Nitrosothiol compounds, methods of synthesis, uses thereof

Abstract

The application discloses a kind of nitroso thiol compounds and synthesis method, purposes thereof, belong to medical field.The application provides a kind of compound shown in formula I or formula II or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopically labeled compound or prodrug, the compound of the present application is relative to existing product clopidogrel and prasugrel, (1) its platelet aggregation inhibition rate is high;(2) faster onset;(3) to the Asian race due to the loss of P450 enzyme, drug is more easily absorbed, and the efficacy is better;It can be used for treating, improving and preventing cardiovascular diseases, and has good application prospect and important clinical significance.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to a class of nitrosothiols and their synthesis methods and uses. Background Technology

[0002] Thrombotic diseases are various conditions caused by thrombosis, which narrows or blocks blood vessels, leading to ischemia and infarction of major organs and resulting in functional disorders. Factors contributing to thrombosis include platelet adhesion and aggregation on the damaged blood vessel wall, blood stasis, activation of coagulation factors promoting thrombin formation, and decreased fibrinolytic activity. Clinically, drugs used to treat thrombosis can be divided into three categories: antiplatelet drugs, anticoagulants, and thrombolytics. Antiplatelet drugs have both therapeutic and preventative effects and are the main category of antithrombotic drugs. Antiplatelet drugs are those that inhibit platelet adhesion, aggregation, and release, preventing thrombus formation, and are used to prevent and treat ischemic heart and brain diseases and peripheral thromboembolic diseases. Currently, antiplatelet drugs are classified into three generations: aspirin is the first generation, thiaclopidogrel is the second generation (thiaphenpyridines, a class of antiplatelet drugs targeting adenosine diphosphate receptors, currently the most widely used antiplatelet aggregation and antithrombotic drugs in clinical practice / non-thiaphenpyridines), such as clopidogrel / prasugrel, and platelet membrane glycoprotein Ilb / IIIa receptor antagonists are the third generation. As a second-generation thiaphenpyridine derivative, the P2Y12-ADP receptor antagonist clopidogrel has better safety than thiaclopidogrel. Aspirin and clopidogrel are currently the standard combination for antiplatelet therapy, becoming the gold standard for antithrombotic drug therapy. However, the combined use of the two drugs increases the incidence of bleeding.

[0003] Clopidogrel, developed by Sanofi, is currently the most widely used antiplatelet aggregation drug worldwide. Clopidogrel is a prodrug that needs to be metabolized in the body to its active product to exert its effect. However, after oral administration, clopidogrel is rapidly metabolized in the liver. Approximately 85% is hydrolyzed by esterases into an inactive carboxylic acid derivative. The remaining approximately 15% undergoes a two-step oxidation process by the hepatic P450 enzyme system, resulting in a ring-opening metabolism that produces a saturated cyclic amine active metabolite. This metabolite covalently binds to the P2Y12 receptor on the platelet surface, inhibiting platelet aggregation by antagonizing the P2Y12 receptor. Furthermore, the problem of "clopidogrel resistance" exists, therefore more effective antithrombotic drugs remain in clinical need.

[0004]

[0005] Sankyo Pharmaceuticals of Japan and Eli Lilly and Company of the United States developed prasugrel, a next-generation antiplatelet drug, based on the structure of clopidogrel. Prasugrel is also a prodrug. Structurally, prasugrel belongs to the classic thienopyridine class of P2Y12 receptor antagonists, preceded by ticlopidine and clopidogrel. Ticlopidine, as an early P2Y12 receptor antagonist, was a pioneer in this structural class. The development of prasugrel, with its stronger activity, further overcomes the shortcomings of clopidogrel's metabolism in vivo, adding another important option for clinical use. However, its relatively high bleeding risk greatly limits its clinical application.

[0006]

[0007] As is well known, NO, also known as endothelial relaxing factor (EDRF), is a highly active substance. Compounds can release nitrogen oxides (NO) into the organism and exhibit certain vascular system activities in many cases, such as vasodilatory activity or inhibition of platelet aggregation, which makes them potentially useful for treating various conditions related to circulatory system dysfunction.

[0008] In the process of studying the metabolic actives of clopidogrel and prasugrel, the inventors discovered a new class of nitrosothiol derivatives. Compared with clopidogrel and prasugrel, these compounds have superior pharmacokinetic properties and stronger antiplatelet activity. It is expected that these compounds will have good therapeutic effects and have good development prospects. Summary of the Invention

[0009] The problem the invention aims to solve

[0010] The purpose of this invention is to provide a novel active metabolite of clopidogrel and prasugrel containing nitrosothiol, which can be used to treat atherosclerotic thrombosis and its related complications.

[0011] Solution for solving the problem

[0012] In a first aspect, the present invention provides a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label, or prodrug thereof.

[0013]

[0014] Among them, R1 and R1' are independently selected from H, -COOR4, and R2 and R2' are each independently selected from fluorine, chlorine, or bromine; R3 and R3' are each independently selected from H or C1-4 alkyl; R4 is a C1-4 alkyl.

[0015] In one embodiment of the present invention, the compound specifically includes the following structure:

[0016]

[0017] In one embodiment of the present invention, the pharmaceutically acceptable salt is an inorganic salt or an organic salt. The inorganic salt includes sodium salts, potassium salts, calcium salts, magnesium salts, iron salts, hydrochloride salts, hydrobromide salts, hydroiodide salts, sulfates, hydrogen sulfate salts, nitrates, phosphates, and acid phosphates. The organic salt is selected from acetates, trifluoroacetates, propionates, pyruvates, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, sulfonate, benzenesulfonate, and salicylates.

[0018] In a second aspect, the present invention also provides pharmaceutical compositions comprising compounds of the structures shown in formulas (I) and (II) above, or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, tautomers, cis-trans isomers, isotope labels, and prodrugs thereof.

[0019] In one embodiment of the invention, the pharmaceutical composition further includes a pharmaceutically acceptable carrier, excipient, or diluent.

[0020] In one embodiment of the invention, the pharmaceutically acceptable carrier is selected from microcapsules, microspheres, nanoparticles, and liposomes.

[0021] Thirdly, the present invention provides the use of compounds with the structures shown in formulas (I) and (II) above, or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, tautomers, cis-trans isomers, isotope labels, and prodrugs thereof in the preparation of drugs for antiplatelet aggregation.

[0022] Fourthly, the present invention provides the use of compounds with the structures shown in formulas (I) and (II) above, or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, tautomers, cis-trans isomers, isotope labels, and prodrugs thereof in the preparation of medicaments for the treatment of thrombosis.

[0023] Fifthly, the present invention provides the use of compounds of the above general formula or pharmaceutically acceptable salts thereof in the preparation of medicaments for the prevention or treatment of thrombosis and embolism-related diseases such as atherosclerotic diseases, myocardial infarction, stroke, ischemic cerebral thrombosis, peripheral artery disease, acute coronary syndrome or thrombosis after coronary intervention.

[0024] In one embodiment of the present invention, the dosage form of the drug includes: injection, lyophilized powder for injection, suspension, implant, embolization, capsule, tablet, pill and oral liquid.

[0025] In one embodiment of the present invention, the dosage form of the drug is an intravenous injection.

[0026] In one embodiment of the present invention, the dosage form of the drug is a solid dosage form for oral administration, including, but not limited to, capsules, tablets, pills, powders, granules, etc. In these solid dosage forms, the compounds of general formulas (I) and (II) of the present invention are mixed as active ingredients with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate. Or it may be mixed with the following components: (1) fillers or solubilizers, such as starch, lactose, sucrose, glucose, mannitol and silica; (2) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, gum arabic; (3) humectants, such as glycerin; (4) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginic acid, certain silicates and sodium carbonate; (5) slowing agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glyceryl monostearate; (8) adsorbents, such as kaolin; (9) lubricants, such as talc, calcium stearate, solid polyethylene glycol, sodium dodecyl sulfate, etc., or mixtures thereof. Buffers may also be included in capsules, tablets and pills.

[0027] The solid dosage forms, such as tablets, sugar pills, capsules, pellets, and granules, can be coated or microencapsulated with coating and shell materials such as enteric coatings and other materials known in the art. They may contain opaque agents, and the release of the active ingredient from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active ingredient may also be formed into microcapsules with one or more of the excipients described above.

[0028] The dosage forms of the compounds of the present invention or their pharmaceutically acceptable salts are liquid dosage forms for oral administration, including, but not limited to, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, tinctures, etc. In addition to the compounds of general formulas (I) and (II) or their pharmaceutically acceptable salts as active ingredients, the liquid dosage forms may contain inert diluents conventionally used in the art, such as water and other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn oil, olive oil, castor oil, sesame oil, etc., or mixtures of these substances. In addition to these inert diluents, the liquid dosage forms of the present invention may also include conventional adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0029] The suspending agent includes, for example, ethoxylated octadecyl alcohol, polyoxyethylene sorbitol, and dehydrated sorbitol, microcrystalline cellulose, agar, or mixtures thereof.

[0030] The dosage forms of the compounds of this invention and their pharmaceutically acceptable salts are for parenteral injection, including, but not limited to, physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions and dispersions. Suitable carriers, diluents, solvents, and excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0031] Dosage forms of the compounds of the present invention or pharmaceutically acceptable salts thereof for topical administration include ointments, powders, suppositories, drops, sprays, and inhalers. The compounds of general formulas (I) and (II) of the present invention or pharmaceutically acceptable salts thereof, as active ingredients, are mixed under sterile conditions with a physiologically acceptable carrier and optionally with preservatives, buffers, and propellants, if necessary.

[0032] The compounds of the present invention, or pharmaceutically acceptable salts thereof, shall be administered to mammals in unit doses ranging from 0.001 to 200 mg / kg, particularly 0.005 to 100 mg / kg, and particularly 0.01 to 50 mg / kg, and this should provide an effective dose. However, the daily dose will necessarily vary depending on the host being treated, the specific route of administration, and the severity of the disease being treated. Therefore, the optimal dose may be determined by the practitioner treating any particular patient.

[0033] The effects of the invention

[0034] The advantages of this invention compared to existing products clopidogrel and prasugrel are mainly reflected in the following aspects:

[0035] (1) It has a high platelet aggregation inhibition rate;

[0036] (2) It takes effect faster;

[0037] (3) For Asians who lack the P450 enzyme, the drug is more easily absorbed and has a better effect.

[0038] It has promising application prospects and significant clinical value. Detailed Implementation

[0039] Before further describing the invention, it should be understood that the invention is not limited to the specific embodiments described herein; it should also be understood that the terminology used herein is for description only and not for limiting the specific embodiments.

[0040] [Terminology Definition]

[0041] The term "pharmaceutically acceptable" means that the salts, solvents, excipients, etc., are generally non-toxic, safe, and suitable for patient use. The term "patient" preferably refers to mammals, and more preferably humans.

[0042] The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt as defined herein and possesses all the functions of the parent compound. Pharmaceutically acceptable salts can be prepared by adding a suitable acid to a suitable organic solvent containing an organic base, following conventional methods. In this invention, "pharmaceutically acceptable salt" can be an inorganic or organic salt. Inorganic salts include hydrochlorides, hydrobroms, hydroiodates, sulfates, hydrogen sulfates, nitrates, phosphates, acid phosphates, etc., while organic salts include acetates, trifluoroacetates, propionates, pyruvates, glycolate, oxalates, malonates, fumarates, maleates, lactates, malates, citrates, tartrates, methanesulfonates, sulfonates, benzenesulfonates, salicylates, etc.

[0043] The term "hydrate" refers to a substance formed by the combination of a compound of the present invention or a pharmaceutically acceptable salt thereof with water through non-covalent intermolecular forces. Common hydrates include (but are not limited to) hemihydrates, monohydrates, dihydrates, and trihydrates.

[0044] The term "solvent" refers to a substance formed by the combination of a compound of the present invention or a pharmaceutically acceptable salt thereof with at least one solvent molecule through non-covalent intermolecular forces. The term "solvent" includes "hydrate." Common solvates include (but are not limited to) hydrates, ethanol compounds, acetone compounds, etc. It should be understood that the present invention covers all solvate forms possessing PRMT5 inhibitory activity.

[0045] The term "isomer" refers to compounds that have the same number and type of atoms and therefore the same molecular weight, but differ in the spatial arrangement or configuration of the atoms.

[0046] The term "stereoisomer" (or "optical isomer") refers to a stable isomer that, due to having at least one chiral element (including a chiral center, chiral axis, chiral plane, etc.), has a perpendicular asymmetric plane, thereby enabling the rotation of plane-polarized light. Since the compounds of this invention contain asymmetric centers and other chemical structures that may lead to stereoisomerism, this invention also includes these stereoisomers and mixtures thereof. Because the compounds of this invention and their salts comprise asymmetric carbon atoms, they can exist as single stereoisomers, racemates, or mixtures of enantiomers and diastereomers. Typically, these compounds can be prepared as racemic mixtures. However, if desired, such compounds can be prepared or isolated to obtain pure stereoisomers, i.e., single enantiomers or diastereomers, or mixtures enriched with single stereoisomers (purity ≥98%, ≥95%, ≥93%, ≥90%, ≥88%, ≥85%, or ≥80%). As described below, a single stereoisomer of a compound is synthesized from an optically active starting material containing the desired chiral center, or prepared by separating or resolving a mixture of enantiomers, for example, by converting it into a mixture of diastereomers and then separating or recrystallizing, chromatographically processing, using chiral resolving reagents, or by directly separating the enantiomers on a chiral chromatographic column. Starting compounds with specific stereochemistry are commercially available or prepared according to the methods described below and then resolved by methods well known in the art. The term "enantiomer" refers to a pair of stereoisomers that are mirror images of each other. The term "diastereomer" or "diastereomer" refers to an optically active isomer that is not mirror images of each other. The term "racemic mixture" or "racemate" refers to a mixture containing equal parts of a single enantiomer (i.e., an equimolar mixture of two R and S enantiomers). The term "non-racemic mixture" refers to a mixture containing unequal parts of a single enantiomer. Unless otherwise stated, all stereoisomers of the compounds of this invention are within the scope of this invention.

[0047] The term "tautomer" (or "tautomer form") refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (or proton transfer tautomers) include (but are not limited to) interconversions via proton transfer, such as keto-enol isomerization, imine-enamine isomerization, amide-imine alcohol isomerization, etc. Unless otherwise stated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0048] The term "cis-trans isomer" refers to stereoisomers formed by the different positions of atoms (or groups) on opposite sides of a double bond or ring system relative to a reference plane; in the cis isomer, the atoms (or groups) are on the same side of the double bond or ring system, and in the trans isomer, the atoms (or groups) are on opposite sides of the double bond or ring system. Unless otherwise stated, all cis-trans isomers of the compounds of this invention are within the scope of this invention.

[0049] The term "isotope-labeled compound" refers to a compound formed by replacing specific atoms in a structure with their isotopic atoms. Unless otherwise indicated, the compounds of the present invention include various isotopes of H, C, N, O, F, P, S, and Cl, such as 2H(D), 3H(T), 13C, 14C, 15N, 17O, 18O, 18F, 31P, 32P, 35S, 36S, and 37Cl.

[0050] The term "prodrug" refers to a derivative compound that, when administered to a patient, can directly or indirectly provide the compounds of the present invention. Particularly preferred derivative compounds or prodrugs are those that, when administered to a patient, can improve the bioavailability of the compounds of the present invention (e.g., facilitate absorption into the bloodstream) or promote the delivery of the parent compound to its site of action (e.g., the lymphatic system). Unless otherwise stated, all prodrug forms of the compounds of the present invention are within the scope of the invention, and various prodrug forms are well known in the art.

[0051] The term "room temperature" or "normal temperature" refers to a temperature that can be between 10-40°C or between 10-30°C, such as 20°C or 25°C.

[0052] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified in the examples, conventional conditions or conditions recommended by the manufacturer are followed. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0053] Example 1: (E)-2-(1-(2-chlorobenzyl)-4-(nitrosopiperidin-3-ylidene)acetic acid (compound 1)

[0054]

[0055] Preparation of (E)-2-(4-oxo-1-tributylpiperidine-3-yl)ethyl acetate (intermediate a-2)

[0056] 1-Triphenylmethyl-4-piperidinone (10 g, 29.3 mmol) was dissolved in toluene (100 mL), and tetrahydropyrrole (3 mL, 35.2 mmol) was added. The mixture was heated under reflux for 3 hours with a water separator. Ethyl glyoxylate (3.5 mL, 35.2 mmol) was added at room temperature, and the mixture was then heated under reflux for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, and water (100 mL) was added. The mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography to give intermediate a-2.5 g, a pale yellow liquid, yield: 40.1%. ESI-MS m / z: 426.3 [M+H] +

[0057] Preparation of (E)-2-(4-hydroxy-1-tributylpiperidine-3-ethylenedimethyl)ethyl acetate (intermediate a-3)

[0058] Ethyl (E)-2-(4-oxo-1-tributylpiperidin-3-yl)ethyl acetate (intermediate a-2) (5 g, 11.7 mmol) was dissolved in methanol (50 mL). Sodium borohydride (486 mg, 12.8 mmol) was added in portions under ice bath conditions. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solution was concentrated under reduced pressure, and water (50 mL) was added. The solution was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to give intermediate a-3. 4.5 g, a pale yellow liquid, yield: 90%. ESI-MS m / z: 428.3 [M+H] +

[0059] Preparation of (E)-2-(4-hydroxypiperidin-3-yl)ethyl acetate 4-methylbenzenesulfonate (intermediate a-4)

[0060] Ethyl (E)-2-(4-hydroxy-1-tributylpiperidin-3-yl)ethyl acetate (intermediate a-3) (4.5 g, 10.5 mmol) was dissolved in tetrahydrofuran (50 mL), and p-toluenesulfonic acid monohydrate (2.4 g, 12.6 mmol) was added. The mixture was heated to 50 °C and stirred for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and toluene (20 mL) was added. The supernatant was decanted, and the residue (3.5 g) was directly used in the next step without purification.

[0061] Preparation of (E)-2-(1-(2-chlorobenzyl)-4-hydroxypiperidine-3-ylidene)ethyl acetate (intermediate a-5)

[0062] The above-mentioned (E)-2-(4-hydroxypiperidin-3-yl)ethyl acetate 4-methylbenzenesulfonate (intermediate a-4) (1 g, 2.8 mmol) was dissolved in acetonitrile (15 mL), and 2-chlorobenzyl 4-methylbenzenesulfonate (994 mg, 3.36 mmol) and potassium carbonate (773 mg, 5.6 mmol) were added. The mixture was heated to 50 °C and stirred for 16 hours. After the reaction was completed, the mixture was filtered, and the filtrate was purified by column chromatography to give intermediate a-5, 650 mg, a pale yellow liquid, yield: 75%. ESI-MS m / z: 310.1 [M+H] +

[0063] Preparation of (E)-2-(1-(2-chlorobenzyl)-4-((methylsulfonyl)oxy)piperidine-3-ylidene)ethyl acetate (intermediate a-6)

[0064] Ethyl (E)-2-(1-(2-chlorobenzyl)-4-hydroxypiperidin-3-yl)ethyl acetate (intermediate a-5) (500 mg, 1.62 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (245 mg, 2.43 mmol) was added. MsCl (222 mg, 1.94 mmol) was slowly added dropwise under ice bath conditions, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was quenched with water, extracted with dichloromethane (20 mL x 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give intermediate a-6, 550 mg, a pale yellow liquid, yield: 87.8%. ESI-MS m / z: 388.2 [M+H] +

[0065] Preparation of (E)-2-(1-(2-chlorobenzyl)-4-mercaptohesperidin-3-ylidene)ethyl acetate (intermediate a-7)

[0066] Ethyl (E)-2-(1-(2-chlorobenzyl)-4-((methanesulfonyl)oxy)piperidin-3-ylidene)acetate (intermediate a-6) (500 mg, 1.29 mmol) and sodium hydrosulfide (72 mg, 1.29 mmol) were dissolved in DMF (10 mL). The mixture was heated to 50 °C and reacted for 16 hours. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography to give intermediate a-7, 385 mg, a pale yellow solid, yield: 91.8%. ESI-MS m / z: 326.2 [M+H] +

[0067] Preparation of (E)-2-(1-(2-chlorobenzyl)-4-mercaptopiridin-3-ylidene)acetic acid (intermediate a-8)

[0068] Ethyl (E)-2-(1-(2-chlorobenzyl)-4-mercaptohesperidin-3-yl)ethyl acetate (intermediate a-7) (100 mg, 0.31 mmol) was dissolved in MeOH (2 mL) and water (0.5 mL), and lithium hydroxide (12 mg, 0.51 mmol) was added. The reaction mixture was stirred at room temperature for 5 hours. After the reaction was completed, the mixture was neutralized with hydrochloric acid, concentrated under reduced pressure, and the crude product was purified by column chromatography to obtain compound 1, 83 mg, a pale yellow solid, yield: 91%. ESI-MS m / z: 298.1 [M+H] +

[0069] Preparation of (E)-2-(1-(2-chlorobenzyl)-4-(nitrosopiperidin-3-ylidene)acetic acid (compound 1): Methanol (2 mL) and dilute hydrochloric acid (2 mL) were mixed, and concentrated sulfuric acid (0.2 mL) was added under ice bath conditions. Then, ethyl acetate (E)-2-(1-(2-chlorobenzyl)-4-mercaptohesperidin-3-ylidene) (intermediate a-7) (80 mg, 0.27 mmol) was added in portions. Sodium nitrite (21 mg, 0.31 mmol) in water (1 mL) was added under ice bath conditions. The reaction mixture was stirred at room temperature in the dark for 1 hour. After the reaction was completed, the mixture was filtered, and the solid was washed with water to give compound 1, 51 mg, a pale yellow solid. Yield: 58%. ESI-MS m / z: 327.1 [M+H] +

[0070] 1 H NMR(400MHz,DMSO-d6)δ11.35(s,1H),7.61-7.54(m,1H),7.26-7.23(m,1H),7.22-7.16(m,3H),4.26-4.20(m,1H),3.52-3.44(m,1H),3.38-3 .28(m,1H),3.12(ddd,J=3.7,3.2,0.6Hz,1H),3.04-2.96(m,1H),2.62 -2.56(m,1H),2.40-2.33(m,1H),2.13-2.00(m,1H),1.91-1.81(m,1H).

[0071] Example 2: (Z)-2-(1-(2-chlorobenzyl)-4-(nitrosopiperidin-3-ylidene)acetic acid (compound 2)

[0072]

[0073] Specific preparation process

[0074] 2.7 g of (E)-2-(4-mercapto)-1-((s)-1-(2-chlorophenyl)-2-methoxy-2-carbonylethylpiperidine-3-vinyl acid (a-6) was dissolved in acetonitrile:water = 1:1 (v / v) (40 mL). The reaction was carried out at 25 °C under irradiation with a 32 W low-pressure mercury lamp for 2 h, and TLC showed that the reaction was complete. The solution was concentrated under reduced pressure, and ethyl acetate (20 mL) was added. A large amount of solid precipitated. The solution was filtered, and the filter cake was washed with ethyl acetate (10 mL x 3). The solution was dried under reduced pressure at 45 °C to give 2.5 g of a deep yellow solid, with a yield of 91.0%. Specific rotation: [α] D 20 =32.1. Subsequent synthesis followed the method for compound 1, 47 mg, pale yellow solid. ESI-MS m / z: 327.1 [M+H] +

[0075] 1 H NMR (400MHz, DMSO-d6) δ11.32(s,1H), δ7.90-7.82(m,1H),7.64-7.53(m,1H),7.26-7.11(m,3H),4.33-4.21(m,1H),3.75-3. 60(m,1H),3.38-3.23(m,1H),3.18-3.03(m,2H),2.77-2.55(m,1H),2.42-2.24(m,1H),2.15-1.98(m,1H),1.89-1.69(m,1H).

[0076] Examples 3-4:

[0077] (S,Z)-2-(1-(2-chlorobenzyl)-4-(nitroso)piperidin-3-ylidene)acetic acid (compound 3) and (R,Z)-2-(1-(2-chlorobenzyl)-4-(nitroso)piperidin-3-ylidene)acetic acid (compound 4)

[0078]

[0079] a-8 was separated by SFC. The chromatographic column was Daicel Chiralpak AD-H SFC (20 mm ID * 250 mmL, 5 μm); flow rate: 38 mL / min; A(CO2):B(MeOH(0.1% NH3)) = 70:30; column temperature: 30℃. Further nitrosation yielded compound 3, 21 mg, a pale yellow solid, ESI-MS m / z: 327.1 [M+H]+, specific rotation: [α]D20 = -22.1° (c = 1, ethanol); compound 4, 20 mg, a pale yellow solid, ESI-MS m / z: 327.1 [M+H]+, specific rotation: [α]D20 = 22.1° (c = 1, ethanol).

[0080] 1 H NMR (400MHz, DMSO-d6) δ11.32(s,1H), δ7.90-7.82(m,1H),7.64-7.53(m,1H),7.26-7.11(m,3H),4.33-4.21(m,1H),3.75-3. 60(m,1H),3.38-3.23(m,1H),3.18-3.03(m,2H),2.77-2.55(m,1H),2.42-2.24(m,1H),2.15-1.98(m,1H),1.89-1.69(m,1H).

[0081] Example 5: (E)-2-(1-(2-fluorobenzyl)-4-(nitrosopiperidin-3-ylidene)acetic acid (compound 5)

[0082]

[0083] The synthesis method is the same as that for compound 1, except that 2-chlorobenzyl 4-methylbenzenesulfonic acid is replaced with 2-fluorobenzyl 4-methylbenzenesulfonic acid. 42 mg, pale yellow solid. ESI-MS m / z: 311.1 [M+H] +

[0084] 1 H NMR(400MHz,DMSO-d6)δ11.27(s,1H),7.55-7.48(m,1H),7.32-7.25(m,1H) ,7.25-7.15(m,1H),7.09-7.03(m,1H),6.26-6.18(m,1H),3.92-3.87(m,1H ),3.66-3.50(m,2H),3.12(ddd,J=8.4,8.0,0.8Hz,1H),2.86-2.79(m,1H), 2.74-2.59(m,1H),2.40-2.16(m,1H),2.13-2.06(m,1H),1.84-1.58(m,1H).

[0085] Example 6: (Z)-2-(1-(2-fluorobenzyl)-4-(nitrosopiperidin-3-ylidene)acetic acid (compound 6)

[0086]

[0087] The synthesis method was the same as that for compound 2, except that compound 1 was replaced by compound 5. 56 mg, pale yellow solid. ESI-MS m / z: 311.1 [M+H] +

[0088] 1 H NMR (400MHz, DMSO-d6) δ11.27(s,1H),7.61-7.47(m,1H),7.31-7.15(m,2H),7.06(ddd,J=8.6,7.5,1.4Hz,1H),6.16-6.04(m,1H),3.91-3. 76(m,1H),3.65(m,1H),3.58-3.42(m,1H),3.19-2.99(m,1H),2.97-2 .90(m,1H),2.71-2.59(m,1H),2.43-2.30(m,1H),2.08-1.85(m,2H).

[0089] Example 7: (E)-2-(1-(1-(2-chlorophenyl)-2-methoxy-2-oxoethyl)-4-(nitrosopiperidin-3-ylidene)acetic acid (compound 7)

[0090]

[0091] The synthesis method is the same as that for compound 1, except that 2-chlorobenzyl 4-methylbenzenesulfonic acid is replaced with methyl 2-(2-chlorophenyl)-2-(toluoxy)acetate. 33 mg, pale yellow solid. ESI-MS m / z: 385.2 [M+H] +

[0092] 1 H NMR(400MHz,DMSO-d6)δ11.51(s,1H),7.66-7.59(m,1H),7.44-7.33(m,1H),7.29-7.16(m,2H),6.23(s,1H),4.85-4.70(m,1H),3.85(m,3 H),3.72-3.66(m,1H),3.18-3.04(m,1H),2.79-2.73(m,1H),2.72-2.64(m,1H),2.46-2.31(m,1H),2.21-2.07(m,1H),1.94-1.75(m,1H).

[0093] Example 8: (Z)-2-(1-(1-(2-chlorophenyl)-2-methoxy-2-oxoethyl)-4-(nitrosopiperidin-3-ylidene)acetic acid (compound 8)

[0094]

[0095] The synthesis method is the same as that for compound 2, except that compound 1 is replaced by compound 7. 90 mg, pale yellow solid. ESI-MS m / z: 385.2 [M+H] +

[0096] 1 H NMR(400MHz,DMSO-d6)δ11.51(s,1H),7.66-7.59(m,1H),7.34-7.20(m,3H),7.13(s,1H),4.75(s,1H),3.84-3.7 6(m,1H),3.72-3.67(m,3H),3.67-3.58(m,1H),3.12(q,J=9.2Hz,1H),2.74-2.66(m,1H),2.54-2.44(m,1H),2.36 -2.27(m,1H),2.22-2.06(m,1H).

[0097] Example 9: (Z)-2-(1-((S)-1-(2-chlorophenyl)-2-methoxy-2-oxoethyl)-4-(nitrosopiperidin-3-ylidene)acetic acid (compound 9)

[0098]

[0099] The synthesis method is the same as that for compound 7, except that methyl 2-(2-chlorophenyl)-2-(toluoxy)acetate is replaced with (S)-2-(2-chlorophenyl)-2-(toluoxy)acetate. 121 mg, pale yellow solid. ESI-MS m / z: 385.1 [M+H] +

[0100] 1 H NMR(400MHz,DMSO-d6)δ11.52(s,1H),7.66-7.59(m,1H),7.34-7.20(m,3H),7.13(s,1H),4.75(s,1H),3.84-3.7 6(m,1H),3.72-3.67(m,3H),3.67-3.58(m,1H),3.12(q,J=9.2Hz,1H),2.74-2.66(m,1H),2.54-2.44(m,1H),2.36 -2.27(m,1H),2.22-2.06(m,1H).

[0101] Example 10: ((Z)-2-(((R)-1-((S)-1-(2-chlorophenyl)-2-methoxy-2-oxoethyl)-4-(nitrosopiperidin-3-ylidene)acetic acid (Compound 10) and Example 11: ((Z)-2-(((S)-1-((S)-1-(2-chlorophenyl)-2-methoxy-2-oxoethyl)-4-(nitrosopiperidin-3-ylidene)acetic acid (Compound 11)

[0102]

[0103] Compound 9 was resolved by SFC. The chromatographic column was a Daicel Chiralpak AD-H SFC (20 mm ID * 250 mm L, 5 μm); flow rate was 38 mL / min; A(CO2):B(MeOH(0.1% NH3)) = 70:30; column temperature was 30 °C. Compounds 10 and 11 were obtained as pale yellow solids (12 mg, ESI-MS m / z: 385.1 [M+H]+, specific rotation: [α]D20 = 12.1° (c = 1, ethanol); and compound 11 was also obtained as a pale yellow solid (20 mg, ESI-MS m / z: 385.1 [M+H]+, specific rotation: [α]D20 = -12.1° (c = 1, ethanol).

[0104] 1 H NMR(400MHz,DMSO-d6)δ11.52(s,1H),7.66-7.59(m,1H),7.34-7.20(m,3H),7.13(s,1H),4.75(s,1H),3.84-3.7 6(m,1H),3.72-3.67(m,3H),3.67-3.58(m,1H),3.12(q,J=9.2Hz,1H),2.74-2.66(m,1H),2.54-2.44(m,1H),2.36 -2.27(m,1H),2.22-2.06(m,1H).

[0105] By using the corresponding intermediates to replace the starting materials for compounds 1-10, compounds 12-23 were synthesized in a similar manner to compounds 1-10 (see Table 1) to obtain the desired products.

[0106] Table 1

[0107]

[0108]

[0109]

[0110] Example 24: Methyl (2S)-2-(2-chlorophenyl)-2-((Z)-3-(2-methoxy-2-oxoethylene)-4-(nitrosopiperidin-1-yl)acetate (Compound 24)

[0111]

[0112] (Z)-2-(1-((S)-1-(2-chlorophenyl)-2-methoxy-2-oxoethyl)-4-(nitrosopiperidin-3-yl)acetic acid (compound 10) (100 mg, 0.26 mmol) was dissolved in DMF (2 mL), sodium bicarbonate (22 mg, 0.26 mmol) was added, and iodomethane (37 mg, 0.26 mmol) in DMF (0.3 mL) was added dropwise under ice bath. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography to give compound 24, 52 mg, a pale yellow solid, yield: 50.2%. ESI-MS m / z: 399.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.16(s,1H),7.34-7.19(m,3H),6.03-5.99(m,1H),4.74(s,1H),3.85(s,3H),3.84-3.79(m,1H),3.75(s,3H) ),3.12(ddd,J=3.7,3.2,0.6Hz,1H),3.03-2.97(m,1H),2.69-2.64(m,1H),2.45-2.38(m,1H),2.30-2.24(m,1H),2.08-1.94(m,1H).

[0113] Example 25: 2-(1-(2-chlorobenzyl)-4-(nitroso)-1,2,5,6-tetrahydropyridin-3-yl)acetic acid (compound 25)

[0114]

[0115] Preparation of 5-(2-chlorobenzyl)-2,4,5,6,7,7a-hexahydrothiophene[3,2-c]pyridine (intermediate c-2)

[0116] 4,5,6,7-Tetrahydrothieno[3,2-c]pyridine (2 g, 14.2 mmol) was dissolved in tetrahydrofuran (30 mL), followed by the addition of sodium carbonate (3 g, 28.4 mmol) and o-chlorobenzyl bromide (3.5 g, 17.0 mmol). The reaction was carried out at room temperature for 4 h. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography to give intermediate c-2, 3 g, a white solid, yield: 80%. ESI-MS m / z: 266.1 [M+H] +

[0117] Preparation of 5-(2-chlorobenzyl)-5,6,7,7-tetrahydrothieno[3,2-c]pyridine-2(4H)-one (intermediate c-3)

[0118] 5-(2-chlorobenzyl)-2,4,5,6,7,7a-hexahydrothiophene[3,2-c]pyridine (intermediate c-2) (1.5 g, 5.66 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL). Butyllithium (2.7 mL, 6.8 mmol, 2.5 M) was slowly added dropwise at -5 °C. After the addition was complete, the temperature was lowered to -10 °C and stirred for 1 h. Then, a tetrahydrofuran (10 mL) solution of tributyl borate (1.56 g, 6.8 mmol) was added dropwise, and the reaction was continued for 1 h. The temperature was then lowered to -15 °C, and 30% hydrogen peroxide (1.1 mL, 10.2 mmol) was slowly added dropwise. The temperature was then raised to 30 °C, and the reaction continued for 5 h. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography to give intermediate c-3, 1.1 g, a yellow solid, yield: 70%. ESI-MS m / z: 280.1 [M+H] +

[0119] Preparation of methyl 2-(1-(2-chlorobenzyl)-4-mercapto-1,2,6,6-tetrahydropyridin-3-yl)acetate (intermediate c-4)

[0120] 5-(2-chlorobenzyl)-5,6,7,7-tetrahydrothieno[3,2-c]pyridin-2(4H)-one (intermediate c-3) (1 g, 3.58 mmol) was dissolved in methanol (15 mL), and potassium carbonate (4.9 g, 35.8 mmol) was added. The mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was filtered, the filtrate was neutralized with dilute hydrochloric acid, water was added, and the extract was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography to give intermediate c-4, 0.65 g, a pale yellow oil, yield: 58.5%. ESI-MS m / z: 312.1 [M+H] +

[0121] Preparation of 2-(1-(2-chlorobenzyl)-4-mercapto-1,2,6,6-tetrahydropyridin-3-yl)acetic acid (intermediate c-5)

[0122] 2-(1-(2-chlorobenzyl)-4-mercapto-1,2,6,6-tetrahydropyridin-3-yl)acetate (intermediate c-4) (150 mg, 0.48 mmol) was dissolved in MeOH (5 mL) and water (1 mL), and lithium hydroxide (32 mg, 1.32 mmol) was added. The reaction mixture was stirred at room temperature for 5 hours. After the reaction was completed, the mixture was neutralized with hydrochloric acid, concentrated under reduced pressure, and the crude product was separated by reverse phase chromatography to obtain intermediate c-5, 100 mg, a pale yellow solid, yield: 70%. ESI-MS m / z: 298.1 [M+H] +

[0123] Preparation of 2-(1-(2-chlorobenzyl)-4-(nitroso)-1,2,5,6-tetrahydropyridin-3-yl)acetic acid (compound 25)

[0124] Methanol (2 mL) and dilute hydrochloric acid (2 mL) were mixed, and concentrated sulfuric acid (0.2 mL) was added under ice bath conditions. Then, 2-(1-(2-chlorobenzyl)-4-mercapto-1,2,6,6-tetrahydropyridin-3-yl)acetic acid (intermediate c-5) (80 mg, 0.27 mmol) was added in portions. Sodium nitrite (21 mg, 0.31 mmol) in water (1 mL) was added under ice bath conditions. The reaction mixture was stirred at room temperature in the dark for 1 hour. After the reaction was complete, the mixture was filtered, and the solid was washed with water to give 25-37 mg of the compound as a pale yellow solid. Yield: 42%. ESI-MS m / z: 327.1 [M+H] +

[0125] 1 H NMR (400MHz, DMSO-d6) δ11.17(s,1H),7.60(ddd,J=6.0,3.5,1.8Hz,1H),7.25-7.17(m,3H),4.16(s,1H),3.59(s,1H),3.38- 3.30(m,2H),3.28-3.20(m,1H),2.95-2.88(m,1H),2.81(t,J=6.5Hz,1H),2.53(d,J=6.9Hz,1H),2.45(dd,J=6.6,6.2Hz,2H).

[0126] Example 26: 2-(1-(2-fluorobenzyl)-4-(nitroso)-1,2,5,6-tetrahydropyridin-3-yl)acetic acid (compound 26)

[0127]

[0128] The synthesis method was the same as that for compound 25, except that o-chlorobenzyl bromide was replaced with o-fluorobenzyl bromide. 73.5 mg, pale yellow solid. ESI-MS m / z: 311.1 [M+H] +

[0129] 1 H NMR (400MHz, DMSO-d6) δ12.07(s,1H),7.54-7.47(m,1H),7.29-7.24(m,1H),7.24-7.19(m,1H),7.07(ddd,J=8.5,7.4,1.4Hz,1H),3.94-3.90(m,1H) ),3.67-3.64(m,1H),3.51-3.48(m,1H),3.42-3.38(m,2H),3.37-3.33(m ,1H),2.79(q,J=5.7Hz,1H),2.55(q,J=5.6Hz,1H),2.44(q,J=5.5Hz,2H).

[0130] By using the corresponding intermediates to replace the starting materials for compound 25, compounds 27-30 were synthesized in a similar manner to those for compound 25 (see Table 2), thereby obtaining the desired products.

[0131] Table 2

[0132]

[0133]

[0134] To illustrate the beneficial effects of the present invention, the following experimental examples are provided.

[0135] Experimental Example 1:

[0136] Antiplatelet aggregation activity test

[0137] Drugs and formulations: The positive control drugs are clopidogrel and prasugrel, and the test compounds are the compounds in the embodiments of this invention.

[0138] Animals: Male SD rats, weighing approximately 250g.

[0139] Methods: The antiplatelet aggregation pharmacological activity of the compounds of this invention was tested using the BORN turbidimetric method. Adenosine diphosphate (ADP), a platelet-rich plasma (PRP), was added and stirred to induce platelet aggregation. The change in optical density caused by platelet aggregation was detected by spectrophotometry. This experiment can evaluate the platelet aggregation effect induced by in vivo or in vitro administration of the test compounds.

[0140] Male SD rats were administered clopidogrel (10 mg / kg) orally and prasugrel (10 mg / kg), and the test drugs (clopidogrel, prasugrel, and the compound of this invention, 1 mg / kg) intravenously. The blank control group was administered the same volume of physiological saline intravenously. Two hours later, blood was collected from the orbital cavity, anticoagulated with 3.8% sodium citrate at a whole blood to anticoagulant ratio of 9:1, and centrifuged at 1000 rpm for 7 min to prepare platelet-rich plasma (PRD). PRD was adjusted with platelet-poor plasma (PPP) to maintain a platelet count of 2 x 10⁻⁶. 6 Platelet aggregation rate / mL. PRI was added to the test cup and incubated at 37°C for 10 minutes. The platelet aggregation was zeroed with PRI and adjusted to 100% with PPP. ADP (final concentration 5 μM) was used as the inducer. The platelet aggregation percentage was determined using a platelet aggregator via t-test. Statistical comparison was performed using the t-test. Platelet aggregation inhibition rate (%) = [1 - (aggregation percentage of the drug tube / aggregation percentage of the control tube)] × 100%.

[0141] Table 3 Platelet aggregation inhibition rate (%) of the compounds in the embodiments of the present invention

[0142]

[0143]

[0144] Experimental Example 2:

[0145] Pharmacokinetics in rats

[0146] Drugs and formulations: The positive control drugs are clopidogrel and prasugrel, and the test compounds are the compounds in the examples.

[0147] Animals: Male SD rats, weighing approximately 250g.

[0148] Test compounds (clopidogrel, prasugrel, and compounds of the present invention) were administered intravenously to fasted rats. Blood samples were collected via jugular vein at time points of 5, 10, 20, 30, 60, and 120 minutes using EDTAK2 (anticoagulant), 3'-methoxybenzoylmethyl bromide (MPBr, derivatizing agent), and phenylmethylsulfonyl fluoride (PMSF, stabilizer). Plasma samples were then collected by centrifugation at 1500 g for 10 minutes at 2–8 °C and stored at 80 °C after separation. After extraction, plasma samples were loaded onto an LC MS / MS instrument to determine the concentration of thiol active metabolites. Table 4 shows the time to peak concentration and concentration results in rat plasma. As shown in Table 4, at a dose level of 10 mg / kg, the compounds of the present invention reached peak concentrations in less than 15 minutes after administration, compared to clopidogrel or prasugrel, which reached peak concentrations of thiol active metabolites approximately 30 minutes after administration.

[0149] Table 4. Peak time of the active metabolites of the compounds in the embodiments of the present invention.

[0150]

[0151]

[0152] Furthermore, the peak concentrations of the thiol active metabolites of the compounds in the examples were significantly higher than those of clopidogrel or prasugrel. The peak concentrations of the thiol active metabolites of compounds 1-30 in the examples were all above 5000 ng / mL, with clopidogrel having a peak concentration of 58 ng / mL and prasugrel having a peak concentration of 94 ng / mL.

[0153] These results indicate that the compounds in this study provide a faster and more effective release of active metabolites.

[0154] Compared to clopidogrel, or clopidogrel or prasugrel, the compound of the embodiments provided in this invention exhibits a faster and more effective release of active metabolites.

[0155] For compounds of general formulas (I) and (II), the linking and substituent groups have a significant impact on the pharmacodynamic properties of the compounds. Although the present invention has been described through specific embodiments above, it should not be construed as limiting; rather, the invention covers the general aspects previously disclosed. Various modifications and embodiments are possible without departing from the spirit and scope of the invention.

[0156] The embodiments provided above are not intended to limit the scope of the invention, nor are the described steps intended to limit the order of execution. Any obvious modifications made to the invention by those skilled in the art based on existing common knowledge also fall within the scope of protection defined by the claims.

Claims

1. A compound with the structure shown in Formula I, or a pharmaceutically acceptable salt thereof, Specifically selected from:

2. A compound with the structure shown in Formula II or a pharmaceutically acceptable salt thereof, in, R1' is independently selected from H, -COOR4, R2' is independently selected from fluorine, chlorine or bromine; R3' is independently selected from H or C1-4 alkyl; R4 is a C1-4 alkyl.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, characterized in that, Specifically selected from:

4. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, characterized in that, The pharmaceutically acceptable salt is an inorganic or organic salt. The inorganic salt is selected from sodium salts, potassium salts, calcium salts, magnesium salts, iron salts, hydrochloride salts, hydrobromide salts, hydroiodide salts, sulfates, hydrogen sulfate salts, nitrates, phosphates, and acid phosphates. The organic salt is selected from acetates, trifluoroacetate salts, propionates, pyruvate salts, glycolate salts, oxalate salts, malonate salts, fumarate salts, maleate salts, lactate salts, malate salts, citrate salts, tartrate salts, methanesulfonate salts, benzenesulfonate salts, and salicylates.

5. A pharmaceutical composition, characterized in that, Includes the compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof.

6. The pharmaceutical composition according to claim 5, characterized in that, The pharmaceutical composition also includes a pharmaceutically acceptable carrier.

7. The pharmaceutical composition according to claim 6, characterized in that, Pharmaceutically acceptable carriers are selected from microcapsules, microspheres, nanoparticles and liposomes.

8. The pharmaceutical composition according to claim 5, characterized in that, The pharmaceutical composition also includes: excipients.

9. The pharmaceutical composition according to claim 5, characterized in that, The pharmaceutical composition also includes a diluent.

10. An antiplatelet aggregation drug, characterized in that, It comprises the compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof.

11. The medicament according to claim 10, characterized in that, The dosage forms of the drug include: injection, lyophilized powder for injection, suspension, implant, capsule, tablet, pill and oral liquid.

12. The medicament according to claim 10, characterized in that, The dosage form of the drug includes embolic agents.

13. Use of the compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating thrombosis.

14. Use of the compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of atherosclerotic diseases, myocardial infarction, stroke, ischemic cerebral thrombosis, peripheral artery disease, acute coronary syndrome or thrombosis following coronary intervention.

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