Bicyclol derivative as well as pharmaceutical composition, preparation method and application thereof

Abstract

The invention belongs to the technical field of medicine, and discloses a bicyclol derivative shown as a formula (I) or pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition thereof and application thereof, especially application of the bicyclol derivative in medicines for treating liver diseases.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a new class of bicyclic alcohol derivatives and their salts, pharmaceutical compositions containing them, and their use in drugs for treating liver diseases. Background Technology

[0002] Natural product libraries are rich sources of diverse structural frameworks and bioactive compounds that can be directly applied to the optimization of innovative drug structures. Chronic liver disease is a common and serious threat to human health worldwide, including viral hepatitis, alcoholic hepatitis, non-alcoholic liver disease, autoimmune hepatitis, and drug-induced liver injury. my country is a country with a high prevalence of liver disease. Currently, there are a large number of patients with liver injury and inflammation caused by various factors in my country, mainly viral hepatitis. Statistics show that the direct economic loss in my country due to chronic hepatitis (including later-stage liver fibrosis, cirrhosis, liver cancer, and liver failure) reaches 900 billion RMB annually. In recent years, the incidence of drug-induced liver disease, alcoholic and non-alcoholic fatty liver disease, and autoimmune liver disease has also shown an increasing trend year by year. The search for safe and effective drugs for the prevention and treatment of liver diseases has always been a hot topic of research and development for major research institutes and pharmaceutical companies worldwide. Bicyclol, trade name Baisano, chemical name 4,4'-dimethoxy-5,6,5',6'-dimethylenedioxy-2'-hydroxymethyl-2-methoxycarbonylbiphenyl. The structure of bicyclol is derived from schisandrin, an active ingredient in the traditional Chinese medicine Schisandra chinensis. Studies have found that schisandrin has a significant effect in lowering serum transaminase levels. The market launch of bicyclol has created significant economic and social benefits for the country and has benefited a large number of liver disease patients. However, bicyclol has poor water solubility and low bioavailability, which to some extent limits its clinical application. Sun Piaoyang et al. synthesized bicyclic alcohol glycoside derivatives, improving the water solubility of bicyclic alcohols; Wang Faping et al. synthesized bicyclic alcohol adefovir dipivoxil, improving the antiviral activity of the derivatives; Su Xianbin et al. synthesized bicyclic alcohol amino acid esters, improving the water solubility of bicyclic alcohols; Li Chuanbo et al. synthesized bicyclic alcohol phosphate esters, improving water solubility and hepatoprotective effects; Liu Lian et al. synthesized bicyclic alcohol acetylcysteine ​​esters and tested their antitumor activity; Wu Song et al. synthesized bicyclic alcohol methylene morpholine derivatives and their salts, testing both their hepatoprotective effects and increasing water solubility. Most of these derivatives improve the water solubility of bicyclic alcohols, but research on their hepatoprotective effects is limited.

[0003] Urea can form complexes with heavy metal ions (such as copper ions, chromium ions, etc.), thereby excreting heavy metals from the body and having a good liver-protective effect. Summary of the Invention

[0004] The technical problem solved by the present invention is to first oxidize bicyclic alcohol as a raw material, and then condense it with substituted aminothiourea or aminourea to obtain the compound of general formula (I) of the present invention, its pharmaceutically acceptable salt, its preparation method, pharmaceutical composition and its use in the treatment of liver disease.

[0005] To solve the technical problem of this invention, the present invention provides the following technical solution:

[0006] The first aspect of the present invention is to provide bicyclic alcohol derivatives represented by the following general formulas and their pharmaceutically acceptable salts:

[0007]

[0008] in:

[0009] X represents S and O;

[0010] R1 is H;

[0011] R2 is C 1-4 Alkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, aryl;

[0012] The aryl group is a substituted or unsubstituted phenyl, furanyl, thiophene, isoxazolyl, pyrimidinyl, pyrazinyl, naphthyl, chromone, quinolinyl, isoquinolinyl, or pyridinyl group. The substituents on the benzene ring are selected from halogens, C1-4 alkyl groups, C1-4 haloalkyl groups, and C1-4 alkoxy groups; or R1 = R2, where R1 and R2 are H, methyl, or morpholine rings.

[0013] The C1-4 alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.

[0014] The C1-4 alkoxy groups are methyl methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.

[0015] The benzene ring substituents are located at para, meta, or ortho positions, and the number of substituents can be monosubstituted, disubstituted, or polysubstituted. The aryl group is phenyl or pyridyl, and the substituents on the benzene ring are selected from halogens. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy;

[0016] The compounds are selected from the following:

[0017]

[0018]

[0019] The preparation method of the compound is as follows:

[0020]

[0021] Reaction step a: First, the bicyclic alcohol is oxidized in an oxidant to generate a bicyclic aldehyde; Reaction step b: The bicyclic aldehyde and the corresponding substituted aminothiourea or aminourea condense to obtain a compound of general formula (I).

[0022] Reaction conditions a: Desmartin reagent / dichloromethane, room temperature;

[0023] Reaction condition b: glacial acetic acid / anhydrous ethanol, 80℃

[0024] The pharmaceutically acceptable salts mentioned include inorganic or organic acid salts formed by the compound and organic or inorganic acids. Inorganic acid salts include hydrochlorides, hydrobroms, sulfates or hydrogen sulfates, nitrates, phosphates or hydrogen phosphates, etc., while organic acid salts include formates, acetates, trifluoroacetates, benzoates, succinates, fumarates, maleates, lactates, citrates, tartrates, succinates, gluconates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, etc.

[0025] A third aspect of the present invention is to provide a pharmaceutical composition comprising the bicyclic alcohol derivative described in the first aspect of the present invention, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0026] The compounds of the present invention can be administered orally, for example, in capsule, tablet, powder, granule, syrup or similar dosage forms, or non-gastrointestinally, by injection, ointment, suppository or similar dosage forms. These pharmaceutical preparations can be generated by conventional methods using adjuvants well known in the art, such as binders, excipients, stabilizers, disintegrants, flavoring agents, lubricants, etc. Although the dosage varies depending on symptoms and the patient's age, the nature and severity of the disease or disorder, and the route and manner of administration, for oral administration to adult patients, the normal dosage of the compounds of the present invention is a total daily dose of 1 to 1000 mg, preferably 5 to 500 mg, as a single dose or in divided doses; for example, twice or three times daily; for intravenous administration, a dose of 0.1 to 100 mg, preferably 0.5 to 50 mg, can be divided into one to three doses daily.

[0027] The present invention also provides a pharmaceutical composition comprising a bicyclic alcohol derivative of formula (I) above, characterized in that the pharmaceutical composition comprises the bicyclic alcohol derivative of any one of claims 1-4 and its pharmaceutically acceptable salt, as well as a pharmaceutically acceptable carrier or excipient.

[0028] When used as a drug, the compounds of this invention can be used directly or in the form of a pharmaceutical composition. The pharmaceutical composition contains 0.1%-99%, preferably 0.5%-90% of the compounds of this invention, with the remainder being pharmaceutically acceptable, non-toxic, and inert pharmaceutically acceptable carriers and / or excipients for human and animal use, or in combination with other anticancer drugs. The pharmaceutical compositions of this invention can be prepared as injections, tablets, capsules, pills, powders, etc.

[0029] The pharmaceutical compositions of the present invention can be controlled-release dosage forms, sustained-release dosage forms, or various microparticle delivery systems.

[0030] The fourth aspect of the present invention is the use of the bicyclic alcohol derivative of formula (I) described in the first aspect and its pharmaceutically acceptable salt or the pharmaceutical composition described in the third aspect in the preparation of a medicament for the prevention or treatment of liver diseases; wherein the liver diseases are preferably viral hepatitis, drug-induced liver disease, alcoholic liver disease, non-alcoholic liver disease, autoimmune liver disease, liver fibrosis due to liver disease progression, cirrhosis, and liver failure, but are not limited to the above-mentioned liver diseases.

[0031] Beneficial technical effects

[0032] This invention focuses on providing bicyclic alcohol derivatives with the general formula (I). Through activity tests in three models—acetaminophen-induced drug-induced hepatocyte injury, hydrogen peroxide-induced oxidative hepatocyte injury, and oleic acid-induced hepatocyte lipid deposition—some of these derivatives showed significant hepatocyte injury protection and lipid-lowering activities. The activities of some derivatives were significantly higher than those of bicyclic alcohols, suggesting that these derivatives have good prospects for treating liver diseases. Detailed Implementation

[0033] Abbreviations:

[0034] APAP: Acetaminophen

[0035] DCM: Dichloromethane

[0036] DMSO: Dimethyl sulfoxide

[0037] EA: Ethyl acetate

[0038] H2O2: Hydrogen peroxide

[0039] OA: Oleic acid

[0040] PE: Petroleum ether (60-90℃)

[0041] TLC: Thin-layer chromatography

[0042] This invention discloses a new class of bicyclic alcohol derivatives, including their salts, solvates, prodrugs, and pharmaceutical compositions. Those skilled in the art can refer to this document and appropriately modify the process parameters to achieve the desired results. It is particularly important to note that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included in this invention. The methods and applications of this invention have been described through preferred embodiments. Those skilled in the art will clearly be able to modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit, and scope of this invention to realize and apply the technology of this invention.

[0043] The present invention will be further illustrated below with reference to the embodiments:

[0044] The preparation method of bicyclic alcohol derivatives of general formula (I) is as follows:

[0045]

[0046] 1. Synthesis of bicyclic aldehydes

[0047]

[0048] 1.500 g (3.8 mmol) of bicyclol was dissolved in 30 mL of dichloromethane, and 1.700 g (4.2 mmol) of Dess-Martin periodinane was slowly added. The reaction mixture was stirred at room temperature for 2 h. After the reaction was detected by TLC, the reaction was quenched with saturated sodium bisulfite solution, extracted three times with 10 mL of DCM, washed with 20 mL of saturated sodium bicarbonate solution and 20 mL of saturated brine, dried over anhydrous sodium sulfate for 2 h, and the concentrated crude product was obtained. The crude product was recrystallized from 7 mL of ethyl acetate to give 0.658 g of white solid, with a yield of 45%. 1 ¹H NMR (400MHz, CDCl₃): δ 9.70 (d, J = 2.6Hz, 1H, -CHO), 7.42 (s, 1H, Ar-H), 7.32 (s, 1H, Ar-H), 6.07–6.00 (m, 4H, 2×-OCH₂O⁻), 3.99 (d, J = 3.7Hz, 6H, 2×-OCH₃), 3.69 (s, 3H, -OCH₃). 2. Synthesis of compounds of general formula (I)

[0049] Example 1: Synthesis of ZT-5

[0050]

[0051] In a 50 ml round-bottom flask, 0.045 g (0.12 mmol) of bicyclic aldehyde, 0.022 g (0.24 mmol) of aminothiourea, and 5 ml of anhydrous ethanol were added sequentially. One drop of glacial acetic acid was added dropwise. The mixture was stirred at 80 °C for 2 h, filtered, washed with ethanol, and dried to give 0.059 g of white solid, with a yield of 100%. 1 ¹H NMR (400MHz, Chloroform-d) δ 9.25 (s, 1H, -NH₄⁻), 7.57 (s, 1H, -NH₄⁻), 7.39 (s, 1H, Ar-H), 7.13 (s, 1H, Ar-H), 6.11–5.95 (m, 4H, 2×-OCH₂O⁻), 3.98 (d, J=7.2Hz, 6H, 2×OCH₃), 3.69 (s, 3H, -OCH₃). HRMS (ESI) m / z calculated values ​​C 20 H 19 N3O8S[M+H] + 462.0966, measured value 462.0964.

[0052] Example 2: Synthesis of ZT-7

[0053]

[0054] In a 50 ml round-bottom flask, 0.118 g (0.30 mmol) of bicyclic aldehyde, 0.048 g (0.40 mmol) of 4,4-dimethyl-3-aminothiourea, and 5 ml of anhydrous ethanol were added sequentially. One drop of glacial acetic acid was added dropwise, and the mixture was stirred at 80 °C for 2 h. After filtration, washing with ethanol, and drying, 0.093 g of a white solid was obtained, with a yield of 63%. 1 H NMR (400MHz, Chloroform-d) δ7.40(s,1H,Ar-H),6.16–5.82(m,4H,2×-OCH2O-),3.98(d,J=15.0Hz,6H,2×-OCH3),3.69(s,3H,-OCH3),3.39(s,6H,2×-CH3). 13 C NMR (126MHz, Chloroform-d) δ 189.58, 181.24, 166.00, 147.86, 146.75, 143.57, 143.05, 140.66, 138.46, 136.49, 126.08, 124.25, 111.75, 111.28, 109.14, 107.46, 104.19, 102.65, 102.08, 56.78, 56.76, 56.70, 56.35, 52.16, 44.00, 34.72. HRMS (ESI) m / z calculated values ​​C 22 H 23N3O8S[M+H] + 490.1279, measured value 490.1283.

[0055] Example 3: Synthesis of ZT-9

[0056]

[0057] In a 50 ml round-bottom flask, 0.117 g (0.30 mmol) of bicyclic aldehyde, 0.056 g (0.42 mmol) of 4-isopropyl-3-aminothiourea, and 5 ml of anhydrous ethanol were added sequentially. One drop of glacial acetic acid was added dropwise, and the mixture was stirred at 80 °C for 2 h. After filtration, washing with ethanol, and drying, 0.120 g of white solid was obtained, with a yield of 79%. 1 H NMR(500MHz,Chloroform-d)δ9.27(s,1H,-CH=N-),7.56(s,1H,-NH-),7.39(s,1H,-NH-),7.06(s,1H,Ar-H),6.86(d,J=8.5Hz,1H,Ar-H ),6.14–5.88(m,4H,2×-OCH2O-),4.53(q,J=7.1Hz,1H,-CH-),3.98(s,6H,2×-OCH3),3.69(s,3H,-OCH3),1.25(d,J=6.5Hz,6H,2×-CH3). 13 C NMR (101MHz, Chloroform-d) δ 175.82, 165.96, 147.71, 147.16, 143.42, 142.94, 141.22, 138.48, 136.83, 125.67, 124.13, 111.74, 110.86, 109.80, 106.75, 102.64, 102.16, 77.24, 56.73, 52.15, 46.44, 22.46, 22.41. HRMS (ESI) m / z calculated values ​​C 23 H 25 N3O8S[M+H] + 504.1435, measured value 504.1437.

[0058] Example 4: Synthesis of ZT-15

[0059]

[0060] In a 50 ml round-bottom flask, 0.077 g (0.20 mmol) of bicyclic aldehyde, 0.034 g (0.23 mmol) of 4-n-butyl-3-aminothiourea, and 5 ml of anhydrous ethanol were added sequentially. One drop of glacial acetic acid was added dropwise, and the mixture was stirred at 80 °C for 2 h. After filtration, the mixture was washed with ethanol and dried to give 0.111 g of a white solid, with a yield of 100%. 1 H NMR(500MHz,Chloroform-d)δ9.19(s,1H,-NH-),7.54(s,1H,-NH-),7.39(s,1H,Ar-H),7.05(s,1H,Ar-H),6.19–5.88(m,4H,2×-OCH2O-),3.98(d,J=5.1Hz ,6H,2×-OCH3),3.68(s,3H,-OCH3),3.61(q,J=6.8Hz,2H,-CH2-),1.60(q,J= 7.4Hz,2H,-CH2-),1.40(h,J=7.4Hz,2H,-CH2-),0.97(t,J=7.4Hz,3H,-CH3). 13 CNMR (101MHz, Chloroform-d) δ 176.91, 165.96, 147.69, 147.14, 143.42, 142.92, 141.25, 138.56, 136.78, 125.74, 124.09, 111.68, 110.84, 109.92, 106.58, 102.67, 102.16, 56.76, 56.65, 52.14, 44.21, 31.32, 20.13, 13.86. HRMS (ESI) m / z calculated value C 24 H 27 N3O8S[M+H] + 518.1592, measured value 518.1598.

[0061] Example 5: Synthesis of ZT-12

[0062]

[0063] In a 50 ml round-bottom flask, 0.078 g (0.20 mmol) of bicyclic aldehyde, 0.033 g (0.22 mmol) of 4-tert-butyl-3-aminothiourea, and 5 ml of anhydrous ethanol were added sequentially. One drop of glacial acetic acid was added dropwise. The mixture was stirred at 80 °C for 2 h, filtered, washed with ethanol, and dried to give 0.085 g of white solid, with a yield of 82%. 1H NMR(500MHz,Chloroform-d)δ9.17(d,J=5.0Hz,1H,-NH-),7.51(s,1H,-NH-),7.39(s,1H),7.33(s,1H,Ar-H),7.16(s ,1H,Ar-H),6.12–5.92(m,4H,2×-OCH2O-),3.97(d,J=6.6Hz,6H,2×-OCH3),3.69(s,3H,-OCH3),1.55(s,9H,3×-CH3). 13 C NMR (101MHz, Chloroform-d) δ 175.28, 166.02, 147.80, 146.91, 143.53, 143.04, 139.88, 138.55, 136.73, 125.91, 124.13, 111.83, 111.55, 109.15, 104.73, 102.69, 102.12, 56.67, 56.42, 53.52, 52.11, 28.91. HRMS (ESI) m / z calculated values ​​C 24 H 27 N3O8S[M+H] + 518.1592, measured value 518.1597.

[0064] Example 6: Synthesis of ZT-6

[0065]

[0066] In a 50 ml round-bottom flask, 0.389 g (1 mmol) of bicyclic aldehyde, 0.172 g (1 mmol) of 4-phenyl-3-aminothiourea, and 5 ml of anhydrous ethanol were added sequentially. One drop of glacial acetic acid was added dropwise. The mixture was stirred at 80 °C for 2 h, filtered, washed with ethanol, and dried to give 0.359 g of white solid, with a yield of 67%. 1 H NMR(400MHz,Chloroform-d)δ9.61(s,1H,-NH-),8.59(s,1H,-CH=N-),7.66(s,1H,-NH-),7.56–

[0067] 7.47(m,2H,Ar-H),7.41(dd,J=8.5,7.2Hz,2H,Ar-H),7.28(d,J=6.1Hz,1H,A r-H),7.03(s,1H,Ar-H),6.12–5.91(m,4H,2×-OCH2O-),3.98(s,3H,-OCH3),

[0068] 3.71(d,J=12.8Hz,6H,2×-OCH3).13 C NMR(126MHz,Chloroform-d)δ166.23,

[0069] 147.64, 147.45, 143.52, 143.04, 138.75, 137.89, 137.18, 128.98, 126.52, 125.56,

[0070] 125.43,124.16,111.49,110.79,110.31,107.95,102.91,102.43,56.89,56.57,52.39.

[0071] HRMS(ESI) m / z calculated value C 26 H 23 N3O8S[M+H] + 538.1279, measured value 538.1288.

[0072] Example 7: Synthesis of ZT-16

[0073]

[0074] In a 50 ml round-bottom flask, 0.078 g (0.2 mmol) of bicyclic aldehyde, 0.037 g (0.2 mmol) of 4-(4-tolyl)-3-aminothiourea, and 5 ml of anhydrous ethanol were added sequentially. One drop of glacial acetic acid was added dropwise, and the mixture was stirred at 80 °C for 2 h. After filtration, washing with ethanol, and drying, 0.111 g of a white solid was obtained, with a yield of 100%. 1 H NMR(500MHz,Chloroform-d)δ9.60(s,1H,-NH-),8.48(s,1H,-CH=N-),7.65(s,1H,-NH-),7.35(d,J=7.8Hz,2H,Ar-H),7.20(d,J=7.9Hz ,2H,Ar-H),7.01(s,1H,Ar-H),6.16–5.93(m,4H,2×-OCH2O-),3.97(s,3H,-OCH3),3.71(d,J=18.1Hz,6H,2×-OCH3),2.37(s,3H,-CH3). 13C NMR (101MHz, Chloroform-d) δ 175.89, 166.05, 147.45, 147.32, 143.36, 142.85, 142.07, 138.56, 136.92, 136.25, 135.15, 129.39, 125.53, 125.35, 124.01, 111.34, 110.49, 110.26, 107.93, 102.67, 102.23, 77.27, 56.73, 56.37, 52.18, 21.11. HRMS (ESI) m / z calculated values ​​C 27 H 25 N3O8S[M+H] + 552.1435, measured value 552.1439.

[0075] Example 8: Synthesis of ZT-8

[0076]

[0077] In a 50 ml round-bottom flask, 0.115 g (0.30 mmol) of bicyclic aldehyde, 0.070 g (0.35 mmol) of 4-(4-ethylphenyl)-3-aminothiourea, and 5 ml of anhydrous ethanol were added sequentially. One drop of glacial acetic acid was added dropwise, and the mixture was stirred at 80 °C for 2 h. After filtration, washing with ethanol, and drying, 0.105 g of white solid was obtained, with a yield of 62%. 1 H NMR(500MHz,Chloroform-d)δ9.18(s,1H,-NH-),8.51(s,1H,-CH=N-),7.59(s,1H,-NH-),7.43–7.15(m,6H),7.02(s,1H,Ar-H),6.15–5.9 0(m,4H,-2×-OCH2O-),3.98(d,J=2.8Hz,3H,-OCH3),3.78–3.63(m,6H,-2×-OCH3),2.67(q,J=8.0Hz,2H,-CH2-),1.34–1.20(m,3H,-CH3). 13C NMR (126MHz, Chloroform-d) δ 212.49, 176.01, 166.20, 147.61, 147.48, 143.53, 143.03, 142.77, 142.13, 138.73, 137.10, 135.45, 128.40, 125.64, 125.51, 125.40, 124.15, 111.43, 110.63, 110.44, 108.03, 102.86, 102.43, 56.86, 56.53, 52.39, 28.67, 15.80. HRMS (ESI) m / z calculated values ​​C 28 H 27 N3O8S[M+H] + 566.1592, measured value 566.1598.

[0078] Example 9: Synthesis of ZT-11

[0079]

[0080] In a 50 mL round-bottom flask, 0.078 g (0.20 mmol) of bicyclic aldehyde, 0.050 g (0.21 mmol) of 4-[3-(trifluoromethyl)phenyl]-3-aminothiourea, and 5 mL of anhydrous ethanol were added sequentially, followed by 1 drop of glacial acetic acid. The mixture was stirred at 80 °C for 2 h. After the reaction was complete, the mixture was filtered, washed with ethanol, and dried to give 0.109 g of a white solid, with a yield of 90%. 1 H NMR(400MHz,Chloroform-d)δ9.27(s,1H,-NH-),8.65(s,1H,-CH=N-),7.92–7.77(m,2H,Ar-H),7.62(s,1H,-NH-),7.56–7.48(m,2H,A r-H),7.30(s,1H,Ar-H),7.02(s,1H,Ar-H),6.03(d,J=22.6Hz,4H,2×-OCH2O-),3.99(s,3H,-OCH3),3.73(d,J=11.2Hz,6H,2×-OCH3). 13C NMR (101MHz, Chloroform-d) δ 166.00, 147.51, 147.43, 143.39, 142.89, 142.60, 138.55, 138.30, 137.22, 131.32, 131.00, 129.24, 128.22, 125.14, 124.08, 122.77, 122.73, 121.54, 121.50, 111.37, 110.57, 110.15, 108.20, 102.66, 102.29, 56.82, 56.42, 52.24. HRMS (ESI) m / z calculated values ​​C 27 H 22 F3N3O8S[M+H] + 606.1152, measured value 606.1147.

[0081] Example 10: Synthesis of ZT-10

[0082]

[0083] In a 50 ml round-bottom flask, 0.078 g (0.20 mmol) of bicyclic aldehyde, 0.049 g (0.21 mmol) of 4-[4-(trifluoromethyl)phenyl]-3-thioaminourea, and 5 ml of anhydrous ethanol were added sequentially. One drop of glacial acetic acid was added dropwise, and the mixture was stirred at 80 °C for 2 h. After filtration, washing with ethanol, and drying, 0.127 g of white solid was obtained, with a yield of 100%. 1 H NMR(500MHz,Chloroform-d)δ9.16(s,1H,-NH-),8.76(s,1H,-CH=N-),7.75(d,J=7.7Hz,2H,Ar-H),7.66(d,J=8.4Hz,2H,Ar-H),7.61(s,1H.-NH-) ,7.33–7.29(m,1H,Ar-H),7.05(s,1H,Ar-H),6.13–5.87(m,4H,-2×-OCH2O-),4.00(d,J=2.6Hz,3H,-OCH3),3.75(dd,J=41.6,2.7Hz,6H,2×-OCH3). 13C NMR(126MHz,Chloroform-d)δ175.18,166.27,147.71,147.53,143.58,143.07,1 43.00,141.07,138.73,137.43,127.97,127.70,127.45,126.17,126.14,126.11, 126.08, 125.33, 125.30, 124.29, 124.22, 124.13, 123.13, 111.60, 111.04, 110.06, 107.84, 102.89, 102.48, 58.68, 56.97, 56.58, 52.43, 18.63. HRMS(ESI) m / z calculated value C 27 H 22 F3N3O8S[M+H] + 606.1152, measured value 606.1154.

[0084] Example 11 Synthesis of ZT-17

[0085]

[0086] In a 50 ml round-bottom flask, 0.078 g (0.20 mmol) of bicyclol, 0.048 g (0.24 mmol) of 4-[(4-methoxy)phenyl]-3-aminothiourea, and 5 ml of anhydrous ethanol were added sequentially. One drop of glacial acetic acid was added dropwise. The mixture was stirred at 80 °C for 2 h, filtered, washed with ethanol, and dried to give 0.091 g of a white solid, with a yield of 80%. 1 H NMR(500MHz,Chloroform-d)δ9.63(s,1H,-NH-),8.37(s,1H,-CH=N-),7.65(s,1H,-NH-),7.34(d,J=8.4Hz,2H,Ar-H),7.05– 6.89(m,3H,Ar-H),6.15–5.87(m,4H,2×-OCH2O-),3.97(s,3H,-OCH3),3.83(s,3H,-OCH3),3.71(d,J=15.1Hz,6H,2×-OCH3). 13C NMR (101MHz, Chloroform-d) δ 166.05, 158.12, 147.43, 147.35, 143.34, 142.83, 142.13, 138.56, 136.90, 130.61, 127.23, 125.52, 124.01, 114.03, 111.24, 110.38, 108.14, 102.67, 102.22, 56.74, 56.38, 55.52, 52.19. HRMS (ESI) m / z calculated values ​​C 27 H 25 N3O9S[M+H] + 568.1384, measured value 568.1387.

[0087] Example 12 Synthesis of ZT-13

[0088]

[0089] In a 50 ml round-bottom flask, 0.078 g (0.20 mmol) of bicyclic aldehyde, 0.044 g (0.20 mmol) of 4-(4-chlorophenyl)-3-aminothiourea, and 5 ml of anhydrous ethanol were added sequentially. One drop of glacial acetic acid was added dropwise, and the mixture was stirred at 80 °C for 2 h. After filtration, washing with ethanol, and drying, 0.090 g of white solid was obtained, with a yield of 79%. 1 H NMR(500MHz,Chloroform-d)δ9.61(s,1H,-NH-),8.55(s,1H,-CH=N-),7.65(s,1H,-NH-),7.48(d,J=9.1Hz,2H,Ar-H),7.40–7.33( m,2H,Ar-H),7.02(s,1H,-Ar-H),6.10–5.94(m,4H,2×-OCH2O-),4.05–3.89(m,3H,-OCH3),3.74(dd,J=42.1,2.0Hz,6H,2×-OCH3). 13 C NMR (101MHz, Chloroform-d) δ 175.54, 166.06, 147.51, 147.37, 143.39, 142.88, 142.51, 138.56, 137.13, 136.31, 131.62, 128.87, 126.26, 125.30, 124.07, 111.38, 110.68, 110.08, 107.91, 102.68, 102.26, 56.81, 56.46, 52.21. HRMS (ESI) m / z calculated values ​​C 26 H 22 ClN3O8S[M+H]+ 572.0889, measured value 572.0888.

[0090] Example 13 Synthesis of ZT-14

[0091]

[0092] In a 50 ml round-bottom flask, 0.077 g (0.20 mmol) of bicyclic aldehyde, 0.039 g (0.21 mmol) of 4-(2-fluorophenyl)-3-aminothiourea, and 5 ml of anhydrous ethanol were added sequentially. One drop of glacial acetic acid was added dropwise, and the mixture was stirred at 80 °C for 2 h. After filtration, washing with ethanol, and drying, 0.111 g of a white solid was obtained, with a yield of 100%. 1 H NMR(500MHz,Chloroform-d)δ9.68(s,1H,-NH-),9.08(s,1H,-NH-),8.39(td,J=7.6,3.2Hz,1H,-CH=N-),7.65(s,1H,Ar-H), 7.34(s,1H,Ar-H),7.23–7.11(m,4H,Ar-H),6.24–5.79(m,4H,2×-OCH2O-),3.99(s,3H,-OCH3),3.90–3.66(m,7H,2×-OCH3). 13 C NMR (101MHz, Chloroform-d) δ 175.13, 166.00, 153.71, 147.68, 147.03, 143.63, 143.01, 141.43, 138.54, 137.14, 126.43, 126.36, 125.35, 125.12, 124.16, 124.10, 124.06, 115.39, 115.19, 111.64, 111.32, 109.43, 105.74, 102.69, 102.26, 56.60, 56.41, 52.20. HRMS (ESI) m / z calculated values ​​C 26 H 22 FN3O8S[M+H] + 556.1184, measured value 556.1184.

[0093] Example 14 Synthesis of ZT-4

[0094]

[0095] In a 50 ml round-bottom flask, 0.077 g (0.20 mmol) of bicyclic aldehyde, 0.042 g (0.23 mmol) of 4-(4-fluorobenzene)-3-aminothiourea, and 5 ml of anhydrous ethanol were added sequentially. One drop of glacial acetic acid was added dropwise, and the mixture was stirred at 80 °C for 2 h. After filtration, washing with ethanol, and drying, 0.122 g of white solid was obtained, with a yield of 100%. 1 H NMR(500MHz,Chloroform-d)δ9.67(s,1H,-NH-),8.45(s,1H,-CH=N-),7.66(s,1H,-NH-),7.44(dd,J=8.9,4.8Hz,2H,Ar-H),7.26(t,J=6.9Hz,3H), 7.13–7.06(m,2H,Ar-H),7.00(d,J=3.4Hz,1H,Ar-H),6.11-5.93(m,4H,2×-OCH2O-),3.97(d,J=3.7Hz,3H,-COOCH3),3.81–3.63(m,6H,,2×-OCH3). 13 C NMR (101MHz, Chloroform-d) δ 176.12, 166.05, 162.13, 159.68, 147.49, 147.39, 143.37, 142.87, 142.37, 138.55, 137.07, 133.71, 133.68, 127.36, 127.28, 125.33, 124.06, 115.71, 115.48, 111.28, 110.55, 110.21, 108.06, 102.68, 102.26, 56.79, 56.40, 52.21. HRMS (ESI) m / z calculated values ​​C 26 H 22 FN3O8S[M+H] + 556.1184, measured value 556.1191.

[0096] Synthesis of Example 15W28

[0097]

[0098] In a 50 ml round-bottom flask, 0.077 g (0.20 mmol) of bicyclic aldehyde, 0.061 g (0.4 mmol) of 4-(2-pyridyl)aminourea, and 8.5 ml of anhydrous ethanol were added sequentially. One drop of glacial acetic acid was added dropwise. The mixture was stirred at 80 °C for 2 h, and then evaporated to dryness. The solution was then subjected to rapid silica gel column chromatography (eluting with PE-EA) to give 0.062 mg of a white solid, with a yield of 59%. 1H NMR (400MHz, DMSO-d6) δ10.69(s,1H,-NH-),8.74(s,1H,-CH=N-),8.31–8.25(m,1H ,Ar-H),7.94(d,J=8.4Hz,1H,Ar-H),7.75(d,J=4.6Hz,2H,Ar-H),7.32(d,J=4.5Hz, 2H, Ar-H), 7.05 (dd, J=7.2, 5.0Hz, 1H, Ar-H), 6.08 (d, J=11.8Hz, 2H, -OCH2O-), 5.96 (d,J=14.6Hz,2H,-OCH2O),3.93(d,J=15.9Hz,6H,2×-OCH3),3.60(s,3H,-COOCH3). 13 C NMR (126MHz, NONE) δ 167.14, 153.45, 153.10, 149.19, 148.81, 147.83, 144.46, 143.74, 142.13, 139.50, 139.32, 137.02, 127.69, 125.52, 119.98, 113.96, 112.34, 111.91, 110.27, 105.86, 103.91, 103.12, 57.79, 53.31. HRMS (ESI) m / z calculated values ​​C 25 H 22 N4O9[M+H] + 523.1460, measured value 523.1478.

[0099] Example 16: Synthesis of W30

[0100]

[0101] In a 50 ml round-bottom flask, 0.077 g (0.20 mmol) of bicyclic aldehyde, 0.067 g (0.4 mmol) of 4-(2-pyridyl)aminothiourea, and 8.5 ml of anhydrous ethanol were added sequentially. One drop of glacial acetic acid was added dropwise. The mixture was stirred at 80 °C for 2 h, filtered, washed with ethanol, and dried to obtain 0.056 g of yellow powder, with a yield of 52%. 1H NMR(400MHz,DMSO-d6)δ11.71(s,1H,-NH-),10.02(s,1H,-NH-),8.67(s,1H,Ar-H),8.43–8 .37(m,1H,-NH=N),7.98(d,J=7.7Hz,2H,Ar-H×2),7.61(d,J=1.9Hz,1H,Ar-H),7.41(t,J=6. 6Hz,1H,Ar-H),7.31(d,J=1.8Hz,1H,Ar-H),6.11(d,J=3.3Hz,2H,-OCH2O-),5.97(d,J=15.1 Hz,2H,OCH2O-),3.93(dd,J=11.4,1.8Hz,6H,-OCH3×2),3.61(d,J=1.8Hz,3H,-COOCH3).13C NMR (126MHz, NONE) δ 176.18, 165.86, 147.57, 146.53, 146.32, 143.32, 142.63, 142.45, 138.13, 136.35, 136.03, 133.79, 126.04, 124.28, 123.10, 111.68, 111.08, 108.74, 105.19, 102.77, 101.94, 56.85, 56.59, 52.14, 52.08. HRMS (ESI) m / z calculated value C 25 H 22 N4O8S[M+H] + 539.1231, measured value 539.1250.

[0102] Synthesis of Example 17W31

[0103]

[0104] Add 0.194 g (0.50 mmol) of bicyclic aldehyde and 0.161 g of 4-morpholine thiocarbonyl hydrazide sequentially to a 50 ml round-bottom flask.

[0105] 1 mmol, 21 ml anhydrous ethanol, 2 drops of glacial acetic acid were added, the mixture was stirred at 80 °C for 2 h, filtered, washed with ethanol, and dried to give 0.213 g of bright yellow powder, yielding 80%. 1 H NMR (400MHz, DMSO-d6)δ

[0106] 11.03(s,1H,-NH-),7.86(s,1H,-CH=N-),7.31(s,1H,Ar-H),7.15(s,1H,Ar-H),

[0107] 6.08(dd,J=10.5,1.1Hz,2H,-OCH2O-),6.00–5.91(m,2H,-OCH2O-),3.95–3.84

[0108] (m, 10H, -COOCH) 3， -OCH 3， -CH2-),3.67(t,J=4.7Hz,4H, -CH2-),3.60(s,3H,

[0109] -OCH3). 13 C NMR(126MHz,NONE)δ181.30,166.47,148.41,147.25,143.85,

[0110] 143.09, 142.69, 138.75, 136.45, 127.32, 124.90, 111.84, 111.67, 109.42, 103.65,

[0111] 103.36, 102.56, 66.77, 57.26, 56.75, 52.70, 51.54. HRMS(ESI) m / z calculated value C 25 H 26 N3O9S[M+H] + 532.1384, measured value 532.1372.

[0112] Synthesis of Example 18W33

[0113]

[0114] In a 50 ml round-bottom flask, 0.194 g (0.50 mmol) of bicyclic aldehyde, 0.203 g (1 mmol) of 4-(3,4-difluorophenyl)aminothiourea, and 20 ml of anhydrous ethanol were added sequentially. Two drops of glacial acetic acid were added dropwise. The mixture was stirred at 80 °C for 2 h, filtered, washed with ethanol, and dried to obtain 0.200 g of a light yellow powder, with a yield of 70%. 1H NMR (400MHz, DMSO-d6) δ11.66(s,1H,-NH-),9.98(s,1H,-NH-),7.96(s,1H,- CH=N-),7.76(dd,J=12.4,7.8Hz,1H,Ar-H),7.60(s,1H,Ar-H),7.47–7.38(m, 2H, Ar-H×2), 7.31 (s, 1H, Ar-H), 6.10 (d, J=4.1Hz, 2H, -OCH2O-), 5.97 (d, J=1 5.0Hz, 2H, -OCH2O-), 3.93 (d, J=11.0Hz, 6H, -OCH3×2), 3.61 (s, 3H, -COOCH3). 13 C NMR(126MHz,NONE)δ176.64,166.79,150.52,150.41,149.08,148.98,148.65,148.57,148.47,1 47.46,147.14,147.04,144.25,143.49,143.39,139.06,139.05,137.28,137.19,137.17,137.1 2,137.10,126.97,125.22,123.79,123.76,123.74,123.71,117.73,117.59,116.33,116.18,112.60,112.01,109.68,109.67,106.14,103.70,102.87,57.76,57.52,53.01.HRMS(ESI) m / z calculated value C 26 H 21 N3O8F2S[M+H] + 574.1090, measured value 574.1054.

[0115] Synthesis of Example 19W36

[0116]

[0117] In a 50 ml round-bottom flask, 0.194 g (0.50 mmol) of bicyclic aldehyde, 0.173 g (1 mmol) of N-cyclohexylthioamide, and 5 ml of anhydrous ethanol were added sequentially. One drop of glacial acetic acid was added dropwise. The mixture was stirred at 80 °C for 2 h, filtered, washed with ethanol, and dried to obtain 0.264 g of white powder, with a yield of 97%. 1H NMR (400MHz, DMSO-d6) δ11.18(s,1H,-NH-),7.88(s,1H,-CH=N-),7.69(d,J=8. 6Hz,1H,-NH-),7.38(s,1H,Ar-H),7.32(s,1H,Ar-H),6.09(dd,J=12.6,1.1Hz, 2H, -OCH2O-), 5.98 (dd, J=15.0, 0.9Hz, 2H, -OCH2O-), 4.13 (d, J=9.6Hz, 1H, -CH =),3.95(d,J=6.1Hz,6H,-OCH3×2),3.61(s,3H,-COOCH3),1.92–1.85(m,2H,-CH 2- ), 1.74 (d, J = 12.0 Hz, 2H, -CH 2- ), 1.62(d, J = 12.3 Hz, 1H, -CH 2- ), 1.45–1.23 (m, 5H, -CH2×2). 13C NMR (126MHz, NONE) δ 176.36, 166.77, 148.52, 147.60, 144.04, 143.29, 142.42, 139.01, 136.92, 127.29, 125.10, 111.90, 110.14, 106.71, 103.61, 102.79, 57.66, 57.49, 55.95, 53.54, 52.97, 32.87, 26.12, 25.91. HRMS (ESI) m / z calculated value C 26 H 29 N3O8S[M+H] + 544.1748, measured value 544.1737.

[0118] Synthesis of Example 20W46

[0119]

[0120] In a 50 ml round-bottom flask, 0.155 g (0.40 mmol) of bicyclic aldehyde, 0.146 g (0.8 mmol) of 4-(3-pyridylmethyl)-3-aminothiourea, and 17 ml of anhydrous ethanol were added sequentially. Two drops of glacial acetic acid were added dropwise, and the mixture was stirred at 80 °C for 2 h. The mixture was then concentrated, and the crude product was subjected to silica gel column chromatography (eluting with PE-EA) to give 0.079 g of white powder, with a yield of 36%. 1H NMR (400MHz, DMSO-d6) δ11.38 (s, 1H, -NH-), 8.93 (t, J = 6.3Hz, 1H, Ar-H), 8.55 (d, J = 2.2Hz, 1H, -NH=N-),8.45(dd,J=4.7,1.6Hz,1H,Ar-H),7.88(s,1H,-NH-),7.77–7.70(m,1H,Ar-H),7.48(s ,1H,Ar-H),7.39–7.28(m,2H,Ar-H),6.09(d,J=6.0Hz,2H,-OCH3O-×2),5.96(d,J=14.7Hz,2H,- OCH3O-×2), 4.85 (d, J=6.2Hz, 2H, -CH2), 3.92 (d, J=3.6Hz, 6H, -OCH3×2), 3.59 (s, 3H, -COOCH3). 13 CNMR (126MHz, DMSO-D6) δ 177.83, 166.25, 149.17, 148.50, 148.08, 146.96, 143.66, 142.83, 142.20, 138.52, 136.54, 135.55, 135.49, 126.72, 124.66, 123.94, 111.86, 111.46, 109.21, 105.38, 103.14, 102.28, 57.29, 57.02, 52.48, 44.74. HRMS (ESI) m / z calculated value C 26 H 24 N4O8S[M+H]+553.1388, measured value 553.1372.

[0121] Pharmacological experiments

[0122] Experimental Example 1: Activity test of bicyclic alcohol derivatives against acetaminophen (APAP)-induced in vitro hepatocyte injury. (Cell line used in this experiment)

[0123] Human hepatocellular carcinoma HepG2 cells, which retain the characteristics of normal human hepatocytes, were cultured in DMEM medium (containing 100 U / ml penicillin and 100 μg / ml streptomycin) with 10% fetal bovine serum at 37°C, 5% CO2, and saturated humidity. Cells were passaged after digestion with 0.25% trypsin and 0.02% EDTA.

[0124] Experimental methods

[0125] (1) Effects of the compound on the proliferation of HepG2 cells

[0126] The MTT assay was used. HepG2 cells were seeded in 96-well cell culture plates and cultured for 24 h. Different concentrations of the test compound were added, with a solvent control group included. Each drug concentration was used in triplicate. After 24 h of drug treatment, the culture medium was discarded, and 100 μl of MTT (0.5 mg / ml) solution was added to each well. Cells were cultured for another 4 h, and the MTT solution was discarded. 150 μl of DMSO was added to each well, and the cells were shaken. The absorbance was measured at 570 nm using a microplate reader. Cell viability (%) = (average OD of treated cells / average OD of solvent control cells) × 100%.

[0127] (2) Protective effect of the compound against acetaminophen (APAP)-induced in vitro hepatocyte damage.

[0128] The MTT assay was used. HepG2 cells were seeded in 96-well cell culture plates and cultured for 24 h. Then, a non-toxic concentration of bicyclic alcohol derivative and acetaminophen (APAP, final concentration 8 mM) were added. Positive control groups (bicyclic alcohol and glutathione (GSH), a solvent blank control group, and a model group were also included. Cells were cultured for another 24 h. The culture medium was discarded, and 100 μl of MTT (0.5 mg / ml) solution was added to each well. Cells were cultured for another 4 h, and the MTT solution was discarded. 150 μl of DMSO was added to each well, and the mixture was shaken. The absorbance was measured at 570 nm using a microplate reader. Cell viability (%) = (average OD of the drug group / average OD of the solvent control group) × 100%.

[0129] Experimental results

[0130] (1) Cytotoxicity

[0131] ZT series compounds and W series compounds, when treated with HepG2 cells at a concentration of 10 μM for 24 h, showed no significant cytotoxicity to HepG2 cells, and the cell viability was greater than 90%. The 10 μM non-toxic concentration was used for subsequent experiments. (2) Protective effect against APAP-induced hepatocyte damage

[0132] APAP at 8 mM caused significant damage to HepG2 cells after 24 h, with cell viability significantly reduced (68.78%) compared to the control group. Under the current experimental protocol, ZT-4, ZT-5, ZT-8, ZT-9, ZT-10, ZT-11, ZT-12, ZT-13, ZT-14, ZT-16, ZT-17, and W33 at a concentration of 10 μM showed significant protective effects against APAP-induced HepG2 cell damage. Compounds ZT-4, ZT-10, ZT-11, ZT-12, ZT-13, and ZT-14 showed slightly better protective activity against APAP-induced human hepatocyte damage than bicyclol at the same dose. The experimental results are shown in Table 1.

[0133] Table 1. Effects of bicyclic alcohol derivatives on the reduction of hepatocyte survival rate by acetaminophen.

[0134]

[0135]

[0136] *** p<0.001, compared with the blank control group; # p<0.05, ## p<0.01, ### p<0.001, compared with the model group. Experimental Example 2: Activity test of bicyclic alcohol derivatives against hydrogen peroxide (H2O2)-induced in vitro hepatocyte injury. Experimental method.

[0137] The MTT assay was used. HepG2 cells were seeded in 96-well cell culture plates and cultured for 24 h. A non-toxic concentration of a bicyclic alcohol derivative was added. Positive control groups (bicyclic alcohol and glutathione (GSH), a solvent control group, and a model group were also included. After 12 h of drug treatment, except for the solvent control group which received an equal volume of culture medium, all other groups received 8 μL / well of 10 mM hydrogen peroxide (H2O2) solution (final concentration: 400 μM) for an additional 3 h of treatment. The culture medium was discarded, and 100 μL of MTT (0.5 mg / ml) solution was added to each well. Cells were cultured for another 4 h, and the MTT solution was discarded. 150 μL of DMSO was added to each well, and the mixture was shaken. The absorbance was measured at 570 nm using a microplate reader. Cell viability (%) = (average OD of cells in the drug-treated group / average OD of cells in the solvent control group) × 100%.

[0138] Experimental results

[0139] Treatment of HepG2 cells with 400 μM H2O2 for 3 hours caused significant cell damage, with cell viability significantly reduced (60.50%) compared to the control group. Under the current experimental protocol, ZT-5, ZT-8, ZT-11, ZT-13, ZT-14, ZT-15, ZT-16, ZT-17, W33, and W36 at a non-toxic concentration of 10 μM showed significant protective effects against H2O2-induced oxidative damage to HepG2 cells. The above-mentioned active compounds showed slightly better protective activity against H2O2-induced hepatocyte oxidative damage than bicyclol at the same dosage, with ZT-8, ZT-13, ZT-14, ZT-15, ZT-16, and ZT-17 exhibiting relatively better activity. The experimental results are shown in Table 2.

[0140] Table 2. Effects of bicyclic alcohol derivatives on the reduction of hepatocyte survival rate by hydrogen peroxide.

[0141]

[0142]

[0143] *** P < 0.001 compared with the blank control group; # P < 0.05 ## P < 0.01, ## P < 0.001, compared with the model group. Experimental Example 3: Activity test of bicyclic alcohol derivatives against oleic acid (OA)-induced hepatocyte lipid deposition.

[0144] Experimental methods

[0145] HepG2 cells were seeded in 96-well cell culture plates and cultured for 24 h. A non-toxic concentration (10 μM) of the test compound was added, along with oleic acid (OA, final concentration 180 μM). The experiment also included a fenofibrate (final concentration 10 μM) positive control group, a solvent control group, and a model group. Cells were cultured for another 24 h, and each well was washed three times with PBS. Cells were fixed with 4% paraformaldehyde for 40 min. They were washed three times with PBS. Oil Red O dye was added, and staining was performed in the dark for 1 h. Cells were washed three times with PBS. 50 μL of isopropanol was added, and the mixture was shaken for 5 min. The OD value was measured at 532 nm using a microplate reader. The OD value was directly proportional to lipid deposition in hepatocytes. The lipid deposition inhibition rate (%) was calculated as: (average OD value of the model group - average OD value of the drug-treated group) / (average OD value of the model group) × 100%.

[0146] Experimental results

[0147] 180 μM oleic acid induced significant lipid deposition in HepG2 cells, as evidenced by a significantly higher OD value after Oil Red O staining compared to the blank control group (p<0.001). Under the current experimental protocol, bicyclic alcohol derivatives all exhibited in vitro lipid-lowering activity. Among them, ZT-7, ZT-8, ZT-12, ZT-13, ZT-14, ZT-16, ZT-17, W33, and W36 showed significant inhibitory activity against oleic acid-induced lipid deposition in HepG2 cells at a dose of 10 μM, with inhibition rates of 20.08%, 15.13%, 16.24%, 12.17%, 20.13%, 14.71%, 14.04%, 15.38%, and 19.42%, respectively, which were statistically different from the model group. Fenofibrate 10 μM also significantly improved oleic acid-induced lipid deposition in hepatocytes; the experimental results are shown in Table 3.

[0148] Table 3. Effects of bicyclic alcohol derivatives on oleic acid-induced lipid deposition in HepG2 cells.

[0149]

[0150]

[0151] *** P < 0.001 compared with the blank control group; # P < 0.05 ## P < 0.01, ## P < 0.001, compared with the model group.

Claims

1. A class of bicyclic alcohol derivatives having the following general formula (I) or pharmaceutically acceptable salts thereof: (I) In the formula: X represents S and O; R1 is H; R2 is C 1-4 Alkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, aryl; The aryl group can be substituted or unsubstituted phenyl, furanyl, thiophene, isoxazolyl, pyrimidinyl, pyrazinyl, naphthyl, chromonel, quinolinyl, isoquinolinyl, or pyridinyl. The substituents on the benzene ring are selected from halogens. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy; Or R1 = R2, where R1 and R2 are H, methyl, or morpholine rings.

2. The bicyclic alcohol derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, C 1-4 The alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl; C 1-4 Alkoxy refers to n-butoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.

3. The bicyclic alcohol derivative or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that, The positions of the substituents on the benzene ring are para, meta, or ortho, and the number of substituents can be monosubstituted, disubstituted, or polysubstituted.

4. The bicyclic alcohol derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, characterized in that, The compounds are selected from the following:

5. A method for preparing the bicyclic alcohol derivative according to any one of claims 1-4, characterized in that, The preparation method of the compound is as follows: Reaction step a: First, the bicyclic alcohol is oxidized in an oxidizing agent to generate a bicyclic aldehyde; Reaction step b: The bicyclic aldehyde is condensed with the corresponding substituted aminothiourea or aminourea to give a compound of general formula (I), X, R 1、 R2 is defined as in any one of claims 1-4.

6. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises a bicyclic alcohol derivative of any one of claims 1-4 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

7. The pharmaceutical composition according to claim 6, characterized in that, The pharmaceutical composition is selected from injections, tablets, capsules, pills, powders, and ointments.

8. The pharmaceutical composition according to claim 7, characterized in that, The pharmaceutical composition is selected from controlled-release dosage forms, sustained-release dosage forms, and various microparticle delivery systems.

9. Use of the bicyclic alcohol derivative of any one of claims 1-4 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of liver-related diseases.

10. The application according to claim 9, characterized in that, The liver-related diseases mentioned are selected from hepatitis A, hepatitis B, hepatitis C, drug-induced liver disease, alcoholic liver disease, non-alcoholic liver disease, autoimmune liver disease, liver fibrosis, cirrhosis, and liver failure.

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