH, CN, C 1-4 Alkoxy, phenyl or

[0106] [ka] is.

[0107] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R C -C(R 21c )(R 21d )-OH is

[0108] [ka] is.

[0109] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R C But -C(R 21c )(R 21d )-OH, R 21c is F and R 21d is C 2-4 It is alkyl (eg, ethyl).

[0110] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R C -C(R 21c )(R 21d )-OH is

[0111] [ka] is.

[0112] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R C But -C(R 21c )(R 21d )-OH, R 21c teeth , CH3 or trifluoromethyl, and R 21d is C 2-4 It is alkyl (eg ethyl) or trifluoromethyl.

[0113] In some embodiments, in the compound of Formula XVI described in any one of the previous embodiments, R C -C(R 21c )(R 21d )-OH is

[0114] [ka] is.

[0115] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, RC But -C(R 21c )(R 21d )-OH, R 21c is C 2-4 Alkyl, C 2-4 Alkenyl (e.g.,

[0116] [ka] ) or C 3-6 cycloalkyl (e.g., cyclopropyl), and R 21d is C 2-4 Alkyl, C 2-4 Alkenyl (e.g.,

[0117] [ka] ) or C 3-6 It is cycloalkyl (eg, cyclopropyl).

[0118] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R C But -C(R 21c )(R 21d )-OH, R 21c is ethyl, n-propyl, isopropyl,

[0119] [ka] or cyclopropyl, and R 21d is ethyl, n-propyl, isopropyl,

[0120] [ka] or cyclopropyl.

[0121] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R C -C(R 21c )(R21d )-OH is

[0122] [ka] is.

[0123] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R C But -C(R 21c )(R 21d )-OH, R 21c and R 21d C together with the carbon atoms connected to them 3-6 Cycloalkyl or 3- to 6-membered heterocycloalkyl (e.g.,

[0124] [ka] ) is formed.

[0125] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R C But -C(R 21c )(R 21d )-OH, R 21c and R 21d together with the carbon atom attached thereto, represents cyclopropyl, cyclobutyl or

[0126] [ka] Form.

[0127] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R C -C(R 21c )(R 21d )-OH is

[0128] [ka] is.

[0129] In some preferred embodiments, in the compound of formula XXI described in any one of the above embodiments, R C -C(R 21c )(R 21d )-OH is

[0130] [ka] is.

[0131] In some preferred embodiments, in the compound of formula XXI described in any one of the above embodiments, R C -C(R 21c )(R 21d )-OH is

[0132] [ka] is.

[0133] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R C is CN. In some embodiments, the compound of formula XXI according to any one of the preceding embodiments is Among the compounds, R C is -C(O)R E is.

[0134] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R E is C 1-4 Alkyl or C 3-6 It is cycloalkyl. In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R E is methyl, ethyl or cyclohexyl.

[0135] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R C is NH2. In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R C is C 1-4 Alkoxy, for example, methoxy.

[0136] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R C teeth,

[0137] [ka] For example,

[0138] [ka] is.

[0139] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R C teeth,

[0140] [ka] For example,

[0141] [ka] is.

[0142] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R C teeth,

[0143] [ka] For example,

[0144] [ka] is.

[0145] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R C is a 5- to 10-membered heteroaryl, and the 5- to 10-membered heteroaryl is unsubstituted or c is replaced by

[0146] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R C The 5- to 10-membered heteroaryl in the definition is

[0147] [ka] is.

[0148] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R C teeth,

[0149] [ka] is.

[0150] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R C is a 3- to 6-membered heterocycloalkyl. In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R C The 3- to 6-membered heterocycloalkyl in the definition is

[0151] [ka] is.

[0152] In some preferred embodiments, in the compound of formula XXI described in any one of the above embodiments, -L 2 -R C teeth,

[0153] [ka] is.

[0154] In some preferred embodiments, in the compound of formula XXI described in any one of the above embodiments, -L 2 -R C teeth,

[0155] [ka] is.

[0156] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R 21 -L 3 -R D is. In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, L 3 teeth,

[0157] [ka] and the b-terminus of the above structure is R D is connected to.

[0158] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R D are -OH, -CH2OH,

[0159] [ka] , —CH(CH3)—OH or —C(CH3)2—OH.

[0160] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R 21 -L in 3 -R D teeth,

[0161] [ka] is.

[0162] In some preferred embodiments, in the compound of formula XXI described in any one of the above embodiments, R 21 -L in 3 -R D teeth,

[0163] [ka] is.

[0164] In some preferred embodiments, in the compound of formula XXI described in any one of the above embodiments, R 21 -L in 3 -R D teeth,

[0165] [ka] is.

[0166] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R 21 teeth,

[0167] [ka] is.

[0168] In some embodiments, in the compound of formula XXI described in any one of the preceding embodiments, R22 teeth,

[0169] [ka] is.

[0170] In some embodiments, in the compound of Formula XXI described in any one of the preceding embodiments, the carbon atom marked with * has the R configuration. In some embodiments, in the compound of Formula XXI described in any one of the preceding embodiments, the carbon atom marked with * has the S configuration.

[0171] In some embodiments, in the compound of Formula XXI described in any one of the above embodiments, the carbon atom marked with * is a mixture of S and R configurations, for example, S:R=1:1.

[0172] In some embodiments, in the compound of Formula XXI described in any one of the preceding embodiments, the carbon atom marked with # has the R configuration. In some embodiments, in the compound of Formula XXI described in any one of the preceding embodiments, the carbon atom labeled with # has the S configuration.

[0173] In some embodiments, in the compound of formula XXI described in any one of the above embodiments, the carbon atom marked with # is a mixture of S and R configurations, for example, S:R=1:1.

[0174] In some embodiments, in the compound of Formula XXI described in any one of the previous embodiments, the carbon atom labeled A is in the R configuration. In some embodiments, in the compound of Formula XXI described in any one of the previous embodiments, the carbon atom labeled A is in the S configuration.

[0175] In some embodiments, in the compound of formula XXI described in any one of the above embodiments, the carbon atom labeled A is a mixture of S and R configurations, for example, S:R=1:1.

[0176] In some embodiments, in the compound of Formula XXI described in any one of the previous embodiments, the carbon atom labeled B is in the R configuration. In some embodiments, in the compound of Formula XXI described in any one of the preceding embodiments, the carbon atom labeled B is in the S configuration.

[0177] In some embodiments, in the compound of formula XXI described in any one of the above embodiments, the carbon atom labeled with B is a mixture of S and R configurations, for example, S:R=1:1.

[0178] In some embodiments, the compound of formula XXI is a compound of formula XXI-1.

[0179] [ka]

[0180] However, #, B, R 4a , R 4b , R 7a , R 7b and R 22 is as defined in any one embodiment of the present invention. In some embodiments, the compound of formula XXI is a compound of formula XXI-2, XXI-3, or XXI-4.

[0181] [ka]

[0182] However, B, R 7a , R 7b and R 22is as defined in any one embodiment of the present invention. In some embodiments, the compound of formula XXI is any one of the following compounds:

[0183] [ka] JPEG2025504580000076.jpg211170

[0184] The present invention provides a compound of formula XVI or a pharmaceutically acceptable salt thereof.

[0185] [ka]

[0186] However, R 3d is H or R 3c and R 3c is —S(O)OH, —C(O)—CHCHCOOH, —C(O)—CHCOOH, —C(O)—CHOH, —C(O)—COOH, —CHCHOH or —CHCOOH, R 4a is H, F, CH3, CF3 or OH, R 4b is H, F, NH2, OH or CF3, Or, R 4a and R 4b together with the carbon atoms connected to them

[0187] [ka] Forming

[0188] R 5 is H or R 5c and R 5c is OH or F, R 22 teeth,

[0189] [ka] or R 21 and R 21 is as defined in formula XXI,

[0190] In Formula XVI, the carbon atom labeled with * is in the R configuration, the S configuration, or a mixture of the two; the carbon atom labeled with #, if a chiral carbon atom, is in the R configuration, the S configuration, or a mixture of the two; and the carbon atom labeled with &, if a chiral carbon atom, is in the R configuration, the S configuration, or a mixture of the two.

[0191] In some embodiments, in the compound of Formula XVI, R 3d is H or R 3c and R 3c is —S(O)OH, —C(O)—CHCOOH, —C(O)—CHOH, —C(O)—COOH, —CHCHOH or —CHCOOH, R 4a is H, F, CH3, CF3 or OH, R 4b is H, F, OH or CF3, Or, R 4a and R 4b together with the carbon atoms connected to them

[0192] [ka] Forming

[0193] R 5 is H or R 5c and R 5c is OH or F, R 22 teeth,

[0194] [ka] or R 21and

[0195] R 21 -L 1 -C(O)R A , -L 1 -S(O)2R A , -L 1 -R B ,

[0196] [ka] , -L 2 -R C or -L 3 -R D and

[0197] Each L 1 and L 2 is independently a single bond, —CH—, —(CH)—, —(CH)—, —(CH)—, —(CH)—, —(CH)—, or —(CH)—, wherein one CH— moiety in said —CH—, —(CH)—, —(CH)—, —(CH)—, and —(CH)— is optionally replaced by —X—; L 3 is —(CH)—, —(CH)—, —(CH)—, —(CH)—, or —(CH)—, wherein one CH— moiety in —(CH)—, —(CH)—, —(CH)—, —(CH)—, or —(CH)— is replaced by —Y—; Each X is independently -CHR 5a -, -CR 5a R 5b - or -Y-, Each R 5a and R 5b are independently F, C 1-4 Alkyl or Fluoro C 1-4 is alkyl, Each Y is independently —O—, —NH—, —N(C 1-4 alkyl)-,

[0198] [ka] , -CH=CH-,

[0199] [ka] or -CHR g - and

[0200] R g -C 1-4 alkylene-OH, Each R A independently -NR 21a R 21b and R B is -N(R 21a )-C(O)R 21b or -N(R 21a )-S(O)2R 21b and R D -OH, -CHOH, R C , —CH(CH3)—OH or —C(CH3)2—OH; Each R C are independently -C(R 21c )(R 21d )-OH, CN, -C(O)R E , NH2, C 1-4 Alkoxy,

[0201] [ka] , 3- to 6-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is unsubstituted or has p R c is replaced by

[0202] R E is C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6The cycloalkyl and 3- to 6-membered heterocycloalkyl are independently unsubstituted or substituted with m R a is replaced by Each R 21a are independently H, C 1-6 Alkyl, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl and 3- to 6-membered heterocycloalkyl are independently unsubstituted or substituted with m R a is replaced by Each R 21b are independently H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are independently unsubstituted or q R b is replaced by Or, -NR 21a R 21b In R 21a and R 21b together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocycloalkyl, wherein said 3- to 10-membered heterocycloalkyl is unsubstituted or has p R c is replaced by each m, p, and q is independently 1, 2, 3, 4, or 5; Each R a , R b and R c are independently F, Cl, OH, COOH, CN, NO2, and C 1-4 Alkyl, Fluoro C 1-4 Alkyl, C 1-4 Alkoxy,

[0203] [ka] and

[0204] R 21c are H, F, and C 1-4 Alkyl, Fluoro C 1-4 Alkyl, C 2-4 Alkenyl or C 3-6 is cycloalkyl, R 21d is F, C 2-4 Alkyl, Fluoro C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl or -L 4 -R 21e wherein the phenyl and 5- to 6-membered heteroaryl are independently unsubstituted or substituted with j R d is replaced by Or, R 21c and R 21d C together with the carbon atoms connected to them 3-6 forming a cycloalkyl or a 3- to 6-membered heterocycloalkyl; L 4 is C 1-4 is alkylene, R 21e OH, CN, C 1-4 alkoxy, phenyl, or 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl are independently unsubstituted or d is replaced by each j is independently 1, 2, 3, or 4; each r is independently 0, 1, 2, 3, or 4; Each R d and R f are independently F, Cl, OH, CN, NO2, C 1-4 Alkyl, Fluoro C 1-4 Alkyl or C 1-4 is an alkoxy; the number of heteroatoms in said heterocycloalkyl and heteroaryl is independently 1, 2, 3, or 4, and each heteroatom is independently N, O, or S; In Formula XVI, the carbon atom labeled with * is in the R configuration, the S configuration, or a mixture of the two; the carbon atom labeled with #, if a chiral carbon atom, is in the R configuration, the S configuration, or a mixture of the two; and the carbon atom labeled with &, if a chiral carbon atom, is in the R configuration, the S configuration, or a mixture of the two.

[0205] In some embodiments, in the compound of Formula XVI, R 3d is H, —C(O)—CH2OH, —C(O)—CH2COOH or —C(O)—CH2CH2COOH. In some embodiments, in the compound of Formula XVI, R 3d is H.

[0206] In some embodiments, in the compound of Formula XVI, R 3d is R 3c is. In some embodiments, in the compound of Formula XVI, R 3c is -S(O)2OH.

[0207] In some embodiments, in the compound of Formula XVI, R 3c is —C(O)—CHCOOH. In some embodiments, in the compound of Formula XVI, R 3c is —C(O)—CHOH.

[0208] In some embodiments, in the compound of Formula XVI, R 3c -C (O)-COOH. In some embodiments, in the compound of Formula XVI, R 3c is -CH2CH2OH.

[0209] In some embodiments, in the compound of Formula XVI, R 3c is -CH2COOH. In some embodiments, in the compound of Formula XVI, R 4a is H and R 4b is OH.

[0210] In some embodiments, in the compound of Formula XVI, R 4a is CH3 and R 4b is F. In some embodiments, in the compound of Formula XVI, R 4a is F and R 4b is F.

[0211] In some embodiments, in the compound of Formula XVI, R 4a is H and R 4b is CF3. In some embodiments, in the compound of Formula XVI, R 4a is CH3 and R 4b is OH.

[0212] In some embodiments, in the compound of Formula XVI, R 4a is OH and R 4b is CF3. In some embodiments, in the compound of Formula XVI, R 4a and R 4b together with the carbon atoms connected to them

[0213] [ka] Form.

[0214] In some embodiments, in the compound of Formula XVI, R 4a is H and R 4b is F. In some embodiments, in the compound of Formula XVI, R 4a is CF3 and R 4b is CF3.

[0215] In some embodiments, in the compound of Formula XVI, R 4a and R 4b together with the carbon atoms connected to them

[0216] [ka] Form.

[0217] In some embodiments, in the compound of Formula XVI, R 4a is H and R 4b is H. In some embodiments, in the compound of Formula XVI, R 4a is H and R 4b is NH2.

[0218] In some embodiments, in the compound of Formula XVI, R 5 is H. In some embodiments, in the compound of Formula XVI, R 5 is OH. In some embodiments, in the compound of Formula XVI, R 5 is F.

[0219] In some embodiments, in the compound of Formula XVI described in any one of the previous embodiments, R 22 teeth,

[0220] [ka] is.

[0221] In some embodiments, in the compound of Formula XVI described in any one of the previous embodiments, R 22 is R 21 and R 21is as defined in any one embodiment of formula XXI.

[0222] In some embodiments, in the compound of Formula XVI described in any one of the previous embodiments, R 21 -L 1 -C(O)R A , -L 2 -R C or

[0223] [ka] is.

[0224] In some embodiments, in the compound of Formula XVI described in any one of the previous embodiments, L 1 is -(CH2)2- or -CH2-CHR 5a and preferably L 1 is -(CH2)2-.

[0225] In some embodiments, in the compound of Formula XVI described in any one of the preceding embodiments, each R 21a are independently H, C 1-4 Alkyl, -C 1-4 Alkylene -OH, -C 1-4 Alkylene-OC 1-4 Alkyl, Fluoro C 1-4 alkyl or cyclopropyl, and preferably each R 21a independently C 1-4 It is alkyl.

[0226] In some embodiments, in the compound of Formula XVI described in any one of the preceding embodiments, each R 21a are independently H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,

[0227] [ka] , cyclopropyl or trifluoromethyl, for example methyl.

[0228] In some embodiments, in the compound of Formula XVI described in any one of the preceding embodiments, each R 21b are independently H, C 1-6 Alkyl, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein 1-6 Alkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are independently unsubstituted or q R b and preferably, each R 21b independently C 6-10 aryl, wherein said C 6-10 Aryl is unsubstituted or q R b is replaced by

[0229] In some embodiments, in the compound of Formula XVI described in any one of the preceding embodiments, each R 21b are independently H, -C 1-4 Alkylene -OH, -C 1-4 Alkylene-OC 1-4 Alkyl, Fluoro C 1-4 alkyl, tetrahydromorpholinyl, phenyl, pyridyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrimidinyl, or benzopyrazolyl, wherein said phenyl, pyridyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrimidinyl, and benzopyrazolyl are independently unsubstituted or q R b and preferably, each R 21b is independently phenyl, wherein said phenyl is unsubstituted or q R b is replaced by

[0230] In some embodiments, in the compound of Formula XVI according to any one of the previous embodiments, q is 1, 2 or 3, for example, 1. In some embodiments, in the compound of Formula XVI described in any one of the preceding embodiments, each R b are independently F, Cl, OH, COOH, CN, NO2, methyl, trifluoromethyl, methoxy,

[0231] [ka] For example, F.

[0232] In some embodiments, in the compound of Formula XVI described in any one of the preceding embodiments, each R 21b independently

[0233] [ka] is.

[0234] In some preferred embodiments, in the compound of formula XVI described in any one of the previous embodiments, each R A independently

[0235] [ka] For example,

[0236] [ka] is.

[0237] In some preferred embodiments, in the compound of formula XXI described in any one of the above embodiments, -L 1 -C(O)R A teeth,

[0238] [ka] For example,

[0239] [ka] is.

[0240] In some embodiments, in the compound of Formula XVI described in any one of the previous embodiments, L 2 is —(CH2)2— or —(CH2)3. In some embodiments, in the compound of Formula XVI described in any one of the preceding embodiments, each R C are independently -C(R 21c )(R 21d )-OH or

[0241] [ka] is.

[0242] In some embodiments, in the compound of Formula XVI described in any one of the previous embodiments, R C But -C(R 21c )(R 21d )-OH, R 21c is H and R 21d is C 2-4 Alkyl, Fluoro C 1-4 Alkyl, C 3-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl or -L 4 -R 21e wherein the phenyl optionally contains one or two R d and each R d are independently F, OH, CN or C 1-4 It is an alkoxy.

[0243] In some embodiments, in the compound of Formula XVI described in any one of the previous embodiments, R C But -C(R 21c )(R21d )-OH, R 21c is H and R 21d is C 2-4 Alkyl, Fluoro C 1-4 Alkyl, C 3-6 cycloalkyl or phenyl, where phenyl optionally has one or two R d and each R d are independently F, Cl, OH, fluoro C 1-4 Alkyl, C 1-4 Alkoxy or Fluoro C 1-4 It is an alkoxy.

[0244] In some embodiments, in the compound of Formula XVI described in any one of the previous embodiments, R C But -C(R 21c )(R 21d )-OH, R 21c and R 21d C together with the carbon atoms connected to them 3-6 Cycloalkyl or 3- to 6-membered heterocycloalkyl (e.g.,

[0245] [ka] ) is formed.

[0246] In some embodiments, in the compound of Formula XVI described in any one of the previous embodiments, R C But -C(R 21c )(R 21d )-OH, R 21c and R 21d together with the carbon atom attached thereto, represents cyclopropyl, cyclobutyl or

[0247] [ka] and is preferably cyclopropyl.

[0248] In some embodiments, in the compound of Formula XVI described in any one of the previous embodiments, R C But -C(R 21c )(R 21d )-OH, R 21c is CH3 or trifluoromethyl, and R 21d is C 2-4 It is alkyl (eg ethyl) or trifluoromethyl.

[0249] In some embodiments, in the compound of Formula XVI described in any one of the previous embodiments, R C -C(R 21c )(R 21d )-OH is

[0250] [ka] is.

[0251] In some embodiments, in the compound of Formula XVI described in any one of the previous embodiments, R C But -C(R 21c )(R 21d )-OH, R 21c is CH3 or trifluoromethyl, and R 21d is phenyl or trifluoromethyl, wherein said phenyl is unsubstituted or has j R d is replaced by

[0252] In some embodiments, in the compound of Formula XVI described in any one of the previous embodiments, R C -C(R 21c )(R 21d )-OH is

[0253] [ka] is.

[0254] In some embodiments, in the compound of Formula XVI described in any one of the previous embodiments, r is 0. In some embodiments, in the compound of Formula XVI described in any one of the previous embodiments, R 21 teeth,

[0255] [ka] is.

[0256] In some embodiments, in the compound of Formula XVI described in any one of the previous embodiments, the carbon atom marked with * has the R configuration. In some embodiments, in the compound of Formula XVI described in any one of the previous embodiments, the carbon atom marked with * has the S configuration.

[0257] In some embodiments, in the compound of Formula XVI described in any one of the above embodiments, the carbon atom marked with * is a mixture of S and R configurations, for example, S:R=1:1.

[0258] In some embodiments, in the compound of formula XVI according to any one of the preceding embodiments, when the carbon atom in formula XVI marked with # is a chiral carbon atom, it is in the R configuration.

[0259] In some embodiments, in the compound of formula XVI according to any one of the preceding embodiments, if the carbon atom in formula XVI marked with # is a chiral carbon atom, it is in the S configuration.

[0260] In some embodiments, in the compound represented by formula XVI described in any one of the above embodiments, the carbon atom marked with # in formula XVI is a mixture of S and R configurations, for example, S configuration:R configuration=1:1.

[0261] In some embodiments, in the compound of Formula XVI according to any one of the preceding embodiments, when the carbon atom in Formula XVI marked with & is a chiral carbon atom, it has the R configuration.

[0262] In some embodiments, in the compound of Formula XVI according to any one of the preceding embodiments, if the carbon atom in Formula XVI marked with & is a chiral carbon atom, it has the S configuration.

[0263] In some embodiments, in the compound represented by Formula XVI according to any one of the above embodiments, the carbon atom marked with & in Formula XVI is a mixture of S and R configurations, for example, S:R=1:1.

[0264] In some embodiments, the compound of formula XVI is a compound of formula XVI-1.

[0265] [ka]

[0266] However, #, &, and R 3d , R 4a , R 4b , R 5 and R 22 is as defined in any one embodiment of the present invention. In some embodiments, the compound of formula XVI is any one of the following compounds:

[0267] [ka] JPEG2025504580000106.jpg199168JPEG2025504580000107.jpg199169JPEG2025504580000108.jpg206168JPEG2025504580000109.jpg223168

[0268] In some embodiments, the compound of formula XVI is a compound of formula VII.

[0269] [ka]

[0270] However, R 3d is H or R 3c and R 3c is as defined in any one embodiment of formula XXI; R 22 teeth,

[0271] [ka] or R 21 and R 21 is as defined in any one embodiment of formula XXI;

[0272] In Formula VII, the carbon atoms marked with an * are in the R configuration, the S configuration, or a mixture of the two. In some embodiments, among the compounds of Formula VII, R 3d is H. In some embodiments, among the compounds of Formula VII, R 3d is R 3c and R 3c is as defined in any one embodiment of formula XXI.

[0273] In some embodiments, in the compound of Formula VII described in any one of the preceding embodiments, R 22 teeth

[0274] [ka] is.

[0275] In some embodiments, in the compound of Formula VII described in any one of the preceding embodiments, R 22 is R 21 and R 21 is as defined in any one embodiment of formula XXI.

[0276] In some embodiments, in the compound of Formula VII described in any one of the previous embodiments, the carbon atom marked with * has the R configuration. In some embodiments, in the compound of Formula VII described in any one of the previous embodiments, the carbon atom marked with * has the S configuration.

[0277] In some embodiments, the compound of formula VII according to any one of the preceding embodiments is In the compounds, the carbon atom marked with * is a mixture of S and R configurations, for example, S:R=1:1.

[0278] In some embodiments, the compound of formula VII is:

[0279] [ka]

[0280] The present invention further provides a compound of formula XIX or a pharmaceutically acceptable salt thereof.

[0281] [ka]

[0282] However, R 3d is H or R 3c and R 3c is as defined in any one embodiment of formula XXI; R 4a is as defined in any one embodiment of formula XXI; R4b is as defined in any one embodiment of formula XXI; R 5 is H or R 5c and R 5c is OH or F, R 6c is H, F, CH3 or CF3, R 6d are CN, NH2, F, COOH, C 1-4 alkoxy (e.g., methoxy) or OH; Or, R 6c and R 6d together with the carbon atoms connected to them

[0283] [ka] Forming

[0284] R 22 teeth,

[0285] [ka] or R 21 and R 21 is as defined in formula XXI,

[0286] In Formula XIX, the carbon atom labeled * is in the R configuration, the S configuration, or a mixture of the two; if the carbon atom labeled # is a chiral carbon atom, it is in the R configuration, the S configuration, or a mixture of the two; if the carbon atom labeled A is a chiral carbon atom, it is in the R configuration, the S configuration, or a mixture of the two; and if the carbon atom labeled B is a chiral carbon atom, it is in the R configuration, the S configuration, or a mixture of the two.

[0287] In some embodiments, in the compound of formula XIX, R 3d is H or R 3c and R 3cis —S(O)OH, —C(O)—CHCOOH, —C(O)—CHOH, —C(O)—COOH, —CHCHOH or —CHCOOH, R 4a is H, F, CH3, CF3 or OH, R 4b is H, F, OH or CF3, Or, R 4a and R 4b together with the carbon atoms connected to them

[0288] [ka] Forming

[0289] R 5 is H or R 5c and R 5c is OH or F, R 6c is H, F, CH3 or CF3, R 6d CN, F, COOH, C 1-4 alkoxy (e.g., methoxy) or OH; Or, R 6c and R 6d together with the carbon atoms connected to them

[0290] [ka] Forming

[0291] R 22 teeth,

[0292] [ka] or R 21 and

[0293] R 21 -L 1 -C(O)R A , -L 1 -S(O)2RA , -L 1 -R B ,

[0294] [ka] , -L 2 -R C or -L 3 -R D and

[0295] Each L 1 and L 2 is independently a single bond, —CH—, —(CH)—, —(CH)—, —(CH)—, —(CH)—, —(CH)—, or —(CH)—, wherein one CH— moiety in said —CH—, —(CH)—, —(CH)—, —(CH)—, and —(CH)— is optionally replaced by —X—; L 3 is —(CH)—, —(CH)—, —(CH)—, —(CH)—, or —(CH)—, wherein one CH— moiety in —(CH)—, —(CH)—, —(CH)—, —(CH)—, or —(CH)— is replaced by —Y—; Each X is independently -CHR 5a -, -CR 5a R 5b - or -Y-, Each R 5a and R 5b are independently F, C 1-4 Alkyl or Fluoro C 1-4 is alkyl, Each Y is independently —O—, —NH—, —N(C 1-4 alkyl)-,

[0296] [ka] , -CH=CH-,

[0297] [ka] or -CHR g - and

[0298] R g -C 1-4 alkylene-OH, Each R A independently -NR 21a R 21b and R B is -N(R 21a )-C(O)R 21b or -N(R 21a )-S(O)2R 21b and R D -OH, -CHOH, R C , —CH(CH3)—OH or —C(CH3)2—OH; Each R C are independently -C(R 21c )(R 21d )-OH, CN, -C(O)R E , NH2, C 1-4 Alkoxy,

[0299] [ka] , 3- to 6-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is unsubstituted or has p R c is replaced by

[0300] R E is C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl and 3- to 6-membered heterocycloalkyl are independently unsubstituted or substituted with m R a is replaced by Each R 21a are independently H, C 1-6 Alkyl, C 3-6cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl and 3- to 6-membered heterocycloalkyl are independently unsubstituted or substituted with m R a is replaced by Each R 21b are independently H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are independently unsubstituted or q R b is replaced by Or, -NR 21a R 21b In R 21a and R 21b together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocycloalkyl, wherein said 3- to 10-membered heterocycloalkyl is unsubstituted or has p R c is replaced by each m, p, and q is independently 1, 2, 3, 4, or 5; Each R a , R b and R c are independently F, Cl, OH, COOH, CN, NO2, and C 1-4 Alkyl, Fluoro C 1-4 Alkyl, C 1-4 Alkoxy,

[0301] [ka] and

[0302] R 21c are H, F, and C 1-4 Alkyl, Fluoro C 1-4 Alkyl, C 2-4 Alkenyl or C 3-6 is cycloalkyl, R 21d is F, C 2-4 Alkyl, Fluoro C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl or -L 4 -R 21e wherein the phenyl and 5- to 6-membered heteroaryl are independently unsubstituted or substituted with j R d is replaced by Or, R 21c and R 21d C together with the carbon atoms connected to them 3-6 forming a cycloalkyl or a 3- to 6-membered heterocycloalkyl; L 4 is C 1-4 is alkylene, R 21e OH, CN, C 1-4 alkoxy, phenyl, or 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl are independently unsubstituted or d is replaced by each j is independently 1, 2, 3, or 4; each r is independently 0, 1, 2, 3, or 4; Each R d and R f are independently F, Cl, OH, CN, NO2, C 1-4 Alkyl, Fluoro C 1-4 Alkyl or C 1-4 is an alkoxy; the number of heteroatoms in said heterocycloalkyl and heteroaryl is independently 1, 2, 3, or 4, and each heteroatom is independently N, O, or S; In Formula XIX, the carbon atom labeled * is in the R configuration, the S configuration, or a mixture of the two; if the carbon atom labeled # is a chiral carbon atom, it is in the R configuration, the S configuration, or a mixture of the two; if the carbon atom labeled A is a chiral carbon atom, it is in the R configuration, the S configuration, or a mixture of the two; and if the carbon atom labeled B is a chiral carbon atom, it is in the R configuration, the S configuration, or a mixture of the two.

[0303] In some embodiments, in the compound of formula XIX, R 3d is H. In some embodiments, in the compound of formula XIX, R 4a is H and R 4b is OH.

[0304] In some embodiments, in the compound of formula XIX, R 4a is H and R 4b is H. In some embodiments, in the compound of Formula XIX described in any one of the preceding embodiments, R 5 is OH.

[0305] In some embodiments, in the compound of Formula XIX described in any one of the preceding embodiments, R 5 is F. In some embodiments, in the compound of Formula XIX described in any one of the preceding embodiments, R 5 is H.

[0306] In some embodiments, in the compound of Formula XIX described in any one of the preceding embodiments, R 6c is H and R 6d is CN. In some embodiments, in the compound of Formula XIX described in any one of the preceding embodiments, R 6c is H and R 6d is COOH.

[0307] In some embodiments, in the compound of Formula XIX described in any one of the preceding embodiments, R 6c is H and R 6d is OH. In some embodiments, in the compound of Formula XIX described in any one of the preceding embodiments, R 6cis H and R 6d is OCH3.

[0308] In some embodiments, in the compound of Formula XIX described in any one of the preceding embodiments, R 6c and R 6d together with the carbon atoms connected to them

[0309] [ka] Form.

[0310] In some embodiments, in the compound of Formula XIX described in any one of the preceding embodiments, R 22 teeth,

[0311] [ka] is.

[0312] In some embodiments, in the compound of Formula XIX described in any one of the previous embodiments, the carbon atom marked with * has the R configuration. In some embodiments, in the compound of Formula XIX described in any one of the previous embodiments, the carbon atom marked with * has the S configuration.

[0313] In some embodiments, in the compound of Formula XIX described in any one of the above embodiments, the carbon atom marked with * is a mixture of S and R configurations, for example, S:R=1:1.

[0314] In some embodiments, in the compound of Formula XIX described in any one of the preceding embodiments, the carbon atom marked with # has the R configuration. In some embodiments, in the compound of Formula XIX described in any one of the previous embodiments, the carbon atom labeled with # has the S configuration.

[0315] In some embodiments, in the compound of Formula XIX described in any one of the above embodiments, the carbon atom marked with # is a mixture of S and R configurations, for example, S:R=1:1.

[0316] In some embodiments, in the compound of Formula XIX described in any one of the previous embodiments, the carbon atom labeled A has the R configuration. In some embodiments, in the compound of Formula XIX described in any one of the previous embodiments, the carbon atom labeled A is in the S configuration.

[0317] In some embodiments, in the compound of formula XIX described in any one of the above embodiments, the carbon atom labeled A is a mixture of S and R configurations, for example, S:R=1:1.

[0318] In some embodiments, in the compound of Formula XIX described in any one of the previous embodiments, the carbon atom labeled B has the R configuration. In some embodiments, in the compound of Formula XIX described in any one of the previous embodiments, the carbon atom labeled B is in the S configuration.

[0319] In some embodiments, in the compound of formula XIX described in any one of the above embodiments, the carbon atom labeled B is a mixture of S and R configurations, for example, S:R=1:1.

[0320] In some embodiments, the compound of formula XIX is a compound of formula XIX-1.

[0321] [ka]

[0322] However, #, A, B, R 4a , R 4b , R5 , R 6c and R 6d is as defined in any one embodiment of the present invention. In some embodiments, the compound of formula XIX is any one of the following compounds:

[0323] [ka] JPEG2025504580000129.jpg136169

[0324] The present invention further provides a compound of formula XXIII or a pharmaceutically acceptable salt thereof.

[0325] [ka]

[0326] However, R 3d is H or R 3c and R 3c is as defined in any one embodiment of formula XXI; R 4a is as defined in any one embodiment of formula XXI; R 4b is as defined in any one embodiment of formula XXI; R 19 is CHOH, CHCN, CHCOOH, CHF or CHF, R 22 teeth,

[0327] [ka] or R 21 and R 21 is as defined in any one embodiment of formula XXI;

[0328] In formula XXIII, the carbon atom marked with * is in the R configuration, the S configuration, or a mixture of the two, and the carbon atom marked with #, when it is a chiral carbon atom, is in the R configuration, the S configuration, or a mixture of the two.

[0329] In some embodiments, in the compound of Formula XXIII, R 3d is H or R 3c and R 3c is —S(O)OH, —C(O)—CHCOOH, —C(O)—CHOH, —C(O)—COOH, —CHCHOH or —CHCOOH, R 4a is H, F, CH3, CF3 or OH, R 4b is H, F, OH or CF3, Or, R 4a and R 4b together with the carbon atoms connected to them

[0330] [ka] Forming

[0331] R 19 is CHOH, CHCN, CHCOOH, CHF or CHF, R 22 teeth,

[0332] [ka] or R 21 and

[0333] R 21 -L 1 -C(O)R A , -L 1 -S(O)2R A , -L 1 -R B ,

[0334] [ka] , -L 2 -R C or -L 3 -R D and

[0335] Each L 1 and L 2 is independently a single bond, —CH—, —(CH)—, —(CH)—, —(CH)—, —(CH)—, —(CH)—, or —(CH)—, wherein one CH— moiety in said —CH—, —(CH)—, —(CH)—, —(CH)—, and —(CH)— is optionally replaced by —X—; L 3 is —(CH)—, —(CH)—, —(CH)—, —(CH)—, or —(CH)—, wherein one CH— moiety in —(CH)—, —(CH)—, —(CH)—, —(CH)—, or —(CH)— is replaced by —Y—; Each X is independently -CHR 5a -, -CR 5a R 5b - or -Y-, Each R 5a and R 5b are independently F, C 1-4 Alkyl or Fluoro C 1-4 is alkyl, Each Y is independently —O—, —NH—, —N(C 1-4 alkyl)-,

[0336] [ka] , -CH=CH-,

[0337] [ka] or -CHR g - and

[0338] R g -C 1-4alkylene-OH, Each R A independently -NR 21a R 21b and R B is -N(R 21a )-C(O)R 21b or -N(R 21a )-S(O)2R 21b and R D -OH, -CHOH, R C , —CH(CH3)—OH or —C(CH3)2—OH; Each R C are independently -C(R 21c )(R 21d )-OH, CN, -C(O)R E , NH2, C 1-4 Alkoxy,

[0339] [ka] , 3- to 6-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is unsubstituted or has p R c is replaced by

[0340] R E is C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl and 3- to 6-membered heterocycloalkyl are independently unsubstituted or substituted with m R a is replaced by Each R 21a are independently H, C 1-6 Alkyl, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl and 3- to 6-membered heterocycloalkyl are independently unsubstituted or substituted with m R ais replaced by Each R 21b are independently H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are independently unsubstituted or q R b is replaced by Or, -NR 21a R 21b In R 21a and R 21b together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocycloalkyl, wherein said 3- to 10-membered heterocycloalkyl is unsubstituted or has p R c is replaced by each m, p, and q is independently 1, 2, 3, 4, or 5; Each R a , R b and R c are independently F, Cl, OH, COOH, CN, NO2, and C 1-4 Alkyl, Fluoro C 1-4 Alkyl, C 1-4 Alkoxy,

[0341] [ka] and

[0342] R 21c are H, F, and C 1-4 Alkyl, Fluoro C 1-4 Alkyl, C 2-4 Alkenyl or C 3-6 is cycloalkyl, R 21d is F, C 2-4 Alkyl, Fluoro C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6cycloalkyl, phenyl, 5- to 6-membered heteroaryl or -L 4 -R 21e wherein the phenyl and 5- to 6-membered heteroaryl are independently unsubstituted or substituted with j R d is replaced by Or, R 21c and R 21d C together with the carbon atoms connected to them 3-6 forming a cycloalkyl or a 3- to 6-membered heterocycloalkyl; L 4 is C 1-4 is alkylene, R 21e OH, CN, C 1-4 alkoxy, phenyl, or 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl are independently unsubstituted or d is replaced by each j is independently 1, 2, 3, or 4; each r is independently 0, 1, 2, 3, or 4; Each R d and R f are independently F, Cl, OH, CN, NO2, C 1-4 Alkyl, Fluoro C 1-4 Alkyl or C 1-4 is an alkoxy; the number of heteroatoms in said heterocycloalkyl and heteroaryl is independently 1, 2, 3, or 4, and each heteroatom is independently N, O, or S; In formula XXIII, the carbon atom marked with * is in the R configuration, the S configuration, or a mixture of the two, and the carbon atom marked with #, when it is a chiral carbon atom, is in the R configuration, the S configuration, or a mixture of the two.

[0343] In some embodiments, in the compound of Formula XXIII, R 3d is H. In some embodiments, in the compound of Formula XXIII, R 4a is H and R 4b is H.

[0344] In some embodiments, in the compound of Formula XXIII described in any one of the preceding embodiments, R 22 teeth,

[0345] [ka] is.

[0346] In some embodiments, in the compound of Formula XXIII described in any one of the preceding embodiments, the carbon atom marked with * has the R configuration. In some embodiments, in the compound of Formula XXIII described in any one of the previous embodiments, the carbon atom marked with * has the S configuration.

[0347] In some embodiments, in the compound of Formula XXIII described in any one of the above embodiments, the carbon atom marked with * is a mixture of S and R configurations, for example, S:R=1:1.

[0348] In some embodiments, in the compound of Formula XXIII described in any one of the preceding embodiments, the carbon atom marked with # has the R configuration. In some embodiments, in the compound of Formula XXIII described in any one of the preceding embodiments, the carbon atom labeled with # has the S configuration.

[0349] In some embodiments, in the compound of Formula XXIII described in any one of the above embodiments, the carbon atom marked with # is a mixture of S and R configurations, for example, S:R=1:1.

[0350] In some embodiments, the compound of formula XXIII is any one of the following compounds:

[0351] [ka]

[0352] The present invention further provides a compound of formula XXIV or a pharmaceutically acceptable salt thereof.

[0353] [ka]

[0354] However, R 3d is H or R 3c and R 3c is as defined in any one embodiment of formula XXI; R 7a is as defined in any one embodiment of formula XXI; R 7b is as defined in any one embodiment of formula XXI; R 8a is H or F, R 22 teeth,

[0355] [ka] or R 21 and R 21 is as defined in any one embodiment of formula XXI;

[0356] In Formula XXIV, the carbon atom labeled with * is in the R configuration, the S configuration, or a mixture of the two; the carbon atom labeled with #, if a chiral carbon atom, is in the R configuration, the S configuration, or a mixture of the two; and the carbon atom labeled with A, if a chiral carbon atom, is in the R configuration, the S configuration, or a mixture of the two.

[0357] In some embodiments, in the compound of formula XXIV, R 3d is H or R 3c and R 3cis —S(O)OH, —C(O)—CHCOOH, —C(O)—CHOH, —C(O)—COOH, —CHCHOH or —CHCOOH, R 7a is H, F, CH3 or CF3, and R 7b is F or OH, or R 7a and R 7b together with the carbon atoms connected to them

[0358] [ka] Forming

[0359] R 8a is H or F, R 22 teeth,

[0360] [ka] or R 21 and

[0361] R 21 -L 1 -C(O)R A , -L 1 -S(O)2R A , -L 1 -R B ,

[0362] [ka] , -L 2 -R C or -L 3 -R D and

[0363] Each L 1 and L 2is independently a single bond, —CH—, —(CH)—, —(CH)—, —(CH)—, —(CH)—, —(CH)—, or —(CH)—, wherein one CH— moiety in said —CH—, —(CH)—, —(CH)—, —(CH)—, and —(CH)— is optionally replaced by —X—; L 3 is —(CH)—, —(CH)—, —(CH)—, —(CH)—, or —(CH)—, wherein one CH— moiety in —(CH)—, —(CH)—, —(CH)—, —(CH)—, or —(CH)— is replaced by —Y—; Each X is independently -CHR 5a -, -CR 5a R 5b - or -Y-, Each R 5a and R 5b are independently F, C 1-4 Alkyl or Fluoro C 1-4 is alkyl, Each Y is independently —O—, —NH—, —N(C 1-4 alkyl)-,

[0364] [ka] , -CH=CH-,

[0365] [ka] or -CHR g - and

[0366] R g -C 1-4 alkylene-OH, Each R A independently -NR 21a R 21b and R B is -N(R 21a )-C(O)R 21b or -N(R 21a)-S(O)2R 21b and R D -OH, -CHOH, R C , —CH(CH3)—OH or —C(CH3)2—OH; Each R C are independently -C(R 21c )(R 21d )-OH, CN, -C(O)R E , NH2, C 1-4 Alkoxy,

[0367] [ka] , 3- to 6-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is unsubstituted or has p R c is replaced by

[0368] R E is C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl and 3- to 6-membered heterocycloalkyl are independently unsubstituted or substituted with m R a is replaced by Each R 21a are independently H, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein said C 1-6 Alkyl, C 3-6 The cycloalkyl and 3- to 6-membered heterocycloalkyl are independently unsubstituted or substituted with m R a is replaced by Each R 21b are independently H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are independently unsubstituted or q R b is replaced by Or, -NR 21a R 21b In R 21a and R 21b together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocycloalkyl, wherein said 3- to 10-membered heterocycloalkyl is unsubstituted or has p R c is replaced by each m, p, and q is independently 1, 2, 3, 4, or 5; Each R a , R b and R c are independently F, Cl, OH, COOH, CN, NO2, and C 1-4 Alkyl, Fluoro C 1-4 Alkyl, C 1-4 Alkoxy,

[0369] [ka] and

[0370] R 21c are H, F, and C 1-4 Alkyl, Fluoro C 1-4 Alkyl, C 2-4 Alkenyl or C 3-6 is cycloalkyl, R 21d is F, C 2-4 Alkyl, Fluoro C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl or -L 4 -R 21e wherein the phenyl and 5- to 6-membered heteroaryl are independently unsubstituted or substituted with j R d is replaced by Or, R 21c and R21d C together with the carbon atoms connected to them 3-6 forming a cycloalkyl or a 3- to 6-membered heterocycloalkyl; L 4 is C 1-4 is alkylene, R 21e OH, CN, C 1-4 alkoxy, phenyl, or 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl are independently unsubstituted or d is replaced by each j is independently 1, 2, 3, or 4; each r is independently 0, 1, 2, 3, or 4; Each R d and R f are independently F, Cl, OH, CN, NO2, C 1-4 Alkyl, Fluoro C 1-4 Alkyl or C 1-4 is an alkoxy, the number of heteroatoms in said heterocycloalkyl and heteroaryl is independently 1, 2, 3, or 4, and each heteroatom is independently N, O, or S; In Formula XXIV, the carbon atom labeled with * is in the R configuration, the S configuration, or a mixture of the two; the carbon atom labeled with #, if a chiral carbon atom, is in the R configuration, the S configuration, or a mixture of the two; and the carbon atom labeled with A, if a chiral carbon atom, is in the R configuration, the S configuration, or a mixture of the two.

[0371] In some embodiments, in the compound of formula XXIV, R 3d is H. In some embodiments, in the compound of formula XXIV, R 7a is H and R 7b is OH.

[0372] In some embodiments, in the compound of formula XXIV, R 7a and R 7b together with the carbon atoms connected to them

[0373] [ka] Form.

[0374] In some embodiments, in the compound of formula XXIV, R 8a is H. In some embodiments, in the compound of Formula XXIV described in any one of the preceding embodiments, R 22 teeth,

[0375] [ka] is.

[0376] In some embodiments, in the compound of Formula XXIV described in any one of the preceding embodiments, the carbon atom marked with * has the R configuration. In some embodiments, in the compound of Formula XXIV described in any one of the preceding embodiments, the carbon atom marked with * has the S configuration.

[0377] In some embodiments, in the compound of formula XXIV described in any one of the above embodiments, the carbon atom marked with * is a mixture of S and R configurations, for example, S:R=1:1.

[0378] In some embodiments, in the compound of Formula XXIV described in any one of the preceding embodiments, the carbon atom marked with # has the R configuration. In some embodiments, in the compound of Formula XXIV described in any one of the preceding embodiments, the carbon atom labeled with # has the S configuration.

[0379] In some embodiments, in the compound of formula XXIV described in any one of the above embodiments, the carbon atom marked with # is a mixture of S and R configurations, for example, S:R=1:1.

[0380] In some embodiments, in the compound of Formula XXIV described in any one of the previous embodiments, the carbon atom labeled A is in the R configuration. In some embodiments, in the compound of Formula XXIV described in any one of the preceding embodiments, the carbon atom labeled A is in the S configuration.

[0381] In some embodiments, in the compound of formula XXIV described in any one of the above embodiments, the carbon atom labeled A is a mixture of S and R configurations, for example, S:R=1:1.

[0382] In some embodiments, the compound of formula XXIV is any one of the following compounds:

[0383] [ka]

[0384] The present invention further provides a compound of formula XXVI or a pharmaceutically acceptable salt thereof.

[0385] [ka]

[0386] R 3a and R 3b is as defined in any one of the groups below. (i)R 3a is H and R 3b is -NH, -NHS(O)CH, -NHS(O)CHCHCH, -NHS(O)CHCHCHCH, -NHS(O)CF, -NH-C(O)-CHOH, -CHOH, -COOH, -C(O)-OCH, -CH(CH)OH, -CH-C(O)-CHOH or -CH(OH)-CHCHOH; (ii)R 3ais CH3 and R 3b is -OH, and (iii)R 3a and R 3b together with the carbon atoms connected to them

[0387] [ka] Forming

[0388] R 4a is as defined in any one embodiment of formula XXI; R 4b is as defined in any one embodiment of formula XXI; R 5 is as defined in any one embodiment of formula XVI; R 22 teeth,

[0389] [ka] or R 21 and R 21 is as defined in any one embodiment of formula XXI;

[0390] In formula XXVI, the carbon atom labeled with * is in the R configuration, the S configuration, or a mixture of the two; the carbon atom labeled with #, if a chiral carbon atom, is in the R configuration, the S configuration, or a mixture of the two; and the carbon atom labeled with &, if a chiral carbon atom, is in the R configuration, the S configuration, or a mixture of the two.

[0391] In some embodiments, in the compound of Formula XXVI, R 3a and R 3b is as defined in any one of the groups below. (i)R 3a is H and R 3bis -NH, -NHS(O)CH, -NHS(O)CHCHCH, -NHS(O)CHCHCHCH, -NHS(O)CF, -NH-C(O)-CHOH, -CHOH, -COOH, -C(O)-OCH, -CH(CH)OH, -CH-C(O)-CHOH or -CH(OH)-CHCHOH; (ii)R 3a is CH3 and R 3b is -OH, and (iii)R 3a and R 3b together with the carbon atoms connected to them

[0392] [ka] Forming

[0393] R 4a is H, F, CH3, CF3 or OH, R 4b is H, F, OH or CF3, Or, R 4a and R 4b together with the carbon atoms connected to them

[0394] [ka] Forming

[0395] R 5 is H or R 5c and R 5c is OH or F, R 22 teeth,

[0396] [ka] or R 21 and

[0397] R 21 -L 1 -C(O)R A , -L1 -S(O)2R A , -L 1 -R B ,

[0398] [ka] , -L 2 -R C or -L 3 -R D and

[0399] Each L 1 and L 2 is independently a single bond, —CH—, —(CH)—, —(CH)—, —(CH)—, —(CH)—, —(CH)—, or —(CH)—, wherein one CH— moiety in said —CH—, —(CH)—, —(CH)—, —(CH)—, and —(CH)— is optionally replaced by —X—; L 3 is —(CH)—, —(CH)—, —(CH)—, —(CH)—, or —(CH)—, wherein one CH— moiety in —(CH)—, —(CH)—, —(CH)—, —(CH)—, or —(CH)— is replaced by —Y—; Each X is independently -CHR 5a -, -CR 5a R 5b - or -Y-, Each R 5a and R 5b are independently F, C 1-4 Alkyl or Fluoro C 1-4 is alkyl, Each Y is independently —O—, —NH—, —N(C 1-4 alkyl)-,

[0400] [ka] , -CH=CH-,

[0401] [ka] or -CHR g - and

[0402] R g -C 1-4 alkylene-OH, Each R A independently -NR 21a R 21b and R B is -N(R 21a )-C(O)R 21b or -N(R 21a )-S(O)2R 21b and R D -OH, -CHOH, R C , —CH(CH3)—OH or —C(CH3)2—OH; Each R C are independently -C(R 21c )(R 21d )-OH, CN, -C(O)R E , NH2, C 1-4 Alkoxy,

[0403] [ka] , 3- to 6-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is unsubstituted or has p R c is replaced by

[0404] R E is C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl and 3- to 6-membered heterocycloalkyl are independently unsubstituted or substituted with m R a is replaced by Each R 21a are independently H, C 1-6 Alkyl, C3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl and 3- to 6-membered heterocycloalkyl are independently unsubstituted or substituted with m R a is replaced by Each R 21b are independently H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5- to 10-membered heteroaryl are independently unsubstituted or q R b is replaced by Or, -NR 21a R 21b In R 21a and R 21b together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocycloalkyl, wherein said 3- to 10-membered heterocycloalkyl is unsubstituted or has p R c is replaced by each m, p, and q is independently 1, 2, 3, 4, or 5; Each R a , R b and R c are independently F, Cl, OH, COOH, CN, NO2, and C 1-4 Alkyl, Fluoro C 1-4 Alkyl, C 1-4 Alkoxy,

[0405] [ka] and

[0406] R 21c are H, F, and C 1-4 Alkyl, Fluoro C 1-4 Alkyl, C 2-4 Alkenyl or C 3-6is cycloalkyl, R 21d is F, C 2-4 Alkyl, Fluoro C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl or -L 4 -R 21e wherein the phenyl and 5- to 6-membered heteroaryl are independently unsubstituted or substituted with j R d is replaced by Or, R 21c and R 21d C together with the carbon atoms connected to them 3-6 Cyclo alkyl or 3- to 6-membered heterocycloalkyl; L 4 is C 1-4 is alkylene, R 21e OH, CN, C 1-4 alkoxy, phenyl, or 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl are independently unsubstituted or d is replaced by each j is independently 1, 2, 3, or 4; each r is independently 0, 1, 2, 3, or 4; Each R d and R f are independently F, Cl, OH, CN, NO2, C 1-4 Alkyl, Fluoro C 1-4 Alkyl or C 1-4 is an alkoxy, the number of heteroatoms in said heterocycloalkyl and heteroaryl is independently 1, 2, 3, or 4, and each heteroatom is independently N, O, or S; In formula XXVI, the carbon atom labeled with * is in the R configuration, the S configuration, or a mixture of the two; the carbon atom labeled with #, if a chiral carbon atom, is in the R configuration, the S configuration, or a mixture of the two; and the carbon atom labeled with &, if a chiral carbon atom, is in the R configuration, the S configuration, or a mixture of the two.

[0407] In some embodiments, in the compound of Formula XXVI, R 3a and R 3b is as defined in any one of the groups below. a)R 3a is H and R 3b is —NHS(O)CH, —CHOH, —COOH, —C(O)—OCH, or —CH(CH)OH, and b)R 3a is CH3 and R 3b is -OH.

[0408] In some embodiments, in the compound of formula XIX, R 4a is H and R 4b is H. In some embodiments, in the compound of Formula XXVI, R 5 is H.

[0409] In some embodiments, in the compound of Formula XXVI, R 22 teeth,

[0410] [ka] is.

[0411] In some embodiments, in the compound of Formula XXVI described in any one of the previous embodiments, the carbon atom marked with * has the R configuration. In some embodiments, in the compound of Formula XXVI described in any one of the previous embodiments, the carbon atom marked with * has the S configuration.

[0412] In some embodiments, in the compound of formula XXVI described in any one of the above embodiments, the carbon atom marked with * is a mixture of S and R configurations, for example, S:R=1:1.

[0413] In some embodiments, in the compound of formula XXVI according to any one of the preceding embodiments, when the carbon atom in formula XXVI marked with # is a chiral carbon atom, it is in the R configuration.

[0414] In some embodiments, the compound of formula XXVI according to any one of the preceding embodiments is In the compounds of formula XXVI, when the carbon atom marked with # in formula XXVI is a chiral carbon atom, it is in the S configuration.

[0415] In some embodiments, in the compound represented by formula XXVI according to any one of the above embodiments, the carbon atom marked with # in formula XXVI is a mixture of S and R configurations, for example, S:R=1:1.

[0416] In some embodiments, in the compound of formula XXVI according to any one of the preceding embodiments, when the carbon atom in formula XXVI marked with & is a chiral carbon atom, it has the R configuration.

[0417] In some embodiments, in the compound of formula XXVI according to any one of the preceding embodiments, when the carbon atom in formula XXVI marked with & is a chiral carbon atom, it has the S configuration.

[0418] In some embodiments, in the compound represented by formula XXVI according to any one of the above embodiments, the carbon atom marked with & in formula XXVI is a mixture of S and R configurations, for example, S:R=1:1.

[0419] In some embodiments, the compound of formula XXVI is a compound of formula XXVI-1.

[0420] [ka]

[0421] However, *, R 3a and R 3b is as defined in any one embodiment of the present invention. In some embodiments, the compound of formula XXVI is any one of the following compounds:

[0422] [ka]

[0423] The compounds of the present invention can be produced from known starting materials (such as lanosterol) by various conventional reaction methods in the art (such as hydroxyl group protection, double bond ozone oxidation, Wittig reaction, hydrolysis reaction, amide condensation reaction, Grignard reagent addition reaction, reduction reaction, nucleophilic substitution reaction, epoxidation reaction, etc.). Exemplary production methods are described in the production examples of this application.

[0424] For example, the method for preparing compound 37 and its analogs can be carried out by using lanosterol as the starting material, followed by hydroxyl group protection, double bond ozone oxidation, Wittig reaction, hydrolysis, and condensation to obtain compound 37 and its analogs, and the reaction pathway is shown below.

[0425] [ka]

[0426] For example, the method for preparing compound 101 and its analogs can be carried out by using lanosterol as the starting material, protecting the hydroxyl group, ozone oxidation of the double bond, Wittig reaction, hydrolysis, and Grignard reagent addition reaction to obtain compound 101 and its analogs, and the reaction pathway is shown below.

[0427] [ka]

[0428] For example, the method for producing compound 80 and its analogs can be carried out by using lanosterol as the raw material, followed by hydroxyl group protection, double bond ozonation, reduction, two-step substitution, and addition reaction to obtain compound 80 and its analogs, and the reaction pathway is shown below.

[0429] [ka]

[0430] For example, the method for producing compound 125 and its analogs can be carried out by using lanosterol as the raw material, followed by hydroxyl group protection, double bond ozone oxidation, Wittig reaction, hydrolysis, epoxidation, and hydrolysis to obtain compound 125 and its analogs, and the reaction pathway is as follows:

[0431] [ka]

[0432] For example, a method for preparing compound 193 and its analogs can use lanosterol as the starting material and perform hydroxyl group protection, double bond ozonation, double bond substitution, double bond ozonation, reductive amination, condensation, and hydrolysis to obtain compound 193. The reaction pathway for the preparation method is shown in the following diagram.

[0433] [ka]

[0434] The present invention further provides a pharmaceutical composition comprising the compound described above or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical auxiliary. The present invention further provides use of the compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described above, in the manufacture of a medicament for preventing and / or treating diseases such as obesity, hyperlipidemia, fatty liver, diabetes, atherosclerosis, cardiovascular disease, cerebrovascular disease, liver cancer, or skin damage.

[0435] The present invention further provides use of the compound described above or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described above, in the manufacture of a medicament for inhibiting the SREBP pathway. The present invention further provides a method for inhibiting the SREBP pathway, comprising administering to a subject a therapeutically effective amount of a compound described above or a pharmaceutically acceptable salt thereof.

[0436] The present invention further provides a method for preventing and / or treating diseases such as obesity, hyperlipidemia, fatty liver, diabetes, atherosclerosis, cardiovascular disease, cerebrovascular disease, liver cancer, or skin injury, which comprises administering to a subject a therapeutically effective amount of the compound described above or a pharmaceutically acceptable salt thereof.

[0437] [Definitions and Explanations] Unless otherwise stated, the following terms and phrases used herein have the following meanings. Unless otherwise defined, a particular term or phrase should be understood to have its ordinary definition, rather than being indefinite or unclear. When a trade name appears in this specification, it refers to the corresponding product or its active ingredient.

[0438] As used herein, the term "substituted" or "substituent" refers to a group in which a hydrogen atom is replaced with a specified group. Unless the substitution position is otherwise specified, the substituent may be present at any position. may be used, but only if they can be formed into stable or chemically viable chemical compounds.

[0439] [ka] The structure is R 8 indicates that the compound is substituted by multiple R 8 If there is, then each R 8 are the same or different.

[0440] When any variable (e.g., R) occurs more than one time in any composition or structure of a compound, its definition is independent at each occurrence. So, for example, if a group is substituted with 0 to 2 R, then that group is optionally substituted with up to 2 R, and each occurrence of R is an independent option. Also, combinations of substituents and / or variants thereof are permissible only if such combinations result in stable compounds.

[0441] When the linking direction of the linking groups listed herein is not specified, the linking direction may be any, including left to right, right to left, etc. For example, the linking group L in -ALB is -CD-, and when the linking direction of L is not specified, -ALB includes -ACDB and -ADCB.

[0442] When one of the variables is selected from a single bond, the two groups connected thereto are directly linked, for example, when L in ALZ represents a single bond, the structure is actually AZ. As used herein, the term "alkyl" refers to a saturated, straight- or branched-chain monovalent hydrocarbon group. C1-C6 alkyl refers to an alkyl having 1 to 6 carbon atoms. In some embodiments, C1-C6 alkyl can be C1-C4 alkyl. C1-C4 alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0443] As used herein, the term "alkenyl" refers to a straight- or branched-chain monovalent hydrocarbon group containing at least one carbon-carbon double bond. When the alkenyl contains both saturated and unsaturated carbon atoms, it may be bonded to another structure via either a saturated carbon atom or an unsaturated carbon atom. C2-C4 alkenyl refers to an alkenyl having 2, 3, or 4 carbon atoms. Specific examples of alkenyl include, but are not limited to, vinyl and allyl.

[0444] As used herein, the term "alkylene" refers to a saturated, straight-chain or branched-chain divalent hydrocarbon group. C1-C4 alkylene refers to an alkylene having 1 to 4 carbon atoms, specifically methylene, ethylene (e.g., -CH2CH2-, -CH(CH3)-), propylene (e.g., -CH2CH2CH2-, -C(CH3)2-, -CH2CH(CH3)-), and butylene (e.g., -CH2CH2CH2CH2-, -CH(CH3)CH(CH3)-, -CH2CH(CH3)CH2-).

[0445] As used herein, the term "fluoroalkyl" refers to a group formed by replacing one or more hydrogen atoms of an alkyl with fluorine, where alkyl is as defined above. Examples of fluoroalkyl include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, and the like. I can't.

[0446] As used herein, the term "alkoxy" refers to -O-alkyl, where alkyl is as defined above. C1-C4 alkoxy refers to -O-(C1-C4 alkyl), where C1-C4 alkyl is as defined above, i.e., C1-C4 alkoxy may specifically be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy.

[0447] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., fused, spirocyclic, or bridged) cyclic hydrocarbon group. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0448] [ka] These include, but are not limited to: C 3-10 Cycloalkyl specifically includes C3, C4, C5, C6, C7, C8, C9, C 10It may be cycloalkyl. 3-6 Cycloalkyl may specifically be C, C, C, or C cycloalkyl. In some embodiments, cycloalkyl is monocyclic. In some embodiments, cycloalkyl is polycyclic (e.g., fused, spirocyclic, or bridged rings).

[0449] As used herein, the term "heterocycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., fused, spiro, or bridged) ring group formed by carbon atoms and at least one heteroatom, where the heteroatoms are independently selected from N, O, and S. Heterocycloalkyls can be linked to other structures through the carbon atoms and heteroatoms on the ring. Examples of heterocycloalkyls include:

[0450] [ka] Examples of heterocycloalkyl include, but are not limited to, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, and the like. A 3- to 10-membered heterocycloalkyl may specifically be a 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl. A 3- to 6-membered heterocycloalkyl may specifically be a 3-, 4-, 5-, or 6-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is monocyclic. In some embodiments, a heterocycloalkyl is polycyclic (e.g., fused, spiro, or bridged rings).

[0451] As used herein, the term "C 6-10 "Aryl" refers to phenyl or naphthyl. As used herein, the term "heteroaryl" refers to an aromatic monocyclic or fused ring group formed by carbon atoms and at least one heteroatom, where the heteroatom is independently selected from N, O, and S. A 5- to 10-membered heteroaryl may specifically be a 5-, 6-, 7-, 8-, 9-, or 10-membered heteroaryl, for example, a 5- or 6-membered heteroaryl. and 8- to 10-membered fused heteroaryl. 5- to 6-membered heteroaryls are monocyclic, and specific examples include, but are not limited to, pyrrole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, pyridine, pyrimidine, and pyrazine. Examples of 8- to 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 dopyrimidine.

[0452] In this specification, in the chemical structural formula

[0453] [ka] represents the linkage position.

[0454] [ka] is included in the cyclic group,

[0455] [ka] If the ring atom to which the is attached is not specified,

[0456] [ka] may be attached to any ring atom, but only if it results in the formation of a stable or chemically viable chemical entity. For example,

[0457] [ka] teeth,

[0458] [ka] It includes structures such as:

[0459] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed from a suitable non-toxic organic acid, inorganic acid, organic base, or inorganic base with a compound that retains the biological activity of the compound. The organic acid may be any of the various organic acids commonly used in the art that can form salts, 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, hydroxyethylsulfonic acid, naphthalenesulfonic acid, and salicylic acid. The inorganic acid may be any of the various inorganic acids commonly used in the art that can form salts, preferably one or more of hydrochloric acid, sulfuric acid, and phosphoric acid. The organic base may be any of the various organic bases commonly used in the art that can form salts, 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 may be any inorganic base commonly used in the art capable of forming a salt, and is 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 hydrides are preferably sodium hydride and / or potassium hydride. The alkali metal hydroxides are preferably one or more of sodium hydroxide, potassium hydroxide, and lithium hydroxide. The alkali metal alkoxides are preferably one or more of sodium methoxide, sodium ethoxide, potassium tert-butoxide, and sodium tert-butoxide.

[0460] In chemical structures, solid wedge bonds (

[0461] [ka] ) and dotted wedge bond (

[0462] [ka] ) to indicate the absolute configuration of one stereocenter, and a solid rod bond (

[0463] [ka] ) and dotted bar bonds (

[0464] [ka] ) represents the relative configuration of the stereocenter.

[0465] [ka] " does not specify the configuration, i.e., when configurational isomerism exists in the chemical structure, the bond "

[0466] [ka] "teeth,"

[0467] [ka] " or "

[0468] [ka] " or "

[0469] [ka] " and "

[0470] [ka] " can simultaneously contain two configurations (e.g., "

[0471] [ka] " and "

[0472] [ka] " is a 1:1 ratio). When a specific configuration of a carbon-carbon double bond is not specified, it may be E or Z. Stereoisomers can be prepared by conventional techniques such as, but not limited to, synthesis using chiral starting materials, chiral separation, or resolved by high performance liquid chromatography (HPLC) using a chiral column.

[0473] As used herein, the term "subject" includes any animal, preferably a mammal, and more preferably a human. As used herein, the term "effective amount" refers to a non-toxic amount of a drug or agent sufficient to achieve a desired effect. Determining an effective amount varies from person to person and depends on the age and general condition of the subject, as well as the specific active substance; an appropriate effective amount in each case can be determined by one skilled in the art based on routine testing.

[0474] The above-mentioned preferred conditions can be arbitrarily combined to obtain each preferred embodiment of the present invention, provided that this does not violate the common knowledge of the art. The reagents and raw materials used in the present invention are commercially available.

[0475] Positive advancement effects of the present invention: The present invention provides novel compounds that have inhibitory activity against the SREBP pathway and can be used to prevent and / or treat diseases such as obesity, hyperlipidemia, fatty liver, diabetes, atherosclerosis, cardiovascular disease, cerebrovascular disease, liver cancer, and skin damage. [Brief explanation of the drawings]

[0476] [Figure 1] 25-hydroxylanosterol inhibits AMLN diet-induced weight gain in mice. [Figure 2] The effect of 25-hydroxylanosterol on food intake in mice. [Figure 3] 2 shows the reduction of total cholesterol content in the blood of mice by 25-hydroxylanosterol. [Figure 4] 1 shows the reduction of total triglyceride content in the blood of mice by 25-hydroxylanosterol. [Figure 5] 1 shows the reduction of total cholesterol content in mouse liver by 25-hydroxylanosterol. [Figure 6] 1 shows the reduction of total triglyceride content in mouse liver by 25-hydroxylanosterol. [Figure 7] Figure 1 shows the reduction of blood aspartate aminotransferase (AST) levels in mice by 25-hydroxylanosterol. [Figure 8] Figure 1 shows the reduction of alanine aminotransferase (ALT) levels in the blood of mice by 25-hydroxylanosterol. [Figure 9] HE staining of mouse liver sections: C57BL / 6J CD group. [Figure 10] HE staining of mouse liver sections: Ldlr- / - CD group. [Figure 11] HE staining results of mouse liver sections: Ldlr- / - AMLN group. [Figure 12] HE staining results of mouse liver sections: Ldlr- / - AMLN+25-HL group. [Figure 13] The results of HE staining of mouse liver sections from the four groups and the quantitative statistical results of NAFLD activity scores are shown. [Figure 14] Oil Red O staining of mouse liver sections: C57BL / 6J CD group. [Figure 15] Oil Red O staining of mouse liver sections: Ldlr- / - CD group. [Figure 16] Oil Red O staining of mouse liver sections: Ldlr- / - AMLN group. [Figure 17] Oil Red O staining of mouse liver sections: Ldlr- / - AMLN+25-HL group. [Figure 18] Quantitative results of Oil Red O staining of mouse liver sections from four groups are shown. [Figure 19] Sirius red staining of mouse liver sections: C57BL / 6J CD group. [Figure 20] Sirius red staining of mouse liver sections: Ldlr- / - CD group. [Figure 21] Sirius red staining of mouse liver sections: Ldlr- / - AMLN group. [Figure 22] Sirius red staining of mouse liver sections: Ldlr- / - AMLN+25-HL group. [Figure 23] Quantitative results of Sirius Red staining of mouse liver sections from four groups are shown. [Figure 24] F4 / 80 immunostaining results of mouse liver sections and polarized light imaging results showing cholesterol crystals: C57BL / 6J CD group. [Figure 25] F4 / 80 immunostaining results of mouse liver sections and polarized light imaging results showing cholesterol crystals: Ldlr − / − CD group. [Figure 26] F4 / 80 immunostaining results of mouse liver sections and polarized light imaging results showing cholesterol crystals: Ldlr − / − AMLN group. [Figure 27] F4 / 80 immunostaining results of mouse liver sections and polarized light imaging results showing cholesterol crystals: Ldlr- / - AMLN+25-HL group. [Figure 28] Quantitative results of F4 / 80 immunostaining in liver sections from four groups of mice are shown. [Figure 29] 1 shows quantitative results of polarized light imaging images showing cholesterol crystals in mouse liver sections from four groups. [Figure 30] Sudan Red IV staining of the aortic tree of mice: C57BL / 6J CD group. [Figure 31] Sudan Red IV staining of the mouse aortic tree: Ldlr- / - CD group. [Figure 32] Sudan Red IV staining results of the mouse aortic tree: Ldlr- / - AMLN group. [Figure 33] Sudan Red IV staining results of the mouse aortic tree: Ldlr- / - AMLN+25-HL group. [Figure 34] Quantitative results of Sudan Red IV staining of the mouse aortic tree from four groups are shown. [Figure 35] We show that 25-hydroxylanosterol reduces the expression of adipogenesis-related genes (Hmgcs, Hmgcr, SCD1, FASN) in liver organoids. [Figure 36] We show that 25-hydroxylanosterol reduces the expression of fibrosis-related genes (ol1a1, αSMA) in liver organoids. [Figure 37] Brightfield imaging of mouse liver organoids: Vehicle control group. [Figure 38] Brightfield imaging results of mouse liver organoids: obeticholic acid 1 μM group. [Figure 39] Brightfield imaging results of mouse liver organoids: obeticholic acid 3 μM group. [Figure 40] Brightfield imaging results of mouse liver organoids: 25-HL 1 μM group. [Figure 41] Brightfield imaging results of mouse liver organoids: 25-HL 3 μM group. [Figure 42] Nile red staining of mouse liver organoids: Vehicle control group. [Figure 43] Nile red staining results for mouse liver organoids: obeticholic acid 1 μM group. [Figure 44] Nile red staining results for mouse liver organoids: obeticholic acid 3 μM group. [Figure 45] Results of Nile Red staining of mouse liver organoids: 25-HL 1 μM group. [Figure 46] Nile red staining of mouse liver organoids: 25-HL 3 μM group. [Figure 47] Quantitative results of Nile Red staining of five groups of mouse liver organoids are shown. [Figure 48] Immunofluorescence staining of the fibrosis marker protein αSMA in mouse liver organoids: Vehicle control group. [Figure 49] Immunofluorescence staining of the fibrosis marker protein αSMA in mouse liver organoids: obeticholic acid 1 μM group. [Figure 50] Immunofluorescence staining of the fibrosis marker protein αSMA in mouse liver organoids: obeticholic acid 3 μM group. [Figure 51] Immunofluorescence staining of the fibrosis marker protein αSMA in mouse liver organoids: 25-HL 1 μM group. [Figure 52] Immunofluorescence staining of the fibrosis marker protein αSMA in mouse liver organoids: 25-HL 3 μM group. [Figure 53] Quantitative results of immunofluorescence staining of the fibrosis marker protein αSMA in five groups of mouse liver organoids are shown. [Figure 54] 1 is a complete 2D NMR spectrum of compound 151-7. [Figure 55] 1 is a partially expanded two-dimensional NMR spectrum of compound 151-7. [Figure 56] 1 is a complete 2D NMR spectrum of compound 151. [Figure 57] 1 is a partially expanded two-dimensional NMR spectrum of compound 151. [Figure 58] 1 is a complete 2D NMR spectrum of compound 203. [Figure 59] 1 is a partially expanded two-dimensional NMR spectrum of compound 203. [Figure 60] 1 is a complete 2D NMR spectrum of compound 206. [Figure 61] 1 is a partially expanded two-dimensional NMR spectrum of compound 206. DETAILED DESCRIPTION OF THE INVENTION

[0477] The present invention will be further described below in the form of examples, but the present invention is not limited to the scope of the examples. In the following examples, experimental methods for which specific conditions are not described are selected according to conventional methods and conditions or product instructions.

[0478] In the examples below, 25-hydroxylanosterol (25-HL) refers to the compound of Example 68. Biological Test Examples Animals: Adult male C57BL / 6J mice were purchased from Shanghai SLAC, and low-density lipoprotein receptor gene knockout mice (Ldlr - / - Mice (T001464) were purchased from Gempharmatech Co., Ltd. All mice were The mice were housed under pathogen-free conditions, maintained under a 12-hour light / dark regime, and allowed free access to water and food. The vehicle for intragastric administration was 0.5% Tween-80, 0.5% methylcellulose, and 0.9% sodium chloride. The AMLN diet (AMLN, Dyets) contained 40% (kcal%) fat (80% of which was trans fat), 22% (mass%) fructose, and 2% (mass%) cholesterol.

[0479] 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 Pharmaceutical Co., Ltd. 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 kits were purchased from Shanghai Kehua Bio-Engineering Co., Ltd. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) kits were purchased from Lai Er Bio-tech. Hematoxylin and 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 Bioengineering (Shanghai) Co., Ltd. Nile Red (HY-D0718) was purchased from MCE.

[0480] Antibodies used for immunofluorescence staining analysis were anti-alpha smooth muscle actin (αSMA, ab7817, 1:500) antibody, purchased from Abcam; secondary antibody fluorescein (FITC)-conjugated goat anti-mouse IgG (H+L) (115-095-003), purchased from Jackson Immunoresearch; primary antibody anti-F4 / 80 (14-4801-85, Invitrogen, 1:100); fluorescent secondary antibody Alexa Fluor Plus 488-conjugated goat anti-rat IgG (A-11006, 1:500), purchased from Invitrogen.

[0481] Biological Test Example 1: Cell Culture Human hepatocellular carcinoma cell line Huh-7 / SRE-Luc was cultured in a medium containing DMEM, 10% fetal bovine serum, 100 units / ml penicillin, 100 μg / ml streptomycin, and 200 μg / ml G418.

[0482] Biological Test Example 2: SREBP Luciferase Reporter Gene System The Huh-7 / SRE-Luc cell line stably expresses LDLR promoter-luciferase and green fluorescent protein (GFP) in the human hepatocellular carcinoma cell line Huh-7. The LDLR promoter region contains a sterol-regulatory element (SRE), enabling it to respond effectively and sensitively to regulation by the transcription factor SREBP. The GFP signal serves as an internal reference for 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 research, we used this cell line to screen for inhibitors that can effectively inhibit the SREBP signaling pathway. Cells were cultured in sterol-deficient medium (5% lipoprotein-depleted serum, 2 μM lovastatin, 10 μM mevalonate) and the corresponding concentrations of compounds were added for 16 h. After compound treatment was completed, cells were lysed with lysis solution (E397A, Promega), luciferase substrate (E1500, Promega) was added, and then the cells were analyzed by BioTek SRE-driven luciferase activity was measured using a Synergy HTX microplate reader (including but not limited to this type of instrument). The fluorescence intensity of enhanced green fluorescent protein (EGFP) was also measured using the BioTek microplate reader (including but not limited to this type of instrument) described above and used as an internal reference. The ratio of SRE-driven fluorescein activity divided by the fluorescence intensity of green fluorescent protein was used as an index of SREBP pathway activity. The test data for each test compound were analyzed using Prism software to determine the compound's IC value. 50 parameters were obtained.

[0483] Biological Test Example 3: Real-time fluorescent quantitative PCR Liver or liver organoid samples were homogenized in TRI Reagent (T9424, Sigma) and total RNA was extracted according to the manufacturer's instructions. 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 the relative amounts of gene mRNA were quantified using the relative CTR method. The primer sequences used are shown below.

[0484] [Table 1] JPEG2025504580000194.jpg82169

[0485] Biological Test Example 4 Measurement of serum and liver metabolic parameters After drug treatment, mice were deprived of food and fasted for 4 hours. Then, they were euthanized, and their blood and livers were collected. After blood clotting, the samples were centrifuged at 1,500 g for 10 minutes at 4°C, and the supernatant was used as serum. Lipids in the liver were extracted using the chloroform / methanol method. The samples were homogenized using a Precelly 24 homogenizer and centrifuged at 1,6000 g for 10 minutes at 4°C. The organic phase was transferred to a new tube, dried with nitrogen gas, and dissolved in ethanol. Total cholesterol and triglyceride levels in blood and liver were measured using cholesterol and triglyceride kits (Shanghai Kehua Bio-Engineering Co., Ltd.), respectively. Serum ALT (LE-M0477, Lai Er Bio-tech) and AST (LE-M0568, Lai Er Bio-tech) were measured using an analytical system from Sysmex Medical Electronics (Shanghai) Co., Ltd., according to the respective manufacturer's instructions.

[0486] Biological Test Example 5: Liver Tissue Section Analysis Hematoxylin-eosin staining: Extracted livers were fixed in 4% paraformaldehyde at 4°C, embedded in paraffin, and sectioned at 7 μm thickness using a paraffin microtome (Leica RM2235). After deparaffinization and rehydration, the sections were stained using a hematoxylin-eosin staining kit (6765001, 6766010, Thermo Scientific). Images were taken with an Olympus VS 120 slide microscope and quantified using ImageJ software. Oil Red O staining: Livers were embedded in OCT embedding medium (Leica), sliced ​​at 7 μm thickness using a Leica CM1950 cryostat, and stained with Oil Red O (O0625, Sigma). Images were taken with an Olympus VS 120 slide microscope and quantified using ImageJ software. Sirius Red collagen staining: Paraffin sections of liver were deparaffinized and rehydrated, then stained using the Sirius Red staining kit (ab150681, Abcam) according to the manufacturer's instructions. Immunofluorescence staining: Livers were embedded in OCT embedding medium (Leica) and sliced ​​at a thickness of 7 μm using a freezing microtome (Leica CM1950). Frozen sections were stained with anti-F4 / 80 rat monoclonal antibody (14-4801-85, Invitrogen, 1:100), Alexa Fluor 100 (F4 / 80), and 100 μM of ... 488-conjugated goat anti-rat IgG secondary antibody (A-11006, Invitrogen, 1 After staining, the sections were stained with F4 / F80 and DAPI (Sigma) and specific cell nuclei were stained with DAPI (Sigma). After staining, photos were taken using a spinning disk confocal microscope (Nikon CSU-W1 SoRa) and quantitative analysis was performed using ImageJ software. Polarized imaging of cholesterol crystals: After staining the frozen sections with F4 / F80 and DAPI, the sections were imaged using a spinning disk confocal microscope (Nikon CSU-W1) equipped with a polarizing filter. Photographs were taken using SoRa) and quantification was performed using ImageJ software.

[0487] Biological Test Example 6 Isolation of Mouse Arterial Tree and Sudan Red IV Staining of Atherosclerotic Plaques After the mouse drug administration experiment was completed, the aorta was isolated and fixed in 4% PFA. Perivascular adipose tissue was removed using ophthalmic forceps under a stereomicroscope. The aorta was then stained with Sudan IV, and the atherosclerotic plaques were washed with 70% ethanol. After staining, the aortic tree was imaged using a ZEISS Axio Zoom.V16 stereomicroscope. Atherosclerotic lesions were quantified using ImageJ software.

[0488] Biological Test Example 7 Production and Culture of Mouse Liver Organoids A fatty liver model was established by feeding 12-week-old C57BL / 6N mice a fatty liver-inducing diet (TrophicDiet, TP2630052A, containing 10.2% kcal of protein, 37.3% kcal of carbohydrate, and 52.6% kcal of fat) and fructose-containing drinking water (23.1 g of fructose and 18.9 g of glucose dissolved in 1 L of water, then filtered and sterilized) for 16 weeks. To generate fatty liver organoids, liver tissue from fatty liver mice was minced and digested for 30–60 min in digestion buffer at 37 °C. The digestion buffer contained DMEM / F-12 (Cytiva, SH30023.01), 2.5 mg / mL collagenase D (Roche, COLLD-RO), and 0.1 mg / mL DNase I (Sigma-Aldrich, DN25). Isolated single hepatocytes were filtered through a 70 μm filter and washed once. Cells were harvested by centrifugation and resuspended in a 1:3 mixture of basement membrane extract (BME) (R&D Systems, 3533-010-02) and the medium was adjusted to 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. Before administration, organoids were digested with trypsin (Gibco, Cat# 25200072) and resuspended. After 24 hours, DMSO was used as a blank control, and the organoids were replaced with medium containing different concentrations of OCA or 25-HL. Fatty liver organoids were divided into five groups (1‰ DMSO, 1 μM OCA, 3 μM OCA, 1 μM 25-HL, and 3 μM 25-HL) and each group underwent drug treatment for 72 hours.

[0489] Biological Test Example 8 Histochemical Staining of Mouse Liver Organoids Immunocytochemistry: Organoids were fixed in immunostaining fixative (Beyotime Biotechnology, P0098) overnight at 4°C. Then, they were washed with PBS and 0.5% The organoids were treated with Triton X-100 in PBS at room temperature for 20 minutes. Then, the organoids were treated with 10% goat serum in PBS blocking solution at room temperature for 1 hour and then incubated with a primary antibody (Anti-alpha smooth muscle actin, ab7817, Abcam, diluted 1:500) at 4°C overnight. The next day, the organoids were washed and incubated with a secondary antibody, fluorescein (FITC)-conjugated goat anti-mouse IgG (H+L) (Jackson Immunoresearch, 115-095-003). Cell nuclei were visualized with a fluorescent shield. TM (Fluorescent Shield TM ) and re-stained with DAPI (Sigma-Aldrich, F6057).

[0490] To observe lipid droplets, organoids were fixed with 4% paraformaldehyde (PFA) for 1 hour and stained with 250 nmol / L Nile Red (MCE, HY-D0718) at room temperature for 3 minutes. Organoids were washed twice with PBS before imaging. Stained organoids were observed using a Dragonfly high-speed confocal microscope system (Andor, Dragonfly 200).

[0491] Biological Test Example 9 Inhibitory Effects of Compounds of the Present Invention on the SREBP Pathway 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. 50 The values ​​are as shown in Table 1.

[0492] [Table 2] JPEG2025504580000196.jpg207170JPEG2025504580000197.jpg215170JPEG20255045800001 98.jpg238170JPEG2025504580000199.jpg213170JPEG2025504580000200.jpg202170JPEG202 5504580000201.jpg215170JPEG2025504580000202.jpg235170JPEG2025504580000203.jpg23 4170JPEG2025504580000204.jpg209170JPEG2025504580000205.jpg239170JPEG20255045800 00206.jpg198170JPEG2025504580000207.jpg238170JPEG2025504580000208.jpg209170JPE G2025504580000209.jpg204170JPEG2025504580000210.jpg241170JPEG2025504580000211.j pg201170JPEG2025504580000212.jpg207170JPEG2025504580000213.jpg193170JPEG2025504 580000214.jpg227170JPEG2025504580000215.jpg174170JPEG2025504580000216.jpg118170

[0493] Biological Testing Example 10 25-Hydroxylanosterol lowers blood lipid levels and reduces fatty liver and liver damage. Elevated blood lipid levels and hepatic lipid accumulation are known to be high risk factors for fatty liver. Therefore, the present inventors further analyzed whether 25-hydroxylanosterol can alleviate typical symptoms of diet-induced fatty liver in mice, namely, lipid accumulation, liver damage, inflammation, and fibrosis.

[0494] 8-week-old male C57BL / 6J mice and male Ldlr - / -Mice (T001464, Gempharmatech Co., Ltd.) were purchased and divided into groups, fed different diets, and treated with different drugs. The mice were randomly divided into four groups, with 8–9 mice per group. One group of C57BL / 6J wild-type mice was fed a basal chow diet (CD) and served as the vehicle control group. The other three groups were all Ldlr - / - These are gene knockout mice, and the mice were fed a basal diet (CD) as a solvent control, and an AMLN diet (AMLN diet, containing 20% ​​fat, 22% fructose, and 2% cholesterol) vehicle control group, AMLN diet 25-hydroxylanosterol-treated group (25-hydroxylanosterol-treated group) The dose was 30 mg / kg / day. Four groups of mice were intragastrically administered once daily, and changes in food intake and body weight were monitored during the treatment period. After 8 weeks, blood and liver samples were collected and analyzed for blood lipids, liver lipids, and liver injury phenotypes.

[0495] The results are shown in Figures 1 to 8, where Figure 1 shows the statistical results of weekly weight measurements of mice in each group, Figure 2 shows the cumulative statistics of food intake of mice in each group, Figure 3 shows that 25-hydroxylanosterol reduces the total cholesterol content in the mouse blood, Figure 4 shows that 25-hydroxylanosterol reduces the total triglyceride content in the mouse blood, Figure 5 shows that 25-hydroxylanosterol reduces the total cholesterol content in the mouse liver, Figure 6 shows that 25-hydroxylanosterol reduces the total triglyceride content in the mouse liver, Figure 7 shows that 25-hydroxylanosterol reduces the blood aspartate aminotransferase (AST) level in the mouse, and Figure 8 shows that 25-hydroxylanosterol reduces the blood alanine aminotransferase (ALT) level in the mouse.

[0496] In Figures 1 and 2, P values ​​were calculated using a statistical two-way (Dunnett's multiple comparisons test) analysis of variance, with * representing P<0.05 and ns representing no statistical difference. In Figures 3-8, data are presented as mean ± standard deviation. P values ​​were calculated using one-way ANOVA, with * representing P<0.05, ** representing P<0.01, and *** representing P<0.001.

[0497] The results showed that LDLr was increased by 25-hydroxylanosterol administration while feeding the AMLN diet. - / - After 8 weeks of continuous administration, mice in the AMLN diet showed significantly reduced weight gain compared to the vehicle control group. This indicates that 25-hydroxylanosterol has a significant inhibitory effect on AMLN diet-induced weight gain. The pathological features of fatty liver disease mainly include hepatic steatosis, liver injury, inflammatory infiltration, and fibrosis. After 8 weeks of administration to four groups of mice, we first examined changes in blood lipid levels (total cholesterol, total triglycerides) and liver lipid levels (total cholesterol and total triglycerides). As shown in Figures 3 and 4, the 25-hydroxylanosterol group significantly reduced serum total cholesterol and total triglyceride levels compared to the control group. At the same time, as shown in Figures 5 and 6, 25-hydroxylanosterol significantly reduced total cholesterol and total triglyceride levels in the mouse liver. These results demonstrate the significant efficacy of 25-hydroxylanosterol in lowering blood lipids and liver lipids. As can be seen from Figures 7 and 8, both aspartate aminotransferase (AST) and alanine aminotransferase (ALT), which are liver damage markers, were significantly reduced by 25-hydroxylanosterol, indicating that 25-hydroxylanosterol has an excellent effect on improving liver damage.

[0498] Biological Test Example 11 25-Hydroxylanosterol Delays Fatty Liver and Atherosclerosis Furthermore, the inventors performed various staining or immunohistochemical procedures on liver tissue sections of mice from each group to analyze changes in hepatic lipid accumulation and fatty liver phenotype. The results are shown in Figures 9 to 29, where Figures 9 to 13 show the results of HE staining of mouse liver sections and the quantitative results of NAFLD activity scores, indicating that 25-hydroxylanosterol alleviates hepatic steatosis and significantly reduces NAFLD activity scores. Figures 14 to 18 show the quantitative results of Oil Red O staining of mouse liver sections, indicating that 25-hydroxylanosterol reduces hepatic lipid droplets. Figures 19 to 23 show the results of Sirius Red staining and quantification of mouse liver sections, indicating that 25-hydroxylanosterol reduces hepatic fibrosis. Figures 24 to 29 show the results of F4 / 80 immunostaining and quantification of mouse liver sections, and cholesterol crystals. Quantitative results from polarized light imaging showed that 25-hydroxylanosterol reduced Kupffer cell aggregation and cholesterol crystal formation in the liver.

[0499] Quantitative analysis in Figures 9-8 was performed using Image J software, and data are expressed as mean ± standard deviation. P values ​​were calculated by one-way ANOVA, with * representing P<0.05, ** representing P<0.01, and *** representing P<0.001.

[0500] The results are shown in hematoxylin-eosin staining in Figures 9-13. - / -After 8 weeks of feeding the AMLN diet, mice had significant liver damage, including large, foamy lipid droplets and foamy degenerated hepatocytes. Compared with the control group, 25-hydroxylanosterol significantly reduced these phenotypes. At the same time, as shown by the results of Oil Red O staining of liver tissue sections in Figures 14-18, 25-hydroxylanosterol significantly reduced the accumulation of lipid droplets containing neutral lipids, including cholesterol and fatty acids, in the liver compared with the control group. These results are consistent with the results of 25-hydroxylanosterol reducing hepatic lipid content in Figures 1-8, demonstrating that 25-hydroxylanosterol effectively ameliorates the hepatic lipid accumulation phenotype induced by the AMLN diet. Furthermore, the present invention analyzed changes in fatty liver-associated inflammation and fibrosis phenotypes in the liver. The immunofluorescence staining results in Figures 24-29 show that the vehicle control LDLr significantly reduced the accumulation of lipid droplets in the liver compared with the control group. - / -In AMLN-fed mice, F4 / 80-specific staining demonstrated that Kupffer cells aggregated with each other and formed coronary structures around cholesterol crystals (enlarged views in Figures 24-27). 25-hydroxylanosterol significantly reduced the coronary structures formed by Kupffer cells, indicating that 25-hydroxylanosterol can significantly alleviate inflammatory infiltration in the liver. Polarized imaging of cholesterol crystals in liver sections showed that in vehicle-controlled mice, the coronary structures formed by Kupffer cells contained a large amount of cholesterol crystals. Compared to simple steatosis, these cholesterol crystals and coronary structures formed by Kupffer cells are a typical feature of fatty liver. Macrophages are attracted to cholesterol crystals and attempt to remove these residual lipid droplets, consistent with the phenomenon described in atherosclerosis. More importantly, 25-hydroxylanosterol significantly reduced the number of coronary structures and cholesterol crystals (Figures 24-29). At the same time, the Sirius Red staining results (Figures 19-23) showed that 25-hydroxylanosterol significantly reduced the fibrotic phenotype of collagen fibrillogenesis in mouse liver tissue sections. These results suggest that 25-hydroxylanosterol can reduce hepatic fat accumulation and symptoms of fatty liver, and may be used to prevent and / or treat diseases such as hyperlipidemia and fatty liver.

[0501] Ldlr given AMLN - / - Mice are also commonly used as a model of atherosclerosis, allowing us to simultaneously study fatty liver and atherosclerosis. - / -Mice were fed an AMLN diet and simultaneously administered intragastrically once daily for a total of 8 weeks. After euthanasia, the aortas were isolated and fixed in 4% paraformaldehyde. Perivascular adipose tissue was removed under a stereomicroscope, stained with Sudan Red IV, and rinsed with 70% ethanol. The aortic tree was imaged using a stereomicroscope (Axio Zoom V16, Zeiss, Germany). Atherosclerotic plaques were quantitatively analyzed using ImageJ software.

[0502] The results are shown in Figures 30 to 34, which show the quantitative results of Sudan Red IV staining of mouse aortic trees, and demonstrate that 25-hydroxylanosterol reduced the formation of atherosclerotic plaques.

[0503] As a result, after 8 weeks of continuous administration, the aortic tree of each group of mice was isolated and the aortic suprarenal When RGB IV lipid-specific staining was performed, 25-hydroxylanosterol significantly reduced the formation and number of atherosclerotic plaques compared to the control group of mice, as shown in Figures 30-34. 25-hydroxylanosterol has the effect of delaying the formation of atherosclerosis.

[0504] The data in Figures 1-8 to 9-34 show that 25-hydroxylanosterol reduces elevated blood lipid levels, reduces liver fat accumulation, cholesterol crystals, liver cell damage, inflammatory infiltration, and fibrosis, and reduces the formation and number of atherosclerotic plaques. This indicates that 25-hydroxylanosterol has excellent therapeutic effects on hyperlipidemia, fatty liver, and atherosclerosis.

[0505] Biological Test Example 12 Using in vitro liver organoids, the inhibitory effect of 25-hydroxylanosterol on lipogenesis and fibrosis in fatty liver was demonstrated. To distinguish whether the inhibitory effect of 25-hydroxylanosterol is due to a direct effect on the liver or a systemic effect, we used 3D liver organoids as an in vitro fatty liver research model and analyzed the effect of 25-hydroxylanosterol on the expression of lipogenesis and fibrosis marker molecules in liver organoids. We established a fatty liver model by administering a fatty liver-inducing diet (TrophicDiet, TP2630052A, containing 10.2 kcal of protein, 37.3 kcal of carbohydrates, and 52.6 kcal of fat) and fructose-containing drinking water (23.1 g of fructose and 18.9 g of glucose dissolved in 1 L of water, then filtered and sterilized) to 12-week-old C57BL / 6N mice for 16 weeks. Hepatic organoids were isolated from the livers of these model mice and cultured in vitro. Organoids were treated in vitro with obeticholic acid (OCA), a farnesoid X receptor (FXR) agonist. This drug demonstrated favorable anti-fatty liver effects in Phase III clinical trials and was used as a control in this study. Organoids were divided into groups and treated with the same concentration gradient of obeticholic acid and 25-hydroxylanosterol for 3 days. Organoid RNA was collected and analyzed for differential expression of lipid synthesis-related genes (Hmgcs, Hmgcr, SCD1, FASN) and fibrosis markers (αSMA, Col1α1) using real-time fluorescent quantitative PCR.

[0506] The results are shown in Figures 35 to 53, where Figure 35 shows that 25-hydroxylanosterol reduces the expression of adipogenesis-related genes (Hmgcs, Hmgcr, SCD1, FASN) in liver organoids and is more effective than the control drug obeticholic acid at the same concentration; Figure 36 shows that 25-hydroxylanosterol reduces the expression of fibrosis-related genes (ol1a1, αSMA) in liver organoids and is more effective than the control drug obeticholic acid at the same concentration; and Figures 37 to 53 show the results of brightfield imaging of liver organoids, the quantitative results of Nile Red staining, and the quantitative results of immunofluorescence staining of the fibrosis marker protein αSMA, i.e., 25-hydroxylanosterol reduced lipid accumulation in liver organoids and simultaneously reduced the expression of the fibrosis marker protein αSMA in liver organoids.

[0507] Data in Figures 35 and 36 are expressed as mean ± standard deviation. P values ​​were calculated by one-way ANOVA, where ns indicates no statistical difference, * indicates P<0.05, ** indicates P<0.01, and *** indicates P<0.001. Quantitative analysis in Figures 47 and 53 was performed using Image J software. Data are expressed as mean ± standard deviation. P values ​​were calculated by one-way ANOVA, where * indicates P<0.05, ** indicates P<0.01, and *** indicates P<0.001.

[0508] The results showed that, compared with obeticholic acid, which failed to inhibit the expression of lipid synthesis genes, 25-hydroxylanosterol significantly inhibited the expression levels of lipid synthesis-related genes (Figure 35) and fibrosis-related genes (Figure 36). Concurrently, Nile Red staining experiments were performed to detect neutral lipid accumulation in organoids. As shown in Figures 37-53, 25-hydroxylanosterol and OCA reduced lipid accumulation in organoids, and the expression of the fibrosis marker protein αSMA was significantly reduced. The results in Figures 35-53 indicate that 25-hydroxylanosterol directly reduces hepatic lipid accumulation and fibrosis by inhibiting adipogenesis and fibrosis gene expression, whereas OCA may indirectly inhibit hepatic lipid accumulation by promoting lipid oxidation. These data indicate that 25-hydroxylanosterol directly targets the hepatic lipid synthesis pathway and regulates fibrosis genes.

[0509] Effect Example 13: Liver microsome metabolic stability experiment PBS solution (100 mM), MgCl solution (100 mM), and NADPH solution (20 mM) were prepared, respectively. Stock solutions of the compounds and testosterone (positive control) were then prepared in dimethyl sulfoxide (DMSO), diluted to 100 μM with methanol, and used for sample incubation. These were then stored at -10 to -30°C. 12.5 μL of rat liver microsomes (purchased from XenoTech, product number R1000, batch number 1310030, specification: 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 uniformly, and incubated at 37 °C for 5 min. 5 μL of substrate (test compound) solution was added to initiate the reaction. Each incubation time was set at 0, 5, 15, 30, 45, and 60 min (0 and 60 min for the negative group). 50 μL of the incubation sample was then transferred to a stop plate containing 100 μL of ice-cold stop solution, vortexed for 1 min to inactivate, and stored at -60 to -90 °C for subsequent analysis. Sample analysis of the test compounds and the control compound testosterone was performed using LC-MS / MS. Analyst software was used to integrate, calculate, and process the chromatographic peaks. Testosterone of both the test compound and the control compound was calculated using a semi-quantitative analysis method based on peak area ratio. The results are shown in Table 2 below.

[0510] [Table 3] JPEG2025504580000218.jpg41170

[0511] Compared with the control compound 68, the metabolic stability of the compounds of the present invention in rat liver microsomes is significantly improved and is significantly superior to that of compound 68. Production of key intermediates Manufacturing Example Example 68 Compound 68 (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)- Preparation of 6-hydroxy-6-methylheptan-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

[0512] [ka]

[0513] Step 1: Starting material lanosterol (3.00 g, 7.03 mmol, 1.0 eq) was dissolved in THF (tetrahydrofuran) (273 mL), water (68 mL) was added, and NBS (0.73 g, 4.08 mmol, 0.58 eq) was added at room temperature. The mixture was stirred at 25 °C for 2 h. TLC (n-hexane: EtOAc = 5:1, phosphomolybdic acid) showed the reaction was complete. The extract was extracted three times with dichloromethane, dried over sodium sulfate, and spin-dried. The resulting mixture was then subjected to 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-methylheptan-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 (68-1) (1.3 g, purity: 90%, yield: 35.3%). 1 H NMR (400 MHz, CDCl3) δ 3.98 (dd, J = 21.0, 12.3 Hz, 1H), 3.27 - 3.19 (m, 1H), 2.14 (d, J = 6.0 Hz, 1H), 2.00 (d, J = 11.7 Hz, 5H), 1.84 - 1.61 (m, 6H), 1.58 (s, 9H), 1.33 (t, J = 10.8 Hz, 9H),1.27 - 1.12 (m, 3H), 1.04 (d, J = 12.2 Hz, 1H), 0.99 (d, J = 7.9 Hz, 7H), 0.94 - 0.84 (m, 7H), 0.80 (s, 3H), 0.69 (d, J = 2.2 Hz, 3H). Step 2: (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-5-bromo-6-hydroxy-6-methylheptan-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 (68-1) (900 mg, 1.72 mmol, 1.0 eq) was dissolved in THF (tetrahydrofuran). The reaction mixture was dissolved in 90 mL of hexane (hydrofuran) 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 h. After monitoring the completion of the reaction by TLC (n-hexane: EtOAc = 5:1, phosphomolybdic acid), the reaction mixture was quenched by pouring it into ice water (10 mL), extracted with DCM (dichloromethane) (30 mL × 3), dried over anhydrous sodium sulfate, and spin-dried to give (1R, 3aR, 5aR, 7S, 9 (aS,11aR)-1-[(2R)-6-hydroxy-6-methylheptan-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%) was obtained. 1 H NMR (400 MHz, CDCl3) δ 3.23 (d, J = 8.8 Hz, 1H), 2.02 (s, 4H), 1.92 (d, J = 8.4 Hz, 1H), 1.69 (d, J = 24.3 Hz, 7H), 1.58 (d, J = 11.1 Hz, 2H), 1.52 - 1.33 (m,8H), 1.30 (s, 2H), 1.18 (d, J = 25.9 Hz, 8H), 1.01 (dd, J = 22.8, 9.8 Hz, 8H), 0.93 - 0.84 (m, 6H), 0.80 (s, 3H), 0.68 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 134.38, 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 Example 146 Preparation of Compound 146 (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-7-hydroxyhept-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,5,5a,6,7,8,9,9a,11,11a-dodecahydro-1H-cyclopenta[1,2-a]phenanthren-7-ol

[0514] [ka]

[0515] Step 1: Dissolve acetic acid (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-4-formylbutan-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-yl ester (II) (500 mg, 1.1 mmol) in tetrahydrofuran (30 mL), purate with N2 three times, cool to 0 °C, add potassium tert-butoxide (253 mg, 2.3 mmol) solid, and stir at 0 °C for 30 min. Dissolve the compound (2-methoxy-2-oxoethyl)phosphonic acid diethyl ester (500 mg, 1.1 mmol) in THF (5 mL). The resulting mixture was added dropwise to the reaction mixture, allowed to warm to room temperature, and stirred for 2 h. TLC (PE: EtOAc = 10:1) showed no remaining starting material. The mixture was cooled to 0 °C, and 2 mL of 1M HCl was added. The mixture was separated, extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, spun dry, and passed through a column to give (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 (67-1) (430 mg, 0.86 mmol, 76.65%) as a white solid. 1 H NMR (399 MHz, CDCl3) δ 7.03 - 6.85 (m, 1H), 5.80 (d, J = 15.6 Hz, 1H), 4.48 (dd, J = 11.7, 4.5 Hz, 1H), 3.77 - 3.62 (m, 3H), 2.25 (s, 1H), 2.12 - 1.92 (m, 8H), 1.89 (d, J = 21.3 Hz, 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, 10.5 Hz, 3H), 0.98 (s, 3H), 0.87 (dd, J = 14.6, 4.9 Hz, 12H), 0.66 (s, 3H) Step 2: (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 (67-1) (380 mg, 0.762 mmol) was dissolved in ethyl acetate (380 mL), Pd / C (palladium on carbon) (38 mg, 0.762 mmol) was added, and the mixture was purged with hydrogen gas three times and stirred at room temperature for 30 min. TLC (PE: EtOAc = 10:1) showed no remaining raw material, and the completion of the reaction was detected by spot plate. The mixture was filtered through diatomaceous earth, rinsed with ethyl acetate, and spin-dried. The mixture was then subjected to column chromatography (PE: EtOAc = 100% to 20%) and concentrated to give a white solid (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 (67-2) (350 mg, 0.629 mmol, 82.56%). 1 H NMR (400 MHz, CDCl3) δ 4.49 (dd, J = 11.5, 4.6 Hz, 1H), 3.66 (d, J = 1.1 Hz, 3H), 2.30 (t, J= 8.0 Hz, 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, 2.2 Hz, 12H), 0.67 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 134.42 , 134.20, 51.46,50.38, 49.77, 44.43,37.78 , 36.86 , 36.25 , 35.77 , 35.24 , 34.18 , 30.92, 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. Step 3: (6R)-6-[(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]heptanoic acid methyl ester (67-1) (100 mg, 0.2 mmol, 1.0 eq.) was weighed and dissolved in dichloromethane (10 mL). Then, m-chloroperbenzoic acid (77.61 mg, 0.45 mmol) was added under ice bath. , 2.3 eq.) was added, and after the addition was complete, the mixture was allowed to return to room temperature, stirring was continued, and the reaction mixture was detected by TLC (PE:EA = 10:1, color development with phosphomolybdic acid, Rf1 = 0.5, Rf2 = 0.3). After the reaction was complete, saturated aqueous sodium bicarbonate solution (5.0 mL) was added, and the mixture was extracted with dichloromethane (5.0 mL × 3). The organic phase was dried and concentrated to obtain a white solid crude product of methyl (6R)-6-((3S,5S,10S,13R,14R,17R)-3-acetoxy-4,4,10,13,14-pentamethyltetradecahydro-11H-8,9-epoxycyclopenta[a]phenanthren-17-yl)heptanoate (146-1) (89 mg, 0.17 mmol, 86%), which was used in the next reaction without purification.

[0516] Step 4: Methyl (6R)-6-((3S,5S,10S,13R,14R,17R)-3-acetoxy-4,4,10,13,14-pentamethyltetradecahydro-11H-8,9-epoxycyclopenta[a]phenanthren-17-yl)heptanoate (146-1) (89 mg, 0.17 mmol) was weighed and dissolved in acetone (10 mL), and concentrated sulfuric acid (1d) was added at room temperature. The mixture was then stirred at room temperature for 5 hours and monitored by TLC (PE: EtOAc = 10:1, developed with phosphomolybdic acid, Rf1 = 0.3, Rf2 = 0.6). After completion of the reaction, the mixture was concentrated to remove acetone and the resulting mixture was washed with saturated sodium bicarbonate. Aqueous ethanol (10.0 mL) was added, and the mixture was further extracted with ethyl acetate (8.0 mL × 3). The organic phase was separated, dried, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 30:1 to 10:1) to give (6R)-6-[(1R,3aR,5aR,7S,9aS,11aR)-7-acetoxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,5,5a,6,7,8,9,9a,11,11a-dodecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]heptanoic acid methyl ester (146-2) (81 mg, 0.16 mmol, 94%). 1 H NMR(399MHz,CDCl3) δ 5.43 (s, 1H), 5.29 (d,J = 5.8Hz, 1H), 4.49 (dd,J = 11.1, 4.8Hz, 1H), 3.65 (s, 3H), 2.29 (t,J = 7.4Hz, 2H), 2.18 (d,J = 17.8Hz, 1H), 2.10 - 2.04 (m, 2H), 2.03 (s, 4H), 2.00 -1.93 (m, 2H), 1.76 - 1.68 (m, 2H), 1.65 - 1.57 (m, 3H), 1.50 (d,J = 4.6Hz, 1H), 1.42 - 1.34 (m, 4H), 1.27 (d,J = 10.2Hz, 2H), 1.20 - 1.11 (m, 2H), 1.07 - 1.00 (m, 1H), 0.98 (s, 3H), 0.93 (s, 3H), 0.86 (d,J =6.9Hz, 9H), 0.53 (s, 3H). 13CNMR(101MHz,CDCl3) d 174.36, 170.99, 145.53, 142.71, 119.83, 116.53, 80.81, 77.31, 76.99, 76.68, 51.46, 50.91, 50.28, 49.20, 43.68, 37.77, 37.57, 37.19, 36.03, 35.70, 35.35, 34.16, 31.44, 28.06, 27.85, 25.90, 25.50, 25.37, 24.22, 22.76, 21.33, 18.40, 16.91, 15.62, 1.00. Step 5: (6R)-6-[(1R,3aR,5aR,7S,9aS,11aR)-7-acetoxy-3a,6,6,9a,11a-pentamethyl-2,3,3a,5,5a,6,7,8,9,9a,11,11a-dodecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]heptanoic acid methyl ester (146-2) (50 mg, 0.1 mmol) was dissolved in tetrahydrofuran (5 mL), purged with N2, and cooled to 0 °C. Lithium aluminum hydride (41 mg, 1.0 mmol) was added and the reaction was allowed to proceed at 0 °C for 1 H. TLC (PE:EA=10:1) showed no remaining raw material, methanol was added, filtered through diatomaceous earth, concentrated, and purified by preparative HPLC to give a white solid (1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-7-hydroxyheptane 12.8 mg (0.03 mmol, 29.8%) of [3a,6,6,9a,11a-pentamethyl-2,3,3a,5,5a,6,7,8,9,9a,11,11a-dodecahydro-1H-cyclopenta[1,2-a]phenanthren-7-ol (146) was obtained. 1H NMR (399 MHz, CDCl3) 5.45 (s, 1H), 5.30 (s, 1H), 3.62 (t, J = 6.6 Hz, 2H), 3.23 (dd, J = 11.2, 4.5 Hz, 1H), 2.18 (d, J = 17.4 Hz, 1H), 2.06 (d, J = 11.3 Hz, 3H), 1.97 (d, J = 13.0 Hz, 2H), 1.64 (m, 4H), 1.43 (m, 2H), 1.34 (dd, J = 20.2, 7.5 Hz, 6H), 1.25 (d, J = 11.6 Hz, 3H), 1.06 (m, 2H), 0.98 (s, 3H), 0.96 (s, 3H), 0.86 (s, 9H), 0.54 (s, 3H). 13 C NMR (101 MHz, CDCl3) 120.13, 116.29, 78.95, 77.31, 77.20, 76.99, 76.67, 63.10, 50.95, 50.29, 49.08, 43.70, 38.68, 37.79, 37.34, 36.13, 36.09, 35.68, 32.86, 31.48, 28.12, 27.90, 27.78, 26.19, 26.14, 25.56, 22.98, 22.73, 18.48, 15.78, 15.62. LC-MS:[M-17] + = 411 Example 151 Compound 151 manufactured by コレスト-5(6)-エン-3β,4β,25-トリオールの

[0517]

change

[0518] Step 1: (22E,24S)-stigmaster-6(5),22(23)-dien-3β-ol (50.0 g, 0.12 mol, 1.0 eq.) and 4-dimethylaminopyridine (2.96 g, 24.23 mmol) were weighed and dissolved in dichloromethane (500 mL), and triethylamine (61.90 g, 605.77 mmol) was added. Then, under stirring at room temperature, acetic anhydride (37.11 g, 0.36 mol) was added. The mixture was stirred at room temperature for 2 hours, and the reaction completion was monitored by TLC (PE: EtOAc = 10:1). After completion of the reaction, the reaction solution was concentrated, and 300 mL of methanol was added to the obtained crude product, followed by stirring and filtration. The cake was washed with methanol (20 mL × 2) and then dried to obtain acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R,3E)-5-ethyl-6-methylhept-3-en-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester (15 1-1) (53.8 g, 112.4 mmol, 92.77%) was obtained as a white solid. 1 HNMR(399MHz, Chloroform-d) δ 5.35 (d,J = 4.9Hz, 1H), 5.14 (dd,J = 15.1, 8.5Hz, 1H), 4.99 (dd,J = 15.2, 8.5Hz, 1H), 4.67 - 4.48 (m, 1H), 2.30 (d,J = 7.8Hz, 2H), 2.01 (s, 3H), 2.00 - 1.91 (m, 2H), 1.84 (d,J = 11.3Hz, 2H), 1.68 (dd,J = 9.4, 4.8Hz, 1H), 1.48 (dt,J = 24.5, 9.2Hz, 7H), 1.28 - 1.07 (m, 6H), 1.00 (d,J = 3.2Hz, 6H), 0.80 (dd,J = 20.1, 6.4Hz, 9H), 0.68 (s, 3H). Step 2 Acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R,3E)-5-ethyl-6-methylhept-3-en-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (151-1) (5.0 g, 11 mmol) was weighed and dissolved in tetrahydrofuran ( The mixture was dissolved in 200 mL of ethyl acetate and water (20.0 mL), and pyridine (2.12 mL, 27.5 mmol), 4-methylmorpholine N-oxide (5.15 g, 43.98 mmol), and potassium osmate (7.3 mL, 1.1 mmol) were added at room temperature. The mixture was stirred overnight at room temperature, and monitored by TLC (PE: EtOAc = 3:1). The mixture was colored with phosphomolybdic acid. Some raw materials, such as an intermediate (ortho-diol was produced), remained. Next, Sodium periodate (9.41 g, 43.98 mmol) was added to the reaction solution at 0°C, and the mixture was stirred at room temperature for 1 hour. The mixture was monitored by TLC (PE: EtOAc = 3:1) and colored with phosphomolybdic acid. Some raw materials remained and the intermediate was converted to the product. Water (50 mL) was then added, and the mixture was extracted with ethyl acetate (50 mL x 3), dried, and concentrated. The crude product was then purified by column chromatography (PE: EtOAc = 60:1). Purification afforded a white solid, which was identified as acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aS)-1-[(1S)-1-formylethyl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (151-2) (0.64 g, 1.6 mmol, 14.73%). 1 HNMR (399 MHz, CDCl3) δ 9.55 (s, 1H), 5.36 (s, 1H), 4.60 (s, 1H), 2.31 (s, 3H), 2.02 (s, 3H), 1.93 (s, 2H), 1.84 (d,J = 11.2Hz, 3H), 1.63 (s, 3H), 1.49 (d,J = 10.9Hz, 4H), 1.42 - 1.19 (m, 3H), 1.15 (s, 1H), 1.11 (d,J = 6.8Hz, 3H), 1.06 (s, 1H), 1.01 (s, 3H), 0.98 (d,J = 5.8Hz, 1H), 0.71 (s, 3H). Step 3: (Methoxymethyl)triphenylphosphonium chloride (8.7 g, 25.0 mmol) was weighed and dissolved in tetrahydrofuran (38 mL), the mixture was purged with nitrogen gas three times, cooled to 0°C, sodium bis(trimethylsilyl)amide (12.8 mL, 25.0 mmol) was added dropwise, and after the addition was completed, the mixture was stirred at 0°C for 30 minutes. Then, acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aS)-1-[(1S)-1-formylethyl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a, A solution of 9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester (151-2) (1.9 g, 5.1 mmol) in tetrahydrofuran (18 mL) was added, and the mixture was warmed to room temperature and stirred for 1 hour. The mixture was monitored by TLC (PE: EtOAc = 10:1) and colored with phosphomolybdic acid. After the raw materials had completely reacted, water (30 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3), dried, concentrated, and the crude product was purified by column chromatography (PE: EtOAc = 100: Purification by HCl (1:100, 1:30) afforded acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2S,3E)-4-methoxybut-3-en-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (151-3) (0.75 g, 1.8 mmol, 34.87%) as a white solid. 1 HNMR(399MHz, CDCl3) δ 6.22 (d,J = 12.6Hz, 1H), 5.71 (d,J = 6.4Hz, 0H), 5.35 (d,J = 4.1Hz, 1H), 4.57 (m, 2H), 4.15 (m, 0H), 3.52 (d,J = 10.6Hz, 1H), 3.46 (d,J = 8.7Hz, 3H), 2.59 (d,J = 6.6Hz, 0H), 2.30(d,J = 7.6Hz, 3H), 2.01 (s, 3H), 1.95 (d,J = 5.8Hz, 3H), 1.84 (d,J = 10.9Hz, 3H), 1.69 (d,J = 4.6Hz, 1H), 1.52 (s, 2H), 1.48 (s, 2H), 1.14 (m, 3H), 1.03 (s, 3H), 1.00 (s, 3H), 0.67 (s, 3H). Step 4: Acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2S,3E)-4-methoxybut-3-en-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (151-3) (0.75 g, 1.87 mmol) was weighed and dissolved in tetrahydrofuran (7.5 mL), and 5 N hydrochloric acid (2.25 mL, 11.2 mmol) was added. The mixture was then heated to 50 °C and stirred for 1 h. The elution was monitored by TLC (PE: EtOAc = 10:1) and the elution was confirmed by phosphomolybdic acid. After the color development and the raw materials were completely reacted, water (15 mL) was added, extracted with ethyl acetate (10 mL × 3), dried, and concentrated. The crude product was purified by column chromatography (PE: EtOAc = 50:1 to 20:1) to give acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-1-formylpropan-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester (151-4) (0.52 g, 1.3 mmol, 68.26%) as a white solid. 1 HNMR (399 MHz, CDCl3) δ 9.74 (s, 1H), 5.36 (d,J = 4.4Hz, 1H), 4.60 (s, 1H), 2.44 (d,J = 16.5Hz, 1H), 2.30 (d,J = 6.7Hz, 2H), 2.20 - 2.10 (m, 1H), 2.01 (s, 3H), 1.95 (d,J = 14.4Hz, 2H), 1.84 (d,J = 11.5Hz,3H), 1.57 (dd,J = 19.7, 8.6Hz, 4H), 1.46 (dd,J = 14.2, 10.3Hz, 3H), 1.29 - 1.16 (m, 3H), 1.15 - 1.03 (m, 3H), 1.01 (d,J = 4.5Hz, 6H), 0.96 - 0.89 (m, 1H), 0.70 (d,J = 12.6Hz, 3H). Step 5 Acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-1-formylpropan-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (151-4) (0.52 g, 1.34 mmol) was weighed and dissolved in tetrahydrofuran (30 mL), ( Methyl triphenylphosphoranylidene acetate (2.25 g, 6.73 mmol) was added, and the reaction mixture was heated to 90°C and stirred for 3 hours. HPLC showed no remaining raw materials. The mixture was then cooled to room temperature, water (15 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). After drying and concentration, the crude product was purified by column chromatography (PE: EtOAc = 50:1 to 20:1) to give (2E,5R)-5-[(1R,3aS,3bS, 7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hex-2-enoic acid methyl ester (151-5) (0.44 g, 0.94 mmol, 70.20%) was obtained as a white solid. 1HNMR(399MHz, CDCl3) δ 6.99 - 6.86 (m, 1H), 5.80 (d,J = 15.6Hz, 1H), 5.36 (s, 1H), 4.59 (s, 1H), 3.71 (s, 3H), 2.30 (d,J = 6.7Hz, 3H), 2.01 (s, 3H), 2.00 - 1.90 (m, 3H), 1.84 (d,J = 10.9Hz, 3H), 1.54 (d,J =16.6Hz, 5H), 1.50 - 1.37 (m, 3H), 1.33 - 1.17 (m, 2H), 1.16 - 1.02 (m, 4H), 1.00 (s, 3H), 0.93 (d,J = 6.6Hz, 3H), 0.67 (s, 3H). Step 6: (2E,5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hex-2-enoic acid methyl ester (151-5) (0.44 g, 1.0 mmol) was weighed and dissolved in a mixture of tetrahydrofuran (9.0 mL) and methanol (4.5 mL). Nickel chloride (130 mg, 1.0 mmol) was added, and sodium borohydride (56.92 mg, 1.5 mmol) was added under stirring at room temperature. A large amount of bubbles were generated in the reaction solution, and the mixture was stirred at room temperature for 1 hour. After stirring, the mixture was sampled, concentrated, and analyzed by NMR. After the starting material had completely reacted, water (15 mL) was added, extracted with ethyl acetate (10 mL × 3), dried, concentrated, and the crude product was purified by column chromatography (PE: EtOAc = 60:1 to 20:1) to give (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester (151-6) (0.36 g, 0.78 mmol, 77.74%) as a white solid. 1HNMR(399MHz, CDCl3) δ 5.36 (s, 1H), 4.59 (s, 1H), 3.65 (s, 3H), 2.35 - 2.18 (m, 4H), 2.01 (s, 3H), 1.94 (d,J = 15.3Hz, 2H), 1.84 (d,J = 10.9Hz, 3H), 1.68 (s, 1H), 1.55 (s, 2H), 1.53 - 1.44 (m, 4H), 1.39 (d,J =10.2Hz, 3H), 1.22 (dd,J = 22.8, 12.0Hz, 2H), 1.15 - 1.09 (m, 2H), 1.08 - 1.03 (m, 2H), 1.00 (s, 3H), 0.96 (s, 1H), 0.91 (d,J = 6.3Hz, 3H), 0.89 - 0.79 (m, 1H), 0.64 (d,J = 12.6Hz, 3H). Step 7 (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester (151-6) (0.15 g, 0.34 mmol) was weighed and dissolved in a mixed solvent of chloroform (6.0 mL) and selenium dioxide (52.4 mg, 0.47 mmol). HCl) was added, followed by the addition of N-methylmorpholine (102.36 mg, 1.01 mmol) with stirring. The reaction mixture was heated to 70°C and refluxed at this temperature. The mixture was stirred for 64 hours and monitored by TLC (PE: EtOAc = 3:1). The formation of a large polar substance and the remaining starting material were observed. Water (10 mL) was then added to quench the reaction mixture, which was then extracted with ethyl acetate (10 mL x 3), dried, concentrated, and the crude product was purified by column chromatography (PE: EtOAc = 100:1 to 20:1). The raw material was acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-6-methoxy-6-oxohexan-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (20 mg) and the product was (5R)-5-[(1R,3aS,3bS,6R,7S,9aR,9 bS,11aR)-7-acetoxy-6-hydroxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester (151-7) (66 mg, 0.14 mmol, 40.35%) was obtained as a white solid. The chiral configuration was confirmed by 2D spectroscopy, as shown in Figures 54-55. 1 HNMR(399MHz, CDCl3) δ 5.69 (s, 1H), 4.70 (d,J = 11.7Hz, 1H), 4.23 (s, 1H), 3.65 (s, 3H), 2.25 (dd,J = 16.6, 8.5Hz, 2H), 2.09 (s, 3H), 2.05 - 1.94 (m, 2H), 1.83 (s, 3H), 1.67 (s, 3H), 1.56 (s, 3H), 1.45 (s, 2H),1.39 (s, 3H), 1.24 (s, 2H), 1.20 (s, 3H), 1.17 - 1.08 (m, 3H), 0.99 (d,J = 9.5Hz, 3H), 0.91 (d,J = 6.4Hz, 3H), 0.65 (s, 3H). Step 8: (5R)-5-[(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-7-acetoxy-6-hydroxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester (151-7) (30 mg, 0.06 mmol) was weighed and dissolved in a mixed solvent of tetrahydrofuran (2.0 mL), purged with nitrogen gas, and cooled to -78 °C. The resulting mixture was then cooled to -78 °C and methyllithium (0 0.2 mL, 0.33 mmol) was added dropwise, then warmed to room temperature and stirred for 3 hours. After the raw materials were completely reacted, the reaction mixture was monitored by TLC (DCM:MeOH = 20:1). After the raw materials were completely reacted, water (5 mL) was added to quench the reaction mixture, extracted with ethyl acetate (3 mL × 3), dried, concentrated, and the crude product was purified by column chromatography (DCM:MeOH = 500:1 to 100:1) to obtain cholest-5(6)-ene-3β,4β,25-triol (151) (13 mg, 0.03 mmol, 45.3%) as a white solid. 1 HNMR(399MHz, Chloroform-d) δ 5.71 - 5.61 (m, 1H), 4.12 (s, 1H), 3.54 (s, 1H), 2.16-1.96 (m, 4H), 1.85 (dd,J = 28.6, 13.7Hz, 3H), 1.64 (s,2H), 1.55 (d,J = 20.5Hz, 3H), 1.42 (s, 4H), 1.36 (d,J = 11.0Hz, 4H), 1.23 (s,2H), 1.19 (s, 6H), 1.16 (s, 3H), 1.10 (d,J = 10.0Hz, 2H), 1.05 (d,J = 10.5Hz, 2H), 0.99 (d,J = 13.0Hz, 2H), 0.91 (d,J = 6.5Hz, 3H), 0.66 (s, 3H). 13 CNMR(100MHz, CDCl3) δ 142.69, 134.69, 128.79, 77.31, 77.24, 77.00, 76.68, 72.46, 71.11, 56.86, 55.96, 50.12, 44.38, 42.29, 39.64, 36.86, 36.40, 35.96, 35.71, 32.05, 31.78, 29.35, 29.18, 28.22, 25.38, 24.22, 21.03, 20.72, 20.50, 18.65, 11.85. The two-dimensional spectrum of compound 151 is shown in Figures 56-57.

[0519] Example 177 Preparation of Compound 177 Cholest-5(6)-ene-3β,25-diol

[0520] [ka]

[0521] Acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-6-methoxy-6-oxohexan-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (151-6) (77 mg, 0.17 mol, 1.0 eq.) was weighed and dissolved in tetrahydrofuran (2 mL). The atmosphere was purged with nitrogen gas, and the mixture was cooled to -78 ° C. with dry ice-acetone. Methyllithium (0.54 mL, 0.87 mmol) was added, and the mixture was then warmed to room temperature and stirred. The mixture was monitored by TLC (petroleum ether:ethyl acetate=10:1). After the reaction was completed, 6 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phase was dried and concentrated, and the crude product was subjected to column chromatography (DCM:MeOH=300:1 to 100:1) to give cholest-5(6)-ene-3β,25-diol (177) (35 mg, 0.083 mmol, 47.66%) as a white solid. 1 H NMR(399MHz, CDCl3) δ 5.32 (s, 1H), 3.50 (s, 1H), 2.24 (m, 2H), 1.98 (dd,J = 18.6, 10.9Hz, 2H), 1.82 (d,J = 10.3Hz, 3H), 1.53 (d,J = 10.0Hz, 3H), 1.46 (d,J = 7.2Hz, 3H), 1.42 (d,J = 10.1Hz, 3H), 1.36 (d,J = 12.5Hz, 4H), 1.21 (s, 3H), 1.19 (s, 6H), 1.12 (dd,J = 14.4, 7.2Hz, 2H), 1.03 (m, 4H), 0.99 (s, 3H), 0.91 (d,J = 6.6Hz, 3H), 0.66 (s, 3H). 13 C NMR (100MHz, CDCl3) δ 140.72, 121.68, 77.31, 77.00, 76.68, 71.76, 71.11, 56.70, 56.00, 50.05, 44.38, 42.57, 42.29, 42.25, 39.72, 37.20, 36.46, 36.39, 35.72, 31.87, 31.85, 31 .61, 29.34, 29.17, 28.70, 28.23, 24.26, 21.04, 20.72, 19.38, 18.66, 11.84. LC-MS:[M-OH] + =385.30 Example 185 Compound 185 manufactured by Koresuto-3β,25-ジオールの

[0522]

change

[0523] Step 1: Acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-6-methoxy-6-oxohexan-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (151-6) (80 mg, 0.180 mmol) was dissolved in tetrahydrofuran (2 mL) and methanol (1 mL). Pd(OH) (20 mg, 0.142 mmol) was added, the mixture was purged with hydrogen gas three times, and the mixture was stirred at 40 °C for 48 h. The reaction mixture was monitored by H NMR. The reaction solution was filtered, and the filtrate was concentrated to give acetic acid-(1R,3aS,3bR,7S,9aS,9bS,11aR)-1-[(2R)-6-methoxy-6-oxohexan-2-yl]-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (185-1) (80 mg, 0.170 mmol, 94.57%) as an off-white solid. 1 H NMR(399MHz,CDCl3) δ 4.74 - 4.58 (m, 1H), 3.64 (s, 3H), 2.32 - 2.17 (m, 2H), 2.00 (s, 3H), 1.92 (d,J = 12.7Hz, 1H), 1.78 (d,J = 9.5Hz, 2H), 1.73 - 1.61 (m, 3H), 1.53 (d,J = 10.1Hz, 3H), 1.48 - 1.40 (m, 3H), 1.33 (dd,J = 23.5, 11.4Hz, 4H), 1.24 (d,J = 9.9Hz, 4H), 1.20 - 1.12 (m, 3H), 1.10 - 1.02 (m, 3H), 0.96 (d,J = 15.7Hz, 2H), 0.89 (d,J = 6.3Hz, 3H), 0.79 (s, 3H), 0.62 (s, 3H) . Step 2: Methylacetic acid-(1R,3aS,3bR,7S,9aS,9bS,11aR)-1-[(2R)-6-methoxy-6-oxohexan-2-yl]-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (185-1) (80 mg, 0.179 mmol) was dissolved in tetrahydrofuran (3 mL), purged with nitrogen three times, cooled to -78 °C, and methyllithium (0.560 mL, 0.896 mmol) was added. The mixture was warmed to room temperature and stirred for 3 h. The reaction mixture was monitored by TLC (petroleum ether:ethyl acetate = 10:1). The reaction mixture was quenched with water (15 mL), extracted with ethyl acetate (10 mL × 3), washed once with brine, dried over anhydrous sodium sulfate, and concentrated to give the crude product (80 mg). Purification by column chromatography (DCM:MeOH = 300:1 to 100:1) gave cholest-3β,25-diol (185) (20 mg, 0.040 mmol, 22.08%). 1 H NMR (399 MHz, CDCl3) δ 5.32 (s, 0H), 3.56 (s, 1H), 1.93 (d, J = 12.9 Hz, 1H), 1.75 (s, 2H), 1.70 - 1.60 (m, 2H), 1.55 (s, 3H), 1.43 (s, 3H), 1.35 (s, 3H), 1.28 (s, 3H), 1.24 (s, 3H), 1.23 (s, 3H), 1.19 (s, 6H), 1.11 - 1.01 (m, 4H), 0.95 (d, J = 10.9 Hz, 3H), 0.89 (d, J = 6.5 Hz, 3H), 0.77 (s, 3H), 0.62 (s, 3H). 13 C NMR(101MHz,CDCl3) δ 77.31, 77.20, 77.00, 76.68, 71.35, 71.10, 56.45, 56.16, 54.30, 44.81, 44.39, 42.58, 40.00, 38.19, 36.97, 36.39, 35.73, 35.47, 35.43, 32.06, 31.50, 30.95, 29.33, 29.18, 28.71, 28.25, 27.19, 24.19, 21.23, 20.74, 18.61, 12.31, 12.06. LC-MS: [M+Na] + =427.15 Example 187 Preparation of Compound 187: 2-fluoro-N-[(3R)-3-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-hydroxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]butyl]-N-methylbenzamide

[0524] [ka]

[0525] Step 1: Acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-1-formylpropan-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (151-4) (100 mg, 0.259 mmol) was dissolved in THF, and methylamine (32.18 mg, 1.036 mmol) and zinc chloride (17.65 mg, 0.130 mmol) were added. After stirring for 1 h, sodium cyanoborohydride (81.38 mg, 1.295 mmol) was added, and the reaction was stirred at room temperature overnight. TLC (petroleum ether:ethyl acetate = 10:1) showed no remaining starting material. The reaction mixture was extracted with water (10 mL) and ethyl acetate (8 mL × 3). The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-9a,11a-dimethyl-1-[(2R)-4-(methylamino)butan-2-yl]-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (187-1) (120 mg, 0.209 mmol, 80.85%), which was carried on directly to the next step without further purification.

[0526] Step 2 Acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-9 a,11a-Dimethyl-1-[(2R)-4-(methylamino)butan-2-yl]-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (187-1) (120 mg, 0.209 mmol) and triethylamine (0.087 mL, 0.627 mmol) were dissolved in dichloromethane (3 mL), and 4-fluorobenzoyl chloride (66.32 mg, 0.418 mmol) was added and stirred at room temperature for 2 h. The reaction mixture was monitored by TLC (petroleum ether:ethyl acetate = 3:1) and LC-MS. The reaction solution was extracted with water (15 mL) and ethyl acetate (10 mL × 3), and the organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 60 mg of crude product (187-2), which was directly carried on to the next step.

[0527] Step 3: Acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-4-{[(2-fluorophenyl)carbonyl](methyl)amino}butan-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (187-2) (60 mg, 0.115 mmol) was weighed and dissolved in tetrahydrofuran (2 mL) and methanol (1 mL). Aqueous sodium hydroxide (1 mL, 1.000 mmol) was added and the mixture was stirred at room temperature for 8 h. The reaction mixture was monitored by TLC (petroleum ether:ethyl acetate = 3:1). The reaction solution was extracted three times with water (10 mL) and ethyl acetate (8 mL × 3). The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 60 mg of crude product, which was purified by preparative liquid phase to give 2-fluoro-N-[(3R)-3-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-hydroxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]butyl]-N-methylbenzamide (187) (30 mg, 0.059 mmol, 51.64%) as a white solid. 1 H NMR (399 MHz, CDCl3) δ 7.39 - 7.28 (m, 2H), 7.17 (t, J = 7.4 Hz, 1H), 7.07 (q, J = 8.4 Hz, 1H), 5.33 (s, 1H), 3.68 (s, 0.5H), 3.55 - 3.47 (m, 1H), 3.46 - 3.37 (m, 0.5H), 3.17 (d, J = 10.5 Hz, 1H), 3.07 (s, 1.5H), 2.86 (s, 1.5H), 2.23 (d, J = 20.6 Hz, 2H), 1.94 (d, J = 40.2 Hz, 3H), 1.82 (t, J = 9.7 Hz, 3H), 1.63 (s, 2H), 1.53 - 1.45 (m, 4H), 1.40 (d, J = 11.5 Hz, 2H), 1.32 (s, 2H), 1.15 (d, J = 9.3 Hz, 2H), 1.08 (d, J = 9.7 Hz, 2H), 1.03 (d, J = 6.5 Hz, 1.5H), 0.99 (s, 1.5H), 0.97 (s, 1.5H), 0.91 (dd, J = 17.3, 7.5 Hz, 2H), 0.69 (s, 1.5H), 0.63 (d, J = 5.8 Hz, 1.5H), 0.59 (s, 1.5H). 13 C NMR (101MHz, CDCl3) δ 140.71, 121.66, 121.57, 77.32, 77.20, 77.00, 76.68, 71.75, 56.72, 56.61, 55.88, 55.52, 50.04, 49.97, 44.89, 42.23, 39.72, 39.58, 37.19, 36.44, 33.77, 33.42, 32.74, 31.87, 31.80, 31.63, 30.95, 28.29, 28.06, 24.26, 24.16, 21.05, 20.97, 19.39, 18.79, 18.49, 11.78, 11.70. 19 F NMR (376MHz, CDCl3) δ -115.21, -115.37. LC-MS: [M+H] + =482.50 Example 198 Compound 198 5α-コレスト-3β,4β,25-トリオールの

[0528]

change

[0529] Step 1: (5R)-5-[(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-7-acetoxy-6-hydroxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester (151-7) (200 mg, 0.43 mol, 1.0 eq.) was weighed and dissolved in acetic acid (10 mL), and platinum dioxide (40 mg, 0.18 mmol) was added. The mixture was then heated to 40 °C and stirred for 16 h, monitored by TLC (petroleum ether:ethyl acetate = 3:1). After completion of the reaction, the reaction solution was filtered and concentrated. The resulting crude product (250 mg) was purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 15:1) to give (5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-7-acetoxy-6-hydroxy-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester (198-1) (130 mg, 0.28 mmol, 65.12%) as a white solid.

[0530] 1 H NMR (399 MHz, Chloroform-d) δ 4.70 (ddd, J = 12.2, 4.7, 3.2 Hz, 1H), 3.81 (t, J = 3.0 Hz, 1H), 3.64 (s, 3H), 2.29 - 2.21 (m, 2H), 2.06 (s, 3H), 1.91 (dt, J = 8.5, 4.6 Hz, 2H), 1.74 (dp, J = 13.0, 5.1, 4.6 Hz, 5H), 1.54 - 1.48 (m, 3H), 1.38 - 1.33 (m, 6H), 1.09 (t, J = 4.7 Hz, 5H), 1.03 (s, 4H), 0.90 (d, J = 6.5 Hz, 4H), 0.83 (d, J = 3.5 Hz, 5H), 0.62 (s, 3H). Step 2: (5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-7-acetoxy-6-hydroxy-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester (198-1) (100 mg, 0.22 mmol) was weighed and dissolved in tetrahydrofuran (10 mL). The mixture was cooled with petroleum ether and dry ice. A solution of methyllithium in tetrahydrofuran (C: 1.6 M, 2.2 mmol, 10.0 eq.) was added dropwise at low temperature. The mixture was allowed to warm to room temperature and stirred for 16 h. The mixture was monitored by TLC (DCM:MeOH = 20:1). After completion of the reaction, water (10 mL) was added, extracted with ethyl acetate (10 mL × 3), dried, concentrated, and the crude product was purified by column chromatography (DCM:MeOH = 300:1 to 100:1) to give 5α-cholest-3β,4β,25-triol (198) (25 mg, 0.06 mmol, 27.47%) as a white solid.

[0531] 1 H NMR(399MHz, Chloroform-d) δ 3.72 (s, 1H), 3.52 (s, 1H), 1.94 (d,J = 12.4Hz, 1H), 1.73 (s, 4H), 1.68 (s, 3H), 1.53 (s, 3H), 1.42 (d,J = 11.3Hz, 3H), 1.33 (d,J = 11.6Hz, 4H), 1.26 (s, 3H), 1.19 (s, 6H), 1.09 - 1.02 (m, 4H), 0.99 (s, 3H), 0.97 - 0.92 (m, 2H), 0.89 (d,J = 6.5Hz, 3H), 0.63 (s, 3H), 0.61 - 0.52 (m, 1H). 13C NMR(101MHz, Chloroform-d) δ 77.31, 76.99, 76.68, 74.80, 72.26, 71.13, 56.53, 56.13, 55.21, 50.87, 48.79, 44.38, 42.58, 39.87, 36.84, 36.39, 35.72, 35.46, 35.36, 32.37, 29.32, 29.16, 28.23, 25.95, 25.83, 24.18, 20.74,20.56, 18.61, 14.65, 12.05. LCMS: [M-OH-H2O] + =385.3. Example 203 Preparation of Compound 203 Cholest-5(6)-ene-3β,4α,25-triol

[0532] [ka]

[0533] Step 1: (5R)-5-[(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-7-acetoxy-6-hydroxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester (151-7) (780 mg, 1.69 mmol, 1.0 eq.) was weighed and dissolved in dichloromethane (24 mL). Tetrapropylammonium perruthenate (30 mg, 0.09 mmol), 4-methylmorpholine N-oxide (290 mg, 2.46 mmol), and 3A molecular sieves (3.9 g) were added and stirred at room temperature. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 5:1). After completion of the reaction, the reaction solution was filtered and concentrated, and the resulting crude product was purified by column chromatography (petroleum ether: ethyl acetate = 20:1 to 10:1) to give (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-6-oxo-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecanoic acid ester]. Hydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester (203-1) (540 mg, 1.12 mmol, 66.06%) was obtained as a white solid. 1H NMR (399 MHz, CDCl3) δ 6.40 - 6.31 (m, 1H), 5.19 (dd, J = 12.6, 7.1 Hz, 1H), 3.65 (d, J = 0.8 Hz, 3H), 2.33 - 2.18 (m, 3H), 2.15 (d, J = 0.7 Hz, 4H), 2.13 - 2.06 (m, 1H), 2.05 - 1.97 (m, 3H), 1.83 (s, 1H), 1.70 (dd, J = 19.2, 10.0 Hz, 2H), 1.53 - 1.29 (m, 5H), 1.27 - 1.18 (m, 2H), 1.17 - 1.00 (m, 5H), 0.97 (s, 3H), 0.92 (d, J = 6.5 Hz, 3H), 0.66 (s, 3H). Step 2: (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-6-oxo-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester (203-1) (80 mg, 0.17 mmol) was weighed and dissolved in tetrahydrofuran (10 mL). Sodium borohydride (13.2 mg, 0.35 mmol, 2.0 eq.) was added at room temperature and stirred for 16 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1). After completion of the reaction, water (10 mL) was added, extracted with ethyl acetate (10 mL × 3), dried, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 20:1, 10:1, 5:1) to give (5R)-5-[(1R,3aS,3bS,6S,7S,9aR,9bS,11aR)-7-acetoxy-6-hydroxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester (203-2) (41 mg, 0.085 mmol, 48.48%) as a white solid.

[0534] 1 H NMR (399 MHz, CDCl3) δ 5.87 - 5.80 (m, 1H), 4.48 (dt, J = 10.7, 5.3 Hz, 1H), 4.21 (d, J = 10.0 Hz, 1H), 3.65 (s, 3H), 2.30 - 2.18 (m, 2H), 2.09 (d, J = 1.4 Hz, 3H), 1.98 (d, J = 12.4 Hz, 1H),1.92 - 1.78 (m, 3H), 1.72 - 1.62 (m, 2H), 1.52 (s, 1H), 1.43 (dt, J = 20.6, 5.6 Hz, 6H), 1.25 (d, J = 11.9 Hz, 2H), 1.17 - 1.02 (m, 5H), 1.00 (s, 3H), 0.91 (d, J = 6.5 Hz, 3H), 0.81 (s, 1H), 0.66 (s, 3H). Step 3: (5R)-5-[(1R,3aS,3bS,6S,7S,9aR,9bS,11aR)-7-acetoxy-6-hydroxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester (203-2) (12 mg, 0.029 mmol) was weighed and dissolved in tetrahydrofuran (5 mL). The mixture was cooled with petroleum ether and dry ice. A solution of methyllithium in tetrahydrofuran (C: 1.6 M, 0.29 mmol, 10.0 eq.) was added dropwise at low temperature. The mixture was allowed to warm to room temperature and stirred for 16 h. The reaction was monitored by TLC (dichloromethane:methanol = 20:1). After the reaction was completed, water (10 mL) was added, extracted with ethyl acetate (10 mL × 3), dried, and concentrated. The crude product was then purified by column chromatography (dichloromethane:methanol = 300:1 to 100:1) to obtain cholest-5(6)-ene-3β,4α,25-triol (203) (5.3 mg, 0. The product was obtained as a white solid (0.011 mmol, 36.58%). 1H NMR (399 MHz, CDCl3) δ 5.71 (dt, J = 5.0, 2.2 Hz, 1H), 4.00 - 3.92 (m, 1H), 3.18 (td, J = 10.4, 9.6, 4.4 Hz, 1H), 2.07 - 1.92 (m, 2H), 1.80 (ddd, J = 18.9, 11.0, 4.2 Hz, 3H), 1.62 - 1.46 (m, 3H), 1.45 - 1.25 (m, 9H), 1.22 (d, J = 12.1 Hz, 3H), 1.15 (s, 6H), 1.09 - 0.99 (m, 4H), 0.97 (s, 3H), 0.92 (d, J = 6.2 Hz, 1H), 0.88 (d, J = 6.5 Hz, 3H), 0.63 (s, 3H). 13 C NMR (100 MHz, Chloroform-d) δ 141.91, 117.78, 71.04, 56.66, 56.01, 49.87, 49.66, 49.44, 49.23, 49.02, 48.81, 44.25, 42.20, 39.66, 37.89, 36.39, 35.70, 31.50, 31.35, 28.20, 27.89, 24.21, 20.84, 20.73. LC-MS: [M+Na] + =441.5. The two-dimensional spectrum of compound 203 is shown in Figures 58-59.

[0535] Example 204 Preparation of Compound 204 5α-cholest-3β,4α,25-triol

[0536] [ka]

[0537] Step 1: Acetic acid-(1R,3aS,3bS,6S,7S,9aR,9bS,11aR)-6-hydroxy-1-[(2R)-6-hydroxyhexan-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (203-2) (64 mg, 0.14 mmol, 1.0 eq.) was weighed and dissolved in glacial acetic acid (10 mL). Platinum dioxide (6.3 mg, 0.03 mmol) was added, and the mixture was purged with hydrogen gas. The mixture was then heated to 40°C with stirring and analyzed by TLC (petroleum ether:ethyl acetate). The reaction was monitored at a pH of 5:1. After completion of the reaction, the reaction solution was filtered and then concentrated to give the crude product (5R)-5-[(1R,3aS,3bS,5aR,6S,7S,9aR,9bS,11aR)-7-acetoxy-6-hydroxy-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester (204-1) (80 mg, 0.14 mmol, 99.56%), which was a white solid crude product and directly used in the next step without purification.

[0538] Step 2: (5R)-5-[(1R,3aS,3bS,5aR,6S,7S,9aR,9bS,11aR)-7-acetoxy-6-hydroxy-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester (204-1) (60 mg, 0.14 mmol) was weighed and dissolved in tetrahydrofuran (5 mL). The mixture was cooled with petroleum ether and dry ice. A solution of methyllithium in tetrahydrofuran (C: 1.6 M, 1.3 mmol, 10.0 eq.) was added dropwise at low temperature. The mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction system was monitored by TLC (dichloromethane:methanol = 20:1). After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). After drying and concentration, the crude product was purified by column chromatography (dichloromethane:methanol = 300:1 to 100:1) to give 5α-cholest-3β,4α,25-triol (204) (12 mg, 0.026 mmol, 19.98%) as a white solid. 1 H NMR (399 MHz, CDCl3) δ 3.38 - 3.23 (m, 2H), 1.95 (d, J = 12.8 Hz, 1H), 1.84 (d, J = 13.1 Hz, 2H), 1.78 - 1.73 (m, 1H), 1.73 - 1.64 (m, 2H), 1.49 - 1.39 (m, 5H), 1.36 (t, J = 6.7 Hz, 4H), 1.30 - 1.25(m, 3H), 1.24 (d, J = 3.2 Hz, 4H), 1.19 (s, 6H), 1.15 - 1.09 (m, 2H), 1.07 - 1.03 (m, 3H), 0.98 (d, J = 10.6 Hz, 2H), 0.89 (d, J = 6.5 Hz, 3H), 0.84 (s, 1H), 0.82 (s, 3H), 0.69 - 0.64 (m, 1H), 0.63 (s, 3H) 13 C NMR (100 MHz, CDCl3+10%CD3OD) δ 76.05, 75.07, 70.93, 56.30, 56.12, 54.34, 50.60, 49.67, 49.46, 49.24, 49.03, 48.82, 48.60, 48.39, 44.16, 42.42, 39.85, 37.07, 36.12, 35.68, 34.92, 28.15, 28.03, 24.04, 22.54,20.85, 18.46, 11.91. LCMS: [M+Na] + = 443.55.

[0539] Example 205 Preparation of the compound cholest-3β,5,25-triol

[0540] [ka]

[0541] Step 1: Acetic acid-(6R,7S,9aR,11aR)-6-hydroxy-1-[(2R)-6-methoxy-6-oxohexan-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester (151-6) (800 mg, 1.8 mmol, 1.0 eq.) was weighed and dissolved in dichloromethane (50 mL). m-Chloroperbenzoic acid (541.41 mg, 2.7 mmol, 1.5 eq.) was added under ice bath, and the mixture was stirred at room temperature for 4 hours. The reaction was detected by TLC (petroleum ether:ethyl acetate=5:1). After completion of the reaction, the mixture was added with saturated sodium bicarbonate. An aqueous solution (30 mL) was added, and the mixture was extracted with dichloromethane (40 mL × 3). The organic phase was dried and concentrated. The resulting crude product was purified by column chromatography (petroleum ether: ethyl acetate = 100:1 to 5:1) to give (5R)-5-[(3S,6aS,6bS,9aR,9R,11aS,11bR)-3-acetoxy-9a,11b-dimethyl-1,2,3,4,5a,6,6a,6b,7,8,9,9a,10,11,11a,11b-hexahydrocyclopenta[1',2':1,2]phenanthro[8a,9-b]oxazepin-9-yl]hexanoic acid methyl ester (205-1) (600 mg, 1.34 mmol, 74.54%) as a white solid. 1 H NMR (399 MHz, CDCl3) δ 4.97 - 4.87 (m, 1H), 2.87 (d, J = 4.4 Hz, 1H), 2.31 - 2.17 (m, 2H), 2.00 (d, J = 6.4 Hz, 3H), 1.96 - 1.86 (m, 2H), 1.77 (ddd, J = 14.8, 9.3, 5.6 Hz, 1H), 1.70 - 1.58 (m, 2H), 1.52 - 1.41 (m, 3H), 1.33 (ddd, J = 12.8, 9.8, 6.1 Hz, 4H), 1.25 - 1.14 (m, 3H), 1.04 (s, 3H), 0.98 - 0.92 (m, 2H), 0.88 (dd, J = 6.5, 1.6 Hz, 3H), 0.59 (d, J = 11.7 Hz, 3H). Step 2: (5R)-5-[(3S,6aS,6bS,9aR,9R,11aS,11bR)-3-acetoxy-9a,11b-dimethyl-1,2,3,4,5a,6,6a,6b,7,8,9,9a,10,11,11a,11b-hexahydrocyclopenta[1',2':1,2]phenanthro[8a,9-b]oxazepin-9-yl]hexanoic acid methyl ester (100 mg, 0.22 mmol, 1.0 eq.) was weighed and dissolved in tetrahydrofuran (10 mL) and brominated at room temperature. Resole green (2.4 mg, 0.22 mmol) and sodium cyanoborohydride (66 mg, 1.06 mmol, 5.0 eq.) were added, and the mixture was heated to 50°C under nitrogen gas protection. Boron trifluoride diethyl etherate (0.11 mmol) was added with stirring until the color of the solution changed from green to yellow. Sodium cyanoborohydride was slowly consumed by dropwise addition, and the mixture was heated to reflux overnight. The reaction system was monitored by TLC (petroleum ether:ethyl acetate = 5:1). After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The mixture was dried and concentrated, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 100:1 to 30:1 to 5:1) to give (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-5a-hydroxy-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl] Hexanoic acid methyl ester (205-2, first component) (30 mg, 0.058 mmol, 26.88%) was obtained as a white solid, and (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-5-hydroxy-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester (205-3, second component) (30 mg, 0.058 mmol, 26.88%) was obtained.

[0542] 205-2 (first component): 11H NMR (400 MHz, CDCl3) δ 4.77 - 4.66 (m, 1H), 3.78 (d, J = 3.1 Hz, 1H), 3.66 (s, 3H), 2.37 - 2.18 (m, 2H), 2.02 (s, 3H), 1.97 (d, J = 12.6 Hz, 1H), 1.84 - 1.75 (m, 4H), 1.72 - 1.64 (m, 4H), 1.52 - 1.45 (m, 3H), 1.43 - 1.31 (m, 4H), 1.29 - 1.20 (m, 6H), 1.15 - 1.07 (m, 4H), 1.03 (s, 3H), 1.01 - 0.95 (m, 2H), 0.91 (d, J = 6.5 Hz, 3H), 0.89 - 0.82 (m, 1H), 0.67 (s, 3H) 205-3 (Second component): 1 1H NMR (400 MHz, CDCl3) δ 5.15 (s, 1H), 3.65 (s, 3H), 2.28 (ddt, J = 25.9, 16.3, 7.8 Hz, 2H), 2.01 (s, 3H), 1.95 (d, J = 12.2 Hz, 1H), 1.90 - 1.75 (m, 2H), 1.68 (d, J = 8.0 Hz, 4H), 1.64 - 1.52 (m, 7H), 1.48 - 1.33 (m, 8H), 1.24 (s, 10H), 1.06 (q, J = 9.8 Hz, 4H), 0.98 (s, 3H), 0.91 (d, J = 6.4 Hz, 3H), 0.88 - 0.79 (m, 1H), 0.63 (s, 3H). Step 3: (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-5a-hydroxy-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoic acid methyl ester (205-2) (30 mg, 0.06 mmol) was weighed and dissolved in tetrahydrofuran (5 mL). The solution was cooled with petroleum ether and dry ice. A solution of methyllithium in tetrahydrofuran (C: 1.6 M, 0.6 mmol, 10.0 eq.) was added dropwise at low temperature. The mixture was then warmed to room temperature and stirred for 16 hours. TLC (dichloromethane:methanol = 2 The reaction was monitored at a ratio of 0:1. After completion of the reaction, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). After drying and concentration, the crude product was purified by column chromatography (dichloromethane:methanol = 300:1 to 100:1) to give cholest-3β,5,25-triol (205) (6.7 mg, 0.015 mmol, 23.06%) as a white solid.

[0543] 1H NMR (399 MHz, CDCl3) δ 4.08 (dd, J = 10.9, 5.9 Hz, 1H), 1.96 (d, J = 12.4 Hz, 1H), 1.83 (d, J = 11.4 Hz, 2H), 1.69 - 1.52 (m, 5H), 1.42 (dd, J = 25.4, 14.2 Hz, 12H), 1.30 - 1.21 (m, 7H), 1.19 (s, 6H), 1.06 (d, J = 21.4 Hz, 5H), 0.97 (s, 3H), 0.89 (d, J = 6.4 Hz, 3H), 0.63 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 77.31, 76.99, 76.68, 75.32, 71.10, 67.34, 56.14, 56.13, 45.87, 44.38, 43.85, 42.70, 39.98, 38.76, 36.39, 35.74, 34.68, 34.36, 30.85, 30.77, 29.31, 29.19, 28.24, 25.91, 24.06, 21.32, 20.79, 18.59, 16.23, 12.11, 0.99. LCMS: [M-H2O-OH] + =385. Example 206 Preparation of the compound cholest-3β,6,25-triol

[0544] [ka]

[0545] (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-5-hydroxy-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoic acid methyl ester (205-3) (50 mg, 0.11 mmol) was weighed and dissolved in tetrahydrofuran (5 mL), cooled with petroleum ether and dry ice, and then a tetrahydrofuran solution of methyllithium (C: 1.6 M, 1.1 mmol, 10.0 eq.) was added dropwise at room temperature. The mixture was heated to RT and stirred for 16 h. The reaction was monitored by TLC (dichloromethane:methanol = 20:1). After completion of the reaction, water (10 mL) was added, extracted with ethyl acetate (10 mL × 3), dried, and concentrated. The crude product was purified by column chromatography (dichloromethane:methanol = 300:1 to 100:1) to give cholest-3β,6,25-triol (206) (8.2 mg, 0.019 mmol, 17.59%) as a white solid. 1H NMR (399 MHz, CDCl3) δ 3.78 (s, 1H), 3.63 (s, 1H), 1.97 (d, J = 12.6 Hz, 1H), 1.78 (d, J = 14.2 Hz, 3H), 1.66 (dd, J = 23.5, 12.0 Hz, 5H), 1.50 (d, J = 28.4 Hz, 6H), 1.42 - 1.29 (m, 8H), 1.23 (s, 5H), 1.19 (s, 6H), 1.10 (s, 4H), 1.01 (s, 3H), 0.90 (d, J = 6.2 Hz, 3H), 0.67 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 77.32, 77.00, 76.68, 72.07, 71.71, 71.12, 56.17, 56.15, 54.20, 47.33, 44.39, 42.67, 39.90, 39.59, 38.49, 36.40, 35.72, 35.36, 31.49, 30.35, 29.70, 29.36, 29.17, 28.21, 24.21, 21.04, 20.74, 18.64, 15.79, 12.10, 1.01. LCMS: [M-H2O-OH] + =385. The two-dimensional spectrum of compound 206 is shown in Figures 60-61.

[0546] Example 207 Preparation of the compound cholest-3β,5,6,25-tetraol

[0547] [ka]

[0548] Step 1 (5R)-5-[(3S,6aS,6bS,9aR,9R,11aS,11bR)-3-acetoxy-9a,11b-dimethyl-1,2,3,4,5a,6,6a,6b,7,8,9,9a,10,11,11a,11b-hexadecahydrocyclopenta[1',2':1,2]phenanthro[8a,9-b]oxazepin-9-yl]hexanoic acid methyl ester (205-1) (100 mg, 0.22 mmol, 1.0 eq.) was weighed and dissolved in a mixed solvent of methanol (8 mL) and water (4.0 mL), and Twain 80 (50 mg, 0.22 mmol) was added. The reaction system was then heated to 100°C and stirred overnight. The reaction was monitored by TLC (dichloromethane:methanol = 10:1). After the reaction was completed, the system was cooled to room temperature, filtered, concentrated, diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), and the organic phase was dried. The crude product obtained after concentration was purified by column chromatography (dichloromethane:methanol = 100:1 to 10:1) to give (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-5,5a-dihydroxy-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoic acid methyl ester (207-1, second component) ( The resulting product was a white solid (20 mg, 0.04 mmol, 17.33%) and (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-5a-hydroxy-5-methoxy-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester (207-2, first component) (30 mg, 0.06 mmol, 25.25%).

[0549] 207-1 (second component): 1 H NMR (399 MHz, CDCl3) δ 5.14 (q, J = 5.6 Hz, 1H), 3.64 (s, 3H), 3.50 (s, 1H), 2.25 (ddd, J = 9.9, 8.6, 6.7 Hz, 2H), 2.15 (dd, J = 12.9, 11.3 Hz, 1H), 2.00 (s, 3H), 1.96 (d, J = 12.1 Hz, 1H), 1.81 (dd, J = 13.6, 7.8 Hz, 2H), 1.71 - 1.58 (m, 7H), 1.57 - 1.44 (m, 4H), 1.42 - 1.31 (m, 5H), 1.25 (dt, J = 18.8, 4.2 Hz, 4H), 1.16 (s, 3H), 1.06 (q, J = 10.4, 10.0 Hz, 4H), 0.90 (d, J = 6.5 Hz, 3H), 0.86 - 0.77 (m, 1H), 0.65 (s, 3H). 207-2 (First component): 1 H NMR (399 MHz, CDCl3) δ 5.10 (dt, J = 11.0, 5.6 Hz, 1H), 3.64 (s, 3H), 3.24 (s, 3H), 2.91 (d, J = 2.8 Hz, 1H), 2.33 - 2.12 (m, 3H), 2.00 (s, 3H), 1.94 (d, J = 12.5 Hz, 1H), 1.86 - 1.66 (m, 5H), 1.61 - 1.49 (m, 5H), 1.46 - 1.30 (m, 7H), 1.30 - 1.16 (m, 5H), 1.05 (d, J = 11.3 Hz, 6H), 0.89 (d, J = 6.4 Hz, 3H), 0.85 - 0.74 (m, 1H), 0.63 (s, 3H). Step 2: (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-5,5a-dihydroxy-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoic acid methyl ester (207-1) (50 mg, 0.11 mmol) was weighed and dissolved in tetrahydrofuran (5 mL). The mixture was cooled with petroleum ether and dry ice. A solution of methyllithium in tetrahydrofuran (C: 1.6 M, 1.1 mmol, 10.0 eq.) was added dropwise at low temperature. The mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction was monitored by TLC (dichloromethane:methanol = 20:1). After the reaction was completed, water (10 mL) was added, extracted with ethyl acetate (10 mL × 3), dried, and concentrated. The crude product was purified by column chromatography (dichloromethane:methanol = 300:1 to 100:1) to give cholest-3β,5,6,25-tetraol (207) (8.2 mg, 0.017 mmol, 16.05%) as a white solid. 1 H NMR (399 MHz, CD3OD) δ 3.98 (dd, J = 11.3, 5.6 Hz, 1H), 3.43 (s, 1H), 2.11 - 1.96 (m, 2H), 1.83 (s, 1H), 1.71 (dd, J = 19.9, 11.4 Hz, 3H), 1.63 - 1.47 (m, 5H), 1.37 (dd, J = 22.6, 10.3 Hz, 9H), 1.27 (q, J = 9.5, 7.9 Hz, 5H), 1.14 (d, J = 3.7 Hz, 10H), 1.06 (d, J = 21.4 Hz, 4H), 0.93 (d, J = 6.4 Hz, 3H), 0.88 (s, 1H), 0.70 (s, 3H). 13 C NMR (101 MHz, CD3OD) δ 141.04, 75.38, 75.07, 70.05, 56.04, 48.20, 48.06, 47.99, 47.84, 47.78, 47.63, 47.56, 47.42, 47.35, 47.26, 47.13, 47.05, 46.92, 45.13, 43.87, 42.50, 40.07, 37.86, 35.72, 33.83, 30.18, 27.82, 27.67, 23.78, 20.86, 17.77, 15.89, 11.16. LC-MS: [M-OH-OH] + =402. Example 208 Preparation of compound 6-methoxycholest-3β,5,25-triol

[0550] [ka]

[0551] (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-5a-hydroxy-5-methoxy-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester (207-2) (50 mg, 0.06 mmol) was weighed and dissolved in tetrahydrofuran (5 mL). The mixture was cooled with petroleum ether and dry ice. A solution of methyllithium in tetrahydrofuran (C: 1.6 M, 0.6 mmol, 10.0 eq.) was added dropwise at low temperature. The mixture was allowed to warm to room temperature and stirred for 16 h. The reaction was monitored by TLC (DCM:MeOH = 20:1). After the reaction was completed, water (10 mL) was added, extracted with ethyl acetate (10 mL × 3), dried, and concentrated. The crude product was purified by column chromatography (dichloromethane:methanol = 300:1 to 100:1) to give 6-methoxycholest-3β,5,25-triol (208) (8.2 mg, 0.018 mmol, 16.36%) as a white solid.

[0552] 1 H NMR (399 MHz, CDCl3) δ 4.05 (dd, J = 11.4, 5.9 Hz, 1H), 3.65 (d, J = 6.0 Hz, 1H), 3.26 (s, 3H), 2.93 (s, 1H), 2.10 (t, J = 12.3 Hz, 1H), 1.96 (d, J = 12.9 Hz, 1H), 1.82 - 1.64 (m, 4H), 1.62 - 1.45 (m, 8H), 1.41 - 1.30 (m, 7H), 1.26 (d, J = 2.5 Hz, 3H), 1.19 (s, 9H), 1.07 (s, 3H), 0.90 (d, J = 6.5 Hz, 3H), 0.82 (s, 2H), 0.65 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 85.56, 77.30, 77.16, 76.99, 76.86, 76.67, 76.30, 71.11, 70.67, 67.68, 57.98, 57.94, 56.13, 55.94, 45.94, 44.38, 42.72, 40.98, 39.92, 38.47, 36.39, 35.74, 32.08, 30.87, 30.50, 29.68, 29.30, 28.22, 27.48, 24.13, 21.10, 20.78, 18.60, 16. 34, 12.14, 1.01. LC-MS: [M-H2O-OH] + =415. Example 210 Compound 210 5α-コレスト-3β,7,25-トリオールの Manufactured

[0553]

change

[0554] Step 1: (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester (151-6) (500 mg, 1.12 mmol) , 1.0 eq.) was weighed and dissolved in acetone (50 mL), and cobalt acetate (9.95 mg, 0.056 mmol), N-hydroxyphthalimide (18.34 mg, 0.11 mmol), and tert-butyl hydroperoxide (405.34 mg, 4.5 mmol) were added, followed by stirring at room temperature and monitoring by TLC (petroleum ether:ethyl acetate=5:1). After completion of the reaction, the reaction solution was filtered and concentrated. The resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate = 50:1 to 30:1 to 10:1) to give (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-4-oxo-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester (210-1) (240 mg, 0.47 mmol, 41.88%) as a white solid. 1 H NMR (399 MHz, Chloroform-d) δ 5.68 (d, J = 1.8 Hz, 1H), 4.76 - 4.63 (m, 1H), 3.65 (s, 3H), 2.58 - 2.32 (m, 3H), 2.23 (dq, J = 18.1, 10.4, 9.2 Hz, 3H), 2.03 (s, 3H), 1.97 (d, J = 10.9 Hz, 2H), 1.66 (d, J = 12.2 Hz, 2H), 1.51 (s, 3H), 1.35 (d, J = 16.7 Hz, 3H), 1.23 (s, 5H), 1.19 (s, 3H), 1.07 (q, J = 8.9 Hz, 4H), 0.92 (d, J = 6.5 Hz, 3H), 0.66 (s, 3H). Step 2: (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-4-oxo-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester (210-1) (64 mg, 0.14 mmol) was weighed and dissolved in methanol (15 mL). Palladium on carbon (1.49 mg, 0.014 mmol, 0.1 eq.) was added at room temperature, the mixture was purged with hydrogen gas, and the mixture was stirred at room temperature for 18 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1). After completion of the reaction, the palladium carbon was removed by filtration, and the organic phase was dried and then purified by column chromatography (petroleum ether:ethyl acetate = 30:1 to 20:1 to 10:1) to give (5R)-5-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-4-oxohexadecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester (210-2) (57 mg, 0.1 mmol, 70.94%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 4.66 (dt, J = 11.1, 5.9 Hz, 1H), 3.66 (s, 3H), 2.39 - 2.22 (m, 4H), 2.22 - 2.15 (m, 1H), 2.03 (d, J = 3.0 Hz, 1H), 2.01 (s, 3H), 1.97 (d, J = 12.9 Hz, 1H), 1.86 (s, 2H), 1.78 (d, J = 13.4 Hz, 1H), 1.71 - 1.58 (m, 3H), 1.55 - 1.44 (m, 5H), 1.39 (dd, J = 11.6, 6.8 Hz, 3H), 1.22 (d, J = 17.8 Hz, 2H), 1.12 (d, J = 6.9 Hz, 1H), 1.08 (s, 5H), 1.05 (d, J = 4.0 Hz, 2H), 0.92 (d, J = 6.5 Hz, 3H), 0.64 (s, 3H). Step 3: (5R)-5-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-4-oxohexahydra-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester (210-2) (50 mg, 0.11 mmol) was weighed and dissolved in a mixture of tetrahydrofuran (8 mL) and methanol (8 mL). The mixture was cooled in an ice bath, and then sodium borohydride (8.21 mg, 0.22 mmol) was added at 0 °C. The mixture was allowed to warm to room temperature and stirred. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1). After completion of the reaction, the reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was separated, dried, and concentrated to give (5R)-5-[(1R,3aS,3bS,5aR,6S,7S,9aR,9bS,11aR)-7-acetoxy-6-hydroxy-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester (210-3) (40 mg, 0.07 mmol, 63.72%) as a white solid, which was used directly in the next step without purification.

[0555] Step 4 (5R)-5-[(1R,3aS,3bS,5aR,6S,7S,9aR,9bS,11aR)-7-acetoxy-6-hydroxy-9a,11a-dimethylhexyl] Sadecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoic acid methyl ester (210-3) (40 mg, 0.09 mmol) was weighed and dissolved in tetrahydrofuran (10 mL). The solution was cooled with dry ice and acetone, and methyllithium (1.6 M, 18.9 mg, 0.86 mmol) was added dropwise at -78 °C. After the addition was completed, the solution was warmed to room temperature, and the solution was analyzed by TLC (dichloromethane:methanol = 20:1). After monitoring, the reaction was completed and quenched by adding saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was separated, dried, and concentrated to obtain the crude product, which was purified by column chromatography (dichloromethane:methanol = 100:1 to 30:1 to 10:1) to obtain 5α-cholest-3β,7,25-triol (210) (10.54 mg, 0.023 mmol, 26.44%) as a white solid. 1 H NMR (399 MHz, CDCl3) δ 3.70 - 3.52 (m, 1H), 2.02 - 1.90 (m, 1H), 1.79 (d, J = 11.9 Hz, 2H), 1.69 (d, J = 13.8 Hz, 3H), 1.49 (s, 2H), 1.46 - 1.35 (m, 7H), 1.33 - 1.22 (m, 9H), 1.19 (s,6H), 1.16 - 0.98 (m, 5H), 0.95 - 0.87 (m, 3H), 0.80 (d, J = 10.2 Hz, 3H), 0.65 (d, J = 8.5 Hz, 3H). 13C NMR (100 MHz, LC-MS: [M-2H2O-OH] + =367.5.

[0556] Example 211 Preparation of Compound 211 (1R,3aS,5aS,7S,9aS,11aR)-1-[(2R)-6-hydroxyoctan-2-yl]-3a,9a,11a-trimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthren-7-ol

[0557] [ka]

[0558] Step 1: Copper(I) iodide (355 mg, 2.98 mmol, 1.0 eq) was dissolved in tetrahydrofuran (THF) (7 mL). The reaction mixture was cooled to approximately -30 °C and methylmagnesium bromide (355.35 mg, 2.980 mmol, 1.5 eq, 3 M in ether) was slowly added. The mixture was stirred for 20 min at the same temperature. Next, 2-(2-bromoethyl)oxirane (300 mg, 1.987 mmol, 0.2 eq) was slowly added and the mixture was stirred at 0 °C for 2 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1). After completion of the reaction, the mixture was extracted with ethyl acetate (25 mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, and the organic phase was spin-dried under vacuum to obtain the crude product. The crude product was separated and purified by flash chromatography (petroleum ether:ethyl acetate = 92:8 to 90:10) to obtain 1-bromopentan-3-ol (211-1) (200 mg, purity: 90.0%, yield: 54.23%) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 3.80 - 3.71 (m, 1H), 3.62 - 3.51 (m, 2H), 2.08 - 1.89 (m, 2H), 1.59 - 1.45 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H). Step 2: 1-Bromopentan-3-ol (211-1) (200 mg, 1.197 mmol, 1.0 eq) was dissolved in DCM (20 mL). The reaction mixture was placed in an ice-water bath and cooled to approximately 5 °C. Acetic anhydride (0.04 mL, 3.60 mmol, 3.0 eq), DMAP (29.25 mg, 0.24 mmol, 0.2 eq), and triethylamine (TEA) (0.5 mL, 3.60 mmol, 5.0 eq) were added sequentially and the mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 10:1). After completion of the reaction, the mixture was quenched with methanol (20 mL). The reaction mixture was washed once with saturated sodium bicarbonate (20 mL) and once with water (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was separated and purified by flash chromatography (petroleum ether:ethyl acetate=97:3 to 95:5) to give 1-bromopentan-3-yl acetate (211-2) (15 mg, purity: 90%, yield: 20.75%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 4.95 (dq, J = 12.4, 6.2 Hz, 1H), 3.45 - 3.28 (m, 2H), 2.12 (dt, J = 7.8, 5.7 Hz, 2H), 2.07 (s, 3H), 1.61 (dt, J = 13.6, 6.9 Hz, 2H), 0.91 (t, J = 7.5 Hz, 3H). Step 3: 1-Bromopentan-3-yl acetate (211-2) (180 mg, 0.86 mmol) (200 mg, 1.20 mmol, 1.0 eq) was dissolved in acetonitrile (10 mL), triphenylphosphine (677 mg, 2.583 mmol, 3 eq) was added, and the reaction mixture was stirred at 90 °C for 18 h under a nitrogen atmosphere. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 10:1). Upon completion, the reaction mixture was concentrated to give the crude product. The crude product was purified by flash chromatography (dichloromethane:methanol = 95:5 to 90:10) to give 1-(bromotriphenyl-λ5-phosphanyl)pentan-3-yl acetate (211-3) (132 mg, purity: 90%, yield: 29.27%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.94-7.63 (m, 15H), 4.83 - 4.74 (m, 1H), 3.95-3.88 (m, 2H), 2.06 (s, 3H), 2.03 - 1.92 (m, 2H), 1.80-1.75 (m, 2H), 0.84 (t, J = 7.4 Hz, 3H). Step 4: The starting materials acetic acid-1-(bromotriphenyl-λ5-phosphanyl)pentan-3-yl ester (211-3) (126 mg, 0.27 mmol, 2.0 eq), 18-crown-6 (35 mg, 0.13 mmol, 1.0 eq), and potassium carbonate (55 mg, 0.40 mmol, 3.0 eq) were dissolved in DCM (dichloromethane) (5 mL), and the reaction mixture was reacted at 50°C for 1 hour under a nitrogen atmosphere. A solution of acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aS)-1-[(1S)-1-formylethyl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (151-2) (50 mg, 0.13 mmol, 1.0 eq) in dichloromethane (5 mL) was added, and the reaction was refluxed and stirred for 48 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 10:1). The reaction was cooled to room temperature and concentrated to give the crude product. The crude product was purified by flash chromatography (petroleum ether:ethyl acetate = 93:7 to 94:4) to give acetic acid-(5E,7R)-7-[(1R,3aS,7S,9aR,11aR)-7-acetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]oct-5-en-3-yl ester (211-4) (15 mg, purity: 90%, yield: 20.75%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 5.37 (d, J = 4.9 Hz, 1H), 5.29 - 5.11 (m, 2H), 4.85 - 4.78 (m, 1H), 4 .61 (ddd, J = 15.9, 8.9, 4.2 Hz, 1H), 2.40 (ddd, J = 16.1, 9.3, 1.8 Hz, 1H), 2.32 (d, J = 6.5 Hz, 2H), 2.28 - 2.16 (m, 1H), 2.03 (t, J = 3.3 Hz, 6H), 1.97 (ddd, J = 15.1, 9.2, 4.1 Hz, 2H), 1.86 (d, J = 10.2 Hz, 2H), 1.70 - 1.43 (m, 10H), 1.26 - 1.07 (m, 5H), 1.03 (s, 4H), 0.97 (dd, J = 6.6, 2.0 Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H), 0.71 (t, J = 8.4 Hz, 3H). Step 5: The starting material, acetic acid-(5E,7R)-7-[(1R,3aS,7S,9aR,11aR)-7-acetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]oct-5-en-3-yl ester (211-4) (20 mg, 0.04 mmol, 1.0 eq) was dissolved in ethanol (3 mL). Palladium on carbon (5 mg, 0.04 mmol, 45%) was added, the reaction mixture was purged with hydrogen gas, and the mixture was stirred at room temperature for 18 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1, heated with phosphomolybdic acid). After completion of the reaction, the reaction solution was filtered through diatomaceous earth, and the filtrate was spin-dried under vacuum to give acetic acid-(7R)-7-[(1R,3aS,7S,9aS,11aR)-7-acetoxy-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]oct-3-yl ester (211-5) (15 mg, purity: 85%, yield: 63.22%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 4.84 - 4.76 (m, 1H), 4.73 - 4.63 (m, 1H), 2.05 (s, 3H), 2.02 (s, 3H), 1.95 (dd, J = 9.3, 3.2 Hz, 1H), 1.85 - 1.77 (m, 2H), 1.76 - 1.70 (m, 1H), 1.68 - 0.95 (m, 29H), 0.89 (s, 2H), 0.88 (s, 3H), 0.81 (s, 3H), 0.64 (s, 3H). Step 6: Acetic acid (7R)-7-[(1R,3aS,7S,9aS,11aR)-7-acetoxy-9a,11a-dimethylhexahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]octan-3-yl ester (211-5) (50 mg, 0.10 mmol, 1 eq) was dissolved in tetrahydrofuran (THF) (1 mL) and methanol (MeOH) (1 mL). 1N lithium hydroxide (0.6 mL) was added dropwise, and the reaction mixture was stirred at 50 °C for 2 h. The reaction was monitored by TLC (dichloromethane:methanol = 20:1). After completion of the reaction, the reaction solution was cooled to room temperature, acidified with 1N HCl to pH 3–4, concentrated to remove ethanol, extracted with EtOAc (20 mL × 3), and the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by flash chromatography (dichloromethane:methanol = 95:5 to 94:6) to give (1R,3aS,5aS,7S,9aS,11aR)-1-[(2R)-6-hydroxyoctan-2-yl]-3a,9a,11a-trimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthren-7-ol (211) (21 mg, yield: 50.43%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 3.59 (s, 1H), 3.54-3.46(m, 1H), 1.99 - 1.92 (m, 1H), 1.79 (d, J = 9.5 Hz, 2H), 1.69 (s, 2H), 1.61 - 1.53 (m, 2H),1.51 - 1.20 (m, 20H), 1.13-0.98(m, 5H), 0.97 - 0.89 (m, 7H), 0.80 (s, 3H), 0.64 (s, 3H).

[0559] Example 216 Preparation of Compound 216 3β,25-dihydroxy-5α-cholest-7-one

[0560] [ka]

[0561] Step 1: Cholest-6(5)-ene-3β,25-diol (177) (300 mg, 0.745 mmol) was dissolved in dichloromethane (30 mL), protected with nitrogen gas, and triethylamine (0.52 mL, 3.73 mmol), 4-dimethylaminopyridine (18.2 mg, 0.15 mmol), and acetic anhydride (0.084 mL, 0.89 mmol) were added. The reaction was allowed to proceed at room temperature for 2 hours, and monitored by TLC (petroleum ether:ethyl acetate = 1:1). After completion of the reaction, the reaction solution was quenched with saturated ammonium chloride and extracted with dichloromethane. The organic phase was separated and dried with anhydrous sodium sulfate. The reaction solution was concentrated and the resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate = 60:1 to 5:1) to give acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester (216-1) (200 mg, 0.41 mmol, 54.33%) as an off-white solid. 1 H NMR (399 MHz, Chloroform-d) δ 5.35 (d, J = 5.0 Hz, 1H), 4.57 (q, J = 6.4, 5.3 Hz, 1H), 2.29 (d, J = 7.9 Hz, 2H), 2.01 (s, 3H), 1.95 (d, J = 18.2 Hz, 2H), 1.84 (d, J = 11.6 Hz, 2H), 1.61 - 1.51 (m, 4H), 1.49 -1.30 (m, 8H), 1.19 (s, 6H), 1.13 - 1.04 (m, 3H), 0.91 (d, J = 6.5 Hz, 3H), 0.66 (s, 3H). Step 2 Acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (216-1) (280 mg, 0. The resulting mixture was stirred at room temperature for 40 hours and monitored by TLC (petroleum ether:ethyl acetate=3:1). After completion of the reaction, the mixture was quenched with water (10 mL), extracted with ethyl acetate (10 mL × 3), washed once with brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 60:1 to 4:1) to give acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-9a,11a-dimethyl-4-oxo-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (216-2) (180 mg, 0.37 mmol, 59.21%). 1 HNMR(399MHz, Chloroform-d) δ 5.68 (s, 1H), 4.69 (s, 1H), 2.57 - 2.34 (m, 3H), 2.21 (s, 1H), 2.03 (s, 3H), 1.94 (d,J = 13.6Hz, 3H), 1.86 (t,J = 8.9Hz, 1H), 1.73 - 1.62 (m, 1H), 1.57 (s, 4H), 1.51 (dd,J = 13.4, 6.2Hz, 2H), 1.44 - 1.39 (m, 3H), 1.35 (dd,J = 11.9, 6.3Hz, 3H), 1.28 - 1.25 (m, 2H), 1.19 (s, 9H), 1.06 (dd,J = 15.2, 9.2Hz, 2H), 0.92 (d,J = 6.5Hz, 3H), 0.66 (s, 3H). Step 3: Acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-9a,11a-dimethyl-4-oxo-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (216-2) (140 mg, 0.31 mmol) was dissolved in ethyl acetate (10 mL), palladium on carbon (30 mg, 0.28 mmol) was added, the mixture was purged with hydrogen gas, and the mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 2:1). After completion of the reaction, the mixture was filtered and spin-dried to obtain 150 mg of crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 60:1 to 5:1) to give acetic acid-(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-9a,11a-dimethyl-4-oxohexadecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (216-3) (100 mg, 0.21 mmol, 67.56%). 1HNMR(399MHz, Chloroform-d) δ 4.67 (s, 1H), 2.29 (d,J = 15.5Hz, 2H), 2.16 (s, 1H), 2.00 (s, 3H), 1.94 (s, 1H), 1.88 (d,J = 19.1Hz, 2H), 1.77 (d,J = 13.7Hz, 1H), 1.64 (d,J = 16.8Hz, 1H), 1.58 (s, 4H), 1.56 -1.44 (m, 5H), 1.44 - 1.39 (m, 2H), 1.36 (d,J = 10.8Hz, 4H), 1.25 (d,J = 11.1Hz, 2H), 1.19 (s, 6H), 1.11 (d,J = 7.2Hz, 1H), 1.08 (s, 3H), 1.03 (d,J = 12.5Hz, 2H), 0.90 (d,J = 6.5Hz, 3H), 0.63 (s, 3H). Step 4: Acetic acid-(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-9a,11a-dimethyl-4-oxohexahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (216-3) (30 mg, 0.065 mmol) was dissolved in a mixture of tetrahydrofuran (3 mL) and methanol (1.5 mL). Lithium hydroxide (0.5 mL, 0.5 mmol) was added at room temperature, and the mixture was stirred at room temperature for 2 hours. The mixture was monitored by TLC (petroleum ether:ethyl acetate = 2:1). After completion of the reaction, the mixture was concentrated to give 50 mg of crude product, which was purified by column chromatography (dichloromethane:methanol=80:1) to give 3β,25-dihydroxy-5α-cholest-7-one (216) (13.8 mg, 0.031 mmol, 48.09%) as a white solid. 1 H NMR (399 MHz, Chloroform-d) δ 3.63 - 3.54 (m, 1H), 2.40 - 2.26 (m, 2H), 2.18 (s, 1H), 2.03 - 1.94 (m, 2H), 1.85 (d, J = 5.9 Hz, 2H), 1.75 (d, J = 13.4 Hz, 1H), 1.52 (d, J = 11.7 Hz, 7H), 1.48 - 1.39 (m, 6H), 1.37 (d, J = 10.2 Hz, 5H), 1.19 (s, 6H), 1.06 (s, 3H), 1.01 - 0.93 (m, 2H), 0.90 (d, J = 6.5 Hz, 3H), 0.63 (s, 3H). 13 C NMR (100 MHz, cdcl3) δ 212.08, 77.30, 77.17, 76.98, 76.66, 71.08, 70.63, 55.19, 54.91, 49.97, 48.85, 46.80, 46.06, 44.35, 42.48, 38.71, 37.85, 36.36, 35.95, 35.59, 31.02, 29.29, 29.20, 28.40, 21.82, 20.70, 18.75, 11.99.LC-MS:[M-OH] + =401.35. Example 217 Preparation of Compound 217 24-[cyclopropyl(hydroxy)methyl]-5α-cholan-3β-ol

[0562] [ka]

[0563] Step 1: The reactant (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-acetoxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester (151-6) (2 g, 4.50 mmol, 1.0 eq) was dissolved in methanol (50 mL) and concentrated sulfuric acid (98%) (1 mL, 18.76 mmol) was added dropwise. The mixture was then heated to reflux and stirred for 1 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 10:1). After completion of the reaction, the reaction solution was concentrated to remove most of the methanol, ethyl acetate was added, and the mixture was washed twice with saturated sodium bicarbonate and once with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain the crude product. The crude product was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate = 90:10 to 80:20, heated with phosphomolybdic acid) to give (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-hydroxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester (217-1) (1.8 g, 4.024 mmol, 89.46%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 5.37 - 5.33 (m, 1H), 3.67 (s, 3H), 3.52 (dd, J = 7.7, 3.3 Hz, 1H), 2.35 - 2.20 (m, 4H), 2.03 - 1.93 (m, 2H), 1.84(ddd, J = 12.5, 7.5, 4.3 Hz, 3H), 1.75 - 1.60 (m, 4H), 1.59 - 1.35 (m, 9H), 1.33 - 1.04 (m, 7H), 1.03 - 0.99 (m, 3H), 0.93 (d, J = 6.6 Hz, 3H), 0.68(s, 3H). Step 2: The reactant (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-hydroxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester (217-1) (1.7 g, 4.38 mmol) was dissolved in DMF (50 mL), and TBSCl (3.3 g, 21.9 mmol, 5.0 eq) and imidazole (0.30 g, 4.38 mmol, 1.0 eq) were added sequentially. The reaction was heated to 100 °C and monitored by TLC (petroleum ether:ethyl acetate = 10:1). After completion of the reaction, the reaction solution was cooled to room temperature, ethyl acetate (100 mL) was added, and the mixture was washed three times with water. The organic phase was then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate = 90:10) to give (5R)-5-[(1R,3aR,3bS,7S,9aR,9bS,11aR)-7-{[-dimethyl(2-methylpropan-2-yl)methylsilyl]oxy}-3b,9a,11a-trimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester (217-2) (1.9 g, 3.40 mmol, 77.73%) as a colorless wax. 1 H NMR (400 MHz, CDCl3) δ 5.26 - 5.18 (m, 1H), 3.57 (s, 3H), 3.43 - 3.33 (m, 1H), 2.16 (d, J = 1.9 Hz, 4H), 1.93 - 1.82 (m, 2H), 1.65 - 1.55(m, 2H), 1.39 (d, J = 3.0 Hz, 9H), 0.99 (s, 7H), 0.90 (s, 5H), 0.85 - 0.79 (m, 21H), 0.57 (s, 3H), -0.00 (s, 6H). Step 3: The reactant (5R)-5-[(1R,3aR,3bS,7S,9aR,9bS,11aR)-7-{[-dimethyl(2-methylpropan-2-yl)methylsilyl]oxy}-3b,9a,11a-trimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanoic acid methyl ester (217-2) (1.8 g, 3.58 mmol, 1.0 eq) was dissolved in tetrahydrofuran (50 mL), and lithium aluminum hydride (0.168 g, 4.269 mmol, 1.2 eq) was added. After stirring at room temperature for 30 min, the reaction was monitored by TLC (petroleum ether:ethyl acetate = 10:1). After completion of the reaction, the reaction solution was quenched with sodium sulfate decahydrate, filtered, and the filtrate was concentrated to obtain the crude product, which was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 80:20 to 70:30) to obtain a white solid (5R)-5-[(1R,3aR,3bS,7S,9aR,9bS,11aR)-7-{[-dimethyl(2-methylpropan-2-yl)methylsilyl]oxy}-3b,9a,11a-trimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexan-1-ol (217-3) (1.7 g, 3.22 mmol, 90.01%). 1 H NMR (400 MHz, CDCl3) δ 5.26 (d, J = 5.3 Hz, 1H), 3.59 (t, J = 6.6 Hz, 2H), 3.47 - 3.37 (m, 1H), 2.27 - 2.17 (m, 1H), 2.11 (ddd, J = 13.4,5.0, 2.2Hz, 1H) , 1.93 (s, 2H), 1.77 (s, 2H), 1.66 (d, J = 12.2 Hz, 1H), 1.47 (ddd, J = 13.9, 8.7, 4.5 Hz, 7H), 1.37 - 1.29 (m, 3H), 1.25 - 1.15 (m,2H), 1.13 - 0.97 (m, 5H), 0.94 (s, 3H), 0.87 (d, J = 6.3 Hz, 4H), 0.84 - 0.81 (m, 10H), 0.62 (s, 3H), 0.02 - -0.02 (m, 6H). Step 4: The compound (5R)-5-[(1R,3aR,3bS,7S,9aR,9bS,11aR)-7-{[-dimethyl(2-methylpropan-2-yl)methylsilyl]oxy}-3b,9a,11a-trimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexan-1-ol (217-3) (1.0 g, 2.11 mmol, 1.0 eq) was added to D The mixture was dissolved in CM (100 mL), Dess-Martin oxidant (1.068 g, 2.532 mmol, 1.2 eq) was added, and the mixture was stirred at room temperature. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 5:1). After completion of the reaction, the reaction solution was quenched with saturated sodium sulfite and washed with saturated sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 90:10 to 80:20) to give a white solid, (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-{[-dimethyl(2-methylpropan-2-yl)methylsilyl]oxy}-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanal (217-4) (0.6 g, 1.142 mmol, 54.23%). 1 H NMR (400 MHz, CDCl3) δ 9.71 (t, J = 1.8 Hz, 1H), 5.26 (d, J = 5.3 Hz, 1H), 3.49 - 3.36 (m, 1H), 2.34 (d, J = 6.6 Hz, 2H), 2.25 - 2.07 (m,2H), 1.93 (s, 2H), 1.81 - 1.60 (m, 4H), 1.48 - 1.30 (m, 8H), 1.03 (ddd, J = 14.6, 12.0, 6.3 Hz, 7H), 0.94 (s, 4H), 0.89 (d, J = 6.5 Hz, 4H), 0.85 -0.81 (m, 9H), 0.62 (s, 3H), 0.02 - -0.02 (m, 7H). Step 5: (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-{[-dimethyl(2-methylpropan-2-yl)methylsilyl]oxy}-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexanal (217-4) (100 mg, 0.205 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 mL), cooled to 0 °C in an ice bath, and after complete dissolution, cyclopropylmagnesium bromide (2.054 mL, 1 mol / L, 2.054 mmol, 10 eq) was added to the reaction mixture. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The completion of the reaction was monitored by TLC (petroleum ether: ethyl acetate = 5:1). Under ice bath conditions, the reaction mixture was quenched with saturated ammonium chloride solution (10 mL). The reaction mixture was washed with water (10 mL × 3), extracted with ethyl acetate (10 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:0 to 94:6) to give (5R)-1-cyclopropyl-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-{[-dimethyl(2-methylpropan-2-yl)methylsilyl]oxy}-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexan-1-ol (217-5) (72 mg, 0.109 mmol, purity: 80.0%, yield: 5 3.02%). 1 H NMR (400 MHz, CDCl3) δ 5.31 (d, J = 5.3 Hz, 1H), 3.47 (td, J = 10.9, 5.4 Hz, 1H), 2.88 - 2.82 (m, 1H), 2.27 (t, J = 11.1 Hz, 1H), 2.18 - 2.13 (m, 1H), 1.99 (s, 2H), 1.82 (s, 2H), 1.71 (d, J = 12.3 Hz, 1H), 1.61 - 1.51 (m, 11H), 1.41 (dd, J = 12.4, 6.8 Hz, 3H), 1.27 (d, J = 12.0 Hz, 3H), 1.16 - 1.01 (m, 5H), 0.96 - 0.84 (m, 15H), 0.67 (s, 3H), 0.58 - 0.44 (m, 2H), 0.24 (d, J = 4.7 Hz, 2H), 0.02 - -0.02 (m, 5H). Step 6: (5R)-1-Cyclopropyl-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-{[dimethyl(2-methylpropan-2-yl)methylsilyl]oxy}-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexan-1-ol (217-5) (72 mg, 0.136 mmol, 1.0 eq) was dissolved in methanol (5 mL) and tetrahydrofuran (2 mL). Palladium carbon was added and the mixture was purged with hydrogen gas three times. The reaction was monitored by HNMR. After completion of the reaction, the palladium-carbon was filtered through diatomaceous earth, and the combined organic phase was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 90:10 to 75:25) to give 24-[cyclopropyl(hydroxy)methyl]-5α-cholan-3β-ol (217) (17.88 mg, 0.122 mmol, purity: 94.86%, yield: 89%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 3.63 - 3.54 (m, 1H), 2.85 (td, J = 7.8, 4.9 Hz, 1H), 1.96 (dt, J = 12.6, 3.4 Hz, 1H), 1.86 - 1.75 (m, 2H), 1.74 - 1.58 (m, 3H), 1.49 - 1.19 (m, 14H), 1.03 (ddd, J = 22.5, 17.2, 8.7 Hz, 7H), 0.90 (t, J = 7.6 Hz, 5H), 0.80 (s, 3H), 0.65 (s, 4H), 0.57 - 0.44 (m, 2H), 0.24 (d, J = 4.7 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 71.40, 64.92, 63.38, 56.51, 56.09, 54.40, 45.03, 42.62, 39.97, 38.29, 37.56, 36.91, 35.76, 35.39, 32.09, 31.44, 28.75, 28.10, 24.22, 21.26, 19.64, 18.67, 18.01, 12.28, 11.99, 3.35, 2.27. LC-MS: [M-OH-H2O] + =381 Example 218 Compound 218 24-(2,2,2-Torotron-1-ヒドロキシエチル)-5α-コラン-3β-オールの

[0564]

change

[0565] 24-(2,2,2-Trifluoro-1-hydroxyethyl)cholan-6(5)-en-3β-ol (219) (52 mg, 0.093 mmol, 1.0 eq) was dissolved in methanol (5 mL) and tetrahydrofuran (2 mL), and palladium carbon was added. The mixture was then purged with hydrogen gas three times. The reaction was monitored by H NMR. Upon completion, the palladium carbon was filtered through diatomaceous earth. The combined organic phase was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 90:10 to 75:25) to give 24-(2,2,2-trifluoro-1-hydroxyethyl)-5α-cholan-3β-ol (218) (32 mg, 0.066 mmol, purity: 94.86%, yield: 89%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 3.95-3.87 (m, 1H), 3.64 - 3.54 (m, 1H), 1.96 (m,1H), 1.79 (m, 2H), 1.73 - 1.62 (m, 4H), 1.47 (m,4H), 1.43 - 1.32 (m, 5H), 1.30 - 1.19 (m, 6H), 1.15 - 0.96 (m, 7H), 0.92 (d, J = 6.5 Hz, 3H), 0.85 (m, 1H), 0.80 (s, 3H), 0.65 (s, 3H) 19 F(376 MHz, CDCl3)δ -80.04. Example 219 Preparation of Compound 219 24-(2,2,2-trifluoro-1-hydroxyethyl)cholan-6(5)-en-3β-ol

[0566] [ka]

[0567] (5R)-5-[(1R,3aS,3bS,7S,9aR,9bS,11aR)-7-{[-dimethyl(2-methylpropan-2-yl)methylsilyl]oxy}-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]hexana The alcohol (217-4) (100 mg, 0.205 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 mL). After complete dissolution, cesium fluoride (15.6 mg, 0.103 mmol, 0.5 eq) and (trifluoromethyl)trimethylsilane (146.03 mg, 0.513 mmol, 5.0 eq) were added sequentially to the reaction system. After the addition was complete, the mixture was stirred at room temperature for 2 hours. After monitoring the appearance of a large pole by TLC (petroleum ether:ethyl acetate = 10:1), tetrabutylammonium fluoride (2 mL, 1 mol / L, 10.0 eq) was added and stirred at room temperature for 1 hour. After monitoring the appearance of a large pole by TLC (petroleum ether:ethyl acetate = 2:1), the mixture was quenched with saturated ammonium chloride solution (50 mL) under ice bath conditions. The reaction solution was washed with water (10 mL × 3) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 90:10 to 75:25) to give 24-(2,2,2-trifluoro-1-hydroxyethyl)cholan-6(5)-en-3β-ol (219) (10.82 mg, 0.075 mmol, purity: 91.82%, yield: 36.37%). 1H NMR (400 MHz, CDCl3) δ 5.37 - 5.33 (m, 1H), 3.96 - 3.87 (m, 1H), 3.52 (ddd, J = 15.7, 11.0, 4.5 Hz, 1H), 2.27 (tdd, J = 12.8, 8.9, 6.6 Hz, 2H), 2.00 (d, J = 3.2 Hz, 3H), 1.84 (dd, J = 14.1, 3.4 Hz, 3H), 1.61 - 1.42 (m, 15H), 1.35 - 1.19 (m, 5H), 1.10 (dd, J = 18.5, 5.5 Hz, 4H), 0.94 (d, J = 6.6 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 155.09, 121.69, 115.18, 71.82, 69.47, 56.76, 55.91, 50.11, 42.35, 37.25, 35.58, 31.90, 28.24, 19.40,11.86 19 F(376 MHz, CDCl3)δ -80.04 LC-MS: [M-OH] + =425 Example 225 Compound 225 3β,5,25-Torotron-6-オンの

[0568]

change

[0569] Step 1: Acetic acid-(3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (216-2) (280 mg, 0.63 mmol) was dissolved in dichloromethane (20 mL) and m-chloroperbenzoic acid (249.9 mg, 1.45 mmol) was added in batches at room temperature. Stirring was then continued at room temperature and monitored by TLC (petroleum ether:ethyl acetate = 3:1). After the reaction was completed, the reaction solution was quenched by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, the reaction solution was concentrated, and the obtained crude product was purified by column chromatography (petroleum ether: ethyl acetate = 30:1 to 10:1 to 5:1) to give acetic acid-(3S, 6aS, 6bS, 9aR, 1 (1aS,11bR)-9-[(2R)-6-hydroxy-6-methylheptan-2-yl]-9a,11b-dimethyl-1,2,3,4,5a,6,6a,6b,7,8,9,9a,10,11,11a,11b-hexadecahydrocyclopenta[1,2-i]oxazepino[2,3-m]phenanthrene-3-yl ester (225-1) (220 mg, 0.41 mmol, 64.47%) was obtained as a white solid. 1 H NMR (399 MHz, Chloroform-d) δ 4.92 (dd, J = 10.8, 5.8 Hz, 1H), 2.87 (d, J = 4.3 Hz, 1H), 2.19 - 2.05 (m, 1H), 2.01 (s, 1H), 1.99 (s, 3H), 1.93 (d, J = 16.2 Hz, 1H), 1.70 - 1.59 (m, 1H), 1.53 (d, J = 15.7 Hz, 3H), 1.47 - 1.40 (m, 3H), 1.38 - 1.30 (m, 7H), 1.29 - 1.20 (m, 4H), 1.19 (s, 6H), 1.05 (s, 3H), 0.98 (s, 1H), 0.96 (s, 1H), 0.89 (d, J = 6.5 Hz, 3H), 0.62 (s, 1H), 0.59 (s, 3H). Step 2: Acetic acid-(3S,6aS,6bS,9aR,11aS,11bR)-9-[(2R)-6-hydroxy-6-methylheptan-2-yl]-9a,11b-dimethyl-1,2,3,4,5a,6,6a,6b,7,8,9,9a,10,11,11a,11b-hexadecahydrocyclopenta[1,2-i]oxazepino[2,3-m]phenanthren-3-yl ester (225-1) (100 mg, 0.22 mmol) was dissolved in acetone (10 mL), cooled to 0 °C in an ice bath, and chromium trioxide (81.39 mg, 0.81 mmol) was added. After the addition was complete, the mixture was warmed to 30 °C and then stirred for 2 h and monitored by TLC (petroleum ether:ethyl acetate = 5:1). After completion of the reaction, the reaction mixture was quenched by adding water (10 mL), extracted with ethyl acetate (10 mL × 3), washed once with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product, acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-5a-hydroxy-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-9a,11a-dimethyl-5-oxohexadecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester (225-2) (65 mg, 0.12 mmol, 53.4%). 1 H NMR (399 MHz, Chloroform-d) δ 5.00 (dt, J = 11.5, 6.0 Hz, 1H), 2.98 (s, 1H), 2.73 (t, J = 12.6 Hz, 1H), 2.08 (dd, J = 13.0, 4.5 Hz, 1H), 1.99 (s, 4H), 1.95 - 1.86 (m, 2H), 1.84 - 1.76 (m, 4H), 1.75 - 1.60 (m, 3H), 1.51 (d, J = 12.2 Hz, 3H), 1.42 (d, J = 9.6 Hz, 3H), 1.37 - 1.29 (m, 4H), 1.26 (d, J = 3.0 Hz, 3H), 1.22 (d, J = 6.1 Hz, 5H), 1.18 (s, 6H), 1.12 (q, J = 9.6 Hz, 2H), 1.03 (dd, J = 12.1, 6.5 Hz, 2H), 0.90 (d, J = 6.4 Hz, 3H), 0.79 (s, 3H), 0.62 (s, 3H). 13 C NMR (100 MHz, Chloroform-d) δ 110.00, 80.14, 71.16, 70.74, 56.24, 56.09, 44.26, 44.18, 43.10, 42.45, 41.69, 39.53, 37.26, 36.34, 35.71, 32.29, 29.67, 29.49, 29.29, 29.13, 28.06, 26.24, 23.88, 21.35, 21.31, 20.81, 18.55, 13.85, 11.98. Step 3 Acetic acid -(1R,3aS,3bS,7S,9aR,9bS,11aR)-5a-hydroxy-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-9a,11a-dimethyl-5-oxohexadecahydro-1H-cyclopenta[1,2- i] Phenanthren-7-yl ester (225-2) (65 mg, 0.14 mmol) was dissolved in a mixture of methanol (3 mL) and tetrahydrofuran (3 mL) and added with aqueous lithium hydroxide (1 M, 0.21 mL, 0.21 mmol) at room temperature. After the addition was complete, the mixture was stirred at room temperature and monitored by TLC (petroleum ether:ethyl acetate = 1:1). After completion of the reaction, the mixture was extracted with water and dichloromethane (10 mL x 3), washed once with brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 10:1, 5:1, then 2:1) to give 3β,5,25-trihydroxycholest-6-one (225) (26 mg, 0.06 mmol, 41.93%). 1 H NMR (400 MHz, Methanol-d4) δ 3.88 (dt, J = 11.4, 6.1 Hz, 1H), 2.74 (t, J = 12.5 Hz, 1H), 2.04 (d, J = 11.7 Hz, 1H), 1.92 (dtd, J = 25.2, 13.0, 5.0 Hz, 3H), 1.81 - 1.59 (m, 5H), 1.54 (d, J = 9.2 Hz, 1H), 1.48 - 1.37 (m, 6H), 1.33 - 1.21 (m, 6H), 1.18 (d, J = 9.8 Hz, 1H), 1.15 (s, 6H), 1.12 - 1.00 (m, 2H), 0.94 (d, J = 6.4 Hz, 3H), 0.77 (s, 3H), 0.67 (s, 3H). 13 C NMR (101 MHz, cd3od) δ 213.88, 79.75, 70.03, 66.42, 56.38, 56.06, 48.19, 47.98, 47.77, 47.55, 47.34, 47.13, 46.92, 44.30, 43.83, 42.89, 42.16, 41.37, 37.48, 36.30, 35.63, 35.13, 29.78, 29.55, 27.82, 23.53, 20.41, 12.92, 10.98. LCMS: [M-OH-H2O] +=399.25. Example 231 Preparation of Compound 231 Cholest-3β,4β,7,25-tetraol

[0570] [ka]

[0571] In a 50 mL round-bottom flask, add 25-hydroxy-4β-hydroxy-3β-hydroxybenzoate. Cholest-7-one (242) (40 mg, 0.092 mmol) was dissolved in tetrahydrofuran (2 mL), and cerium(III) chloride heptahydrate (86 mg, 0.23 mmol), sodium borohydride (8.7 mg, 0.23 mmol), and methanol (0.2 mL) were added at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction was monitored for completion by TLC (ethyl acetate / petroleum ether = 2 / 1). After completion of the reaction, the reaction solution was added to ice water (30 mL), extracted with ethyl acetate (15 mL x 3), washed with saturated brine (20 mL), and the organic solution was extracted. The extract was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was separated and purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether=2 / 1) to obtain a white solid, cholest-3β,4β,7,25-tetraol (231) (28 mg, purity: 92.41%, yield: 64.38%). 1 H NMR (400 MHz, DMSO) δ 4.30 - 4.28 (m, 1H), 4.03 (s, 1H), 4.00 - 3.95 (m, 2H), 3.44 - 3.38 (m, 1H), 3.29 - 3.25 (m, 1H), 3.13 - 3.02 (m, 1H),1.92 - 1.54 (m, 8H), 1.41 - 1.27 (m, 10H), 1.19 - 1.14 (m, 4H), 1.05 (s, 6H), 1.01 - 0.97 (m, 3H), 0.94 - 0.92 (m, 3H), 0.88 (d, J = 6.4 Hz, 3H), 0.84- 0.80 (m, 1H), 0.61 - 0.59 (m, 3H). 13 C NMR (101 MHz, DMSO) δ 74.55, 73.98, 72.09, 71.90, 69.23, 56.43, 56.22, 55.43, 53.40, 50.54, 46.16, 44.61, 43.41, 43.20, 42.37, 37.47, 37.16,36.72, 35.75, 35.64, 35.02, 29.89, 29.70, 29.46, 28.83, 27.20, 26.23, 22.57, 20.91, 20.77, 19.17, 19.03, 15.28, 14.20, 12.55, 12.17.LCMS [M+ H-3H2O] + =401 Example 232 Preparation of Compound 232 24-(2,2,2-trifluoro-1-hydroxyethyl)-5α-cholane-3β,4β-diol

[0572] [ka]

[0573] Step 1: Compound 24-(2,2,2-trifluoro-1-hydroxyethyl)cholan-5(6)-en-3β-ol hexanal (219) (89 mg, 0.20 mmol, 1 eq) was dissolved in chloroform (10 mL). Selenium dioxide (33.46 mg, 0.30 mmol, 1.50 eq) and N-methylmorpholine (60.99 mg, 0.60 mmol, 3.0 eq) were added, and the reaction mixture was stirred at 80 °C for 18 h. Completion of the reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1). 20 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was collected and dried over anhydrous sodium sulfate. The organic phase was then spin-dried under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=76:24) to give a white solid, 24-(2,2,2-trifluoro-1-hydroxyethyl)-5α- Cholan-3β,4β-diol (232-1) (40 mg, purity: 90%, yield: 41%) was obtained. 1 H NMR (400 MHz, DMSO) δ 6.04 (d, J = 6.7 Hz, 1H), 5.49 (s, 1H), 4.42 (d, J = 6.2 Hz, 1H), 4.28 (d, J = 2.3 Hz, 1H), 3.91 - 3.81 (m, 2H), 3.25 (d, J = 9.6 Hz, 1H), 2.03 - 1.91 (m, 3H), 1.74 (dd, J = 22.2, 13.5 Hz, 3H), 1.58 - 1.34 (m, 12H), 1.27 - 1.18 (m, 4H), 1.11 (s, 3H), 0.98 (d, J = 10.4 Hz, 2H), 0.90 (d, J = 6.3 Hz, 3H), 0.86 - 0.79 (m, 1H), 0.65 (s, 3H). Step 2: The reactant 24-(2,2,2-trifluoro-1-hydroxyethyl)-5α-cholane-3β,4β-diol (232-1) (40 mg, 0.087 mmol, 1 eq) was dissolved in acetone (8 mL). p-Toluenesulfonic acid (11.61 mg, 0.061 mmol, 0.7 eq) and 4A molecular sieves were added, and the reaction was stirred at room temperature for 1 h. Completion of the reaction was monitored by TLC (petroleum ether:ethyl acetate = 10:1) and quenched with saturated sodium sulfite. 20 mL of water was added to the reaction mixture, followed by extraction with ethyl acetate (25 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, and spun under vacuum to obtain the crude product. The crude product was dissolved in ethyl acetate and purified by column chromatography (petroleum ether:ethyl acetate = 82:18) to obtain the crude white solid (6R)-6-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetradecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]-1,1,1-trifluoroheptan-2-ol (232-2) (35 mg, purity: 90%, yield: 72%).

[0574] Step 3: The compound (6R)-6-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetradecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]-1,1,1-trifluoroheptan-2-ol (232-2) (16 mg, 0.032 mmol, 1.0 eq) was dissolved in ethyl acetate (5 mL). Platinum dioxide (10 mg, 0.044 mmol, 1.0 eq) was then added, the reaction mixture was purged with hydrogen gas, and the mixture was stirred at room temperature for 1 hour. The reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 5:1). The reaction was filtered, and the organic phase was collected and concentrated to give the crude white solid (6R)-6-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetradecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]-1,1,1-trifluoroheptan-2-ol (232-3) (16 mg). The crude product was used directly in the next step.

[0575] Step 4: The reactant (6R)-6-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetradecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]-1,1,1-trifluoroheptan-2-ol (232-3) (16 mg, 0.03 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 mL). Dilute hydrochloric acid (0.2 mL, 3 mol / L) was added, and the reaction mixture was stirred at room temperature for 40 minutes. The completion of the reaction was monitored by TLC (petroleum ether:ethyl acetate = 2:1). Water (10 mL) was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (3 × 25 mL). The combined ethyl acetate layers were washed with saturated brine (3 × 10 mL). The ethyl acetate layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 73:27) to obtain 24-(2,2,2-trifluoro-1-hydroxyethyl)-5α-cholane-3β,4β-diol (232) (12.01 mg, purity: 96.9%, yield: 79.06%) as a white solid.

[0576] 1 H NMR (400 MHz, DMSO) δ 6.02 (d, J = 6.8 Hz, 1H), 4.29 (d, J = 6.0 Hz, 1H), 3.90 (d, J = 3.1 Hz, 1H), 3.85 (s, 1H), 3.47 (d, J = 2.4 Hz, 1H),3.27 (dd, J = 6.2, 4.5 Hz, 1H), 1.91 (d, J = 12.2 Hz, 1H), 1.81 - 1.49 (m, 7H), 1.44 - 1.15 (m, 15H), 1.11 - 0.99 (m, 4H), 0.94 (s, 3H), 0.88 (d, J = 6.4Hz, 3H), 0.61 (s, 3H), 0.56 (dd, J = 15.2, 7.3 Hz, 1H). 13 C NMR (101 MHz, DMSO) δ 124.67, 82.56, 74.28, 71.92, 56.59, 56.14, 56.00, 55.16, 42.61, 37.48, 35.57, 35.55, 35.49, 32.67, 28.22, 26.43, 26.19, 24.29, 21.43, 20.64, 19.54, 18.95, 18.90, 15.18, 12.34, 0.57.LCMS [M+ H-2H2O]+ = 425.5 Example 233 Preparation of Compound 233 24-[cyclopropyl(hydroxy)methyl]-5α-cholane-3β,4β-diol

[0577] [ka]

[0578] Step 1: The reactant (5R)-5-[(1R,3aS,3bR,5aR,6R,7S,9aR,9bS,11aR)-7-acetoxy-6-hydroxy-3a,9a,11a-trimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoic acid methyl ester (198-1) (200 mg, 0.43 mmol, 1.0 eq) was dissolved in methanol (30 mL), potassium carbonate (597.45 mg, 4.323 mmol, 10.0 eq) was added, and the reaction mixture was stirred at room temperature for 30 min. The reaction completion was monitored by TLC plate (petroleum ether:ethyl acetate = 5:1). Water (10 mL) was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (3 × 25 mL). The ethyl acetate layer The extracts were combined and washed with saturated brine (3 × 10 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 77:23 to 75:25) to give a white solid, (5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6,7-dihydroxy-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoic acid methyl ester (233-1) (150 mg, purity: 80%, yield: 66%). 1 H NMR (400 MHz, CDCl3) δ 3.74 (s, 1H), 3.66 (s, 3H), 3.56 (s, 1H), 2.27 (dd, J = 16.8, 8.6 Hz, 2H), 1.95 (d, J = 12.5 Hz, 1H), 1.84 - 1.67 (m, 8H), 1.53 (s, 4H), 1.43 - 1.31 (m, 6H), 1.29 - 1.19 (m, 3H), 1.08 (dd, J = 18.6, 8.9 Hz, 5H), 1.02 (s, 3H), 0.92 (d, J = 6.5 Hz, 3H), 0.64 (s, 3H), 0.60 (dd, J = 15.1, 7.3 Hz, 1H). Step 2: (5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6,7-dihydroxy-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoic acid methyl ester (233-1) (150 mg, 0.36 mmol, 1 eq) was dissolved in acetone (8 mL), p-toluenesulfonic acid (47.48 mg, 0.250 mmol, 0.7 eq) and 4A molecular sieves were added, and the reaction was stirred at room temperature for 1 h. The reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 10:1) and quenched with saturated sodium sulfite. 20 mL of water was added to the reaction system, extracted with ethyl acetate (25 mL x 3), the organic phase was collected and dried over anhydrous sodium sulfate, and the organic phase was spin-dried under vacuum to obtain the crude product. The crude product was dissolved in ethyl acetate and subjected to column chromatography (petroleum ether:ethyl acetate = 95:5) to give (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]hexanoic acid methyl ester (233-2) (126 mg, purity: 90%, yield: 69%) as a white solid.

[0579] 1H NMR (400 MHz, CDCl3) δ 3.98 (d, J = 15.0 Hz, 2H), 3.67 (s, 3H), 2.27 (dd, J = 17.0, 8.5 Hz, 1H), 1.95 (d, J = 12.9 Hz, 1H), 1.83 - 1.65 (m, 3H), 1.51 (s, 2H), 1.42 (dd, J = 24.1, 13.0 Hz, 3H), 1.30 (s, 1H), 1.24 (t, J = 12.4 Hz, 2H), 1.04 (s, 2H), 0.92 (d, J = 6.4 Hz, 2H), 0.85 (d, J = 12.5 Hz, 1H), 0.66 (s, 1H), 0.59 (s, 1H). Step 3: Compound (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8- d) [1,3]Dioxol-8-yl]hexanoic acid methyl ester (233-2) (158 mg, 0.34 mmol, 1.0 eq) was dissolved in ethyl ether (20 mL), the reaction mixture was cooled to -78 °C, diisobutylaluminum hydride (1.029 mL, 1.02 mmol, 1.0 eq, 1 mol / L) was added, and the reaction mixture was heated at -78 °C for 30 min. The reaction was monitored for completion on a TLC plate (petroleum ether:ethyl acetate = 10:1). Ethyl acetate (20 mL) was added to dilute the reaction, and the reaction was quenched with saturated sodium tartrate (20 mL). The reaction was extracted with ethyl acetate (10 mL x 3). The organic phase was collected, washed twice with 20 mL of water, dried over anhydrous sodium sulfate, and spun dry under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 96:4 to 95:5) to give a white solid (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]hexanal (233-3) (125 mg, purity: 90%, yield: 76%).

[0580] 1 H NMR (400 MHz, CDCl3) δ 9.76 (s, 1H), 4.12 (q, J = 7.2 Hz, 0H), 3.99 (d, J = 14.3 Hz, 2H), 2.47 - 2.32 (m, 2H), 1.95 (d, J = 12.1 Hz, 1H), 1.85 - 1.61 (m, 4H), 1.51 (s, 3H), 1.43 (dd, J = 20.7, 12.2 Hz, 3H), 1.30 (s, 3H), 1.28 - 1.20 (m, 2H), 1.09 (dd, J = 15.8, 6.7 Hz, 2H), 1.04 (s, 3H), 1.02 (s, 1H), 0.93 (d, J = 6.5 Hz, 3H), 0.66 (s, 3H), 0.61 (d, J = 9.0 Hz, 1H). Step 4 The compound (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]hexanal (233-3) (50 mg, 0.116 mmol, 1.0 eq) was dissolved in tetrahydrofuran (8 mL). The reaction mixture was cooled to 0 °C, and cyclopropylmagnesium bromide (0.580 mL, 0.580 mmol, 5 eq) was slowly added. The reaction mixture was stirred at room temperature for 1 h. The completion of the reaction was monitored by TLC plate (petroleum ether: ethyl acetate = 5:1). 20 mL of water was added to the reaction system, and extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with water (30 mL), the organic phases were combined, dried and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 92:8) to give a white solid (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]-1-cyclopropylhexan-1-ol (233-4) (49 mg, purity: 90%, yield: 80%). 1 H NMR (400 MHz, CDCl3) δ 4.04 - 3.93 (m, 2H), 2.89 - 2.82 (m, 1H), 1.96 (d, J = 12.4 Hz, 1H), 1.84 - 1.73 (m, 2H), 1.66 (t, J = 13.9 Hz, 1H), 1.51 (s, 2H), 1.42 (ddd, J = 25.8, 16.4, 9.2 Hz, 3H), 1.31 (s, 1H), 1.29 - 1.20 (m, 4H), 1.14 - 1.06 (m, 2H), 1.04 (s, 2H), 0.91 (d, J = 6.5 Hz, 2H), 0.66 (s, 1H), 0.61 (dd, J = 15.3, 7.5 Hz, 1H), 0.56 - 0.44 (m, 1H), 0.24 (dtd, J = 13.1, 9.0, 4.4 Hz, 1H). Step 5: The reactant (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]-1-cyclopropylhexan-1-ol (233-4) (25 mg, 0.05 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 mL), and dilute hydrochloric acid (0.2 mL, 3 mol / L) was added. The reaction mixture was stirred at room temperature for 40 min. The completion of the reaction was monitored by TLC plate (petroleum ether:ethyl acetate = 2:1). Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 × 25 mL). The EA layers were combined and washed with saturated brine (3 × 10 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 73:27) to obtain 24-[cyclopropyl(hydroxy)methyl]-5α-cholane-3β,4β-diol (233) (3.38 mg, purity: 95.09%, yield: 14.17%) as a white solid.

[0581] 1H NMR (400 MHz, DMSO) δ 4.32 - 4.25 (m, 2H), 3.90 (d, J = 2.6 Hz, 1H), 3.47 (s, 1H), 3.29 - 3.27 (m, 1H), 2.78 (dd, J = 7.3, 4.0 Hz, 1H), 1.91 (d, J = 12.4 Hz, 1H), 1.74 (d, J = 15.2 Hz, 1H), 1.69 - 1.53 (m, 5H), 1.40 - 1.22 (m, 17H), 1.08 - 0.98 (m, 4H), 0.94 (s, 3H), 0.87 (d, J = 6.5 Hz, 3H), 0.61 (s, 3H), 0.58 - 0.50 (m, 1H), 0.36 - 0.26 (m, 2H), 0.23 - 0.07 (m, 2H). 13 C NMR (101 MHz, DMSO) δ 74.28, 73.66, 71.92, 56.60, 56.19, 55.16, 48.91, 35.57, 35.55, 32.53, 30.29, 28.28, 26.44, 26.19, 24.29, 22.22, 20.64, 20.51, 18.99, 18.97, 18.08, 12.30, 0.64.LCMS [M+ H-2H2O] + = 397.5 Example 234 Compound 234 24-[シクロプロピル(ヒドロキシ)メチル]-5α-コラン-3β,4β-ジオールの

[0582]

change

[0583] Step 1: Compound 2-bromo-1-fluorobenzene (163 mg, 0.93 mmol, 10 eq) was dissolved in tetrahydrofuran (5 mL), and the mixture was purged with nitrogen gas three times. The reaction system was cooled to -78 °C in a dry ice bath, and then n-butyllithium, 2.5 M n-hexane solution (0.41 mL, 1.02 mmol, 11 eq) was added dropwise with a syringe. The reaction system was kept warm for 1 hour, and compound (5R)-5-[(3aS, 5aR, 5bS, 7aR, 8R, 10aS, 10bS, 12aR, 12bR]-2 2,5a,7a-Tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]hexanal (233-3) (40 mg, 0.093 mmol, 1.0 eq) was dissolved in tetrahydrofuran (1 mL) and added to the reaction mixture. The mixture was allowed to warm to room temperature for 30 minutes. Completion of the reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1). 20 mL of ice water was added to the reaction system, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined and washed with saturated brine (30 mL). The combined organic phases were dried and concentrated to obtain a crude product. The crude product was purified by flash column chromatography (petroleum ether: ethyl acetate = 92:8) to give a white solid (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]-1-(2-fluorophenyl)hexan-1-ol (234-1) (30 mg, purity: 80%, yield: 49%). 1 H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 7.3 Hz, 1H), 7.23 (d, J = 7.0 Hz, 1H), 7.15 (t, J = 7.4 Hz, 1H), 7.02 (m, 1H), 5.00 (d, J = 7.0 Hz, 1H),3.98 (d, J = 14.3 Hz, 2H), 1.75 (m, 5H), 1.67 (d, J = 15.3 Hz, 3H), 1.51 (s, 4H), 1.41 (dd, J = 23.4, 11.9 Hz, 7H), 1.28 (m, 12H), 1.05 (d, J = 13.5 Hz, 6H), 0.88 (m, 5H), 0.64 (s, 3H). Step 2: The reactant (5R)-5-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]-1-(2-fluorophenyl)hexan-1-ol (234-1) (25 mg, 0.05 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 mL), and dilute hydrochloric acid (0.3 mL, 3 mol / L) was added. The reaction mixture was stirred at room temperature for 60 min. The reaction completion was monitored by TLC plate (petroleum ether:ethyl acetate = 2:1). Water (10 mL) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (3 × 25 mL). The ethyl acetate layers were combined and washed with saturated brine (10 mL). The ethyl acetate layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 73:27) to obtain 24-[cyclopropyl(hydroxy)methyl]-5α-cholane-3β,4β-diol (234) (19.5 mg, purity: 93.21%, yield: 78.69%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.47 (t, J = 7.5 Hz, 1H), 7.25 (m, 1H), 7.17 (t, J = 7.4 Hz, 1H), 7.09 (m, 1H), 5.22 (s, 1H), 4.79 (s, 1H), 4.30 (d, J = 5.2 Hz,1H), 3.91 (s, 1H), 3.46 (s, 1H), 3.27 (m, 0.93 (s, 3H), 0.84 (d, J = 3.3 Hz, 4H), 0.74 (d, J = 6.2 Hz, 1H), 0.59 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 160.73, 133.32, 128.00, 124.78, 121.54, 115.12, 74.28, 71.93, 56.58, 56.15, 55.14, 49.99, 48.90, 42.60, 37.47,35.55, 32.52, 29.43, 28.24, 28.23, 26.43, 26.19, 24.26, 22.04, 21.90, 20.79, 20.64, 18.87, 15.17, 12.28. LCMS [M+ H-2H2O] + = 451 Example 235 Compound 235 25-ヒドロキシ-4β-ヒドロキシ-3β-ヒドロキシ-5α-コレスト-6-オンの

[0584]

change

[0585] Step 1: Cholest-6(5)-ene-3β,4β,25-triol (151) (300 mg, 0.717 mmol) was dissolved in acetone (30 mL), 3A molecular sieves (100 mg, 3.583 mmol) and p-toluic anhydride (7.3 mg, 0.054 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Completion of the reaction was monitored by TLC (petroleum ether:ethyl acetate = 2:1). Water was added, and the mixture was extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (petroleum ether:ethyl acetate (100% to 20%)) to obtain compound (6R)-6-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetradecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]-2-methylheptan-2-ol (235-1) (200 mg, 0.392 mmol, 54.76%), as a white solid. 1 H NMR (399 MHz, Chloroform-d) δ 5.78 (dd, J = 4.8, 2.2 Hz, 1H), 4.39 (d, J = 5.7 Hz, 1H), 1.98 (dd, J = 15.9, 12.6 Hz, 1H), 1.67 - 1.57 (m, 4H), 1.55 (s, 4H), 1.51 (s, 3H), 1.47 -1.37 (m, 5H), 1.33 (s, 3H), 1.26 (d, J = 3.6 Hz, 3H), 1.20 (s, 6H), 1.15 (s, 3H), 1.08 - 1.00 (m, 3H), 0.92 (d, J = 6.6 Hz, 3H), 0.82 (d, J = 6.7 Hz, 3H), 0.68 (s, 3H). Step 2: (6R)-6-[(3aS,5aR,5bS,7aR,8R,10aS,10bS,12bR)-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12b-tetradecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-8-yl]-2-methylheptan-2-ol (235-1) (50 mg, 0.109 mmol) was added to 100 mL of ... The mixture was dissolved in water and tetrahydrofuran (5 mL), protected with nitrogen gas, cooled to 0°C, and borane tetrahydrofuran (49.68 mg, 0.654 mmol) was added. The mixture was stirred at room temperature for 3 hours, cooled to 0°C, and sodium hydroxide (0.436 mL, 1.308 mmol) and hydrogen peroxide (85%) (44.48 mg, 1.308 mmol) were added. The mixture was stirred at room temperature for 16 hours, and the completion of the reaction was monitored by TLC (petroleum ether:ethyl acetate=3:1). Water was added, and the mixture was extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (petroleum ether:ethyl acetate (100% to 20%)) to give (3aS,5aR,5bS,7aR,8R,10aS,10bS,12aS,12bR)-8-[(2R)-6-hydroxy-6-methylheptan-2-yl]-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-12-ol (235-2) (3 mg, 0.006 mmol, 5.20%). 1 H NMR (399 MHz, Chloroform-d) δ 4.21 (d, J = 6.1 Hz, 1H), 4.16 (s, 1H), 3.82 (dd, J = 10.5, 5.9 Hz, 1H), 2.03 - 1.93 (m, 1H), 1.82 - 1.65 (m, 4H), 1.47 (s, 4H), 1.43 - 1.33 (m, 6H), 1.31 (s, 5H), 1.27 - 1.22 (m, 3H), 1.19 (s, 6H), 1.13 (s, 3H), 1.06 - 0.99 (m, 3H), 0.90 (d, J = 6.5 Hz, 3H), 0.87 - 0.76 (m, 3H), 0.66 (s, 3H). Step 3 (3aS,5aR,5bS,7aR,8R,10aS,10bS,12aS,12bR)-8-[(2R)-6-hydroxy-6-methylheptan-2-yl]-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-12-ol (235-2) The reaction mixture was cooled to 0°C under nitrogen gas protection and added with tetrapropylammonium perruthenate (7.37 mg, 0.021 mmol), 4-methylmorpholine N-oxide (4.94 mg, 0.042 mmol), and 3A molecular sieves (100 mg, 0.210 mmol). The mixture was stirred at room temperature for 2 hours and monitored for completion by TLC (petroleum ether:ethyl acetate = 3:1). The resulting mixture was directly filtered, concentrated, and subjected to column chromatography (petroleum ether:ethyl acetate (0-80%)) to give compound (3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-8-[(2R)-6-hydroxy-6-methylheptan-2-yl]-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-12-one (235-3) (10 mg, 0.019 mmol, 45.19%).1 H NMR (399 MHz, CDCl3) δ 4.40 - 4.22 (m, 2H), 2.31 - 2.21 (m, 2H), 2.11 (d, J = 9.5 Hz, 1 H), 2.02 (d, J = 12.5 Hz, 1H), 1.89 - 1.79 (m, 1H), 1.72 - 1.55 (m, 2H), 1.50 (s, 5H), 1.42 (s, 3H), 1.36 (dd, J = 19.4, 6.7 Hz, 5H), 1.30 (s, 3H), 1.23 (s, 3H), 1.19 (s, 6H), 1.13 - 0.98 (m,4H), 0.91 (d, J = 6.5 Hz, 3H), 0.85 (s, 3H), 0.63 (s, 3H). Step 4 (3aS,5aR,5bS,7aR,8R,10aS,10bS,12aR,12bR)-8-[(2R)-6-hydroxy-6-methylheptan-2-yl]-2,2,5a,7a-tetramethyl-4,5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a,12b-hexadecahydro-3aH-cyclopenta[1',2':1,2]phenanthro[7,8-d][1,3]dioxol-12-one (235-3) (3 mg, 0.006 mmol) was dissolved in methanol (5 mL), and hydrochloric acid (0.063 mL, 0.063 mmol) was added. The mixture was stirred at room temperature for 1 h and monitored for completion by TLC (petroleum ether:ethyl acetate = 1:1). Extraction with ethyl acetate twice, drying over anhydrous sodium sulfate, concentration, and column chromatography (petroleum ether:ethyl acetate (0–80%)) gave compound 25-hydroxy-4β-hydroxy-3β-hydroxy-5α-cholest-6-one (235) (10 mg, 0.002 mmol, 32.77%). 1 H NMR (399 MHz, CDCl3) δ 4.00 (d, J = 8.8 Hz, 2H), 2.33 - 2.24 (m, 2H), 2.21 (d, J = 12.4 Hz, 1H), 2.03 (d, J = 12.4 Hz, 1H), 1.77 (d, J = 14.7 Hz, 4H), 1.67 - 1.51 (m, 7H), 1.38 (dt, J = 27.8, 12.6 Hz, 9H), 1.19 (s, 3H), 1.14 - 0.99 (m, 4H), 0.91 (d, J = 6.5 Hz, 3H), 0.87 (s, 3H), 0.83 (s, 1H), 0.64 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 214.09, 77.30, 76.98, 76.66, 71.11, 56.89, 56.07, 44.30, 43.10, 41.07, 40.80, 39.57, 37.15, 36.30, 35.62, 29.16, 28.08, 25.52, 23.92, 23.52, 21.27, 20.73, 18.58, 11.96, 0.99.ELSD-MS:[M+ H] + =435.0. Example 237 Preparation of Compound 237 (1R,3aS,5aR,7S,9aR,11aR)-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-3a,6,6,9a,11a-pentamethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-4,7-diol

[0586] [ka]

[0587] Step 1: Acetic acid-(1R,3aR,5aR,7S,9aS,11aR)-1-[(2R)-6-methoxy-6-oxohexan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,5,5a,6,7,8,9,9a,11,11a-dodecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (146-2) (500 mg, 1.03 mmol) was weighed into a 100 mL one-neck flask and dissolved in acetic acid (10 mL). Hydrogen peroxide (1.6 mL, 14.832 mmol) was then added dropwise at room temperature. After the addition was complete, stirring was continued at room temperature and the reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 5:1). The reaction solution was freeze-dried, adjusted to pH 7 with saturated aqueous sodium bicarbonate, extracted with ethyl acetate, and the organic phase was separated, dried, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 50:1 to 20:1) to obtain a crude product mixture (220 mg). The crude product was slurried with ethyl ether (1 mL), filtered, and purified to obtain acetic acid-(1R,3aS,5aR,7S,9aS,11aR)-1-[(2R)-6-methoxy-6-oxohexan-2-yl]-3a,6,6,9a,11a-pentamethyl-4-iso-2,3,3a,3b,4,5,5 a,6,7,8,9,9a,11,11a-Tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester (237-1) (44.9 mg, 0.09 mmol, 8.71%) was obtained as a white solid. 1 H NMR (399 MHz, Chloroform-d) δ 5.52 - 5.46 (m, 1H), 4.58 (dd, J = 11.1, 4.9 Hz, 1H), 3.65 (d, J = 0.8 Hz, 3H), 3.13 (s, 1H), 3.02 - 2.90 (m, 1H), 2.40 - 2.33 (m, 1H), 2.30 - 2.20 (m, 3H), 2.05 (d, J =2.0 Hz, 4H), 2.00 (d, J = 3.5 Hz, 2H), 1.89 (d, J = 13.4 Hz, 2H), 1.77 - 1.67 (m, 3H), 1.48 (t, J = 5.2 Hz, 1H), 1.46 - 1.34 (m, 4H), 1.24 - 1.15 (m, 1H), 1.09 (d, J = 3.8 Hz, 4H), 1.05 - 1.00 (m, 1H), 0.92 (d, J = 10.3 Hz, 6H), 0.86 (d, J = 6.0 Hz, 3H), 0.81 (d, J = 1.0 Hz, 3H), 0.61 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 209.12, 174.29, 170.87, 142.50, 121.71, 80.12, 77.33, 77.01, 76.70, 56.19, 51.42, 50.46, 47.58, 47.15, 47.12, 46.62, 44.57, 42.49, 38.93, 38.54, 38.31, 37.96, 37.83, 37.34, 36.99, 35.83, 35.67, 35.61, 35.57, 35.33, 34.47, 34.34, 28.45, 28.34, 27.52, 27.25, 26.01, 24.77, 24.60, 23.88, 21.70, 21.23, 20.37, 18.36, 18.25, 17.71, 16.99, 16.71, 15.67, 15.14. Step 2: Acetic acid-(1R,3aS,5aR,7S,9aS,11aR)-1-[(2R)-6-methoxy-6-oxohexan-2-yl]-3a,6,6,9a,11a-pentamethyl-4-oxo-2,3,3a,3b,4,5,5a,6,7,8,9,9a,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (237-1) (91 mg, 0.182 mmol) was weighed and dissolved in a mixture of methanol (2 mL) and tetrahydrofuran (4 mL). Sodium borohydride (6.88 mg, 0.182 mmol) was added at room temperature, followed by stirring overnight. The reaction was monitored for completion by TLC (petroleum ether:ethyl acetate = 3:1). Saturated aqueous sodium bicarbonate and ethyl acetate were added, and the organic phase was separated, dried, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 5:1) to give acetic acid-(1R,3aS,5aR,7S,9aS,11aR)-4-hydroxy-1-[(2R)-6-methoxy-6-oxohexan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,3b,4,5,5a,6,7,8,9,9a,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (237-2) (45 mg, 0.081 mmol, 44.33%) as a white solid. 1 H NMR (399 MHz, Chloroform-d) δ 5.29 (d, J = 5.9 Hz, 1H), 4.46 (dd, J = 11.5, 4.2 Hz, 1H), 3.67 (s, 1H), 3.65 (s, 3H), 2.26 (q, J = 8.2 Hz, 2H), 2.16 - 2.07 (m, 1H), 2.03 (s, 4H), 1.93 (dd, J = 19.6, 8.4 Hz, 3H), 1.82 - 1.59 (m, 6H), 1.49 (d, J = 13.7 Hz, 4H), 1.44 - 1.25 (m, 7H), 1.07 (s, 3H), 1.06 - 0.91 (m, 2H), 0.89 (t, J = 3.3 Hz, 6H), 0.85 (d, J = 3.0 Hz, 3H), 0.81 (s, 3H), 0.64 (s, 3H). Step 3 Acetic acid-(1R,3aS,5aR,7S,9aS,11aR)-4-hydroxy-1-[(2R)-6-methoxy-6-oxohexan-2-yl]-3a,6,6,9a,11a-pentamethyl-2,3,3a,3b,4,5,5a,6,7,8,9,9a,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (237-2) (20 mg, 0.040 mmol) was weighed and dissolved in a mixed solvent of ethyl acetate (3 mL) and acetic acid (0.3 mL). Palladium on carbon (10%), 40-60% water (30 mg, 0.282 mmol), and platinum dioxide (3 mg, 0.013 mmol) were added, and the mixture was then purged with hydrogen gas, heated to 80°C, and stirred under a pressure of 200 psi. The reaction was monitored by HNMR. After stirring overnight (~48 h × 3), the mixture was removed from the heat, cooled to room temperature, and filtered. The filtrate was added saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phase was separated, dried, and concentrated to give acetic acid-(1R,3aS,5aR,7S,9aR,11aR)-4-hydroxy-1-[(2R)-6-methoxy-6-oxohexan-2-yl]-3a,6,6,9a,11a-pentamethylhexadecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester (237-3) (15.6 mg, 0.029 mmol, 70%). 1H NMR (400 MHz, Chloroform-d) δ 4.50 - 4.40 (m, 1H), 3.65 (s, 3H), 3.59 (d, J = 4.2 Hz, 1H), 2.26 (q, J = 8.4 Hz, 2H), 2.03 (s, 3H), 1.90 - 1.82 (m, 1H), 1.63 (d, J = 6.7 Hz, 6H), 1.43 (s, 2H), 1.38 (s, 2H), 1.35 (s, 3H), 1.31 (s, 1H), 1.26 (s, 3H), 1.23 (s, 3H), 1.09 - 1.02 (m, 2H), 0.92 (s, 3H), 0.88 (d, J = 4.9 Hz, 3H), 0.86 (d, J = 1.2 Hz, 6H), 0.84 (s, 3H), 0.81 (s, 1H), 0.75 (s, 3H). 13 C NMR (100 MHz, Chloroform-d) δ 174.33, 170.98, 110.00, 47.26, 46.18, 45.96, 37.61, 36.57, 35.73, 34.49, 31.71, 31.49, 23.97, 21.71. Step 4: Acetic acid-(1R,3aS,5aR,7S,9aR,11aR)-4-hydroxy-1-[(2R)-6-methoxy-6-oxohexan-2-yl]-3a,6,6,9a,11a-pentamethylhexadecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (237-3) (25 mg, 0.050 mmol) was weighed and dissolved in THF (3 mL). The solution was cooled in an ice bath and methyllithium (0.464 mL, 0.743 mmol) was added dropwise. After the addition was complete, the reaction was monitored for completion by TLC (dichloromethane:methanol = 10:1). Saturated aqueous sodium bicarbonate was added, extracted with ethyl acetate, and the organic phase was separated, dried, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) to give (1R,3aS,5aR,7S,9aR,11aR)-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-3a,6,6,9a,11a-pentamethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-4,7-diol (237) (12 mg, 0.021 mmol, 43.04%). 1 H NMR (400 MHz, Methanol-d4) δ 3.45 (td, J = 10.4, 4.8 Hz, 1H), 3.16 - 3.08 (m, 1H), 1.94 - 1.78 (m, 2H), 1.68 - 1.49 (m, 8H), 1.41 (d, J = 13.4 Hz, 7H), 1.27 (q, J = 12.6, 10.3 Hz, 4H), 1.15 (s, 6H), 1.05 - 0.96 (m, 3H), 0.94 (d, J = 4.1 Hz, 6H), 0.90 (d, J = 5.3 Hz, 3H), 0.87 (s, 3H), 0.86 - 0.82 ( m, 1H), 0.79 (d, J = 7.6 Hz, 6H). 13 C NMR (100 MHz, Methanol-d4) δ 78.12, 72.24, 70.04, 52.10, 49.88, 45.64, 45.57, 43.86, 38.35, 37.32, 36.81, 36.34, 36.00, 35.87, 31.87, 31.78, 28.14, 27.83, 27.67, 27.23, 26.91, 20.59, 19.95, 17.95, 15.39, 14.82, 13.52, 12.97.LCMS:[M-2H2O-OH] + =409.5. Example 238 Preparation of Compound 238 3β,25-dihydroxy-5α-cholest-4-one

[0588] [ka]

[0589] Step 1: Acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (254-1) (1.4 g, 3.261 mmol) was dissolved in chloroform (22 mL), and selenium dioxide (455.37 mg, 4.104 mmol) and N-methylmorpholine (989.44 mg, 9.782 mmol) were added. The reaction was stirred at 75 °C overnight and monitored by TLC (petroleum ether:ethyl acetate = 2:1). The reaction solution was concentrated to obtain 2 g of crude product, which was purified by column chromatography (petroleum ether:ethyl acetate = 2 Purification by HPLC with a 0:1 to 10:1 mixture gave acetic acid-(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-6-hydroxy-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (238-1) (750 mg, 1.547 mmol, 47.43%), a pale yellow solid. 1 H NMR (399 MHz, Chloroform-d) δ 5.68 (d, J = 4.7 Hz, 1H), 4.75 - 4.66 (m, 1H), 4.26 - 4.20 (m, 1H), 2.08 (s, 3H), 2.06 - 1.97 (m, 3H), 1.89 - 1.79 (m, 3H), 1.69 - 1.58 (m, 3H), 1.55 (t, J = 7.4 Hz, 6H), 1.46 -1.41 (m, 4H), 1.36 (d, J = 12.0 Hz, 5H), 1.25 (d, J = 12.0 Hz, 4H), 1.20 (d, J = 2.1 Hz, 9H), 1.17 - 1.08 (m, 4H), 1.08 - 0.98 (m, 4H), 0.91 (d, J = 6.5 Hz, 3H), 0.90 - 0.80 (m, 2H), 0.66 (s, 3H). Step 2: Acetic acid-(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-6-hydroxy-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (238-1) (750 mg, 1.628 mmol) was dissolved in dichloromethane (15 mL), and Dess-Martin oxidant (1380.96 mg, 3.256 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 3:1), filtered, and the filtrate was diluted with water and extracted three times with ethyl acetate. The organic phase was washed once with brine, dried over anhydrous sodium sulfate, and concentrated to give 1 g of crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 15:1 to 5:1) to give acetic acid-(1R, 3aS, 3bS, 7S, 9aR, 9bS, 11 aR)-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-9a,11a-dimethyl-6-oxo-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (238-2) (400 mg, 0.828 mmol, 50.89%) was obtained as a pale yellow solid. 1 H NMR (399 MHz, Chloroform-d) δ 6.35 (dd, J = 5.0, 2.6 Hz, 1H), 5.19 (dd, J = 12.5, 7.1 Hz, 1H), 2.24 - 2.16 (m, 1H), 2.15 (s, 3H), 2.12 (d, J = 6.8 Hz, 1H), 2.06 - 2.00 (m, 3H), 1.84 (d, J = 11.2 Hz, 1H), 1.70 (dd, J = 19.3, 11.2 Hz, 1H), 1.53 - 1.44 (m, 3H), 1.43 - 1.37 (m, 4H), 1.32 (d, J = 6.2 Hz, 1H), 1.24 (s, 2H), 1.20 (s, 6H), 1.15 - 1.08 (m, 3H), 1.08 - 1.00 (m, 3H), 0.97 (s, 3H), 0.92 (d, J = 6.5 Hz, 3H), 0.67 (s, 3H). Step 3: Acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-9a,11a-dimethyl-6-oxo-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (238-2) (420 mg, 0.916 mmol) was dissolved in tetrahydrofuran (20 mL) and methanol (10 mL), palladium (palladium carbon) (200 mg, 1.879 mmol) was added, and the mixture was stirred at room temperature for 1 hour under a hydrogen gas atmosphere. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 3:1). After filtration, the cake was washed with ethyl acetate, and the filtrate was concentrated to give 420 mg of crude product, which was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give acetic acid-(1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-9a,11a-dimethyl-6-oxohexadecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (238-3) (30 mg, 0.062 mmol, 6.76%) as a white solid. 1H NMR (399 MHz, Chloroform-d) δ 5.14 (dd, J = 12.2, 7.2 Hz, 1H), 2.18 (d, J = 10.4 Hz, 2H), 2.13 (s, 3H), 1.94 (d, J = 14.8 Hz, 2H), 1.89 - 1.78 (m, 2H), 1.72 (d, J = 12.8 Hz, 2H), 1.52 - 1.44 (m, 3H), 1.42 (s, 3H), 1.34 (t, J = 7.9 Hz, 3H), 1.25 (d, J = 12.1 Hz, 3H), 1.19 (s, 6H), 1.15 - 1.06 (m, 3H), 1.02 - 0.93 (m, 3H), 0.90 (d, J = 6.6 Hz, 3H), 0.86 - 0.77 (m, 2H), 0.73 (s, 3H), 0.63 (s, 3H). Step 4: Acetic acid-(1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-9a,11a-dimethyl-6-oxohexadecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (238-3) (30 mg, 0.065 mmol) was dissolved in tetrahydrofuran (1 mL) and methanol (2 mL). Potassium carbonate (45.00 mg, 0.326 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 3:1). The reaction solution was filtered, and the filtrate was directly concentrated to give 30 mg of crude product, which was purified by column chromatography (petroleum ether:ethyl acetate=10:1) to give 3β,25-dihydroxy-5α-cholest-4-one (238) (5 mg, 0.011 mmol, 17.42%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 4.79 (d, J = 5.1 Hz, 1H), 4.01 (s, 2H), 2.18 (d, J = 12.1 Hz, 1H), 2.08 (d, J = 9.8 Hz, 1H), 1.94 - 1.87 (m, 1H), 1.72 (d, J = 9.1 Hz, 2H), 1.64 - 1.56 (m, 1H), 1.54 - 1.36 (m, 6H), 1.30-1.25 (m, 4H), 1.16 - 1.07 (m, 5H), 1.01 (s, 6H), 0.98 - 0.88 (m, 4H), 0.85 (d, J = 6.4 Hz, 3H), 0.83 - 0.67 (m, 3H), 0.58 (d, J = 3.8 Hz, 6H). 13 C NMR (101 MHz, DMSO) δ 212.35, 74.51, 69.22, 56.16, 56.11, 56.05, 53.85, 44.54, 42.61, 42.55, 36.57, 35.70, 35.64, 34.86, 32.56, 31.13, 30.38, 29.83, 29.64, 28.23, 24.19, 21.65, 20.68, 20.62, 18.94, 13.81, 12.30. H] + =419.30. Example 239 Preparation of Compound 239: Acetic acid-(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester

[0590] [ka]

[0591] Step 1: Acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-6-acetoxy-6-methylheptan-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (254-2) (800 mg, 1.644 mmol) was dissolved in acetone (16 mL), and cobalt acetate (2.91 mg, 0.016 mmol), N-hydroxyphthalimide (26.81 mg, 0.164 mmol), and tert-butyl hydroperoxide (592.48 mg, 6.574 mmol) were added. The reaction was stirred at room temperature for 18 hours, and TLC ( The reaction was monitored with petroleum ether:ethyl acetate (5:1). After completion of the reaction, water was added to the reaction solution, which was then extracted three times with ethyl acetate. The organic phase was washed once with brine, dried over anhydrous sodium sulfate, and concentrated to give 1 g of crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate (30:1)) to give acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-6-acetoxy-6-methylheptan-2-yl]-9a,11a-dimethyl-4-oxo-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (239-1) (450 mg, 0.854 mmol, 51.95%) as a pale yellow solid. 1 H NMR (399 MHz, Chloroform-d) δ 5.68 (d, J = 1.8 Hz, 1H), 4.76 - 4.62 (m, 1H), 2.56 - 2.34 (m, 3H), 2.21 (s, 1H), 2.03 (s, 3H), 2.01 - 1.95 (m, 2H), 1.94 (d, J = 1.5 Hz, 3H), 1.86 (d, J = 9.7 Hz, 1H), 1.73 - 1.60 (m, 3H), 1.56 - 1.49 (m, 3H), 1.40 (s, 6H), 1.35 (d, J = 8.8 Hz, 3H), 1.29 (d, J = 17.6 Hz, 2H), 1.23 (t, J = 9.0 Hz, 4H), 1.19 (s, 3H), 1.16 (d, J = 5.6 Hz, 3H), 1.09 - 0.96 (m, 2H), 0.91 (d, J = 6.5 Hz, 3H), 0.82 (d, J = 6.4 Hz, 1H), 0.66 (d, J = 2.7 Hz, 3H). Step 2: Acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-6-acetoxy-6-methylheptan-2-yl]-9a,11a-dimethyl-4-oxo-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (239-1) (400 mg, 0.799 mmol) was dissolved in tetrahydrofuran (12 mL) and methanol (24 mL) and palladium on carbon (200 mg, 1.879 mmol) was added. The reaction was stirred under hydrogen gas at room temperature for 1 h and monitored for completion by TLC (petroleum ether:ethyl acetate = 5:1). The filtrate was concentrated to give 50 g of crude product, which was purified by column chromatography (petroleum ether:ethyl acetate = 30:1) to give acetic acid-(1R,3aS,3bR,7S,9aS,9bS,11aR)-1-[(2R)-6-acetoxy-6-methylheptan-2-yl]-9a,11a-dimethyl-4-oxohexadecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (239-2) (250 mg, 0.472 mmol, 59.14%) as a pale yellow solid. 1 H NMR (399 MHz, Chloroform-d) δ 4.64 (d, J = 11.3 Hz, 1H), 2.31 (t, J = 12.5 Hz, 2H), 2.18 (d, J = 11.9 Hz, 1H), 2.00 (s, 3H), 1.94 (d, J = 1.9 Hz, 3H), 1.87 (d, J = 9.9 Hz, 2H), 1.77 (d, J = 13.8 Hz, 1H), 1.70 (s, 1H), 1.64 - 1.59 (m, 2H), 1.50 (d, J = 11.7 Hz, 3H), 1.45 (d, J = 10.6 Hz, 1H), 1.40 (s, 6H), 1.35 (d, J = 7.2 Hz, 3H), 1.23 (s, 3H), 1.19 - 1.09 (m, 2H), 1.08 (s, 3H), 1.02 (d, J = 17.7 Hz, 2H), 0.89 (d, J = 6.3 Hz, 2H), 0.81 (d, J = 6.7 Hz, 1H), 0.63 (d, J = 2.6 Hz, 3H). Step 3 Acetic acid-(1R,3aS,3bR,7S,9aS,9bS,11aR)-1-[(2R)-6-acetoxy-6-methylheptan-2-yl]-9a,11a-dimethyl-4-oxohexadecahydro-1H-cyclopenta[1,2-i]phenanthrene The 2-methyl-7-yl ester (239-2) (250 mg, 0.497 mmol) was dissolved in bis(2-methoxyethyl)aminosulfur trifluoride (10 mL), heated to 80° C., stirred for 2 h, and monitored for completion by TLC (petroleum ether:ethyl acetate=10:1). The reaction solution was cooled to room temperature, diluted with ethyl acetate, and then added to water to quench the reaction. The mixture was extracted three times with ethyl acetate. The organic phase was washed once with brine, dried over anhydrous sodium sulfate, and concentrated to give 300 mg of crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 100:1) to give acetic acid-(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(2R)-6-methylhept-5-en-2-yl]hexadecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (239-3) (70 mg, 0.143 mmol, 28.78%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 5.04 (d, J = 7.1 Hz, 1H), 4.55 (dt, J = 11.2, 6.1 Hz, 1H), 1.93 (s, 3H), 1.89 (d, J = 12.6 Hz, 2H), 1.75 (d, J = 15.7 Hz, 2H), 1.70 (s, 3H), 1.63 (d, J = 7.3 Hz, 2H), 1.60 (s, 3H), 1.52 (s, 3H), 1.44 (d, J = 22.1 Hz, 2H), 1.30 (t, J = 11.7 Hz, 4H), 1.21 (d, J = 11.5 Hz, 2H), 1.09 (d, J = 6.7 Hz, 1H), 1.04 - 0.97 (m, 2H), 0.93 (s, 1H), 0.87 (d, J = 6.6 Hz, 3H), 0.79 (s, 3H), 0.63 - 0.53 (m, 3H). Step 4: Acetic acid-(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-9a,11a-dimethyl-1-[(2R)-6-methylhept-5-en-2-yl]hexadecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (239-3) (70 mg, 0.151 mmol) was dissolved in tetrahydrofuran (3 mL) and water (0.75 mL), and N-bromosuccinimide (26.8 mg, 0.15 mmol) was added. The mixture was stirred at room temperature for 2 hours and monitored by TLC (petroleum ether:ethyl acetate = 5:1). The reaction mixture was diluted with water and extracted three times with ethyl acetate. The organic phase was washed once with brine, dried over anhydrous sodium sulfate, and concentrated to give 100 mg of crude product, which was purified by column chromatography (petroleum ether:ethyl acetate=20:1) to give acetic acid-(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-1-[(2R)-5-bromo-6-hydroxy-6-methylheptan-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (239-4) (50 mg, 0.085 mmol, 56.15%), as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 4.74 (s, 1H), 4.55 (dt, J = 11.2, 5.9 Hz, 1H), 3.78 (dd, J = 22.2, 11.1 Hz, 1H), 1.93 (s, 3H), 1.88 (s, 1H), 1.70 (s, 4H), 1.59 (d, J = 22.7 Hz, 2H), 1.49 (d, J = 20.7 Hz, 2H), 1.39 (d, J = 13.0 Hz, 3H), 1.30 (t, J = 11.9 Hz, 5H), 1.22 (s, 3H), 1.15 (d, J = 1.5 Hz, 3H), 1.09 (d, J = 17.9 Hz, 2H), 1.04 - 0.95 (m, 2H), 0.87 (t, J = 7.2 Hz, 3H), 0.79 (s, 3H), 0.61 (d, J = 3.8 Hz, 3H). Step 5 -(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-1-[(2R)-5-bromo-6-hydroxy-6-methylheptan-2-yl]-4,4-difluoro-9a,11a-dimethylhexadecahydro-1H-cyclopentaacetic acid [1,2-i]Phenanthren-7-yl ester (239-4) (50 mg, 0.089 mmol) was dissolved in tetrahydrofuran (3 mL), and lithium aluminum hydride (33.79 mg, 0.890 mmol) was added. The mixture was stirred at 70 °C for 1 h and monitored by TLC (petroleum ether:ethyl acetate = 2:1). The reaction mixture was quenched with water and extracted three times with ethyl acetate. The organic phase was washed once with brine, dried over anhydrous sodium sulfate, and concentrated to give 60 mg of crude product, which was purified by column chromatography (petroleum ether:ethyl acetate=10:1) to give acetic acid-(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-4,4-difluoro-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (239) (10 mg, 0.020 mmol, 22.11%) as a white solid.

[0592] 1 H NMR(400 MHz, DMSO-d6) δ 4.53 (d,J = 5.1 Hz, 1H), 4.03 (s, 1H), 3.30 (s, 1H), 1.92 - 1.85 (m, 1H), 1.73 (d,J = 8.5 Hz, 2H), 1.67 - 1.54 (m, 5H), 1.50 - 1.38 (m, 2H), 1.35 - 1.29 (m, 3H), 1.25 (s, 3H), 1.21 (d,J = 9.6 Hz, 4H), 1.15 (d,J = 8.6 Hz, 3H), 1.12 - 1.03 (m, 3H), 1.01 (s, 6H), 0.93 (d,J = 17.4 Hz, 2H), 0.86 (d,J = 6.3 Hz, 3H), 0.72 (d,J = 20.4 Hz, 3H), 0.58 (d,J = 18.8 Hz, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 69.22, 55.15, 50.26, 48.68, 44.54, 43.11, 37.19, 36.60, 36.27, 35.60, 35.00, 31.45, 29.82, 28.41, 25.60, 21.16, 20.68, 19.02, 12.07, 11.48. LC-MS:[M-H2O-HF] + = 403.40. Example 240 Compound 240 manufactured by Koresuto-3β,6α,25-Torotron

[0593]

change

[0594] Cholest-6(5)-ene-3β,25-diol (177) (50 mg, 0.07 mmol) was dissolved in tetrahydrofuran (5 mL), protected with nitrogen gas, and cooled to -10 °C. 1 M borane dimethyl sulfide solution (0.37 mL, 0.42 mmol) was added dropwise, and the mixture was allowed to warm to room temperature and stirred for 3 h. The mixture was then cooled to 0 °C in an ice bath, and sodium hydroxide (10 M, 57.6 mg, 0.84 mmol) was added. Hydrogen peroxide (31%, 48 mg, 0.84 mmol) was then added dropwise. The mixture was stirred at room temperature for 16 h and monitored for completion by TLC (petroleum ether:ethyl acetate = 1:1). The mixture was quenched with water, washed twice with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate=30:1 to 2:1) to obtain compound cholest-3β,6α,25-triol (240) (10 mg, 0.021 mmol, 17.23%) as a white solid. 1 H NMR (399 MHz, Chloroform-d) δ3.56 (s, 1H), 3.40 (s, 1H), 2.18 (d, J = 11.5 Hz, 1H),1.96 (d, J = 11.5 Hz, 1H),1.79 (s, 2H), 1.56 (s, 6H), 1.40 (s, 7H), 1.25 (d, J = 11.1 Hz, 6H), 1.19 (s, 6H),1.03 (s, 2H),1.03 (s, 4H), 0.90 (d, J = 6.6 Hz, 2H), 0.81 (d, J = 9.5 Hz, 3H), 0.63 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 71.22, 71.09, 69.40, 56.09, 53.74, 51.64, 43.08, 42.64, 41.64, 37.22, 35.69, 34.25, 31.01, 29.65, 23.99, 20.95, 20.49, 18.18, 0.99. ELSD-MS:[M-H2O-OH] + =385.7. Example 241 Preparation of Compound 241 24-(1-hydroxypropyl)-5α-cholane-3β,4β-diol

[0595] [ka]

[0596] Step 1: The compound (5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6,7-dihydroxy-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanoic acid methyl ester (233-1) (40 mg, 0.08 mmol, 1.0 eq) was dissolved in ethyl ether (10 mL). The reaction mixture was cooled to -78 °C. Diisobutylaluminum hydride (0.5 mL, 0.5 mmol, 6.0 eq, 1 mol / L) was added and the reaction mixture was stirred at -78 °C for 1 h. The reaction completion was monitored by TLC (petroleum ether:ethyl acetate = 1:1). The reaction mixture was diluted with ethyl acetate (20 mL), quenched with saturated sodium tartrate (20 mL), extracted with ethyl acetate (10 mL × 3), and the organic phase was collected, washed twice with 20 mL of water, dried over anhydrous sodium sulfate, and spun under vacuum to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 74:26) to give (5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6,7-dihydroxy-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanal (241-1) (30 mg, purity: 40%, yield: 35%) as a white solid.

[0597] Step 2: (5R)-5-[(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6,7-dihydroxy-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-1-yl]hexanal (241-1) (30 mg, 0.031 mmol, 1.0 eq) was dissolved in tetrahydrofuran (8 mL). The reaction mixture was cooled to 0 °C, and then ethylmagnesium bromide (0.077 mL, 0.154 mmol, 5 eq) was slowly added. The reaction mixture was stirred at room temperature for 1 h. The reaction completion was monitored by TLC (petroleum ether:ethyl acetate = 5:1). The reaction mixture was added with 20 mL of water and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with water (30 mL), dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 74:26) to give 24-(1-hydroxypropyl)-5α-cholane-3β,4β-diol (241) (10.55 mg, purity: 93.23%, yield: 76%) as a white solid.

[0598] 1 H NMR (400 MHz, DMSO) δ 4.28 (d, J = 6.0 Hz, 1H), 4.19 (dd, J = 5.2, 3.0 Hz, 1H), 3.88 (d, J = 2.9 Hz, 1H), 3.47 (d, J = 2.2 Hz, 1H), 3.29 - 3.24 (m, 2H), 1.90 (d, J = 12.7 Hz, 1H), 1.70 - 1.54 (m, 5H), 1.43 - 1.33 (m, 4H), 1.30 (s, 3H), 1.25 (d, J = 9.8 Hz, 8H), 1.19 (s, 3H), 1.08 - 0.99 (m, 4H), 0.94 (s, 3H), 0.87 (d, J = 6.5 Hz, 3H), 0.83 (t, J = 7.4 Hz, 4H), 0.61 (s, 3H), 0.54 (d, J = 9.5 Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ 74.86, 73.49, 72.31, 56.57, 56.10, 55.26, 48.84, 42.61, 39.91, 37.50, 36.88, 35.50, 35.40, 32.40, 31.44, 30.20, 29.71, 28.25, 26.00, 25.87, 24.21, 22.10, 20.59, 18.65, 14.68, 12.07, 9.90.LCMS [M+ H-2H2O] + = 385 Example 242 Preparation of Compound 242 25-Hydroxy-4β-hydroxy-3β-hydroxy-5α-cholest-7-one

[0599] [ka]

[0600] Step 1: Prepare cholest-6(5)-ene-3β,4β,25-triol (1 51) (363 mg, 0.87 mmol) was dissolved in dichloromethane (10 mL) in a 50 mL round-bottom flask, and triethylamine (702 mg, 6.94 mmol), 4-dimethylaminopyridine (106 mg, 0.87 mmol), and acetic anhydride (265 mg, 2.60 mmol) were added at room temperature. The mixture was then stirred at room temperature for 16 hours. After monitoring the completion of the reaction by TLC (petroleum ether:ethyl acetate=8:1), the mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL × 3), and the organic phase was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=8:1) to give acetic acid-(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-7-acetoxy-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthren-6-yl ester (242-1) (334 mg, purity: 95%, yield: 72.79%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 5.89 - 5.73 (m, 1H), 5.50 (d, J = 2.3 Hz, 2H), 4.78 - 4.72 (m, 1H), 2.07 (s, 3H), 2.05 - 2.01 (m, 1H), 2.01 (s, 3H), 1.93 - 1.80 (m, 2H), 1.72 - 1.64 (m, 1H), 1.63 - 1.31 (m, 15H), 1.28 - 1.25 (m, 2H), 1.21 (s, 6H), 1.13 (s, 3H), 1.09 - 0.96 (m, 4H), 0.93 (d, J = 6.5 Hz, 3H), 0.90 - 0.81 (m, 1H), 0.67 (s, 3H). Step 2: Acetic acid-(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-7-acetoxy-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthren-6-yl ester (242-1 ) (170 mg, 0.34 mmol) was dissolved in acetone (5 mL) in a 50 mL round-bottom flask, and N-hydroxyphthalimide (11 mg, 0.068 mmol), cobalt acetate (6 mg, 0.034 mmol), and tert-butyl hydroperoxide (122 mg, 1.35 mmol) were added at room temperature. The mixture was then stirred at room temperature for 16 hours. After monitoring the completion of the reaction by TLC (petroleum ether: ethyl acetate = 5:1), the mixture was quenched with water (20 mL), extracted with ethyl acetate (10 mL × 3), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain a white solid, acetic acid-(1R, 3aS, 3bS, 6R, 7S, 9aR, 9bS, 1R ...bS, 6R, 7S, 9aR, 9bS, 1R, 3aS, 3bS, 6R, 7S 1aR)-7-Acetoxy-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-9a,11a-dimethyl-4-oxo-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-6-yl ester (242-2) (90 mg, purity: 90%, yield: 46.36%) was obtained. 1 H NMR (400 MHz, CDCl3) δ 5.91 (d, J = 14.2 Hz, 1H), 5.61 (d, J = 2.4 Hz, 1H), 4.80 (dt, J = 12.2, 4.0 Hz, 1H), 2.43 - 2.27 (m, 2H), 2.10 (s, 3H),2.03 (s, 3H), 2.00 - 1.80 (m, 4H), 1.51 - 1.24 (m, 16H), 1.21 (s, 6H), 1.20 - 0.98 (m, 5H), 0.94 (d, J = 6.5 Hz, 3H), 0.68 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 202.20, 170.06, 169.47, 158.31, 131.14, 73.61, 71.51, 71.12, 54.68, 50.80, 49.91, 45.95, 44.37, 43.06, 38.53, 37 .93, 36.42, 35.80, 35.69, 29.31, 29.27, 28.52, 26.20, 22.21, 21.15, 20.99, 20.78, 18.83, 17.91, 11.92. Step 3: In a 50 mL round-bottom flask, acetic acid-(1R,3aS,3bS,6R,7S,9aR,9bS,11aR)-7-acetoxy-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-9a,11a-dimethyl-4-oxo-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthrene-6-yl ester (242-2) (50 mg, 0.097 mmol) was dissolved in tetrahydrofuran (1 mL) and methanol (1 mL) in a 50 mL round-bottom flask and added to potassium carbonate (67 mg, 0.4 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, and the reaction mixture was monitored for completion by TLC (petroleum ether:ethyl acetate=3:1). The mixture was then diluted with water (20 mL), extracted with ethyl acetate (10 mL x 3), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate=3:1) to give 2,5-hydroxy-4β-hydroxy-3β-hydroxycholest-6(5)-en-7-one (242-3) (40 mg, purity: 90%, yield: 85.99%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 5.83 (s, 1H), 4.28 (t, J = 10.2 Hz, 1H), 3.65 (dt, J = 11.8, 4.0 Hz, 1H), 2.41 - 2.28 (m, 2H), 2.06 - 1.88 (m, 5H), 1.78 -1.71 (m,, 4H), 1.58 -1.35 (m, 7H), 1.37 (s, 3H), 1.21 (s, 6H), 1.19 - 1.00 (m, 5H), 0.94 (d, J = 6.5 Hz, 3H), 0.69 (s, 3H). Step 4: In a 50 mL round-bottom flask, 25-hydroxy-4β-hydroxy-3β-hydroxycholest-6(5)-en-7-one (242-3) (30 mg, 0.069 mmol) was dissolved in tetrahydrofuran (1 mL) and ethyl acetate (1 mL). 10% Pd / C (30 mg) was added at room temperature, and the mixture was stirred under a hydrogen atmosphere for 3 h. The reaction was monitored for completion by TLC (ethyl acetate / petroleum ether = 1:1). After completion, the reaction solution was diluted with ethyl acetate (20 mL), filtered through diatomaceous earth, and the organic phase was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give a white solid, 2,5-hydroxy-4β-hydroxy-3β-hydroxycholest-7-one (242) (23 mg, purity: 98.06%, yield: 74.78%).

[0601] 1 H NMR (400 MHz, DMSO) δ 4.39 (d, J = 6.1 Hz, 1H), 4.28 (d, J = 3.5 Hz, 1H), 4.03 (s, 1H), 3.43 (s, 1H), 2.80 (t, J = 13.4 Hz, 1H), 2.37 (t, J = 11.3 Hz, 1H), 2.12 - 2.05 (m, 1H), 1.92 - 1.89 (m, 1H), 1.83 - 1.76 (m, 2H), 1.72 - 1.55 (m, 3H), 1.45 - 1.41 (m, 3H), 1.34 - 1.28 (m, 6H), 1.25 - 1.23 (m, 4H), 1.19 (s, 3H), 1.04 (s, 6H), 1.00 - 0.91 (m, 5H), 0.88 (d, J = 6.5 Hz, 3H), 0.60 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 212.65, 73.62, 71.66, 69.23, 55.58, 55.04, 50.12, 49.56, 49.40, 44.60, 44.39, 42.60, 38.81, 36.68, 36.49, 36.06, 35.60, 29.88, 29.71, 28.49, 26.02, 25.07, 21.12, 20.74, 19.12, 14.50 , 12.37. LCMS(M+ Na) + =457.3 Example 244 Compound 244 manufactured by Koretsu-3β,4β,6,25-Torotron

[0602]

change

[0603] Cholest-6(5)-ene-3β,4α,25-triol (151) (30 mg, 0.072 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), protected with nitrogen gas, and cooled to -10 °C. Borane (0.717 mL) was added dropwise, and the mixture was allowed to warm to room temperature and stirred for 3 h. Water (0.2 mL) was added dropwise at 0 °C, and sodium perborate (28 mg, 0.717 mmol) was added. The mixture was stirred at room temperature for 16 h and monitored by TLC (dichloromethane:methanol = 10:1). The reaction was quenched with water, extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography (dichloromethane:methanol = 100% to 20%) to give compound cholest-3β,4β,6,25-tetraol (244) (10 mg, 0.005 mmol, 24%). 1 H NMR (399 MHz, Chloroform-d) δ 4.41 (s, 0.77H), δ 4.25 (s, 0.22H),3.94 (s, 1H), 3.59 - 3.50 (m, 1H), 1.82 (m, 9H),1.66(m,5H) 1.37 (ddd, J = 26.5, 13.5, 6.2 Hz, 8H), 1.23 (s, 2H), 1.19 (s, 4H), 1.14 (s, 3H), 1.08 - 0.96 (m, 4H), 0.90 (d, J = 6.6 Hz, 2H), 0.80 (d, J = 6.6 Hz, 1H), 0.66 (s, 2H), 0.63 (s, 1H). 13 C NMR (101 MHz, CDCl3) δ, 71.14, 56.46, 56.27, 44.37, 42.65, 35.73, 29.33, 29.12, 28.31, 25.77, 20.81, 18.63, 12.07, 1.00. ELSD-MS:[M-OH] + =419.3, [M+ Na] + =459. 4. Example 245 Preparation of Compound 245 (1R,3aS,5aR,6R,7S,9aR,11aR)-1-[(2R)-5-(hydroxycyclopropyl)pentan-2-yl]-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol

[0604] [ka]

[0605] The compound acetic acid-(1R,3aS,3bS,5aR,6R,7S,9aR,9bS,11aR)-6-hydroxy-1-[(2R)-6-methoxy-6-oxohexan-2-yl]-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (198-1) (50 mg, 0.112 mmol) was dissolved in tetrahydrofuran (5 mL), titanium tetraisopropoxide (95.6 mg, 0.670 mmol) was added, and the mixture was purged with nitrogen gas three times. Ethyl magnesium bromide (1.080 mL) was added dropwise at room temperature. The mixture was stirred at room temperature for 1 hour and monitored for completion by TLC (petroleum ether:ethyl acetate = 5:1). The mixture was extracted with water and ethyl acetate, the organic phase was separated, and the crude product was dried and purified by column chromatography (petroleum ether:ethyl acetate = 60:1 to 1:1) to give (1R,3aS,5aR,6R,7S,9aR,11aR)-1-[(2R)-5-(hydroxycyclopropyl)pentan-2-yl]-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-a]phenanthrene-6,7-diol (245) (10 mg, 0.022 mmol, 20.56%) as a white solid. 1 H NMR (399 MHz, Chloroform-d) δ 3.72 (s, 1H), 3.54 (s, 1H), 1.91 (s, 3H), 1.74 (s, 6H), 1.37 (s, 7H), 1.24 (s, 5H), 1.05 (s, 4H), 1.00 (s, 4H), 0.90 (d, J = 6.4 Hz, 3H), 0.84 (d, J = 15.5 Hz, 2H), 0.71 (s, 2H), 0.63 (s, 3H), 0.42 (s, 2H). 13 C NMR (100 MHz, CDCl3) δ, 76.66,72.17, 55.93, 42.57, 38.81, 36.86, 35.36, 29.50, 28.37, 25.95, 24.16, 20.28, 13.43, 0.99.LC-MS:[M-H2O-OH] + =383.4. Example 246 Preparation of Compound 246 4-(trifluoromethyl)-5α-cholest-3β,4,25-triol

[0606] [ka]

[0607] Step 1: Acetic acid-(1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-1-[(2R)-6-acetoxy-6-methylheptan-2-yl]-9a,11a-dimethyl-6-oxohexadecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (254-5) (60 mg, 0.12 mmol) was dissolved in tetrahydrofuran (5 mL), and tetrabutylammonium fluoride (3.12 mg, 0.012 mmol) and (trifluoromethyl)trimethylsilane (339.42 mg, 2.387 mmol) were added. The mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1). The mixture was diluted with water, extracted three times with ethyl acetate, and the organic phase was washed once with brine, dried over anhydrous sodium sulfate, and concentrated to give 80 mg of crude product, which was purified by column chromatography (petroleum ether:ethyl acetate = 50:1) to give acetic acid-(1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-1-[(2R)-6-acetoxy-6-methylheptan-2-yl]-6-hydroxy-9a,11a-dimethyl-6-(trifluoromethyl)hexadecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (246-1) (40 mg, 0.066 mmol, 55.59%). 1 H NMR (400 MHz, DMSO-d6) δ 4.89 (s, 1H), 4.85 (d, J = 5.8 Hz, 1H), 1.96 (s, 1H), 1.86 (s, 3H), 1.56 (td, J = 32.5, 29.8, 9.7 Hz, 5H), 1.32 (s, 6H), 1.27 (d, J = 10.8 Hz, 3H), 1.16 - 0.99 (m, 4H), 0.97 (s, 3H), 0.89 (s, 1H), 0.84 (d, J = 6.2 Hz, 3H), 0.76 (s, 1H), 0.58 (s, 3H). Step 2: Acetic acid-(1R,3aS,3bS,5aR,7S,9aR,9bS,11aR)-1-[(2R)-6-acetoxy-6-methylheptan-2-yl]-6-hydroxy-9a,11a-dimethyl-6-(trifluoromethyl)hexadecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (246-1) (40 mg, 0.070 mmol) was dissolved in methanol (1 mL) and tetrahydrofuran (2 mL), and lithium hydroxide (1 mL, 1.000 mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction was monitored for completion by TLC (petroleum ether:ethyl acetate=5:1), concentrated to give 50 mg of crude product, which was purified by column chromatography (petroleum ether:ethyl acetate=15:1) to give 4-(trifluoromethyl)-5α-cholest-3β,4,25-triol (246) (25 mg, 0.049 mmol, 69.59%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 4.89 (s, 1H), 4.85 (d, J = 6.1 Hz, 1H), 4.00 (s, 1H), 3.52 (d, J = 7.0 Hz, 1H), 1.99 - 1.72 (m, 2H), 1.60 (d, J = 21.0 Hz, 5H), 1.48 (d, J = 12.2 Hz, 2H), 1.38 (d, J = 12.8 Hz, 2H), 1.28 (d, J = 14.5 Hz, 4H), 1.16 (d, J = 11.3 Hz, 4H), 1.09 (d, J = 18.4 Hz, 3H), 1.01 (s, 6H), 0.97 (s, 2H), 0.93 (s, 3H), 0.89 (d, J = 7.0 Hz, 2H), 0.84 (d, J = 6.4 Hz, 3H), 0.81 - 0.68 (m, 2H), 0.58 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 69.19, 69.11, 56.32, 56.09, 55.16, 47.34, 44.54, 42.41, 36.58, 36.37, 36.08, 35.64, 34.60, 32.14, 29.85, 29.64, 28.28, 27.51, 24.10, 20.67, 18.92, 14.50, 12.29. 19 F NMR (376 MHz, DMSO-d6) δ -70.57. ELSD-MS:[M-OH] + =471.4. Examples 248 & 249 Preparation of Compound 248 Cholest-3β,4,5,25-tetraol isomer 2 Preparation of Compound 249 Cholest-3β,4,5,25-tetraol Isomer 1 Here, Compound 248 and Compound 249 are both single-configuration isomers, each being one of the isomers shown below.

[0608] [ka]

[0609] Step 1: (1R,3aS,7S,9aR,11aR)-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-7-ol (177) (1.0 g, 2.48 mmol) was dissolved in anhydrous toluene (30 mL) in a 100 mL round-bottom flask at room temperature. The mixture was heated to 110 °C, and a methanol solution of cyclohexanone (10 mL) and aluminum isopropoxide (1.7 g, 2.48 mmol) was slowly added dropwise thereto. The mixture was then stirred at 110 °C for 3 hours. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 5:1), and after completion, it was quenched with saturated ammonium chloride (50 mL). The resulting mixture was extracted with ethyl acetate (40 mL x 3), and the organic phase was washed with saturated brine (800 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give a white solid of 2,5-hydroxycholest-5(4)-en-3-one (248-1) (767 mg, purity: 90%, yield: 69.38%).

[0610] 1 H NMR (400 MHz, CDCl3) δ 5.72 (s, 1H), 2.47 - 2.27 (m, 4H), 2.05 - 2.01 (m, 2H), 1.87 - 1.82 (m, 2H), 1.70 - 1.24 (m, 15H), 1.22 (s, 6H), 1.18 (s, 3H), 1.12 - 1.00 (m, 5H), 0.93 (d, J = 6.5 Hz, 3H), 0.71 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 199.69, 171.71, 123.76, 71.09, 56.03, 55.87, 53.80, 44.39, 42.41, 39.62, 38.60, 36.38, 35.72, 35.69, 35.61, 33.99, 32.95, 32.04, 29.36, 29.23, 28.20, 24.17, 21.02, 20.77, 18.61, 17.39, 11.96. Step 2: In a 50 mL round-bottom flask, 25-hydroxycholest-5(4)-en-3-one (248-1) (600 mg, 1.50 mmol) was dissolved in methanol (25 mL). Cerium(III) chloride heptahydrate (1.39 g, 3.75 mmol) and sodium borohydride (141.63 mg, 3.75 mmol) were added at room temperature, and the mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC (ethyl acetate / petroleum ether = 1 / 4). Upon completion, the reaction solution was added to ice water (50 mL), extracted with dichloromethane (30 mL x 3), and the organic solution was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was separated and purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20%) and concentrated under vacuum to remove the solvent, yielding a white solid, cholest-5(4)-ene-3β,25-diol (248-2) (510 mg, purity: 80%, yield: 67.66%). 1 H NMR (400 MHz, CDCl3) δ 5.27 (d, J = 1.5 Hz, 1H), 4.17 - 4.13 (m, 1H), 2.23 - 2.15 (m, 2H), 2.04 - 1.96 (m, 4H), 1.86 - 1.69 (m, 6H), 1.43 -1.35 (m, 12H), 1.21 (s, 6H), 1.14 - 1.05 (m, 5H), 1.05 (s, 3H), 0.92 (d, J = 6.6 Hz, 3H), 0.68 (s, 3H) Step 3: Cholest-5(4)-ene-3β,25-diol (248-2) (450 mg, 1.12 mmol) was dissolved in dichloromethane (10 mL) in a 50 mL round-bottom flask at room temperature, and triethylamine (340 mg, 3.36 mmol), 4-dimethylaminopyridine (27.31 mg, 0.224 mmol), and acetic anhydride (171.14 mg, 1.68 mmol) were added at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1). After completion of the reaction, the mixture was quenched with water (50 mL), extracted with ethyl acetate (30 mL × 3), and the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,5,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (248-3) (440 mg, purity: 90%, yield: 79.68%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 5.26 - 5.20 (m, 2H), 2.24 - 2.15 (m, 1H), 2.05 (s, 3H), 2.02 - 1.95 (m, 2H), 1.88 - 1.68 (m, 4H), 1.62 - 1.27 (m,168H), 1.21 (s, 6H), 1.18 - 1.08 (m, 3H), 1.06 (s, 3H), 1.03 - 0.95 (m, 1H), 0.92 (d, J = 6.5 Hz, 3H), 0.68 (s, 3H). Step 4: Acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-9a,11a-dimethyl-2,3,3a,3b,4,5,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (248-3) (250 mg, 0.562 mmol) was dissolved in dichloromethane (5 mL) in a 50 mL round-bottom flask at room temperature, and m-chloroperbenzoic acid (145.51 mg, 0.843 mmol) was added at room temperature. The mixture was stirred for 2 hours at room temperature. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1). After completion of the reaction, the mixture was quenched with saturated sodium sulfite (20 mL) and saturated aqueous sodium bicarbonate (20 mL), extracted with dichloromethane (20 mL × 3), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give a white solid, (2S,4aR,4bS,6aR,7R,9aS,9bS)-7-((R)-6-hydroxy-6-methylheptan-2-yl)-4a,6a-dimethylhexadecanehydrocyclopenta[7,8]phenanthrene[1,10a-b]-2-acetate (248-4) (230 mg, purity: 90%, yield: 79.92%). 1 H NMR (400 MHz, CDCl3) δ 5.14 - 5.10 (m, 0.57H), 4.92 (d, J = 3.6 Hz, 1H), 4.31 - 4.26 (m, 1H), 3.16 (d, J = 3.3 Hz, 0.5H), 2.13 (s, 3H), 2.10 (s, 1.73H), 2.03 - 1.94 (m, 2H), 1.93 - 1.88(m, 1H), 1.86 - 1.71 (m, 5H), 1.69 - 1.33 (m, 32H), 1.21 (s, 9.44H), 1.11 (s, 3H), 1.04 (s, 1.72H), 1.03 - 0.97 (m, 4H), 0.92 (d, J = 6.4 Hz, 4.74H), 0.68 (s, 1.74H), 0.65 (s, 3H). Step 6: (2S,4aR,4bS,6aR,7R,9aS,9bS)-7-[(2R)-6-hydroxy-6-methylheptan-2-yl]-4a,6a-dimethyl-1a,2,3,4,4a,4b,5,6,6a,7,8,9,9a,9b,10,11-hexadecahydrocyclopenta[1',2':1,2]phenanthro[8,8a-b]oxazepin-2-ol (248-4) (40 mg, 0.087 mmol) was dissolved in acetone (2 mL) in a 50 mL round-bottom flask at room temperature. A 10% aqueous solution of perchloric acid (0.087 mL, 0.087 mmol) was added dropwise to the reaction solution, which was then stirred at room temperature for 16 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 1:1). After the reaction was completed, the reaction solution was added to saturated sodium bicarbonate (10 mL), extracted with dichloromethane (5 mL × 3), and the organic solution extracted with saturated brine (10 mL) was washed, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-5a,6-dihydroxy-1-[( 2R)-6-Hydroxy-6-methylheptan-2-yl]-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester isomer 1 (248-6) (Rf=0.24) (15 mg, purity: 80%, yield: 28.87%) (15 mg, purity: 80%, yield: 28.87%) and isomer 2 (248-5) (Rf value 0.4) (20 mg, purity: 80%, yield: 38.50%) were obtained.

[0611] 248-5(Rf=0.4): 1 H NMR (400 MHz, CDCl3) δ 5.46 - 5.16 (m, 1H), 3.65 (d, J = 3.0 Hz, 1H), 2.30 - 2.18 (m, 1H), 2.08 (s, 3H), 2.02 - 1.96 (m, 2H), 1.88 - 1.77 (m, 3H), 1.76 - 1.70 (m, 2H), 1.63 - 1.52 (m, 7H), 1.47 - 1.35 (m, 10H), 1.21 (s, 6H),1.18 (s, 3H), 1.11 - 1.01 (m, 5H), 0.92 (d, J = 6.4 Hz, 3H), 0.66 (s, 3H). 248-6(Rf=0.24): 1 H NMR (400 MHz, CDCl3) δ 4.92 (d, J = 3.6 Hz, 1H), 4.44 - 3.99 (m, 1H), 2.13 (s, 3H), 1.99 (d, J = 12.3 Hz, 1H), 1.92 - 1.80 (m, 2H), 1.75 - 1.50 (m, 11H), 1.47 - 1.31 (m, 12H), 1.21 (s, 6H), 1.11 (s, 3H), 1.07 - 0.98 (m, 4H), 0.92 (d, J = 6.5 Hz, 3H), 0.65 (s, 3H). Step 7: Acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-5a,6-dihydroxy-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester isomer (248-5) (Rf=0.4) (15 mg, 0.031 mmol) was dissolved in tetrahydrofuran (0.5 mL) and methanol (0.5 mL) in a 50 mL round-bottom flask at room temperature, and lithium hydroxide monohydrate (6.57 mg, 0.157 mmol) and water (0.3 mL) were added at room temperature, followed by stirring at room temperature for 2 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate=1:2). After completion of the reaction, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (5 mL x 3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:2) to obtain a white solid, cholest-3β,4,5,25-tetraol isomer 1 (248).

[0612] 248: 1 H NMR (400 MHz, CDCl3) δ 4.14 (s, 1H), 3.54 (s, 1H), 2.24 - 2.16 (m, 1H), 2.05 - 1.93 (m, 2H), 1.80 - 1.58 (m, 10H), 1.51 - 1.33 (m, 13H), 1.21 (s, 6H), 1.15 (s, 3H), 1.11 - 0.99 (m, 5H), 0.92 (d, J = 6.4 Hz, 3H), 0.66 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 78.14, 75.68, 71.16, 68.40, 56.28, 56.14, 46.97, 44.41, 42.77, 39.96, 38.40, 36.43, 35.76, LCMS: [ M+ H-2H2O] + =401

[0111] Referring to Example 248, acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-5a,6-dihydroxy-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester isomer (248-5) (Rf=0.4) was reacted with acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-5a,6-dihydroxy-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester isomer (248-5) (Rf=0.4). S,9aR,9bS,11aR)-5a,6-dihydroxy-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester isomer (248-6) (Rf = 0.24) was converted to cholest-3β,4,5,25-tetraol isomer 2 (249) as a white solid.

[0613] 249: 1 H NMR (400 MHz, CDCl3) δ 4.19 - 4.12 (m, 1H), 3.54 (d, J = 3.5 Hz, 1H), 2.24 - 2.17 (m, 1H), 2.04 - 1.94 (m, 2H), 1.83 - 1.58 (m, 10H), 1.49- 1.33 (m, 13H), 1.21 (s, 6H), 1.15 (s, 3H), 1.10 - 0.99 (m, 5H), 0.92 (d, J = 6.5 Hz, 3H), 0.66 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 78.14, 75.67, 71.15, 68.40, 56.28, 56.14, 46.97, 44.41, 42.77, 39.96, 38.40, 36.43, 35.76, 34.56, 31.51, 31.44, 30.65, 30.19, 29.71, 29.34, 29.21, 28.27, 25.84, 25.69, 24.10, 20.81, 20.53, 18.62, 15.59, 12.16.LCMS: [ M+ H-2H2O] + = 401 Example 250 Preparation of Compound 250 5-Fluorocholest-3β,4,25-triol

[0614] [ka]

[0615] Step 1: (2S,4aR,4bS,6aR,7R,9aS,9bS)-7-((R)-6-hydroxy-6-methylheptan-2-yl)-4a,6a-dimethylhexadecanehydrocyclopentane[7,8]phenanthrene[1,10a-b]-2-acetate (10 mg, 0.022 mmol) was dissolved in triethylamine trihydrofluoride (0.301 mL, 1.845 mmol) in a 50 mL round-bottom flask at room temperature. The mixture was stirred at 100 °C for 16 h and monitored by TLC (petroleum ether:ethyl acetate = 3:1). After completion of the reaction, the mixture was diluted with water (10 mL), extracted with ethyl acetate (5 mL × 3), and the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain a white solid, acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-5a-fluoro-6-hydroxy-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester (15 mg, purity: 80%, yield: 23.00%). 1 H NMR (400 MHz, CDCl3) δ 5.09 (dd, J = 10.1, 5.3 Hz, 1H), 3.81 (d, J = 4.0 Hz, 1H), 2.34 (t, J = 7.5 Hz, 1H), 2.26 - 2.20 (m, 1H), 2.09 (s, 4H), 2.05 - 1.98 (m, 4H), 1.82 - 1.46 (m, 22H), 1.21 (s, 6H), 1.15 (s, 4H), 0.92 (d, J = 6.4 Hz, 4H), 0.66 (s, 3H). 19 F NMR (376 MHz, CDCl3) δ -165.13 (s, 1F). Step 2: Acetic acid-(1R,3aS,3bS,7S,9aR,9bS,11aR)-5a-fluoro-6-hydroxy-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-9a,11a-dimethylhexadecahydro-1H-cyclopenta[1,2-i]phenanthren-7-yl ester (250-1) (12 mg, 0.025 mmol) was dissolved in tetrahydrofuran (1 mL) and methanol (1 mL) in a 50 mL rou...

Claims

1. A compound having a structure represented by Formula XXI, XVI, XIX, XXIII, XXIV or XXVI, or a pharma- ceutically acceptable salt thereof. 【Chemistry 1】 (However, R ３ｄ is H or R ３ｃ and R ３ｃ is -S(O) ２ OH, -C(O)-CH ２ CH ２ COOH, -C(O)-CH ２ COOH, -C(O)-CH ２ OH, -C(O)-COOH, -CH ２ CH ２ OH or -CH ２ COOH, R ３ａ and R ３ｂ As defined in any one of the groups below. (i) R ３ａ is H, R ３ｂ is -NH ２ , -NHS(O) ２ CH ３ , -NHS(O) ２ CH ２ CH ３ , -NHS(O) ２ CH ２ CH ２ CH ３ , -NHS(O) ２ CF ３ , -NH-C(O)-CH ２ OH, -CH ２ OH, -COOH, -C(O)-OCH ３ , -CH(CH ３ )OH, -CH ２ —C(O)—CH ２ OH or -CH(OH)-CH ２ CH ２ OH, (ii) R ３ａ is CH ３ and R ３ｂ is —OH, and (iii) R ３ａ and R ３ｂ together with the carbon atoms connected to them 【Chemistry 2】 Forming R ４ａ is H, F, CH ３ , C.F. ３ or OH, R ４ｂ H, F, NH ２ , OH or CF ３ and R ４ａ and R ４ｂ together with the carbon atoms connected to them 【Chemistry 3】 Forming R ５ is H or R ５ｃ and R ５ｃ is OH or F, R ６ｃ is H, F, CH ３ Or CF ３ and R ６ｄ CN, NH ２ , F, COOH or C １－４ is an alkoxy; Or, R ６ｃ and R ６ｄ together with the carbon atoms connected to them 【Chemistry 4】 Forming R ７ａ , H, F, NH ２ , C.H. ３ Or CF ３ and R ７ｂ is F or OH, Or, R ７ａ and R ７ｂ together with the carbon atoms connected to them 【Chemistry 5】 Forming R ８ａ is H or F, R １４ａ is H, R １９ is CH ２ O.H., C.H. ２ C.N., C.H. ２ COOH, CH ２ F or CHF ２ and R ２２ teeth, 【Chemistry 6】 Or R ２１ and R ２１ Is, -L １ -C(O)R Ａ , -L １ -S (O) ２ R Ａ , -L １ -R Ｂ , 【Chemistry 7】 , -L ２ -R Ｃ Or -L ３ -R Ｄ and Each L １ and L ２ are independently a single bond, -CH ２ -, -(CH ２ ) ２ -, -(CH ２ ) ３ -, -(CH ２ ) ４ -, -(CH ２ ) ５ - or - (CH ２ ) ６ -, wherein said -CH ２ -, -(CH ２ ) ２ -, -(CH ２ ) ３ -, -(CH ２ ) ４ -, -(CH ２ ) ５ - and - (CH ２ ) ６ -One CH in ２ the - moiety is optionally replaced by -X-; L ３ is -(CH ２ ) ２ -, -(CH ２ ) ３ -, -(CH ２ ) ４ -, -(CH ２ ) ５ - or - (CH ２ ) ６ -, wherein the -(CH ２ ) ２ -, -(CH ２ ) ３ -, -(CH ２ ) ４ -, -(CH ２ ) ５ - and - (CH ２ ) ６ -One CH in ２ the - moiety is replaced by -Y-, Each X is independently -CHR ５ａ -, -CR ５ａ R ５ｂ - or -Y-, Each R ５ａ and R ５ｂ are each independently F, C １－４ Alkyl or Fluoro C １－４ is alkyl, Each Y is independently -O-, -NH-, -N(C １－４ alkyl)-, 【Chemistry 8】 , -CH=CH-, 【Chemistry 9】 or -CHR ｇ - and R ｇ is -C １－４ alkylene-OH, Each R Ａ are independently -NR ２１ａ R ２１ｂ and R Ｂ is -N(R ２１ａ )-C(O)R ２１ｂ Or -N(R ２１ａ ) -S(O) ２ R ２１ｂ and R Ｄ is -OH, -CH ２ O.H., R. Ｃ , -CH(CH ３ )-OH or -C(CH ３ ) ２ -OH, Each R Ｃ are independently -C(R ２１ｃ ) (R ２１ｄ )-OH, CN, -C(O)R Ｅ , N.H. ２ , C １－４ Alkoxy, 【Chemistry 10】 , 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is unsubstituted or has p R ｃ is replaced by R Ｅ is C １－４ Alkyl, C １－４ Alkoxy, C ３－６ cycloalkyl or 3- to 6-membered heterocycloalkyl, １－４ Alkyl, C １－４ Alkoxy, C ３－６ Cycloalkyl and 3- to 6-membered heterocycloalkyl are independently unsubstituted or ａ is replaced by Each R ２１ａ are independently H, C １－６ Alkyl, C ３－６ cycloalkyl or 3- to 6-membered heterocycloalkyl, １－６ Alkyl, C ３－６ Cycloalkyl and 3- to 6-membered heterocycloalkyl are independently unsubstituted or ａ is replaced by Each R ２１ｂ are independently H, C １－６ Alkyl, C ３－１０ Cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ aryl or 5- to 10-membered heteroaryl, １－６ Alkyl, C ３－１０ Cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ Aryl and 5- to 10-membered heteroaryl are independently unsubstituted or ｂ is replaced by Or, -NR ２１ａ R ２１ｂ In the above, R ２１ａ and R ２１ｂ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocycloalkyl, wherein said 3- to 10-membered heterocycloalkyl is unsubstituted or has p R ｃ is replaced by each m, p, and q is independently 1, 2, 3, 4, or 5; Each R ａ , R ｂ and R ｃ are each independently F, Cl, OH, COOH, CN, or NO ２ , C １－４ Alkyl, Fluoro C １－４ Alkyl, C １－４ Alkoxy, 【Chemistry 11】 and R ２１ｃ is H, F, C １－４ Alkyl, Fluoro C １－４ Alkyl, C ２－４ Alkenyl or C ３－６ is cycloalkyl, R ２１ｄ , F, C ２－４ Alkyl, Fluoro C １－４ Alkyl, C ２－４ Alkenyl, C ３－６ Cycloalkyl, phenyl, 5- to 6-membered heteroaryl or -L ４ -R ２１ｅ wherein the phenyl and 5- to 6-membered heteroaryl are independently unsubstituted or ｄ is replaced by Or, R ２１ｃ and R ２１ｄ C together with the carbon atoms connected to them ３－６ forming a cycloalkyl or 3- to 6-membered heterocycloalkyl; L ４ is C １－４ is alkylene, R ２１ｅ OH, CN, C １－４ alkoxy, phenyl, or 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl are independently unsubstituted or ｄ is replaced by each j is independently 1, 2, 3, or 4; each r is independently 0, 1, 2, 3, or 4; Each R ｄ and R ｆ are independently F, Cl, OH, CN, NO ２ , C １－４ Alkyl, Fluoro C １－４ Alkyl, C １－４ Alkoxy or Fluoro C １－４ is an alkoxy; the number of heteroatoms in said heterocycloalkyl and heteroaryl is independently 1, 2, 3 or 4, and each heteroatom is independently N, O or S; A carbon atom labeled with * is in the R configuration, S configuration or a mixture of both, a carbon atom labeled with # is a chiral carbon atom, if it is an R configuration, S configuration or a mixture of both, a carbon atom labeled with & is a chiral carbon atom, if it is an R configuration, S configuration or a mixture of both, a carbon atom labeled with A is a chiral carbon atom, if it is an R configuration, S configuration or a mixture of both, and a carbon atom labeled with B is a chiral carbon atom, if it is an R configuration, S configuration or a mixture of the two.)

2. (1) In the compound represented by formula XXI, R ３ｄ is H or R ３ｃ and R ３ｃ is -S(O) ２ OH, -C(O)-CH ２ COOH, -C(O)-CH ２ OH, -C(O)-COOH, -CH ２ CH ２ OH or -CH ２ COOH, R ４ａ is H, F, CH ３ , C.F. ３ or OH, R ４ｂ is H, F, OH, CH ２ OH, CN, COOH, CF ３ or cyclopropyl, Or, R ４ａ and R ４ｂ together with the carbon atoms connected to them 【Chemistry 12】 Forming R ７ａ is H, F, CH ３ Or CF ３ and R ７ｂ is F or OH, or R ７ａ and R ７ｂ together with the carbon atoms connected to them 【Chemistry 13】 Forming R ８ａ is H or F, R １４ａ is H, R ２２ teeth, 【Chemistry 14】 Or R ２１ and R ２１ Is, -L １ -C(O)R Ａ , -L １ -S (O) ２ R Ａ , -L １ -R Ｂ , 【Chemistry 15】 , -L ２ -R Ｃ Or -L ３ -R Ｄ and Each L １ and L ２ are independently a single bond, -CH ２ -, -(CH ２ ) ２ -, -(CH ２ ) ３ -, -(CH ２ ) ４ -, -(CH ２ ) ５ - or - (CH ２ ) ６ -, wherein said -CH ２ -, -(CH ２ ) ２ -, -(CH ２ ) ３ -, -(CH ２ ) ４ -, -(CH ２ ) ５ - and - (CH ２ ) ６ -One CH in ２ the - moiety is optionally replaced by -X-; L ３ is -(CH ２ ) ２ -, -(CH ２ ) ３ -, -(CH ２ ) ４ -, -(CH ２ ) ５ - or - (CH ２ ) ６ -, wherein the -(CH ２ ) ２ -, -(CH ２ ) ３ -, -(CH ２ ) ４ -, -(CH ２ ) ５ - and - (CH ２ ) ６ -One CH in ２ the - moiety is replaced by -Y-, Each X is independently -CHR ５ａ -, -CR ５ａ R ５ｂ - or -Y-, Each R ５ａ and R ５ｂ are each independently F, C １－４ Alkyl or Fluoro C １－４ is alkyl, Each Y is independently -O-, -NH-, -N(C １－４ alkyl)-, 【Chemistry 16】 , -CH=CH-, 【Chemistry 17】 or -CHR ｇ - and R ｇ is -C １－４ alkylene-OH, Each R Ａ are independently -NR ２１ａ R ２１ｂ and R Ｂ is -N(R ２１ａ )-C(O)R ２１ｂ Or -N(R ２１ａ ) -S(O) ２ R ２１ｂ and R Ｄ is -OH, -CH ２ O.H., R. Ｃ , -CH(CH ３ )-OH or -C(CH ３ ) ２ -OH, Each R Ｃ are independently -C(R ２１ｃ ) (R ２１ｄ )-OH, CN, -C(O)R Ｅ , N.H. ２ , C １－４ Alkoxy, 【Chemistry 18】 , 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is unsubstituted or has p R ｃ is replaced by R Ｅ is C １－４ Alkyl, C １－４ Alkoxy, C ３－６ cycloalkyl or 3- to 6-membered heterocycloalkyl, １－４ Alkyl, C １－４ Alkoxy, C ３－６ Cycloalkyl and 3- to 6-membered heterocycloalkyl are independently unsubstituted or ａ is replaced by Each R ２１ａ are independently H, C １－６ Alkyl, C ３－６ cycloalkyl or 3- to 6-membered heterocycloalkyl, １－６ Alkyl, C ３－６ Cycloalkyl and 3- to 6-membered heterocycloalkyl are independently unsubstituted or ａ is replaced by Each R ２１ｂ are independently H, C １－６ Alkyl, C ３－１０ Cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ aryl or 5- to 10-membered heteroaryl, １－６ Alkyl, C ３－１０ Cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ Aryl and 5- to 10-membered heteroaryl are independently unsubstituted or ｂ is replaced by Or, -NR ２１ａ R ２１ｂ In the above, R ２１ａ and R ２１ｂ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocycloalkyl, wherein said 3- to 10-membered heterocycloalkyl is unsubstituted or has p R ｃ is replaced by each m, p, and q is independently 1, 2, 3, 4, or 5; Each R ａ , R ｂ and R ｃ are each independently F, Cl, OH, COOH, CN, or NO ２ , C １－４ Alkyl, Fluoro C １－４ Alkyl, C １－４ Alkoxy, 【Chemistry 19】 and R ２１ｃ is H, F, C １－４ Alkyl, Fluoro C １－４ Alkyl, C ２－４ Alkenyl or C ３－６ is cycloalkyl, R ２１ｄ , F, C ２－４ Alkyl, Fluoro C １－４ Alkyl, C ２－４ Alkenyl, C ３－６ Cycloalkyl, phenyl, 5- to 6-membered heteroaryl or -L ４ -R ２１ｅ wherein the phenyl and 5- to 6-membered heteroaryl are independently unsubstituted or ｄ is replaced by Or, R ２１ｃ and R ２１ｄ C together with the carbon atoms connected to them ３－６ forming a cycloalkyl or 3- to 6-membered heterocycloalkyl; L ４ is C １－４ is alkylene, R ２１ｅ OH, CN, C １－４ alkoxy, phenyl, or 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl are independently unsubstituted or ｄ is replaced by each j is independently 1, 2, 3, or 4; each R is independently 0, 1, 2, 3, or 4; Each R ｄ and R ｆ are independently F, Cl, OH, CN, NO ２ , C １－４ Alkyl, full Oro C １－４ Alkyl or C １－４ is an alkoxy; the number of heteroatoms in said heterocycloalkyl and heteroaryl is independently 1, 2, 3 or 4, and each heteroatom is independently N, O or S; In formula XXI, the carbon atom labeled with * is in the R configuration, the S configuration or a mixture of both, the carbon atom labeled with #, if a chiral carbon atom, it is in the R configuration, the S configuration or a mixture of both, the carbon atom labeled with A, if a chiral carbon atom, it is in the R configuration, the S configuration or a mixture of both, the carbon atom labeled with B, if a chiral carbon atom, it is in the R configuration, the S configuration or a mixture of both, (2) A compound represented by formula XVI, wherein R ３ｄ is H or R ３ｃ and R ３ｃ is -S(O) ２ OH, -C(O)-CH ２ COOH, -C(O)-CH ２ OH, -C(O)-COOH, -CH ２ CH ２ OH or -CH ２ COOH, R ４ａ is H, F, CH ３ , C.F. ３ or OH, R ４ｂ is H, F, OH or CF ３ and Or, R ４ａ and R ４ｂ together with the carbon atoms connected to them 【Chemistry 20】 Forming R ５ is H or R ５ｃ and R ５ｃ is OH or F, R ２２ teeth, 【Chemistry 21】 Or R ２１ and R ２１ Is, -L １ -C(O)R Ａ , -L １ -S (O) ２ R Ａ , -L １ -R Ｂ , 【Chemical 22】 , -L ２ -R Ｃ Or -L ３ -R Ｄ and Each L １ and L ２ are independently a single bond, -CH ２ -, -(CH ２ ) ２ -, -(CH ２ ) ３ -, -(CH ２ ) ４ -, -(CH ２ ) ５ - or - (CH ２ ) ６ -, wherein said -CH ２ -, -(CH ２ ) ２ -, -(CH ２ ) ３ -, -(CH ２ ) ４ -, -(CH ２ ) ５ - and - (CH ２ ) ６ -One CH in ２ the - moiety is optionally replaced by -X-; L ３ is -(CH ２ ) ２ -, -(CH ２ ) ３ -, -(CH ２ ) ４ -, -(CH ２ ) ５ - or - (CH ２ ) ６ -, wherein the -(CH ２ ) ２ -, -(CH ２ ) ３ -, -(CH ２ ) ４ -, -(CH ２ ) ５ - and - (CH ２ ) ６ -One CH in ２ - part is -Y- is replaced by Each X is independently -CHR ５ａ -, -CR ５ａ R ５ｂ - or -Y-, Each R ５ａ and R ５ｂ are each independently F, C １－４ Alkyl or Fluoro C １－４ is alkyl, Each Y is independently -O-, -NH-, -N(C １－４ alkyl)-, 【Chemistry 23】 , -CH=CH-, 【Chemistry 24】 or -CHR ｇ - and R ｇ is -C １－４ alkylene-OH, Each R Ａ are independently -NR ２１ａ R ２１ｂ and R Ｂ is -N(R ２１ａ )-C(O)R ２１ｂ Or -N(R ２１ａ ) -S(O) ２ R ２１ｂ and R Ｄ is -OH, -CH ２ O.H., R. Ｃ , -CH(CH ３ )-OH or -C(CH ３ ) ２ -OH, Each R Ｃ are independently -C(R ２１ｃ ) (R ２１ｄ )-OH, CN, -C(O)R Ｅ , N.H. ２ , C １－４ Alkoxy, 【Chemistry 25】 , 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is unsubstituted or has p R ｃ is replaced by R Ｅ is C １－４ Alkyl, C １－４ Alkoxy, C ３－６ cycloalkyl or 3- to 6-membered heterocycloalkyl, １－４ Alkyl, C １－４ Alkoxy, C ３－６ Cycloalkyl and 3- to 6-membered heterocycloalkyl are independently unsubstituted or ａ is replaced by Each R ２１ａ are independently H, C １－６ Alkyl, C ３－６ cycloalkyl or 3- to 6-membered heterocycloalkyl, １－６ Alkyl, C ３－６ Cycloalkyl and 3- to 6-membered heterocycloalkyl are independently unsubstituted or ａ is replaced by Each R ２１ｂ are independently H, C １－６ Alkyl, C ３－１０ Cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ aryl or 5- to 10-membered heteroaryl, １－６ Alkyl, C ３－１０ Cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ Aryl and 5- to 10-membered heteroaryl are independently unsubstituted or ｂ is replaced by Or, -NR ２１ａ R ２１ｂ In the above, R ２１ａ and R ２１ｂ are connected to them Together with the nitrogen atom form a 3- to 10-membered heterocycloalkyl, wherein the 3- to 10-membered heterocycloalkyl is unsubstituted or has p R ｃ is replaced by each m, p, and q is independently 1, 2, 3, 4, or 5; Each R ａ , R ｂ and R ｃ are each independently F, Cl, OH, COOH, CN, or NO ２ , C １－４ Alkyl, Fluoro C １－４ Alkyl, C １－４ Alkoxy, 【Chemistry 26】 and R ２１ｃ is H, F, C １－４ Alkyl, Fluoro C １－４ Alkyl, C ２－４ Alkenyl or C ３－６ is cycloalkyl, R ２１ｄ , F, C ２－４ Alkyl, Fluoro C １－４ Alkyl, C ２－４ Alkenyl, C ３－６ Cycloalkyl, phenyl, 5- to 6-membered heteroaryl or -L ４ -R ２１ｅ wherein the phenyl and 5- to 6-membered heteroaryl are independently unsubstituted or ｄ is replaced by Or, R ２１ｃ and R ２１ｄ C together with the carbon atoms connected to them ３－６ forming a cycloalkyl or 3- to 6-membered heterocycloalkyl; L ４ is C １－４ is alkylene, R ２１ｅ OH, CN, C １－４ alkoxy, phenyl, or 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl are independently unsubstituted or ｄ is replaced by each j is independently 1, 2, 3, or 4; each r is independently 0, 1, 2, 3, or 4; Each R ｄ and R ｆ are independently F, Cl, OH, CN, NO ２ , C １－４ Alkyl, Fluoro C １－４ Alkyl or C １－４ is an alkoxy; the number of heteroatoms in said heterocycloalkyl and heteroaryl is independently 1, 2, 3 or 4, and each heteroatom is independently N, O or S; In formula XVI, the carbon atom marked with * is in the R configuration, the S configuration or a mixture of both, the carbon atom marked with #, if a chiral carbon atom, it is in the R configuration, the S configuration or a mixture of both, and the carbon atom marked with &, if a chiral carbon atom, it is in the R configuration, the S configuration or a mixture of both; (3) In the compound represented by formula XIX, R ３ｄ is H or R ３ｃ and R ３ｃ is -S(O) ２ OH, -C(O)-CH ２ COOH, -C(O)-CH ２ OH, -C(O)-COOH, -CH ２ CH ２ OH or -CH ２ COOH, R ４ａ is H, F, CH ３ , C.F. ３ or OH, R ４ｂ is H, F, OH or CF ３ and Or, R ４ａ and R ４ｂ together with the carbon atoms connected to them 【Chemical 27】 Forming R ５ is H or R ５ｃ and R ５ｃ is OH or F, R ６ｃ is H, F, CH ３ Or CF ３ and R ６ｄ is CN, F, COOH or C １－４ alkoxy (e.g., methoxy); Or, R ６ｃ and R ６ｄ together with the carbon atoms connected to them 【Chemistry 28】 Forming R ２２ teeth, 【Chemical Formula 29】 Or R ２１ and R ２１ Is, -L １ -C(O)R Ａ , -L １ -S (O) ２ R Ａ , -L １ -R Ｂ , 【Chemistry 30】 , -L ２ -R Ｃ Or -L ３ -R Ｄ and Each L １ and L ２ are independently a single bond, -CH ２ -, -(CH ２ ) ２ -, -(CH ２ ) ３ -, -(CH ２ ) ４ -, -(CH ２ ) ５ - or - (CH ２ ) ６ -, wherein said -CH ２ -, -(CH ２ ) ２ -, -(CH ２ ) ３ -, -(CH ２ ) ４ -, -(CH ２ ) ５ - and - (CH ２ ) ６ -One CH in ２ the - moiety is optionally replaced by -X-; L ３ is -(CH ２ ) ２ -, -(CH ２ ) ３ -, -(CH ２ ) ４ -, -(CH ２ ) ５ - or - (CH ２ ) ６ -, wherein the -(CH ２ ) ２ -, -(CH ２ ) ３ -, -(CH ２ ) ４ -, -(CH ２ ) ５ - and - (CH ２ ) ６ -One CH in ２ the - moiety is replaced by -Y-, Each X is independently -CHR ５ａ -, -CR ５ａ R ５ｂ - or -Y-, Each R ５ａ and R ５ｂ are each independently F, C １－４ Alkyl or Fluoro C １－４ is alkyl, Each Y is independently -O-, -NH-, -N(C １－４ alkyl)-, 【Chemistry 31】 , -CH=CH-, 【Chemistry 32】 or -CHR ｇ - and R ｇ is -C １－４ alkylene-OH, Each R Ａ are independently -NR ２１ａ R ２１ｂ and R Ｂ is -N(R ２１ａ )-C(O)R ２１ｂ Or -N(R ２１ａ ) -S(O) ２ R ２１ｂ and R Ｄ is -OH, -CH ２ O.H., R. Ｃ , -CH(CH ３ )-OH or -C(CH ３ ) ２ -OH, Each R Ｃ are independently -C(R ２１ｃ ) (R ２１ｄ )-OH, CN, -C(O)R Ｅ , N.H. ２ , C １－４ Alkoxy, 【Chemical 33】 , 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is unsubstituted or has p R ｃ is replaced by R Ｅ is C １－４ Alkyl, C １－４ Alkoxy, C ３－６ cycloalkyl or 3- to 6-membered heterocycloalkyl, １－４ Alkyl, C １－４ Alkoxy, C ３－６ Cycloalkyl and 3- to 6-membered heterocycloalkyl are independently unsubstituted or ａ is replaced by Each R ２１ａ are independently H, C １－６ Alkyl, C ３－６ cycloalkyl or 3- to 6-membered heterocycloalkyl, １－６ Alkyl, C ３－６ Cycloalkyl and 3- to 6-membered heterocycloalkyl are independently unsubstituted or ａ is replaced by Each R ２１ｂ are independently H, C １－６ Alkyl, C ３－１０ Cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ aryl or 5- to 10-membered heteroaryl, １－６ Alkyl, C ３－１０ Cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ Aryl and 5- to 10-membered heteroaryl are independently unsubstituted or ｂ is replaced by Or, -NR ２１ａ R ２１ｂ In the above, R ２１ａ and R ２１ｂ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocycloalkyl, wherein said 3- to 10-membered heterocycloalkyl is unsubstituted or has p R ｃ is replaced by each m, p, and q is independently 1, 2, 3, 4, or 5; Each R ａ , R ｂ and R ｃ are each independently F, Cl, OH, COOH, CN, or NO ２ , C １－４ Alkyl, Fluoro C １－４ Alkyl, C １－４ Alkoxy, 【Chemical 34】 and R ２１ｃ is H, F, C １－４ Alkyl, Fluoro C １－４ Alkyl, C ２－４ Alkenyl or C ３－６ is cycloalkyl, R ２１ｄ , F, C ２－４ Alkyl, Fluoro C １－４ Alkyl, C ２－４ Alkenyl, C ３－６ Cycloalkyl, phenyl, 5- to 6-membered heteroaryl or -L ４ -R ２１ｅ wherein the phenyl and 5- to 6-membered heteroaryl are independently unsubstituted or ｄ is replaced by Or, R ２１ｃ and R ２１ｄ C together with the carbon atoms connected to them ３－６ forming a cycloalkyl or 3- to 6-membered heterocycloalkyl; L ４ is C １－４ is alkylene, R ２１ｅ OH, CN, C １－４ alkoxy, phenyl, or 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl are independently unsubstituted or ｄ is replaced by each j is independently 1, 2, 3, or 4; each r is independently 0, 1, 2, 3, or 4; Each R ｄ and R ｆ are independently F, Cl, OH, CN, NO ２ , C １－４ Alkyl, Fluoro C １－４ Alkyl or C １－４ is an alkoxy; the number of heteroatoms in said heterocycloalkyl and heteroaryl is independently 1, 2, 3 or 4, and each heteroatom is independently N, O or S; In formula XIX, the carbon atom labeled with * is in the R configuration, the S configuration or a mixture of both, the carbon atom labeled with #, if a chiral carbon atom, it is in the R configuration, the S configuration or a mixture of both, the carbon atom labeled with A, if a chiral carbon atom, it is in the R configuration, the S configuration or a mixture of both, the carbon atom labeled with B, if a chiral carbon atom, it is in the R configuration, the S configuration or a mixture of both, (4) In the compound represented by formula XXIII, R ３ｄ is H or R ３ｃ and R ３ｃ is -S(O) ２ OH, -C(O)-CH ２ COOH, -C(O)-CH ２ OH, -C(O)-COOH, -CH ２ CH ２ OH or -CH ２ COOH, R ４ａ is H, F, CH ３ , C.F. ３ or OH, R ４ｂ is H, F, OH or CF ３ and Or, R ４ａ and R ４ｂ together with the carbon atoms connected to them 【Chemistry 35】 Forming R １９ is CH ２ O.H., C.H. ２ C.N., C.H. ２ COOH, CH ２ F or CHF ２ and R ２２ teeth, 【Chemical 36】 Or R ２１ and R ２１ Is, -L １ -C(O)R Ａ , -L １ -S (O) ２ R Ａ , -L １ -R Ｂ , 【Chemical 37】 , -L ２ -R Ｃ Or -L ３ -R Ｄ and Each L １ and L ２ are independently a single bond, -CH ２ -, -(CH ２ ) ２ -, -(CH ２ ) ３ -, -(CH ２ ) ４ -, -(CH ２ ) ５ - or - (CH ２ ) ６ -, wherein said -CH ２ -, -(CH ２ ) ２ -, -(CH ２ ) ３ -, -(CH ２ ) ４ -, -(CH ２ ) ５ - and - (CH ２ ) ６ -One CH in ２ the - moiety is optionally replaced by -X-; L ３ is -(CH ２ ) ２ -, -(CH ２ ) ３ -, -(CH ２ ) ４ -, -(CH ２ ) ５ - or - (CH ２ ) ６ -, wherein the -(CH ２ ) ２ -, -(CH ２ ) ３ -, -(CH ２ ) ４ -, -(CH ２ ) ５ - and - (CH ２ ) ６ -One CH in ２ the - moiety is replaced by -Y-, Each X is independently -CHR ５ａ -, -CR ５ａ R ５ｂ - or -Y-, Each R ５ａ and R ５ｂ are each independently F, C １－４ Alkyl or Fluoro C １－４ is alkyl, Each Y is independently -O-, -NH-, -N(C １－４ alkyl)-, 【Chemical 38】 , -CH=CH-, 【Chemical 39】 or -CHR ｇ - and R ｇ is -C １－４ alkylene-OH, Each R Ａ are independently -NR ２１ａ R ２１ｂ and R Ｂ is -N(R ２１ａ )-C(O)R ２１ｂ Or -N(R ２１ａ ) -S(O) ２ R ２１ｂ and R Ｄ is -OH, -CH ２ O.H., R. Ｃ , -CH(CH ３ )-OH or -C(CH ３ ) ２ -OH, Each R Ｃ are independently -C(R ２１ｃ ) (R ２１ｄ )-OH, CN, -C(O)R Ｅ , N.H. ２ , C １－４ Alkoxy, 【Chemistry 40】 , 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is unsubstituted or has p R ｃ is replaced by R Ｅ is C １－４ Alkyl, C １－４ Alkoxy, C ３－６ cycloalkyl or 3- to 6-membered heterocycloalkyl, １－４ Alkyl, C １－４ Alkoxy, C ３－６ Cycloalkyl and 3- to 6-membered heterocycloalkyl are independently unsubstituted or ａ is replaced by Each R ２１ａ are independently H, C １－６ Alkyl, C ３－６ cycloalkyl or 3- to 6-membered heterocycloalkyl, １－６ Alkyl, C ３－６ Cycloalkyl and 3- to 6-membered heterocycloalkyl are independently unsubstituted or ａ is replaced by Each R ２１ｂ are independently H, C １－６ Alkyl, C ３－１０ Cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ aryl or 5- to 10-membered heteroaryl, １－６ Alkyl, C ３－１０ Cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ Aryl and 5- to 10-membered heteroaryl are independently unsubstituted or ｂ is replaced by Or, -NR ２１ａ R ２１ｂ In the above, R ２１ａ and R ２１ｂ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocycloalkyl, wherein said 3- to 10-membered heterocycloalkyl is unsubstituted or has p R ｃ is replaced by each m, p, and q is independently 1, 2, 3, 4, or 5; Each R ａ , R ｂ and R ｃ are each independently F, Cl, OH, COOH, CN, or NO ２ , C １－４ Alkyl, Fluoro C １－４ Alkyl, C １－４ Alkoxy, 【Chemistry 41】 and R ２１ｃ is H, F, C １－４ Alkyl, Fluoro C １－４ Alkyl, C ２－４ Alkenyl or C ３－６ is cycloalkyl, R ２１ｄ , F, C ２－４ Alkyl, Fluoro C １－４ Alkyl, C ２－４ Alkenyl, C ３－６ Cycloalkyl, phenyl, 5- to 6-membered heteroaryl or -L ４ -R ２１ｅ wherein the phenyl and 5- to 6-membered heteroaryl are independently unsubstituted or ｄ is replaced by Or, R ２１ｃ and R ２１ｄ C together with the carbon atoms connected to them ３－６ forming a cycloalkyl or 3- to 6-membered heterocycloalkyl; L ４ is C １－４ is alkylene, R ２１ｅ OH, CN, C １－４ alkoxy, phenyl, or 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl are independently unsubstituted or ｄ is replaced by each j is independently 1, 2, 3, or 4; each r is independently 0, 1, 2, 3, or 4; Each R ｄ and R ｆ are independently F, Cl, OH, CN, NO ２ , C １－４ Alkyl, Fluoro C １－４ Alkyl or C １－４ is an alkoxy; the number of heteroatoms in said heterocycloalkyl and heteroaryl is independently 1, 2, 3 or 4, and each heteroatom is independently N, O or S; In formula XXIII, the carbon atom marked with * may be in the R configuration, the S configuration or a mixture of both, and the carbon atom marked with #, when it is a chiral carbon atom, may be in the R configuration, the S configuration or a mixture of both; (5) In the compound represented by formula XXIV, R ３ｄ is H or R ３ｃ and R ３ｃ is -S(O) ２ OH, -C(O)-CH ２ COOH, -C(O)-CH ２ OH, -C( O) -COOH, -CH ２ CH ２ OH or -CH ２ COOH, R ７ａ is H, F, CH ３ Or CF ３ and R ７ｂ is F or OH, or R ７ａ and R ７ｂ together with the carbon atoms connected to them 【Chemistry 42】 Forming R ８ａ is H or F, R ２２ teeth, 【Chemistry 43】 Or R ２１ and R ２１ Is, -L １ -C(O)R Ａ , -L １ -S (O) ２ R Ａ , -L １ -R Ｂ , 【Chemistry 44】 , -L ２ -R Ｃ Or -L ３ -R Ｄ and Each L １ and L ２ are independently a single bond, -CH ２ -, -(CH ２ ) ２ -, -(CH ２ ) ３ -, -(CH ２ ) ４ -, -(CH ２ ) ５ - or - (CH ２ ) ６ -, wherein said -CH ２ -, -(CH ２ ) ２ -, -(CH ２ ) ３ -, -(CH ２ ) ４ -, -(CH ２ ) ５ - and - (CH ２ ) ６ -One CH in ２ the - moiety is optionally replaced by -X-; L ３ is -(CH ２ ) ２ -, -(CH ２ ) ３ -, -(CH ２ ) ４ -, -(CH ２ ) ５ - or - (CH ２ ) ６ -, wherein the -(CH ２ ) ２ -, -(CH ２ ) ３ -, -(CH ２ ) ４ -, -(CH ２ ) ５ - and - (CH ２ ) ６ -One CH in ２ the - moiety is replaced by -Y-, Each X is independently -CHR ５ａ -, -CR ５ａ R ５ｂ - or -Y-, Each R ５ａ and R ５ｂ are each independently F, C １－４ Alkyl or Fluoro C １－４ is alkyl, Each Y is independently -O-, -NH-, -N(C １－４ alkyl)-, 【Chemistry 45】 , -CH=CH-, 【Chemistry 46】 or -CHR ｇ - and R ｇ is -C １－４ alkylene-OH, Each R Ａ are independently -NR ２１ａ R ２１ｂ and R Ｂ is -N(R ２１ａ )-C(O)R ２１ｂ Or -N(R ２１ａ ) -S(O) ２ R ２１ｂ and R Ｄ is -OH, -CH ２ O.H., R. Ｃ , -CH(CH ３ )-OH or -C(CH ３ ) ２ -OH, Each R Ｃ are independently -C(R ２１ｃ ) (R ２１ｄ )-OH, CN, -C(O)R Ｅ , N.H. ２ , C １－４ Alkoxy, 【Chemistry 47】 , 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is unsubstituted or has p R ｃ is replaced by R Ｅ is C １－４ Alkyl, C １－４ Alkoxy, C ３－６ cycloalkyl or 3- to 6-membered heterocycloalkyl, １－４ Alkyl, C １－４ Alkoxy, C ３－６ Cycloalkyl and 3- to 6-membered heterocycloalkyl are independently unsubstituted or ａ is replaced by Each R ２１ａ are independently H, C １－６ Alkyl, C ３－６ cycloalkyl or 3- to 6-membered heterocycloalkyl, １－６ Alkyl, C ３－６ Cycloalkyl and 3- to 6-membered heterocycloalkyl are independently unsubstituted or ａ is replaced by Each R ２１ｂ are independently H, C １－６ Alkyl, C ３－１０ Cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ aryl or 5- to 10-membered heteroaryl, １－６ Alkyl, C ３－１０ Cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ Aryl and 5- to 10-membered heteroaryl are independently unsubstituted or ｂ is replaced by Or, -NR ２１ａ R ２１ｂ In the above, R ２１ａ and R ２１ｂ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocycloalkyl, wherein said 3- to 10-membered heterocycloalkyl is unsubstituted or has p R ｃ is replaced by each m, p, and q is independently 1, 2, 3, 4, or 5; Each R ａ , R ｂ and R ｃ are each independently F, Cl, OH, COOH, CN, or NO ２ , C １－４ Alkyl, Fluoro C １－４ Alkyl, C １－４ Alkoxy, 【Chemistry 48】 and R ２１ｃ is H, F, C １－４ Alkyl, Fluoro C １－４ Alkyl, C ２－４ Alkenyl or C ３－６ is cycloalkyl, R ２１ｄ , F, C ２－４ Alkyl, Fluoro C １－４ Alkyl, C ２－４ Alkenyl, C ３－６ Cycloalkyl, phenyl, 5- to 6-membered heteroaryl or -L ４ -R ２１ｅ wherein the phenyl and 5- to 6-membered heteroaryl are independently unsubstituted or ｄ is replaced by Or, R ２１ｃ and R ２１ｄ C together with the carbon atoms connected to them ３－６ forming a cycloalkyl or 3- to 6-membered heterocycloalkyl; L ４ is C １－４ is alkylene, R ２１ｅ OH, CN, C １－４ alkoxy, phenyl, or 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl are independently unsubstituted or ｄ is replaced by each j is independently 1, 2, 3, or 4; each r is independently 0, 1, 2, 3, or 4; Each R ｄ and R ｆ are independently F, Cl, OH, CN, NO ２ , C １－４ Alkyl, Fluoro C １－４ Alkyl or C １－４ is an alkoxy; the number of heteroatoms in said heterocycloalkyl and heteroaryl is independently 1, 2, 3 or 4, and each heteroatom is independently N, O or S; In formula XXIV, the carbon atom labeled with * is in the R configuration, the S configuration or a mixture of both, the carbon atom labeled with #, if a chiral carbon atom, it is in the R configuration, the S configuration or a mixture of both, the carbon atom labeled with A, if a chiral carbon atom, it is in the R configuration, the S configuration or a mixture of both, and (6) In the compound represented by formula XXVI, R ３ａ and R ３ｂ is as defined in any one of the following groups: (i) R ３ａ is H, R ３ｂ is -NH ２ , -NHS(O) ２ CH ３ , -NHS(O) ２ CH ２ CH ３ , -NHS(O) ２ CH ２ CH ２ CH ３ , -NHS(O) ２ CF ３ , -NH-C(O)-CH ２ OH, -CH ２ OH, -COOH, -C(O)-OCH ３ , -CH(CH ３ )OH, -CH ２ —C(O)—CH ２ OH or -CH(OH)-CH ２ CH ２ OH, (ii) R ３ａ is CH ３ and R ３ｂ is —OH, and (iii) R ３ａ and R ３ｂ together with the carbon atoms connected to them 【Chemistry 49】 Forming R ４ａ is H, F, CH ３ , C.F. ３ or OH, R ４ｂ is H, F, OH or CF ３ and Or, R ４ａ and R ４ｂ together with the carbon atoms connected to them 【Chemistry 50】 Forming R ５ is H or R ５ｃ and R ５ｃ is OH or F, R ２２ teeth, 【Chemistry 51】 Or R ２１ and R ２１ Is, -L １ -C(O)R Ａ , -L １ -S (O) ２ R Ａ , -L １ -R Ｂ , 【Chemistry 52】 , -L ２ -R Ｃ Or -L ３ -R Ｄ and Each L １ and L ２ are independently a single bond, -CH ２ -, -(CH ２ ) ２ -, -(CH ２ ) ３ -, -(CH ２ ) ４ -, -(CH ２ ) ５ - or - (CH ２ ) ６ -, wherein said -CH ２ -, -(CH ２ ) ２ -, -(CH ２ ) ３ -, -(CH ２ ) ４ -, -(CH ２ ) ５ - and - (CH ２ ) ６ -One CH in ２ the - moiety is optionally replaced by -X-; L ３ is -(CH ２ ) ２ -, -(CH ２ ) ３ -, -(CH ２ ) ４ -, -(CH ２ ) ５ - or - (CH ２ ) ６ -, wherein the -(CH ２ ) ２ -, -(CH ２ ) ３ -, -(CH ２ ) ４ -, -(CH ２ ) ５ - and - (CH ２ ) ６ -One CH in ２ the - moiety is replaced by -Y-, Each X is independently -CHR ５ａ -, -CR ５ａ R ５ｂ - or -Y-, Each R ５ａ and R ５ｂ are each independently F, C １－４ Alkyl or Fluoro C １－４ is alkyl, Each Y is independently -O-, -NH-, -N(C １－４ alkyl)-, 【Chemistry 53】 , -CH=CH-, 【Chemical 54】 or -CHR ｇ - and R ｇ is -C １－４ alkylene-OH, Each R Ａ are independently -NR ２１ａ R ２１ｂ and R Ｂ is -N(R ２１ａ )-C(O)R ２１ｂ Or -N(R ２１ａ ) -S(O) ２ R ２１ｂ and R Ｄ is -OH, -CH ２ O.H., R. Ｃ , -CH(CH ３ )-OH or -C(CH ３ ) ２ -OH, Each R Ｃ are independently -C(R ２１ｃ ) (R ２１ｄ )-OH, CN, -C(O)R Ｅ , N.H. ２ , C １－４ Alkoxy, 【Chemistry 55】 , 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is unsubstituted or has p R ｃ is replaced by R Ｅ is C １－４ Alkyl, C １－４ Alkoxy, C ３－６ cycloalkyl or 3- to 6-membered heterocycloalkyl, １－４ Alkyl, C １－４ Alkoxy, C ３－６ Cycloalkyl and 3- to 6-membered heterocycloalkyl are independently unsubstituted or ａ is replaced by Each R ２１ａ are independently H, C １－６ Alkyl, C ３－６ cycloalkyl or 3- to 6-membered heterocycloalkyl, １－６ Alkyl, C ３－６ Cycloalkyl and 3- to 6-membered heterocycloalkyl are independently unsubstituted or ａ is replaced by Each R ２１ｂ are independently H, C １－６ Alkyl, C ３－１０ Cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ aryl or 5- to 10-membered heteroaryl, １－６ Alkyl, C ３－１０ Cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６－１０ Aryl and 5- to 10-membered heteroaryl are independently unsubstituted or ｂ is replaced by Or, -NR ２１ａ R ２１ｂ In the above, R ２１ａ and R ２１ｂ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocycloalkyl, wherein said 3- to 10-membered heterocycloalkyl is unsubstituted or has p R ｃ is replaced by each m, p, and q is independently 1, 2, 3, 4, or 5; Each R ａ , R ｂ and R ｃ are each independently F, Cl, OH, COOH, CN, or NO ２ , C １－４ Alkyl, Fluoro C １－４ Alkyl, C １－４ Alkoxy, 【Chemistry 56】 and R ２１ｃ is H, F, C １－４ Alkyl, Fluoro C １－４ Alkyl, C ２－４ Alkenyl or C ３－６ is cycloalkyl, R ２１ｄ , F, C ２－４ Alkyl, Fluoro C １－４ Alkyl, C ２－４ Alkenyl, C ３－６ Cycloalkyl, phenyl, 5- to 6-membered heteroaryl or -L ４ -R ２１ｅ wherein the phenyl and 5- to 6-membered heteroaryl are independently unsubstituted or ｄ is replaced by Or, R ２１ｃ and R ２１ｄ C together with the carbon atoms connected to them ３－６ forming a cycloalkyl or 3- to 6-membered heterocycloalkyl; L ４ is C １－４ is alkylene, R ２１ｅ OH, CN, C １－４ alkoxy, phenyl, or 5- to 6-membered heteroaryl, wherein the phenyl and 5- to 6-membered heteroaryl are independently unsubstituted or ｄ is replaced by each j is independently 1, 2, 3, or 4; each r is independently 0, 1, 2, 3, or 4; Each R ｄ and R ｆ are independently F, Cl, OH, CN, NO ２ , C １－４ Alkyl, Fluoro C １－４ Alkyl or C １－４ is an alkoxy; the number of heteroatoms in said heterocycloalkyl and heteroaryl is independently 1, 2, 3 or 4, and each heteroatom is independently N, O or S; In formula XXVI, the carbon atom marked with * is in the R configuration, the S configuration or a mixture of both, the carbon atom marked with #, if a chiral carbon atom, it is in the R configuration, the S configuration or a mixture of both, and the carbon atom marked with &, if a chiral carbon atom, it is in the R configuration, the S configuration or a mixture of both.

2. A compound according to claim 1 or a pharma- ceutically acceptable salt thereof, characterized in that it satisfies one or more of the following conditions:

3. (1) In the compound represented by formula XXI, R ３ｄ is H, (2) In the compound represented by formula XXI, R ４ａ is H, R ４ｂ is H or OH, or R ４ａ and R ４ｂ together with the carbon atoms connected to them 【Chemistry 57】 Forming Preferably, R ４ａ and R ４ｂ is as defined in any one of the following groups: a) R ４ａ is H, R ４ｂ is H, b) R ４ａ is H, R ４ｂ is OH, and c) R ４ａ and R ４ｂ together with the carbon atoms connected to them 【Chemistry 58】 Forming (3) In the compound represented by formula XXI, R ８ａ is H, (4) In the compound represented by formula XXI, R ７ａ and R ７ｂ is as defined in any one of the following groups: a) R ７ａ is H, R ７ｂ is F, b) R ７ａ is F and R ７ｂ is F, c) R ７ａ is H, R ７ｂ is OH, d) R ７ａ and R ７ｂ together with the carbon atoms connected to them 【Chemistry 59】 Forming e) R ７ａ and R ７ｂ together with the carbon atoms connected to them 【Chemistry 60】 and f) R ７ａ is H, R ７ｂ NH ２ and (5) In the compound represented by formula XXI, R ２１ Is, -L ２ -R Ｃ and (6) In the compound represented by formula XXI, L ２ is -(CH ２ ) ３ - and (7) In the compound represented by formula XXI, each R Ｃ are independently -C(R ２１ｃ ) (R ２１ｄ ) —OH, (8) In the compound represented by formula XXI, R Ｃ -C(R ２１ｃ ) (R ２１ｄ ) —OH is 【Chemistry 61】 and preferably, R Ｃ -C(R ２１ｃ ) (R ２１ｄ ) —OH is 【Chemistry 62】 and (9) In the compound represented by formula XVI, R ３ｄ is H, -C(O)-CH ２ OH, -C(O)-CH ２ COOH or -C(O)-CH ２ CH ２ COOH, (10) In the compound represented by formula XVI, R ４ａ and R ４ｂ is as defined in any one of the following groups: a) R ４ａ is H, R ４ｂ is OH, b) R ４ａ is CH ３ and R ４ｂ is F, c) R ４ａ is F and R ４ｂ is F, d) R ４ａ is H, R ４ｂ CF ３ and e) R ４ａ is CH ３ and R ４ｂ is OH, f) R ４ａ is OH, R ４ｂ CF ３ and g) R ４ａ and R ４ｂ together with the carbon atoms connected to them 【Chemistry 63】 Forming h) R ４ａ is H, R ４ｂ is F, i) R ４ａ CF ３ and R ４ｂ CF ３ and j) R ４ａ and R ４ｂ together with the carbon atoms connected to them 【Chemistry 64】 Forming k) R ４ａ is H, R ４ｂ is H, and l) R ４ａ is H, R ４ｂ NH ２ and (11) In the compound represented by formula XVI, R ２１ Is, -L １ -C(O)R Ａ , -L ２ -R Ｃ or 【Chemistry 65】 and (12) In the compound represented by formula XVI, L １ is -(CH ２ ) ２ -or-CH ２ -CHR ５ａ -, preferably L １ is -(CH ２ ) ２ - and (13) In the compound represented by formula XVI, each R ２１ａ are independently methyl; (14) In the compound represented by formula XVI, each R ２１ｂ is independently 【Chemistry 66】 and (15) In the compound represented by formula XVI, L ２ is -(CH ２ ) ２ - or - (CH ２ ) ３ and (16) In the compound represented by formula XVI, each R Ｃ are independently -C(R ２１ｃ ) (R ２１ｄ )-OH or 【Chemistry 67】 and (17) In the compound represented by formula XVI, R Ｃ -C(R ２１ｃ ) (R ２１ｄ ) —OH is 【Chemistry 68】 and (18) In the compound represented by formula XVI, r is 0; (19) In the compound represented by formula XIX, R ３ｄ is H, (20) In the compound represented by formula XIX, R ４ａ is H, R ４ｂ is OH, or R ４ａ is H, R ４ｂ is H, (21) In the compound represented by formula XIX, R ５ is OH, or R ５ is H, (22) In the compound represented by formula XIX, R ６ｃ and R ６ｄ is as defined in any one of the following groups: a) R ６ｃ is H, R ６ｄ is CN, b) R ６ｃ is H, R ６ｄ is COOH, c) R ６ｃ is H, R ６ｄ is OCH ３ and d) R ６ｃ and R ６ｄ together with the carbon atoms connected to them 【Chemistry 69】 Forming (23) In the compound represented by formula XIX, R ２２ teeth, 【Chemistry 70】 and (24) In the compound represented by formula XXIII, R ３ｄ is H, (25) In the compound represented by formula XXIII, R ４ａ is H, R ４ｂ is H, (26) In the compound represented by formula XXIII, R ２２ teeth, 【Chemistry 71】 and (27) In the compound represented by formula XXIV, R ３ｄ is H, (28) In the compound represented by formula XXIV, R ７ａ is H, R ７ｂ is OH, or R ７ａ and R ７ｂ together with the carbon atoms connected to them 【Chemical Formula 72】 Forming (29) In the compound represented by formula XXIV, R ８ａ is H, (30) In the compound represented by formula XXIV, R ２２ teeth, 【Chemical 73】 and (31) In the compound represented by formula XXVI, R ３ａ and R ３ｂ is as defined in any one of the following groups: a) R ３ａ is H, R ３ｂ is -NHS(O) ２ CH ３ , -CH ２ OH, -COOH, -C(O)-OCH ３ or -CH(CH ３ ) OH, and b) R ３ａ is CH ３ and R ３ｂ is —OH, (32) In the compound represented by formula XIX, R ４ａ is H, R ４ｂ is H, (33) In the compound represented by formula XXVI, R ５ is H, and (34) In the compound represented by formula XXVI, R ２２ teeth, 【Chemical Formula 74】 That is, 3. A compound according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof, characterized in that it satisfies one or more of the following conditions:

4. (1) In the compound represented by formula XXI, R Ｃ But -C(R ２１ｃ ) (R ２１ｄ ) —OH, R ２１ｃ is H, R ２１ｄ is C ２－４ Alkyl, Fluoro C １－４ Alkyl, C ３－６ Cycloalkyl, phenyl, 5- to 6-membered heteroaryl or -L ４ -R ２１ｅ wherein phenyl optionally has one or two R ｄ and each R ｄ are independently F, OH, CN or C １－４ is an alkoxy; (2) Each R ２１ａ are independently H, C １－４ Alkyl, -C １－４ Alkylene -OH, -C １－４ Alkylene-OC １－４ Alkyl, Fluoro C １－４ alkyl or cyclopropyl, for example, each R ２１ａ are independently H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 【Chemistry 75】 , cyclopropyl or trifluoromethyl; Preferably, each R ２１ａ is independently C １－４ is alkyl, (3) In the compound represented by formula XVI according to any one of the above embodiments, each R ２１ｂ are independently H, C １－６ Alkyl, C ６－１０ aryl or 5- to 10-membered heteroaryl, １－６ Alkyl, C ６－１０ Aryl and 5- to 10-membered heteroaryl are independently unsubstituted or ｂ For example, each R ２１ｂ are independently H, -C １－４ Alkylene -OH, -C １－４ Alkylene-OC １－４ Alkyl, Fluoro C １－４ Alkyl, tetrahydromorpholinyl, phenyl, pyridyl, thienyl phenyl, pyridyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrimidinyl or benzopyrazolyl, wherein said phenyl, pyridyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrimidinyl and benzopyrazolyl are independently unsubstituted or ｂ Preferably, each R ２１ｂ is independently phenyl, wherein said phenyl is unsubstituted or ｂ is replaced by Preferably, each R ２１ｂ is independently C ６－１０ aryl, wherein said C ６－１０ Aryl is unsubstituted or has q R ｂ is replaced by (4) In the compound represented by formula XVI, q is 1, 2 or 3, for example, 1; (5) In the compound represented by formula XVI, each R ｂ are independently F, Cl, OH, COOH, CN, NO ２ , methyl, trifluoromethyl, methoxy, 【Chemical 76】 For example, F; and (6) In the compound represented by formula XVI, R Ｃ But -C(R ２１ｃ ) (R ２１ｄ ) —OH, R ２１ｃ and R ２１ｄ is as defined in any one of the following groups: a) R ２１ｃ is H, R ２１ｄ is C ２－４ Alkyl, Fluoro C １－４ Alkyl, C ３－６ Cycloalkyl, phenyl, 5- to 6-membered heteroaryl or -L ４ -R ２１ｅ wherein phenyl optionally has one or two R ｄ and each R ｄ are independently F, OH, CN or C １－４ is an alkoxy; b) R ２１ｃ and R ２１ｄ C together with the carbon atoms connected to them ３－６ Cycloalkyl or 3-6 membered heterocycloalkyl (e.g., 【Chemical Formula 77】 ), preferably R ２１ｃ and R ２１ｄ together with the carbon atom attached thereto, represents cyclopropyl, cyclobutyl or 【Chemical 78】 and c) R ２１ｃ is CH ３ or trifluoromethyl, R ２１ｄ is C ２－４ alkyl (e.g., ethyl) or trifluoromethyl, e.g., —C(R ２１ｃ ) (R ２１ｄ ) —OH is 【Chemical 79】 That is, 3. A compound according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof, characterized in that it satisfies one or more of the following conditions:

5. (1) In the compound represented by formula XXI, R Ｃ But -C(R ２１ｃ ) (R ２１ｄ ) —OH, R ２１ｃ is H, R ２１ｄ is phenyl, where phenyl optionally has one or two R ｄ or R ２１ｃ and R ２１ｄ C together with the carbon atoms connected to them ３－６ forming a cycloalkyl (e.g., cyclopropyl), ｄ are independently F or C １－４ is an alkoxy; (2) In the compound represented by formula XVI, each R Ａ is independently 【Chemistry 80】 For example, 【Chemistry 81】 and (3) In the compound represented by formula XVI, R Ｃ But -C(R ２１ｃ ) (R ２１ｄ ) —OH, R ２１ｃ and R ２１ｄ is as defined in any one of the following groups: a) R ２１ｃ is H, R ２１ｄ is C ２－４ Alkyl, Fluoro C １－４ Alkyl, C ３－６ cycloalkyl or phenyl, where phenyl optionally has one or two R ｄ and each R ｄ are independently F, Cl, OH, fluoro C １－４ Alkyl, C １－４ Alkoxy or Fluoro C １－４ is an alkoxy; b) R ２１ｃ and R ２１ｄ C together with the carbon atoms connected to them ３－６ Forms a cycloalkyl, preferably R ２１ｃ and R ２１ｄ together with the carbon atom attached thereto form a cyclopropyl, and (4) R ２１ｃ is CH ３ or trifluoromethyl, R ２１ｄ is phenyl or trifluoromethyl, wherein the phenyl is unsubstituted or ｄ is replaced by 3. A compound according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof, characterized in that it satisfies one or more of the following conditions:

6. (1) In the compound represented by formula XXI, -L ２ -R Ｃ teeth, 【Chemistry 82】 and (2)--In the compound of formula XXI, L １ -C(O)R Ａ teeth, 【Chemistry 83】 For example, 【Chemistry 84】 That is, 3. A compound according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof, characterized in that it satisfies one or more of the following conditions:

7. (1) In the compound represented by formula XXI, R ２１ teeth, 【Chemistry 85】 and (2) In the compound represented by formula XVI, R ２１ teeth, 【Chemistry 86】 That is, 2. A compound according to claim 1 or a pharma- ceutically acceptable salt thereof, characterized in that it satisfies one or more of the following conditions:

8. (1) The compound represented by formula XXI is a compound represented by formula XXI-1, 【Chemistry 87】 In formula XXI-1, #, B, R ４ａ , R ４ｂ , R ７ａ , R ７ｂ and R ２２ is as defined in any one of claims 1 to 6, Preferably, the compound of formula XXI is a compound of formula XXI-2, XXI-3 or XXI-4, 【Chemistry 88】 In the formula XXI-2, XXI-3 or XXI-4, B, R ７ａ , R ７ｂ and R ２２ is as defined in any one of claims 1 to 7, (2) The compound represented by formula XVI is a compound represented by formula XVI-1, 【Chemistry 89】 In formula XVI, #, &, R ３ｄ , R ４ａ , R ４ｂ , R ５ and R ２２ is as defined in any one of claims 1 to 7, (3) The compound represented by formula XIX is a compound represented by formula XIX-1, 【Chemistry 90】 In formula XIX, #, A, B, R ４ａ , R ４ｂ , R ５ , R ６ｃ and R ６ｄ is as defined in any one of claims 1 to 7, and (4) The compound represented by formula XXVI is a compound represented by formula XXVI-1, 【Chemistry 91】 In formula XXVI, *, R ３ａ and R ３ｂ is as defined in any one of claims 1 to 7, 2. A compound according to claim 1 or a pharma- ceutically acceptable salt thereof, characterized in that it satisfies one or more of the following conditions:

9. The compound according to claim 1 or 2, characterized in that the compound represented by formula XVI is a compound represented by formula VII, or a pharma- ceutically acceptable salt thereof. 【Chemistry 92】 (However, R ３ｄ is H or R ３ｃ and R ３ｃ is as defined in claims 1 to 7, R ２２ teeth, 【Chemistry 93】 Or R ２１ and R ２１ is as defined in claims 1 to 7, In formula VII, the carbon atom marked with an * may be in the R configuration, the S configuration, or a mixture of both; Preferably, R ３ｄ is H, Preferably, R ２２ teeth, 【Chemistry 94】 and More preferably, the compound represented by formula VII is the compound shown below: 【Chemistry 95】

10. A compound or a pharma- ceutically acceptable salt thereof, characterized in that it is any one of the following compounds: 【Chemistry 96】 【change】 【Chemistry 97】 【change】 【change】 【change】 【change】 【Chemistry 98】 【change】 【Chemistry 99】 【Chemistry 100】 【Chemistry 101】

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 or a pharma- ceutically acceptable salt thereof, and at least one pharmaceutical auxiliary.

12. Use of the compound according to any one of claims 1 to 10 or a pharma- ceutical composition according to claim 11 in the manufacture of a medicament for preventing and / or treating obesity, hyperlipidemia, fatty liver, diabetes, atherosclerosis, cardiovascular disease, cerebrovascular disease, liver cancer, or skin damage.

13. Use of a compound according to any one of claims 1 to 10 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, in the manufacture of a medicament for inhibiting the SREBP pathway.

Images