Hexahydropyridine compound and use thereof

Abstract

Disclosed in the present invention are a hexahydropyridine compound and a use thereof. Specifically, the present invention relates to compounds of formula I and formula II, or isomers and pharmaceutically acceptable salts thereof, which show high activity in inhibiting platelet aggregation, and can be used for preventing or treating thrombus, embolism and / or cardiovascular diseases.

Description

A hexahydropyridine compound and its uses Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to a P2Y12 receptor antagonist and its preparation method, as well as its use as a drug for the treatment of cardiovascular and cerebrovascular diseases. Background Technology

[0002] Thrombosis is a core pathological mechanism in atherosclerosis-related diseases such as acute coronary syndrome (ACS), stroke, and peripheral artery embolism. Antiplatelet therapy is widely used due to its crucial role in the prevention and treatment of arterial thrombosis. Among numerous antiplatelet targets, the P2Y12 receptor has attracted much attention due to its key role in platelet activation. Clopidogrel is currently the most widely used oral P2Y12 receptor antagonist in clinical practice. This drug is a prodrug and is inactive on its own. It requires two steps of metabolic conversion by the hepatic CYP450 enzyme system (especially CYP2C19) to generate the thiol metabolite H4, which has antiplatelet activity. The latter can selectively and irreversibly bind to and inhibit platelet P2Y12 receptors, thereby exerting an antithrombotic effect.

[0003] However, the clinical application of clopidogrel has significant drawbacks: First, its metabolism is highly dependent on the activity of the CYP2C19 enzyme, and genetic polymorphisms of this enzyme (such as CYP2C192 and CYP2C193 alleles) lead to metabolic disorders in approximately 30%-58% of patients, significantly increasing the risk of thrombotic events. Second, the complex metabolic pathway results in an active metabolite conversion rate of less than 15%, requiring not only high-dose administration (600 mg loading dose) but also resulting in a slow onset of action (peak effect in 2-4 hours). Finally, the chemical instability of the active metabolite H4 limits the development of injectable formulations, making it difficult to meet the needs of acute scenarios such as emergency PCI. Therefore, there is an urgent need to develop a novel P2Y12 receptor antagonist to overcome these problems and provide a more reliable antiplatelet therapy. Summary of the Invention

[0004] To achieve the above objectives, the inventors of this patent have developed an innovative design using H4, the active metabolite of clopidogrel, which has solved problems such as clopidogrel resistance, clopidogrel interactions, slow onset of action, and poor stability that prevents the preparation of injectable formulations.

[0005] On the one hand, the present invention provides compounds of formula I and II or isomers thereof, and pharmaceutically acceptable salts:

[0006] in,

[0007] Representing type Z and / or type E;

[0008] X is selected from N, S, or O;

[0009] n is selected from 0 to 6;

[0010] R1 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, or substituted or unsubstituted aromatic heterocyclic.

[0011] R2 and R3 are each independently selected from hydrogen, substituted or unsubstituted alkyl groups, substituted or unsubstituted cycloalkyl groups, or R2 and R3 are linked to form a 3-6 member cyclo group;

[0012] R4 is selected from hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl;

[0013] R5 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted saturated or partially unsaturated cycloalkyl, substituted or unsubstituted saturated or partially unsaturated heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0014] In some embodiments, the compounds of formula I and formula II of the present invention, wherein,

[0015] Representing type Z and / or type E;

[0016] X is selected from N or O;

[0017] and / or n is selected from 0 to 3;

[0018] And / or R1 is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C4-C8 heterocyclic group, or substituted or unsubstituted 5-6 membered heterocyclic aryl group;

[0019] And / or R2 and R3 are each independently selected from hydrogen, substituted or unsubstituted C1 to C6 alkyl, substituted or unsubstituted C3 to C6 cycloalkyl, or R2 and R3 connected to form a C3 to C6 cyclogroup;

[0020] And / or R4 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C6 cycloalkyl;

[0021] And / or R5 is selected from hydrogen, substituted or unsubstituted C1 to C5. 20 Alkyl, substituted or unsubstituted C3-C 20 Cycloalkyl, substituted or unsubstituted 4-20 membered heterocycloalkyl, substituted or unsubstituted C6-C 20 aryl, substituted or unsubstituted C6-C 20aryl-C1 to C8 alkyl, or substituted or unsubstituted 5 to 12-membered heteroaryl, substituted or unsubstituted 5 to 12-membered heteroaryl-C1 to C8 alkyl, or substituted or unsubstituted C1 to C4 alkyl-(substituted or unsubstituted C1 to C4 alkyl-O)m-substituted or unsubstituted C1 to C4 alkyl, wherein m is a positive integer from 1 to 8, and substitution refers to substitution by one or more substituents selected from the group consisting of: deuterium, C1 to C4 alkyl ... 20 Alkyl, halogenated C1-C 20 Alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic alkyl, C6-C 10 Aryl, halogenated C6-C 10 Aryl, C5~C 10 heteroaryl, halogen, amino, alkylamine, nitro, -COR6, -COOR6, -OCOOR6, cyano, hydroxyl, amide or sulfonamide;

[0022] R6 is selected from: hydrogen, substituted or unsubstituted C1 to C2. 18 Alkyl, substituted or unsubstituted C1-C 20 Deuterated alkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Cycloalkenyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted amino, or substituted or unsubstituted 4- to 10-membered heterocyclic alkyl, wherein substitution refers to being substituted by one or more C6- to C76 groups. 10 Aryl substitution.

[0023] In some embodiments, the compounds of formula I and formula II of the present invention, wherein,

[0024] Representing type Z and / or type E;

[0025] X is selected from O;

[0026] and / or n is selected from 0 to 2;

[0027] And / or R1 is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, oxabutylcycloyl, azircyclobutyl, cyclobutyl, or cyclopentyl;

[0028] R2 and / or R3 are each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, oxabutylcycloyl, azircyclobutyl, cyclobutyl, cyclopentyl, or R2 and R3 are linked to form cyclopropyl, cyclobutyl, cyclopentyl, oxabutylcycloyl or azircyclobutyl.

[0029] In some embodiments, the compounds of formula I and formula II of the present invention, wherein,

[0030] R4 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, oxabutylcycloyl, azircyclobutyl, cyclobutyl, or cyclopentyl;

[0031] And / or R5 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopentyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, oxabutylcyclol, aziridine, etc.

[0032] Where p is selected from 1 to 18; k is selected from 4 to 20.

[0033] In some embodiments, the compounds of formula I and formula II of the present invention, wherein,

[0034] Represents type Z or type E;

[0035] X is selected from O;

[0036] n is selected from 0;

[0037] R1 is selected from methyl, ethyl, propyl, or isopropyl;

[0038] R2 and R3 are selected from hydrogen, methyl, ethyl, propyl, isopropyl, or R2 and R3 are linked to form cyclopropyl, cyclobutyl, or cyclopentyl;

[0039] R4 is selected from hydrogen, methyl, ethyl, propyl, or isopropyl;

[0040] R5 is selected from hydrogen, C1 to C2. 20 alkyl or

[0041] Furthermore, the aforementioned R5 is selected from hydrogen, C1 to C2. 20 straight-chain alkyl or

[0042] In some embodiments, the compounds of the present invention are selected from the following:

[0043] In some implementations, the hydrogen in the above-described compound structure can be replaced by one or more deuterium atoms.

[0044] Secondly, the present invention provides the use of any of the above-mentioned compounds or their isomers, or pharmaceutically acceptable salts, in the preparation of P2Y12 receptor antagonists.

[0045] Thirdly, the present invention provides the use of any of the above-mentioned compounds or their isomers, or pharmaceutically acceptable salts, in the preparation of medicaments for the treatment and / or prevention of cardiovascular and cerebrovascular diseases.

[0046] Furthermore, the aforementioned cardiovascular and cerebrovascular diseases are selected from atherosclerotic thrombosis, acute coronary syndrome, recent myocardial infarction, ischemic stroke, cerebral thrombosis, venous thrombosis, arterial thrombosis, thrombotic cerebrovascular disease, thrombotic cardiovascular disease, thrombosis, or embolism.

[0047] Fourthly, the present invention provides a method for inhibiting platelet aggregation in an individual in need, comprising administering to the individual an effective amount of any of the above-mentioned compounds or isomers thereof, or a pharmaceutically acceptable salt.

[0048] Compared with existing technologies, this invention has the following beneficial effects: The compound of this invention innovatively utilizes hydrolytic enzymes to metabolize into the active ingredient, without requiring CYP2C19 metabolic activation, thus fundamentally overcoming the drug resistance problem caused by clopidogrel resistance. This is expected to benefit a large number of patients affected by pharmacogenetics (approximately 58% of Chinese patients are troubled by this problem). The compound of this invention has a rapid onset of action, achieving a faster onset of action compared to existing first-line drugs (peak effect in rats in approximately 30 minutes), thereby meeting the application needs of more clinical scenarios. Simultaneously, the compound of this invention has good stability, and can be formulated into both injectable injections and oral tablets, solving the problem of clopidogrel's instability and inability to be used for injection. These two sequentially usable dosage forms significantly expand the clinical application scenarios and ease of use of the compound of this invention. The compound of this invention uses the active metabolite H4 as a lead compound in drug design, resulting in a significantly increased amount of H4 converted in vivo compared to clopidogrel and 2-oxoclopidogrel at the same molar dose. Therefore, the drug dosage can be greatly reduced clinically, and it is expected to further significantly improve the safety of long-term use. Detailed Implementation

[0049] The present invention will be further described in detail below with reference to embodiments and experimental examples. The embodiments and experimental examples of the present invention are only used to illustrate the technical solutions of the present invention and are not intended to limit the present invention. Any equivalent substitutions made in the art based on the content disclosed in the present invention shall fall within the protection scope of the present invention.

[0050] The structure of the compound was determined using nuclear magnetic resonance (NMR). 1 It can be determined by ¹H NMR or liquid chromatography-mass spectrometry (LC-MS).

[0051] The liquid chromatography-mass spectrometry (LC-MS) system was an Agilent G6120B (compatible with an Agilent 1260 liquid chromatography system); nuclear magnetic resonance (NMR) 1¹H NMR shifts (δ) are given in parts per million (ppm), the solvent is DMSO-d6 or CDCl3, the internal standard is tetramethylsilane (TMS), and the chemical shift is expressed in 10⁻¹⁰ ppm. －6 (ppm) is given as the unit.

[0052] In this invention, the term "room temperature" refers to a temperature between 10 and 25°C.

[0053] Example 1: Preparation of Compound 1:

[0054] Step 1: Preparation of Intermediate 1-1

[0055] In a 25 mL three-necked flask, methyl (S)-2-hydroxypropionate (1 g, 9.60 mmol) and pyridine (1.37 g, 17.3 mmol), along with 10 mL of DCM, were added. The flask was cooled in an ice bath, and methyl chloroformate (1.49 g, 11.5 mmol) was added dropwise. The reaction was allowed to proceed at room temperature for 2 h. After the reaction was complete, 10 mL of saturated 10% citric acid aqueous solution, 10 mL of saturated NaHCO3 aqueous solution, and 10 mL of water were added sequentially for washing. The organic phase was dried over anhydrous Na2SO4 and concentrated to give intermediate 1-1, a colorless liquid, 1.5 g in yield (79.4%), which was used directly in the next reaction.

[0056] ESI-MS: m / z = 197.01 (M+H) + .

[0057] 1 H NMR (400MHz, CDCl3-d) δ: 5.80 (d, 1H), 5.70 (d, 1H), 5.10 (q, 1H), 3.79 (s, 3H), 1.57 (d, 3H).

[0058] Step 2: Preparation of intermediates 1-2

[0059] Intermediate 1-1 (1.40 g, 7.12 mmol), 3-{[dimethyl(2-methylprop-2-yl)silyl]oxy}-4-mercaptohexahydropyridine-1-carboxylic acid-2-methylprop-2-yl ester (1.20 g, 3.45 mmol), acetone (14 mL), potassium carbonate (1.48 g, 10.68 mmol), and NaI (1.08 g, 7.12 mmol) were added to a 25 mL reaction flask. The mixture was heated to 50 °C and reacted for 8 h. After the reaction was completed, the mixture was cooled to room temperature, filtered, concentrated to dryness, and purified by silica gel column chromatography (PE:EA = 50:1 → 20:1). The product was collected, concentrated to dryness, and intermediate 1-2 was obtained as 1.6 g of an oily substance, with a yield of 91.56% and a purity of 97.39%.

[0060] ESI-MS: m / z = 508.23 (M+H) + .

[0061] Step 3: Preparation of intermediates 1-3

[0062] Intermediate 1-2 (8.3 g, 16.35 mmol), THF (50 mL), and Et3N.3HF (10.54 g, 65 mmol) were added to a 100 mL reaction flask, and the mixture was heated to 50 °C and reacted for 5 h. After the reaction was complete, the solvent was concentrated to dryness, and 100 mL of DCM was added to dissolve the product. The mixture was then washed successively with 100 mL of water and 100 mL of saturated NaCl. The organic phase was concentrated to dryness and purified by silica gel column chromatography (PE:EA = 10:1 → 10:4). The product was collected, concentrated to dryness, and 6 g of yellow oil 1-3 was obtained, with a yield of 93.28% and a purity of 97.50%.

[0063] ESI-MS: m / z = 394.14 (M+H) + .

[0064] Step 4: Preparation of intermediates 1-4

[0065] Intermediate 1-3 (6 g, 15.24 mmol) and 60 mL of DCM were added to a 250 mL reaction flask. Desmartin oxidant (9.9 g, 23.33 mmol) was added in portions at room temperature. After 3 h of reaction, 60 mL of saturated Na₂S₂O₃ / NaHCO₃ aqueous solution and two 60 mL solutions of purified water were added sequentially for washing. The organic phase was concentrated to dryness and purified by silica gel column chromatography (PE:EA = 20:1 → 1:1). The product was collected, concentrated to dryness, and yielded 5.5 g of oily substance 1-4, with a yield of 92.1% and a purity of 97.90%.

[0066] ESI-MS: m / z = 392.13 (M+H) + .

[0067] Step 5: Preparation of intermediates 1-5 and 1E-5

[0068] Intermediate 1-4 (1.35 g, 3.45 mmol), toluene (6 mL), 18-crown ether-6 (1.46 g, 5.53 mmol), and BrLi (389 mg, 4.49 mmol) were added to a 50 mL reaction flask. The mixture was purged with nitrogen and cooled to -78 °C with dry ice. LiHMDS (5.53 mL, 5.53 mmol) was added dropwise. After the addition was complete, the mixture was kept at -78 °C for 30 min. Diethylphosphonoacetate tert-butyl (1.39 g, 5.53 mmol) was dissolved in 6 mL of toluene and added dropwise to the reaction solution. After the addition was complete, the mixture was slowly heated to -10 °C and reacted for 1 h. At the end of the reaction, saturated ammonium chloride was added to quench the reaction, and the mixture was extracted with EA. The organic phase was concentrated to dryness and purified by silica gel column chromatography (PE:EA = 10:1 → 10:3). The product was collected in fractions and concentrated to dryness to give 622 mg of oil 1-5, with a yield of 36.8% and a purity of 96.87%. 611 mg of oily substance 1E-5 was obtained, with a yield of 34.5% and a purity of 97.01%.

[0069] Intermediate 1-5 / 1E-5: ESI-MS: m / z = 490.20 (M+H) + .

[0070] Intermediates 1-5: 1 H NMR(400MHz, CDCl3-d)δ:5.77(s,1H),5.51(s,1H),5.46-5.14(m,2H),5.04(m,1H),4.49-4.12 (m,1H),3.97(s,2H),3.77(s,3H),3.17(s,1H),2.06(m,1H),1.88(m,1H),1.52-1.45(m,21H).

[0071] Intermediate 1E-5: 1 H NMR(CDCl3-d)δ:5.73-5.67(m,1H),5.62-5.41(m,1H),5.39-5.21(m,1H),5.15-4.89(m,2H),4.03 -3.87(m,2H),3.86-3.72(m,4H),3.21(s,1H),2.27-2.11(m,1H),1.92(m,1H),1.55-1.45(m,21H).

[0072] Step Six: Preparation of Intermediates 1-6

[0073] Intermediate 1-5 (620 mg, 1.27 mmol), 5 mL of DCM, and TFA (2.17 g, 19 mmol) were added to a 25 mL reaction flask, and the mixture was reacted at room temperature for 3 h. After the reaction was complete, saturated NaHCO3 aqueous solution was added to neutralize the solution.， The organic phase was concentrated and dried to obtain 376 mg of product 1-6, with a yield of 76.2%.

[0074] ESI-MS: m / z = 390.15 (M+H) + .

[0075] Step 7: Preparation of intermediates 1-7

[0076] Intermediate 1-6 (376 mg, 0.98 mmol), 4-chlorobenzenesulfonic acid-(1R)-1-(2-chlorophenyl)-2-methoxy-2-oxomethylene ethyl ester (552 mg, 1.47 mmol), KHCO3 (245 mg, 2.44 mmol), and 4 mL of acetonitrile were added to a 25 mL reaction flask. The reaction was carried out at room temperature for 24 h. After the reaction was completed, the mixture was filtered, concentrated to dryness, and purified by silica gel chromatography (PE:EA = 100:10 → 100:25). The product was collected, concentrated to dryness, and 116 mg of solid product 1-7 was obtained, with a yield of 20.8% and a purity of 97.10%.

[0077] ESI-MS: m / z = 572.16 (M+H) + .

[0078] 1 H NMR(400MHz, CDCl3-d)δ:7.62(s,1H),7.40(m,1H),7.29(m,2H),5.64(m,1 H),5.46(s,1H),5.43-5.13(m,2H),5.08-4.98(m,1H),4.78(s,1H),3.76( m,3H),3.71(m,3H),3.57-3.31(m,1H),3.02(m,1H),2.66(m,1H),2.47-2. 11(m,1H),1.94-1.79(m,1H),1.60(s,1H),1.56-1.49(m,3H),1.46(m,9H).

[0079] Step 8: Preparation of Compound 1

[0080] Intermediate 1-7 (252 mg, 0.44 mmol) and 1 mL of TFA were added to a 25 mL reaction flask, and the reaction was carried out at room temperature for 30 min. After the reaction was completed, saturated NaHCO3 aqueous solution was added for neutralization, the layers were separated, the organic phase was concentrated, and preparative TLC purification was performed to obtain 130 mg of compound 1, with a yield of 57.3%. Compound 1 was further separated by chiral column chromatography to obtain 35 mg of 1-a with a purity of 98.60% and 30 mg of 1-b with a purity of 98.81%.

[0081] Compound 1:

[0082] ESI-MS: m / z = 516.1 (M+H) + .

[0083] 1 H NMR(400MHz, CDCl3-d)δ:7.58(m,1H),7.45-7.36(m,1H),7.33-7.20(m,2H),5 .79-5.68(m,1H),5.47-5.33(m,1H),5.32-5.16(m,1H),5.19-5.16(m,1H),5.0 4(m,1H),4.83-4.79(m,1H),3.78(m,3H),3.71(s,3H),3.52(m,1H),3.19-3.01 (m,1H),2.90-2.65(m,2H),2.34-2.20(m,1H),2.01-1.88(m,1H),1.53(m,3H).

[0084] Compound 1-a:

[0085] ESI-MS: m / z = 516.1 (M+H) + .

[0086] 1 H NMR (400MHz, CDCl3-d)δ:7.63-7.56(m,1H),7.43-7.36(m,1H),7.33-7.21(m,2H),5.79(s,1H),5.47-5.39(m,1H),5.33(t,1H),5.19(d, 1H),5.04(m,1H),4.79(s,1H),3.77(s,3H),3.71(s,3H),3.52(m,1H),3.19(d,1H),2.63(m,2H),2.20(m,1H),1.88(m,1H),1.53(m,3H).

[0087] Compound 1-b:

[0088] ESI-MS: m / z = 516.1 (M+H) + .

[0089] 1H NMR(400MHz, CDCl3-d)δ:7.62(m,1H),7.45-7.36(m,1H),7.29(m,2H),5.68(s,1H),5.39-5.33(m,1H),5.16(s,2H),5.03(m,1H),4.8 3(s,1H),3.80(s,3H),3.71(s,3H),3.52(m,1H),3.01(d,1H),2.90(s,1H),2.74(m,1H),2.34(s,1H),2.03-1.91(m,1H),1.53(m,3H).

[0090] The preparation method of compound 1E is the same as that of compound 1, except that steps 1-5 in step six are replaced with an equimolar amount of 1E-5, and steps seven and eight are the same. Preparative TLC purification yielded 105 mg of compound 1E, with a yield of 63.9%. Compound 1E was further purified by chiral column chromatography to obtain 30 mg of 1E-a with a purity of 98.11%, and 27 mg of 1E-b with a purity of 98.54%.

[0091] Compound 1E:

[0092] ESI-MS: m / z = 516.1 (M+H) + .

[0093] 1 H NMR(400MHz, CDCl3-d)δ:7.64(m,1H),7.47-7.38(m,1H),7.35-7.23(m,2H),5 .79-5.68(m,1H),5.49-5.31(m,1H),5.35-5.16(m,1H),5.21-5.16(m,1H),5.0 4(m,1H),4.83-4.81(m,1H),3.80(m,3H),3.71(s,3H),3.52(m,1H),3.19-3.01 (m,1H),2.90-2.63(m,2H),2.35-2.20(m,1H),2.04-1.92(m,1H),1.60(m,3H).

[0094] Compound 1E-a:

[0095] ESI-MS: m / z = 516.1 (M+H) + .

[0096] 1H NMR(400MHz, CDCl3-d)δ:7.65(m,1H),7.46-7.38(m,1H),7.35-7.23(m,2H),5.80(s,1H),5.49-5.41(m,1H),5.35(t,1H),5.21(d,1H) ),5.06(m,1H),4.81(s,1H),3.79(s,3H),3.72(s,3H),3.53(m,1H),3.19(d,1H),2.63(m,2H),2.22(m,1H),1.92(m,1H),1.59(m,3H).

[0097] Compound 1E-b:

[0098] ESI-MS: m / z = 516.1 (M+H) + .

[0099] 1 H NMR(400MHz, CDCl3-d)δ:7.64(m,1H),7.47-7.39(m,1H),7.31(m,2H),5.68(s,1H),5.39-5.33(m,1H),5.16(s,2H),5.03(m,1H),4 .83(s,1H),3.80(s,3H),3.71(s,3H),3.52(m,1H),3.01(d,1H),2.90(s,1H),2.74(m,1H),2.35(s,1H),2.04(m,1H),1.60(m,3H).

[0100] Example 2: Preparation of Compound 3

[0101] The preparation method was the same as in Example 1, except that in step one, methyl (S)-2-hydroxypropionate was replaced with an equimolar amount of methyl glycolate, and steps two through eight were synthesized using the same method. TLC purification yielded 95 mg of compound 3, with a yield of 41.9%. Similarly, compound 3 was separated by chiral column chromatography to obtain 35 mg of 3-a with a purity of 98.50%, and 30 mg of 3-b with a purity of 98.41%.

[0102] Compound 3:

[0103] ESI-MS: m / z = 502.1 (M+H) + .

[0104] 1H NMR(400MHz, CDCl3-d)δ:7.58(m,1H),7.45(m,1H),7.40-7.27(m,2H),5.83(m,1H),5.22(m,2H),4.96( s,2H),4.87(m,1H),3.91-3.82(m,2H),3.72(m,6H),3.60(m,1H),3.00-2.82(m,2H),2.04-1.86(m,2H).

[0105] Compound 3-a:

[0106] ESI-MS: m / z = 502.1 (M+H) + .

[0107] 1 H NMR(400MHz, CDCl3-d)δ:7.59(m,1H),7.44(m,1H),7.41-7.29(m,2H),5.86(m,1H),5.25(m,2H),4.9 8(s,2H),4.89(m,1H),3.91-3.82(m,2H),3.73(m,6H),3.61(m,1H),2.83(m,2H),2.05-1.87(m,2H).

[0108] Compound 3-b:

[0109] ESI-MS: m / z = 502.1 (M+H) + .

[0110] 1 H NMR(400MHz, CDCl3-d)δ:7.59(m,1H),7.44(m,1H),7.41-7.29(m,2H),5.86(m,1H),5.25(m,2H),4.9 8(s,2H),4.89(m,1H),3.91-3.82(m,2H),3.73(m,6H),3.61(m,1H),3.00(m,2H),2.05-1.87(m,2H).

[0111] Similarly, compound 3E was prepared, and 3E-a was prepared by chiral resolution.

[0112] Compound 3E-a: ESI-MS: m / z = 502.1 (M+H) + .

[0113] Example 3: Preparation of Compound 4

[0114] The preparation method was the same as in Example 1, except that chloromethyl chloroformate in step one was replaced with an equimolar amount of 1-chloroethyl chloroformate, and steps two through eight were synthesized using the same method. TLC purification yielded 85 mg of compound 4, with a yield of 37.3% and a purity of 98.55%. Similarly, compounds 4-a and 4-b were obtained by chiral resolution.

[0115] Compound 4:

[0116] ESI-MS: m / z = 530.1 (M+H) + .

[0117] 1 H NMR(400MHz, CDCl3-d)δ:7.57(m,1H),7.43(m,1H),7.39-7.26(m,2H),5.96(m,1H),5.82(m,1H),5.47(m,1H),4.79(m ,1H),3.93(m,1H),3.80(m,1H),3.77(s,3H),3.71(s,3H),3.61(m,1H),3.01-2.82(m,2H),1.95(m,2H),1.49(m,6H).

[0118] Compound 4-a:

[0119] ESI-MS: m / z = 530.1 (M+H) + .

[0120] Similarly, compound 4E was prepared, and 4E-a was prepared by chiral resolution.

[0121] Compound 4E-a:

[0122] ESI-MS: m / z = 530.2(M+H) + .

[0123] Example 4: Preparation of Compound 5

[0124] The preparation method was the same as in Example 1, except that in step one, (S)-2-hydroxypropionate methyl ester was replaced with an equimolar amount of 2-hydroxy-2-methylpropionate methyl ester, and steps two through eight were synthesized using the same method. 116 mg of compound 5 was obtained by TLC purification and separation, with a yield of 50.9% and a purity of 98.21%. Similarly, compounds 5-a and 5-b were obtained by chiral resolution.

[0125] Compound 5:

[0126] ESI-MS: m / z = 530.1 (M+H) + .

[0127] 1 H NMR(400MHz, CDCl3-d)δ:7.56(m,1H),7.42(m,1H),7.39-7.27(m,2H),5.88(m,1H),5.28-5.16(m,2H),4.8 7(d,1H),3.97-3.85(m,2H),3.72(d,6H),3.60(m,1H),2.99-2.82(m,2H),2.04-1.86(m,2H),1.56(d,6H).

[0128] Compound 5-a:

[0129] ESI-MS: m / z = 530.1 (M+H) + .

[0130] Similarly, compound 5E was prepared, and 5E-a was prepared by chiral resolution.

[0131] Compound 5E-a:

[0132] ESI-MS: m / z = 530.1 (M+H) + .

[0133] Example 5: Preparation of Compound 6

[0134] The preparation method was the same as in Example 1, except that in step one, (S)-2-hydroxypropionate methyl ester was replaced with an equimolar amount of 1-hydroxy-1-cyclopropanoic acid methyl ester, and steps two through eight were synthesized using the same method. TLC purification yielded 123 mg of compound 6, with a yield of 54.2% and a purity of 98.61%. Similarly, compounds 6-a and 6-b were obtained by chiral resolution.

[0135] Compound 6:

[0136] ESI-MS: m / z = 528.1 (M+H) + .

[0137] 1H NMR(400MHz, CDCl3-d)δ:7.59(m,1H),7.44(m,1H),7.40-7.28(m,2H),5.84(dt,1H),5.29-5.17(m,2H),4.89(d,1H),3.91-3.82(m,2H),3. 73(d,6H),3.60(dd,1H),2.99-2.82(m,2H),2.41-2.34(m,1H),2.38- 2.32(m,1H),2.30-2.22(m,1H),2.25-2.18(m,1H),2.04-1.86(m,2H).

[0138] Compound 6-a: ESI-MS: m / z = 528.1 (M+H) + .

[0139] Similarly, compound 6E was prepared, and 6E-a was prepared by chiral resolution; ESI-MS: m / z = 528.1 (M+H) + .

[0140] Example 6: Preparation of Compound 15

[0141] The preparation method is the same as that in Example 1, except that in step five, diethylphosphonoacetate tert-butyl ester is replaced with an equimolar amount of diethylphosphonoacetate methyl ester. Steps two through seven are synthesized using the same method. 100 mg of compound 15 was obtained by TLC purification, with a yield of 17.5% and a purity of 98.65%. Compound 15-a was obtained by chiral resolution. Similarly, compound 15E was prepared, and 15E-a was prepared by chiral resolution.

[0142] ESI-MS: m / z = 530.1 (M+H) + .

[0143] 1 H NMR(400MHz, CDCl3-d)δ:7.57(m,1H),7.45-7.39(m,1H),7.37-7.27(m,2H),5.78(dt,1H),5.40(q,1H),5.22(d,2H),4.87(d, 1H),3.98(dd,1H),3.88(td,1H),3.77(s,3H),3.71(d,6H),3.62(dd,1H),2.99-2.82(m,2H),2.04-1.86(m,2H),1.47(s,3H).

[0144] Example 7: Preparation of Compound 19

[0145] Compound 1 (87.7 mg, 0.17 mmol), acetonitrile (2 mL), and K₂CO₃ (47 mg) were added to a 10 mL reaction flask.

[0146] 0.34 mmol), 1-(2-bromoethyl)pyrrolidine-2,5-dione (70 mg, 0.34 mmol), and the reaction was carried out at room temperature for 12 h. After the reaction was completed, water was added, and the mixture was extracted with EA. The layers were separated, and the organic phase was concentrated to dryness. The product was purified by silica gel column chromatography (PE:EA = 10:1 → 2:1), and the product was collected and concentrated to dryness to give 65 mg of product compound 19, with a yield of 59.6% and a purity of 98.66%. Compound 19-a was obtained by chiral resolution. Similarly, compound 19E was prepared, and 19E-a was prepared by chiral resolution.

[0147] ESI-MS: m / z = 641.1(M+H)+.

[0148] 1 H NMR(400MHz, CDCl3-d)δ:7.61(m,1H),7.48-7.41(m,1H),7.38-7.26(m,2H),5.74(dt,1H),5.40(q,1H),5.22(d,2H),4.87(d,1H),4.48(td,2 H),4.15-3.98(m,3H),3.95(td,1H),3.77(s,3H),3.71(s,3H),3.65(d d,1H),2.99-2.82(m,2H),2.61(m,4H),2.04-1.86(m,2H),1.47(s,3H).

[0149] Example 8: Preparation of Compound 27

[0150] Compound 1 (87.7 mg, 0.17 mmol), DCM (2 mL), 1-tridecyl alcohol (68.1 mg, 0.34 mmol), DCC (70.1 mg, 0.34 mmol), and DMAP (8.6 mg, 0.07 mmol) were added to a 10 mL reaction flask and reacted at room temperature for 12 h. After the reaction was complete, water was added, the layers were separated, and the organic phase was concentrated to dryness. The product was purified by silica gel column chromatography (PE:EA = 12:1 → 2:1), collected, and concentrated to dryness to give 60 mg of product compound 27, with a yield of 50.5% and a purity of 97.65%. Compound 27-a was obtained by chiral resolution. Similarly, compound 27E was prepared, and 27E-a was prepared by chiral resolution.

[0151] ESI-MS: m / z = 698.3 (M+H) + .

[0152] 1 H NMR(400MHz, CDCl3-d)δ:7.60(m,1H),7.47-7.31(m,1H),7.30-7.26(m,2H),5.74(dt,1H) ),5.40(q,1H),5.22(d,2H),4.87(d,1H),4.22(t,2H),3.99(dd,1H),3.95(td,1H),3.87( s,3H),3.81(s,3H),3.72(dd,1H),2.99-2.82(m,2H),2.02-1.87(m,2H),1.66(tt,2H),1 .47(d,3H),1.43-1.35(m,1H),1.38-1.31(m,1H),1.35-1.23(m,18H),0.95-0.84(m,3H).

[0153] Note: The examples only describe the compounds coded; their structures are described in the corresponding descriptions in the invention.

[0154] Comparative Example 1 (clopidogrel):

[0155] Comparative Example 2 (2-Ochloropidogrel):

[0156] Comparative Example 3:

[0157] Experimental Example 1: Rat Pharmacokinetic Study

[0158] 1. Test samples: Comparative Examples 1-3 and compounds from the examples.

[0159] 2. Experimental animals: Healthy adult male SD rats, 250-300g.

[0160] 3. Implementation Methods

[0161] Preparation of the test solution: Take 5 mg of the compound, first add 1-2 drops of DMSO, sonicate until clear and transparent, then add 1-2 drops of HS-15, mix and sonicate until clear and transparent, finally add an appropriate amount of 0.9% sodium chloride injection, dilute to the target concentration, sonicate and mix thoroughly. Prepare and use immediately, invert and mix well before use.

[0162] In the comparative and example compounds, the dosage in a single oral administration test in rats was equimolar. Blood collection time points for administration were designed as follows: 0 h, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, and 24 h.

[0163] Sample Collection Type: Blood collection from the orbital cavity.

[0164] Anticoagulant: EDTA-K2.

[0165] Preparation method of derivatization reagent: 2-bromo-3'-methoxyacetophenone:acetonitrile LC (1.7531:10, g / mL), after preparation, it can be stored under yellow light and on ice for 24 hours; after preparation, it can be stored at 2-8℃ and protected from light for 7 days. The entire preparation and use process should be carried out under yellow light.

[0166] Sample collection method:

[0167] Under yellow light conditions, within 2 hours before blood collection, pre-add a derivatizing reagent (whole blood volume: derivatizing reagent volume = 100:1) to an EDTA-K2 anticoagulant glass vacuum blood collection tube. After adding the derivatizing reagent, the blood collection tube should be placed in a refrigerator at 2-8℃ or on a slushie. Collect venous blood at each collection time point. Immediately after blood collection, gently invert and mix at least 10 times to ensure thorough mixing of the blood and its contents (anticoagulant, derivatizing reagent).

[0168] After mixing, place the blood collection tube vertically in an ice bath for at least 10 minutes, and then place it in a low-temperature centrifuge 1 hour later to start centrifugation. Centrifugation conditions: centrifuge temperature set at 4℃, centrifugal force at 1700g, centrifugation time at 10min.

[0169] After centrifugation, the sample was placed in an ice bath. The supernatant plasma was aliquoted into appropriately labeled plasma cryovials. The separated plasma samples were then flash-frozen on dry ice to obtain plasma treated with the derivatization reagent. The resulting plasma samples were stored at -60°C or below for pharmacokinetic analysis.

[0170] Note: Whole blood: derivatization reagent = 100:1. Please pay attention to the amount of whole blood collected to avoid the influence of derivatization on the detected compounds. For example, if 0.5 mL of rat whole blood is collected, the ratio of whole blood: derivatization reagent is 0.5 mL: 0.005 mL.

[0171] Sample protection from light: The entire process, including drug administration, whole blood collection, centrifugation, plasma aliquoting, sample pretreatment, and detection, must be carried out under yellow light.

[0172] 4. Results Analysis

[0173] 4.1 All PK plasma samples were analyzed by LC / MS / MS. Because the racemic active metabolite H4 is unstable, the derivatization reagent 2-bromo-3'-methoxyacetophenone was added before the pharmacokinetic characteristics of the racemic derivative of the active metabolite H4 (see formula H4'-MP below) in each sample were tested. The results are shown in Table 1.

[0174] Table 1: Pharmacokinetic characteristics of rats after a single oral administration (Comparative Example 2: 10 mg / kg; other rats: equimolar doses)

[0175] As shown in Table 1, the compounds in the examples exhibit better oral pharmacokinetic characteristics compared to the compounds in Comparative Examples 2 and 3. In particular, compounds 1, 3, 6, 15, and 19 have higher AUC and Cmax, demonstrating higher bioavailability and better efficacy.

[0176] 4.2 All PK plasma samples were analyzed by LC / MS / MS. Because the active metabolite H4 is unstable, the derivatization reagent 2-bromo-3'-methoxyacetophenone was added before the pharmacokinetic characteristics of the active metabolite H4 derivative H4-MP in each group of samples were tested. The results are shown in Table 2.

[0177] Table 2: Pharmacokinetic characteristics of rats after a single oral administration (Comparative Example 1: 12.4 mg / kg; others: equimolar administration)

[0178] As shown in Table 2, the compounds in the examples exhibit better oral absorption and conversion rates compared to compounds in Comparative Examples 1 and 3. In particular, compounds 1-a, 3-a, 4-a, 5-a, 6-a, and 27-a show higher AUC and Cmax, demonstrating higher bioavailability and better efficacy.

[0179] Experimental Example 2: Antiplatelet Aggregation

[0180] 1. Test samples: Comparative Examples 1-3 and compounds from the examples.

[0181] 2. Experimental animals: Sprague-Dawley (SD) rats.

[0182] 3. Surgical Procedure

[0183] 3.1 Anesthesia Induction

[0184] Rats were anesthetized by intraperitoneal injection of 1.5% sodium pentobarbital.

[0185] 3.2 Fixed

[0186] After anesthesia, the animals are transferred to the operating table to observe the rats' eyelid reflexes and pain responses. Surgery can only begin after the eyelid reflexes and pain responses in the limbs and tail have disappeared.

[0187] 3.3 Surgical Procedure for Blood Collection from the Abdominal Aorta of Rats

[0188] After administering anesthesia, wait until the rat's entire body is pliable before fixing it supine on the operating table. After routine disinfection, use surgical scissors to cut open the abdominal cavity along the midline. Gently separate the fat around the blood vessels with small forceps, and then wipe away any excess fat covering the vessels with cotton balls until the vessels are clearly visible (the abdominal aorta is located above the spine; the abdominal veins are thicker and darker in color than the abdominal aorta). First, fix the blood vessels to minimize displacement. Use the thumb and forefinger of the left hand to stabilize the fat and other organs on either side of the blood vessel, and press the upper end of the puncture site with the ring finger to lower blood pressure and prevent spurting blood. Hold the puncture needle in the right hand with the bevel facing down, inserting it at an angle of approximately 30 degrees towards the heart, to a depth of about 5 mm. Once blood returns from the needle tip, insert the other end of the puncture needle into a vacuum tube. After insertion, use a hemostatic clamp to hold the needle tip to prevent the rat from struggling and puncturing the blood vessel if anesthesia is insufficient.

[0189] 4. Experimental Methods

[0190] 4.1 Platelet Preparation

[0191] Ten male SD rats were administered the drug orally by gavage. One hour later, the rats were anesthetized with sodium pentobarbital, and blood was collected from the abdominal aorta. The blood was anticoagulated with 3.8% sodium citrate at a ratio of 1:9, mixed, and centrifuged at 200g for 10 min. The supernatant was collected as platelet-rich plasma (PRP). The remaining plasma was centrifuged at 1600g for 15 min, and the supernatant was collected as platelet-anemic plasma (PPP).

[0192] 4.2 ADP-induced platelet aggregation

[0193] Platelet aggregation rate was determined using a platelet aggregation analyzer (Helena Laboratories, USA, model: AgG RAM): First, the transmittance of the PPP corresponding to the PRP to be tested in each channel was calibrated. After calibration, the PPP was removed, and then cuvettes containing 225 μl of the PRP to be tested were placed in each channel. A stir bar was added, and then ADP (final concentration of 20 μM) was added. Platelet aggregation rate detection was started immediately.

[0194] 5. Statistical Analysis

[0195] Measurement indicators are expressed as mean ± standard deviation (X ± SD). Data from groups with a sample size of less than 3 were not included in the statistical comparison. Data were entered and statistically analyzed using Excel 2010 and GraphPad Prism 7 software. The differences between the control and treatment groups were calculated using t-tests.

[0196] 6. Result Determination

[0197] The effect of each drug at each dose on platelet aggregation in ADP-induced platelet-rich plasma (PRP) of rats was determined by comparing the maximum platelet aggregation rate of each drug administration group with that of the solvent control group.

[0198] Table 3. Platelet aggregation rate in rats of each treatment group

[0199] Note: * indicates P<0.0001 when comparing the drug-treated group with the solvent control group; & indicates P<0.01 when comparing the drug-treated group with Comparative Example 3.

[0200] As shown in Table 3, the compounds in the examples all significantly reduced the ADP-induced platelet aggregation rate in rats (P<0.0001), demonstrating a strong anti-platelet aggregation effect.

[0201] Experimental Example 3: 14-day toxicity test in rats

[0202] 1. Test samples: Compounds of Comparative Example 3 and Examples.

[0203] 2. Test methods:

[0204] Healthy adult rats were randomly divided into groups of 10 each, with half males and half females.

[0205] All drugs were administered by gavage. All animals were fasted for 12 hours before administration, but water was allowed. The drugs were administered once a day for 14 consecutive days.

[0206] After administration, the rats were fed and observed for 14 consecutive days. The toxic reactions (such as death) of the rats were observed and recorded daily. After the observation period, all surviving animals were dissected to observe whether there were any obvious lesions in the organs.

[0207] 3. Test Results

[0208] Table 4. Results of repeated-dose oral administration toxicity test in rats

[0209] As shown in Table 4, the incidence of organ abnormalities after oral administration of the compounds in the examples was lower than that of the compound in Comparative Example 3, indicating higher safety.

[0210] The above embodiments are merely one of the preferred embodiments of the present invention and should not be used to limit the scope of protection of the present invention. Any modifications or refinements made to the main design concept and spirit of the present invention that are not of substantial significance, but solve the same technical problem as the present invention, should be included within the scope of protection of the present invention.

Claims

1. A compound of Formula I or Formula I: ###0001### or an isomer, a pharmaceutically acceptable salt thereof: wherein, represents Z-form and / or E-form; X is selected from N, S or O; n is selected from 0-6; R1is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted arylheterocyclyl; R2, R3are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or R2, R3are linked to form a 3-6 membered cyclyl; R4is selected from hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl; R5is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted saturated or partially unsaturated cycloalkyl, substituted or unsubstituted saturated or partially unsaturated heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

2. The compound or isomer, pharmaceutically acceptable salt thereof according to claim 1, wherein, represents Z-form and / or E-form; X is selected from N or O; and / or n is selected from 0-3; and / or R1is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C4-C8 heterocyclyl, or substituted or unsubstituted 5-6 membered heteroaromatic; and / or R2, R3are each independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, or R2, R3are linked to form a C3-C6 cyclyl; and / or R4is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C6 cycloalkyl; And / or R5 is selected from hydrogen, substituted or unsubstituted C1 to C5. 20 Alkyl, substituted or unsubstituted C3-C 20 Cycloalkyl, substituted or unsubstituted 4-20 membered heterocycloalkyl, substituted or unsubstituted C6-C 20 aryl, substituted or unsubstituted C6-C 20 aryl-C1 to C8 alkyl, or substituted or unsubstituted 5 to 12-membered heteroaryl, substituted or unsubstituted 5 to 12-membered heteroaryl-C1 to C8 alkyl, or substituted or unsubstituted C1 to C4 alkyl-(substituted or unsubstituted C1 to C4 alkyl-O)m-substituted or unsubstituted C1 to C4 alkyl, wherein m is a positive integer from 1 to 8, and the substitution refers to substitution by one or more substituents selected from the group consisting of: deuterium, C1 to C4 alkyl ... 20 Alkyl, halogenated C1-C 20 Alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic alkyl, C6-C 10 Aryl, halogenated C6-C 10 Aryl, C5~C 10 heteroaryl, halogen, amino, alkylamine, nitro, -COR6, -COOR6, -OCOOR6, cyano, hydroxyl, amide or sulfonamide; R6is selected from: hydrogen, substituted or unsubstituted Ci to C 18 substituted or unsubstituted Ci to C 20 substituted or unsubstituted Ci to C 10 substituted or unsubstituted Ci to C 10 substituted or unsubstituted Ci to C 10 substituted or unsubstituted Ci to C 10 substituted or unsubstituted Ci to C 3. The compound or isomer, pharmaceutically acceptable salt thereof according to any one of claims 1-2, wherein, represents Z-form and / or E-form; X is selected from O; and / or n is selected from 0-2; and / or R1is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, oxetanyl, azetidinyl, cyclobutyl, or cyclopentyl; and / or R2, R3are each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, oxetanyl, azetidinyl, cyclobutyl, cyclopentyl, or R2, R3are linked to form cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl or azetidinyl.

4. The compound or isomer, pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein, R4is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, oxetanyl, azetidinyl, cyclobutyl or cyclopentyl; and / or R5is selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopentyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, oxetanyl, azetidinyl, wherein, p is selected from 1-18; k is selected from 4-20.

5. The compound according to any one of claims 1 to 4, or an isomer, a pharmaceutically acceptable salt thereof, selected from:

6. The compound or isomer, pharmaceutically acceptable salt thereof according to any one of claims 1-5, wherein the hydrogen in the structure of the compound is substituted by 1 to multiple deuterium.

7. Use of the compound or isomer, pharmaceutically acceptable salt thereof according to any one of claims 1-6 in the preparation of a P2Y12 receptor antagonist.

8. Use of the compound or isomer, pharmaceutically acceptable salt thereof according to any one of claims 1-6 in the preparation of a medicament for treating and / or preventing cardiovascular and cerebrovascular diseases.

9. The use according to claim 8, wherein the cardiovascular and cerebrovascular disease is atherosclerotic thrombosis, acute coronary syndrome, recent myocardial infarction, ischemic stroke, cerebral thrombosis, venous thrombosis, arterial thrombosis, thrombotic cerebrovascular disease, thrombotic cardiovascular disease, thrombus, or embolism.

10. A method of inhibiting platelet aggregation in an individual in need thereof, comprising administering to the individual an effective amount of a compound according to any one of claims 1-6, or an isomer, a pharmaceutically acceptable salt thereof.

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