A tetrahydrothienopyridine derivative, a preparation method and application thereof

Abstract

The application provides a tetrahydrothienopyridine derivative and a preparation method and application thereof, and the structure is shown as formula (I). Based on the classic structure of 2-oxo clopidogrel and 2-oxo prasugrel, a series of novel tetrahydrothienopyridine derivatives are designed and synthesized, the novel tetrahydrothienopyridine derivatives have stable chemical properties, have better anti-platelet aggregation activity, effectively delay the release speed of active metabolites while reducing the dosage, improve the safety of the compounds, balance the effectiveness and safety to a certain extent, reduce the risk of bleeding, have no clopidogrel resistance phenomenon, and meanwhile, the drug property is improved, are novel safe anti-platelet aggregation drugs, have high medicinal research value, and have wide application prospects in preparation of anti-platelet aggregation drugs.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a tetrahydrothiophenepyridine derivative, its preparation method, and its application. Background Technology

[0002] Anticoagulants are drugs that prevent blood from clotting by interfering with certain steps of the body's physiological coagulation process. They are used to inhibit the formation and spread of thrombi and are mainly used clinically for the prevention and treatment of thromboembolic diseases. Thrombosis or embolism is the final critical step leading to cardiovascular, cerebrovascular, and peripheral vascular events, and is a direct cause of death and disability.

[0003] Currently, there are three classes of anticoagulants in clinical practice: direct anticoagulants, antiplatelet aggregation drugs, and thrombolytic drugs. Among them, antiplatelet aggregation drugs are the most prominent. Antiplatelet aggregation drugs include two types: those that inhibit arachidonic acid metabolism and those that inhibit ADP-activated platelets. The former is represented by aspirin, while the latter is represented by tetrahydrothiophene pyridine compounds, such as clopidogrel and prasugrel. In particular, clopidogrel occupies an important position in the anticoagulant market due to its excellent efficacy and safety, ranking among the top-selling drugs.

[0004] A significant drawback in the clinical application of clopidogrel is termed "clopidogrel resistance." This is primarily because clopidogrel requires two steps of hepatic enzyme metabolism to exert its effect. However, some patients have weak or absent liver enzymes involved in the first step of hepatic metabolism, leading to the drug losing its pharmacological activity. While other similar drugs have been marketed to address this issue and resolve clopidogrel resistance, their rapid drug release poses a significant risk of bleeding. Therefore, minimizing the bleeding risk while ensuring drug efficacy remains a critical challenge that urgently needs to be addressed. Summary of the Invention

[0005] In response to the "clopidogrel resistance" phenomenon and high bleeding risk that arises from clopidogrel clinical treatment, this invention provides a tetrahydrothiophenepyridine derivative, its preparation method, and its application.

[0006] To solve the above-mentioned technical problems, the technical solution provided by the present invention is as follows:

[0007] A substituted tetrahydrothiophenepyridine derivative, the structure of which is shown in formula (I):

[0008]

[0009] Wherein, R1 is a C1-C5 alkoxy or C3-C5 cycloalkyl; R2 is F, Cl, Br or I;

[0010] R3 is

[0011] Or C3-C6 cycloalkyl groups;

[0012] R4 is a C1-C5 alkyl or 2-methoxyphenyl; R5 and R6 are C1-C5 alkyl; n = 1-4.

[0013] Based on the classic structures of 2-oxoclopidogrel and 2-oxoprasugrel, this invention designs and synthesizes a series of novel tetrahydrothiophene-pyridine derivatives. These derivatives possess stable chemical properties and superior antiplatelet activity. While reducing the dosage, they effectively delay the release rate of active metabolites, improving the safety of the compounds. To a certain extent, they balance efficacy and safety, reducing the risk of bleeding and eliminating clopidogrel resistance. Furthermore, they improve drug-likeness, making them novel and safe antiplatelet aggregation drugs with high pharmaceutical research value and broad application prospects in the preparation of antiplatelet aggregation drugs.

[0014] Preferably, R1 is methoxy or cyclopropyl; R2 is F or Cl; R3 is

[0015] R4 is ethyl or 2-methoxyphenyl.

[0016] Furthermore, the structural formula of the substituted tetrahydrothiophenepyridine derivative is as follows:

[0017]

[0018]

[0019] Furthermore, the structural formula of the substituted tetrahydrothiophenepyridine derivative is as follows:

[0020]

[0021] Preferred substituted tetrahydrothiophenepyridine derivatives have high safety and better antiplatelet aggregation effect than clopidogrel, making them promising antiplatelet candidates that can replace clopidogrel.

[0022] When R1 is a C1-C5 alkoxy group, the method for preparing the substituted tetrahydrothiophenepyridine derivative includes the following steps:

[0023] Step a: Add the compound shown in formula (II), triethylamine and 4-dimethylaminopyridine to an inert solvent, cool to 0℃-5℃, add 4-nitrobenzenesulfonyl chloride solution under an inert atmosphere, and keep the reaction at the temperature to obtain the compound shown in formula (III);

[0024]

[0025] Step b: The compound shown in formula (Ⅲ), potassium carbonate and 4,5,6,7-tetrahydrothiopheno[3,2-c]pyridine-2(3H)-one are added to a polar solvent and reacted at 10℃-30℃ to obtain the compound shown in formula (Ⅳ);

[0026]

[0027] Step c: Add the compound shown in formula (Ⅳ) and triethylamine to an inert solvent, cool to 0℃-10℃, add dropwise the solution of the compound shown in formula (Ⅴ), and after the dropwise addition is completed, react at 10℃-30℃ under an inert atmosphere to obtain the tetrahydrothiophenepyridine derivative shown in formula (Ⅰ).

[0028]

[0029] The specific reaction route is shown below:

[0030]

[0031] Preferably, in steps a and c, the inert solvent is dichloromethane, dichloroethane, carbon tetrachloride, or benzene.

[0032] More preferably, in steps a and c, the inert solvent is dichloromethane.

[0033] Preferably, in step a, the heat preservation reaction time is 2h-6h.

[0034] More preferably, in step a, the heat preservation reaction time is 4h-5h.

[0035] It should be noted that in step a, the 4-nitrobenzenesulfonyl chloride solution is a dichloromethane solution of 4-nitrobenzenesulfonyl chloride solution.

[0036] Specifically, in step a, after the heat preservation reaction is completed, the compound is washed, dried, and concentrated to obtain the compound shown in formula (Ⅲ).

[0037] Preferably, the reaction time is 8h-20h.

[0038] More preferably, in step b, the reaction time is 15-16 hours.

[0039] Preferably, in step b, the polar solvent is acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, acetone, or N,N-dimethylacetamide.

[0040] Preferably, in step b, the polar solvent is acetonitrile.

[0041] In this invention, there are no special limitations on the ratio of raw materials used in the above preparation process, which can be adjusted by those skilled in the art through conventional experiments.

[0042] When R1 is a C3-C5 cycloalkyl group, the method for preparing the substituted tetrahydrothiophenepyridine derivative includes the following steps:

[0043] Step a: 4,5,6,7-tetrahydrothiopheno[3,2-c]pyridine-2(3H)-one and potassium carbonate are added to a polar solvent, cooled to 0℃-10℃, and a solution of the compound shown in formula (VI) is added dropwise. The reaction is carried out at 10℃-30℃ to obtain the compound shown in formula (VII).

[0044]

[0045] Step b: Add the compound shown in formula (Ⅶ) and triethylamine to an inert solvent, cool to 0℃-10℃, add the solution of the compound shown in formula (Ⅴ) dropwise, and after the dropwise addition is completed, react at 10℃-30℃ under an inert atmosphere to obtain the tetrahydrothiophenepyridine derivative shown in formula (Ⅰ).

[0046]

[0047] The specific reaction equation is as follows:

[0048]

[0049] Preferably, in step a, the reaction time is 8h-20h.

[0050] More preferably, in step a, the reaction time is 15-16 hours.

[0051] Preferably, in step a, the polar solvent is acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, acetone, or N,N-dimethylacetamide.

[0052] More preferably, in step a, the polar solvent is acetonitrile.

[0053] Preferably, in step b, the inert solvent is dichloromethane, dichloroethane, carbon tetrachloride, or benzene.

[0054] More preferably, in step b, the inert solvent is dichloromethane.

[0055] In this invention, there are no special limitations on the ratio of raw materials used in the above preparation process, which can be adjusted by those skilled in the art through conventional experiments.

[0056] The method for preparing substituted tetrahydrothiophenepyridine derivatives provided by this invention is simple, the reaction conditions are mild, and it is suitable for large-scale production applications.

[0057] The present invention also provides the use of the above-mentioned substituted tetrahydrothiophenepyridine derivatives or pharmaceutically acceptable salts thereof in the preparation of antiplatelet aggregation drugs.

[0058] It should be noted that the compounds of formula (I) described in this invention, their pharmaceutically acceptable salts, solvates, racemates, enantiomers or mixtures thereof can all be used to prepare drugs that can prevent and treat thrombotic diseases.

[0059] The marketed drug clopidogrel has different pharmacological activities in its S and R configurations. The compound described in this invention is mainly in the S configuration, and preliminary activity studies were conducted on the R configuration and racemic mixture.

[0060] Pharmaceutically acceptable salts may be hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, phosphate, acetate, propionate, butyrate, lactate, methanesulfonate, p-toluenesulfonate, maleate, benzoate, succinate, tartrate, citrate, fumarate, taurine, gluconate, or amino acid salts of the above-mentioned clopidogrel prodrug.

[0061] The tetrahydrothiophenepyridine derivative provided by this invention has good water solubility. While maintaining the high efficacy of clopidogrel, it effectively reduces the risk of bleeding, thereby significantly reducing the toxic side effects of the drug. It can be used as a drug to prevent or treat diseases caused by thrombosis or embolism and has high application potential in the preparation of antiplatelet aggregation drugs.

[0062] The present invention also provides a pharmaceutical composition for inhibiting platelet aggregation, comprising a pharmaceutically acceptable salt of the tetrahydrothiophenepyridine derivative described in any one of the preceding claims and at least one pharmaceutically acceptable carrier.

[0063] In preparing drugs that inhibit platelet aggregation, the above-mentioned tetrahydrothiophenepyridine derivatives or their salts provided by this invention can be mixed with suitable pharmacologically acceptable excipients, diluents, etc., to prepare tablets, capsules, granules, or powder dosage forms.

[0064] Specifically, these formulations can be manufactured using known methods with the following excipients. Optional excipients include: excipients such as sugar derivatives like lactose, sucrose, glucose, mannitol, and sorbitol; lubricants such as stearic acid, calcium stearate, and magnesium stearate; binders such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, and polyethylene glycol; disintegrants such as cellulose derivatives like low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, and calcium carboxymethyl cellulose; and flavoring agents such as commonly used sweeteners, acidulants, flavorings, and diluents.

[0065] Other commonly used excipients in this field can also be selected to formulate other drug dosage forms using conventional formulation methods in this field, such as suspensions, aerosols, oral solutions, syrups, sustained-release tablets, controlled-release tablets, or dry powder formulations, etc. The administration route can be injection, oral administration, etc.

[0066] Pharmacodynamic experiments showed that the substituted tetrahydrothiophenepyridine derivatives provided by this invention have significant inhibitory effects on platelet aggregation. Some compounds have significantly better antiplatelet aggregation effects than clopidogrel, and do not increase bleeding complications, with higher safety. They are suitable for preparing drugs to prevent or treat thrombosis and embolism-related diseases, and are expected to become safe and effective candidate drugs to replace clopidogrel, with broad application prospects. Detailed Implementation

[0067] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0068] Example 1

[0069] This embodiment provides a method for preparing the tetrahydrothiophene-pyridine derivative (S)-5-(1-(2-chlorophenyl)-2-methoxy-2-oxoethyl)-4,5,6,7-tetrahydrothiophene-[3,2-c]pyridin-2-yl(2-methoxyphenyl)succinate hydrochloride (QY-1):

[0070] 30.0 g (0.24 mol) of guaiacol, 150 mL of tetrahydrofuran, and 150 mL of dichloromethane were added to a 1000 mL three-necked flask. 73.4 g (0.73 mol) of triethylamine was added under stirring. The mixture was cooled to 0-10 °C in an ice-water bath. 72.5 g (0.72 mol) of succinic anhydride was added. After the addition was complete, the mixture was stirred at room temperature for 5 h. The reaction solution was evaporated to dryness under reduced pressure, dissolved in dichloromethane, washed with hydrochloric acid and water, and the organic phase was evaporated to dryness under reduced pressure. The mixture was then slurried with a 20:1 (v / v) mixture of petroleum ether and ethyl acetate, filtered, and the filter cake was evaporated to dryness to obtain 30.0 g of compound QY-1-1, with a yield of 55.4%.

[0071] 50.0 g (0.25 mol) of methyl 2-chloromandelate was added to a 1000 mL three-necked flask, followed by 250 mL of dichloromethane and stirring to dissolve. Then, 32.8 g (0.32 mol) of triethylamine and 3.0 g (0.025 mol) of 4-dimethylaminopyridine were added. The mixture was cooled to 0-5 °C and, under nitrogen protection, 60.8 g (0.27 mol) of a dichloromethane solution of 4-nitrobenzenesulfonyl chloride was added dropwise. After the addition was complete, the mixture was stirred at 0-5 °C for 3.5 h. The reaction solution was washed with water and saturated brine and evaporated to dryness under reduced pressure to obtain 82.5 g of QY-1-2, with a yield of 85.8%.

[0072] Add 82.5 g (0.21 mol) of the prepared QY-1-2 to a 2000 mL three-necked flask, add 800 mL of acetonitrile and stir, then add 54.2 g (0.54 mol) of potassium bicarbonate and 46.3 g (0.24 mol) of 4,5,6,7-tetrahydrothiopheno[3,2-c]pyridine-2(3H)-one. After the addition is complete, stir the reaction at room temperature for 15 h, filter, evaporate the filtrate to dryness under reduced pressure, and purify by column chromatography (200-300 mesh silica gel) to obtain 26.2 g of QY-1-3, with a yield of 36.3%.

[0073] 24.7 g (0.11 mol) of the prepared QY-1-1 was added to a 500 mL single-necked flask, followed by 250 mL of dichloromethane and 1 mL of N,N-dimethylformamide. The mixture was stirred, and 40.0 g (0.34 mol) of thionyl chloride was added at room temperature. The mixture was heated to reflux and reacted for 1 h. The mixture was then evaporated under reduced pressure to obtain 26.4 g of QY-1-4, with a yield of 98.8%.

[0074] 26.0 g (0.077 mol) of QY-1-3 was added to a 500 mL three-necked flask, followed by 300 mL of dichloromethane and stirring. Then, 11.7 g (0.12 mol) of triethylamine was added, and the mixture was cooled to 0-10 °C in an ice-water bath. A 100 mL solution of QY-1-4 (24.3 g, 0.10 mol) in dichloromethane was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 15 h under nitrogen protection. The reaction solution was evaporated to dryness under reduced pressure and purified by column chromatography to obtain 20.8 g of free QY-1, with a yield of 49.6%.

[0075] Add the above-prepared free QY-1 (5.0 g, 0.009 mol) to a 250 mL three-necked flask, dissolve it in 15 mL of ethyl acetate, cool it to 0-10 °C in an ice-water bath, add dropwise 2.5 mL of 4 mol / L hydrochloric acid-ethyl acetate solution, stir at 0-10 °C for 60 min, filter, and evaporate the filter cake to dryness under reduced pressure to obtain 5.0 g of QY-1, with a yield of 95.0%, chemical purity of 96.63%, and ee value of 95.2%.

[0076]

[0077] 1H-NMR(400MHz, CDCl3)δ7.732-7.689(m,1H),7.453-7.413(m,1H),7.285- 7.242(m,2H),7.220-7.176(m,1H),7.051-7.047(m,1H),7.031-6.912(m, 2H),6.282(s,1H),4.903(s,1H),3.800(s,3H),3.719(s,3H),3.676(m,1H ),3.568(m,1H),2.921(m,4H),2.893-2.865(m,2H),2.781-2.755(m,2H).

[0078] 13 C-NMR (600MHz, CDCl3) δ174.72,168.97,167.85,149.96,138.54,133.87,129.69,129.30,129.10,129.07,128.87,128.82,127.20,126.04,125 .90,121.75,121.66,110.45,110.59,66.16,54.85,52.31,51.31,50.59 ,49.99,48.87,48.59,48.02,47.16,28.06,28.01,27.85,27.68,19.76.

[0079] LCMS(ESI) m / z: 544.0 [M+H] + .

[0080] Example 2

[0081] This embodiment provides a method for preparing the tetrahydrothiophene-pyridine derivative (S)-5-(1-(2-chlorophenyl)-2-methoxy-2-oxyethyl)-4,5,6,7-tetrahydrothiophene-[3,2-c]pyridine-2-yl 2-aminobenzoate hydrochloride (QY-8):

[0082] QY-1-3 was prepared using the same method as in Example 1;

[0083] Add 10.0 g of o-nitrobenzoic acid (0.060 mol) to a 500 mL single-necked flask, add 200 mL of methanol and stir to dissolve, add 0.5 g of palladium on carbon catalyst, replace with hydrogen three times, react at room temperature for 48 h, and the reaction is complete as detected by TLC. Filter, concentrate the filtrate to dryness under reduced pressure to obtain 8.1 g of o-aminobenzoic acid, with a yield of 98.7%.

[0084] 2-Aminobenzoic acid (2.6 g, 0.019 mol) was added to a 250 mL single-necked flask, followed by the addition of dichloromethane (50 mL) and stirring to dissolve. Then, the prepared QY-1-3 (5.0 g, 0.015 mol) and 4-dimethylaminopyridine (0.2 g, 0.0015 mol) were added. The mixture was cooled to 0-10 °C in an ice-water bath, and N,N'-dicyclohexylcarboimide (4.6 g, 0.022 mol) was added in portions. After the addition was complete, the mixture was stirred at room temperature for 4 h. The reaction solution was then diluted with water (50 mL), separated, and the organic phase was washed with saturated brine, evaporated to dryness under reduced pressure, and purified by column chromatography to obtain 2.7 g of free QY-8, yield: 40.0%.

[0085] Add 2.7 g (0.0059 mol) of free QY-8 to a 250 mL single-necked flask, add 27 mL of ethyl acetate and stir to dissolve. Cool to 0-10 °C in an ice-water bath, and add 4.4 mL of 4 mol / L hydrochloric acid-ethyl acetate solution dropwise. After the addition is complete, place at room temperature and stir for 1 h. Filter, and remove the solvent by rotary evaporation of the filter cake to obtain 2.7 g of QY-8, with a yield of 91.2%, chemical purity of 97.10%, and ee value of 97.8%.

[0086]

[0087] 1 H-NMR(600MHz,CD3OD)δ7.911-7.895(m,1H),7.700-7.698(m,1H),7.686-7.684(m,1H),7.650-7.605(m,1H),7.594-7.536(m,1H),7.342-7.337 (m,1H),6.843-6.829(m,1H),6.669-6.644(m,1H),6.575(s,1H),5.871 (s,1H),4.614-4.089(m,2H),3.863-3.712(m,5H),3.299-3.154(m,2H).

[0088] 13 C-NMR (600MHz, DMSO-d6) δ167.19,164.10,151.71,151.48,135.33,135.20,13.73,130.95,130.63,130. 09,128.52,126.61,124.13,122.63,117.02,116.03,110.92,107.27,66.03,53.38,50.24,39.05,21.44.

[0089] LCMS(ESI) m / z: 457.1 [M+H] + .

[0090] Example 3

[0091] This embodiment provides a method for preparing the tetrahydrothiophene-pyridine derivative (S)-5-(1-(2-chlorophenyl)-2-methoxy-2-oxoethyl)-4,5,6,7-tetrahydrothiophene-[3,2-c]pyridine-2-yl ethyl succinate hydrochloride (QY-12):

[0092] QY-1-3 was prepared using the same method as in Example 1;

[0093] Add the prepared QY-1-3 (5.0 g, 0.015 mol) to a 150 mL three-necked flask, then add 50 mL of dichloromethane and stir. Add triethylamine (5.2 g, 0.051 mol) dropwise, cool to -20 to -10 °C, and add a mixed solution of succinic acid monoethyl ester chloride (4.4 g, 0.027 mol) and dichloromethane (10 mL) dropwise. After the addition is complete, heat to 25 °C and stir for 4 h under nitrogen protection. Wash the reaction solution successively with water and saturated brine, dry with anhydrous sodium sulfate, filter, evaporate to dryness, and purify by column chromatography (100-200 mesh silica gel) to obtain 3.0 g of free QY-12, yield: 43.5%.

[0094] Add 3.0 g (0.0064 mol) of free QY-12 to a 100 mL single-necked flask, add 50 mL of ethyl acetate and stir to dissolve. Add 6.5 mL of 2 mol / L ethyl hydrochloride solution and continue stirring for 60 min. Filter and dry under vacuum to obtain 3.0 g of QY-12. Yield: 93.2%, chemical purity: 94.95%, ee value: 94.8%.

[0095]

[0096] 1 H-NMR(600MHz,DMSO-d6)δ7.684(s,1H),7.595(s,1H),7.481-7.476(s,1H),6.512(s,1H),4.088-4.052(m,3H),3 .715(s,3H),3.399-3.053(m,3H),2.850-2.829(m,4H),2.662-2.650(m,2H),2.502(s,2H),1.186-1.163(m,3H).

[0097] LCMS(ESI) m / z: 466.1 [M+H] + .

[0098] Example 4

[0099] This embodiment provides a method for preparing the tetrahydrothiophene-pyridine derivative (S)-5-(1-(2-chlorophenyl)-2-methoxy-2-oxyethyl)-4,5,6,7-tetrahydrothiophene-[3,2-c]pyridin-2-yl 4-(dipropylamino)methyl)benzoate hydrochloride (QY-16):

[0100] QY-1-3 was prepared using the same method as in Example 1;

[0101] 30.0 g (0.18 mol) of 4-aldehyde benzoate was added to a 500 mL three-necked flask and dissolved by stirring with 300 mL of dichloromethane. 22.2 g (0.22 mol) of di-n-propylamine was added, and the mixture was cooled to 0-10 °C in an ice-water bath. Sodium triacetoxyborohydride (58.5 g, 0.28 mol) was added in portions. After the addition was complete, the mixture was stirred at room temperature for 4 h. 100 mL of water was added to the reaction solution, and the pH was adjusted to 8-9 with saturated sodium carbonate. The mixture was separated, and the aqueous phase was extracted once with 100 mL of dichloromethane. The organic phases were combined, washed with saturated brine, evaporated under reduced pressure, and purified by column chromatography (100-200 mesh silica gel) to obtain 35.0 g of QY-16-1, yield: 76.8%.

[0102] Add QY-16-1 (35.0 g, 0.14 mol) to a 1000 mL three-necked flask, dissolve in methanol (175 mL), and add an aqueous solution of sodium hydroxide (16.8 g, 0.42 mol) (175 mL) at room temperature. After the addition is complete, heat to reflux for 2 h, remove methanol by rotary evaporation under reduced pressure, cool to 0-10 °C, adjust pH to 4-5 with 3 mol / L hydrochloric acid, stir for 30 min, filter, and evaporate the filter cake to dryness to obtain 20.0 g of QY-16-2, yield 60.6%.

[0103] Add QY-16-2 (10.0 g, 0.042 mol) to a 500 mL three-necked flask, then add dichloromethane (100 mL), thionyl chloride (15.2 g, 0.13 mol) and N,N-dimethylformamide (10 drops). Heat to reflux for 2 h, then evaporate the reaction solution to dryness under reduced pressure to obtain 12.5 g of QY-16-3, with a yield of 100.0%.

[0104] Add QY-1-3 (6.0 g, 0.016 mol) to a 500 mL single-necked flask, then add dichloromethane (60 mL) and triethylamine (6.5 g, 0.064 mol) and stir. At room temperature, add 4-dimethylaminopyridine (0.2 g, 0.0016 mol), cool to 0-10 °C in an ice-water bath, and add dropwise a dichloromethane solution (50 mL) of QY-16-3 (5.6 g, 0.019 mol). After the addition is complete, under nitrogen protection, place the reaction solution at room temperature for 4 h. Add water (100 mL) to the reaction solution, separate the layers, add dichloromethane to the aqueous phase for extraction, combine the organic phases, wash with saturated brine, evaporate to dryness under reduced pressure, and purify by column chromatography (100-200 mesh silica gel column) to obtain 6.0 g of free QY-16, yield 67.4%.

[0105] Add 6.0 g (0.011 mol) of free QY-16 to a 250 mL single-necked flask, add 60 mL of ethyl acetate and stir to dissolve. Cool to 0-10 °C in an ice-water bath, add 8 mL of 4 mol / L ethyl acetate hydrochloride solution dropwise. After the addition is complete, place at room temperature and stir for 1 h. Filter, and dry the filter cake in a forced-air drying oven for 15 h to obtain 4.5 g of QY-16, with a yield of 70.0%, chemical purity of 98.54%, and ee value of 98.2%.

[0106]

[0107] 1 H-NMR (600MHz, CDCl3) δ12.346(s,1H),8.239-8.227(m,1H),8.124-8.111(m,2H),7.909-7.896(m,2H),7.442-7.392(m,3H),6.487(s ,1H),5.570(s,1H),4.268-4.259(m,3H),3.764(s,4H),3.109-2.837(m,6H),2.278-2.239(m,2H),1.973(s,4H),1.864-1.832(m,6H).

[0108] 13 C-NMR (600MHz, CDCl3) δ166.83,162.21,151.18,135.52,135.12,132.10,131.76,131.05,130.95,130.66 ,129.15,128.64,127.17,123.86,111.44,63.78,56.44,53.88,53.75,49.81,48.49,20.92,16.81,11.18.

[0109] LCMS(ESI) m / z: 555.4 [M+H]+ .

[0110] Example 5

[0111] This embodiment provides a method for preparing the tetrahydrothiophene-pyridine derivative (S)-5-(1-(2-chlorophenyl)-2-methoxy-2-oxyethyl)-4,5,6,7-tetrahydrothiophene-[3,2-c]pyridin-2-yl 4-(morpholinomethyl)benzoate hydrochloride (QY-18):

[0112] QY-1-3 was prepared using the same method as in Example 1;

[0113] 30.0 g (0.18 mol) of 4-aldehyde benzoate was added to a 500 mL three-necked flask and dissolved by stirring with 300 mL of dichloromethane. Morpholine (19.1 g, 0.22 mol) was added, and the mixture was cooled to 0-10 °C in an ice-water bath. Sodium triacetoxyborohydride (58.5 g, 0.28 mol) was added in portions. After the addition was complete, the mixture was stirred at room temperature for 4 h. Water (100 mL) was added to the reaction solution, and the pH was adjusted to 8-9 with saturated sodium carbonate. The mixture was separated, and the aqueous phase was extracted with 100 mL of dichloromethane. The organic phases were combined, washed with saturated brine, and evaporated to dryness under reduced pressure to obtain 40.0 g of QY-18-1, with a yield of 93.0%.

[0114] Add 40.0 g (0.17 mol) of QY-18-1 to a 1000 mL three-necked flask, dissolve it in 200 mL of methanol, and add 200 mL of an aqueous solution of sodium hydroxide (20.5 g, 0.51 mol) at room temperature. After the addition is complete, heat to reflux for 2 h, remove methanol by rotary evaporation under reduced pressure, cool to 0-10 °C, adjust pH to 4-5 with 3 mol / L hydrochloric acid, stir for 30 min, filter, and evaporate the filter cake to dryness to obtain 25.0 g of QY-18-2, with a yield of 66.5%.

[0115] Add QY-18-2 (10.0 g, 0.045 mol) to a 500 mL three-necked flask, then add dichloromethane (100 mL), thionyl chloride (16.2 g, 0.14 mol), and N,N-dimethylformamide (10 drops). Heat to reflux for 2 h, then evaporate the reaction solution to dryness under reduced pressure to obtain 12.5 g of QY-18-3, with a yield of 100.0%.

[0116] Add QY-1-3 (6.0 g, 0.016 mol) to a 500 mL single-necked flask, then add dichloromethane (60 mL) and triethylamine (6.5 g, 0.064 mol) and stir. Add 4-dimethylaminopyridine (0.2 g, 0.0016 mol) at room temperature, cool to 0-10 °C in an ice-water bath, and add a dichloromethane solution (60 mL) of QY-18-3 (5.3 g, 0.019 mol) dropwise. After the addition is complete, under nitrogen protection, the reaction solution is placed at room temperature for 4 h. Add water (100 mL) to the reaction solution, separate the layers, extract the aqueous phase with dichloromethane, combine the organic phases, wash with saturated brine, evaporate to dryness under reduced pressure, and purify by column chromatography (200-300 mesh silica gel column) to obtain 4.0 g of free QY-18, yield 46.1%.

[0117] Add 6.0 g (0.011 mol) of free QY-18 to a 250 mL single-necked flask, add 40 mL of ethyl acetate and stir to dissolve. Cool to 0-10 °C in an ice-water bath, and add 5.5 mL of 4 mol / L hydrochloric acid-ethyl acetate solution dropwise. After the addition is complete, stir at room temperature for 1 h, filter, and dry the filter cake in a forced-air drying oven for 15 h to obtain 2.5 g of QY-18, with a yield of 58.5%, chemical purity of 97.40%, and ee value of 98.4%.

[0118]

[0119] 1 H-NMR(400MHz, CDCl3)δ13.400(s,1H),8.23-8.21(m,3H),7.99-7.97(m,2H),7.54-7.50( m,3H),6.56(s,1H),5.57(s,1H),4.36-4.31(m,5H),4.01-3.75(m,7H),3.35-3.06(m,7H).

[0120] 13 C-NMR (600MHz, CDCl3) δ166.86,162.10,151.07,135.20,134.59,132.38,132.22,131.06, 130.76,129.10,128.64,123.93,111.30,64.16,63.58,59.78,58.28,53.95,51.58,18.43.

[0121] LCMS(ESI) m / z: 541.2 [M+H] + .

[0122] Example 6

[0123] This embodiment provides a method for preparing the tetrahydrothiophene-pyridine derivative 5-(1-(2-chlorophenyl)-2-methoxy-2-oxoethyl)-4,5,6,7-tetrahydrothiophene-[3,2-c]pyridin-2-yl-4-(morpholinomethyl)benzoate hydrochloride (QY-3):

[0124] QY-18-3 was prepared using the same method as in Example 5;

[0125] 50 g (0.25 mol) of racemic methyl 2-chloromandelate was added to a 1000 mL three-necked flask, followed by 250 mL of dichloromethane and stirring to dissolve. Triethylamine (32.8 g, 0.32 mol) and 4-dimethylaminopyridine (3.04 g, 0.025 mol) were then added. The mixture was cooled to 0-5 °C and, under nitrogen protection, 250 mL of a dichloromethane solution of 60.75 g (0.27 mol) of 4-nitrobenzenesulfonyl chloride was added dropwise. After the addition was complete, the mixture was stirred at 0-5 °C for 3.5 h. The reaction solution was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then evaporated to dryness under reduced pressure to obtain 182.5 g of QY-3-1, yield: 85.8%.

[0126] QY-3-1 (82.50 g, 0.21 mol) was added to a 2000 ml three-necked flask, followed by anhydrous acetonitrile (800 ml) and stirring. Potassium bicarbonate (54.17 g, 0.54 mol) and 4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2(3H)-one (46.32 g, 0.24 mol) were then added. After the addition was complete, the mixture was stirred at room temperature for 15 h. The mixture was then filtered, and the filtrate was evaporated to dryness under reduced pressure. The filtrate was purified by column chromatography (200-300 mesh silica gel) to obtain 26.2 g of QY-3-2, with a yield of 36.3%.

[0127] Add QY-3-2 (12.0 g, 0.032 mol) to a 500 mL single-necked flask, then add dichloromethane (120 mL) and triethylamine (13 g, 0.13 mol) and stir. Add 4-dimethylaminopyridine (0.4 g, 0.0032 mol) at room temperature, cool to 0-10 °C in an ice-water bath, and add 80 mL of dichloromethane solution of QY-18-3 (10.6 g, 0.038 mol) dropwise. After the addition is complete, under nitrogen protection, the reaction solution is placed at room temperature for 4 h. The reaction solution is washed with water-saturated brine, evaporated to dryness under reduced pressure, and purified by column chromatography (200-300 mesh silica gel column) to obtain 8.0 g of free QY-3, with a yield of 46.1%.

[0128] Add 6.0 g (0.011 mol) of free QY-3 to a 250 mL single-necked flask, add 40 mL of ethyl acetate and stir to dissolve. Cool to 0-10 °C in an ice-water bath, and add 5.5 mL of 4 mol / L hydrochloric acid-ethyl acetate solution dropwise. After the addition is complete, stir at room temperature for 1 h, filter, and dry the filter cake in a forced-air drying oven for 15 h to obtain 3.0 g of QY-3, with a yield of 46.9% and a chemical purity of 98.56%.

[0129]

[0130] 1 H-NMR(400MHz,CD3OD)δ8.300-8.283(m,2H),7.862-7.843(m,2H),7.740-7.560(m,4H),6.715(s,1H),5.923 (s,1H),4.454(s,2H),4.161-4.059(m,3H),3.901-3.806(m,7H),3.446-3.416(m,2H),3.311-3.269(m,5H).

[0131] 13 C-NMR (600MHz, CDCl3) δ166.36,162.05,151.29,135.25,134.56,132.41,131.08, 129.08,128.84,123.65,111.18,77.31,63.74,63.58,60.46,59.85,54.13,51.61.

[0132] LCMS(ESI) m / z: 541.1 [M+H] + .

[0133] Example 7

[0134] This embodiment provides a method for preparing the tetrahydrothiophene-pyridine derivative (S)-5-(1-(2-chlorophenyl)-2-methoxy-2-oxoethyl)-4,5,6,7-tetrahydrothiophene-[3,2-c]pyridin-2-yl 3-((4-methylpiperazin-1-yl)methyl)benzoate hydrochloride (QY-20):

[0135] QY-1-3 was prepared using the same method as in Example 1;

[0136] 25 g of methyl 3-bromomethylbenzoate (0.11 mol) was added to a 500 mL three-necked flask, followed by acetonitrile (250 mL) and stirring to dissolve. N-methylpiperazine (43.7 g, 0.44 mol) was then added, and the mixture was heated to 50 °C and reacted for 4 h. The reaction solution was evaporated to dryness under reduced pressure, dissolved in ethyl acetate (200 mL), washed once with water (150 mL) and once with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 25.0 g of QY-20-1, with a yield of 92.2%.

[0137] Add 25g (0.10mol) of QY-20-1 to a 1000mL three-necked flask, dissolve it in 125mL of methanol, add 125mL of an aqueous solution of sodium hydroxide (12.1g, 0.30mol) at room temperature, and reflux for 2 hours. Remove methanol by rotary evaporation under reduced pressure, cool to 0-10℃, adjust pH to 3-4 with 3mol / L hydrochloric acid, evaporate the aqueous phase to dryness under reduced pressure, add methanol and hot beat to remove salt, filter, and evaporate the filtrate to dryness at 45℃ to obtain 15.0g of QY-20-2, with a yield of 63.6%.

[0138] Add QY-20-2 (6.5 g, 0.028 mol) to a 500 mL three-necked flask, then add dichloromethane (70 mL) and N,N-dimethylformamide (10 drops), followed by the addition of thionyl chloride (9.9 g, 0.083 mol). The mixture is then heated to reflux for 2 h. The reaction solution is evaporated to dryness under reduced pressure to obtain 7.0 g of QY-20-3, with a yield of 100%.

[0139] Add QY-1-3 (8.0 g, 0.021 mol) to a 500 mL single-necked flask, then add dichloromethane (80 mL) and triethylamine (8.7 g, 0.086 mol) and stir. Add 4-dimethylaminopyridine (0.26 g, 0.0021 mol) at room temperature, cool to 0-10 °C in an ice-water bath, and add dropwise a dichloromethane solution (100 mL) of the prepared QY-20-3 (7.0 g, 0.028 mol). After the addition is complete, under nitrogen protection, place the reaction solution at room temperature for 4 h. Wash the reaction solution with water and saturated brine, evaporate to dryness under reduced pressure, and purify by column chromatography (200-300 mesh silica gel column) to obtain 3.5 g of free QY-20, with a yield of 29.6%.

[0140] Add 3.5 g (0.0063 mol) of free QY-20 to a 250 mL single-necked flask, add 35 mL of ethyl acetate and stir to dissolve. Cool to 0-10 °C in an ice-water bath, and add 5.0 mL of ethyl acetate solution of 4 mol / L hydrochloric acid dropwise. After the addition is complete, stir at room temperature for 1 h, filter, and dry the filter cake by blowing air for 15 h to obtain 3.5 g of QY-20, with a yield of 90.0%, a chemical purity of 95.03%, and an ee value of 97.9%.

[0141]

[0142] 1 H-NMR(400MHz,CD3OD)δ8.24-8.22(m,2H),7.76-7.74(m,2H),7.59-7.53(m,2H),7.38-7.31(m,2H),6.60(s,1H),5 .41(s,1H),4.27(s,2H),3.89(s,5H),3.79-3.75(m,1H),3.11-3.01(m,8H),2.16-2.10(m,1H),1.11-0.91(m,4H).

[0143] 13 C-NMR (600MHz, CDCl3) δ167.41,162.65,151.24,135.84,135.28,132.58,131.40,130.87,129.31,128 .46,126.98,124.63,123.18,111.47,66.12,59.94,53.29,51.92,50.18,48.88,42.07,26.58,22.30.

[0144] LCMS(ESI) m / z: 554.2 [M+H] + .

[0145] Example 8

[0146] This embodiment provides a method for preparing the tetrahydrothiophene-pyridine derivative (S)-5-(1-(2-chlorophenyl)-2-methoxy-2-oxoethyl)-4,5,6,7-tetrahydrothiophene-[3,2-c]pyridin-2-yl-3-aminopropionate hydrochloride (QY-22):

[0147] QY-1-3 was prepared using the same method as in Example 1;

[0148] Add 5.0 g of 3-morpholinopropionate (0.026 mol) to a 500 mL three-necked flask, then add 50 mL of dichloromethane and 10 drops of N,N-dimethylformamide, followed by 8.1 g of thionyl chloride (0.068 mol). Heat to reflux for 2 h, and evaporate the reaction solution to dryness under reduced pressure to obtain 7.0 g of QY-22-1, with a yield of 100.0%.

[0149] Add QY-1-3 (5.0 g, 0.015 mol) to a 150 mL three-necked flask, add dichloromethane (50 mL) and stir. Add triethylamine (7.8 g, 0.077 mol) dropwise. Cool to -20 to -10 °C. Add a mixed solution of QY-22-1 (7 g, 0.043 mol) and dichloromethane (10 mL) dropwise. After the addition is complete, heat to 25 °C under nitrogen protection and stir for 4 h. Wash the reaction solution once with water and once with saturated brine, dry with anhydrous sodium sulfate, evaporate to dryness, and purify by column chromatography (100-200 mesh silica gel column) to obtain 2.5 g of free QY-22, yield 25.0%.

[0150] Add 2.5 g (0.0052 mol) of free QY-22 to a 100 mL single-necked flask, add 50 mL of ethyl acetate and stir to dissolve. Add 5.2 mL of 2 mol / L ethyl hydrochloride solution and continue stirring for 60 min. Filter and dry under vacuum to obtain 2.4 g of QY-22. Yield: 88.5%, chemical purity: 95.00%, ee value: 97.3%.

[0151]

[0152] 1 H-NMR(600MHz,DMSO-d6)δ11.30(s,1H),7.61-7.60(m,1H),7.53-7.52(m,1H),7.42-7.41(m,2H),6.52(s,1H),4.90-4.88(m,1H) ,3.97-3.95(m,2H),3.80-3.76(m,2H),3.67-3.61(m,5H),3.25-3.23(m,2H),3.10-3.09(m,2H),2.94-2.89(m,2H),2.74(s,2H).

[0153] LCMS(ESI) m / z: 479.1 [M+H] + .

[0154] Example 9

[0155] This embodiment provides a method for preparing the tetrahydrothiophene-pyridine derivative (S)-5-(1-(2-chlorophenyl)-2-methoxy-2-oxoethyl)-4,5,6,7-tetrahydrothiophene-[3,2-c]pyridin-2-yl-3-(2-acetoxy-4,6-dimethylphenyl)-3-methylbutyrate hydrochloride (QY-28):

[0156] QY-1-3 was prepared using the same method as in Example 1;

[0157] 3-(2-acetoxy-4,6-dimethylphenyl)-3-methylbutyric acid (4.0 g, 0.015 mol) was added to a 250 mL single-necked flask, followed by dichloromethane (40 mL), N,N-dimethylformamide (5 drops), and sulfoxide (5.4 g, 0.045 mol). The mixture was stirred until homogeneous, and the mixture was heated to reflux for 3 h. The mixture was then evaporated to dryness under reduced pressure to obtain 4.1 g of QY-28-1, with a yield of 95.4%.

[0158] Add QY-1-3 (4.53 g, 0.012 mol) to a 250 mL three-necked flask, add dichloromethane (45 mL) and stir, then add triethylamine (4.6 g, 0.045 mol) and 4-dimethylaminopyridine (0.2 g, 0.0016 mol), cool to 0-10 °C in an ice-water bath, and add dropwise a dichloromethane solution (20 mL) of the prepared QY-28-1 (4.1 g, 0.014 mol). After the addition is complete, under nitrogen protection, stir at room temperature for 5 h, wash with water and saturated saline, dry with anhydrous sodium sulfate, evaporate to dryness under reduced pressure, and purify by column chromatography (200-300 mesh silica gel column) to obtain 4.0 g of free QY-28, with a yield of 47.2%.

[0159] Add 4.0 g (0.007 mol) of free QY-28 to a 250 mL three-necked flask, add 20 mL of ethyl acetate and stir to dissolve. Cool to 0-10 °C in an ice-water bath, add 2.5 mL of 4 mol / L hydrochloric acid-ethyl acetate solution, stir at 0-10 °C for 30 min, filter, and evaporate the filter cake under reduced pressure to remove the solvent to obtain 4.2 g of QY-28, with a yield of 95.0%, chemical purity of 95.32%, and ee value of 95.7%.

[0160]

[0161] 1 H-NMR (400MHz, CDCl3) δ8.35-8.34(m,1H),7.54-7.44(m,3H),6.86(s,1H),6.64(s,1H),6.24(s,1H),5.58(s,1H ),4.29(s,1H),3.78-3.73(m,5H),3.25-3.08(m,5H),2.58(s,3H),2.34(s,3H),2.26(s,3H),1.67-1.65(m,6H).

[0162] 13C-NMR (600MHz, CDCl3) δ169.86,168.11,166.35,151.33,149.32,137.93,136.61,134.97,132.61,132.13,131.16, 130.56,128.79,126.80,123.15,123.02,122.07,111.10,62.92,60.40,53.92,47.59,39.08,25.33,21.56,20.27.

[0163] LCMS(ESI) m / z: 584.2 [M+H] + .

[0164] Example 10

[0165] This embodiment provides a method for preparing the tetrahydrothiophene pyridine derivative (S)-5-(1-(2-chlorophenyl)-2-methoxy-2-oxoethyl)-4,5,6,7-tetrahydrothiophene [3,2-c]pyridin-2-yl-4-(neovaleroxy)benzoate hydrochloride (QY-79):

[0166] QY-1-3 was prepared using the same method as in Example 1;

[0167] Add 50 g of 4-hydroxybenzoic acid (0.36 mol) to a 2000 mL three-necked flask, dissolve pyridine (500 mL) in it, add 13.3 g of 4-dimethylaminopyridine (0.11 mol) at room temperature, cool to 0-5 °C, add 300 mL of a dichloromethane solution of 131 g of trimethylacetyl chloride (1.09 mol) dropwise, stir at room temperature for 2 h, add 1000 mL of water to the reaction solution, stir at room temperature for 3 h, extract with dichloromethane, wash with 3 mol / L hydrochloric acid and saturated brine, dry with anhydrous sodium sulfate, evaporate to dryness under reduced pressure, add petroleum ether and stir at room temperature for 60 min, filter, evaporate the filter cake to dryness to obtain 70.0 g of QY-79-1, yield 87.1%;

[0168] Add QY-79-1 (2.2 g, 0.0099 mol) to a 250 mL single-necked flask, add dichloromethane (30 mL) and N,N-dimethylformamide (3 drops), stir, add thionyl chloride (3.8 g, 0.032 mol) at room temperature, heat to reflux for 3 h, evaporate to dryness under reduced pressure to obtain 7.5 g of QY-79-2, yield 97.5%;

[0169] Add QY-1-3 (3.0 g, 0.080 mol) to a 250 mL three-necked flask, add dichloromethane (30 mL) and stir, then add triethylamine (2.1 g, 0.021 mol) and 4-dimethylaminopyridine (0.1 g, 0.00081 mol), cool to 0-10 °C in an ice-water bath, and add dropwise a dichloromethane solution (20 mL) of the prepared QY-79-2 (7.5 g, 0.031 mol). After the addition is complete, under nitrogen protection, stir at room temperature for 3 h. Wash the reaction solution with water and saturated brine, dry with anhydrous sodium sulfate, evaporate to dryness under reduced pressure, and purify by column chromatography (200-300 mesh silica gel column) to obtain 2.5 g of free QY-79, yield 46.6%.

[0170] Add 2.5 g (0.0046 mol) of free QY-79 to a 250 mL three-necked flask, add 10 mL of ethyl acetate and stir to dissolve. Cool to 0-10 °C in an ice-water bath, add 2.0 mL of 4 mol / L hydrochloric acid-ethyl acetate solution, stir at 0-10 °C for 30 min, filter, and evaporate the filter cake under reduced pressure at 45 °C to remove the solvent, yielding 1.5 g of QY-79, with a yield of 57.0%, chemical purity of 98.40%, and ee value of 95.9%.

[0171]

[0172] 1 H-NMR(400MHz,CD3OD)δ8.24-8.22(m,2H),7.74-7.62(m,3H),7.59-7.57(m,1H),7.33-7.31(m,2H ),6.68(s,1H),5.89(s,1H),4.40-4.12(m,2H),3.81-3.79(m,5H),3.33-3.26(m,2H),1.41(s,9H).

[0173] 13 C-NMR (600MHz, CDCl3) δ176.45,1673.23,162.29,162.29,156.08,151.36,135.31,132.69,131.46,130.11, 128.52,126.70,125.13,124.48,122.88,122.07,111.32,66.06,60.15,53.36,50.19,38.84,25.99,21.48.

[0174] LCMS(ESI) m / z: 542.1 [M+H] + .

[0175] Example 11

[0176] This embodiment provides a method for preparing the tetrahydrothiophene-pyridine derivative 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-4,5,6,7-tetrahydrothiophene-[3,2-c]pyridin-2-yl(2-methoxyphenyl)succinate hydrochloride (QY-2):

[0177] QY-1-4 was prepared using the same method as in Example 1;

[0178] Add 30.0 g (0.16 mol) of 4,5,6,7-tetrahydrothiopheno[3,2-c]pyridine-2(3H)-one to a 1000 mL three-necked flask, add 250 mL of acetonitrile and stir, add 39.2 g (0.39 mol) of potassium bicarbonate, cool to 0-10 °C, and under nitrogen protection, add dropwise a solution of 44.3 g (0.17 mol) of 2-bromo-2-(2-fluorophenyl)-1-cyclopropyl ethyl ketone in 50 mL of acetonitrile. After the addition is complete, place at room temperature and stir for 15 h, filter, evaporate the filtrate to dryness under reduced pressure, and purify by column chromatography (100-200 mesh silica gel column) to obtain 25.0 g of QY-2-1, with a yield of 48.2%.

[0179] Add QY-2-1 (15.0 g, 0.045 mol) to a 500 mL three-necked flask, add dichloromethane (150 mL) and stir to dissolve, add triethylamine (9.2 g, 0.091 mol), cool to 0-10 °C in an ice-water bath, add dropwise a dichloromethane solution of QY-1-4 (16.5 g, 0.068 mol) (50 mL), after which, under nitrogen protection, place at room temperature and stir for 15 h, evaporate the reaction solution to dryness under reduced pressure, and purify by column chromatography (200-300 mesh silica gel column) to obtain 1.5 g of free QY-2, yield 6.2%;

[0180] Add 1.5 g (0.003 mol) of free QY-2 to a 250 mL single-necked flask, add 15 mL of ethyl acetate and stir. Cool the flask to 0-10 °C in an ice-water bath, add 2 mL of 1 mol / L hydrochloric acid-ethyl acetate solution, stir at 0-10 °C for 60 min, filter, and evaporate the filter cake under reduced pressure to remove the solvent to obtain 1.5 g of QY-2, with a yield of 94.0% and a chemical purity of 98.96%.

[0181]

[0182] 1H-NMR(600MHz, CDCl3)δ8.105-7.783(m,1H),7.479-7.457(m,1H),7.319-7.294(m,1H), 7.196-7.121(m,3H),6.977-6.962(m,1H),6.903-6.858(m,2H),6.418-6.199(m,1H),5. 587(s,1H),4.564(s,1H),4.183-3.630(m,5H),3.628-3.102(m,2H),2.955-2.811(m,5H ),1.731(m,1H),1.227-1.189(m,1H),1.079(s,1H),0.963(s,1H),0.821-0.810(s,1H).

[0183] 13 C-NMR (600MHz, CDCl3) δ200.39,169.97,168.78,162.04,160.36,151.27,150.97,139.54,133.54,127.08,126.22, 123.43,122.66,122.45,120.76,116.72,116.58,112.48,66.69,55.90,49.74,47.70,29.06,28.67,19.91,13.39.

[0184] LCMS(ESI) m / z: 538.3 [M+H] + .

[0185] Example 12

[0186] This embodiment provides a method for preparing the tetrahydrothiophene-pyridine derivative 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-4,5,6,7-tetrahydrothiophene-[3,2-c]pyridin-2-yl 2-aminobenzoate hydrochloride (QY-7):

[0187] QY-2-1 was prepared using the same method as in Example 10;

[0188] Add 10.0 g of o-nitrobenzoic acid (0.060 mol) to a 500 mL single-necked flask, add 200 mL of methanol and stir to dissolve, add 0.5 g of palladium on carbon catalyst, replace with hydrogen three times, react at room temperature for 48 h, and the reaction is complete as detected by TLC. Filter, concentrate the filtrate to dryness under reduced pressure to obtain 8.1 g of o-aminobenzoic acid, with a yield of 98.7%.

[0189] Add 1.6 g (0.012 mol) of o-aminobenzoic acid to a 100 mL single-necked flask, add 30 mL of dichloromethane and stir to dissolve, add 3.0 g (0.0091 mol) of QY-2-1, add 0.1 g (0.0008 mol) of 4-dimethylaminopyridine, cool to 0-10 °C in an ice-water bath, add 2.8 g (0.014 mol) of N,N'-dicyclohexylcarbodiimide, stir at room temperature for 4 h after the addition is complete, add 30 mL of water to the reaction solution, separate the solution, wash with saturated brine, evaporate to dryness under reduced pressure, and purify by column chromatography (100-200 mesh silica gel column) to obtain free QY-71.6 g, yield 39.0%;

[0190] Add 1.6 g (0.0036 mol) of free QY-7 to a 250 mL single-necked flask, add 16 mL of ethyl acetate and stir to dissolve. Cool to 0-10 °C in an ice-water bath, and add 2.7 mL of 4 mol / L ethyl hydrochloride solution dropwise. After the addition is complete, place at room temperature and stir for 1 h. Filter to obtain 1.6 g of compound QY-7 as filter cake, with a yield of 92.5% and a chemical purity of 95.89%.

[0191]

[0192] 1 H-NMR(400MHz,CD3OD-d4)δ8.207-8.187(m,1H),7.769-7.712(m,1H),7.697-7.655(m, 1H),7.613(s,1H),7.496-7.449(m,2H),7.355-7.335(m,1H),7.299-7.261(m,1H),6.7 01(s,1H),6.149(s,1H),4.828-3.513(m,4H),3.338-3.334(m,1H),3.267-3.226(m,1H ),1.977-1.928(m,1H),1.364-1.305(m,1H),1.211-1.104(m,2H),1.038-0.971(m,1H).

[0193] 13 C-NMR(600MHz,DMSO-d6)δ201.75,163.12,162.46,160.81,150.94,143.78,135.40,134.03,133.97,131.30,125.91 ,125.83,123.14,121.62,120.37,116.88,116.74,113.28,111.50,70.13,51.97,49.24,21.63,19.38,12.83,12.40.

[0194] LCMS(ESI) m / z: 451.2 [M+H] + .

[0195] Example 13

[0196] This embodiment provides a method for preparing the tetrahydrothiophene-pyridine derivative 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-4,5,6,7-tetrahydrothiophene-[3,2-c]pyridin-2-yl ethyl succinate hydrochloride (QY-13):

[0197] QY-2-1 was prepared using the same method as in Example 10;

[0198] Add QY-2-1 (5.0 g, 0.015 mol) to a 150 mL three-necked flask, add dichloromethane (50 mL) and stir, then add triethylamine (6.1 g, 0.060 mol) dropwise. Cool to -20 to -10 °C, then add a mixed solution of succinic acid monoethyl ester chloride (4.9 g, 0.030 mol) and dichloromethane (10 mL). After the addition is complete, heat to 25 °C and stir for 4 h under nitrogen protection. Wash the reaction solution successively with water and saturated brine, dry with anhydrous sodium sulfate, evaporate to dryness under reduced pressure, and purify by column chromatography (100-200 mesh silica gel column) to obtain 34.2 g of free QY-1, with a yield of 60.6%.

[0199] Add 4.2 g (0.0091 mol) of free QY-13 to a 100 mL single-necked flask, add 50 mL of ethyl acetate and stir to dissolve. Add 9 mL of 2 mol / L ethyl acetate hydrochloride solution dropwise and continue stirring for 60 min. Cool to 5–10 °C, stir for 30 min, filter, and dry under vacuum to obtain 4.0 g of QY-13, with a yield of 88.6% and a chemical purity of 93.45%.

[0200]

[0201] 1 H-NMR,600MHz,DMSO-d6)δ7.658-7.650(s,2H),7.474(m,1H),7.424-7.399(m,1H),6.575(s,1H),6.153(s,1H),4.074-4.062(m,2H),3 .076(s,3H),2.849-2.837(m,2H),2.665-2.644(m,2H),2.506-2.500(m,2H),1.185-1.161(m,3H),1.106(s,9H),0.921-0.910(m,2H).

[0202] LCMS(ESI) m / z: 460.2 [M+H] + .

[0203] Example 14

[0204] This embodiment provides a method for preparing the tetrahydrothiophene-pyridine derivative 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxyethyl)-4,5,6,7-tetrahydrothiophene-[3,2-c]pyridin-2-yl 4-(dipropylamino)methyl)benzoate hydrochloride (QY-17):

[0205] QY-16-3 was prepared using the same method as in Example 4; QY-2-1 was prepared using the same method as in Example 10.

[0206] Add QY-2-1 (10.0 g, 0.030 mol) to a 500 mL single-necked flask, then add dichloromethane (100 mL) and triethylamine (9.2 g, 0.091 mol) and stir. At room temperature, add 4-dimethylaminopyridine (0.4 g, 0.0033 mol), cool to 0-10 °C in an ice-water bath, and add dropwise a dichloromethane solution (45 mL) of QY-16-3 (10.5 g, 0.036 mol). After the addition is complete, under nitrogen protection, place the reaction solution at room temperature for 4 h. Wash the reaction solution with water and saturated saline, evaporate to dryness under reduced pressure, and purify by column chromatography (200-300 mesh silica gel column) to obtain 7.5 g of free QY-17, with a yield of 45.3%.

[0207] Add 10.0 g (0.014 mol) of free QY-17 to a 250 mL single-necked flask, add 75 mL of ethyl acetate and stir to dissolve. Cool to 0-10 °C in an ice-water bath, and add 10 mL of 4 mol / L hydrochloric acid-ethyl acetate solution dropwise. After the addition is complete, stir the mixture at room temperature for 1 h, filter, and dry the filter cake in a forced-air drying oven for 15 h to obtain 7.0 g of QY-17, with a yield of 87.5% and a chemical purity of 98.03%.

[0208]

[0209] 1H-NMR(600MHz, CDCl3)δ12.470(s,1H),8.123-8.111(m,2H),7.955-7.871(m,3H),7.503-7.493( m,1H),7.334-7.309(m,1H),7.218-7.188(m,1H),6.489-6.377(m,1H),5.658(s,1H),4.616-4.60 6(s,1H),4.234-4.226(m,2H),3.870-3.817(m,2H),3.264-3.231(s,1H),2.943-2.835(m,5H),1. 857-1.838(m,6H),1.747(s,1H),1.252(s,1H),1.094(s,1H),0.984(s,6H),0.904-0.892(m,1H).

[0210] 13 C-NMR (600MHz, CDCl3) δ200.56,162.16,160.44,151.14,135.81,133.70,132.81,131.83,130.84,128.91,126.19,12 3.83,122.57,116.88,116.74,114.97,111.25,56.40,53.82,50.04,48.48,47.78,21.05,20.00,16.88,13.48,11.20.

[0211] LCMS(ESI) m / z: 549.2 [M+H] + .

[0212] Example 15

[0213] This embodiment provides a method for preparing the tetrahydrothiophene-pyridine derivative 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxyethyl)-4,5,6,7-tetrahydrothiophene-[3,2-c]pyridin-2-yl-4-(morpholinomethyl)benzoate hydrochloride (QY-19):

[0214] QY-2-1 was prepared using the same method as in Example 10; QY-18-3 was prepared using the same method as in Example 5.

[0215] Add QY-2-1 (10.0 g, 0.030 mol) to a 500 mL single-necked flask, then add dichloromethane (100 mL) and triethylamine (9.2 g, 0.091 mol) and stir. Add 4-dimethylaminopyridine (0.4 g, 0.0033 mol) at room temperature, cool to 0-10 °C in an ice-water bath, and add 50 mL of dichloromethane solution of QY-18-3 (10.0 g, 0.036 mol) dropwise. After the addition is complete, under nitrogen protection, place the reaction solution at room temperature for 4 h. Wash the reaction solution with water and saturated saline, evaporate to dryness under reduced pressure, and purify by column chromatography (200-300 mesh silica gel column) to obtain 7.5 g of free QY-19, with a yield of 46.5%.

[0216] Add 7.5 g (0.014 mol) of free QY-19 to a 250 mL single-necked flask, add 75 mL of ethyl acetate and stir to dissolve. Cool to 0-10 °C in an ice-water bath, and add 10.5 mL of 4 mol / L hydrochloric acid-ethyl acetate solution dropwise. After the addition is complete, stir at room temperature for 1 h, filter, and dry the filter cake in a forced-air drying oven for 15 h to obtain 6.0 g of QY-19, with a yield of 78.5% and a chemical purity of 98.13%.

[0217]

[0218] 1 H-NMR(400MHz,CD3OD)δ8.24-8.22(m,2H),7.76-7.74(m,2H),7.59-7.53(m,2H),7.38-7.31(m,2H),6.60(s,1H),5 .41(s,1H),4.27(s,2H),3.89(s,5H),3.79-3.75(m,1H),3.11-3.01(m,8H),2.16-2.10(m,1H),1.11-0.91(m,4H).

[0219] 13 C-NMR(600MHz,DMSO-d6)δ205.67,162.16,162.33,160.69,150.20,131.75,131.26,131.16,131.01,130.24,129.03,1 25.44,125.04,116.13,115.98,111.73,70.94,64.20,60.32,52.08,50.13,50.10,49.14,23.21,18.71,11.67,11.64.

[0220] LCMS(ESI) m / z: 535.6 [M+H] + .

[0221] Example 16

[0222] This embodiment provides a method for preparing the tetrahydrothiophene-pyridine derivative 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxyethyl)-4,5,6,7-tetrahydrothiophene-[3,2-c]pyridin-2-yl-3-((4-methylpiperazin-1-yl)methyl)benzoate hydrochloride (QY-21):

[0223] QY-2-1 was prepared using the same method as in Example 10; QY-20-2 was prepared using the same method as in Example 6.

[0224] Add QY-20-2 (6.5 g, 0.028 mol) to a 500 mL three-necked flask, add dichloromethane (70 mL) and N,N-dimethylformamide (10 drops), add thionyl chloride (9.9 g, 0.083 mol), heat to reflux for 2 h, and evaporate the reaction solution to dryness under reduced pressure to obtain QY-21-1, 7.0 g, yield 100%;

[0225] Add 8.0 g (0.024 mol) of QY-2-1 to a 500 mL single-necked flask, then add 80 mL of dichloromethane and 8.7 g (0.086 mol) of triethylamine and stir. Add 0.26 g (0.0021 mol) of 4-dimethylaminopyridine at room temperature. Cool the mixture to 0-10 °C in an ice-water bath. Add 40 mL of a dichloromethane solution of the above-mentioned QY-21-1 (7.0 g, 0.028 mol). After the addition is complete, the reaction solution is placed at room temperature for 4 h under nitrogen protection. The reaction solution is washed with water and saturated saline, evaporated to dryness under reduced pressure, and purified by column chromatography (200-300 mesh silica gel column) to obtain 3.5 g of free QY-21, with a yield of 24.9%.

[0226] Add 3.5 g (0.0064 mol) of free QY-21 to a 250 mL single-necked flask, add 35 mL of ethyl acetate and stir to dissolve. Cool to 0-10 °C in an ice-water bath, add 5.0 mL of 4 mol / L hydrochloric acid-ethyl acetate solution dropwise. After the addition is complete, place at room temperature and stir for 1 h. Add 35 mL of petroleum ether and stir for 15 min. Filter under vacuum, and dry the filter cake in a forced-air drying oven for 15 h to obtain 3.5 g of QY-21, with a yield of 90.0% and a chemical purity of 99.00%.

[0227]

[0228] 1H-NMR(400MHz,CD3OD)δ8.29(s,1H),8.18-8.16(m,1H),7.86-7.84(m,1H),7 .75-7.73(m,1H),7.67-7.63(m,1H),7.58(s,1H),7.50-7.46(m,2H),6.75(s ,1H),6.13(s,1H),4.07(s,4H),3.95-3.72(m,6H),3.26-3.22(m,4H),2.96( s,5H),1.98-1.94(m,1H),1.36-1.31(m,1H),1.19-1.02(m,2H),1.00(m,1H).

[0229] 13 C-NMR(600MHz,DMSO-d6)δ201.85,162.73,160.46,151.26,135.89,134.10,131.45,130.09,129.41,128.46,125.94,12 4.56,123.22,116.93,116.68,115.13,114.95,114.42,70.15,59.94,51.96,48.88,42.05,21.65,19.41,12.84,12.43.

[0230] LCMS(ESI) m / z: 548.2 [M+H] + .

[0231] Example 17

[0232] This embodiment provides a method for preparing the tetrahydrothiophene-pyridine derivative 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-4,5,6,7-tetrahydrothiophene-[3,2-c]pyridin-2-yl-3-aminopropionate hydrochloride (QY-23):

[0233] QY-2-1 was prepared using the same method as in Example 10; QY-22-1 was prepared using the same method as in Example 7;

[0234] Add QY-2-1 (5.0 g, 0.015 mol) to a 150 mL three-necked flask, add dichloromethane (50 mL) and stir. Add triethylamine (7.8 g, 0.077 mol) dropwise. Cool to -20 to -10 °C. Add a mixed solution of QY-22-1 (7.0 g, 0.043 mol) and dichloromethane (10 mL) dropwise. After the addition is complete, heat to 25 °C under nitrogen protection and stir for 4 h. Wash the reaction solution with water and saturated brine in sequence, dry with anhydrous sodium sulfate, filter and evaporate to dryness. Purify by column chromatography (100-200 mesh silica gel column) to obtain free QY-233.0 g, yield 41.7%.

[0235] Add 3.0 g (0.0064 mol) of free QY-23 to a 100 mL single-necked flask, add 50 mL of ethyl acetate and stir to dissolve. Add 6.5 mL of 2 mol / L ethyl acetate hydrochloride solution dropwise, continue stirring for 60 min, cool to 5–10 °C, stir for 30 min, filter, and dry under vacuum to obtain 3.0 g of QY-23, with a yield of 93.5% and a chemical purity of 92.30%.

[0236]

[0237] 1 H-NMR (400MHz, CDCl3) δ7.91(s,1H),7.60-7.82(m,1H),7.42-7.38(m,1H),7.28-7.30(m,1H),6.45(s,1H),5.80(s,1H ),4.23-4.04(m,6H),3.54-3.49(m,8H),3.17(s,4H),1.84(s,1H),1.33-1.31(s,1H),1.17-1.069(d,2H),0.93(d,1H).

[0238] LCMS(ESI) m / z: 473.1 [M+H] + .

[0239] Example 18

[0240] This embodiment provides a method for preparing the tetrahydrothiophene-pyridine derivative 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-4,5,6,7-tetrahydrothiophene-[3,2-c]pyridine-2-yl cinnamic acid ester hydrochloride (QY-63):

[0241] QY-2-1 was prepared using the same method as in Example 10;

[0242] Cinnamic acid (2.7 g, 0.018 mol) was added to a 250 mL single-necked flask, followed by dichloromethane (30 mL) and N,N-dimethylformamide (3 drops). The mixture was stirred, and thionyl chloride (7.2 g, 0.061 mol) was added at room temperature. The mixture was heated to reflux and reacted for 3 h. The mixture was then evaporated to dryness under reduced pressure to obtain 3 g of QY-63-1, with a yield of 100%.

[0243] Add QY-2-1 (5.0 g, 0.015 mol) to a 250 mL three-necked flask, add dichloromethane (50 mL) and stir, then add triethylamine (3.1 g, 0.031 mol) and 4-dimethylaminopyridine (0.18 g, 0.0014 mol), cool to 0-10 °C in an ice-water bath, and add dropwise a dichloromethane solution (20 mL) of the above QY-63-1 (3 g, 0.018 mol). After the addition is complete, under nitrogen protection, stir at room temperature for 3 h, wash with water and saturated brine, dry with anhydrous sodium sulfate, and purify by vacuum rotary cyclohexane chromatography (200-300 mesh silica gel column) to obtain 5.0 g of free QY-63, yield 71.0%.

[0244] Add 5.0 g (0.010 mol) of free QY-63 to a 250 mL three-necked flask, add 50 mL of ethyl acetate and stir to dissolve. Cool to 0-10 °C in an ice-water bath, add 4.0 mL of 4 mol / L hydrochloric acid-ethyl acetate solution, stir at 0-10 °C for 30 min, filter, and evaporate the filter cake under reduced pressure at 45 °C to remove the solvent, to obtain 4.0 g of QY-63, with a yield of 74.0% and a chemical purity of 90.01%.

[0245]

[0246] 1 HNMR (400MHz, CDCl3) δ7.98 (s, 1H), 7.85 (dd, J = 4.0Hz, J = 4.0Hz, 1H), 7.58-7 .51(m,4H),7.44-7.36(m,5H),7.30-7.23(m,1H),6.55-6.43(m,2H),5.95(s ,1H),4.01-4.92(m,2H),3.99-3.40(m,2H),2.80-3.39(s,2H),1.82(s,1H), 1.35-1.30(m,1H),1.23(s,1H),1.18(t,J=4.0Hz,J=8.0Hz,1H),0.93(m,1H).

[0247] LCMS(ESI) m / z: 462.2 [M+H] + .

[0248] Example 19

[0249] This embodiment provides a method for preparing the tetrahydrothiophene-pyridine derivative 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-4,5,6,7-tetrahydrothiophene-[3,2-c]pyridin-2-yl-4-(neopentyloxy)benzoate hydrochloride (QY-80):

[0250] QY-2-1 was prepared using the same method as in Example 10; QY-79-1 was prepared using the same method as in Example 9.

[0251] Add QY-79-1 (2.65 g, 0.012 mol) to a 250 mL single-necked flask, add dichloromethane (30 mL) and N,N-dimethylformamide (3 drops), stir, add thionyl chloride (4.2 g, 0.035 mol) at room temperature, heat to reflux for 3 h, and evaporate to dryness under reduced pressure to obtain 6.3 g of QY-80-1, yield 98.0%;

[0252] Add QY-2-1 (3.0 g, 0.009 mol) to a 250 mL three-necked flask, add dichloromethane (30 mL) and stir, then add triethylamine (1.4 g, 0.014 mol) and 4-dimethylaminopyridine (0.15 g, 0.0012 mol), cool to 0-10 °C in an ice-water bath, and add dropwise a dichloromethane solution (20 mL) of the prepared QY-80-1 (6.3 g, 0.012 mol) above. After the addition is complete, under nitrogen protection, stir at room temperature for 3 h, wash with water and saturated saline, dry with anhydrous sodium sulfate, evaporate to dryness under reduced pressure, and purify by column chromatography (200-300 mesh silica gel column) to obtain 3.5 g of free QY-80, yield 73.0%.

[0253] Add 3.5 g (0.0065 mol) of free QY-80 to a 250 mL three-necked flask, add 35 mL of ethyl acetate, stir, cool in an ice-water bath to 0-10 °C, add 2.5 mL of 4 mol / L hydrochloric acid-ethyl acetate solution, stir at 0-10 °C for 30 min, filter, and evaporate the filter cake under reduced pressure to remove the solvent, to obtain 3.0 g of QY-80, with a yield of 81.0% and a chemical purity of 98.52%.

[0254]

[0255] 1H-NMR(400MHz,CD3OD)δ8.24-8.21(m,2H),7.77-7.71(m,1H),7.56-7.45(m,3H),7.33-7.31(m,2H),6.68(s,1H),6.09(s,1H), 4.17-3.35(m,4H),3.35-3.33(m,2H),1.99-1.94(m,1H),1.41(s,9H),1.41-1.32(m,1H),1.19-1.12(m,2H),1.04-0.97(m,1H).

[0256] 13 C-NMR(600MHz,DMSO-d6)δ201.82,176.46,162.47,162.30,160.81,156.07,151.26,133.99,133.93,131.45,125.89 ,125.86,125.14,124.47,123.18,122.08,116.87,116.73,111.29,70.10,38.85,25.99,21.64,19.37,12.80,12.38.

[0257] LCMS(ESI) m / z: 536.2 [M+H] + .

[0258] Pharmacological trials

[0259] 1. Single-time-point platelet aggregation inhibition test in rats

[0260] Experimental procedure:

[0261] Wistar rats were acclimatized for about one week, fasted for 12 hours, and the following day, positive control drug (clopidogrel bisulfate) and test compounds prepared in Examples 1-19 were prepared. The solvent was 1% sodium carboxymethyl cellulose solution, and the drug concentrations were 1 mg / mL and 0.3 mg / mL, respectively, with an administration volume of 10 mL / kg for both. Four hours after administration, the rats were anesthetized by intraperitoneal injection of 0.35 mL / 100 g of 10% chloral hydrate. Blood was collected from the abdominal aorta using a sodium citrate blood collection tube, with 3 mL collected per tube (containing 0.3 mL of sodium citrate). The tubes were inverted 5-8 times to mix, and centrifuged at 190 g for 10 min using a horizontal centrifuge. The supernatant was collected as platelet-rich plasma (PRP), and the supernatant was collected as platelet-anemic plasma (PPP) after centrifugation at 1900 g for 10 min. According to the platelet aggregator operating procedure, platelet-poor plasma (PPP) and platelet-rich plasma (PRP) samples were placed sequentially in their respective channels. Finally, 25 μL of adenosine diphosphate (ADP) aqueous solution (final concentration 5 μmol / L) was added, and the maximum platelet aggregation rate was measured within 5 min. The results are shown in Tables 1 and 2.

[0262] Table 1

[0263]

[0264]

[0265] The results showed that compounds QY-1, QY-16, QY-18, QY-20, and QY-22 had essentially the same activity as clopidogrel (10 mg / kg) at a dose of 3 mg / kg. QY-12 (3 mg / kg) showed superior activity compared to clopidogrel (10 mg / kg).

[0266] Table 2

[0267] serial number Maximum platelet aggregation rate (%) Blank control 61.67±7.39 Clopidogrel bisulfate (10 mg / kg) 33.26±12.82 QY-2 (1mg / kg) 49.58±8.15 QY-7 (1mg / kg) 41.53±2.86 QY-13 (1mg / kg) 18.95±1.22 QY-17 (1mg / kg) 48.57±2.79 QY-19 (1mg / kg) 36.3±4.67 QY-21 (1mg / kg) 34.60±7.7 QY-23 (1mg / kg) 45.42±11.61 QY-63 (1mg / kg) 51.07±4.31 QY-80 (1mg / kg) 37.83±4.50

[0268] Compounds QY-19, QY-21, and QY-80 at a dose of 1 mg / kg showed essentially the same activity as clopidogrel (10 mg / kg).

[0269] 2. Study on the time-effect curve of anticoagulation in rats

[0270] Experimental procedure:

[0271] Wistar rats were acclimatized for about one week and fasted for 12 hours. The next day, positive control drug clopidogrel bisulfate and compounds QY-16, QY-18, QY-20, and QY-22 were prepared in 1% sodium carboxymethyl cellulose solution at concentrations of 1 mg / mL and 0.3 mg / mL, respectively. The administration volume for each drug was 10 ml / kg. Anesthetized rats by intraperitoneal injection of 0.35 mL / 100 g of 10% chloral hydrate at 0.5 h, 2 h, 4 h, 12 h, and 24 h after administration. Blood was collected from the abdominal aorta using a sodium citrate blood collection tube, and 3 mL / tube (containing 0.3 mL of sodium citrate) was collected. The tube was inverted 5-8 times to mix the blood, and centrifuged at 180 g for 10 min using a horizontal centrifuge. The supernatant was collected as PRP, and centrifuged at 1910 g for 10 min. The supernatant was collected as PPP. According to the platelet aggregator operating procedure, each sample's PPP and PRP were placed in the corresponding channel in sequence. Finally, 25 μL of ADP aqueous solution (final concentration of 5 μmol / L) was added, and the maximum platelet aggregation rate was detected within 5 min. The platelet aggregation rate change curve within 24 h was plotted, and the results are shown in Table 3.

[0272] Table 3

[0273]

[0274] The results showed that compounds QY-16, QY-18, QY-20, and QY-22 reached their maximum inhibition rates between 2 and 4 hours, and the inhibition rates recovered somewhat after 12 hours. Moreover, their inhibitory effects were superior to those of clopidogrel bisulfate.

[0275] 3. Acute toxicity test studies

[0276] Based on a comprehensive assessment of physical properties and anticoagulant activity, acute toxicity tests were conducted on compounds QY-2, QY-8, QY-16, QY-18, QY-19, and QY-20.

[0277] Experimental procedure:

[0278] SD rats were acclimatized for about one week and fasted for 12 hours. The next day, a mixture of clopidogrel bisulfate (positive control) and the aforementioned compounds was prepared using a solution of 10% dimethyl sulfoxide and 90% physiological saline. In one group, the dosage of clopidogrel bisulfate, QY-2, QY-8, QY-16, QY-18, QY-19, and QY-20 was 1500 mg / kg; in the other group, the dosage of clopidogrel bisulfate, QY-16, and QY-18 was 2500 mg / kg. Rats were observed for 14 days after administration. Each group consisted of 6 rats (half male and half female). Observational indicators included spontaneous movement, respiratory status, salivation and collapse, mydriasis, vomiting, gastrointestinal bleeding, and pulmonary congestion. The results are shown in Table 4.

[0279] Table 4: Comparison of Acute Toxicity Test Results of Clopidogrel and Compounds

[0280]

[0281]

[0282] 4. Study on the time-effect curve of anticoagulation function in beagle dogs

[0283] Experimental procedure:

[0284] ① Dosing regimen: Beagle dogs were randomly divided into several groups of 4 dogs each (half male and half female). The dosage of clopidogrel bisulfate was 3 mg / kg, and the dosage of the QY-18 clopidogrel prodrug compound prepared in the example was 1 mg / kg.

[0285] ② Blood sample collection: Groom and disinfect the dog's forelimbs. Use a lancet to collect two tubes of whole blood from the forelimbs. Collect blood at 0h before administration and at 1h, 4h, 6h, 12h, and 24h after administration (3-6 mL / time point). The blood is collected into an anticoagulant tube with the inner wall filled with 3.8% sodium citrate solution (the volume ratio of sodium citrate to blood is 1:9). After collecting one tube, invert it slowly 5-8 times to ensure that the blood and anticoagulant are fully mixed and prevent clotting.

[0286] ③ Blood sample processing: Centrifuge the blood sample at 1100 rpm for 10 min, and take the supernatant as PRP. Centrifuge the remaining blood sample at 3500 rpm for 10 min, and take the supernatant as PPP. Transfer the supernatant PRP to the same EP tube and set the temperature to 22-25℃.

[0287] ④ Blood sample testing: 225 μL of PRP and 250 μL of PPP were added to the test cups of the platelet aggregator. Then, 25 μL of ADP (1:3) was added to each test cup through the machine to induce platelet aggregation.

[0288] ⑤ Calculation formula: Platelet aggregation inhibition rate (%) = [1 - (aggregation percentage of administration tube / aggregation percentage of control tube)] × 100%

[0289] The results are shown in Tables 5 and 6.

[0290] Table 5. Intracanal efficacy of clopidogrel bisulfate

[0291]

[0292] Table 6. Drug efficacy of compounds in dogs

[0293]

[0294]

[0295] The experimental results show that clopidogrel bisulfate at 3 mg / kg is as effective as QY-18, QY-16, QY-20, and QY-22 at 1 mg / kg.

[0296] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A tetrahydrothiophenepyridine derivative, characterized in that, Its structural formula is: 、 or .

2. The method for preparing the tetrahydrothiophenepyridine derivative according to claim 1, characterized in that, Includes the following steps: Step a: Add the compound shown in formula (II), triethylamine and 4-dimethylaminopyridine to an inert solvent, cool to 0℃-5℃, add 4-nitrobenzenesulfonyl chloride solution under an inert atmosphere, keep the reaction at the temperature, and obtain the compound shown in formula (III); Formula (II) Formula (III); Step b: The compound shown in formula (III), potassium carbonate and 4,5,6,7-tetrahydrothiopheno[3,2-c]pyridine-2(3H)-one are added to a polar solvent and reacted at 10℃-30℃ to obtain the compound shown in (IV); Formula (Ⅳ); Step c: Add the compound shown in formula (Ⅳ) and triethylamine to an inert solvent, cool to 0℃-10℃, add dropwise the solution of the compound shown in formula (Ⅴ), and after the dropwise addition is completed, react at 10℃-30℃ under an inert atmosphere to obtain the tetrahydrothiophenepyridine derivative shown in formula (Ⅰ). Formula (V); Where R1 is methoxy, R2 is Cl, and R3 is... , or .

3. The method for preparing the tetrahydrothiophenepyridine derivative as described in claim 2, characterized in that, In steps a and c, the inert solvent is dichloromethane, dichloroethane, carbon tetrachloride, or benzene; and / or In step a, the heat preservation reaction time is 2h-6h; and / or In step b, the reaction time is 8h-20h; and / or In step b, the polar solvent is acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, acetone, or N,N-dimethylacetamide.

4. The use of the tetrahydrothiophenepyridine derivative of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of an antiplatelet aggregation drug.

5. A pharmaceutical composition for inhibiting platelet aggregation, characterized in that, It includes a pharmaceutically acceptable salt of the tetrahydrothiophenepyridine derivative of claim 1 and at least one pharmaceutically acceptable carrier.

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