Benzyl-substituted phenanthrene compound as well as synthesis method and application thereof

Abstract

The invention provides an application of 9, 10-hydrophenanthrene (saturated type) and phenanthrene (unsaturated type) in a medicine for treating fatty liver, and a benzyl-substituted compound of the type, which shows a sufficiently obvious pharmacological effect of reducing liver lipid accumulation on a cell model of palmitic acid-induced hepatocyte triglyceride (TG) accumulation and a non-alcoholic steatohepatitis (NASH) animal model.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, in particular to a class of benzyl-substituted phenanthrene compounds, and pharmaceutical compositions with the class of compounds as active ingredients, the preparation method, and the use of the class of compounds and its pharmaceutical compositions in the preparation of drugs for treating and / or preventing liver lipid accumulation-mediated diseases and related diseases, including metabolic syndrome and related indications such as non-alcoholic fatty liver disease, obesity, hyperlipidemia, diabetes, cardiovascular disease, liver damage, liver fibrosis, etc. BACKGROUND

[0002] Metabolic syndrome is a series of diseases characterized by metabolic abnormalities and cardiovascular disease risk factors, reflecting a series of diseases related to nutrition and sedentary lifestyle, including type 2 diabetes, non-alcoholic fatty liver disease, obesity, dyslipidemia, and hypertension. Patients with obesity, lipodystrophy, and diabetes are all accompanied by fatty liver. Among them, non-alcoholic fatty liver disease (NAFLD) is characterized by abnormal accumulation of triglycerides (TG) in the liver, and has become one of the most common liver diseases in the world. NAFLD can be divided into simple fatty liver, non-alcoholic steatohepatitis (NASH), fatty liver fibrosis, and cirrhosis according to different stages of disease development. Non-alcoholic steatohepatitis is the result of the further development of simple fatty liver, and its pathological manifestations are lipid deposition, inflammatory cell infiltration, liver tissue necrosis, and fibrosis, further developing into more severe cirrhosis and hepatocellular carcinoma (HCC). Currently, there is only one drug (Resmetirom) approved for the market for metabolic-related fatty liver disease, there is a huge unmet clinical need, and the development of new drugs for treating related diseases has important scientific significance and economic value.

[0003] Lipid deposition-induced lipotoxicity is one of the key driving factors of metabolic disorders in NAFLD, and the accumulated lipids in hepatocytes are mainly triglycerides, so hepatocyte triglyceride metabolism disorder is the main reason for the occurrence of fatty liver. The content of triglycerides in the liver is affected by multiple metabolic pathways, including liver uptake of free fatty acids released by lipolysis of triglycerides from adipose tissue, de novo synthesis of liver lipids, liver fatty acid oxidation, and very low density lipoprotein (VLDL)-triglyceride secretion, and the accumulation of triglycerides in the liver is the final result of the complex interaction of multiple metabolic pathways. Hepatocyte triglyceride accumulation can cause lipotoxicity, metabolic disorders, insulin resistance, and oxidative stress, leading to hepatocyte steatosis, damage, and death; it can also cause an increase in hepatocyte very low density lipoprotein secretion, raising blood lipids. Therefore, effectively inhibiting liver triglyceride accumulation has great potential application value for the intervention of non-alcoholic fatty liver, obesity, and diabetes, and other diseases with liver lipid metabolism disorders. Finding small molecule compounds that can effectively inhibit liver triglyceride accumulation has been a technical problem that the industry is eager to solve.

[0004] Phenanthrene compounds are a relatively small number of secondary metabolites in plants. At present, about 500 phenanthrene compounds are found in plants. Monomers can be further divided into 9,10-dihydrophenanthrene (saturated type) and phenanthrene (unsaturated type) according to the bond saturation degree of C9-C10. Benzyl-substituted 9,10-dihydrophenanthrene / phenanthrene refers to a class of compounds with benzyl substitution on the parent skeleton of 9,10-dihydrophenanthrene / phenanthrene, and the benzyl substitution is mostly at C-1 or C-8. The present application relates to a class of natural or natural-like benzyl 9,10-dihydrophenanthrene / phenanthrene with benzyl substitution at C-8 of 9,10-dihydrophenanthrene / phenanthrene. The biological activity of phenanthrene compounds has been sporadically reported in the literature. Individual compounds have antibacterial, antitumor, antioxidant, anti-inflammatory and other activities. So far, there is no C-8 benzyl-substituted 9,10-dihydrophenanthrene / phenanthrene compound provided by the present application in the prior art, and no direct pharmacological activity related to the treatment of fatty liver has been reported. SUMMARY

[0005] In view of the above reasons, the inventors have developed a drug related to fatty liver during the development of the drug, and have unexpectedly found that the benzyl-substituted 9,10-dihydrophenanthrene / phenanthrene compound has related activity in the preparation of hepatocyte triglyceride accumulation, which suggests that the compound has application prospects in the preparation of drugs for liver lipid accumulation related metabolic diseases. Specifically, the present application provides the use of a compound represented by formula (I) in the preparation of a drug for treating diseases related to liver lipid metabolism disorders,

[0006]

[0007] R 1～ R 5 each independently selected from the group consisting of hydrogen, hydroxyl, halogen atom, methyl, halogenated methyl, methoxy, carboxyl, carboxyl C1-3 alkyl ester, R 1 and R 5 may be connected to form a ring structure, represents a single bond or a double bond.

[0008] In a preferred embodiment, the compound represented by formula (I) has a structure represented by formula (II),

[0009]

[0010] R 2～ R 4 The meaning of the expression is the same as in formula (I).

[0011] In a preferred embodiment, the compound represented by formula (I) is the following specific compound,

[0012]

[0013]

[0014]

[0015]

[0016] In a preferred embodiment, the compound represented by formula (II) is a specific compound,

[0017]

[0018] Compound name [R 2 ]] [R 3 ]] [R 4 ]] 9,10 position bond F16 OMe OMe OH double bond EQF16 OMe OMe OH single bond F18 OMe OMe OMe double bond EQF18 OMe OMe OMe single bond

[0019] Another aspect of the present application provides a pharmaceutical composition for treating a disease related to a disorder of lipid metabolism in the liver, comprising a compound represented by formula (I)

[0020]

[0021] R 1～ R 5 each independently selected from a group selected from hydrogen, hydroxyl, halogen atom, methyl, halogenated methyl, methoxyl, carboxyl, carboxyl C1-3 alkyl ester group, R 1 and R 5 may be linked to form a ring structure,

[0022] represents a single bond or a double bond.

[0023] In a preferred embodiment, the compound represented by formula (I) has a structure represented by formula (II),

[0024]

[0025] R 2～ R 4 The meaning of the expression is the same as in formula (I).

[0026] The present application also provides the following novel compounds having anti-fatty liver activity,

[0027]

[0028] R 5 are both H

[0029]

[0030]

[0031] In a preferred embodiment,

[0032]

[0033]

[0034] As a pharmacological model, the present application uses a cell model of palmitic acid-induced accumulation of triglyceride (TG) in hepatocytes to screen the activity of YS36 series compounds and study the structure-activity relationship, aiming to discover several new compounds with significant activity in inhibiting the accumulation of TG in hepatocytes.

[0035] The present application aims to provide a class of benzyl-substituted 9,10-dihydrophenanthrene / phenanthrene compounds, a pharmaceutical composition taking the same as an active ingredient, a synthetic method thereof, and the application of the compounds in preparing a triglyceride accumulation inhibitor, and also provides the application of the compounds in preparing a drug for metabolic diseases related to liver lipid metabolism disorders (non-alcoholic fatty liver disease, obesity, hyperlipidemia, diabetes, cardiovascular disease, liver damage, liver fibrosis, etc.). BRIEF DESCRIPTION OF DRAWINGS

[0036] Figure 1 is a graph showing the effect of the compound YS36 of the present application on the pathological characteristics of liver steatosis, ballooning degeneration and inflammatory cell infiltration of NASH mice induced by high-fat diet combined with carbon tetrachloride after 6 weeks of administration. DETAILED DESCRIPTION

[0037] According to the above content of the present disclosure, according to the ordinary technical knowledge and means in the art, other various forms of modifications, substitutions or changes can be made without departing from the above basic technical ideas of the present disclosure.

[0038] Definitions and Terminology

[0039] It should be noted that, unless otherwise explicitly stated, throughout the specification and claims of this disclosure, the term "comprise" or its variants such as "comprises" or "comprising" will be understood to encompass the stated element or elements or components, without excluding the presence of other elements or components.

[0040] The compounds of the present disclosure can be asymmetric, for example, having one or more stereoisomers. Unless otherwise specified, all stereoisomers are included, such as enantiomers and diastereomers. Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically active form or racemic form. The optically active form can be separated from a racemic mixture, or synthesized by using chiral starting materials or chiral reagents. The racemates, diastereomers, enantiomers are all included within the scope of the present disclosure.

[0041] The term "optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and this description includes instances where the event or circumstance occurs and instances where it does not.

[0042] The term "substituted" or "to substitute" means that any one or more hydrogen atoms on a particular atom or group are replaced with a substituent, as long as the valence of the particular atom or group is normal and the compound after substitution is stable. When the substituent is a keto group (i.e., =O), it means that two hydrogen atoms are replaced. Unless otherwise specified, the species and number of substituents can be arbitrary on a chemical basis.

[0043] When any variable (e.g., R n ) occurs more than one time in a compound, each occurrence of that variable is independent.

[0044] The term "alkyl" refers to saturated aliphatic hydrocarbon groups, including straight-chain or branched-chain saturated hydrocarbon groups having the number of carbon atoms indicated. As the term "C 1-6 alkyl" includes C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, examples include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, n-hexyl, 2-hexyl, 3-hexyl, and the like. It can be divalent, e.g., methylene, ethylene.

[0045] The term "alkoxy" can be linear, branched, or cyclic. The number of carbon atoms of the alkoxy group is not particularly limited, but is preferably 1 to 20. Specific examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, i-propyloxy, n-butoxy, isobutoxy, t-butoxy, sec-butoxy, n-pentyloxy, neopentyloxy, isopentyloxy, n-hexyloxy, 3,3-dimethylbutoxy, 2-ethylbutoxy, n-octyloxy, n-nonyloxy, n-decyloxy, and the like, but are not limited thereto.

[0046] The term "carbonyl" or "carboxyl" includes structures in which a carbon of a compound or fragment is connected to an oxygen atom through a double bond. Examples of moieties containing carbonyl groups include aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, and the like.

[0047] The term "acyl" is a carbonyl structure in which the carbon atom of the carbonyl group is attached to a hydrogen (i.e., formyl), an aliphatic group (C1-C6alkyl, C1-C6alkenyl, C1-C6alkynyl, e.g., acetyl), a cycloalkyl group (C3-C8cycloalkyl), a heterocyclyl group (C3-C8heterocycloalkyl and C5-C6heteroaryl), an aryl group (C6aryl, e.g., benzoyl). The acyl group can be unsubstituted or substituted acyl (e.g., salicyloyl).

[0048] In the present disclosure, examples of the halogen group can include fluorine, chlorine, bromine, or iodine.

[0049] In the present disclosure, the term "cycloalkyl" refers to a monocyclic saturated hydrocarbon system, free of heteroatoms and double bonds. For example, the term "C 3-6 Examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0050] In the present disclosure, the term "aryl" refers to a fully carbon monocyclic or fused polycyclic aromatic ring group having a conjugated pi-electron system, which is obtained by removing one hydrogen atom from a single carbon atom of a parent aromatic ring system. It includes a bicyclic group of a saturated, partially unsaturated ring, or an aromatic carbocyclic ring fused aromatic ring. Specific examples thereof include phenyl or naphthyl, but are not limited thereto.

[0051] In the present disclosure, the term "heterocycloalkyl" refers to a 5-12 membered saturated non-aromatic system having ring carbon atoms and 1 to 2 ring heteroatoms. Specific examples of the heterocyclyl group include piperidinyl or tetrahydropyrrolyl, but are not limited thereto.

[0052] In the present disclosure, the term "heteroaryl" refers to a monovalent aromatic group containing at least one heteroatom independently selected from nitrogen, oxygen, and sulfur. The heteroaryl group can be a monocyclic ring, or a polycyclic ring system, for example, a bicyclic ring in which two or more rings exist in a form of a fused ring, a bridged ring, or a spiro ring, in which at least one ring contains one or more heteroatoms. Specific examples of the heteroaryl group include pyridyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, furanyl, pyrazinyl, thiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, imidazopyridinyl, benzofuranyl, pyridazinyl, isoindolyl, pyridinone, but are not limited thereto.

[0053] The term "heterocycle" refers to a 5-12 membered saturated non-aromatic system having ring carbon atoms and 1 to 2 ring heteroatoms, wherein the heteroatoms are independently selected from a nitrogen, a sulfur, or an oxygen atom. In a heterocyclic group containing one or more nitrogen atoms, the point of attachment can be a carbon or a nitrogen atom, as valency permits. The heterocycle can be a monocyclic ring, or a polycyclic ring system, for example, a bicyclic ring in which two or more rings exist in a form of a fused ring, a bridged ring, or a spiro ring, in which at least one ring contains one or more heteroatoms. In a spirocyclic heterocyclic group, two different rings share one atom, an example of the spirocyclic heterocyclic group is azaspiro pentane, but is not limited thereto.

[0054] The term "partially unsaturated bicyclic heterocycle" means a bicyclic group containing C atoms and at least one of N, O, S, etc. as ring members, which is partially unsaturated, containing at least one C-C double bond, the maximum number of C-C double bonds being allowed by the ring size for the fully unsaturated heterocycle and the C atoms and heteroatoms, the partially unsaturated bicyclic heterocycle containing less than the number of double bonds allowed by the ring size, specific examples of partially unsaturated bicyclic heterocycles include, but are not limited to, benzofuranyl, benzothiophenyl, quinoxalinyl, quinazolinyl, isoindolinonyl, pteridinyl, etc.

[0055] Obtaining of the compounds

[0056] The compounds of the present application can be obtained via the following synthetic routes

[0057]

[0058] The synthetic methods of the present application can be modified based on the known technology without departing from the spirit of the present application, and such modifications are also included in the scope of the present application.

[0059] Examples

[0060] The pharmacological effects of the compounds of the present application are further illustrated by the following specific examples, the scope of the present application is not limited by the scope of the following examples. These examples are not intended to limit the scope of the present application, but to illustrate the elements of the present application in more detail. The structure of the compounds is confirmed by nuclear magnetic resonance spectrum (H NMR) and / or mass spectrum (MS). 1 H NMR) and / or mass spectrum (MS).

[0061] Chemical shifts (δ) are given in parts per million (ppm). 1 The determination of H NMR was performed on a Bruker 400 or Bruker 600 or Varian 300 nuclear magnetic instrument, the test solvent was deuterated methanol (CD3OD), deuterated chloroform (CDCl3) or hexadeuterated dimethyl sulfoxide (DMSO-d6), and the internal standard was tetramethylsilane (TMS).

[0062] The determination of LC-MS was performed on an Agilent LC-MS-1110 liquid chromatograph-mass spectrometer, an Agilent LC-MS-6110 liquid chromatograph-mass spectrometer, an Agilent LC-MS-6120 liquid chromatograph-mass spectrometer (manufacturer: Agilent) or a Shimadzu LC-MS2020.

[0063] Preparative high performance liquid chromatography was performed using a MS-triggered automated purification system (Waters), a Gilson GX-281 (Gilson), or a semi-preparative liquid chromatograph (Ddlsogel, C18, 30 mm x 250 mm 10 μm).

[0064] Thin layer chromatography (TLC) was performed using yellow HSGF 254 (5 x 20 cm) silica gel plates, and preparative thin layer chromatography was performed using Yantai GF 254 (0.4-0.5 nm) silica gel plates.

[0065] Thin layer chromatography (TLC) or LC-MS was used to monitor the reactions, and the developing solvent systems used included dichloromethane and methanol, n-hexane and ethyl acetate, and petroleum ether and ethyl acetate, which were adjusted according to the polarity of the compounds to be separated (by adjusting the volume ratio of the solvents or adding triethylamine, etc.).

[0066] Unless otherwise specified in the examples, the temperature of the reaction was room temperature (20-30 °C).

[0067] The reagents used in the examples were purchased from Aldrich Chemical Company, Shanghai Reagent Co., Ltd., Bailingwei Reagent Co., Ltd., Shaoyuan Technology (Shanghai) Co., Ltd., or Abi Technology Co., Ltd., etc.

[0068] Synthesis Example One: Total synthesis of key intermediates S3, S4, S6, S7, S8, S10, and S11

[0069] 1. Total synthesis of methyl 2-bromo-3,5-dimethoxybenzoate S3

[0070] Commercially available methyl 3,5-dihydroxybenzoate (10000 mg, 59.5 mmol) was added to a 250 mL single-necked flask, followed by anhydrous potassium carbonate (18078 mg, 131 mmol), 120 mL of acetone, and stirring at room temperature for ten minutes. Dimethyl sulfate (12.4 mL, 131 mmol) was then added, and stirring was continued at room temperature for 12 h. TLC detection showed that the starting material had all reacted. The reaction mixture was added to 5 mL of water, and the acetone was removed by reduced pressure concentration. Then 100 mL of water was added, and the mixture was extracted three times with 100 mL of ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by reduced pressure to remove the solvent. The resulting crude product was separated and purified using 200-300 mesh silica gel (PE:EA = 20:1). White solid S2 (molecular weight, 196.20; 10.49 g, yield 90%) was obtained.

[0071] The starting material S2 (10490 mg, 53.5 mmol) was added to a 250 mL single-necked flask, followed by the addition of NBS (10469 mg, 58.85 mmol), acetonitrile 100 mL, and stirring at room temperature for 12 h. TLC plate detection showed a small amount of starting material, and a suitable amount of saturated sodium thiosulfate was added to quench the reaction, most of the acetonitrile was removed under reduced pressure, 100 mL of water was added, and 100 mL of ethyl acetate was extracted three times, the organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure, and the obtained crude product was separated and purified using 200-300 mesh silica gel (PE:EA = 10:1). White solid S3 (molecular weight 290.02; 12.46 g, yield 85%) was obtained.

[0072] 2. Full synthesis of 2-(4-benzyloxy-phenyl)-3,5-dimethoxybenzoic acid methyl ester S4

[0073]

[0074] The starting material S3 (12460 mg, 45.47 mmol) was added to a 250 mL pressure tube, followed by the addition of p-benzyloxyphenylboronic acid (10298 mg, 68.20 mmol), PdCl2(dppf) (1659 mg, 2.27 mmol), K2CO3 (18768 mg, 136 mmol), dioxane (60 mL), and water (15 mL), and the pressure tube was deoxygenated using an argon-filled balloon, and stirred at 100°C for 20 h under anaerobic conditions. TLC plate detection showed that all the starting material had reacted, the reaction mixture was added to 80 mL of water, and 80 mL of ethyl acetate was extracted three times, the organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure, and the obtained crude product was separated and purified using 200-300 mesh silica gel (PE:EA = 20:1). White solid S4 (15.46 g, yield 90%) was obtained. Molecular formula C 23 H 22 O5, molecular weight 378.15. 1 H NMR (400 MHz, CDCl3) δ 7.50-7.29 (m, 5H), 7.21-7.13 (m, 2H), 7.03-6.95 (m, 2H), 6.87 (d, J = 2.5 Hz, 1H), 5.09 (s, 2H), 3.87 (s, 3H), 3.74 (s, 3H), 3.55 (s, 3H).

[0075] 3. Full synthesis of 2-(4-benzyloxy-phenyl)-6-benzyl-3,5-dimethoxyphenyl acrylate S7

[0076]

[0077] The starting material S4 (15460 mg, 40.89 mmol) was added to a 250 mL single-necked flask, followed by lithium hydroxide (4860 mg, 202.95 mmol), methanol (60 mL), water (15 mL), and refluxing for 5 h. TLC detection showed that the starting material was completely reacted. The reaction mixture was adjusted to pH 1-2 with 2 mol / L hydrochloric acid, and then an appropriate amount of water was added. The organic phase was extracted with 80 mL of ethyl acetate three times, and then dried over anhydrous sodium sulfate. The solvent was removed by reduced pressure concentration to obtain white solid S5 (14.58 g, yield 98%), which was directly used in the next step without further purification.

[0078] The starting material S5 (14580 mg, 40.07 mmol) was added to a 250 mL single-necked flask, followed by HATU condensing agent (22851 mg, 60.1 mmol), super dry DMF (50 mL), stirring at room temperature for 10 min, then DIPEA (20.9 mL, 120.21 mmol) was added and stirring was continued for 10 min. Finally, p-toluenethiol (5465 mg, 44.1 mmol) was added, and stirring was continued at room temperature for 9 h. TLC detection showed that the starting material was completely reacted. 100 mL of ethyl acetate was added, and then the organic phase was washed with 150 mL of saturated brine. The salt washing was repeated 5 times, and then the mixture was dried over anhydrous sodium sulfate. The solvent was removed by reduced pressure concentration to obtain the crude product. The crude product was separated and purified using 200-300 mesh silica gel (PE:EA = 10:1) to obtain yellowish solid S6 (16.9 g, yield 90%).

[0079]

[0080] The starting material S6 (1500 mg, 3.19 mmol) was added to a 100 mL pressure tube, followed by palladium acetate (36 mg, 0.16 mmol), TFP (183.2 mg, 0.79 mmol), NBE-6 (1209.3 mg, 4.78 mmol), cuprous oxide (683.5 mg, 4.78 mmol), benzyl bromide (544 mL, 4.78 mmol), ethyl acrylate (510 mL, 4.78 mmol), super dry acetonitrile (15 mL), and the pressure tube was deoxygenated using an argon-filled balloon. The mixture was stirred vigorously at 120°C under anaerobic conditions for 12 h. TLC detection showed that the starting material was completely reacted. The reaction mixture was absorbed into an appropriate amount of silica gel for sample mixing, and then separated and purified using 200-300 mesh silica gel (PE:EA = 30:1) to obtain colorless oil S7 (486 mg, yield 30%). Molecular formula: C 33 H 32 O5, molecular weight: 508.22. 1H NMR (600 MHz, CDC13) δ 7.48-7.44 (m, 3H), 7.41-7.37 (m, 2H), 7.35-7.30 (m, 1H), 7.12-7.09 (m, 2H), 7.08-7.05 (m, 2H), 7.00-6.93 (m, 5H), 6.61 (s, 1H), 5.46 (d, J = 16.4 Hz, 1H), 5.06 (s, 2H), 4.09 (q, J = 7.1 Hz, 2H), 4.03 (s, 2H), 3.87 (s, 3H), 3.76 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H).

[0081] 4. Total synthesis of 2-(4-benzyloxy-phenyl)-6-benzyl-3,5-dimethoxybenzaldehyde S8

[0082]

[0083] The starting material S7 (500 mg, 0.98 mmol) was added to a 100 mL single-necked flask, followed by the addition of potassium osmate dihydrate (72 mg, 0.196 mmol), sodium periodate (2087 mg, 9.8 mmol), tetrahydrofuran (16 mL), water (8 mL), and reaction at 50 °C for 24 h. TLC plate detection showed that the starting material was not completely reacted, so potassium osmate dihydrate (72 mg, 0.196 mmol) and sodium periodate (2087 mg, 9.8 mmol) were added again and the reaction was continued for 24 h. After 48 h of reaction, TLC plate detection showed that the starting material was completely reacted. The reaction was quenched with saturated sodium thiosulfate, and then an appropriate amount of water was added. The organic phase was extracted with 20 mL of ethyl acetate three times, and then washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to obtain a crude product. The crude product was separated and purified using 200-300 mesh silica gel (PE:EA = 10:1) to obtain colorless oil S8 (molecular weight 438.18; 364 mg, yield 85%).

[0084] 5. Total synthesis of 2-(4-benzyloxy-phenyl)-6-benzyl-3,5-dimethoxybenzaldehyde S10

[0085]

[0086] S9 was added to a 50 mL single necked flask, 2 mol / L hydrochloric acid (2 mL, 4.15 mmol), tetrahydrofuran (10 mL) were added successively, and the mixture was heated to reflux for 2 h. TLC plate detection until the raw material was completely reacted, the reaction mixture was added to 20 mL ethyl acetate, washed with saturated brine three times, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent to obtain the crude product, the crude product was separated and purified using 200-300 mesh silica gel (PE:EA = 20:1) to obtain colorless oil S10 (molecular weight 452.20; 286 mg, total yield 77%).

[0087] S9 was added to a 50 mL single necked flask, 2 mol / L hydrochloric acid (2 mL, 4.15 mmol), tetrahydrofuran (10 mL) were added successively, and the mixture was heated to reflux for 2 h. TLC plate detection until the raw material was completely reacted, the reaction mixture was added to 20 mL ethyl acetate, washed with saturated brine three times, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent to obtain the crude product, the crude product was separated and purified using 200-300 mesh silica gel (PE:EA = 20:1) to obtain colorless oil S10 (molecular weight 452.20; 286 mg, total yield 77%).

[0088] 6, Full synthesis of 1-benzyloxy-8-benzyl-5,7-dimethoxy-phenanthrene S11

[0089]

[0090] S9 was added to a 50 mL single necked flask, 2 mol / L hydrochloric acid (2 mL, 4.15 mmol), tetrahydrofuran (10 mL) were added successively, and the mixture was heated to reflux for 2 h. TLC plate detection until the raw material was completely reacted, the reaction mixture was added to 20 mL ethyl acetate, washed with saturated brine three times, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent to obtain the crude product, the crude product was separated and purified using 200-300 mesh silica gel (PE:EA = 20:1) to obtain colorless oil S10 (molecular weight 452.20; 286 mg, total yield 77%).

[0091] Synthesis Example Two: Synthesis of Compound F1

[0092]

[0093] The starting material S11 (100 mg, 0.23 mmol) was added to a 100 mL single-necked flask, followed by palladium on carbon (30 mg, 30%), ethyl acetate (2 mL), anhydrous ethanol (2 mL), the reaction flask was deoxygenated using an argon-filled balloon, then an air balloon was inserted into the rubber stopper, and triethylsilane (350 μL, 2.3 mmol) was slowly added dropwise to the reaction flask, which was stirred at room temperature for 15 min, TLC detection until the starting material was completely reacted, and then 100-200 mesh silica gel was added to the reaction mixture after partial solvent was removed by reduced pressure concentration, and 200-300 mesh silica gel was used for separation and purification (PE:EA = 6:1) to obtain a yellowish powder F1 (75 mg, yield 95%). Molecular formula is C 23 H 20 O3, molecular weight 344.14. 1 H NMR (600 MHz, CDC13) δ 9.50 (d, J = 10.1 Hz, 1H), 7.79 (d, J = 9.2 Hz, 1H), 7.52 (d, J = 9.2 Hz, 1H), 7.21 (t, J = 7.6 Hz, 2H), 7.17-7.10 (m, 5H), 6.94 (s, 1H), 4.96 (s, 1H), 4.48 (s, 2H), 4.15 (s, 3H), 3.97 (s, 3H). ESI HRMS m / z 345.1490 [M+H] + (Calcd for C 23 H 21 O3 + ,345.1491)。

[0094] Synthesis Example Three: Synthesis of Compound EQF1

[0095]

[0096] The starting material S11 (147 mg, 0.33 mmol) was added to a 100 mL single-necked flask, followed by palladium on carbon (29 mg, 20%), palladium hydroxide (29 mg, 20%) ethyl acetate (10 mL), anhydrous ethanol (10 mL), hydrogen was introduced at 60°C for 48 h, TLC detection until the starting material was completely reacted, and then 100-200 mesh silica gel was added to the reaction mixture after partial solvent was removed by reduced pressure concentration, and 200-300 mesh silica gel was used for separation and purification (PE:EA = 6:1) to obtain white powder EQF1 (102 mg, yield 90%). Molecular formula is C 23 H 22 O3, molecular weight 346.14. 1H NMR (600 MHz, CDC13) δ 8.10 (d, J = 8.6 Hz, 1H), 7.24-7.18 (m, 2H), 7.18-7.06 (m, 3H), 6.71 (dd, J = 8.6, 2.8 Hz, 1H), 6.66 (d, J = 2.8 Hz, 1H), 6.54 (s, 1H), 4.69 (s, 1H), 4.10 (s, 2H), 3.91 (s, 3H), 2.69-2.62 (m, 2H), 2.62-2.55 (m, 2H). ESI HRMS m / z 347.1651 [M+H] + (Calcd for C 23 H 23 O3 + ,347.1647)。

[0097] Synthesis Example Four: Synthesis of Compound F2, EQF2

[0098] F2 and EQF2 can be synthesized by replacing benzyl bromide with p-benzyloxy-protected benzyl bromide in the synthesis of key intermediate S7, and then following the procedures for the synthesis of F1 and EQF1.

[0099]

[0100] Compound F2: light yellow powder (20 mg, overall yield 51%). Molecular Formula: C 23 H 20 O4, Molecular Weight: 360.14. 1 H NMR (600 MHz, CDC13) δ 9.49 (d, J = 9.1 Hz, 1H), 7.79 (d, J = 9.3 Hz, 1H), 7.53 (d, J = 9.3 Hz, 1H), 7.19-7.13 (m, 2H), 7.00 (d, J = 8.3 Hz, 2H), 6.93 (s, 1H), 6.67 (d, J = 8.4 Hz, 2H), 4.39 (s, 2H), 4.15 (s, 3H), 3.97 (s, 3H). ESI HRMS m / z 361.1447 [M+H] + (Calcd for C 23 H 21 O4 + ,361.1440)。

[0101] Compound EQF2: light yellow powder (6 mg, yield 90%). Molecular Formula: C 23 H 22 O4, Molecular Weight: 362.15. 1HNMR (600 MHz, CDC13) δ 8.09 (d, J = 8.6 Hz, 1H), 7.01-6.94 (m, 2H), 6.73-6.63 (m, 4H), 6.53 (s, 1H), 4.01 (s, 2H), 3.91 (s, 3H), 3.85 (s, 3H), 2.67-2.62 (m, 2H), 2.59 (dd, J = 8.7, 4.1 Hz, 2H).

[0102] Synthesis Example Five: Synthesis of Compound F5, EQF5

[0103]

[0104] F5 and EQF5 can be synthesized by using 4-methoxy-phenylboronic acid instead of 4-benzyloxy-phenylboronic acid in the synthesis of key intermediate S4, and using 4-benzyloxybenzyl bromide instead of benzyl bromide in the synthesis of key intermediate S7, then following the synthetic procedures of Fl and EQFl.

[0105] Compound F5: light yellow powder (60 mg, overall yield 51%). Molecular Formula: C 24 H 22 O4, Molecular Weight: 374.15. 1 HNMR (600 MHz, CDC13) δ 9.50 (d, J = 9.3 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.59 (d, J = 9.2 Hz, 1H), 7.25-7.20 (m, 1H), 7.19 (s, 1H), 7.04-6.98 (m, 2H), 6.93 (s, 1H), 6.71-6.64 (m, 2H), 4.40 (s, 2H), 4.15 (s, 3H), 3.97 (s, 3H), 3.94 (s, 3H). 、 ESI HRMS m / z 375.1591 [M+H] + (Calcd for C 24 H 23 O4 + , 375.1595).

[0106] Compound EQF5: light yellow powder (18 mg, overall yield 90%). Molecular Formula: C 24 H 24 O4, Molecular Weight: 376.17. 1H NMR (600 MHz, CDC13) δ 8.15 (d, J = 8.7 Hz, 1H), 7.00-6.95 (m, 2H), 6.80 (dd, J = 8.7, 2.8 Hz, 1H), 6.74 (d, J = 2.8 Hz, 1H), 6.71-6.66 (m, 2H), 6.54 (s, 1H), 4.01 (s, 2H), 3.91 (s, 3H), 3.85 (s, 3H), 3.83 (s, 3H), 2.65 (qq, J = 7.3, 3.5 Hz, 4H). ESI HRMS m / z 377.1760 [M+H] + (Calcd for C 24 H 25 O4 + ,377.1753)。

[0107] Synthesis Example Six: Synthesis of compounds F7, EQF7

[0108] F7 and EQF7 can be synthesized by using 4-fluorobenzyl bromide instead of benzyl bromide in the synthesis of key intermediate S7, and then following the synthetic procedures of F1 and EQF1.

[0109]

[0110] White powder (35 mg, total yield 43%). Molecular formula: C 23 H 19 FO3, Molecular weight: 362.13. 1 H NMR (600 MHz, CDC13) δ 9.49 (d, J = 9.0 Hz, 1H), 7.75 (d, J = 9.2 Hz, 1H), 7.53 (dd, J = 9.0, 1.4 Hz, 1H), 7.20-7.13 (m, 2H), 7.11-7.06 (m, 2H), 6.93 (s, 1H), 6.90-6.86 (m, 2H), 4.43 (s, 2H), 4.15 (s, 3H), 3.97 (s, 3H). ESI HRMS m / z 363.1393 [M+H] + (Calcd for C 23 H 20 O3F + ,363.1396)。

[0111] Compound EQF7: White powder (10 mg, yield 81%). Molecular formula: C 23 H 21 O3F, Molecular weight: 364.15. 1H NMR (500 MHz, CDC13) δ 8.09 (d, J = 8.6 Hz, 1H), 7.07-7.03 (m, 2H), 6.91-6.87 (m, 2H), 6.71 (dd, J = 8.6, 2.8 Hz, 1H), 6.67 (d, J = 2.7 Hz, 1H), 6.54 (s, 1H), 4.04 (s, 2H), 3.91 (s, 3H), 3.85 (s, 3H), 2.65-2.61 (m, 2H), 2.59 (q, J = 3.9, 3.1 Hz, 2H). ESI HRMS m / z 365.1556 [M + H] + (Calcd for C 23 H 22 O3F + , 365.1553).

[0112] Synthesis Example Seven: Synthesis of Compound F8, EQF8

[0113] F8 and EQF8 can be synthesized by using p-methylbenzyl bromide instead of benzyl bromide in the synthesis of key intermediate S7, and then following the synthetic procedures of Fl and EQFl.

[0114]

[0115] Compound F8: white powder (35 mg, overall yield 56%). Molecular Formula: C 24 H 22 O3, Molecular Weight: 358.16. 1 H NMR (500 MHz, CDC13) δ 9.58-9.41 (m, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.51 (d, J = 9.2 Hz, 1H), 7.16-7.13 (m, 2H), 7.03 (d, J = 4.1 Hz, 4H), 6.93 (s, 1H), 4.44 (s, 2H), 4.15 (s, 3H), 3.96 (s, 3H), 2.27 (s, 3H). ESI HRMS m / z 359.1642 [M + H] + (Calcd for C 24 H 23 O3 + , 359.1647).

[0116] Compound EQF8: white powder (10 mg, yield 89%). Molecular Formula: C 24 H 24 O3, Molecular Weight: 360.17. 1H NMR (500 MHz, CDC13) δ 8.09 (d, J = 8.6 Hz, 1H), 7.01 (q, J = 8.2 Hz, 4H), 6.71 (dd, J = 8.6, 2.8 Hz, 1H), 6.66 (d, J = 2.8 Hz, 1H), 6.53 (s, 1H), 4.05 (s, 2H), 3.91 (s, 3H), 3.84 (s, 3H), 2.67-2.62 (m, 2H), 2.62-2.57 (m, 2H), 2.28 (s, 3H). ESI HRMS m / z 361.1797 [M+H] + (Calcd for C 24 H 25 O3 + ,361.1804.

[0117] Synthesis Example Eight: Synthesis of Compound F11, EQF11

[0118] F11 and EQF11 can be synthesized by using p-trifluoromethylbenzyl bromide instead of benzyl bromide in the synthesis of key intermediate S7, and then following the synthetic procedures of F1 and EQF1.

[0119]

[0120] Compound F11: white powder (60 mg, total yield 48%). Molecular Formula: C 24 H 19 F3O3, Molecular Weight: 412.13. 1 HNMR (500 MHz, CDC13) δ 9.52-9.47 (m, 1H), 7.71 (d, J = 9.3 Hz, 1H), 7.54 (d, J = 9.2 Hz, 1H), 7.45 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.0 Hz, 3H), 7.17 (d, J = 8.2 Hz, 2H), 6.94 (s, 1H), 4.51 (s, 2H), 4.16 (s, 3H), 3.97 (s, 3H). ESI HRMS m / z 413.1362 [M+H] + (Calcd for C 24 H 20 O3F3 + ,413.1365).

[0121] Compound EQF11: white powder (14 mg, yield 91%). Molecular Formula: C 24 H 21 F3O3, Molecular Weight: 414.14. 1H NMR (500 MHz, CDC13) δ 8.10 (d, J = 8.6 Hz, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 6.72 (dd, J = 8.6, 2.8 Hz, 1H), 6.67 (d, J = 2.7 Hz, 1H), 6.55 (s, 1H), 4.14 (s, 2H), 3.92 (s, 3H), 3.85 (s, 3H), 2.61 (s, 4H). ESI HRMS m / z 415.1524 [M + H] + (Calcd for C 24 H 22 O3F3 + ,415.1521).

[0122] Synthesis Example Nine: Synthesis of Compound F16, EQF16

[0123] F16 and EQF16 can be synthesized by using 3,4-methylenedioxybenzyl bromide instead of benzyl bromide in the synthesis of key intermediate S7, and then following the synthetic procedures of Fl and EQFl.

[0124]

[0125] Compound F16: light yellow powder (100 mg, total yield 45%). Molecular Formula: C 24 H 20 O5, Molecular Weight: 388.13. 1 H NMR (500 MHz, CDC13) δ 9.47 (d, J = 10.1 Hz, 1H), 7.77 (d, J = 9.2 Hz, 1H), 7.52 (d, J = 9.2 Hz, 1H), 7.18 - 7.12 (m, 2H), 6.91 (s, 1H), 6.68 - 6.61 (m, 3H), 5.84 (d, J = 1.8 Hz, 2H), 4.38 (s, 2H), 4.13 (s, 3H), 3.97 (s, 3H). ESI HRMS m / z 389.1391 [M + H] + (Calcd for C 24 H 21 O5 + ,389.1389).

[0126] Compound EQF16: light yellow powder (20 mg, total yield 89%). Molecular Formula: C 24 H 22 O5, Molecular Weight: 390.15. 1H NMR (600 MHz, CDC13) δ 8.11 (d, J = 8.6 Hz, 1H), 6.76-6.71 (m, 1H), 6.71-6.67 (m, 2H), 6.65-6.58 (m, 2H), 6.56 (s, 1H), 5.90 (s, 2H), 4.02 (s, 2H), 3.93 (s, 3H), 3.89 (s, 4H), 2.67 (dt, J = 7.3, 2.6 Hz, 2H), 2.63 (dd, J = 9.4, 5.1 Hz, 2H). ESI HRMS m / z 391.1539 [M+H] + (Calcd for C 24 H 23 O5 + , 391.1545).

[0127] Synthesis Example Ten: Synthesis of Compound F21, EQF21

[0128] F21 and EQF21 can be synthesized by using 4-trifluoromethoxy-phenylboronic acid instead of 4-benzyloxy-phenylboronic acid in the synthesis of key intermediate S4, and using p-trifluoromethylbenzyl bromide instead of benzyl bromide in the synthesis of key intermediate S7, then following the synthetic procedures of Fl and EQFl.

[0129]

[0130] Compound F21: white powder (63 mg, overall yield 55%). Molecular Formula: C 25 H 18 F6O3, Molecular Weight: 480.12. 1 H NMR (500 MHz, CDC13) δ 9.63 (d, J = 9.5 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.65-7.60 (m, 2H), 7.45 (dd, J = 7.8, 2.9 Hz, 3H), 7.24 (d, J = 8.0 Hz, 2H), 6.97 (s, 1H), 4.53 (s, 2H), 4.18 (s, 3H), 4.00 (s, 3H). ESI HRMS m / z 481.1238 [M+H] + (Calcd for C 25 H 19 O3F6 + , 481.1238).

[0131] Compound EQF21: white powder (15 mg, yield 83%). Molecular Formula: C 25 H 20 F6O3, Molecular Weight: 482.13. 1H NMR (600 MHz, CDC13) δ 8.21 (d, J = 8.7 Hz, 1H), 7.48-7.44 (m, 2H), 7.22-7.18 (m, 2H), 7.07 (ddd, J = 8.8, 2.8, 1.2 Hz, 1H), 7.02 (dd, J = 2.7, 1.2 Hz, 1H), 6.55 (s, 1H), 4.13 (s, 2H), 3.93 (s, 3H), 3.86 (s, 3H), 2.64 (s, 2H), 2.63 (s, 2H). ESI HRMS m / z 483.1393 [M + H] + (Calcd for C 25 H 21 O3F6 + ,483.1395)。

[0132] Synthesis Example Eleven: Synthesis of Compound F24, EQF24

[0133] F24 and EQF24 can be synthesized by using phenylboronic acid instead of 4-benzyloxy-phenylboronic acid in the synthesis of key intermediate S4, and using p-trifluoromethylbenzyl bromide instead of benzyl bromide in the synthesis of key intermediate S7, and then following the synthetic procedures of Fl and EQFl.

[0134]

[0135] Compound F24: white powder (140 mg, overall yield 55%). Molecular Formula: C 24 H 19 F3O2, Molecular Weight: 396.13. 1 H NMR (500 MHz, CDC13) δ 9.60 (dd, J = 8.6, 1.0 Hz, 1H), 7.82 (dd, J = 7.9, 1.6 Hz, 1H), 7.74 (d, J = 9.1 Hz, 1H), 7.68 (d, J = 9.1 Hz, 1H), 7.63 (ddd, J = 8.7, 6.9, 1.6 Hz, 1H), 7.53 (ddd, J = 7.9, 6.9, 1.2 Hz, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.29-7.23 (m, 2H), 6.96 (s, 1H), 4.54 (s, 2H), 4.18 (s, 3H), 3.99 (s, 3H). ESI HRMS m / z 397.1414 [M + H] + (Calcd for C 24 H 20 O2F3 + ,397.1415)。

[0136] Compound EQF24: white powder (20 mg, 87% yield). Molecular Formula: C 24 H 21 F3O2, Molecular Weight: 398.15. 1 HNMR (500 MHz, CDC13) δ 8.18 (dd, J = 7.9, 1.2 Hz, 1H), 7.44 (d, J = 8.1 Hz, 2H), 7.22-7.17 (m, 3H), 7.13 (ddd, J = 17.4, 7.4, 1.5 Hz, 2H), 6.53 (s, 1H), 4.11 (s, 2H), 3.89 (s, 3H), 3.83 (s, 3H), 2.65-2.58 (m, 4H). ESI HRMS m / z 399.1572 [M + H] + (Calcd for C 24 H 22 O2F3 + , 399.1572).

[0137] Synthesis Example Twelve: Synthesis of Compound F26, EQF26

[0138] F26 and EQF26 can be synthesized by using 4-fluorophenylboronic acid instead of 4-benzyloxy-phenylboronic acid in the synthesis of key intermediate S4, and using p-trifluoromethylbenzyl bromide instead of benzyl bromide in the synthesis of key intermediate S7, then following the synthetic procedures of Fl and EQFl.

[0139]

[0140] Compound F26: yellow powder (110 mg, 60% overall yield). Molecular Formula: C 24 H 18 F4O2, Molecular Weight: 414.12. 1 HNMR (500 MHz, CDC13) δ 9.60 (dd, J = 9.6, 5.8 Hz, 1H), 7.77 (d, J = 9.2 Hz, 1H), 7.60 (d, J = 9.2 Hz, 1H), 7.46 (d, J = 8.0 Hz, 3H), 7.28-7.22 (m, 3H), 6.96 (s, 1H), 4.52 (s, 2H), 4.18 (s, 3H), 3.99 (s, 3H). ESI HRMS m / z 415.1319 [M + H] + (Calcd for C 24 H 19 O2F4 + , 415.1321).

[0141] Compound EQF26: light yellow powder (19 mg, 91% yield). Molecular Formula: C24 H 20 F4O2, 416.14. 1 HNMR (500 MHz, CDC13) δ 8.17 (dd, J = 8.8, 5.9 Hz, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.24-7.19 (m, 2H), 6.96-6.86 (m, 2H), 6.56 (s, 1H), 4.14 (s, 2H), 3.93 (s, 3H), 3.87 (s, 3H). ESI HRMS m / z 417.1474 [M + H] + (Calcd for C 24 H 21 O2F4 + , 417.1478).

[0142] Synthesis Example XIII: Synthesis of compound F28, EQF28

[0143] F28 and EQF28 can be synthesized by using 4-trifluoromethylphenylboronic acid instead of 4-benzyloxy-phenylboronic acid in the synthesis of key intermediate S4, and using p-trifluoromethylbenzyl bromide instead of benzyl bromide in the synthesis of key intermediate S7, then following the synthetic procedures of Fl and EQFl.

[0144]

[0145] Compound F28: white powder (145 mg, overall yield 59%). Molecular formula: C 25 H 18 F6O2, 464.12. 1 HNMR (500 MHz, CDC13) δ 9.69 (d, J = 9.0 Hz, 1H), 8.09-8.04 (m, 1H), 7.85-7.75 (m, 2H), 7.70 (d, J = 9.2 Hz, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 6.97 (d, J = 8.2 Hz, 1H), 4.53 (s, 2H), 4.20 (s, 3H), 4.01 (s, 3H). ESI HRMS m / z 465.1292 [M + H] + (Calcd for C 25 H 19 O2F6 + , 465.1289).

[0146] Compound EQF28: white powder (30 mg, yield 90%). Molecular formula: C 25 H 20 F6O2, 466.14.1 HNMR (500 MHz, CDC13) δ 8.27 (d, J = 8.3 Hz, 1H), 7.44 (d, J = 8.1 Hz, 3H), 7.39 (d, J = 2.1 Hz, 1H), 7.18 (d, J = 8.1 Hz, 2H), 6.54 (s, 1H), 4.11 (s, 2H), 3.91 (s, 3H), 3.84 (s, 3H), 2.68-2.64 (m, 2H), 2.63-2.58 (m, 2H). ESI HRMS m / z 467.1448 [M+H] + (Calcd for C 25 H 21 O2F6 + ,467.1446)。

[0147] Synthesis Example XIII: Synthesis of compounds F6, F31

[0148] In the synthesis of key intermediate S7, methyl 4-bromomethyl benzoate is used instead of benzyl bromide, and then the synthesis method of F1 is followed to synthesize F6.

[0149]

[0150] Compound F6: light yellow powder (20 mg, overall yield 38%). Molecular formula: C 25 H 22 O5, molecular weight: 402.15. 1 HNMR (600 MHz, CDC13) δ 9.49 (d, J = 10.2 Hz, 1H), 7.91-7.85 (m, 2H), 7.70 (dd, J = 9.2, 1.3 Hz, 1H), 7.51 (dd, J = 9.1, 1.8 Hz, 1H), 7.20 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 2.6 Hz, 2H), 6.93 (s, 1H), 4.51 (s, 2H), 4.16 (s, 3H), 3.97 (s, 3H), 3.86 (s, 3H). ESI HRMS m / z 403.1543 [M+H] + (Calcd for C 25 H 23 O5 + ,403.1545)。

[0151] In the synthesis of key intermediate S7, ethyl 4-bromomethyl benzoate is used instead of benzyl bromide, and then the synthesis method of F1 is followed to synthesize F31.

[0152]

[0153] Compound F31 : Light yellow powder (5 mg, 40% overall yield). Molecular Formula: C 26 H 24 O5, Molecular Weight: 416.16. 1 HNMR (500 MHz, Methanol-d4) δ 9.44 (d, J = 9.2 Hz, 1H), 7.88-7.83 (m, 2H), 7.71 (d, J = 9.3 Hz, 1H), 7.51 (d, J = 9.2 Hz, 1H), 7.24 (d, J = 8.2 Hz, 2H), 7.15-7.05 (m, 3H), 4.50 (s, 2H), 4.31 (q, J = 7.1 Hz, 2H), 4.17 (s, 3H), 4.00 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H). ESI HRMS m / z 417.1701 [M+H] + (Calcd for C 26 H 25 O5 + , 417.1702).

[0154] Synthesis Example Fourteen: Synthesis of Compound F33

[0155] In the synthesis of key intermediate S4, 4-(tert-butoxycarbonyl)phenylboronic acid was used instead of 4-benzyloxy-phenylboronic acid; in the synthesis of key intermediate S7, methyl 4-bromomethylbenzoate was used instead of benzyl bromide, then following the synthetic procedure of Fl, F33 was synthesized.

[0156]

[0157] Compound F33: White powder (20 mg, 35% overall yield). Molecular Formula: C 25 H 19 F3O4, Molecular Weight: 440.12. 1 HNMR (500 MHz, Acetone-d6) δ 9.67 (d, J = 9.0 Hz, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.16 (dd, J = 9.1, 1.9 Hz, 1H), 7.93 (d, J = 9.3 Hz, 1H), 7.84 (d, J = 9.2 Hz, 1H), 7.55 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 8.1 Hz, 2H), 7.25 (s, 1H), 4.57 (s, 2H), 4.26 (s, 3H), 4.06 (s, 3H). ESI HRMS m / z 441.1311 [M+H] + (Calcd for C 25 H 20 O4F3 +,441.1314).

[0158] Synthesis Example Fifteen: Synthesis of compound F20

[0159] Compound F6 (21 mg, 0.053 mmol) was dissolved in 4 ml of methanol, 1 ml of aqueous LiOH (11.1 mg of lithium hydroxide monohydrate dissolved in 1 ml of distilled water) was added, and the reaction solution was heated to reflux for 5 hours until the starting material completely disappeared. After adding 106 μL of 2M aqueous hydrochloric acid to the reaction solution to neutralize the excess LiOH, the reaction solution was concentrated under reduced pressure to remove the organic solvent and water, and then dissolved in acetone and filtered. The filtrate was dried by evaporation to obtain compound F20.

[0160]

[0161] Compound F20: yellow powder (20 mg, yield 98%). Molecular formula: C 24 H 20 O5, molecular weight: 388.13. 1 H NMR (800 MHz, Acetone-d6) δ 9.48 (d, J = 9.3 Hz, 1H), 8.55 (s, 1H), 7.91-7.87 (m, 2H), 7.79 (d, J = 9.2 Hz, 1H), 7.57 (d, J = 9.2 Hz, 1H), 7.32-7.29 (m, 2H), 7.22 (d, J = 2.8 Hz, 1H), 7.19-7.15 (m, 2H), 4.54 (s, 2H), 4.21 (s, 3H), 4.03 (s, 3H). ESI HRMS m / z 389.1392 [M+H] + (Calcd for C 24 H 21 O5 + ,389.1389).

[0162] Synthesis Example Sixteen: Synthesis of compound F3, EQF3

[0163]

[0164] The starting material F1 (50 mg, 0.14 mmol) was added to a 25 mL single-necked flask, followed by the addition of super-dry dichloromethane (3 mL), and 1 mol / L boron tribromide (dissolved in dichloromethane) (1.4 mL, 1.4 mmol) was slowly added dropwise at -78 °C. The stirring was continued at -78 °C for 30 min, and then the temperature was raised to room temperature for 9 h. TLC detection showed that all the starting materials were completely reacted. The reaction was quenched by slowly adding methanol at -78 °C, and after the removal of part of the solvent under reduced pressure, 100-200 mesh silica gel was added to the sample, and 200-300 mesh silica gel was used for separation and purification (PE:EA = 2:1) to obtain brown yellow powder F3, 28 mg (yield 64%).

[0165] Referring to the above method of synthesizing F3, EQF3 can be synthesized from EQF1.

[0166] Compound F3: Brown yellow powder (5 mg, yield 48%). Molecular formula: C 21 H 16 O3, molecular weight: 316.11. 1 H NMR (600 MHz, CDC13) δ 9.48 (d, J = 9.1 Hz, 1H), 7.79 (d, J = 9.2 Hz, 1H), 7.56 (d, J = 9.2 Hz, 1H), 7.24 (t, J = 7.7 Hz, 2H), 7.17 (ddt, J = 8.9, 6.4, 3.1 Hz, 5H), 6.63 (s, 1H), 5.62 (s, 1H), 4.90 (d, J = 11.8 Hz, 2H), 4.43 (s, 2H). ESI HRMS m / z 317.1175 [M+H] + (Calcd for C 21 H 17 O3 + , 317.1178).

[0167] Compound EQF3: Brown yellow powder (83 mg, yield 80%). Molecular formula: C 21 H 18 O3, molecular weight: 318.13. 1 H NMR (600 MHz, CDC13) δ 7.88 (dd, J = 8.0, 0.9 Hz, 1H), 7.27-7.22 (m, 2H), 7.19-7.12 (m, 3H), 6.73 (d, J = 8.0 Hz, 2H), 6.33 (s, 1H), 5.40 (s, 1H), 5.06 (s, 1H), 4.97 (s, 1H), 4.05 (s, 2H), 2.68-2.58 (m, 4H). ESI HRMS m / z 319.1340 [M+H] +(Calcd for C 21 H 19 O3 + ,319.1334)。

[0168] Synthesis Example Seventeen: Synthesis of Compound F4, EQF4

[0169] Referring to the above method of synthesizing F3, F4, EQF4, YS36 can be synthesized from F2, EQF2, respectively.

[0170]

[0171] Compound F4: Brown yellow powder (30 mg, yield 69%). Molecular formula: C 21 H 16 O4, molecular weight: 332.10. 1 H NMR (600 MHz, Methanol-d4) δ 9.54 (d, J = 9.3 Hz, 1H), 7.67 (d, J = 9.3 Hz, 1H), 7.39 (d, J = 9.2 Hz, 1H), 7.06 (d, J = 2.8 Hz, 1H), 7.02 (dd, J = 9.3, 2.8 Hz, 1H), 6.98-6.95 (m, 2H), 6.76 (s, 1H), 6.61-6.59 (m, 2H), 4.25 (s, 2H). ESI HRMS m / z 333.1124 [M+H] + (Calcd for C 21 H 17 O4 + ,333.1127)。

[0172] Compound EQF4: Brown yellow powder (24 mg, yield 73%). Molecular formula: C 21 H 18 O4, molecular weight: 334.12. 1 H NMR (800 MHz, Methanol-d4) δ 8.11 (d, J = 8.6 Hz, 1H), 6.97-6.93 (m, 2H), 6.66-6.58 (m, 4H), 6.39 (s, 1H), 3.92 (s, 2H), 2.55 (dt, J = 6.8, 4.6 Hz, 2H), 2.51 (dd, J = 8.4, 4.5 Hz, 2H).

[0173] Compound YS36: Brown yellow powder (8 mg, yield 24%). Molecular formula: C 22 H 20 O4, molecular weight: 348.12. 1HNMR (600 MHz, Methanol-d4) δ 7.97 (d, J = 8.5 Hz, 1H), 6.94 (d, J = 8.6 Hz, 2H), 6.64 (d, J = 8.6 Hz, 2H), 6.61 (dd, J = 8.1, 2.7 Hz, 1H), 6.59 (d, J = 2.7 Hz, 1H), 6.51 (s, 1H), 3.93 (s, 2H), 3.80 (s, 3H), 2.53 and 2.47 (m, each 2H).

[0174] Synthesis Example Eighteen: Synthesis of compounds F12, EQF12, F13, EQF13, EQF14

[0175] Referring to the above method of synthesizing F3, F12, EQF12, F13, EQF13 can be synthesized from F11, EQF11, respectively. EQF14 can be obtained from EQF11 as well.

[0176]

[0177] Compound F12: yellow powder (18 mg, yield 46%). Molecular formula: C 22 H 15 F3O3, molecular weight: 384.10. 1 HNMR (500 MHz, CDC13) δ 9.48 (d, J = 8.9 Hz, 1H), 7.70 (d, J = 9.2 Hz, 1H), 7.57 (d, J = 9.2 Hz, 1H), 7.47 (d, J = 7.9 Hz, 2H), 7.28 (d, J = 7.7 Hz, 2H), 7.18 (d, J = 9.2 Hz, 2H), 6.63 (s, 1H), 5.83 (s, 1H), 5.03 (s, 2H), 4.48 (s, 2H). ESI HRMS m / z 385.1059 [M+H] + (Calcd for C 22 H 16 O3F3 + , 385.1052).

[0178] Compound F13: light yellow powder (16 mg, yield 43%). Molecular formula: C 23 H 17 F3O3, molecular weight: 398.11. 1H NMR (600 MHz, CDC13) δ 9.49 (d, J = 9.2 Hz, 1H), 7.71 (d, J = 9.2 Hz, 1H), 7.57 (d, J = 9.1 Hz, 1H), 7.47 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.19-7.15 (m, 2H), 6.76 (s, 1H), 4.50 (s, 2H), 4.11 (s, 3H). ESI HRMS m / z 399.1209 [M + H] + (Calcd for C 23 H 18 O3F3 + , 399.1208).

[0179]

[0180] Compound EQF12: Light yellow powder (14 mg, yield 40%). Molecular Formula: C 22 H 17 F3O3, Molecular Weight: 386.11. 1 H NMR (500 MHz, CDC13) δ 7.86 (dd, J = 7.8, 1.1 Hz, 1H), 7.49 (d, J = 8.1 Hz, 2H), 7.27 (s, 1H), 7.25 (s, 1H), 6.75 (d, J = 7.8 Hz, 2H), 6.35 (s, 1H), 4.11 (s, 2H), 2.61 (s, 4H). ESI HRMS m / z 387.1207 [M + H] + (Calcd for C 22 H 18 O3F3 + , 387.1208).

[0181] Compound EQF13: Light yellow powder (11 mg, yield 31%). Molecular Formula: C 23 H 19 F3O3, Molecular Weight: 400.13. 1 H NMR (500 MHz, CDC13) δ 8.08 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 8.1 Hz, 2H), 7.26 (s, 1H), 7.25 (s, 1H), 6.71 (dd, J = 8.6, 2.8 Hz, 1H), 6.68 (d, J = 2.7 Hz, 1H), 6.43 (s, 1H), 4.13 (s, 2H), 3.86 (s, 3H), 2.63 (s, 4H). ESI HRMS m / z 401.1364 [M + H] + (Calcd for C23 H 20 O3F3 + ,401.1365)。

[0182] Compound EQF14: light yellow powder (9 mg, yield 25%). Molecular formula: C 23 H 19 F3O3, molecular weight: 400.13. 1 HNMR (500 MHz, CDC13) δ 7.86 (d, J = 8.2 Hz, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 6.79-6.72 (m, 2H), 6.46 (s, 1H), 4.11 (s, 2H), 3.80 (s, 3H), 2.61 (s, 4H). ESI HRMS m / z 401.1364 [M+H] + (Calcd for C 23 H 20 O3F3 + ,401.1365)。

[0183] Synthesis Example Nineteen: Synthesis of compounds F22, F29, F30

[0184] Referring to the above method of synthesizing F3, F22, F29, F30 can be synthesized from F21, F24, F28, respectively.

[0185]

[0186] Compound F22: light yellow powder (8 mg, yield 75%). Molecular formula: C 23 H 14 F6O3, molecular weight: 452.08. 1 HNMR (500 MHz, CDC13) δ 9.63 (d, J = 9.4 Hz, 1H), 7.78 (d, J = 9.2 Hz, 1H), 7.64 (d, J = 12.5 Hz, 2H), 7.48 (d, J = 8.4 Hz, 3H), 7.27 (d, J = 7.8 Hz, 2H), 6.68 (s, 1H), 6.09 (s, 1H), 5.27 (s, 2H), 4.50 (s, 2H). ESI HRMS m / z 453.0923 [M+H] + (Calcd for C 23 H 15 O3F6 + ,453.0925)。

[0187]

[0188] Compound F29: Light yellow powder (14 mg, yield 69%). Molecular formula: C 22 H 15 F3O2, Molecular weight: 368.10. 1 HNMR (500 MHz, CDC13) δ 9.55 (d, J = 8.7 Hz, 1H), 7.82 (dd, J = 7.9, 1.5 Hz, 1H), 7.70 (q, J = 9.2 Hz, 2H), 7.61 (ddd, J = 8.6, 6.8, 1.6 Hz, 1H), 7.52 (t, J = 7.3 Hz, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.1 Hz, 2H), 6.65 (s, 1H), 4.49 (s, 2H). ESI HRMS m / z 369.1106 [M + H] + (Calcd for C 22 H 16 O2F3 + , 369.1102).

[0189]

[0190] Compound F30: Light yellow powder (9 mg, yield 65%). Molecular formula: C 23 H 14 F6O2, Molecular weight: 436.09. 1 HNMR (500 MHz, CDC13) δ 9.71 (d, J = 9.1 Hz, 1H), 8.09 - 8.05 (m, 1H), 7.84 - 7.76 (m, 2H), 7.72 (d, J = 9.2 Hz, 1H), 7.48 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 6.71 (s, 1H), 4.50 (s, 2H). ESI HRMS m / z 437.0980 [M + H] + (Calcd for C 23 H 15 O2F6 + , 437.0976).

[0191] Synthesis Example Twenty: Synthesis of Compound F10, EQF10

[0192] Compound F5 (18.7 mg, 0.05 mmol) was dissolved in dry acetone (5 mL), dimethyl sulfate (9.5 μL, 12.6 mg, 0.1 mmol) and anhydrous K2CO3(13.6 mg, 0.1 mmol) were added successively, the reaction was stirred at room temperature overnight, TLC showed that all the starting material was consumed, water was added to dissolve K2CO3completely, then the solvent was removed by concentration under reduced pressure, 100-200 mesh silica gel was added to the sample, and 200-300 mesh silica gel was used for separation and purification to obtain brown yellow powder F10.

[0193] Referring to the same method, EQF10 can be obtained from EQF5.

[0194]

[0195] Compound F10: white powder (9 mg, yield 89%). Molecular formula: C 25 H 24 O4, molecular weight: 388.17. 1 H NMR (500 MHz, CDC13) δ 9.50 (d, J = 9.4 Hz, 1H), 7.81 (d, J = 9.2 Hz, 1H), 7.59 (d, J = 9.2 Hz, 1H), 7.22 (dd, J = 9.3, 2.9 Hz, 1H), 7.19 (d, J = 2.9 Hz, 1H), 7.07-7.04 (m, 2H), 6.93 (s, 1H), 6.76-6.74 (m, 2H), 4.41 (s, 2H), 4.15 (s, 3H), 3.97 (s, 3H), 3.94 (s, 3H), 3.73 (s, 3H). ESI HRMS m / z 389.1572 [M+H] + (Calcd for C 25 H 25 O4 + , 389.1573).

[0196] Compound EQF10: white powder (10 mg, yield 91%). Molecular formula: C 25 H 26 O4, molecular weight: 390.18. 1HNMR (500 MHz, CDC13) δ 8.14 (d, J = 8.7 Hz, 1H), 7.05-7.00 (m, 2H), 6.82-6.71 (m, 4H), 6.54 (s, 1H), 4.02 (s, 2H), 3.91 (s, 3H), 3.85 (s, 3H), 3.82 (s, 3H), 3.75 (s, 3H), 2.68-2.64 (m, 2H), 2.63 (d, J = 2.8 Hz, 2H). ESI HRMS m / z 391.1914 [M+H] + (Calcd for C 25 H 27 O4 + , 391.1909).

[0197] Synthesis Example Twenty-one: Synthesis of Compound F15, EQF15

[0198] Referring to the method of synthesis of F10, EQF10, F15, EQF15 can be synthesized from F1, EQF1, respectively.

[0199]

[0200] Compound F15: white powder (24 mg, yield 89%). Molecular formula: C 24 H 22 O3, molecular weight: 358.16. 1 H NMR (500 MHz, CDC13) δ 9.55 (d, J = 9.4 Hz, 1H), 7.84 (d, J = 9.2 Hz, 1H), 7.62 (d, J = 9.2 Hz, 1H), 7.29-7.26 (m, 1H), 7.25 (s, 1H), 7.23 (q, J = 3.0, 2.5 Hz, 2H), 7.21-7.14 (m, 3H), 6.96 (s, 1H), 4.52 (s, 2H), 4.17 (s, 3H), 4.00 (s, 3H), 3.97 (s, 3H). ESI HRMS m / z 359.1645 [M+H] + (Calcd for C 24 H 23 O3 + , 359.1647).

[0201] Compound EQF15: light yellow powder (38 mg, yield 92%). Molecular formula: C 24 H 24 O3, molecular weight: 360.17. 1H NMR (500 MHz, CDC13) δ 8.20 (d, J = 8.7 Hz, 1H), 7.26 (dd, J = 8.6, 6.6 Hz, 2H), 7.22 - 7.13 (m, 3H), 6.84 (dd, J = 8.7, 2.8 Hz, 1H), 6.78 (d, J = 2.8 Hz, 1H), 6.59 (s, 1H), 4.15 (s, 2H), 3.96 (s, 3H), 3.89 (s, 3H), 3.86 (s, 3H), 2.69 (th, J = 7.7, 3.7 Hz, 4H). ESI HRMS m / z 361.1804 [M+H] + (Calcd for C 24 H 25 O3 + , 361.1804).

[0202] Synthesis Example Twenty-two: Synthesis of Compound F18, EQF18

[0203] Referring to the method of synthesis of F10, EQF10, F18, EQF18 can be synthesized from F16, EQF16, respectively.

[0204]

[0205] Compound F18: light yellow powder (19 mg, yield 80%). Molecular formula: C 25 H 22 O5, molecular weight: 402.15. 1 H NMR (500 MHz, CDC13) δ 9.50 (d, J = 9.4 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.72 (dd, J = 5.7, 3.3 Hz, 1H), 7.60 (d, J = 9.2 Hz, 1H), 7.53 (dd, J = 5.6, 3.3 Hz, 1H), 7.23 (dd, J = 9.4, 2.8 Hz, 1H), 7.20 (d, J = 2.9 Hz, 1H), 6.93 (s, 1H), 6.64 (s, 1H), 5.85 (s, 2H), 4.39 (s, 2H), 4.15 (s, 3H), 3.98 (s, 3H), 3.94 (s, 3H). ESI HRMS m / z 403.1545 [M+H] + (Calcd for C 25 H 23 O5 + , 403.1548).

[0206] Compound EQF18: white powder (15 mg, yield 75%). Molecular formula: C 25 H 24O5, 404.16. 1 HNMR (500 MHz, CDC13) δ 8.13 (d, J = 8.8 Hz, 1H), 6.79 (dd, J = 8.8, 2.8 Hz, 1H), 6.73 (d, J = 2.8 Hz, 1H), 6.66 (d, J = 7.9 Hz, 1H), 6.61 (d, J = 1.7 Hz, 1H), 6.57 (dd, J = 7.9, 1.7 Hz, 1H), 6.53 (s, 1H), 5.87 (s, 2H), 4.00 (s, 2H), 3.91 (s, 3H), 3.86 (s, 3H), 3.82 (s, 3H), 2.67-2.62 (m, 4H). ESI HRMS m / z 405.1707 [M+H] + (Calcd for C 25 H 25 O5 + , 405.1702).

[0207] Synthesis Example Twenty-Three: Synthesis of Compound F19, EQF19

[0208] Referring to the method of synthesis of F10, EQF10, F19, EQF19 can be synthesized from F11, EQF11, respectively.

[0209]

[0210] Compound F19: white powder (14 mg, yield 83%). Molecular formula: C 25 H 21 F3O3, 426.14. 1 HNMR (600 MHz, CDC13) δ 9.50 (d, J = 9.4 Hz, 1H), 7.72 (d, J = 9.2 Hz, 1H), 7.60 (d, J = 9.2 Hz, 1H), 7.47-7.42 (m, 2H), 7.25-7.23 (m, 3H), 7.19 (d, J = 2.9 Hz, 1H), 6.93 (s, 1H), 4.52 (s, 2H), 4.16 (s, 3H), 3.97 (s, 3H), 3.94 (s, 3H). ESI HRMS m / z 427.1522 [M+H] + (Calcd for C 25 H 22 O3F3 + , 427.1521).

[0211] Compound EQF19: white powder (17 mg, yield 85%). Molecular formula: C 25 H 23F3O3, molecular weight: 428.16. 1 HNMR (600 MHz, CDC13) δ 8.14 (d, J = 8.8 Hz, 1H), 7.49-7.44 (m, 2H), 7.24-7.19 (m, 2H), 6.80 (dd, J = 8.7, 2.9 Hz, 1H), 6.74 (d, J = 2.8 Hz, 1H), 6.55 (s, 1H), 4.14 (s, 2H), 3.92 (s, 3H), 3.85 (s, 3H), 3.82 (s, 3H), 2.62 (dq, J = 4.5, 2.7 Hz, 4H). ESI HRMS m / z 429.1673 [M+H] + (Calcd for C 25 H 24 O3F3 + ,429.1678).

[0212] Synthesis Example Twenty-Four: Synthesis of compound F32

[0213] Referring to the method of synthesis of F10, F32 can be synthesized from F20, respectively.

[0214]

[0215] Compound F32: light yellow powder (20 mg, yield 89%). Molecular formula: C 26 H 24 O5, molecular weight: 416.16. 1 HNMR (600 MHz, CDC13) δ 9.49 (d, J = 9.4 Hz, 1H), 7.90-7.84 (m, 2H), 7.71 (d, J = 9.2 Hz, 1H), 7.57 (d, J = 9.2 Hz, 1H), 7.22 (dd, J = 9.4, 2.9 Hz, 1H), 7.21-7.17 (m, 3H), 6.92 (s, 1H), 4.51 (s, 2H), 4.14 (s, 3H), 3.95 (s, 3H), 3.92 (s, 3H), 3.84 (s, 3H). ESI HRMS m / z 417.1704 [M+H] + (Calcd for C 26 H 25 O5 + ,417.1702).

[0216] Pharmacological Experiment Part

[0217] YS36 series of compounds were screened for activity and structure-activity relationship research using a cell model of palmitic acid-induced accumulation of triglyceride (TG) in hepatocytes, and then verified based on animal experiments.

[0218] Test Example 1: Cell Experiment

[0219] 1. Test method for inhibiting TG accumulation induced by palmitic acid in HepG2 cells:

[0220] Human hepatoma cell line HepG2 cells were cultured in MEM medium containing 10% FBS, and the culture conditions were 37°C, 5% CO2 constant temperature and humidity incubator. When the cell confluence reached 80%, the cells were digested with 0.25% trypsin, the passage ratio was 1:3, and the seeding density was 7x10 4 HepG2 cells were cultured to 80% confluence, and MEM medium containing or not containing 0.1 mM palmitic acid was added, and 10 μM of the compound was added at the final concentration. After 24 h, the culture medium was discarded, and the cells were lysed with lysis buffer. At the end of the experiment, 200 μL of 0.1% Triton X-100 solution was added to each well to lyse the cells, and the cell lysate was transferred to a 1.5 mL EP tube and sonicated. 50 μL of cell lysate was transferred to an enzyme-labeled plate, 80 μL of triglyceride detection enzyme solution was added, and the plate was incubated at 37°C for 15 min. The absorbance value was detected at 546 nm, and the protein concentration was corrected and the triglyceride content was calculated. The results were shown as the average value ± SEM compared with the control group.

[0221] 2. Experimental results: The experimental results are shown in Table 1.

[0222] Table 1 Effect of compounds on TG accumulation induced by palmitic acid (PA) in liver cells

[0223]

[0224]

[0225] Inhibition rate >10% is effective, inhibition rate >15% is effective, and inhibition rate >25% is very effective;

[0226] The in vitro biological activity evaluation experiment showed that YS36, F5, F11, EQF11, F16, F18 and F30 had very good TG accumulation inhibition activity, and most of the compounds had obvious TG accumulation inhibition effect.

[0227] Test Example 2: Animal Experiment Verification

[0228] 1. Method for pharmacodynamic evaluation of YS36 on non-alcoholic fatty liver disease mouse model induced by high-fat diet combined with carbon tetrachloride:

[0229] Male C57 mice, 5-6 weeks old, were given high-fat diet and control feed respectively, and after 8 weeks of induction, CCl4 (0.05 μL / g) was injected intraperitoneally, twice a week, and carbon tetrachloride injection was stopped after 6 weeks; at the same week of starting CCl4 injection, YS36 (20 mg / kg) was given by gavage, once a day, and the administration was continued until the end of the experiment. During the experiment, the body weight and food intake of the mice were recorded daily, and after the experiment, the liver was separated, fixed and embedded in the main leaf, sectioned, stained with hematoxylin-eosin (H&E), and the pathological features of liver steatosis, ballooning degeneration and inflammatory cell infiltration of mice were evaluated.

[0230] 2. Experimental results:

[0231] The results of HE staining of liver sections are shown in Figure 1 The results showed that compared with the model control group, YS36 significantly improved liver steatosis, improved ballooning degeneration, and had a downward trend in inflammatory infiltration, and the NAS score was significantly decreased; the above results suggest that YS36 improves the pathological features of liver steatosis, ballooning degeneration and inflammatory cell infiltration in mice with non-alcoholic steatohepatitis induced by high-fat diet combined with carbon tetrachloride. Compounds such as F5, F11, EQF11, F16, F18 and F30 with obvious in vitro activity as described above all show similar pharmacological activity.

[0232] However, the present disclosure is not limited to the above-mentioned embodiments, i.e., it does not mean that the present disclosure must rely on the above-mentioned embodiments to be implemented. It should be understood by those skilled in the art that any improvement of the present disclosure, equivalent replacement of each raw material of the product of the present disclosure, addition of auxiliary ingredients, selection of specific modes, etc., all fall within the protection scope and disclosure scope of the present disclosure.

[0233] The above describes the preferred embodiments of the present disclosure in detail, but the present disclosure is not limited to the specific details in the above-mentioned embodiments, and within the technical concept range of the present disclosure, various simple modifications can be made to the technical solutions of the present disclosure, and these simple modifications all belong to the protection scope of the present disclosure.

[0234] In addition, it should be noted that each specific technical feature described in the above specific embodiments can be combined in any suitable manner without contradiction, and in order to avoid unnecessary repetition, the present disclosure will not further describe various possible combination manners.

Claims

1. The use of the compound represented by formula (I) in the preparation of drugs for treating diseases related to hepatic lipid metabolism disorders. R 1～ R 5 Each group is independently selected from hydrogen, hydroxyl, halogen atom, methyl, halomethyl, methoxy, ethoxy, carboxyl, and carboxyl C1-3 alkyl ester groups, R 1 and R 5 They can be connected to form a ring structure. It indicates a single or double bond.

2. The application according to claim 1, wherein the compound represented by formula (I) has the structure represented by formula (II), R 2～ R 4 The meaning of the expression is the same as that in equation (I).

3. The application according to claim 1, wherein the compound represented by formula (I) is one of the following specific compounds, 4. The application according to claim 2, wherein the compound represented by formula (II) is one of the following specific compounds, 。 5. A pharmaceutical composition for treating diseases related to hepatic lipid metabolism disorders, characterized in that, Includes the compound represented by formula (I) R 1～ R 5 Each group is independently selected from hydrogen, hydroxyl, halogen atom, methyl, halomethyl, methoxy, carboxyl, and carboxyl C1-3 alkyl ester groups, R 1 and R 5 They can be connected to form a ring structure. It indicates a single or double bond.

6. The pharmaceutical composition according to claim 5, characterized in that, The compound shown in formula (I) has the structure shown in formula (II). R 2 ~R 4 The meaning of the expression is the same as that in equation (I).

7. Compounds with the structure shown in formula (I) R 5 Both are H 8. Compounds with the structure shown in formula (II),

Images